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1.
Front Immunol ; 11: 1948, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33178177

RESUMO

In 2017, in the Polish-German transborder area of West Pomerania, Mecklenburg-Western Pomerania, and Brandenburg, in collaboration with two centers in Warsaw, a partnership in the field of newborn screening (NBS) for severe primary immunodeficiency diseases (PID), mainly severe combined immunodeficiency (SCID), was initiated. SCID, but also some other severe PID, is a group of disorders characterized by the absence of T and/or B and NK cells. Affected infants are susceptible to life-threatening infections, but early detection gives a chance for effective treatment. The prevalence of SCID in the Polish and German populations is unknown but can be comparable to other countries (1:50,000-100,000). SCID NBS tests are based on real-time polymerase chain reaction (qPCR) and the measurement of a number of T cell receptor excision circles (TREC), kappa-deleting recombination excision circles (KREC), and beta-actin (ACTB) as a quality marker of DNA. This method can also be effective in NBS for other severe PID with T- and/or B-cell lymphopenia, including combined immunodeficiency (CID) or agammaglobulinemia. During the 14 months of collaboration, 44,287 newborns were screened according to the ImmunoIVD protocol. Within 65 positive samples, seven were classified to immediate recall and 58 requested a second sample. Examination of the 58 second samples resulted in recalling one newborn. Confirmatory tests included immunophenotyping of lymphocyte subsets with extension to TCR repertoire, lymphoproliferation tests, radiosensitivity tests, maternal engraftment assays, and molecular tests. Final diagnosis included: one case of T-BlowNK+ SCID, one case of atypical Tlow BlowNK+ CID, one case of autosomal recessive agammaglobulinemia, and one case of Nijmegen breakage syndrome. Among four other positive results, three infants presented with T- and/or B-cell lymphopenia due to either the mother's immunosuppression, prematurity, or unknown reasons, which resolved or almost normalized in the first months of life. One newborn was classified as truly false positive. The overall positive predictive value (PPV) for the diagnosis of severe PID was 50.0%. This is the first population screening study that allowed identification of newborns with T and/or B immunodeficiency in Central and Eastern Europe.

2.
J Diabetes Sci Technol ; : 1932296820966353, 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33218279

RESUMO

BACKGROUND: Each measurement is subject to measurement uncertainty (MU). Consequently, each measurement of plasma glucose concentration used for diagnosis and monitoring of diabetes mellitus (DM) is affected. Although concepts and methods of MU are well established in many fields of science and technology, they are presently only incompletely implemented by medical laboratories, neglecting MU of target values of internal quality control (IQC) materials. METHODS: An empirical and practical approach for the estimation of MU based on the analysis of routine IQC using control samples with assigned target values is presented. Its feasibility is demonstrated exemplarily by analyzing IQC data from one year obtained for glucose employing the hexokinase method with IQC of two different concentrations. RESULTS: Combined relative extended (k = 2) MU comprising bias, coefficient of variation (CV), and MU of the target values assigned to control materials were about 9% with a lower (~ 56 mg/dL; ~3.1 mmol/L) and 8% with a higher (~ 346 mg/dL; ~19.2 mmol/L) concentration sample, analyzing IQC of one year from three different devices. CONCLUSIONS: Estimation of MU in this study is quite reliable due to the large number of IQC data from one year. The MU of the target values of the commercial control material in this study was considerably larger than other MU contributions, ie, standard deviation and bias. In the future, the contribution of MU of commercial IQC should be addressed more carefully and technologies to measure glucose should be geared toward smaller MU possible, as needed, especially for glucose concentration measurements in diagnosis and management of DM.

3.
Gut ; 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168600

RESUMO

OBJECTIVE: The intestinal microbiome affects the prevalence and pathophysiology of a variety of diseases ranging from inflammation to cancer. A reduced taxonomic or functional diversity of the microbiome was often observed in association with poorer health outcomes or disease in general. Conversely, factors or manifest diseases that determine the long-term stability or instability of the microbiome are largely unknown. We aimed to identify disease-relevant phenotypes associated with faecal microbiota (in-)stability. DESIGN: A total of 2564 paired faecal samples from 1282 participants of the population-based Study of Health in Pomerania (SHIP) were collected at a 5-year (median) interval and microbiota profiles determined by 16S rRNA gene sequencing. The changes in faecal microbiota over time were associated with highly standardised and comprehensive phenotypic data to determine factors related to microbiota (in-)stability. RESULTS: The overall microbiome landscape remained remarkably stable over time. The greatest microbiome instability was associated with factors contributing to metabolic syndrome such as fatty liver disease and diabetes mellitus. These, in turn, were associated with an increase in facultative pathogens such as Enterobacteriaceae or Escherichia/Shigella. Greatest stability of the microbiome was determined by higher initial alpha diversity, female sex, high household income and preserved exocrine pancreatic function. Participants who newly developed fatty liver disease or diabetes during the 5-year follow-up already displayed significant microbiota changes at study entry when the diseases were absent. CONCLUSION: This study identifies distinct components of metabolic liver disease to be associated with instability of the intestinal microbiome, increased abundance of facultative pathogens and thus greater susceptibility toward dysbiosis-associated diseases.

4.
Sci Rep ; 10(1): 19111, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33154486

RESUMO

In subclinical hypothyroidism, the presence of depressive symptoms is often a reason for starting levothyroxine treatment. However, data are conflicting on the association between subclinical thyroid dysfunction and depressive symptoms. We aimed to examine the association between subclinical thyroid dysfunction and depressive symptoms in all prospective cohorts with relevant data available. We performed a systematic review of the literature from Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library from inception to 10th May 2019. We included prospective cohorts with data on thyroid status at baseline and depressive symptoms during follow-up. The primary outcome was depressive symptoms measured at first available follow-up, expressed on the Beck's Depression Inventory (BDI) scale (range 0-63, higher values indicate more depressive symptoms, minimal clinically important difference: 5 points). We performed a two-stage individual participant data (IPD) analysis comparing participants with subclinical hypo- or hyperthyroidism versus euthyroidism, adjusting for depressive symptoms at baseline, age, sex, education, and income (PROSPERO CRD42018091627). Six cohorts met the inclusion criteria, with IPD on 23,038 participants. Their mean age was 60 years, 65% were female, 21,025 were euthyroid, 1342 had subclinical hypothyroidism and 671 subclinical hyperthyroidism. At first available follow-up [mean 8.2 (± 4.3) years], BDI scores did not differ between participants with subclinical hypothyroidism (mean difference = 0.29, 95% confidence interval = - 0.17 to 0.76, I2 = 15.6) or subclinical hyperthyroidism (- 0.10, 95% confidence interval = - 0.67 to 0.48, I2 = 3.2) compared to euthyroidism. This systematic review and IPD analysis of six prospective cohort studies found no clinically relevant association between subclinical thyroid dysfunction at baseline and depressive symptoms during follow-up. The results were robust in all sensitivity and subgroup analyses. Our results are in contrast with the traditional notion that subclinical thyroid dysfunction, and subclinical hypothyroidism in particular, is associated with depressive symptoms. Consequently, our results do not support the practice of prescribing levothyroxine in patients with subclinical hypothyroidism to reduce the risk of developing depressive symptoms.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33034626

RESUMO

CONTEXT: Osteoporosis and anemia are amongst the most common diseases in the aging population with a worldwide increasing prevalence. OBJECTIVE: As the bone-derived hormone fibroblast-growth factor-23 (FGF-23) was recently reported to regulate erythropoiesis, we examined age-related associations between hemoglobin levels and bone quality, bone turnover and FGF-23 concentrations. DESIGN: We used data from more than 5,000 adult subjects who participated in the population-based cohorts of the Study of Health in Pomerania (SHIP and SHIP-Trend). Bone quality was assessed by quantitative ultrasound at the heel, bone turnover by measurement of carboxy-terminal telopeptide of type I collagen (CTX) and intact amino-terminal propeptide of type I procollagen (P1NP) serum concentrations, respectively. Anemia was defined as hemoglobin <13 g/dl in men and <12 g/dl in women. C-terminal FGF-23 levels were measured in plasma in a subset of 852 subjects. RESULTS: Anemic subjects had poorer bone quality, higher fracture risk, and lower serum levels of P1NP than non-anemic individuals. Linear regression models revealed positive associations between hemoglobin and bone quality in subjects aged 40 or above and inverse associations with CTX in subjects aged 60 or above. Hemoglobin and FGF-23 concentrations were inversely associated, while FGF-23 was not related to bone quality or turnover. CONCLUSION: Our data corroborates a close link between FGF-23 and anemia, which is related to poor bone quality in the elderly. Yet, we observed no direct association of FGF-23 with bone parameters. Therefore, further studies are needed clarifying the role of FGF-23 on bone and red blood cell production.

6.
Bone ; 141: 115675, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33031973

RESUMO

OBJECTIVE: YKL-40, also known as chitinase-3-like protein 1, is a new proinflammatory biomarker, that might play a role in tissue remodeling and bone resorption. Here we evaluated the associations of the YKL-40 plasma concentration with heel ultrasound parameters and bone turnover markers (BTMs) in adult men and women from the general population. We tested for a causal role of YKL-40 on bone metabolism using published single nucleotide polymorphisms (SNPs) with consequences for YKL-40 expression and function. METHODS: Data were obtained from two population-based cohorts: the Study of Health in Pomerania (SHIP) and SHIP-Trend. Quantitative ultrasound (QUS) measurements at the heel were performed and bone turnover was assessed by measurement of intact amino-terminal propeptide of type I procollagen (PINP) and carboxy-terminal telopeptide of type I collagen (CTX). Associations between the YKL-40 plasma concentration and the QUS-based parameters, bone turnover marker (BTM) concentrations and 44 SNPs, including the lead SNP rs4950928, were evaluated in 382 subjects. Furthermore, we assessed the associations between the same SNPs and the QUS-based parameters (n = 5777) or the BTM concentrations (n = 7190). RESULTS: Sex-specific linear regression models adjusted for a comprehensive panel of interfering covariantes revealed statistically significant inverse associations between YKL-40 and all QUS-based parameters as well as positive associations with CTX in women. The rs4950928 polymorphism was associated with YKL-40 in men and women but none of the tested SNPs was associated with the QUS-based parameters or the BTMs after correction for multiple testing. CONCLUSIONS: Plasma YKL-40 concentrations are associated with QUS-based parameters as well as CTX concentrations in women but these associations are probably not causal.

7.
Artigo em Inglês | MEDLINE | ID: mdl-32948648

RESUMO

OBJECTIVE: To test the hypothesis that the intrathecal synthesis of free light chain kappa (FLC-k) can be used as a CSF biomarker to differentiate patients with myelitis due to multiple sclerosis (MS), myelitis due to neuromyelitis optica spectrum disease (NMOSD), and noninflammatory myelopathy, we analyzed FLC-k in 26 patients with MS myelitis, 9 patients with NMOSD myelitis, and 14 patients with myelopathy. METHODS: This is a retrospective monocentric cohort study. FLC-k were analyzed using the nephelometric Siemens FLC-k kit in paired samples of CSF and sera. Intrathecal fraction (IF) of FLC-k was plotted in a FLC-k quotient diagram. RESULTS: Ninety-six percent of patients with MS myelitis had an intrathecal synthesis of FLC-k in comparison with 55.6% for NMOSD and 14.3% of patients with noninflammatory myelopathy. The locally synthesized absolute amount of FLC-k was significantly higher in patients with myelitis due to MS than in patients with NMOSD (p = 0.038) or noninflammatory myelopathy (p < 0.0001). The sensitivity of FLC-k synthesis to detect inflammation in patients with myelitis is 85.7%. Using a receiver operating characteristic analysis, FLC-k IF >78% can discriminate patients with myelitis due to MS and NMOSD with a sensitivity of 88.5% and a specificity of 88.9% CONCLUSIONS: With the hyperbolic reference range in quotient diagrams for FLC-k, it is possible to distinguish inflammatory myelitis from noninflammatory myelopathies. An FLC-k IF >78% can be a hint to suspect myelitis due to MS rather than NMOSD.

8.
Clin Oral Investig ; 2020 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-32827080

RESUMO

OBJECTIVES: We aimed at investigating whether the interaction between the local inflammation, periodontitis, and obesity is independently associated with systemic inflammation. METHODS: From the population-based Study of Health in Pomerania, 3366 participants, without (2366) and with (1000) obesity, were studied for the association of periodontitis, measured as probing depth (PD) and plaque together with body mass index (BMI) on C-reactive protein (CRP). Quantile regression was used to evaluate the association between periodontal, anthropometric, and inflammatory variables (outcomes). RESULTS: The overall prevalence of obesity in this adult population was 31.4% in men and 28.1% in women. Both PD and plaque were positively associated with CRP, revealing an increasing impact across the CRP concentration distribution. Adjusting the regression of CRP or fibrinogen on PD for waist circumference attenuated but did not abolish the PD coefficients. Dental plaque was similarly associated with these interrelations. Association between PD and a dental plaque was different among participants with low-, medium-, or high-risk CRP concentrations. CONCLUSION: Local and systemic sources of inflammation contribute to blood levels of inflammatory markers. The respective contributions depend on the relative rate in each of the inflammation-inducing risks and are dominated by adiposity. CLINICAL RELEVANCE: Keeping systemic inflammation low in order to prevent age-related disease sequelae.

9.
Obesity (Silver Spring) ; 28(8): 1550-1559, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32627926

RESUMO

OBJECTIVE: This study provides a comprehensive overview of the associations of five adipokines (adiponectin, chemerin, galectin-3, leptin, and resistin) with fat deposits, behavioral risk factors, and metabolic phenotypes. METHODS: Using multivariable linear and logistic regression models, cross-sectional data from 4,116 participants of the population-based Study of Health in Pomerania were analyzed. RESULTS: Participants with obesity showed higher chemerin, galectin-3, and leptin but showed lower adiponectin concentrations. Independently of other fat compounds, liver fat content, visceral adipose tissue, and subcutaneous adipose tissue (SAT) were inversely associated with adiponectin. Independent positive associations of liver fat content and SAT with chemerin as well as of SAT with galectin-3 and leptin were observed. Physically inactive participants had higher chemerin and leptin concentrations. Smokers had higher chemerin and galectin-3 as well as lower leptin. Alcohol consumption was associated with adiponectin (positive) and resistin (inverse). All adipokines were associated with at least one lipid marker. Associations with glucose metabolism were seen for adiponectin, chemerin, galectin-3, and leptin. CONCLUSIONS: High adiponectin concentrations were related to favorable metabolic conditions, whereas high chemerin, galectin-3, and leptin were associated with an unfavorable metabolic profile. High leptin seems to be primarily indicative of obesity, whereas high adiponectin and chemerin are associated with a broader range of metabolic phenotypes.

10.
J Neuroimmunol ; 346: 577287, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32599341

RESUMO

OBJECTIVES: Free light chain kappa (FLC-k) in cerebrospinal fluid (CSF) is involved in intrathecal immune responses and is being investigated frequently for its diagnostic sensitivity. The objective of this study was the application and interpretation of FLC-k data in quotient diagrams with a hyperbolic reference range and to confirm the superior evaluation in comparison with another proposed reference method and cut-off values. Secondly, the performance of the FLC-k quotient diagram was analyzed in respect to MS and CIS patients and in relation to the polyspecific immune response. MATERIALS AND METHODS: FLC-k was analyzed in a control cohort (n = 302) and in patients with MS/CIS (n = 98) using a nephelometric FLC-k kit. The intrathecal fraction of FLC-k based on the hyperbolic reference range was calculated in comparison to various linear FLC-k indices and routine CSF parameters [oligoclonal bands (OCB), polyspecific antiviral immune response]. RESULTS: Using the new hyperbolic reference range, intrathecal FLC-k synthesis was found in 20 / 302 OCB negative controls. The sensitivity in the definitive MS cohort was 100%, compared to 93% positive OCB. The linear FLC-k Index interpretation with similar sensitivity for MS, however, bares the risk for the control samples,depending on the reference range, of false positive interpretations (up to 7 at low QAlb) or false negative interpretations (up to 17/20 FLC-k positives at high QAlb). The quantitative mean intrathecal FLC-k synthesis in the CIS cohort (later MS) was even slightly higher than in initially definitive MS questioning a pathophysiological difference. A positive MRZ reaction found in 53% percent of CIS patients with intrathecal FLC-k synthesis could have allowed diagnosis of MS immediately, i.e. earlier than with the Mc Donald criteria. CONCLUSIONS: The evaluation of FLC-k with hyperbolic reference range in quotient diagrams is superior to other analytical methods like the linear FLC-k index. We suggest a sequential CSF testing with FLC-k Reibergram evaluation, potentially followed by isoelectric focusing. With the MRZ reaction we obtain highest specificity for MS diagnosis.

11.
12.
Clin Chim Acta ; 507: 205-209, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32353362

RESUMO

OBJECTIVES: Oligoclonal band (OCB) determination in cerebrospinal fluid (CSF) is the gold standard to detect intrathecal inflammation. However, there is uncertainty about the significance of one isolated band in CSF. Free light chains kappa (FLC-k) are gaining interest as a complementary method to detect intrathecal inflammation. The aim of this study was to investigate the performance of an additive measurement of FLC-k in patients with one isolated band in CSF. MATERIALS & METHODS: FLC-k were analyzed using the nephelometric Siemens FLC-k kit in paired samples of CSF and sera (n = 56) in patients with one isolated band in isoelectric focusing. According to medical diagnosis, samples were subdivided in inflammatory neurological disease, non-inflammatory neurological disease controls and symptomatic controls. Intrathecal fraction of FLC-k was plotted in a FLC-k quotient diagram. OCB interpretation was done blinded by three experienced raters. RESULTS: Of 6695 OCB analyses, 91 (1.4%) had one isolated band in CSF. After exclusion of patient samples due to unclear OCB pattern after reevaluation and sample availability, 56 patient samples were included in the study. All patients with an inflammatory origin of disease (n = 13) had FLC-k values above the upper discrimination line (Qlim) in the FLC-k quotient diagram, resulting in a sensitivity of 100% with a positive predictive value of 52% and a negative predictive value of 100%. Fourteen patients (36%) with a non-inflammatory origin of disease (n = 39) had FLC-k values above Qlim. CONCLUSIONS: In patients with one isolated band in CSF, a lack of intrathecal fraction of FLC-k strongly favors a non-inflammatory orgin of disease. Implementation of FLC-k measurement can help the clinician in the diagnostic process of neurological diseases.

13.
Diabetes Res Clin Pract ; 163: 108149, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32304796

RESUMO

AIMS: To assess the role of serum ferritin and transferrin with prevalent and incident type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) and whether these associations are independent of inflammatory markers and hepatic enzymes. METHODS: We analyzed data from 3,232 participants aged 20-81 years of the population-based Study of Health in Pomerania (SHIP) from Northeast Germany with a median follow-up time of 10.6 years. Logistic and Cox regression analyses were performed. RESULTS: Serum ferritin concentrations were associated with a higher prevalence of T2DM (total population OR: 1.16 [95% CI: 1.07, 1.26]; men OR: 1.18 [95% CI: 1.08, 1.30) and MetS (total population OR: 1.27 [95% CI: 1.16, 1.38]; men OR: 1.26 [95% CI: 1.15, 1.38]) in the total population and men independently of inflammatory markers and hepatic enzymes. In longitudinal analyses, baseline ferritin concentrations were associated with a higher risk of incident T2DM in women (HR: 1.38 [95% CI: 1.10, 1.71]), but not in men or in the total population and also with a higher risk of incident MetS (HR: 1.09 [95% CI: 1.01, 1.17]) in the total population. These longitudinal associations attenuated considerably after adjustment for hepatic enzymes but not inflammatory markers. Transferrin was not associated with any of the outcomes. CONCLUSIONS: Our results suggest a link between ferritin and T2DM and MetS, which might be partially explained by hepatic dysfunction.


Assuntos
Biomarcadores/sangue , Diabetes Mellitus Tipo 2/sangue , Ferritinas/sangue , Ferro/metabolismo , Síndrome Metabólica/diagnóstico , Transferrina/metabolismo , Adulto , Feminino , Humanos , Masculino , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Estudos Prospectivos
15.
Sci Rep ; 10(1): 1487, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32001750

RESUMO

Obesity is one of the major risk factor for cardiovascular and metabolic diseases. A disproportional accumulation of fat at visceral (VAT) compared to subcutaneous sites (SAT) has been suspected as a key detrimental event. We used non-targeted metabolomics profiling to reveal metabolic pathways associated with higher VAT or SAT amount among subjects free of metabolic diseases to identify possible contributing metabolic pathways. The study population comprised 491 subjects [mean (standard deviation): age 44.6 yrs (13.0), body mass index 25.4 kg/m² (3.6), 60.1% females] without diabetes, hypertension, dyslipidemia, the metabolic syndrome or impaired renal function. We associated MRI-derived fat amounts with mass spectrometry-derived metabolites in plasma and urine using linear regression models adjusting for major confounders. We tested for sex-specific effects using interactions terms and performed sensitivity analyses for the influence of insulin resistance on the results. VAT and SAT were significantly associated with 155 (101 urine) and 49 (29 urine) metabolites, respectively, of which 45 (27 urine) were common to both. Major metabolic pathways were branched-chain amino acid metabolism (partially independent of insulin resistance), surrogate markers of oxidative stress and gut microbial diversity, and cortisol metabolism. We observed a novel positive association between VAT and plasma levels of the potential pharmacological agent piperine. Sex-specific effects were only a few, e.g. the female-specific association between VAT and O-methylascorbate. In brief, higher VAT was associated with an unfavorable metabolite profile in a sample of healthy, mostly non-obese individuals from the general population and only few sex-specific associations became apparent.


Assuntos
Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Redes e Vias Metabólicas , Tecido Adiposo/diagnóstico por imagem , Adulto , Alcaloides/sangue , Ácido Ascórbico/análogos & derivados , Ácido Ascórbico/urina , Benzodioxóis/sangue , Biomarcadores/sangue , Biomarcadores/urina , Estudos Transversais , Feminino , Humanos , Hidrocortisona/sangue , Hidrocortisona/urina , Resistência à Insulina , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Imagem por Ressonância Magnética , Masculino , Metaboloma , Pessoa de Meia-Idade , Tamanho do Órgão , Piperidinas/sangue , Alcamidas Poli-Insaturadas/sangue , Fatores Sexuais , Gordura Subcutânea/diagnóstico por imagem , Gordura Subcutânea/metabolismo , Gordura Subcutânea/patologia
16.
Cereb Cortex ; 30(4): 2307-2320, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32109272

RESUMO

We analyzed the genomic architecture of neuroanatomical diversity using magnetic resonance imaging and single nucleotide polymorphism (SNP) data from >26 000 individuals from the UK Biobank project and 5 other projects that had previously participated in the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. Our results confirm the polygenic architecture of neuroanatomical diversity, with SNPs capturing from 40% to 54% of regional brain volume variance. Chromosomal length correlated with the amount of phenotypic variance captured, r ~ 0.64 on average, suggesting that at a global scale causal variants are homogeneously distributed across the genome. At a local scale, SNPs within genes (~51%) captured ~1.5 times more genetic variance than the rest, and SNPs with low minor allele frequency (MAF) captured less variance than the rest: the 40% of SNPs with MAF <5% captured

17.
Nat Genet ; 52(2): 167-176, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31959995

RESUMO

The kidneys integrate information from continuous systemic processes related to the absorption, distribution, metabolism and excretion (ADME) of metabolites. To identify underlying molecular mechanisms, we performed genome-wide association studies of the urinary concentrations of 1,172 metabolites among 1,627 patients with reduced kidney function. The 240 unique metabolite-locus associations (metabolite quantitative trait loci, mQTLs) that were identified and replicated highlight novel candidate substrates for transport proteins. The identified genes are enriched in ADME-relevant tissues and cell types, and they reveal novel candidates for biotransformation and detoxification reactions. Fine mapping of mQTLs and integration with single-cell gene expression permitted the prioritization of causal genes, functional variants and target cell types. The combination of mQTLs with genetic and health information from 450,000 UK Biobank participants illuminated metabolic mediators, and hence, novel urinary biomarkers of disease risk. This comprehensive resource of genetic targets and their substrates is informative for ADME processes in humans and is relevant to basic science, clinical medicine and pharmaceutical research.


Assuntos
Biotransformação/genética , Rim/metabolismo , Locos de Características Quantitativas , Insuficiência Renal Crônica/urina , Acetiltransferases/genética , Acetiltransferases/metabolismo , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Biomarcadores/urina , Estudos de Coortes , Citocromo P-450 CYP2D6/genética , Estudo de Associação Genômica Ampla , Humanos , Inativação Metabólica , Rim/citologia , Metoprolol/farmacocinética , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Urina/fisiologia , Xenobióticos/farmacocinética , Xenobióticos/urina
18.
Scand J Clin Lab Invest ; 80(3): 202-209, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31971449

RESUMO

Measurement uncertainties in clinical chemistry are commonly regarded as heteroscedastic - having a constant relative standard deviation irrespective of the concentration of the measurand. The uncertainty is usually determined at two concentrations using stabilized control materials and assumed to represent the analytical goal. The purpose of the present study was to use duplicates of unselected patient samples to calculate the absolute and relative repeatability component of the intra-laboratory measurement uncertainty from duplicates, using the Dahlberg formula and analysis of variance components. Estimates were made at five different concentration intervals of ALT, AST, Calcium, Cholesterol, Creatinine, CRP, Triglycerides and TSH covering the entire concentration interval of the patient cohort. This partioning allows detailing their repeatability profiles. The calculations of the profiles were based on randomly selected results from sets of duplicates ranging from 12,000 to 65,000 pairs. The repeatability of the measurands showed substantial variability within the measuring interval. Therefore, characterizing imprecision profiles as purely homo- or heteroscedastic or by a single number may not be optimal for the intended use. The present data make a case for nuancing the evaluation of analytical goals and minimal differences of measurement results by establishing uncertainty profiles under repeatability conditions, using natural patient samples.

19.
ESC Heart Fail ; 7(3): 973-983, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31991063

RESUMO

AIMS: Treating patients with acute decompensated heart failure (ADHF) presenting with volume overload is a common task. However, optimal guidance of decongesting therapy and treatment targets are not well defined. The inferior vena cava (IVC) diameter and its collapsibility can be used to estimate right atrial pressure, which is a measure of right-sided haemodynamic congestion. The CAVA-ADHF-DZHK10 trial is designed to test the hypothesis that ultrasound assessment of the IVC in addition to clinical assessment improves decongestion as compared with clinical assessment alone. METHODS AND RESULTS: CAVA-ADHF-DZHK10 is a randomized, controlled, patient-blinded, multicentre, parallel-group trial randomly assigning 388 patients with ADHF to either decongesting therapy guided by ultrasound assessment of the IVC in addition to clinical assessment or clinical assessment alone. IVC ultrasound will be performed daily between baseline and hospital discharge in all patients. However, ultrasound results will only be reported to treating physicians in the intervention group. Treatment target is relief of congestion-related signs and symptoms in both groups with the additional goal to reduce the IVC diameter ≤21 mm and increase IVC collapsibility >50% in the intervention group. The primary endpoint is change in N-terminal pro-brain natriuretic peptide from baseline to hospital discharge. Secondary endpoints evaluate feasibility, efficacy of decongestion on other scales, and the impact of the intervention on clinical endpoints. CONCLUSIONS: CAVA-ADHF-DZHK10 will investigate whether IVC ultrasound supplementing clinical assessment improves decongestion in patients admitted for ADHF.

20.
Eur J Endocrinol ; 182(1): 79-90, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31705797

RESUMO

Objective: Several studies revealed relations between low or high insulin-like growth factor I (IGF-I) levels and risk of cardiovascular diseases or mortality, whereas the mechanisms behind these associations are still unknown. Design: The study aimed to explore the relations between IGF-I and changes in surrogate markers of cardiovascular disease including carotid intima-media thickness (IMT), left ventricular mass index (LVMI) and N-terminal pro-brain natriuretic peptide (NT-proBNP). Methods: Longitudinal data of the population-based cohort Study of Health in Pomerania (SHIP) were used. IMT was measured by ultrasonography and LVMI was determined based on echocardiography. IGF-I and IGF-binding protein-3 (IGFBP-3) levels were measured by chemiluminescent immunoassays and the IGF-I/IGFBP-3 ratio was calculated. Mixed linear regression models adjusted for known cardiovascular confounders were performed. Results: Statistical analyses demonstrated relations between low baseline IGF-I levels (beta for ΔIMT per s.d. increase -0.044 (s.e. 0.012)) or IGF-I/IGFBP-3 ratio (beta -0.045 (0.012)) and a long-term IMT increase. No associations between IGF-I, IGFBP-3 or IGF-I/IGFBP-3 ratio and changes in LVMI were detected. With respect to NT-proBNP sex-specific associations with IGF-I were found. In women, higher baseline IGF-I levels (beta for ΔNT-proBNP per s.d. increase 5.92 (2.2)) or IGF-I/IGFBP-3 ratio (beta 4.48 (2.2)) were related to an increase in NT-proBNP levels. Among men, U-shaped relations of baseline levels of IGF-I, IGFBP-3 and the IGF-I/IGFBP-3 ratio with an increase in NT-proBNP were found. Conclusions: The study detected significant relations between IGF-I and long-term changes in IMT and NT-proBNP but not LVMI. These findings argue for different effects of the IGF-I axis with respect to various cardiovascular entities.


Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/patologia , Fator de Crescimento Insulin-Like I/metabolismo , Peptídeo Natriurético Encefálico/sangue , Adulto , Idoso , Artérias Carótidas/metabolismo , Artérias Carótidas/fisiologia , Espessura Intima-Media Carotídea , Estudos de Coortes , Ecocardiografia , Feminino , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/metabolismo , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/metabolismo
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