Meningococcus

MMWR Morb Mortal Wkly Rep, 2001 Mar 30, 50(12), 221 - 2
Update: assessment of risk for meningococcal disease associated with the Hajj 2001; Presenting features of meningococcal disease et al.; University of AucklandAIMS: To investigate whether the presenting features of meningococcal disease as promoted in public health awareness material and in the print media accurately reflect the clinical features in patients admitted to Auckland hospitals with meningococcal disease January 1998 to June 1999 . METHODS: Hospital record, public health message and newspaper article review, with analysis by presenting feature, age group and disease complex . RESULTS: The most common presenting features were fever (95%), rash (65%), vomiting and nausea (64%), lethargy (62%), headache (44%), refusing food and drink (35%), irritability (33%), muscle ache and joint pains (27%) and stiff neck (26%) . Public health messages gave appropriate emphasis to the key features, whereas newspaper articles under-emphasised these . The term 'meningitis' was used more frequently in newspapers (65%) than in public health messages (30%), despite meningitis alone presenting less frequently (38% of cases) than meningococcal septicaemia, and having a less serious prognosis . CONCLUSIONS: Presenting features currently noted in the Ministry of Health's health education resource material are appropriate . Public health specialists dealing with the media should ensure that appropriate messages are incorporated into media reports . A greater use of the term 'meningococcal disease' by both public health agencies and media would convey to the public the message that this disease has a spectrum of presenting features, with those of septicaemia more common, but also indicating an even greater need for urgency of action than with 'classical' meningitic features.

Rev Med Liege, 2001 Feb, 56(2), 124 - 5
{Pharmacy clinics . Medication of the month . Meningitec}; Lepage P; Meningitec (Wyeth Lederle) is a new antimeningococcal C conjugate vaccine . This vaccine contains a group C meningococcal oligosaccharide coupled to a carrier protein (CRM197, a non toxic variant of diphteria toxoid) . This vaccine has been shown to be immunogenic both in adults and young children . Meningitec is well tolerated and its efficacy has been recently demonstrated in England (vaccine efficacy: 97% among adolescents; 92% among toddlers).

Infect Immun, 2001 May, 69(5), 3203 - 13
Functional opsonic activity of human serum antibodies to inner core lipopolysaccharide (galE) of serogroup B meningococci measured by flow cytometry; Plested JS et al.; A recently described flow cytometric opsonophagocytic assay (OPA) was adapted to quantify the functional activity of serum antibodies specifically directed against serogroup B inner core lipopolysaccharide (LPS) of Neisseria meningitidis . The percentage of human peripheral polymorphonuclear leukocytes and monocytes (PMNms) ingesting fluorescently labeled, ethanol-fixed N . meningitidis organisms (phagocytic activity) in the presence of human sera was measured to reflect the serum opsonic activity against the bacterium . The contribution to opsonophagocytic activity of antibodies to inner core LPS was estimated by comparing the opsonic activities of adult and infant sera before and after adsorbing anti-LPS antibodies from the sera using purified LPS extracted from an LPS mutant (galE) of N . meningitidis strain MC58 (B:15:P1.7,16:L3) . The specificity of the assay was further investigated using monoclonal antibody (MAb) B5, which binds to an inner core LPS epitope of N . meningitidis . A dose-dependent decrease in phagocytic activity was observed when MAb B5 was incubated with LPS from an inner core LPS (galE) mutant . Similarly, the number of PMNms ingesting fluorescently labeled polystyrene beads coated with inner core (galE) LPS decreased in a dose-dependent fashion when MAb B5 was incubated with various concentrations of the homologous inner core LPS . Strong correlations were found between the concentration of serum antibodies to inner core LPS (galE) versus the phagocytic activity using healthy adult sera (r(2) = 0.89) . There was a correlation between phagocytic ingestion and initiation of intracellular oxidative burst (r(2) = 0.99) using polystyrene beads coated with inner core LPS and opsonized with the same sera using the oxidative burst indicator system dihydrorhodamine123/rhodamine 123 . OPA results were also found to correlate closely with the results of the serum bactericidal assay using MAb B5 against the N . meningitidis MC58 galE mutant in the presence of human complement (r(2) = 0.994, P = 0.003, two-tailed test) . These studies demonstrate that functional antibodies are produced in humans against meningococcal inner core LPS and that the OPA is a useful approach to study the opsonic activity of antibodies to inner core LPS in health and disease.

Braz J Infect Dis, 2001 Feb, 5(1), 37 - 9
Two family members with a syndrome of headache and rash caused by human parvovirus B19; Pereira AC et al.; Human parvovirus B19 infection can cause erythema infectiosum (EI) and several other clinical presentations . Central nervous system (CNS) involvement is rare, and only a few reports of encephalitis and aseptic meningitis have been published . Here, we describe 2 cases of B19 infection in a family presenting different clinical features . A 30 year old female with a 7-day history of headache, malaise, myalgias, joint pains, and rash was seen . Physical examination revealed a maculopapular rash on the patient's body, and arthritis of the hands . She completely recovered in 1 week . Two days before, her 6 year old son had been admitted to a clinic with a 1-day history of fever, headache, abdominal pain and vomiting . On admission, he was alert, and physical examination revealed neck stiffness, Kerning and Brudzinski signs, and a petechial rash on his trunk and extremities . Cerebrospinal fluid analysis was normal . He completely recovered in 5 days . Acute and convalescent sera of both patients were positive for specific IgM antibody to B19 . Human parvovirus B19 should be considered in the differential diagnosis of aseptic meningitis, particularly during outbreaks of erythema infectiosum . The disease may mimic meningococcemia and bacterial meningitis.

Trends Microbiol, 2001 Apr, 9(4), 181 - 5
Exploring the evolution of diversity in pathogen populations; Gupta S et al.; Pathogen biodiversity is an under-exploited source of inference regarding disease processes and the evolution of pathogens and pathogenesis . In addition, the structure of pathogen populations, especially for diverse organisms such as the meningococcus, has implications for public health interventions including vaccination and antibiotic use . The predominant paradigm for interpreting bacterial diversity has been the clonal population structure, which has been modified by the incorporation of the effects of horizontal genetic exchange . Multilocus models of variable antigens, which explore the effects of immune selection, provide alternative explanations for structured diversity in pathogen populations.

Br J Biomed Sci, 2001, 58(1), 17 - 9
Meningococcal disease due to serogroup Y in Scotland, 1992-1999; Clarke SC et al.; Meningococcal disease is an important cause of morbidity and mortality . A retrospective analysis was performed of all cases of invasive group-Y disease that were laboratory-confirmed in Scotland between 1992 and 1999 . A total of 1881 meningococcal isolates were characterised, 78 of which were serogroup Y . The incidence of non-invasive group-Y disease remained level between 1992 and 1999 . Only 12 isolates were from invasive disease, comprising five strain types . Invasive group-Y disease was associated mostly with the young or old . Serogroup-Y meningococcal disease was uncommon and a rare cause of invasive disease in Scotland between 1992 and 1999; however, it is essential that microbiologists are aware of its potential for increasing in incidence due to the recent introduction of the MenC vaccine, and its increased incidence in the USA.

J Clin Microbiol, 2001 Apr, 39(4), 1622 - 5
Random amplified polymorphic DNA assay as a rapid tool in screening for Neisseria meningitidis serogroup C isolates of electrophoretic type 24; Schmink S et al.; Neisseria meningitidis serogroup C (NMSC) isolates of electrophoretic type 24 (ET-24), as identified by multilocus enzyme electrophoresis, are the main cause of serogroup C meningococcal disease outbreaks and sporadic meningococcal disease in the United States . We evaluated a random amplified polymorphic DNA assay as a rapid tool to screen for isolates of ET-24 by testing 199 NMSC isolates of 51 different ETs . A sensitivity of 88% and a specificity of 87% was achieved in identification of ET-24 isolates when the patterns obtained by two primers, P1 and P5, were analyzed together.

J Clin Microbiol, 2001 Apr, 39(4), 1235 - 40
Phenotypic and genotypic approaches to characterization of isolates of Neisseria meningitidis from patients and their close family contacts; Tzanakaki G et al.; Characterization of isolates of Neisseria meningitidis obtained from patients with meningococcal disease or from pharyngeal swabs of asymptomatic carriers can be achieved by several approaches which provide different levels of discrimination . A total of 45 gram negative, oxidase-positive diplococcus strains isolated from 15 individuals with meningococcal disease and 30 of their family contacts were examined by three approaches: serological typing, multilocus enzyme electrophoresis (MLEE), and multilocus sequence typing (MLST) . For 10 of the 15 patient and contact groups, all of the isolates were confirmed as meningococci, and the bacteria obtained from the patients and contacts, including their mother or principal caregiver in the case of children, were indistinguishable by all three methods . In the remaining five groups the isolates from the patients were distinct from those recovered from the contacts, and in three examples, in two separate groups, the contacts were shown by MLST to be carrying strains of Neisseria lactamica . The data obtained from the three techniques were consistent, although complete serological typing was possible for only a minority of isolates . Both MLEE and MLST established the genetic relationships of the isolates and identified members of known hypervirulent lineages, but MLST was faster than MLEE and had the additional advantages that it could be performed on noninfective material distributed by mail and that the results from different laboratories could be compared via the internet .

Commun Dis Public Health, 2000 Dec, 3(4), 298 - 9
Effectiveness of the meningococcal vaccination programme for British Armed Forces recruits; Bergman BP et al.; After several clusters of meningococcal disease arose among recruits to the British Armed Forces, vaccination against A + C meningococcal disease was introduced for military recruits in 1992 . From 1993 onwards, no further clusters of group C infection were reported and incidence of meningococcal disease among trained soldiers fell, but there was no significant reduction in the overall incidence of meningococcal disease in recruits.

Commun Dis Public Health, 2000 Dec, 3(4), 271 - 3
Survey of the prescribing of chemoprophylaxis to index cases of invasive meningococcal disease; Heywood P et al.; Chemoprophylaxis is given to contacts of cases of invasive meningococcal disease to reduce the risk of secondary cases by eradicating carriage . In the United Kingdom index cases are also recommended to receive chemoprophylaxis . This is usually undertaken by the clinical team managing the case . One hundred and fifty cases of probable meningococcal infection notified to the consultants in communicable disease control in a local health authority were reviewed to identify the proportion receiving chemoprophylaxis and to examine the final clinical outcome, in terms of diagnosis, of each case . Twenty-five per cent of notified cases (37) did not receive chemoprophylaxis and this proportion varied significantly between three local hospitals . We estimate that 15 of the 37 index cases who did not receive chemoprophylaxis were likely to have had invasive meningococcal disease.

Commun Dis Public Health, 2000 Dec, 3(4), 267 - 70
Media management of a community outbreak of meningococcal meningitis; Singleton CD et al.; Cases and, particularly, clusters of meningococcal meningitis often create high levels of public concern and attract the interest of news media . We describe below our experience of managing intense local and national media interest during a community outbreak of meningococcal disease in Derbyshire . Our learning is set out as ten key recommendations . Four of these are around managing the media, including using a proactive press release, providing detailed briefings, using a single spokesperson and coordination of the response by a press officer experienced in media management . Another four describe how to deliver an appropriate on-site response, often requested during community intervention programmes . The two final recommendations relate to ensuring good communication and supporting staff during what is an intensely stressful period . We hope our experiences may help others if faced with a similar problem.

Biotechnol Appl Biochem, 2001 Apr, 33(Pt 2), 91 - 8
Solution stability studies of the subunit components of meningococcal C oligosaccharide-CRM197 conjugate vaccines; Ho MM et al.; Spectroscopic methods were used to detect modifications in the structures of CRM197, the mutant diphtheria toxin, and meningococcal C capsular oligosaccharide following their conjugation and incubation at various temperatures . Meningococcal C oligosaccharide-CRM197 conjugate vaccines obtained from two different manufacturers were incubated at -20, 4, 23, 37 or 55 degrees C for 5 weeks or subjected to ten cycles of freeze-thawing . The CRM197 carrier protein and the saccharide components of the treated vaccines were monitored by CD and NMR spectroscopic techniques . CD data indicated incubation temperature-dependent conformational changes in the carrier protein from vaccine A . Modifications appeared in both secondary and tertiary structures of the conjugated CRM(197) when incubated at 23 degrees C or above . This was characteristic of the 'open' conformation previously observed for this protein component . The NMR spectra also indicated modification of the structure of the conjugated CRM197 component of vaccine A when incubated at 23 degrees C or above, but failed to show any modification in the conjugated oligosaccharide . On the other hand, the structure of the oligosaccharide chains in vaccine B appeared to be degraded following incubation at 55 degrees C, even though the thermal effect on the conjugated CRM197 was less apparent . Repeated freeze-thawing did not affect the CD or NMR spectra . In conclusion, the two meningococcal C oligosaccharide-CRM197 conjugate vaccines were stable when stored at their recommended temperatures, but were differently affected by elevated temperatures . The conjugates differ in their conjugation chemistry, attachment positions, oligosaccharide chain length and loading, as well as recommended pH and storage buffer, and their different stability properties can probably be attributed to a combination of these factors.

J Bacteriol, 2001 Apr, 183(8), 2570 - 5
Genetic isolation of meningococci of the electrophoretic type 37 complex; Claus H et al.; Neisseria meningitidis (the meningococcus) is a naturally competent bacterial species in which intra- and interspecific horizontal gene transfer is a major source of genetic diversity . In strains of the electrophoretic type 37 (ET-37) complex and of the A4 cluster, we identified genomic DNA coding for a novel restriction-modification system and for the tail of a previously unidentified prophage . Furthermore, a novel 7.2-kb DNA segment restricted to clones of the ET-37 complex and the A4 cluster was isolated and shown to occur both as a plasmid (pJS-B) and as a chromosomal integration . Neither the genomic loci nor pJS-B was present in ET-5 complex, lineage 3, or serogroup A meningococci . The differential distribution of the DNA segments described herein, as well as of opcA, porB, nmeAI, nmeBI, and nmeDI described previously, supports the concept of genetic isolation of hypervirulent lineages responsible for most cases of serogroup C disease worldwide.

Microb Pathog, 2001 Mar, 30(3), 139 - 48
Murine monoclonal antibodies to PorA of Neisseria meningitidis show reduced protective activity in vivo against B:15:P1.7,16 subtype variants in an infant rat infection model; Toropainen M et al.; The major outer membrane protein PorA of Neisseria meningitidis is the target for bactericidal serosubtyping antibodies and is currently considered as a potential vaccine candidate against group B meningococcal disease . Although the minor antigenic variability of the PorA has been increasingly recognized and described, its implication for vaccine design remains unclear . In this study, the protective activity of murine monoclonal PorA specific antibodies against four isogenic meningococcal P1.7,16 target strains, the prototype P1.7,16a and three loop 4 point mutation variants (designated P1.7,16b to d) constructed from reference strain H44/76 (B:15:P1.7,16a), was evaluated in the infant rat infection model . All monoclonal antibodies had been obtained by immunization of mice with outer membrane protein preparations from meningococcal serosubtype P1.7,16 reference strain H44/76 . A challenge dose of 10(5)cfu/pup was given i.p . 1-2 h after the i.p . injection of 1:100 diluted antibodies, and the development of bacteremia was assessed by culturing blood samples taken 6 h after challenge . MN14C11.6, a reference monoclonal antibody for serosubtype P1.7 epitope located in predicted loop 1 (VR1) identical in all the variants, was equally protective against all loop 4 variants . The three P1.16 specific monoclonal antibodies tested (MN5C11G, MN12H2 and 62D12-8) all completely protected animals against the prototype P1.7,16a, variably against the P1.7,16b and P1.7,16c, but not against the P1.7,16d variant . Our findings therefore suggest that certain subtype variants may escape protection in vivo conferred by PorA specific antibodies .

Gac Sanit, 2000 Nov-Dec, 14(6), 422 - 8
{Shared surveillance: meningococcal disease vs influenza}; Moreno-Civantos A et al.; OBJECTIVE: To analyse the association between the behavior of meningococcal disease and influenza, using for this purpose population statistics for Spain for the period of 1964 to 1997 . METHODS: Ecological study of the incidence of meningococcal disease and influenza in Spain from 1964 to 1997, inclusive . The study used weekly statistical data for these diseases supplied by the Compulsory Disease Reporting System (Enfermedades de Declaracion Obligatoria, EDO) . The deterministic component of the meningococcal disease and influenza series was studied by means of spectral analysis based on the Fast Fourier Transformation, and the non-deterministic component was studied using the ARIMA model . The Box-Jenkins method was used for pre-bleaching the series, and a cross-correlation was subsequently established between the residuals in order to detect the presence of any significant correlations between the meningococcal disease and influenza series . RESULTS: During the period from 1964 to 1997, the week that showed, on average, the greatest number of cases for the season was week 7 in the case of meningococcal disease and week 6 in the case of influenza . Spectral analysis of the meningococcal disease and influenza series clearly demonstrated the annual periodicity of both series, and periodicity of nearly 11 years for meningococcal disease and slightly over 10 years for influenza . When cross-correlation is established after prebleaching the series, positive correlations are obtained in the results of lags 0, 1, 2, and 3 . Introducing influenza as an exogenous variable in the multivariate model of meningococcal disease corroborates these results . There was a statistically significant relationship between the two processes during the same week and with a three-week lapse . CONCLUSIONS: By means of a methodology not previously applied to this subject, and by the use of prolonged time-span, country-comprehensive population statistics (which includes several epidemics waves), an association was shown to exist between meningococcal disease and influenza . This suggests the need for the surveillance of the two processes in an interrelated manner.

Aten Primaria, 2000 Oct 31, 26(7), 439 - 45
{Research activity on pediatric vaccines in Spain: descriptive analysis of prospective studies published between 1990 and 1998}; Dal-Re Saavedra R et al.; OBJECTIVE: To describe the overall characteristics of prospective studies on vaccines in children, performed by Spanish investigators and published between 1990 and 1998 . METHODS: Through a bibliographic research on MEDLINE and EMBASE, 24 prospective studies, performed in Spain, published as original papers, and with objectives directly related to the administration of vaccines to children have been identified . These studies were grouped as: clinical trials (group A), studies performed on established vaccination programmes (group B), and those that could not be included in the above mentioned groups (group C) . RESULTS: 5, 9 and 10 studies belonged to groups A, B and C, respectively . More than 12,800 subjects participated in these studies, belonging to both normal population or specific risk groups . In 11 studies, the study population comprised newborns and infants . The vaccines under investigation were: hepatitis B (10 studies), DTPe/Pa (6), MMR (3), flu (2), Hib (1), hepatitis A (1), and meningococcus A and C (1) to address different objectives (in most of them, immunogenicity and/or reactogenicity) . Nine had external financial support; 21 were performed by hospital and/or primary care investigators, and 18 in the Vasque Coutry, Madrid or Valencia . 13 publications reported obtaining informed consent, and 8 on the approval of the study protocol by an independent committee . Ten studies were published by international journals . CONCLUSIONS: This study shows that most of the studies are conducted by clinicians, with vaccines targetted to newborns and infants, with no external financial support, in a small number of autonomous communities, and usually published in Spanish Journals . The submission of this type of studies to a research ethics committee is desirable, something done to a lesser extent than obtaining informed consent.

Clin Infect Dis, 2001 Apr 1, 32(7), 1004 - 9 Epub 2001 Mar 15.
Meningococcal disease among children who live in a large metropolitan area, 1981-1996; Wang VJ et al.; Neisseria meningitidis is an important cause of serious bacterial infections in children . We undertook a study to identify meningococcal infections of the blood, cerebrospinal fluid, or both of children in a defined geographic area to describe the burden of disease and the spectrum of illness . We reviewed the medical records of all children aged <18 years who had meningococcal infections at the 4 pediatric referral hospitals in Boston, Massachusetts, from 1981 through 1996 . We identified 231 patients with meningococcal disease; of these 231 patients, 194 (84%) had overt disease and 37 (16%) had unsuspected disease . Clinical manifestations included meningitis in 150 patients, hypotension in 26, and purpura in 17 . Sixteen patients (7%) died . Although meningococcal disease is devastating to a small number of children, we found that the burden of pediatric disease that it caused at the 4 pediatric referral centers in this geographic region was limited; that patients with overt meningococcal disease are most likely to have meningitis; and that individual practitioners are unlikely to encounter a patient with unsuspected meningococcal disease.

MMWR Morb Mortal Wkly Rep, 2001 Feb 16, 50(6), 97 - 8
Risk for meningococcal disease associated with the Hajj 2001; Reverse vaccinology et al.; IRIS, Chiron S.p.A., Via Fiorentina, 1, 53100, Siena, Italy . rino-rappuoli@chiron.it

The conventional approach to vaccine development requires cultivation of the pathogenic microorganism and its dissection using biochemical, immunological, and microbiological methods in order to identify the components important for immunity . This method, while successful in many cases, failed to provide a solution for many of those pathogens for which a vaccine is not yet available . Today, the possibility of using genomic information allows us to study vaccine development in silico, without the need of cultivating the pathogen . This approach, which we have named 'reverse vaccinology', reduces the time required for the identification of candidate vaccines and provides new solutions for those vaccines which have been difficult or impossible to develop . The potential of this new approach is illustrated by the use of reverse vaccinology for the development of a vaccine against serogroup B meningococcus . The application of reverse vaccinology to other fields, including viral vaccines is discussed.

Infect Immun, 2001 Apr, 69(4), 2718 - 22
Differential gene expression during meningeal-meningococcal interaction: evidence for self-defense and early release of cytokines and chemokines; Wells DB et al.; Using microarray technology, we studied the early differential expression of 3,528 genes in human meningothelial cells in response to meningococcal challenge . Thirty-two genes were up-regulated, and four were down-regulated . Those up-regulated included the tumor necrosis factor alpha, interleukin-6 (IL-6), and IL-8 (but not IL-1beta) genes, suggesting that meningeal cells may be a local and early source of these cytokines . Also, a trend in up-regulation of anti-apoptotic genes and down-regulation of pro-apoptotic genes was observed . This is the first evidence that meningothelial cells may mount cytoprotective responses to pathogenic bacteria.

Infect Immun, 2001 Apr, 69(4), 2502 - 11
Transcriptional regulation of divergent capsule biosynthesis and transport operon promoters in serogroup B Neisseria meningitidis; Tzeng YL et al.; The clinically important serogroups B, C, Y, and W-135 of Neisseria meningitidis produce sialic acid capsules that are critical in pathogenesis . In each of these serogroups, the capsule transport (ctrABCD) and capsule biosynthesis (synABCD) operons are divergently transcribed from putative promoters located in a 134-bp intergenic region (J . S . Swartley, J . H . Ahn, L . J . Liu, C . M . Kahler, and D . S . Stephens, J . Bacteriol . 178:4052-4059, 1996) . In this study we further assessed the role of the intergenic sequence in the transcriptional regulation of the sialic acid capsules of N . meningitidis . Insertional mutagenesis or deletions of the 134-bp sequence in the serogroup B meningococcal strain NMB resulted in a marked reduction or elimination of ctrABCD and synABCD transcription, with a concomitant loss of encapsulation . Chromosomal transcriptional lacZ-ermC reporter fusions of syn and ctr promoters were constructed through allelic exchange . Using these constructs, both operons were found to be constitutively transcribed in meningococci, the biosynthesis operon about fourfold higher than the transport operon . Both promoters showed increased activity during stationary-phase growth . In addition to the promoters, a 70-bp 5' untranslated region (UTR) upstream of synA was found to have a direct repeat and an inverted repeat that overlapped three putative integration host factor binding sites . Mutation of this 70-bp UTR and of the direct repeat upregulated both syn and ctr transcription . Regulation through the synA UTR was absent in a K1 Escherichia coli strain that produces identical capsular polysaccharide, implicating species-specific regulation . Meningococcal sialic acid capsule expression is initiated by divergent promoters in a 134-bp intergenic region, is repressed at the transcriptional level by the 5' UTR of synA, is increased during stationary-phase growth, and shows species-specific regulation . Transcriptional regulation is another important control point for sialic capsule expression in N . meningitidis.

Wien Klin Wochenschr, 2001 Feb 15, 113(3-4), 107 - 12
Sepsis-associated purpura fulminans in adults; Gamper G et al.; Sepsis-associated purpura fulminans is defined as septicemia, shock, disseminated intravascular coagulation and circulatory failure leading to multiple organ dysfunction . 40-70% of patients with sepsis-associated purpura fulminans die . Early prognostic factors in adults have not been well delineated yet . Aim of our study was 1) to evaluate currently used scoring systems for meningococcal septicemia in the setting of sepsis-associated purpura fulminans and 2) to assess if other parameters are feasible as early prognostic factors . From 1.1 1994-31.12.1998 twelve patients (female: 7; mean age: 31 (21; 43) years) were studied . Six patients (50%) died within 2 hours and 7 days after admission despite standard intensive treatment . On admission non-survivors had a more pronounced degree of disseminated intravascular coagulation compared to survivors (platelet count 18000 (15000; 45000) G/l vs . 119.000 (111000; 152000) G/l, (p = 0.03); fibrinogen 67 (50; 108) mg/dl vs . 356 (234; 483) mg/dl, (p = 0.02); PTZ 28% (20%; 30%) vs . 44% (35%; 51%), (p = 0.05); aPTT 120 (120; 128) sec vs . 46 (44; 69) sec, (p = 0.001) . Severity of lactic acidosis was significantly higher in non-survivors than in survivors (pH 7.08 (6.92; 7.21) vs . pH 7.4 (7.25; 7.4), (p = 0.02); lactate 13.5 (11; 15) mval/l vs . 6.0 (4.4; 6) mval/l, (p = 0.02); data presented as median (25-75% interquartile range) . In our patients the Glasgow Meningococcal Septicemia Prognostic Score (GMSPS) and the Niklasson-Score failed to distinguish between survivors and non-survivors (GMSPS 7 (6; 11) vs 7.5 (7; 9) out of 15; predicted mortality according to Niklasson-Score 73% vs 88%) . There was no difference in the APACHE II Score (22 (18.5, 24) vs 22 (20.25, 26)) . The severity of disseminated intravascular coagulation assessed by routine laboratory parameters and the degree of lactic acidosis on admission were the strongest predictors of outcome in patients with sepsis-associated purpura fulminans . Scoring systems developed for patients with meningococcal septicemia are of limited value in the setting of sepsis-associated purpura fulminans.

Am J Med Genet, 2001 Apr 1, 99(4), 325 - 7
High prevalence of complement C7 deficiency among healthy blood donors of Moroccan Jewish ancestry; Halle D et al.; The incidence of the specific component deficiencies in various ethnic groups is not known, although there appears to be an ethnic predilection for C6 and C8alpha-gamma deficiencies in blacks, whereas C7 and C8beta deficiencies are predominantly noted in Caucasians . Infectious diseases, particularly recurrent meningococcal infections, are observed more commonly with late component deficiencies . In the current study, we have simplified the PCR technique by using site-directed mutagenesis and designer primers in a cohort of Israeli Moroccan Jewish blood donors to ascertain allele frequency in this ethnic group, which, based on earlier studies, was considered to be at risk for C7 deficiency . The total mutant allele frequency in this ethnic cohort was 1.1% of a total of 365 healthy Israeli Moroccan Jews, including one homozygote . The identification of mutant alleles was efficient and inexpensive, and hence a large cohort was studied . The finding of complement deficiency identifies individuals at risk for Neisserial infections, which are known to be potentially life-threatening . Conversely, when a patient of Moroccan ancestry is diagnosed with a Neisserial infection, it is important to determine the complement status .

Mol Microbiol, 2001 Mar, 39(5), 1345 - 55
Generation and characterization of a PhoP homologue mutant of Neisseria meningitidis; Johnson CR et al.; Two-component regulatory systems are important regulators of virulence genes in a number of bacteria . Genes encoding a two-component regulator system, with homology to the phoP/phoQ system in salmonella, were identified in the meningococcal genome . Allele replacement was used to generate a meningococcal knock-out mutant of the regulator component of this system, and its phenotype was examined . The mutant displayed many differences in protein profiles compared with wild type, consistent with it being a gene-regulatory mutation . Many of the growth characteristics of the mutant were similar to those of phoP mutants of salmonella: it was unable to grow at low concentrations of magnesium and was sensitive to defensins and other environmental stresses . Magnesium-regulated differences in protein expression were abrogated in the mutant, indicating that the meningococcal PhoP/PhoQ system may, as in salmonella, respond to changes in environmental magnesium levels . These results are consistent with the PhoP homologue playing a similar role in the meningococcus to PhoP in salmonella and suggest that it may similarly be involved in the regulation of virulence genes in response to environmental stimuli in the meningococcus . In support of this conclusion, we found the mutant grew was unable to grow in mouse serum and was attenuated in its ability to traverse through a layer of human epithelial cells . Identification of those genes regulated by the meningococcal PhoP may provide a route towards the identification of virulence genes in the meningococcus.

Thromb Haemost, 2001 Feb, 85(2), 240 - 4
Tissue factor pathway inhibitor (TFPI) levels in the plasma and urine of children with meningococcal disease; Eling M et al.; Tissue factor pathway inhibitor (TFPI) is a potent inhibitor of the TF-dependent coagulation system . In meningococcal disease, up-regulation of tissue factor expression on blood monocytes and possibly on endothelial cells has the potential to trigger the activation of the TF-dependent pathway of coagulation . Intravascular coagulation is considered to be a major pathogenic factor in meningococcal disease . We postulated that imbalance between TF expression and TFPI concentration might lead to uncontrolled coagulation in meningococcal disease . The aim of this study was to assess the levels of total TFPI in the plasma of patients with meningococcal disease and assess whether increased leaking of the TFPI was occurring . TFPI antigen levels and activity were measured in the plasma of 54 patients with meningococcal disease, and 13 healthy control children . TFPI antigen level were also determined in the urines of 14 of the 54 and 9 healthy control children . Plasma TFPI activity was reduced in the meningococcal diseased patients (mean of 0.503 +/- 0.341 U/ml; control, 1.010 +/- 0.199 U/ml: p <0.0001), as was the TFPI antigen levels (mean of 54.85 +/- 35.05 ng/ml; Control, 94.51 +/- 11.44 ng/ml; p <0.0001) . In contrast, TFPI antigen levels were increased in the urine of these patients when compared to the levels found in the urine of the healthy control children (mean of 12.96 +/- 5.392 ng/mmol creatinine; Control, 0.239 +/- 0.191 ng/mmol creatinine; p <0.035) . A lack of correlation between TFPI-activity and TFPI-antigen plasma levels was observed (r = 0.002, p = 0.85) . This data is consistent with the hypothesis that in meningococcal disease there is increased inactivation of plasma TFPI by the up regulation of tissue factor expression but in addition increased clearance of TFPI in urine is occurring.

Rev Med Liege, 2000 Oct, 55(10), 915 - 20
{Meningococcemia, recrudescence, diagnosis and treatment}; Tomat AM et al.; Meningococcemia is a severe Gram negative septicemia whose mortality may be as high as 30% . It occurs more frequently in children but the proportion of teenagers is increasing in Belgium . During the past decade, a slow but sustained rise in the incidence of this illness has been noted, with a predominance of the serogroup B . We describe the symptoms, which often are poor in the early stage, the different therapies, most of them being still under investigation, and the chemoprophylaxis . Without being alarmist, the diagnosis must be considered in any child with cutaneous rash, even atypical and tachycardia.

Bone Marrow Transplant, 2001 Jan, 27(1), 79 - 84
Tetravalent meningococcal polysaccharide vaccine is immunogenic in adult allogeneic BMT recipients; Parkkali T et al.; Forty-four adult BMT recipients transplanted from an HLA-identical sibling donor were randomized to receive meningococcal polysaccharide (Men PS) vaccine either 8 (early group; 22 patients) or 20 (late group; 22 patients) months after BMT . The geometric mean concentrations (GMC) of antibodies to serogroup A Neisseria meningitidis (Men A) and serogroup C Neisseria meningitidis (Men C), determined by an EIA method, decreased during the first 6 months after BMT but remained at a stable level thereafter . Before vaccination the GMCs of anti-Men A were 1.53 microg/ml and 1.61 microg/ml, but 1 month after vaccination they were significantly higher, 3.46 microg/ml and 6.39 microg/ml, in the early and late groups . The GMCs of anti-Men C increased from 0.37 microg/ml and 0.44 microg/ml before vaccination to 3.31 microg/ml and 4.62 microg/ml at 1 month after vaccination in the early and late groups, respectively . By 6 months after vaccination the GMCs of Men antibodies had decreased to levels of about 50% of those measured at 1 month after vaccination . Two-fold responses to Men A PS were seen in 52% and 74% and to Men C PS in 76% and 89% of the BMT recipients in the early and late groups, respectively . Chronic GVHD had no influence on the vaccination response . In the present study, Men PS vaccine induced good and equal antibody responses to Men A and Men C PSs in allogeneic BMT recipients regardless of timing after BMT . Vaccination against Neisseria meningitidis should be considered, especially in the event of travelling or military service > or = 8 months after BMT.

J Epidemiol Community Health, 2001 Apr, 55(4), 283 - 7
Dramatic decline of serogroup C meningococcal disease incidence in Catalonia (Spain) 24 months after a mass vaccination programme of children and young people; Salleras L et al.; STUDY OBJECTIVES: The objective of this study was to evaluate the effectiveness of a mass vaccination programme carried out in Catalonia (Spain) in the last quarter of 1997 in response to an upsurge of serogroup C meningococcal disease (SCMD) . DESIGN: Vaccination coverage in the 18 month to 19 years age group was investigated by means of a specific vaccination register . Vaccination effectiveness was calculated using the prospective cohort method . Cases of SCMD were identified on the basis of compulsory reporting and microbiological notification by hospital laboratories . Vaccination histories were investigated in all cases . Unadjusted and age adjusted vaccination effectiveness referred to the time of vaccination and the corresponding 95% confidence intervals (CI) were estimated at 6, 12, 18 and 24 months of follow up . SETTING: All population aged 18 months to 19 years of Catalonia . MAIN RESULTS: A total of seven cases of SCMD were detected at six months of follow up (one in the vaccinated cohort), 12 cases at 12 months (one in the vaccinated cohort), 19 cases at 18 months (two in the vaccinated cohort) and 24 at 24 months (two in the vaccinated cohort) . The age adjusted effectiveness was 84% (95%CI 30, 97) at six months, 92% (95%CI 63, 98) at 12 months, 92% (95% CI 71, 98) at 18 months and 94% (95%CI 78, 98) at 24 months . In the target population, cases have been reduced by more than two thirds (68%) two years after the vaccination programme . In the total population the reduction was 43% . CONCLUSION: Vaccination effectiveness has been high in Catalonia, with a dramatic reduction in disease incidence in the vaccinated cohort accompanied by a relevant reduction in the overall population . Given that vaccination coverage was only 54.6%, it may be supposed that this vaccination effectiveness is attributable, in part, to the herd immunity conferred by the vaccine.

J Infect Dis, 2001 Apr 1, 183(7), 1079 - 86 Epub 2001 Mar 08.
Active immunization with a detoxified Escherichia coli J5 lipopolysaccharide group B meningococcal outer membrane protein complex vaccine protects animals from experimental sepsis; Cross AS et al.; The passive infusion of antibodies elicited in rabbits with a detoxified J5 lipopolysaccharide (LPS)/group B meningococcal outer membrane protein complex vaccine protected neutropenic rats from heterologous lethal gram-negative bacterial infection . In this study, active immunization was studied in neutropenic rats infected with Pseudomonas aeruginosa, in the presence or absence of ceftazidime therapy, and with Klebsiella pneumoniae . This vaccine elicited a > 200-fold increase in anti-J5 LPS antibody, which remained elevated throughout the duration of cyclophosphamide-induced neutropenia and for < or = 3 months . There was improved survival among immunized versus control animals: 48% (13/28) versus 7% (2/29) in Pseudomonas-challenged rats; 61% (11/18) versus 0% (0/10) in Pseudomonas- and ceftazidime-treated rats; and 64% (9/14) versus 13% (2/15) in Klebsiella-challenged rats (P < 0.01 for each comparison) . Immunized animals had lower levels of bacteria in organs and lower levels of circulating endotoxin at the onset of fever . In conclusion, active immunization with an anti-endotoxin vaccine improved survival after infection with > or = 2 heterologous, clinically relevant bacterial species in immunocompromised animals . Active immunization with this vaccine merits further investigation.

Scand J Infect Dis, 2001, 33(1), 56 - 9
Acute cellulitis: an unusual manifestation of meningococcal disease; Porras MC et al.; We describe 2 patients who both developed cellulitis due to Neisseria meningitidis and review 8 other cases reported since 1966 . Female patients outnumbered male patients by 8 to 2, and there were 5 children and 5 adults . Four cases were caused by the serogroup C meningococcus, 2 cases by serogroup B and 2 others by serogroup Y (the nature of the meningococcal group was not available in 2 cases) . Diverse medical underlying conditions were present in 4 of the adult patients . The periorbital region (in all 5 children), limb (in 3 adults), neck (in 1 adult) and face and neck (in 1 adult) were the locations of the meningococcal cellulitis . In all 10 patients, a favorable clinical response to the antibiotic therapy was documented and no relapses occurred . These cases indicate that N . meningitidis should be considered as a causative agent of cellulitis in the appropriate clinical setting, particularly in children with signs of periorbital infection or adults with underlying diseases.

Vaccine, 2001 Feb 28, 19(15-16), 2020 - 8
IL-12-mediated increases in protection elicited by pneumococcal and meningococcal conjugate vaccines; Buchanan RM et al.; Interleukin-12 (IL-12) may be a beneficial adjuvant for augmenting vaccine efficacy against encapsulated bacteria such as Streptococcus pneumoniae and Neisseria meningitidis since it can stimulate production of interferon-gamma (IFN-gamma) and secretion of antibody isotypes that are efficient at mediating complement fixation and opsonophagocytosis . In this study, we demonstrate the ability of IL-12 to enhance murine antibody responses, particularly IgG2a levels, to both pneumococcal and meningococcal conjugate vaccines . Transfer of immune serum from mice immunized with the meningococcal conjugate vaccine and IL-12 resulted in increased survival times, whereas transfer of serum from mice immunized with the pneumococcal conjugate and IL-12 resulted in protection from death upon bacterial challenge . Although treatment with vaccine and IL-12 increased levels of IFN-gamma mRNA, IL-12-mediated enhancement of antibody responses still occurred in IFN-gamma(-/-) mice . The results demonstrate the effectiveness of IL-12 as an adjuvant for polysaccharide conjugate vaccines, especially the pneumococcal conjugate vaccine.

Vaccine, 2001 Feb 28, 19(15-16), 2006 - 11
Surveillance of infectious diseases in the Italian military as pre-requisite for tailored vaccination programme; D'Amelio R et al.; Surveillance and control of infectious diseases in the Italian military include prompt reporting of all occurring cases and prophylaxis through compulsory vaccination practices . The last mandatory immunisation programme in the Italian military was launched in 1998 (more than 10 years after the previous programme was introduced in 1986-1987) and it was planned according to the epidemiological data herein reported . The incidence rates (number of cases x 100000 subjects) of infectious diseases notified during the period 1976-1980 were compared with the corresponding figures notified 15 years later (1991-1995) . An increase of three airborne-transmitted viral diseases--varicella, rubella and measles--counterbalanced by a decrease of other infectious diseases, such as mumps, typhoid fever, tuberculosis, viral hepatitis, scabies, syphilis and gonorrhea, was observed . This may be related to improvements in the general hygienic conditions and more responsible sexual behaviour among Italian military recruits . Moreover, incidence rates of cases notified in the military were compared with those notified in the general population of the same sex- and similar age-range (15-24 years) over a 12-year period (1986-1997), to monitor the epidemiological situation in relation to (a) potential risk factors specifically linked to military life and (b) protective effects induced by specific vaccinations . Airborne-transmitted viral diseases, such as varicella, rubella, measles and mumps--which are usually underreported among civilians--show higher incidence rates in the military . Meningococcal meningitis shows higher incidence rates in the military in 1986 and 1987 (before the introduction of mandatory specific vaccination) as well as in 1995-1997 (main etiologic agent N . meningitidis serogroup B); similar rates were instead observed in the other years . Incidence rates for typhoid fever are generally lower in the military, despite the community life, probably reflecting the protective efficacy of specific vaccine . Hepatitis A and B show similar rates between military and civilian population . Finally, pulmonary tuberculosis generally shows higher rates in the military . These data therefore allow the conclusion that the only infectious diseases, for which possible risk factors in the military life may be hypothesised, seem to be meningococcal meningitis and perhaps pulmonary tuberculosis . Epidemiological surveillance of infectious diseases in the military as a pre-requisite for appropriate public health intervention strategy represents a good model to be followed also in larger contexts.

Vaccine, 2001 Feb 28, 19(15-16), 1989 - 97
Development of a new method for the quantitative analysis of the extracellular polysaccharide of Neisseria meningitidis serogroup A by use of high-performance anion-exchange chromatography with pulsed-amperometric detection; Ricci S et al.; A new method for the quantitative determination of Neisseria meningitidis group A (MenA) capsular polysaccharide (CPS) has been developed . The method is based on trifluoracetic acid (TFA) hydrolysis of the CPS (2 M at 80 degrees C for 3 h), followed by chromatographic separation and quantification of the liberated mannosamine-6-phosphate from the area of the peak obtained using an IonPac AS11 column coupled to the sensitive pulsed amperometric detector ED40 . The highly selective nature of this method circumvents the interference problems associated with the classical method based on a colorimetric assay for phosphorus . Provided that suitable hydrolysis conditions can be found, this chromatographic approach might be applicable to the quantification of other bacterial antigens containing phosphorylated sugars such as meningococcal groups H, L, X and Z, and pneumococcal serotypes 6, 10A and 19.

Pediatr Infect Dis J, 2001 Feb, 20(2), 153 - 9
Safety and immunogenicity of four doses of Neisseria meningitidis group C vaccine conjugated to CRM197 in United States infants; Rennels MB et al.; BACKGROUND: Following widespread use of conjugate pneumococcal vaccine, Neisseria meningitidis likely will become the leading cause of bacterial sepsis and meningitis in US children . This report describes the safety and immunogenicity in US children of four consecutive doses of a meningococcal group C vaccine conjugated to CRM197 via reductive amination (MnCC) . METHODS: One hundred six healthy 2-month-old infants received MnCC at 2, 4 and 6 months of age in a randomized, controlled double blind study; children in the other treatment arm were given a 7-valent conjugate pneumococcal vaccine . Parents reenrolled 64 of these children at 12 to 15 months to receive a fourth dose of MnCC . Routine childhood vaccines, including DTP, were coadministered . Temperatures and symptoms were recorded for 3 days after each immunization . Serum enzyme-linked immunosorbent assay IgG and bactericidal antibodies were measured prevaccination and before and 1 month after Doses 3 and 4 . RESULTS: Moderate to severe local reactions, defined as erythema or induration > or =2.4 cm or pain that interfered with limb movement was reported after 0 to 3.2% of MnCC injections, depending on the reaction and dose . Fever occurred in 23 to 37% of children, but the contribution of MnCC to the febrile reactions is unknown . Geometric mean concentrations of IgG antibody to group C meningococcal polysaccharide were 3.72 microg/ml after Dose 3 and 8.03 microg/ml after the booster . Geometric mean functional serum bactericidal antibody titers after Doses 3 and 4 were 1:463 and 1:2341, respectively . One hundred percent of children had a serum bactericidal antibody titer of > or =1:64 after three doses and > or = 1:128 after the booster . CONCLUSIONS: The MnCC vaccine had an acceptable safety profile and generated high titers of bactericidal antibody in immunized US infants and toddlers . It appears to be an attractive candidate vaccine for the prevention of serogroup C meningococcal disease in young children.

J Antimicrob Chemother, 2001 Mar, 47(3), 285 - 96
Polymorphism of Neisseria meningitidis penA gene associated with reduced susceptibility to penicillin; Antignac A et al.; We studied polymorphism of penA (which encodes penicillin-binding protein 2) in 13 strains of Neisseria meningitidis susceptible to penicillin (pen(S)) and 12 strains with reduced susceptibility to penicillin (pen(I)) . These strains differed in geographical origin . Serological and genetic typing showed that they were highly diverse and belonged to several genetic lineages . Restriction analysis and DNA sequencing of penA showed that all pen(S) strains had the same penA allele regardless of genetic group, whereas pen(I) strains harboured various penA alleles . Transformation with amplicons of penA and genomic DNA from several pen(I) strains conferred the pen(I) phenotype on a pen(S) strain . Thus, reduction in susceptibility to penicillin is directly related to changes in penA and analysis of penA polymorphisms could be used as a reliable tool for characterizing meningococcal strains in terms of their susceptibility to penicillin.

Rev Med Interne, 2001 Jan, 22(1), 75 - 8
{Primary Neisseria meningitidis arthritis of the knee without meningitis: contribution of synovial fluid culture in blood-culture vial}; Cartolano GL et al.; INTRODUCTION: Primary meningococcal arthritis is a rare form of meningococcal disease . It occurs as an isolated acute purulent arthritis without meningitis, and presence of Neisseria meningitidis in articular fluid . We report a new case of typical primary meningococcal arthritis . EXEGESIS: A previously healthy 23-year-old female patient was admitted for purpuric lesions of the legs . At admission, conscience was normal and symptoms of meningitis were absent . During the 2nd day of hospitalisation, a warm and painful effusion in the right knee appeared . Aspiration from the right knee yielded a purulent fluid . N . meningitidis was isolated from a blood-culture vial inoculated with the synovial fluid, while blood cultures remained sterile . Anti-biotherapy was initiated as soon as microbiological diagnosis was established . The patient was symptom-free 1 month later . CONCLUSION: We emphasize the fact that agar cultures of the synovial fluid remained sterile, while N . meningitidis grew in a blood-culture vial . We suggest that diagnosis of primary meningococcal arthritis may be underestimated when inappropriate culture media are used.

Epidemiol Infect, 2000 Dec, 125(3), 555 - 60
Determinants of case fatality rates of meningococcal disease during outbreaks in Makkah, Saudi Arabia, 1987-97; El Bushra HE et al.; We studied case-fatality rates (CFRs) among cases of meningococcal disease (MCD) admitted to Makkah (Saudi Arabia) hospitals during the period 1988-97 . Of 483 cases, 431 (89.2%) were due to strains of serogroup A, 31 (6.4%) to serogroup W135, 16 (3.3%) to serogroup C, and 5 (10%) to serogroup B . Eighty-one patients died (case fatality rate (CFR)) 16.8%, 95% CI 13.5%, 20.4%) . The CFR in infections due to serogroup A strains was 14.8%, and for other serogroups it was 32.7% (95% CI 20.3%, 47.1%) . The CFR of MCD due to N . meningitidis serogroup A increased steadily with age (P<0.05) . Seeking first medical help at a foreign Hajj medical mission and being treated in a non-specialized hospital were associated with a higher case fatality rate.

Bull World Health Organ, 2001, 79(1), 22 - 7 Epub 2003 Nov 05.
The use of hospital-based nurses for the surveillance of potential disease outbreaks; Durrheim DN et al.; OBJECTIVE: To study a novel surveillance system introduced in Mpumalanga Province, a rural area in the north-east of South Africa, in an attempt to address deficiencies in the system of notification for infectious conditions that have the potential for causing outbreaks . METHODS: Hospital-based infection control nurses in all of Mpumalanga's 32 public and private hospitals were trained to recognize, report, and respond to nine clinical syndromes that require immediate action . Sustainability of the system was assured through a schedule of regular training and networking, and by providing feedback to the nurses . The system was evaluated by formal review of hospital records, evidence of the effective containment of a cholera outbreak, and assessment of the speed and appropriateness of responses to other syndromes . FINDINGS: Rapid detection, reporting and response to six imported cholera cases resulted in effective containment, with only 19 proven secondary cholera cases, during the two-year review period . No secondary cases followed detection and prompt response to 14 patients with meningococcal disease . By the end of the first year of implementation, all facilities were providing weekly zero-reports on the nine syndromes before the designated time . Formal hospital record review for cases of acute flaccid paralysis endorsed the value of the system . CONCLUSION: The primary goal of an outbreak surveillance system is to ensure timely recognition of syndromes requiring an immediate response . Infection control nurses in Mpumalanga hospitals have excelled in timely weekly zero-reporting, participation at monthly training and feedback sessions, detection of priority clinical syndromes, and prompt appropriate response . This review provides support for the role of hospital-based nurses as valuable sentinel surveillance agents providing timely data for action.

Med Pregl, 2000 Jul-Aug, 53(7-8), 401 - 4
{Acute meningococcemia in a 4-month-old infant}; Topalovic R et al.; INTRODUCTION: What causes meningococcial diseases (MD) is a Gramm-negative diplococcus Neisseria meningitidis (meningococcus) . Most frequently it manifests itself in the form of meningitis and meningococcemia . The mortality rate of those suffering from MD has not significantly changed for three decades and ranges from 7% to 19%, and for meningococcemia from 18% to 53% . According to the data presented by domestic authors, of the total of the diseased with bacterial meningitis 75% are children with mortality rate from 6% to 15% . Severe forms of meningococcemia sometimes have extremely rapid development and lethal outcome within a few hours . Key elements for establishing the diagnosis of meningococcemia are presence of hemorrhagic rash with high fever, loss of interest in the environment, loss of consciousness and paleness . CASE REPORT: The boy was admitted to hospital as an emergency case on 29 December 1988 at 11:45 . The disease manifested abruptly the day before . He burst into tears easily, would take very little food and in the evening his temperature rose T degree 40.8 degrees C . Before midnight, in the village he was given injections of: lincomycin 300 mg and lasdol 250 i.m . During admittance the infant was agitated, kept moaning . His skin was pail gray with dot-like and spot-like hematoma which were more numerous and intense on the left ear, lower part of the body, scrotum and legs . The infant breathed heavily and fast (FR: 100/min) Cardiologist's finding showed: tahicardia over 200/min, buffled tones, gallop rhythm, pulsating neck veins and edema point to acute heart failure . Large fontanelles remained swollen even after lumbar puncture (LP) and extraction of 15 ml of clear cerebro-spinal fluid . Soon after admittance the boy stopped moaning but didn't cry when pricked and slipped deeper into coma . During the third hour of treatment generalized convulsions began which lasted approximately 10 minutes and stopped after i.v . administered diazepam . The boy remained in coma the second day in lethargy and with swollen fontanelles on the third day, so the first subdural puncture was then performed bilaterally . On that occasion only from the right side 8 ml of reddish liquid was obtained . Right after he was admitted we began permanent transfusion, which lasted 17 days . On the first day he received fresh blood transfusion . He was administered benzinpenicilline, chloramphenicol-succinate, lanatoside, human albumins, dexamethasone... . Blood oxygenation was carried out in the first few days of illness during the exhibited cardio-respiratory failure . DISCUSSION: Among risk factors, which contribute to occurrence of meningococcemia, is also artificial infant food . The reported boy was incorrectly fed with overdiluted cow milk . That and apparent hemostasis brake-down only worsened anemia and increased susceptibility to infections . Although LP was performed when the boy was admitted and the nutritious foundation was soaked with cerebro-spinal fluid, no bacteria were isolated or their presence confirmed in cerebro-spinal fluid colored after Gramm's method, because the child was given linkomycin the previous night . CONCLUSION: On the basis of clinical findings, hemorrhagic rush, convulsions, coma and acute heart failure as well as the laboratory findings it was concluded that it was a case of severe meningococcemia, meningitis and subdural effusion . Listed therapy and six subdural punctures led to full recovery of the patient . Further examination by a pediatrician and a psychologist eliminated the possibility of mental deficiency . The boy is now a good fifth grade elementary school pupil.

Dev Biol (Basel), 2000, 103, 93 - 104
Characterization of saccharide-CRM197 conjugate vaccines; Hsieh CL; A seven-valent pneumococcal conjugate and a Group C Meningococcal conjugate are at the late stage of development . Clinical studies have demonstrated the efficacy and safety of these vaccines and licensure of these vaccines will be approved in the near future . Several new techniques have been proposed for characterizing polysaccharide-protein conjugates and their production intermediates . We are evaluating some of these new techniques, particularly NMR and MALLS, to determine whether or not they provide useful information for conjugate production . In the production of polysaccharide protein conjugates, the degree of saccharide activation, location of activation site, and the molecular weight of activated saccharides may typically be determined . In our evaluation, techniques such as NMR and MALLS may have a limited applicability for testing polysaccharides and activated saccharides.

Dev Biol (Basel), 2000, 103, 259 - 64
Quantification of free polysaccharide in meningococcal polysaccharide-diphtheria toxoid conjugate vaccines; Lei QP et al.; A precipitation method using deoxycholate/HCI has been applied successfully to separate unconjugated free polysaccharide from carrier protein-bound material in meningococcal polysaccharide-diphtheria toxoid conjugate vaccines . The method effectively separated free and bound polysaccharide in conjugate vaccines prepared from Neisseria meningitidis serotypes A, C, W135 and Y . Free polysaccharide remained in the supernatant after deoxycholate treatment while protein-bound polysaccharide was fully precipitated . Testing by both colorimetric assay and high performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD) has confirmed the selective loss of protein-bound polysaccharide in samples of conjugate vaccine or conjugate vaccine mixed with known amounts of free polysaccharide . This rapid separation method requires minimum sample handling and is specific, reproducible, and allows assessment of free polysaccharide levels in vaccines at final container concentration.

Dev Biol (Basel), 2000, 103, 251 - 8
Capillary electrophoretic analysis of meningococcal polysaccharide-diphtheria toxoid conjugate vaccines; Lamb DH et al.; Protein-polysaccharide conjugate vaccines are large, complex molecules that present challenges in terms of characterization . Free solution capillary electrophoresis using alkaline (pH 9-10) borate or glycine/NaOH buffers permitted electrophoresis of diphtheria toxoid (Dt) or meningococcal polysaccharide-Dt conjugates as well-formed, relatively broad peaks . Resolution was observed between the conjugate and the Dt peaks for some serotypes; however, overlap between Dt and one or more conjugate peaks was observed with both buffers . Inclusion of SDS in the separation buffer at a level above the critical micelle concentration allowed separation of Dt and Dt-conjugates of meningococcal serotypes A, C, Y and W135 . Using borate/SDS, a linear relationship between peak area and Dt concentration was observed between approximately 2 mg/ml and 20 microg/ml . A linear relationship between Dt peak area and injection times from 10 to 50 seconds was also observed . Capillary electrophoresis may therefore be a useful method for quantifying free protein level in meningococcal-Dt conjugate vaccines.

Dev Biol (Basel), 2000, 103, 151 - 60
Structure activity studies on group C meningococcal polysaccharide-protein conjugate vaccines: effect of O-acetylation on the nature of the protective epitope; Michon F et al.; A series of group C meningococcal polysaccharide-tetanus toxoid (GCMP-TT) conjugates were prepared as vaccines with varying percentages of O-acetylation at the C-7 and C-8 positions of sialic acid residues in the polysaccharide (PS) . The immune response in mice was highly dependent on the degree of O-acetylation . Less O-acetylation resulted in higher serum bactericidal activity (SBA) towards the O-acetylated (OA) meningococcal strain, C11 . In addition, since an unconjugated de-O-acetylated (dOA) GCMP vaccine was previously shown to be highly immunogenic in humans, we had chosen this dOA form to couple with TT by reductive amination for clinical evaluation . This conjugate vaccine was shown to be well-tolerated and highly immunogenic in adults, children, and infants in the UK . To understand the nature of the GCMP protective epitope, a series of spectroscopic and serological studies were conducted, using high resolution H-NMR spectroscopy at 500 MHz and competitive inhibition SBA assays . The dOA GCMP was 10-1000 times better at inhibiting the SBA for an OA strain than the OA GCMP, suggesting that the GCMP-based protective epitope on the bacterium exists in a dOA form . In addition, SBA for an OA strain is highly correlated with dOA GCMP-specific IgG . NMR data on freshly isolated GCMP indicated that, on the surface of the organism, most of the O-acetylation exists at position C-8, with some regions containing dOA or OA C-7 sialic acid . After extraction of PS and storage in solution, most of the O-acetyl groups migrate to C-7, leaving an epitope that is conformationally related, but not quite identical (due to the presence of the O-acetyl group), to the one contained in the dOA PS . We speculate that the role of the O-acetyl group at the C-8 position of the PS on the organism is to form less immunogenic epitopes, or mask the protective epitope, and thus escape immune surveillance . The dOA form of the vaccine may therefore provide better protection against group C meningococcal disease than the OA form by eliciting a greater proportion of functional antibodies that are directly aimed at the protective epitope.

Dev Biol (Basel), 2000, 103, 139 - 50
Monitoring stability of meningococcal group C conjugate vaccines; correlation of physico-chemical methods and immunogenicity assays; Ho MM et al.; Two meningococcal C-CRM197 conjugates differing in oligosaccharide chain length, number of conjugation sites, conjugation chemistry and process were monitored for stability at various temperatures or after repeated freeze-thawing by physico-chemical assays . The results were compared with assessment of immunogenicity in mice, previously shown to correlate with performance of the vaccine in clinical trials . The structural stability of the oligosaccharide chains and the protein carrier varied between the two types of conjugates . Neither was adversely affected by repeated freeze-thawing but one developed conformational changes in the protein carrier, detected by optical (CD, fluorescence) and NMR spectroscopy, when incubated at 23 degrees C or above, although integrity of the oligosaccharide structure was maintained . This was not associated with any reduction in primary IgM or IgG antibody responses to meningococcal C polysaccharide . Exposure to more extreme conditions resulting in release of a substantial proportion of free saccharide from the other conjugate sample was accompanied by significant reduction in both IgG and IgM antibody responses . In conclusion, FPLC-SEC, HPAEC-PAD and NMR spectroscopy were found useful for monitoring the stability of meningococcal C-CRM197 conjugates . Although optical spectroscopy was a sensitive method for detecting modification of the protein carrier, the results did not correlate with reduced immunogenicity.

Lancet, 2001 Jan 20, 357(9251), 195 - 6
Efficacy of meningococcal serogroup C conjugate vaccine in teenagers and toddlers in England; Ramsay ME et al.; The UK was the first country to use meningococcal serogroup C conjugate (MCC) vaccines, which were licensed on the basis of immunogenicity and safety data but without a formal efficacy study . Increased surveillance during the first 9 months since introduction has shown that short-term efficacy of the MCC vaccine in England was 97% (95% CI 77-99) for teenagers and 92% (65-98) for toddlers . These early results confirm the superiority of MCC over plain C polysaccharide vaccines, which are ineffective in young children.

Minerva Pediatr, 2000 Nov, 52(11), 659 - 60
Early onset neonatal sepsis due to Neisseria meningitidis B; Casanova-Roman M et al.; The onset of meningococcal infection in the first 72 hours after birth has only been reported on a few occasions; The authors describe a case where it was confirmed that the bacteria responsible, Neisseria meningitidis group B, grew in the newborn's blood and in the mother's lochia . The transmission mechanisms are also reviewed.

Ann Ital Med Int, 2000 Oct-Dec, 15(4), 291 - 5
{Meningococcal meningitis in the adult complicated by cutaneous necrosis: description of a clinical case}; Porro F et al.; Meningitis and meningococcal sepsis are emergency conditions associated with high mortality . The outcome is worsened by the onset of disseminated intravascular coagulation . This may present, particularly in children, with the clinical picture of purpura fulminans, characterized by extensive necrotic-hemorrhagic skin lesions, ischemia of the extremities and multiorgan failure . It has been observed that depletion of coagulation inhibitors, particularly protein C, plays a key role in the development of this severe complication . We describe the case of a woman who presented in the Emergency Room with signs of meningitis, drowsiness, hypotension and petechie . Bacterioscopic examination of the cerebrospinal fluid evidenced characteristic gram-negative diplococci . Laboratory data disclosed initial disseminated intravascular coagulation with low levels of proteins C and S . Following intravenous infusion of antibiotics, fluids and fresh frozen plasma, the patient's condition rapidly improved . However, multiple skin lesions appeared on her fingers, toes and heels . It is likely that the infusion of coagulation inhibitors contained in fresh frozen plasma, prevented evolution to full-blown purpura fulminans . The first choice treatment for purpura fulminans in meningococcal sepsis is infusion of protein C concentrate, which is not, however, currently available on the market.

Sex Transm Dis, 2001 Jan, 28(1), 29 - 32
An unusual transmission of Neisseria meningitidis: neonatal conjunctivitis acquired at delivery from the mother's endocervical infection; Fiorito SM et al.; BACKGROUND: Primary meningococcal conjunctivitis is assumed to be due to the direct inoculation of Neisseria meningitidis into the conjunctival sac from an exogenous source . According to a literature review, no case of neonatal conjunctivitis infection acquired at delivery from maternal endocervicitis has been published . GOAL: To report a case of meningococcal neonatal conjunctivitis acquired at delivery because of the mother's endocervical infection and cross-transmission of the strain with her partner . STUDY DESIGN: Strains were characterized by bacteriologic and serologic methods including grouping (agglutination), typing, and subtyping (enzyme-linked immunoabsorbent assay) . Molecular analysis was done by pulsed-field gel electrophoresis . RESULTS: The three strains (newborn infant, mother, partner) were of the same antigenic formula (C:NT:P1.NT) and exhibited similar NheI and SpeI pulsed-field gel electrophoresis patterns . CONCLUSION: The identical phenotypic and genomic analysis of strains is the evidence for N meningitidis transmission at delivery from a maternal endocervical infection to the newborn infant and cross transmission between sexual partners.

Lancet . 2000 Dec 23-30;356(9248):2159.
Serogroup W135 meningococcal disease in Hajj pilgrims; Taha MK et al.; An outbreak of W135 meningococcal disease occurred in the spring of 2000 among pilgrims returning from Saudi Arabia and their contacts . Clinical isolates from England and France were examined and compared with reference strains from other countries . Characterisation of isolates by a range of typing methods showed them to be of clonal origin (ET-37) and closely related to other meningococci with an established propensity to cause disease clusters . A reappraisal of vaccination strategies for travellers is required.

Commun Dis Intell, 2000 Nov, 24(11), 332 - 5
Enhanced surveillance for meningococcal disease in Queensland in 1999; Ward J et al.; Enhanced surveillance of invasive meningococcal disease commenced in Queensland in 1999 . There were 93 cases, an incidence of 2.8/100,000 population . Most (87%) cases were laboratory confirmed, but 12 per cent were probable cases without laboratory confirmation . The highest age-specific attack rates were in the under 1, 1 to 4 and 15 to 24 year age groups . Most of the serologically characterised isolates were group B (70%), followed by group C (24%) . There were 12 deaths, resulting in a case fatality rate of 13 per cent . Those who died were more likely to have group C than group B disease (OR 5.04, CI 1.05-25.14) . Only 14 per cent of cases that saw a general practitioner (GP) prior to hospitalization received parenteral antibiotics, 23 per cent of the 35 cases referred to hospital by a GP received pre-hospital parenteral antibiotics and 33 per cent of cases were notified to health authorities within 24 hours of hospital admission . Thirty per cent were notified two or more days after hospitalization, delaying the start of public health action . Enhanced surveillance has demonstrated a need to promote the use of pre-hospital parenteral antibiotics by GPs and a need to encourage more timely reporting of cases to health authorities.

J Bacteriol, 2001 Feb, 183(3), 934 - 41
Analysis of lipooligosaccharide biosynthesis in the Neisseriaceae; Arking D et al.; Neisserial lipooligosaccharide (LOS) contains three oligosaccharide chains, termed the alpha, beta, and gamma chains . We used Southern hybridization experiments on DNA isolated from various Neisseria spp . to determine if strains considered to be nonpathogenic possessed DNA sequences homologous with genes involved in the biosynthesis of these oligosaccharide chains . The presence or absence of specific genes was compared to the LOS profiles expressed by each strain, as characterized by their mobilities on sodium dodecyl sulfate-polyacrylamide gel electrophoresis gel and their reactivities with various LOS-specific monoclonal antibodies . A great deal of heterogeneity was seen with respect to the presence of genes encoding glycosyltransferases in Neisseria . All pathogenic species were found to possess DNA sequences homologous with the lgt gene cluster, a group of genes needed for the synthesis of the alpha chain . Some of these genes were also found to be present in strains considered to be nonpathogenic, such as Neisseria lactamica, N . subflava, and N . sicca . Some nonpathogenic Neisseria spp . were able to express high-molecular-mass LOS structures, even though they lacked the DNA sequences homologous with rfaF, a gene whose product must act before gonococcal and meningococcal LOS can be elongated . Using a PCR amplification strategy, in combination with DNA sequencing, we demonstrated that N . subflava 44 possessed lgtA, lgtB, and lgtE genes . The predicted amino acid sequence encoded by each of these genes suggested that they encoded functional proteins; however, structural analysis of LOS isolated from this strain indicated that the bulk of its LOS was not modified by these gene products . This suggests the existence of an additional regulatory mechanism that is responsible for the limited expression of these genes in this strain.

Med Sci Monit, 2000 Sep-Oct, 6(5), 1008 - 12
Subdural empyemas--a rare complication of meningococcal cerebrospinal meningitis in children; Bako W et al.; Subdural empyemas are a rare, life-threatening complication of cerebrospinal meningitis . Two cases of subdural empyemas which occurred as early complications after cerebrospinal meningitis in infants are presented . Utilization of modern diagnostic methods, such as US and CT allowed to establish an early diagnosis, which made it possible to institute appropriate treatment, involving evacuation of the purulent content with local application of antibiotics followed by intravenous antibiotics well penetrating the fluid-filled compartments of the CNS . Early institution of treatment gave a chance of complete recovery in both presented cases.

An Esp Pediatr, 2001 Jan, 54(1), 65 - 8
{Meningococcal disease . new prevention strategies}; Soult Rubio JA et al.; Because conjugate C meningococcal vaccines represent a significant advance in the prevention of meningococcal disease, currently accepted recommendations on vaccination should be revised . The health authorities are responsible for carrying out national surveillance programs and for evaluating the need for vaccination programs . These programs should target all groups at risk for this disease and should confer adequate and lasting protection in vaccinated children.

Infect Immun, 2001 Mar, 69(3), 1971 - 3
Circumvention of herd immunity during an outbreak of meningococcal disease could be correlated to escape mutation in the porA gene of Neisseria meningitidis; Taha MK et al.; Meningococcal strains isolated during an outbreak were shown to belong to the ET-5 complex and to harbor a mutation in the VR2 region of the porA gene . They were less susceptible to the bactericidal effect of normal human serum than was the ET-5 wild-type strain . These results are of concern, as PorA is a potential target in vaccine design.

Infect Immun, 2001 Mar, 69(3), 1816 - 20
NmeSI restriction-modification system identified by representational difference analysis of a hypervirulent Neisseria meningitidis strain; Bart A et al.; Neisseria meningitidis is a gram-negative bacterium that may cause meningitis, sepsis, or both . The increase in the incidence of meningococcal disease in various countries in the past 2 decades is mainly due the genotypically related lineage III meningococci . The chromosomal DNA differences between lineage III strains and non-lineage III strains were identified using representational difference analysis . Thus, a 1.8-kb locus that is specific for lineage III meningococci was identified . The locus contains three open reading frames encoding the NmeSI restriction-modification system . The methyltransferase gene was cloned and expressed in Escherichia coli . Site AGTACT was found to be modified by the enzyme . In conclusion, lineage III strains differ from endemic strains by the presence of a specific restriction-modification system . This restriction-modification system may contribute to the clonal and hypervirulent character of lineage III strains by influencing horizontal gene transfer and transcription.

Infect Immun, 2001 Mar, 69(3), 1687 - 96
exl, an exchangeable genetic island in Neisseria meningitidis; Kahler CM et al.; The genetic structure and evolution of a novel exchangeable meningococcal genomic island was defined for the important human pathogen Neisseria meningitidis . In 125 meningococcal strains tested, one of three unrelated nucleotide sequences, designated exl (exchangeable locus), was found between a gene required for heme utilization, hemO, and col, encoding a putative Escherichia coli collagenase homologue . The 5' boundary of each exl cassette was the stop codon of hemO, whereas the 3' boundary was delineated by a 33-bp repeat containing neisserial uptake sequences located downstream of col . One of the three alternative exl cassettes contained the meningococcal hemoglobin receptor gene, hmbR (exl3) . In other meningococcal strains, hmbR was absent from the genome and was replaced by either a nucleotide sequence containing a novel open reading frame, exl2, or a cassette containing exl3 . The proteins encoded by exl2 and exl3 had no significant amino acid homology to HmbR but contained six motifs that are also present in the lipoprotein components of the lactoferrin (LbpB), transferrin (TbpB), and hemoglobin-haptoglobin (HpuA) uptake systems . To determine the evolutionary relationships among meningococci carrying hmbR, exl2, or exl3, isolates representing 92 electrophoretic types were examined . hmbR was found throughout the population structure of N . meningitidis (genetic distance, >0.425), whereas exl2 and exl3 were found in clonal groups at genetic distances of <0.2 . The commensal neisserial species were identified as reservoirs for all of the exl cassettes found in meningococci . The structure of these cassettes and their correlation with clonal groups emphasize the extensive gene pool and frequent horizontal DNA transfer events that contribute to the evolution and virulence of N . meningitidis.

Infect Immun, 2001 Mar, 69(3), 1568 - 73
Serological basis for use of meningococcal serogroup C conjugate vaccines in the United Kingdom: reevaluation of correlates of protection; Borrow R et al.; The antibody data supporting the use of meningococcal serogroup C conjugate (MCC) vaccines in the United Kingdom were generated by serum bactericidal assay (SBA) using rabbit complement (rSBA) . This may give higher titers than those obtained with human complement (hSBA), for which the "gold standard" correlate of protection for meningococcal C disease is a titer of > or =4 . Comparison of rSBA and hSBA titers in sera from unvaccinated adults with an rSBA titer of > or =8 showed that for 93% (27 of 29) the titer was > or =4 by hSBA, confirming natural protection . Furthermore, sera from MCC vaccinees showed that an rSBA titer of <8 or > or =128 discriminated susceptibility and protection well (85% with rSBA titers of <8 had hSBA titers of <4, and 99% with rSBA titers of > or =128 had hSBA titers of > or =4) . However, discrimination was poor in the rSBA titer range 8 to 64, with only 60% having hSBA titers of > or =4 . In such cases we propose that protection can be assumed if there is a fourfold rise in titer between pre- and postvaccination sera or if there is a characteristic booster response to a polysaccharide challenge dose with, if available, evidence of antibody avidity maturation or an hSBA titer of result > or =4 . Applying these criteria to toddlers, 10 to 40% of whom had titers in the range 8 to 64 after a single dose of MCC vaccine, showed that 94% had a fourfold rise in titer, including 98% of those in the titer range 8 to 64 . In addition, of those with titers of <128 post-MCC vaccination, 90% had titers of > or =128 after a 10-microg polysaccharide booster dose, compared with only 7% of unprimed age-matched toddlers given a full 50-microg dose . Furthermore, the increase in geometric mean avidity index pre- and postbooster was independent of post-primary MCC titer . These results indicated that the majority of toddlers with an rSBA titer between 8 and 64, and some of those with an hSBA result of <4, have mounted a protective immune response with the induction of immunological memory.

Infect Immun, 2001 Mar, 69(3), 1561 - 7
Recombinant Neisseria meningitidis transferrin binding protein A protects against experimental meningococcal infection; West D et al.; To better characterize the vaccine potential of Neisseria meningitidis transferrin binding proteins (Tbps), we have overexpressed TbpA and TbpB from Neisseria meningitidis isolate K454 in Escherichia coli . The ability to bind human transferrin was retained by both recombinant proteins, enabling purification by affinity chromotography . The recombinant Tbps were evaluated individually and in combination in a mouse intraperitoneal-infection model to determine their ability to protect against meningococcal infection and to induce cross-reactive and bactericidal antibodies . For the first time, TbpA was found to afford protection against meningococcal challenge when administered as the sole immunogen . In contrast to the protection conferred by TbpB, this protection extended to a serogroup C isolate and strain B16B6, a serogroup B isolate with a lower-molecular-weight TbpB than that from strain K454 . However, serum from a TbpB-immunized rabbit was found to be significantly more bactericidal than that from a TbpA-immunized animal . Our evidence demonstrates that TbpA used as a vaccine antigen may provide protection against a wider range of meningococcal strains than does TbpB alone . This protection appears not to be due to complement-mediated lysis and indicates that serum bactericidal activity may not always be the most appropriate predictor of efficacy for protein-based meningococcal vaccines.

JAMA, 2001 Jan 10, 285(2), 177 - 81
Effectiveness of a mass immunization campaign against serogroup C meningococcal disease in Quebec; De Wals P et al.; CONTEXT: An outbreak of meningococcal disease in Quebec province prompted a mass immunization program . The impact of this campaign on the epidemiology of meningococcal disease has not been studied . OBJECTIVES: To study the impact of a mass immunization campaign using polysaccharide vaccine on the epidemiology of meningococcal disease (MCD) and to assess serogroup C vaccine effectiveness (VE) . DESIGN, SETTING, AND SUBJECTS: Analysis of MCD cases reported in Quebec from 1990 to 1998, before and after the mass immunization campaign was conducted during the winter of 1992-1993, when 84% of residents aged 6 months to 20 years (the target population, approximately 1.9 million individuals) were vaccinated . MAIN OUTCOME MEASURES: Incidence of MCD in 1990-1998; incidence of culture-proven serogroup C MCD between April 1, 1993, and March 31, 1998, compared among vaccinated and unvaccinated persons in the target population . RESULTS: The incidence of serogroup C disease decreased after the mass immunization campaign, from 1.4 per 100 000 in 1990-1992 to 0.3 per 100 000 in 1993-1998, and the overall incidence of other serogroups remained stable at 0.7 per 100 000, with a small increase in the proportion of cases caused by serogroup Y (P =.009) . Protection from serogroup C MCD was indicated in the first 2 years after vaccine administration (VE, 65%; 95% confidence interval {CI}, 20%-84%), but not in the next 3 years (VE, 0%; 95% CI, -5% to 65%) . Vaccine effectiveness was strongly related to age at vaccination: 83% (95% CI, 39%-96%) for ages 15 through 20 years, 75% (95% CI, - 17% to 93%) for ages 10 through 14 years, and 41% (95% CI, -106% to 79%) for ages 2 through 9 years . There was no evidence of protection in children younger than 2 years; all 8 MCD cases in this age group occurred in vaccinees . CONCLUSIONS: Serogroup C polysaccharide vaccine is effective for controlling outbreaks in teenaged individuals but should not be used in children younger than 2 years . The mass campaign did not induce significant serogroup switching.

Rev Saude Publica, 2000 Dec, 34(6), 589 - 95
{Fatality rate in the epidemiology of meningococcal disease: study in the region of Campinas, SP, Brazil, 1993 to 1998}; Donalisio MR et al.; OBJECTIVE: To analyze the trends of the meningococcal disease cumulative incidence and case-fatality rate in the region of Campinas, Brazil, an area that encircles five cities and 1.2 million inhabitants, from 1993 to 1998 . METHODS: A longitudinal retrospective study of all case records (375) obtained from the regional epidemiological surveillance system was carried out . A logistic regression analysis allowed identifying the risk factors related to fatal outcomes of meningococcal disease . RESULTS: The highest fatality rates (23.8%) were seen in the period of 1996 and 1997, coinciding with the incidence peaks of serogroup B Neisseria and a high percentage of septicemia cases . Also at the same period there was registered a poor etiological investigation of the cases . A seasonal pattern and the predomination of strains B:4:P1.15 and C:2b:P1.3 were observed . In the logistic regression analysis, the risk factors related to fatality were: septicemia with or without meningitis (adjusted odds ratio {OR(aj)} = 13.88 and 95% confidence interval {CI} = 4.68 - 42.13); age over 30 years (OR(aj) = 6.42; CI = 2.32 - 17.80); age under 1 year (OR(aj) = 2.95; CI = 1.55 - 5.63); and serogroup B (OR(aj) = 2.33; CI = 1.14 - 4.79) . CONCLUSIONS: Septicemia, age and serogroup were predictive variables related to a fatal outcome . In 1996 and 1997, case-fatality rates were high, indicating the need to further assessment of the quality of the services delivered and their readiness to take preventive action . The lack of etiological identification in many cases precluded more accurate inferences about the epidemiological behavior of Neisseria meningitidis in the region.

Curr Opin Microbiol, 2001 Feb, 4(1), 47 - 52
Meningococcal pathogenesis: at the boundary between the pre- and post-genomic eras; Tinsley C et al.; Meningococcal disease remains an important public health burden worldwide and, indeed, cause of death, particularly in poorer countries . The rapidly progressive nature of infections means that antibiotic therapy often comes too late . Vaccines are of limited efficacy in infants, one of the most vulnerable age groups, and do not exist for bacteria of serogroup B . Hence, much remains to be achieved in terms of vaccine design and the understanding of the pathogenesis of meningococcal disease . The causative bacterium, Neisseria meningitidis, is usually a commensal of the nasopharynx . Factors that lead to the invasion of the bloodstream, often followed by the crossing of the blood-brain barrier and meningitis, may be partly host- and partly bacterium-dependent, but are ill-understood . It is hoped that, taken together with the fundamental knowledge gained from biochemical and genetic studies, the huge amount of new information made available with the recent publication of the genome sequences will help to unlock more of the secrets of the lifestyle and pathogenic potential of this still poorly understood pathogen.

Clin Microbiol Infect, 2000 May, 6(5), 259 - 62
Increasing microbiological confirmation and changing epidemiology of meningococcal disease on Merseyside, England; Carrol ED et al.; OBJECTIVES: To determine, for the last 5 years in children on Merseyside with clinical meningococcal disease (MCD), the impact on diagnostic yield of newer bacteriologic methods; bacterial antigen detection (AD) and polymerase chain reaction (PCR) . METHODS: Prospective data collection at Royal Liverpool Children's Hospital over two epochs: 1 September 1992 to 30 April 1994 (epoch A, n = 126) and 17 November 1997 to 15 September 1998 (epoch B, n = 85) . RESULTS: Epoch A was compared with epoch B . Diagnosis was confirmed by detection of meningococci in 78 of 126 (61.9%) versus 64 of 85 (75.3%, P = 0.04), but with a significantly lower rate of positive blood and cerebrospinal fluid culture in the later epoch . The proportion of cases receiving penicillin pretreatment was unchanged at 32%, but the proportion undergoing lumbar puncture decreased significantly . Median ages were higher in epoch B: 1.7 years versus 2.49 years (P = 0.013, Mann-Whitney) . There was a significant increase in the proportion of cases due to serogroup C (14/78 (18%) versus 30/64 (46.9%), P = 0.001) . CONCLUSIONS: Culture detection of meningococci from children with MCD has reduced, as less lumbar punctures are done . However, improved diagnosis by PCR and AD has increased microbiological confirmation overall . Serogroup C disease and the median age of cases continue to rise.

Clin Microbiol Infect, 2000 Jan, 6(1), 29 - 33
Use of an automated DNA analysis system (DARAS) for sequence-specific recognition of Neisseria meningitidis DNA; Seward RJ et al.; OBJECTIVES: To combine use of the polymerase chain reaction (PCR) for rapid diagnosis of meningococcal meningitis with a novel automated detection system for sequence-specific recognition of PCR products . METHODS: DNA was extracted from cerebrospinal fluid (CSF) by a quick boil-lysis method, followed by PCR with primers specific for Neisseria meningitidis . Sequence-specific recognition of N . meningitidis DNA was performed with an automated DNA analysis system (DARAS) and the data were compared with results following agarose gel electrophoresis or conventional microbiological culture . RESULTS: The DARAS system had a sensitive detection limit of 102 meningococci/mL with spiked samples, compared with a detection limit of 104 meningococci/mL following agarose gel electrophoresis . When the system was used to examine 74 CSF samples, the 19 CSF samples positive for N . meningitidis by conventional microbiological methods were also all positive in the DARAS system and the 55 samples negative by DARAS for meningococci were also negative by conventional microbiological methods . CONCLUSION: The sensitivity and specificity of the DARAS system makes it a useful tool for the diagnosis of meningococcal meningitis . The system is user-friendly, requires minimal hands-on time and generates data in an informative numerical format.

APMIS, 2000 Jul-Aug, 108(7-8), 509 - 16
Genosubtyping by sequencing group A, B and C meningococci; a tool for epidemiological studies of epidemics, clusters and sporadic cases; Molling P et al.; Genosubtyping, by sequencing variable regions (VRs) 1, 2 and 3 of the porA gene, was evaluated as a tool to detect clonality of isolates in meningococcal epidemics in Africa and clusters of disease in Sweden . All 63 examined meningococcal isolates were successfully genosubtyped . The isolates belonging to group A type 4 with genosubtype P1.20,9,35a showed little heterogeneity in African epidemics in 1988 and onwards . In Sweden, two meningococcal clones of group B type 15, with genosubtypes P1.7,16,35 and P1.7,16f,35, dominated during two clusters of meningococcal disease in 1995-96 and in sporadic cases thereafter . The characterisation of group C meningococci isolated during 1992 in Sweden indicated a cluster (type 2a with genosubtype P1.5a,10d,36b) connected with a discotheque visit . Two variants of VR2 (10p and 25b), not previously described, were found among the examined isolates . Nucleotide sequence analysis of VRs in the porA gene proved a valuable epidemiological tool since almost all isolates could be genosubtyped, in contrast to the phenotypic methods presently used.

Int J Pediatr Otorhinolaryngol, 2001 Feb, 57(2), 161 - 4
Meningococcal septicemia post adenotonsillectomy in a child: case report; Guirguis M et al.; Hemorrhage, nausea and vomiting and poor oral intake remain the most commonly encountered complications after adenotonsillectomy in the pediatric population . Life-threatening infectious complications such as meningitis have rarely been reported . We report a case of meningococcal septicemia complicating adenotonsillectomy in a 3-year-old male child . Possible etiologies postulated include: septicemia following transient bacteremia, increased meningococcal carrier rate, transient immune deficiency, and mucosal damage promoting bacterial translocation . This case highlights the responsibility of the otolaryngologist to maintain medical review, especially when recovery following TA is slow.

Vaccine, 2001 Jan 8, 19(11-12), 1327 - 46
Development of natural immunity to Neisseria meningitidis; Pollard AJ et al.; Although meningococcal disease is rare in industrialized nations, Neisseria meningitidis holds a prominent position amongst pediatric infections because of the dramatic clinical presentation of the disease, high mortality, epidemic potential and the recent disappearance of many other important infectious diseases in developed countries through improvements in public health and vaccination . The precise nature of natural immunity to meningococci remains unknown, although a complex interaction between the organism and nasopharyngeal mucosal barrier, innate immune mechanisms and acquired immunity is involved . Study of the mechanisms of natural immunity may provide the key to development of vaccines that can reduce the burden of disease in early childhood.

J Bacteriol, 2001 Feb, 183(4), 1233 - 41
A putatively phase variable gene (dca) required for natural competence in Neisseria gonorrhoeae but not Neisseria meningitidis is located within the division cell wall (dcw) gene cluster; Snyder LA et al.; A cluster of 18 open reading frames (ORFs), 15 of which are homologous to genes involved in division and cell wall synthesis, has been identified in Neisseria gonorrhoeae and Neisseria meningitidis . The three additional ORFs, internal to the dcw cluster, are not homologous to dcw-related genes present in other bacterial species . Analysis of the N . meningitidis strain MC58 genome for foreign DNA suggests that these additional ORFs have not been acquired by recent horizontal exchange, indicating that they are a long-standing, integral part of the neisserial dcw gene cluster . Reverse transcription-PCR analysis of RNA extracted from N . gonorrhoeae strain FA19 confirmed that all three ORFs are transcribed in gonococci . One of these ORFs (dca, for division cluster competence associated), located between murE and murF, was studied in detail and found to be essential for competence in the gonococcal but not in the meningococcal strains tested . Computer analysis predicts that dca encodes an inner membrane protein similar to hypothetical proteins produced by other gram-negative bacteria . In some meningococcal strains dca is prematurely terminated following a homopolymeric tract of G's, the length of which differs between isolates of N . meningitidis, suggesting that dca is phase variable in this species . A deletion and insertional mutation was made in the dca gene of N . gonorrhoeae strain FA19 and N . meningitidis strain NMB . This mutation abrogated the ability of the gonococci to be transformed with chromosomal DNA . Thus, we conclude that the dca-encoded gene product is an essential competence factor for gonococci.

J Antimicrob Chemother, 2001 Feb, 47(2), 219 - 22
Rifampicin-resistant meningococci causing invasive disease: detection of point mutations in the rpoB gene and molecular characterization of the strains; Stefanelli P et al.; Mutations in the rpoB gene affecting two amino acids were found in eight rifampicin-resistant Neisseria meningitidis group B and C strains isolated in Italy . The Asp542-->Val substitution, documented for the first time in N . meningitidis, was found in four of the isolates; the His552-->Tyr or Asn substitution in the other four resistant strains . Mutations in the mtr gene did not seem to be involved in the resistance since the same mutations occurred in both resistant and susceptible strains . Two different clusters were identified among these resistant strains, without any correlation with the specific mutations detected in the rpoB gene.

Rev Med Chil, 1999 Sep, 127(9), 1086 - 92
{Non linear analysis of infection diseases dynamics in Chile}; Canals M et al.; BACKGROUND: The incidence of infectious diseases generally has large fluctuations, probably due to interactions between seasonal fluctuations and those secondary to case-susceptible host interactions . AIM: To analyze the complexity and attractant topological resemblance of seven infectious diseases in Chile . MATERIAL AND METHODS: The annual incidence of measles, whooping cough, scarlet fever, meningococcal meningitis, diphtheria, typhoid fever and poliomyelitis was obtained from the annual reports of diseases . Correlation dimensions and the largest Lyapunov series exponents were estimated . The resemblance among their attractants was assessed by Hausdorff distance . The measures were performed both before and after seasonal filtering . RESULTS: All series showed a dynamics near low dimensional chaos . The correlation dimensions ranged between 2.12 and 2.76 . The correlation dimensions did not change after seasonal differentiation . Apart from one, all disease dynamics had large Lyapunov exponents, near 0.6 Bits/year . These decreased if series were differentiated . Before differentiation, the topological resemblance was mainly caused by the seasonal component of the dynamics but thereafter, the resemblance increased . In spite of different transmission mechanisms and etiologies, all analyzed infectious diseases conformed a truly single group, during cluster analyses . CONCLUSIONS: These results suggest that beneath the dynamics of infectious diseases, obscured by seasonal environmental factors, lays a very consistent nonlinear agent-susceptible host dynamics.

Med Dosw Mikrobiol, 2000, 52(3), 257 - 66
{Characterization of Neisseria meningitidis strains isolated from carriers}; Grzybowska W et al.; Neisseria meningitidis carriers strains were isolated from 17-19 teenagers (n = 14) and recruits (n = 267) . The longitudinal study comprises three meningococcal carriage trials performed on healthy young men during two--six months of their service in Polish military units . Altogether 54, 124 and 89 meningococcal strains were obtained during spring 1998 and autumn 1998, 1999 trials . Sixty two percent of meningococcal carrier strains were non-groupable, however among the remaining strains, serogroup B was predominant (29.5%) . During spring 1998 and autumn 1999 trials the predominant phenotypes were N . meningitidis NG:21:P1.7, but during the autumn 1998 NG:21:P1.7 or NG:NT:P1.5 . Ribotyping of type 21 and/or subtype P1.7 strains (n = 27) showed presence of 2 main ribotypes . Pulsed Field Gel Electrophoresis of consecutive isolates recovered from the same carrier showed great similarity of the patterns.

Med Dosw Mikrobiol, 2000, 52(3), 247 - 55
{Tests for Neisseria meningitidis in adolescents and adults (recruits)}; Tyski S et al.; No N . meningitidis strain was isolated from 168 children 14 years old . However, among 17-19 years old young people 14% meningococcal carriage rate was demonstrated . In three surveillance trials performed in military units in spring 1998 and autumn 1998 and 1999; 81, 225 and 153 isolates of N . meningitidis, respectively were obtained . A change in N . meningitidis carrier status was observed . At the autumn study, two times more N . meningitidis intermittent carriers were found than in the spring investigations . Among these population we found short-term and long-term carriers--last day of the longest trial--162 day . Meningococcal carriage rate increases among recruits in overcrowded living conditions.

Cytokine, 2001 Jan 21, 13(2), 91 - 7
Outer membrane vesicles from Neisseria meningitidis: effects on cytokine production in human whole blood; Mirlashari MR et al.; The Norwegian group B meningococcal outer membrane vesicle (OMV) vaccine consists of outer membrane proteins (OMPs) as main antigens with significant amounts of lipopolysaccharide (LPS; 5-9% relative to protein) . We have studied the ability of this OMV vaccine preparation to induce secretion of pro-inflammatory cytokines, tumour necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta), interleukin 6 (IL-6), interleukin 8 (IL-8) and anti-inflammatory cytokines, interleukin 4 (IL-4), interleukin 10 (IL-10) and interleukin 13 (IL-13) in a human whole blood model . Plasma levels of TNF-alpha, IL-1beta, IL-6 and IL-8 were massively increased; mean peak levels of TNF-alpha 44 696+/-7764, IL-1beta 38 043+/-5411, IL-6 10 057+/-1619 and IL-8 30 449+/-5397 pg/ml were obtained with an OMV-LPS concentration of 1 microg/ml; corresponding levels in control plasmas were below the detection limit of the assay . Mean maximal level of IL-10 (2540+/-144 pg/ml) was obtained at OMV-LPS concentration of 10 microg/ml, after 24 h; while the level in control plasma was below detection limit . OMV-LPS did not induce release of IL-4 and IL-13 in doses from 0.001-10 microg/ml . The present results show that OMVs from meningococci have potent pro-inflammatory properties and are likely to contribute to the observed local and systemic inflammatory effects .

Lancet, 2000 Dec 16, 356(9247), 2065 - 6
Production of low-avidity antibody by infants after infection with serogroup B meningococci; Pollard AJ et al.; Experimental serogroup B meningococcal vaccines have induced only poor immune responses and have had little protective efficacy in children younger than 1 year of age . We used ELISA with potassium thiocyanate to compare the average avidity of antibody produced by infants with that of children older than 10 years after systemic disease . Infants produced specific antibody of lower average avidity than older children--a finding that correlates with absence of serum bactericidal activity in the serum samples of the same infants.

Schweiz Rundsch Med Prax, 2000 Nov 23, 89(47), 1959 - 62
{Wxanthema and acute polyarthritis in a young patient}; Germann D et al.; A young woman developed acute polysynovitis and vasculitis-like changes to the skin . Her blood cultures were positive for Neisseria meningitidis, enabling us to diagnose chronic meningococcemia . This finding was a surprise; in retrospect this diagnosis would not have been expected in light of the fact that there was no meningism, the patient's general condition was only slightly diminished and the temperatures were subfebrile . Besides an episode of vasculitis, the primary differential diagnosis of acute polysynovitis in young women should include a bacterial infection, for example with Neisseria . Usually, Neisseria gonorrhoeae (gonococci) are involved and, as in the case described, only very rarely Neisseria meningitidis (meningococci) . The present case report is given to illustrate new clinical aspects of known, but rare disease, to remind clinicians to consider the differential diagnosis of acute polyarthritis and to generate discussion about the clinical signs and pathogenesis of reactive arthritides, in particular, Neisseria.

Nurs Crit Care, 2000 Mar-Apr, 5(2), 87 - 97
Use of a theoretical framework in paediatric intensive care to provide support for parents of children with severe meningococcal disease; Haines C; The impact on parents of having a child admitted to a paediatric intensive care unit (PICU) with meningococcal disease (MD) is discussed . Analysis, synthesis and evaluation of how nurses within a PICU can use a theoretical framework to identify and facilitate a decision-making process, regarding the support required by the parents of these children, is outlined . Peplau's interpersonal/conceptual framework is used as a basis for the investigation.

Int J Antimicrob Agents, 2001 Jan, 17(1), 27 - 31
Meningococcal disease in Slovenia (1993-1999): serogroups and susceptibility to antibiotics . Slovenian Meningitis Study Group; Cizman M et al.; The epidemiology of meningococcal disease was studied prospectively in Slovenia from 1993 to 1999 in children and from 1995 to 1999 in adults . Patients with meningococci isolated from normally sterile body sites were included in the study . Altogether 75 patients (57 children, 18 adults) were found with meningococcal diseases . The overall yearly incidence was 0.43 per 100000 inhabitants . The highest annual incidence (18.5/100000) was found in children between 1 month and 1 year of age . The case to fatality ratio was 4.1% . Group B meningococci were isolated most frequently (84.7%), followed by group C (11.1%) . In six patients (8.3%) isolates were less susceptible to penicillin . Four of these were successfully treated with penicillin alone.

Vaccine, 2000 Dec 8, 19(9-10), 1232 - 8
A randomised, double-blind, controlled trial of the immunogenicity and tolerability of a meningococcal group C conjugate vaccine in young British infants; English M et al.; A double-blind, randomised, controlled trial was conducted in 248 British infants to assess the immunogenicity and tolerability of three doses of a meningococcal group C/CRM (197) conjugate vaccine (Lederle Laboratories, USA) given at 2, 3 and 4 months . Control children received three doses of Hepatitis B vaccine (Engerix B(R); SmithKline Beecham) . At 5 months of age, 100% of children receiving the conjugate vaccine had specific immunoglobulin G concentrations >2.0 microg/ml (n=116) compared with only 4% of control children (n=121) . Those receiving the conjugate also had 2.5- and 1.6-fold higher geometric mean concentrations of PRP and diphtheria antibodies, respectively . The vaccine was well tolerated.

Vaccine, 2000 Dec 8, 19(9-10), 1141 - 8
Immunogenicity and safety of monovalent p1.7(h),4 meningococcal outer membrane vesicle vaccine in toddlers: comparison of two vaccination schedules and two vaccine formulations; de Kleijn ED et al.; The safety and immunogenicity of two PorA-based meningococcal outer membrane vesicle (OMV) vaccines against the P1.4 serosubtype adsorbed with AlPO(4) or Al(OH)(3) were studied in 134 toddlers . Vaccinations were given three times with an interval of 3-6 weeks or twice with an interval of 6-10 weeks . A vaccination was repeated after 20-40 weeks . Pre- and post-immunization sera were tested for bactericidal activity against an isogenic strain expressing P1.7(h), 4 PorA . Both meningococcal OMV vaccines were well tolerated . The percentage of children with a fourfold increase in bactericidal activity was 96% (AlPO(4)-adjuvated vaccine/2+1 schedule), 100% (AlPO(4)-adjuvated vaccine/3+1 schedule), 93% (Al(OH)(3)-adjuvated vaccine/2+1 schedule) and 97% (Al(OH)(3)-adjuvated vaccine/3+1 schedule) . Adsorption with AlPO(4) makes the OMV vaccine more immunogenic than adsorption with Al(OH)(3) . Bactericidal activity was highest after the 3+1 schedule, although the response shortly after the primary series was higher in the two-dose priming group.

Vaccine, 2000 Dec 8, 19(9-10), 1129 - 32
Reduced antibody response to revaccination with meningococcal serogroup A polysaccharide vaccine in adults; Borrow R et al.; Widespread use of meningococcal A and C polysaccharide (MACP) vaccines has raised concerns about induction of hyporesponsiveness to these polysaccharides . Immunological hyporesponsiveness to C polysaccharide has been clearly documented in infants, children and adults but only limited data from Gambian children are available for A polysaccharide . We investigated whether a second dose of MACP, given 6 months after an initial dose affected the immunological response as measured by the serum bactericidal assay (SBA) and enzyme-linked immunosorbent assay (ELISA), to serogroup A meningococci in young adults (university students, n=36) . Serogroup A SBA responses 1 month following the second dose of MACP (geometric mean titre (GMT) 103.6, 95% CI 45.6-235.1) were approximately one third of the levels observed 1 month post first dose (GMT 281.9, 95% CI 134.9-581.4) . The serogroup A-specific IgG levels post second dose (GMC 21.2, 95% CI 15.3-29.4) were also significantly lower at an average of three-quarters the level post first dose (GMC 28.7, 95% CI 20.8-39.7) . This confirms that revaccination with MACP vaccine, 6 months following the initial dose, results in a reduced immunological response to A polysaccharide in adults . Repeated vaccination with MACP vaccine may be ineffective and development and use of meningococcal serogroup A conjugate vaccines should be encouraged.

J Clin Microbiol, 2001 Jan, 39(1), 75 - 85
Evaluation of pulsed-field gel electrophoresis in epidemiological investigations of meningococcal disease outbreaks caused by Neisseria meningitidis serogroup C; Popovic T et al.; Since 1990, the frequency of Neisseria meningitidis serogroup C (NMSC) outbreaks in the United States has increased . Based on multilocus enzyme electrophoresis (MEE), the current molecular subtyping standard, most of the NMSC outbreaks have been caused by isolates of several closely related electrophoretic types (ETs) within the ET-37 complex . We chose 66 isolates from four well-described NMSC outbreaks that occurred in the United States from 1993 to 1995 to evaluate the potential of pulsed-field gel electrophoresis (PFGE) to identify outbreak-related isolates specific for each of the four outbreaks and to differentiate between them and 50 sporadic isolates collected during the outbreak investigations or through active laboratory-based surveillance from 1989 to 1996 . We tested all isolates collected during the outbreak investigations by four other molecular subtyping methods: MEE, ribotyping (ClaI), random amplified polymorphic DNA assay (two primers), and serotyping and serosubtyping . Among the 116 isolates, we observed 11 clusters of 39 NheI PFGE patterns . Excellent correlation between the PFGE and the epidemiological data was observed, with an overall sensitivity of 85% and specificity of 71% at the 95% pattern relatedness breakpoint using either 1.5 or 1.0% tolerance . For all four analyzed outbreaks, PFGE would have given public health officials additional support in declaring an outbreak and making appropriate public health decisions.

J Med Microbiol, 2000 Dec, 49(12), 1079 - 84
Investigation for a more virulent variant among the c:2b:P1.2,5 Spanish meningococcal epidemic strains by molecular epidemiology; Arreaza L et al.; A rise in the incidence of meningococcal disease has occurred in Spain in recent years, especially in some regions in the north-west of the country . Most cases have been caused by meningococci characterised as Neisseria meningitidis C:2b:P1.2,5 . A total of 107 C:2b:P1.2,5 meningococcal isolates (60 from patients and 47 from carriers) and 12 isolates showing related antigenic combinations (C:2b:NST, C:2b:P1.2, C:2b:P1.5, C:NT:P1.2,5) was analysed by pulsed-field gel electrophoresis to determine the genetic variability of the epidemic and related strains . Endonucleases BglII and NheI were used to cut chromosomal DNA . When BglII was used, most of the C:2b:P1.2,5 isolates showed the same pulsotype regardless of whether they were from clinical cases or carriers . Isolates showing the principal profile after digestion with endonuclease BglII were analysed with NheI . Four pulsotypes were identified, of which two were found in only one isolate each . The major profiles (1 and 2) showed differential distribution among clinical and carrier isolates; pulsotype 1 was the most frequent among clinical isolates . However, the proportions of isolates showing profiles 1 and 2 were similar among carrier isolates . This could indicate that there are two variants of the C:2b:P1.2,5 strain with differing pathogenicity.

J Reconstr Microsurg, 2000 Nov, 16(8), 603 - 7
Limb salvage after fulminant septicemia using a free latissimus dorsi cross-leg flap; Ninkovic MM et al.; A 15-year-old boy survived fulminant meningococcal septicemia, with extensive tissue necrosis involving the face and the right arm, complicated by peripheral gangrene of the fingers on both hands and the distal parts of the feet . Although still often fatal, the mortality of fulminant septicemia has dropped substantially in the past decades, leading to more survivors, and requiring concurrent reconstruction of all extremities . This report discusses the advantages of using a single, free, latissimus dorsi (LD) myocutaneous cross-leg flap to salvage both feet, and the use of pedicled groin flaps bilaterally for coverage of fingers and hands, as illustrated by this case.

Nihon Rinsho Meneki Gakkai Kaishi, 1999 Apr, 22(2), 53 - 62
{Clinical findings and genetic bases of congenital complement deficiencies}; Kira R et al.; The clinical findings and genetic bases of inherited deficiencies of plasma complement components and complement control proteins are reviewed . In Japan, since the frequencies of late complement component deficiencies (LCCD) are high, clinical features of neisserial infections associated with LCCD are described in details . C 9 deficiency is one of the most frequent genetic disorders in Japan and most of them are healthy . However, C 9 deficiency is weakly but significantly associated with the development of meningococcal meningitis but not of systemic lupus erythematosus . The common Arg 95 Stop mutation was found in most individuals with C 9 deficiency . Molecular epidemiologic study revealed that homozygous and heterozygous Arg 95 Stop mutation of C 9 gene is found in approximately one of 1000 individuals and one of 15 individuals, respectively . Complement studies including C 9 antigen and DNA analyses should be performed in patients with meningococcal meningitis or recurrent bacterial infections.

Clin Exp Immunol, 2000 Dec, 122(3), 312 - 5
Gram-negative bacteria induce proinflammatory cytokine production by monocytes in the absence of lipopolysaccharide (LPS); Uronen H et al.; Tumour necrosis factor-alpha (TNF-alpha), IL-1alpha and IL-6 production by human monocytes in response to a clinical strain of the Gram-negative encapsulated bacteria Neisseria meningitidis and an isogenic lpxA- strain deficient in LPS was investigated . Wild-type N . meningitidis at concentrations between 105 and 108 organisms/ml and purified LPS induced proinflammatory cytokine production . High levels of these cytokines were also produced in response to the lpxA- strain at 107 and 108 organisms/ml . The specific LPS antagonist bactericidal/permeability-increasing protein (rBPI21) inhibited cytokine production induced by LPS and wild-type bacteria at 105 organisms/ml but not at higher concentrations, and not by LPS-deficient bacteria at any concentration . These data show that proinflammatory cytokine production by monocytes in response to N . meningitidis does not require the presence of LPS . Therapeutic strategies designed to block LPS alone may not therefore be sufficient for interrupting the inflammatory response in severe meningococcal disease.

Clin Infect Dis, 2001 Jan, 32(1), 170 - 2 Epub 2000 Dec 13.
Choosing a route of administration for quadrivalent meningococcal polysaccharide vaccine: intramuscular versus subcutaneous; Ruben FL et al.; A clinical trial was conducted to compare intramuscular (im) with subcutaneous (sc) routes for administration of quadrivalent meningococcal polysaccharide vaccine in 141 adults . Safety assessment showed the im route had reduced erythema (P<.01) and reduced headache on days 1 and 2 (P<.05) . Serological testing for serum bactericidal antibody titers against capsular groups A and C did not detect significant differences.

Epidemiol Infect, 2000 Oct, 125(2), 277 - 83
Improved methods of detection of meningococcal DNA from oropharyngeal swabs from cases and contacts of meningococcal disease; Sadler F et al.; In the UK the increasing use of pre-admission parenteral antibiotic therapy in meningococcal disease has lessened the value of routine cultures as a tool to confirm diagnosis, and laboratory confirmation of invasive meningococcal infection is achieved increasingly by non-culture, nucleic acid amplification methods . The purpose of this study was to evaluate a DNA extraction and meningococcal-specific DNA amplification methodology for detection of meningococci from oropharyngeal swabs . One hundred and six swabs from suspected or confirmed cases of meningococcal disease, and 94 swabs from contacts of meningococcal disease cases were examined . Of laboratory-confirmed cases, 38/65 (58.5%) yielded a positive oropharyngeal swab PCR result and 5/24 (20.8%) swabs from suspected but laboratory-unconfirmed cases were PCR positive . No significant differences in PCR positivity rates were found between the types of swab transport systems utilized, but transport time to the testing laboratory was found to affect PCR positivity (P < 0.05) . Application of meningococcus-specific PCR to oropharyngeal swabs, in addition to routine culture of swabs, can provide valuable epidemiological information as well as case confirmation for contact management . PCR amplification of meningococcal PCR from oropharyngeal swabs will also increase the ascertainment in swabbing surveys carried out as part of meningococcal disease outbreak investigation and management.

Vaccine, 2000 Nov 22, 19(7-8), 716 - 25
Assessment of the stability and immunogenicity of meningococcal oligosaccharide C-CRM197 conjugate vaccines; Ho MM et al.; In this stability study, meningococcal C-CRM(197) conjugate vaccines from two different manufacturers that differ in oligosaccharide chain length, number of conjugation sites, conjugation chemistry, manufacturing process and formulation were used . Both the bulk concentrated and final fill preparations were incubated at -20, 4, 23, 37 or 55 degrees C for 5 weeks or subjected to ten cycles of freeze-thawing . The structural stability, hydrodynamic size and integrity of the treated vaccines were monitored by size exclusion chromatography (FPLC-SEC), high performance anion exchange chromatography coupled with pulsed amperometric detection (HPAEC-PAD) and fluorescence spectroscopy techniques . The data showed that the structural stability of the oligosaccharide chains and of the protein carrier varied between the two conjugates . The experimental immunogenicity was not severely affected by repeated freeze-thawing, incubation at -20 or 4 degrees C, but one developed conformational changes in the protein carrier when incubated at 23 degrees C or above, although the integrity of the oligosaccharide structure was maintained . This was not associated with any reduction in primary IgG or IgM antibody responses to meningococcal C polysaccharide . In the other conjugate vaccine, exposure to 55 degrees C resulted in the release of a substantial proportion of free saccharide that was accompanied by significant reduction in both IgG and IgM antibody responses to immunisation in the model system . In conclusion, the two meningococcal C-CRM(197) conjugate vaccines were stable when stored at the recommended temperatures, although their structural stability and subsequent immunogenicity were influenced by their conjugation chemistry and formulation.

J Paediatr Child Health, 2000 Dec, 36(6), 606 - 8
Meningococcal pericarditis in a 2-year-old child: reactive or infectious?
Beggs S, Marks M.
Pericarditis is an uncommon manifestation of infection of Neisseria meningitidis . Pericarditis may be caused by direct invasion or immune-complex-mediated (reactive) inflammation . We outline the case of a two-year-old girl with probable reactive pericarditis, review the cases reported in the English literature since 1966 and discuss the pathogenesis of meningococcal pericarditis.

Braz J Infect Dis, 1997 Oct, 1(5), 230 - 240
Efficacy and Tolerability of Liposomal Amphotericin B (Ambisome) in the Treatment of Visceral Leishmaniasis in Brazil; Freire M et al.; Thirty-two patients were enrolled in an open-label, dose/schedule ranging clinical trial to evaluate the efficacy and tolerability ofliposomal amphotericin B (Ambisome) in the treatment of visceral leishmaniasis . All patients received a dose of 2mg/kg daily for the first 4 days, followed by a single repeat dose of 2mg/kg at day 10 in 4 patients (total dose 10mg/kg); repeat doses on days 5, 6, and 10 in 13 patients (total dose 14mg/kg); or daily doses were continued on days 5 through 10 in 15 patients (total dose 20mg/kg) . Patients had a mean age of 9 years, ranging between 3 and 26 years . Their mean weight was 25.9kg, ranging between 9.5kg and 75kg . All patients had splenomegaly, 31/32 had hepatomegaly, and 20 patients tested had leishmania documented on splenic aspirate . Six of the 32 patients were treated after relapse following antimony therapy . The duration of illness prior to therapy was a mean of 2 months, ranging between 2 weeks and 23 months . During and after treatment, there were significant reductions in liver and spleen sizes, and significant increases in body weight, hemoglobin levels and white blood cell counts . All patients showed initial cure at the 1 month follow-up . Seven patients relapsed between 2 and 6 months after the start of treatment . There was no dose relationship to the occurrence of relapse . The relapse rate in children 5 years of age or less was 7/15 (47%) . Associated causes of relapse were refractory disease (i.e., previous relapses) in 2, severe malnutrition in 1, and concurrent disease (meningococcal meningitis) in 1 . In the other 2 cases, no associated event was observed except young age (ages 3 and 5 years) . One relapsed patient was treated successfully with 14 days of lipid amphotericin B, and the others were cured by use of antimony for 20 to 30 days . There were no dose related adverse events . The most common event was fever which occurred in 13/32 patients (41%); 3/4 patients in the 10mg dose group, 7/13 in the 14mg dose group, and 3/15 in the 20mg dose group . Three patients had cardiac arrhythmia, one also with myocarditis diagnosed 2 weeks after therapy was discontinued . One patient developed hepatitis after dose 3 and the drug was discontinued . We concluded that liposomal amphotericin B is effective in a daily dose of 2mg/kg given for 5-10 doses as an initial cure, but that relapse occurs in young children, particularly those with documented treatment resistant disease or concurrent malnutrition or infection . Patients should be carefully monitored for these risk factors before and during the months alter therapy, and for the occurrence of arrhythmia, cardio-pulmonary effects or hepatotoxicity . This treatment provides an important advance over previously used antimony therapy and appears to be more effective and well-tolerated than non-lipid amphotericin B.

J Clin Microbiol, 2000 Dec, 38(12), 4580 - 5
Fluorescent amplified-fragment length polymorphism genotyping of Neisseria meningitidis identifies clones associated with invasive disease; Goulding JN et al.; Fluorescent amplified-fragment length polymorphism (FAFLP), a genotyping technique with phylogenetic significance, was applied to 123 isolates of Neisseria meningitidis . Nine of these were from an outbreak in a British university; 9 were from a recent outbreak in Pontypridd, Glamorgan; 15 were from sporadic cases of meningococcal disease; 26 were from the National Collection of Type Cultures; 58 were carrier isolates from Ironville, Derbyshire; 1 was a disease isolate from Ironville; and five were representatives of invasive clones of N . meningitidis . FAFLP analysis results were compared with previously published multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE) results . FAFLP was able to identify hypervirulent, hyperendemic lineages (invasive clones) of N . meningitidis as well as did MLST . PFGE did not discriminate between two strains from the outbreak that were classified as similar but distinct by FAFLP . The results suggest that high resolution of N . meningitidis for outbreak and other epidemiological analyses is more cost efficient by FAFLP than by sequencing procedures.

J Clin Microbiol, 2000 Dec, 38(12), 4492 - 8
Carried meningococci in the Czech Republic: a diverse recombining population; Jolley KA et al.; Population and evolutionary analyses of pathogenic bacteria are frequently hindered by sampling strategies that concentrate on isolates from patients with invasive disease . This is especially so for the gram-negative diplococcus Neisseria meningitidis, a cause of septicemia and meningitis worldwide . Meningococcal isolate collections almost exclusively comprise organisms originating from patients with invasive meningococcal disease, although this bacterium is a commensal inhabitant of the human nasopharynx and very rarely causes pathological effects . In the present study, molecular biology-based techniques were used to establish the genetic relationships of 156 meningococci isolated from healthy young adults in the Czech Republic during 1993 . None of the individuals sampled had known links to patients with invasive disease . Multilocus sequence typing (MLST) showed that the bacterial population was highly diverse, comprising 71 different sequence types (STs) which were assigned to 34 distinct complexes or lineages . Three previously identified hyperinvasive lineages were present: 26 isolates (17%) belonged to the ST-41 complex (lineage 3); 4 (2.6%) belonged to the ST-11 (electrophoretic type {ET-37}) complex, and 1 (0.6%) belonged to the ST-32 (ET-5) complex . The data were consistent with the view that most nucleotide sequence diversity resulted from the reassortment of alleles by horizontal genetic exchange.

Int J Med Microbiol, 2000 Oct, 290(6), 511 - 8
The evolution of human pathogens: examples and clinical implications; Vogel U et al.; Recent advances in sequencing of complete bacterial genomes, molecular typing of micro-organisms, and research on microbial pathogenicity factors changed our view on the evolution of human bacterial pathogens . We review current evolutionary concepts on plague and meningococcal disease to illustrate the interplay of molecular phylogeny, epidemiology, and pathogenicity research . Furthermore, examples of the tremendous velocity of bacterial evolution under changing environmental conditions will be discussed.

Folia Microbiol (Praha), 1999, 44(6), 689 - 94
Direct PCR assay for detection of Neisseria meningitidis in human cerebrospinal fluid; Abdel-Salam HA; A PCR amplification was performed to detect Neisseria meningitidis insertion sequence 1106 (IS-1106) in the human CerebroSpinal Fluid (CSF) in cases of meningitis . The study included 27 CSF samples from suspected meningitis patients . Although the inflammatory response in most of the samples was slightly increased, the results showed that 7 (26%) and 8 (30%) CSF samples were diagnosed as meningococcal meningitis by Gram staining and by culture, respectively . The primers of the IS-1106 were used for direct diagnosis of N . meningitidis in the human spinal fluid after a minor treatment of the CSF samples . The sample was diagnosed as meningococcal meningitis, if a DNA band of about 600 bp was detected in the ethidium bromide-stained agarose gel . The 27 CSF samples were analyzed in a random manner . Of these, 18 samples including the Gram staining- and culture-positive samples were also positive in PCR amplification . However, a CSF sample, which was diagnosed to be meningococcal meningitis in culture was negative in both Gram staining and PCR analysis . The specificity of the IS-1106 primers was determined to be 95%, with 100% sensitivity in comparison to Gram staining and culture . The primers were sensitive to 10 pg or more of meningococcal DNA . In addition, the PCR amplification showed high predictive values (89 and 100%) in diagnosing meningitis in patients that were negative and positive responders when tested by culture and by Gram staining . In conclusion, the PCR amplification of IS-1106 of N . meningitidis is specific and sensitive to both culture-positive and -negative meningococcal meningitis . Hence, PCR assay is highly recommended for use in a rapid diagnosis of suspected meningitis patients.

Blood, 2000 Dec 1, 96(12), 3719 - 24
An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia; White B et al.; Activated protein C (APC) is a natural anticoagulant that plays a pivotal role in coagulation homeostasis . Severe inherited or acquired deficiency results in a clinical syndrome called purpura fulminans . In addition, APC also appears to have potent cytokine-modifying properties and is protective in animal models of sepsis . The dual functional properties of APC are particularly relevant to severe meningococcemia, where acquired PC deficiency is accompanied by multiorgan failure and purpura fulminans . The authors conducted an open-label prospective study assessing the efficacy of PC replacement therapy in patients with severe meningococcal septicemia, purpura fulminans, and multiorgan failure . The morbidity and mortality were compared with predicted morbidity using the Glasgow Meningococcal Septicemia Prognostic Score . Thirty-six patients with a mean age of 12 years (range 3 months to 72 years) were enrolled in the study . The mean +/- SD for plasma PC was 18 +/- 7 IU/mL . PC was significantly lower than antithrombin or protein S and was also significantly lower than PC levels in a cohort of patients who developed meningococcemia without multiorgan failure and purpura fulminans . A total of 3 of 36 (8%) patients died, which compares favorably with predicted mortality of 18 of 36 (50%) . Amputations were required in 4 of 33 (12%) survivors and in 2 of 31 (6.5%) patients who received PC within 24 hours of admission into the hospital, in comparison with the predicted amputation rate of 11 of 33 (30%) . In conclusion, PC replacement therapy in severe meningococcal septicemia was associated with a reduction in predicted morbidity and mortality . The beneficial effect of PC replacement may reflect both the anticoagulant and anti-inflammatory properties of the PC pathway . (Blood . 2000;96:3719-3724)

Lancet, 2000 Nov 11, 356(9242), 1654 - 5
Risk of secondary meningococcal disease in health-care workers; Gilmore A et al.; Guidelines on chemoprophylaxis vary between countries and reflect uncertainty about the risk of meningococcal disease in healthcare workers . In a retrospective survey of risk in healthcare workers in England and Wales, three pairs of primary cases and health-care workers with secondary infections were identified between 1982 and 1996 . Secondary infections were probably caused by exposure to primary cases' respiratory droplets around the time of admission . We estimated an attack rate of 0.8 per 100000 health-care workers at risk, a risk 25 times that in the general population (p=0.0003) . The excess risk is small and inappropriate use of prophylactic antibiotics should be avoided.

Lancet, 2000 Nov 11, 356(9242), 1653 - 4
Underestimation of meningococci in tonsillar tissue by nasopharyngeal swabbing; Sim RJ et al.; The relation between carriage of Neisseria meningitidis and progression to invasive disease is not fully understood . We assessed the rate of N . meningitidis carriage by conventional swabbing and immunohistochemistry in patients undergoing tonsillectomy . Swabbing detected only a quarter of carriers, and bacteria were identified beneath the mucosal surface in tonsillar tissue by immunochemical testing . Our results indicate that N . meningitidis is more widespread in the population than previously thought, and have broad implications for disease prevention and cure.

Arch Dis Child, 2000 Dec, 83(6), 510 - 3
Hypocalcaemia in severe meningococcal infections; Baines PB et al.; AIM: To determine the incidence of hypocalcaemia in critically ill children with meningococcal disease . METHODS: In a prospective cohort study, 70 of 80 patients admitted consecutively with a clinical diagnosis of meningococcal disease to intensive care had measurements of total and ionised calcium on admission . Parathormone and calcitonin were measured in a proportion of the children . RESULTS: Total and ionised calcium concentrations were low in 70% of the children . There was a weak relation of calcium concentration to the volume of blood derived colloid which had been given, but a good relation to disease severity, where sicker children had lower calcium concentrations . Although the parathormone concentration was higher in children with lower calcium concentrations, some children had low ionised calcium concentrations, without an increase of parathormone concentration . Serum calcitonin concentration was not related to calcium concentrations . CONCLUSION: Hypocalcaemia is common in meningococcal disease.

Arch Dis Child, 2000 Dec, 83(6), 508 - 9
Early filtration and mortality in meningococcal septic shock?
Pearson G, Khandelwal PC, Naqvi N.
Following the introduction of a policy of early therapeutic filtration for presumed meningococcal septicaemic shock, the overall mortality has decreased.

J Infect Dis, 2001 Jan 1, 183(1), 97 - 104 Epub 2000 Nov 15.
Immunologic memory 5 years after meningococcal A/C conjugate vaccination in infancy; MacLennan J et al.; Infant vaccination with meningococcal conjugates may provide long-term protection against disease . Antibody levels and immunologic memory were assessed in 5-year-old Gambian children who received meningococcal A/C conjugate vaccination (MenA/C) in infancy . At 2 years, they were randomized to receive a booster of MenA/C (conjugate group), meningococcal A/C polysaccharide (MPS group), or inactivated polio vaccine (IPV group) . All groups were revaccinated with 10 microg MPS at 5 years of age, as were 39 previously unvaccinated age-matched control subjects . Before revaccination, titers were higher in the conjugate and MPS groups than in control subjects (P<.001); titers for the IPV group were similar to those for control subjects . Ten days after revaccination, the conjugate and IPV groups had similar serogroup C serum bactericidal antibody titers (3421 vs . 2790, respectively) . These levels were significantly higher than those in the MPS (426) and control (485) groups (P<.001) . Thus, immunologic memory was sustained for > or =5 years; however, MPS challenge at 2 years interfered with a subsequent memory response.

Rev Esp Cardiol, 2000 Nov, 53(11), 1541 - 4
{Primary meningococcal pericarditis caused by meningococcus serogroup C}; Rayo Gutierrez M et al.; We report the case of a 15-year-old female, with no previous medical history, who presented cardiac tamponade secondary to purulent pericarditis caused by Neisseria meningitidis serogroup C . This microorganism is the etiologic agent in 6-16% of the cases of purulent pericarditis, most in association with previous or concomitant central nervous system involvement (meningitis) . Exceptionally, as in this case, the pericarditis is not accompanied by meningitis (Primary Meningococcal Pericarditis) . The patient was treated with antibiotics, pericardiocentesis and steroids with excellent response . It is important to point out that meningococcal disease may present in unusual forms which may lead to diagnostic and therapeutics difficulties.

J Biol Chem, 2001 Feb 23, 276(8), 5883 - 91 Epub 2000 Nov 17.
Construction of acetate auxotrophs of Neisseria meningitidis to study host-meningococcal endotoxin interactions; Giardina PC et al.; To facilitate studies of the molecular determinants of host-meningococcal lipooligosaccharide (endotoxin) interactions at patho-physiologically relevant endotoxin concentrations (i.e . < or =10 ng/ml), we have generated acetate auxotrophs NMBACE1 from encapsulated Neisseria meningitidis (serogroup B, strain NMB) and NMBACE2 from an isogenic bacterial mutant lacking the polysialic acid capsule . Growth of the auxotrophs in medium containing {(14)C}acetate yielded (14)C-lipooligosaccharides containing approximately 600 cpm/ng . Gel sieving resolved 14C-lipooligosaccharide-containing aggregates with an estimated molecular mass of > or =20 x 10(6) Da (peak A) and approximately 1 x 10(6) Da (peak B) from both strains . Lipooligosaccharides in peaks A and B had the same fatty acid composition and SDS-polyacrylamide gel electrophoresis profile . 14C-Labeled capsule copurified with (14)C-lipooligosaccharides in peak B from NMBACE1, whereas the other aggregates contained only 14C-lipooligosaccharide . For all aggregates, lipopolysaccharide-binding protein and soluble CD14-induced delivery of lipooligosaccharides to endothelial cells and cell activation correlated with disaggregation of lipooligosaccharides . These processes were inhibited by the presence of capsule but unaffected by the size of the aggregates . In contrast, endotoxin activation of cells containing membrane CD14 was unaffected by capsule but diminished when endotoxin was presented in larger aggregates . These findings demonstrate that the physical presentation of lipooligosaccharide, including possible interactions with capsule, affect the ability of meningococcal endotoxin to interact with and activate specific host targets.

Infect Immun, 2000 Dec, 68(12), 6917 - 23
Gene expression and production of tumor necrosis factor alpha, interleukin-1beta (IL-1beta), IL-8, macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, and gamma interferon-inducible protein 10 by human neutrophils stimulated with group B meningococcal outer membrane vesicles; Lapinet JA et al.; Accumulation of polymorphonuclear neutrophils (PMN) into the subarachnoidal space is one of the hallmarks of Neisseria meningitidis infection . In this study, we evaluated the ability of outer membrane vesicles (OMV) from N . meningitidis B to stimulate cytokine production by neutrophils . We found that PMN stimulated in vitro by OMV produce proinflammatory cytokines and chemokines including tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-8, macrophage inflammatory protein 1alpha (MIP-1alpha), and MIP-1beta . A considerable induction of gamma interferon (IFN-gamma)-inducible protein 10 (IP-10) mRNA transcripts, as well as extracellular IP-10 release, was also observed when neutrophils were stimulated by OMV in combination with IFN-gamma . Furthermore, PMN stimulated by OMV in the presence of IFN-gamma demonstrated an enhanced capacity to release TNF-alpha, IL-1beta, IL-8, and MIP-1beta compared to stimulation with OMV alone . In line with its downregulatory effects on neutrophil-derived proinflammatory cytokines, IL-10 potently inhibited TNF-alpha, IL-1beta, IL-8, and MIP-1beta production triggered by OMV . Finally, a neutralizing anti-TNF-alpha monoclonal antibody (MAb) did not influence the release of IL-8 and MIP-1beta induced by OMV, therefore excluding a role for endogenous TNF-alpha in mediating the induction of chemokine release by OMV . In contrast, the ability of lipopolysaccharide from N . meningitidis B to induce the production of IL-8 and MIP-1beta was significantly inhibited by anti-TNF-alpha MAb . Our results establish that, in response to OMV, neutrophils produce a proinflammatory profile of cytokines and chemokines which may not only play a role in the pathogenesis of meningitis but may also contribute to the development of protective immunity to serogroup B meningococci.

Infect Immun, 2000 Dec, 68(12), 6685 - 90
Multiple mechanisms of phase variation of PorA in Neisseria meningitidis; van der Ende A et al.; Previously, we reported that PorA expression in Neisseria meningitidis is modulated by variation in the length of the homopolymeric tract of guanidine residues between the -35 and -10 regions of the promoter or by deletion of porA . To reveal additional mechanisms of variation in PorA expression, the meningococcal isolates from 41 patients and 19 carriers were studied . In addition, at least 3 meningococcal isolates from different body parts of each of 11 patients were analyzed . Sequence analysis of the porA promoter showed that the spacer between the -35 and -10 regions varies in length between 14 and 24 bp . PorA expression was observed in strains with a porA promoter spacer of 16 to 24 bp . All but one strain with a porA promoter spacer of 16 to 20 bp and undetectable PorA expression have a homopolymeric tract of 8 or 6 instead of 7 adenine residues in the porA coding region . The other PorA-negative strain had a single-base-pair deletion in the coding region . The highest level of PorA expression was observed in strains with a promoter spacer of 17 or 18 bp . PorA expression was reduced twofold in strains with a porA promoter spacer of 16 or 19 bp . Strains with a 16-bp promoter spacer with substitutions in the polyguanidine tract displayed increased levels of PorA expression compared to strains with a homopolymeric tract of guanidine residues in the porA promoter . In conclusion, meningococci display multiple mechanisms for varying PorA expression.

Public Health Rev, 1999, 27(4), 297 - 310
Secular trends in the epidemiology of major infectious diseases among Israeli soldiers; Gdalevich M et al.; BACKGROUND: Army personnel, albeit in general young and healthy, are at greater risk for infectious morbidity owing to higher crowding, compromised hygienic conditions, and exposure to new geographic and climatic factors . We describe the changing trends in the incidence of major infectious diseases of public health importance in the Israeli military: hepatitis A, measles, meningococcal disease, and diarrheal diseases . METHODS: Departments of Epidemiology and Medical Statistics of the Israel Defense Forces Medical Corps monitor the incidence of infectious diseases within the military . Notifiable diseases are predefined and their reporting is mandatory . RESULTS: The incidence of hepatitis has declined significantly since the introduction of prophylaxis with immune serum globulin in the 1970s, and complete control of outbreaks has been achieved . Outbreaks of diarrheal diseases have decreased, probably as a result of intensive control measures begun in the last decade . However, sporadic diarrheal morbidity continues to rise . The vaccination of recruits against Neisseria meningitidis was begun in 1994, following an increase in cases caused by serogroup C bacteria . So far, the program has proved efficacious in reducing morbidity . Measles morbidity in the military was much higher than in the civilian sector over the years . It has become negligible since 1995, when the first cohorts with 2 vaccination doses began their service . CONCLUSION: Despite improvements in personal and environmental health measures, immunization remains the most efficient means for preventing infectious diseases in the military.

Plasmid, 2000 Nov, 44(3), 275 - 9
A new vector for insertion of any DNA fragment into the chromosome of transformable Neisseriae; Salvatore P et al.; A useful method for inserting any DNA fragment into the chromosome of Neisseriae has been developed . The method relies on recombination-proficient vector plasmid pNLE1, a pUC19 derivative containing (1) genes conferring resistance to ampicillin and erythromycin, as selectable markers; (2) a chromosomal region necessary for its integration into the Neisseria chromosome; (3) a specific uptake sequence which is required for natural transformation; (4) a promoter capable of functioning in Neisseria; and (5) several unique restriction sites useful for cloning . pNLE1 integrates into the leuS region of the neisserial chromosome at high frequencies by transformation-mediated recombination . The usefulness of this vector has been demonstrated by cloning the tetracycline-resistance gene (tet) and subsequently inserting the tet gene into the meningococcal chromosome .

J Infect Dis, 2001 Jan 1, 183(1), 160 - 3 Epub 2000 Nov 14.
Ability of 3 different meningococcal C conjugate vaccines to induce immunologic memory after a single dose in UK toddlers; Richmond P et al.; To test for immunologic memory after a single dose of meningococcal C conjugate (MCC) vaccine in toddlers, 226 children 12-18 months old were randomized to receive 1 of 3 MCC vaccines, with a C polysaccharide booster 6 months later . The protein conjugate was diphtheria mutant toxoid in 2 vaccines (MCC-CRM(197)) and was tetanus toxoid in the third (MCC-TT) . One month after the MCC vaccines, 91%-100% of children had serum bactericidal antibody (SBA) titers > or =8, and 89%-100% had a > or =4-fold increase . Geometric mean titer (GMT) increased from <4 to 215 (95% confidence interval {CI}, 166-279) . MCC-TT induced higher SBA GMTs (P<.001) and higher proportions with SBA > or =8 (P=.02) than did the MCC-CRM(197) vaccines . By 6 months, GMTs had decreased to 55.1 (95% CI, 40-76), but IgG antibody avidity increased (P<.001) . Induction of immunologic memory was confirmed by a GMT of 1977 (range, 1535-2547) after the polysaccharide booster and a further increase in avidity . This evidence justified the use of a single dose in a catch-up immunization program for children 1-18 years old.

Emerg Infect Dis, 2000 Nov-Dec, 6(6), 646 - 8
Meningococcemia in a patient coinfected with hepatitis C virus and HIV; Nelson CG et al.; We describe the first reported case of meningococcemia in a patient coinfected with hepatitis C virus and HIV . Hypocomplementemia secondary to hepatic dysfunction may have enhanced the patient's susceptibility to meningococcal infection.

J Infect Dis, 2001 Jan 1, 183(1), 89 - 96 Epub 2000 Nov 10.
A lipopolysaccharide-deficient mutant of Neisseria meningitidis elicits attenuated cytokine release by human macrophages and signals via toll-like receptor (TLR) 2 but not via TLR4/MD2; Pridmore AC et al.; Meningococcal disease severity correlates with circulating concentrations of lipopolysaccharide (LPS) and proinflammatory cytokines . Disruption of the lpxA gene of Neisseria meningitidis generated a viable strain that was deficient of detectable LPS . The potency of wild-type N . meningitidis to elicit tumor necrosis factor (TNF)-alpha production by human monocyte-derived macrophages was approximately 10-fold greater than that of the lpxA mutant . Killed wild-type N . meningitidis and its soluble products induced interleukin (IL)-8 and TNF-alpha secretion by transfected HeLa cells expressing Toll-like receptor (TLR) 4/MD2, but the lpxA mutant was inactive via this pathway . In contrast, both strains induced IL-8 promoter activity in TLR2-transfected HeLa cells . These data provide evidence that N . meningitidis contains components other than LPS that can elicit biological responses via pathways that are independent of the TLR4/MD2 receptor system, and TLR2 is one of these alternate pathways . These findings have implications for future therapeutic strategies against meningococcal disease on the basis of the blockade of TLRs and the modulation of LPS activity.

Infection, 2000 Sep, 28(5), 305 - 8
Ex vivo bactericidal activity against group C Neisseria meningitidis in seronegative subjects; Gomez-Lus ML et al.; BACKGROUND: To determine the anti-meningococcal C immunological activity by adding functional tests (opsonophagocytosis) to the classical serology techniques . SUBJECTS AND METHODS: 42 adult volunteers were screened using serological methods (determination of total and bactericidal antibodies) . Seronegative subjects were tested by opsonophagocytosis . RESULTS: 24 subjects (57%) showed serological evidence of previous contact with Neisseria meningitidis group C antigens: 19 subjects had both total and bactericidal antibodies, two subjects had only total antibodies and three subjects had only bactericidal antibodies . Of the 18 seronegative subjects, five showed ex vivo activity in killing curves with or without polymorphonuclear cells: two subjects exhibited only complement-mediated bactericidal activity, one subject only opsonophagocytosis, and two subjects exhibited both activities . CONCLUSION: The addition of functional tests to the classical serological determination increases the evidence of previous contact with N . meningitidis antigens by 12%.

Int J Clin Pract, 2000 Sep, 54(7), 470 - 1
'Acute abdomen' with a rash; Lannon DA et al.; A previously fit and healthy 17-year-old male presented with the clinical symptoms and signs of an acute abdomen and with the secondary complaint of a rash . In view of the primary presenting complaint he was admitted to the surgical ward . The patient was initially booked for an emergency exploratory laparotomy, but after reassessment on the ward a clinical diagnosis of meningococcal septicaemia was made . The patient was treated medically with intravenous antibiotics and supportive therapy, and made a complete recovery . Medical causes of abdominal pain, as exemplified here, can be more life threatening than surgical causes and should be considered in all patients.

J Infect Dis, 2000 Dec, 182(6), 1784 - 7 Epub 2000 Nov 08.
Bioactive cytidine deaminase, an inhibitor of granulocyte-macrophage colony-forming cells, is massively released in fulminant meningococcal sepsis; Boyum A et al.; Cytidine deaminase (CDD) catalyzes the hydrolytic deamination of cytidine, which thereby is converted to uridine . CDD is found in serum and different tissues, with particularly high concentrations in polymorphonuclear neutrophils (PMN) . We measured the CDD levels in plasma from patients with systemic meningococcal disease . Thirty-seven patients had significantly higher plasma levels of CDD than did 29 healthy control subjects (P=.0001) . CDD levels in plasma or serum increased from a median of 96 ng/mL in healthy control subjects to medians of 168 ng/mL in patients without persistent shock (n=23; P=.001) and 422 ng/mL in patients with fulminant meningococcal septicemia (n=14; P=.0001) . In most patients with fulminant septicemia, CDD levels in plasma increased during the first 3-53 h after the initiation of therapy (P=.003) . CDD alone had no immediate harmful effect when injected into mice during a 4-day period . CDD may modulate the stimulatory effect of colony-stimulating factors on PMN in patients.

Kansenshogaku Zasshi, 2000 Sep, 74(9), 720 - 3
{Meningococcemia associated with C7 deficiency}; Ozaki M et al.; We report a 20-year-old woman who developed meningococcemia . The patient developed fever, vomiting and skin rash, then was sent to our hospital for shock . Physical and laboratory examination revealed septic shock and DIC . Her blood culture grew Neisseria meningitidis (W135) . She recovered promptly with PCG, gabexate mesilate and intensive care for shock . Hemolytic activities of the patient's complement were less than 12/CH50 during the course . Screening for each component of the complements suggested that this patient had deficiency of C7 . Meningococcal disease has seldom seen in Japan . Early recognition is essential so that appropriate antibiotic therapy and supportive care can be promptly started because shock and death may ensure within hours after onset of symptoms.

FEMS Immunol Med Microbiol, 2000 Nov, 29(3), 169 - 76
Genetic and immunologic characterization of a novel serotype 4, 15 strain of Neisseria meningitidis; Bash MC et al.; The porin proteins of Neisseria meningitidis are important components of outer membrane protein (OMP) vaccines . The class 3 porin gene, porB, of a novel serogroup B, serotype 4, 15 isolate from Chile (Ch501) was found to be VR1-4, VR2-15, VR3-15 and VR4-15 by porB variable region (VR) typing . Rabbit immunization studies using outer membrane vesicles revealed immunodominance of individual PorB (class 3) VR epitopes . The predominant anti-Ch501 PorB response was directed to the VR1 epitope . Anti-PorB VR1 mediated killing was suggested by the bactericidal activity of Ch501 anti-sera against a type 4 strain not expressing PorA or class 5 OMPs . Studies that examine the molecular epidemiology of individual porB VRs, and the immune responses to PorB epitopes, may contribute to the development of broadly protective group B meningococcal vaccines.

Nat Med, 2000 Nov, 6(11), 1269 - 73
Functional genomics of Neisseria meningitidis pathogenesis; Sun YH et al.; The pathogenic bacterium Neisseria meningitidis is an important cause of septicemia and meningitis, especially in childhood . The establishment and maintenance of bacteremic infection is a pre-requisite for all the pathological sequelae of meningococcal infection . To further understand the genetic basis of this essential step in pathogenesis, we analyzed a library of 2,850 insertional mutants of N . meningitidis for their capacity to cause systemic infection in an infant rat model . The library was constructed by in vitro modification of Neisseria genomic DNA with the purified components of Tn10 transposition . We identified 73 genes in the N . meningitidis genome that are essential for bacteremic disease . Eight insertions were in genes encoding known pathogenicity factors . Involvement of the remaining 65 genes in meningocoocal pathogenesis has not been demonstrated previously, and the identification of these genes provides insights into the pathogenic mechanisms that underlie meningococcal infection . Our results provide a genome-wide analysis of the attributes of N . meningitidis required for disseminated infection, and may lead to new interventions to prevent and treat meningococcal infection.

J Clin Endocrinol Metab, 2000 Oct, 85(10), 3746 - 53
Endocrine and metabolic responses in children with meningoccocal sepsis: striking differences between survivors and nonsurvivors; Joosten KF et al.; To get insight in the endocrine and metabolic responses in children with meningococcal sepsis 26 children were studied the first 48 h after admission . On admission there was a significant difference in cortisol/ACTH levels between nonsurvivors (n = 8) and survivors (n = 18) . Nonsurvivors showed an inadequate cortisol stress response in combination to very high ACTH levels, whereas survivors showed a normal stress response with significantly higher cortisol levels (0.62 vs . 0.89 micromol/L) in combination with moderately increased ACTH levels (1234 vs . 231 ng/L) . Furthermore, there was a significant difference between nonsurvivors and survivors regarding pediatric risk of mortality score (31 vs . 17), TSH (0.97 vs . 0.29 mE/L), T3 (0.53 vs . 0.38 nmol/L), reverse T3 (rT3) (0.75 vs . 1.44 nmol/L), C-reactive protein (34 vs . 78 mg/L), nonesterified fatty acids (0.32 vs . 0.95 mmol/L), and lactate (7.3 vs . 3.2 mmol/L) . In those who survived, the most important changes within 48 h were seen in a normalization of cortisol and ACTH levels, but without a circadian rhythm; a decrease of rT3 and an increase in the T3/rT3 ratio; and a decrease in the levels of the nonesterified free fatty acids and an unaltered high urinary nitrogen excretion . At this moment, it is yet unknown whether the hormonal abnormalities are determining factors in the outcome of acute meningococcal sepsis or merely represent secondary effects . Understanding the metabolic and endocrine alterations is required to design possible therapeutic approaches . The striking difference between nonsurvivors and survivors calls for reconsideration of corticosteroid treatment in children with meningococcal sepsis.

Expert Opin Investig Drugs, 2000 Aug, 9(8), 1723 - 9
Cationic antimicrobial peptides: towards clinical applications; Hancock RE; Cationic antimicrobial peptides are important components of the innate immune defences of all species of life . Variants of these natural molecules have a broad range of antibiotic, antifungal, antiviral and anti-endotoxic activity . Two of these cationic peptides have shown signs of efficacy in early clinical trials of oral mucositis and the sterilisation of central venous catheters, respectively and are currently proceeding through Phase III clinical trials . Thus, cationic antimicrobial peptides are currently being investigated as topical agents . In addition, the cationic protein rBPI 21 has recently completed Phase III clinical trials of parenteral use for meningococcaemia.

Pediatr Int, 2000 Oct, 42(5), 534 - 40
Septic arthritis in childhood; Caksen H et al.; BACKGROUND: The purpose of the present study was to determine whether there was a difference between septic arthritis (SA) combined with osteomyelitis and SA alone with regard to clinical and laboratory findings, such as symptoms on admission, age, sex, joint involvement and isolated micro-organisms, and a relationship between age and joint involvement in SA . In addition, we also aimed to determine the prognostic factors in SA . METHODS: The clinical and laboratory findings of 40 patients who were diagnosed with SA in our hospital were reviewed retrospectively . The diagnosis of SA was made according to the following criteria: immediate joint fluid aspiration (culture and Gram's stain positive, leukocyte count markedly elevated and glucose level low), blood culture positive and positive cultures from other possible sites of infection . RESULTS: Of the 40 patients, 22 were boys, 18 were girls and the male to female ratio was 1.2/1 . Patient ages ranged from 6 months to 14 years (mean (+/- SD) 8.44 +/- 4.18 years) . The most observed symptoms were fever (52.5%), arthralgia (50%) and joint swelling (45%) . Thirty-four (85%) patients had only one joint and six patients (15%) had more than one joint involved . In total, arthritis was diagnosed in 49 joints . The joints diagnosed as having arthritis were the following: knee (n = 18), hip (n = 12), ankle (n = 12), elbow (n = 3), shoulder (n = 2), wrist (n = 1) and interphalangeal joint (n = 1) . Of the 40 patients, 21 (52.5%) had SA alone and 19 (47.5%) had arthritis together with osteomyelitis . While arthritis was diagnosed in 27 joints in the group of patients with SA, it was diagnosed in 22 joints in the group of patients with SA combined with osteomyelitis; in the latter, an increase was not observed in the number of joints involved . Joint fluid culture was positive in 22 (55%) patients; the growth of Staphylococcus aureus was observed in 20 cases and Pseudomonas aeruginosa and Staphylococcus epidermidis were isolated in each patient . In contrast, in one patient, arthritis occured during meningococcal meningitis (in this patient, Gram-negative diplococci was isolated from a cerebrospinal fluid culture) . Patients with SA combined with osteomyelitis and those with SA alone were compared for symptoms on admission, the history of trauma and antibiotic use, sex, age, fever, joint involvement, anemia, leukocytosis and micro-organisms isolated from joint fluid and blood; there were no significant differences for these parameters between the two groups (P > 0.05) . In addition, we found that there was no relationship between age and joint involvement in SA and there was no effect of micro-organisms on mortality . Three of 40 patients died; the mortality rate was 7.3% . Of the three patients who died, two had SA alone and one had SA combined with osteomyelitis . The primary disease was sepsis in these three patients; S . aureus was cultured from blood in two patients and Gram-positive cocci was observed following examination of the joint fluid in the other patient . CONCLUSIONS: We would like to emphasize that SA is mono-articular, frequently localized in the knee, hip and ankle in 85% of patients, joint fluid culture was positive in 55% of patients, bacteria was isolated from one or more cultures of blood, joint fluid, pus or bone in 70% of patients and the most common isolated micro-organism was S . aureus . In addition, it must be pointed out that children younger than 2 years of age with fever, a positive trauma history and/or abnormal joint findings should be carefully examined for SA because the rate of SA was lower (7.5%) than expected in this age group . We also found that the mortality of SA was not influenced by age, joint involvement and bacterial agents, and there was no significant difference in symptoms on admission, the history of trauma and antibiotic use, sex, age, fever, joint involvement,anemia, leukocytosis and micro-organisms isolated from joint fluid and blood between patients with SA

Epidemiol Infect, 2000 Aug, 125(1), 99 - 104
Carriage of N . lactamica in a population at high risk of meningococcal disease; Simmons G et al.; Carriage of Neisseria lactamica among household contacts of meningococcal disease (MCD) cases was investigated during an epidemic in Auckland, New Zealand . The overall carriage rate for N . lactamica was 10.5% (95% CI 7.4-13.5%) with a peak carriage rate in 2-year-olds of 61.5% (95% CI 26.6-88.1%) . Factors associated with a significant (P < 0.05) increase in the likelihood of carriage included runny nose, the number of people per bedroom and youth . Genetic analysis of isolates revealed a striking correlation of strains within the same household but a high level of diversity between households, suggesting that household contact is an important factor in acquisition . For household contacts aged less than 5 years, there was a higher rate of carriage amongst those in contact with MCD cases under 8 years old than for contacts of cases aged 8 years and over . It is likely that development of MCD is a reflection of the nature and intensity of the exposure to a virulent strain of N . meningitidis, coupled with an absence of host resistance among those individuals not carrying N . lactamica.

Scand J Infect Dis, 2000, 32(5), 527 - 31
Surveillance of cases of meningococcal disease associated with military recruits studied for meningococcal carriage; Andersen J et al.; Through a 14-months extended surveillance of meningococcal disease in Denmark, all 322 notified cases were investigated for possible connection with a military camp where 3 cohorts of recruits (n = 1069) were studied prospectively for meningococcal carriage . One case occurred in a recruit who was a constant non-carrier during the preceding 3 months . The invasive Neisseria meningitidis B:1:P1.1,7 strain was isolated from the pharynx only in 3 out of 17 room-mates (18%); the strains were identical as assessed by genotyping (PFGE and ribotyping) . Two civilian cases outside the camp had direct contact with 2 recruits, but neither these 2 nor other recruits in the relevant divisions carried the invasive strains on any occasion . Six civilian cases had marginal relationship with the camp, but no contact with the recruits . In conclusion, pheno- and genotyping concordantly demonstrated a high carriage rate of the invasive strain among the room-mates to a recruit with meningococcal disease . Transmission to the patient most likely occurred shortly before onset of illness . The extended surveillance did, however, not identify any unexpected epidemiological links and restriction of antibiotic chemoprophylaxis to household/sleeping/kissing contacts in sporadic cases of meningococcal disease seems appropriate and relevant.

Pediatr Infect Dis J, 2000 Oct, 19(10), 983 - 90
Household crowding a major risk factor for epidemic meningococcal disease in Auckland children; Baker M et al.; BACKGROUND: New Zealand is in its ninth year of a serogroup B meningococcal disease epidemic with annual rates of up to 16.9 cases per 100,000 . The highest incidence is in Maori and Pacific Island children in the Auckland region . We conducted a case-control study to identify potentially modifiable risk factors for this disease . METHODS: A case-control study of 202 cases of confirmed and probable meningococcal disease in Auckland children younger than 8 years of age recruited from May, 1997, to March, 1999, was undertaken . Controls (313) were recruited door-to-door by a cluster sampling method based on starting points randomly distributed in the Auckland region . They were frequency matched with the expected distribution of age and ethnicity in the meningococcal disease cases . RESULTS: With the use of a multivariate model and controlling for age, ethnicity, season and socioeconomic factors, risk of disease was strongly associated with overcrowding as measured by the number of adolescent and adult (10 years or older) household members per room {odds ratio (OR), 10.7; 95% confidence interval (CI), 3.9 to 29.5} . This would result in a doubling of risk with the addition of 2 adolescents or adults to a 6-room house . Risk of disease was also associated with analgesic use by the child, which was thought to be a marker of recent illness (OR 2.4, CI 1.5 to 4.0); number of days at substantial social gatherings (10 or more people for > 4 h; OR 1.8, CI 1.2 to 2.6); number of smokers in the household (OR 1.4, CI 1.0 to 1.8); sharing an item of food, drink or a pacifier (OR 1.6, CI 1.0 to 2.7); and preceding symptoms of a respiratory infection (cough, "cold or flu," runny nose, sneezing) in a household member (OR 1.5, CI 1.0 to 2.5) . CONCLUSION: Some of these identified risk factors for meningococcal disease are modifiable . Measures to reduce overcrowding could have a marked effect on reducing the incidence of this disease in Auckland children.

Lancet, 2000 Sep 16, 356(9234), 961 - 7
Recombinant bactericidal/permeability-increasing protein (rBPI21) as adjunctive treatment for children with severe meningococcal sepsis: a randomised trial . rBPI21 Meningococcal Sepsis Study Group; Levin M et al.; BACKGROUND: Endotoxin is a primary trigger of the inflammatory processes that lead to shock, multiorgan failure, and purpura fulminans in meningococcal sepsis . Bactericidal/permeability-increasing protein (BPI) is a natural protein, stored within the neutrophil granules, that binds to and neutralises the effects of endotoxin in vitro, in laboratory animals, and in humans . To establish whether a recombinant 21-kDa modified fragment of human BPI (rBPI21), containing the active antimicrobial and endotoxin-neutralising moiety, would decrease death and long-term disability from meningococcal sepsis, we did a randomised, double-blind, placebo-controlled trial of rBPI21 in children with severe meningococcal sepsis . METHODS: We enrolled children (2 weeks to 18 years of age) presenting to 22 centres in the UK and the USA with a clinical picture suggestive of meningococcal sepsis, and with evidence of severe disease . Children were randomly assigned rBPI21 (2 mg/kg over 30 min followed by 2 mg/kg over 24 h) or placebo (0.2 mg/mL human albumin solution) in addition to conventional medical therapy . Primary outcome variables were mortality, amputations, and change in paediatric overall performance category (POPC) from before illness to day 60 . Analysis was by intention to treat . FINDINGS: Of 1287 patients screened, 892 were excluded, including 57 patients who died or who met criteria for imminent death before receiving the study drug . 190 patients received rBPI21, and 203 placebo . 34 (8.7%) of 393 patients died during the study: 14 (7.4%) in the rBPI21 group and 20 (9.9%) in the placebo group (odds ratio 1.31 {95% CI 0.62-2.74}, p=0.48) . Compared with patients randomised to placebo, fewer patients treated with rBPI21 had multiple severe amputations (six of 190 {3.2%} vs 15 of 203 {7.4%}, odds ratio 2.47 {0.94-6.51}, p=0.067), and more had a functional outcome similar to that before illness (as measured by the POPC scale) at day 60 (136 of 176 {77.3%} vs 126 of 190 {66.3%}, p=0.019) . INTERPRETATION: Because most deaths occurred in the interval between identification of patients and study drug administration, the mortality rate in the placebo group was substantially lower than predicted . The trial was therefore underpowered to detect significant differences in mortality . However, patients receiving rBPI21 had a trend towards improved outcome in all primary outcome variables . Given the excellent severity match between placebo and rBPI21 groups at study entry, the results overall indicate that rBPI21 is beneficial in decreasing complications of meningococcal disease.

Mech Ageing Dev, 2000 Oct 20, 119(1-2), 9 - 13
Postnatal mortality from meningococcal infections during the period 1950-1991 in the US; Dolejs J et al.; Research has been conducted on the relationship between postnatal mortality from meningococcal infections and age, using data from the US during the period 1950-1991 . The logarithm of mortality caused by meningococcal infections fell linearly with the logarithm of age, during the interval of 1-30 years for men and women in the US . The slope of this straight line is equal to -1 . The mortality from meningococcal infections is inversely proportional to the age in the US . The risk of death at age 2 is one half of the risk at age 1, at age 3 it is one third of the risk of death at age 1, etc . up to the age of 30 in the US . The same decline was observed for the risk of death from congenital anomalies and pneumonia.

Int J Epidemiol, 2000 Oct, 29(5), 933 - 40
Effectiveness of incidence thresholds for detection and control of meningococcal meningitis epidemics in northern Togo; Kaninda AV et al.; BACKGROUND: Early outbreak detection is necessary for control of meningococcal meningitis epidemics . A weekly incidence of 15 cases per 100 000 inhabitants averaged over 2 consecutive weeks is recommended by the World Health Organization (WHO) for detection of meningitis epidemics in Africa . This and other thresholds are tested for ability to predict outbreaks and timeliness for control measures . METHODS: Meningitis cases recorded for 1990-1997 in health centres of northern Togo were reviewed . Weekly and annual incidences were determined for each district . Ability of different weekly incidence thresholds to detect outbreaks was assessed according to sensitivity, specificity, and positive and negative predictive values . The number of cases potentially prevented by reactive vaccination in 1997 was calculated for each threshold . RESULTS: Outbreaks occurred in 1995-1996 and in 1996-1997 . The WHO-recommended threshold had good specificity but low sensitivity . Thresholds of 10 and 7 cases per 100,000 inhabitants in one week had sensitivity and specificity of 100% and increased the time available for intervention by more than one or two weeks, respectively . A maximum of 65% of cases could have been prevented during the 1997 epidemic, with up to 8% fewer cases prevented for each week of delay in achieving vaccine coverage . CONCLUSIONS: In northern Togo, thresholds of 7 or 10 cases per 100,000 inhabitants per week were excellent predictors of meningitis epidemics and allowed more time for a reactive vaccination strategy than current recommendations.

J Immunol Methods, 2000 Oct 20, 244(1-2), 9 - 15
IgG antibody levels to meningococcal porins in patient sera: comparison of immunoblotting and ELISA measurements; Wedege E et al.; IgG antibody levels to the meningococcal PorA and PorB proteins in 56 acute and convalescent phase sera from 25 patients with meningococcal disease were compared by immunoblotting and ELISA . Heat-treated outer membrane vesicles from strain 44/76 (B:15:P1.7, 16) served as antigens for immunoblotting, whereas purified P1.7,16 PorA and P15 PorB from the same strain were used as antigens in the ELISA . In the blotting method, IgG binding to the porins was determined by digital scanning of the immunoreactive bands and calculated relative to the PorA binding of a reference serum on each blot . The coefficient of variation for the reference serum was 21.6% (a total of 144 strips) with smaller variations for each day's experiments . Blotting of all 56 sera at the standard 1/200 dilution measured anti-PorA and anti-PorB levels that correlated with those obtained by ELISA (Spearman rank-order correlation coefficient r(s)=0.48; P<0.001) . At this dilution, the anti-PorA (r(s)=0.52; P<0 . 004) and anti-PorB (r(s)=0.60; P<0.001) levels of the convalescent phase sera (n=29) corresponded with the ELISA measurements, whereas no correlation was found with the results for the acute phase sera, which mostly had low ELISA antibody levels (<2 microg/ml IgG) . A corresponding blot analysis of convalescent sera from the seven patients, who had received the 44/76 outer membrane vesicle vaccine, demonstrated a high correlation coefficient for the anti-PorA levels (r(s)=0.95; P<0.001) vs . the ELISA results . No such correlation was observed for the PorB response in these sera, being nine-fold higher than the PorA response, because of a prozone effect on the blots at the standard dilution . However, blotting at a higher serum dilution (1/2000) resulted in anti-PorB levels that also correlated strongly (r(s)=0.93 P<0.001) with the ELISA measurements.

Rev Esp Salud Publica, 2000 Jul-Aug, 74(4), 445 - 8
{Results of a serologic study after vaccination against serogroup C Neisseria meningitidis in children}; Espin Rios MI; BACKGROUND: An increase in the incidence of meningococcal disease in the Region of Murcia, Spain, during the 1996/97 season led the General Directorate for Health to carry out a Vaccination Campaign against the serogroup C meningococcus in September-October 1997 . The purpose of this study was to ascertain the percentage of children under 5 years of age who revealed post-vaccinal seroconversion one month following vaccination, and the percentage who retained immunity after one year . METHOD: The monitoring of 296 children between 18 and 59 months of age . The serological determinations were performed prior to vaccination, one month following vaccination and after one year . The antibody titres were determined according to a "bactericidal test" in the Center for Disease Control . RESULTS: Of the 296 children studied, only 11 (3.7%) revealed bactericidal antibody titres prior to vaccination . After one month, of the children who did not show antibodies prior to vaccination, 167 (63.7%) seroconverted . A statistically significant linear tendency (p < 0.001) of increase in the percentage of seroconversion in relation to the vaccination age was observed . One year after vaccination, from among the children seroconverted one month following vaccination, only 6 (4.3%) revealed bactericidal antibodies . CONCLUSION: The percentage of seroconversion in children under 5 years of age, following administration of the capsular polysaccharide C vaccine, was seen to clearly increase with the age of the subjects . The seroprotection acquired in vaccinated children declined quickly during the year following vaccination.

Rev Esp Salud Publica, 2000 Jul-Aug, 74(4), 433 - 44
{Levels of bactericidal antibodies against meningococcus C after vaccination in 2- to 6-year-old children in Andalusia}; Delgado Torralbo E et al.; BACKGROUND: In 1997, 18.5% of the cases of Meningococcal Disease caused b serogroup C in Andalusia were children between 2 and 4 years of age; ages where the initial immune response and the duration of the capsular A + C meningococcal polysaccharide vaccine is less than in older age groups . Research was designed in order to measure the immune response produced by this vaccine in children from 2 to 6 years of age and to compare it with the natural immunity present in unvaccinated children . METHODS: I . Dual monitoring study: a) groups of children vaccinated previously and control groups, b) groups of children who were going to be vaccinated, for pre and post-vaccination (1, 6 and 12 months) analysis and a control group . II . The bactericidal activity was measured according to the standardised protocol of the CDC with regard to the strain of N . meningitidis C-11 . The sera with bactericidal activity (TAB) > 1:8 were considered to be protective . RESULTS: 1 and 2 months following vaccination, the proportion of TAB > 1:8 was significantly higher than that of the control group (65.6% and 73% in comparison to 2.2% and 12%) . In the pre-vaccine and post-vaccine (after 6, 7, 12 and 13 months) verification, no significant difference between vaccinated individuals and controls was observed . CONCLUSIONS: The differences between vaccinated and unvaccinated individuals 1 and 2 months following vaccination indicate seroconversion in the vaccinated individuals . For the age group of between 2 to 6 years of age, the bactericidal activity acquired decline quickly, as, after 6 months, differences between this group and the control group are no longer observed.

Rev Esp Salud Publica, 2000 Jul-Aug, 74(4), 425 - 31
{Effectiveness and duration of the immunity of the vaccine against serogroup A+C meningococcus}; Garcia Comas L et al.; BACKGROUND: In 1995 the Community of Madrid detected an increase in the number of cases of meningococcal disease caused by serogroup C . In 1997 a mass vaccination campaign was carried out in relation to the population between 18 months and 19 years of age . The purpose of this study is to ascertain the immune response produced by the vaccine and its relationship to the age of the subjects . METHODS: A sample group of 1,003 children vaccinated during the campaign was selected . A blood sample was extracted prior to vaccination and after one, six (only a under 5 years old) and twelve months had transpired . In order to assess the immune response, the levels of bactericidal and total antibodies were measured . RESULTS: The prevalence of seroconversion measured by bactericidal antibodies is 89.6% . The response is low in children under 3 (34.8%), increases with age and, from 7 years on, surpasses the 90% mark . After 6 months, the prevalence of protective levels in children under 5 years of age drops noticeably (31.3%) . After one year, the prevalence drops significantly, particularly in children under 7 years of age . The proportion of individuals with total antibody response after one month is over 90%, and remains high after one year in all of the age groups (97.5%) . CONCLUSIONS: The response measured by means of total antibodies contradicts the clinical response to the vaccination and the measurement by means of bactericidal antibodies underestimates the protection if it is compared with the results of vaccinal efficacy, for which reason, we need to search for biological indicators that would correlate adequately with the clinical response following immunisation.

Rev Esp Salud Publica, 2000 Jul-Aug, 74(4), 413 - 7
{Surveys on the rates of healthy carriers of Neisseria meningitidis and charaterization of circulating strains}; Ramos Aceitero JM; BACKGROUND: During the epidemic season of 1996-97, the increase in the incidence of Meningococcal Disease caused by N . Meningitidis serogroup C led to the initiation of vaccination programmes and to the performance of a number of studies, among which, two were designed to ascertain the prevalence of healthy carriers and are presented here . METHODS: Healthy carriers in the population at large: cross survey performed between March and May 1998, among residents in Extremadura . We took two age groups: 0-19 years of age, vaccinated (n = 1,140) and 20 years of age and over (n = 1,193), unvaccinated . Healthy carriers in a military barracks: cross survey on a military base in May 1998 (n = 619), taking two groups: < 20 years of age (n = 453) vaccinated, and 20 years of age and over (n = 166) unvaccinated . RESULTS: Healthy carrier in the population at large . The percentage of carriers for all of the serogroups was: 0-19 years of age 7.98, 20 years of age and older 3.32, total 4.60, for serogroup B: 4.43, 2.25 and 2.84; for C: 0.04, 0.10 and 0.08 respectively . The differences between the two age groups in serogroup B and the total are statistically significant, as well as the greater prevalence of B over C . The subtype of the three samples with isolation of serogroup C was: one strain NT:P1.6, another strain 2b:P1.2, and one that could not be sub-typed . A strain that could not be classified into a serogroup was sub-typed as 2b:P1.5 . Healthy carriers in a military barracks . The percentage of carriers for all of the serogroups was: < 20 years 8.43, 20 years of age and over 6.84, total 7.27, for serogroup B: 4.82, 3.75 and 4.04; and for C: 0.60, 0.00 and 0.16 respectively . The higher prevalence obtained in military subjects in comparison with the population at large revealed statistically significant differences . Also, the prevalence of serogroup B was significantly higher than C . The only isolated C strain was sub-typed as: p1.2,5 . CONCLUSIONS: The prevalence of healthy carriers of N . meningitidis in the population at large was 4.60%, being higher in the lower age group and the barracks . Very low prevalence of serogroup C . Impossible to conclude that the strain N . meningitidis serogroup C was circulating during the 1997/98 season.

Rev Esp Salud Publica, 2000 Jul-Aug, 74(4), 405 - 11
{Evaluation of the vaccination campaign in Cantabria 2 years of epidemiological evolution}; Gonzalez de Aledo A et al.; The results of the meningococcal vaccination campaign carried out in Cantabria in February-March 1997 are presented . In the short term, the campaign reduced the rate of incidence in the risk group from 21.33/100,000 in the previous 12 months, to zero in the 12 months following the campaign . In the medium term (2 and a half years later), the rate of incidence was maintained 80% lower in the risk group and 77.3% lower in the population overall . The vaccinal efficacy in the third year following the campaign remained above 91% for all age groups, although some biases commented upon in the study have meant that this efficacy has been underestimated . Also, the vaccinal efficacy is much higher than the percentages of seroprotection measured by the rate of bactericidal antibodies, particularly in the younger age groups . The clinical cases in vaccinated individuals experienced a benign clinical course.

Rev Esp Salud Publica, 2000 Jul-Aug, 74(4), 397 - 403
{Evolution of meningococcal disease in the community of Madrid . Effectiveness of antimeningococcal A+C vaccination}; Gutierrez Rodriguez MA et al.; BACKGROUND: In 1997 (between 22 September and 14 November) an A + C meningococcal mass vaccination campaign was carried out in Madrid, targeting the age group of from 18 months to 19 years of age, in the face of an increase in the number of cases of meningococcal disease caused by serogroup C occurring in the 1996-97 season . This study forms a part of the impact assessment of that campaign . METHODS: The evolution of the meningococcal disease, by means of the comparison of rates of incidence; and the efficacy of the vaccination campaign was determined after one year (1997-98 season) and after two years (1997-98 and 1998-99 seasons) of monitoring . The vaccine efficacy has been calculated as {1-(Incidence rate in vaccinated/Incidence rate in unvaccinated)}* 100 . RESULTS: A significant drop was registered in the incidence of serogroup C meningococcal disease on comparing the 1997-98 and 1998-99 seasons with the epidemic season (1996-97) . The vaccine efficacy after two years of monitoring subsequent to the vaccination campaign was 76.9% for the global population between 18 months and 19 years of age and 88.5% in the group of vaccinated individuals between 15 and 19 years of age . CONCLUSIONS: The vaccine efficacy obtained is compatible with that described in the relevant literature . The significant reduction in the incidence of meningococcal disease caused by serogroup C was due to the vaccine efficacy obtained.

Rev Esp Salud Publica, 2000 Jul-Aug, 74(4), 387 - 96
{Meningococcal disease in Spain, 1990-1997 . Change in its epidemiological pattern}; de Mateo Ontanon S; BACKGROUND: In Spain, the presentation of meningococcal disease in the 1980s was closely linked to the predominance of N . Meningitidis serogroup B . This situation changed at the beginning of the 1990s, observing a growing trend of serogroup C strains in the isolation procedures carried out in some areas of the country, together with an increase in the incidence of the disease starting in the 1995-1996 season . The purpose of this study is to characterise the epidemiological pattern of meningococcal disease in Spain during the 1990-97 season and, in particular, where the disease was caused by the phenotype C:2b:P1.2.5 in this period of etiological change . METHODS: Retrospective study of the cases of meningococcal disease in Spain, with the exception of the Autonomous Communities of Andalusia, Cantabria, Madrid, Basque Country and Valencia, between 1990-1997 . The epidemiological data were obtained from the Compulsory Disease Reporting system, through individualised notification of cases, and the microbiological data from the Meningococcus Reference Laboratory of the National Microbiology Centre . RESULTS: The incidence of meningococcal disease in the period studied, 1990-1997, was 3.81 x 10 - 6 person-years, increasing by 0.1851 cases per 100,000 inhabitants per year . Starting in 1995, the incidence caused by serogroup C practically tripled with respect to the preceding period, with a rate of incidence in 1997 of 2 cases per 100,000 inhabitants . This increase was to a large extent due to the emergence of the phenotype C:2b:P1.2,5, which in that same year registered an incidence of 1 case per 100,000 inhabitants . The increase in incidence affected all age groups, but was particularly significant in the 5-19 year-old group (annual rate of growth: 13.3%; P < 0.001) . It was also found that there was an increase in the number of outbreaks reported and cases associated to them . The overall mortality rate was 7.7% (95% confidence interval: 7.0-8.4), and the mortality associated with the phenotype C:2b:P1.2.5 was significantly higher than that of the serogroup B chosen as reference (odds ratio: 1.69; 95% CI: 1.05-2.71), following adjustment for age, sex, clinical form and year . CONCLUSIONS: The pattern of meningococcal disease in the territory studied, during 1990-1997, was characterised by an increase in the incidence of serogroup C, particularly the emerging phenotype C:2b:P1.2,5 . Together with this increase, a displacement of the incidence to higher age groups was observed, together with a tendency towards temporospatial aggregations of cases and an increase in the mortality associated with the new phenotype . This pattern is characteristic of epidemic situations of meningococcal disease caused by serogroup C.

Rev Esp Salud Publica, 2000 Jul-Aug, 74(4), 381 - 6
{Results of a study on the under-detection of meningococcus in vaccinated subjects in Galicia}; Malvar Pintos A; BACKGROUND: On the basis of active surveillance and the monitoring of Meningococcal Disease (MD) following the vaccination campaign carried out in Galicia, it was observed that the proportion of isolations of the serogroups responsible for the disease among individuals suspected of Meningococcal Disease (SMD) who had been vaccinated was lower than among unvaccinated individuals . In view of this situation, a study was made in order to determine whether in the origin of those SMDs that were not isolated, we would find N . Meningitidis serogroup C, and to quantify the significance of the sub-detection of same . METHODS: For this purpose, and during the period under study (from the 26th week of 1997 to the 14th week of 1999), blood and cephalorachidian fluid samples were taken from the SMDs without isolation for their study with C protein reagent for type and serogroup . The analysis of the samples was performed by the microbiology laboratory of the Clinical Hospital of Santiago de Compostela . RESULTS: Of the 120 cases notified during the period under study, 65 were analysed by C protein reagent (38 vaccinated and 27 unvaccinated), with a positive reading for N . meningitidis in 65% (42 samples) 74% in vaccinated individuals and 52% in unvaccinated . By estimating, on the basis of the cases studied, the results for the total, and excluding the C protein reagent negative cases, we find that, for serogroup C, in only 27% of the cases occurring in vaccinated individuals was it possible to isolate it, in comparison with 80% in the case of unvaccinated subjects (p < 0.0001) . These percentages are, in the case of serogroup B, 59% and 71%, respectively, a difference which is not statistically significant . CONCLUSIONS: The vaccine brought about an true sub-detection of serogroup C meningococci in the vaccinated cases.

Rev Esp Salud Publica, 2000 Jul-Aug, 74(4), 377 - 9
{Situation of the epidemic strain C:2b:P1.2,5 of Neisseria meningitidis after A+C vaccination}; Alcala Galicia B et al.; Following the use of an extensive immunisation campaign targeting the population between ages 2 and 19 in the majority of the Autonomous Communities (Regions), for the purpose of controlling the "outbreak or epidemic wave" caused by serogroup C in 1996-97, there was great interest in ascertaining the situation of the well-known epidemic strain C:2b:P1.2.5, which had been identified as the cause of the changes brought about in the epidemiological profile of meningococcal disease in Spain, as this would enable us to analyse some of the possible future tendencies of this disease in our country . An analysis of the situation in the first 10 months of 1999 reveals that we have reverted to figures similar to those which, both insofar as the number of cases as well as the frequency of serogroups, were observed in Spain at the beginning of the decade of the nineties, although the epidemic strain C:2b:P1.2.5 represents 56% of the total cases of serogroup C . The strains of serotype 2a, very frequent in serogroup C in European countries, continue to represent a minority in Spain . Finally, it is of interest to mention the appearance of antigen variants which could be the result of processes of intra-specific genetic recombination and which would presumably have been selected in terms of their evolutive advantages.

Rev Esp Salud Publica, 2000 Jul-Aug, 74(4), 369 - 75
{Meningococcal disease . The situation in Spain in the 1998-1999 period}; Cano Portero R et al.; BACKGROUND: The change in the epidemiological pattern undergone by meningococcal disease in a large part of the country in the 1996-1997 season and the decision to intervene by means of a mass vaccination campaign in the age group between 18 months and 19 years of age, using a bivalent polysaccharide vaccine, justified to enhance the epidemiological surveillance of this disease . METHODS: Rates and other indicators of incidence and mortality were calculated for the 1998-1999 campaign by serogroup and age, according to the data notified to the Compulsory Disease Reporting System . RESULTS: The overall incidence was higher than the previous season, although, the rate ratio did not indicate a significantly greater risk . A statistically significant increase in the rate of incidence caused by serogroup B was registered, and for the second consecutive year, the serogroup C rate dropped, although not significantly . There was an increase in the number of deaths . The fatality rate due to serogroup C increased in the group between 1 and 4 years of age . The incidence remained high and with a clear seasonal pattern in the Communities that did not vaccinate . In the remainder, the incidence dropped and the seasonal pattern disappeared . CONCLUSIONS: Two years after the campaign, the predominance of serogroup B cases is generalised in all of the Autonomous Communities, except in the three where the immunisation was not performed . In the latter, in the course of the last two years, serogroup C has predominated . In the Communities where the vaccination campaign was carried out, there is an increase in the incidence, although not significantly, among children under 4 years of age.

Annu Rev Cell Dev Biol, 2000, 16, 423 - 57
Interactions of pathogenic neisseriae with epithelial cell membranes; Merz AJ et al.; The closely related bacterial pathogens Neisseria gonorrhoeae (gonococci, GC) and N . meningitidis (meningococci, MC) initiate infection at human mucosal epithelia . Colonization begins at apical epithelial surfaces with a multistep adhesion cascade, followed by invasion of the host cell, intracellular persistence, transcytosis, and exit . These activities are modulated by the interaction of a panoply of virulence factors with their cognate host cell receptors, and signals are sent from pathogen to host and host to pathogen at multiple stages of the adhesion cascade . Recent advances place us on the verge of understanding the colonization process at a molecular level of detail . In this review we describe the Neisseria virulence factors in the context of epithelial cell biology, placing special emphasis on the signaling functions of type IV pili, pilus-based twitching motility, and the Opa and Opc outermembrane adhesin/invasin proteins . We also summarize what is known about bacterial intracellular trafficking and growth . With the accelerated integration of tools from cell biology, biochemistry, biophysics, and genomics, experimentation in the next few years should bring unprecedented insights into the interactions of Neisseriae with their host.

Vaccine, 2000 Oct 15, 19(4-5), 547 - 56
Salivary antibody response to vaccination with meningococcal A/C polysaccharide vaccine in previously vaccinated and unvaccinated Gambian children; Nurkka A et al.; Development of salivary antibodies at the age of 4 or 5 years to group A and C meningococcal polysaccharides (MenA/C PS) was studied among Gambian children, who had received MenA/C conjugate or PS vaccine in infancy . There was also a control group of 64 age matched children . IgG, IgA, and secretory Ig concentrations were measured by enzyme immuno assay . MenA/C PS vaccine induced antibodies both in previously vaccinated and unvaccinated children . The previous vaccination had not induced long lasting IgA-mediated memory . IgA antibodies were secretory, and most of IgG was serum derived . The IgG salivary response seen was similar to the serum response.

Biochem Biophys Res Commun, 2000 Oct 14, 277(1), 51 - 4
Anti-PorA antibodies elicited by immunization with peptides conjugated to P64k; Sardinas G et al.; To increase the humoral immune response against two cyclic synthetic peptides, derived from variable regions within the outer membrane meningococcal protein PorA (subtypes 19 and 15), we conjugated the peptides to P64k, a novel carrier protein from the same bacterium expressed in Escherichia coli . In addition, one of these peptides was restricted to a linear conformation before it was chemically coupled to the carrier . The conjugates were administered to mice in a three-dose immunization schedule, resulting in a potent anti-peptide immune response, which suggested that chemical conjugation to this carrier provided T-cell help . Antisera directed to the three conjugates reacted with Neisseria meningitidis outer membrane PorA upon immunoblot analysis . Moreover, in two out of three conjugates, the anti-peptide sera reacted with native meningococcal outer membrane vesicles in ELISA .

J Infect, 2000 Sep, 41(2), 190 - 1
Acute meningococcaemia complicated by late onset gastrointestinal vasculitis; Seaton RA et al.; Extra-meningeal and non-cutaneous manifestations of meningococcal infection are well recognized but rare . Herein we report a little recognized complication of meningococcaemia, namely late-onset gastrointestinal vasculitis . In the case presented, the prostacycline analogue iloprost was used in an attempt to minimize incipient digital gangrene ina patient with evidence of protracted immunological phenomena . In addition, diclofenac was used to treat severe arthralgia . Withdrawal of iloprost on day 19 was associated with abdominal pain and peritonism . Laparotomy demonstrated ischaemia and ulceration in the caecum, and histology revealed full thickness mucosal ulceration with a prominent vasculitic process . It is postulated that these findings were immunologically mediated, with possible rebound vasoconstriction following withdrawal of iloprost . It is also possible that NSAID use contributed to the findings via cyto-toxicity to mucosal cells .

J Infect Dis, 2000 Nov, 182(5), 1557 - 60 Epub 2000 Oct 09.
An interleukin-1 genotype is associated with fatal outcome of meningococcal disease; Read RC et al.; To determine whether known variants of the interleukin-1 (IL-1) and tumor necrosis factor (TNF) gene families are associated with severe manifestations of meningococcal disease, 276 white patients 4-70 years of age (median, 17 years) were genotyped . All patients had microbiologically proven Neisseria meningitidis infection; 39 died and 237 survived . A significant association (P<.001) was found between fatal outcome and genotype at IL1B (nucleotide position -511) . Homozygous individuals, both for the common (1/1) and the rare (2/2) alleles, had increased odds ratios (ORs) for death, compared with heterozygous individuals (1/2): ORs (95% confidence intervals {CIs}) were 3.39 (1.39-8.29) and 7.35 (2.51-21.45), respectively . The mortality rates according to genotype at IL1B (-511) were 18.0% (1/1), 6.1% (1/2), and 32.3% (2/2), compared with 14.2% overall . The composite genotype, consisting of heterozygosity of IL1B (-511) together with homozygosity of the common allele of the IL-1 receptor antagonist gene (IL1RN) at +2018, was significantly associated with survival (P=.018; OR, 7.78 {95% CI, 1 . 05-59.05}) . There was no association between TNF genotype and fatal outcome . These data suggest that IL-1 genotype influences the severity of meningococcal disease.

J Med Microbiol, 2000 Oct, 49(10), 853 - 9
Diagnostic particle agglutination using ultrasound: a new technology to rejuvenate old microbiological methods; Ellis RW et al.; Microbial antigen in clinical specimens can be detected rapidly by commercial test-card latex agglutination, but poor sensitivity is a potential difficulty . Antigen detection by immuno-agglutination of coated latex micro-particles can be enhanced in comparison with the conventional test-card method in both rate and sensitivity by the application of a non-cavitating ultrasonic standing wave . Antibody-coated micro-particles suspended in the acoustic field are subjected to physical forces that promote the formation of agglutinates by increasing particle-particle contact . This report reviews the application of ultrasound to immuno-agglutination testing with several commercial antibody-coated diagnostic micro-particles . This technique is more sensitive than commercial card-based agglutination tests by a factor of up to 500 for fungal cell-wall antigen, 64 for bacterial polysaccharide and 16 for viral antigen (in buffer) . The detection sensitivity of meningococcal capsular polysaccharide in patient serum or CSF has been increased to a stage where serotyping by ultrasound-enhanced agglutination is comparable to that achievable with the PCR, but is available more rapidly . Serum antigen concentration as measured by ultrasonic agglutination has prognostic value . Increasing the sensitivity of antigen detection by increasing the acoustic forces that act on suspended particles is considered . Employing turbidimetry to measure agglutination as part of an integrated ultrasonic system would enable the turnover of large numbers of specimens . Ultrasound-enhanced latex agglutination offers a rapid, economical alternative to molecular diagnostic methods and may be useful in situations where microbiological and molecular methods are impracticable.

Eur Cytokine Netw, 2000 Sep, 11(3), 407 - 13
Activated protein C inhibits tumor necrosis factor and macrophage migration inhibitory factor production in monocytes; Schmidt-Supprian M et al.; The precise regulatory mechanisms of amplification and downregulation of the pro- and anti-inflammatory cytokines in the inflammatory response have not been fully delineated . Although activated protein C (APC) and its precursor protein C (PC) have recently been reported to be promising therapeutic agents in the management of meningococcal sepsis, direct evidence for the anti-inflammatory effect remains scarce . We report that APC inhibits in vitro the release of tumor necrosis factor (TNF) and macrophage migration inhibitory factor (MIF), two known cytokine mediators of bacterial septic shock, from lipopolysaccharide (LPS)-stimulated human monocytes . The THP-1 monocytic cell line, when stimulated with LPS and concomitant APC, exhibited a marked reduction in the release of TNF and MIF protein in a concentration-dependent manner compared to cells stimulated with LPS alone . This effect was observed only when incubations were performed in serum-free media, but not in the presence of 1-10% serum . Serum-mediated inhibition could only be overcome by increasing APC concentrations to far beyond physiological levels, suggesting the presence of endogenous serum-derived APC inhibitors . Inhibition of MIF release by APC was found to be independent of TNF, as stimulation of MIF release by LPS was unaltered in the presence of anti-TNF antibodies . Our data confirm that the suggested anti-inflammatory properties of APC are due to direct inhibition of the release of the pro-inflammatory monokine TNF, and imply that the anti-inflammatory action of APC is also mediated via inhibition of MIF release.

Commun Dis Public Health, 2000 Sep, 3(3), 177 - 80
Outbreak of group C meningococcal infection affecting two preschool nurseries; O'Donovan D et al.; Five cases of meningococcal infection caused by Neisseria meningitidis group C type 2a, subtype P1.5, P1.2 occurred within six days . Two of the affected children attended the same preschool nursery . The mother of two other children at the nursery was affected, as were the mother and sibling of another child (not a case) at the nursery . The 'sibling' case attended a different nursery . As the situation evolved, the control aspects of the outbreak changed . Antibiotic prophylaxis and vaccination were given to all staff and children attending both nurseries, and to parents, siblings, and household contacts of all children attending the first nursery.

Commun Dis Public Health, 2000 Sep, 3(3), 175 - 6
Optimising investigation of meningococcal disease to enhance surveillance; Khoobarry KC et al.; Efforts were made to implement guidelines for microbiologists in order to optimise investigation and improve laboratory confirmation in children admitted to hospital with suspected meningococcal disease . In 1998, 75% of diagnoses (30/40) were confirmed microbiologically, compared with 51% (209/411) of cases elsewhere in the West Midlands . Thirty-two of the children admitted to our paediatric unit (80%) were investigated according to the guidelines; 94% of these cases were laboratory confirmed . Microbiological confirmation of clinical meningococcal disease is all the more important with the advent of mass vaccination . Our study shows that implementation of guidelines for the investigation of clinically suspected meningococcal disease improves the rate of confirmation.

Commun Dis Public Health, 2000 Sep, 3(3), 172 - 4
Carriage of Neisseria meningitidis in residents and staff at a residential home for elderly people following a case of invasive disease; Irwin DJ et al.; A study of the carriage of Neisseria meningitidis among staff and residents of a 'closed community' (a residential home for elderly people) was conducted after a resident developed invasive meningococcal disease . All 39 other residents and 49 staff who worked at the home during the previous seven days were offered a throat swab and 38 residents and 49 staff consented . Two residents (none in the index case's social group) and one staff member were found to be carrying N . meningitidis, all phenotypically distinct from the infecting isolate . Thus, all four individuals carried different organisms and the index case was sporadic . Our findings suggest that residents or staff in long stay residential settings where a sporadic case occurs need not be offered meningococcal prophylaxis unless they fulfil the existing definition of 'close personal contacts' of the case.

Commun Dis Public Health, 2000 Sep, 3(3), 168 - 71
Outbreak of meningococcal disease in Rotherham illustrates the value of coordination, communication, and collaboration in management; Perrett K et al.; On New Year's Eve 1998, two teenagers from the same school in Rotherham died of serogroup C meningococcal septicaemia . A third linked case occurred three days later . Over eight days starting on New Year's Eve, a further five cases of meningococcal disease arose across Rotherham district, four of whom were severely ill with serogroup C meningococcal septicaemia . Intense media interest, high levels of public concern, and anxieties caused by several 'false alarm' cases added to the challenge faced by a small health district . This article describes the epidemiology of the incident and policy decisions made, but focuses on the operational aspects of outbreak management (coordination, communication, and collaboration), an area often neglected in outbreak reports.

Ultrastruct Pathol, 2000 Jul-Aug, 24(4), 273 - 7
Apparent progression of acute glomerulonephritis to dense deposit disease; Shahidi-Asl M et al.; One week after the diagnosis of meningococcal meningitis, an 8-year-old boy presented with acute renal failure and hypocomplementemia . A renal biopsy showed "postinfectious glomerulonephritis" and acute tubular necrosis . Hematuria, proteinuria, and low complement levels persisted, and 2 years later a follow-up renal biopsy revealed dense deposit disease . The apparent progression of postinfectious glomerulonephritis to dense deposit disease as observed in this patient has not been previously described.

Lancet . 2000 Sep 23;356(9235):1078.
Carriage of serogroup W-135, ET-37 meningococci in The Gambia: implications for immunisation policy?
MacLennan JM, Urwin R, Obaro S, Griffiths D, Greenwood B, Maiden MC.
We found high levels of symptomless carriage of a hyperinvasive Neisseria meningitidis strain (electrophoretic type 37 {ET-37}, serogroup W-135) during a vaccine trial in Gambian children in 1996 . Serogroup C, ET-37 complex meningococci cause 30-40% of meningococcal disease in countries such as the UK, and have a point prevalence of 0.5-1.0% . The recent Haj-associated spread of serogroup W-135, ET-37 complex meningococci, which has been accompanied by numerous secondary cases, might be explained by the apparently raised carriage rates reported here.

Crit Care Med, 2000 Sep, 28(9 Suppl), S64 - 7
Meningococcal disease as a model to evaluate novel anti-sepsis strategies; Cohen J; OBJECTIVE: To consider the appropriateness of meningococcemia as a clinical entity for the evaluation of anti-endotoxin agents . DATA SOURCES: English language published literature concerning meningococcemia, sepsis, and endotoxin . STUDY SELECTION: The purpose of this work is to consider some of the practical and scientific issues that arise in designing clinical trials to evaluate anti-endotoxin agents . A selected review of recently published articles was undertaken . DATA EXTRACTION AND SYNTHESIS: Relevant literature has been cited to support factual statements in the text . CONCLUSION: Meningococcemia as a paradigm of endotoxin-mediated Gram-negative sepsis has many advantages . It is a homogeneous population, and it represents a single, measurable, bacterial target that is unequivocally implicated in the pathogenesis of the disease . However, it is an uncommon disease that may develop so quickly that attempts to intervene may be too late to have an effect . There is considerable morbidity, but how best to measure the outcome and the extent to which the results can be extrapolated to adult populations with sepsis secondary to nosocomial infection remain unclear.

Crit Care Med, 2000 Sep, 28(9 Suppl), S60 - 3
Do new strategies in meningococcemia produce better outcomes?
Leclerc F, Leteurtre S, Cremer R, Fourier C, Sadik A.
Meningococcal septic shock (MSS) has high mortality and morbidity rates . In addition to the traditional prompt antibiotics and respiratory and circulatory support, new treatment strategies have been proposed . AGAINST THE INFLAMMATORY CASCADE: Immunotherapy, such as antiserum to Escherichia coli J5 and human antilipid A monoclonal antibodies/centoxin (HA-1A), did not significantly alter the mortality rate of MSS; we are awaiting the results of the bactericidal/permeability-increasing protein multicenter trial . Two series reported the effects of hemofiltration and hemodiafiltration in MSS, but the true benefits remain unknown . TO TREAT HEMOSTATIC ABNORMALITIES: In MSS, heparin is still controversial and antithrombin concentrate use has been reported in only one child . Several case reports on protein C and recombinant tissue plasminogen activator have been published; the efficacy (improvement in shock and organ dysfunction and reduction in amputation rate) and safety (intracerebral hemorrhage with recombinant tissue plasminogen activator) of these treatments need further evaluation . Blood and plasma exchange appear to be safe and are supposed to reduce mortality, but it is difficult to draw firm conclusions from published studies . Finally, local application of medicinal leeches has been reported to improve purpuric lesions . TO INDUCE VASODILATION: Prostacyclin, or epoprostenol, infusion, sodium nitroprussiate infusion, sympathetic blockade, and topical nitroglycerin have been reported to improve distal perfusion; however, these reports are all anecdotal . OTHER STRATEGIES: Improvement in limb perfusion was achieved after hyperbaric oxygenation in patients with purpura fulminans caused by different pathogens . Most authors recommend monitoring of compartment pressures and performing fasciotomy as indicated . Finally, extracorporeal membrane oxygenation was recently proposed to support seven children with intractable MSS . CONCLUSIONS: There is no proof that unconventional treatments have a significant impact on outcome in MSS; prospective multicenter trials are needed . At present, early recognition of meningococcal sepsis and appropriate treatment seem to be the optimal methods of improving outcome . Efforts to find an effective meningococcal vaccine must be continued.

Crit Care Med, 2000 Sep, 28(9 Suppl), S57 - 9
Meningococcemia as a model for testing the hypothesis of antisepsis therapies; Giroir BP; OBJECTIVE: To critically review the advantages and disadvantages of pediatric meningococcemia as a model for testing antisepsis therapies . DATA SOURCES: Research and review articles on the pathogenesis and treatment of human meningococcemia, as well as editorial commentaries discussing the failure of clinical trials for adult sepsis or Systemic Inflammatory Response Syndrome . Data from these sources are presented in the context of the author's experience as principal investigator in a large, randomized trial on children with invasive meningococcal disease . STUDY SELECTION AND DATA EXTRACTION: Studies were selected to include aspects of epidemiology, pathophysiology, outcome prediction, and therapeutic trials . DATA SYNTHESIS: Compared with an adult sepsis population, meningococcemia is a single disease, diagnosed clinically with high reliability . Patients are previously healthy, without underlying medical or surgical conditions . In contrast to sepsis trials, nearly all patients with meningococcal disease receive effective antibiotics . Finally, meningococcemia most closely resembles animal models of endotoxin infusion, in which most antisepsis therapies have been highly effective . However, the meningococcal model carries major disadvantages, among them that meningococcemia is rare and rapidly progressive and patients are widely dispersed geographically . In addition, a wide range of experimental therapies is routinely provided in an attempt to preserve life or limbs . CONCLUSIONS: Meningococcemia is an ideal model of a rapidly progressive bacterial infection associated with marked endotoxemia . Problems with the model can be overcome by extensive pretrial logistic planning, as well as close coordination and cooperation with national regulatory agencies.

FEMS Microbiol Lett, 2000 Oct 1, 191(1), 45 - 50
Peptide mimics elicit antibody responses against the outer-membrane lipooligosaccharide of group B neisseria meningitidis; Charalambous BM et al.; As an alternative approach towards the development of a meningococcal vaccine, the potential of peptide mimics of lipooligosaccharide (LOS) to elicit cross-reactive immune responses against LOS was investigated . The heptapeptides SMYGSYN and APARQLP were identified by enrichment from a coliphage display library with a LOS-specific monoclonal antibody . Mice immunised with these peptides conjugated to diphtheria toxoid elicited a total IgG response to LOS with geometric mean titres 2-4 times higher compared with non-immunised controls . There was an increase in LOS-specific IgG1 immunoglobulin, whereas specific IgG2a and IgG3 decreased slightly in response to immunisation . The data demonstrated that peptide mimics can elicit immune responses against meningococcal LOS.

J Biotechnol, 2000 Sep 29, 83(1-2), 27 - 31
Candidate Neisseria meningitidis NspA vaccine; Martin D et al.; The highly conserved NspA protein has been found in the outer membrane of every Neisseria meningitidis strain tested so far . Two monoclonal antibodies (MAbs) directed against this protein were used to demonstrate that biologically important epitopes of the NspA protein are exposed at the surface of serologically distinct meningococcal strains . Analysis of sera collected from mice that survived a deadly meningococcal challenge following immunization with recombinant NspA protein (rNspA) revealed the presence of cross-reactive antibodies which efficiently attached to and killed the four serogroup B strains tested . These data are additional proof that the NspA protein is exposed at the surface of intact meningococcal cells, which is an important characteristic for a vaccine candidate.

Microb Drug Resist, 2000 Summer, 6(2), 99 - 104
Transfer of penicillin resistance between Neisseriae in microcosm; Orus P et al.; Horizontal gene transfer between commensal and pathogenic Neisseriae is the mechanism proposed to explain how pathogenic species acquire altered portions of the penA gene, which encodes penicillin binding protein 2 . These changes resulted in a moderately penicillin-resistant phenotype in the meningococci, whose frequency of isolation in Spain increased at the end of the 1980s . Little has been published about the possibility of this gene transfer in nature or about its simulation in the laboratory . We designed a simple microcosm, formed by solid and liquid media, that partially mimics the upper human respiratory tract . In this microcosm, penicillin-resistant commensal strains and the fully susceptible meningococcus were co-cultivated . The efficiency of gene transfer between the strains depended on the phase of bacterial growth and the conditions of culture . Resistance of penicillin was acquired in different steps irrespective of the source of the DNA . The presence of DNase in the medium had no effect on gene transfer, but it was near zero when nicked DNA was used . Cell-to-cell contact or membrane blebs could explain these results . The analysis of sequences of the transpeptidase domain of PBP2 from transformants, and from donor and recipient strains demonstrated that the emergence of moderately resistant transformants was due to genetic exchange between the co-cultivated strains . Finally, mechanisms other than penA modification could be invoked to explain decreased susceptibility.

J Bacteriol, 2000 Oct, 182(19), 5391 - 8
Mutagenesis of Neisseria meningitidis by in vitro transposition of Himar1 mariner; Pelicic V et al.; Now that the meningococcal genome sequence has been completed, the lack of a suitable method for saturation mutagenesis remains a major obstacle to the unraveling of the pathogenic propensity of Neisseria meningitidis . Here, we demonstrate that in vitro Himar1 mariner transposition on chromosomal or PCR-amplified meningococcal DNA, which is subsequently reintroduced into N . meningitidis by natural transformation, is an extremely efficient mutagenesis method . Southern blot analysis, sequencing the Himar1 insertion point in numerous transposition mutants, and a limited screening of the mutant libraries for clones impaired in maltose catabolism confirmed that Himar1 transposed randomly in N . meningitidis . Taken together, these data demonstrate that Himar1 in vitro transposition can lead to the exhaustive mutagenesis of N . meningitidis, allowing for the first time a genomic-scale mutational analysis of this important human pathogen.

Epidemiol Infect, 2000 Jun, 124(3), 433 - 40
Prevention of secondary cases of meningococcal disease in Denmark; Samuelsson S et al.; Close contacts of cases of meningococcal disease are at increased risk of disease themselves . We identified household-like contacts of index cases, to investigate whether relevant target groups are informed, receive and follow recommended chemoprophylaxis and vaccination, and to ascertain the time delay for implementation of these measures . A telephone interview of 172 households of index cases and a questionnaire survey among 634 parents of contacts of cases in institutions were carried out . Results were compared with reports from Medical Officers of Health . In 21% of the cases, Medical Officers reported fewer household-like contacts than were identified in this study . Written information was effective . However, 59% of households, and 36% of parents of contacts in institutions felt a lack of information about how the disease is acquired, the risk and signs of illness . For household-like contacts the coverage rate for chemoprophylaxis with an appropriate drug was 90% and for vaccination 59% . No secondary cases occurred among those treated with chemoprophylaxis, but among those not treated, there were two secondary cases . The study design provided a useful audit methodology to evaluate the completeness of implementation and the success of prophylactic measures for meningococcal disease.

Epidemiol Infect, 2000 Jun, 124(3), 427 - 32
Induction of immunological memory in UK infants by a meningococcal A/C conjugate vaccine; Borrow R et al.; The induction of immunological memory to serogroup A and C polysaccharides in UK infants immunized with three doses of a meningococcal A/C oligosaccharide CRM197 conjugate vaccine was investigated . Forty UK infants vaccinated previously with three doses of a meningococcal A/C oligosaccharide-CRM197 conjugate vaccine at 2, 3 and 4 months of age, were revaccinated at a mean age of 145.6 weeks with either a 10 or 50 microg dose of licensed meningococcal A/C polysaccharide vaccine . Serogroup-specific antibody and serum bactericidal antibody (SBA) responses were measured by enzyme-linked immunosorbent assay and serum bactericidal assays, respectively . Following challenge, anti-serogroup A and C polysaccharide antibody levels rose from pre-booster geometric mean concentrations (GMC) of 3.1 and 2.1 microg/ml respectively to 19.6 and 21.0 microg/ml 1 month post-booster . Serum bactericidal antibody geometric mean titres (GMTs) for serogroups A and C increased 156- and 113-fold from 2.1 and 7.1 pre-booster respectively to 327.4 and 800.7 post-booster . A serogroup A control group of 45 children received a 10 microg dose of licensed meningococcal A/C polysaccharide vaccine (with no prior history of serogroup A vaccination) had serogroup A SBA GMTs of 2.3 pre-vaccination rising to 8 post-vaccination with corresponding GMCs of 0.8 and 10.8 microg/ml . These rises in SBA following serogroup A/C conjugate vaccination are indicative of immunological priming.

Commun Dis Intell, 2000 Jul, 24(7), 181 - 9
Annual report of the Australian Meningococcal Surveillance Programme, 1999; Group-C meningococcal conjunctivitis in a neonate; Department of Ophthalmology, Doncaster Royal Infirmary, Doncaster, United Kingdom . dina@thefree.net

Meningococcal conjunctivitis, although rare, may be complicated by ocular damage and systemic spread . Identification of the infecting organism is important for appropriate management . Meningococcal infection needs treatment of both the patient and the contacts . We report the use of meningococcal group-C vaccine in the prophylaxis of adult contacts of a neonate with meningococcal conjunctivitis . This measure, we believe, has not been reported before in the management of meningococcal conjunctivitis.

J Pak Med Assoc, 2000 Jun, 50(6), 184 - 6
Meningococcal infection among pilgrims visiting Madinah Al-Munawarah despite prior A-C vaccination; Yousuf M et al.; OBJECTIVE: To study the profile of meningococcal infection among pilgrims despite prior A-C vaccination . SETTING: King Abdul Aziz Hospital, Madinah Al-Munawarah, Saudi Arabia . SUBJECTS AND METHODS: Fifteen patients admitted to the hospital during the study period of April 1992 to June 1993 were evaluated prospectively regarding their clinical and laboratory features, culture and antibiotic sensitivity and meningococcal serotypes . RESULTS: Twelve cases presented as meningitis while 3 cases had meningococcaemia . Most (53.3%) were from Pakistan while rest were from 6 other countries . Clinical and laboratory features at presentation were similar as reported in the literature . In 13 cases where serotyping could be done, most belonged to group A (54%) and C (23%) . Antimicrobial sensitivity showed the isolates to be sensitive to most of the antibiotics commonly used to treat this infection . Mortality was 33% with the poorest outcome in patients with W135 infection . CONCLUSION: This study underscores the need of further studies in Makkah and Madinah, Saudi Arabia to find out the serotypes and immunological factors responsible for meningococcal infection in A-C vaccinated pilgrims so as to explore the possibility of use of polyvalent meningococcal vaccine.

Trans R Soc Trop Med Hyg, 2000 May-Jun, 94(3), 265 - 70
A severe epidemic of meningococcal meningitis in Nigeria, 1996; Mohammed I et al.; A particularly severe epidemic of meningococcal meningitis (cerebrospinal meningitis, CSM) occurred in Nigeria between January and June 1996 . There were 109,580 recorded cases and 11,717 deaths, giving a case fatality rate of 10.7% overall . This is the most serious epidemic of CSM ever recorded in Nigeria, and may be the largest in Africa this century . It took over 3 months and the combined efforts of a National Task Force set up by the Federal Ministry of Health, the WHO, UNICEF, UNDP, Medecins Sans Frontieres, the International Red Cross and several other non-governmental organizations to bring the epidemic under control . The main control measures centred on active treatment of infected persons, mass vaccination and health education . The exact number of persons treated cannot be ascertained, but there were treatment centres in almost every Local Government Area in the affected States . A study of 1577 patients admitted at the Infectious Diseases Hospital, Kano, showed that 84% of those infected were aged < or = 20 years and that, for the first time, infants aged < or = 2 months were affected . Despite intervention, the case fatality rate of 9.1% among this group of patients was similar to the nationwide figure of 10.7% . Long-acting oily chloramphenicol proved highly effective in the treatment of patients, and its routine use in epidemic CSM is recommended . Over 13 million persons were vaccinated in the course of the epidemic . For the first time, cases of CSM were reported from States south of the 'African meningitis belt', suggesting an extension of the belt . The severity of this epidemic yet again underscores the need for a clear policy regarding control measures aimed at forestalling future epidemics . The availability of the recently developed polysaccharide-protein conjugate vaccine should facilitate a decision on mass vaccination for the prevention of epidemic CSM in Africa.

Clin Diagn Lab Immunol, 2000 Sep, 7(5), 764 - 8
Relationship between serum bactericidal activity and serogroup-specific immunoglobulin G concentration for adults, toddlers, and infants immunized with neisseria meningitidis serogroup C vaccines; Sikkema DJ et al.; A new meningococcal group C-CRM(197) conjugate vaccine (MnCC; Meningitec) has been evaluated in multiple clinical trials in the United States and most recently has been approved for routine administration in the United Kingdom . Meningococcal serogroup C (MnC)-specific immunoglobulin G (IgG) antibodies in pre- and postimmunization sera obtained from healthy U.S . adults, toddlers, and infants were quantitated by enzyme-linked immunosorbent assay (ELISA) and by an antibody-dependent, complement-mediated serum bactericidal assay (SBA) . Serogroup-specific IgG antibody (micrograms per milliliter) in adults immunized either with the quadrivalent polysaccharide (A, C, Y, and W-135) vaccine or with MnCC showed a strong correlation (r = 0.848 and 0.934, respectively) by linear regression analysis with SBA . Sera from infants immunized with the MnCC (n = 30) and an age-matched unimmunized control group (n = 15) were also analyzed . Linear regression analysis of serum bactericidal and IgG ELISA data from sera obtained at 2 months of age (preimmunization) showed no correlation; however, a high degree of correlation was observed at time points after two (r = 0.877) and three (r = 0.951) immunizations, where significant rises in anti-MnC polysaccharide antibodies occurred relative to the age-matched control group . Infants previously primed with 3 doses of MnCC were given a booster dose of conjugate vaccine at 12 to 15 months of age . The correlation coefficient of ELISA to SBA for combined pre- and postbooster data was r = 0.836 (n = 48 pairs) . In conclusion, increases in serum bactericidal activity in immunized adult, toddler, and infant populations were found to correlate very well with increases in serogroup-specific IgG concentrations, whereas the correlation between these two assays in nonimmunized 2-month-old infants was poor . Characterizing the relationship between these methods is important for understanding the significance of antigen-specific antibody concentrations relative to vaccine performance and protection from disease.

Mol Microbiol, 2000 Sep, 37(5), 1094 - 105
Auto-transporter A protein of Neisseria meningitidis: a potent CD4+ T-cell and B-cell stimulating antigen detected by expression cloning; Ait-Tahar K et al.; A meningococcal genomic expression library was screened for potent CD4+ T-cell antigens, using patients' peripheral blood lymphocytes (PBLs) . One of the most promising positive clones was fully characterized . The recombinant meningococcal DNA contained a single, incomplete, open reading frame (ORF), which was fully reconstructed with reference to available genomic sequence data . The gene was designated autA (auto-transporter A) as its peptide sequence shares molecular characteristics of the auto-transporter family of proteins . Only a single copy of this gene was detected in the meningococcal, and none in the gonococcal, genomic sequence databases . The complete autA gene, when cloned into an expression vector, expressed a protein of approximately 68 kDa . Purified rAutA recalled strong secondary T-cell responses in PBLs of patients and some healthy donors, and induced strong primary T-cell responses in healthy donors . The human B-cell immunogenicity and cross-reactivity of AutA, purified under native conditions, was confirmed in dot immunoblot experiments . Immunoblots with rabbit polyclonal antibodies to rAutA demonstrated the conserved nature, antigenicity and cross-reactivity of AutA amongst meningococci of different serogroups and strains representing different hypervirulent lineages . AutA showed homology with another meningococcal and gonococcal ORF (designated AutB) . AutB was cloned and expressed and used to raise an autB-specific antiserum . Immunoblot experiments indicated that AutB is not expressed in meningococci and does not cross-react with AutA . Thus, AutA, being a potent CD4+ T-cell and B-cell-stimulating antigen, which is highly conserved, deserves further investigation as a potential vaccine candidate.

J Clin Microbiol, 2000 Sep, 38(9), 3323 - 8
Distribution of Neisseria meningitidis serogroup B serosubtypes and serotypes circulating in the United States . The Active Bacterial Core Surveillance Team; Tondella ML et al.; Because the Neisseria meningitidis serogroup B (NMSB) capsule is poorly immunogenic in humans, immunization strategies have focused on noncapsular antigens . Both PorA and to a lesser extent PorB are noncapsular protein antigens capable of inducing protective bactericidal antibodies, and vaccines based on the outer membrane protein (OMP) components of serogroup B meningococci have been shown to be effective in clinical trials . Multiple PorA antigens seem to be needed to prevent endemic meningococcal disease around the world, and a hexavalent PorA-based meningococcal vaccine has recently been developed in The Netherlands . To evaluate the distribution of NMSB PorA and PorB antigens in the United States, serosubtyping and serotyping were done on 444 NMSB strains isolated in the active surveillance areas of the United States (total population, 32 million) during the period 1992 to 1998 . A total of 244 strains were isolated from sporadic cases of meningococcal disease, and 200 strains were isolated from an epidemic in Oregon . A panel of 16 mouse monoclonal antibodies reactive with PorA and 15 monoclonal antibodies reactive with PorB were used . Among the NMSB isolates obtained from sporadic cases, the most prevalent serosubtypes were P1.7,16 (14.3%), P1.19,15 (9.8%), P1.7,1 (8.6%), P1.5,2 (7.8%), P1 . 22a, 14 (7.8%), and P1.14 (5.3%) and the most prevalent serotypes were 4,7 (27.5%), 15 (16%), 14 (8.6%), 10 (6.1%), 1 (4.9%), and 2a (3.7%) . A multivalent PorA-based OMP vaccine aimed at the six most prevalent serosubtypes could have targeted about half of the sporadic cases of NMSB disease that occurred between 1992 and 1998 in the surveillance areas . Twenty serosubtypes would have had to be included in a multivalent vaccine to achieve 80% coverage of strains causing sporadic disease . The relatively large number of isolates that did not react with murine monoclonal antibodies indicates that DNA sequence-based variable region typing of NMSB will be necessary to provide precise information on the distribution and diversity of PorA antigens and correlation with nonserosubtypeable isolates . The high degree of variability observed in the PorA and PorB proteins of NMSB in the United States suggests that vaccine strategies not based on OMPs should be further investigated.

Am Fam Physician, 2000 Aug 15, 62(4), 804 - 16
Evaluating the febrile patient with a rash; McKinnon HD Jr et al.; The differential diagnosis for febrile patients with a rash is extensive . Diseases that present with fever and rash are usually classified according to the morphology of the primary lesion . Rashes can be categorized as maculopapular (centrally and peripherally distributed), petechial, diffusely erythematous with desquamation, vesiculobullous-pustular and nodular . Potential causes include viruses, bacteria, spirochetes, rickettsiae, medications and rheumatologic diseases . A thorough history and a careful physical examination are essential to making a correct diagnosis . Although laboratory studies can be useful in confirming the diagnosis, test results often are not available immediately . Because the severity of these illnesses can vary from minor (roseola) to life-threatening (meningococcemia), the family physician must make prompt management decisions regarding empiric therapy . Hospitalization, isolation and antimicrobial therapy often must be considered when a patient presents with fever and a rash.

J Am Coll Health, 2000 Jul, 49(1), 7 - 11
Predictors of vaccination rates during a mass meningococcal vaccination program on a college campus; Paneth N et al.; Factors contributing to students' compliance with mass vaccination programs during meningococcal outbreaks have not been well described . A 1997 mass vaccination campaign at Michigan State University provided an opportunity to study such factors . Of 34,024 students in the target population, 17,538 (51.5%) were vaccinated in 5 days . Vaccination rates were higher for women (47.9%) than for men (43.1%) and higher for on-campus residents (65.3%) than for off-campus residents (35.6%) . For each year of students' age beyond 19, the adjusted odds of vaccination were reduced by 0.82 . Adjusted odds ratios for vaccination, with White students as the reference group at 1.0, were 1.33 for Asian American students, 0.97 (not significant) for Hispanic students, 0.82 for African American students, and 0.80 for Native American students . Students from the Colleges of Business, Engineering, Communication, and Natural Science had the highest vaccination rates; those from the College of Arts and Letters had the lowest rates.

Crit Care Med, 2000 Aug, 28(8), 3002 - 8
Increased excretion of urinary glycosaminoglycans in meningococcal septicemia and their relationship to proteinuria; Oragui EE et al.; OBJECTIVES: Meningococcal septic shock is a devastating illness associated with an increase in vascular permeability leading to hypovolemia and accumulation of plasma proteins and fluid in tissues . The capillary leak syndrome is often associated with widespread thrombosis in the skin, limbs, and digits . We postulated that the increase in vascular permeability and the intravascular thrombosis might be caused by an inflammation-induced loss of endothelial and basement membrane glycosaminoglycans (GAGs), which play a role in the permeability and thromboresistant properties of the microvasculature . DESIGN: Prospective, single-center observational study . SETTING: University-affiliated meningococcal research unit and pediatric intensive care unit . PATIENTS: Eighteen children requiring intensive care for meningococcal sepsis, 18 children with steroid-responsive nephrotic syndrome, and 18 healthy control children . INTERVENTIONS: None . MEASUREMENTS AND MAIN RESULTS: Serum concentrations and urine excretion of glycosaminoglycans were measured and related to changes in glomerular permeability to plasma proteins . The size-distribution and nature of glycosaminoglycans were defined by Polyacrylamide Gel Electrophoresis and specific enzyme digestion . Urinary excretion of heparan sulfate, chondroitin-4-sulfate, and chondroitin-6-sulfate were significantly increased in meningococcal disease (MD) relative to healthy controls and children with steroid-responsive nephrotic syndrome . The urinary GAGs in MD were of similar size to those in controls when analyzed after pronase digestion . However, analysis of proteoglycan size before proteolytic digestion showed the urinary GAGs in MD were of lower molecular weight and unattached to proteins . The fractional excretion of albumin and immunoglobulin G in MD increased with severity of disease . Patients with severe or fatal MD had albumin clearances overlapping those seen in steroid-responsive nephrotic syndrome . There was a significant correlation between proteinuria in MD and urinary excretion of heparan sulfate (r2 = 0.611, p < .0001), chondroitin-4-sulfate (r2 = 0.721, p < .0001), and chondroitin-6-sulfate (r2 = 0.395, p < .0001) . CONCLUSIONS: The capillary leak in meningococcal disease is associated with increased plasma and urine concentrations of GAGs, which may be proteolytically cleaved from endothelial and basement membrane sites . The correlation between the severity of protein leakage and the urine excretion of GAGs suggests that loss of GAGs may be causally related to the increase in permeability to proteins.

Crit Care Med, 2000 Aug, 28(8), 2979 - 83
A myocardial cytotoxic process is involved in the cardiac dysfunction of meningococcal septic shock; Thiru Y et al.; OBJECTIVE: Myocardial dysfunction is a characteristic component of meningococcal septic shock and contributes to the persisting high mortality from the disease . Specific treatment of the myocardial failure has been hampered by the lack of understanding of its pathophysiology . We were interested to determine whether myocardial cell death was occurring in the presence of meningococcal septicemia and whether it correlated with the degree of left ventricular dysfunction and disease severity . We therefore investigated the release of cardiac troponin I (cTnI), a sensitive and specific marker of myocardial cell death, and related this to the severity of disease and cardiac dysfunction . DESIGN: Prospective study SETTING: Pediatric intensive care unit SUBJECTS: Patients admitted to the pediatric intensive care unit with a diagnosis of meningococcal septicemia . INTERVENTIONS: Serum concentrations of cTnI were determined at admission to intensive care in 101 children with meningococcal septicemia and serially in 37 children . Changes in cTnI were related to disease severity as measured by the Pediatric Risk of Mortality score and two markers of cardiac dysfunction . MEASUREMENTS AND MAIN RESULTS: Serum concentrations of cTnI were elevated above the range for healthy children in 24% of children with meningococcal septicemia at admission and in 62% of patients within 48 hrs . The peak concentrations occurred between 12 and 36 hrs after admission . There were significant correlations between cTnI levels and disease severity and between cTnI levels and the degree of myocardial depression measured by quantitative transthoracic echocardiography and peak inotrope requirements . CONCLUSIONS: The elevated serum concentrations of cTnI indicate that myocardial cell death is occurring in meningococcal septicemia . The relationship between cTnI and markers of myocardial function suggest that the cell death may have a role in the pathogenesis of myocardial dysfunction in meningococcal septicemia . Elucidation of the mechanism responsible for myocardial injury may lead to the development of therapeutic interventions to prevent or limit this cardiac damage.

Crit Care Med, 2000 Aug, 28(8), 2967 - 73
Comparison of the performance of two general and three specific scoring systems for meningococcal septic shock in children; Castellanos-Ortega A et al.; OBJECTIVE: To evaluate the performance at admission to the pediatric intensive care unit (PICU) of five severity scores, two general (the Pediatric Risk of Mortality {PRISM} II and III scores) and three specific for meningococcal septic shock (Leclerc, Glasgow Meningococcal Septicemia Prognostic Score {GMSPS}, and Gedde-Dahl's MOC score) in children with this condition . DESIGN: Multicenter, retrospective, cohort study . SETTING: The PICUs from four tertiary centers . PATIENTS: Patients were 192 children ranging in age from 1 month to 14 yrs consecutively admitted to the participating PICUs during a period of 12 yrs and 6 months (January 1983 to June 1995), who were diagnosed with presumed or confirmed meningococcal septic shock . Patients with a length of stay <2 hrs were excluded from the study . INTERVENTIONS: Clinical and laboratory data gathered during the first 2 hrs after admission were used to compute the scoring systems tested . MEASUREMENTS AND MAIN RESULTS: There were 66 deaths (34%) . Neisseria meningitidis was cultured from 142 (74%) children . GMSPS and PRISM II provided the best discriminative capability, as measured by the area under the receiver operating characteristic curve (SEM): 0.816 (0.036) and 0.803 (0.041), respectively . The other three scores gave lower receiver operating characteristic areas: PRISM III = 0.777 (0.043), MOC = 0.775 (0.037), and Leclerc = 0.661 (0.045) . There was a statistically significant difference between the areas under the receiver operating characteristic curve of GMSPS and Leclerc (p < .01) but not between the GMSPS and the remaining three scores . All five scores presented good calibration with no significant differences between observed and predicted mortality (Hosmer-Lemeshow goodness-of-fit test) . CONCLUSIONS: The specific GMSPS and the general pediatric severity system PRISM II performed better than the other three scores, being appropriate tools to assess severity of illness at admission to the PICU in children with presumed meningococcal septic shock.

Res Microbiol, 2000 Jul-Aug, 151(6), 465 - 9
Estimating the relative contributions of mutation and recombination to clonal diversification: a comparison between Neisseria meningitidis and Streptococcus pneumoniae; Feil EJ et al.; Both Neisseria meningitidis and Streptococcus pneumoniae are naturally transformable species and are known to be freely recombining in the wild . Large multilocus sequence typing (MLST) datasets have been generated for these species . Here we outline an approach which exploits these data sets in order to quantify the extent of recombination, thus enabling meaningful comparisons between the two species . Two parameters are estimated; the rate at which recombination changes alleles, compared to point mutation, and the rate at which recombination changes individual nucleotide sites, compared to point mutation . Estimates for the former parameter are 4:1 in the meningococcus (i.e . alleles are changed four-fold more frequently by recombination than by mutation), and 10:1 in the pneumococcus . However, estimates for the latter parameter are at least 80:1 in the meningococcus (i.e . an individual nucleotide site is at least 80-fold more likely to change by recombination than by mutation) and 50:1 in the pneumococcus . These data imply that recombination events, compared to mutational events, may be more common in the pneumococcus than in the meningococcus . However, because it is a more diverse species, each recombinational exchange in the meningococcus results in more nucleotide changes on average.

Hawaii Med J, 2000 Jul, 59(7), 308 - 9
Dexamethasone use in adult meningococcal meningitis; Hui L et al.; The use of dexamethasone in the management of bacterial meningitis in adults remains controversial . This report illustrates the case of a 27-year-old male with severe meningococcal meningitis and meningococcemia who completely recovered after receiving antibiotics and dexamethasone . In adults with suspected bacterial meningitis, especially in high risk cases, the adjunctive use of dexamethasone may be beneficial.

Hosp Pract (Off Ed), 2000 Aug 15, 35(8), 75 - 6, 79-82, 85-6
Management and prevention of meningococcal disease; Mehta N et al.; While many other illnesses affecting children have been contained or even eliminated, meningococcal disease has become a leading infectious cause of death . The major management challenge may be increased intracranial pressure or toxic shock, depending on whether meningitis or septicemia predominates . A new protein-conjugated group C vaccine is expected to reduce deaths by as much as 40%.

Arch Dis Child, 2000 Sep, 83(3), 271 - 3
Performance characteristics of the polymerase chain reaction assay to confirm clinical meningococcal disease; Carrol ED et al.; BACKGROUND: Confirmation of clinical meningococcal disease (MCD) is essential for management of patients, contacts, and outbreaks . Blood and CSF cultures, the traditional gold standard diagnostic tests, have been adversely affected by preadmission parenteral penicillin and fewer lumbar punctures . Rapid, reliable serogroup determination without the need to grow isolates could improve laboratory confirmation of MCD . AIMS: To determine performance characteristics of the currently available meningococcal polymerase chain reaction (PCR) assays in a clinical setting . METHODS: Prospective study of 319 children presenting with a suspected diagnosis of MCD (fever and a rash, or suspected bacterial meningitis) over a 16 month period . RESULTS: A total of 166 (52% of all) children had clinical MCD: diagnosis was confirmed microbiologically in 119 (72%) of these . Performance characteristics (sensitivity, specificity, negative predictive value, positive predictive value) in confirmation of clinical MCD were respectively (95% confidence interval): blood culture 31% (24-38%), 100%, 57% (49-65%), 100%; blood PCR 47% (39-55%), 100%, 65% (58-73%), 100%; any test positive 72% (65-79%), 100%, 77% (70-84%), 100% . CONCLUSIONS: Meningococcal DNA detection in blood or CSF by PCR is a useful method of diagnosis of MCD . PCR of peripheral blood performs better than blood culture . In a child with clinically suspected MCD, PCR assays, bacterial antigen tests, and oropharyngeal swabbing for meningococcal carriage should be performed in addition to blood or CSF culture, to improve case confirmation.

Infect Immun, 2000 Sep, 68(9), 4938 - 47
Allelic diversity of the two transferrin binding protein B gene isotypes among a collection of Neisseria meningitidis strains representative of serogroup B disease: implication for the composition of a recombinant TbpB-based vaccine; Rokbi B et al.; The distribution of the two isotypes of tbpB in a collection of 108 serogroup B meningococcal strains belonging to the four major clonal groups associated with epidemic and hyperendemic disease (the ET-37 complex, the ET-5 complex, lineage III, and cluster A4) was determined . Isotype I strains (with a 1.8-kb tbpB gene) was less represented than isotype II strains (19.4 versus 80.6%) . Isotype I was restricted to the ET-37 complex strains, while isotype II was found in all four clonal complexes . The extent of the allelic diversity of tbpB in these two groups was studied by PCR restriction analysis and sequencing of 10 new tbpB genes . Four major tbpB gene variants were characterized: B16B6 (representative of isotype I) and M982, BZ83, and 8680 (representative of isotype II) . The relevance of these variants was assessed at the antigenic level by the determination of cross-bactericidal activity of purified immunoglobulin G preparations raised to the corresponding recombinant TbpB (rTbpB) protein against a panel of 27 strains (5 of isotype I and 22 of isotype II) . The results indicated that rTbpB corresponding to each variant was able to induce cross-bactericidal antibodies . However, the number of strains killed with an anti-rTbpB serum was slightly lower than that obtained with an anti-TbpA(+)B complex . None of the sera tested raised against an isotype I strain was able to kill an isotype II strain and vice versa . None of the specific antisera tested (anti-rTbpB or anti-TbpA(+)B complex) was able to kill all of the 22 isotype II strains tested . Moreover, using sera raised against the C-terminus domain of TbpB M982 (amino acids 352 to 691) or BZ83 (amino acids 329 to 669) fused to the maltose-binding protein, cross-bactericidal activity was detected against 12 and 7 isotype II strains, respectively, of the 22 tested . These results suggest surface accessibility of the C-terminal end of TbpB . Altogether, these results show that although more than one rTbpB will be required in the composition of a TbpB-based vaccine to achieve a fully cross-bactericidal activity, rTbpB and its C terminus were able by themselves to induce cross-bactericidal antibodies.

Eur J Clin Microbiol Infect Dis, 2000 Jun, 19(6), 475 - 6
Neisseria meningitidis serogroup W-135 primary monarthritis of the hip in an immunocompetent child; Apfalter P et al.; Reported here is the first known case of primary monoarthritis of the hip due to Neisseria meningitidis W-135 . The isolate was obtained from an immunocompetent child suffering from acute hip pain as the only symptom upon presentation at the hospital . Meningococcal infection must be considered in the diagnosis of any child presenting with arthritis, even if afebrile and without rash.

Eur J Clin Microbiol Infect Dis, 2000 Jun, 19(6), 452 - 9
Genetic and antigenic characteristics of Neisseria meningitidis strains isolated in the Czech Republic in 1997-1998; Kriz P et al.; Strains of Neisseria meningitidis isolated from patients and asymptomatic individuals who had been in contact with patients were investigated using four typing methods with the aim of identifying any heterogeneity and/or homogeneity among the strains . In 1993, a dramatic change in the incidence and severity of invasive meningococcal disease in the Czech Republic occurred as a consequence of the appearance of a Neisseria meningitidis strain of phenotype C:2a:P1.5,2 and electrophoretic type ET-15, belonging to the ET-37 complex, which had not previously been identified in this country . Presented here are the results of a study of the relationships between 58 Neisseria meningitidis isolates collected between January 1997 and June 1998 . Forty-nine isolates originating from patients with invasive meningococcal disease and nine from healthy contacts were analyzed using the following four methods: whole-cell enzyme immunoassay, multilocus enzyme electrophoresis, pulsed-field gel electrophoresis, and randomly amplified polymorphic DNA analysis . A high prevalence of phenotype C:2a:P1.5,2 electrophoretic type ET-15 was confirmed among the patients' strains . Nevertheless, during the study period, they became heterogeneous . Strains isolated from healthy contacts showed greater heterogeneity in serological phenotypes and electrophoretic types from the beginning of the study, and electrophoretic type ET-15 strains were less frequent . Within the electrophoretic type ET-15 clone, strains showing the identical serological phenotype (with the exception of one isolate) were indistinguishable using randomly amplified polymorphic DNA analysis, while pulsed-field gel electrophoresis revealed heterogeneity with 12 pulsed-field gel electrophoretic types identified . The strains from the same cluster displaying the same serological phenotype were indistinguishable with any of the methods used.

Eur J Clin Microbiol Infect Dis, 2000 Jun, 19(6), 418 - 21
Validation of a diagnosis model for differentiating bacterial from viral meningitis in infants and children under 3.5 years of age; Jaeger F et al.; The aim of this study was to validate, in a population of infants and children under 3.5 years of age, a diagnosis model that provides a figure for the probability of bacterial meningitis (pABM), based on four parameters collected at the time of the first lumbar tap: the cerebrospinal fluid (CSF) protein level, CSF polymorphonuclear cell count, blood glucose level, and leucocyte count . The best cut-off value for distinguishing between bacterial and viral meningitis was previously found to be 0.1, since 99% of meningitides associated with pABM<0.1 were viral . The charts of 103 consecutive children aged 0.1-3.5 years who had been hospitalised for acute meningitis were reviewed . Each case was sorted into the following three categories for aetiology: bacterial (positive CSF culture, n=48); viral (negative CSF culture and no other aetiology, and no antibiotic treatment after diagnosis, n=36); and undetermined (fitting neither of the first two definitions, n=19) . After computation of pABM values in each case, the predictive values of the model were calculated for different pABM cut-off values . The results confirmed that the best cut-off pABM value was 0.1, for which the positive and negative predictive values in this model were 96% and 97%, respectively . Only one case of bacterial meningitis (lumbar tap performed early in an infant with meningococcal purpura fulminans with negative CSF culture) was associated with a pABM value of <0.1 . This model is quite reliable for differentiating between bacterial and viral meningitis in children under 3.5 years of age, and it may enable physicians to withhold antibiotics in cases of meningitis of uncertain aetiology.

Curr Opin Pediatr, 2000 Aug, 12(4), 413 - 25
Neonatal jaundice, animal-induced injuries, and immunizations; Koh AY et al.; The authors describe current investigation and most recent developments in three areas of pediatrics commonly faced by the office practitioner . The impetus of earlier newborn discharge places increased emphasis on pediatricians to accurately predict clinically significant jaundice . A better understanding of the pathophysiology of breastfeeding and breast milk jaundice, and the realization that Gilbert's syndrome may play a greater role in neonatal jaundice, only help confirm that the story of neonatal jaundice is still unfolding . Animal (particularly canine) bite injuries continue to be the most common animal-induced injuries, and a thorough review of appropriate antibiotic treatment and rabies prophylaxis guidelines are essential for the pediatric practitioner . During the past year, several major changes involving the use of rotavirus, pneumococcal, polio, meningococcal, and hepatitis A vaccines have taken place, which will have marked impact not only on pediatric office practice, but also on society as a whole.

Paediatr Drugs, 1999 Oct-Dec, 1(4), 263 - 82
Recognition, treatment and complications of meningococcal disease; Riordan FA et al.; Meningococcal disease remains a major cause of death in young children . A decrease in mortality requires recognition and treatment of the disease at a number of stages in the illness . Life-threatening meningococcal disease usually presents as septicaemia rather than meningitis . The cardinal feature of meningococcal septicaemia is the purpuric rash . Many parents recognise the rash and seek medical advice because of it . When primary care physicians recognise the rash, the administration of parenteral penicillin may decrease mortality . However, antibacterials are not given promptly if there is no rash or if the disease presents in an atypical form . In hospital, antibacterial therapy with a third-generation cephalosporin should be given . Disease severity needs to be assessed by a valid method, such as the Glasgow Meningococcal Septicaemia Prognostic Score (GMSPS) . This can identify those patients who need intensive care and/or might benefit from new therapies . The 2 life-threatening complications are septic shock and meningoencephalitis with raised intracranial pressure . Despite numerous case reports of success with potential new treatments, none has been proven safe and/or effective by controlled trials . Although it is tempting to focus on new treatments, the early recognition of severe meningococcal disease by parents, primary care physicians and junior hospital doctors is equally, if not more, important as a potential means of decreasing mortality.

Microbiology, 2000 Aug, 146 ( Pt 8), 1901 - 11
The membrane phospholipids of Neisseria meningitidis and Neisseria gonorrhoeae as characterized by fast atom bombardment mass spectrometry; Rahman MM et al.; The phospholipids of Neisseria meningitidis and Neisseria gonorrhoeae were characterized by fast atom bombardment (FAB)-MS and GLC-MS . The major phospholipids were phosphatidylethanolamine (PE), followed by phosphatidylglycerol (PG), with minor amounts of phosphatidic acid (PA) and trace levels of cardiolipin (DPG) . All of the phospholipid preparations were variable in their fatty acyl substituents, which included C16:1, C16:0, C18:1, C14:0, C14:1 and C12:0 . By MS/MS analysis, all pathogenic Neisseria spp . phospholipids contained a saturated fatty acyl substituent and either a saturated or unsaturated fatty acyl substituent in the sn-1 and sn-2 positions, respectively . Compared with enteric bacterial species, the phospholipids of N . meningitidis and N . gonorrhoeae have increased levels of phospholipids with short-chain fatty acyl residues (i.e . increases in C12:0, C14:1 and C14:0) and variable amounts of C18:1 . The percentage of total PE and PG molecules with the shorter-chain fatty acids ranges from 35 to 47% and 42 to 66%, respectively, for N . meningitidis while these respective values are <10% and <5% for Escherichia coli . The variability and variety of meningococcal and gonococcal phospholipids suggest novel genetic mechanisms of neisserial phospholipid assembly and regulation, which may be important for the biology and pathogenesis of N . meningitidis and N . gonorrhoeae.

Scand J Immunol, 2000 Aug, 52(2), 113 - 6
P64k meningococcal protein as immunological carrier for weak immunogens; Gonzalez S et al.; Previously, the P64k meningococcal protein, an antigen of 64 kDa expressed in Escherichia coli, has been extensively characterized . We have successfully conjugated several synthetic peptides and meningococcal group C polysaccharide to P64k . In three out of four model peptides, the murine humoral immune response against the homologous peptide, evaluated after three doses of conjugate, was higher in the animals immunized with the coupled peptide than in those that received free peptide . The fourth and largest was immunogenic by itself . Similarly, the antigroup C polysaccharide levels reached by conjugated polysaccharide were significantly higher than those produced against unconjugated polysaccharide . As a carrier for one of the peptides, P64k was compared with bovine serum albumin (BSA) and tetanus toxoid (TT), being able to induce slightly higher or similar antipeptide antibody levels than these well-establish protein carriers . Our results suggest that recombinant P64k protein could be a readily available immunological carrier, as efficient as other commonly used large carrier molecules.

Zh Mikrobiol Epidemiol Immunobiol, 2000 May-Jun, (3), 58 - 62
{Antibodies to meningococcal antibodies in the sera of patients and donors}; Filatova TN et al.; The comparative study of sera taken from healthy persons (pooled sera of 100 donors, 6 individual serum specimens) and sera taken from patients with meningococcal meningitis (pooled sera of 10 patients with meningococcal infection, group A, and 6 individual serum specimens from patients with meningococcal infection, groups A, B, C) was carried out by the method of immunoblotting . All proteins from healthy donors were found to contain antibodies to meningococcal iron-regulated protein (IRP) of 85 kD, designated as TbpB . In 30% of donor sera the presence of antibodies to meningococcal IRP of 34 kD (FbpA) was registered . Moreover, donor sera were found to contain antibodies to meningococcal IRP of 45 kD . The sera taken from convalescents were found to have the increased content of antibodies to IRP of 70 and 85 kD and somewhat lesser content of antibodies to proteins of 98, 44 and 34 kD . As regards other (non iron-regulated) proteins, in the process of convalescence the most intensive antibody production was observed with respect to minor protein with a molecular weight of 50 kD, as well as proteins of class 5, characterized by molecular weights of 30 kD and less.

Biotechnol Appl Biochem, 2000 Aug, 32 ( Pt 1), 1 - 8
B-cell epitope mapping of the Neisseria meningitidis P64k protein using overlapping peptides; Gonzalez S et al.; A common meningococcal antigen designated P64k has been identified, cloned and expressed in Escherichia coli . The recombinant antigen is highly immunogenic in several animal species and its immunogenicity in healthy human volunteers is under investigation . Recently, P64k has been used as an immunological carrier for weak immunogens . To characterize the B-cell epitopes on P64k, recognized by immune sera obtained from mice, rabbits and monkeys, multiple overlapping peptides were synthesized and screened for antibody binding . Peptides covering the complete sequence of the P64k protein, 59 in all, of 20 amino acids each (overlapped by 10 residues), were synthesized . A number of continuous epitopes were detected with all sera, when immune and pre-immune bleeds were compared . For mouse and monkey sera, a few major antigenic peptides were identified, while the recognition of the rabbit serum was much more heterogeneous . Despite variation in the exact location of continuous epitopes defined by different anti-P64k sera, we found an immunogenic core region within the molecule, composed of amino acids Asp(524)-Gly(533) . Consistently, in this protein segment there was an amino acid stretch located in a beta-hairpin loop, which is exposed to the solvent in the previously determined three-dimensional structure of the protein . This region is protruding and accessible to a sphere with a radius of 9 A.

Med Clin (Barc), 2000, 114 Suppl 2, 88 - 92
{Preventive activities in primary health care: identifying the agreement among evidence-based guidelines}; Gosalbes Soler V et al.; BACKGROUND: The purpose of this article is to identify the agreement among evidence-based guidelines about recommendations on preventive activities in low risk adults . METHODS: For which we identified, from the 1996 US Task Force on Preventive Services Guide those preventives activities classified like A or B (recommendation in favour of provision) and like D or E (recommendation against provision), excepting those D and E recommendations based on descriptives studies or expert opinions . Both preventive activities aimed at pregnant women and children and those which are not applicable to our context were excluded . Selected preventive services were compared with the range of age, sex and periodicity in which agreement with the recommendations of American College of Physicians and Canadian Task Force on Preventive Services existed . RESULTS: We found the following agreements . Screening activities . In favour: screening for hypercholesterolemia, hypertension, breast cancer, colorectal cancer, uterine cervix cancer, rubella, visual and hearing impairment and problem drinking . Against: cancer of prostate, lung, bladder and thyroid, and asymptomatic bacteriuria . Counseling activities . In favour: smoking, motor-vehicles injuries, alcohol consumption, unintended pregnancy . Immunizations and quimioprophylaxis . In favour: Vaccines for influenza, tetanus-diphtheria, hepatitis B and measles-mumps-rubella . Postexposure prophylaxis to hepatitis A, hepatitis B, meningococcal, rabies and tetanus . CONCLUSIONS: We see then, that a high degree in agreement among the main guidelines exists; about the preventive activities to perform in Primary Health Services, nevertheless we observed low fulfillment of certain preventive activities in Primary Health Services, different barriers for the accomplishment from these activities were described.

Rev Esp Quimioter, 2000 Jun, 13(2), 182 - 6
{Susceptibility to antimicrobial drugs used in the prophylaxis of meningococcal disease: situation after an epidemic wave}; Arreaza L et al.; In the early 1990s a rise in the incidence of meningococcal disease was observed in Galicia, Spain, most cases of which were caused by serogroup C meningococcal strains . As part of the epidemiological analysis of this epidemic wave, two studies of asymptomatic carriers of neisseria meningitidis were carried out: the first took place during the period of maximum incidence and coincided with a massive immunization campaign (December 1996 to January 1997); and the second was conducted one year later (January 1998) . A total of 1234 meningococcal strains were isolated in both studies (789 in the first and 445 in the second study) and the susceptibility to rifampin, ciprofloxacin, ceftriaxone and sulfadiazine was determined . The susceptibility to rifampin, ciprofloxacin and cetriaxone was high among the strains isolated in both studies . For sulfadiazine, the percentage of resistant strains was 92.6% for the first and 86.3% for the second study.

Am J Kidney Dis, 2000 Aug, 36(2), 396 - 400
Waterhouse-Friderichsen syndrome and bilateral renal cortical necrosis in meningococcal sepsis; Agraharkar M et al.; Waterhouse-Friderichsen syndrome and bilateral renal cortical necrosis (BRCN) are rare complications of meningococcal sepsis associated with high mortality rates . We describe a 20-year-old man who presented with a 1-day history of fever, chills, malaise, and vomiting . He collapsed in the emergency room, requiring mechanical ventilation and intravenous vasopressors for resuscitation . He was noted to be anuric, and computed tomography showed adrenal hemorrhage and BRCN . Blood cultures later confirmed Neisseria meningitidis sepsis, and a biopsy confirmed renal cortical infarction . The patient was treated aggressively with intravenous antibiotics, corticosteroids, and immunoglobulins, in addition to plasmapheresis, dialysis, and supportive measures . He recovered his adrenal function and was discharged from the hospital, but he remains dialysis dependent . To our knowledge, this is the first reported case of concomitant Waterhouse-Friderichsen syndrome and BRCN in a patient with meningococcal sepsis.

J Clin Microbiol, 2000 Aug, 38(8), 2878 - 84
Detection of complement-mediated antibody-dependent bactericidal activity in a fluorescence-based serum bactericidal assay for group B Neisseria meningitidis; Mountzouros KT et al.; Serum bactericidal assays (SBAs) for Group B meningococci are considered the methods of choice for the evaluation of functional antimeningococcal antibodies . Many investigators regard SBAs as time- and labor-intensive . Variations in SBA protocols among different laboratories make interpretation of results difficult . Here we describe a fluorescence-based serum bactericidal assay (fSBA) and compare the results obtained with the fSBA to the results obtained with a more conventional SBA . The results generated by both assays were dependent upon the surviving bacteria after incubation, and the assay mixtures contained identical components . Differences between assays lie in how the surviving bacteria are quantified . The fSBA described in the paper uses the fluorescent dye alamarBlue (M . V . Lancaster and R . D . Fields, U.S . patent 5501959, March 1996) . The fluorescent signals generated in the fSBA correlate to the oxidative respiration of surviving bacteria . Viable bacteria were detected between 6 and 8 h directly from reaction mixtures in 96-well plates by the fSBA, whereas colonies isolated on semisolid media could be counted after 24 h of incubation . The bactericidal titers generated by both assays were nearly identical . The fSBA described here can be used as an assay for the screening of large quantities of individual sera as complement sources or as a method for the detection of functional antibodies directed against group B Neisseria meningitidis in both human and mouse antisera.

Crit Care Med, 2000 Jul, 28(7), 2591 - 4
Procalcitonin and cytokine levels: relationship to organ failure and mortality in pediatric septic shock; Hatherill M et al.; BACKGROUND: Procalcitonin (PCT), a marker of bacterial sepsis, may also act as a mediator of the inflammatory response to infection, and thus influence outcome . OBJECTIVE: To investigate the relationship between PCT, interleukin (IL)-10, tumor necrosis factor (TNF), organ failure, and mortality in pediatric septic shock . DESIGN: Prospective observational study . SETTING: A 16-bed pediatric intensive care unit of a university hospital . PATIENTS: A total of 75 children with septic shock having a median age of 43.1 months (range, 0.1-192 months) . Children who had received antibiotics for >24 hrs were excluded . A total of 37 patients (49%) had meningococcal disease, and 72 patients (96%) required mechanical ventilation . INTERVENTIONS: The pediatric risk of mortality (PRISM) score, multiple organ system failure (MOSF) score, duration of ventilation, length of ICU stay, and outcome were recorded . PCT, IL-10, and TNF were measured at admission to the intensive care unit . Sequential PCT levels were available at 0 hrs and 24 hrs in 39 patients (52%) . RESULTS: Observed mortality was 21/75 (28%) . Data are median (range) . The admission PCT (p = .0002) and TNF levels (p = .0001) were higher in children with higher MOSF scores . In survivors and nonsurvivors, the admission PCT was 82 ng/mL vs . 273 ng/mL (p = .03), IL-10 was 62 pg/mL vs . 534 pg/mL (p = .03), and TNF was 76 pg/mL vs . 480 pg/mL (p = .001), respectively . Area under the mortality receiver operating characteristic curve was 0.73 for PCT, 0.67 for IL-10, and 0.76 for TNF, compared with 0.83 for the PRISM score . Of 39 children, 16 (41%) with sequential PCT measurements showed no fall in PCT after 24 hrs treatment . These children had higher admission levels of IL-10 (p = .03), and TNF (p = .03) compared with children who demonstrated a subsequent fall in PCT . Although the former did not have a higher median PRISM (p = .28) or MOSF score (p = .19), observed mortality was 44% (7 of 16) compared with 9% (2 of 23) (p = .02) . CONCLUSION: The admission PCT, like TNF and IL-10, is related to the severity of organ failure and mortality in children with septic shock . A fall in PCT after 24 hrs of treatment may have favorable prognostic significance.

Crit Care Med, 2000 Jul, 28(7), 2373 - 8
Protein C substitution in sepsis-associated purpura fulminans; Rintala E et al.; OBJECTIVE: To assess the effect of protein C (PC) substitution on imminent peripheral necroses and overall outcome in patients with sepsis-associated purpura fulminans . DESIGN: Case series . SETTING: Intensive care units of two university hospitals . PATIENTS: A total of 12 patients with purpura fulminans, disseminated intravascular coagulation and imminent peripheral necroses in association with sepsis caused by Neisseria meningitidis (n = 5), Streptococcus pneumoniae (n = 2), Capnocytophaga canimorsus (n = 2), and Staphylococcus aureus (n = 1) . In two patients, no pathogens were identified . INTERVENTIONS: Intravenous administration of PC concentrate (100 IU/kg every 6 hrs) . In addition, antithrombin III substitution, antimicrobial therapy, hemodynamic support, and mechanical ventilation in all patients and hemodiafiltration in 10 patients . MAIN RESULTS: After the onset of PC, progressive peripheral ischemia was reversed irrespective of the etiology of infection . Laboratory variables reflecting disseminated intravascular coagulation improved rapidly, although the recovery of the platelet count was retarded in the patients who subsequently died . No drug-related adverse events were noted . Amputations were necessary in two patients, and necrotic tips of fingers and toes were macerated in a third . The hospital mortality was 42% . Of the five lethal cases, two were caused by S . pneumoniae, one by N . meningitidis, one by C . canimorsus, and one by an unknown pathogen . CONCLUSIONS: This article provides encouraging results on the use of PC substitution in meningococcal purpura and presents new data on the administration of this drug to patients with septic purpura caused by other bacterial species . By clinical judgment, PC limited the extent of tissue necrosis . The small number of patients does not allow for any conclusions on the potential effect of PC on mortality . A controlled and randomized study with a larger number of patients is needed before any recommendations can be given on the use of PC in sepsis-related purpura fulminans and shock.

FEMS Microbiol Lett, 2000 Jul 15, 188(2), 111 - 4
Representational difference analysis of Neisseria meningitidis identifies sequences that are specific for the hyper-virulent lineage III clone; Bart A et al.; Neisseria meningitidis may cause meningitis and septicemia . Since the early 1980s, an increased incidence of meningococcal disease has been caused by the lineage III clone in many countries in Europe and in New Zealand . We hypothesized that lineage III meningococci have specific DNA sequences, providing an opportunity to facilitate epidemiological studies by detecting lineage III isolates rapidly . Applying representational difference analysis on one lineage III tester strain and two non-lineage III driver strains, we identified three lineage III-specific sequences, probably part of a single locus encoding a restriction modification system . A PCR based on one of these sequences identified lineage III meningococcal isolates with a sensitivity of 100% and a specificity of 93%, which is superior to the serological identification of lineage III isolates.

J Public Health Med, 2000 Jun, 22(2), 129 - 32
Help--we need a helpline! A public health audit case study; Lowe G et al.; Multi-disciplinary public health audit involving whole departments is often perceived as difficult to carry out in areas other than the annual report of the Director of Public Health . This paper describes the audit of an emergency telephone helpline set up during a meningococcal disease outbreak and provides standards that could be applied to any emergency helpline set up in response to issues of public health concern.

Acta Paediatr Taiwan, 1999 Mar-Apr, 40(2), 119 - 20
Purpura fulminans in children: report of two cases; Hwang CC et al.; Purpura fulminans, usually seen in previously healthy children acquiring severe infections, especially meningococcal sepsis and meningitis, is a rare catastrophic disease with initial hemorrhagic skin lesions rapidly progressing to gangrene accompanied by shock and frequently resulting in death . We report 2 cases of purpura fulminans who were diagnosed in the past 2 years . Both blood cultures yielded Neisseria meningitidis . One of them expired within 48 hours after admission despite aggressive therapy . The second patient, who received the treatment of heparin, antibiotics, and blood product replacement, survived with minimal sequelae . We deem young age and severe coagulopathy are especially associated with a fatal outcome in children with purpura fulminans . Early recognition of this disease and prompt appropriate therapy may be lifesaving for these patients.

Acta Paediatr Taiwan, 1999 Mar-Apr, 40(2), 116 - 8
Endophthalmitis as a complication of meningococcal meningitis: report of one case; Chien SY et al.; Metastatic meningococcal endophthalmitis, although rare, is a rapidly progressive and sight-threatening infection . We present a 10-month-old infant with meningococcal meningitis who developed unilateral metastatic endophthalmitis . If patients develop a sepsis-like picture with cloudy cornea and purulent conjunctivitis, we have to consider the possibility of endophthalmitis and full ophthalmological evaluations are indicated . Treatment should be started as early as possible . The outcome of endophthalmitis is frequently permanent visual impairment . Endophthalmitis is a true medical emergency requiring early antibiotic therapy with full dose of antimicrobials to avoid morbidity and blindness.

Eur J Hum Genet, 2000 Jul, 8(7), 513 - 8
Molecular characterisation of 10 Dutch properdin type I deficient families: mutation analysis and X-inactivation studies; van den Bogaard R et al.; Properdin type I deficiency is characterised by complete absence of extracellular properdin, a positive regulator of the alternative pathway of complement activation . Properdin deficiency is associated with increased susceptibility to severe meningococcal disease . We have identified the genetic defect in 10 Dutch families . Six different mutations and one sequence polymorphism in the properdin gene were found . All amino acid substitutions were limited to conserved amino acids in exons 7 and 8 in contrast to the premature stops that were found in other exons . The missense mutations may alter the protein conformation in such a way that properdin will not be secreted and therefore catabolised intracellularly . The decreased properdin levels found in some healthy females carrying one mutated properdin gene were studied for X-inactivation . Most carriers with extreme low or high properdin levels showed preferential X-inactivation for the normal or mutated X chromosome, respectively . We observed some exceptions, suggesting additional regulation of properdin excretion apart from X-inactivation.

Arch Dis Child, 2000 Aug, 83(2), 117 - 21
Parental smoking, socioeconomic factors, and risk of invasive meningococcal disease in children: a population based case-control study; Kriz P et al.; AIMS: To investigate the effects of parental smoking, socioeconomic characteristics, and indoor environment on the risk of invasive meningococcal disease in children . METHODS: Population based case-control study . A total of 68 incident cases of invasive meningococcal disease in children less than 15 years old were compared with 135 controls selected from the same school and matched for year of birth, sex, and place of residence . Information on exposures was obtained in interviews with parents . RESULTS: Invasive meningococcal disease was strongly associated with parental smoking; rate ratios adjusted for socioeconomic factors were 3.5 (95% confidence interval 1.4-8.7) for smoking of mother, 3.2 (1.5-6.9) for smoking of father, and 2.7 (1.3-5.4) for every 20 cigarettes smoked at home on an average day . The risk of the disease was strongly inversely related to maternal education and, less strongly, to ownership of a car and of a weekend house, father's education, crowding, and the number of siblings, but these associations were reduced or eliminated in multivariate models . The type of heating and cooking (used as proxies for indoor air pollution) were not associated with the disease . CONCLUSION: The risk of invasive meningococcal disease in children is strongly influenced by parental smoking and unfavourable socioeconomic circumstances.

Tidsskr Nor Laegeforen, 2000 Jun 10, 120(15), 1735 - 9
{Meningococcal disease in Africa--epidemiology and prevention}; Norheim G et al.; Neisseria meningitidis is one of the most common causes of purulent meningitis all over the world . Large epidemics caused by meningococci have spread during the last decade throughout vast areas of Africa, also outside the region referred to as the classic "Meningitis Belt" . Globally, this organism each year causes about 300,000 cases and 30,000 deaths; most of these are children . Meningococci of serogroup A cause a major part of these epidemics, and a remarkable feature of the epidemical situation is that the bacteria differ very little in antigenic properties as they belong to the same clonal group of meningococci . Immunization with safe and effective vaccines is the most efficient way of combatting these epidemics . The currently available polysaccharide vaccines against serogroup . A meningococcal disease do not induce long-term immunological memory and do not provide adequate protection of children below two years of age . There is an urgent need for a vaccine that induces long-term immunological memory in all age groups, so it can be included in the routine vaccination program . In contrast to serogroup C, the development of conjugate vaccines against serogroup A meningococcal disease has not yielded the positive results hoped for . The development of alternative protein-based vaccines therefore needs to be intensified.

J Clin Lab Anal, 2000, 14(4), 193 - 9
One-step heminested PCR for amplification of Neisseria meningitidis DNA in cerebrospinal fluid; Atobe JH et al.; A one-step polymerase chain reaction (Heminested-PCR) was designed to target the 16S rRNA fragment simultaneously using a set of primers for the universal bacterial group and a Neisseria meningitidis species-specific sequence for diagnostic purposes . The diagnostic features of the Heminested-PCR were evaluated in the study of 168 cerebrospinal fluid (CSF) specimens from 84 patients with a N . meningitidis infection, meningitis caused by unrelated bacteria and other etiologies (57 patients), or suspicious cases (27 patients) with clinical symptoms of bacterial meningitis but with negative results from bacteriological procedures . About 90% of patients with bacterial meningitis, including those suspicious cases, had prior antibiotic therapy . The sensitivity, specificity, positive, and negative predictive values found in relation to culture and/or microscopy were 91.7, 100, 100, 100, and 90.5%, respectively . In patients suspected of having bacterial meningitis, the Heminested-PCR revealed 51.9% (14 patients) positive for N . meningitidis infection and 40.7% (11 patients) positive for unrelated bacterial infections . The agreement of the Heminested-PCR with culture and/or microscopy was high and ranked as almost perfect (kappa indices > 0.856), in contrast to its agreement with other techniques . These findings speak in favor of the molecular diagnosis of meningococcal meningitis in patients who are culture- and/or microscopy-negative, due to their prior antibiotic treatment .

MMWR Recomm Rep, 2000 Jun 30, 49(RR-7), 13 - 20
Meningococcal disease and college students . Recommendations of the Advisory Committee on Immunization Practices (ACIP); Prevention and control of meningococcal disease . Recommendations of the Advisory Committee on Immunization Practices (ACIP); This report summarizes and updates an earlier published statement issued by the Advisory Committee on Immunization Practices concerning the control and prevention of meningococcal disease (MMWR 1997:46{No . RR-5}:1-21) and provides updated recommendations regarding the use of meningococcal vaccine.

S Afr Med J, 2000 May, 90(5), 513 - 7
Meningococcal disease in South African goldmines--epidemiology and strategies for control; Sonnenberg P et al.; OBJECTIVES: To describe the epidemiology of meningococcal disease in South African goldmines and to suggest strategies for the prevention and control of further outbreaks . DESIGN: We prospectively investigated a meningococcal outbreak that occurred in 1996 and describe the control measures that were implemented . In addition, we conducted a retrospective analysis of routinely collected data on meningococcal disease in these mines from 1972 to 1996 . SETTING: Four goldmines in Gauteng, employing 30,000 workers who live in hostels . SUBJECTS: All cases of meningococcal disease at the mine hospital . RESULTS: Between 1972 and 1976, 588 cases were diagnosed, with peaks in 1972 (203 cases, 727/100,000) and 1975 (147 cases, 564/100,000) . Since 1978 less than 5 cases have been reported in most years, but smaller outbreaks occurred in 1990 (30 cases, 89/100,000) and 1996 (14 cases, 50/100,000) . The 1996 outbreak (group A, clone I-1) was part of a larger outbreak in Gauteng that originated in Mozambique and began in one mine in July 1996, after which a mass vaccination campaign was implemented . This was followed by a smaller outbreak among non-vaccinated workers at an adjacent mine . Five patients were new recruits . CONCLUSIONS: Despite a dramatic reduction in meningococcal disease over the last 25 years due mainly to changes in the work force, there are still outbreaks in this community . Those most at risk are young men who are new to the industry . Suggestions for prevention include effective surveillance, routine vaccination of new recruits and a rapid response to outbreaks, with mass vaccination and provision of chemoprophylaxis to close contacts.

Ned Tijdschr Geneeskd, 2000 Jun 17, 144(25), 1214 - 9
{Immunology in the medical practice . XXVII . Mannose-binding lectin, an important link for nonspecific or hereditary immune reaction}; van Deuren M; In the course of the past two decennia, a 3rd route of complement activation (next to the classical and the alternative routes) has been identified: the lectin route in which mannose-binding lectin (MBL) plays an essential role . MBL is produced in the liver . From the phylogenetic and functional points of view, complement activation via MBL falls in between the alternative and the classical routes and combines the advantages of the former (an early response, without the intervention of antibodies) with those of the latter (high specificity) . The binding of MBL to the surface of a microorganism results in the activation of two serine proteases (MASP1 and MASP2) that are coupled to MBL . These enzymes can activate C4 and C2 so that, via the MBL route, the C3-convertase of the classical route (C4b2b) is produced long before there are any specific antibodies . The gene for MBL is located on the long arm of chromosome 10 and consists of a promoter gene and 4 exons coding for the protein . The prevalence of mutations in the MBL gene is about 10%, but in Africa South of the Sahara it is as high as 30% . MBL deficiency predisposes both children and adults to all sorts of infectious diseases, chronic diarrhoea, tonsillitis, otitis media, pneumonia, (meningococcal) meningitis, sepsis and osteomyelitis . Remarkably, MBL deficiency may actually be advantageous in some infections, because certain microorganisms use MBL or complement to invade the cell.

FEMS Immunol Med Microbiol, 2000 Aug, 28(4), 319 - 27
Bactericidal antibody response to Neisseria meningitidis serogroup B in patients with bacterial meningitis: effect of immunization with an outer membrane protein vaccine; Milagres LG et al.; We evaluated the bactericidal antibody response to Neisseria meningitidis serogroup B in convalescent patients (n=65) from bacterial meningitis . Patients infected with B meningococci were stratified according to their vaccination status (Cuban BC vaccine) into group 1 (immunized) (n=12) and group 2 (non-immunized) (n=15) . The results suggested that antibody titers > or =2 (log(2)) indicate a specific immune response to N . meningitidis . In group 1, 64% of patients had a significant antibody titer (> or =2) in their acute sera against a B:4:P1.15 strain, compared to only 21% of group 2 patients . All patients from group 1 without bactericidal antibodies in their acute sera had a significant increase (at least 2-fold increase in log(2) titers) in antibody titers in their convalescent sera, in contrast, to only 27% of patients from group 2 (P=0.06) . Using mutant strains lacking OMP1 or OMP5, it was shown that OMP1 was an important antigen recognized by immunized patients but not by non-immunized patients.

Rev Cubana Med Trop, 1999 Sep-Dec, 51(3), 189 - 93
{VA-MENGOC-BC vaccine: its impact on meningococcal disease in children 1-4 years old}; Perez Rodriguez A et al.; VA-MENGOC-BC vaccine has been administered to Cuban infants since 1991 through the National Immunization Program (NIP) so it was necessary to evaluate its effects on 1-4 years-old children included in the highest risk group . To this end, a descriptive study of the morbidity and mortality from meningococal disease was carried out taking the vaccine histories of 145 cases occurred from 1991 to 1996 into account . The decreasing trend of the incidence density (ID) of meningococcal disease in all the age groups in the studied period was among the most important results, the highest decline was observed in one-year old infants with an ID of . 10.8 per 100,000 children/years at the end of the period . The percent distribution of occurrence showed a predominance of one-year old group at the beginning of the program . Implementation, and a change to 3-4 years old group at the end of the period . A high of percent of vaccinated sick children had been immunized against MD over one year ago (697.5 days as average) . 35 children died during the period and the highest mortality density decline (1 per 100,000 children a year) was observed as of 1993; 2 years-old children were at highest risk of death . Seventy three percent (73.1%) of those vaccinated had been immunized for over once year . The general lethality was 24.1%, the lowest was 14.3% in one year old children . The changes occurred in meningococcal disease behaviour within this high risk group, which are attributed to the administration of vaccine as part of the NIP fully justifies the continuation of the application of this vaccine.

Lancet . 2000 Jun 10;355(9220):2052.
Meningococcal disease among children of Indian subcontinent ethnic origin; Robinson JM et al.; The rate of meningococcal septicaemia and meningitis was significantly lower in children of Indian subcontinent ethnic origin than in children of other origins over 12 years in the Blackburn area of the UK.

Rev Argent Microbiol, 2000 Apr-Jun, 32(2), 97 - 103
Detection of Neisseria meningitidis in cerebrospinal fluid samples from suspicious cases of meningococcal meningitis using polymerase chain reaction and counterimmunoelectrophoresis; De Gaspari EN; Rapid diagnosis of meningococcal disease followed by an early treatment is essential . However, blood or cerebrospinal fluid cultures may not be successful because antibiotic treatment is often started before proper specimens are collected and because bacteria may die during transportation to the laboratory . Improvements in antibiotic therapy for specific microorganisms will require the use of more than one method for immunodiagnosis . In this study a collection of cerebrospinal fluid samples from Brazilian patients was analyzed . Gram stains, culture, counterimmunoelectrophoresis and clinical evaluations for meningococcal diseases were available . The sensitivity of nested PCR (nPCR) was 73% for cerebrospinal fluid of clinically suspected cases, whereas both sensitivity and specificity were 100% when subtypes of Brazilian epidemic strains (P1.7, P1.9 and P1.15) isolated from the samples were used.

Microbes Infect, 2000 May, 2(6), 687 - 700
Epidemiology and pathogenesis of Neisseria meningitidis; Tzeng YL et al.; Neisseria meningitidis, an exclusive pathogen of humans, remains the leading worldwide cause of meningitis and fatal sepsis, usually in otherwise healthy individuals . In recent years, significant advances have improved our understanding of the epidemiology and genetic basis of meningococcal disease and led to progress in the development of the next generation of meningococcal vaccines . This review summarizes current knowledge of the human susceptibility to and the epidemiology and molecular pathogenesis of meningococcal disease.

Cad Saude Publica, 1997 Apr, 13(2), 295 - 303
{Epidemiology of meningococcal disease in the city of Rio de Janeiro: changes after vaccination against B and C serogroups}; Noronha CP et al.; Meningococcal disease has been a serious public health problem in the city of Rio de Janeiro, with high attack rates among younger children, high case fatality rates, and predominance of serogroup B . In December 1994 the second vaccination drive against B and C meningococcal disease was performed with the objective of protecting children ages 6 months to 13 years . A total of 950 thousand children received 2 doses of vaccine produced by the Finlay Institute of Cuba . In 1995 a change was observed in the disease pattern with a predominance of serogroup C and a higher global attack rate, particularly among children under 1 year of age, teenagers, and young adults . In vaccinated groups the attack rate was lower than in 1994, due to a decrease in serogroup B . No change was observed in the case fatality rate.

Infection, 1999, 27(4-5), 261 - 4
Invasive meningococcal disease: patient and strain characteristics set new challenge for prevention and control; Paret G et al.; Differences in the course of invasive meningococcal disease, in prevalence, case-to-carrier ratio, geographical pattern, age distribution and antibiotic resistance have been related to major serogroups and their serotypes . The relationships between Neisseria meningitidis serogroups and clinical manifestation, outcome and patient characteristics are assessed . All hospitalized patients in six major hospitals in central Israel with a verified meningococcal disease during 1990-1994 were included (n = 66).Their personal and clinical data and the results of bacteriological and serological tests of their blood and cerebrospinal fluid (CSF) were recorded . Meningococci were isolated from both blood and CSF, from blood alone, and from CSF alone in 60.6%, 18.2%, and 21.2% of the cases, respectively . The highest proportion of isolations were from infants < 1 year (34.8%), followed by children aged 1 to 5 years (25.8%) . Serogroup B prevailed in 62.1%, while groups C and W135 accounted for 28.8% and 9.1%, respectively . Serogroup B predominated in children < 1 year, while in patients aged 5-22 years, C strains were the major pathogen (P < 0.001) . Serogroup B accounted for 93% of the cases of meningitis, 58% of meningococcemia and 42% of fulminant meningococcemia, while group C strains were the major cause of fulminant meningococcemia (50%) . The overall case fatality rate was 7.6%: fulminant meningococcemia 8.3%, and meningococcemia 10% . It was concluded that N . meningitidis group C continues to account for almost a third of the cases of meningococcal disease and is the major cause of fulminant meningococcemia.

J Infect Dis, 2000 Jul, 182(1), 363 - 6 Epub 2000 Jun 30.
The role of RANTES in meningococcal disease; Carrol ED et al.; The chemokine RANTES (regulated on activation, normal T cell expressed and secreted) is a potent regulator of leukocyte trafficking . RANTES preferentially attracts mature CD4 cells as well as macrophages and eosinophils, but not neutrophils . In total, 128 children with meningococcal disease were prospectively studied, and the role of RANTES in the pathophysiology of meningococcal disease was assessed . Plasma RANTES, interleukin (IL)-8, IL-6, IL-1 receptor agonist, and tumor necrosis factor-alpha were measured at admission . Severity of disease was stratified by the Glasgow meningococcal septicemia prognostic score (GMSPS) . RANTES levels correlated significantly with IL-8 levels, admission lactate levels, platelets, prothrombin time, and activated partial thromboplastin time . RANTES levels were lower in children with severe disease (GMSPS>/=8; P=.001), in those with septic shock (P<.0005), and in nonsurvivors (P=.048; Mann-Whitney test) . RANTES is a potential mediator in the pathophysiology of meningococcal disease.

J Med Microbiol, 2000 Jul, 49(7), 669 - 73
Detection and characterisation of the genes encoding glyoxalase I and II from Neisseria meningitidis; Kizil G et al.; Glyoxalase enzymes I and II are involved in a detoxification process consisting of conversion of reactive dicarbonyl compounds (e.g., methylglyoxal) to less reactive hydroxy acids . The structural gene for meningococcal glyoxalase I (gloA) was identified by screening an expression library with a rabbit antiserum . The meningococcal gloA gene consisted of 138 deduced amino acids, with a calculated mol . wt of 15.7 kDa . The DNA and deduced protein sequence of gloA was compared to known sequences of glyoxalase I enzymes and showed high homology with gloA of several eukaryotic and prokaryotic species . Insertion of a gloA-containing plasmid in Escherichia coli increased the host organism's tolerance to methylglyoxal from <2 mM to >4 mM, thus demonstrating its functional identity . A databank search also revealed the presence of a putative gloB gene, encoding glyoxalase II (GlxII), in the recently released genomic sequences of Neisseria meningitidis and N . gonorrhoeae.

Rev Soc Bras Med Trop, 1999 Sep-Oct, 32(5), 517 - 22
Frequency of myocarditis in cases of fatal meningococcal infection in children: observations on 31 cases studied at autopsy; Garcia NS et al.; The frequency of myocarditis associated with meningococcal disease in children was reported only in two autopsied series (United States and South Africa) . Here we report the frequency of associated myocarditis in 31 children who died of meningococcal infection at Hospital Infantile N.S . da Gloria in Vitoria, Espirito Santo State, Brazil . The diagnosis was confirmed by isolation of Neisseria meningitidis . At least three sections of fragments of both atria and ventricles were studied using the Dallas Criteria for the morphologic diagnosis of myocarditis . The mean age was 47.6 +/- 39.8 months and the mean survival time after the onset of symptoms was 46.1 +/- 26.5 h (12-112 h) . Myocarditis was present in 13 (41.9%) patients, being of minimal severity in 11 cases and of moderate severity in 2 cases . There were no cases with severe diffuse myocarditis . The frequency of myocarditis was not influenced by sex, presence of meningitis, survival time after the onset of symptoms or use of vasoactive drugs . The frequency of myocarditis reported here was intermediate between the values reported in the only two case series published in the literature (57% in the United States and 27% in South Africa) . Although our data confirm the high frequency of myocarditis in meningococcal disease, further investigations are necessary to elucidate the contribution of myocarditis to myocardial dysfunction observed in cases of meningococcal infection in children.

Rev Soc Bras Med Trop, 1999 Sep-Oct, 32(5), 469 - 73
{Isolation of Rickettsia in vero cell culture}; Melles HH et al.; The diagnosis of spotted fever is based on characteristic signs and symptoms but requires laboratorial confirmation because of the possible differential diagnosis from other diseases like leptospirosis, enterovirus, meningococcemia and typhoid fever . Laboratorial confirmation may be done by detection of specific antibodies which is possible only 5-10 days after the onset of the symptoms or by the isolation of Rickettsiae from blood and/or skin biopsy and from ticks collected in the patient or in the animal reservoir . The isolation of Rickettsiae from blood or skin biopsy results in an early diagnosis of spotted fever since in the rickettsiemic phase of the disease there is no detectable level of antibodies in the serum . With the purpose of facilitating the diagnosis of Spotted Fever we have standardized the isolation of Rickettsiae in cell culture by a method that is less time consuming and that reduces the biological risks than isolation in guinea pigs . Vero cell cultures were inoculated with the Sheyla Smith strain of Rickettsia rickettsii provided by CDC (Atlanta-USA) . The identification was performed by indirect immunofluorescence technique . The presence of green fluorescent organisms characterized the growth of the agent . Ulterior confirmation of the methodology was done by isolation of the spotted fever agent from skin biopsy of a patient from an endemic area and from Amblyomma ticks that are the reservoir and vector of the Brazilian spotted fever.

Infection, 2000 May-Jun, 28(3), 157 - 60
Six different strains of Neisseria meningitidis in a case with meningococcal sepsis and five contact persons in a boys' home; Linde H et al.; BACKGROUND: It is routine practice to provide chemoprophylaxis for close contacts of a patient infected with meningococci . PATIENTS: When a 17-year-old boy living in a boys' home was admitted to the hospital with septic shock caused by Neisseria meningitidis, we immediately identified contact persons in the boys' home . RESULTS: 104 contact persons were identified and screened for oropharyngeal colonization . 77 persons received chemoprophylaxis . N . meningitidis was isolated from the index case and from five of 104 throat swabs of the contact persons (three home dwellers, one staff member, one visitor) . The overall carrier rate was 4.8% . All isolates showed different patterns when analyzed by pulsed-field gel electrophoresis, which was in accordance with results of serotyping by the German National Reference Center for Meningococci . CONCLUSION: In this non-epidemic situation, contacts between the index case, home mates, home personnel, and visitors were not close enough for effective transmission of meningococci, since no strain was found twice.This supports recommendations for the use of chemoprophylaxis in persons with intimate contact to the index patient.

Klin Lab Diagn, 2000 Apr, (4), 44 - 7
{Development and testing of polymerase chain reaction method for detection of meningococcal infection pathogen}; Limanskii AP et al.; A system of primers has been developed for the diagnosis of meningococcal infection has been developed on the basis of the polymerase chain reaction (PCR) . Specificity and sensitivity of detection of N . meningitidis has been evaluated in analysis of the model clinical specimens . The proposed test system was tried in detection of N . meningitidis in nasopharyngeal discharge specimens from patients with acute nasopharyngitis and normal subjects from the focus of meningococcal infection.

Br J Plast Surg, 2000 Mar, 53(2), 142 - 8
Meningococcal septicaemia and plastic surgery--a strategy for management; Potokar TS et al.; Meningococcal septicaemia is a severe life threatening illness that is part of the spectrum of meningococcal disease . It is of particular concern to the plastic and reconstructive surgeon because as the medical and intensive care of these patients improves, more are surviving the acute phase of the septicaemia and suffering from the associated complications such as skin necrosis and extremity loss . Recently there have been several reports in the literature concerning the management of skin infarction with both skin grafting and free flap surgery . This paper will provide an update on the proposed pathophysiological mechanisms involved, summarise the present data on plastic surgical care and suggest a stratagem for future management of these difficult cases.

Zh Mikrobiol Epidemiol Immunobiol, 1999 Nov-Dec, (6), 30 - 3
{Dried nutrient media for the cultivation of pneumococcus and meningococcus}; Omarova SM et al.; Dried synthetic nutrient medium for the cultivation of meningococci and the accumulation of their biomass has been developed . The kinetics of the culture growth, changes in pH and in the content of dissolved oxygen in the medium during prolonged controlled processes of the cultivation of meningococci in a bioreactor with the use of this medium have been studied . The stable physico-chemical properties and composition of the polysaccharide-protein complex isolated from the biomass of meningococci grown in the above-mentioned medium have made it possible to use it for the preparation of the samples of group B meningococcal vaccine . In addition, dried semi-synthetic nutrient medium for the accumulation of pneumococci without the necessity of introducing blood or serum into the medium has been developed . As regards its biological properties, this newly developed medium make it not inferior to meat media, containing blood or serum, and ensures good yield of biomass.

Methods, 2000 Jul, 21(3), 203 - 20
Concurrent measurement of antigen- and antibody-dependent oxidative burst and phagocytosis in monocytes and neutrophils; Bassoe CF et al.; The current study aims to review flow cytometric (FCM) parameters for the quantification of phagocytosis . A limitation of existing methods is their difficulty with accurate quantification of the phagocytic index, i.e., number of beads per phagocyte, in individual cell lines in mixed cell suspensions . We have quantified phagocytosis and the oxidative burst simultaneously using fluorescent beads coated with meningococcal outer membrane vesicles (OMV beads) by the conversion of dihydrorhodamine 123 (DHR-123) to rhodamine 123 (R-123) . Both these processes depend on specific serum opsonins . After the incubation, staining with a fluorescent anti-CD14 monoclonal antibody succeeded in discriminating phagocytosing monocytes from neutrophils . The spectral overlaps between OMV beads, R-123, and anti-CD14 could be completely compensated . Percentage of phagocytosis and the phagocytic index were similar in monocytes and neutrophils, but the oxidative burst behaved differently . Two monocyte subpopulations were observed . Both subpopulations spontaneously converted some DHR-123 into R-123, whereas the reaction was triggered by phagocytosis in neutrophils . The total oxidative response increased with increasing phagocytic index in both cell types, but the oxidative burst in monocytes was about twice that of neutrophils . The oxidative ratio (mean R-123 fluorescence value divided by the phagocytic index) declined with time in monocytes, but increased in neutrophils . Our results demonstrate the need for careful attention to technical details . This single-laser, three-color FCM method facilitates the comparative research of phagocytosis and the oxidative burst in monocytes and neutrophils and provides a basis for a number of applications in hematology, infectious medicine, and immunology .

New Microbiol, 2000 Apr, 23(2), 185 - 200
Interactions of invasive and noninvasive strains of Neisseria meningitidis with monkey epithelial cells, mouse monocytes and human macrophages; Kalmusova J et al.; Adherence and phagocytosis of invasive and noninvasive Neisseria meningitidis strains was investigated using light, fluorescence and electron microscopy . Invasive strains were isolated from the cerebrospinal fluid and/or blood of the patients with invasive meningococcal disease and noninvasive strains from the nasopharynx and/or larynx of healthy carriers . Adherence/endocytosis was studied on monkey kidney cells (the LLC-MK2 cell line) and phagocytosis on mouse monocytes and human macrophages (the P388D1 and U-937 cell lines, respectively) . Although invasive and noninvasive meningococci isolated in the same cluster showed identical genotype and phenotype markers, they were found to interact differently with epithelial cells as well as with monocytes/macrophages . Invasive isolates displayed higher adherence to the surface of LLC-MK2 cells compared to noninvasive ones . Phagocytosis by P388D1 cells of noninvasive strains was effective and the bacteria were damaged by cytolysis . In contrast, invasive bacteria frequently persisted in "coiling" vacuoles and in effect could destroy the host cell . This is the first demonstration of coiling phagocytosis induced by meningococci . Efficiency of phagocytosis by U-937 cells was significantly higher for the noninvasive than invasive strains . Different behaviour of invasive and noninvasive strains of N . meningitidis observed during 4 hours of interactions with epithelial cells and monocytes/macrophages reflects well the higher pathogenic potential of invasive bacteria.

Intensive Care Med, 2000 Apr, 26(4), 471 - 3
Meningococcal septicaemia: treatment with protein C concentrate; Clarke RC et al.; Meningococcal septicaemia is a devastating disease with the potential to develop severe vascular complications . The incidence in Northern Ireland has risen from 27 cases notified in 1992 to 56 notified in 1997 . We describe the first use of protein C concentrate in addition to antithrombin III infusion in the management of a life-threatening case of meningococcal septicaemia in the Regional Intensive Care Unit, Royal Group of Hospitals, Belfast, UK . The rationale and the evidence to support the use of protein C concentrate are discussed . Despite the apparent efficacy and safety of this treatment, subsequent cases of meningococcal septicaemia have not received protein C concentrate due to a lack of availability.

Microbes Infect, 2000 Apr, 2(5), 447 - 53
Species, population and age diversity in cell resistance to adhesion of Neisseria meningitidis serogroups A, B and C; Rumyantsev SN et al.; The variation of cell adherence of meningococci serogroups A, B and C and influenza viruses was investigated in 11 animal species and in humans of different age groups (1st, 2nd, 3rd and 4th weeks; 2nd-3rd months; 4th-12th months, 2nd-3rd years; and 18th-60th years of life) as well as in women during pregnancy (17th-36th weeks) and childbirth . Red blood cells of all animals tested as well as of human newborns were absolutely resistant to attachment of meningococci . In neonatal and the later periods the human cells become far differently sensitive individually to meningococcal adhesion . In contrast, the viral adhesion was characterized by different individual cell sensitivity in all age groups tested . Pregnancy and childbirth did not influence the women's cell sensitivity to adhesion of Neisseria meningitidis . Different receptors are involved in interactions of human cells with influenza viruses and meningococci . The function of meningococcal receptors on human cells develops during postnatal ontogenesis . The variations express both specific (genetic) and ontogenetic (individual) differences in natural resistance to meningococcal infection.

FEMS Immunol Med Microbiol, 2000 Jul, 28(3), 189 - 91
Prevalence of de-O-acetylated serogroup C meningococci before the introduction of meningococcal serogroup C conjugate vaccines in the United Kingdom; Borrow R et al.; Meningococcal serogroup C conjugate (MCC) vaccines have been introduced in the UK to combat the rise in serogroup C meningococcal disease . Serogroup C meningococci may occur naturally expressing either O-acetylated (Oac(+)) or de-O-acetylated (Oac(-)) polysaccharide capsules . In a small study in the USA in the 1970s 15% of serogroup C meningococcal case isolates were reported to be Oac(-) though the prevalence of these Oac(-) isolates has not been recorded in the UK . This is of interest as the first MCC vaccines to be introduced are Oac(+) and the potential impact of this on Oac(-) serogroup C isolates is unclear . Serogroup C isolates submitted to the Public Health Laboratory Service Meningococcal Reference Unit in January 1998 (n=113) and January 1999 (n=162) were investigated by dot blotting using monoclonals specific for Oac(+) and Oac(-) serogroup C polysaccharides . This revealed 12% Oac(-) isolates for both January 1998 and January 1999 . The proportion of fatal cases was found to similar for both Oac(-) and Oac(+), 14 and 9% for 1998 and 5 and 3% for 1999, indicating that the pathogenic potential of these Oac(-) isolates is similar to Oac(+) . The acetylation status of serogroup C isolates needs to be monitored throughout and after the introduction of MCC vaccines.

Ugeskr Laeger, 2000 May 15, 162(20), 2882 - 5
{Antibiotic pre-hospital treatment and the course of meningococcal disease}; Sorensen HT et al.; The aim of the study was to assess the effect of pre-hospital antibiotic treatment given by general practitioners to patients with meningococcal disease . It was carried out as a 16-year population-based historical follow-up study based on referral letters and hospital records in the County of North Jutland, Denmark, and included 320 patients with meningococcal disease, of whom 302 were examined by a general practitioner before admission to hospital . The main outcome measure was death . We found that 44 patients (14.6%) were given antibiotic treatment by the referring general practitioner . Nine of these (20.5%) died, compared with 16 (6.2%) patients who did not receive pre-hospital antibiotic treatment . The presence of skin bleeding, petechiae and impaired consciousness were strongly associated with case fatality . Even after adjustment for these variables the odds ratio for death in patients treated with antibiotics was high (3.2; 95% CI 0.9-10.6) . In the 15 patients with skin bleeding (ecchymoses, suggillations) the case fatality rate was 100% in patients treated with antibiotics, and 50% in patients who did not receive antibiotics before hospitalization . It is concluded that pre-hospital treatment is mainly given to the most severe cases with expected high case fatality, and this confounding by indication was probably not fully adjusted for with the available data . The results contradict previous findings and provide reason to doubt the benefit of pre-hospital antibiotic treatment in patients with meningococcal disease.

Cent Eur J Public Health, 2000 May, 8(2), 114 - 6
Cyclicity in incidence variations of meningococcal infections in Bulgaria is similar to that of solar activity; Dimitrov BD; This is a retrospective study on meningococcal meningitis (MM) in Bulgaria that has, for the first time, reported results on non-linear temporal patterns of incidence and its variations . Methods of descriptive statistics, linear and non-linear modelling as well as periodogram regression analysis have been applied . A non-linear decreasing trend in crude incidence rates per 100 persons over the years 1940-1990 has been described (p < 0.0001) and cyclic variations revealed (periods T = 8.00, 18.75, 24.75 and 33.50 years, p < 0.05-0.01) . Above cycles have been detected after the reciprocal trend has been removed (y = 1.04 + 15.78/t) . A similar cyclicity (periods T = 8.25 and 27.5 years) in the variations of solar activity (sunspot number Rz) over the same time interval of 51 years has been established after the main cycle of 10.5-13 years has been removed by a two-step procedure . The results from this study have added to our previous findings on cyclic variations in mortality and lethality from meningococcal infections in Bulgaria (1, 2) . Above similarity is also in accordance with earlier conclusions on relations of solar activity cycles with epidemics of cerebrospinal meningitis in New York and USA over the years 1800-1935 (3, 4).

Zh Mikrobiol Epidemiol Immunobiol, 1999 May-Jun, (3), 46 - 52
{The bactericidal action of human neutrophils on meningococci in vitro}; Platonov AE et al.; 32 Russian patients with late complement component deficiency (LCCD) were immunize with tetravalent meningococcal polysaccharide vaccine (A + C + W135 + Y) . Their immune response and infectious morbidity rate were followed for 6 years and the partial protective efficacy of vaccination was demonstrated . As the antibody-mediated complement-induced bactericidal activity of plasma was completely absent in persons with LCCD, the bactericidal action of human neutrophils on meningococci of groups A, W135 and B was studied under the conditions of incubation with serum samples collected from persons with LCCD before and after vaccination . In LCCD serum alone the exponential growth of meningococci was observed, while the addition of human neutrophils resulted in the essential inhibition of the growth of meningococci (up to their complete elimination) . The proportion of serum samples stimulating the elimination of group A and W 135 meningococci by neutrophils was almost 40% of the serum samples collected before vaccination and significantly increased among the serum samples collected after vaccination (up to 84%) or revaccination (up to 90%) . At the same time the capacity of an individual serum sample to promote the bactericidal effect of neutrophils against meningococci correlated with its content of specific anti-polysaccharide IgG and IgM antibodies, as well as antibodies to the inner core of lipopolysaccharide . The interaction of neutrophils with meningococci was significantly inhibited after incubation in heat-inactivated serum, suggesting that this interaction was partly mediated along the following path: the binding of IgM and IgG antibodies with bacteria--the activation of complement and the deposition of C3 complement on bacteria--the binding of meningococci with CR3 receptors of neutrophils.

Arch Pediatr Adolesc Med, 2000 Jun, 154(6), 556 - 60
Antibiotic treatment of children with unsuspected meningococcal disease; Wang VJ et al.; BACKGROUND: Data from an earlier study suggest that patients with unsuspected meningococcal disease (UMD) cannot be differentiated easily from febrile children with viral syndromes on the basis of physical examinations or peripheral blood counts . Some children with meningococcal disease therefore are treated inadvertently as outpatients . OBJECTIVE: To determine whether antibiotic therapy administered at the outpatient visit prevents complications, permanent sequelae, or death in children with UMD . METHODS: We reviewed the medical records of patients younger than 20 years with invasive meningococcal disease at 7 pediatric referral centers from January 1, 1981, through December 31, 1996 . Patients were considered to have UMD if they underwent evaluation and discharge as outpatients and if blood and/or cerebrospinal fluid cultures obtained at evaluation yielded Neisseria meningitidis . We compared the frequency of development of complications (meningitis, sepsis, and pericarditis), permanent sequelae (limb amputation, skin grafting, and persistent neurologic disability) or death between patients who did and did not receive antibiotics at the outpatient visits . RESULTS: Of 58 children with UMD, 19 (33%) received antibiotics and 39 (67%) did not . Complications occurred significantly less frequently in the antibiotic-treated group (7/19 {37%} vs 27/39 {69%}; odds ratio {OR}, 0.26; 95% confidence interval {CI}, 0.08-0.81; P = .03) . There was no significant difference in death or permanent sequelae between groups (0/19 vs 3/39 {8%}; OR, 0; 95% CI, 0-2.61; P=.54) . There was insufficient power, however, to exclude the possibility of a clinically meaningful difference between the groups with regard to these latter outcomes . CONCLUSIONS: Antibiotic administration to young patients with UMD at the time of the outpatient visit is associated with a reduction in complications from this disease . Although the routine use of antibiotics in febrile outpatients younger than 20 years cannot be advocated, empirical treatment should be considered in the setting of higher probability of meningococcal disease.

J Paediatr Child Health, 2000 Jun, 36(3), 240 - 3
Hearing in children after meningococcal meningitis; Drake R et al.; OBJECTIVE: To review the outcome of sensorineural hearing loss in children who have had confirmed meningococcal meningitis . METHODS: A retrospective audit of children admitted to the Starship Children's Hospital with a confirmed diagnosis of meningococcal meningitis during a 4-year period . RESULTS: Sixty-five children had confirmed meningococcal meningitis . Dexamethasone was administered according to recommended guidelines in 46 children (72%) while 12 children (19%) did not receive steroids at any stage . All children were appropriately referred for hearing assessment . Forty-nine children (75%) had their hearing tested and reliable sensorineural evaluation was obtained in all but one case . Thirty-four children (70%) were seen up to 6 weeks from discharge, 86% by 12 weeks . Sixteen cases (25%) did not attend for audiological assessment . Sensorineural hearing impairment was found in two children (4.2%) . CONCLUSIONS: Children with meningococcal meningitis were reliably referred for audiological assessment but 39% either failed to attend for an outpatient hearing evaluation (25%) or had an unacceptable delay between discharge and testing (14%) . Of those reliably tested, two children (4.2%) had significant sensorineural hearing loss.

Mol Microbiol, 2000 Jun, 36(5), 1049 - 58
Frequent interspecific genetic exchange between commensal Neisseriae and Neisseria meningitidis; Linz B et al.; Natural sequence variation was investigated among serogroup A subgroup IV-1 Neisseria meningitidis isolated from diseased patients and healthy carriers in The Gambia, West Africa . The frequencies of DNA import were analysed by sequencing fragments of four linked genes encoding the immunogenic outer membrane proteins TbpB (transferrin binding protein B) and OpaA (an adhesin) plus two housekeeping enzymes . Seventeen foreign tbpB alleles were independently imported into the 98 strains tested, apparently due to immune selection . The median size of the imported DNA fragments was 5 kb, resulting in the occasional concurrent import of linked housekeeping genes by hitchhiking . Sequences of tbpB from other strains of N . meningitidis as well as commensal Neisseria lactamica and Neisseria spp . isolated from the same geographical area revealed that these species share a common tbpB gene pool and identified several examples of interspecific genetic exchange . These observations indicate that recombination can be more frequent between related species than within a species and indicate that effective vaccination against serogroup B meningococcal disease may be difficult to achieve.

Mol Microbiol, 2000 May, 36(4), 817 - 29
Interactions of Neisseria meningitidis with cells of the human meninges; Hardy SJ et al.; The interaction of Neisseria meningitidis with the meninges that surround and protect the brain is a pivotal event in the progression of bacterial meningitis . Two models of the human meninges were established in vitro, using (i) sections of fresh human brain and (ii) cultures of viable cells grown from human meningiomas . Neisseria meningitidis showed a specific predilection for binding to the leptomeninges and meningeal blood vessels in human brain and not to the cerebral cortex . There was a close correlation between the adherence of different Neisseria species to leptomeninges and cultured cells . The major ligand that mediated adherence was the pilus, and pilin variation modulated the interactions . The presence of Opa protein increased the association of Cap+ meningococci that expressed low-adhesive pili, but did not influence the association of high-adhesive pili . In contrast, Opc did not influence the adherence of Cap+ meningococci, whereas loss of capsule was associated with a more intimate interaction between the bacteria and the meningioma cell that was not apparent with Cap+ meningococci . There was no evidence of internalization of meningococci by meningioma cells in vitro, an observation that is consistent with the barrier properties of the leptomeninges to N . meningitidis observed in vivo.

APMIS, 2000 Apr, 108(4), 276 - 82
The effects of live Neisseria meningitidis and tumour necrosis factor-alpha on neutrophil oxidative burst and beta2-integrin expression; Kragsbjerg P et al.; The effects of human recombinant tumour necrosis factor-alpha (TNF-alpha) on neutrophil (PMNL) oxidative burst and on CD11b/CD18 and CD14 expression after stimulation with pathogenic or nonpathogenic Neisseria meningitidis were studied using chemiluminescence and flow cytometry . PMNL oxidative burst increased more when stimulated with the apathogenic 29E strain than with the pathogenic B strain both when studied by chemiluminescence and by flow cytometry . When TNF-alpha was added to whole blood or PMNL together with bacteria a significant increase in the oxidative burst was seen for the B strain only . When whole blood was preincubated for 30 min with TNF-alpha the increase in oxidative burst was significant for both meningococcal strains . TNF-alpha caused a significant increase in PMNL CD 11b/CD18 expression after 30 min of incubation at 37 degrees C . TNF-alpha added simultaneously with the bacteria induced a significant increase in PMNL CD11b/CD18 in both strains . Incubation with the B strain alone caused a low but significant increase in CD11b/CD18 expression, but the addition of TNF-alpha increased this expression to the same high level as incubation with TNF-alpha alone or the 29E strain alone . Only TNF-alpha and the 29E strain caused significant increases in CD14 expression . In conclusion, human PMNLs react differentially when stimulated with pathogenic and nonpathogenic N . meningitidis and the activating effect of TNF-alpha is variable depending on the bacteria involved.

Biomed Environ Sci, 1999 Dec, 12(4), 296 - 303
Preparation and immunogenicity of serogroup B meningococcal OS-OMPC conjugates; Sun YY et al.; The objective of the present study is to purify oligosaccharides (OSs) from serogroup B meningococci (3407 or 542852) with common lipooligosaccharide (LOS) immunotypes prevalent in China and to successfully conjugate them to their outer membrane protein complexes (OMPCs) . Conjugates possessing broad cross-reactivity with different serogroup B meningococci were obtained . Both LOSs from the above two strains were purified on a Sephadex G75 column and hydrolyzed with acetic acid, and then the pure OSs were obtained by using a Sephadex G50 chromatographic column . The pure OSs were conjugated to corresponding OMPCs by carbodiimide mediated condensation . Mice were immunized with the OS-OMPC conjugates to produce antibodies . Immunogenicities of the conjugates were tested by ELISA, bactericidal test and Western-blotting . The titers of antibodies against OS and LOS elicited by the two OS-OMPC conjugates increased respectively by 2.5 and 2 to 10 times as compared with those of antibodies against unconjugated OS and LOS . The sera elicited by the conjugates possessed a stronger bactericidal activity to the strains (3407, 542852, 29021) with the same LOS immunotype than to the strain with different LOS immunotype (86155) . The results determined by ELISA indicated that the sera against the conjugates showed strong response to the strains with the same or different LOS immunotypes . It was confirmed by western-blotting analysis that the sera elicited by the two conjugates reacted with 42, 39 and 26 kDa proteins from the OMPC . Among the reactive bands, the 42 kDa proteins were class 1 OMPs . The two serogroup B meningococcal OMPCs were strong immunogens and good carriers coupling with OSs as well . The immunogenicity of the conjugated OS was increased and the OS-OMPC conjugates of the serogroup B meningococci showed a broad antigenic response to the strains tested.

JAMA, 2000 Jun 7, 283(21), 2795 - 801
Safety, immunogenicity, and induction of immunologic memory by a serogroup C meningococcal conjugate vaccine in infants: A randomized controlled trial; MacLennan JM et al.; CONTEXT: Neisseria meningitidis is a common cause of meningitis and septicemia in infants worldwide . Whether a meningococcal C conjugate vaccine protects infants against the serogroup C strain is unknown . OBJECTIVES: To determine whether a meningococcal C conjugate vaccine is safe and immunogenic and induces immunologic memory in infants . DESIGN: Single-center, double-blind, randomized controlled trial in 1995 and 1996 . SETTING: Community, Oxfordshire, England . PARTICIPANTS: One hundred eighty-two healthy infants . INTERVENTIONS: Participants were randomly assigned to receive vaccination with 0 . 5-mL doses of 1 of 2 lots of meningococcal C conjugate vaccine (groups 1 and 2; n=60 in each group) or a hepatitis B control vaccine (group 3; n=62), administered with routine immunizations at 2, 3, and 4 months of age . Approximately half of each group received meningococcal C conjugate vaccine and half received plain meningococcal polysaccharide vaccine (MPS) at 12 months of age . MAIN OUTCOME MEASURES: Serum antibodies to meningococcal C polysaccharide, assayed by enzyme-linked immunosorbent assay, and serum bactericidal activity (SBA), at 2, 3, 4, 5, 12, and 13 months of age; local and systemic reactions, recorded for 6 days after each vaccination, compared by intervention group . RESULTS: Meningococcal C conjugate vaccine was well tolerated . After 3 doses, children in groups 1 and 2 achieved significantly higher meningococcal C IgG geometric mean concentrations (21 and 17 U/mL, respectively, vs 0.20 U/mL; P<.001) and SBA titers (629 and 420, respectively, vs 4.1; P< . 001) than controls . At 12 months, antibody concentrations had decreased in all groups but remained significantly higher in children vaccinated with meningococcal C conjugate vaccine (SBA, 24 and 16 in groups 1 and 2, respectively, vs 4.2 in group 3; P<.001) . Following vaccination with MPS at 12 months of age, SBA in the meningococcal C conjugate vaccine group was significantly higher than in controls (SBA, 789 vs 4.5; P<.001) . CONCLUSIONS: Our data indicate that meningococcal C conjugate vaccine is safe and immunogenic and results in immunologic memory when given with other routinely administered vaccines to infants at 2, 3, and 4 months of age . JAMA . 2000;283:2795-2801

J Antimicrob Chemother, 2000 Jun, 45(6), 909 - 11
Equivalence of ceftriaxone and rifampicin in eliminating nasopharyngeal carriage of serogroup B Neisseria meningitidis; Simmons G et al.; The efficacy of ceftriaxone in eliminating nasopharyngeal carriage of Neisseria meningitidis was compared with that of rifampicin during an epidemic of serogroup B meningococcal disease in Auckland, New Zealand . Household contacts of cases had a throat swab taken and were randomized to treatment . Carriers had a repeat swab taken 6 days later to determine efficacy of treatment . Ceftriaxone (98.2%) was equivalent to rifampicin (97.6%) in eliminating serogroup B N . meningitidis . It is cheaper than rifampicin and has the advantage of full compliance and fewer contraindications, but its acceptability by patients may limit its use as a first-line prophylactic agent.

J Clin Microbiol, 2000 Jun, 38(6), 2311 - 6
Dynamics of meningococcal long-term carriage among university students and their implications for mass vaccination; Ala'Aldeen DA et al.; In the 1997-98 academic year, we conducted a longitudinal study of meningococcal carriage and acquisition among first-year students at Nottingham University, Nottingham, United Kingdom . We examined the dynamics of long-term meningococcal carriage with detailed characterization of the isolates . Pharyngeal swabs were obtained from 2,453 first-year students at the start of the academic year (October), later on during the autumn term, and again in March . Swabs were immediately cultured on selective media, and meningococci were identified and serologically characterized . Nongroupable strains were genetically grouped using a PCR-based assay . Pulsed-field gel electrophoresis was used to determine the link between sequential isolates . Of the carriers initially identified in October, 44.1% (98 of 222) were still positive later on in the autumn (November or December); 57.1% of these remained persistent carriers at 6 months . Of the index carriers who lost carriage during the autumn, 16% were recolonized at 6 months . Of 344 index noncarriers followed up, 22.1% acquired carriage during the autumn term and another 13.7% acquired carriage by March . Overall, 43.9% (397 of 904) of the isolates were noncapsulated (serologically nongroupable); by PCR-based genogrouping, a quarter of these belonged to the capsular groups B and C . The ratio of capsulated to noncapsulated forms for group B and C strains was 2.9 and 0.95, respectively . Sequential isolates of persistent carriers revealed that individuals may carry the same or entirely different organisms at different times . We identified three strains that clearly switched their capsular expression on and off at different times in vivo . One student developed invasive meningococcal disease after carrying the same organism for over 7 weeks . The study revealed a high rate of turnover of meningococcal carriage among students . Noncapsulated organisms are capable of switching their capsular expression on and off (both ways) in the nasopharynx, and group C strains are more likely to be noncapsulated than group B strains . Carriage of a particular meningococcal strain does not necessarily protect against colonization or invasion by a homologous or heterologous strain.

Eur J Clin Microbiol Infect Dis, 2000 Apr, 19(4), 260 - 6
Measurement of serum antigen concentration by ultrasound-enhanced immunoassay and correlation with clinical outcome in meningococcal disease; Sobanski MA et al.; The distribution of Neisseria meningitidis serogroup B and C polysaccharide antigen in blood and the prognostic significance of antigen concentration was examined by ultrasound-enhanced immunoagglutination of coated microparticles . Specimens (169 sera/plasma from 145 patients with confirmed meningococcal disease) were tested retrospectively . The ultrasonic immunoassay detected serum antigen in 136 samples from 112 patients . Titration of antigen-positive specimens allowed estimation of blood antigen concentration . The modal blood antigen titre was 1/16, corresponding to an estimated polysaccharide concentration of 0.85 microg/ml . The lowest mean blood antigen concentration found ultrasonically was 0.05 microg/ml; compared to the 1.98 microg/ml found by conventional latex agglutination, this represents an approximately 30-fold improvement in sensitivity . Three grades of outcome were correlated with the presenting antigen titre in 83 patients: (i) <2 weeks hospitalisation, (ii) > or =2 weeks hospitalisation and (iii) mortality . High polysaccharide concentrations correlated with mortality . Nine of 15 patients with a serum antigen titre of 1/64 or greater (> or =3.4 microg/ml polysaccharide) died, whereas no patient with titres equal to or less than 1/4 (< or = 0.21 microg/ml) died, including those patients in whom antigen was undetectable by ultrasonic immunoassay . Increasing antigen concentration significantly correlated with severity of outcome (P<0.001) . Ultrasound-enhanced agglutination provides a rapid prognostic indicator by sensitive measurement of serum antigen level.

Health Educ Behav, 2000 Jun, 27(3), 363 - 70
Taking public health to the streets: the 1998 Auckland Meningococcal Disease Awareness Program; Bullen C; Since 1991, New Zealand has experienced a dramatic increase in cases of serogroup B meningococcal disease . Early in 1998, a program was initiated in Auckland to raise awareness among high-risk communities about the early clinical features of meningococcal disease and appropriate action to take . The campaign was conducted largely through door-to-door visiting by Maori and Pacific Islands lay educators, who visited more than 11,000 households and engaged more than 9,000 people in discussion . Significantly greater awareness was found in people visited by lay educators than those not visited . For the first time in 5 years, there were no meningococcal deaths among the target population for the 6 months from the start of the campaign . Home visiting by lay educators is an effective and highly acceptable means of communicating important health information to populations at high risk of meningococcal disease in New Zealand and should be considered for other public health campaigns.

Curr Microbiol, 2000 Jun, 40(6), 372 - 9
Genomic rearrangements in neisseria meningitidis strains of the ET-5 complex; Froholm LO et al.; A physical map of the chromosome of Neisseria meningitidis strain 44/76, which belongs to the epidemic clone ET-5, was constructed . DNA fragments obtained after SfiI and NheI digestion were resolved by pulsed field gel electrophoresis (PFGE) . The overall arrangement of 26 genetic markers localized on the 2.3-Mb chromosome was conserved in comparison with that in meningococcal strains B1940 and Z2491 . Simplified physical maps of 29 additional strains belonging to the ET-5 complex isolated from various parts of the world were compared with that of strain 44/76 . Ten distinct patterns of hybridization were identified . While two of the seven probes hybridized to fragments of the same size in all strains, the remaining probes hybridized to different fragments, in some cases to fragments not adjacent on the chromosome of 44/76 . These results indicated the occurrence of genetic rearrangements in the genome of the ET-5 meningococcal clone in the course of its epidemic spread . </HEA

Scand J Infect Dis, 2000, 32(2), 185 - 7
Molecular characteristics and susceptibility to antibiotics of serogroup A Neisseria meningitidis strains isolated in Senegal in 1999; Sow AI et al.; A total of 22 strains of Neisseria meningitidis isolated from cerebrospinal fluid samples of patients in Dakar, Senegal, in the course of an epidemic of meningococcal meningitis in 1999 were studied . All the strains were serogroup A, serotype 21:P1.9 and belonged to clonal subgroup III-1 . The strains were resistant to sulphonamide, but were susceptible to ampicillin, ceftriaxone and chloramphenicol, which are used in the treatment of cerebrospinal meningitis in Senegal.

Clin Infect Dis, 1999 Apr, 28(4), 770 - 7
Randomized, placebo-controlled trial of HA-1A, a human monoclonal antibody to endotoxin, in children with meningococcal septic shock . European Pediatric Meningococcal Septic Shock Trial Study Group; Derkx B et al.; Meningococcal septic shock has a rapid onset and characteristic skin hemorrhages that allow bedside diagnosis . Initial plasma endotoxin levels are high and correlate closely with clinical outcome . In a double-blind, randomized, placebo-controlled trial (planned, n = 270; actual, n = 269), we compared the effectiveness of HA-1A (6 mg/kg of body weight iv; maximum, 100 mg), a human monoclonal antibody to endotoxin, and placebo in reducing the 28-day all-cause mortality rate among children with a presumptive clinical diagnosis of meningococcal septic shock . Treatment groups were well balanced for baseline characteristics and prespecified prognostic variables . In this trial no significant benefit of HA-1A could be demonstrated . The 28-day mortality rates in the intention-to-treat analysis were as follows: placebo, 28%; HA-1A, 18%; reduction in mortality, 33% (P = .11, per Fisher's exact test, two-tailed; odds ratio = 0.59; 95% confidence interval for the difference, 0.31-1.05) . All patients tolerated HA-1A well, and no antibodies to HA-1A were detected.

Br J Anaesth, 2000 Apr, 84(4), 514 - 7
Spinal cord infarction and tetraplegia--rare complications of meningococcal meningitis; O'Farrell R et al.; A previously healthy 25-yr-old female developed flaccid areflexic tetraplegia, with intact cranial nerve function, 36 h after the diagnosis of bacterial meningitis . Polymerase chain reaction studies of cerebrospinal fluid and blood were positive for Neisseria meningitidis, serogroup B . Magnetic resonance of the cervicothoracic spine revealed increased signal intensity and expansion in the lower medulla, upper cervical cord and cerebellar tonsils . Neurosurgical consultation recommended hyperventilation, dexamethasone and regular mannitol therapy rather than decompressive intervention . The clinical course over the following 12 days was complicated by the development of progressive central nervous and multisystem organ failure with disseminated intravascular coagulopathy . Autopsy revealed cerebral oedema with cystic infarction extending from the medulla to the upper cervical cord and cerebellar tonsils . Flaccid areflexic tetraplegia with spinal cord infarction has not been reported following bacterial infection in an adult . The clinical implications would suggest complete central nervous system evaluation of patients recovering from meningococcal meningitis, since spinal cord lesions, although uncommon, do occur . In those very rare situations where a patient develops significant peripheral neurological deficits, urgent magnetic resonance imaging is warranted, to rule out an infective focus or an underlying anatomical anomaly.

Antimicrob Agents Chemother, 2000 Jun, 44(6), 1705 - 7
Antibiotic susceptibility patterns of Neisseria meningitidis isolates from patients and asymptomatic carriers; Arreaza L et al.; The activities of seven antimicrobial agents used for treatment and prophylaxis of meningococcal disease was investigated against 901 Neisseria meningitidis isolates, 112 of which were recovered from patients and 789 of which were recovered from asymptomatic carriers . The proportions of isolates with decreased susceptibility to penicillin were 55.3 and 39.0%, respectively . Penicillin- and ampicillin-intermediate strains were more common among serogroup C meningococci than among non-serogroup C meningococci from both patients and carriers.

MMWR Morb Mortal Wkly Rep, 2000 Apr 28, 49(16), 345 - 6
Serogroup W-135 meningococcal disease among travelers returning from Saudi Arabia--United States, 2000; Carcinoembryonic antigen family receptor specificity of Neisseria meningitidis Opa variants influences adherence to and invasion of proinflammatory cytokine-activated endothelial cells; Abteilung, Infektionsbiologie, Max-Planck-Institut fur Biologie, 72076 Tubingen, GermanyThe carcinoembryonic antigen (CEA) family member CEACAM1 (previously called biliary glycoprotein or CD66a) was previously shown to function as a receptor that can mediate the binding of Opa protein-expressing Neisseria meningitidis to both neutrophils and epithelial cells . Since neutrophils and polarized epithelia have both been shown to coexpress multiple CEACAM receptors, we have now extended this work to characterize the binding specificity of meningococcal Opa proteins with other CEA family members . To do so, we used recombinant Escherichia coli expressing nine different Opa variants from three meningococcal strains and stably transfected cell lines expressing single members of the CEACAM family . These infection studies demonstrated that seven of the nine Opa variants bound to at least one CEACAM receptor and that binding to each of these receptors is sufficient to trigger the Opa-dependent bacterial uptake by these cell lines . The other two Opa variants do not appear to bind to either CEACAM receptors or heparan sulfate proteoglycan receptors, which are bound by some gonococcal Opa variants, thus implying a novel class of Opa proteins . We have also extended previous studies by demonstrating induction of CEACAM1 expression after stimulation of human umbilical vein endothelial cells with the proinflammatory cytokine tumor necrosis factor alpha, which is present in high concentrations during meningococcal disease . This induced expression of CEACAM1 leads to an increased Opa-dependent bacterial binding and invasion into the primary endothelia, implying that these interactions may play an important role in the pathogenesis of invasive meningococcal disease.

J Bone Joint Surg Br, 2000 Apr, 82(3), 383 - 6
The orthopaedic management of peripheral ischaemia in meningococcal septicaemia in children; Davies MS et al.; Between March 1993 and February 1999, 14 children aged from eight months to 14.75 years were admitted to the paediatric intensive-care unit with meningococcal septicaemia in association with severe peripheral ischaemia . Of these, 13 were operated upon, eight of whom had early fasciotomies . Five children died . Of the nine survivors, one had no amputations while in the other eight 14 limb segments were amputated . We review the case histories and propose a protocol for the early management of these children.

Epidemiol Infect, 2000 Apr, 124(2), 337 - 40
Distribution of the meningococcal insertion sequence IS1301 in clonal lineages of Neisseria meningitidis; Hilse R et al.; The distribution of the meningococcal insertion sequence IS1301 was analysed in 496 strains of different serogroups and clonal lineages of Neisseria meningitidis, and in 64 neisserial strains other than N . meningitidis . IS1301 was found in meningococci, but not in apathogenic Neisseria sp . and Neisseria gonorrhoeae . The copy numbers of IS1301 varied between 2 and 17 per genome . IS1301 positive strains were mostly found among the serogroups 29E, W135, X, and Y . Clonal lineages of serogroup A, B, and C meningococci associated with epidemic meningococcal disease were rarely positive for IS1301.

Mil Med, 2000 Apr, 165(4), 283 - 6
Pediatric diseases and operational deployments; Pearn J; Many nations now export military health as a proactive arm of the nation's contribution to the maintenance of international peace in trouble regions of the world; and all nations are called upon from time to time in emergency and disaster situations to help out in their regions of interest . Children and young teenagers constitute some 50% of war-stricken populations . This paper explores this increasingly important role of military medicine from the point of view of a practicing pediatrician and career doctor-soldier . Many international operational deployments undertaken in the last 5 years have required the insertion of pediatric clinical and preventive health resources . Deployments to Rwanda, the countries of the former Yugoslavia, Somalia, Bougainville (in Papua New Guinea), Irian Jaya (in Indonesia), and the Aitape tsunami disaster response (the Sepik region of Papua New Guinea) have all necessitated major pediatric interventions . In some operational deployments, in excess of one-third of patient and clinical contacts have involved the care of children, including clinical treatments ranging from life-saving resuscitation to the care of children with both tropical and subtropical illnesses . They have also involved mass immunization campaigns (e.g., in Rwanda) to prevent measles and meningococcal septicemia . In developing countries, at any time approximately 1 to 4 teenage and adult women is pregnant; and of these, 1 in 15 is suffering a miscarriage during any 2-week period . The implications of this audit are that service members must be multi-skilled not only in the traditional aspects of military medicine and nursing but also in (a) the developmental aspects of childhood; (b) the prevention of infectious childhood diseases by immunization and other means; (c) the recognition and management of diseases of childhood; and (d) the management of the normal neonate and infant, especially those orphaned in refugee disaster and other emergency situations . Doctor-soldiers hold special credentials to be advocates for the protection of children caught up in armed conflict and its aftermath . In this context, advocacy to ban anti-personnel land mines is topical, because unfortunately the more than 2,000 deaths and injuries each month involve children and their families, often injured long after the cessation of hostilities . Pediatric issues are now the business of all who serve in the health disciplines in the broader profession of arms.

FEMS Immunol Med Microbiol, 2000 Jun, 28(2), 173 - 9
Evaluation of the Applied Biosystems automated Taqman polymerase chain reaction system for the detection of meningococcal DNA; Guiver M et al.; In a period where the proportion of culture confirmed cases in the UK has been steadily declining, diagnosis by PCR has been used to increase the number of confirmed cases and provide additional epidemiological data . This report presents a comparative evaluation of the fluorogenic probe-based 5' exonuclease assay (Taqman) using the Perkin-Elmer Applied Biosystems automated sequence detection system 7700 with previously reported polymerase chain reaction enzyme-linked immunosorbent (PCR ELISA) assays for the detection of meningococcal DNA in CSF, plasma and serum samples . Taqman assays developed were based on the detection of a meningococcal capsular transfer gene (ctrA), the insertion sequence IS1106 and the sialytransferase gene (siaD) for serogroup B and C determination and compared with similar assays in a PCR ELISA format . The Taqman ctrA assay was specific for Neisseria meningitidis, however the IS1106 assay gave false positive reactions with a number of non-meningococcal isolates . Sensitivity of the Taqman ctrA, IS1106 and siaD assays testing samples from culture-confirmed cases were 64, 69 and 50%, respectively, compared with 26, 67 and 43% for the corresponding PCR ELISA assays . Improvements to the DNA extraction procedure has increased the sensitivity to 93 and 91% for the TaqMan ctrA and siaD assays, respectively, compared to culture confirmed cases . Since the introduction of Taqman PCR a 56% increase in laboratory confirmed cases of meningococcal disease has been observed compared to culture only confirmed cases . The developed Taqman assays for the diagnosis of meningococcal disease enables a high throughput, rapid turnaround of samples with considerable reduced risk of contamination.

Clin Diagn Lab Immunol, 2000 May, 7(3), 390 - 5
Sequence variation in the porA gene of a clone of Neisseria meningitidis during epidemic spread; Jelfs J et al.; The ET-15 clone within the electrophoretic type (ET)-37 complex of Neisseria meningitidis was first detected in Canada in 1986 and has since been associated with outbreaks of meningococcal disease in many parts of the world . While the majority of the strains of the ET-37 complex are serosubtype P1.5,2, serosubtype determination of ET-15 strains may often be incomplete, with either only one or none of the two variable regions (VRs) of the serosubtype PorA outer membrane protein reacting with monoclonal antibodies . DNA sequence analysis of the porA gene from ET-15 strains with one or both unidentified serosubtype determinants was undertaken to identify the genetic basis of the lack of reaction with the monoclonal antibodies . Fourteen different porA alleles were identified among 38 ET-15 strains from various geographic origins . The sequences corresponding to subtypes P1.5a,10d, P1.5,2, P1.5,10d, P1.5a,10k, and P1.5a,10a were identified in 18, 11, 2, 2, and 1 isolate, respectively . Of the remaining four strains, which all were nonserosubtypeable, two had a stop codon within the VR1 and the VR2, respectively, while in the other two the porA gene was interrupted by the insertion element, IS1301 . Of the strains with P1.5,2 sequence, one had a stop codon between the VR1 and VR2, one had a four-amino-acid deletion outside the VR2, and another showed no expression of PorA on sodium dodecyl sulfate-polyacrylamide gel electrophoresis . Our results reveal that numerous genetic events have occurred in the porA gene of the ET-15 clone in the short time of its epidemic spread . The magnitude of microevolutionary mechanisms available in meningococci and the remarkable genetic flexibility of these bacteria need to be considered in relation to PorA vaccine development.

Arch Dis Child, 2000 May, 82(5), 388 - 9
Angiotensin for septic shock unresponsive to noradrenaline; Yunge M et al.; Two children with severe septic shock are reported . One had meningococcal septicaemia and the other Escherichia coli septicaemia . They remained hypotensive despite high concentrations of conventional inotropes and vasopressors . In one child, using a pulmonary artery catheter, extended haemodynamic variables were measured . To restore blood pressure, in both cases, an infusion of angiotensin II was used; there was significant improvement in clinical status, resulting in a rapid reduction in the concentration of inotropes required . Both patients successfully survived their septic episodes . Angiotensin II in cases of severe refractory septic hypotension in the paediatric population offers an extra therapeutic manoeuvre.

J Clin Immunol, 2000 Jan, 20(1), 46 - 53
Phagocytic killing and antibody response during the first year after tetravalent meningococcal vaccine in complement-deficient and in normal individuals; Schlesinger M et al.; Seven individuals with late complement component (LCC) deficiency and seven control subjects were vaccinated with tetravalent meningococcal vaccine . The response to vaccination was evaluated by measuring the antibody titer and the phagocyte killing of the bacteria, before, 5-7 weeks, and 12-14 months after vaccination . Prior to vaccination, no phagocytic killing and a low titer of antibody was found in the LCC-deficient group and a low killing (mean of 40-58%, according to the serogroup) in normal controls . The phagocytic killing increased significantly 5-7 weeks after vaccination . However, while in normal controls the phagocytic killing was close to 100% after 5-7 weeks and decreased only slightly during the first year, the mean killing of the various meningococcal subgroups in LCC-deficient individuals was 70-89% and dropped to only 53-71% one year after vaccination . Six weeks after vaccination the mean antimeningococcal antibody titer increased similarly in the sera of LCC-deficient patients and controls . One year after vaccination the controls maintained the high concentration, while the LCC-deficient patients had tendency toward a decrease . In addition, the interpersonal variability of the antibody concentration, both in LCC-deficient individuals and in normal controls, was much higher than the phagocytic killing, with only a very mild increase in some individuals . Thus, it is possible that in spite of adequate increase of antimeningococcal antibody titer after vaccination of LCC-deficient individuals their immunity against the bacteria may not be optimal . Our data show also that phagocytic killing of meningococci is probably a more consistent assay than antibody titer levels for antimeningococcal immunity, especially in LCC-deficient patients.

J Med Microbiol, 2000 May, 49(5), 451 - 6
Evaluation of a PCR-immunoassay technique for detection of Neisseria meningitidis in cerebrospinal fluid and peripheral blood; Seward RJ et al.; A multiplex PCR-immunoassay for the rapid diagnosis of bacterial meningitis from cerebrospinal fluid (CSF) or peripheral blood was compared with conventional microbiological techniques used in the routine diagnostic laboratory . The multiplex PCR was designed to detect simultaneously a universal conserved sequence coding for bacterial 16S rRNA and the Neisseria meningitidis porA gene . The PCR-immunoassay had a detection limit of (3-5) x 10(2) cfu/ml (equivalent to 1-3 cfu/PCR) with spiked CSF or blood samples, compared with (3-5) x 10(3) cfu/ml for PCR followed by conventional agarose gel electrophoresis for detection of PCR products . Of 294 CSF samples from patients suspected on clinical grounds of suffering from meningitis, the PCR-immunoassay detected bacterial DNA in 29 CSF samples, 15 of which were also positive for N . meningitidis DNA . The 29 positive CSF samples comprised 25 samples that were also reported positive and four that were reported negative by conventional methodology; the latter four were all positive for N . meningitidis by the PCR-immunoassay . Of 173 peripheral blood samples examined, the PCR-immunoassay detected bacterial DNA in 18 samples, 14 of which were also positive for N . meningitidis DNA . In comparison, only 10 samples were reported positive for N . meningitidis by conventional methodology . All negative PCR-immunoassay results correlated with those obtained by conventional methodology for both CSF and blood samples . The sensitivity and speed of the PCR-immunoassay system indicated that it could be used as a routine diagnostic test for meningococcal meningitis, enabling a diagnosis to be made within 4 h of receipt of the specimen.

Cochrane Database Syst Rev . 2000;(2):CD001093.
Polysaccharide vaccines for preventing serogroup A meningococcal meningitis; Patel M; BACKGROUND: Controlled trials over two decades ago showed that the polysaccharide vaccine prevented meningococcal meningitis . Subsequent observational studies suggested variations in the level and duration of protection, particularly among young children . OBJECTIVES: To determine the effect of polysaccharide serogroup A vaccine for preventing serogroup A meningococcal meningitis . SEARCH STRATEGY: MEDLINE and the Cochrane Controlled Trials Register . SELECTION CRITERIA: Randomised and other prospective controlled trials . DATA COLLECTION AND ANALYSIS: One reviewer collected data and assessed the methodologic quality of the trials . Data were pooled using the Exact method to assess vaccine efficacy at one, two and three years post-vaccination . MAIN RESULTS: The protective effect within the first year was consistent across all eight trials, including one with participants exclusively under six years of age (in Finland); overall vaccine efficacy was 95% (Exact 95% CI 87%, 99%) . The Finnish trial lacked statistical power to assess the effect of a booster dose given to children less than 18 months old . In the three other trials that included children less than six years old (one in Sudan and two in Nigeria), none of the vaccinated children developed meningitis, but the statistical significance of this finding was undetermined . Protection extended into the second (in two studies) and third (in one study) years after vaccination, but these results were also not statistically significant . REVIEWER'S CONCLUSIONS: When compared with current recommendations, the methodological quality and relative incompleteness of the published reports could arguably render the trials invalid for this review . However, it was unlikely that the results of the trials in such diverse settings would have been biased towards a strong and consistent protective effect . Immunogenicity trials were not included in this review . Stage two of the review will assess the vaccine effect from observational studies.

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