Inflammation: good or bad for ADHD?

Attention deficit hyperactivity disorder (ADHD) is characterised by the typical behavioural core symptoms of inattentiveness, hyperactivity and impulsiveness. ADHD is a usually chronic health conditions, mostly diagnosed in childhood, creating a significant challenge for youth, their families and professionals who treat it. This disorder requires long-term treatments, including psychotherapeutic and pharmacological interventions, which in some cases may lead to adverse effects. Understanding the mechanism by which ADHD risk factors affect the biochemical processes in the human brain and consequentially the behaviour will help to identify novel targets for the development of therapeutics with less adverse results and better efficacy including higher responder rates. Although inflammatory responses in the brain have been recognised for years as critical in neurodegeneration and behaviour in a number of neurological and psychiatric disorders, their role for the development, treatment and prevention of ADHD has been so far largely overlooked, although historically, ADHD symptoms were initially observed in patients who survived an ONJ infection, i.e. inflammation. In this review, we discuss the interrelationship between different ADHD risk factors and inflammation with respect to the triggered molecular mechanisms and the contribution they are likely to have to this disorder. This paper provides a rationale for future studies on ADHD with an intent to inspiring the development of new agents for a more efficient management of this disorder.     

Nitric oxide, a biological double-faced janus--is this good or bad?

Nitric oxide (NO) is a biological messenger molecule produced by one of the essential amino acids L-arginine by the catalytic action of the enzyme NO synthase (NOS). The dual role of NO as a protective or toxic molecule is due to several factors, such as; the isoform of NOS involved, concentration of NO and the type of cells in which it is synthesised, the availability of the substrate L-arginine, generation of guanosine 3,5'-cyclic monophosphate (cGMP) from soluble guanylate cyclase and the overall extra and intracellular environment in which NO is produced. NOS activation as a result of trauma (calcium influx) or infection leads to NO production, which activates its downstream receptor sGC to synthesise cGMP and/or leads to protein nitrosylation. This may lead to one or more systemic effects including altered neurotransmission which can be protective or toxic, vaso/bronchodilatation in the cardiovascular and respiratory systems and enhanced immune activity against invading pathogens. In addition to these major functions, NO plays important role in thermoregulation, renal function, gastrointestinal motility, endocrine function, and various functions of the urogenital system ranging from renin secretion to micturation; spermatogenesis to penile erection; and ovulation to implantation and parturition. A schematic summary of the functions of NO and the various isoforms of NOS expressed in body systems is shown in figure 1. In this review, the historical background, biochemistry and biosynthesis of NO and its enzymes together with the mechanism of NO actions in physiology and pathophysiology are discussed.     

Beta-carotene: a cancer chemopreventive agent or a co-carcinogen?

Evidence from both epidemiological and experimental observations have fueled the belief that the high consumption of fruits and vegetables rich in carotenoids may help prevent cancer and heart disease in humans. Because of its well-documented antioxidant and antigenotoxic properties, the carotenoid beta-carotene (betaCT) gained most of the attention in the early 1980s and became one of the most extensively studied cancer chemopreventive agents in population-based trials supported by the National Cancer Institute. However, the results of three randomized lung cancer chemoprevention trials on betaCT supplementation unexpectedly contradicted the large body of epidemiological evidence relating to the potential benefits of dietary carotenoids. Not only did betaCT show no benefit, it was associated with significant increases in lung cancer incidence, cardiovascular diseases, and total mortality. These findings aroused widespread scientific debate that is still ongoing. It also raised the suspicion that betaCT may even possess co-carcinogenic properties. In this review, we summarize the current data on the co-carcinogenic properties of betaCT that is attributed to its role in the induction of carcinogen metabolizing enzymes and the over-generation of oxidative stress. The data presented provide convincing evidence of the harmful properties of this compound if given alone to smokers, or to individuals exposed to environmental carcinogens, as a micronutrient supplement. This has now been directly verified in a medium-term cancer transformation bioassay. In the context of public health policies, while the benefits of a diet rich in a variety of fruits and vegetables should continue to be emphasized, the data presented here point to the need for consideration of the possible detrimental effects of certain isolated dietary supplements, before mass cancer chemoprevention clinical trials are conducted on human subjects. This is especially important for genetically predisposed individuals who are environmentally or occupationally exposed to mutagens and carcinogens, such as those found in tobacco smoke and in industrial settings.     

Reporter genes: too much of a good thing?

Advances in viral vector design and identification of new reporter genes have allowed the development of novel delivery systems. In the presence of reporter genes, cellular transduction frequency, expression of the gene of interest and phenotypic effects in cells expressing the gene under study can now be easily monitored both in vitro and in vivo. Moreover, the presence of unique cell markers allows for the enrichment of transduced cells for research studies or patient infusion. The ideal reporter gene product should be biologically inert and not influence the cell population under investigation. Recent reports suggest that reporter gene products may not be biologically benign.     

Meiotic recombination: too much of a good thing?

Proper chromosome segregation in meiosis requires the right number and distribution of crossovers. Recent work in budding yeast has revealed a meiosis-specific role for RecQ helicase in limiting crossovers, distinct from its known somatic role in maintaining genome stability.     

Are anti-HIV IgAs good guys or bad guys?

An estimated 90% of all HIV transmissions occur mucosally. Immunoglobulin A (IgA) molecules are important components of mucosal fluids. In a vaccine efficacy study, in which virosomes displaying HIV gp41 antigens protected most rhesus monkeys (RMs) against simian-human immunodeficiency virus (SHIV), protection correlated with vaginal IgA capable of blocking HIV transcytosis in vitro. Furthermore, vaginal IgG exhibiting virus neutralization and/or antibody-dependent cellular cytotoxicity (ADCC) correlated with prevention of systemic infection. In contrast, plasma IgG had neither neutralizing nor ADCC activity. More recently, a passive mucosal immunization study provided the first direct proof that dimeric IgAs (dIgAs) can prevent SHIV acquisition in RMs challenged mucosally. This study compared dimeric IgA1 (dIgA1), dIgA2, or IgG1 versions of a human neutralizing monoclonal antibody (nmAb) targeting a conserved HIV Env epitope. While the nmAb neutralization profiles were identical in vitro, dIgA1 was significantly more protective in vivo than dIgA2. Protection was linked to a new mechanism: virion capture. Protection also correlated with inhibition of transcytosis of cell-free virus in vitro. While both of these primate model studies demonstrated protective effects of mucosal IgAs, the RV144 clinical trial identified plasma IgA responses to HIV Env as risk factors for increased HIV acquisition. In a secondary analysis of RV144, plasma IgA decreased the in vitro ADCC activity of vaccine-induced, Env-specific IgG with the same epitope specificity. Here we review the current literature regarding the potential of IgA – systemic as well as mucosal – in modulating virus acquisition and address the question whether anti-HIV IgA responses could help or harm the host.     

Complement-regulatory proteins in severe malaria: too little or too much of a good thing?

Data from several laboratories suggest that erythrocyte complement-regulatory proteins, in particular complement receptor 1 (CR1), are important in the pathogenesis of severe malaria. Additional studies suggest that the levels of expression of CR1 and the complement regulator CD55 on erythrocytes vary with age, being low in young children and increasing with age. It is proposed that the interplay between the rate at which immunity develops during malaria exposure and the changes in levels of erythrocyte complement-regulatory proteins that occur with age might contribute to the differences in epidemiology of severe malaria-associated anaemia and cerebral malaria.     

Recapitulate development to promote axonal regeneration: good or bad approach?

In the past decade there has been an explosion in our understanding, at the molecular level, of why axons in the adult, mammalian central nervous system (CNS) do not spontaneously regenerate while their younger counterparts do. Now a number of inhibitors of axonal regeneration have been described, some of the receptors they interact with to transduce the inhibitory signal are known, as are some of the steps in the signal transduction pathway that is responsible for inhibition. In addition, developmental changes in the environment and in the neurons themselves are also now better understood. This knowledge in turn reveals novel, putative sites for drug development and therapeutic intervention after injury to the brain and spinal cord. The challenge now is to determine which of these putative treatments are the most effective and if they would be better applied in combination rather than alone. In this review I will summarize what we have learnt about these molecules and how they signal. Importantly, I will also describe approaches that have been shown to block inhibitors and encourage regeneration in vivo. I will also speculate on what the differences are between the neonatal and adult CNS that allow the former to regenerate and the latter not to.     

Platelet-activating factor acetylhydrolase: is it good or bad for you?

PURPOSE OF REVIEW: Although findings obtained from various studies are inconclusive in determining whether plasma platelet-activating factor acetylhydrolase, or lipoprotein-associated phospholipase A2, plays a proatherogenic or antiatherogenic role in atherosclerosis, many recent reviews appear to favor it as a risk factor for coronary artery disease. To provide a contrasting view, this review focuses on the enzyme's antiatherogenic and antiinflammatory properties. RECENT FINDINGS: A recent report demonstrates that plasma platelet-activating factor acetylhydrolase activity increases in men and women with stable angina or acute coronary syndromes, supporting previously published data that plasma levels of the protein are independently and positively associated with the risk of coronary artery disease. In contrast, at least four lines of evidence indicate that the enzyme has strong antiatherogenic properties: (1) it inhibits the effects of LDL oxidation, (2) genetic deficiency of plasma levels constitutes a risk factor for vascular diseases including atherosclerosis, (3) adenoviral transfer of the protein reduces atherosclerosis in apolipoprotein E-deficient mice, and (4) pretreatment of an electronegative LDL subfraction isolated from hypercholesterolemic human plasma with a recombinant platelet-activating factor acetylhydrolase completely abolishes the proapoptotic effects of the electronegative LDL on vascular endothelial cells. Additionally, treatment with the recombinant product reduced mortality from severe sepsis in a phase IIb clinical trial. In an animal study, transfection of tumor cells with platelet-activating factor acetylhydrolase inhibited tumor growth at the site of implantation. SUMMARY: Plasma platelet-activating factor acetylhydrolase becomes progressively activated as atherosclerosis progresses, but lines of evidence indicate that the enzyme possesses potent antiatherogenic and antiinflammatory properties. This raises the question of whether increased activity is a cause or a result of atherosclerosis and, consequently, whether inhibiting the enzyme's activities may decelerate or accelerate the progress of the disease.     

p53 and ageing: too much of a good thing?

A recent report by Tyner et al.(1) suggests that p53 is bad for longevity. Heterozygotic mice carrying a p53 mutation that apparently enhances the stability of the wild-type protein showed shorter lifespans and faster ageing while also developing fewer tumours. This fits with the idea that cellular ageing is the price paid for better protection against unlimited proliferation of cancer cells. But other work shows that there is a strong positive association between DNA repair-mediated protection against cancer and ageing. So what are we to make of the new data with regard to overall understanding of the mechanisms of ageing?     

Tumour escape: antitumour effectors too much of a good thing?

Although even spontaneous tumours are immunogenic and are commonly infiltrated by tumour antigen-specific T cells (at least in melanoma), most tumours are not completely rejected by the host, and cancer progresses. There is a growing realisation that many responses defined as antitumour effector mechanisms act as double-edged swords and under different conditions either become ineffective or even protumorigenic. Examples are interleukin 2 (also proapoptotic for activated T cells), interferon (by induction of ligands for T and NK cell inhibitory receptors), angiogenesis inhibition (by hypoxia-mediated induction of growth factors promoting metastasis), and macrophage free radical-mediated cytotoxicity (by inhibiting T cells). Immune selection pressure itself, resulting in outgrowth of resistant tumour variants could also be viewed in this light. On the other hand, knowledge of the many tumour escape pathways offers the theoretical possibility of reconstituting antitumour immunity. Tumour escape from immunosurveillance represents the last series of hurdles to be overcome in formulating truly effective cancer immunotherapy, but given the immense plasticity of the tumour cell, and the complex balance between pro- and antitumour activity of the very same effector pathways, this remains a major challenge.This article is based on presentations made at the first Cancer Immunology and Immunotherapy Summer School, 8–13 September 2003, Ionian Village, Bartholomeio, Peloponnese, Greece.     

Red wines good,white wines bad?

A review of the literature on the 'antioxidant' action of white wines on the cardiovascular system is given. The conclusion is that ingestion only of white wines very low, or lacking, in polyphenolics leads to a reduction in the antioxidant action of blood serum, and to an increase in the low density lipoprotein to high density lipoprotein ratio.