Publications by authors named "Erik Fransen"

206 Publications

Genetics of otosclerosis: finally catching up with other complex traits?

Hum Genet 2021 Sep 9. Epub 2021 Sep 9.

Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.

Otosclerosis is a relatively common cause of hearing impairment, characterized by abnormal bone remodeling of the middle and inner ear. In about 50-60% of the patients, the disease is present in a familial form. In most of these families, otosclerosis seems to be caused by a small number of genetic factors (oligogenic) while only in a small number of families the disease seems to be truly monogenic. In the remaining patients a complex genetic form of otosclerosis is present. Several studies have aimed to identify the genetic factors underlying otosclerosis, which has led to the identification of eight published loci for monogenic otosclerosis, as well as several genes and one chromosomal region (11q13.1) with a clear association with otosclerosis. Implementation of next-generation sequencing (NGS) in otosclerosis research has led to the identification of pathogenic variants in MEPE, ACAN and SERPINF1, although the pathogenic role of the latter is under debate. In addition, a recent GWAS can be considered a breakthrough for otosclerosis as it identified several strong associations with otosclerosis and suggested new potential candidate genes. These recent findings are important for unraveling the genetic architecture of otosclerosis. More future studies will help to understand the complete pathogenesis of the disease.
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http://dx.doi.org/10.1007/s00439-021-02357-1DOI Listing
September 2021

Hearing Function: Identification of New Candidate Genes Further Explaining the Complexity of This Sensory Ability.

Genes (Basel) 2021 Aug 10;12(8). Epub 2021 Aug 10.

Institute for Maternal and Child Health-IRCCS, Burlo Garofolo, 34127 Trieste, Italy.

To date, the knowledge of the genetic determinants behind the modulation of hearing ability is relatively limited. To investigate this trait, we performed Genome-Wide Association Study (GWAS) meta-analysis using genotype and audiometric data (hearing thresholds at 0.25, 0.5, 1, 2, 4, and 8 kHz, and pure-tone averages of thresholds at low, medium, and high frequencies) collected in nine cohorts from Europe, South-Eastern USA, Caucasus, and Central Asia, for an overall number of ~9000 subjects. Three hundred seventy-five genes across all nine analyses were tagged by single nucleotide polymorphisms (SNPs) reaching a suggestive -value ( < 10). Amongst these, 15 were successfully replicated using a gene-based approach in the independent Italian Salus in the Apulia cohort ( = 1774) at the nominal significance threshold ( < 0.05). In addition, the expression level of the replicated genes was assessed in published human and mouse inner ear datasets. Considering expression patterns in humans and mice, eleven genes were considered particularly promising candidates for the hearing function: , , , , , , , and . These findings represent a further contribution to our understanding of the genetic basis of hearing function and its related diseases.
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http://dx.doi.org/10.3390/genes12081228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394865PMC
August 2021

A wide range of protective and predisposing variants in aggrecan influence the susceptibility for otosclerosis.

Hum Genet 2021 Aug 19. Epub 2021 Aug 19.

Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.

In this study, we investigated the association of ACAN variants with otosclerosis, a frequent cause of hearing loss among young adults. We sequenced the coding, 5'-UTR and 3'-UTR regions of ACAN in 1497 unrelated otosclerosis cases and 1437 matched controls from six different subpopulations. The association between variants in ACAN and the disease risk was tested through single variant and gene-based association tests. After correction for multiple testing, 14 variants were significantly associated with otosclerosis, ten of which represented independent association signals. Eight variants showed a consistent association across all subpopulations. Allelic odds ratios of the variants identified four predisposing and ten protective variants. Gene-based tests showed an association of very rare variants in the 3'-UTR with the phenotype. The associated exonic variants are all located in the CS domain of ACAN and include both protective and predisposing variants with a broad spectrum of effect sizes and population frequencies. This includes variants with strong effect size and low frequency, typical for monogenic diseases, to low effect size variants with high frequency, characteristic for common complex traits. This single-gene allelic spectrum with both protective and predisposing alleles is unique in the field of complex diseases. In conclusion, these findings are a significant advancement to the understanding of the etiology of otosclerosis.
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http://dx.doi.org/10.1007/s00439-021-02334-8DOI Listing
August 2021

Genotype-Phenotype Correlation Study in a Large Series of Patients Carrying the p.Pro51Ser (p.P51S) Variant in COCH (DFNA9) Part II: A Prospective Cross-Sectional Study of the Vestibular Phenotype in 111 Carriers.

Ear Hear 2021 Aug 6. Epub 2021 Aug 6.

Department of Otorhinolaryngology-Head & Neck Surgery, Jessa Hospital, Hasselt, Belgium Department of Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Belgium Department of ENT HNS, University Hospital Brussels, Belgium Center of Medical Genetics, University of Antwerp, Belgium StatUa, University of Antwerp, Belgium Department of Otorhinolaryngology Head & Neck Surgery, Medisch Universitair Medisch Centrum (MUMC), Maastricht, The Netherlands Hearing and Genes, Department of Otorhinolaryngology-Head and Neck Surgery, Radboud University Medical Center, Nijmegen, The Netherlands Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands Department of Medical Genetics, Antwerp University Hospital, Belgium.

Introduction: DFNA9 is characterized by adult-onset hearing loss and evolution toward bilateral vestibulopathy (BVP). The genotype-phenotype correlation studies were conducted 15 years ago. However, their conclusions were mainly based on symptomatic carriers and the vestibular data exclusively derived from the horizontal (lateral) semicircular canal (SCC). The last decade was marked by the emergence of new clinical diagnostic tools, such as the video head impulse test (vHIT) and vestibular-evoked myogenic evoked potentials (VEMPs), expanding our evaluation to all six SCCs and the otolith organs (saccule and utricule).

Aim: The aim of this study was to comprehensively evaluate vestibular function in the largest series presymptomatic as well as symptomatic p.P51S variant carriers, to determine which labyrinthine part shows the first signs of deterioration and which SCC function declines at first and to determine the age at which p.P51S variant carriers develop caloric areflexia on VNG and vHIT vestibulo-ocular reflex (VOR)-gain dysfunction as defined by the Barany Society criteria for BVP.

Material And Methods: One hundred eleven p.P51S variant carriers were included. The following vestibular function tests were applied in two different centers: ENG/VNG, vHIT, and VEMPs. The following parameters were analyzed: age (years), hearing loss (pure-tone average of 0.5-4 kHz [PTA0.5-4, dB HL]), sum of maximal peak slow-phase eye velocity obtained with bi-thermal (30°C and 44°C, water irrigation; 25°C and 44°C, air irrigation) caloric test (°/s), vHIT VOR-gain on LSCC, superior SCC and posterior SCC, C-VEMP both numerical (threshold, dB nHL) and categorical (present or absent), and O-VEMP as categorical (present or absent). The age of onset of vestibular dysfunction was determined both with categorical (onset in decades using Box & Whisker plots) and numeric approach (onset in years using regression analysis). The same method was applied for determining the age at which vestibular function declined beyond the limits of BVP, as defined by the Barany Society.

Results: With the categorical approach, otolith function was declining first (3rd decade), followed by caloric response (5th decade) and vHIT VOR-gains (5th-6th decade). Estimated age of onset showed that the deterioration began with C-VEMP activity (31 years), followed by caloric responses (water irrigation) (35 years) and ended with vHIT VOR-gains (48-57 years). Hearing deterioration started earlier than vestibular deterioration in female carriers, which is different from earlier reports. BVP was predicted at about 53 years of age on average with VNG caloric gain (water irrigation) and between 47 and 57 years of age for the three SCCs. Loss of C-VEMP response was estimated at about 46 years of age.

Conclusion: Former hypothesis of vestibular decline preceding hearing deterioration by 9 years was confirmed by the numeric approach, but this was less obvious with the categorical approach. Wide confidence intervals of the regression models may explain deviation of the fits from true relationship. There is a typical vestibular deterioration hierarchy in p.P51S variant carriers. To further refine the present findings, a prospective longitudinal study of the auditory and vestibular phenotype may help to get even better insights in this matter.
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http://dx.doi.org/10.1097/AUD.0000000000001070DOI Listing
August 2021

Genotype-phenotype Correlation Study in a Large Series of Patients Carrying the p.Pro51Ser (p.P51S) Variant in COCH (DFNA9): Part I-A Cross-sectional Study of Hearing Function in 111 Carriers.

Ear Hear 2021 Aug 6. Epub 2021 Aug 6.

Department of Otorhinolaryngology-Head & Neck Surgery, Jessa Hospital, Hasselt, Belgium Department of Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium Department of Otorhinolaryngology and Head-Neck Surgery, Antwerp University Hospital, Antwerp, Belgium; Center of Medical Genetics, University of Antwerp, Belgium StatUa, University of Antwerp, Antwerp, Belgium Department of Otorhinolaryngology Head & Neck Surgery, Medisch Universitair Medisch Centrum (MUMC), Maastricht, The Netherlands Hearing and Genes, Department of Otorhinolaryngology-Head and Neck Surgery, Radboud University Medical Center, Nijmegen, The Netherlands Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands Department of Medical Genetics, Antwerp University Hospital, Antwerp, Belgium.

Introduction: DFNA9 is characterized by adult-onset progressive sensorineural hearing loss (SNHL) and vestibular impairment. More than 15 years ago, genotype-phenotype correlation studies estimated the initial age of hearing deterioration in the fourth to fifth decade (ranging from 32 to 43 years). However, these analyses were based on relatively limited numbers of mainly symptomatic carriers using markedly different methodologies. The starting point for the hearing deterioration is more correctly determined with larger numbers of carriers and with a more clearly defined starting point of the hearing deterioration.

Aim: The aim of this study was to determine milestone ages (start and maximal hearing deterioration, potential eligibility for hearing aids and cochlear implants based on pure-tone average [PTA]) in a large series of p.Pro51Ser COCH variant carriers. The degree of individual interaural asymmetry and the degree of variability (interquartile range) with which the hearing deterioration progresses across ages were also studied, and age-related typical audiograms (ARTA) were constructed.

Material And Methods: One hundred eleven Belgian and Dutch p.P51S variant carriers were identified and recruited for audiological investigation. Their hearing thresholds were compared with p50th, p95th, and p97.5th percentile values of presbyacusis (ISO 7029 standards). The onset and degree of hearing deterioration were defined and assessed for each frequency and with three PTAs (PTA0.5-4 [0.5, 1, 2, and 4 kHz]; PTA4-8 [4 and 8 kHz]; and PTA6-8 [6 and 8 kHz]). The milestones ages were derived from nonlinear regression model of hearing thresholds against age, for male and female carriers separately, because of different age-referenced limits. Interaural right-left asymmetry was assessed, and variability of hearing thresholds were calculated using interquartile range. ARTAs were built with both observed data and a prediction model.

Results: Hearing dysfunction in p.P51S carriers begins at about 38 years of age (ranging from 28 to 43 years) on average in female and 46 years (ranging from 42 to 49 years) in male carriers (third decade: female, fifth decade: male carriers), depending on the hearing frequency and with differences in deterioration sequence between both genders. These differences, however, were mainly due to more stringent age-referenced limits for men. In contrast, predictions (ARTA) did not show any difference of phenotypic expression between genders. At about 48 to 50 years of age on average, the majority of DFNA9 patients may need conventional hearing aids (PTA ≥ 40 dB HL), whereas this is about 56 to 59 years for cochlear implants (PTA ≥ 70 dB HL). There is a high degree of individual interaural asymmetry and interindividual variability throughout all ages.

Conclusion: This study demonstrates that the onset of sensorineural hearing deterioration starts in the third decade and probably even earlier. Regardless of differences in estimates, DFNA9 expresses similarly in male and female carriers, but male carriers are much more difficult to identify in early stages of the disease. Comprehensive assessment of the natural course of DFNA9 is of particular interest to predict the age of onset or critical period of most significant function deterioration in individual carriers of the pathogenic variant. This will help to design studies in the search for disease-modifying therapies.
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http://dx.doi.org/10.1097/AUD.0000000000001099DOI Listing
August 2021

Diagnostic Performance of Automated MRI Volumetry by icobrain dm for Alzheimer's Disease in a Clinical Setting: A REMEMBER Study.

J Alzheimers Dis 2021 ;83(2):623-639

Reference Center for Biological Markers of Dementia (BIODEM), Laboratory of Neurochemistry and Behavior, University of Antwerp, Antwerp, Belgium.

Background: Magnetic resonance imaging (MRI) has become important in the diagnostic work-up of neurodegenerative diseases. icobrain dm, a CE-labeled and FDA-cleared automated brain volumetry software, has shown potential in differentiating cognitively healthy controls (HC) from Alzheimer's disease (AD) dementia (ADD) patients in selected research cohorts.

Objective: This study examines the diagnostic value of icobrain dm for AD in routine clinical practice, including a comparison to the widely used FreeSurfer software, and investigates if combined brain volumes contribute to establish an AD diagnosis.

Methods: The study population included HC (n = 90), subjective cognitive decline (SCD, n = 93), mild cognitive impairment (MCI, n = 357), and ADD (n = 280) patients. Through automated volumetric analyses of global, cortical, and subcortical brain structures on clinical brain MRI T1w (n = 820) images from a retrospective, multi-center study (REMEMBER), icobrain dm's (v.4.4.0) ability to differentiate disease stages via ROC analysis was compared to FreeSurfer (v.6.0). Stepwise backward regression models were constructed to investigate if combined brain volumes can differentiate between AD stages.

Results: icobrain dm outperformed FreeSurfer in processing time (15-30 min versus 9-32 h), robustness (0 versus 67 failures), and diagnostic performance for whole brain, hippocampal volumes, and lateral ventricles between HC and ADD patients. Stepwise backward regression showed improved diagnostic accuracy for pairwise group differentiations, with highest performance obtained for distinguishing HC from ADD (AUC = 0.914; Specificity 83.0%; Sensitivity 86.3%).

Conclusion: Automated volumetry has a diagnostic value for ADD diagnosis in routine clinical practice. Our findings indicate that combined brain volumes improve diagnostic accuracy, using real-world imaging data from a clinical setting.
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http://dx.doi.org/10.3233/JAD-210450DOI Listing
January 2021

A Panel-Based Sequencing Analysis of Patients with Paget's Disease of Bone Suggests Enrichment of Rare Genetic Variation in regulators of NF-κB Signaling and Supports the Importance of the 7q33 Locus.

Calcif Tissue Int 2021 Jun 25. Epub 2021 Jun 25.

Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, Antwerp, Belgium.

Paget's disease of bone (PDB) is a common bone disorder characterized by focal lesions caused by increased bone turnover. Monogenic forms of PDB and PDB-related phenotypes as well as genome-wide association studies strongly support the involvement of genetic variation in components of the NF-κB signaling pathway in the pathogenesis of PDB. In this study, we performed a panel-based mutation screening of 52 genes. Single variant association testing and a series of gene-based association tests were performed. The former revealed a novel association with NFKBIA and further supports an involvement of variation in NR4A1, VCP, TNFRSF11A, and NUP205. The latter indicated a trend for enrichment of rare genetic variation in GAB2 and PRKCI. Both single variant tests and gene-based tests highlighted two genes, NR4A1 and NUP205. In conclusion, our findings support the involvement of genetic variation in modulators of NF-κB signaling in PDB and confirm the association of previously associated genes with the pathogenesis of PDB.
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http://dx.doi.org/10.1007/s00223-021-00881-wDOI Listing
June 2021

DNA Methylation as a Diagnostic Biomarker for Malignant Mesothelioma: A Systematic Review and Meta-Analysis.

J Thorac Oncol 2021 09 31;16(9):1461-1478. Epub 2021 May 31.

Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Wilrijk, Belgium; Infla-Med Centre of Excellence, University of Antwerp, Wilrijk, Belgium; Department of Pulmonology, Antwerp University Hospital, Edegem, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium. Electronic address:

Malignant mesothelioma is an aggressive cancer type linked to asbestos exposure. Because of several intrinsic challenges, mesothelioma is often diagnosed in an advanced disease stage. Therefore, there is a need for diagnostic biomarkers that may contribute to early detection. Recently, the epigenome of tumors is being extensively investigated to identify biomarkers. This manuscript is a systematic review summarizing the state-of-the-art research investigating DNA methylation in mesothelioma. Four literature databases (PubMed, Scopus, Web of Science, MEDLINE) were systematically searched for studies investigating DNA methylation in mesothelioma up to October 16, 2020. A meta-analysis was performed per gene investigated in at least two independent studies. A total of 53 studies investigated DNA methylation of 97 genes in mesothelioma and are described in a qualitative overview. Furthermore, ten studies investigating 13 genes (APC, CDH1, CDKN2A, DAPK, ESR1, MGMT, miR-34b/c, PGR, RARβ, RASSF1, SFRP1, SFRP4, WIF1) were included in the quantitative meta-analysis. In this meta-analysis, the APC gene is significantly hypomethylated in mesothelioma, whereas CDH1, ESR1, miR-34b/c, PGR, RARβ, SFRP1, and WIF1 are significantly hypermethylated in mesothelioma. The three genes that are the most appropriate candidate biomarkers from this meta-analysis are APC, miR-34b/c, and WIF1. Nevertheless, both study number and study objects comprised in this meta-analysis are too low to draw final conclusions on their clinical applications. The elucidation of the genome-wide DNA methylation profile of mesothelioma is desirable in the future, using a standardized genome-wide methylation analysis approach. The most informative CpG sites from this signature could then form the basis of a panel of highly sensitive and specific biomarkers that can be used for the diagnosis of mesothelioma and even for the screening of an at high-risk population of asbestos-exposed individuals.
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http://dx.doi.org/10.1016/j.jtho.2021.05.015DOI Listing
September 2021

A human importin-β-related disorder: Syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8.

Am J Hum Genet 2021 06 18;108(6):1115-1125. Epub 2021 May 18.

Department of Paediatric Neurology, University Hospitals Bristol NHS Foundation Trust, Bristol BS2 8BJ, UK.

Importin 8, encoded by IPO8, is a ubiquitously expressed member of the importin-β protein family that translocates cargo molecules such as proteins, RNAs, and ribonucleoprotein complexes into the nucleus in a RanGTP-dependent manner. Current knowledge of the cargoes of importin 8 is limited, but TGF-β signaling components such as SMAD1-4 have been suggested to be among them. Here, we report that bi-allelic loss-of-function variants in IPO8 cause a syndromic form of thoracic aortic aneurysm (TAA) with clinical overlap with Loeys-Dietz and Shprintzen-Goldberg syndromes. Seven individuals from six unrelated families showed a consistent phenotype with early-onset TAA, motor developmental delay, connective tissue findings, and craniofacial dysmorphic features. A C57BL/6N Ipo8 knockout mouse model recapitulates TAA development from 8-12 weeks onward in both sexes but most prominently shows ascending aorta dilatation with a propensity for dissection in males. Compliance assays suggest augmented passive stiffness of the ascending aorta in male Ipo8 mice throughout life. Immunohistological investigation of mutant aortic walls reveals elastic fiber disorganization and fragmentation along with a signature of increased TGF-β signaling, as evidenced by nuclear pSmad2 accumulation. RT-qPCR assays of the aortic wall in male Ipo8 mice demonstrate decreased Smad6/7 and increased Mmp2 and Ccn2 (Ctgf) expression, reinforcing a role for dysregulation of the TGF-β signaling pathway in TAA development. Because importin 8 is the most downstream TGF-β-related effector implicated in TAA pathogenesis so far, it offers opportunities for future mechanistic studies and represents a candidate drug target for TAA.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206384PMC
June 2021

Resequencing of candidate genes for Keratoconus reveals a role for Ehlers-Danlos Syndrome genes.

Eur J Hum Genet 2021 Mar 19. Epub 2021 Mar 19.

Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Antwerp, Belgium.

The involvement of genetic factors in the pathogenesis of KC has long been recognized but the identification of variants affecting the underlying protein functions has been challenging. In this study, we selected 34 candidate genes for KC based on previous whole-exome sequencing (WES) and the literature, and resequenced them in 745 KC patients and 810 ethnically matched controls from Belgium, France and Italy. Data analysis was performed using the single variant association test as well as gene-based mutation burden and variance components tests. In our study, we detected enrichment of genetic variation across multiple gene-based tests for the genes COL2A1, COL5A1, TNXB, and ZNF469. The top hit in the single variant association test was obtained for a common variant in the COL12A1 gene. These associations were consistently found across independent subpopulations. Interestingly, COL5A1, TNXB, ZNF469 and COL12A1 are all known Ehlers-Danlos Syndrome (EDS) genes. Though the co-occurrence of KC and EDS has been reported previously, this study is the first to demonstrate a consistent role of genetic variants in EDS genes in the etiology of KC. In conclusion, our data show a shared genetic etiology between KC and EDS, and clearly confirm the currently disputed role of ZNF469 in disease susceptibility for KC.
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http://dx.doi.org/10.1038/s41431-021-00849-2DOI Listing
March 2021

Dutch Translation and Validation of the FACE-Q Rhinoplasty Module.

Facial Plast Surg 2021 Jun 27;37(3):296-301. Epub 2021 Jan 27.

Department of Otorhinolaryngology, GZA Ziekenhuizen Campus Sint-Vincentius, Antwerp, Belgium.

FACE-Q was developed by Klassen et al in 2010 as a validated psychometric evaluation instrument for patients undergoing aesthetic surgery. The aim of this study was to translate, adapt, and validate the FACE-Q rhinoplasty module into a Dutch version of the FACE-Q questionnaire conceptually equivalent to the original English version. "Satisfaction with nose" and "satisfaction with nostrils" questionnaires were used and translated from English into Dutch. The translation process and cross-cultural adaptation were conducted in accordance to the International Society for Pharmacoeconomics and Outcomes Research and World Health Organization guidelines. Psychometric validation was performed prospectively on a patient cohort of 30 patients. Each step in the translation process allowed us to make changes to achieve a conceptual translation equivalent to the original version. Psychometric validation revealed highly significant values for internal consistency, test-retest reliability, and responsiveness. The use of international translation guidelines, with a strict translation-back-translation process, led to a Dutch version of the FACE-Q rhinoplasty module. Statistical validation proved the conceptual correspondence with the original English version. The FACE-Q rhinoplasty module is an adequate instrument for determining successful aesthetic surgery based on patient satisfaction. This tool measures twofold: the degree of success with respect to the patient as well as being an assessment tool for the surgeon. We hope this will provide an additional tool to the clinician evaluating the Dutch-speaking rhinoplasty patient.
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http://dx.doi.org/10.1055/s-0040-1721099DOI Listing
June 2021

Predictive Sensitivity and Concordance of Machine-learning Tools for Diagnosing DFNA9 in a Large Series of p.Pro51Ser Variant Carriers in the COCH-gene.

Otol Neurotol 2021 06;42(5):671-677

Department of Otorhinolaryngology, University Hospital Antwerp.

Objective: In this study we aimed to evaluate the predictive cross-sectional sensitivity and longitudinal concordance of a machine-learning algorithm in a series of genetically confirmed p.(Pro51Ser) variant carriers (DFNA9).

Study Design: Cross-sectional study.

Setting: Tertiary and secondary referral center.

Patients: Audiograms of 111 subjects with the p.(Pro51Ser) mutation in the COCH-gene were analyzed cross-sectionally. A subset of 17 subjects with repeated audiograms were used for longitudinal analysis.

Interventions: All audiological thresholds were run through the web-based AudioGene v4.0 software.

Main Outcome Measures: Sensitivity for accurate prediction of DFNA9 for cross-sectional data and concordance of correct prediction for longitudinal auditory data.

Results: DFNA9 was predicted with a sensitivity of 93.7% in a series of 222 cross-sectionally collected audiological thresholds (76.1% as first gene locus). When using the hearing thresholds of the best ear, the sensitivity was 94.6%. The sensitivity was significantly higher in DFNA9 patients aged younger than 40 and aged 60 years or older, compared to the age group of 40 to 59 years, with resp. 97.6% (p < 0.0001) and 98.8% (p < 0.0001) accurate predictions. An average concordance of 91.6% was found to show the same response in all successive longitudinal audiometric data per patient.

Conclusions: Audioprofiling software can accurately predict DFNA9 in an area with a high prevalence of confirmed carriers of the p.(Pro51Ser) variant in the COCH-gene. This algorithm yields high promises for helping clinicians in directing genetic testing in case of a strong family history of progressive hearing loss, especially for very young and old carriers.
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http://dx.doi.org/10.1097/MAO.0000000000003028DOI Listing
June 2021

The Synapse Diversity Dilemma: Molecular Heterogeneity Confounds Studies of Synapse Function.

Front Synaptic Neurosci 2020 2;12:590403. Epub 2020 Oct 2.

Department of Computational Science and Technology, School of Electrical Engineering and Computer Science, KTH Royal Institute of Technology, Stockholm, Sweden.

Recent studies have shown an unexpectedly high degree of synapse diversity arising from molecular and morphological differences among individual synapses. Diverse synapse types are spatially distributed within individual dendrites, between different neurons, and across and between brain regions, producing the synaptome architecture of the brain. The spatial organization of synapse heterogeneity is important because the physiological activation of heterogeneous excitatory synapses produces a non-uniform spatial output of synaptic potentials, which confounds the interpretation of measurements obtained from population-averaging electrodes, optrodes and biochemical methods that lack single-synapse resolution. Population-averaging measurements cannot distinguish between changes in the composition of populations of synapses and changing synaptic physiology. Here we consider the implications of synapse diversity and its organization into synaptome architecture for studies of synapse physiology, plasticity, development and behavior, and for the interpretation of phenotypes arising from pharmacological and genetic perturbations. We conclude that prevailing models based on population-averaging measurements need reconsideration and that single-synapse resolution physiological recording methods are required to confirm or refute the major synaptic models of behavior.
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http://dx.doi.org/10.3389/fnsyn.2020.590403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561708PMC
October 2020

A novel serine protease inhibitor as potential treatment for dry eye syndrome and ocular inflammation.

Sci Rep 2020 10 14;10(1):17268. Epub 2020 Oct 14.

Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.

Dry eye syndrome (DES), a multifactorial disorder which leads to ocular discomfort, visual disturbance and tear film instability, has a rising prevalence and limited treatment options. In this study, a newly developed trypsin-like serine protease inhibitor (UAMC-00050) in a tear drop formulation was evaluated to treat ocular inflammation. A surgical animal model of dry eye was employed to investigate the potential of UAMC-00050 on dry eye pathology. Animals treated with UAMC-00050 displayed a significant reduction in ocular surface damage after evaluation with sodium fluorescein, compared to untreated, vehicle treated and cyclosporine-treated animals. The concentrations of IL-1α and TNF-α were also significantly reduced in tear fluid from UAMC-00050-treated rats. Additionally, inflammatory cell infiltration in the palpebral conjunctiva (CD3 and CD45), was substantially reduced. An accumulation of pro-MMP-9 and a decrease in active MMP-9 were found in tear fluid from animals treated with UAMC-00050, suggesting that trypsin-like serine proteases play a role in activating MMP-9 in ocular inflammation in this animal model. Comparative qRT-PCR analyses on ocular tissue indicated the upregulation of tryptase, urokinase plasminogen activator receptor (uPAR) and protease-activated receptor 2 (PAR2). The developed UAMC-00050 formulation was stable up to 6 months at room temperature in the absence of light, non-irritating and sterile with compatible pH and osmolarity. These results provide a proof-of-concept for the in vivo modifying potential of UAMC-00050 on dry eye pathology and suggest a central role of trypsin-like serine proteases and PAR2 in dry eye derived ocular inflammation.
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http://dx.doi.org/10.1038/s41598-020-74159-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560718PMC
October 2020

Bimodal Therapy for Chronic Subjective Tinnitus: A Randomized Controlled Trial of EMDR and TRT Versus CBT and TRT.

Front Psychol 2020 10;11:2048. Epub 2020 Sep 10.

Faculty of Medicine and Health Sciences, Department Translational Neuroscience, University of Antwerp, Antwerp, Belgium.

Introduction: To date, guidelines recommend the use of a stepped care approach to treat tinnitus. The current clinical management of tinnitus frequently consists of audiologic interventions and tinnitus retraining therapy (TRT) or cognitive behavioral therapy (CBT). Due to the high heterogeneity of the tinnitus population and comorbidity of tinnitus with insomnia, anxiety, and depression, these interventions may not be sufficient for every patient. The current study aims to determine whether a bimodal therapy for chronic, subjective tinnitus consisting of the combination of TRT and eye movement desensitization reprocessing (EMDR) results in a clinically significant different efficacy in comparison with the prevailing bimodal TRT and CBT therapy.

Methods: Patients were randomized in two treatment groups. The experimental group received the bimodal therapy TRT/EMDR and the active control group received the bimodal therapy TRT/CBT. Evaluations took place at baseline (T), at the end of the treatment (T), and 3 months after therapy (T). The tinnitus functional index (TFI) was used as primary outcome measurement. Secondary outcome measurements were the visual analog scale of tinnitus loudness (VAS), tinnitus questionnaire (TQ), hospital anxiety and depression scale (HADS), hyperacusis questionnaire (HQ), global perceived effect (GPE), and psychoacoustic measurements.

Findings: The TFI showed clinically significant improvement in both bimodal therapies (mean decrease 15.1 in TRT/CBT; < 0.001 vs. 16.2 in TRT/EMDR; < 0.001). The total score on the TQ, HADS, HQ, and VAS all demonstrated significant decrease after treatment and follow-up ( < 0.001) in the experimental and the active control group. GPE-measurements revealed that more than 80% (i.e., 84% in TRT/CBT vs. 80% in TRT/EMDR) of the patients experienced substantial improvement of tinnitus at follow up. Treatment outcome remained stable after 3 month follow-up and no adverse events were observed.

Conclusion: Both psychotherapeutic protocols result in a clinically significant improvement for patients with chronic subjective tinnitus. No significant different efficacy was found for the TRT/EMDR treatment compared to the combination of TRT and CBT.

Clinical Trial Registration: ClinicalTrials.gov, ID: NCT03114878. April 14, 2017.
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http://dx.doi.org/10.3389/fpsyg.2020.02048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511540PMC
September 2020

Delineation of a new fibrillin-2-opathy with evidence for a role of in the pathogenesis of carpal tunnel syndrome.

J Med Genet 2020 Sep 8. Epub 2020 Sep 8.

Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium

Background: Although carpal tunnel syndrome (CTS) is the most common form of peripheral entrapment neuropathy, its pathogenesis remains largely unknown. An estimated heritability index of 0.46 and an increased familial occurrence indicate that genetic factors must play a role in the pathogenesis.

Methods And Results: We report on a family in which CTS occurred in subsequent generations at an unusually young age. Additional clinical features included brachydactyly and short Achilles tendons resulting in toe walking in childhood. Using exome sequencing, we identified a heterozygous variant (c.5009T>G; p.Phe1670Cys) in the fibrillin-2 () gene that co-segregated with the phenotype in the family. Functional assays showed that the missense variant impaired integrin-mediated cell adhesion and migration. Moreover, we observed an increased transforming growth factor-β signalling and fibrosis in the carpal tissues of affected individuals. A variant burden test in a large cohort of patients with CTS revealed a significantly increased frequency of rare (6.7% vs 2.5%-3.4%, p<0.001) and high-impact (6.9% vs 2.7%, p<0.001) variants in patient alleles compared with controls.

Conclusion: The identification of a novel variant (p.Phe1670Cys) in a unique family with early onset CTS, together with the observed increased frequency of rare and high-impact variants in patients with sporadic CTS, strongly suggest a role of in the pathogenesis of CTS.
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http://dx.doi.org/10.1136/jmedgenet-2020-107085DOI Listing
September 2020

The Virtual Morris Water Task in 64 Patients With Bilateral Vestibulopathy and the Impact of Hearing Status.

Front Neurol 2020 11;11:710. Epub 2020 Aug 11.

Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.

Previous studies have demonstrated spatial cognitive deficits in patients with bilateral vestibulopathy (BVP). However, BVP patients frequently present with a concomitant sensorineural hearing loss, which is a well-established risk factor of cognitive impairment and incident dementia. Nonetheless, previous research on spatial cognitive deficits in BVP patients have not taken hearing status into account. This study aims to compare spatial cognition of BVP patients with healthy controls, with analyses adjusting for hearing status. Spatial cognition was assessed in 64 BVP patients and 46 healthy controls (HC) by use of the Virtual Morris Water Task (VMWT). All statistical analyses were adjusted for hearing (dys)function, sex, age, education, and computer use. Overall, patients with BVP performed worse on all outcome measures of the VMWT. However, these differences between BVP patients and healthy controls were not statistically significant. Nonetheless, a statistically significant link between sensorineural hearing loss and spatial cognition was observed. The worse the hearing, the longer subjects took to reach the hidden platform in the VMWT. Furthermore, the worse the hearing, the less time was spent by the subjects in the correct platform quadrant during the probe trial of the VMWT. In this study, no difference was found regarding spatial cognition between BVP patients and healthy controls. However, a statistically significant link was observed between sensorineural hearing loss and spatial cognition.
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http://dx.doi.org/10.3389/fneur.2020.00710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431773PMC
August 2020

Polysomnographic phenotype of isolated REM sleep without atonia.

Clin Neurophysiol 2020 10 28;131(10):2508-2515. Epub 2020 Jul 28.

Department of Neurology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium; Faculty of Medicine and Health Sciences, Translational Neurosciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium; Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.

Objective: Isolated REM sleep without atonia (iRSWA) is regarded as a prodromal phase of REM sleep behavior disorder and synucleinopathies. In iRSWA patients, we investigated the polysomnographic characteristics that are known to be altered in (prodromal) Parkinson's disease (PD): periodic limb movements of sleep [PLMS] (increased), REM density (reduced), and heart rate variability ([HRV] (reduced).

Methods: We compared video-polysomnographic studies of 49 iRSWA subjects with 41 controls. RSWA and PLMS were scored visually. REM density (REM/hour) and HRV were calculated automatically.

Results: We found a higher median total (15.90 vs 7.20; p = 0.001), REM (21.80 vs 11.0; p < 0.001) and non-REM (11.75 vs 5.72; p = 0.027) PLMS index, and a higher mean REM density (342.45 vs 275.96; p = 0.010) in the iRSWA group, with a significant positive correlation between RSWA severity and these variables (r = 0.39; p < 0.00, r = 0.48; p < 0.001, r = 0.24; p = 0.021, r = 0.28; p = 0.012). We found no significant difference in HRV between groups.

Conclusions: Our results suggest an association between RWSA and REM density and PLMS, but not HRV. The positive correlation between these variabilities may imply overlapping pathophysiological processes.

Significance: The evidence of higher REM density and normal HRV weakens the hypothesis that iRWSA is a prodromal PD stage. An alternative interpretation is, however, that REM density and HRV change during caudal-rostral neurodegeneration.
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http://dx.doi.org/10.1016/j.clinph.2020.07.005DOI Listing
October 2020

Progressive tau aggregation does not alter functional brain network connectivity in seeded hTau.P301L mice.

Neurobiol Dis 2020 09 10;143:105011. Epub 2020 Jul 10.

Laboratory of Cell Biology and Histology, University of Antwerp, Belgium. Electronic address:

Progressive accumulation of hyperphosphorylated tau is a hallmark of various neurodegenerative disorders including Alzheimer's disease. However, to date, the functional effects of tau pathology on brain network connectivity remain poorly understood. To directly interrogate the impact of tau pathology on functional brain connectivity, we conducted a longitudinal experiment in which we monitored a fibril-seeded hTau.P301L mouse model using correlative whole-brain microscopy and resting-state functional MRI. Despite a progressive aggravation of tau pathology across the brain, the major resting-state networks appeared unaffected up to 15 weeks after seeding. Targeted analyses also showed that the connectivity of regions with high levels of hyperphosphorylated tau was comparable to that observed in controls. In line with the ostensible retention of connectivity, no behavioural changes were detected between seeded and control hTau.P301L mice as determined by three different paradigms. Our data indicate that seeded tau pathology, with accumulation of tau aggregates throughout different regions of the brain, does not alter functional connectivity or behaviour in this mouse model. Additional correlative functional studies on different mouse models should help determine whether this is a generalizable trait of tauopathies.
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http://dx.doi.org/10.1016/j.nbd.2020.105011DOI Listing
September 2020

Pelvic floor activation upon stimulation of the sacral spinal nerves in sacral neuromodulation patients.

Neurourol Urodyn 2020 08 25;39(6):1815-1823. Epub 2020 Jun 25.

Department of Urology, Antwerp University Hospital (UZA), Edegem, Belgium.

Purpose: To assess the activation of the different parts of the pelvic floor muscles (PFM) upon electrical stimulation of the sacral spinal nerves while comparing the different lead electrode configurations.

Material And Methods: PFM electromyography (EMG) was recorded using an intravaginal multiple array probe with 12 electrodes pairs, which allows to make a distinction between the different sides and depths of the pelvic floor. In addition concentric needle EMG of the external anal sphincter was performed to exclude far-field recording. A medtronic InterStim tined lead (model 3889) was used as stimulation source. Standard SNM parameters (monophasic pulsed square wave, 210 microseconds, 14 Hz) were used to stimulate five different bipolar electrode configurations (3+0-/3+2-/3+1-/0+3-/1+3-) up to and around the sensory threshold. Of each EMG signal the stimulation intensity needed to evoke the EMG signals as well as its amplitude and latency were determined. Linear mixed models was used to analyse the data.

Results: Twenty female patients and 100 lead electrode configurations were stimulated around the sensory response threshold resulting in 722 stimulations and 12 times as many (8664) EMG recordings. A significant increase in EMG amplitude was seen upon increasing stimulation intensity (P < .0001). Large differences were noted between the EMG amplitude recorded at the different sides (ipsilateral>posterior>anterior>contralateral) and depths (deep>center>superficial) of the pelvic floor. These differences were noted for all lead electrodes configurations stimulated (P < .0001). Larger EMG amplitudes were measured when the active electrode was located near the entry point of the sacral spinal nerves through the sacral foramen (electrode #3). No differences in EMG latency could be withheld, most likely due to the sacral neuroanatomy (P > .05).

Conclusions: A distinct activation pattern of the PFM could be identified for all stimulated lead electrode configurations. Electrical stimulation with the most proximal electrode (electrode #3) as the active one elicited the largest PFM contractions.
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http://dx.doi.org/10.1002/nau.24425DOI Listing
August 2020

Pelvic Floor Muscle Electromyography as a Guiding Tool During Lead Placement and (Re)Programming in Sacral Neuromodulation Patients: Validity, Reliability, and Feasibility of the Technique.

Neuromodulation 2020 Dec 19;23(8):1172-1179. Epub 2020 Jun 19.

Department of Urology, Antwerp University Hospital (UZA), Edegem, Belgium.

Purpose: To assess the validity, reliability, and feasibility of electromyography (EMG) as a tool to measure pelvic floor muscle (PFM) contractions during placement and (re)programming of the tined lead electrodes in sacral neuromodulation (SNM) patients.

Materials And Methods: Single tertiary center, prospective study conducted between 2017 and 2019 consisting of three protocols including a total of 75 patients with overactive bladder (wet/dry) or nonobstructive urinary retention. PFM EMG was recorded using the multiple array probe (MAPLe), placed intravaginally. All stimulations (monophasic pulsed square wave, 210 μsec, 14 Hz) were performed using Medtronic's standard SNM stimulation equipment. During lead implantation, all four lead electrodes were stimulated with fixed increasing stimulation intensities (1-2-3-5-7-10 V). During lead electrode (re)programming, five bipolar lead electrode configurations were stimulated twice up to when an electrical PFM motor response (EPFMR), sensory response, and pain response were noted (i.e., the threshold), respectively. Additionally, amplitude and latency of the EPFMRs were determined. Validity, reliability, and feasibility were statistically analyzed using the intraclass correlation coefficient, weighted Cohen's kappa and linear regression, respectively.

Results: Validity: EPFMRs were strongly associated with visually detected PFM motor responses (κ = 0.90). Reliability: EPFMR amplitude (ICC = 0.99) and latency (ICC = 0.93) showed excellent repeatability. Feasibility: linear regression (EPFMR threshold = 0.18 mA + 0.76 * sensory response threshold) showed an increase in the sensory response threshold is associated with a smaller increase in EPFMR threshold, with the EPFMR occurring before or on the sensory response threshold in 83.8% of all stimulations.

Conclusions: Measuring PFM contractions with EMG during placement and (re)programming of lead electrodes in SNM patients is valid, reliable, and feasible. Therefore, the use of PFM EMG motor responses could be considered as a tool to assist in these procedures.
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http://dx.doi.org/10.1111/ner.13177DOI Listing
December 2020

A brainwide atlas of synapses across the mouse life span.

Science 2020 07 11;369(6501):270-275. Epub 2020 Jun 11.

Genes to Cognition Program, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH16 4SB, UK.

Synapses connect neurons together to form the circuits of the brain, and their molecular composition controls innate and learned behavior. We analyzed the molecular and morphological diversity of 5 billion excitatory synapses at single-synapse resolution across the mouse brain from birth to old age. A continuum of changes alters synapse composition in all brain regions across the life span. Expansion in synapse diversity produces differentiation of brain regions until early adulthood, and compositional changes cause dedifferentiation in old age. The spatiotemporal synaptome architecture of the brain potentially accounts for life-span transitions in intellectual ability, memory, and susceptibility to behavioral disorders.
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http://dx.doi.org/10.1126/science.aba3163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115813PMC
July 2020

Postoperative ileus after laparoscopic primary and incisional abdominal hernia repair with intraperitoneal mesh (DynaMesh®-IPOM versus Parietex™ Composite): a single institution experience.

Langenbecks Arch Surg 2021 Feb 31;406(1):209-218. Epub 2020 May 31.

Department of General Surgery, Heilig-Hart Hospital, Mechelsestraat 24, Lier, Belgium.

Purpose: Laparoscopic primary or incisional abdominal hernia repair with intraperitoneal mesh placement is a well-accepted and safe technique. Evidence for complications however remains inconclusive, and little is known about the occurrence of postoperative ileus secondary to postoperative intra-abdominal adhesions with different types of IPOM meshes used. Therefore, we retrospectively compared the occurrence of postoperative ileus between two of the different meshes used in our center.

Methods: Three hundred seventy-five patients who underwent ventral hernia repair with intraperitoneal mesh placement, either with a DynaMesh®-IPOM (FEG Textiltechnik mbH, Aachen, Nordrhein-Westfalen, Germany) or a Parietex™ Composite mesh (Medtronic, Minneapolis, MN, USA), at the Heilig-Hart Hospital in Lier (Antwerp, Belgium) between 2012 and 2017 were retrospectively compared with regard to the occurrence of postoperative ileus until 6 weeks postoperatively. Baseline demographics and clinical data up to 6 weeks postoperatively of the patients in the two mesh groups are provided.

Results: The DynaMesh®-IPOM mesh group was associated with a significantly higher incidence of postoperative ileus compared with the Parietex™ Composite mesh group with a cutoff limit at postoperative day 1 (n = 17, 6.8% vs. n = 0, 0.0%; P = 0.003) and postoperative day 4 (n = 13, 5.2% vs. n = 0, 0.0%, P = 0.006), even with a mesh surface area of ≤ 300 cm and when both meshes were fixated with the same method of fixation (Securestrap™) with a cutoff limit for postoperative ileus at postoperative day 1 (n = 4, 7.7% vs. n = 0, 0.0%; P = 0.013) and postoperative day 4 (n = 3, 5.8% vs. n = 0, 0.0%, P = 0.040). Of the 17 patients with a postoperative ileus, 9 (52.9%) had a suspicion of adhesive small bowel obstruction on CT scan (P = 0.033) with definitive confirmation of small bowel adhesions with the DynaMesh®-IPOM mesh at laparoscopy in 2 patients.

Conclusion: Our results confirm current literature available regarding postoperative ileus secondary to postoperative intra-abdominal adhesions with the DynaMesh®-IPOM mesh. However, further research with well-designed, multicenter randomized controlled studies to evaluate the use and related complications of these meshes is needed.
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http://dx.doi.org/10.1007/s00423-020-01898-9DOI Listing
February 2021

Neural pathway of bellows response during SNM treatment revisited: Conclusive evidence for direct efferent motor response.

Neurourol Urodyn 2020 06 2;39(5):1576-1583. Epub 2020 Jun 2.

Department of Urology, Antwerp University Hospital, Edegem, Belgium.

Background: In sacral neuromodulation (SNM) patients, it is thought the bellows response elicited upon sacral spinal nerve stimulation is reflex-mediated. Therefore the mechanism of action of SNM is considered to be at the spinal or supraspinal level. These ideas need to be challenged.

Objective: To identify the neural pathway of the bellows response upon sacral spinal nerve stimulation.

Design, Setting, And Participants: Single tertiary center, prospective study (December 2017-June 2019) including 29 patients with overactive bladder refractory to first-line treatment.

Intervention: Recording of the pelvic floor muscle response (PFMR) using a camcorder and electromyography (EMG) (intravaginal probe and concentric needles) upon increasing stimulation during lead or implantable pulse generator placement.

Outcome Measurements And Statistical Analysis: The lowest stimulation intensity needed to elicit a visual PFMR and electrical PFMR was determined. Electrical PFMRs were subdivided according to their latency.

Outcome: the association between visual and electrical PFMRs. Statistical analyses were performed using the weighted kappa coefficient.

Results: Three different electrical PFMRs could be identified by surface and needle EMG, corresponding with a direct efferent motor response (R1), oligosynaptic (R2), and polysynaptic (R3) afferent reflex response. Only the R1 electrical PFMR was perfectly associated with the visual PFMR (κ = 0.900).

Conclusions: The visual PFMRs upon sacral spinal nerve stimulation are direct efferent motor responses. A reopening of the discussion on the mechanism of action of SNM is possibly justified.
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http://dx.doi.org/10.1002/nau.24408DOI Listing
June 2020

Prenatally detected copy number variants in a national cohort: A postnatal follow-up study.

Prenat Diagn 2020 09 24;40(10):1272-1283. Epub 2020 Jun 24.

Center for Medical Genetics, Universiteit Antwerpen, Antwerpen, Belgium.

Objective: Belgian genetic centers established a database containing data on all chromosomal microarrays performed in a prenatal context. A study was initiated to evaluate postnatal development in children diagnosed prenatally with a non-benign copy number variant (CNV).

Methods: All children diagnosed with a prenatally detected non-benign CNV in a Belgian genetic center between May 2013 and February 2015 were included in the patient population. The control population consisted of children who had undergone an invasive procedure during pregnancy, with no or only benign CNVs. Child development was evaluated at 36 months using three (3) questionnaires: Ages and Stages Questionnaire Third edition, Ages and Stages Questionnaire Social-Emotional Second Edition and a general questionnaire.

Results: A significant difference in communication and personal-social development was detected between children with a reported susceptibility CNV and both children with an unreported susceptibility CNV and the control population. The outcome of children with a particular CNV is discussed in a case-by-case manner.

Conclusion: Our postnatal follow-up project of children with a prenatally detected non-benign CNV is the first nationwide project of its kind. A higher number of cases for each CNV category is however needed to confirm our findings.
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http://dx.doi.org/10.1002/pd.5751DOI Listing
September 2020

Phosphorus addition increased carbon partitioning to autotrophic respiration but not to biomass production in an experiment with Zea mays.

Plant Cell Environ 2020 09 3;43(9):2054-2065. Epub 2020 Jun 3.

Research Centre of Excellence Plants and Ecosystems, Ecology in a Time of Change, University of Antwerp, Wilrijk, Belgium.

Plant carbon (C) partitioning-the relative use of photosynthates for biomass production, respiration, and other plant functions-is a key but poorly understood ecosystem process. In an experiment with Zea mays, with or without arbuscular mycorrhizal fungi (AMF), we investigated the effect of phosphorus (P) fertilization and AMF on plant C partitioning. Based on earlier studies, we expected C partitioning to biomass production (i.e., biomass production efficiency; BPE) to increase with increasing P addition due to reduced C partitioning to AMF. However, although plant growth was clearly stimulated by P addition, BPE did not increase. Instead, C partitioning to autotrophic respiration increased. These results contrasted with our expectations and with a previous experiment in the same set-up where P addition increased BPE while no effect on autotropic respiration was found. The comparison of both experiments suggests a key role for AMF in explaining these contrasts. Whereas in the previous experiment substantial C partitioning to AMF reduced BPE under low P, in the current experiment, C partitioning to AMF was too low to directly influence BPE. Our results illustrate the complex influence of nutrient availability and mycorrhizal symbiosis on plant C partitioning.
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http://dx.doi.org/10.1111/pce.13785DOI Listing
September 2020

Dysregulated activities of proline-specific enzymes in septic shock patients (sepsis-2).

PLoS One 2020 21;15(4):e0231555. Epub 2020 Apr 21.

Laboratory of Medical Biochemistry, University of Antwerp, Antwerp, Belgium.

The proline-specific enzymes dipeptidyl peptidase 4 (DPP4), prolylcarboxypeptidase (PRCP), fibroblast activation protein α (FAP) and prolyl oligopeptidase (PREP) are known for their involvement in the immune system and blood pressure regulation. Only very limited information is currently available on their enzymatic activity and possible involvement in patients with sepsis and septic-shock. The activity of the enzymes was measured in EDTA-plasma of patients admitted to the intensive care unit (ICU): 40 septic shock patients (sepsis-2) and 22 ICU control patients after major intracranial surgery. These data were used to generate receiver operating characteristic (ROC) curves. A survival analysis (at 90 days) and an association study with other parameters was performed. PRCP (day 1) and PREP (all days) enzymatic activities were higher in septic shock patients compared to controls. In contrast, FAP and DPP4 were lower in these patients on all studied time points. Since large differences were found, ROC curves were generated and these yielded area under the curve (AUC) values for PREP, FAP and DPP4 of 0.88 (CI: 0.80-0.96), 0.94 (CI: 0.89-0.99) and 0.86 (CI: 0.77-0.95), respectively. PRCP had a lower predicting value with an AUC of 0.71 (CI: 0.58-0.83). A nominally significant association was observed between survival and the DPP4 enzymatic activity at day 1 (p<0.05), with a higher DPP4 activity being associated with an increase in survival. All four enzymes were dysregulated in septic shock patients. DPP4, FAP and PREP are good in discriminating between septic shock patients and ICU controls and should be further explored to see whether they are already dysregulated in earlier stages, opening perspectives for their further investigation as biomarkers in sepsis. DPP4 also shows potential as a prognostic biomarker. Additionally, the associations found warrant further research.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231555PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7173796PMC
July 2020

Between Pleasure and Pain: A Pilot Study on the Biological Mechanisms Associated With BDSM Interactions in Dominants and Submissives.

J Sex Med 2020 04 7;17(4):784-792. Epub 2020 Feb 7.

Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine and Health Sciences, Campus Drie Eiken, University of Antwerp, Antwerp, Belgium; University Department of Psychiatry, University Psychiatric Centre Duffel, Duffel, Belgium.

Background: BDSM is an abbreviation used to reference the concepts of bondage and discipline, dominance and submission, sadism, and masochism, enacted by power exchanges between consensual partners.

Aim: To shed light upon the rewarding biological mechanisms associated with BDSM interactions.

Methods: A group of 35 BDSM couples (dominant and submissive counterparts) were recruited and tested during a BDSM interaction, with an additional control group of 27 non-BDSM interested people tested in a normal social interaction.

Outcomes: We compared the evolution of the stress and reward hormone levels of cortisol, beta-endorphins, and endocannabinoids (2AG and anandamide) in a group of BDSM practitioners before and after an active BDSM interaction with the levels in control individuals.

Results: We showed that submissives showed increases in cortisol and endocannabinoid levels due to the BDSM interaction, with dominants only showing increased endocannabinoid levels when the BDSM interaction was associated with power play.

Clinical Implications: This study effectively provides a link between behavior that many think of as aberrant on one hand, and biological pleasure experience on the other, in the hope that it may relieve some of the stigma these practitioners still endure.

Strengths & Limitations: It is one of the first and largest studies of its kind, but is still limited in sample size and only represents a specific population of Flemish BDSM practitioners.

Conclusion: Even though this is one of the first studies of its kind, we can conclude that there is a clear indication for increased pleasure in submissives when looking at biological effects of a BDSM interaction, which was related to the increases in experienced stress. Wuyts E, De Neef N, Coppens V, et al. Between Pleasure and Pain: A Pilot Study on the Biological Mechanisms Associated With BDSM Interactions in Dominants and Submissives. J Sex Med 2020;17:784-792.
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http://dx.doi.org/10.1016/j.jsxm.2020.01.001DOI Listing
April 2020

Immune and Neuroendocrine Trait and State Markers in Psychotic Illness: Decreased Kynurenines Marking Psychotic Exacerbations.

Front Immunol 2019 17;10:2971. Epub 2020 Jan 17.

Faculty of Medicine and Health Sciences, Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Antwerp, Belgium.

Different patterns of immune system upregulation are present in the acute vs. post-treatment states of psychotic illness. We explored the existence of state and trait markers in the peripheral immune system and two immune-associated neuroendocrine pathways (IDO and GTP-CH1 pathway) in a longitudinal sample of psychosis patients. We also evaluated the association of these markers with neuropsychiatric symptomatology. Plasma concentrations of peripheral blood markers were measured in a transdiagnostic group of 49 inpatients with acute psychosis and 52 matched healthy control subjects. Samples were obtained in patients within 48 h after hospital admission for an acute psychotic episode (before initiation of antipsychotics), after 1-2 weeks and again after 8 weeks of treatment. Kynurenine, kynurenic acid (KA), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), phenylalanine, tyrosine, nitrite, and neopterin were measured using HPLC and LC-MS/MS analysis. Concentrations of CRP, CCL2 (MCP1) and cytokines were determined with multiplex immunoassay. PANSS interviews and cognitive tests were performed at baseline and follow-up. Mixed model analyses were used to identify trait and state markers. Patients had significantly higher plasma concentrations of CRP, CCL2, IL1RA, and lower concentrations of KA and KA/Kyn at all time points (F7.5-17.5, all < 0.001). Increased concentrations of IL6, IL8, IL1RA, TNFα, and CCL2 and decreased QA and 3-HK (F8.7-21.0, all < 0.005) were found in the acute psychotic state and normalized after treatment. Low nitrite concentrations at admission rose sharply after initiation of antipsychotic medication (F42.4, < 0.001). PANSS positive scale scores during the acute episode correlated with pro-inflammatory immune markers ( ≥ |0.5|), while negative scale scores correlated inversely with IDO pathway markers ( ≥ |0.4|). Normalization of KA and 3-HK levels between admission and follow-up corresponded to a larger improvement of negative symptoms ( = 0.5, < 0.030) A reverse association was found between relative improvement of SDST scores and decreasing KA levels ( = 0.5, < 0.010). The acute psychotic state is marked by state-specific increases of immune markers and decreases in peripheral IDO pathway markers. Increased CRP, CCL2, and IL1RA, and decreased KA and KA/Kyn are trait markers of psychotic illness.
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http://dx.doi.org/10.3389/fimmu.2019.02971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978914PMC
December 2020
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