Emerg Infect Dis, 2002 Mar, 8(3), 327 - 9 Recent increase in meningitis Caused by Neisseria meningitidis serogroups A and W135, Yaoundé, Cameroon; Fonkoua MC et al.; From 1991 to 1998, Neisseria meningitidis serogroups A, B, and C represented 2%-10% of strains isolated from cases of bacterial meningitis in Yaounde . During 1999 to 2000, the percentage of meningococci reached 17%, a proportion never reported since recordkeeping began in 1984 . The increase of serogroup A meningococci and the emergence of W135 strains highlight the need for increased surveillance for better diagnosis and prevention. J Biol Chem, 2002 Jun 7, 277(23), 20468 - 76 Epub 2002 Mar 28. Characterization of oligopeptides that cross-react with carbohydrate-specific antibodies by real time kinetics, in-solution competition enzyme-linked immunosorbent assay, and immunological analyses; Brett PJ et al.; Phage displaying random cyclic 7-mer, and linear 7-mer and 12-mer peptides at the N terminus of the coat protein, pIII, were panned with the murine monoclonal antibody, 9-2-L379 specific for meningococcal lipo-oligosaccharide . Five cyclic peptides with two sequence motifs, six linear 7-mers, and five linear 12-mers with different sequence motifs were identified . Only phage displaying cyclic peptides were specifically captured by and were antigenic for 9-2-L379 . Monoclonal antibody 9-2-L379 exhibited "apparent" binding affinities to the cyclic peptides between 11 and 184 nm, comparable with lipo-oligosaccharide . All cyclic peptides competed with the binding of 9-2-L379 to lipo-oligosaccharide with EC(50) values in the range 10-105 microm, which correlated with their apparent binding affinities . Structural modifications of the cyclic peptides eliminated their ability to bind and compete with monoclonal antibody 9-2-L379 . Mice (C3H/HeN) immunized with the cyclic peptide with optimal apparent binding affinity and EC(50) of competition elicited cross-reactive antibodies to meningococcal lipo-oligosaccharide with end point dilution serum antibody titers of 3200 . Cyclic peptides were converted to T-cell-dependent immunogens without disrupting these properties by C-terminal biotinylation and complexing with NeutrAvidin . The data indicate that constrained peptides can cross-react with a carbohydrate-specific antibody with greater specificity than linear peptides, and critical to this specificity is their structural conformation. Arch Dis Child, 2002 Apr, 86(4), 282 - 5 Procalcitonin as a diagnostic marker of meningococcal disease in children presenting with fever and a rash; Carrol ED et al.; BACKGROUND: Procalcitonin (PCT), a precursor of calcitonin, is a recognised marker of bacterial sepsis, and high concentrations correlate with the severity of sepsis . PCT has been proposed as an earlier and better diagnostic marker than C reactive protein (CRP) and white cell count (WCC) . This comparison has never been reported in the differentiation of meningococcal disease (MCD) in children presenting with a fever and rash . AIM: To determine if PCT might be a useful marker of MCD in children presenting with fever and rash . METHODS: PCT, CRP, and WCC were measured on admission in 108 children . Patients were classified into two groups: group I, children with a microbiologically confirmed clinical diagnosis of MCD (n = 64); group II, children with a self limiting illness (n = 44) . Median ages were 3.57 (0.07-15.9) versus 1.75 (0.19-14.22) years respectively . Severity of disease in patients with MCD was assessed using the Glasgow Meningococcal Septicaemia Prognostic Score (GMSPS) . RESULTS: PCT and CRP values were significantly higher in group I than in group II (median 38.85 v 0.27 ng/ml and 68.35 v 9.25 mg/l; p < 0.0005), but there was no difference in WCC between groups . Sensitivity, specificity, and positive and negative predictive values were higher for PCT than CRP and WCC . In group I, procalcitonin was significantly higher in those with severe disease (GMSPS >/=8) . CONCLUSIONS: PCT is a more sensitive and specific predictor of MCD than CRP and WCC in children presenting with fever and a rash. J Reconstr Microsurg, 2002 Jan, 18(1), 17 - 22 Sequential microsurgical flap reconstruction following purpura fulminans during infancy and childhood; Jester A et al.; Purpura fulminans is a potentially lethal complication of meningococcal septicemia, characterized by progressive hemorrhagic skin lesions, which can result in extensive necrosis and mummification of all the extremities . With improving survival rates in infancy and childhood, plastic surgeons are challenged more often to provide sufficient and stable soft-tissue coverage . Usually, conservative methods, such as skin grafting or amputation, are favored by many pediatric surgeons, since further specialized departments and training are not required . Often secondary reconstructive procedures to improve soft-tissue coverage have to be performed to achieve proper prosthetic fitting . Microsurgical techniques are used only in selected cases, after failure of other procedures for defect coverage . In two cases of post-acute purpura fulminans, two free flaps and three microsurgically dissected flaps were used as primary measures for defect coverage and preservation of stump length . Despite the presence of vasculitis, all flaps survived . In a third case, secondary reconstructive measures had to be performed 1 year after purpura fulminans due to insufficient soft-tissue coverage after lower leg amputation . This patient also had contractures on both hands and no grip function after complete finger loss . Several microsurgical procedures were performed to improve grip function and soft-tissue coverage . The primary use of microsurgical techniques prevents lengthy secondary reconstructive measures. Rev Prat, 2002 Jan 15, 52(2), 139 - 44 {Intermittent fever of infectious origin}; Le Moing V et al.; Intermittent fever is rare during the course of infectious diseases but it represents a diagnostic and therapeutic challenge . The most frequent infectious causes of intermittent fever are focal bacterial infections, mainly infections localised to canals like urinary or biliary ducts or the colon and also infections of a foreign material . Other causes are less frequent, like infective endocarditis, tuberculosis, infections due to Yersinia enterocolitica or malaria, or exceptional like borreliosis, ratbite fever, chronic meningococcemia or chronic Epstein-Barr Virus infection . Careful anamnesis and clinical examination as well as a few simple complementary investigations, preferably performed during a febrile episode, are often sufficient to set the limits of possible further more complex investigations. Med Dosw Mikrobiol, 2001, 53(2), 117 - 32 {Characteristics of Neisseria meningitidis strains isolated from patients with symptoms of meningococcal meningitis in Poland in 1995-2000}; Grzybowska W et al.; Phenotype and genotype identification of 179 Neisseria meningitidis strains isolated from cerebrospinal fluid or blood of patients with meningococcal infection, hospitalized in Poland, was performed . This is the first analysis of that type conducted in Poland . We analyzed strains collected in 1995-2000 from laboratories located all over the country . Phenotype Neisseria meningitidis B:22:P1.14 was the predominant among analyzed invasive strains in Poland . Type 22 is characteristic to most of the strains isolated in our country . No strain from analyzed group belonged to known epidemic clusters . One penicillin resistant strain (MIC = 2 mg/l) and about 27% strains with decreased susceptibility to penicillin (0.1 = < MIC < 1.0 mg/l) were present among 166 N . meningitidis tested . All strains were susceptible to ciprofloxacin and rifampicin. MMWR Morb Mortal Wkly Rep, 2002 Feb 22, 51(7), 141 - 4 Laboratory-acquired meningococcal disease--United States, 2000. {An estimation of imported infections concerning 2002 FIFA world cup Korea/Japan} Takahashi H, Kaku K, Tanaka T, Matsui T, Osaka K, Ohyama T, Okabe N. The FIFA World Cup 2002 Korea/Japan, which will be held during May 31 through June 30, 2002, is a mass-gathering and high-profile event . The Ministry of Transport announced that approximately 430,000 people visit Japan for the event . We estimated the incidence of major imported infections using data from the national epidemiological surveillance of infectious diseases and the statistics of immigration . Estimated incidences are 5.88 (shigellosis), 3.41 (malaria), 1.40 (typhoid/paratyphoid fever), 0.42 (cholera), and 0.0032 (meningococcal meningitis) . The incidence for viral hemorrhagic fever was estimated 0.0018 under assumption that "it correlates with the malaria incidence from Africa" and that "the incidence occurs every 15 years" . These results indicate little possibility of remarkable increase of exotic infections during the event . These incidences, however, may occur in the rural prefectures where few cases are reported . It is highly needed to strengthen surveillance and educate physicians and public health experts especially for malaria cases. Intensive Care Med, 2002 Mar, 28(3), 341 - 51 Epub 2002 Feb 14. A new prognostic scoring system for meningococcal septic shock in children . Comparison with three other scoring systems; Castellanos-Ortega A et al.; OBJECTIVE: To develop a quick and sensitive method for identification of children with presumed meningococcal septic shock at risk of death at admission to the pediatric intensive care unit (PICU) and to compare its performance with three other prognostic systems: Glasgow Meningococcal Septicaemia Prognostic Score (GMSPS), Malley score and the Paediatric Index of Mortality (PIM) . DESIGN: Multicenter retrospective cohort study . SETTING: PICUs of 14 tertiary hospitals . PATIENTS: The developmental sample included 192 children consecutively admitted to the PICUs with presumed or confirmed meningococcal septic shock from 1983 to 1995 . The validation sample included 158 children consecutively admitted from 1996 to 1998 . INTERVENTIONS: Clinical and laboratory data gathered during the first 2 h after admission were used to develop the new score and to compute the other scoring systems . Logistic regression was applied to identify the independent predictors of death . MEASUREMENTS AND RESULTS: Overall mortality was 31.5% . The new score included seven variables: cyanosis (2 points), Glasgow coma scale less than 8 (2 points), refractory hypotension (2 points), oliguria (1 point), leukocytes less than 4000/mm(3) (1 point), partial thromboplastin time more than 150% of control value (1 point) and base deficit more than 10 mmol/l (1 point) . The new score provided the best discriminative capability, as measured by the area under the ROC curve (SEM) in the validation sample =0.88 (0.03), PIM =0.82 (0.04), Malley I =0.80 (0.04), GMSPS =0.79 (0.04) and Malley II =0.76 (0.04) . CONCLUSIONS: A new prognostic score is proposed for therapeutic stratification of children with presumed meningococcal septic shock. Mol Microbiol, 1997 Jul, 25(1), 11 - 25 PilC of pathogenic Neisseria is associated with the bacterial cell surface; Rahman M et al.; Adherence of pathogenic Neisseria to target host cells is mediated by pili . PilC1 and PilC2 are two high-molecular-weight proteins involved in pilus assembly and cellular adherence functions of the pili . Inactivation of pilC1 or pilC2 in N . meningitidis resulted in clones that expressed the same number of pili as the parent, contained no alterations in pilE and showed no detectable differences in PilE glycosylation . However, the PilC2+ pilC1- mutant showed much reduced adherence to target cells, indicating that production of PilC1 is essential for pilus-mediated adherence . To study further the functional differences between the meningococcal pilC genes, we determined the complete nucleotide sequence of pilC1 and pilC2 of N . meningitidis . Alignment of six PilC sequences demonstrated that PilC is composed of both conserved and variable regions . By immunogold labelling of bacterial sections we showed that PilC is present in the membranes of both piliated and non-piliated bacteria . Further, we demonstrated that PilC is associated with the bacterial cell surface. Medsurg Nurs, 2002 Feb, 11(1), 9 - 12; quiz 13 Preventing and treating meningococcal meningitis; Michael PA; Meningitis is a bacterial or viral inflammation of the meninges . Three thousand cases are reported each year with a mortality rate of 5% to 40% . Socioeconomic factors play a role in meningitis and may affect the speed of diagnosis and subsequent initiation of treatment . Transmission and pathogenesis of the disease enables nurses to recognize signs and symptoms and implement treatment and prevention strategies. Platelets, 2002 Mar, 13(2), 91 - 9 Platelet-platelet and platelet-leukocyte interactions induced by outer membrane vesicles from N . meningitidis; Mirlashari MR et al.; A large part of native meningococcal lipopolysaccharide (LPS), i.e., LPS integrated in the outer cell membrane, is released in the form of 'blebs' from surplus outer membrane material . In the present study we investigated the effects of purified outer membrane vesicles (OMVs) on blood platelet-platelet and platelet-leukocyte interactions . Citrated whole blood was stimulated in vitro with equal amounts (on a weight basis) of OMV-integrated LPS, purified LPS (P-LPS) from the same meningococcal strain and purified E . coli-LPS . The samples were analyzed by flow cytometry . Upon OMV stimulation platelet aggregation increased 2.1-fold, platelet degranulation 1.8-fold, (measured as CD62P expression), platelet binding to monocytes 2.6-fold, whereas platelet binding to granulocytes increased 2.8-fold . Also, the fraction of large heteroconjugates, i.e., large CD45-positive cell aggregates increased 15.7-fold compared to control . P-LPS and E . coli-LPS also significantly increased platelet aggregation and heteroconjugate formation but did not influence platelet degranulation and binding of platelets to leukocytes in whole blood . When using platelet-rich plasma (PRP), OMVs increased platelet aggregation 2.1-fold and CD62P expression 1.9-fold . P-LPS and E . coli-LPS also significantly increased platelet aggregation in PRP but did not influence platelet degranulation . None of the LPS preparations induced platelet microvesiculation, either in whole blood or in PRP . CONCLUSION: Meningococcal-derived OMVs as well as purified meningococcal LPS, contribute to increased platelet-platelet and platelet-leukocyte aggregation and may thus be of great importance in the development of microthrombosis and organ dysfunction related to fulminant meningococcal septicemia. Infect Immun, 2002 Apr, 70(4), 2245 - 8 Role of Neisseria meningitidis luxS in cell-to-cell signaling and bacteremic infection; Winzer K et al.; Numerous pathogenic bacteria contain luxS, which is required for autoinducer-2 production . Here, we demonstrate that Neisseria meningitidis contains a functional copy of luxS that is necessary for full meningococcal virulence; strains with a luxS deletion are defective for bacteremia, a prerequisite of meningococcal pathogenesis. Epidemiol Infect, 2002 Feb, 128(1), 7 - 14 Increase in meningococcal disease associated with the emergence of a novel ST-11 variant of serogroup C Neisseria meningitidis in Victoria, Australia, 1999-2000; Tribe DE et al.; In the years 1999-2000, there was an increase in the incidence of meningococcal disease in Victoria, largely caused by Neisseria meningitidis serogroup C . This change was associated with a shift in age distribution of cases, with relatively more disease appearing in the 15-29 year age group, and with 40/58 serogroup C isolates in 2000 exhibiting a new macrorestriction pattern (pattern A) . Thirty-four of 52 pattern A isolates tested displayed the novel phenotype C:2a:P1.4, and were consistently porA VR type P1.7-2,4 by DNA sequencing . Nine of 10 representative pattern A isolates analysed displayed a housekeeping gene allele profile (ST-11) that is characteristic of the electrophoretic type (ET)-15 variant that has caused outbreaks in Canada, the Czech Republic and Greece . Meningococci belonging to the ST-11 complex that were isolated in Victoria prior to 1999 did not display either restriction pattern A or PorA VR type P1.7-2,4. Aust J Rural Health, 2000 Dec, 8(6), 318 - 21 Meningococcal infections and meningitis: what is new? Kumar RK. Meningococcal infection is one of the very few severe bacterial infections, in this era, that still can kill a relatively healthy child within minutes . Fortunately, it is a relatively rare disease . Rural practitioners may see one affected child once every 2-3 years, but once seen they will never forget it . The present article gives some examples of case scenarios along with a brief overview of the problem, with emphasis on early diagnosis, prevention and possible future developments. Proc Natl Acad Sci U S A, 2002 Mar 19, 99(6), 3417 - 21 Epub 2002 Mar 12. Crystal structure of the OpcA integral membrane adhesin from Neisseria meningitidis; Prince SM et al.; OpcA is an integral outer membrane protein from Neisseria meningitidis, the causative agent of meningococcal meningitis and septicemia . It mediates the adhesion of N . meningitidis to epithelial and endothelial cells by binding to vitronectin and proteoglycan cell-surface receptors . Here, we report the determination of the crystal structure of OpcA to 2.0 A resolution . OpcA adopts a 10-stranded beta-barrel structure with extensive loop regions that protrude above the predicted surface of the membrane . The second external loop adopts an unusual conformation, traversing the axis of the beta-barrel and apparently blocking formation of a pore through the membrane . Loops 2, 3, 4, and 5 associate to form one side of a crevice in the external surface of the structure, the other side being formed by loop 1 . The crevice is lined by positively charged residues and would form an ideal binding site for proteoglycan polysaccharide . The structure, therefore, suggests a model for how adhesion of this important human pathogen to proteoglycan is mediated at the molecular level. Gene, 2002 Feb 6, 284(1-2), 133 - 40 Genetic linkage analysis to identify a gene required for the addition of phosphoethanolamine to meningococcal lipopolysaccharide; Tang CM et al.; Lipopolysaccharide (LPS) is important for the virulence of Neisseria meningitidis, and is the target of immune responses . We took advantage of a monoclonal antibody (Mab B5) that recognises phosphoethanolamine (PEtn) attached to the inner core of meningococcal LPS to identify genes required for the addition of PEtn to LPS . Insertional mutants that lost Mab B5 reactivity were isolated and characterised, but failed to yield genes directly responsible for PEtn substitution . Subsequent genetic linkage analysis was used to define a region of DNA containing a single intact open reading frame which is sufficient to confer B5 reactivity to a B5 negative meningococcal isolate . The results provide an initial characterisation of the genetic basis of a key, immunodominant epitope of meningococcal LPS. Int J Med Microbiol, 2002 Feb, 291(6-7), 419 - 23 Genomics of Neisseria meningitidis; Nassif X; An important feature of disease caused by Neisseria meningitidis is the propensity to invade the meninges . Much progress has been made in our understanding of how this pathogen circumvents the physical properties of this cellular barrier . This review will address the new possibilities offered by the recent availability of meningococcal genome sequences. Ned Tijdschr Geneeskd, 2002 Feb 23, 146(8), 356 - 9 {Negative effects of passive smoking on the (unborn) child}; Hofhuis W et al.; The negative effects of passive smoking on the health of the foetus or child continue to receive little attention, despite the large volume of research in this area . Passive smoking during pregnancy is associated with low birth weight, a reduction in head circumference at birth, and a far higher incidence of sudden infant death syndrome . Exposure to cigarette smoke also leads to a decreased lung function, an increased risk of severe infections, including respiratory syncytial virus bronchiolitis, meningococcal disease and middle ear infections . There is no association between passive smoking and the development of allergic asthma, but passive smoking does cause an increase in the prevalence of respiratory symptoms in children with or without asthma . Finally, there is a relation between passive smoking and behavioural disorders including attention deficit/hyperactivity disorder (ADHD) . Passive smoking before birth seems even more harmful than after birth . A causal relationship is suggested in most studies, or has been proven by animal experiments . A decreased birth weight in general increases the risk of developing chronic diseases as an adult, such as hypertension, cardiovascular disease and type 2 diabetes mellitus . This extensive knowledge about the adverse health effects of smoke exposure in (unborn) children deserves greater attention in the counselling of pregnant women, and in anti-smoking campaigns. Br J Haematol, 2002 Mar, 116(4), 905 - 8 Plasma exchange as a source of protein C for acute onset protein C pathway failure; Hodgson A et al.; Severe bacterial sepsis, particularly secondary to meningococcaemia, is a well-recognized cause of purpura fulminans resulting from severe acquired protein C (PC) deficiency . Recently, PC and activated protein C (APC) concentrate replacement therapy has been shown to improve outcome in patients with meningococcaemia- associated purpura fulminans and severe sepsis respectively . Despite these impressive findings, PC and APC concentrates are not currently widely available . We describe a 31-year-old patient with pneumococcal septic shock, purpura fulminans (PF) and severe acquired PC deficiency, whom we successfully treated with conventional therapy and high-volume plasma exchange as a source of PC. J Paediatr Child Health, 2001 Oct, 37(5), S7 - 12 Laboratory enhanced surveillance for meningococcal disease in Victoria; Robinson P et al.; OBJECTIVE: To describe the epidemiological and microbiological characteristics and notification patterns of invasive meningococcal disease (IMD) in Victoria between 1990 and 1999 . METHODS: Cases of IMD occurring between 1990 and 1995 identified in any of three databases were combined, matching where possible . Statistical modelling provided estimates of cases missing from all datasets . Notification sources for 1999 and 2000 cases were identified . Cases identified from notification and laboratory results provided the data to describe IMD epidemiology between 1990 and 1999 . RESULTS: Between 1990 and 1995, 479 cases of IMD were identified . Three individual datasets each identified between 62 and 82% of cases and 47% of cases were identified in all three datasets . Statistical modelling estimated that between 37 and 83 additional cases were not identified by any dataset . Serogroup B and C strains caused 63 and 33% of culture-positive cases, respectively, with a substantial rise in serogroup C cases in 1999 . Epidemiological characteristics remained relatively constant between 1990 and 1998, but an increase in patient age was seen in cases with serogroup C disease in 1999 . In addition to three clonal strains seen elsewhere, an additional strain was identified that was unique to Victoria . Since January 1999, only 72% of notifications have come from treating doctors . CONCLUSIONS: Meningococcal disease is of increasing public health significance in Victoria . Laboratory enhanced notification has improved case identification and detailed microbiological information has improved our understanding of the changing epidemiology of this disease . Collaboration with laboratories and other agencies, active investigation of putative cases and microbiological monitoring are important elements in supporting public health decisions about the control of IMD. J Paediatr Child Health, 2001 Oct, 37(5), S34 - 6; discussion 37 Introduction of a conjugate meningococcal type C vaccine programme in the UK; Salisbury D; OBJECTIVE: The purpose of the UK initiative was to accelerate the development and introduction of new conjugate meningococcal C vaccine into the routine immunisation programme, and to implement a catch-up campaign based on the disease epidemiology . METHODOLOGY: Collaboration between Government supported institutions and the vaccine industry lead to a collaborative programme of research designed to answer policy specific questions and to accelerate the availability of new vaccines . RESULTS: Three new conjugate meningococcal C vaccines were developed and licensed for use in the UK after satisfactory data on safety and immunogenicity had been generated . A nationwide campaign was designed to offer vaccine to all infants at the same time as their three doses of primary immunisations, two doses were offered to children over 4 months and under 1 year old; all those over 1 and under 18 years old were offered a single dose of vaccine . The programme was on course for completion within approximately twelve months, with around 15 million immunisations being offered . The programme was implemented simultaneously through school and primary care services . CONCLUSIONS: A safe and effective new vaccine, against group C meningococcal disease, has been introduced into the UK immunisation programme after just a 5 year development to implementation process . Early indications point to high coverage and impacts on disease are already apparent in the groups that have been immunised . These vaccines may play an equally important role in other countries where there is a significant burden from Group C meningococcal disease. J Paediatr Child Health, 2001 Oct, 37(5), S3 - 6 Epidemiology of meningococcal disease in Australia; Jelfs J et al.; A review of the epidemiology of meningococcal disease (MD) in Australia was undertaken, with particular emphasis on the 1990s, when national strain differentiation data became available . The data included a review of clinical and laboratory notification data and published reports on clusters and outbreaks . There have been considerable changes in the patterns of MD in the 1990s . In some cases, these changes can be related to the dominance of a particular phenotype . In the early 1990s, widely scattered urban and rural clusters were associated with the phenotype C:2b:P1.2 and strains were closely genetically related . Larger urban clusters and increased numbers of cases in adolescents and young adults were most obvious in New South Wales in the mid-1990s and were associated with a phenotype C:2a:P1.5 . This ET-15 clone of the ET-37 complex caused similar patterns of MD to those seen in other countries as part of the global spread of the clone . In contrast, the B:4:P1.4 phenotype, with close genetic similarities to New Zealand strains, did not cause the hyperendemic disease seen in New Zealand this decade . The epidemiology of MD will continue to exhibit considerable variation due, at least in part, to the genetic flexibility of meningococci . Information about strain variation expands our understanding of changing patterns of disease. J Paediatr Child Health, 2001 Oct, 37(5), S28 - 33 Meningococcal vaccination for adolescents? An economic evaluation in Victoria; Skull SA et al.; OBJECTIVE: To undertake an economic evaluation of the options for vaccination of adolescents using meningococcal polysaccharide vaccine based on Victorian data . METHODOLOGY: Cost-effectiveness and cost-benefit analyses of three options for vaccination were undertaken for hypothetical populations aged 15-19 years . Baseline analyses assumed a single year of programme implementation and vaccine protection of 5 years . Sensitivity analyses of key variables were performed . Outcomes included the number of people vaccinated, cases averted, life years saved and disability adjusted life years (DALY) averted . Lost earnings avoided were included as a measure of vaccination benefit in cost-benefit analyses . RESULTS: Vaccination of people in Years 10-12 (secondary school) and first year university within a defined population with a high rate of disease was the most cost-effective option . Excluding direct cost savings and compared with no vaccination, this resulted in a discounted cost per DALY avoided of $17646 and benefits exceeding costs in discounted terms . The 'break-even' incidence rate for this option in the cost-benefit analysis was 11.9/100000 . CONCLUSIONS: Economic evidence favours the use of vaccination within well-defined populations with a high rate of disease. J Paediatr Child Health, 2001 Oct, 37(5), S20 - 7 Meningococcal disease and vaccination in North America; Pollard AJ et al.; In North America, meningococcal disease occurs at a rate of I case per 100000 population per year, producing 2725 cases notified in the US in 1998 and 155 laboratory confirmed cases in Canada in the same year . A majority of these cases occur in the winter season and in early childhood, with a case fatality rate of approximately 10% . There has been an increase in the proportion of cases due to serogroup Y meningococci over the past decade: in 1995-98 in the US, 33% of cases were due to serogroup B, 28% were due to serogroup C and 34% were due to serogroup Y; in Canada in 1995-96, 47% of cases were due to serogroup B, 40% were due to serogroup C and 10% were due to serogroup Y . Outbreaks due to serogroup C were more common in the 1990s in the US and a number of outbreaks have occurred in Canada due to organisms from the hypervirulent ET-37 complex . College freshmen in the US in dormitories were found to be at an increased risk of disease . In addition, over the past 10 years, an outbreak of serogroup B disease occurred in the Pacific North-west of the US, with a fourfold increased rate of disease in that region . The explanations for these changes in epidemiology are unknown, but probably reflect the appearance of hypervirulent clones of meningococci and/or changing levels of population immunity . Meningococcal serogroup C polysaccharide-protein conjugate vaccines have been introduced recently in the UK, seem efficacious and offer the potential to reduce the burden of disease in the US and Canada too . Because serogroups other than serogroup C are prevalent in North America, a combination polysaccharide-protein vaccine, including C, Y and possibly W135 serogroups, would be attractive for this population . Although not currently an issue in industrialized nations, inclusion of serogroup A conjugates in any future vaccine policy would be an important decision in driving global prevention of meningococcal disease . A meningococcal conjugate vaccine against serogroup C was licensed in Canada in April 2001. J Paediatr Child Health, 2001 Oct, 37(5), S13 - 9 A 10-year serogroup B meningococcal disease epidemic in New Zealand: descriptive epidemiology, 1991-2000; Baker MG et al.; OBJECTIVE: New Zealand has experienced an epidemic of meningococcal disease since 1991 . This paper describes the characteristics of this epidemic during its first 10 years (1991-2000), current control measures, and potential future interventions . METHODOLOGY: Meningococcal disease surveillance in New Zealand uses combined notification and laboratory data . Population census data from 1991 and 1996 were used to calculate disease rates . RESULTS: The annual incidence of meningococcal disease increased from 53 cases (1.6 per 100 000 population) in the pre-epidemic year of 1990 to a peak of 613 (16.9 per 100000) in 1997, followed by consistently raised rates . Over the 1996-2000 period, there was an average of 502 cases per year (13.9 per 100 000) . The epidemic has resulted in 3547 cases since 1991 approximately 3000 in excess of the number expected based on pre-epidemic disease incidence . Of the total cases, 158 (4.5%) were fatal . A disproportionately large number of cases have been in Maori and Pacific Islands children in the northern part of the North Island of New Zealand . Since 1991, the epidemic has increasingly been dominated by serogroup B meningococci with subtype P1.7b,4, which by 2000 accounted for 84.6% of all cases for whom this testing was carried out . The majority of these organisms were characterised as B:4:P1.7b,4 . CONCLUSION: Meningococcal disease rates are likely to remain elevated in New Zealand for at least several more years . A vaccine which could induce immunity to the P1.7b,4 PorA subtype may have a role in controlling this epidemic . Efforts are underway to obtain and trial such a vaccine . Measures are also underway to reduce overcrowded living conditions which are contributing to the epidemic . Early recognition and antibiotic treatment of cases improves outcomes and should continue to be promoted . Integrated notification and laboratory-based surveillance of meningococcal disease provides relatively complete surveillance of this disease in New Zealand and has supported the development of public health interventions. J Clin Microbiol, 2002 Mar, 40(3), 1083 - 4 Neisseria meningitidis serogroups W135 and A were equally prevalent among meningitis cases occurring at the end of the 2001 epidemics in Burkina Faso and Niger; Taha MK et al.; Meningococcal infections occur as epidemics in the African meningitis belt . Neisseria meningitidis serogroup A is predominantly involved in these epidemics . We report here new data on the involvement of both serogroups A and W135 in meningitis cases in Burkina Faso and Niger at the end of the 2001 epidemic. Am J Orthop, 2002 Feb, 31(2), 88 - 9 Serous flexor tenosynovitis as an associated finding in meningococcal septic polyarthritis; Chin KR et al.; Flexor tenosynovitis complicating meningococcal septic polyarthritis may be sterile and could be misdiagnosed as disseminated gonococcal infection . Awareness of clinical findings associated with meningococcal polyarthritis is recommended to prevent onset of fulminant meningococcemia (Waterhouse-Friderichsen syndrome). Clin Diagn Lab Immunol, 2002 Mar, 9(2), 485 - 8 Opsonophagocytosis of fluorescent polystyrene beads coupled to Neisseria meningitidis serogroup A, C, Y, or W135 polysaccharide correlates with serum bactericidal activity; Martinez J et al.; We developed a polysaccharide-specific flow cytometric opsonophagocytic assay (OPA) for the simultaneous measurement of functional antibody to Neisseria meningitidis serogroups A, C, Y, and W135 . OPA titers significantly correlated with serum bactericidal assay titers for all serogroups tested (mean r = 0.96; P < 0.001) . OPA could be used in meningococcal vaccine evaluation. J Infect, 2001 Nov, 43(4), 221 - 5 The causes of fever in children attending hospital in the north of England; Nademi Z et al.; OBJECTIVES: Fever is a common symptom in children presenting to casualty . Identifying the seriously ill is difficult . Previous studies, mainly from North America, suggest that symptoms, signs and simple investigations may help to do this . The aim of the present study was to assess the causes of fever and identify clinical and laboratory features suggesting serious disease in U.K . children presenting to hospital with temperatures >or=38 degrees C . METHODS: All children with a temperature of >or=38 degrees C seen in two hospitals between August and October 1999 . RESULTS: One hundred and forty one children between 8 days and 16 years of age were studied, 64% male, 55% aged under 2 years . Eighty three percent had temperatures between 38 and 39 degrees C . Ninety six percent were casualty or GP referrals and 4% were tertiary referrals . Twenty nine percent (41/141) had serious disease but microbiologically or radiologically proven in only 22% (31/141); pneumonia (nine), meningitis (seven), sepsis (five), urinary tract infection (five), brain abscess (two), toxic shock syndrome (one), appendicitis (one), ischiorectal abscess (one) . Forty two percent (5/12) of microbiologically proven meningitis and sepsis and 36% (8/22) of all meningitis and sepsis were meningococcal . Seventy one percent had non-serious diseases . In cases of serious disease the temperature was >39 degrees C in 15% (sensitivity: 14%, specificity: 82%, PPV: 25%) . Poor feeding and restlessness predicted serious disease with a sensitivity of 78% and 76%, respectively . Full blood count (FBC) was taken in 50% of patients on admission; in 44% of serious and 24% of non-serious diseases WBC was between 5000 and 15,000/mm(3) and WBC >or=15,000/mm(3) was seen in 39% of serious diseases (sensitivity:10%, specificity: 95%, PPV: 44%) . CONCLUSIONS: One out of three of children referred with fever had a serious disease . Degree of temperature and WBC count were poor predictors of serious disease . Interestingly, poor feeding and restlessness were more sensitive predictors, suggesting high fever and WBC count can not replace clinical assessment of the child with a temperature . Scand J Infect Dis, 2001, 33(12), 929 - 30 Meningococcemia following tonsillectomy; Sharma M et al.; A 22-y-old male developed fever, arthralgias and skin rash 2 d after tonsillectomy . Blood culture grew Neisseria meningitidis . He responded well to antibiotics . Only 1 other case of meningococcal sepsis following adenotonsillectomy has previously been reported . These cases suggest a temporal association of meningococcemia with tonsillectomy. Blood Purif, 2002, 20(3), 282 - 8 A review of plasma exchange in sepsis; Reeves JH; BACKGROUND: Severe sepsis involves a generalised inflammatory response, mediated by a number of cellular and humoral factors . Modulation of this response holds the promise of improved survival . Plasma exchange has been suggested as an adjunctive therapy in grave infective illnesses such as meningococcaemia, because it might remove harmful bacterial products and excessive endogenous inflammatory mediators . AIMS: The aim of this article is to outline plasma exchange as an adjunctive therapy in sepsis, with an emphasis on the available clinical and experimental evidence for its use . METHODS: A literature review was performed using Medline including all English language references to exchange transfusion, plasma exchange, plasmapheresis, plasma filtration and sepsis . Relevant texts and conference proceedings booklets were also hand searched . RESULTS: Uncontrolled human data from case reports of more than 40 patients treated with plasma exchange for severe sepsis suggest a survival rate of over 70% . Animal studies produced conflicting results depending on the species and the model of sepsis employed . The only controlled clinical trial was too small to make conclusions regarding mortality . CONCLUSIONS: Plasma exchange remains an intuitively attractive but unproven therapy in sepsis . More controlled clinical trials are needed . Lancet, 2002 Feb 16, 359(9306), 582 - 3 W135 meningococcal disease in England and Wales associated with Hajj 2000 and 2001; Hahne SJ et al.; An outbreak of W135 meningococcal disease was seen in 2000 and 2001 among pilgrims returning from Saudi Arabia and their contacts . The Public Health Laboratory Service set up enhanced surveillance to monitor spread and virulence of the outbreak strain, and to collect data on case characteristics . The number of cases reported from England and Wales in 2001 was similar to the number reported during 2000, despite a change in the recommendation for pilgrims to receive quadrivalent vaccine (against serogroup A, C, W135, and Y) instead of the A/C vaccine recommended in 2000 . Both the recommendation and vaccine were not available until January, 2001, and coverage among pilgrims to the Hajj 2001 was low . The case--fatality ratio was high, and sustained transmission of the virulent outbreak strain was seen . Current control policies, both in primary and secondary prevention, might need better implementation. Clin Microbiol Infect, 1996 Feb, 2(3), 168 - 178 Endemic meningococcal disease in Cerdanyola, Spain, 1987--93: molecular epidemiology of the isolates of Neisseria meningitidis; Verdu ME et al.; OBJECTIVE: To establish the relationships between 30 Neisseria meningitidis strains isolated in Cerdanyola (Spain) from 30 out of 36 sporadic cases of meningococcal disease (MD) during 1987--93 and their spread in this population by multilocus enzyme electrophoresis (MEE) and by pulsed-field gel electrophoresis (PFGE), and to evaluate the usefulness of PFGE versus serologic typing methods and MEE as an alternative epidemiologic marker to study meningococcal infection . METHODS: Serotyping, electrophoretic mobility of seven isoenzymes determined by MEE and chromosomal DNA macrorestriction with NheI resolved by PFGE were analyzed . RESULTS: Of these 30 strains, 25 were serogroup B and the remaining five were serogroup C, with the 4:P1.15 and the 2b:NT as the most common antigenic phenotypes, respectively . There were 13 electrophoretic types (ETs) by MEE, with 14 isolates showing an identical ET, 8 . Sixteen pulse types (PTs) were generated by PFGE . The 14 ET 8 isolates were clustered into six PTs, A1, A2, A4, A5, A6 and A8 . However, by combining both methods, 19 genetically distinct groups were obtained . Eleven of these groups (20 serogroup B strains) and two of these (four serogroup C strains) were genetically related . CONCLUSIONS: We conclude that, according to the clonal population structure, these 30 N . meningitidis strains are heterogeneous although a great number are related . Moreover, PFGE is a useful method to establish clonal structure in N . meningitidis strains under endemic conditions . Finer discrimination of these strains was achieved by combining both MEE and PFGE methods. J Infect Dis, 2002 Mar 1, 185(5), 618 - 26 Epub 2002 Feb 14. Prospective study of a serogroup X Neisseria meningitidis outbreak in northern Ghana; Gagneux SP et al.; After an epidemic of serogroup A meningococcal meningitis in northern Ghana, a gradual disappearance of the epidemic strain was observed in a series of five 6-month carriage surveys of 37 randomly selected households . As serogroup A Neisseria meningitidis carriage decreased, an epidemic of serogroup X meningococcal carriage occurred, which reached 18% (53/298) of the people sampled during the dry season of 2000, coinciding with an outbreak of serogroup X disease . These carriage patterns were unrelated to that of Neisseria lactamica . Multilocus sequence typing and pulsed-field gel electrophoresis of the serogroup X bacteria revealed strong similarity with other strains isolated in Africa during recent decades . Three closely related clusters with distinct patterns of spread were identified among the Ghanian isolates, and further microevolution occurred after they arrived in the district . The occurrence of serogroup X outbreaks argues for the inclusion of this serogroup into a multivalent conjugate vaccine against N . meningitidis. Clin Microbiol Infect, 1998 Mar, 4(3), 123 - 128 Characteristics of pathogenic Neisseria meningitidis in Moscow: prevalence of 'non-European' strains; Koroleva IS et al.; OBJECTIVE: To investigate the distribution of serogroups, serotypes and subtypes, and susceptibility to antibiotics, of 75 strains isolated from patients with systemic meningococcal disease in Moscow in 1993--95 . RESULTS: In contrast to the situation in most European countries, 21% of group A strains were found . Sixty-nine per cent of the strains were non-serotypeable using the current panel of antibodies, and 21% of strains were non-subtypeable . Twenty-nine different serotype---subtype combinations were found among 69 strains of group A, B and C . No combination predominated clearly; relatively more frequent strains had the formulae B:NT:P1.2, A:4:P1.5, 10 and C:4:P1.10 . Recently, such strains have been very rare in western Europe; in contrast, the strains predominating in western Europe were not found in Moscow . All strains were sensitive to penicillin, chloramphenicol and rifampicin . CONCLUSIONS: Moscow strains of Neisseria meningitidis demonstrated a substantial diversity of serotypes and subtypes that probably corresponded to a post-epidemic situation in Russia . The obvious difference in circulating strains and presumably in immunity of populations in western Europe and Russia increases the probability of mutual exchange of pathogenic strains and stresses the need for group B vaccine protecting from both western and eastern European variants of meningococci. Arch Dis Child, 2002 Mar, 86(3), 215 - 7 Investigation for complement deficiency following meningococcal disease; Hoare S et al.; BACKGROUND AND AIMS: The incidence of complement abnormalities in the UK is not known . It is suggested in at least three major paediatric textbooks to test for abnormalities of the complement system following meningococcal disease (MCD) . METHODS: Over a four year period, surviving children with a diagnosis of MCD had complement activity assessed . A total of 297 children, aged 2 months to 16 years were screened . RESULTS: All children except one had disease caused by B or C serogroups . One child, with group B meningococcal septicaemia (complicated by disseminated intravascular coagulation and who required ventilation and inotropic support) was complement deficient . C2 deficiency was subsequently diagnosed . She had other major pointers towards an immunological abnormality prior to her MCD . CONCLUSION: It is unnecessary to screen all children routinely following MCD if caused by group B or C infection . However, it is important to assess the previous health of the child and to investigate appropriately if there have been previous suspicious infections, abnormal course of infective illnesses, or if this is a repeated episode of neisserial infection. Sante, 2001 Oct-Dec, 11(4), 251 - 5 {Detection of meningococcal meningitis epidemics in Africa: a new recommendation}; Lewis R et al.; In sub-Saharan Africa, the control of meningococcal meningitis epidemics relies on early epidemic detection and mass vaccination . However, experience shows that interventions are often initiated too late to have a significant impact on the epidemic . A new recommendation drafted by participants of a consensus meeting proposes an alert threshold and an epidemic threshold based on the weekly number or incidence of meningitis cases, according to the population size and the epidemic risk, resulting in indicators with high sensitivity and specificity for the detection of an emerging epidemic . Meningitis outbreak investigations must include an assessment of the quality of epidemiologic surveillance . The new recommendation is published in English and French in the Weekly Epidemiologic Record {12} . The success of this consensus meeting shows the value of integrating results from surveillance, field experience and operational research for designing new health strategies. Infect Immun, 2002 Mar, 70(3), 1461 - 7 Replication of Neisseria meningitidis within epithelial cells requires TonB-dependent acquisition of host cell iron; Larson JA et al.; Neisseria meningitidis (meningococcus {MC}) is able to enter and replicate within epithelial cells . Iron, an essential nutrient for nearly all organisms, is an important determinant in the ability of MC to cause disease; however, its role in MC intracellular replication has not been investigated . We analyzed the growth of MC within the A431 human epithelial cell line and the dependence of this growth on iron uptake . We present evidence here that chelation of iron from infected tissue culture cells with Desferal strongly inhibited intracellular replication of wild-type (wt) MC . We also provide genetic evidence that iron must be acquired by MC from the host cell in order for it to replicate . An hmbR mutant that is unable to use hemoglobin iron and could not grow in tissue culture media without iron supplementation replicated more rapidly within epithelial cells than its wt parent strain . An fbpA mutant that is unable to utilize human transferrin iron or lactoferrin iron replicated normally within cells . In contrast, a tonB mutant could not replicate intracellularly unless infected cultures were supplemented with ferric nitrate . Taken together, these findings strongly suggest that MC intracellular replication requires TonB-dependent uptake of a novel host cell iron source. Infect Immun, 2002 Mar, 70(3), 1301 - 9 Characterization of humoral and cellular immune responses elicited by meningococcal carriage; Robinson K et al.; In order to study the immune response elicited by asymptomatic carriage of Neisseria meningitidis, samples of serum, peripheral blood mononuclear cells (PBMCs), and saliva were collected from a cohort of more than 200 undergraduate students in Nottingham, United Kingdom, who were subject to high rates of acquisition and carriage of meningococci . Serum immunoglobulin G levels were elevated following increases in the rate of carriage, and these responses were specific for the colonizing strains . In order to investigate T-cell responses, PBMCs from 15 individuals were stimulated with a whole-cell lysate of the H44/76 meningococcal strain (B:15:P1.7,16), stained to detect cell surface markers and intracellular cytokines, and examined by flow cytometry . The cells were analyzed for expression of CD69 (to indicate activation), gamma interferon (IFN-gamma) (a representative T-helper 1 subset {Th1}-associated cytokine), and interleukin-5 (IL-5) (a Th2-associated cytokine) . Following a brief meningococcal stimulation, the numbers of CD69(+) IFN-gamma(+) CD56/16(+) NK cells were much higher than cytokine-positive CD4(+) events . Both IFN-gamma(+) and IL-5(+) events were detected among the CD69(+) CD4(+) population, leading to the conclusion that an unbiased T-helper subset response was elicited by meningococcal carriage. Infect Immun, 2002 Mar, 70(3), 1293 - 300 Cross-reactive polyclonal antibodies to the inner core of lipopolysaccharide from Neisseria meningitidis; Andersen SR et al.; Sera from mice immunized with native or detergent-extracted outer membrane vesicles derived from lipopolysaccharide (LPS) mutant 44/76(Mu-4) of Neisseria meningitidis were analyzed for antibodies to LPS . The carbohydrate portion of 44/76(Mu-4) LPS consists of the complete inner core, Glc beta 1-->4{GlcNAc alpha 1-->2Hep alpha 1-->3}Hep alpha 1-->5KDO{4-->2 alpha KDO} . Immunoblot analysis revealed that some sera contained antibodies to wild-type LPS which has a fully extended carbohydrate chain of immunotype L3,7, as well as to the homologous LPS . Sera reacted only weakly to LPS from 44/76(Mu-3), which lacks the terminal glucose of the inner core . No binding to more truncated LPS was observed . Consequently, the cross-reactive epitopes are expressed mainly by the complete inner core . Dephosphorylation of wild-type LPS abolished antibody binding to LPS in all but one serum . Thus, at least two specificities of cross-reactive antibodies exist: one is dependent on phosphoethanolamine groups in LPS, and one is not . Detection of these cross-reactive antibodies strongly supports the notion that epitopes expressed by meningococcal LPS inner core are also accessible to antibodies when the carbohydrate chain is fully extended . Also, these inner core epitopes are sufficiently immunogenic to induce antibody levels detectable in polyclonal antibody responses . Meningococci can escape being killed by antibodies to LPS that bind only to a specific LPS variant, by altering the carbohydrate chain length . Cross-reactive antibodies may prevent such escape . Therefore, inner core LPS structures may be important antigens in future vaccines against meningococcal disease. Curr Infect Dis Rep, 2002 Feb, 4(1), 50 - 58 Recent Advances and New Challenges in Travel Medicine; Chen LH et al.; Recent advances in travel medicine include the use of computer resources to obtain information on outbreaks and recommendations to travelers, the introduction of atovaquone/proguanil as chemoprophylaxis and treatment for malaria, the use of azithromycin as an alternative in the self-treatment of traveler's diarrhea, and the combination of hepatitis A and hepatitis B vaccines . At the same time, new challenges continue to appear . Shifts in the distribution of infections, such as West Nile virus and dengue fever, underscore the need for up-to-date information . Well-known infectious diseases, such as polio, meningococcal meningitis, and influenza are appearing in unexpected ways and settings . It is increasingly clear that travelers, while at risk for infections, also play a role in the global dispersal of pathogens, such as certain serogroups of Neisseria meningitidis and influenza . Increasing drug resistance affects the choice of drugs for treatment and chemoprophylaxis, and decisions about use of vaccines . Newly identified adverse events associated with yellow fever vaccine have prompted enhanced surveillance after vaccination and careful scrutiny of appropriate indications for the vaccine. Am J Infect Control, 2002 Feb, 30(1), 57 - 65 Infection control in Saudi Arabia: meeting the challenge; Memish ZA; Hospital-acquired infection poses significant clinical and economic burden worldwide . In the Kingdom of Saudi Arabia, infection control is a young, rapidly growing specialty . An infrastructure to expedite the growth of this important discipline is fast being established . The kingdom faces unique challenges when addressing infection control, which are the subject of this review.Much of the policy-making in domestic infection control is driven by the preventive medicine concerns of the annual pilgrimage (Hajj) to Mecca, which are unparalleled . The Saudi Ministry of Health acts to contain and control public health risks at this gathering of 2 million . Infectious hazards at the Hajj include meningococcal meningitis, respiratory tract infections, bloodborne diseases, and zoonotic diseases, all of which have international ramifications as pilgrimaging Muslims return home.In the wake of the extraordinary pace of modernization in Saudi Arabia, deficiencies in infection control remain, which are slowly being redressed . This review examines the anatomy of infection control and its evolution in the kingdom . Future goals and infection control policy-making are given particular emphasis.Saudi Arabia seeks increasing international partnership in the area of infection control and preventive medicine . The Saudi health care system was formed on the basis of Western models to resounding success . Saudi Arabia is now in a position to provide experience and knowledge in return . International dialogue in the infection control arena is of mutual value . Important public health progress is afoot in this young kingdom, and these advances translate both regionally and on the international platform. Biologicals, 2002 Mar, 30(1), 7 - 13 Quantification of lipopolysaccharides in outer membrane vesicle vaccines against meningococcal disease . High-performance liquid chromatographic determination of the constituent 3-hydroxy-lauric acid; Lyngby J et al.; A high-performance liquid chromatographic (HPLC) assay for quantification of lipopolysaccharides (LPSs, endotoxins) in outer membrane vesicle vaccines against meningococcal disease has been developed . The LPS constituent, 3-hydroxy-lauric acid, served as marker substance for the quantification . LPS from the vaccine was precipitated by ethanol and the fatty acid constituents, including 3-hydroxy-lauric acid, were released by acidic hydrolysis, collected and purified by solid phase extraction on C18 disc-cartridges and converted into phenacyl esters for UV detection at 240 nm . Quantification of the derivatized 3-hydroxy-lauric acid was achieved by HPLC using a Brownlee RP-18 reversed phase column with acetonitrile/water (68:32, v/v) as mobile phase . The method was found to be linear over the range 3-49 microg LPS/ml with a sensitivity of 1.6 (microg/ml)(-1) . The repeatability (within-day precision) of the method at three levels (3-49 microg LPS/ml) was 6-14% relative standard deviation and the intermediate (between-day) precision was 7% relative standard deviation (at level 15 microg LPS/ml) . The method has been successfully used in the quality control of a meningococcal B outer membrane vesicle vaccine, containing 4-8% LPS relative to protein (w/w), in our laboratory for three years . Vestn Ross Akad Med Nauk, 2001, (12), 39 - 42 {Bacterial IgA1-protease: production, properties and prospects for use}; Surovtsev VI et al.; Some pathogenic bacteria have been demonstrated to secrete specific IgA1-proteases, the enzymes cleaving the molecules of the first subclass of human immunoglobulin (IgA1) in the single point from the hinge with the formation of Fab- and Fc-fragments . Cleavage generally deprives immunoglobulins having defense properties and the enzymes are considered as pathogenic factors . How to determine the activity, purification, and the promises of use of IgA-proteases is described . Whether inactivated meningococcal IgA1-protease as a vaccine against any of the five (A, B, C, Y, W135) serotypes of pathogenic meningococci is discussed. Lijec Vjesn, 2001 Sep-Oct, 123(9-10), 231 - 3 {Neisseria meningitidis with a decreased sensitivity to penicillin in the Zagreb District}; Boras A et al.; Of the total of 35 clinical isolates from blood and/or cerebrospinal fluid in patients from the Zagreb area in the period from 1996-1999 Neisseria meningitidis serogroup B was identified in 33 (94%) . N . meningitidis strains with decreased susceptibility to penicillin have been occurring in Zagreb since 1998, and during the two-year period in this study we isolated 3/19 (16%) such strains (MIC, 0.12 microgram/ml) . Molecular typization of strains with decreased susceptibility to penicillin shows that they do not belong to a particular meningococcal clonal group . All isolated N . meningitidis strains were susceptible to the third generation cephalosphorins, quinolones and chloramphenicol . A single strain (3%) was resistant to rifampin, but 13/35 (37%) were resistant to trimethoprim/sulfamethoxazole . Consequently, trimethoprim/sulfamethoxazole is not recommended for chemoprophylaxis of meningococcal disease . Initially patients with meningococcal disease should be treated with the third generation cephalosporins, and further treatment should be continued in accordance with the antimicrobial susceptibility testing results . This study emphasizes the utility and importance of meningococcal disease monitoring throughout the Republic of Croatia. Pediatr Infect Dis J, 2002 Feb, 21(2), 112 - 9 No evidence for short or long term morbidity after increased titer measles vaccination in Sudan; Libman MD et al.; BACKGROUND: Increased mortality rates have been reported after high titer measles {>10(5.0) plaque-forming units (PFU)} vaccination in several large studies in the developing world . An increased titer measles vaccine study conducted in Sudan included a prolonged prospective evaluation of childhood morbidity after vaccination . METHODS: Five hundred ten children (170 per group) were randomized to receive 1 of 3 regimens at 5 and 9 months of age: (1) meningococcal vaccine, then standard titer (50% tissue culture-infective dose, 103.8) Schwarz measles vaccine; (2) increased titer (10(4.7) PFU) Edmonston-Zagreb measles vaccine followed by meningococcal vaccine; and (3) increased titer (10(4.7) PFU) Connaught vaccine followed by standard titer Schwarz measles vaccine . RESULTS: Health workers collected information at 31,582 semi-monthly and monthly visits during 5 years . No increase in infant mortality was observed, but the statistical power was limited . There were 13, 13 and 10 deaths in the Schwarz, Edmonston-Zagreb and Connaught groups, respectively . There were no differences in duration or incidence of illness between groups at any time during the 5-year follow-up, with comparisons stratified by age and sex . Statistical power for each pairwise comparison was good, with at least 80% power to detect a difference of 1 day per month of illness and a 12% difference in the proportion of visits with an illness recorded . CONCLUSIONS: We were unable to document increased morbidity in recipients of the increased titer measles vaccines used in this study . These data do not support the hypothesis that increased mortality after increased titer vaccine exposure is the result of increased and cumulative morbidity. Expert Opin Investig Drugs, 2002 Feb, 11(2), 159 - 67 Therapeutic potential of the bactericidal/permeability-increasing protein; Levy O; Innate immune mechanisms respond rapidly to bacterial infection . A key cellular component of the innate immune response is the neutrophil, whose cytoplasmic granules contain a variety of antimicrobial proteins and peptides . Among these is the bactericidal/permeability-increasing protein (BPI), a cationic 55 kDa protein whose selective anti-infective action against Gram-negative bacteria is based on its high (nM) affinity for lipopolysaccharide (LPS, or "endotoxin") . Binding of BPI to Gram-negative bacteria results in growth inhibition, serves as an opsonin that enhances phagocytosis of bacteria and inhibits bacteria-induced inflammatory responses by blocking the interaction of LPS with host pro-inflammatory pathways . Expression of BPI appears to be developmentally regulated as human newborns apparently have lower neutrophil BPI levels than adults . BPI expression has also recently been demonstrated in human epithelial cells where it appears to be inducible by endogenous anti-inflammatory lipids (lipoxins) . BPI's potent anti-endotoxic activity against a broad range of Gram-negative bacterial pathogens is manifest in biological fluids and renders it an attractive template for pharmaceutical development . Indeed, rBPI(21), an active recombinant protein derived from human BPI, has proven safe in Phase I human trials, shown promise in Phase II trials and has recently completed a Phase III trial for severe meningococcaemia with apparent benefit . Identification and evaluation of additional disease entities characterised by Gram-negative bacteraemia and/or endotoxaemia as possible targets for BPI therapy continues. J Clin Pathol, 2002 Jan, 55(1), 37 - 40 Ultrasound enhanced detection of individual meningococcal serogroups by latex immunoassay; Sobanski MA et al.; AIMS: To examine A, C, Y, and W135 Neisseria meningitidis serogroup characterisation by ultrasonic standing wave enhanced latex agglutination tests (USELATs) of clinical samples . In addition, to determine USELAT enhancement of detection sensitivity for the individual antigens compared with conventional card latex agglutination tests (LATs) . METHODS: Wellcogen (Abbott Murex), Slidex meningite kit 5 (bioMerieux), and Pastorex (Sanofi) kits and beads coated in house with antibodies to Y and to W135 alone were tested . Positive control antigens consisted of A and C polysaccharide preparations and the Pastorex Y/W135 kit sample . The limiting concentrations of antigen detection were determined by USELAT and by LAT . Thirty five clinical samples (plasma), previously characterised by the polymerase chain reaction (PCR) and culture, were tested by USELAT and, when sample volume allowed, by LAT . RESULTS: USELAT enhancement of control antigen detection ranged from 16 to 128 fold for the different latex systems . Enhancements for the different control antigens were comparable between kits . USELAT tests of clinical (A/C/Y/W135) samples (n = 15) with the Wellcogen (A/C/Y/W135) and Slidex meningite (A/C/Y/W135) kits showed comparable specificities . A set (n = 22) of Y and W135 samples gave 18, 19, and 17 positive results for Wellcogen (A/C/Y/W135), Pastorex (A/C/Y/W135), and in house beads (Y/W135), respectively . Positive USELAT PCR and culture results were concordant . A typical sensitivity for the commercial kits was 80% (Wellcogen) . CONCLUSIONS: USELAT identified serogroups for 80% of samples, whereas LATs identified only 40% . The USELAT detection of the A, C, Y, and W135 antigen serogroups showed comparable enhancement for the kits tested . The commercial availability of latex beads coated with antibody to the Y and W135 serogroups would expedite their identification. J Clin Pathol, 2002 Jan, 55(1), 32 - 6 Laboratory confirmation of meningococcal disease in Scotland, 1993-9; Clarke SC et al.; AIMS: To describe the laboratory confirmation of meningococcal disease, using culture and non-culture based techniques, between 1993 and 1999 as part of a national service in Scotland . METHODS: Samples from patients with suspected meningococcal disease in Scotland were analysed by culture and non-culture based techniques to gain a laboratory confirmation of disease . Data were analysed to establish the number of disease cases, the serogroups of the organisms involved, and the importance of the techniques used . RESULTS: Between 1993 and 1999, there was a total of 1749 notified cases of meningococcal disease in Scotland . Culture based methods provided a laboratory confirmation of 788 cases whereas non-culture techniques confirmed 461 cases . CONCLUSIONS: Non-culture techniques were a useful addition to culture based techniques in Scotland and improved the dataset required for public health management, disease surveillance, and vaccine policy. Int J Epidemiol, 2001 Dec, 30(6), 1440 - 6 Survival and sequelae of meningococcal meningitis in Ghana; Hodgson A et al.; BACKGROUND: Meningococcal meningitis epidemics are frequent in the Sahel zone of Africa but there is little information on the frequency of long-term sequelae . We analysed excess mortality in the two years following the 1997 epidemic in northern Ghana and carried out a case-control study to assess sequelae in the survivors . METHODS: Two-year survival of 696 meningitis cases recorded at the War Memorial Hospital, Navrongo, was analysed using data from a demographic surveillance system . A structured questionnaire on disability and on psychiatric, neuropsychological and behavioural problems was administered to 505 of the survivors and 505 age- sex- and location-matched controls as well as to their respective relatives . Cases and controls underwent full neurological and neuropsychological examination and were evaluated for hearing impairment by audiometry . RESULTS: Survival rates after the first month following the attack were similar in cases and controls . Hearing impairment was the major sequela, and was reported in 6 per cent of cases and 2 per cent of controls (odds ratio {OR} = 3.10; 95% CI : 1.48-7.09) . Audiometry detected severe and profound hearing loss in the worse affected ear (> or =70 db) in 8/496 (1.6%) survivors but in only one control . Survivors of meningitis were more likely to suffer from feelings of tiredness (OR = 1.47; 95% CI : 1.03-2.11) and were more often reported by relatives to have insomnia (OR = 2.31; 95% CI : 1.17-4.82) and daily alcohol consumption . INTERPRETATION: Meningococcal meningitis annually causes approximately 10 000 cases of deafness in sub-Saharan Africa; there is a need for early detection of affected survivors and promotion of simple hearing devices . There is a sizeable burden of depressive disorders secondary to meningitis which should be identified and looked after appropriately. FEMS Immunol Med Microbiol, 2002 Jan 14, 32(2), 119 - 23 O-Acetylation status of the capsular polysaccharides of serogroup Y and W135 meningococci isolated in the UK; Longworth E et al.; At a time when tetravalent conjugate vaccines for meningococcal serogroups A/C/Y/W135 are being formulated the O-acetylation status of their respective capsular polysaccharides has not previously been studied in the UK for all components . Although this has been elucidated for serogroup C, little is known about the O-acetylation status of serogroups W135 and Y . Meningococcal serogroup W135 (n=181) and Y (n=90) isolates submitted to the PHLS Meningococcal Reference Unit in 1996, 2000 and 2001 were investigated for O-acetylation capsular status by dot blot assay . Eight per cent of W135 and 79% of Y isolates respectively were found to be O-acetylated with a similar distribution found in both carrier and case isolates . An increase in O-acetylated W135 isolates was noted between 2000 (0%) and 2001 (21%) which was not due to the introduction of the Hajj associated W135 (ET 37 complex; serosubtype P1.5,2) isolates, all of which were de-O-acetylated . Although the biological relevance of O-acetylation status is unknown for these serogroups, an understanding of O-acetylation status of the respective polysaccharides may provide useful insights into the optimal vaccine formulation. FEMS Immunol Med Microbiol, 2002 Jan 14, 32(2), 91 - 5 A modified ex vivo human whole blood model of infection for studying the pathogenesis of Neisseria meningitidis during septicemia; Nolte O et al.; For the purpose of establishing a model to study host-bacteria interaction and virulence mechanisms of Neisseria meningitidis during the septic phase of disease a modified human whole blood model of infection is proposed . Compared to published whole blood models the current model was modified with respect to the initial number of viable bacteria (10(4) cfu ml(-1)), the anticoagulant used and the incubation time . The results obtained after incubation of a number of human blood samples from healthy volunteers for 24 h with serogroup B meningococci were in good agreement with findings reported from patients who suffered severe meningococcal disease. Rev Assoc Med Bras, 2001 Oct-Dec, 47(4), 332 - 7 {Drug prescription for hospitalized pediatric patients: how can the quality be evaluated?}; Meiners MM et al.; BACKGROUND: Pediatric patients called "therapeutic orphans" are usually excluded from clinical trials for development of new drugs, which, sometimes, are used empirically . This study evaluates the prescriptions for pediatric inpatients, and proposes criteria for evaluation of the quality of the prescriptions . METHODS: The hospital pharmacist determined the prevalence of drug prescription in five pediatric wards . One day collection of all prescriptions for pediatric inpatients was performed in March, April, May and June 1999, and the data were jointly analyzed . Six criteria were proposed for quality evaluation of the drug prescriptions . The drugs were classified according to the ATC classification index . RESULTS: The prescriptions of a total of 322 patients were collected in the four collection days . The three most common diagnoses were: pneumonia 40.4%, meningitis and meningococcemia 6%, diarrhea and dehydration 6% . The three most prescribed therapeutic classes were: nervous system (N ) 109%, general antiinfectives for systemic use ( J ) 81.9% and respiratory system ( R ) 69,0% . The three most prescribed drugs were: metamizole 88.3%, fenoterol 30.7% and penicillin G 25.0% . The quality evaluation showed 1 . an excessive use of the intravenous route, 2 . appropriate dose schedule for drugs with narrow therapeutic index, 3 . no therapeutic duplication, 4 . prescription of unapproved and off-label drugs, 5 . frequent potential adverse drug interactions, and 6 . prescription of drugs not in the therapeutic formulary of the hospital . CONCLUSION: Very simple measures can improve the quality of the health care of pediatric inpatients as inclusion of adequate drug presentations in the hospital formulary, and a careful evaluation of the need of the intravenous route . This study also shows the hospital pharmacists acting as part of the multidisciplinary health care team. Am J Med, 2002 Jan, 112(1), 19 - 25 Associations between Fc gamma receptor IIA polymorphisms and the risk and prognosis of meningococcal disease; Domingo P et al.; BACKGROUND: In vitro studies have shown that the neutrophil Fc gamma receptor IIA (FcgammaRIIA) polymorphism influences the phagocytic capacity of neutrophils and the removal of encapsulated bacteria from the bloodstream . In particular, the R/R131 allotype is associated with less phagocytic activity . SUBJECTS AND METHODS: We performed a case-control study to determine the influence of the FcgammaRIIA polymorphism (R/R131, R/H131, H/H131) on the risk and outcome of meningococcal disease . The polymorphisms were measured in 130 patients with microbiologically proven meningococcal disease diagnosed from 1987 to 1998 (cases) and 260 asymptomatic sex-matched blood donors (controls) . Clinical manifestations and complications of meningococcal disease were recorded, and a prognostic score (based on age, hemorrhagic diathesis, neurologic signs, and the absence of preadmission antibiotic) therapy was calculated . RESULTS: The distributions of FcgammaRIIA allotypes were similar in cases and controls . However, among patients with meningococcal infection, fulminant meningococcal disease (odds ratio {OR} = 3.9; 95% confidence interval {CI}: 1.0 to 16; P = 0.04) and meningococcemia without meningitis (OR = 3.0; 95% CI: 1.4 to 7.8; P = 0.004) were more common in those with the FcgammaRIIA-R/R131 allotype . Complications were also significantly more frequent in these patients . Of the 42 patients with the R/R131 allotype, 31 (74%) had an adverse prognostic score, compared with 7% (4 of 59) of those with the R/H131 allotype and 3% (1 of 29) of those with the H/H131 allotype (P <0.0001) . CONCLUSION: The FcgammaRIIA-R/R131 allotype is associated with more severe forms of meningococcal disease. Epidemiol Infect, 2001 Dec, 127(3), 425 - 33 Prevalence of Neisseria meningitidis carriers in the school population of Catalonia, Spain; Dominguez A et al.; The aim of this study was to determine the prevalence of healthy Neisseria meningitidis pharyngeal carriers in a representative sample of the Catalonian school population, as well as its associated factors . The sample was divided into age groups: < or = 5, 6-7 and 13-14 years old . Parents were given a questionnaire to collect information on sociodemographic and epidemiological variables . Oropharyngeal swabs were collected with a cotton-tipped swab in an Amies transport medium and cultured on Thayer Martin plates at 35 degrees C in 5% CO2 . The isolates were serogrouped and sero/subtyped . Of the 1406 children studied, 75 (5.34%) meningococcal carriers were detected: 63 B (4.5%), 9 non groupable (0.7%), 2 29E (0.1%) and 1X (0.07%) . No serogroup C meningococci were found in this study, probably due to the high A+C vaccination coverage of up to 68.9% in children 6-7 years old . Bivariate analysis identified six statistically significant risk factors for meningococcal carriage: increasing age, recent upper respiratory tract infection, previous antibiotic treatment, number of students in the class, size of the classroom and social class . Multivariate analysis found that only age and previous antibiotic treatment remained statistically significant when the other factors were controlled. Epidemiol Infect, 2001 Dec, 127(3), 421 - 4 Epidemiology of meningococcal meningitis in Angola, 1994-2000; Gaspar M et al.; We describe six meningococcal disease outbreaks that occurred in Angola during the period 1994-2000 . In total, 7140 cases were documented . The age groups most affected were 15-29 years and 5-14 years; there were no differences in incidence between the sexes . Circulation of both serogroup A and sporadic serogroup B strains was demonstrated . Mass vaccination campaigns with A+C meningococcal polysaccharide vaccine were implemented, except in Yambala province in 1999 where insecure conditions precluded this intervention . Outbreaks of serogroup A meningococcal disease in Angola may indicate an extension of these epidemics outside the meningitis belt . Mass vaccination campaigns stopped the Angolan epidemics within weeks . Civil conflict and displaced persons living in crowded areas created serious difficulties for surveillance and impeded timely public health responses. South Med J, 2001 Dec, 94(12), 1192 - 4 Cluster of serogroup C meningococcal disease associated with attendance at a party; Finn R et al.; BACKGROUND: An unexplained increase has occurred in the incidence of invasive meningococcal disease in adolescents and young adults . METHODS: We investigated a cluster of serogroup C meningococcal disease in 3 previously healthy young adults who had attended a party in Maryland . Molecular subtyping was done on the isolates from the 3 cluster cases and 4 control isolates by pulsed-field gel electrophoresis (PFGE) . The only common exposure was attendance at the party, where a large number of people reportedly smoked tobacco or marijuana and/or drank alcohol . RESULTS: The PFGE analysis of the 3 case isolates showed identical molecular subtypes . CONCLUSION: This investigation strongly suggests that transmission of the cluster strain occurred at the party . Transmission may have occurred in part as a result of the recently described risk factors of binge drinking and smoking . Taken together, these findings suggest that some of the recent increase in invasive meningococcal disease may be due to modifiable risk factors. J Infect Dis, 2002 Feb 1, 185(3), 397 - 400 Epub 2002 Jan 10. Natural and vaccine-induced immunity and immunologic memory to Neisseria meningitidis serogroup C in young adults; Goldblatt D et al.; The immune response to polysaccharides and conjugate vaccines in adults is poorly understood . This study assessed meningococcal serogroup C responses after AC polysaccharide (MACP) and C conjugate (MCC) vaccine administration in young adults and explored immune memory by measuring antibody avidity . The geometric mean avidity indices (GMAIs) measured 1 month after MACP vaccination were relatively high and failed to increase significantly in the 6 months before and after a second dose of MACP/MCC . Although the GMAI of naive adults increased immediately following MCC vaccination to 215.7 (95% confidence interval, 181.0-257.1), a level similar to that seen after MACP vaccination, no further maturation in the subsequent 6 months was seen . Antibody induced by polysaccharide antigens in adults is already of relatively high avidity (compared with that in infants and toddlers) and fails to mature further, probably because both MACP and MCC predominantly stimulate memory B cells. J Infect Dis, 2002 Jan 15, 185(2), 220 - 8 Epub 2002 Jan 03. Complement activation induced by purified Neisseria meningitidis lipopolysaccharide (LPS), outer membrane vesicles, whole bacteria, and an LPS-free mutant; Bjerre A et al.; Complement activation is closely associated with plasma endotoxin levels in patients with meningococcal infections . This study assessed complement activation induced by purified Neisseria meningitidis lipopolysaccharide (Nm-LPS), native outer membrane vesicles (nOMVs), LPS-depleted outer membrane vesicles (dOMVs), wild-type meningococci, and an LPS-free mutant (lpxA(-)) from the same strain (44/76) in whole blood anticoagulated with the recombinant hirudin analogue . Complement activation products (C1rs-C1 inhibitor complexes, C4d, C3bBbP, and terminal SC5b-9 complex) were measured by double-antibody EIAs . Nm-LPS was a weak complement activator . Complement activation increased with preparations containing nOMVs, dOMVs, and wild-type bacteria at constant LPS concentrations . With the same protein concentration, complement activation induced by nOMVs, dOMVs, and the LPS-free mutant was equal . The massive complement activation observed in patients with fulminant meningococcal septicemia is, presumably, an indirect effect of the massive endotoxemia . Outer membrane proteins may be more potent complement activators than meningococcal LPSs. Arch Dis Child, 2002 Jan, 86(1), 44 - 6 Meningococcal bacterial DNA load at presentation correlates with disease severity; Hackett SJ et al.; AIMS: To determine bacterial loads in meningococcal disease (MCD), their relation with disease severity, and the factors which determine bacterial load . METHODS: Meningococcal DNA quantification was performed by the Taqman PCR method on admission and sequential blood samples from patients with MCD . Disease severity was assessed using the Glasgow Septicaemia Prognostic Score (GMSPS, range 0-15, severe disease > or =8) . RESULTS: Median admission bacterial load was 1.6 x 10(6) DNA copies/ml of blood (range 2.2 x 10(4) to 1.6 x 10(8)) . Bacterial load was significantly higher in patients with severe (8.4 x 10(6)) compared to milder disease (1.1 x 10(6), p = 0.018) . This difference was greater in septicaemic patients (median 1.6 x 10(7) versus 9.2 x 10(5), p < 0.001) . Bacterial loads were significantly higher in patients that died (p = 0.017) . Admission bacterial load was independent of the duration of clinical symptoms prior to admission, with no difference between the duration of symptoms in mild or severe cases (median, 10.5 and 11 hours respectively) . Bacterial loads were independent of DNA elimination rates following treatment . CONCLUSION: Patients with MCD have higher bacterial loads than previously determined with quantitative culture methods . Admission bacterial load is significantly higher in patients with severe disease (GMSPS > or =8) and maximum load is highest in those who die . Bacterial load is independent of the duration of clinical symptoms or the decline in DNA load. BMC Public Health . 2001;1(1):16 . Epub 2001 Dec 11. Variations in chemoprophylaxis for meningococcal disease: a retrospective case note review, analysis of routine prescribing data and questionnaire of general practitioners; Marks PJ et al.; BACKGROUND: Invasive meningococcal disease is a significant cause of mortality and morbidity in the UK . Administration of chemoprophylaxis to close contacts reduces the risk of a secondary case . However, unnecessary chemoprophylaxis may be associated with adverse reactions, increased antibiotic resistance and removal of organisms, such as Neisseria lactamica, which help to protect against meningococcal disease . Limited evidence exists to suggest that overuse of chemoprophylaxis may occur . This study aimed to evaluate prescribing of chemoprophylaxis for contacts of meningococcal disease by general practitioners and hospital staff . METHODS: Retrospective case note review of cases of meningococcal disease was conducted in one health district from 1st September 1997 to 31st August 1999 . Routine hospital and general practitioner prescribing data was searched for chemoprophylactic prescriptions of rifampicin and ciprofloxacin . A questionnaire of general practitioners was undertaken to obtain more detailed information . RESULTS: Prescribing by hospital doctors was in line with recommendations by the Consultant for Communicable Disease Control . General practitioners prescribed 118% more chemoprophylaxis than was recommended . Size of practice and training status did not affect the level of additional prescribing, but there were significant differences by geographical area . The highest levels of prescribing occurred in areas with high disease rates and associated publicity . However, some true close contacts did not appear to receive prophylaxis . CONCLUSIONS: Receipt of chemoprophylaxis is affected by a series of patient, doctor and community interactions . High publicity appears to increase demand for prophylaxis . Some true contacts do not receive appropriate chemoprophylaxis and are left at an unnecessarily increased risk. Commun Dis Intell, 2001 Nov, 25(4), 281 - 2 An exercise in communication:-analysis of calls to a meningococcal disease hotline; Ward JD et al.; We describe our experience with a hotline which was set up to deal with enquiries relating to a secondary school mass vaccination campaign against meningococcal disease . Three thousand, three hundred calls were received over 6 days, mostly from the general public but also from contacts of the school and health practitioners . The hotline served as an important means of providing consistent advice and reassurance to the public and reduced the burden of calls to hospitals and public health units. Commun Dis Intell, 2001 Nov, 25(4), 279 - 80 Invasive meningococcal disease and HIV coinfection; Couldwell DL; Three cases of meningococcal disease which occurred over a 3 year period in HIV-infected people living in the Wentworth Health Area of Sydney, Australia, are described . None of the 3 had ever received antiretroviral therapy which may, have contributed to development of invasive meningococcal disease. Infect Immun, 2002 Feb, 70(2), 702 - 7 Immunogenicity and safety testing of a group B intranasal meningococcal native outer membrane vesicle vaccine; Katial RK et al.; The presently licensed meningococcal vaccine is a tetravalent capsular polysaccharide vaccine that induces immunity to serogroups A, C, Y, and W-135 but not to group B, which causes nearly half of the meningitis cases in the United States . The purpose of this study was to evaluate the safety and immunogenicity of an intranasal native outer membrane vesicle (NOMV) vaccine prepared from a capsule negative strain of group B of Neisseria meningitidis . In this study all volunteers received the same dose of vaccine, but we evaluated two different immunization schedules and the oropharyngeal and intranasal routes of vaccine delivery, assessed nasal cytology for cellular infiltration, and measured antibody-secreting cells (enzyme-linked immunospot assay {ELISPOT}) as an early marker for systemic immune response . Additionally, both intranasal and serum vaccine-specific antibodies were measured as well as serum bactericidal activity . Four groups with a total of 42 subjects were immunized on days 0, 28, and 56 . Group 3 received an additional dose on day 7 . Group 2 subjects were immunized both intranasally and oropharyngeally . Group 4 received a different lot of vaccine . All groups received approximately 1,200 microg of vaccine per subject . Patients were evaluated for side effects . The vaccine was well tolerated without evidence of inflammation on nasal cytology . The group receiving the extra vaccine dose showed the maximum increase in bactericidal activity . Thirty of 42 subjects demonstrated an increase in meningococcus-specific intranasal immunoglobulin A (IgA) titers, while 23 of 42 demonstrated an increase in specific IgG titers . The group receiving vaccine intranasally and oropharyngeally showed the highest rise in intranasal titers for both IgA and IgG . Groups 1, 3, and 4 showed a significant increase in antibody-secreting cells on ELISPOT . Eighteen of 42 volunteers demonstrated a fourfold or greater rise in bactericidal titers, with 81% showing an increase over baseline . We have demonstrated the immunogenicity and safety of a group B lipopolysaccharide-containing, intranasal, NOMV vaccine. Infect Immun, 2002 Feb, 70(2), 584 - 90 Antibody avidity and immunoglobulin G isotype distribution following immunization with a monovalent meningococcal B outer membrane vesicle vaccine; Vermont CL et al.; The avidity maturation and immunoglobulin G (IgG) isotype distribution of antibodies after vaccination with a meningococcal B outer membrane vesicle (OMV) vaccine were evaluated as indicators of protective immunity . Pre- and postvaccination sera from 134 healthy toddlers (ages, 2 to 3 years) immunized with a monovalent meningococcal B OMV (serosubtype P1.7-2,4) vaccine adsorbed with AlPO(4) or Al(OH)(3) were analyzed by enzyme-linked immunosorbent assay (ELISA) methods . The children were vaccinated three times with intervals of 3 to 6 weeks between vaccinations or twice with an interval of 6 to 10 weeks between vaccinations . A booster was given after 20 to 40 weeks . The avidity index (AI) of antibodies increased significantly during the primary series of vaccinations and after the booster was given . No differences in AIs were found when the results obtained with the two vaccination schedules or with the two adjuvants were compared . After vaccination, IgG1 was the predominant IgG isotype, followed by IgG3 . No IgG2 or IgG4 was detected . There was a strong correlation between serum bactericidal activity (SBA) and ELISA titers (r = 0.85 {P < 0.0001} for total IgG, r = 0.83 for IgG1 {P < 0.0001}, r = 0.82 for IgG3 {P < 0.0001}, and r = 0.84 {P < 0.0001} for the avidity titer) . When two subgroups with similar anti-OMV IgG levels were compared before and after the booster vaccination, the higher AI after the booster vaccination was associated with significantly increased SBA . We concluded that avidity maturation occurs after vaccination with a monovalent meningococcal B OMV vaccine, especially after boosting, as indicated by a significant increase in the AI . Vaccination with the monovalent OMV vaccine induced mainly IgG1 and IgG3 isotypes, which are considered to be most important for protection against meningococcal disease . An increase in the AI of antibodies is associated with increased SBA, independent of the level of specific IgG and the IgG isotype distribution . Measuring the AI and IgG isotype distribution of antibodies after vaccination can be a supplementary method for predicting protective immunity for evaluation in future phase III trials with meningococcal serogroup B vaccines. Chest, 2002 Jan, 121(1), 292 - 5 Human recombinant activated protein C in meningococcal sepsis; Wcisel G et al.; A 19-year-old woman presented with purpura fulminans and septic shock; subsequently, progressive coagulopathy, widespread purpura fulminans associated with meningococcemia, severe shock, respiratory, and renal failure developed . This clinical course was associated with depletion of functional protein C levels to < 5% . We describe her clinical course and therapy with human recombinant activated protein C. Br J Biomed Sci, 2001, 58(4), 230 - 4 Automated non-culture-based sequence typing of meningococci from body fluids; Clarke SC et al.; In recent years, the polymerase chain reaction has been used for the non-culture diagnosis of meningococcal disease, and sequence-based typing takes this further by providing the full characterisation normally only available by culture . In this study, porA gene sequencing was used to perform non-culture-based sequence typing of Neisseria meningitidis strains direct from body fluids . Non-culture porA gene sequencing provided the serosubtype of the infecting organism, and proved to be a useful method as N . meningitidis was not isolated from any of the patients in this study . In conclusion, porA gene sequencing is a very useful tool for the non-culture characterisation of meningococci and provides important information for public health management of cases and contacts. Rev Prat, 2001 Nov 1, 51(17), 1914 - 8 {Drugs for pediatric emergencies}; Cheron G et al.; Drugs for pediatric emergencies are useful for respiratory (croup, asthma), cardiologic (hypertensive crisis, acute congestive heart failure, arrhythmias, hypoxic spells), neurologic (seizures), metabolic (dehydration, hypoglycaemia), infectious (meningococcemia) or allergic (anaphylaxis) distresses . Pain management is always important whether to relieve or to prevent the discomfort which would happen during diagnosis or therapeutic procedures. Rev Prat, 2001 Nov 1, 51(17), 1898 - 902 {Bacterial meningitis and purpura fulminans in the child}; Bourrillon A; Antimicrobial therapy must start promptly . Antimicrobial regimen is adapted to the data of epidemiological trends . Bacterial meningitis of children are a matter of therapeutical urgency . Diagnosis must be easily considered according to the clinical analysis . Fulminant meningococcal sepsis is the most alarming clinical presentation of the meningococcal diseases. Clin Diagn Lab Immunol, 2002 Jan, 9(1), 109 - 14 Standardization of Neisseria meningitidis serogroup B colorimetric serum bactericidal assay; Rodriguez T et al.; The correlate of protection for serogroup B meningococci is not currently known, but for serogroup C it is believed to be the serum bactericidal assay (SBA) . The current SBAs are labor intensive and the variations in protocols among different laboratories make interpretation of results difficult . A colorimetric SBA (cSBA), based on the ability of Neisseria meningitidis serogroup B to consume glucose, leading to acid production, was standardized by using group B strain Cu385-83 as the target . The cSBA results were compared to those obtained for a traditional colony-counting microassay (mSBA) . Glucose and bromocresol purple pH indicator were added to the medium in order to estimate growth of cSBA target cell survivors through color change . Different variants of the assay parameters were optimized: growth of target cells (Mueller Hinton agar plates), target cell number (100 CFU/per well), and human complement source used at a final concentration of 25% . After the optimization, three other group B strains (H44/76, 490/91, and 511/91) were used as targets for the cSBA . The selection of the assay parameters and the standardization of cSBA were done with 13 sera from vaccinated volunteers . The titers were determined as the higher serum dilution that totally inhibited the bacterial growth marked by the color invariability of the pH indicator . This was detected visually as well as spectrophotometrically and was closely related to a significant difference in the growth of target cell survivors determined using Student's t test . Intralaboratory reproducibility was +/-1 dilution . The correlation between bactericidal median titers and specific immunoglobulin G serum concentration by enzyme immunoassay was high (r = 0.910, P < 0.01) . The bactericidal titers generated by the cSBA and the mSBA were nearly identical, and there was a high correlation between the two assays (r = 0.974, P < 0.01) . The standardized cSBA allows easy, fast, and efficient evaluation of samples. J Microbiol Methods, 2002 Mar, 49(1), 97 - 101 A one-step method for genetic transformation of non-piliated Neisseria meningitidis; Bogdan JA et al.; A one-step method to chemically transform non-piliated Neisseria meningitidis strains previously resistant to conventional electrochemical transformation procedures has been developed . This method has been used to generate genetically engineered meningococcal strains disrupted in the structural rmpM gene encoding Rmp. J Clin Microbiol, 2002 Jan, 40(1), 75 - 9 Detection of meningococcal carriage by culture and PCR of throat swabs and mouth gargles; Jordens JZ et al.; The standard method for detecting meningococcal carriage is culture of throat swabs on selective media, but the levels of carriage determined depend heavily on the skills of the individuals taking the swab and interpreting the cultures . This study aimed to determine the most sensitive detection method for meningococcal carriage . Throat swabs and saline mouth gargles, obtained from 89 university students, were processed in parallel by conventional culture and TaqMan ctrA PCR . Carriage of meningococci, as detected by the combined methods, was 20% . The sensitivities of throat swab culture, throat swab PCR, gargle culture, and gargle PCR were 72, 56, 56, and 50%, respectively, and the probabilities that these techniques would correctly identify the absence of carriage (negative predictive value {NPV}) were 93.4, 89.9, 89.9, and 88.8% . Culturing both throat swabs and gargles increased the NPV to 98.6% . The further addition of throat swab PCR increased this to 100% . Testing gargles by both culture and PCR was as sensitive as testing throat swabs by both methods, suggesting that gargles may be a suitable alternative for large-scale screening studies when throat swabs are difficult to obtain, although they required more lengthy laboratory processing . PCR was a useful adjunct to culture for detecting nasopharyngeal carriage, but it failed to detect some nongroupable strains . For maximum sensitivity, a combination of techniques was required . This study indicates the confidence with which health care professionals involved in meningococcal screening can regard laboratory results. Expert Opin Biol Ther, 2002 Jan, 2(1), 87 - 96 Meningococcal serogroup C conjugate vaccine; Lakshman R et al.; Meningococcal meningitis and septicaemia are important causes of morbidity and mortality in many parts of the world . More than 90% of the cases are caused by serogroups A, B and C; the remaining 10% are largely caused by the W-135 and Y strains . During the mid-to-late 1990s there was an increase in meningococcal serogroup (MS) C disease in the UK and some parts of Europe . MS C polysaccharide vaccines that were developed in the 1960s are weakly immunogenic and not protective in infants under 2 years of age, but are effective in older recipients . Meningitec (Wyeth-Ayerst) is produced by conjugation of serogroup C oligosaccharide with a mutant diphtheria protein (CRM197), with the aim of inducing T-cell dependent immune responses . It has been found to be immunogenic in infants, toddlers, older children and adults . The vaccine has also been shown to induce immunological memory and therefore is likely to give long-term protection against disease . It received a license for use in the UK in October 1999 and was introduced into the UK immunisation schedule in November 1999 . Surveillance studies after introduction of this and similar vaccines have demonstrated a dramatic fall in the incidence of MS C disease . Pre-licensure research studies and post-licensure adverse event data have confirmed that the vaccine is safe. Expert Opin Investig Drugs, 2001 Aug, 10(8), 1487 - 500 New therapies and vaccines for meningococcal disease; Carrol ED et al.; Meningococcal disease (MCD) is an important cause of morbidity and mortality . The pathophysiology consists of a complex interaction of bacterial and host factors, triggered by the release of endotoxin which initiates the inflammatory cascade, resulting in multi-organ failure, coagulopathy, capillary leak, metabolic derangement and eventually death . Prompt recognition and aggressive management are essential in reducing mortality . Over the past decade, there has been intense research into novel therapies and vaccines, with largely disappointing results . Therapies have been broadly divided into anti-endotoxin and anti-TNF-alpha therapies, treatment aimed at correcting coagulopathy and at blood purification and anti-inflammatory cytokine therapy . The reasons for the disappointing results in the search for new therapeutic strategies are difficult to identify . The disordered physiology in MCD results from a complex interaction of several mediators; therefore attempts to correct this by altering just one step represents a gross oversimplification of the process . In addition, the experimental model of endotoxaemia, which is often used, is a poor representation of an acutely ill patient with rapidly progressive shock . There have been several small or poorly designed trials, which have failed to reach definite conclusions . In order to yield conclusive results any future trials must be multicentre, randomised, controlled trials, but these are expensive and, in practice, difficult to conduct . The BPI trial (vide infra) was a significant step forward in this regard and demonstrated the ability to organise a large multicentred trial which can act as a template for future trials . Although the results were not significant there was an overall trend towards improved outcome in the treatment arm . Whilst the development of effective therapies and vaccines are awaited, the priorities at present must be the prompt recognition and aggressive management of disease. Eur J Public Health, 2001 Dec, 11(4), 431 - 6 Public health management of an outbreak of group C meningococcal disease in university campus residents; Round A et al.; BACKGROUND: Increasing numbers of outbreaks of Group C meningococcal disease in teenagers and young adults led to a new policy in the UK in 1999 of vaccinating all new college students . The largest of these outbreaks involved seven students in one university, six of whom were from one hall of residence, and two of whom died . METHODS: Control of the outbreak involved close medical surveillance of resident students, mass chemoprophylaxis and vaccination, and wide dissemination of daily information bulletins . Investigation of the epidemiology of the outbreak involved searching for the network of close contacts between cases, a prevalence survey of carriage of meningogocci and a case control study of risk factors for carriage . RESULTS: Clinical cases could be linked by a discrete network of social contacts within the halls of residence, but the Group C epidemic strain (2a P1.5) was not detected in 454 students (upper 95% confidence interval 0.7%) . Carriage of any meningococcal strain (19%) was associated with patronage of the campus bar (OR = 3.0, 0.99-9.1) . CONCLUSION: Important factors in the control of the outbreak were rapid institution of mass chemopropylaxis and immunisation of residents, and involvement of student organizations in the dissemination of information about the disease and its control . The role of campus bars in dissemination of the carriage of meningogocci deserves further investigation. Eur J Emerg Med, 2000 Dec, 7(4), 313 - 5 Fulminant purpuric rash; Famularo G et al.; We report on a fatal case of purpura fulminans caused by severe meningococcaemia . Despite early and aggressive treatment with the use of a specific algorithm and the maintenance of a stable haemodynamic status in the first hour since admission, purpura fulminans developed impressively over a few minutes . Necropsy showed microvascular thrombosis in the dermis but not in visceral organs, suggesting the diagnosis of meningococcal septic shock with purpura fulminans limited to the skin . Acquired deficiency of protein C, which exerts anticoagulant and antiinflammatory functions, is the central mechanism ultimately responsible for purpura fulminans . The disorder predicts a poor outcome of meningococcaemia and early and aggressive resuscitation is recommended in the emergency department with antibiotics, volume expansion, inotropic drugs, and protein C replacement . An attitude of scepticism is appropriate in the management of these patients even when early resuscitation is successful and haemodynamic parameters remain stable. Rev Port Cardiol, 2001 Sep, 20(9), 877 - 80 Neisseria meningitidis native valve endocarditis . A case report; Joao I et al.; The so-called nonpathogenic neisseriae are common inhabitants of the upper respiratory tract in humans and are not usually regarded as pathogens . Neisseria meningitidis on the contrary may cause severe disease . These organisms are an uncommon cause of infective endocarditis . The authors report a case of a 64 year-old male, type II diabetic, previously asymptomatic, admitted to hospital because of fever, aphasia and right hemi-paresis . A systolic murmur was heard at the cardiac apex, and three blood cultures were positive for Neisseria meningitidis . The echocardiogram showed a vegetation on the posterior leaflet of the mitral valve, allowing the diagnosis of meningococcal endocarditis . The patient's clinical condition improved on intravenous penicillin therapy, and regression of fever, disappearance of the neurological signs and of the mitral valve vegetation were observed. J Formos Med Assoc, 2001 Oct, 100(10), 696 - 8 Meningitis due to penicillin-resistant Neisseria meningitidis in a 20-year-old man; Ben RJ et al.; The emergence of meningococcal strains with reduced susceptibility to penicillin has been reported in several countries during the past two decades, but not in Taiwan . We report a case of meningococcal meningitis with intermediate resistance to penicillin . A 20-year-old male soldier complained of chills, fever, and headache for 2 days, followed by drowsiness . Physical examination revealed erythema of the pharynx, stiff neck, erythematous maculopapules, and petechiae over the trunk and four limbs including palms and soles . Analysis of the cerebrospinal fluid (CSF) showed a white blood cell count of 9.06 x 10(6)/L, a glucose concentration of 0.165 mmol/L, and a protein concentration of 7.85 g/L . CSF culture yielded Neisseria meningitidis, serogroup B . The minimum inhibitory concentration of penicillin was determined using an E-test (0.125 microgram/mL); there was no beta-lactamase production . He recovered after high-dose penicillin G treatment with six doses of 24 million units per day for 11 days . The emergence of penicillin resistance in N . meningitidis in Taiwan requires surveillance . High-dose penicillin may be successful in treating penicillin-insensitive meningococcal meningitis . Alternative treatment with third-generation cephalosporins should be considered if poor response to penicillin is encountered. J Endotoxin Res, 2001, 7(6), 401 - 20 Neisseria meningitidis lipopolysaccharides in human pathology; Brandtzaeg P et al.; Neisseria meningitidis causes meningitis, fulminant septicemia or mild meningococcemia attacking mainly children and young adults . Lipopolysaccharides (LPS) consist of a symmetrical hexa-acyl lipid A and a short oligosaccharide chain and are classified in 11 immunotypes . Lipid A is the primary toxic component of N . meningitidis . LPS levels in plasma and cerebrospinal fluid as determined by Limulus amebocyte lysate (LAL) assay are quantitatively closely associated with inflammatory mediators, clinical symptoms, and outcome . Patients with persistent septic shock, multiple organ failure, and severe coagulopathy reveal extraordinarily high levels of LPS in plasma . The cytokine production is compartmentalized to either the circulation or to the subarachnoid space . Mortality related to shock increases from 0% to > 80% with a 10-fold increase of plasma LPS from 10 to 100 endotoxin units/ml . Hemorrhagic skin lesions and thrombosis are caused by up-regulation of tissue factor which induces coagulation, and by inhibition of fibrinolysis by plasminogen activator inhibitor 1 (PAI-1) . Effective antibiotic treatment results in a rapid decline of plasma LPS (half-life 1-3 h) and cytokines, and reduced generation of thrombin, and PAI-1 . Early antibiotic treatment is mandatory . Three intervention trials to block lipid A have not significantly reduced the mortality of meningococcal septicemia. Emerg Infect Dis, 2001 Sep-Oct, 7(5), 849 - 54 Clonal expansion of sequence type (ST-)5 and emergence of ST-7 in serogroup A meningococci, Africa; Nicolas P et al.; One hundred four serogroup A meningococci in our collection, isolated in Africa from 1988 to 1999, were characterized by multilocus sequence typing (MLST) . Our results and data from the Internet indicate that sequence type 5 (ST-5) strains were responsible for most of African outbreaks and sporadic cases during this period . In 1995, a new clone, characterized by ST-7 sequence, emerged and was responsible for severe outbreaks in Chad (1998) and Sudan (1999) . MLST and epidemiologic data indicate that ST-5 and ST-7 represent two virulent clones . These two STs, which belong to subgroup III, differ only in the pgm locus: allele pgm3 is characteristic for ST-5 and allele pgm19 for ST-7 . Subgroup III strains were responsible for two pandemics in the 1960s and 1980s . Our data show that the third subgroup III pandemic has now reached Africa. Emerg Infect Dis, 2001 Sep-Oct, 7(5), 767 - 72 Emerging infectious diseases in an island ecosystem: the New Zealand perspective; Crump JA et al.; Several unique features characterize infectious disease epidemiology in New Zealand . Historically, well-organized, government-run control programs have eliminated several zoonoses . More recently, however, communicable disease control has been mixed . Rates of rheumatic fever, tuberculosis, and enteric infectious are high, and rates of meningococcal disease are increasing . These diseases are over-represented in New Zealanders of Polynesian descent, who generally live in more deprived and overcrowded conditions than do those of European descent . Measles and pertussis epidemics are recurring because of inadequate vaccine coverage, despite a well-developed childhood immunization program . A progressive response to the HIV epidemic has resulted in relatively low rates of infection, particularly among injecting drug users; however, the response to other sexually transmitted infections has been poor . A key challenge for the future is to build on successful strategies and apply them to persisting and emerging infectious disease threats in a small, geographically isolated country with limited economic resources. EMBO J, 2001 Dec 17, 20(24), 6937 - 45 Outer membrane composition of a lipopolysaccharide-deficient Neisseria meningitidis mutant; Steeghs L et al.; In the pathogen Neisseria meningitidis, a completely lipopolysaccharide (LPS)-deficient but viable mutant can be obtained by insertional inactivation of the lpxA gene, encoding UDP-GlcNAc acyltransferase required for the first step of lipid A biosynthesis . To study how outer membrane structure and biogenesis are affected by the absence of this normally major component, inner and outer membranes were separated and their composition analysed . The expression and assembly of integral outer membrane proteins appeared largely unaffected . However, the expression of iron limitation-inducible, cell surface-exposed lipoproteins was greatly reduced . Major changes were seen in the phospholipid composition, with a shift towards phosphatidylethanolamine and phosphatidylglycerol species containing mostly shorter chain, saturated fatty acids, one of which was unique to the LPS-deficient outer membrane . The presence of the capsular polysaccharide turned out to be essential for viability without LPS, as demonstrated by using a strain in which LPS biosynthesis could be switched on or off through a tac promoter-controlled lpxA gene . Taken together, these results can help to explain why meningococci have the unique ability to survive without LPS. J Hosp Infect, 2001 Dec, 49(4), 282 - 4 Risk of laboratory-acquired meningococcal disease; Boutet R et al.; Five probable secondary cases of meningococcal disease were identified in microbiology laboratory workers in England and Wales during a 15-year period . All cases had prepared suspensions of Neisseria meningitidis outside a safety cabinet upto seven days before onset of illness . Relative risk in laboratory workers compared with the background adult population was 184 (95% CI 60-431) . In view of the potentially serious outcome from this infection, a safety cabinet should always be used when preparing or working with suspensions of meningococci . Vaccination policy for microbiology laboratory workers should be reviewed . J Infect Dis, 2001 Dec 15, 184(12), 1548 - 55 Epub 2001 Dec 03. Relevance of Fcgamma receptor and interleukin-10 polymorphisms for meningococcal disease; van der Pol WL et al.; The contribution of individual Fcgamma receptor (FcgammaR) subclasses to meningococcal phagocytosis was studied . In addition, functional FcgammaR polymorphisms were determined in 50 patients with meningococcal disease (MD), in 183 first-degree relatives of MD patients, and in 239 healthy control subjects, to study the association of FcgammaR genotypes with disease . Efficient internalization of opsonized Neisseria meningitidis serogroup B was mediated via multiple FcgammaR subclasses on phagocytes . Accordingly, a low-efficiency combination of FcgammaRIIa-R/R131, FcgammaRIIIa-F/F158, and FcgammaRIIIb-NA2/2 genotypes was increased significantly in relatives of patients with MD, compared with healthy control subjects (P<.05; odds ratio, 2.6; 95% confidence interval, 1.1-6.3) . FcgammaRIIa and FcgammaRIIIa genotype distributions differed between patients with sepsis and those with meningitis . Combined genotypes of FcgammaRIIa and interleukin-10 -1082, which was previously reported as being associated with MD outcome, were distributed randomly in control subjects but not in relatives of patients with MD (P<.01) . These data provide further evidence for the association of polymorphic genes on chromosome 1 and MD. J Infect Dis, 2001 Dec 15, 184(12), 1532 - 7 Epub 2001 Dec 03. Adrenocorticotropic hormone and cortisol levels in relation to inflammatory response and disease severity in children with meningococcal disease; van Woensel JB et al.; This prospective observational study investigated the relationship of the hypothalamic-pituitary-adrenal axis to inflammatory markers and to disease severity in children with meningococcal disease . In total, 32 children were studied: 10 with distinct meningococcal meningitis (MM), 10 with MM and septic shock, and 12 with fulminant meningococcal septicemia (FMS) . Levels of adrenocorticotropic hormone (ACTH) and interleukin (IL)-6, IL-8, and IL-10 were lowest in the MM group and dramatically elevated in the FMS group . Cortisol and C-reactive protein levels were highest in the MM group and relatively low in the FMS group . Levels of ACTH and inflammatory markers decreased within the first 24 h of admission, but cortisol levels did not fluctuate . Cortisol was significantly inversely correlated with IL-6, IL-8, and IL-10 (P < or =.04) . These results suggest that the adrenal reserve in children is insufficient to handle the extreme conditions and stress associated with severe meningococcal disease. Semin Thromb Hemost, 2001 Dec, 27(6), 605 - 17 The tissue factor pathway in disseminated intravascular coagulation; Osterud B et al.; In most instances, tissue factor (TF) exposed to the circulation is the sole culprit underlying the initiation of disseminated intravascular coagulation (DIC), although notable exceptions because of a more direct activation of the coagulation system, by snake venoms, for example, do occur . Peripheral monocytes and subendothelial structures are the potential sources of such TF; in the former, TF emerges on the cell surface on synthesis induction and in the latter it becomes available subsequent to permeability changes or damage to the endothelium . Subendothelial TF is constitutively present in fibroblasts, pericytes, and macrophages and at a higher than normal level in tumor-associated macrophages . This scenario of coagulation activation probably describes the principal events underlying emerging acute DIC states under pathophysiological conditions such as abruptio placentae, septic abortion, amniotic fluid embolization, and pregnancy toxemia . Under disease conditions associated with DIC, the continuous exposure to excess TF typically exhausts the available tissue factor pathway inhibitor (TFPI), leading to rampant thrombin generation, persistent feedback activation of factor XI (FXI) by the generated thrombin, and hence virtually uncheckable ongoing fibrin generation (DIC) . Recently, it was shown that patients subject to meningococcal sepsis had comparatively large amounts of mainly monocyte-derived circulating TF-containing microparticles . Because phosphatidylserine (PS) is exposed on such particles, in additio