Glucocorticoid Receptor Variants Modulate the Sensitivity to Cortisol

Synthetic glucocorticoids are used therapeutically for numerous indications. However, due to their broad physiological effects across many systems, side effects of GC therapy can be extensive and limit the clinical utility of GCs as a drug. One of the main urgent questions at this moment is to develop insights into the cause of the differences in the response between individuals to therapeutically applied GCs. Some patients respond to low doses, with or without side effects, while others do not respond at all. This thesis discusses a number of possible explanations for these differences in GC sensitivity and is focused on genetic, but also on transcriptional and translational aspects of the GR gene. Furthermore, it is also described how glucocorticoid sensitivity disorders can be characterized clinically and biochemically. An important tool in these studies has been a newly developed bioassay, measuring cellular GC sensitivity ex vivo, based on GR action at the transcriptional level by studying GC-regulated mRNA expression (chapter 2). Various polymorphism in the GR gene (N363S, ER22/23EK, and 9beta) are shown to affect GC sensitivity in vivo and in/ex vitro and result in a wide variety of phenotypic signs (chapters 3, 4, and 5). Furthermore, studies described in chapter 4, 5, 6, and 7 have demonstrated that also transcriptional and translational variants of the GR and the use of different promoters could modulate GC sensitivity. These factors modulating inter- individual sensitivity to GCs may have consequences for the use of GCs in a clinical setting. When treating patients with GCs, they need an individually determined optimal dose to obtain a balance between beneficial and adverse effects

On the Automatic Guidance System with Crab-Steering

Among the steering modes of farm tractor, the crab-steering has hardly been taken up in production and also in research. That mode of steering may be unapplicable to manual operating that has made familiar with normal mode of steering for long time, but because the vehicle with that mode can always hold its body in a certine direction, that type has a profitable property for the automatic guidance in field operation, and positional relation of sensor and implement is one-dimensional problem and attaching point of sensor to body is unrestricted. This type vehicle can not turn, but travelling of field operation necessitates no turning in many kinds of operations except at head land. At head land, it may be solved to change steering mode. The authors aspect to the property of crab-steering and aimed to develop the automatic guidance system with this steering mode. In this paper, the stability of relay-control system of automatic guidance was considered with describing-function method, and the results of tracking tests with trial vehicle were discussed and considered by means of time varying Fourier coefficients of tracking pass

Chronic Air Pollution Exposure during Pregnancy and Maternal and Fetal C-Reactive Protein Levels: The Generation R Study

Background: Exposure to air pollution has been associated with higher C-reactive protein (CRP) levels, suggesting an inflammatory response. Not much is known about this association in pregnancy

Mass Spectrometry for Identification, Monitoring, and Minimal Residual Disease Detection of M-Proteins

BACKGROUND: Monoclonal gammopathies (MGs) are plasma cell disorders defined by the clonal expansion of plasma cells, resulting in the characteristic excretion of a monoclonal immunoglobulin (M-protein). M-protein detection and quantification are integral parts of the diagnosi

Klinische chemie voor iedereen: het Wikipedia-project

Public relations (PR) and information to patients are key goals of the Dutch Society of Clinical Chemistry (NVKC). In this paper several initiatives will be discussed that have been undertaken to meet this statement. The Wikipedia project is one of those initiatives in which information concerning clinical chemistry is added or revised to the Dutch version of the online encyclopaedia Wikipedia. Over 100 tests and items of clinical chemistry have been added or revised and are recognized as a separate category within this online encyclopaedia. Statistical analysis showed an increase in the number of visitors to these articles of Wikipedia. Furthermore, by adding and improving the available information, the quality of the information provided online is enhanced. In conclusion: the attribution of health care professionals to this public domain leads to enhanced access of high quality information for the main public to clinical chemistry in general and to specific laboratory blood tests

A novel haemocytometric covid-19 prognostic score developed and validated in an observational multicentre european hospital-based study

COVID-19 induces haemocytometric changes. Complete blood count changes, including new cell activation parameters, from 982 confirmed COVID-19 adult patients from 11 European hospitals were retrospectively analysed for distinctive patterns based on age, gender, clinical severity, symptom duration and hospital days. The observed haemocytometric patterns formed the basis to develop a multi-haemocytometric-parameter prognostic score to predict, during the first three days after presentation, which patients will recover without ventilation or deteriorate within a two-week timeframe, needing intensive care or with fatal outcome. The prognostic score, with ROC curve AUC at baseline of 0.753 (95% CI 0.723-0.781) increasing to 0.875 (95% CI 0.806-0.926) on day 3, was superior to any individual parameter at distinguishing between clinical severity. Findings were confirmed in a validation cohort. Aim is that the score and haemocytometry results are simultaneously provided by analyser software, enabling wide applicability of the score as haemocytometry is commonly requested in COVID-19 patients

A summary of the diagnostic and prognostic value of hemocytometry markers in COVID-19 patients

Many studies have reported hemocytometric changes in COVID-19 infection at admission and during the course of disease, but an overview is lacking. We provide a summary of the literature of hemocytometric changes and evaluate whether these changes may assist clinicians in diagnosing and predicting disease progression of COVID-19. Eighty-three out of 250 articles from December 2019 to 20 May 2020 were included from the databases, PubMed, Web of Science Core Collection, Embase, Cochrane and MedRxiv. Our review of the literature indicates that lymphopenia and an elevated neutrophil/lymphocyte ratio are the most consistent abnormal hemocytometric findings and that these alterations may augment in the course of time, especially in those with severe disease

Differential regulation of synthetic glucocorticoids on gene expression levels of glucocorticoid-induced leucine zipper and interleukin-2.

Individual glucocorticoid (GC) sensitivity was determined by measuring the effects of several clinically used GCs on transactivation of the GC-induced leucine zipper (GILZ) gene and on transrepression of the IL-2 gene using quantitative real-time PCR. A clear difference in relative potencies for transactivation and transrepression of the various GCs was observed, suggesting differential effects. To determine whether the in vitro outcomes could predict in vivo effects of GCs, 15 individuals underwent a 0.25-mg dexamethasone (DEX) suppression test (DST) while determining GILZ and IL-2 mRNA levels in their peripheral blood mononuclear cells incubated with hydrocortisone, DEX, budesonide, and prednisolone. No correlations were found between the DST and the two expression assays. However, significant correlations existed between hydrocortisone and DEX (r = 0.52; P = 0.046), hydrocortisone and budesonide (r = 0.48; P = 0.069), and hydrocortisone and prednisolone (r = 0.86; P = 0.007) regarding GILZ mRNA levels, and between hydrocortisone and DEX (r = 0.62; P = 0.014), hydrocortisone and budesonide (r = 0.71; P = 0.003), and hydrocortisone and prednisolone (r = 0.71; P = 0.047) regarding IL-2 mRNA levels. In conclusion, intra- and inter-individual variations in GC sensitivity were observed using two expression assays representing GC-mediated transactivation and transrepression. The two expression assays did not correlate with each other or with the results of the DST. This suggests that regulation of the hypothalamic-pituitary-adrenal axis is more complex. However, within an individual person, these two tests combined might predict what type and dosage of GC will be preferable in individual patients for its inhibitory clinical effects, together with relatively fewer transactivating effects related to adverse effects