In January 2002, 12 patients with Serratia marcescens bloodstream infection (BSI) were identified in a hospital in Tokyo, Japan. We conducted an epidemiological investigation of this outbreak. We undertook a medical-records review and employee interviews, and performed a case-control study to determine risk factors for S. marcescens BSI. An observational study of the hospital's procedures and an environmental microbiologic sampling were performed. We identified 12 suspected and 12 confirmed patients with S. marcescens BSI, including 7 who died. A case-control study showed that vascular access devices (odds ratio [OR] = 30.46; 95% confidence interval [CI] = 3.5-685.6) and the use of heparin-locks, between December 26 and January 15 (OR = 25.7; 95% CI = 2.3-680.4) were significant risk factors for S. marcescens BSI. The observational study revealed multiple lapses in infection control, including use of multi-dose vials of heparin. The outbreak strain was isolated from a hand-towel in the nurse station. The use of multi-dose vials of heparinized-saline during a particularly busy period was associated with BSI risk. The results underscore the risks inherent in infection-control lapses and the use of multi-dose vials.

The study describes the first attempt to record leptospirosis in Erode by isolation and serological tests such as the microscopic agglutination test and IgM-based enzyme-linked immunosorbent assay. Twenty-nine clinically suspected cases showing fever, headache, body ache associated with jaundice, decreased urine output, and conjunctival suffusion were included. The age of the patients ranged between 10-71 years and most of them were agricultural workers. Paired sera were possible among 12 cases. All the patients had fever and headache and other more common symptoms were myalgia and icterus. Leptospiral culture was positive in 7 (24.1%) patients. Out of 29 patients, 26 (89.7%) were diagnosed as having current leptospiral infection based on serology and isolation. The leptospiral isolates KSR 1 - 6 were further characterized by using randomly amplified polymorphic DNA fingerprinting shown genetic similarities with Leptospira interrogans spp. This study shows the presence of leptospirosis among the hospital cases of Erode and that this disease is a potential health hazard of agricultural workers in Cauvery basin.

Chloroquine (CQ)-resistant Plasmodium falciparum appears to decrease CQ accumulation in its food vacuole by enhancing its efflux via an active membrane pump, which has been reported to be a P-glycoprotein-like transporter. Rifampicin (RIF) is a P-glycoprotein inhibitor and also has some antimalarial activity. It is hoped that a combination of choloroquine-rifampicin (CQ + RIF) would be advantageous in the treatment of CQ-resistant malaria. Swiss albino mice were inoculated with CQ-resistant P. berghei intraperitoneally, and studied for the effect of CQ versus the combination of CQ + RIF at various doses on the clearance of parasitemia, the survival of the mice, and the recrudescence of malaria. Paradoxically, RIF decreased the survival rate and rate of clearance of parasitemia and increased the rate of recrudescence significantly when combined with various doses of CQ. Our results indicated that RIF worsened the course of the disease, and we concluded that RIF should not be combined with CQ in the treatment of malaria.

Fungal infection of the genitourinary system is a relatively uncommon presentation. Cryptococcuria has rarely been recognized in clinical practice. Patients with positive urine culture for Cryptococcus neoformans from 1992 to 2003 were retrospectively reviewed. Sixteen patients were identified. Nine (56%) patients were male, with a mean age of 44 ± 21 (range, 16-88) years. Fifteen (94%) patients had underlying conditions such as HIV infection, diabetes mellitus, hypertension, and/or systemic lupus erythematosus. Thirteen (81%) patients had cryptococcuria as a manifestation of disseminated cryptococcosis, and the rest had only isolated cryptococcuria. Urinary analysis revealed proteinuria (75%), pyuria (31%), and budding yeast (13%). Nine (56%) patients received antifungal therapy. Other patients were misdiagnosed or died before treatment. The mortality rate was 64%. In conclusion, cryptococcuria is not extremely rare and can present as a manifestation of disseminated cryptococcosis or isolated urinary tract infection.

Over a period of 6 months from January to June 2002, an unusual increase in the isolation of highly resistant Pseudomonas aeruginosa strains was observed in the various wards and intensive care units of a large general hospital in Johor Bahru, Malaysia. An equal number of multidrug-resistant (MDR) and drug-susceptible strains were collected randomly from swabs, respiratory specimens, urine, blood, cerebral spinal fluid, and central venous catheters to determine the clonality and genetic variation of the strains. Macrorestriction analysis by pulsed-field gel electrophoresis showed that the 19 MDR strains were genetically very homogenous; the majority showed the dominant profile S1 (n = 10), the rest very closely related profiles S1a (n = 1), S2 (n = 4), and S2a (n = 3), indicating the endemicity of these strains. In contrast, the 19 drug-sensitive strains isolated during the same time period were genetically more diverse, showing 17 pulsed-field profiles (F = 0.50 - 1.00), and probably derived from the patients themselves. The presence of the MDR clone poses serious therapeutic problems as it may become endemic in the hospital and give rise to future clonal outbreaks. There is also the potential for wider geographical spread.

We describe the case of a patient Who became ill with Salmonella Blockley food poisoning while working in Cyprus in August 1994. As his diarrhoea resolved he began to suffer from lower limb joint pains which were diagnosed as acute salmonella reactive arthritis. His condition deteriorated, then improved somewhat over a period of 2 years, but he continued to suffer symptoms over 5 years after infection. This case predates other reported cases of S. Blockley infection in Cyprus by 4 years. S. Blockley is associated with chickens, and the chicken meal is the probable source of his infection. This case is of interest since it demonstrates the emergence of the serovar outside Southeast Asia where it is common, and shows that information on the incidence and duration of reactive arthritis caused by serovars other than S. Enteritidis and S. Typhimurium is limited.

Nevirapine is a non-nucleoside reverse transcriptase inhibitor used in the treatment of human immunodeficiency virus (HIV)-infected patients and in post-exposure prophylaxis. However, its use has recently been limited because of adverse cutaneous and hepatic effects. We report an HIV-infected woman who developed mild leukopenia as the first sign of a nevirapine-related adverse event, which was followed by skin and hepatic toxicity associated with a more severe leukopenia.

Chryseobacterium meningosepticum is an uncommon pathogen causing adult bacterial meningitis. Herein, we report the case history of one 21-year-old woman with this uncommon central nervous system infection. A diagnosis of adult C. meningosepticum meningitis can only be confirmed by a positive cerebrospinal fluid (CSF) culture. The patient had insulin-dependent diabetes mellitus as the underlying condition associated with this infection. The clinical presentations were fever, headache, disturbance of consciousness, and seizure. CSF analysis revealed a purulent inflammatory reaction. After a 21-day course of intravenous cefepime (6 g/day) treatment, this patient was discharged in a state of complete recovery.

This report presents the results of a study conducted at the Child Health Department, Korle-Bu Teaching Hospital, Accra, Ghana, between the months of October 2001 and June 2002. Stool samples from 227 children with diarrhea and 77 children without diarrhea, aged less than 5 years, were tested for Cryptosporidium spp. Prevalence rates were 27.8 and 15.6% in children with and without diarrhea, respectively. Cryptosporidium infection was found to be high in children between the ages of 6 and 24 months. Cryptosporidium spp. was more common in malnourished children, but was not isolated in children under 6 months of age who were exclusively breastfed. Neither the presence of domestic animals, abdominal pain, blood in stool, nausea, vomiting, nor the consumption of untreated water was associated with Cryptosporidium spp. infection. Shigella, Salmonella, and yeast-like organisms were the most frequently identified enteropathogenic bacteria. In summary, this study demonstrates the prevalence of Cryptosporidium spp. among Ghanaian children.

Virus-specific CD8⁺ cytotoxic T lymphocyte (CTL) responses play an important role in the control of immunodeficiency virus infections. Therapeutic immunization with antigen-pulsed dendritic cells (DC) may be a promising strategy for stimulating CTL. However, decreases in DC number and function have been suggested in the host persistently infected with the virus, and this may constitute an obstacle to DC-based immunotherapy in the chronic phase. In this study, we show that virus-specific CTL responses were augmented by therapeutic immunization with inactivated virus-pulsed autologous DC in rhesus macaques that had maintained prophylactic vaccine-based control of virus replication for more than 3 years after simian or simian-human immunodeficiency virus challenge. Our results indicate the potential of DC in the chronic phase for efficiently stimulating CTL in vivo, suggesting the feasibility of therapeutic DC immunization for replenishing virus-specific CTL responses in the chronic phase after the prophylactic vaccine-based control of primary immunodeficiency virus infection.

Peroxidases figure prominently in biology and contribute significantly to cell biology, host defense against infection, and pathogenesis of several inflammatory diseases. These varied and diverse aspects of peroxidase biochemistry and its clinical implications will be the subjects of in-depth analysis at the 4th International peroxidase meeting held in Kyoto. Specific topics range from the molecular basis of peroxidase structure and function to the clinical consequences of autoantibodies generated against myeloperoxidase (MPO), the peroxidase present in circulating neutrophils. Consideration of novel aspects of peroxidase biology, both unanticipated biochemical properties of MPO and the potential role of MPO in the pathogenesis of inflammatory diseases such as atherosclerosis, will also be included. In addition to peroxidases, the newly expanded family of NADPH oxidases will be discussed. We hope that this collection of scientists who share a common interest in peroxidase biology but each possess expertise in distinctly different aspects of the subject will provide a setting for spirited discussion and a lively exchange of views to yield advances in understanding and to create new applications of those insights to benefit clinical medicine, agriculture and industry.

Infiltrated neutrophils is believed to contribute to the progression of vasculitis. In particular, myeloperoxidase (MPO)-specific antibodies against neutrophils, anti-neutrophil cytoplasmic antibodies (MPO-ANCA) is involved in the development of vasculitis microscopic polyangiitis etc. In Japan a higher percentage of MPO-ANCA than that in Europe has been reported In addition, we showed a correlation of MPO-ANCA epitopes of Kawasaki disease patients by 47% with that of mothers'. On the other hand, mice having CADS/CAWS-induced vasculitis is a good model for the analysis of the production of MPO-ANCA. We have clarified that MPO is a major antigen for MPO-ANCA production using MPO KO mice. We also investigated the role of activated neutrophils in nephritis renal lesions using SCG/Kj mice. In the phase of nephritis with low grade of proteinuria, the spontaneous release of MPO from peripheral neutrophils increased, indicating that neutrophils are activated and contribute to the development of active crescentic lesion in SCG/Kj mice.

Genetic abnormalities often serve as the catalyst to stimulate critical insights into normal biology. In many cases, examining such experiments of Nature explicates not only the abnormal but also serves to illustrate underlying normal principles. Within the context of myeloperoxidase biosynthesis, we have examined the impact of specific missense mutations that cause inherited myeloperoxidase deficiency. Such studies have provided novel insights not otherwise possible. We have described three such mutations and are completing the analysis of a fourth.

Autoantibodies to myeloperoxidase (MPO) are associated with small vessel systemic vasculitis. Interactions of these autoantibodies with MPO target antigen, Fcγ receptors and β2 integrins at the neutrophil surface, can set in train a sequence of intracellular signal transduction events that culminate with functional responses. These include a respiratory burst with release of superoxide ions, degranulation, cytokine release, enhanced adhesion and induction of an accelerated apoptotic program.

In recent years there have been substantial developments in the understanding of the aetiology and pathogenesis of ANCA-associated vasculitides, including myeloperoxidase (MPO) associated autoimmunity. This review will describe genetic and environmental factors that may increase the risk for the disease and will summarise findings demonstrating that T-cells, B-cells and ANCA themselves are of pathogenetic significance. Leukocyte gene expression profiles indicate that the reactivation of granule protein genes contributes to the pathogenesis of AASV. Finally, data derived from closely related autoantibodies against proteinase 3 (PR3) suggest anti-idiotypic antibodies induced by antisense transcripts as potential pathological agents.

Intraperitoneal administration of CAWS (water-soluble extracellular polysaccharide fraction obtained from the culture supernatant of Candida albicans) to mice induces coronary arteritis similar to Kawasaki disease. We analyzed differences in the production of cytokines involved in the occurrence of coronary arteritis among mouse strains, C3H/HeN, C57BL/6, DBA/2 and CBA/J. The incidence of arteritis was 100% in C57BL/6, C3H/HeN and DBA/2 mice, but only 10% in CBA/J mice. The coronary arteritis observed in DBA/2 mice was the most serious, with several mice expiring during the observation period. The CAWS-sensitive strains revealed increased levels of IL-6 and IFN-γ during the course of a specific response to CAWS by spleen cells. In contrast, IL-10 levels were observed to increase markedly in CAWS-resistant CBA/J mice, but not the CAWS-sensitive strains. However, TNF-α levels were more elevated only in DBA/2 mice. The difference in disease development and cytokine production strongly suggests that the genetic background of the immune response to CAWS contributes to the occurrence of coronary arteritis.

Hereditary myeloperoxidase (MPO) deficiency is the most common neutrophil biochemical defect characterized by the lack of peroxidase activity. In order to extend the epidemiological studies on hereditary MPO deficiency in Italy, approximately 40,000 individuals were analyzed and 7 partial and 8 total MPO deficient subjects were identified. The genetic characterization of the subjects showed the presence of 3 already-known mutations (c.752T>C, c.1705C>T and c.1566_1579del14) and 6 novel mutations: four missense mutations (c.995C>T, c.1112A>G, c.1715T>G and c.1927T>C), then a deletion of an adenine within exon 3 (c.325delA) and a mutation within the 3' splice site of intron 11 (c.2031-2A>C). The novel missense mutations cause the substitution of residues the p.A332V, p.D371G, p.L572W and p.W643R, respectively, and can cause potential structural changes. The c.325delA deletion causes a shift of the reading frame with the occurrence of a premature stop codon within the pro-peptide. An eukaryotic expression system was set up to investigate how the c.2031-2A>C mutation alters the MPO pre-mRNA splicing. The activation of a cryptic 3' splice site located 109nt upstream of the authentic 3' splice site was observed. The 109nt-insertion might cause the rapid degradation of the MPO mRNA or, alternatively, might lead to the generation of an abnormal MPO precursor lacking the enzymatic activity.

Myeloperoxidase (MPO; EC 1.11.1.7) is a lysosomal hemeprotein that plays an important role in the host defense mechanism against microbial diseases. This neutrophil disorder, characterized by the lack of MPO, may result in a weakened defense activity. Complete MPO deficiency has been postulated to be to originate from genomic mutation. Recently, two Japanese patients were reported with MPO deficiency. Both had base substitutions in the exon 9 region of the MPO gene; a region in close proximity functionally important residue, His502. Genomic DNA from 387 Japanese individuals was examined to determine the prevalence of these recently discovered base substitutions. None of these DNA samples possessed the mutations found in the MPO deficient cases, though two synonymous and one non-synonymous mutation were found. The frequency of mutation in the exon 9 coding region was estimated to be one heterozygote in 129, thus the homozygote of such mutations would be revealed one in 16,000 in the Japanese population.

The neutrophil granulocytes have a critical role in innate immunity through killing of phagocytized microorganisms, in which myeloperoxidase (MPO) participates. MPO is stored in cytoplasmic azurophil lysosome-like granules together with other antibiotic proteins and digestive enzymes. During passage in the secretory pathway pro-MPO is folded, subjected to oligosaccharide modification, and retrieval from constitutive secretion to become targeted to azurophil granules for final processing and storage. Propeptide-deleted MPO precursor was found not to be processed to mature MPO and not to be targeted for storage but instead degraded or secreted. This indicated that the propeptide of the MPO precursor was a prerequisite for the final processing and granule targeting of proMPO. When the MPO propeptide was expressed as a chimera with a normally secretory protein, the ER retention of the chimera was prolonged compared with that of the native protein. Thus, the propeptide of MPO precursor may also mediate the normally long ER-residence of proMPO. Both mature MPO and secreted proMPO contained complex oligosaccharide side chains indicating that proMPO and, thus, mature MPO has passed the medial Golgi stack where complex oligosaccharides are formed, and exited at TGN like other proteins targeted for azurophil granules.

Myeloperoxidase (MPO) is located within neutrophils capable of producing HOCl. To define the in vivo role of MPO, we have generated MPO-knockout (MPO-KO) mice. The mice without MPO developed normally. However, MPO-KO mice showed severely reduced cytotoxicity to various microorganisms such as Candida albicans, Aspergillus fumigatus, and Klebsiella pneumoniae, demonstrating that MPO-dependent oxidative system is important for host defense against fungi and bacteria, although the effect varies from species to species of pathogens. To compare the importance of MPO and NADPH-oxidase for host defense, MPO-KO and chronic granulomatous disease (CGD) mice were infected with different doses of C. albicans, and their infection severity was analyzed. CGD mice exhibited increased mortality and tissue fungal burden in a dose-dependent manner, whereas normal mice showed no symptoms. Interestingly, at the highest dose, the mortality of MPO-KO mice was comparable to CGD mice, but was the same as normal mice at the lowest dose. These results suggest that MPO and NADPH-oxidase are equally important for early host defense against a large inocula of Candida.

Autoantibodies to myeloperoxidase (MPO) are associated with the autoimmune disease, systemic vasculitis, in humans. This results in severe inflammation and microscopic necrosis of multiple organs, especially the kidneys, leading to renal failure and death. The discovery of MPO autoantibodies has permitted the development of new diagnostic tests allowing earlier diagnosis and more effective therapy. Furthermore these antibodies are directly implicated in tissue injury by binding to MPO on the neutrophil cell membrane and stimulating neutrophil activation and degranulation. The causes for the breakdown in tolerance to MPO are not known although rare cases are drug-induced and remit on drug withdrawal. An understanding of the biology of MPO and its involvement in the pathogenesis of vasculitis is of importance in understanding the pathogenesis of vasculitis and the development of newer therapies.

For 30 myeloperoxidase (MPO) antineutrophil cytoplasmic antibody (ANCA) related rapidly progressive glomerulonephritis patients (male 17, female 13 , average age of 68 ± 11.8 years old), intravenous immunoglobulin (IVIg) (400 mg/kg/day) was administered for 5 consecutive days before or along with conventional immunosuppressive therapy in Japan. Twenty patients were treated with IVIg before the start or newly increase of conventional therapy and evaluated the independent effect of this therapy. In these patients, just after IVIg, significant decrease of CRP from 8.61 ± 5.77 to 5.47 ± 4.50 mg/dl (P < 0.001) was noted with improvement of elevated serum creatinine in 12 out of 19 patients (63%). In the analysis of the overall outcome of 30 patients, at 3 months after IVIg and following conventional therapy, no patients showed renal death except 4 for whom hemodialysis had been started before IVIg. At 6 months, renal survival rate were 92% (newly renal death 2 out of 26) and 2 patients died due to cerebral bleeding (survival rate was 93%). No fatal infection was noted. IVIg might be the potent inducible therapy which can be promoted before the beginning of conventional immunosuppressant treatment for relatively aged and lower immunopotent MPO-ANCA patients in Japan.

When a constant gene replacement sequence is introduced into bacteria to produce mutants and the flanking chromosomal sequences are known, it is possible to use a quantitative polymerase chain reaction method (QPCR) to compare the concurrent survival of the different bacterial mutants under identical conditions. We describe Escherichia coli survival following neutrophil phagocytosis among three mutants deleted respectively for araB, dps or oxyR. Comparisons were made both by traditional and QPCR methods with similar results and indicate that the survival defect of an oxyR and oxyS mutant described previously can be attributed to the loss of oxyR alone. Deletion of dps, a prominent member of the regulon controlled by the oxyR gene product does not engender a survival defect. We suggest that QPCR analysis can readily compare the relative survival of 10 or more mutants concurrently. QPCR analysis would seem to be especially valuable when experimental conditions are subject to a high degree of sample to sample variability or when the stress producing system involves use of expensive or scarce resources like rare patient cells, cells from children, or the use of genetically modified animal hosts.

A growing body of evidence continues to emerge implicating the role of myeloperoxidase (MPO) and its oxidant products in the promotion of atherogenesis. A major mechanism by which MPO impacts the arterial wall is through its modification of net cellular cholesterol flux. MPO promotes lipid peroxidation and conversion of LDL to an atherogenic form, where it is taken up by macrophages, a critical step in foam cell formation. Emerging evidence suggests that HDL can also be modified by MPO derived oxidants, resulting in an impairment of cholesterol efflux. In addition, modified HDL appears to be a strong predictor of clinical risk. These features highlight MPO and its products as potential predictive markers and targets in atheroprotection.

The members of the NOX family of enzymes are expressed in a variety of tissues and serve a number of functions. There is a high level of conservation of primary protein sequence, as well as functional features, although specialized responses are beginning to emerge. In this context, our data demonstrate that the NOX1 cytoplasmic domains interact efficiently with the cytoplasmic subunits of the phagocyte NADPH oxidase and identify the second cytoplasmic loop of NOX electron transporters as a crucial domain for enzyme function. Studies of cytosolic co-factors showed that the C-terminal cytoplasmic domain of NOX1 was absolutely required for activation with NOXO1 and NOXA1 and that this activity required interaction of the putative NADPH-binding region of this domain with NOXA1. Finally, we have provided the first example of how alternative splicing of a NOX co-factor may be involved in the regulation of NADPH oxidase function.

The phagocyte NADPH oxidase is dormant in resting cells but becomes activated during phagocytosis to produce superoxide, a precursor of microbicidal oxidants, thereby playing a crucial role in host defence. The catalytic core of this enzyme comprises the two membranous subunits gp91^phox /Nox2 and p22^phox . The oxidase activation requires the small GTPase Rac and the SH3 domain-containing proteins p47^phox and p67^phox ; they normally exist in the cytoplasm and translocate upon cell stimulation to the membrane. The translocation depends on a stimulus-induced conformational change of p47^phox , which leads to the SH3 domain-mediated interaction with p22^phox , a binding required for the gp91^phox /Nox2-dependent superoxide production. Activation of Nox1, an oxidase that is likely involved in host defence at the colon, requires novel proteins homologous to p47^phox and p67^phox , designated Noxo1 and Noxa1, respectively. Noxo1 and Noxa1, both expressed abundantly in the colon, are capable of constitutively activating Nox1. The constitutive activation may be due to the property of Noxo1: in contrast with p47^phox , Noxo1 seems to normally associate with p22^phox , which is required for the Nox1 activation. We will also describe the mechanism underlying regulation of the third oxidase Nox3, which exits in fetal kidney and inner ears.

IFN-γ dependent increase of superoxide production by neutrophils was observed in three patients with Chronic Granulomatous disease from one family. The patients have the gp91-phox defect due to a splicing abnormality derived from a silent mutation adjacent to the third intron of CYBB gene. Apparent differences of splicing pattern of CYBB gene transcripts in patients' neutrophils were detected between 1 and 25 days after administration of IFN-γ. Furthermore, the transcript containing all missing exons could be detected in all specimens after the treatment. The changes of splicing pattern in the transcripts and prolonged effect on superoxide generating ability of patients' neutrophils indicate that IFN-γ induced an ability to correct abnormal splicing of CYBB gene transcripts in progenitor cells at least in part.

Previous clinical studies of ex vivo gene therapy for chronic granulomatous disease (CGD) without marrow conditioning have resulting in transient correction of the oxidase defect in over 0.1% of circulation neutrophils. Use of improved RD114 envelope pseudotyped vectors capable of transducing >95% of CD34⁺ stem cells ex vivo, together with non-ablative marrow conditioning will be incorporated into the next generation of clinical trials of ex vivo gene therapy for CGD. These maneuvers might result in clinical benefit to CGD patients from gene therapy.

The NOX family of ROS-generating NADPH oxidases consists of 7 members: NOX1 to NOX5, DUOX1 and 2. NOX1 is predominantly found in the colon, where it possibly plays a role in the host defense. NOX2 is the phagocyte NADPH oxidase, a clearly established host defense enzyme. NOX3 is almost exclusively expressed in the inner ear, where it is involved in otoconia morphogenesis, but based on its localization might also play a role in the auditory system. NOX4, widely expressed in kidney, vascular cells, osteoclasts etc.; it might be a constitutively active enzyme, regulated on the level of gene expression but its precise physiological function remains unknown. NOX5, a Ca²⁺ activated enzyme is predominantly expressed in lymphoid tissues and testis, where it might be involved in signaling processes. DUOX1 is expressed in the thyroid and in respiratory epithelia, and DUOX2 in the thyroid and in gastrointestinal glandular epithelia. Both DUOX enzymes are involved in thyroid hormone synthesis, but possibly also in epithelial host defense.

Myeloperoxidase, eosinophil peroxidase and lactoperoxidase are heme-containing oxidoreductases, which undergo a series of redox reactions. Though sharing functional and structural homology, reflecting their phylogenetic origin, differences are observed regarding their spectral features, substrate specificities, redox properties and kinetics of interconversion of the relevant redox intermediates ferric and ferrous peroxidase, compound I, compound II and compound III. Depending on substrate availability, these heme enzymes path through the halogenation cycle and/or the peroxidase cycle and/or act as poor (pseudo-) catalases.

Myeloperoxidase (MPO) uses hydrogen peroxide to oxidize chloride to hypochlorous acid. It also converts numerous substrates to reactive free radicals. When released by neutrophils, the enzyme operates in the presence of a flux of superoxide. We show that superoxide has a profound influence on oxidative reactions catalysed by MPO. It reacts directly with the enzyme to modulate production of hypochlorous acid. Within neutrophil phagosomes, where MPO functions to kill micro-organisms, it may be the preferred substrate for the enzyme. Superoxide also reacts rapidly with radicals generated by MPO, e.g. from tyrosine and tyrosyl peptides. Initial products are organic peroxides. These species are likely to be toxic and contribute to the pathophysiological actions of MPO.

Reactions of thioureylene antithyroid drugs (1- methyl-2-mercaptoimidazole and carbimazole) with hypochlorous acid (HOCl) and superoxide were followed optically and products were analyzed by mass spectrometry. 1-Methyl-2-mercaptoimidazole (MMI) and carbimazole reacted rapidly with HOCl with a rate constant of 1 × 10⁷ and 7 × 10⁶ M^-1 s^-1 , respectively. The characteristic spectrum assigned to MMI disulfide appeared immediately after addition of HOCl, followed by a slow conversion to a final spectrum. The conversion was dependent upon the ratio of HOCl to MMI and both antithyroid drugs uptake 3 moles HOCl for complete conversion. A similar sequence of spectral changes was also observed when the HOCl was replaced by myeloperoxidase (MPO)/H₂O₂/Cl^- system. The final oxidation product of MMI and carbimazole with HOCl and superoxide was 1-methylimidazole.