The V.O.C. Ship 'Zeewijk' 1727. Report on the 1976 survey of the Site

The Dutch East Indiaman 'Zeewijk', which foundered in 1727, is the youngest of five East Indiamen known to have been wrecked off the Western Australian coast. This paper deals with the different types of work carried out on the 'Zeewijk' site: the hydrographic survey, and the surveys and excavations both on land and underwater. It is hoped that the different techniques and methods used to overcome the problems involved might be of use to others working in similar situations

Preservation of vaccine-induced long-term B cell memory and the effects of immunosuppressive treatment

Immune memory after vaccination is largely dependent on the combination of antibody production from long-lived plasma cells, and a supporting pool of antigen-primed memory B cells. It has been observed that individuals with certain immunosuppressive conditions or treatments have a weakened B cell memory, but the mechanisms behind remain elusive. The aim of this thesis was to evaluate B cell immunity in healthy children, and how HIV-1 infection, antineoplastic therapy, and rheumatic disease and treatment can impact on various features of B cell memory induction and maintenance. In paper I, we explored the hyperactivation of B cells observed in patients carrying HIV-1 infection, and showed that it can be partly induced by ligation of soluble cleaved CD27 to CD70 on the surface of memory B cells. In paper II, we aimed at comparing the establishment of serum antibody titers and memory B cells after vaccination against measles and rubella in healthy children. We found that the memory B cell pool remained stable also early after vaccination, whereas the corresponding serum IgG titers decayed with time. In contrast, both the serum IgG levels and frequency of blood memory B cells in healthy young adults appeared stable. This implied that the antibody production and memory B cell compartment are two separate entities with independent regulation, and that it takes longer time to establish a stable pool of circulating antibodies. How these two parts of B cell memory are affected by immunosuppressive disease and treatment was addressed in papers III and IV. In paper III, we used a rhesus macaque model for high-dose Doxorubicin treatment, and concluded that the established vaccine-induced memory B cell pool was depleted, contrary to long-lived plasma cells and the resulting serum IgG titers. These observations supported the finding of independent regulation of the two B cell memory compartments, and revealed different sensitivity to chemotherapy. The bone marrow plasma cell niche was additionally studied in an in vitro model for plasma cell – stromal cell cross talk, where we discovered that in vivo relevant concentrations of Doxorubicin could hamper the output of pivotal survival factors from stromal cells. In paper IV, we examined memory B cells and circulating IgG titers in children with rheumatic disease, treated with low-dose Methotrexate and TNF-α inhibition. We noted that serum IgG titers against tetanus were lower in rheumatic patients than in healthy controls, and that patients who had only received one measles vaccine dose had lower levels of measles-specific memory B cells. This stresses the importance for children with rheumatic disease and treatment to follow the full vaccine schedule. To summarize, this thesis has contributed to enhanced knowledge on how B cell memory is induced, preserved and at risk of disruption by common immune disorders and treatment. Hopefully, our findings can aid future improvement of functional vaccine regimes for immunocompromised children

Implications of polymorphic cytochrome P450-dependent drug metabolism for drug development

ABSTRACT: The main part of human cytochrome P450-dependent drug metabolism is carried out by polymorphic enzymes that can cause abolished, quantitatively or qualitatively altered, or enhanced drug metabolism. Ultrarapid metabolism is due to stable duplication, multiduplication, or amplification of active genes. Several examples exist where subjects carrying certain alleles suffer from a lack of drug efficacy due to ultrarapid metabolism or, alternatively, adverse effects from the drug treatment due to the presence of defective alleles. The polymorphic enzymes create a problem for the drug industry because of the extensive interindividual variability in the metabolism of candidate drugs that are substrates for such enzymes. The new area for lead generation has a more preclinical emphasis and involves combinatorial chemistry in conjunction with high-throughput-based analysis of thousands of substances with respect to their absorption, metabolism, and excretion characteristics. The outcome is that companies drop substrates for polymorphic enzymes at an early stage in development, which will of course create fewer problems with polymorphic enzymes in the future. The risk is that very valuable candidates, which cannot be replaced easily, never come out on the market. The alternative, however, of using the patient's genotype as a basis for individualized drug treatment constitutes, in light of rapid methodological developments, a very feasible approach to safer and more efficient drug therapies. Pharmacokinetics and drug metabolism have been shown to be of greater importance during drug development today. It is evident that drugs that are too rapidly metabolized by drug-metabolizing enzymes mainly localized in the liver and the intestine are nonoptimal therapeutic candidates. In published overviews, it has been concluded that as many as 30 to 40% of the drugs undergoing clinical trials were withdrawn from further development due to unfavorable pharmacokinetic propertie

CYP2E1 in Alcoholic and Non-Alcoholic Liver Injury. Roles of ROS, Reactive Intermediates and Lipid Overload

CYP2E1 is one of the fifty-seven cytochrome P450 genes in the human genome and is highly conserved. CYP2E1 is a unique P450 enzyme because its heme iron is constitutively in the high spin state, allowing direct reduction of, e.g., dioxygen, causing the formation of a variety of reactive oxygen species and reduction of xenobiotics to toxic products. The CYP2E1 enzyme has been the focus of scientific interest due to (i) its important endogenous function in liver homeostasis, (ii) its ability to activate procarcinogens and to convert certain drugs, e.g., paracetamol and anesthetics, to cytotoxic end products, (iii) its unique ability to effectively reduce dioxygen to radical species causing liver injury, (iv) its capability to reduce compounds, often generating radical intermediates of direct toxic or indirect immunotoxic properties and (v) its contribution to the development of alcoholic liver disease, steatosis and NASH. In this overview, we present the discovery of the enzyme and studies in humans, 3D liver systems and genetically modified mice to disclose its function and clinical relevance. Induction of the CYP2E1 enzyme either by alcohol or high-fat diet leads to increased severity of liver pathology and likelihood to develop ALD and NASH, with subsequent influence on the occurrence of hepatocellular cancer. Thus, fat-dependent induction of the enzyme might provide a link between steatosis and fibrosis in the liver. We conclude that CYP2E1 has many important physiological functions and is a key enzyme for hepatic carcinogenesis, drug toxicity and liver disease.Peer reviewe

Pharmacogenomics in treatment of depression and psychosis: an update

Genetic factors can, to a certain extent, successfully predict the therapeutic effects, metabolism, and adverse reactions of drugs. This research field, pharmacogenomics, is well developed in oncology and is currently expanding in psychiatry. Here, we summarize the latest development in pharmacogenomic psychiatry, where results of several recent large studies indicate a true benefit and cost-effectiveness of pre-emptive genotyping for more successful psychotherapy. However, it is apparent that we still lack knowledge of many additional heritable genetic factors of importance for explanation of the interindividual differences in response to psychiatric drugs. Thus, more effort to further develop pharmacogenomic psychiatry should be invested to achieve a broader clinical implementation

Assessing Cumulative Health Risks from Exposure to Environmental Mixtures—Three Fundamental Questions

Differential exposure to mixtures of environmental agents, including biological, chemical, physical, and psychosocial stressors, can contribute to increased vulnerability of human populations and ecologic systems. Cumulative risk assessment is a tool for organizing and analyzing information to evaluate the probability and seriousness of harmful effects caused by either simultaneous and/or sequential exposure to multiple environmental stressors. In this article we focus on elucidating key challenges that must be addressed to determine whether and to what degree differential exposure to environmental mixtures contributes to increased vulnerability of exposed populations. In particular, the emphasis is on examining three fundamental and interrelated questions that must be addressed as part of the process to assess cumulative risk: a) Which mixtures are most important from a public health perspective? and b) What is the nature (i.e., duration, frequency, timing) and magnitude (i.e., exposure concentration and dose) of relevant cumulative exposures for the population of interest? c) What is the mechanism (e.g., toxicokinetic or toxicodynamic) and consequence (e.g., additive, less than additive, more than additive) of the mixture’s interactive effects on exposed populations? The focus is primarily on human health effects from chemical mixtures, and the goal is to reinforce the need for improved assessment of cumulative exposure and better understanding of the biological mechanisms that determine toxicologic interactions among mixture constituents

The clinically relevant CYP2C8*3 and CYP2C9*2 haplotype is inherited from Neandertals

Genetic variation in genes encoding cytochrome P450 enzymes influences the metabolism of drugs and endogenous compounds. The locus containing the cytochrome genes CYP2C8 and CYP2C9 on chromosome 10 exhibits linkage disequilibrium between the CYP2C8*3 and CYP2C9*2 alleles, forming a haplotype of ~300 kilobases. This haplotype is associated with altered metabolism of several drugs, most notably reduced metabolism of warfarin and phenytoin, leading to toxicity at otherwise therapeutic doses. Here we show that this haplotype is inherited from Neandertals