Bill C-91: the debate continues

Agricultural chemical companies have invested in the discovery and development of biological pesticides to complement synthetic pesticides for the control of insects, diseases, and weeds on agronomic and horticultural crops. For plant disease control, companies envisage biological fungicides entering markets where they have the best chance of performing and which are most receptive to using biological control methods. Fewer regulatory requirements can mean faster registration for a biological than a synthetic pesticide. However, industry's requirements for competitive performance, effective formulations, and economic production can mean significant investments in time and money for a biological pesticide, although total investment may be less than for a synthetic pesticide. One biocontrol project in which industry has invested is baculoviruses for insect control. Insect baculoviruses, genetically modified to kill insects faster than wild-type viruses, are attractive biocontrol agents because their selectivity to insect pests and safety to beneficial insects and mammals enable them to compete with synthetic insecticides. Industry is looking for similar biocontrol opportunities in disease control. Biocontrol agents for seedling disease, root rot, and postharvest disease control have been registered by the EPA and are trying to compete with synthetic fungicides for market share. To date, effective biocontrol agents have not been identified for the control of serious foliar diseases, such as grape downy mildew, potato late blight, wheat powdery mildew, and apple scab. Farmers must rely on synthetic fungicides and agronomic methods to control these diseases for the foreseeable future.     

Insect-pathogen dynamics: stage-specific susceptibility and insect density dependence

The control of insect pests by using insect pathogens as dynamic biological control agents is a recent effort. Model studies on insect-pathogen relations can help in the development of biocontrol programs. Except for the work of Briggs and Godfray [1], insect-pathogen models ignore the stage-specific susceptibility of insects. Moreover most models do not incorporate insect self-regulation. We develop stage-structured models of insect-pathogen relations incorporating insect-density dependence and disease transmitted through direct contact between susceptible and infective individuals. The models are analyzed by using steady-state and stability analysis. Numerical solutions are used as sources of further insight into the dynamics of the insect-pathogen systems. It is shown that there are major differences in the dynamics of adult- and juvenile-infecting diseases. Moreover, the interplay between insect-density dependence and stage-specific susceptibility has important consequences for the dynamics of insect-pathogen systems.     

Treatment of postprostatectomy urinary incontinence with behavioral methods

Neurodegeneration is characterized by a marked accumulation of iron in the affected brain regions. The reason for this is still unknown. In this article we review the available data on the possible involvement of iron and mediated oxidative stress in the aetiology of Parkinson's disease and related disorders. Iron chelators, if they effectively prevent radical formation, have great therapeutic potential against ischaemia/reperfusion, rheumatoid arthritis, and anthracycline toxicity, which are most likely free radical-mediated. The efficacy of the best established chelating drug desferal in neurodegenerative disease is limited due to its high cerebro- and oculotoxicity. New bioactive chelating agents are currently being developed, among them are oxidative stress activatable iron chelators which are most likely less toxic and can flexibly respond to an increase of free radical formation in the cell.     

Significance of prion protein in transmission of prions and in pathogenesis of spongiform encephalopathies

Prion disease or transmissible spongiform encephalopathies are caused by novel pathogens termed prions. Unlike classical infectious agents such as viruses or bacteria, prions lack an independent genome and consist largely if not entirely of an abnormal form of the host-encoded prion protein. How prions multiply is not known. A wealth of experimental evidence supports an essential role for the host-encoded prion protein in susceptibility and pathogenesis of prion diseases and in the propagation and spread of prions. In addition, B lymphocytes have been found to play a crucial role in the neuroinvasiveness of prions.     

Staphylococcal iron requirements, siderophore production, and iron-regulated protein expression

Despite the ability of staphylococci to grow in iron-restricted conditions in vivo, their iron requirements and the mechanisms possessed by them for the uptake of iron are poorly understood. Many bacteria are known to produce siderophores. By using the chrome azurol S universal method for the detection of siderophores, all 14 isolates of Staphylococcus aureus tested grew well under conditions of iron restriction and produced iron-regulated siderophore in large quantities, while all 19 isolates of coagulase-negative staphylococci (CoNS) grew poorly under conditions of iron restriction and produced low levels of iron chelator. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis profiles of S. aureus isolates revealed altered protein patterns due to iron restriction, while altered profiles were not seen in the CoNS group. The ability to grow in iron-restricted conditions, possibly with the assistance of siderophore-mediated iron uptake, may contribute to the increased pathogenicity of S. aureus when compared with that of the CoNS.     

Oxidative stress and the brain

Although the cause of Parkinson's disease is unknown, oxidative stress has been implicated in its pathogenesis. This theory postulates that normal metabolic processes in the nigrostriatal dopaminergic system may lead to loss of neurons, and that iron-dependent membrane lipid peroxidation may play an important role in the neuronal death. Recent research concerning iron-dependent lipid peroxidation is presented. First, catechols (including dopa and dopamine) and iron form strong oxidizing complexes and induce lipid peroxidation (LPO) in phospholipid liposomes. Active oxygen species including superoxide, hydrogen peroxide, hydroxyl radical and singlet oxygen, do not participate in this LPO, which is inhibited by an excess of dopa (dopamine). Cultured neurons and the substantia nigra are vulnerable to LPO. Second, synthetic melanin prepared by the autooxidation of catechols promotes LPO in the presence of iron. The effects of scavenging agents indicate that this LPO is mediated by superoxide, but not by other oxygen free radicals. Neuronal cell cultures are destroyed by this LPO. Third, catechols and superoxide produced by microglia cause the release of iron from ferritin. Microglia stimulated by phorbol myristate acetate produce superoxide and cause the release of iron from ferritin. Catechols also induce mobilization of ferritin iron. The released iron (i.e. loosely-bound iron) is available to iron-dependent LPO. These data suggest that the biochemical and morphological characteristics of the substantia nigra, which are concomitant with its functional role, provoke iron-dependent lipid peroxidation. It is essential to elucidate how iron bound loosely to low molecules comes into contact with catechols, neuromelanin and superoxide. Drugs that chelate iron site-specifically or modulate the microglial function may bring about some favorable changes in the disease process.     

Iron acquisition by Helicobacter pylori: importance of human lactoferrin

Helicobacter pylori is known to be an etiologic agent of gastritis and peptic ulcer disease in humans. However, the mechanism by which this organism acquires iron has not been studied. For this investigation, H. pylori was grown in iron-restricted medium. Siderophore production was not detected by chemical assays, and the strains were unable to use enterochelin and pyochelin for growth in low-iron media. Human lactoferrin supported full growth of the bacteria in media lacking other iron sources, but neither human transferrin, bovine lactoferrin, nor hen ovotransferrin served as a source for iron. Since lactoferrin was found in significant amounts in human stomach resections with superficial or atrophic gastritis, the iron acquisition system of H. pylori by the human lactoferrin receptor system may play a major role in the virulence of H. pylori infection.     

Molecular basis of leukemogenesis

Reactive arthritis was originally defined as a sterile joint inflammation after infection elsewhere in the body, but this view has been challenged in the past decade since different antigens and DNA and RNA of various triggering microbes have been shown to exist at the sites of inflammation in the joints. It has been suggested that microbial antigens, or intact pathogens, are important for the pathogenesis of reactive arthritis, at least in the early phase of the disease, but the exact mechanism of how the pathogens contribute to the development of this usually self-limiting polyarthritis has not been discovered. This article reviews the theories on the role of infectious agents as triggers of reactive arthritis.     

Identification of a Mycobacterium tuberculosis gene cluster encoding the biosynthetic enzymes for assembly of the virulence-conferring siderophore mycobactin

BACKGROUND: Many pathogenic bacteria secrete iron-chelating siderophores as virulence factors in the iron-limiting environments of their vertebrate hosts to compete for ferric iron. Mycobacterium tuberculosis mycobactins are mixed polyketide/nonribosomal peptides that contain a hydroxyaryloxazoline cap and two N-hydroxyamides that together create a high-affinity site for ferric ion. The mycobactin structure is analogous to that of the yersiniabactin and vibriobactin siderophores from the bacteria that cause plague and cholera, respectively. RESULTS: A ten-gene cluster spanning 24 kilobases of the M. tuberculosis genome, designated mbtA-J, contains the core components necessary for mycobactin biogenesis. The gene products MbtB, MbtE and MbtF are proposed to be peptide synthetases, MbtC and MbtD polyketide synthases, MbtI an isochorismate synthase that provides a salicylate activated by MbtA, and MbtG a required hydroxylase. An aryl carrier protein (ArCP) domain is encoded in mbtB, and is probably the site of siderophore chain initiation. Overproduction and purification of the mbtB ArCP domain and MbtA in Escherichia coli allowed validation of the mycobactin initiation hypothesis, as sequential action of PptT (a phosphopantetheinyl transferase) and MbtA (a salicyl-AMP ligase) resulted in the mbtB ArCP domain being activated as salicyl-S-ArCP. CONCLUSIONS: Mycobactins are produced in M. tuberculosis using a polyketide synthase/nonribosomal peptide synthetase strategy. The mycobactin gene cluster has organizational homologies to the yersiniabactin and enterobactin synthetase genes. Enzymatic targets for inhibitor design and therapeutic intervention are suggested by the similar ferric-ion ligation strategies used in the siderophores from Mycobacteria, Yersinia and E. coli pathogens.     

Interferon-gamma-activated primary enterocytes inhibit Toxoplasma gondii replication: a role for intracellular iron

Toxoplasma gondii is an obligate intracellular parasite that infects a wide variety of nucleated cells in its numerous intermediate hosts including man. The oral route is the natural portal of entry of T. gondii. Ingested organisms are released from cysts or oocysts within the gastrointestinal tract and initially invade the intestinal epithelium. We show that T. gondii invades and proliferates in cultured primary rat enterocytes, obtained with an original procedure. Activation of the enterocytes with rat recombinant interferon-gamma (IFN-gamma) inhibits T. gondii replication, the inhibition being dose dependent. Neither nitrogen and oxygen derivatives nor tryptophan starvation appear to be involved in the inhibition of parasite replication by IFN-gamma. Experiments using Fe2+ salt, carrier and chelator indicate that intracellular T. gondii replication is iron dependent, suggesting that IFN-gamma-treated enterocytes inhibit T. gondii replication by limiting the availability of intracellular iron to the parasite. Our data show that enterocytes probably play a major role on mucosal surfaces as a first line of defence against this coccidia, and possibly other pathogens, through an immune mechanism. The results suggest that limiting the availability of iron could represent a broad antimicrobial mechanism through which the activated enterocytes exert control over intracellular pathogens.     

Determination of the structure of exochelin MN, the extracellular siderophore from Mycobacterium neoaurum

BACKGROUND: Siderophores are compounds produced by bacteria to acquire iron. Exochelin MN, the extracellular siderophore from Mycobacterium neoaurum, is of particular interest because it has been shown to transport iron into M. leprae, which is responsible for the disease leprosy. Exochelins from other species cannot mediate iron transport in M. leprae, suggesting a specific uptake mechanism involving exochelin MN. We set out to determine the structure of exochelin MN and identify the features of the molecule that may account for this specificity. RESULTS: The structure of exochelin MN was elucidated by a combination of techniques including nuclear magnetic resonance, mass spectrometry, derivatization and gas chromatography. Exochelin MN is a peptide, containing the unusual amino acid beta-hydroxyhistidine and an unusual N-methyl group. The peptide coordinates iron(III) octahedrally using its two cis-hydroxamate groups plus the hydroxyl and imidazole nitrogen of the beta-hydroxyhistidine. The three-dimensional structure of the hexadentate exochelin/gallium complex was deduced from NMR data. CONCLUSIONS: Exochelin MN has some structural features in common with other siderophores, but has a unique three-dimensional structure, which is presumably important for its specific activity in M. leprae. Exochelin MN may be a target for drug design in the fight against infection with this pathogen.     

Recovery of EDTA from Power Plant Boiler Chemical Cleaning Wastewater

The deposition of iron oxides, metallic copper, and other impurities on boiler tube surfaces causes loss of heat transfer efficiency at electrical power plants. Hence, the tubes are cleaned every 3–5 years in order to restore the heat transfer efficiency. Chelating agents, mainly ethylenediaminetetraacetate (EDTA) and its salts, have been extensively used for the removal of metal deposits from the boiler tube surfaces. Consequently, the boiler chemical cleaning wastewater (BCCW) contains large amounts of iron, copper, and chelating agents. An electrochemical reduction process that reduces metal ions to their elemental state is tested and evaluated in order to provide the potential option to recover EDTA for reuse from power plant BCCW. Results from controlled direct current electrolysis experiments show that the electroreduction process can successfully remove metal ions from the synthetic solution and field BCCW samples and can deposit elemental metals on the cathodic plate. At a current density of 15.5 mA∕cm2 and a temperature of 40°C, the percentage metal removal and current efficiency were 94.16 and 8.27%, respectively, with a cadmium cathodic plate. Moreover, results also indicate that the percentage of metal removal and overall current efficiency increase with increasing current density and temperature under the optimal condition (15.5 mA∕cm2 and 40°C). The electroreduction process is able to separate metal ions from their EDTA complexes. The free EDTA can be recovered from field power plant BCCW and be reused again as cleaning agent.     

Chelate mediated transfer of iron from transferrin to desferrioxamine

Desferrioxamine, widely used for the treatment of iron overload in Cooley's anaemia, binds iron so tightly that it should quantitatively remove iron from transferrin. Studies conducted in vivo and in vitro, however, have failed to demonstrate significant depletion of transferrin-bound iron by a stoichiometric excess of desferrioxamine. However, low molecular weight chelating agents, capable of forming ternary complexes with transferrin and ferric iron, can promote a rapid transfer of iron from transferrin to desferrioxamine. A possible mechanism for this facilitated exchange is offered.     

The Propionibacterium freudenreichii hemYHBXRL gene cluster, which encodes enzymes and a regulator involved in the biosynthetic pathway from glutamate to protoheme

Alterations in the biochemistry of mitochondria have been associated with cell transformation and the acquisition of drug resistance to certain chemotherapeutic agents, suggesting that mitochondria may play a supportive role for the cancer cell phenotype. Mitochondria are multifunctional organelles that contribute to the cellular adenosine triphosphate (ATP) pool and cellular redox balance through the production of reactive oxygen intermediates (ROI). Our laboratory has focused on these mitochondrial functions in the context of cancer cell physiology to evaluate the potential role of mitochondria as controllers of tumour cell proliferation. Low concentrations of ROI have been implicated as messengers in intracellular signal transduction mechanisms; thus an imbalance of ROI production from the mitochondria may support cancer cell growth. In addition, suppression of mitochondrial ATP production can halt cell cycle progression at two energetic checkpoints, suggesting that the use of tumor-selective agents to reduce ATP production may offer a therapeutic target for cancer growth control.     

Infectious causes of chronic inflammatory diseases and cancer

Powerful diagnostic technology, plus the realization that organisms of otherwise unimpressive virulence can produce slowly progressive chronic disease with a wide spectrum of clinical manifestations and disease outcomes, has resulted in the discovery of new infectious agents and new concepts of infectious diseases. The demonstration that final outcome of infection is as much determined by the genetic background of the patient as by the genetic makeup of the infecting agent is indicating that a number of chronic diseases of unknown etiology are caused by one or more infectious agents. One well-known example is the discovery that stomach ulcers are due to Helicobacter pylori. Mycoplasmas may cause chronic lung disease in newborns and chronic asthma in adults, and Chlamydia pneumoniae, a recently identified common cause of acute respiratory infection, has been associated with atherosclerosis. A number of infectious agents that cause or contribute to neoplastic diseases in humans have been documented in the past 6 years. The association and causal role of infectious agents in chronic inflammatory diseases and cancer have major implications for public health, treatment, and prevention.     

Systemic aluminum toxicity: effects on bone, hematopoietic tissue, and kidney

Although the full mechanisms are not yet elucidated, research into the mechanism of toxicity of aluminum (Al) on bone formation and remodeling and on hematopoietic tissue is ongoing. In contrast little information exists on the interactive effects of systemic Al and the kidney. In bone, both clinically and experimentally, high doses of Al inhibit remodeling, slowing both osteoblast and osteoclast activities and producing osteomalacia and adynamic bone disease. In contrast, while very low levels of Al are mitogenic in bones of experimental animals, the effect of low levels of Al in humans is unknown. Aluminum has been shown to have its mitogenic action at the osteoblast, but whether the effect on resorption is viz osteoblast-directed changes in osteoclast activity has not yet been determined. Parathyroid hormone (PTH) levels are disrupted by Al in humans and animals. Whether altered PTH levels play a major or even a minor role in Al-dependent osteotoxicity requires clarification. In hematopoietic tissue, Al causes a microcytic anemia, not reversible by iron. Friend leukemia cells treated with Al have been reported to accumulate excess iron, without incorporating it into ferritin or heme. It is not yet known which steps in iron metabolism are disrupted by Al, if they involve a single mechanism of action, or even if this disruption in iron metabolism accounts for the anemia seen in Al toxicosis. In kidney, research is needed to evaluate Al nephrotoxicity; there are almost no studies in this area. Furthermore, research is needed to evaluate mechanisms of renal Al excretion, presently shown by one study to occur at the distal tubule. Such studies might well throw light on whether Al plays a role in aggravating renal insufficiency, or whether the role of the kidney in Al toxicosis is limited to the causative effect of renal compromise on Al accumulation. In summary, while a number of mechanisms have been proposed for the toxic action of Al, no single mechanism emerges to explain these diverse effects of systemic Al. Recommendations for future research are presented and summarized in Table 1.     

P-selectin glycoprotein ligand 1 is a ligand for L-selectin on neutrophils, monocytes, and CD34+ hematopoietic progenitor cells

Inter-regional trade in live fish as eggs, larvae or juveniles provides the potential for parallel movements of pathogens. Pathogens that exist in a carrier state and/or can be transmitted by vertical means pose the greatest threat since casual observation, and even periods of quarantine or pathogen inspections, may fail to indicate their presence. Additional complications arise with the movements of non-target species for which health examinations may not be required, or for which criteria for pathogen inspections have not been developed. Although international trade in salmonids has been responsible for most of the disease regulations currently in place, an equal or stronger effort should be expected with other species. At the same time, ensuring equal treatment of all trading partners with respect to the level and sophistication of the health examinations to which the product will be subjected is a major problem. There are several examples of past and potential pathogen movements with fish or fish products. Unfortunately, these are often confused by a poor understanding of the current situation in the region into which the animal or product has been imported. The technology, experience or extent of surveillance in the importing region may be insufficient to assess the situation. Distinguishing between exotic imported pathogens and unknown pathogens which are already present in indigenous fish stocks can therefore often be difficult. The author discusses examples of clearly-documented imports of pathogens, as well as the potential for the spread of agents which pose an equal or greater danger. In addition, the author discusses the confusion which often arises when the background into which these pathogens are to move is poorly understood in the importing region.     

The challenge of health care social work with gay men and lesbians

Inflammation in the subarachnoid space represents the pathological hallmark of bacterial meningitis. The intrathecal accumulation of leukocytes, in response to bacterial pathogens, and the subsequent release of endogenous inflammatory mediators are associated with a breakdown of the blood-brain barrier function and poor prognosis. Complement has been shown to play a major role in the inflammatory response within the intrathecal compartment in bacterial meningitis. In the present review, we provide an outline of the current understanding of the involvement of the complement system in the pathophysiology of bacterial meningitis, and propose future directions of investigation.