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1.
Nat Genet ; 53(2): 147-155, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33462482

RESUMO

The intestinal microbiome is implicated as an important modulating factor in multiple inflammatory1,2, neurologic3 and neoplastic diseases4. Recent genome-wide association studies yielded inconsistent, underpowered and rarely replicated results such that the role of human host genetics as a contributing factor to microbiome assembly and structure remains uncertain5-11. Nevertheless, twin studies clearly suggest host genetics as a driver of microbiome composition11. In a genome-wide association analysis of 8,956 German individuals, we identified 38 genetic loci to be associated with single bacteria and overall microbiome composition. Further analyses confirm the identified associations of ABO histo-blood groups and FUT2 secretor status with Bacteroides and Faecalibacterium spp. Mendelian randomization analysis suggests causative and protective effects of gut microbes, with clade-specific effects on inflammatory bowel disease. This holistic investigative approach of the host, its genetics and its associated microbial communities as a 'metaorganism' broaden our understanding of disease etiology, and emphasize the potential for implementing microbiota in disease treatment and management.

2.
Sci Total Environ ; 753: 141915, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33207447

RESUMO

In this study we focused on urban bird diversity across Mexico, a megadiverse country, with a special focus on the relative role of urban greenspaces and heavily-built sites. We considered a country-wide approach, including 24 different sized Mexican cities. Our aims were to describe the urban bird diversity in focal cities and further assess the relationships between it and the biogeographic region where cities are located, their size, elevation, and annual rainfall. Additionally, we evaluated differences in the functional composition of bird communities in both studied urban scenarios (i.e., urban greenspaces, heavily-built sites). Our results confirm that urban greenspaces are home to a large proportion of species when contrasted with heavily-built sites. While total species richness and species richness of greenspaces were related with the cities' biogeographic region -with higher species richness in the Neotropical region and Transition Zone-, the relationship did not hold true in heavily-built sites. We found that annual rainfall was negatively related to bird richness in heavily-built sites, suggesting that species from arid systems can be more tolerant to urbanization. Regarding the bird functional group assessment, results show a clear differentiation between the functional groups of greenspaces and those of heavily-built sites, with granivores and omnivores associated with the latter and a highly diverse array of functional groups associated with urban greenspaces.


Assuntos
Biodiversidade , Aves , Animais , Cidades , Ecossistema , México , Urbanização
3.
Knee ; 28: 64-71, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33310667

RESUMO

BACKGROUND: Unicompartmental osteoarthrosis increasingly affects younger patients who have high expectations concerning their postoperative level of activity. However, there is no available data on the activity level after fixed-bearing lateral unicompartmentalkneearthroplasty (UKA). The aim of this study was to report sports activity after fixed-bearing lateral UKA with a minimum two-year follow up. METHODS: Nineteen patients were surveyed to determine their sporting activities at a mean follow up of 4.6 years (range 2.0-9.7 years) after fixed-bearing lateral UKA. We also assessed the Knee Injury and Osteoarthritis Outcome Score Joint Replacement (KOOS JR) Score and the University of California, Los Angeles activity scale (UCLA scale) at baseline and latest follow up. RESULTS: Before the onset of the first symptoms, 15 of 19 patients were active in at least one sport compared with 13 of 19 patients after surgery. Eighty-six per cent of the patients returned to activity. Within 6 months, 68% returned to their activities after surgery. The mean postoperative UCLA score was 6.4 (±1.3). Half of the patients reached a high activity level (UCLA ≥ 7). Most common activities after surgery were long walks, biking and hiking. High-impact activities showed a significant decrease. CONCLUSION: Eighty-six per cent of the patients were able to return to regular recreational and sporting activities. In general, a shift from high-impact to low-impact activities was observed. There was no difference in the number of disciplines performed. Overall, the session length and frequency remained unchanged. However, male patients and younger patients participated in sports less frequently compared with preoperative levels.

4.
PLoS One ; 15(11): e0230035, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33186364

RESUMO

BACKGROUND: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome. METHODS AND RESULTS: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event. CONCLUSION: This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.

5.
Anal Bioanal Chem ; 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33215313

RESUMO

Since the detection of per- and polyfluoroalkyl substances (PFAS) in humans and different environmental media in the last two decades, this substance group has attracted a lot of attention as well as increasing concerns. The fluorine mass balance approach, by comparing the levels of targeted PFAS after conversion to fluorine equivalents with those of extractable organic fluorine (EOF), showed the presence of unidentified organofluorine in different environmental samples. Out of the thousands of PFAS in existence, only a very small fraction is included in routine analysis. In recent years, liquid chromatography coupled with tandem-mass spectrometry (LC-MS/MS) has demonstrated the ability to analytically cover a wide spectrum of PFAS. In contrast, conventional extraction methods developed 10 to 15 years ago were only evaluated for a limited number of PFAS. The aim of the present study was to evaluate the advantages and disadvantages of three different extraction methods, adapted from the literatures without further optimization (ion-pair liquid-liquid extraction, solid-phase extraction (SPE), using hydrophilic-lipophilic (HLB) or weak anion exchange (WAX) sorbents), for human biomonitoring of 61 PFAS in serum and placental tissue samples. In addition, levels of EOF were compared among these extraction methods via spiked samples. Results showed that performance, in terms of recovery, differed between the extraction methods for different PFAS; different extraction methods resulted in different EOF concentrations indicating that the choice of extraction method is important for target PFAS and EOF analysis. Results of maternal serum samples, analyzed in two different laboratories using two different extraction methods, showed an accordance of 107.6% (± 21.3); the detected perfluoroalkyl acids (PFAAs) in maternal and cord serum samples were in the range of 0.076 to 2.9 ng/mL.Graphical abstract.

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-33013684

RESUMO

Bone production, maintenance, and modeling are a well-balanced process involving mineralization by osteoblasts and resorption by osteoclasts. Sex steroid hormones, including their conjugated forms, contribute majorly to maintaining this balance. Recently, variants in the SLC22A9 gene have been associated with osteoporosis in Korean females. We had recently shown that SLC22A9, encoding organic anion transporter 7 (OAT7), is an uptake transporter of estrone sulfate and identified several genetic variants in Europeans leading to functional consequences in vitro. We therefore hypothesized that SLC22A9 genetic variants may contribute to the pathophysiology of osteoporosis in Europeans. To test this hypothesis, we examined the associations of SLC22A9 variants with bone quality, fractures, and bone turnover markers. We genotyped SLC22A9 variants in 5,701 (2,930 female) subjects (age range, 20-93 years) extracted from the population-based Study of Health in Pomerania (SHIP and SHIP-TREND) covered by the Illumina Infinium HumanExome BeadChip version v1.0 (Exome Chip). Descriptive data (e.g., history of fractures), ultrasonography of the calcaneus, as well as serum concentrations of carboxy-terminal telopeptide of type I collagen, amino-terminal propeptide of type I procollagen, and vitamin D were determined. Comprehensive statistical analyses revealed no association between low-frequency and rare SLC22A9 variants and bone quality, fractures, and bone turnover markers. Our results indicate that single genetic SLC22A9 variants do not have a major impact on osteoporosis risk prediction in Europeans, yet findings need to be replicated in larger-scale studies.

8.
Int J Mol Sci ; 21(16)2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32806598

RESUMO

While ionizing radiation (IR) is a powerful tool in medical diagnostics, nuclear medicine, and radiology, it also is a serious threat to the integrity of genetic material. Mutagenic effects of IR to the human genome have long been the subject of research, yet still comparatively little is known about the genome-wide effects of IR exposure on the DNA-sequence level. In this study, we employed high throughput sequencing technologies to investigate IR-induced DNA alterations in human gingiva fibroblasts (HGF) that were acutely exposed to 0.5, 2, and 10 Gy of 240 kV X-radiation followed by repair times of 16 h or 7 days before whole-genome sequencing (WGS). Our analysis of the obtained WGS datasets revealed patterns of IR-induced variant (SNV and InDel) accumulation across the genome, within chromosomes as well as around the borders of topologically associating domains (TADs). Chromosome 19 consistently accumulated the highest SNVs and InDels events. Translocations showed variable patterns but with recurrent chromosomes of origin (e.g., Chr7 and Chr16). IR-induced InDels showed a relative increase in number relative to SNVs and a characteristic signature with respect to the frequency of triplet deletions in areas without repetitive or microhomology features. Overall experimental conditions and datasets the majority of SNVs per genome had no or little predicted functional impact with a maximum of 62, showing damaging potential. A dose-dependent effect of IR was surprisingly not apparent. We also observed a significant reduction in transition/transversion (Ti/Tv) ratios for IR-dependent SNVs, which could point to a contribution of the mismatch repair (MMR) system that strongly favors the repair of transitions over transversions, to the IR-induced DNA-damage response in human cells. Taken together, our results show the presence of distinguishable characteristic patterns of IR-induced DNA-alterations on a genome-wide level and implicate DNA-repair mechanisms in the formation of these signatures.

9.
J Bone Miner Res ; 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32786095

RESUMO

Osteoporosis is a debilitating and costly disease that causes fractures in 33% of women and 20% of men over the age of 50 years. Recent studies have shown that beta blocker (BB) users have higher bone mineral density (BMD) and decreased risk of fracture compared with non-users. The mechanism underlying this association is thought to be due to suppression of adrenergic signaling in osteoblasts, which leads to increased BMD in rodent models; however, the mechanism in humans is unknown. Also, several miRNAs are associated with adrenergic signaling and BMD in separate studies. To investigate potential miRNA mechanisms, we performed a cross-sectional analysis using clinical data, dual-energy X-ray absorptiometry (DXA) scans, and miRNA and mRNA profiling of whole blood from the Framingham Study's Offspring Cohort. We found nine miRNAs associated with BB use and increased BMD. In parallel network analyses, we discovered a subnetwork associated with BMD and BB use containing two of these nine miRNAs, miR-19a-3p and miR-186-5p. To strengthen this finding, we showed that these two miRNAs had significantly higher expression in individuals without incident fracture compared with those with fracture in an external data set. We also noted a similar trend in association between these miRNA and Z-score as calculated from heel ultrasound measures in two external cohorts (SOS-Hip and SHIP-TREND). Because miR-19a directly targets the ADRB1 mRNA transcript, we propose BB use may downregulate ADRB1 expression in osteoblasts through increased miR-19a-3p expression. We used enrichment analysis of miRNA targets to find potential indirect effects through insulin and parathyroid hormone signaling. This analysis provides a starting point for delineating the role of miRNA on the association between BB use and BMD. © 2020 American Society for Bone and Mineral Research (ASBMR).

10.
J Clin Med ; 9(7)2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32630629

RESUMO

(1) Background: High primary stability is important for the long-term survival of cementless femoral stems in total hip arthroplasty (THA). The objective of this study was to investigate the migration pattern of a hydroxyapatite-coated cementless hip stem developed for minimally invasive surgery using model-based radiostereometric analysis (RSA). (2) Methods: In this randomized controlled trial, 44 patients with an indication for cementless primary THA were randomly allocated to receive either the SL-PLUS MIA stem, developed for minimally invasive surgery, or the SL-PLUS stem (Smith & Nephew Orthopaedics, Baar, Switzerland) which served as a control group. Unlimited weight-bearing was permitted postoperatively in both groups. Model-based RSA was performed after six weeks and after 3, 6, 12 and 24 months postoperatively. (3) Results: Mean total stem subsidence at two-year follow-up was 0.40 mm (SD 0.66 mm) in the SL-PLUS group and 1.08 mm (SD 0.93 mm) in the SL-PLUS MIA group (p = 0.030). Stem subsidence occurred during the first six weeks after surgery, indicating initial settling of the stem under full weight-bearing. Both stem designs showed good osseointegration and high secondary stability with no further migration after initial settling. (4) Conclusions: Settling of a cementless straight femoral stem occurs during the first six weeks after surgery under full weight-bearing. Although initial stem migration was higher in the SL-PLUS MIA group, it had no influence on secondary stability. All implants showed good osseointegration and high secondary stability with no signs of implant loosening during this two-year follow-up period.

11.
Health Phys ; 119(1): 109-117, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32483046

RESUMO

Little is known about the mutational impact of ionizing radiation (IR) exposure on a genome-wide level in mammalian tissues. Recent advancements in sequencing technology have provided powerful tools to perform exome-wide analyses of genetic variation. This also opened up new avenues for studying and characterizing global genomic IR-induced effects. However, genotypes generated by next generation sequencing (NGS) studies can contain errors, which may significantly impact the power to detect signals in common and rare variant analyses. These genotyping errors are not explicitly detected by the standard Genotype Analysis ToolKit (GATK) and Variant Quality Score Recalibration (VQSR) tool and thus remain a potential source of false-positive variants in whole exome sequencing (WES) datasets. In this context, the transition-transversion ratio (Ti/Tv) is commonly used as an additional quality check. In case of IR experiments, this is problematic when Ti/Tv itself might be influenced by IR treatment. It was the aim of this study to determine a suitable threshold for variant filters for NGS datasets from irradiated cells in order to achieve high data quality using Ti/Tv, while at the same time being able to investigate radiation-specific effects on the Ti/Tv ratio for different radiation doses. By testing a variety of filter settings and comparing the obtained results with publicly available datasets, we observe that a coverage filter setting of depth (DP) 3 and genotype quality (GQ) 20 is sufficient for high quality single nucleotide variants (SNVs) calling in an analysis combining GATK and VSQR and that Ti/Tv values are a consistent and useful indicator for data quality assessment for all tested NGS platforms. Furthermore, we report a reduction in Ti/Tv in IR-induced mutations in primary human gingiva fibroblasts (HGFs), which points to an elevated proportion of transversions among IR-induced SNVs and thus might imply that mismatch repair (MMR) plays a role in the cellular damage response to IR-induced DNA lesions.

12.
J Alzheimers Dis ; 76(2): 753-768, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32568204

RESUMO

BACKGROUND: Alzheimer's disease (AD) is characterized by amyloid-ß (Aß) plaque and neurofibrillary tangle formation, respectively. Neurofibrillary tangles form as a result of the intracellular accumulation of hyperphosphorylated tau. Telomerase activity and levels of the human reverse transcriptase (hTERT) subunit of telomerase are significantly decreased in AD. Recently, it has been demonstrated that the 37 kDa/67 kDa laminin receptor (LRP/LR) interacts with telomerase and is implicated in Aß pathology. Since both LRP/LR and telomerase are known to play a role in the Aß facet of AD, we hypothesized that they might also play a role in tauopathy. OBJECTIVE: This study aimed to determine if LRP/LR has a relationship with tau and whether overexpression of LRP::FLAG has an effect on tauopathy-related proteins. METHODS: We employed confocal microscopy and FRET to determine whether LRP/LR and tau co-localize and interact. LRP::FLAG overexpression in HEK-293 and SH-SY5Y cells as well as analysis of tauopathy-related proteins was assessed by western blotting. RESULTS: We demonstrate that LRP/LR co-localizes with tau in the perinuclear cell compartment and confirmed a direct interaction between LRP/LR and tau in HEK-293 cells. Overexpression of LRP::FLAG in HEK-293 and SH-SY5Y cells decreased total and phosphorylated tau levels with a concomitant decrease in PrPc levels, a tauopathy-related protein. LRP::FLAG overexpression also resulted in increased hTERT levels. CONCLUSION: This data suggest that LRP/LR extends its role in AD through a direct interaction with tau, and recommend LRP::FLAG as a possible alternative AD therapeutic via decreasing phosphorylated tau levels.

13.
Arch Orthop Trauma Surg ; 140(9): 1285-1291, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32572595

RESUMO

PURPOSE: Coxarthrosis is a common disease of the adult hip joint. Elderly patients have mainly been treated with total hip arthroplasty (THA); however, younger patients are increasingly affected. Short-stem prostheses were developed for this special patient group. There have been few studies on the clinical outcomes of this type of prosthesis. This study compared the mid-term results of a short-stem prosthesis and a standard-stem prosthesis 8 years after implantation. METHODS: According to our clinical registry, patients who received a short-stem prosthesis before 2011 were identified. Patients in the standard-stem prosthesis group were matched based on the sex, age, height, weight, and degree of arthrosis. At the follow-up time, the modified Harris Hip Score (mHHS), University of California Los Angeles (UCLA) activity score and visual analog scale (VAS) pain score were collected and compared with the preoperative values. RESULTS: Fifty-five patients could be matched and analyzed for both groups. No patients needed revision surgery. In both groups, there were significant improvements at the follow-up time. The pre- and postoperative mHHSs, UCLA scores, and VAS scores were 41.9 and 95 (p < 0.0001), 3.75 and 7.9 (p < 0.0001), and 7.6 and 0.9 (p < 0.0001), respectively, in the short-stem group and 44.8 and 96.25 (p < 0.0001), 3.6 and 7.7 (p < 0.0001), and 7.7 and 0.9 (p < 0.0001), respectively, in the control group, with no significant differences between the groups at the follow-up time. CONCLUSION: The short-stem prosthesis provides mid-term results comparable to those of a standard-stem prosthesis. In both groups, excellent patient-reported outcomes were achieved after an average of 8 years. LEVEL OF EVIDENCE: IV.

14.
J Clin Med ; 9(6)2020 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-32471233

RESUMO

BACKGROUND: Significant coronary artery disease (CAD) is a common finding in patients undergoing transcatheter aortic valve implantation (TAVI). Assessment of CAD prior to TAVI is recommended by current guidelines and is mainly performed via invasive coronary angiography (ICA). In this study we analyzed the ability of coronary CT-angiography (cCTA) to rule out significant CAD (stenosis ≥ 50%) during routine pre-TAVI evaluation in patients with high pre-test probability for CAD. METHODS: In total, 460 consecutive patients undergoing pre-TAVI CT (mean age 79.6 ± 7.4 years) were included. All patients were examined with a retrospectively ECG-gated CT-scan of the heart, followed by a high-pitch-scan of the vascular access route utilizing a single intravenous bolus of 70 ml iodinated contrast medium. Images were evaluated for image quality, calcifications, and significant CAD; CT-examinations in which CAD could not be ruled out were defined as positive (CAD+). Routinely, patients received ICA (388/460; 84.3%; Group A), which was omitted if renal function was impaired and CAD was ruled out on cCTA (Group B). Following TAVI, clinical events were documented during the hospital stay. RESULTS: cCTA was negative for CAD in 40.2% (188/460). Sensitivity, specificity, PPV, and NPV in Group A were 97.8%, 45.2%, 49.6%, and 97.4%, respectively. Median coronary artery calcium score (CAC) was higher in CAD+-patients but did not have predictive value for correct classification of patients with cCTA. There were no significant differences in clinical events between Group A and B. CONCLUSION: cCTA can be incorporated into pre-TAVI CT-evaluation with no need for additional contrast medium. cCTA may exclude significant CAD in a relatively high percentage of these high-risk patients. Thereby, cCTA may have the potential to reduce the need for ICA and total amount of contrast medium applied, possibly making pre-procedural evaluation for TAVI safer and faster.

15.
J Cardiol ; 76(2): 154-162, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32273155

RESUMO

OBJECTIVES: The prognostic value of biomarkers in aortic stenosis (AS) remains understudied. We investigated whether a combination of biomarkers related to cardiovascular stress, inflammation, and damage is associated with mortality in patients with severe AS undergoing surgical aortic valve replacement (SAVR). METHODS: From a prospective registry of patients with severe AS referred for SAVR, 499 participants (mean age, 68 ± 8.5 years; 292 male) with available preoperative echocardiograms and biomarker data were included. Preoperative concentrations of NT-pro-B-type natriuretic peptide, high-sensitivity cardiac troponin T, and C-reactive protein were dichotomized as high or low, according to calculated cut-off values. RESULTS: The mean follow-up time was 775 ± 410 days; 25 patients died. Only patients with elevated levels of all three biomarkers (n = 55) showed increased mortality [hazard ratio (HR), 7.26; 95% confidence interval (CI), 2.52-20.93; p < 0.001; reference group, no elevated biomarkers, n = 159]. Patients with elevated levels of the three biomarkers had higher 3-year all-cause mortality (24% vs. 4.5%); this remained true after multivariable adjustment (HR, 4.08; 95% CI, 1.87-8.87; p < 0.001). Patients with EuroSCOREs (logES) >3.0% tended to exhibit a higher risk of all-cause mortality (HR, 2.19; 95% CI, 0.98-4.87; p = 0.055); the mortality rate was 12-fold higher when logES >3 was combined with the three elevated biomarkers. This combination also showed a net reclassification improvement of 33% and significant likelihood-ratio test results. CONCLUSIONS: A multiple biomarker approach might be useful for predicting postoperative mid-term mortality in patients with severe AS undergoing SAVR. Further large-scale prospective validation should be performed.

16.
Eur J Cardiothorac Surg ; 58(1): 130-137, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32211779

RESUMO

OBJECTIVES: Elective treatment of aortic valve disease by transcatheter aortic valve replacement (TAVR) is becoming increasingly popular, even in patients with low risk and intermediate risk. Even patients with a bicuspid aortic valve (BAV) are increasingly considered eligible for TAVR. Permanent pacemaker implantation (PMI) is a known-frequently understated-complication of TAVR affecting 9-15% of TAVR patients with a potentially significant impact on longevity and quality of life. BAV patients are affected by the highest PMI rates, although they are frequently younger compared to their tricuspid peers. The aim of the study is to report benchmark data-from a high-volume centre (with a competitive TAVR programme) on PMI after isolated surgical aortic valve replacement (SAVR) in patients with BAV and tricuspid aortic valve (TAV). METHODS: We performed a retrospective single-centre analysis on 4154 patients receiving isolated SAVRs (w/o concomitant procedures), between 2000 and 2019, of whom 1108 had BAV (27%). PMI rate and early- and long-term outcomes were analysed. For better comparability of these demographically unequal cohorts, 1:1 nearest neighbour matching was performed. RESULTS: At the time of SAVR, BAV patients were on average 10 years younger than their TAV peers (59.7 ± 12 vs 69.3 ± 9; P < 0.001) and had less comorbidities; all relevant characteristics were equally balanced after statistical matching. Overall PMI rate was significantly higher in BAV patients (5.4% vs 3.8%; P = 0.03). BAV required PMI exclusively (100%) and TAV required predominately (96%) for persistent postoperative high-degree atrioventricular block. After matching, the PMI rate was similar (5.1% vs 4.4%, P = 0.5). In-hospital mortality in the matched cohort was 1% in both groups. Long-term survival was more favourable in BAV patients (94% vs 90% in TAV at 5 years; 89% vs 82% in TAV at 9 years; P = 0.013). CONCLUSIONS: With SAVR, the overall incidence of PMI among BAV patients seems significantly higher; however, after propensity matching, no difference in PMI rates between BAV and TAV is evident. The PMI rate was remarkably lower among BAV patients after SAVR compared to the reported incidence after TAVR.

17.
Hum Mol Genet ; 29(5): 864-875, 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-31960908

RESUMO

Saliva, as a biofluid, is inexpensive and non-invasive to obtain, and provides a vital tool to investigate oral health and its interaction with systemic health conditions. There is growing interest in salivary biomarkers for systemic diseases, notably cardiovascular disease. Whereas hundreds of genetic loci have been shown to be involved in the regulation of blood metabolites, leading to significant insights into the pathogenesis of complex human diseases, little is known about the impact of host genetics on salivary metabolites. Here we report the first genome-wide association study exploring 476 salivary metabolites in 1419 subjects from the TwinsUK cohort (discovery phase), followed by replication in the Study of Health in Pomerania (SHIP-2) cohort. A total of 14 distinct locus-metabolite associations were identified in the discovery phase, most of which were replicated in SHIP-2. While only a limited number of the loci that are known to regulate blood metabolites were also associated with salivary metabolites in our study, we identified several novel saliva-specific locus-metabolite associations, including associations for the AGMAT (with the metabolites 4-guanidinobutanoate and beta-guanidinopropanoate), ATP13A5 (with the metabolite creatinine) and DPYS (with the metabolites 3-ureidopropionate and 3-ureidoisobutyrate) loci. Our study suggests that there may be regulatory pathways of particular relevance to the salivary metabolome. In addition, some of our findings may have clinical significance, such as the utility of the pyrimidine (uracil) degradation metabolites in predicting 5-fluorouracil toxicity and the role of the agmatine pathway metabolites as biomarkers of oral health.

18.
Thorac Cardiovasc Surg ; 68(6): 486-491, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-31891950

RESUMO

BACKGROUND: Concomitant use of tricuspid valve (TV) surgery and minimally invasive mitral valve (MV) repair is debatable due to a prolonged time of surgery with presumably elevated operative risk. Herein, we examined cardiopulmonary bypass times and 30-day mortality in patients who underwent MV repair with and without concomitant TV surgery. METHODS: We retrospectively evaluated 3,962 patients with MV regurgitation who underwent minimally invasive MV repair without (n = 3,463; MVr group) and with (n = 499; MVr + TVr group) concomitant TV surgery between 1999 and 2014. Preoperative parameters between the groups were significantly different; therefore, propensity score matching was performed. RESULTS: Mean cardiopulmonary bypass time for all patients was 125.5 ± 55.8 minutes in MVr and 162.0 ± 58.0 minutes in MVr + TVr (p < 0.001). Overall 30-day mortality was significantly different between these groups (4.8 vs. 2.1%; p < 0.001); however, after adjustment, there was no significant difference (3.3 vs. 1.2%; p = 0.07). Backward logistic regression revealed that cardiopulmonary bypass time was not a significant predictor for early mortality within the MVr + TVr cohort. CONCLUSION: Concomitant TV repair using prosthetic rings through a minimally invasive approach is safe and does not lead to elevated early mortality in our patient cohort. Therefore, prolonged cardiopulmonary bypass time should not be the sole reason to rule out MV repair with concomitant TV repair and to prefer the use of suture techniques, which saves only a few minutes compared with prosthetic ring implantation.

19.
Nat Commun ; 10(1): 5121, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31719535

RESUMO

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.


Assuntos
Loci Gênicos , Lipídeos/genética , Filogenia , Polimorfismo de Nucleotídeo Único/genética , Sono/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Mapeamento Cromossômico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
Expert Opin Ther Pat ; 29(12): 987-1009, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31722579

RESUMO

Introduction: The ubiquitously expressed 37 kDa/67 kDa high-affinity laminin receptor (laminin receptor precursor/laminin receptor, LRP/LR) is a protein found to play several roles within cells. The receptor is located in the nucleus, cytosol and the cell surface. LRP/LR mediates cell proliferation, cell adhesion and cell differentiation. As a result, it is seen to enhance tumor angiogenesis as well as invasion and adhesion, key steps in the metastatic cascade of cancer. Recent findings have shown that LRP/LR is involved in the maintenance of cell viability through apoptotic evasion, allowing for tumor progression. Thus, several patented therapeutic approaches targeting the receptor for the prevention and treatment of cancer have emerged.Areas covered: The several roles that LRP/LR plays in cancer progression as well as an overview of the current therapeutic patented strategies targeting LRP/LR and cancer to date.Expert opinion: Small molecule inhibitors, monoclonal antibodies and small interfering RNAs might act used as powerful tools in preventing tumor angiogenesis and metastasis through the induction of apoptosis and telomere erosion in several cancers. This review offers an overview of the roles played by LRP/LR in cancer progression, while providing novel patented approaches targeting the receptor as potential therapeutic routes for the treatment of cancer as well as various other diseases.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Receptores de Laminina/antagonistas & inibidores , Proteínas Ribossômicas/antagonistas & inibidores , Animais , Progressão da Doença , Desenho de Fármacos , Humanos , Terapia de Alvo Molecular , Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Patentes como Assunto , Receptores de Laminina/metabolismo , Proteínas Ribossômicas/metabolismo
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