Beta-2 adrenergic effects on the sympathetic nervous system

The origin of the studies, described in this thesis, dates back to 1979. In that year my colleague, R.P. Verhoeven, studied the responsiveness of hyperthyroid patients to beta adrenoceptor activation [1]. In his experiments he made the serendipitous observation that the plasma levels of the sympathetic transmitter, noradrenaline, increased during infusion of the beta adrenoceptor agonist isoprenaline. At the time most of us felt that this could be explained by reflex increase in sympathetic nervous activity, due to the vasodilatation caused by isoprenaline, my promotor, Prof. Schalekamp, took a different view. He suggested that the increase in noradrenaline during infusion of isoprenaline could be mediated by presynaptic beta adrenoceptors, which would serve to facilitate the release of noradrenaline [2,3,4]. He gave the impetus to the studies that followed

An analytical solution to solute transport in continuous arterio-venous hemodiafiltration (CAVHD)

In conventional intermittent hemodialysis, the overall mass transfer coefficient (Ko) of a dialyser is mostly calculated at zero ultrafiltration and at relatively high dialysate flow rates. In continuous arterio-venous hemodiafiltration (CAVHD), the dialysate flow rates are low as comparable to the rates of ultrafiltration flows, making the dialysis treatment as slow as possible. Therefore the overall mass transfer coefficient (Kd) of a CAVHD hemofilter has to be calculated in the presence of ultrafiltration. A mathematical model of CAVHD is presented in order to calculate the diffusive mass transfer coefficient (Kd) for a solute when blood, filtrate and dialysate flow rates and solute concentrations are known. The ultrafiltration volume flux (Jv) is assumed to vary linearly along the axial direction of the hemofilter. The calculated mass transfer coefficient Kd shows that at high values of dialysate flow and low values of ultrafiltration, the overall mass transfer coefficient (Kd) of a CAVHD hemofilter equals mass transfer coefficient (Ko) of a dialyser in conventional intermittent hemodialysis. Also, the calculated mass transfer coefficient Kd shows no significant differences when the ultrafiltration volume flux is assumed to be constant along the length of the hemofilter if no backfiltration occurs in the hemofilter

A mathematical model of continuous arterio-venous hemodiafiltration (CAVHD)

Abstract Continuous arterio-venous hemodiafiltration (CAVHD) differs from conventional hemofiltration and dialysis by the interaction of convection and diffusion, the use of very low dialysate flow rates and by the deterioration of membrane conditions during the treatment. In order to study the impact of these phenomena on diffusive transport, we developed a mathematical model of the kinetics of CAVHD solute transport from plasma water to dialysate. The model yields an expression of the diffusive mass transfer coefficient, Kd, as a function of blood, filtrate and dialysate flow rates and solute concentrations, which can be measured in the clinical setting. This paper gives a description of the model derivation. Kd is demonstrated to vary depending on dialysate flow and duration of treatment

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

Colorectal liver metastases: Surgery versus thermal ablation (COLLISION) - a phase III single-blind prospective randomized controlled trial

Background: Radiofrequency ablation (RFA) and microwave ablation (MWA) are widely accepted techniques to eliminate small unresectable colorectal liver metastases (CRLM). Although previous studies labelled thermal ablation inferior to surgical resection, the apparent selection bias when comparing patients with unresectable disease to surgical candidates, the superior safety profile, and the competitive overall survival results for the more recent reports mandate the setup of a randomized controlled trial. The objective of the COLLISION trial is to prove non-inferiority of thermal ablation compared to hepatic resection in patients with at least one resectable and ablatable CRLM and no extrahepatic disease. Methods: In this two-arm, single-blind multi-center phase-III clinical trial, six hundred and eighteen patients with at least one CRLM (≤3cm) will be included to undergo either surgical resection or thermal ablation of appointed target lesion(s) (≤3cm). Primary endpoint is OS (overall survival, intention-to-treat analysis). Main secondary endpoints are overall disease-free survival (DFS), time to progression (TTP), time to local progression (TTLP), primary and assisted technique efficacy (PTE, ATE), procedural morbidity and mortality, length of hospital stay, assessment of pain and quality of life (QoL), cost-effectiveness ratio (ICER) and quality-adjusted life years (QALY). Discussion: If thermal ablation proves to be non-inferior in treating lesions ≤3cm, a switch in treatment-method may lead to a reduction of the post-procedural morbidity and mortality, length of hospital stay and incremental costs without compromising oncological outcome for patients with CRLM. Trial registration:NCT03088150 , January 11th 2017

Thoracic outlet syndrome (TROTS) registry: A study protocol for the primary upper extremity deep venous thrombosis section

Introduction There is a lack of comprehensive and uniform data on primary upper extremity deep venous thrombosis (pUEDVT). pUEDVT includes venous thoracic outlet syndrome related upper extremity deep venous thrombosis (UEDVT) and idiopathic UEDVT. Research on these conditions has been hampered by their rarity, lack of uniform diagnostic criteria, and heterogeneity in therapeutic strategies. To improve current research data collection using input of all various pUEDVT treating medical specialists, we initiated the ThoRacic OuTlet Syndrome (TROTS) registry. The aim of the TROTS registry is to a) collect extensive data on all pUEDVT patients through a predefined protocol, b) give insight in the long term outcome using patient reported outcome measures, c) create guidance in the diagnostic and clinical management of these conditions, and thereby d) help provide content for future research. Methods and analysis The TROTS registry was designed as an international prospective longitudinal observational registry for data collection on pUEDVT patients. All pUEDVT patients, regardless of treatment received, can be included in the registry after informed consent is obtained. All relevant data regarding the initial presentation, diagnostics, treatment, and follow-up will be collected prospectively in an electronic case report form. In addition, a survey containing general questions, a Health-related Quality of Life questionnaire (EQ-5D-5L), and Functional Disability questionnaire (Quick-DASH) will be sent periodically (at the time of inclusion, one and two years after inclusion, and every five years after inclusion) to the participant. The registry protocol was approved by the Medical Ethical Review Board and registered in the Netherlands Trial Register under Trial-ID NL9680. The data generated by the registry will be used for future research on pUEDVT and published in peer reviewed journals. Conclusion TROTS registry data will be used to further establish the optimal management of pUEDVT and lay the foundation for future research and guidelines

Thoracic outlet syndrome (TROTS) registry:A study protocol for the primary upper extremity deep venous thrombosis section

Introduction There is a lack of comprehensive and uniform data on primary upper extremity deep venous thrombosis (pUEDVT). pUEDVT includes venous thoracic outlet syndrome related upper extremity deep venous thrombosis (UEDVT) and idiopathic UEDVT. Research on these conditions has been hampered by their rarity, lack of uniform diagnostic criteria, and heterogeneity in therapeutic strategies. To improve current research data collection using input of all various pUEDVT treating medical specialists, we initiated the ThoRacic OuTlet Syndrome (TROTS) registry. The aim of the TROTS registry is to a) collect extensive data on all pUEDVT patients through a predefined protocol, b) give insight in the long term outcome using patient reported outcome measures, c) create guidance in the diagnostic and clinical management of these conditions, and thereby d) help provide content for future research. Methods and analysis The TROTS registry was designed as an international prospective longitudinal observational registry for data collection on pUEDVT patients. All pUEDVT patients, regardless of treatment received, can be included in the registry after informed consent is obtained. All relevant data regarding the initial presentation, diagnostics, treatment, and follow-up will be collected prospectively in an electronic case report form. In addition, a survey containing general questions, a Health-related Quality of Life questionnaire (EQ-5D-5L), and Functional Disability questionnaire (Quick-DASH) will be sent periodically (at the time of inclusion, one and two years after inclusion, and every five years after inclusion) to the participant. The registry protocol was approved by the Medical Ethical Review Board and registered in the Netherlands Trial Register under Trial-ID NL9680. The data generated by the registry will be used for future research on pUEDVT and published in peer reviewed journals. Conclusion TROTS registry data will be used to further establish the optimal management of pUEDVT and lay the foundation for future research and guidelines

Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based study - Supplemental data

This file contains the supplemental data to the article entitled "Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based study". It contains additional methods paragraphs 1 to 4, supplemental tables 1 to 17, supplemental figures 1 to 7, and additional reference

Data from: Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Objective: We explored genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely small sub-cortical BI (SSBI), in eighteen population-based cohorts (N=20,949) from five ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in seven population-based cohorts (N=6,862, 1,483 with BI, 630 with SBBI), and tested associations with related phenotypes including ischemic stroke and pathologically-defined BI. Results: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, P=1.77×10-8 and LINC00539/ZDHHC20, P=5.82×10-9. Both have been associated with blood pressure (BP) related phenotypes, but did not replicate in the smaller follow-up sample nor show associations with related phenotypes. Age and sex-adjusted associations with BI and SSBI were observed for BP traits (P-value for BI, P[BI]=9.38×10-25; P[SSBI]=5.23×10-14 for hypertension), smoking (P[BI]=4.4×10-10; P[SSBI]=1.2×10-4), diabetes (P[BI]=1.7×10-8; P[SSBI]=2.8×10-3), previous cardiovascular disease (P[BI]=1.0×10-18; P[SSBI]=2.3×10-7), stroke (P[BI]=3.9×10-69; P[SSBI]=3.2×10-24), and MRI-defined white matter hyperintensity burden (P[BI]=1.43×10-157; P[SSBI]=3.16×10-106), but not with body-mass-index or cholesterol. GRS of BP traits were associated with BI and SSBI (P≤0.0022), without indication of directional pleiotropy. Conclusions: In this multi-ethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness