Relationship between impaired BMP signalling and clinical risk factors at early-stage vascular injury in the preterm infant.

INTRODUCTION: Chronic lung disease, that is, bronchopulmonary dysplasia (BPD) is the most common complication in preterm infants and develops as a consequence of the misguided formation of the gas-exchange area undergoing prenatal and postnatal injury. Subsequent vascular disease and its progression into pulmonary arterial hypertension critically determines long-term outcome in the BPD infant but lacks identification of early, disease-defining changes. METHODS: We link impaired bone morphogenetic protein (BMP) signalling to the earliest onset of vascular pathology in the human preterm lung and delineate the specific effects of the most prevalent prenatal and postnatal clinical risk factors for lung injury mimicking clinically relevant conditions in a multilayered animal model using wild-type and transgenic neonatal mice. RESULTS: We demonstrate (1) the significant reduction in BMP receptor 2 (BMPR2) expression at the onset of vascular pathology in the lung of preterm infants, later mirrored by reduced plasma BMP protein levels in infants with developing BPD, (2) the rapid impairment (and persistent change) of BMPR2 signalling on postnatal exposure to hyperoxia and mechanical ventilation, aggravated by prenatal cigarette smoke in a preclinical mouse model and (3) a link to defective alveolar septation and matrix remodelling through platelet derived growth factor-receptor alpha deficiency. In a treatment approach, we partially reversed vascular pathology by BMPR2-targeted treatment with FK506 in vitro and in vivo. CONCLUSION: We identified impaired BMP signalling as a hallmark of early vascular disease in the injured neonatal lung while outlining its promising potential as a future biomarker or therapeutic target in this growing, high-risk patient population.

Verification of immunology-related genetic associations in BPD supports ABCA3 and five other genes.

BACKGROUND: Inflammatory processes are key drivers of bronchopulmonary dysplasia (BPD), a chronic lung disease in preterm infants. In a large sample, we verify previously reported associations of genetic variants of immunology-related genes with BPD. METHODS: Preterm infants with a gestational age ≤32 weeks from PROGRESS and the German Neonatal Network (GNN) were included. Through a consensus case/control definition, 278 BPD cases and 670 controls were identified. We identified 49 immunity-related genes and 55 single-nucleotide polymorphisms (SNPs) previously associated with BPD through a comprehensive literature survey. Additionally, a quantitative genetic association analysis regarding oxygen supplements, mechanical ventilation, and continuous positive air pressure (CPAP) was performed. RESULTS: Five candidate SNPs were nominally associated with BPD-related phenotypes with effect directions not conflicting the original studies: rs11265269-CRP, rs1427793-NUAK1, rs2229569-SELL, rs1883617-VNN2, and rs4148913-CHST3. Four of these genes are involved in cell adhesion. Extending our analysis to all well-imputed SNPs of all candidate genes, the strongest association was rs45538638-ABCA3 with CPAP (p = 4.9 × 10-7, FDR = 0.004), an ABC transporter involved in surfactant formation. CONCLUSIONS: Most of the previously reported associations could not be replicated. We found additional support for SNPs in CRP, NUAK1, SELL, VNN2, and ABCA3. Larger studies and meta-analyses are required to corroborate these findings. IMPACT: Larger cohort for improved statistical power to detect genetic associations with bronchopulmonary dysplasia (BPD). Most of the previously reported genetic associations with BPD could not be replicated in this larger study. Among investigated immunological relevant candidate genes, additional support was found for variants in genes CRP, NUAK1, SELL, VNN2, and CHST3, four of them related to cell adhesion. rs45538638 is a novel candidate SNP in reported candidate gene ABC-transporter ABCA3. Results help to prioritize molecular candidate pathomechanisms in follow-up studies.

Dynamics of cytokines, immune cell counts and disease severity in patients with community-acquired pneumonia - Unravelling potential causal relationships.

BACKGROUND: Community acquired pneumonia (CAP) is a severe and often rapidly deteriorating disease. To better understand its dynamics and potential causal relationships, we analyzed time series data of cytokines, blood and clinical parameters in hospitalized CAP patients. METHODS: Time series data of 10 circulating cytokines, blood counts and clinical parameters were related to baseline characteristics of 403 CAP patients using univariate mixed models. Bivariate mixed models were applied to analyze correlations between the time series. To identify potential causal relationships, we inferred cross-lagged relationships between pairs of parameters using latent curve models with structured residuals. RESULTS: IL-6 levels decreased faster over time in younger patients (Padj = 0.06). IL-8, VCAM-1, and IL-6 correlated strongly with disease severity as assessed by the sequential organ failure assessment (SOFA) score (r = 0.49, 0.48, 0.46, respectively; all Padj < 0.001). IL-6 and bilirubin correlated with respect to their mean levels and slopes over time (r = 0.36 and r = 0.46, respectively; Padj < 0.001). A number of potential causal relationships were identified, e.g., a negative effect of ICAM-1 on MCP-1, or a positive effect of the level of creatinine on the subsequent VCAM-1 concentration (P < 0.001). CONCLUSIONS: These results suggest that IL-6 trajectories of CAP patients are associated with age and run parallel to bilirubin levels. The time series analysis also unraveled directed, potentially causal relationships between cytokines, blood parameters and clinical outcomes. This will facilitate the development of mechanistic models of CAP, and with it, improvements in treatment or surveillance strategies for this disease. TRIAL REGISTRATION: clinicaltrials.gov NCT02782013, May 25, 2016, retrospectively registered.

Neutralizing Complement C5a Protects Mice with Pneumococcal Pulmonary Sepsis.

BACKGROUND: Community-acquired pneumonia and associated sepsis cause high mortality despite antibiotic treatment. Uncontrolled inflammatory host responses contribute to the unfavorable outcome by driving lung and extrapulmonary organ failure. The complement fragment C5a holds significant proinflammatory functions and is associated with tissue damage in various inflammatory conditions. The authors hypothesized that C5a concentrations are increased in pneumonia and C5a neutralization promotes barrier stabilization in the lung and is protective in pneumococcal pulmonary sepsis. METHODS: The authors investigated regulation of C5a in pneumonia in a prospective patient cohort and in experimental pneumonia. Two complementary models of murine pneumococcal pneumonia were applied. Female mice were treated with NOX-D19, a C5a-neutralizing L-RNA-aptamer. Lung, liver, and kidney injury and the inflammatory response were assessed by measuring pulmonary permeability (primary outcome), pulmonary and blood leukocytes, cytokine concentrations in lung and blood, and bacterial load in lung, spleen, and blood, and performing histologic analyses of tissue damage, apoptosis, and fibrin deposition (n = 5 to 13). RESULTS: In hospitalized patients with pneumonia (n = 395), higher serum C5a concentrations were observed compared to healthy subjects (n = 24; 6.3 nmol/l [3.9 to 10.0] vs. 4.5 nmol/l [3.8 to 6.6], median [25 to 75% interquartile range]; difference: 1.4 [95% CI, 0.1 to 2.9]; P = 0.029). Neutralization of C5a in mice resulted in lower pulmonary permeability in pneumococcal pneumonia (1.38 ± 0.89 vs. 3.29 ± 2.34, mean ± SD; difference: 1.90 [95% CI, 0.15 to 3.66]; P = 0.035; n = 10 or 11) or combined severe pneumonia and mechanical ventilation (2.56 ± 1.17 vs. 7.31 ± 5.22; difference: 4.76 [95% CI, 1.22 to 8.30]; P = 0.011; n = 9 or 10). Further, C5a neutralization led to lower blood granulocyte colony-stimulating factor concentrations and protected against sepsis-associated liver injury. CONCLUSIONS: Systemic C5a is elevated in pneumonia patients. Neutralizing C5a protected against lung and liver injury in pneumococcal pneumonia in mice. Early neutralization of C5a might be a promising adjunctive treatment strategy to improve outcome in community-acquired pneumonia.

[Self-reported infections in the German National Cohort (GNC) in the context of the current research landscape]. / Selbst berichtete Infektionen in der NAKO Gesundheitsstudie ­ Einordnung in die gegenwärtige Forschungslandschaft.

BACKGROUND: Infectious diseases continue to play an important role for disease perception, health-economic considerations and public health in Germany. In recent years, infectious diseases have been linked to the development of non-communicable diseases. Analyses of the German National Cohort (GNC) may provide deeper insights into this issue and pave the way for new targeted approaches in disease prevention. OBJECTIVES: The aim was to describe the tools used to assess infectious diseases and to present initial data on infectious disease frequencies, as well as to relate the GNC assessment tools to data collection methods in other studies in Germany. METHODS: As part of the baseline examination, questions regarding infectious diseases were administered using both an interview and a self-administered touchscreen questionnaire. Data from the initial 101,787 GNC participants were analysed. RESULTS: In the interview, 0.2% (HIV/AIDS) to 8.6% (shingles) of respondents reported ever having a medical diagnosis of shingles, postherpetic neuralgia (in cases where shingles was reported), hepatitis B/C, HIV/AIDS, tuberculosis or sepsis if treated in hospital. In the questionnaire, 12% (cystitis) to 81% (upper respiratory tract infections) of respondents reported having experienced at least one occurrence of upper or lower respiratory tract infections, gastrointestinal infections, cystitis or fever within the past 12 months. OUTLOOK: The cross-sectional analyses of data and tools presented here - for example on determinants of susceptibility to self-reported infections - can be anticipated from the year 2021 onward. Beyond that, more extensive research into infectious disease epidemiology will follow, particularly once analyses of GNC biological materials have been performed.

Sequential organ failure assessment score is an excellent operationalization of disease severity of adult patients with hospitalized community acquired pneumonia - results from the prospective observational PROGRESS study.

BACKGROUND: CAP (Community acquired pneumonia) is frequent, with a high mortality rate and a high burden on health care systems. Development of predictive biomarkers, new therapeutic concepts, and epidemiologic research require a valid, reproducible, and quantitative measure describing CAP severity. METHODS: Using time series data of 1532 patients enrolled in the PROGRESS study, we compared putative measures of CAP severity for their utility as an operationalization. Comparison was based on ability to correctly identify patients with an objectively severe state of disease (death or need for intensive care with at least one of the following: substantial respiratory support, treatment with catecholamines, or dialysis). We considered IDSA/ATS minor criteria, CRB-65, CURB-65, Halm criteria, qSOFA, PSI, SCAP, SIRS-Score, SMART-COP, and SOFA. RESULTS: SOFA significantly outperformed other scores in correctly identifying a severe state of disease at the day of enrollment (AUC = 0.948), mainly caused by higher discriminative power at higher score values. Runners-up were the sum of IDSA/ATS minor criteria (AUC = 0.916) and SCAP (AUC = 0.868). SOFA performed similarly well on subsequent study days (all AUC > 0.9) and across age groups. In univariate and multivariate analysis, age, sex, and pack-years significantly contributed to higher SOFA values whereas antibiosis before hospitalization predicted lower SOFA. CONCLUSIONS: SOFA score can serve as an excellent operationalization of CAP severity and is proposed as endpoint for biomarker and therapeutic studies. TRIAL REGISTRATION: clinicaltrials.gov NCT02782013 , May 25, 2016, retrospectively registered.

Association of Human FOS Promoter Variants with the Occurrence of Knee-Osteoarthritis in a Case Control Association Study.

Our aim was to analyse (i) the presence of single nucleotide polymorphisms (SNPs) in the JUN and FOS core promoters in patients with rheumatoid arthritis (RA), knee-osteoarthritis (OA), and normal controls (NC); (ii) their functional influence on JUN/FOS transcription levels; and (iii) their associations with the occurrence of RA or knee-OA. JUN and FOS promoter SNPs were identified in an initial screening population using the Non-Isotopic RNase Cleavage Assay (NIRCA); their functional influence was analysed using reporter gene assays. Genotyping was done in RA (n = 298), knee-OA (n = 277), and NC (n = 484) samples. For replication, significant associations were validated in a Finnish cohort (OA: n = 72, NC: n = 548). Initially, two SNPs were detected in the JUN promoter and two additional SNPs in the FOS promoter in perfect linkage disequilibrium (LD). JUN promoter SNP rs4647009 caused significant downregulation of reporter gene expression, whereas reporter gene expression was significantly upregulated in the presence of the FOS promoter SNPs. The homozygous genotype of FOS promoter SNPs showed an association with the susceptibility for knee-OA (odds ratio (OR) 2.12, 95% confidence interval (CI) 1.2⁻3.7, p = 0.0086). This association was successfully replicated in the Finnish Health 2000 study cohort (allelic OR 1.72, 95% CI 1.2⁻2.5, p = 0.006). FOS Promoter variants may represent relevant susceptibility markers for knee-OA.

Dissecting the genetics of the human transcriptome identifies novel trait-related trans-eQTLs and corroborates the regulatory relevance of non-protein coding loci†.

Genetics of gene expression (eQTLs or expression QTLs) has proved an indispensable tool for understanding biological pathways and pathomechanisms of trait-associated SNPs. However, power of most genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclear cells of 2112 individuals increasing the power to detect trans-effects genome-wide. Going beyond univariate SNP-transcript associations, we analyse relations of eQTLs to biological pathways, polygenetic effects of expression regulation, trans-clusters and enrichment of co-localized functional elements. We found eQTLs for about 85% of analysed genes, and 18% of genes were trans-regulated. Local eSNPs were enriched up to a distance of 5 Mb to the transcript challenging typically implemented ranges of cis-regulations. Pathway enrichment within regulated genes of GWAS-related eSNPs supported functional relevance of identified eQTLs. We demonstrate that nearest genes of GWAS-SNPs might frequently be misleading functional candidates. We identified novel trans-clusters of potential functional relevance for GWAS-SNPs of several phenotypes including obesity-related traits, HDL-cholesterol levels and haematological phenotypes. We used chromatin immunoprecipitation data for demonstrating biological effects. Yet, we show for strongly heritable transcripts that still little trans-chromosomal heritability is explained by all identified trans-eSNPs; however, our data suggest that most cis-heritability of these transcripts seems explained. Dissection of co-localized functional elements indicated a prominent role of SNPs in loci of pseudogenes and non-coding RNAs for the regulation of coding genes. In summary, our study substantially increases the catalogue of human eQTLs and improves our understanding of the complex genetic regulation of gene expression, pathways and disease-related processes.

Body surface assessment with 3D laser-based anthropometry: reliability, validation, and improvement of empirical surface formulae.

PURPOSE: Body surface area is a physiological quantity relevant for many medical applications. In clinical practice, it is determined by empirical formulae. 3D laser-based anthropometry provides an easy and effective way to measure body surface area but is not ubiquitously available. We used data from laser-based anthropometry from a population-based study to assess validity of published and commonly used empirical formulae. METHODS: We performed a large population-based study on adults collecting classical anthropometric measurements and 3D body surface assessments (N = 1435). We determined reliability of the 3D body surface assessment and validity of 18 different empirical formulae proposed in the literature. The performance of these formulae is studied in subsets of sex and BMI. Finally, improvements of parameter settings of formulae and adjustments for sex and BMI were considered. RESULTS: 3D body surface measurements show excellent intra- and inter-rater reliability of 0.998 (overall concordance correlation coefficient, OCCC was used as measure of agreement). Empirical formulae of Fujimoto and Watanabe, Shuter and Aslani and Sendroy and Cecchini performed best with excellent concordance with OCCC > 0.949 even in subgroups of sex and BMI. Re-parametrization of formulae and adjustment for sex and BMI slightly improved results. CONCLUSION: In adults, 3D laser-based body surface assessment is a reliable alternative to estimation by empirical formulae. However, there are empirical formulae showing excellent results even in subgroups of sex and BMI with only little room for improvement.

PROGRESS - prospective observational study on hospitalized community acquired pneumonia.

BACKGROUND: Community acquired pneumonia (CAP) is a high incidence disease resulting in about 260,000 hospital admissions per year in Germany, more than myocardial infarction or stroke. Worldwide, CAP is the most frequent infectious disease with high lethality ranging from 1.2 % in those 20-29 years old to over 10 % in patients older than 70 years, even in industrial nations. CAP poses numerous medical challenges, which the PROGRESS (Pneumonia Research Network on Genetic Resistance and Susceptibility for the Evolution of Severe Sepsis) network aims to tackle: Operationalization of disease severity throughout the course of disease, outcome prediction for hospitalized patients and prediction of transitions from uncomplicated CAP to severe CAP, and finally, to CAP with sepsis and organ failure as a life-threatening condition. It is a major aim of PROGRESS to understand and predict patient heterogeneity regarding outcome in the hospital and to develop novel treatment concepts. METHODS: PROGRESS was designed as a clinical, observational, multi-center study of patients with CAP requiring hospitalization. More than 1600 patients selected for low burden of co-morbidities have been enrolled, aiming at a total of 3000. Course of disease, along with therapy, was closely monitored by daily assessments and long-term follow-up. Daily blood samples allow in depth molecular-genetic characterization of patients. We established a well-organized workflow for sample logistics and a comprehensive data management system to collect and manage data from more than 50 study centers in Germany and Austria. Samples are stored in a central biobank and clinical data are stored in a central data base which also integrates all data from molecular assessments. DISCUSSION: With the PROGRESS study, we established a comprehensive data base of high quality clinical and molecular data allowing investigation of pressing research questions regarding CAP. In-depth molecular characterization will contribute to the discovery of disease mechanisms and establishment of diagnostic and predictive biomarkers. A strength of PROGRESS is the focus on younger patients with low burden of co-morbidities, allowing a more direct look at host biology with less confounding. As a resulting limitation, insights from PROGRESS will require validation in representative patient cohorts to assess clinical utility. TRIAL REGISTRATION: The PROGRESS study was retrospectively registered on May 24(th), 2016 with ClinicalTrials.gov: NCT02782013.

The role of HPV RNA transcription, immune response-related gene expression and disruptive TP53 mutations in diagnostic and prognostic profiling of head and neck cancer.

Stratification of head and neck squamous cell carcinomas (HNSCC) based on HPV16 DNA and RNA status, gene expression patterns, and mutated candidate genes may facilitate patient treatment decision. We characterize head and neck squamous cell carcinomas (HNSCC) with different HPV16 DNA and RNA (E6*I) status from 290 consecutively recruited patients by gene expression profiling and targeted sequencing of 50 genes. We show that tumors with transcriptionally inactive HPV16 (DNA+ RNA-) are similar to HPV-negative (DNA-) tumors regarding gene expression and frequency of TP53 mutations (47%, 8/17 and 43%, 72/167, respectively). We also find that an immune response-related gene expression cluster is associated with lymph node metastasis, independent of HPV16 status and that disruptive TP53 mutations are associated with lymph node metastasis in HPV16 DNA- tumors. We validate each of these associations in another large data set. Four gene expression clusters which we identify differ moderately but significantly in overall survival. Our findings underscore the importance of measuring the HPV16 RNA (E6*I) and TP53-mutation status for patient stratification and identify associations of an immune response-related gene expression cluster and TP53 mutations with lymph node metastasis in HNSCC.

Three gangliogliomas: results of GTG-banding, SKY, genome-wide high resolution SNP-array, gene expression and review of the literature.

According to the World Health Organization gangliogliomas are classified as well-differentiated and slowly growing neuroepithelial tumors, composed of neoplastic mature ganglion and glial cells. It is the most frequent tumor entity observed in patients with long-term epilepsy. Comprehensive cytogenetic and molecular cytogenetic data including high-resolution genomic profiling (single nucleotide polymorphism (SNP)-array) of gangliogliomas are scarce but necessary for a better oncological understanding of this tumor entity. For a detailed characterization at the single cell and cell population levels, we analyzed genomic alterations of three gangliogliomas using trypsin-Giemsa banding (GTG-banding) and by spectral karyotyping (SKY) in combination with SNP-array and gene expression array experiments. By GTG and SKY, we could confirm frequently detected chromosomal aberrations (losses within chromosomes 10, 13 and 22; gains within chromosomes 5, 7, 8 and 12), and identify so far unknown genetic aberrations like the unbalanced non-reciprocal translocation t(1;18)(q21;q21). Interestingly, we report on the second so far detected ganglioglioma with ring chromosome 1. Analyses of SNP-array data from two of the tumors and respective germline DNA (peripheral blood) identified few small gains and losses and a number of copy-neutral regions with loss of heterozygosity (LOH) in germline and in tumor tissue. In comparison to germline DNA, tumor tissues did not show substantial regions with significant loss or gain or with newly developed LOH. Gene expression analyses of tumor-specific genes revealed similarities in the profile of the analyzed samples regarding different relevant pathways. Taken together, we describe overlapping but also distinct and novel genetic aberrations of three gangliogliomas.

The LIFE-Adult-Study: objectives and design of a population-based cohort study with 10,000 deeply phenotyped adults in Germany.

BACKGROUND: The LIFE-Adult-Study is a population-based cohort study, which has recently completed the baseline examination of 10,000 randomly selected participants from Leipzig, a major city with 550,000 inhabitants in the east of Germany. It is the first study of this kind and size in an urban population in the eastern part of Germany. The study is conducted by the Leipzig Research Centre for Civilization Diseases (LIFE). Our objective is to investigate prevalences, early onset markers, genetic predispositions, and the role of lifestyle factors of major civilization diseases, with primary focus on metabolic and vascular diseases, heart function, cognitive impairment, brain function, depression, sleep disorders and vigilance dysregulation, retinal and optic nerve degeneration, and allergies. METHODS/DESIGN: The study covers a main age range from 40-79 years with particular deep phenotyping in elderly participants above the age of 60. The baseline examination was conducted from August 2011 to November 2014. All participants underwent an extensive core assessment programme (5-6 h) including structured interviews, questionnaires, physical examinations, and biospecimen collection. Participants over 60 underwent two additional assessment programmes (3-4 h each) on two separate visits including deeper cognitive testing, brain magnetic resonance imaging, diagnostic interviews for depression, and electroencephalography. DISCUSSION: The participation rate was 33 %. The assessment programme was accepted well and completely passed by almost all participants. Biomarker analyses have already been performed in all participants. Genotype, transcriptome and metabolome analyses have been conducted in subgroups. The first follow-up examination will commence in 2016.

Impact of pre-imputation SNP-filtering on genotype imputation results.

BACKGROUND: Imputation of partially missing or unobserved genotypes is an indispensable tool for SNP data analyses. However, research and understanding of the impact of initial SNP-data quality control on imputation results is still limited. In this paper, we aim to evaluate the effect of different strategies of pre-imputation quality filtering on the performance of the widely used imputation algorithms MaCH and IMPUTE. RESULTS: We considered three scenarios: imputation of partially missing genotypes with usage of an external reference panel, without usage of an external reference panel, as well as imputation of completely un-typed SNPs using an external reference panel. We first created various datasets applying different SNP quality filters and masking certain percentages of randomly selected high-quality SNPs. We imputed these SNPs and compared the results between the different filtering scenarios by using established and newly proposed measures of imputation quality. While the established measures assess certainty of imputation results, our newly proposed measures focus on the agreement with true genotypes. These measures showed that pre-imputation SNP-filtering might be detrimental regarding imputation quality. Moreover, the strongest drivers of imputation quality were in general the burden of missingness and the number of SNPs used for imputation. We also found that using a reference panel always improves imputation quality of partially missing genotypes. MaCH performed slightly better than IMPUTE2 in most of our scenarios. Again, these results were more pronounced when using our newly defined measures of imputation quality. CONCLUSION: Even a moderate filtering has a detrimental effect on the imputation quality. Therefore little or no SNP filtering prior to imputation appears to be the best strategy for imputing small to moderately sized datasets. Our results also showed that for these datasets, MaCH performs slightly better than IMPUTE2 in most scenarios at the cost of increased computing time.

Likelihood of Post-COVID Condition in people with hybrid immunity; data from the German National Cohort (NAKO).

OBJECTIVES: The risk of Post-COVID-19 condition (PCC) under hybrid immunity remains unclear. METHODS: Using data from the German National Cohort (NAKO Gesundheitsstudie), we investigated risk factors for self-reported post-infection symptoms (any PCC is defined as having at least one symptom, and high symptom burden PCC as having nine or more symptoms). RESULTS: Sixty percent of 109,707 participants reported at least one previous SARS-CoV-2 infection; 35% reported having had any symptoms 4-12 months after infection; among them 23% reported nine or more symptoms. Individuals, who did not develop PCC after their first infection, had a strongly reduced risk for PCC after their second infection (50%) and a temporary risk reduction, which waned over 9 months after the preceding infection. The risk of developing PCC strongly depended on the virus variant. Within variants, there was no effect of the number of preceding vaccinations, apart from a strong protection by the fourth vaccination compared to three vaccinations for the Omicron variant (odds ratio = 0.52; 95% confidence interval 0.45-0.61). CONCLUSIONS: Previous infections without PCC and a fourth vaccination were associated with a lower risk of PCC after a new infection, indicating diminished risk under hybrid immunity. The two components of risk reduction after a preceding infection suggest different immunological mechanisms.

The pore size of PLGA bone implants determines the de novo formation of bone tissue in tibial head defects in rats.

PURPOSE: The influence of the pore size of biodegradable poly(lactic-co-glycolic acid) scaffolds on bone regeneration was investigated. METHODS: Cylindrical poly(lactic-co-glycolic acid) scaffolds were implanted into a defect in the tibial head of rats. Pore sizes of 100-300, 300-500, and 500-710 µm were tested and compared to untreated defects as control. Two and four weeks after implantation, the specimens were explanted and defect regeneration and de novo extracellular matrix generation were investigated by MRI, quantitative solid-state NMR, and mass spectrometry. RESULTS: The pore size of the scaffolds had a pronounced influence on the quantity of the extracellular matrix synthesized in the graft; most collagen was synthesized within the first 2 weeks of implantation, while the amount of hydroxyapatite increased in the second 2 weeks. After 4 weeks, the scaffolds contained large quantities of newly formed lamellar bone while the control defects were filled by inhomogenous woven bone. Best results were obtained for scaffolds of a pore size of 300-500 µm. CONCLUSION: Our analysis showed that the structure and dynamics of the regenerated extracellular matrix was very similar to that of the native bone, suggesting that biomineralization was significantly enhanced by the choice of the most appropriate implant material.

Risk of tumorigenicity in mesenchymal stromal cell-based therapies--bridging scientific observations and regulatory viewpoints.

In the past decade, the therapeutic value of mesenchymal stromal cells (MSCs) has been studied in various indications, thereby taking advantage of their immunosuppressive properties. Easy procurement from bone marrow, adipose tissue or other sources and conventional in vitro expansion culture have made their clinical use attractive. Bridging the gap between current scientific knowledge and regulatory prospects on the transformation potential and possible tumorigenicity of MSCs, the Cell Products Working Party and the Committee for Advanced Therapies organized a meeting with leading European experts in the field of MSCs. This meeting elucidated the risk of potential tumorigenicity related to MSC-based therapies from two angles: the scientific perspective and the regulatory point of view. The conclusions of this meeting, including the current regulatory thinking on quality, nonclinical and clinical aspects for MSCs, are presented in this review, leading to a clearer way forward for the development of such products.

First genome-wide association study of 99 body measures derived from 3-dimensional body scans.

Body height, body mass index, hip and waist circumference are important risk factors or outcome variables in clinical and epidemiological research with complex underlying genetics. However, these classical anthropometric traits represent only a very limited view on the human body and other traits with potentially higher functional specificity are not yet studied to a larger extent. Participants of LIFE-Adult were assessed by three-dimensional body scanner VITUS XXL determining 99 high-quality anthropometric traits in parallel. Genotyping was performed by Axiom Genome-Wide CEU 1 Array Plate microarray technology and imputation was done using 1000 Genomes phase 3 reference panel. Combined phenotype and genetic information are available for a total of 7,562 participants. Largest heritabilities were estimated for height traits (maximum heritability with h2 = 44% for neck height) and 61 traits achieved values larger than 20%. By genome-wide analyses, we identified 16 loci associated with at least one of the 99 traits. Ten of these loci were not described for association with classical anthropometric traits so far. The strongest novel association was observed for 7p14.3 (rs11979006, P = 2.12 × 10-9) for the trait Back Width with ZNRF2 as the most plausible candidate gene. Loci established for association with classical anthropometric traits were subjected to anthropometric phenome-wide association analysis. From the reported 709 loci, 211 are co-associated with body scanner traits (enrichment: OR = 1.96, P = 1.08 × 10-61). We conclude that genetics of 3D laser-based anthropometry is promising to identify novel loci and to improve the functional understanding of established ones.

Modelling of human torso shape variation inferred by geometric morphometrics.

Traditional body measurement techniques are commonly used to assess physical health; however, these approaches do not fully represent the complex shape of the human body. Three-dimensional (3D) imaging systems capture rich point cloud data that provides a representation of the surface of 3D objects and have been shown to be a potential anthropometric tool for use within health applications. Previous studies utilising 3D imaging have only assessed body shape based on combinations and relative proportions of traditional body measures, such as lengths, widths and girths. Geometric morphometrics (GM) is an established framework used for the statistical analysis of biological shape variation. These methods quantify biological shape variation after the effects of non-shape variation-location, rotation and scale-have been mathematically held constant, otherwise known as the Procrustes paradigm. The aim of this study was to determine whether shape measures, identified using geometric morphometrics, can provide additional information about the complexity of human morphology and underlying mass distribution compared to traditional body measures. Scale-invariant features of torso shape were extracted from 3D imaging data of 9,209 participants form the LIFE-Adult study. Partial least squares regression (PLSR) models were created to determine the extent to which variations in human torso shape are explained by existing techniques. The results of this investigation suggest that linear combinations of body measures can explain 49.92% and 47.46% of the total variation in male and female body shape features, respectively. However, there are also significant amounts of variation in human morphology which cannot be identified by current methods. These results indicate that Geometric morphometric methods can identify measures of human body shape which provide complementary information about the human body. The aim of future studies will be to investigate the utility of these measures in clinical epidemiology and the assessment of health risk.

A biomathematical model of atherosclerosis in mice.

Atherosclerosis is one of the leading causes of death worldwide. Biomathematical modelling of the underlying disease and therapy processes might be a useful aid to develop and improve preventive and treatment concepts of atherosclerosis. We here propose a biomathematical model of murine atherosclerosis under different diet and treatment conditions including lipid modulating compound and antibiotics. The model is derived by translating known biological mechanisms into ordinary differential equations and by assuming appropriate response kinetics to the applied interventions. We explicitly describe the dynamics of relevant immune cells and lipid species in atherosclerotic lesions including the degree of blood vessel occlusion due to growing plaques. Unknown model parameters were determined by fitting the predictions of model simulations to time series data derived from mice experiments. Parameter fittings resulted in a good agreement of model and data for all 13 experimental scenarios considered. The model can be used to predict the outcome of alternative treatment schedules of combined antibiotic, immune modulating, and lipid lowering agents under high fat or normal diet. We conclude that we established a comprehensive biomathematical model of atherosclerosis in mice. We aim to validate the model on the basis of further experimental data.