Verhandelingen - Koninklijke Academie voor Geneeskunde van Belgie最新文献

In the first years of life, children acquire many of the physical attributes, and also the social and psychological structures for life and learning. Because unhealthy lifestyle patterns might continue into adulthood, it is important to strive as early in life as possible for a high-quality diet with optimal levels of food and nutrients to help maintain optimal health. In this manuscript the dietary habits of preschool children in Flanders in 2002-2003 are described and discussed in comparison with the recommendations. This first large-scale dietary survey executed in Flanders revealed remarkable gaps in Flemish preschoolers' diets and should be seen as an alarming signal that urges for more and deeper research in this area of childhood nutrition. Furthermore, some results raised the question whether our current dietary recommendations for Flemish preschoolers require some revisions or clarifications in order to strive against a threatening obesity epidemic and its concomitant chronic diseases. Therefore, some suggestions to improve the current Flemish dietary guidelines and food policies with regard to young children have been formulated. At last this study revealed some methodological recommendations for future dietary surveys in preschool-aged children. New methods have been developed and evaluated for use in future preschool dietary surveys and an European perspective for future pan-European food consumption surveys in children was discussed.

Although the general principles of disposition and elimination of exogenous compounds apply in neonates, their specific characteristics warrant a tailored approach. Children display maturation in drug disposition, and these maturational changes are most prominent in the first year of life. Elimination clearance is mainly either through metabolic or renal elimination clearance. Almost all phase I and phase II metabolic processes display ontogeny in a iso-enzyme specific pattern. Variation in phenotypic metabolic clearance is based on constitutional, environmental and genetics factors. In early life, it mainly reflects ontogeny, but other covariates may also become relevant. The impact of various covariates like postmenstrual age, postnatal age, disease state characteristics and polymorphisms are illustrated based or 'probe' drugs (paracetamol, tramadol, propofol) administered as part of their medical treatment in critically ill neonates. Renal elimination clearance in early life is low and almost completely depends on glomerular filtration. Despite this overall low clearance, interindividual variability is already extensive and can be explained by covariates like postmenstrual age, postnatal age, co-administration of a non-selective cyclo-oxygenase inhibitor or growth restriction. These findings are illustrated by observations on amikacin, vancomycin and cefazolin disposition in perinatal life. These maturational changes all have impact on the pharmaco/toxicokinetics and -dynamics. We hereby would like to extent the adagio of Paracelsus that 'all is toxic, it only depends on the dose' by making the point that the 'patient' is also relevant.

Randomised controled trials (RCT's) and meta analyses of RCT's are known as the best research designs to evaluate if interventions are doing more good than bad. Some interventions can not be evaluated by RCT's because of the heterogeneity of the problems, the cost of the evaluation study or ethical arguments against the study. This is often the case with population based interventions. A typical example is suicide prevention. The shortcomings of the "classic" research designs for the evaluation of suicide prevention are discussed and feasible solutions are suggested for future research.

In a first part of this historical article, the author overviews how, over the half century since the first in vitro demonstration of interferon, systems for large-scale production of human interferon have been elaborated and how these efforts have allowed for evaluation of the clinical potential of the different molecular types of interferon. In a second part the author reflects in more detail on research activities in Belgium aimed at production of human interferon.

Since the discovery that interferons responses constitute an efficient transition between innate and adaptive immunity to infectious microorganisms, the function and role of these cytokines are better understood. Interferons act on specific cell receptors, which activate well-defined transduction pathways to enhance the expression of hundreds of different Interferon-Stimulated Genes (ISGs) leading to the so-called antiviral state. Several of these genes including those encoding proteins (such as PKR, OAS, and ADAR1) depending on the presence of intracellular double stranded RNA for the activation of their enzymatic function, were studied in more detail. Considerable progress has been made recently in understanding how type I interferons expression is induced in response to virus infection. These imply several Toll-like Receptors (TLRs) and several newly described cytoplasmic protein sensors (RIG-I, MDA5, DAI) that detect the presence of viral nucleic acids and transduce intracellular signals leading to the activation of several members of the family of interferon regulatory factors (IRFs) required for the expression of type I interferons or directly some of the ISGs themselves. The discovery of these transduction pathways derives largely from the study of gene deficient cells and animals. The importance of these proteins is further attested by the discovery of several virally encoded antagonists that can interrupt specifically various steps of either the induction or the action of type I interferons.

The concept of antiviral therapy with interferon for chronic hepatitis B emerged in the middle of the seventies and was supported by the suppressive effect of human interferon on HBV-DNA polymerase levels in 3 patients. This effect of leukocyte interferon was confirmed in a small controlled study of patients with HBeAg-positive chronic hepatitis B; however, no effect was found on other indices of hepatitis B. More than 10 years elapsed before one large RCT demonstrated clinically relevant virological responses in 35% vs. < 10% in placebo and led to registration of interferon for hepatitis B. Responses in HBeAg-negative chronic hepatitis B were very high during treatment but high relapse rates eliminated most of the long-time treatment effect. Interferon has now to compete with highly effective nucleoside analog therapy, but still has a prominent place as a limited duration therapy leading to sustained and sometimes complete responses. In the middle of the eighties, interferon was tested in 10 patients with non-A, non-B chronic hepatitis and ALT normalization was observed in the majority. After the discovery of the hepatitis C virus and the introduction of the HCVRNA PCR test it became clear that interferon therapy can cure hepatitis C infections. Widespread therapy was introduced after a co-drug ribavirin was found to reduce relapse rates and two pivotal trials with recombinant interferon showed sustained virological responses in about 50% of patients, with much higher positive outcomes in genotype 2 and 3. Therapy-induced sustained virological remission has been shown to reduce liver-related death, liver failure and to a lesser extent hepatocellular carcinoma. Interferon has become the key drug for hepatitis C.

Genetic factors have been suggested depending on the drug, to account for 20 to 95 % of the variability in drug disposition and effects. Pharmacogenetics is defined as the study of interindividual variations in DNA sequence related to drug disposition or drug action that can influence clinical response. In contrast, pharmacogenomics is defined more broadly as the application of genomics to elucidate disease susceptibility, drug discovery, pharmacological function, drug disposition and therapeutic response. The best recognized examples of genetic polymorphisms that influence drug response in humans are highly penetrant monogenic traits of drug metabolizing enzymes (DME). Inherited difference in a single gene of DME has such a profound effect on the pharmacokinetics of a drug resulting in more than a 100 fold difference in systemic drug exposure with clinically important effect on drug response. Loss of function or gene duplication of DME genes have been identified as mechanisms of severe and life-threatening toxicity and poor treatment response, respectively. There is a growing list of genetic polymorphisms in drug transporters and targets that have been shown to influence drug response. However, drug response involves many genes and therefore new strategies are needed to identify, for a given drug, the relevant genes and genetic polymorphisms and the pathways and processes in their interaction. These new strategies include genome-wide haplotype mapping, gene expression analyses, proteomic methods. In addition nongenetic factors will modify drug response. A major limitation in implementing pharmacogenetic testing in the clinical setting is the lack of clinical trials demonstrating that such testing can improve drug therapy by reducing toxicity and increasing efficacy.

Multiple sclerosis (MS) is the most common chronic neurological disease among young adults. The unknown etiology, the various disease courses, the broad range of symptoms, and the lack of efficient treatments contribute to the complexity of the disease, and complicate the exact understanding of this disease. MS is a heterogeneous disease in many of its aspects. The pathophysiology concerns inflammatory as well as neurodegenerative mechanisms, which translate clinically in relapses versus progressive increase of disability. The disease course is different between individuals and within an individual. Clinical symptoms range from weakness to sensory disturbances, fatigue, cognitive problems, bladder problems. Radiological and pathological differences do not always correlate with clinical characteristics. Various disease modifying drugs are currently available, but the effect of these varies from person to person. Finally, there is a genetic heterogeneity determining the susceptibility to the disease as well. The challenge for the future mainly consists in providing within this complexity the right treatment to the right individual and at the right moment.

Now more than 50 years after interferon was discovered, in 1957, by Isaacs and Lindenmann, this quinquagenarian has evidently come to age. Its major indications for clinical use are, for interferon-alpha, now mostly used in its pegylated form, the treatment of chronic hepatitis B and chronic hepatitis C, the latter generally in combination with ribavirin; and for interferon-beta, the treatment of multiple sclerosis (MS). Of quintessence in the 50 years with interferon has been the cloning of interferon-alpha and -beta in 1980, which not only proved its identity, but also laid the basis for its application in the treatment of hepatitis (B and C) and multiple sclerosis, respectively.

Viruses have learned to multiply in the face of a powerful innate and adaptive immune response of the host. They have evolved multiple strategies to evade the interferon (IFN) system which would otherwise limit virus growth at an early stage of infection. IFNs induce the synthesis of a range of antiviral proteins which serve as cell-autonomous intrinsic restriction factors. For example, the dynamin-like MxA GTPase inhibits the multiplication of influenza and bunyaviruses (such as La Crosse virus, Hantaan virus, Rift Valley Fever virus, and Crimean-Congo hemorrhagic fever virus) by binding and sequestering the nucleocapsid protein into large perinuclear complexes. To overcome such intracellular restrictions, virulent viruses either inhibit IFN synthesis, bind and inactivate secreted IFN molecules, block IFN-activated signaling, or disturb the action of IFN-induced antiviral proteins. Many viruses produce specialized proteins to disarm the danger signal or express virulence genes that target members of the IFN regulatory factor family (IRFs) or components of the JAK-STAT signaling pathway. An alternative evasion strategy is based on extreme viral replication speed which out-competes the IFN response. The identification of viral proteins with IFN antagonistic functions has great implications for disease prevention and therapy. Virus mutants lacking IFN antagonistic properties represent safe yet highly immunogenic candidate vaccines. Furthermore, novel drugs intercepting viral IFN-antagonists could be used to disarm the viral intruders.