Are beta defensin 1 and beta defensin 2 key innate immune effector peptides against urinary tract infection in women?

PhD ThesisIntroduction & Hypothesis Recurrent urinary tract infection (rUTI) is a debilitating problem affecting 5% of women. Current treatment using intermittent or long-term antibiotics gives limited symptomatic benefit and encourages bacterial resistance. The aetiology of rUTI is unclear but may involve altered innate defence mechanisms in susceptible individuals. Colonisation of vaginal mucosa by uropathogenic Escherichia coli (UPEC) is the initiating event for UTI, with subsequent migration up the urethra and attachment to bladder epithelium. Protective innate immunological mechanisms include epithelial synthesis of cationic antimicrobial peptides (AMPs) such as the beta defensins. These may be expressed constitutively or induced via Toll-like-receptor (TLR) activation by pathogen associated molecular patterns (PAMPs). This study investigates the hypothesis that women suffering from rUTI have altered tolerance to infecting bacteria related to differences in expression of endogenous AMPs and that identification of such deficiency gives a potentially useful opportunity for novel preventive therapy. Methods and Patients A synergistic methodological approach of in vitro modelling with validation in clinical samples from the relevant patient group and controls was used. In vitro, cell culture was carried out using RT4 immortalised urothelial-cells, VK2 E6/E7 immortalised vaginal cells and finite primary culture of normal human urothelium. Cells were challenged with E. coli and PAMPs. Assays for Beta defensin AMP gene expression, secretion and antimicrobial activity were carried out. Clinically, 98 women (60 rUTI, 38 controls) were recruited with ethical approval. All subjects provided symptom and health state questionnaires; blood for single nucleotide polymorphism (SNP) analysis; vaginal and bladder biopsies for AMP gene expression analysis; plus vaginal washings and overnight urine samples for AMP peptide secretion assays. Results In vitro, cell culture experiments demonstrated that beta defensin 1 (BD1) was constitutively expressed and secreted in urothelial and vaginal cells. Beta defensin 2 (BD2) expression and secretion was induced by E. coli flagellin and is a potent antimicrobial against UPEC. In vaginal cells, BD2 expression and secretion was enhanced by estrogen. Clinically, women with rUTI were identified as having significantly lower basal levels of vaginal BD2 expression and secretion than controls but no difference in BD1 expression. Postmenopausal women had significantly lower BD2 levels than pre-menopausal women. 392Stop During active UTI, women with history of rUTI and the TLR5 SNP showed significantly lower BD2 expression and secretion in both the bladder and vagina than women with wild type TLR5 gene and rUTI. Discussion This study identifies flagellin induced BD2 expression as a novel and important urogenital innate immune response against invading E. coli, which is reduced in a significant proportion of women with rUTI particularly those with the TLR5 392Stop SNP. Observations in vitro on the BD2 inducing effect of estrogen, and clinically in pre- and post-menopausal women, raise the possibility that BD2 expression can be modulated by exogenous factors.The Wellcome Trus

Schizophrenia and apolipoprotein: a 10-year bibliometric analysis

Introduction: Schizophrenia is a chronic and complex mental disorder that significantly impacts one’s quality of life. The expansion of proteomic studies over the past decade offers a better understanding of the underlying pathophysiology of schizophrenia and the formulation of a protein targeted therapeutic approach. This study aimed to conduct a bibliometric analysis on the role of apolipoprotein as a biomarker in schizophrenia to provide a summary of its chronicle, present state and to identify potential future research directions. Materials and method: Publications on the association between schizophrenia and apolipoprotein were retrieved from the Scopus database using the search terms “schizophrenia” and “apolipoprotein”. Only original or review articles in English published between 2013 and 2023 were included. The bibliometric analysis was carried out using the R software packages Bibliometrix and Biblioshiny. Results: The filtered search identified 89 documents (80 original articles and 9 review articles) that generally showed an increasing trend with an annual growth rate of 10.31 percent. There were 580 authors that contributed to this field, with an average of eight to nine people co-authoring each paper. Altogether, 64 journals contributed to this field, with Neuropsychiatric Disease and Treatment, Frontiers in Psychiatry, and Translational Psychiatry being the three most productive. China leads in scientific production, followed by the Netherlands and the United States. In terms of country collaboration, the United Kingdom and Germany had the highest level of collaboration. The important keywords in the clusters were schizophrenia, biomarkers, proteomics, apolipoprotein E, antipsychotic drugs, bipolar disorder, and obesity. According to the thematic evolution analysis, apolipoprotein E has been frequently discussed and associated with schizophrenia and antipsychotic drugs. Conclusion: The association between schizophrenia and apolipoprotein has grown in significance over the past decade. Our findings highlight the potential role of apolipoprotein E in the establishment of schizophrenia and warrant further exploration

Applications and Experiences of Quality Control

The rich palette of topics set out in this book provides a sufficiently broad overview of the developments in the field of quality control. By providing detailed information on various aspects of quality control, this book can serve as a basis for starting interdisciplinary cooperation, which has increasingly become an integral part of scientific and applied research

Group B streptococcus and pregnancy : towards an optimal prevention strategy for neonatal Group B Streptococcal Disease

Group B Streptococcus (GBS, Streptococcus agalactiae) has been recognized as an important cause of perinatal morbidity and mortality. The frequency of GBS colonization ranges from 10% to 35% in women of reproductive age. GBS colonization can be transient, intermittent or persistent. Vertical transmission of GBS from mother to child occurs during labor. Studies on vertical GBS transmission in colonized mothers during labor report incidences of colonization of the infant between 16 and 69%. Early-onset group B streptococcal disease (GBS-EOD) occurs in approximately 1% of newborns who are colonized with GBS. Established risk factors for acquiring GBS-EOD are prolonged rupture of membranes, preterm labor, intrapartum fever, GBS bacteriuria during pregnancy or a previous child with GBS-EOD. Intrapartum antibiotic prophylaxis (IAP) given to women at risk of transmitting GBS to their baby may prevent GBS-EOD. Identification of mothers at risk may be performed by screening (taking a culture during pregnancy to detect maternal colonization) and/ or by identifying pregnancies with one or more of the established risk factors for GBS-EOD. Since the overall effect of the Dutch guideline on the incidence of GBS-EOD is disappointing, adaptation of the Dutch guidelines should be reconsidered. The aim of this thesis is to contribute to the information needed for the establishment of an optimal prevention strategy for GBS-EOD. In this thesis, studies on prevalence of GBS carriage, risk factors for GBS-sepsis in relation to GBS carriage, timing of GBS cultures, association of GBS carriage and preterm labor and resistance of GBS for antibiotics are combined.Astellas Pharma BV, BMA BV (Mosos), Memidis Pharma BV, Raad van Bestuur Medisch Centrum Haaglanden, Stichting Ouders van Groep B Streptokokken PatiëntenUBL - phd migration 201

Decision-theoretic planning of clinical patient management

When a doctor is treating a patient, he is constantly facing decisions. From the externally visible signs and symptoms he must establish a hypothesis of what might be wrong with the patient; then he must decide whether additional diagnostic procedures are required to verify this hypothesis, whether therapeutic action is necessary, and which post-therapeutic trajectory is to be followed. All these bedside decisions are related to each other, and the whole task of clinical patient management can therefore be regarded as a form a planning. In Artificial Intelligence, planning is traditionally studied for situations that are highly predictable. An important characteristic of medical decisions is however that they often must be made under conditions of uncertainty; this is due to errors in the results of diagnostic tests, limitations in medical knowledge, and unpredictability of the future course of disease. Decision making under uncertainty is traditionally studied in the field decision theory; in this thesis, we investigate the problem of clinical patient management as action planning using decision-theoretic principles, or decision-theoretic planning for short

Informatics for Health 2017 : advancing both science and practice

Conference report, The Informatics for Health congress, 24-26 April 2017, in Manchester, UK.Introduction : The Informatics for Health congress, 24-26 April 2017, in Manchester, UK, brought together the Medical Informatics Europe (MIE) conference and the Farr Institute International Conference. This special issue of the Journal of Innovation in Health Informatics contains 113 presentation abstracts and 149 poster abstracts from the congress. Discussion : The twin programmes of “Big Data” and “Digital Health” are not always joined up by coherent policy and investment priorities. Substantial global investment in health IT and data science has led to sound progress but highly variable outcomes. Society needs an approach that brings together the science and the practice of health informatics. The goal is multi-level Learning Health Systems that consume and intelligently act upon both patient data and organizational intervention outcomes. Conclusions : Informatics for Health demonstrated the art of the possible, seen in the breadth and depth of our contributions. We call upon policy makers, research funders and programme leaders to learn from this joined-up approach.Publisher PDFPeer reviewe

The EBMT Handbook

This Open Access edition of the European Society for Blood and Marrow Transplantation (EBMT) handbook addresses the latest developments and innovations in hematopoietic stem cell transplantation and cellular therapy. Consisting of 93 chapters, it has been written by 175 leading experts in the field. Discussing all types of stem cell and bone marrow transplantation, including haplo-identical stem cell and cord blood transplantation, it also covers the indications for transplantation, the management of early and late complications as well as the new and rapidly evolving field of cellular therapies. This book provides an unparalleled description of current practices to enhance readers’ knowledge and practice skills