Marijn M. Speeckaert

Acute generalized exanthematous pustulosis: an overview of the clinical, immunological and diagnostic concepts

Acute generalized exanthematous pustulosis (AGEP) is a significant adverse cutaneous reaction, most often provoked by drugs and acute infections. The recognition of AGEP is important, in order to avoid confusion with a systemic infection and consequently to avoid incorrect treatment. The clinical hallmark is the presence of multiple disseminated sterile pustules on an erythematous background, associated with fever and a massive neutrophilia and sometimes eosinophilia. The disease is characterised by an acute onset and a spontaneous resolution within 2 weeks. The involvement of drug-specific T cells in the pathomechanism can be confirmed by positive skin patch tests and lymphocyte transformation tests. In this review, we highlight the main clinical, pathophysiological and diagnostic aspects of this peculiar form of drug allergy.

Glycosylation of prostate specific antigen and its potential diagnostic applications

Prostate specific antigen (PSA) assays are widely used for early detection of prostate cancer. However, those analyses are associated with considerable sensitivity and specificity problems. Several approaches have been developed to tackle this issue. PSA is a glycoprotein, which is primarily produced by the prostatic epithelial cells. Aberrant glycosylation modification of proteins is a fundamental characteristic of tumorigenesis. Study of PSA glycoforms offers interesting diagnostic perspectives. Modern technology allows us to analyze PSA glycoforms in a variety of clinical samples (serum or plasma, urine, seminal fluid, tissue). A number of novel techniques, such as lectin-based detection methods, mass spectrometry, 2-dimensional electrophoresis and capillary electrophoresis have been developed to analyze PSA glycosylation. This article reviews the technical and diagnostic aspects of PSA glycoforms.

Creatinine determination according to Jaffe—what does it stand for?

In 1886, Max Jaffe discovered a reaction of creatinine with picric acid in an alkaline environment. Although the manuscript describes the nature of a precipitate and does not deal with an analytical assay, Jaffes landmark paper elucidated the basic principles of the creatinine determination method (originally developed by Otto Folin), which became immensely popular and has easily withstood the test of time. Despite the advent of the enzymatic creatinine analysis, the analytical method is still popular due to its simplicity and low cost. As there is no standard recipe for the ‘Jaffe’ method, much methodological variation has occurred over time. This lack of methodological standardization implies that even in the 21st century, improving the interchangeability of Jaffe results is still an issue.

Tumor Necrosis Factor Receptors: Biology and Therapeutic Potential in Kidney Diseases

The major evolutionary advance represented in the human immune system is a mechanism of antigen-directed immunity in which tumor necrosis factor (TNF)-α and TNF receptors (TNFRs) play essential roles. Binding of TNF-α to the 55-kDa type I TNFR (TNFR1, TNFRSF1A, CD120a, p55) or the 75-kDa type II TNFR (TNFR2, TNFRSF1B, CD120b, p75) activates signaling pathways controlling inflammatory, immune and stress responses, as well as host defense and apoptosis. Multiple studies have investigated the role of TNFRs in the development of early and late renal failure (diabetic nephropathy, nephroangiosclerosis, acute kidney transplant rejection, renal cell carcinoma, glomerulonephritis, sepsis and obstructive renal injury). This article reviews the general characteristics, the analytical aspects and the biology of TNFRs in this domain. In addition, the potential therapeutic application of specific TNFR blockers is discussed.

Biological and clinical aspects of soluble transferrin receptor.

Soluble transferrin receptor (sTfR), one of the main regulators of cellular iron homeostasis, is the truncated form of the tissue receptor that is encoded by the human TfR gene (chromosome 3). Serum sTfR levels are determined to detect iron deficiency (ID) in inflammatory states and in anemia of chronic disease (ACD) and to monitor the efficiency of erythropoietin (EPO) treatment. The levels of sTfR reflect the receptor density on cells (tissue iron status) and the number of cells with receptors (erythropoietic activity). Currently assays for the measurements of sTfR are standardized using different reference materials, give different results, and have different reference ranges. The recent development of a lyophilized preparation of recombinant soluble transferrin receptor (rsTfR) as a World Health Organization (WHO) reference reagent should help in the standardization of sTfR immunoassays. This article reviews the general characteristics of (s)TfR, the assays for sTfR, biological confounders in the assays, and the clinical applications for measuring sTfR.

Indoleamine 2,3-dioxygenase, a new prognostic marker in sentinel lymph nodes of melanoma patients

BACKGROUND Indoleamine 2,3-dioxygenase (IDO), an enzyme with immunosuppressive properties is considered as a factor that impairs the antitumour immune response in melanoma. In this study, we investigated the expression of IDO in sentinel nodes of melanoma patients to determine its prognostic relevance. PATIENTS AND METHODS One hundred and sixteen melanoma patients were enrolled in this study with a median follow-up time after diagnosis of 71 months. The expression of IDO and forkhead box P3 (Foxp3) in the sentinel lymph nodes was determined by immunohistochemistry and correlated with progression-free survival and overall survival. In 42 patients, regulatory T cells were investigated by flow cytometry. RESULTS Cox regression survival analysis showed a significant negative effect of IDO expression on progression-free survival (p = 0.015) and overall survival (p = 0.010). High IDO expression was correlated with a significant higher frequency of Foxp3-positive cells in uninvaded lymph nodes (p = 0.016). The presence of IDO expression in the sentinel nodes was not associated with an increased frequency of circulating regulatory T cells (Tregs) but was significantly correlated with an increased mean fluorescence intensity of Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) in Tregs (p = 0.019). After CD3CD28 stimulation, peripheral blood mononuclear cells of patients with high IDO expression showed a lower production of interferon-gamma (IFN-γ) (p = 0.025). CONCLUSIONS This study points to an independent predictive role of IDO on survival, especially in melanoma patients with uninvolved sentinel nodes. Investigating IDO expression in the sentinel nodes of melanoma patients may be a useful marker to pre-identify patients with a less favourable prognosis in stage I and II disease.

Are there better alternatives than haemoglobin A1c to estimate glycaemic control in the chronic kidney disease population

BACKGROUND Although measurement of haemoglobin A1c has become the cornerstone for diagnosing diabetes mellitus in routine clinical practice, the role of this biomarker in reflecting long-term glycaemic control in patients with chronic kidney disease has been questioned. METHODS Consensus review paper based on narrative literature review. RESULTS As a different association between glycaemic control and morbidity/mortality might be observed in patients with and without renal insufficiency, the European Renal Best Practice, the official guideline body of the European Renal Association-European Dialysis and Transplant Association, presents the current knowledge and evidence of the use of alternative glycaemic markers (glycated albumin, fructosamine, 1,5-anhydroglucitol and continuous glucose monitoring). CONCLUSION Although reference values of HbA1C might be different in patients with chronic kidney disease, it still remains the cornerstone as follow-up of longer term glycaemic control, as most clinical trials have used it as reference.

Preanalytical requirements of urinalysis

Urine may be a waste product, but it contains an enormous amount of information. Well-standardized procedures for collection, transport, sample preparation and analysis should become the basis of an effective diagnostic strategy for urinalysis. As reproducibility of urinalysis has been greatly improved due to recent technological progress, preanalytical requirements of urinalysis have gained importance and have become stricter. Since the patients themselves often sample urine specimens, urinalysis is very susceptible to preanalytical issues. Various sampling methods and inappropriate specimen transport can cause important preanalytical errors. The use of preservatives may be helpful for particular analytes. Unfortunately, a universal preservative that allows a complete urinalysis does not (yet) exist. The preanalytical aspects are also of major importance for newer applications (e.g. metabolomics). The present review deals with the current preanalytical problems and requirements for the most common urinary analytes.

Why treatments do(n't) work in vitiligo: An autoinflammatory perspective.

Vitiligo is a recalcitrant depigmentary skin disorder with significant effects on the quality of life and a frequent association with other autoimmune disorders. The results of the current therapeutic options remain variable and treatment resistance is often encountered. The mainstay of treatment remains topical corticosteroids, topical calcineurin inhibitors and UVB therapy. In more extensive or progressive cases, systemic corticosteroids are effective although their prolonged use is hampered due to safety concerns. A lot of topical and systemic treatments have been investigated during the last decades. Given the elevated TNF-α levels in vitiligo lesions, the failure and even paradoxal effects of TNF-α inhibitors were highly remarkable. Nonetheless, a lot of progress has been made to unravel the pathophysiology of vitiligo. In this review, we provide an overview of the currently known underlying mechanisms leading to vitiligo and link this to the success or failure of treatments that have been used in clinical trials. We believe that this overview can direct future vitiligo research and rationalise the treatment options.

Vitamin D binding protein: a multifunctional protein of clinical importance.

Since the discovery of group-specific component and its polymorphism by Hirschfeld in 1959, research has put spotlight on this multifunctional transport protein (vitamin D binding protein, DBP). Besides the transport of vitamin D metabolites, DBP is a plasma glycoprotein with many important functions, including sequestration of actin, modulation of immune and inflammatory responses, binding of fatty acids, and control of bone development. A considerable DBP polymorphism has been described with a specific allele distribution in different geographic area. Multiple studies have shed light on the interesting relationship between polymorphisms of the DBP gene and the susceptibility to diseases. In this review, we give an overview of the multifunctional character of DBP and describe the clinical importance of DBP and its polymorphisms. Finally, we discuss the possibilities to use DBP as a novel therapeutic agent.