Meningococcus

Przegl Epidemiol, 1998, 52(3), 227 - 35
{Meningococcal infections in Warsaw's district}; Dulny G et al.; The epidemiological situation of meningococcal meningitis in Warsaw's district in comparison to the situation in Poland in the years 1980-1997 in discussed . In September 1997, the local population of Zielonka--small city in Warsaw's district, was alarmed by two meningococcal septicaemia cases in girls attending to the same kindergarten . Anti-epidemic measures undertaken were described.

Epidemiol Mikrobiol Imunol, 1998 Dec, 47(4), 131 - 6
{Factors affecting Neisseria meningitidis and Neisseria lactamica carrier state}; Krizova P et al.; Invasive meningococcal diseases have become in the Czech Republic since 1993 a serious epidemiological and clinical problem due to a clonus which was not present previously: Neisseria meningitidis C:2a:P1.2,P1.5, ET-15/37 . In 1996 a trial was conducted focused on the problem how this altered epidemiological and clinical situation is reflected in carriership of Neisseria meningitidis and Neisseria lactamica in the healthy population . Two age groups were followed up which were most severely affected by the new clonus of the meningococcus: 15-19 years (410 subjects) and 1-4 years (116 subjects) . The trial was implemented in Olomouc where in 1993 the new epidemiological situation of the incidence of the invasive meningococcal disease was so serious that targeted vaccination was introduced . Of 116 children in the age group from 1-4 years in none Neisseria meningitidis was detected, in 9 Neisseria lactamica was found (7.7%) . On repeated examination of children with a positive cultivation of Neisseria lactamica after two weeks in none Neisseria meningitidis nor Neisseria lactamica were found . Of 410 subjects in the age group from 15-19 years in none Neisseria lactamica was detected and in 35 Neisseria meningitidis (8.5%) . Examinations were repeated after two weeks in 33 carriers: in 31 Neisseria meningitidis was again cultivated . Analysis of factors influencing carriership revealed in Neisseria lactamica two factors in young children which significantly promote this carriership: cold and close contact/kissing . A risk factor at the limit of significance are frequent respiratory diseases . In the carriership of Neisseria meningitidis in 15-19 year-old subjects six factors were revealed which promote carriership . A significant risk factor is close contact/kissing, the existence of partnership, participation in activities of the "disco" type, living in a town, flats in the centre of the town . Effort is a risk factor at the limit of significance.

Nurs Stand, 1998 Oct 21-27, 13(5), 49 - 52; quiz 55-6
Meningococcal disease; Bowler S; This article discusses meningococcal disease and outlines the role of the nurse in treating patients who may suffer from meningitis, one of the illnesses caused by meningococcal disease . It goes on to discuss how nurses can support the relatives of these patients.

Infect Immun, 1999 Feb, 67(2), 954 - 7
Role of lipopolysaccharide sialylation in serum resistance of serogroup B and C meningococcal disease isolates; Vogel U et al.; alpha-2,3-Sialyltransferase mutants of three genetically and phenotypically diverse Neisseria meningitidis strains were compared with regard to resistance to human serum and systemic spread in the infant rat . Lipopolysaccharide sialylation was found to be of minor importance for the resistance of serogroup B and C meningococcal disease isolates to complement attack.

Infect Immun, 1999 Feb, 67(2), 921 - 7
Antigen-specific T-cell responses in humans after intranasal immunization with a meningococcal serogroup B outer membrane vesicle vaccine; Oftung F et al.; We have studied the ability of the Norwegian group B meningococcal outer membrane vesicle (OMV) vaccine, when administered intranasally without adjuvant, to induce T-cell responses in humans . A group of 12 vaccinees was immunized with four doses of OMVs (250 micrograms of protein/dose) at weekly intervals, and a single booster dose was given 5 months later . In vitro T-cell proliferation in response to the OMV vaccine, purified PorA (class 1) protein, PorB (class 3) protein, and one unrelated control antigen (Mycobacterium bovis BCG) was measured by {3H}thymidine incorporation into peripheral blood mononuclear cells obtained from the vaccinees before and after the immunizations . The nasal OMV immunizations induced antigen-specific T-cell responses in the majority of the vaccinees when tested against OMVs (7 of 12) and the PorA antigen (11 of 12) . None of the vaccinees showed a vaccine-induced T-cell response to the PorB antigen after the initial four doses . Although some individuals responded to all the vaccine antigens after the booster dose, this response was not significant when the vaccinees were analyzed as a group . We have also demonstrated that the PorA antigen-specific T-cell responses correlated with anti-OMV immunoglobulin A (IgA) levels in nasal secretions, with anti-OMV IgG levels in serum, and with serum bactericidal activity . In conclusion, we have shown that it is possible to induce antigen-specific T-cell responses in humans by intranasal administration of a meningococcal OMV vaccine without adjuvant.

Schweiz Med Wochenschr, 1998 Dec 12, 128(50), 1988 - 93
{Chronic meningococcemia--a rare, but characteristic disease picture}; Grob H et al.; Chronic meningococcaemia is a rare clinical manifestation of invasive infection by Neisseria meningitidis . The clinical signs and symptoms are recurrent fever, skin rash, arthralgias and headache . This constellation is rather typical and may enable the clinician to establish the diagnosis . The clinical diagnosis is confirmed by the growth of Neisseria meningitidis in the blood culture . In addition, the clinical course under antibiotic treatment leads to a dramatic improvement within 24-48 hours . Positive cultures may be obtained by needle aspiration or skin biopsy . There are a few reports on patients with deficiency of late complement components or immunoglobulin deficiency . We report on two patients with the typical findings of chronic meningococcaemia.

Crit Rev Microbiol, 1998, 24(4), 281 - 334
Genetic basis for biosynthesis, structure, and function of meningococcal lipooligosaccharide (endotoxin); Kahler CM et al.; The exclusive human pathogen Neisseria meningitidis expresses lipooligosaccharide (LOS), an endotoxin that is structurally distinct from the lipopolysaccharides (LPS) of enteric Gram-negative bacilli . Differences that appear to be biologically important occur in the composition and attachment of acyl chains to lipid A, phosphorylation patterns of lipid A, and the incorporation and phosphorylation of sugar residues in the LOS inner core . Further, unlike most enteric LPS, only two to five sugar residues are attached to the meningococcal LOS inner core, and there are no multiple repeating units of O-antigens . In contrast to Escherichia coli, where the LPS biosynthesis genes are organized as large operons, the meningococcal LOS biosynthesis genes are organized into small operons or are located individually in the chromosome . Some of these genetic loci in meningococci and gonococci display polymorphisms caused by localized chromosomal rearrangements . One mechanism of antigenic variation of meningococci LOS is the regulation of glycosyltransferase activity by slipped strand mispairing of homopolymeric tracts within the 5' end of the genes encoding these enzymes, resulting in the addition of different sugar residues to the LOS molecule . Meningococcal LOS is a critical virulence factor in N . meningitidis infections and is involved in many aspects of pathogenesis, including the colonization of the human nasopharynx, survival after bloodstream invasion, and the inflammation associated with the morbidity and mortality of meningococcemia and meningitis . Meningococcal LOS, which is a component of serogroup B meningococcal vaccines currently in clinical trials, has been proposed as a candidate for a new generation of meningococcal vaccines . The rapidly expanding knowledge of the genetic basis for biosynthesis, structure, and regulation of meningococcal LOS provides insights into unique endotoxin structures and the precise role of LOS in the pathogenesis of meningococcal disease.

Burns, 1998 Nov, 24(7), 680 - 2
Purpura fulminans localising to a recent burn injury; Wharton SM et al.; The development of progressive, severe skin changes (purpura fulminans) is a serious complication of septicaemia, particularly meningococcal septicaemia . Purpura fulminans almost invariably leads to some full thickness skin loss and may lead to limb amputation . The pathophysiology may involve microemboli, endotoxins and direct bacterial damage to the vessels . We describe a case of purpura fulminans, probably as a result of meningococcal septicaemia, localising to a recent, healed burn with complete resolution . We can find no other record of the skin manifestations of meningococcal septicaemia localising to a previous injury.

J Biol Chem, 1999 Jan 15, 274(3), 1495 - 501
Bactericidal antibody recognition of meningococcal PorA by induced fit . Comparison of liganded and unliganded Fab structures; van den Elsen J et al.; MN12H2 is a bactericidal antibody directed against outer membrane protein PorA epitope P1.16 of Neisseria meningitidis . Binding of MN12H2 to PorA at the meningococcal surface activates the classical complement pathway resulting in bacterial lysis . We have determined the crystal structure of the unliganded MN12H2 Fab fragment in two different crystal forms and compared it with the structure of the Fab in complex with a P1.16-derived peptide . The unliganded Fabs have elbow bend angles of 155 degrees and 159 degrees, whereas the liganded Fab has a more closed elbow bend of 143 degrees . Substantial differences in quaternary and tertiary structure of the antigen binding site are observed between the unliganded and liganded MN12H2 Fab structures that can be attributed to peptide binding . The variable light and heavy chain interface of the liganded Fab is twisted by a 5 degrees rotation along an axis approximately perpendicular to the plane of the interface . Hypervariable loops H1, H2, and framework loop FR-H3 follow this rotation . The hypervariable loop H3 undergoes conformational changes but remains closely linked to hypervariable loop L1 . In contrast with the binding site expansion seen in other Fab-peptide structures, the MN12H2 binding site is narrowed upon peptide binding due to the formation of a "false floor" mediated by arginine residue 101 of the light chain . These results indicate that PorA epitope P1.16 of N . meningitidis is recognized by the complement-activating antibody MN12H2 through induced fit, allowing the formation of a highly complementary immune complex.

JAMA, 1998 Dec 23-30, 280(24), 2094 - 8
Serogroup Y meningococcal disease in Chicago, 1991-1997; Racoosin JA et al.; CONTEXT: In 1994, surveillance by the Chicago Department of Public Health detected a growing trend in the proportion of invasive meningococcal infections caused by serogroup Y . OBJECTIVE: To examine the emergence of serogroup Y meningococcal disease and compare its clinical characteristics with those of other meningococcal serogroups . DESIGN: Population-based retrospective review of surveillance records; medical record review and cohort analysis of serogroup Y vs non-serogroup Y case patients . SETTING: Chicago, III . PARTICIPANTS: City residents with Neisseria meningitidis isolated from a normally sterile site from January 1, 1991, through December 31, 1997; cohort analysis included those identified through March 31, 1996 . MAIN OUTCOME MEASURES: Serogroup-specific incidence, demographics, and clinical outcomes . RESULTS: We identified 214 case patients; 53 (25%) had serogroup Y . The attack rate of serogroup Y meningococcal disease increased from 0.04 cases per 100000 in 1991 to a peak of 0.82 cases per 100000 in 1995 and subsequently decreased to 0.26 cases per 100000 and 0.34 cases per 100000 in 1996 and 1997, respectively . Compared with patients infected by other serogroups, patients with serogroup Y were older (median age, 16 years vs 1 year; P = .001) and more likely to have a chronic underlying illness (prevalence ratio, 2.3; 95% confidence interval, 1.2-4.4) . Outcome did not differ significantly between the 2 groups . Multilocus enzyme electrophoresis typing of isolates from 19 case patients identified 5 different types . We found no clustering among the enzyme types by age, race/ethnicity, community area, or time . CONCLUSIONS: Serogroup Y emerged as the most frequent cause of meningococcal disease in Chicago in 1995 and accounted for a substantial proportion of cases in 1996 and 1997 . Current data suggest that the magnitude of serogroup Y meningococcal disease is sufficient for vaccine developers to incorporate serogroup Y into new vaccines.

Intern Med, 1998 Nov, 37(11), 990 - 4
Adrenal hemorrhage associated with Klebsiella oxytoca bacteremia; Hori K et al.; Septic adrenal hemorrhage is classically caused by meningococcemia . An autopsied case is presented of a 45-year-old man with adrenal hemorrhage due to Klebsiella oxytoca bacteremia following placement of a central venous catheter . He died 5 hours after developing disseminated intravascular coagulation (DIC) . The bacterial entry site may have been the catheter . The cause of death was considered to be pulmonary edema due to bacteremia rather than adrenal insufficiency due to hemorrhage . Septic adrenal hemorrhage should be recognized as a subtype of sepsis rather than adrenal insufficiency, and may be caused in conditions of severe sepsis with DIC, independent of the microorganic variety.

Eur J Clin Microbiol Infect Dis, 1998 Oct, 17(10), 690 - 4
Trend in incidence and case fatality of meningococcal disease over 16 years in Northern Denmark; Sorensen HT et al.; The incidence and case fatality rates of meningococcal disease were assessed in the county of Northern Jutland, Denmark, during the 16-year period from 1980 to 1995 . A total of 320 patients were identified from the Meningococcal Research Database, which comprises information from the following sources: (i) the Department of Public Health, to whom notification of meningococcal disease is obligatory; (ii) the Regional Hospital Discharge Registry; and (iii) the register of the regional department of clinical microbiology . In order to assess prognostic indicators assessable at admission, information was collected for each patient from hospital records regarding contacts, symptoms and signs on arrival, laboratory data, and course of disease . The mean incidence was 4.3 cases per 100000 persons per year (range, 2.7-7.7) . The incidence increased slightly during the period studied . Overall, the case fatality rate was 9.7%, with a significant rise occurring during the period (P=0.016) and a peak occurring in 1992 . Advanced age (> or = 50 years), seizures, impaired consciousness, and skin bleeding on arrival at hospital were predictors of death.

Infect Immun, 1999 Jan, 67(1), 113 - 9
Immunogenicity of intranasally administered meningococcal native outer membrane vesicles in mice; Saunders NB et al.; Colonization of the human nasopharyngeal region by Neisseria meningitidis is believed to lead to natural immunity . Although the presence of bactericidal antibody in serum has been correlated with immunity to meningococcal disease, mucosal immunity at the portal of entry may also play an important role . This study was undertaken to examine in mice the possibility of safely using native outer membrane vesicles (NOMV) not exposed to detergent as an intranasal (i.n.) vaccine . The mucosal and systemic responses of mice to intranasal and intraperitoneal (i.p.) vaccination with NOMV were compared over a range of doses from 0.1 to 20 microgram . Intranasal vaccination of mice with NOMV induced a strong systemic bactericidal antibody response, as well as a strong local immunoglobulin A immune response in the lung as determined by assay of lung lavage fluid by enzyme-linked immunosorbent assay and lung antibody secreting cells by enzyme-linked immunospot assay . However, 8- to 10-fold-higher doses of NOMV were required i.n . compared to i.p . to elicit an equivalent bactericidal antibody response in serum . Some NOMV vaccine was aspirated into the lungs of mice during i.n . immunization and resulted in an acute inflammatory response that peaked at 1 to 2 days postimmunization and was cleared by day 7 . These results indicate that i.n . delivery of meningococcal NOMV in mice is highly effective in eliciting the production of both a mucosal immune response and a systemic bactericidal antibody response.

Hum Genet, 1998 Oct, 103(4), 506 - 12
The molecular basis of C6 deficiency in the western Cape, South Africa; Hobart MJ et al.; Deficiency of the sixth component of human complement (C6) has been reported in a number of families from the western Cape, South Africa . Meningococcal disease is endemic in the Cape and almost all pedigrees of total C6 deficiency (C6Q0) have been ascertained because of recurrent disease . We have sequenced the expressed exons of the C6 gene from selected cases and have found three molecular defects leading to total deficiency: 879delG, which is the common defect in the Cape and hitherto unreported, and 1195delC and 1936delG, which have been previously reported in African-Americans . We also show that the 879delG and 1195delC defects are associated with characteristic C6/C7 region DNA marker haplotypes, although small variations were observed . The 1936delG defect was observed only once in the Cape, but its associated haplotype could be deduced . The data from the haplotypes indicate that these three molecular defects account for the defects in all the 38 unrelated C6Q0 individuals we have studied from the Cape . We have also observed the 879delG defect in two Dutch C6-deficient kindreds, but the 879delG defect in the Cape probably did not come from The Netherlands.

Scott Med J . 1998 Oct;43(5):148.
Neisseria meningitidis W135 pneumonia with sepicaemia in a nonogenarian; Cadwgan AM et al.; Neisseria meningitidis infection is generally considered a disease of children or young adults, classically presenting as meningitis or sepicaemia . This infection is rare but recognised in the elderly . We present the case of a nonogenarian with meningococcal pneumonia and sinusitis with bacteraemia caused by N.meningitidis W135 a rare serogroup . We therefore thought this unusual situation of interest and worthwhile reporting.

Arch Pediatr, 1998 Nov, 5(11), 1232 - 5
{Chronic meningococcemia: 3 cases in the immunocompetent child}; Grouteau E et al.; Chronic meningococcemia is a part of extra meningeal manifestations of meningococcal disease . Its diagnosis can be difficult because of lack of sensitivity of blood cultures . CASE REPORT: Three cases, concerning immunocompetent children, respectively aged of 14, 10 and 4 years are reported . The clinical course was characterized by recurrent fever, inflammatory joint manifestations and diffuse maculopapules secondary centered by petechiae . Microbiological findings revealed in one case a positive throat culture and presence of meningococcal soluble antigens in blood and urine . In the other two cases, diagnosis was done after done after positive blood culture at the 7th, and 13th days of course . CONCLUSION: The diagnosis should be considered in any children with a prolonged, recurrent fever and cutaneous and joint manifestations even if blood cultures remain negative . The response to therapy by usual antimeningococcal antibiotics is dramatic and curative while a prolonged untreated course may be complicated by metastatic infection.

Ann Med Interne (Paris), 1998 Oct, 149(6), 332 - 9
{Vaccinations of the traveller}; Marchou B et al.; Travelers' immunization has 2 aims: for the traveler, to prevent the risk of contracting an endemic disease during his stay abroad; for the community to prevent the risk of importing an infectious agent yet unknown in the country . Travelling offers an opportunity to update routine immunizations: tetanus, diphtheria, poliomyelitis, hepatitis B; for young people: measles and rubella; for elderly people: influenza . Two vaccinations are compulsory: yellow fever for travelers to tropical Africa and Amazonian forest; meningococcus A + C for Mecca pilgrims . Other vaccines are recommended for travelers to specific areas: typhoid fever, hepatitis A, cholera in countries with poor hygiene; rabies for exposed travelers (expatriates, trekkers...); Japanese encephalitis for persons spending a month or longer in rural agricultural areas during the monsoon season; tickborne encephalitis for persons visiting forested areas of central Europe from may to september . Yet, most of travelers' diseases such as malaria cannot be prevented by vaccination and appropriate preventive measures (chemoprophylaxis and protection against insects) should be taken.

FEMS Microbiol Lett, 1998 Dec 1, 169(1), 171 - 7
Both the full-length and the N-terminal domain of the meningococcal transferrin-binding protein B discriminate between human iron-loaded and apo-transferrin; Renauld-Mongenie G et al.; We have readdressed the ability of the transferrin-binding protein B (TbpB) from Neisseria meningitidis to discriminate between the iron-loaded and the iron-free human transferrin (hTf) by using the BIAcore technology, a powerful experimental technique for the observation of direct interactions between a receptor and its ligands, without the use of labels . Recombinant full-length TbpB from five N . meningitidis strains were produced and purified from Escherichia coli as fusion proteins . They showed a preference for the binding to iron-loaded hTf . As for the full-length molecule, we have demonstrated that the minimal N-terminal hTf binding domain of meningococcal TbpB from B16B6 and M982 strains was able to discriminate between both hTf forms.

Commun Dis Rep CDR Suppl, 1998 Nov, 8(5), S1 - 12
PHLS overview of communicable diseases 1997: results of a priority setting exercise; Rushdy A et al.; In early 1997, the PHLS Overview of Communicable Diseases (OVCD) Committee carried out a consultation exercise to inform the development of PHLS priorities in communicable diseases for the years 1997 to 1999 . The views of PHLS senior staff and scientific committees and consultants in communicable disease control in district health authorities were sought by postal questionnaire, and several organisations of health professionals were asked for their views on the initial findings . The main findings of the exercise are summarised in three areas of priority . Priority 1 diseases--those of major importance to public health--included food poisoning, meningitis, tuberculosis, sexually transmitted diseases, vaccine preventable diseases, hospital acquired infections, and antimicrobial resistance . Priority 2 diseases--those of moderate importance to public health--included respiratory syncytial virus and varicella zoster virus infections and emerging problems such as travel associated infections . Priority 3 diseases included those whose prevalence is declining as a result of public health action, such as listeriosis, and diseases of low prevalence and/or associated morbidity . The exercise identified four areas of possible future work for the PHLS: activities in prion diseases, helping to tackle inequalities in health, taking a more active approach to documenting the socioeconomic burden of disease, and engaging more with those consulted . The PHLS has used the results of the priority setting exercise to guide major programme initiatives in tuberculosis, measles, mumps, and rubella, meningococcal and pneumococcal diseases, and in antibiotic resistance . In addition, they have helped to shape agenda in service delivery and research in hospital acquired infections, sexually transmitted diseases, and gastrointestinal diseases . This exercise of engaging corporately with key professionals in communicable disease has paved the way for a wider engagement with stakeholders in the setting of future priorities.

Eur J Emerg Med, 1998 Jun, 5(2), 225 - 30
Evaluation of scoring systems in acute meningococcaemia; Hachimi-Idrissi S et al.; Patients expected to develop life-threatening complications in acute meningococcal infections require early recognition and appropriate monitoring . Different prognostic scoring systems have been developed . Three of them, chosen according to their bedside availability, were compared with our clinical observations . Twenty consecutive cases of proven meningococcal infection were admitted to the paediatric intensive care unit (PICU) of the Free University of Brussels (AZ-VUB) . Biological and clinical features required for prognostic scoring were evaluated as soon as possible after admission . Glasgow meningococcal sepsis prognostic score (GMSPS), Neisseria sepsis index (NESI) and Algren criteria were retrospectively calculated and evaluated for their prognostic significance . Neisseria meningitidis was cultured from blood and cerebrospinal fluid in 11 patients and from blood in only nine patients . The age of the patients was between 1 and 15 years (mean 4.1 years) . All patients received the same therapy on admission . Four patients died with a multiorgan failure within 18 hours . The three scoring systems in these four patients predicted death . Overall, the GMSPS score, the NESI score and the Algren criteria predicted death in respectively 10, nine and five patients . Death was falsely predicted in six patients by the GMSPS score, in five patients by the NESI score and in one patient by the Algren criteria . The Algren criteria predicted the severity of the clinical process more accurately than did the GMSPS and NESI scores . However, such predictability should be cautiously used even when 100% mortality is predicted . It might be used in decision-making in regard to the following issues: patient transfer to tertiary centres and mode of transportation, monitoring of patients in intensive care units, early insertion of invasive cardiovascular monitoring catheters and consideration of new or even experimental therapy . However, one should be extremely cautious of taking any therapeutically or ethical decision on the basis of one or more of the described scoring system, since we showed the lack of precision concerning the outcome of paediatric patients with meningococcaemia.

Microbiology, 1998 Nov, 144 ( Pt 11), 3027 - 37
Immunization with recombinant class 1 outer-membrane protein from Neisseria meningitidis: influence of liposomes and adjuvants on antibody avidity, recognition of native protein and the induction of a bactericidal immune response against meningococci; Christodoulides M et al.; The porA gene from Neisseria meningitidis was cloned into the pRSETA vector and recombinant class 1 outer-membrane protein expressed at high levels in Escherichia coli . The protein was readily purified by affinity chromatography on a Ni2+ matrix and used for immunization of mice with conventional AI(OH)3 adjuvant, with experimental adjuvants which have the potential for human use, and with liposomes . The resulting sera were analysed for the magnitude, subclass distribution and antigenic specificity of the immune response . In addition, surface plasmon resonance (SPR) was used to quantify antibody avidity by analysis of the kinetics of binding to native class 1 protein . Immunization with conventional and experimental adjuvants induced antibodies of low avidity that did not recognize native class 1 protein . In contrast, immunization with recombinant protein in liposomes induced antibodies of high avidity which recognized native class 1 protein, as measured by their ability to label meningococcal cells in immunofluorescence assays and to inhibit the binding of a protective mAb . These properties were associated with the presence in sera of high levels of antibodies with the ability to induce complement-mediated killing of meningococci . These data show that liposomes containing recombinant class 1 protein represent a potential basis of future vaccines, of defined composition, designed for the prevention of group B meningococcal infections.

Cytometry, 1998 Dec 1, 33(4), 406 - 13
Flow cytometric quantitation of human opsonin-dependent phagocytosis and oxidative burst responses to meningococcal antigens; Lehmann AK et al.; A one-step flow cytometric (FCM) assay has been developed to quantify both opsonin- and antigen-dependent phagocytosis and intraphagocyte oxidative burst responses . Meningococcal outer membrane structures (OMV) were adsorbed to fluorescent polystyrene beads, opsonized with serum, and exposed to leukocytes . FCM parameters of phagocytosis were evaluated in combinations with oxidative burst indicators . Rhodamine-123 was the most sensitive indicator and was compatible with quantitation of phagocytosis . The phagocytosis and oxidative burst responses induced by OMV beads were dependent on both antigens and opsonins . Increased human opsonic responses against OMV were induced during clinical meningococcal disease . A dissociation was noted between phagocytosis and oxidative burst in individual cells, indicating that functional opsonins against OMV components may differ in their ability to stimulate phagocytosis and oxidative burst responses . The method facilitates evaluation of purified bacterial structures as mediators of opsonin-dependent phagocytosis and intracellular oxidative microbicidal mechanisms, which is of interest in the complex process of selecting bacterial antigens as constituents of certain vaccines.

Clin Exp Immunol, 1998 Dec, 114(3), 362 - 9
Protection against meningococcal serogroup ACYW disease in complement-deficient individuals vaccinated with the tetravalent meningococcal capsular polysaccharide vaccine; Fijen CA et al.; Individuals with properdin, C3 or late complement component deficiency (LCCD) frequently develop meningococcal disease . Vaccination of these persons has been recommended, although reports on efficacy are scarce and not conclusive . We immunized 53 complement-deficient persons, of whom 19 had properdin deficiency, seven a C3 deficiency syndrome and 27 had LCCD with the tetravalent (ACYW) meningococcal capsular polysaccharide vaccine . Serological studies were performed in 43 of them . As controls 25 non-complement-deficient relatives of the complement-deficient vaccinees and 21 healthy non-related controls were vaccinated . Post-vaccination, complement-deficient individuals and controls developed a significant immunoglobulin-specific antibody response to capsular polysaccharides group A, C, Y, W135, but a great individual variation was noticed . Also, the proportion of vaccinees of the various vaccinated groups with a significant increase in bactericidal titre (assayed with heterologous complement) was similar . Opsonization of meningococci A and W135 with sera of the 20 LCCD individuals yielded in 11 (55%) and eight (40%) sera a significant increase of phagocytic activity after vaccination, respectively . Despite vaccination, four complement-deficient patients experienced six episodes of meningococcal disease in the 6 years post-vaccination . Four episodes were due to serogroup B, not included in the vaccine . Despite good response to serogroup Y upon vaccination, disease due to serogroup Y occurred in two C8beta-deficient patients, 3.5 and 5 years post-vaccination . These results support the recommendation to vaccinate complement-deficient individuals and to revaccinate them every 3 years.

Clin Exp Immunol, 1998 Dec, 114(3), 355 - 61
C7 deficiency in an Irish family: a deletion defect which is predominant in the Irish; O'Hara AM et al.; Human deficiencies of terminal complement components are known to be associated with increased susceptibility to Neisseria meningitidis infection . Polymorphic DNA marker studies in complement deficient investigations allow identification of haplotypes associated with the deficiency and enable the possible identification of heterozygote carriers of the defect . We report studies of an Irish family in which the index case had suffered recurrent meningococcal disease and was found to be deficient in the seventh component of complement (C7) . The availability of all family members enabled us to determine the segregating haplotypes . The defects in the family segregated with two very closely related C6 and C7 DNA haplotypes, one of which is known to be associated with the large Irish C7 DNA deletion defect . The index case and two C7 deficient siblings were found to be homozygous for this defect, a deletion that spans approx . 6.8 kbp and encompasses exons 7 and 8 . The deletion defect of exons 7 and 8 of C7 has been found in homozygous form in another C7 deficient Irish individual, and is present in heterozygous form in C7 deficient members of a third Irish family . Therefore, this deletion defect occurs in five of the six deficient chromosomes of these three unrelated Irish families, raising the interesting question of how prevalent this defect may be within the Irish community.

Commun Dis Rep CDR Wkly, 1998 Nov, 8 Suppl 5, S1 - 12
PHLS overview of communicable diseases 1997: results of a priority setting exercise; Rushdy A et al.; In early 1997, the PHLS Overview of Communicable Diseases (OVCD) Committee carried out a consultation exercise to inform the development of PHLS priorities in communicable diseases for the years 1997 to 1999 . The views of PHLS senior staff and scientific committees and consultants in communicable disease control in district health authorities were sought by postal questionnaire, and several organisations of health professionals were asked for their views on the initial findings . The main findings of the exercise are summarised in three areas of priority . Priority 1 diseases-those of major importance to public health-included food poisoning, meningitis, tuberculosis, sexually transmitted diseases, vaccine preventable diseases, hospital acquired infections, and antimicrobial resistance . Priority 2 diseases-those of moderate importance to public health-included respiratory syncytial virus and varicella zoster virus infections and emerging problems such as travel associated infections . Priority 3 diseases included those whose prevalence is declining as a result of public health action, such as listeriosis, and diseases of low prevalence and/or associated morbidity . The exercise identified four areas of possible future work for the PHLS: activities in prion diseases, helping to tackle inequalities in health, taking a more active approach to documenting the socioeconomic burden of diseases, and engaging more with those consulted . The PHLS has used the results of the priority setting exercise to guide major programme initiatives in tuberculosis, measles, mumps, and rubella, meningococcal and pneumococcal diseases, and in antibiotic resistance . In addition, they have helped to shape agenda in service delivery and research in hospital acquired infections, sexually transmitted diseases, and gastrointestinal diseases . This exercise of engaging corporately with key professionals in communicable disease has paved the way for a wider engagement with stakeholders in the setting of future priorities.

Eur J Pediatr, 1998 Nov, 157(11), 869 - 80
Pathophysiology of meningococcal sepsis in children; de Kleijn ED et al.; Septic shock with purpura is a syndrome frequently diagnosed in children and predominantly caused by Neisseria meningitidis . Despite improvements in management and therapy the mortality and morbidity in these patients are still high . During the last few years much effort has been put into understanding of the systemic host response during this acute infectious disease . This host response can be divided into the process of recognition of endotoxin, the cascade of pro- and counter inflammatory mediators, the endothelial damage resulting in capillary leakage and inappropriate vascular tone, and the procoagulant state . CONCLUSION: This paper reviews the recent insights in the pathophysiology of the host response and their possible consequences for novel therapies in meningococcal sepsis.

JAMA, 1998 Nov 18, 280(19), 1685 - 9
Induction of immunologic memory by conjugated vs plain meningococcal C polysaccharide vaccine in toddlers: a randomized controlled trial; MacDonald NE et al.; CONTEXT: Meningococcal polysaccharide vaccines are not used routinely in infants and toddlers, the groups at highest risk of invasive disease, because of poor immunologic responses to the Neisseria meningitidis serogroup C polysaccharide in these age groups . Meningococcal C conjugate vaccines offer the prospect of circumventing this problem . OBJECTIVE: To assess the immunogenicity and the induction of immunologic memory in toddlers by meningococcal C conjugate vaccine . DESIGN: A multicenter, randomized, observer-blinded controlled trial . SETTING: Urban and suburban family medicine or pediatric practices . PARTICIPANTS: Two hundred eleven healthy toddlers aged 15 to 23 months . INTERVENTION: Two injections at 2 months apart of meningococcal C conjugate (group 1, n = 69), plain meningococcal polysaccharide (group 2, n = 72), or hepatitis B virus vaccine (group 3, n = 70) . All toddlers received a follow-up dose of plain meningococcal polysaccharide vaccine 12 months later . MAIN OUTCOME MEASURES: IgG meningococcal C anticapsular antibody concentrations determined by enzyme-linked immunosorbent assay and complement-mediated bactericidal antibody . RESULTS: In group 1, the magnitude of the IgG response to meningococcal C conjugate vaccine was more than 4-fold higher after dose 1 and more than 10-fold higher after dose 2 compared with meningococcal polysaccharide vaccine (group 2) (P<.001) . Higher titers persisted in the meningococcal C conjugate group for at least 12 months (P<.001) . Group 1, primed with meningococcal C conjugate, had 25-fold higher IgG responses to the meningococcal polysaccharide 1-year booster dose than the controls who had received hepatitis B virus vaccine initially and were given meningococcal polysaccharide vaccine 1 year later for the first time (P<.001) . In contrast, group 2, primed with meningococcal polysaccharide, had a 2-fold lower response to the 1-year booster meningococcal polysaccharide dose than the hepatitis B virus control group (P = .006) . Serum bactericidal responses paralleled the enzyme-linked immunosorbent assay responses . CONCLUSIONS: Immunization of toddlers with meningococcal C conjugate vaccine induces high titers of anticapsular and bactericidal antibody . Furthermore, this vaccine induces immunologic memory to meningococcal C polysaccharide . In contrast, meningococcal polysaccharide vaccine is less immunogenic than the conjugate vaccine and also induces a hyporesponsive state that persists for at least 12 months.

Infect Immun, 1998 Dec, 66(12), 5939 - 47
The (alpha2-->8)-linked polysialic acid capsule and lipooligosaccharide structure both contribute to the ability of serogroup B Neisseria meningitidis to resist the bactericidal activity of normal human serum; Kahler CM et al.; The molecular basis for the resistance of serogroup B Neisseria meningitidis to the bactericidal activity of normal human sera (NHS) was examined with a NHS-resistant, invasive serogroup B meningococcal isolate and genetically and structurally defined capsule-, lipooligosaccharide (LOS)-, and sialylation-altered mutants of the wild-type strain . Expression of the (alpha2-->8)-linked polysialic acid serogroup B capsule was essential for meningococcal resistance to NHS . The very NHS-sensitive phenotype of acapsular mutants (99.9 to 100% killed in 10, 25, and 50% NHS) was not rescued by complete LOS sialylation or changes in LOS structure . However, expression of the capsule was necessary but not sufficient for a fully NHS-resistant phenotype . In an encapsulated background, loss of LOS sialylation by interrupting the alpha2,3 sialyltransferase gene, lst, increased sensitivity to 50% NHS . In contrast, replacement of the lacto-N-neotetraose alpha-chain (Galbeta1-4GlcNAcbeta1-3Galbeta1-4Glc) with glucose extensions (GlcN) in a galE mutant resulted in a strain resistant to killing by 50% NHS at all time points . Encapsulated meningococci expressing a Hep2(GlcNAc)-->KDO2-->lipid A LOS without an alpha-chain demonstrated enhanced sensitivity to 50% NHS (98% killed at 30 min) mediated through the antibody-dependent classical complement pathway . Encapsulated LOS mutants expressing truncated Hep2-->KDO2-->lipid A and KDO2-->lipid A structures were also sensitive to 50% NHS (98 to 100% killed at 30 min) but, unlike the wild-type strain and mutants with larger oligosaccharide structures, they were killed by hypogammaglobulinemic sera . These data indicate that encapsulation is essential but that the LOS structure contributes to the ability of serogroup B N . meningitidis to resist the bactericidal activity of NHS.

Mol Microbiol, 1998 Nov, 30(3), 647 - 56
A gonococcal porA pseudogene: implications for understanding the evolution and pathogenicity of Neisseria gonorrhoeae; Feavers IM et al.; Members of the genus Neisseria, including the human pathogens Neisseria meningitidis and Neisseria gonorrhoeae, express at least one member of a family of related porins . N . meningitidis is the only species known to express a second porin, the meningococcal serosubtyping antigen PorA, the most divergent member of this family . Unexpectedly, a porA gene was identified in the gonococcal genome . Both the gonococcal and meningococcal porA loci were adjacent to a homologue of the Escherichia coli greA gene, although the IS1106 element downstream of porA in some meningococci was absent in the gonococcus . Almost identical porA loci were present in four unrelated gonococcal isolates and clinical specimens from patients with gonorrhoea . Lack of PorA expression in the gonococcus resulted from mutations in the promoter region, which prevented transcription, and frameshift mutations in the coding region of the porA gene . Hybridization and amplification experiments, showing the absence of a porA gene in seven other Neisseria species, suggested that porA was acquired by a common ancestor of the gonococcus and meningococcus but inactivated in the gonococcus on speciation . This implies that, while advantageous during colonization of the upper respiratory tract, this protein has no function in, or hinders, colonization of the urogenital tract.

J Trop Pediatr, 1998 Oct, 44(5), 263 - 5
Changing patterns of antibiotic sensitivity and resistance during an outbreak of meningococcal infection in Jos, Nigeria; Angyo IA et al.; Isolates of Neisseria meningitidis from blood and cerebrospinal fluid (CSF) of 87 children admitted to the emergency paediatric unit (EPU) at the Jos University Teaching Hospital (JUTH) during an outbreak of meningococcal infection (between February and April 1996) were tested against the commonly used antibiotics in an attempt to determine the sensitivity and resistance pattern . There were 11 (15.1 per cent) positive for N . meningitidis out of 73 blood cultures and 61 (70 per cent) positive out of 87 CSF cultures . Seventy-seven and thirty-eight per cent respectively of the CSF isolates were resistant to benzylpenicillin and ampicillin . Sensitivity to chloramphenicol and erythromycin was 97 and 95 per cent, respectively . Out of the 11 positive blood cultures, 82 and 27 per cent were resistant to benzylpenicillin and ampicillin, respectively, while all the isolates (100 per cent) were sensitive to chloramphenicol and erythromycin . It is concluded that in view of the high level of resistance of the meningococci to benzylpenicillin in our environment, this drug should no longer be the drug of choice for the empirical and initial treatment of meningococcal infection . We recommend that chloramphenicol be the drug of choice for the empirical and initial treatment of meningococcal infection in our environment.

J Med Microbiol, 1998 Nov, 47(11), 993 - 8
Identification of nasopharyngeal carriage of an outbreak strain of Neisseria meningitidis by pulsed-field gel electrophoresis versus phenotypic methods; Bevanger L et al.; The clustering of four cases of meningococcal disease during a 3-month period in a small community with 2233 inhabitants prompted an interventional carrier survey in persons < 19 years old and in family members of the patients . The aims of the survey were to identify the nasopharyngeal carriers and the carriage rate of the outbreak strain, to offer chemoprophylaxis to those carrying the outbreak strain, and to study the discriminatory power of phenotypic methods versus pulsed-field gel electrophoresis (PFGE) on carrier isolates during an outbreak . A high percentage of the population in the age group 0-19 years (73.7%) participated in the study . Among the 469 samples collected in this age group, meningococci were grown from 43 (9.2%) . The highest carriage rates were in the age group 18-19 years (36.4%) . With a provisional definition of the outbreak strain (group B or non-groupable Neisseria meningitidis with reduced sulphonamide sensitivity), six carriers were identified . All were treated with a single dose of ofloxacin . Four of these persons (0.76% of all tested) were later shown to have harboured the outbreak strain when analysed by PFGE . Three of them were epidemiologically closely related to one of the index cases . Serogrouping alone is not sufficient for the identification of an epidemic strain of N . meningitidis . Complete concordance of type and subtype antigens correctly identified the outbreak strain in this study . PFGE is well suited for the identification of an outbreak strain of N . meningitidis versus non-epidemic strains in tonsillo-pharyngeal specimens.

Clin Exp Immunol, 1998 Nov, 114(2), 215 - 9
Endotoxin release and cytokine production in acute and chronic meningococcaemia; Prins JM et al.; Chronic meningococcaemia is a relatively benign manifestation of meningococcal disease . Whether bacterial virulence factors are responsible for this benign course has not been studied . We compared the in vitro endotoxin-liberating ability and cytokine-inducing potential of 31 Neisseria meninigitidis isolates obtained from children with acute septic shock with that of nine isolates obtained from patients with chronic meningococcaemia and 12 isolates obtained from carriers with respiratory symptoms . The median endotoxin level released in vitro after 3 h of incubation was significantly higher for isolates causing septic shock compared with isolates from the other two groups (P=0.01 and 0.02, Mann-Whitney test) . This was not explained by differences in bacterial growth rate in vitro . The median IL-6 levels in whole blood ex vivo after 4 h of incubation were also significantly lower for isolates causing chronic meningococcaemia (P=0.04, Mann-Whitney test) . The endotoxin and cytokine levels measured on admission in the 31 children with acute meningococcal septic shock showed a 1000-fold variation . No relationship was established between the amount of endotoxin released by the causative microorganisms in vitro and the endotoxin or cytokine levels in the corresponding 31 children . These results suggest a diminished bacterial virulence for isolates causing chronic meningococcaemia . However, other factors than the endotoxin-releasing potential of the microorganism involved are responsible for the wide variation in endotoxin and therefore cytokine levels in patients with acute meningococcal septic shock.

J Immunol, 1998 Nov 15, 161(10), 5525 - 33
IL-12 enhances antibody responses to T-independent polysaccharide vaccines in the absence of T and NK cells; Buchanan RM et al.; Polysaccharide vaccines to encapsulated bacteria such as Neisseria meningitidis and Streptococcus pneumoniae are weakly immunogenic due to their T-independent (TI) nature . Even when converted to T-dependent forms through conjugation to foreign proteins, polysaccharides induce responses that are deficient in many respects, such as induction of murine IgG2a Ab, the isotype that mediates optimal complement fixation and opsonization . We now show that IL-12 treatment of mice induces significantly increased levels of IgG2a Ab to the model TI-2 Ag, DNP-Ficoll, and to vaccines composed of polysaccharides from pneumococci and meningococci . Use of immunodeficient mice lacking T cells and/or NK cells demonstrated that such cells were not responsible for the observed Ab enhancement . Furthermore, the use of IFN-gamma knockout mice showed that stimulation of TI-2 Ab responses by IL-12 was only partially dependent on IFN-gamma . The ability of IL-12 to dramatically enhance TI Ab responses suggests that IL-12 will be useful as a powerful vaccine adjuvant to induce protective immune responses against encapsulated pathogens.

Cas Lek Cesk, 1998 Oct 5, 137(19), 598 - 600
{Association of class I HLA antigens with invasive meningococcal disease}; Holub M et al.; BACKGROUND: The majority of meningococcal infections are characterized by nasopharyngeal carriership . In some patients invasive disease with a mild course develops, while some cases have a lethal outcome . The reasons of this wide variation range are not clear . The objective of the present work was to assess whether the development of invasive meningococcal disease or its prognosis are associated with HLA class I . METHODS AND RESULTS: The group of patients was formed by 40 patients (29 females, 11 males, mean age 16 years, range 8 months to 52 years) . In 28 patients the disease was caused by N . meningitidis group C, in 9 cases group B, in three cases the serotype was not assessed . The etiology was confirmed by cultivation or latex agglutination . Twenty-three patients had a mild course of the disease, 8 a medium severe one, 9 patients a severe clinical course (score according to Stiehme, Damrosch and Rosenblat) . The patients were compared with 227 non-related blood donors (114 women, 113 men, 18 to 50 years old) . In patients and controls 24 lymphocytic HLA antigens class I were identified as to type . Typing was done using the standard microlymphocytotoxic test in the NIH modification . The results were processed by statistical methods using Fisher's exact test and the 2 x 2 test with Yates correction . In patients with a mild course HLA antigens B7 and B12 predominate (p = 0.03; p = 0.02), in medium severe cases antigen A11 (p = 0.03), in patients with the most severe course antigen A9 (p = 0.04) . In invasive infections caused by N . meningitidis serotype B antigen B17 predominates (p = 0.05) . CONCLUSIONS: The severity of meningococcal invasive infections is associated with HLA class I . Invasive disease caused by N . meningitidis serotype B are more likely to occur in carriers of HLA B17 . No relationship was found between HLA class I and invasive disease caused by N . meningitidis regardless of serotype and with serotype C.

J Clin Microbiol, 1998 Dec, 36(12), 3680 - 2
Heterogeneity of the PorB protein in serotype 22 Neisseria meningitidis; Urwin R et al.; The genetic diversity of porB genes from meningococcal isolates characterized as serotype 22 was investigated by gene sequencing . This procedure identified seven distinct porB sequences, demonstrating variation in the PorB protein recognized by the serotype 22 monoclonal antibody . This is consistent with the genetic heterogeneity of serotype 22 meningococci reported previously.

J Travel Med, 1994 Jun 1, 1(2), 72 - 78
Inadequacies in Health Recommendations Provided for International Travelers by North American Travel Health Advisors; Keystone JS et al.; The rise of international travel has increased the need for more, improved travel advice from physicians and public health facilities . The quality of the health information given has not been examined on a large-scale basis by many studies, however . Surveys in Canada, Switzerland, and the United States, for example, report that only 20% to 50% of practitioners could give accurate information regarding immunization and prophylaxis about travel-related disease . Anonymous surveys were sent to 1165 American and 96 Canadian public health units and travel clinics . Using five scenarios on travel to developing countries, each source was asked to complete a standardized form giving their recommendations for immunization, antimalarials, travelers' diarrhea, and other travel issues . Of the American respondents, 60% were physicians equally distributed among private practice, university, and corporate clinics; nurses comprised 75% of the Canadian respondents, primarily from public health clinics . The number of travelers counseled per year ranged from 3 to 40,000 (American mean, 448; Canadian mean, 2180) . Depending on the scenario, 20 to 75% of the immunization groups recommended were inadequate or inappropriate: most frequently, lack of tetanus/polio boosters; indiscriminant use of yellow fever/cholera vaccines; haphazard advice about meningococcal, rabies, and typhoid vaccines; and a lack of consideration of measles in young adults . Of the antimalarial recommendations given, 20 to 60% were incorrect, including prescribing medication for nonrisk areas, failure to recognize chloroquine-resistant areas, and failure to understand the use of, or contraindications to, mefloquine . Frequently, acclimatization, altitude sickness, sunscreens, and safe-sex issues were omitted . The prevention and treatment of travelers' diarrhea were adequately covered, however . Pre-travel advice given by North American health advisors shows a considerable variability in the accuracy and extent necessary for effective travel disease prevention and treatment . Despite the growing efforts to further educate those responsible, higher quality of health advice needs to become a priority.

J Travel Med, 1994 Mar 1, 1(1), 4 - 7
Meningococcal Disease in Travelers: Vaccination Recommendations; Koch S et al.; The object of the study was to determine the incidence rate of meningococcal disease in travelers originating in industrialized countries and visiting developing countries . Subjects were intercontinental travelers with meningococcal diseases acquired from 1986 to 1989 . Health authorities in 108 countries were contacted; data obtained by postal survey were analyzed . The 56 replying health authorities reported 13 cases of meningococcal disease in tourist or business persons as well as 40 primary and 26 secondary cases in pilgrims in Mecca . The majority of cases were due to serogroup A . The case fatality rate in both groups of patients slightly exceeded 20% . Among the tourists and business persons, several patients had stayed in hotels; in several the onset of symptoms occurred during the flight home . The incidence rate per month of stay was estimated to be 0.4 per million travelers in this group, but 2000 per million in pilgrims to Mecca . Vaccination of pilgrims to Mecca is highly recommended, presently even compulsory . For the usual traveler to endemic countries, the risk of infection abroad seems not to exceed the one at home, thus vaccination may be limited to high-risk groups, such as trekkers.

Intensive Crit Care Nurs, 1998 Apr, 14(2), 91 - 5
Nursing perspectives in meningococcal disease; Moore E et al.; Meningococcal sepsis is a potentially life threatening disease . Recent advances have led towards increased emphasis being placed on early identification and prompt aggressive management of these patients . This article outlines the disease pathology, describing a case study to illustrate the management and nursing care of a child with meningococcal sepsis . Current therapies are also discussed.

J Bacteriol, 1998 Nov, 180(22), 6043 - 7
Transport of intact porphyrin by HpuAB, the hemoglobin-haptoglobin utilization system of Neisseria meningitidis; Lewis LA et al.; The meningococcal hemA gene was cloned and used to construct a porphyrin biosynthesis mutant . An analysis of the hemA mutant indicated that meningococci can transport intact porphyrin from heme (Hm), hemoglobin (Hb), and Hb-haptoglobin (Hp) . By constructing a HemA- HpuAB- double mutant, we demonstrated that HpuAB is required for the transport of porphyrin from Hb and Hb-Hp.

Rev Esp Salud Publica, 1998 Jul-Aug, 72(4), 365 - 74
{Seroprevalence of bactericidal anti-meningococcal antibodies in Cantabria 10 months following a vaccination campaign}; Gonzalez de Aledo Linos A et al.; BACKGROUND: The Self Governing Region of Cantabria within the state of Spain has a population of 541,885, of which 107,787 individuals are aged from 18 months to 19 years . A vaccination campaign against meningitis was conducted in this Region in February and March, 1997 . It was directed at children from the age of 18 months up to 19 years old, and included all municipal areas, achieving a coverage of more than 95% . In the following 12 months the efficacy achieved by the vaccination was 95.68% for all age groups . To help decide on the need for re-vaccination, a study of the prevalence in serum of bactericide antibodies in the vaccinated population was carried out . METHODS: In December 1997 blood samples from 414 vaccinated children were analysed, obtained at random in opportunist sampling in First-Aid Centres and Public Hospitals within this Region, as well as from children in public kindergartens run by the General Board of Social Well-Being in Cantabria . The number of bactericide antibodies was analysed in the National Centre for Microbiology, and the level of "vaccination effect" was set at a dilution of 1/8 . RESULTS: The following percentages of titres > or = 1/8 were obtained (the age groups of school pupils are shown in brackets): 0% (18-24 months old), 4% (1.5-4 years old), 7.1% (1.5 to 6 years old), 51.3% (6 to 12 years old) . Due to the fact that the definition of the "vaccine effect" was artificially set at a dilution of 1/8, while other studies set it at a dilution of 1/4, in 287 serum samples with a result of < 1/8 the bactericide assay was repeated with a dilution of 1/4, with the result that 286 (99.6%) were negative . I.e., the final result does not vary if we set the cut-off point at 1/4 instead of 1/8 . No significant differences were found due to whether or not the samples came from children in municipalities where there had been cases of meningitis C . CONCLUSIONS: Bactericide activity is very low in those children aged less than 4-6 years old, and is less than has been published, although it is greater above this age . This contrasts with the excellent clinical-epidemiological results, as there was no case amongst the least serologically "protected" population, in spite of the fact that meningococcus C remains in circulation in Cantabria, within the population that was not targeted by the campaign.

Rev Cubana Med Trop, 1995, 47(2), 108 - 12
{The seasonality of meningococcal disease in infants less than 1 year old . Cuba, 1983-1990}; Rico Cordeiro O et al.; Children less than one year old behave as the group with the highest incidence of meningococcal disease during all the epidemic period in the past '80s decade in Cuba . There were used chronological series of monthly incidence rates between 1983 and 1990, in order to identify the behavior of seasonality, taking into account the clinical form and the insert of years 1989 and 1990 in the series: in both of them a massive antimeningococcal vaccination campaign took place . It is evident that seasonality has a different behavior in accordance with the clinical form: it is like the countries from the northern hemisphere with a moderate climate for the meningoencephalitis, and like the countries of the southern hemisphere with a warm climate for the meningococcal syndrome . Months of the rainy period have the lowest seasonal index . Modifications of these seasonal patterns are not found after executing the vaccination.

Rev Cubana Med Trop, 1995, 47(1), 59 - 64
{The post-licensing efficacy of VA-MENGOC-BC in children under 6 in Holguín, Cuba . The first year of observation}; Rico Cordeiro O et al.; The assessment of the after-licensing efficacy of the Cuban vaccine VA-MENGOC-BC was performed one year after the mass immunization campaign was completed in children under 6 years of age in the Province of Holguin which had the second highest incidence rate of meningococcal disease during 1988 in Cuba . In the design of the study the following aspects were taking into account: case definition; case detection, determination of the state of vaccination, and comparability of exposure . The utilization of 2 case definitions with different sensitivity and specificity is introduced within the methodology, as well as 2 estimation methods . Incidence rates from exposed and nonexposed subjects, as well as the ratio of cases and of the vaccinated population are used . The impact of this prophylactic intervention was determined by the estimation of the percentual preventive population fraction . Among outstanding results, the high efficacy of more than 98% found in both variants of case definition is to be mentioned . It is evidenced that the effect of the vaccine accounts for more than 80% of the observed case reduction . Such reduction in the number of cases was obtained without changing diagnostic criteria since the isolation of the agents was hept at levels similar to the ones from previous years.

Commun Dis Intell, 1998 Oct 1, 22(10), 205 - 11
Annual report of the Australian Meningococcal Surveillance Programme, 1997; Age-related immunogenicity of meningococcal polysaccharide vaccine in aboriginal children and adolescents living in a Northern Manitoba reserve community; Department of Medical Microbiology, University of Manitoba, Canada . blaw@ms.umanitoba.ca

OBJECTIVE: To determine the total and functional serogroup C antibody response to a quadrivalent meningococcal polysaccharide vaccine in a group of aboriginal infants, children and adolescents . A secondary objective was to determine their prevalence of meningococcal carriage . DESIGN: Open prospective, before and after intervention study . SUBJECTS: Aboriginal children ages 0.5 to 19.9 years, living in a single Northern community and eligible for a public health immunization campaign conducted in all Manitoba native reserve communities to control a meningococcal serogroup C, electrophoretic type (ET) 15 outbreak . No outbreak cases had occurred in the community at the time of the study . METHODS: Total serogroup C capsular polysaccharide antibody (CPA) and functional bactericidal antibody (BA) responses were measured by enzyme-linked immunosorbent assay and bactericidal assay, respectively . RESULTS: Neisseria meningitidis was recovered from the oropharynx of 13 (5.2%) of 249 aboriginal children including 4 (1.6%) serogroup C isolates, all with the designation C:2a:P1.2,5 ET15 . Paired sera from 152 children were available for assay . For CPA the geometric mean concentrations and proportions with > or =2 microg/ml before and after immunization were 0.69, 18% and 12.3, 96%, respectively . A significant increase in serum CPA was achieved by children of all ages, with the greatest response occurring after age 11 years . Among infants < lyear old 89% achieved concentrations of > or =2 microg/ml . For BA the pre- and post-vaccine geometric mean titers were 1.02 and 45.9 . The response was significantly associated with age . BA titers > or =1:8 were present, before and after immunization, respectively, in 0 and 0% of infants <1 year old, 0 and 20% of 1- to 1.4-year-olds, 0 and 50% of 1.5- to 1.9-year-olds and 1 and 100% of > or =2-year-olds . CONCLUSION: The age-related total and functional group C meningococcal antibody response after quadrivalent polysaccharide vaccine among aboriginals is similar to that reported for Caucasian children . After age 2 all children made excellent CPA and BA responses . In the younger age groups the BA response was blunted but 82 to 95% achieved CPA titers of > or =2 microg/ml.

Pediatr Infect Dis J, 1998 Oct, 17(10), 855 - 9
Cerebrospinal fluid pleocytosis and prognosis in invasive meningococcal disease in children; Malley R et al.; BACKGROUND: The absence of cerebrospinal fluid (CSF) pleocytosis in invasive meningococcal disease (IMD) has been associated with an increased risk of death . It is unknown whether patients who lack a cellular response to central nervous system (CNS) infection are at the same risk of adverse outcome as patients who lack CNS infection . OBJECTIVES: To determine the frequency of presentation and outcome of three groups of children with IMD: Group 1, children with CSF pleocytosis; Group 2, children without CSF pleocytosis and with negative CSF cultures (bacteremia alone); and Group 3, children without CSF pleocytosis but with positive CSF cultures (CNS infection without CSF pleocytosis) . METHODS: We reviewed the medical records of children with IMD at four pediatric referral hospitals between 1985 and 1996 . Clinical and laboratory indices and severe adverse outcomes (defined as death or limb loss) were compared in the three groups . Multivariable logistic regression analysis was performed to determine whether CNS infection without CSF pleocytosis was independently associated with adverse outcome in IMD . RESULTS: Three hundred seventy-seven children with IMD were identified . Eighty-six patients were excluded because their CSF analysis either was not done or was unevaluable; of these patients 22 (25.6%) had an adverse outcome . Of the 291 evaluable patients 204 (70.1%) had CSF pleocytosis, 52 (17.9%) had bacteremia alone and 35 (12.0%) had CNS infection without CSF pleocytosis . Patients with CNS infection without CSF pleocytosis had significantly lower white blood cell and platelet counts and more coagulopathy than patients with bacteremia alone (P < or = 0.05) or patients with CSF pleocytosis (P < or = 0.01) . The frequency of adverse outcome was 40% for patients with CNS infection without CSF pleocytosis compared with 9.6% for patients with bacteremia alone (P = 0.001) and 3.4% for patients with CSF pleocytosis (P < 0.001) . CNS infection without CSF pleocytosis was independently associated with adverse outcome by multivariable logistic regression analysis (P = 0.003) . CONCLUSIONS: Approximately 30% of all children with IMD present without CSF pleocytosis . Of these patients those with CNS infection without pleocytosis are at higher risk of adverse outcome than either patients with CSF pleocytosis or patients with bacteremia alone.

Clin Infect Dis, 1998 Oct, 27(4), 746 - 50
Association of human Fc gamma RIIa (CD32) polymorphism with susceptibility to and severity of meningococcal disease; Platonov AE et al.; Phagocytosis of bacteria constitutes an important defense mechanism against invasive bacterial diseases . Efficacy of phagocytosis by polymorphonuclear neutrophils is known to vary between allotypes of Fc gamma RIIa (a class of Fc receptors for immunoglobulins that is constitutively expressed on neutrophils) . We compared the distribution of Fc gamma RIIa-R131 and Fc gamma RIIa-H131 allotypes in 98 Slavic complement-sufficient patients with meningococcal disease with that of the allotypes in 107 healthy controls . A strong association was found between the IIa-R/R131 allotype and the development of meningococcal disease after the age of 5 years, compared with IIa-R/H131 and IIa-H/H131 allotypes (P < .03; odds ratio {OR}, 2.9) . A severe course of meningococcal disease was observed in 21 (68%) of 31 episodes in patients with IIa-R/R131 genotype and in 22 (54%) of 41 episodes in patients with IIa-R/H131 genotype, in contrast to eight (31%) of 26 episodes in patients with IIa-H/H131 genotype (P < .02; OR, 4.7) . Our data show that individuals older than 5 years of age who have the IIa-H/H131 allotype are less susceptible to severe meningococcal disease than are individuals with the IIa-R/R131 or IIa-R/H131 genotype.

Ann Emerg Med, 1998 Nov, 32(5), 620 - 3
Meningococcal meningitis presenting as stroke in an afebrile adult; Hsu SS et al.; We describe a healthy, afebrile 26-year-old man who presented to the emergency department with left hemiparesis and cranial nerve deficits caused by meningococcal meningitis . The results of the computed tomographic scan of the head were negative . Magnetic resonance imaging showed lesions in the basal ganglia and caudate consistent with ischemic infarcts . The neurologic deficits initially progressed but improved to near-resolution after 1 month . This case was unusual in that the patient was afebrile despite a high bacterial load and significant neurologic deficits . His presentation thus mimicked a straightforward stroke . Close attention to the physical examination findings led to a comprehensive evaluation that yielded the correct diagnosis.

Mol Gen Genet, 1998 Sep, 259(4), 363 - 71
Identification of a hotspot for transformation of Neisseria meningitidis by shuttle mutagenesis using signature-tagged transposons; Claus H et al.; Shuttle mutagenesis using signature-tagged transposons was employed to generate a library of individually tagged mutants of the Neisseria meningitidis strain B1940, which belongs to serogroup B . The use of tagged transposons allowed us to monitor for enrichment for single mutants during the process of shuttle mutagenesis, by amplification of the tags and subsequent sequence determination . Enrichment of a single clone occurred during the transformation of the meningococci with transposon-containing plasmid DNA . Sequence determination around the site of transposon insertion revealed that the transposon had mutagenized a previously unknown locus, which was designated hrtA (high rate of transformation) . hrtA-mediated transformation was independent of TnMax5 and tag sequences, and it most probably involved recombination events . The hrtA locus is restricted to meningococci and gonococci and is present in few apathogenic neisserial species . Chromosomal mapping of hrtA and six further hrt sites revealed a random distribution of highly transforming DNA fragments on the meningococcal chromosome . In conclusion, our data demonstrate that shuttle mutagenesis of naturally competent bacteria using signature-tagged transposons allows the isolation of chromosomal DNA fragments, which exhibit a high transformation efficiency, and which, therefore, are likely to be involved in horizontal gene transfer.

Scand J Infect Dis, 1998, 30(3), 263 - 4
Meningococcal polysaccharide vaccination of military recruits in Israel: preliminary assessment of vaccine effect; Mimouni D et al.; Meningococcal disease in the Israel Defense Force is caused mainly by serogroups C and Y . Immunization of recruits with quadrivalent polysaccharide vaccine was introduced in November 1994 . The person-time incidence rate dropped from 1.33 cases per 100,000 person-years for the preceding decade to 0 for the 32 months following immunization (p = 0.025).

Cent Eur J Public Health, 1998 Aug, 6(3), 219 - 24
Active surveillance of meningococcal meningitis in Poland; Tyski S et al.; Starting from 1970, the notification of N . meningitidis cases in Poland was compulsory and separated from other cases of meningitis purulenta . Based on the experience of European Monitoring Group on Meningococci, the active surveillance of meningococcal meningitis in Poland was initiated in April 1995 . It was the first time that such study was conducted to recognise the actual situation of meningococcal meningitis infections in our country . Ninety seven N . meningitidis strains were isolated (31 in 1995 and 66 in 1996) from cerebrospinal fluid (CSF) of meningitis patients hospitalized in 54 hospitals located in 33 out of 49 provinces of Poland . Most patients were below 2 years of age and 43% belonged to infant group . Meningococcal strains were phenotypically characterized as follow: identification of N . meningitidis was performed by Gram staining, oxidase and catalase tests as well as latex or diagnostic sera agglutination assays . Meningococcal serotypes and subtypes were determined by whole-cell ELISA with monoclonal antibodies . The predominant meningococcal serogroup during 1995 and 1996 was B (80% of all isolates tested), the serogroup C (12.6%) and W-135 (3.5%) . Only two non-groupable and two serogroup A strains were isolated in Poland . Active surveillance allowed to determine B:22:P1.14 to be the most prevalent N . meningitidis phenotype in Poland . Two isolates of N . meningitidis phenotype C:2a:P1.2,5, which caused emergency situation in Czech Republic since 1993, were isolated from CSF of patients in October 1996 in southern Poland . All strains were susceptible to cefotaxime, chloramphenicol, ciprofloxacin, rifampin and tetracycline; some strains were resistant to sulphonamides (60.6% - MIC = 32 mg/l and 14.8% - MIC = 128 mg/l) . Only one of the tested strains in two years surveillance study in Poland was resistant to penicillin (MIC = 2 mg/l).

J Antimicrob Chemother, 1998 Sep, 42(3), 303 - 7
The detection of penicillin insensitivity in Neisseria meningitidis by polymerase chain reaction; Maggs AF et al.; Strains of penicillin-sensitive and -insensitive Neisseria meningitidis were examined using a range of polymerase chain reaction (PCR) primers directed at the meningococcal penicillin-binding protein 2 gene . DNA from isolates whose penicillin MIC was <0.2 mg/L yielded a product of the expected size with all the primers, but many amplification patterns were seen with DNA from isolates whose MIC was above this level . All strains whose MIC was >0.25 mg/L failed to produce a product of the expected size with at least one of the primers used . The changes seen in penicillin-insensitive strains were consistent with horizontal gene transfer from Neisseria flavescens in some isolates, although the source for others remains unknown . PCR-based methods for the detection of antibiotic resistance are becoming increasingly important with the expanding use of molecular techniques for bacteriological diagnosis.

J Accid Emerg Med, 1998 Sep, 15(5), 298 - 303
Avoidable deficiencies in the delivery of health care to children with meningococcal disease; Nadel S et al.; OBJECTIVES: It is apparent that delays and inadequate or inappropriate management occur frequently and may contribute to the continued high mortality seen in meningococcal disease . An attempt has been made to define the major sources of delay or inappropriate treatment . METHODS: A prospective, descriptive study of children with meningococcal disease referred to a tertiary centre paediatric intensive care and infectious disease unit . Definitions of optimal care were established at three stages: parental; general practitioner (GP)/accident and emergency (A&E) department; and hospital . Duration of symptoms and management were recorded from direct questioning of parents and carers, and from hospital records . RESULTS: 54 consecutive children with meningococcal disease were recruited to the study . Delayed parental recognition occurred in 16 children . GPs correctly diagnosed 19 of 35 children . Delay of 2.5-21 hours occurred in those who were incorrectly diagnosed . Two of 15 children who presented to the A&E department with specific features were incorrectly diagnosed . Hospital treatment was suboptimal in 71% . Shock was not recognised or treated in 50%, 20% of children had unnecessary lumbar punctures . Time from illness onset to treatment was longer in fatal disease (median 18.3, range 8-24 hours), compared with survivors (median 12, range 2-48 hours; p < 0.01, Mann-Whitney U test) . CONCLUSION: Suboptimal treatment in meningococcal disease is due to failure of parents, GPs, and hospital doctors to recognise specific features of the illness . Improvement by public education and better training of clinicians in recognition, resuscitation, and stabilisation of seriously ill children.

Infect Immun, 1998 Nov, 66(11), 5350 - 6
Complement activation in relation to capillary leakage in children with septic shock and purpura; Hazelzet JA et al.; To assess the relationship between capillary leakage and inflammatory mediators during sepsis, blood samples were taken on hospital admission, as well as 24 and 72 h later, from 52 children (median age, 3.3 years) with severe meningococcal sepsis, of whom 38 survived and 14 died . Parameters related to cytokines (interleukin 6 {IL-6} IL-8, plasma phospholipase A2, and C-reactive protein {CRP}), to neutrophil degranulation (elastase and lactoferrin), to complement activation (C3a, C3b/c, C4b/c, and C3- and C4-CRP complexes), and to complement regulation (functional and inactivated C1 inhibitor and C4BP) were determined . The degree of capillary leakage was derived from the amount of plasma infused and the severity of disease by assessing the pediatric risk of mortality (PRISM) score . Levels of IL-6, IL-8, C3b/c, C3-CRP complexes, and C4BP on admission, adjusted for the duration of skin lesions, were significantly different in survivors and nonsurvivors (C3b/c levels were on average 2.2 times higher in nonsurvivors, and C3-CRP levels were 1.9 times higher in survivors) . Mortality was independently related to the levels of C3b/c and C3-CRP complexes . In agreement with this, levels of complement activation products correlated well with the PRISM score or capillary leakage . Thus, these data show that complement activation in patients with severe meningococcal sepsis is associated with a poor outcome and a more severe disease course . Further studies should reveal whether complement activation may be a target for therapeutical intervention in this disease.

Pediatr Infect Dis J, 1998 Sep, 17(9), 816 - 9
Azithromycin compared with rifampin for eradication of nasopharyngeal colonization by Neisseria meningitidis; Girgis N et al.; OBJECTIVES: To evaluate the efficacy and safety of azithromycin compared with rifampin for eradication of nasopharyngeal carriage of Neisseria meningitidis METHODS: Pharyngeal swabs were obtained from 500 students attending nursing school in Cairo, Egypt, to determine the colonization rate with N . meningitidis . Colonized individuals were randomized to receive azithromycin (500 mg once) or rifampin (600 mg twice daily for four doses) . Subjects were then recultured 1 and 2 weeks posttreatment to determine the effectiveness of the antibiotic therapy for eradication of meningococcal nasopharyngeal colonization . RESULTS: Individuals treated with azithromycin had a 93% eradication rate at 1 and 2 weeks posttreatment comparable with 95 and 91%, respectively, for rifampin . No significant side effects were reported by any subjects treated with either antibiotic . CONCLUSION: Azithromycin is effective in the eradication of N . meningitidis from the nasopharynx of asymptomatic colonized individuals and deserves further evaluation for use as prophylaxis against N . meningitidis.

MMWR Morb Mortal Wkly Rep, 1998 Oct 9, 47(39), 833 - 7
Outbreaks of group B meningococcal disease--Florida, 1995 and 1997; Matrix metalloproteinases contribute to the blood-brain barrier disruption during bacterial meningitis; Department of Neurology, Ludwig-Maximilians-University of Munich, Klinikum Brosshadern, GermanyIn this study, we investigated the involvement of matrix metalloproteinases (MMPs) in the pathophysiology of bacterial meningitis . By using an enzyme immunoassay, high concentrations of MMP-9 were detected in the cerebrospinal fluid (CSF) of adult patients with bacterial meningitis but not in controls, and in patients with Guillain-Barre syndrome . Moreover, we observed significantly elevated concentrations of the tissue inhibitor of metalloproteinase-1 (TIMP-1) in the CSF of patients with bacterial meningitis, compared with controls . In a rat model of meningococcal meningitis, intracisternal injection of heat-killed meningococci caused a disruption of the blood-brain barrier (BBB), an increase in intracranial pressure, and CSF pleocytosis paralleled by the occurrence of MMP-9 activity in the CSF 6 hours after meningococcal challenge . The MMP inhibitor batimastat (BB-94) significantly reduced the BBB disruption and the increase in intracranial pressure irrespective of the time of batimastat administration (15 minutes before and 3 hours after meningococcal challenge) but failed to significantly reduce CSF white blood cell counts . In conclusion, our results suggest that MMPs are involved in the alterations of BBB permeability during experimental meningococcal meningitis.

Rev Cubana Med Trop, 1996, 48(1), 34 - 9
{Meningococcal disease and VA-MENGOC BC in minors less than 1 year of age . Cuba, 1983 to 1991}; Rico Cordeiro O et al.; A study of the chronological series of mortality due to meningococcal disease in children under one year old, the group of highest incidence during the last epidemy in Cuba, was carried out . Data were collected by doing a survey in an uniform way since 1983 throughout the country . More than 90% of the population between 3 months and 5 years old were vaccinated with VAMENGOC BC since the end of 1988 until April, 1990 . The behaviour of this disease was studied in order to identify the influence of this vaccine . It is stressed that the mortality incidence reached its epidemic achme in 1986 and begins a slow descence which is accentuated in 1990 and 1991, with an annual relative decrease of 26.1 and 34.9%, respectively . The highest mortality rate was found in 1984, with a significant reduction in 1990 (-23.8%) and 1991 (-41.8%), after the culmination of the vaccination campaign with VA-MENGOC BC . It was detected that morbimortality, which is lower in children under one month because of the probable protection provided by maternal antibodies, started to increase until the fifth month of life, when it is observed a trend towards the reduction of morbidity and mortality . According to the present immunization chronogram, overall protection in only attained after the sixth mont of life.

Mol Microbiol, 1998 Aug, 29(4), 975 - 84
Identification of a novel gene involved in pilin glycosylation in Neisseria meningitidis; Jennings MP et al.; The pili of Neisseria meningitidis are a key virulence factor, being major adhesins of this capsulate organism that contribute to specificity for the human host . Recently it has been reported that meningococcal pili are post-translationally modified by the addition of an O-linked trisaccharide, Gal (beta1-4) Gal (alpha1-3) 2,4-diacetimido-2,4,6-trideoxyhexose . Using a set of random genomic sequences from N . meningitidis strain MC58, we have identified a novel gene homologous to a family of glycosyltransferases . A plasmid clone containing the gene was isolated from a genomic library of N . meningitidis strain MC58 and its nucleotide sequence determined . The clone contained a complete copy of the gene, here designated pglA (pilin glycosylation) . Insertional mutations were constructed in pglA in a range of meningococcal strains with well-defined lipopolysaccharide (LPS) or pilin-linked glycan structures to determine whether pglA had a role in the biosynthesis of these molecules . There was no alteration in the phenotype of LPS from pglA mutant strains as judged by gel migration and the binding of monoclonal antibodies . In contrast, decreased gel migration of the pilin subunit molecules of pglA mutants was observed, which was similar to the migration of pilins of galE mutants of same strains, supporting the notion that pglA is a glycosyltransferase involved in the biosynthesis of the pilin-linked trisaccharide structure . The pglA mutation, like the galE mutation reported previously, had no effect on pilus-mediated adhesion to human epithelial or endothelial cells . Pilin from pglA mutants were unable to bind to monospecific antisera recognizing the Gal (beta1-4) Gal structure, suggesting that PglA is a glycosyltransferase involved in the addition of galactose of the trisaccharide substituent of pilin.

Res Microbiol, 1998 Jun, 149(6), 381 - 7
Cooperation between the components of the meningococcal transferrin receptor, TbpA and TbpB, in the uptake of transferrin iron by the 37-kDa ferric-binding protein (FbpA); Gomez JA et al.; Meningococcal TbpAB complexes TbpA, TbpB and FbpA were purified and used to study their role in the uptake of iron from transferrin to FbpA . Purification was achieved by affinity chromatography techniques, yielding homogeneous, non-denatured and functional material . TbpA could not be separated from TbpB and had to be purified from a TbpB-defective mutant strain . FbpA was able to bind iron from transferrin only when TbpAB complexes, TbpA and/or TbpB, were also present during the interaction . The highest uptake efficiences were obtained with TbpAB complexes or TbpA/TbpB mixtures . We conclude that the TbpA and TbpB molecules form true functional transferrin receptors, that FbpA is able to take iron directly from transferrin when in the presence of the components of the receptor, and that both Tbps are necessary for an optimal operation of the uptake system.

Acta Crystallogr D Biol Crystallogr, 1998 Sep 1, 54 ( Pt 5), 1005 - 7
Crystallization and preliminary X-ray diffraction analysis of antigen-binding fragments which are specific for antigenic conformations of sialic acid homopolymers; Patenaude SI et al.; Meningococcal meningitis is a severe childhood disease which often results in significant disability or death . Two major etiological agents of meningitis are the group B meningococci and capsular type K1 E . coli . The virulence of these organisms is attributable to structural mimicry between their common alpha(2-8)-polysialic acid capsular polysaccharide and human tissue antigens, which allows the bacteria to evade immune surveillance . There is currently no effective vaccine to protect against this infection . It has been demonstrated that the capsular polysaccharide of the bacteria can adopt a unique 'antigenic conformation' . This antigenic conformation has formed the basis for the development of an N-propionylated polysialic acid vaccine . Immunization trials in mice with this vaccine show the production of two groups of antibodies, of which only N-propionylated polysialic acid-specific were protective . Knowledge of the structure of the antigen-binding site which recognizes the protective epitope is essential to determining the antigenic conformation of the polysaccharides, and is a critical aspect in understanding and improving the action of potential vaccines . The antigen-binding fragments (Fab) of one protective (13D9) and one non-protective (6B9) monoclonal antibody specific for the capsular polysaccharides of group B meningococci have been crystallized and have undergone preliminary X-ray diffraction analysis . Both crystals are observed to scatter X-rays to approximately 1.7 A resolution at the A1 station at the Cornell High-Energy Synchrotron Source . 13D9 has an orthorhombic unit cell with a = 41.8, b = 102.3, c = 134.7 A, with space group P212121 . Fab 6B9 has an orthorhombic unit cell with a = 89.6, b = 132.0 and c = 36.9 A, with space group P21212.

Rev Inst Med Trop Sao Paulo, 1998 Mar-Apr, 40(2), 113 - 7
The use of oligonucleotide probes for meningococcal serotype characterization; Sacchi CT et al.; In the present study we examine the potential use of oligonucleotide probes to characterize Neisseria meningitidis serotypes without the use of monoclonal antibodies (MAbs) . Antigenic diversity on PorB protein forms the bases of serotyping method . However, the current panel of MAbs underestimated, by at least 50% the PorB variability, presumably because reagents for several PorB variable regions (VRs) are lacking, or because a number of VR variants are not recognized by serotype-defining MAbs . We analyzed the use of oligonucleotide probes to characterize serotype 10 and serotype 19 of N . meningitidis . The porB gene sequence for the prototype strain of serotype 10 was determined, aligned with 7 other porB sequences from different serotypes, and analysis of individual VRs were performed . The results of DNA probes 21U (VR1-A) and 615U (VR3-B) used against 72 N . meningitidis strains confirm that VR1 type A and VR3 type B encode epitopes for serotype-defined MAbs 19 and 10, respectively . The use of probes for characterizing serotypes possible can type 100% of the PorB VR diversity . It is a simple and rapid method specially useful for analysis of large number of samples.

Rev Inst Med Trop Sao Paulo, 1998 Mar-Apr, 40(2), 65 - 70
Meningococcal disease caused by Neisseria meningitidis serogroup B serotype 4 in São Paulo, Brazil, 1990 to 1996; Sacchi CT et al.; A large epidemic of serogroup B meningococcal disease (MD), has been occurring in greater Sao Paulo, Brazil, since 1988 . A Cuban-produced vaccine, based on outer-membrane-protein (OMP) from serogroup B: serotype 4: serosubtype P1.15 (B:4:P1.15) Neisseria meningitidis, was given to about 2.4 million children aged from 3 months to 6 years during 1989 and 1990 . The administration of vaccine had little or no measurable effects on this outbreak . In order to detect clonal changes that could explain the continued increase in the incidence of disease after the vaccination, we serotyped isolates recovered between 1990 and 1996 from 834 patients with systemic disease . Strains B:4:P1.15, which was detected in the area as early as 1977, has been the most prevalent phenotype since 1988 . These strains are still prevalent in the area and were responsible for about 68% of 834 serogroup B cases in the last 7 years . We analyzed 438 (52%) of these strains by restriction fragment length polymorphism (RFLPs) of rRNA genes (ribotyping) . The most frequent pattern obtained was referred to as Rb1 (68%) . We concluded that the same clone of B:4:P1.15-Rb1 strains was the most prevalent strain and responsible for the continued increase of incidence of serogroup B MD cases in greater Sao Paulo during the last 7 years in spite of the vaccination trial.

Trop Med Int Health, 1998 Sep, 3(9), 742 - 6
Meningitis caused by a serogroup W135 clone of the ET-37 complex of Neisseria meningitidis in West Africa; Kwara A et al.; Meningococci belonging to serogroup W135 caused several cases of meningococcal meningitis in The Gambia in 1995 and were isolated during a serogroup A epidemic in Mali in 1994 . The eight isolates tested belonged to the same clone of the ET-37 complex and differed in several bands from the pulsed-field gel electrophoresis restriction pattern of serogroup C meningococci of the ET-37 complex isolated in Mali . Three of 6 patients infected in The Gambia died, indicating that this W135 clone is virulent . Vaccines that protect only against infections with meningococci belonging to serogroups A and C are usually used to control outbreaks in Africa, although vaccines containing the W135 polysaccharide are available . The findings of this study indicate that outbreaks of meningococcal meningitis in Africa can be associated with serogroup W135 infections and that serogrouping is essential before vaccination campaigns are started.

Epidemiol Infect, 1998 Aug, 121(1), 95 - 101
Molecular variation of meningococcal serotype 4 antigen genes; Urwin R et al.; Changes in the frequency of serogroup B non serotypable (B:NT) meningococci isolated in England and Wales were investigated by T-track fingerprint analysis, DNA nucleotide sequence determination, and serotyping by whole cell ELISA and dot blot assay . Seventy-three per cent of the isolates designated as B:NT by the Meningococcal Reference Unit (MRU) dot blot assay during 1993-4, expressed variants of the serotyping antigen, PorB, that were serotype 4 by whole cell ELISA . T-track fingerprint patterns of these and other 'serotype 4' isolates revealed five distinct porB alleles which were shown by nucleotide sequence determination to encode different peptide sequences . Differential binding of the 'serotype 4' mAbs MN14G21 and 5DC4C8G8 in whole cell ELISA and dot blot assays was the result, (i) of differences in the peptide sequence of predicted surface loop I and (ii) an amino acid deletion in predicted loop VI of the PorB protein.

Epidemiol Infect, 1998 Aug, 121(1), 85 - 94
Dynamics of the meningococcal carrier state and characteristics of the carrier strains: a longitudinal study within three cohorts of military recruits; Andersen J et al.; Three cohorts of Danish male military recruits (n = 1069) were studied for pharyngeal meningococcal carriage during 3 months at different seasons: 39-47% of entrants were meningococcal carriers and the carriage rate remained constant over time and season . However, individual changes in the carrier state occurred frequently, and after 3 months 34% had changed carrier state on one or more occasions . Initially, a loss of carriage predominated; on the other hand almost 20% of non-carriers had acquisition of meningococci within the first month . The serological phenotypes of the 670 carrier strains were compared with those of 261 invasive strains recovered concurrently from patients with meningococcal disease country-wide . Both carrier strains and invasive strains were phenotypically heterogeneous . Almost 60% of the invasive strains belonged to three phenotypes: B:15:P1.7, 16, C:2a:P1.2, 5 and C:2b:P1.2, 5 . In contrast, these phenotypes only amounted to 3.2% of the carrier strains, among which no phenotype was found with a prevalence above 4.9% . However, 30% of the carrier strains had serological phenotypes identical to those of 80% of the invasive strains . Our results indicated that the transmission rate of potential pathogenic carrier strains did not differ from that of other carrier strains.

Infect Immun, 1998 Oct, 66(10), 4755 - 61
Specificity of bactericidal antibody response to serogroup B meningococcal strains in Brazilian children after immunization with an outer membrane vaccine; Milagres LG et al.; Pre- and postvaccination serum samples from 77 children aged 2 to 6 years, who received the Cuban BC vaccine (B:4:P1.15), were analyzed for bactericidal antibodies against a local B:4:P1.15 strain (N44/89) . Sera from 16 individuals with bactericidal antibodies against the B:4:P1.15 strain were tested against 23 Brazilian isolates . These include B:4 strains of distinct serosubtypes: P1.15, P1.7,1, P1.3, P1.9, P1.nt, and a B:8,19,23:P1.16 strain . A Cuban B:4:P1.15 strain (Cu385/83) was also included in the study . The specificities of bactericidal antibodies were analyzed by using mutant strains lacking a class 1 protein (PorA protein) or a class 5 protein or both . The results indicated that PorA and class 5 proteins are the main targets recognized by the bactericidal antibodies of vaccinees . Nonetheless, a complex pattern of recognition by bactericidal antibodies was found, and vaccinees were grouped according to antibody specificity . Antibodies from some individuals recognized PorA of serosubtype P1.15 . However, antibodies from these individuals could not kill all P1.15 strains tested . Antibodies from a second group recognized both PorA and class 5 proteins, and antibodies from a third group recognized an as yet unidentified target antigen . The results demonstrate the importance of determining the fine epitope specificity of bactericidal antibodies to improve the existing vaccines against B meningococci.

J Clin Microbiol, 1998 Oct, 36(10), 3103 - 4
Unreliability of disc diffusion test for screening for reduced penicillin susceptibility in Neisseria meningitidis; Block C et al.; The 2-U penicillin and microgram oxacillin discs proposed for screening meningococci for susceptibility to penicillin were evaluated by using MICs measured by the E test . The discs yielded unacceptably high frequencies of misclassification of susceptibility category and should be abandoned in favor of MIC estimations . An agreed breakpoint for reduced penicillin susceptibility in meningococci is needed for the E test.

J Clin Microbiol, 1998 Oct, 36(10), 2828 - 34
Molecular epidemiology of recent belgian isolates of Neisseria meningitidis serogroup B; Van Looveren M et al.; In Belgium an increase in the incidence of meningococcal disease has been noted since the early 1990s . Four hundred twenty clinical strains isolated during the period from 1990 to 1995, along with a set of 30 European reference strains, and 20 Dutch isolates were examined by random-primer and repetitive-motif-based PCR . A subset was investigated by multilocus enzyme electrophoresis and pulsed-field gel electrophoresis . The data were compared with results obtained by serotyping (M . Van Looveren, F . Carion, P . Vandamme, and H . Goossens, Clin . Microbiol . Infect . 4:224-228, 1998) . Both phenotypic and molecular epidemiological data suggest that the lineage III of Neisseria meningitidis, first encountered in The Netherlands in about 1980, has been introduced in Belgium . The epidemic clone, as defined by oligonucleotide D8635-primed PCR, encompasses mainly phenotypes B:4:P1.4 and B:nontypeable:P1.4, but strains with several other phenotypes were also encountered . Therefore, serotyping alone would underestimate the prevalence of the epidemic clone.

J Biol Chem, 1998 Sep 25, 273(39), 25329 - 38
Characterization of the structure, function, and conformational stability of PorB class 3 protein from Neisseria meningitidis . A porin with unusual physicochemical properties; Minetti CA et al.; PorB proteins constitute the vast majority of channels in neisserial outer membranes and can be subdivided within meningococcal strains into two distinct and mutually exclusive families that are designated as class 2 and class 3 proteins . We recently characterized the functional activity and conformational stability of a PorB class 2 protein from Neisseria meningitidis (Minetti, C . A . S . A., Tai, J . Y., Blake, M . S., Pullen, J . K., Liang, S . M., and Remeta, D . P . (1997) J . Biol . Chem . 272, 10710-10720) . To evaluate the structure-function relatedness among the PorB proteins, we have employed a combination of electrophoretic and spectroscopic techniques to assess the conformational stability of zwittergent-solubilized class 3 trimers . The functional, physicochemical, and structural properties of the meningococcal class 2 and class 3 proteins are comparable with the notable exception that the latter exhibits a significantly higher susceptibility to SDS . The SDS-induced dissociation and partial unfolding of PorB class 3 is characterized by a single two-state transition with a midpoint at 0.35% SDS . The native trimeric assembly dissociates reversibly, forming partially folded monomers that retain the characteristic beta-sheet content of the transmembrane domain with a concomitant increase in random coil structure arising from unfolding the rigid surface loops . These results provide new insight into the elucidation of porin folding pathways and the factors that govern the overall structural stability of meningococcal proteins.

J Med Microbiol, 1998 Sep, 47(9), 757 - 60
Analysis of TbpA and TbpB functionality in defective mutants of Neisseria meningitidis; Pintor M et al.; Iron uptake analysis suggested that the Neisseria meningitidis transferrin (Tf) binding proteins, TbpA and TbpB, form only one type of receptor complex . Mutants defective in the synthesis of either TbpA or TbpB, but not defective in both proteins, can bind Tf, suggesting that both proteins are surface exposed and function in Tf binding . Also, iron uptake from Tf into the meningococci did not require the presence of both Tbps . The TbpB-defective mutant incorporated c . 37% of the iron taken up by the wild-type strain, but this was insufficient for bacterial growth . The TbpA-defective mutant incorporated c . 50% of the iron taken up by the wild-type strain and was able to grow with Tf as the only iron source . Mouse antibodies specific for TbpA were able to block c . 70% of the iron uptake from Tf in the wild-type strain, whereas they blocked only 22% of iron uptake in the TbpB-defective mutant and did not block uptake in the TbpA-defective strain . These results emphasise that TbpA should be considered in future vaccine trials in which iron-restricted proteins are to be included in the vaccine formulation.

Lancet, 1998 Mar 28, 351(9107), 950 - 3
Anti-inflammatory cytokine profile and mortality in febrile patients; van Dissel JT et al.; BACKGROUND: An anti-inflammatory cytokine profile on whole-blood stimulation in vitro is associated with fatal outcome of meningococcal disease . We investigated whether an anti-inflammatory cytokine profile in the circulation is associated with adverse outcome in other infectious diseases . METHODS: We enrolled 464 consecutive patients (272 men, 192 women) who presented to hospital with fever (> or = 38.2 degrees C) . On admission we measured plasma interleukin 10 (IL-10) and tumour necrosis factor alpha (TNF alpha), and collected clinical and microbiological data on the febrile illness, then followed up all patients for clinical outcome . FINDINGS: In at least 399 of the 464 patients fever was caused by infection . 33 patients died after a median hospital stay of 11 days (interquartile range 3-20) . Concentrations of IL-10 were significantly higher in non-survivors (median 169 pg/mL {IQR 83-530}) than in survivors (median 88 pg/mL {42-235}, p=0.042) . When dichotomised around the median, the mortality risk was two times higher in patients who had high concentrations of IL-10 than in those with low concentrations (relative risk 2.39 {95% CI 1.07-5.33}), in patients with low and high concentrations of TNF alpha . In the 406 patients without haemodynamic deterioration in the first 24 h, IL-10 was higher and TNF alpha lower in patients who died than in those who survived . The ratio of IL-10 to TNF alpha was higher in non-survivors (median 6.9 {3.0-21.0}) than in survivors (median 3.9 {2.0-7.0}, p=0.040) . This ratio was highest in patients who died without underlying disease (median 21.5 {5.0-25.0}) . Age, sex, and duration of fever before admission did not explain the differences in IL-10 and TNF alpha . INTERPRETATION: An anti-inflammatory cytokine profile of a high ratio of IL-10 to TNF alpha is associated with fatal outcome in febrile patients with community-acquired infection . Our findings caution against a widespread use of proinflammatory cytokine inhibition in patients with sepsis.

J Clin Epidemiol, 1998 Sep, 51(9), 717 - 21
Outcome of pre-hospital antibiotic treatment of meningococcal disease; Sorensen HT et al.; OBJECTIVE: To assess the effect of pre-hospital antibiotic treatment given by general practitioners to patients with meningococcal disease . DESIGN: A 16-year population-based historical follow-up study based on referral letters and hospital records in the County of North Jutland, Denmark . SUBJECTS: 320 patients with meningococcal disease, of whom 302 were examined by a general practitioner before admission to hospital . MAIN OUTCOME MEASURES: Death . RESULTS: 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 (OR) for death in patients treated with antibiotics was high (OR = 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 . If skin bleeding was replaced in the models by the presence of disseminated intravascular coagulation on admission, the OR for death in patients with pre-hospital antibiotic treatment was 35.9 (95% CI, 2.9-441.8) in the presence of disseminated intravascular coagulation and 1.9 (95% CI, 0.2-19.5) in its absence . CONCLUSIONS: 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 but provide reason to doubt the benefit of pre-hospital antibiotic treatment in patients with meningococcal disease.

Scand J Infect Dis, 1998, 30(2), 198 - 200
Pharyngolaryngitis caused by Neisseria meningitidis; Mattila PS et al.; Neisseria meningitidis is a causative agent of life-threatening cases of meningitis and sepsis, but it can also cause mild and self-limiting bacteraemia . Patients with N . meningitidis sepsis or meningitis often describe signs of upper respiratory tract infection before the onset of invasive disease . Viral respiratory infections have been associated with invasive meningococcal diseases and they may contribute to these prodromal symptoms . N . meningitidis can be cultivated from the throats of asymptomatic carriers and it likely enters the circulation through the upper respiratory tract . However, it is unclear whether N . meningitidis can cause simple pharyngitis . Here we describe a case of acute fulminant pharyngolaryngitis caused by N . meningitidis as verified by positive blood cultures.

Scand J Infect Dis, 1998, 30(2), 196 - 8
Acute meningococcal epiglottitis and septicaemia in a 65-y-old man; Sivalingam P et al.; We report a case of acute meningococcal epiglottitis in a 65-y-old man . He was noted to have stridor of acute onset . We highlight the importance of the diagnosis of acute epiglottitis, early establishment of an airway and appropriate antibiotic therapy . This case report mainly concerns the association of unusual pathogen Neisseria meningitidis and adult acute epiglottitis.

J Infect Dis, 1998 Sep, 178(3), 870 - 4
Induction of immunologic refractoriness in adults by meningococcal C polysaccharide vaccination; Granoff DM et al.; Thirty-four adults were vaccinated with 1/50 of the usual dose of meningococcal polysaccharide vaccine (1 microg of A, C, Y, and W135 polysaccharides, given intramuscularly) . This dose was selected as a probe to assess B cell memory . The probe elicited meningococcal C bactericidal antibody responses in all 18 adults who had been vaccinated 4 years earlier with an investigational meningococcal A and C oligosaccharide-protein conjugate vaccine and in the majority of the 11 subjects vaccinated for the first time . In contrast, the responses of the 5 adults given a full dose of licensed polysaccharide vaccine 4 years earlier were <1/10 of those of the other 2 groups . Thus, adults previously given a full dose of meningococcal polysaccharide vaccine show evidence of immunologic refractoriness to group C polysaccharide, whereas refractoriness is not observed after conjugate vaccination . These findings have implications for the use of meningococcal polysaccharide vaccine when the risk of disease is low.

BMJ, 1998 Sep 5, 317(7159), 621 - 5
Which contacts of patients with meningococcal disease carry the pathogenic strain of Neisseria meningitidis? A population based study; Kristiansen BE et al.; OBJECTIVES: To determine the prevalence of the pathogenic strain of Neisseria meningitidis in contacts of patients with meningococcal disease, and to determine which contact groups are likely to be carriers and warrant chemoprophylaxis . DESIGN: Population based study . SETTING: Norwegian county of Telemark . SUBJECTS: 1535 primary contacts of 48 patients with meningococcal disease, and 78 secondary contacts . INTERVENTIONS: Carriers of the pathogenic strain were treated with rifampicin . All household members and kissing contacts under 15 years of age were treated with oral penicillin . Contacts were taught to recognise the symptoms of meningococcal disease . RESULTS: In 27 of 48 cases investigated, contacts carrying the pathogenic strain of N meningitidis were found . A total of 42 such contacts were identified . Contacts were stratified into three classes according to the assumed closeness of contact with patients . In class 1 (household members and kissing contacts) the prevalence of the pathogenic strain was 12.4% (95% confidence interval 5.5% to 19.3%) . In classes 2 and 3 the prevalence was 1.9% (0.9% to 3.4%) and 1.6% (0.14% to 3.1%) . CONCLUSIONS: There is a high rate of carriage of the pathogenic strain of N meningitidis in patients' household members and kissing contacts, and this supports the practice of giving chemoprophylaxis to these contacts . The prevalence of carriage among other contacts is 2-3 times that found in the general population (0.7%); the benefits of chemoprophylaxis to these contacts may be marginal.

Commun Dis Public Health, 1998 Mar, 1(1), 54 - 6
Creating a national service for the diagnosis of meningococcal disease by polymerase chain reaction; Kaczmarski EB et al.; The widening gap observed between numbers of culture confirmed and notified cases of meningococcal infection has driven the development of non-culture based polymerase chain reactions (PCRs) to enhance the detection of meningococcal disease . The development of a national PCR-based service increased the number of laboratory confirmed cases of meningococcal disease by 35% in the first year . Advancing technology in the laboratory is reducing in-lab processing time.

Nurse Pract, 1998 Aug, 23(8), 30, 33 - 6, 39-40 passim
Meningococcal disease: recognition, treatment, and prevention; Herf C et al.; Meningococcal disease is an infection caused by Neisseria meningitidis, a gram-negative diplococcus that is the leading cause of bacterial meningitis in children and young adults in the United States, with an estimated 2,600 cases reported each year . N . meningitidis infection rates are highest in children 3 to 12 months of age . Four distinct clinical situations are associated with meningococcal infection . The most common is asymptomatic nasopharyngeal colonization . Benign bacteremia is discovered in the absence of classical clinical findings of meningococcemia, but blood cultures are positive for N . meningitidis . Meningitis, the most common pathologic presentation, is associated with fever, headache, and nuchal rigidity . The mortality rate is about 5% in children and 10% to 15% in adults . Meningococcemia, the most severe form of infection, may involve petechial rash, hypotension, and disseminated intravascular coagulation . It is a fulminant condition that can, if untreated, progress from initial symptoms to coma and death in 12 to 48 hours . Spread of these endemic cases can be controlled by administering prophylactic antibiotics to close contacts of patients.

Vaccine, 1998 Oct, 16(17), 1633 - 9
Effect of adjuvants in the isotypes and bactericidal activity of antibodies against the transferrin-binding proteins of Neisseria meningitidis; Gomez JA et al.; Twenty-eight Neisseria meningitidis strains of different serogroups, serotypes, and TbpB isotypes were used to test the effect of five adjuvant formulations on the immune response to the meningococcal transferrin-binding proteins (Tbps) in mice . Levels of anti-Tbps antibodies were relatively low when purified TbpA-TbpB complexes were used for immunization, those obtained with the RAS adjuvant being the highest, and the isotype distribution reveals a prevalence of the non-bactericidal IgG1 . Specific anti-Tbps antibody levels were five to 125 times higher immunizing with whole outer membrane vesicles, with bactericidal isotypes prevailing, which suggests that presentation of these antigens in their natural conformation is crucial to elicit a good response . Nevertheless, bactericidal activity did not correlate with these characteristics, confirming that it must be also influenced by other factors, and direct evaluation of the killing ability is necessary to draw conclusions about the efficacy of antigens or adjuvants in vaccine design.

J Clin Immunol, 1998 Jul, 18(4), 272 - 82
Expression of properdin in complete and incomplete deficiency: normal in vitro synthesis by monocytes in two cases with properdin deficiency type II due to distinct mutations; Fredrikson GN et al.; Three properdin deficiency phenotypes have been reported--complete deficiency (type I), incomplete deficiency (type II), and dysfunction of properdin protein (type III)--all associated with increased susceptibility to meningococcal disease . Expression of properdin by monocytes was examined in type I deficiency and in two unrelated cases with type II deficiency, one from a Swedish and one from a Danish family . The properdin gene in the Danish family contained a point mutation in exon 8 causing a Gln316-->Arg substitution, distinct from a point mutation in exon 4 previously found in the Swedish family . Both genes coded for physicochemically abnormal properdin molecules with changed hydrophilicity . Monocytes from all the properdin-deficient individuals produced properdin mRNA in a normal fashion . In type I deficiency no intracellular or secreted properdin was found, indicating rapid intracellular degradation . Monocytes from the males with type II deficiency expressed and secreted properdin normally . Properdin in sera with type II deficiency showed abnormal oligomerization with a relative decrease in properdin trimers and tetramers . Our findings suggest that the low concentration of circulating properdin in type II deficiency is caused by increased extracellular catabolism . Analysis of properdin expression by monocytes in a female carrier in the family with properdin deficiency type I provided direct evidence of lyonization at the cellular level.

J Burn Care Rehabil, 1998 Jul-Aug, 19(4), 324 - 9
Integra Artificial Skin as a useful adjunct in the treatment of purpura fulminans; Besner GE et al.; Purpura fulminans is a devastating disorder characterized by rapidly progressing hemorrhagic necrosis of the skin, vascular collapse, and disseminated intravascular coagulation . It is most often seen in children, and it is usually preceded by meningococcemia or another infection . Most often, the disorder results in severe skin loss, but it can also result in the need for extremity amputations . In extreme cases, wound coverage after excision may be problematic because of the limited existence of donor sites and the need for amputation revisions . The case of a 21/2-year-old male requiring amputations of all four extremities due to severe purpura fulminans is presented to illustrate the use of Integra Artificial Skin (Integra Lifesciences Corp., Plainsboro, NJ) to obtain immediate wound closure . Integra Artificial Skin is a bilayered skin substitute that engrafts to a viable wound bed . In the case presented here, where the viability of the underlying tissue of the amputated stumps was questionable, the artificial skin acted as an indicator of that viability . It engrafted well onto the upper extremity stumps, which were of excellent viability, but it needed to be replaced on the lower extremity stumps, which required further debridement and amputation revisions . The use of artificial skin spared the patient the immediate use of his limited and valuable autograft sites . In conclusion, Integra Artificial Skin can be a useful adjunct in the treatment of severe purpura fulminans that includes skin and extremity necrosis.

Anaesthesia, 1998 Jun, 53(6), 580 - 3
Pneumopericardium: an unusual cause for cardiac arrest; Djaiani G et al.; A 1-year-old boy breathing via a T-piece system and recovering from meningococcal septicaemia in the intensive care unit suffered a severe bout of coughing and developed bilateral pneumothoraces and tension pneumopericardium resulting in electromechanical dissociation and asystole . Conventional cardiopulmonary resuscitation and adrenaline boluses were unsuccessful . Administration of 20 ml.kg-1 of colloid and 3 mmol.kg-1 of sodium bicarbonate solutions produced instantaneous return of cardiac, output . The deleterious effects of cardiac tamponade appeared to decrease with increasing cardiac filling pressures . The patient was managed conservatively and he made a full recovery with no signs of residual neurological deficit.

J Clin Microbiol, 1998 Sep, 36(9), 2623 - 8
Clonal distribution of invasive Neisseria meningitidis isolates from the Norwegian county of Telemark, 1987 to 1995; Aakre RK et al.; Forty-two Neisseria meningitidis isolates were obtained from patients with meningococcal disease in the Norwegian county of Telemark (January 1987 to March 1995), and all were compared by PCR amplicon restriction endonuclease analysis (PCR-AREA) of the dhps gene, chromosomal DNA fingerprinting, and serological analysis . PCR-AREA divided the isolates into 11 classes, of which 4, comprising 15, 8, 6, and 2 isolates, were clonal while the remaining 8 classes were genetically heterogeneous or contained only 1 isolate . Three of the four clonal classes could be tentatively equated with recognized epidemic clones (ET5, ET37, and cluster A4) on the basis of their phenotypic characteristics, while the remaining clone appears to be new . There were significant differences in the geographical distribution of clones, with class 1 (ET5-like) isolates significantly overrepresented in rural parts of Telemark . Class 1 (ET5-like) isolates occurred throughout the study period and were dominant in 1987 . Class 2 (ET37-like) isolates occurred from 1988 to 1992, and class 3 isolates (with no recognizable ET affinities) were found only in 1991 and 1992.

J Clin Microbiol, 1998 Sep, 36(9), 2465 - 70
Necessity of molecular techniques to distinguish between Neisseria meningitidis strains isolated from patients with meningococcal disease and from their healthy contacts; Vogel U et al.; Serogroup C strains of Neisseria meningitidis were isolated from a Germany patient with severe meningococcal disease after a trip to the Czech Republic . These strains (case isolates) were characterized by classical and molecular techniques, as were other strains (carrier isolates) isolated from healthy contacts . Five of 10 carrier isolates had switched off the expression of capsular polysaccharide, as demonstrated by a serogroup-specific PCR . The two case isolates were indistinguishable by multilocus sequence typing and belonged to the ET-37 complex . The carrier isolates belonged to four different sequence types, all unrelated to that of the case strains . Pulsed-field gel electrophoresis showed that the case isolates differed from reference ET-37 complex strains from the Czech Republic and Canada as well as from all the carrier isolates . The isolate from the patient's nasopharynx was indistinguishable from the blood isolate except for a 40,000-bp chromosomal deletion that had occurred during systemic spread.

Hum Genet, 1998 Jun, 102(6), 605 - 10
Nonsense mutation in exon 4 of human complement C9 gene is the major cause of Japanese complement C9 deficiency; Kira R et al.; Deficiency of the ninth component of human complement (C9) is the most common complement deficiency in Japan but is rare in other countries . We studied the molecular basis of C9 deficiency in four Japanese C9-deficient patients who had suffered from meningococcal meningitis . Direct sequencing of amplified C9 cDNA and DNA revealed a nonsense substitution (CGA-->TGA) at codon 95 in exon 4 in the four C9-deficient individuals . An allele-specific polymerase chain reaction system designed to detect exclusively only one of the normal and mutant alleles indicated that all the four patients were homozygous for the mutation in exon 4 and that the parents of patient 2 were heterozygous . The common mutation at codon 95 in exon 4 might be responsible for most Japanese C9 deficiency.

Rev Saude Publica, 1998 Feb, 32(1), 89 - 97
{Meningococcal disease: epidemiology and control of secondary cases}; Barroso DE et al.; Epidemiological features of meningococcal disease described as from the second half of the 80's inclusive, have motivated a revision of current guidelines for sporadic disease and outbreak control . The increase of disease among teenagers and linked cases involving schools are the two most significant aspects that have prompted the revision of control measures . Vaccination routines and advice for the disease management of clusters are also relevant features recently revised . This present paper describes the management and some epidemiological features of secondary cases.

J Infect Dis, 1998 Aug, 178(2), 451 - 9
Dynamics of carriage of Neisseria meningitidis in a group of military recruits: subtype stability and specificity of the immune response following colonization; Jones GR et al.; Meningococcal carriage and the immune response to colonization were studied in a group of military recruits undergoing basic training . Subtyping by determination of the class 1 protein sequence clearly differentiated between strains and demonstrated the dynamics of carriage and transmission . Expression of class 1 protein by each strain remained stable during prolonged carriage by different subjects . Following colonization, a marked increase in serum bactericidal response occurred, which was specific for the subtype of the acquired strain and was associated with an increase in reactivity by Western blot to the homologous class 1 protein . Subjects colonized by multiple strains showed evidence of a specific immune response to the class 1 protein of each strain acquired . The subtype specificity of the bactericidal response to meningococci and the stability of expression of the class 1 protein have important implications for the design of vaccines for prevention of serogroup B meningococcal disease.

J Emerg Med, 1998 Jul-Aug, 16(4), 643 - 7
Rupert Waterhouse and Carl Friderichsen: adrenal apoplexy; Varon J et al.; The Waterhouse-Friderichsen (WFS) syndrome, also known as purpura fulminans, is described as acute hemorrhagic necrosis of the adrenal glands and is most often caused by meningococcal infection . This clinical entity is more frequently seen in the pediatric than the adult population and is associated with a high morbidity and mortality . The initial presenting complaints for patients with the WFS usually include a diversity of nonspecific, vague symptoms such as cough, dizziness, headache, sore throat, chills, rigors, weakness, malaise, restlessness, apprehension, myalgias, arthralgias, and fever . These symptoms are usually abrupt in their onset . Petechiae are present in approximately 50-60% of patients . The clinical diagnosis of WFS may be relatively straightforward or extremely challenging . Patients who appear in the initial and nontoxic-appearing stage without any skin lesions may be difficult to distinguish from a benign viral illness . When a patient presents with fever and petechiae, WFS must be considered, even when the patient has a non-toxic appearance . Due to the rapid progression and often devastating consequences, therapy should be instituted as soon as the diagnosis is suspected.

Biochem J, 1998 Aug 15, 334 ( Pt 1), 269 - 73
Transferrin-binding protein B isolated from Neisseria meningitidis discriminates between apo and diferric human transferrin; Boulton IC et al.; Neisseria meningitidis utilization of human serum transferrin (hTF)-bound iron is an important pathogenicity determinant . The efficiency of this system would clearly be increased through preferential binding of diferric hTF over the iron-free form . To characterize this process, functionally active meningococcal transferrin-binding protein A (TbpA) and TbpB have been purified from N . meningitidis using a novel purification procedure . The association of isolated Tbps and Tbps in the presence of hTF was investigated by gel filtration . Co-purified TbpA+B formed a complex of molecular mass 300 kDa which bound 1-2 molecules of hTF . Purified TbpA formed a complex of 200 kDa, indicating association as a dimer, whereas TbpB aggregated to form multimers of variable sizes . On recombining TbpA and TbpB, a stable complex of equivalent size to co-purified TbpA+B was formed . This complex may be composed of a single TbpA dimer and 1 molecule of TbpB . The technique of surface plasmon resonance (SPR) was used to demonstrate clearly that TbpB of either high (85 kDa) or low (68 kDa) molecular-mass preferentially bound diferric hTF in comparison with iron-free hTF . This selectivity was not observed with TbpA, but was found at low levels with co-purified TbpA+B . Individual TbpA and TbpB, recombined in a 1:1 molecular ratio, showed iron-mediated discriminatory binding at an intermediate level . SPR was also used to show that TbpA and TbpB bound to distinct regions of hTF, and that prior saturation with TbpB reduced subsequent TbpA binding . The results demonstrated that hTF bound more TbpA than TbpB, with an approximate ratio of 2:1 . We have demonstrated that in vitro, TbpA+B exists as a receptor complex composed of a TbpA dimer and one molecule of TbpB, and that TbpB selectively binds diferric hTF . We propose that, in vivo, TbpA and TbpB also exist as a receptor complex, with TbpB selectively binding diferric hTF, bringing it close to TbpA, the transmembrane component, where the ferric iron can be transported to the periplasm.

Epidemiol Infect, 1998 Jun, 120(3), 263 - 70
A cluster of meningococcal disease in western Sydney, Australia initially associated with a nightclub; Jelfs J et al.; Fourteen cases of meningococcal disease (MD) occurred in August September 1996 in western Sydney, Australia . Seven of the 10 young adults affected had a direct or indirect link with a local nightclub . Ten of 11 systemic meningococcal isolates had the phenotype C:2a:P1.5 and showed close genetic relationship by pulsed-field gel electrophoresis (PFGE) . Organisms of this phenotype have not previously caused outbreaks in Australia, but have been associated with outbreaks and hyperendemic serogroup C MD in Europe, Canada, and the United States . This is the largest cluster of serogroup C MD reported in urban Australia, and the first involving a nightclub . The strain differentiation results were available rapidly enough to augment epidemiological investigations on a daily basis . Public health staff could thus establish links between cases quickly, follow the spread of new cases in the community, give accurate information to health officials and the press, and utilize existing knowledge about the characteristics of this phenotype to predict likely developments during the outbreak and afterwards . The strain differentiation data was also very helpful when the role of vaccination was considered, and existing guidelines on the management of outbreaks of MD could be used effectively for the first time in western Sydney.

Epidemiol Infect, 1998 Jun, 120(3), 257 - 62
Amplification of the meningococcal porB gene for non-culture serotype characterization; Urwin R et al.; Since 1992, the proportion of culture-confirmed meningococcal infections compared with numbers of notified cases of meningococcal disease has decreased in England and Wales . As most meningococcal strain characterization methods depend on a clinical isolate, this has resulted in a loss of epidemiological information . To address this problem, and to aid nonculture diagnosis, a semi-nested PCR protocol for the amplification of the meningococcal porB gene from clinical specimens was developed . This gene encodes the meningococcal serotyping antigen; strain typing data was provided by hybridization of allele-specific oligonucleotide probes to the digoxigenin-labelled porB amplicon in a 'PCR ELISA' . This assay was specific for meningococcal DNA and sensitivities of 0.81 for cerebrospinal fluid (CSF), 0.57 for serum, and 0.62 for whole blood taken from patients with proven meningococcal infection were obtained.

Sante, 1998 May-Jun, 8(3), 245 - 8
{Optimizing the response to epidemics of meningococcal meningitis: report of a workshop of experts at CERMES (Niamey, Niger, 12th to 14th January 1998)}; Chippaux JP et al.; Recent meningitis epidemics in West Africa have drawn attention to shortcomings in the response of the health services . The health ministries of the countries involved have identified particular requirements . Following WHO recommendations, OCCGE organized a meeting of experts at CERMES, Niamey, in January 1998 . The aim of this workshop was to consider the problems common to these countries, identify their needs and to produce concrete recommendations defining the roles of OCCGE and CERMES . Difficulties in mobilization, as no procedure had been established, and a lack of resources limited the efficiency of the response to epidemics . There was also insufficient training of personnel and laboratory facilities were often inadequate . OCCGE could draft a procedure manual specifying tasks and responsibilities for the control of an epidemic . It was suggested that a sub-regional stock of drugs, vaccines and injection equipment should be set up at CERMES . This should improve the speed of the response and complement national and international distribution systems . The group stressed the importance of improving the surveillance of meningitis epidemics . This approach depends on a structured network based around a reference laboratory . CERMES plans to support government initiatives by training and by maintaining the network . Efforts will be made to report and make best use of epidemiological information at all levels of the "health pyramid" . Some OCCGE institutes (e.g . IPR and CERMES) have computer tools such as the Geographical Information System, which can be made available to governments . Analysis of sub-regional epidemics demonstrated the limitations of an alert threshold of 15 cases per 100,000 people . The sensitivity and specificity of this threshold differs between climatic zones OCCGE recommends that each country carry out its own research to determine the most appropriate alert threshold for each zone . Epidemics are currently managed by treatment with short courses of chloramphenicol in oil (injected into muscle) . This approach may change as ceftriaxone becomes more affordable . The systematic use of ceftriaxone in infants under the age of 1 year presenting with meningitis is justified by the frequency of non-meningococcal bacterial causes . A consensus was reached on the most appropriate vaccination strategies: Emergency vaccination implemented rapidly in response to an epidemic . The entire population of a district between the age of 6 months and 30 years are vaccinated . Prophylactic vaccination in high-risk zones . This is carried out in the zone itself or in neighboring regions where there was an epidemic the preceding year . There is evidence that those not infected during an epidemic are at high risk the following year . These vaccinations should be carried out as soon as possible, at least before the start of the next epidemic season . Systematic vaccination is currently limited to special groups (e.g . school children, military personnel and pilgrims) . It is hoped that the conjugated vaccine will become available for integration into the infant vaccination program.

Rev Cubana Med Trop, 1997, 49(3), 196 - 203
{Adverse reactions and immune response to Heberbiovac-HB vaccine administered to infants simultaneously with DPT and VA-MENGOC-BC}; Diaz Gonzalez M et al.; The Cuban recombinant yeast-derived hepatitis B vaccine (Heberbiovac-HB) was administered to 2 groups of infants aged 3 months . A dosage of 10 micrograms was used through a scheme of 0, 1 and 6 and 0, 1, 2 and 12, coinciding with the DPT and anti-meningococcal vaccines, according to the immunization schedule . Reactogenicity and immunogenicity were studied in both groups . The reactions observed were mild and similar to other studies, where fever , erythema and induration were the most common signs . These 2 groups had high percentages of children with titres of antibodies anti HBs above 100 UI/L-1 . It is demonstrated the acceptable reactogenicity of the vaccine and the non-immunological interference of other vaccines.

Intensive Care Med, 1998 Jun, 24(6), 616 - 9
Combined lung injury, meningitis and cerebral edema: how permissive can hypercapnia be?
Tasker RC, Peters MJ.
We describe a patient with combined meningococcal septicemia and meningitis, cerebral edema and acute respiratory distress syndrome, in whom we balanced the conflicting carbon dioxide strategies for optimal pulmonary and neurological management using jugular oxygen saturation (SjvO2) monitoring to identify the upper limit of "tolerable" hypercapnia . Our observations suggest that significant acidosis was not well tolerated; however, cautious induction of pH down to 7.32 and an arterial carbon dioxide tension (PaCO2) < 5.9 kPa was tolerated acutely without significant cerebral hyperemia . Moreover, with the development of metabolic compensation and normal pH, higher levels of PaCO2 could be permitted . In similar cerebro-pulmonary circumstances we suggest that these findings warrant consideration . Alternatively, invasive monitoring of SjvO2 could be undertaken so that patient-specific criteria for permissive hypercapnia can be determined.

J Accid Emerg Med, 1998 Jul, 15(4), 249 - 51
Prospective study of "door to needle time" in meningococcal disease; Riordan FA et al.; OBJECTIVE: To measure the promptness of antibiotic treatment in children with meningococcal disease . METHODS: "Door to needle time" for parenteral antibiotics in children with meningococcal disease was recorded prospectively as part of a larger study . The time from arrival at hospital until the first dose of parenteral antibiotics was recorded in 100 children with meningococcal disease (median (range) age 21 (3-168) months) admitted to four Merseyside hospitals . RESULTS: Forty five children presented directly to the accident and emergency (A&E) department . Parenteral penicillin was given before admission to 19 of the 55 children referred by general practitioners (GPs) . Median door to needle time was 36 minutes . All children with a typical petechial rash on arrival received antibiotics within 60 minutes . Antibiotics were given sooner to those with severe disease (p = 0.01) and later to those without a rash (p = 0.007) . CONCLUSIONS: The first dose of parenteral antibiotics for most children with meningococcal disease was given in A&E . When awareness of meningococcal disease is heightened by ongoing research, those with a petechial rash are treated within 60 minutes . Strategies to improve immediate treatment of meningococcal disease should include education of A&E staff as well as GPs.

Mol Microbiol, 1998 Jun, 28(6), 1153 - 63
Pilus-mediated adhesion of Neisseria meningitidis: the essential role of cell contact-dependent transcriptional upregulation of the PilC1 protein; Taha MK et al.; Pilus-mediated adherence makes an essential contribution to the pathogenesis of Neisseria meningitidis by allowing the initial localized adherence . Pili are assembled from a protein subunit called pilin . Two proteins, PilC1 and PilC2, are also key elements in the formation of pili as the production of at least one PilC protein is required for pilus assembly . In addition, PilC1 but not PilC2 modulates adhesiveness, most probably by being the adhesin . Recently, both genes have been demonstrated to be controlled by different promoters, pilC2 is expressed from a single transcription starting point (TSP), whereas pilC1 has three TSPs . One of these, PC1.1, corresponds to the unique TSP of pilC2, and two others, PC1.2 and PC1.3, are located in a region upstream of pilC1 but not pilC2 . This suggests that both genes may be under the control of separate regulatory pathways . In this work, by engineering pilC1-lacZ and pilC2-lacZ transcriptional fusions, we provide evidence that expression of pilC1, but not that of pilC2, is transiently induced by bacterial cell contact . This induction required viable cells, did not need the presence of pili and relied on the expression of pilC1 from PC1.3 . Destruction of this TSP by site-directed mutagenesis did not significantly diminish the piliation level or the basal expression of PilC1, but led to the loss of cell contact-dependent upregulation of pilC1 and to a dramatic decrease in bacterial adhesiveness . Taken together, these data demonstrate that cell contact-dependent upregulation of the transcription of pilC1 at PC1.3 is essential for meningococcal pilus-mediated adhesion.

Ugeskr Laeger, 1998 Jul 13, 160(29), 4325 - 6
{Parvovirus B19 infection--a meningococcus-like sepsis}; Frederiksen EH et al.; Two otherwise healthy adults with fever and haemorrhagic exanthema are described . In both, primary human parvovirus infection was diagnosed . The clinical picture of fever and haemorrhagic exanthema should always arouse suspicion of serious disease such as meningococcal infection . If the patient is unaffected, however, primary human parvovirus infection should be borne in mind.

Burns, 1998 May, 24(3), 272 - 4
Surgical treatment of extensive skin necrosis secondary to purpura fulminans in a patient with meningococcal sepsis; Arevalo JM et al.; Meningococcal sepsis is associated with a high mortality rate . These patients may show severe disseminated intravascular coagulation (DIC) and skin necrosis . There is very little published experience regarding the surgical treatment of this complication . The similarity between skin necrosis secondary to DIC and full thickness cutaneous burns provides the rationale for its treatment as if it was a deep burn . We report the surgical treatment of extensive skin necrosis in a patient with meningococcal sepsis and DIC . This treatment is similar to that used in full thickness burns, including excision of necrotic tissue and coverage with autografts, as well as amputation of extremities if distal coverage is not possible.

Carbohydr Res, 1998 Feb, 307(3-4), 311 - 24
The lipooligosaccharide (LOS) of Neisseria meningitidis serogroup B strain NMB contains L2, L3, and novel oligosaccharides, and lacks the lipid-A 4'-phosphate substituent; Rahman MM et al.; The complete structure of the lipooligosaccharide (LOS) from Neisseria meningitidis strain NMB (serotype 2b:P1.2,5), a serogroup B cerebrospinal fluid isolate, was determined.Two oligosaccharide (OS) fractions and lipid-A were obtained following mild acid hydrolysis of the LOS . The structures in these fractions were determined using glycosyl composition and linkage analyses, N spectroscopy and mass spectrometry . One oligosaccharide fraction (OS1) consists of a molecule having a glycosyl sequence identical to that previously reported for the LOS from immunotype L2 N . meningitidis {A . Gamain, M . Beurret, F . Michon, J.-R . Brisson, and H.J . Jennings, J . Biol . Chem.,267,(112) 922-925} i.e., a lacto-N-neotetraose is attached to heptose I (Hep I), with terminally linked N-acetylglucosaminosyl and glucosyl residues attached to Hep II of the inner core . Approximately 70% of this structure is acetylated at O-6 of the terminally linked alpha-N-acetyl-glucosaminosyl residue . As with the L2 structure, the NMB LOS contained phosphoethanolamine (PEA) at O-6 or O-7 of the Hep II residue . The second oligosaccharide fraction (OS2) contains a a mixture of three different molecules, all of which vary from one another in their glycosyl substitution patterns of the Hep II residue . The most abundant molecule in OS2 has a structure identical to that of OSI, i.e., it has the L2 glycosyl sequence . A second molecule (OS2a) lacks the terminal glucosyl residue at O-3 of Hep II; i.e., it has a glycosyl sequence identical to that of the mild acid released oligosaccharide of N . meningitidis immunotype L3, L4, or L7 LOSs . The third molecule (OS2b) is a novel structure that lacks the terminal N-acetylglucosaminosyl residue linked to O-2 of Hep II . Overall, 76% of OS released from NMB LOS has the L2 structure, 15% is OS2a (L3), and 9% is OS2b . A portion (20%) of the molecules in the NMB LOS preparation also contained terminally linked sialic acid attached to O-3 of the lacto-N-neotetraose galactosyl residue, which is also consistent with the L3, or L4 LOS structures . In contrast to the previously reported structure of N . meningitidis lipid-A {V . A . Kulshin, U . Zahringer, B . Linder, C.E . Frasch, C-M . Tsai, B.A . Dmitriev, and E.T Rietschel, J . Bacteriol., 174, (1992)1793-1800}, only 30% of the lipid-A from NMB LOS possesses 4'-phosphate . Comparison with the lipid-A of LOS purified from an isogenic acapsulate mutant, M7, revealed that the 4'-position was almost completely occupied with phosphate . These data emphasize the structural heterogeneity of the OS and phosphate substituents of Hep II, and 4'-phosphorylation of lipid-A of meningococcal LOS.

APMIS, 1998 May, 106(5), 505 - 25
Population genetics and molecular epidemiology of Neisseria meningitidis; Caugant DA; Under non-epidemic conditions, Neisseria meningitidis causes disease primarily in children under the age of 5 and the cases are sporadic without any evident relationship between them . Occasionally, localized outbreaks of meningococcal disease occur, and sometimes epidemic waves of disease may spread to several countries or even continents and constitute a pandemic . In the past 10 years or so, population genetic analyses have provided insights into the biology of the bacterium and the epidemiology of meningococcal disease, improving our understanding of the cause of epidemics . Through the application of molecular methods, and especially multilocus enzyme electrophoresis, to N . meningitidis strains of worldwide origin, it has been possible to identify virulent clones and provide a surveillance system to warn of meningococcal epidemics . The characteristics of the predominant clones which are nowadays causing meningococcal disease in the world are summarized here and the importance of population genetics in interpreting the epidemiological data is illustrated.

Lik Sprava, 1998 Mar-Apr, (2), 118 - 21
{The clinical use of Amoxiclav in patients with suppurative meningoencephalitis}; Kononenko VV et al.; Clinical use of Amoxiclav showed high therapeutic efficacy in patients with purulent meningoencephalitis both alone and in combination with cefalosporinum of the first generation . Against the background of treatment of patients with overt manifestations of meningoencephalitis and neurotoxicosis meningeal and encephalitic manifestations got attenuated during the first week, with liquorodynamics being stabilized, cerebrospinal fluid ameliorating by day 8-10 of the disease course . Bacteriologic assays showed that up to 83.4% of bacterial flora most common in Ukraine are sensitive to Amoxiclav, with such pathogenic organisms as Pneumococcus, Meningococcus, hemophilia bacillus that are actually main pathogens implicated in acute meningoencephalitis in Ukraine being sensitive to the above drug preparation in 100% of cases.

Scand J Infect Dis, 1998, 30(1), 69 - 75
Epidemiological markers in Neisseria meningitidis: an estimate of the performance of genotyping vs phenotyping; Weis N et al.; In order to estimate the performance of genotypic vs phenotypic characterization of Neisseria meningitidis, 2 methods, DNA fingerprinting and multilocus enzyme electrophoresis (MEE), were assessed as regards applicability, reproducibility and discriminating capacity . 50 serogroup B and 52 serogroup C Neisseria meningitidis strains from 96 patients with meningococcal disease and 22 serogroup C strains from healthy carriers were investigated . Both methods were 100% applicable to meningococcal strains and results of DNA fingerprinting as well as of MEE were reproducible . The number of types defined by DNA fingerprinting and MEE as compared to that defined by phenotypic characteristics (serogroup, serotype, serosubtype and sulphonamide resistance) was as follows: for serogroup B strains from patients, 11 and 12 vs 8; for serogroup C strains from patients, 10 and 15 vs 8; and for serogroup C carrier strains, 12 and 19 genotypes vs 10 phenotypes were defined . By use of both DNA fingerprinting and MEE the number of genotypes defined for the 3 groups of strains was 14, 17 and 19, respectively . DNA fingerprinting and MEE showed a discriminating capacity superior to that of phenotyping, and as applied in the study MEE was superior to DNA fingerprinting . Clusters of invasive strains were reliably identified by phenotyping alone, whereas determination of identity of carrier strains and an invasive strain required genotyping.

ASDC J Dent Child, 1998 May-Jun, 65(3), 191 - 3
Meningococcal septicemia and disseminated intravascular coagulation affecting the premaxillary permanent tooth germs; Walton AG et al.; The following case describes the dental effects resulting from a case of meningococcal septicemia which caused a disseminated intravascular coagulation and premaxillary osteomyelitis at age two years . The effects went unnoticed for eight years when delayed development of the maxillary incisors was noted . Treatment involved surgical removal of the dental remnants and provision of a removable partial denture . Implants and ridge augmentation will be considered in early adulthood.

Br J Gen Pract, 1998 Apr, 48(429), 1167 - 71
Recognizing meningococcal disease: the case for further research in primary care; Granier S et al.; Most studies describing the clinical presentation of meningococcal disease use data derived from hospital-based studies . This paper reviews current knowledge on the presentation of meningococcal disease from a primary care perspective . In a small proportion of cases with classical features, making the diagnosis may be relatively simple . In many cases, however, the general practitioner (GP) is faced with the difficulty of discriminating between the rare patient with life-threatening illness and the vast majority who present with similar symptoms secondary to self-limiting viral illness . In the absence of reliable means of excluding the disease, GPs will need to consider the possibility of meningococcal disease in all ill and febrile patients in whom no cause is apparent . Planned follow-up and clearer explanation to patients may increase the chance of identifying earlier those cases that evolve with time . More research is required to identify key clinical and contextual features that help GPs to predict or exclude serious disease, and to describe how this information is used in decision-making . A framework for conceptualizing the problems of researching illness is provided, which takes into account the many factors that influence clinical practice in primary care.

J Clin Microbiol, 1998 Aug, 36(8), 2342 - 5
Characterization of Neisseria meningitidis strains causing disease in complement-deficient and complement-sufficient patients; Fijen CA et al.; Serotyping and serosubtyping of meningococci showed no difference between isolates from 44 complement-deficient persons and from 50 complement-sufficient persons with meningococcal disease . Multilocus enzyme electrophoretic typing of the meningococci revealed 54 electrophoretic types that were equally distributed among isolates from complement-deficient and complement-sufficient patients . Analysis of strains isolated from eight complement-deficient persons with 11 recurrences of meningococcal disease showed that one strain was identical to the strain previously isolated from the same individual . Our results indicate that there are no differences between the clonal distributions of strains infecting complement-deficient and complement-sufficient patients . Most recurrences were infections caused by different strains.

J Clin Microbiol, 1998 Aug, 36(8), 2205 - 9
Diagnosis of meningococcal meningitis by broad-range bacterial PCR with cerebrospinal fluid; Kotilainen P et al.; We used broad-range bacterial PCR combined with DNA sequencing to examine prospectively cerebrospinal fluid (CSF) samples from patients with suspected meningitis . Fifty-six CSF samples from 46 patients were studied during the year 1995 . Genes coding for bacterial 16S and/or 23S rRNA genes could be amplified from the CSF samples from five patients with a clinical picture consistent with acute bacterial meningitis . For these patients, the sequenced PCR product shared 98.3 to 100% homology with the Neisseria meningitidis sequence . For one patient, the diagnosis was initially made by PCR alone . Of the remaining 51 CSF samples, for 50 (98.0%) samples the negative PCR findings were in accordance with the negative findings by bacterial culture and Gram staining, as well as with the eventual clinical diagnosis for the patient . However, the PCR test failed to detect the bacterial rRNA gene in one CSF sample, the culture of which yielded Listeria monocytogenes . These results invite new research efforts to be focused on the application of PCR with broad-range bacterial primers to improve the etiologic diagnosis of bacterial meningitis . In a clinical setting, Gram staining and bacterial culture still remain the cornerstones of diagnosis.

Clin Diagn Lab Immunol, 1998 Jul, 5(4), 479 - 85
A modified enzyme-linked immunosorbent assay for measurement of antibody responses to meningococcal C polysaccharide that correlate with bactericidal responses; Granoff DM et al.; The standardized enzyme-linked immunosorbent assay (ELISA) for measurement of serum immunoglobulin G (IgG) antibody responses to meningococcal C polysaccharide has been modified to employ assay conditions that ensure specificity and favor detection primarily of high-avidity antibodies . The modified and standard assays were used to measure IgG antibody concentrations in sera of toddlers vaccinated with meningococcal polysaccharide vaccine or a meningococcal C conjugate vaccine . The results were compared to the respective complement-mediated bactericidal antibody titers . In sera obtained after one or two doses of vaccine, the correlation coefficients, r, for the results of the standard assay and bactericidal antibody titers were 0.45 and 0.29, compared to 0.85 and 0.87, respectively, for the modified assay . With the standard assay, there were no significant differences between the geometric mean antibody responses of the two vaccine groups . In contrast, with the modified assay, 5- to 20-fold higher postvaccination antibody concentrations were measured in the conjugate than in the polysaccharide group . Importantly, the results of the modified assay, but not the standard ELISA, paralleled the respective geometric mean bactericidal antibody titers . Thus, by employing conditions that favor detection of higher-avidity IgG antibody, the modified ELISA provides results that correlate closely with measurements of antibody functional activity that are thought to be important in protection against meningococcal disease.

J Leukoc Biol, 1998 Jul, 64(1), 14 - 8
The bactericidal/permeability-increasing protein (BPI) in antibacterial host defense; Elsbach P; The bactericidal/permeability-increasing protein (BPI) is a 456-residue cationic protein produced only by precursors of polymorphonuclear leukocytes (PMN) and is stored in the primary granules of these cells . The potent (nM) cytotoxicity of BPI is limited to gram-negative bacteria (GNB), reflecting the high affinity (<10 nM) of BPI for bacterial lipopolysaccharides (LPS) . The biological effects of isolated BPI are linked to complex formation with LPS . Binding of BPI to live bacteria via LPS causes immediate growth arrest . Actual killing coincides with later damage to the inner membrane . Complex formation of BPI with cell-associated or cell-free LPS inhibits all LPS-induced host cell responses . BPI-blocking antibodies abolish the potent activity of whole PMN lysates and inflammatory fluids against BPI-sensitive GNB . The antibacterial and the anti-endotoxin activities of BPI are fully expressed by the amino terminal half of the molecule . These properties of BPI have prompted preclinical and subsequent clinical testing of recombinant amino-terminal fragments of BPI . In animals, human BPI protein products protect against lethal injections of isolated LPS and inocula of GNB . Phase I trials in healthy human volunteers and multiple Phase I/II clinical trials have been completed or are in progress (severe pediatric meningococcemia, hemorrhagic trauma, partial hepatectomy, severe peritoneal infections, and cystic fibrosis) and two phase III trials (meningococcemia and hemorrhagic trauma) have been initiated . In none of >900 normal and severely ill individuals have issues of safety or immunogenicity been encountered . Preliminary evidence points to overall benefit in BPI-treated patients . These results suggest that BPI may have a place in the treatment of life-threatening infections and conditions associated with bacteremia and endotoxemia.

Biotechnol Appl Biochem, 1998 Jun, 27 ( Pt 3), 189 - 96
Expression in Escherichia coli of the lpdA gene, protein sequence analysis and immunological characterization of the P64k protein from Neisseria meningitidis; Guillen G et al.; By making use of recombinant DNA technology it is possible to characterize meningococcal outer membrane proteins (OMPs) capable of stimulating a host immune response . The lpdA gene, which codes for an OMP (P64k) from Neisseria meningitidis, was cloned in Escherichia coli . The recombinant protein was recognized by sera from patients convalescing from meningococcal disease . The monoclonal antibodies obtained against the recombinant protein recognized the natural protein on a Western blot, and monoclonal antibody 114 was assayed in ELISA with a panel of 85 N . meningitidis strains . The protein was recognized in 81 strains (95.3%); the strains that were not recognized were neither epidemic nor isolated from systemic disease . The complete amino acid sequence of P64k was obtained by automatic sequencing and MS.

Arq Bras Cardiol, 1998 Feb, 70(2), 115 - 8
{Meningococcemia complicated by myocarditis}; Albanesi Filho FM et al.; We report a case of a 26-year old man with meningococcemia complicated with myocarditis (ventricular dysfunction and myocardial ischemia), that required treatment for heart failure . Regression of myocardial dysfunction was observed six months after the infection.

Pediatr Dermatol, 1998 May-Jun, 15(3), 169 - 83
Acute infectious purpura fulminans: pathogenesis and medical management; Darmstadt GL; Purpura fulminans (PF) is a potentially disabling and life-threatening disorder characterized by acute onset of progressive cutaneous hemorrhage and necrosis, and disseminated intravascular necrosis . Acute infectious PF occurs most commonly in the setting of meningococcemia due to elaboration of endotoxin . Presence of purpura, particularly when generalized, is an important predictor of a poor outcome following meningococcal infection . Histopathologic hallmarks of acute infectious PF are dermal vascular thrombosis and secondary hemorrhagic necrosis, findings which are identical to those of the Shwartzman reaction . Acute infectious PF and the Shwartzman reaction have a common pathogenesis, involving a disturbance in the balance of anticoagulant and procoagulant activities of endothelial cells . This disturbance, which is triggered by endotoxin, appears to be mediated by cytokines, particularly interleukin-12, interferon-gamma, tumor necrosis factor-alpha, and interleukin-1, leading to the consumption of proteins C and S and antithrombin III . State-of-the-art therapeutic interventions based on recent advances in our understanding of the pathogenesis of acute infectious PF are discussed.

J Infect Dis, 1998 Jul, 178(1), 266 - 9
Disco fever: epidemic meningococcal disease in northeastern Argentina associated with disco patronage; Cookson ST et al.; Neisseria meningitidis is a leading cause of adult meningitis worldwide . From 5 to 14 August 1996, 8 cases of meningococcal disease occurred in Corrientes city (population 306,000) in northeastern Argentina . Those infected ranged in age from 15 to 45 years (median, 18.5) . To determine risk factors for infection, a case-control study was done . Infecting isolates were serogrouped and underwent phenotyping by multilocus enzyme electrophoresis (MLEE) and pulsed-field gel electrophoresis (PFGE) . Those infected were significantly more likely than those not infected to have had exposure to passive or active cigarette smoke or to have attended a particular disco . Isolates available from 6 case-patients were all serogroup C; all had identical MLEE and PFGE patterns . These data suggest that dance clubs or discos may be a focus of transmission of N . meningitidis among young people.

Neth J Med, 1998 May, 52(5), 193 - 6
Primary oligoarthritis in a parent of a child with meningococcal group B sepsis and meningitis; Bongers V et al.; The mother of an eight-month-old child with meningitis presented with petechiae on her trunk and lower extremities, fever, and oligoarthritis . Although pathogens were never revealed by Gram stain nor cultured from the aspirated joint fluid, the diagnosis was primary meningococcal arthritis . This diagnosis was based on the simultaneous occurrence of Neisseria meningitidis group B infection in her son and the clinical presentation.

Bull World Health Organ, 1998, 76(2), 149 - 52
Prognostic scores for use in African meningococcal epidemics; Ajayi-Obe EK et al.; Current WHO guidelines for the case management of meningococcal infections during epidemics in developing countries often cannot be applied, largely because of the limited health resources in such countries . Several scoring scales based on clinical and laboratory features in numerous combinations have been developed for the management of meningococcal infections in developed countries, and these have facilitated early identification of patients with fulminant disease and thus early intervention and reduction in mortality . Unfortunately such scoring scales are not appropriate for use in developing countries . We identified hypotension, tachycardia, tachypnoea, delay in capillary refill time, coma, absence of neck stiffness and petechiae and/or purpura as simple prognostic factors of meningococcal disease . Two scores were developed: score I, which includes all seven prognostic factors, had a sensitivity and specificity of 80% and 94%, respectively . Score II, which excluded hypotension, had a sensitivity and specificity of 73.3% and 89.7%, respectively . Quick and simple scoring scales are therefore not only applicable but useful for the case management of patients in meningococcal epidemics in developing countries.

Aust Fam Physician, 1998 Jun, 27(6), 495 - 7
Meningococcal disease . Is early diagnosis possible?
Charlton R.
Meningococcal disease is a public health problem because of its high mortality and is one disease that many GPs have not seen . Case reports illustrate that presentation is rarely classic 'meningitis' and further research is required to enable earlier detection.

Pathology, 1998 May, 30(2), 188 - 91
Detection of decreased penicillin susceptibility in viridans group streptococci; Pottumarthy S et al.; One hundred consecutive clinically significant viridans group streptococcal isolates had their susceptibility to penicillin determined by the penicillin E-test method . The ability of penicillin 2 and 10 unit disks and the oxacillin 1 microg disk to detect reduced penicillin susceptibility, ie; MIC > or = 0.25 microg/ml, in viridans group streptococci was determined by comparing the zone diameters against the penicillin E-test MICs . The sensitivity, specificity and predictive values of previous, existing and proposed interpretative criteria to detect decreased penicillin susceptibility were determined . Thirty-seven per cent of the isolates had reduced susceptibility to penicillin . The previous 1993 NCCLS interpretative criteria for the penicillin 10 unit disk, ie; resistant < or = 27 mm failed to detect 16 of 37 (43%) isolates with reduced penicillin susceptibility . The 1 microg oxacillin disk using existing meningococcal interpretative criteria, ie; resistant < or = 10 mm, failed to detect 11 of 37 (40%) isolates with reduced penicillin susceptibility . When the oxacillin 1 microg disk pneumococcal interpretative criteria were used, ie; resistant < or = 19 mm, all the isolates with reduced penicillin susceptibility were detected but 42 of 63 (67%) susceptible isolates were misclassified as resistant . Based on our data, we set new interpretative criteria to detect all isolates with decreased penicillin susceptibility for each of the three disks . Using our proposed zone diameters to detect decreased penicillin susceptibility of < or = 27 mm for the penicillin 2 unit disk, < or = 35 mm for the penicillin 10 unit disk, and < or = 17 mm for the oxacillin disk, 34 (54%), 44 (70%),and 21 (33%) of the 63 susceptible isolates, respectively, were misclassified as having decreased penicillin susceptibility . Our data show that the oxacillin 1 microg disk is able to detect decreased susceptibility to penicillin in viridans group streptococci with greater specificity than either penicillin 2 or 10 unit disks.

Infect Immun, 1998 Jul, 66(7), 3223 - 31
Immune responses against major outer membrane antigens of Neisseria meningitidis in vaccinees and controls who contracted meningococcal disease during the Norwegian serogroup B protection trial; Wedege E et al.; Sera from vaccinees and controls who contracted serogroup B meningococcal disease during the blinded and open parts of a two-dose protection trial in Norway were compared for antigen-specific and bactericidal antibodies against vaccine strain 44/76 (B:15:P1.7,16) . From 16 of 20 (80%) vaccinees and 26 of 35 (74%) controls, one or more serum samples (n = 104) were collected during the acute phase (1 to 4 days), early convalescent phase (5 to 79 days), and late convalescent phase (8 to 31 months) after onset of disease . Binding of immunoglobulin G (IgG) to the major outer membrane antigens (80- and 70-kDa proteins, class 1, 3, and 5 proteins, and lipopolysaccharide {LPS}) on immunoblots was measured by digital image analysis . Specific IgG levels in vaccinees increased from acute to early convalescent phases, followed by a decline, while controls showed a small increase over time . Vaccinees had significantly higher levels than controls against class 1 and 3 porins and LPS in acute sera, against all antigens during early convalescence, and against class 1 and 3 porins in the later sera . Vaccinees who were infected with strains expressing subtype P1.7,16 proteins demonstrated a level of IgG binding to protein P1.7,16 with early-convalescent-phase sera that was fourfold higher than that of those infected with other strains . Bactericidal titers in serum against the vaccine strain were 192-fold higher for vaccinees than those for controls during early convalescence, but similarly low levels were found during late convalescence . A vaccine-induced anamnestic response of specific and functional antibody activities was thus shown, but the decrease in protection over time after vaccination indicated that two vaccine doses did not induce sufficient levels of long-term protective antibodies.

Infect Immun, 1998 Jul, 66(7), 3218 - 22
Immunological and molecular characterization of three variant subtype P1.14 strains of Neisseria meningitidis; Saunders NB et al.; Epidemic outbreaks of group B meningococcal disease exhibit a clonal nature consisting of a common serotype-subtype . Subtype-specific monoclonal antibodies (MAbs) directed toward two variable regions (VR1 and VR2) of the class 1 protein of Neisseria meningitidis are used in this classification scheme . A new MAb was developed to classify a nonsubtypeable (NST) strain of N . meningitidis, 7967 . This MAb bound to both the NST strain and the prototype subtype P1 . 14 strain, S3446, by dot blot analysis . However, a MAb produced to the prototype P1.14 strain did not bind to strain 7967 . Sixteen additional strains were further identified as P1.14 with the prototype MAb; of these, 15 strains bound both MAbs . Differences in the characteristics of binding of both antibodies to the three apparently diverse P1.14 strains were studied further by using outer membrane complex proteins, immobilized peptides, and soluble peptides . Deduced amino acid analysis suggested that both MAbs bind to VR2 and that single amino acid changes within VR2 (KM, NM, or KK) might explain the differences in binding characteristics . These results demonstrated that minor variations which exist within subtype variable regions may be clearly identified only by a combination of molecular and immunologic testing . The impact of subtype variation will become more evident as subtype-specific vaccines are developed and tested for efficacy.

Pediatr Radiol, 1998 Jun, 28(6), 426 - 8
Preamputation MR imaging in meningococcemia and comparison to conventional arteriography; Hogan MJ et al.; Meningococcemia is a life-threatening infection which produces purpura fulminans and extremity gangrene in its most severe form . In patients with gangrene, amputation is usually necessary . The amputations frequently need revision as ischemic changes in the underlying soft tissues and bone are difficult to evaluate at the time of surgery . These ischemic changes often have non-vascular distributions and progress over time . We present two patients in whom MR imaging and MR angiography were performed prior to planned amputation . These cases demonstrate the potential utility of MR imaging in this setting, and compare the MR angiographic results to conventional arteriography in one of these patients.

Eur J Clin Microbiol Infect Dis, 1998 Feb, 17(2), 85 - 9
Increasing incidence of meningococcal disease in Spain associated with a new variant of serogroup C; Berron S et al.; Serogroup B has been the main cause of meningococcal disease in Spain since at least 1979, but in recent years an increase in the prevalence of infection due to serogroup C meningococci has been detected . In 1996, for the first time, most cases of meningococcal disease were caused by serogroup C strains . The sero/subtype of all serogroup C meningococci received from 1993 to June 1996 was determined, and the results showed that C:2b:P1.2,5, the most common phenotype in 1995 and 1996 (63% and 65%, respectively), represented only 4.8% of strains in 1993 . The C:2b: P1.2,5 epidemic strains appear to be responsible for the high prevalence of serogroup C in Spain . One hundred fifty-one randomly selected serogroup C strains were analyzed by multilocus enzyme electrophoresis, ribotyping, and pulsed-field gel electrophoresis . Pulsed-field gel electrophoresis provided the most accurate information: more than 80% of the C:2b:P1.2,5 and C:2b:P1.2 isolates exhibited one of two very closely related profiles, while most of the C:2b:NST and C:2b:P1.5 strains had a pattern located at a genetic distance of 0.24 from those two profiles . The results show that C:2b:P1.2,5 strains represent a subclone or a genetic variant of the previously identified Spanish epidemic clone C:2b:non-subtypable strains.

Arq Neuropsiquiatr, 1997 Sep, 55(3B), 632 - 5
{Acute disseminated encephalomyelitis and meningococcal A and C vaccine: case report}; Py MO et al.; A 25-year-old women developed acute disseminated post-vaccinal encephalomyelitis (ADEM) following vaccination with A plus C meningococcal vaccine (Pasteur-Merieux) . Fast disappearance of symptoms and gradual resolution of MRI demyelinating lesions occurred after steroid treatment with high doses of intravenous methylprednisolone . To our knowledge, ADEM has not been previously described in association with meningococcal vaccine . Although most cases of ADEM occur following viral infections and vaccination, the syndrome has previously been related to leptospirosis and Mycoplasma pneumoniae infections . This suggests that it may also be related to exposure to polysaccharide-protein vaccines such as the Group A plus Group C meningococcal vaccine.

Arq Neuropsiquiatr, 1997 Sep, 55(3B), 584 - 7
{Clinical and laboratory characteristics of pyogenic meningitis in adults}; Gomes I et al.; We reviewed the charts of 176 adult patients, admitted with a diagnosis of acute bacterial meningitis, in the Hospital Couto Maia, from January 1990 to December 1992 . All the patients had community-acquired meningitis . In 120 patients we could identify the causative agent on Gram's staining and culture . The most common pathogens were N . meningitidis (56.7%) S . pneumoniae (37.5%) and E . coli (3.3%) . The overall lethality rate was 19.8% and the lethality was greater in the group with streptococcus meningitis (31.8%) . The mean age and the leukocyte in the peripheral blood were greater in the group with S . pneumoniae meningitis than in the meningococal group . Cutaneous hemorrhagic lesions was and excellent predictor meningococcal meningitis.

FEMS Microbiol Lett, 1998 May 15, 162(2), 215 - 8
False positive diagnosis of meningococcal infection by the IS1106 PCR ELISA; Borrow R et al.; At a time when optimal case ascertainment for meningococcal infection is a high priority, the need for non-culture case confirmation, in particular by DNA amplification, is seen as being of vital importance to assist contact management and cluster recognition . A solution hybridisation assay with colorimetric microtitre plate detection (polymerase chain reaction-enzyme-linked immunosorbent assay (PCR ELISA) inverted question mark has been developed using the multicopy insertion sequence IS1106 which had reportedly achieved a specificity of 100% and was described as being meningococcal specific . This PCR ELISA assay was evaluated on specimens from over 5000 patients at the national Meningococcal Reference Unit (MRU) between late 1995 and early 1997 and was found to be highly sensitive . Insertion sequences, however, are genetically mobile with the ability to spread between species and even genera . During the evaluation period of the IS1106 PCR ELISA a number of false positives proved to be caused by organisms other than N . meningitidis were recorded resulting in the withdrawal of this assay as a front line screening assay for routine confirmation of meningococcal infection.

Ann Trop Med Parasitol, 1997 Oct, 91(7), 777 - 85
Meningococcal disease in Africa; Hart CA et al.; Neisseria meningitidis (the meningococcus) is responsible for endemic and meningococcal disease in Africa . Meningococci are placed into 12 serogroups based on their capsular polysaccharide antigens . Group-B meningococci are responsible for sporadic endemic disease . In the meningitis belt of sub-Saharan Africa, the large spreading epidemics which occur every 5-10 years are usually caused by group-A meningococci, with attack rates of 400-500/100,000 population . In the last epidemic, infection spread from the original meningitis belt to Kenya, Uganda, Rwanda, Zambia and Tanzania . Most cases of meningococcal disease are of meningitis and meningococcal septicaemia is a rare presentation except in South Africa . It is important to exclude meningococcal septicaemia since this carries the highest mortality (up to 75%) . Treatment involves intravenous chloramphenicol (or intramuscular, oily chloramphenicol), a drug which is preferable to penicillin because penicillin-resistant meningococci have already emerged in Africa . Dexamethasone treatment of meningococcal meningitis is unproven and may even be deleterious in developing countries . Prevention of epidemic meningococcal disease could be achieved by mass vaccination with protein-conjugate, group-A and -C polysaccharides, but these new vaccines are likely to be expensive.

Clin Infect Dis, 1998 Apr, 26(4), 918 - 23
Plasma patterns of tumor necrosis factor-alpha (TNF) and TNF soluble receptors during acute meningococcal infections and the effect of plasma exchange; van Deuren M et al.; In 39 patients with acute meningococcal infections, the plasma concentrations of tumor necrosis factor-alpha (TNF) and its soluble receptors (sRs) TNFsR-p55 and TNFsR-p75 were measured from admission till recovery . At admission, patients with shock had significantly higher TNF, TNFsR-p55, and TNFsR-p75 values than patients without shock . In addition, during the first 24 hours, patients with shock had higher TNFsR-p75 to TNFsR-p55 ratios, indicating that in shock the increase of TNFsR-p75 exceeds that of TNFsR-p55 . TNF measured more than 12 hours after admission failed to differentiate between shock and nonshock because TNF concentrations normalized within 12-24 hours . However, because concentrations of TNFsRs remained elevated for 5-6 days, at that time plasma TNFsRs still differentiated between shock and nonshock . Plasma exchange or whole blood exchange (PEBE), performed in 20 patients with shock, accelerated the decrease of plasma TNFsRs . However, because of a rebound after each PEBE session, the overall half-lives of both TNFsRs were not affected by PEBE.

Int J Infect Dis, 1998 Jan-Mar, 2(3), 137 - 42
Meningococcal meningitis among Rwandan refugees: diagnosis, management, and outcome in a field hospital; Heyman SN et al.; OBJECTIVE: To study the diagnostic process, clinical course, and outcome of Rwandan refugees with meningococcal meningitis, treated in an Israeli field hospital in Goma, Zaire, in the summer of 1994 . METHODS: Patient hospital charts and laboratory records were reviewed with critical evaluation of clinical presentation and diagnostic tests . Patients were treated as part of a disaster relief effort in a refugee camp experiencing several coexisting lethal epidemics . RESULTS: A total of 65 patients were identified as having group A meningococcal meningitis . Latex agglutination test for Neisseria meningitidis soluble antigen in the cerebrospinal fluid was found to be a superior diagnostic tool, as compared to Gram stain, and at least as effective as culture . The mortality rate was 14%; mortality was markedly affected by co-morbidity (e.g., dysentery, pneumonia, and malnutrition) . CONCLUSIONS: The outcome of patients with meningococcal meningitis, treated in referral centers within a disaster area may be favorable, despite overwhelming coexisting epidemics, and may be comparable to that achieved in advanced medical facilities . Encephalopathy may be a diagnostic pitfall in the perspective of coexisting epidemics, requiring a high index of suspicion and routine lumbar puncture . The latex agglutination test is highly useful in achieving prompt diagnosis of meningococcal meningitis, in particular when sample handling for culture and microscopy is suboptimal.

J Clin Microbiol, 1998 Jun, 36(6), 1746 - 9
Randomly amplified polymorphic DNA genotyping of serogroup A meningococci yields results similar to those obtained by multilocus enzyme electrophoresis and reveals new genotypes; Bart A et al.; Randomly amplified polymorphic DNA (RAPD) genotyping was applied to one representative strain of each of the 84 electrophoretic types (ETs) of Neisseria meningitidis serogroup A previously defined by multilocus enzyme electrophoresis (MEE) (J.-F . Wang et al., Infect . Immun . 60:5267-5282, 1992) . Twenty-seven additional isolates comprising six ETs were also tested . MEE and RAPD genotyping yielded similar dendrograms at the subgroup level . Similar results were obtained by both methods for 18 serogroup A meningococci isolated in The Netherlands between 1989 and 1993 . Ten of these isolates defined a new subgroup, designated subgroup IX . One isolate belonged to the ET-5 complex, normally associated with serogroup B strains (D . A . Caugant et al., Proc . Natl . Acad . Sci . USA 83:4927-4931, 1986) . By RAPD genotyping, meningococci can be linked to previously characterized genotypes by using a computerized database, and dendrograms based on cluster analyses can easily be generated . RAPD analysis offers advantages over MEE since intermediate numbers of isolates of serogroup A meningococci can quickly be assigned to known subgroups and new subgroups can be defined.

Drugs, 1998 Jun, 55(6), 767 - 77
Current drug treatment strategies for disseminated intravascular coagulation; de Jonge E et al.; Disseminated intravascular coagulation (DIC) can be caused by a variety of diseases . Experimental models of DIC have provided substantial insight into the pathogenesis of this disorder, which may ultimately result in improved treatment . Disseminated coagulation is the result of a complex imbalance of coagulation and fibrinolysis . Simultaneously occurring tissue factor-dependent activation of coagulation, depression of natural anticoagulant pathways and shutdown of endogenous fibrinolysis all contribute to the clinical picture of widespread thrombotic deposition in the microvasculature and subsequent multiple organ failure . Cornerstone for the treatment of DIC is the optimal management of the underlying disorder . At present, specific treatment of the coagulation disorders themselves is not based on firm evidence from controlled clinical trials . Plasma and platelet transfusion are used in patients with bleeding or at risk for bleeding and low levels of coagulation factors or thrombocytopenia . The role of heparin and low molecular weight heparin is controversial, but their use may be justified in patients with active DIC and clinical signs of extensive fibrin deposition such as those with meningococcal sepsis . There is some evidence to indicate that low molecular weight heparin is as effective as unfractionated heparin but may be associated with a decreased bleeding risk . Antithrombin III (AT III) replacement appears to be effective in decreasing the signs of DIC if high doses are administered, but effects on survival or other clinically significant parameters are at best uncertain . If AT III supplementation is used, the dosage should be selected to achieve normal or supranormal plasma levels of 100% or higher . Results of studies on protein C concentrate, thrombomodulin or inhibitors of tissue factor are promising, but the efficacy and safety of these novel strategies remains to be established in appropriate clinical trials.

Glycobiology, 1998 Apr, 8(4), 359 - 65
Characterization of terminal NeuNAcalpha2-3Galbeta1-4GlcNAc sequence in lipooligosaccharides of Neisseria meningitidis; Tsai CM et al.; Group B and C Neisseria meningitidis are the major cause of meningococcal disease in the United States and in Europe . N . meningitidis lipooligosaccharide (LOS), a major surface antigen, can be divided into 12 immunotypes of which L1 through L8 were found among Group B and C organisms . Groups B and C but not Group A may sialylate their LOSs with N-acetylneuraminic acid (NeuNAc) at the nonreducing end because they synthesize CMP-NeuNAc . Using sialic acid-galactose binding lectins as probes in an ELISA format, six of the eight LOS immunotypes (L2, L3, L4, L5, L7, and L8) in Groups B and C bound specifically to Maackia amurensis leukoagglutinin (MAL), which recognizes NeuNAcalpha2-3Galbeta1-4GlcNAc/Glc sequence, but not to Sambucus nigra agglutinin, which binds NeuNAcalpha2-6Gal sequence . The combination of SDS-PAGE and MAL-blot analyses revealed that these six LOSs contained only the NeuNAcalpha2-3Galbeta1-4GlcNAc trisaccharide sequence in their 4.1 kDa LOS components, which have a common terminal lacto-N-neotetraose (LNnT, Galbeta1-4GlcNAcbeta1-3Galbeta1-4Glc) structure when nonsialylated as shown by previous studies . The LOS-lectin binding was abolished when the LOSs were treated with Newcastle disease viral neuraminidase which cleaves alpha2-->3 linked sialic acid . Methylation analysis of a representative LOS (L2) confirmed that NeuNAc is 2-->3 linked to Gal . Thus, these LOSs structurally mimic certain glycolipids, i.e., paragloboside (LNnT-ceramide) and sialylparagloboside and some glycoproteins in having LNnT and N-acetyllactosamine sequences, respectively, with or without alpha2-->3 linked NeuNAc . The molecular mimicry of the LOSs may play a role in the pathogenesis of N.meningitidis by assisting the organism to evade host immune defenses in man.

J Infect Dis, 1998 Jun, 177(6), 1754 - 7
Serogroup B, electrophoretic type 15 Neisseria meningitidis in Canada; Kertesz DA et al.; Invasive meningococcal disease is nationally reportable in Canada . In recent years, a serogroup C genotype, designated electrophoretic type 15 (ET15), has been the most frequently isolated meningococcal genotype in Canada and has caused epidemics across the country . Between August 1993 and September 1995, there were 9 cases of invasive meningococcal disease caused by a variant of this genotype, expressing group B capsular polysaccharide . The appearance of serogroup B:ET15 was related temporally and geographically to mass immunization campaigns designed to control serogroup C meningococcal disease in Canada . Since there is no vaccine available to control serogroup B meningococcal disease, the appearance of this variant may have public-health significance if it demonstrates the same epidemic potential as its serogroup C counterpart.

J Infect Dis, 1998 Jun, 177(6), 1614 - 21
Avidity of IgG for Streptococcus pneumoniae type 6B and 23F polysaccharides in infants primed with pneumococcal conjugates and boosted with polysaccharide or conjugate vaccines; Anttila M et al.; Relative avidity of IgG to Streptococcus pneumoniae type 6B and 23F polysaccharides (PSs) was measured in sera of children immunized with pneumococcal vaccines, using an EIA and the chaotropic agent thiocyanate . Infants were immunized at 2, 4, and 6 months of age with pneumococcal PS-diphtheria toxoid conjugate vaccine, and boosted at 14 months with the homologous conjugate or a pneumococcal PS vaccine . The concentrations of antibodies to 6B and 23F PSs increased significantly after the booster with both vaccines . A significant increase in the avidity of anti-6B and anti-23F antibodies was seen after the booster with conjugate but not with PS vaccine . Avidity also increased in another group of infants primed and boosted with pneumococcal PS-meningococcal protein conjugate but not in a group boosted with PS vaccine after priming with pneumococcal PS-tetanus toxoid conjugate . In the latter group, however, the avidity of anti-6B was high before boosting.

Clin Diagn Lab Immunol, 1998 May, 5(3), 348 - 54
Correlation between serological and sequencing analyses of the PorB outer membrane protein in the Neisseria meningitidis serotyping system; Sacchi CT et al.; The current serological typing scheme for Neisseria meningitidis is not comprehensive; a proportion of isolates are not serotypeable . DNA sequence analysis and predicted amino acid sequences were used to characterize the structures of variable-region (VR) epitopes on N . meningitidis PorB proteins (PorB VR typing) . Twenty-six porB gene sequences were obtained from GenBank and aligned with 41 new sequences . Primary amino acid structures predicted from those genes were grouped into 30 VR families of related variants that displayed at least 60% similarity . We correlated VR families with monoclonal antibody (MAb) reactivities, establishing a relationship between VR families and epitope locations for 15 serotype-defining MAbs . The current panel of serotype-defining MAbs underestimates by at least 50% the PorB VR variability because reagents for several major VR families are lacking or because a number of VR variants within some families are not recognized by serotype-defining MAbs . These difficulties, also reported for serosubtyping based on the PorA protein, are shown as inconsistent results between serological and sequence analyses, leading to inaccurate strain identification and incomplete epidemiological data . The information from this study enabled the expansion of the panel of MAbs currently available for serotyping, by including MAbs of previously undetermined specificities . Use of the expanded serotype panel enabled us to improve the sensitivity of serotyping by resolving a number of formerly nonserotypeable strains . In most cases, this information can be used to predict the VR family placement of unknown PorB proteins without sequencing the entire porB gene . PorB VR typing complements serotyping, and a combination of both techniques may be used for full characterization of meningococcal strains . The present work represents the most complete and integrated data set of PorB VR sequences and MAb reactivities of serogroup B and C meningococci produced to date.

Infect Immun, 1998 Jun, 66(6), 3017 - 23
Identification and molecular analysis of lbpBA, which encodes the two-component meningococcal lactoferrin receptor; Lewis LA et al.; We identified lbpB, encoding the lipoprotein component of the meningococcal lactoferrin receptor . An LbpB mutant was unable to acquire Fe from lactoferrin and exhibits decreased surface binding to lactoferrin . Primer extension and reverse transcription-PCR analysis indicate that lbpB and lbpA are cotranscribed on a polycistronic Fe-repressible mRNA.

Scand J Immunol, 1998 Apr, 47(4), 388 - 96
Opsonophagocytic and bactericidal activity mediated by purified IgG subclass antibodies after vaccination with the Norwegian group B meningococcal vaccine; Aase A et al.; To study how the different immunoglobulin (Ig)G subclass antibodies may confer protection against systemic meningococcal disease, we isolated IgG1, IgG2 and IgG3 antibodies from plasma from vaccinees immunized with the Norwegian meningococcal outer membrane vesicle vaccine . Four IgG1, one IgG2 and four IgG3 preparations were purified . The IgG2 and IgG3 subclass preparations were free from contaminating subclasses, whereas the IgG1 preparations contained from 0 to 14% of IgG2 and/or IgG3 . Immunoblotting against whole-cell meningococcal antigens showed broad specificities of the various preparations, both within and between subclasses . These subclass preparations were tested for opsonophagocytic and bactericidal activity . As targets we used two different variants of the meningococcal vaccine strain, with low (44/76-SL) and high (44/76-1) expression of the outer membrane protein Opc . Using polymorphonuclear leucocytes as effector cells in the presence of human complement, all three IgG subclass preparations revealed high, and similar, opsonophagocytic activities against 44/76-SL, whereas against 44/76-1 the IgG2 preparation showed a reduced activity and most IgG3 preparations were slightly more active than the IgG1 preparations . Regarding bactericidal activity, all the three subclasses were highly active against 44/76-SL . Against 44/76-1 the bactericidal activities were somewhat more varied: all IgG1 and three IgG3 preparations exhibited higher activities than against 44/76-SL . Due to the low concentration in the IgG2 preparations, only a weak activity was seen against 44/76-1 . One IgG3 preparation that was highly opsonophagocytic revealed no bactericidal activity against either of the two bacterial variants examined . In conclusion, we have shown that the IgG subclass effector functions differ from person to person, but that antibodies of IgG1, IgG2 and IgG3 subclasses, judged by their behaviour in the functional tests, may all contribute to protection against meningococcal disease.

Clin Infect Dis, 1998 May, 26(5), 1159 - 64
Complications and sequelae of meningococcal disease in Quebec, Canada, 1990-1994; Erickson L et al.; To study complications and sequelae of serogroup B and C meningococcal disease, a retrospective survey examined the outcome of all culture-proven cases reported in the province of Quebec, Canada, from January 1990 through December 1994 (serogroup B, 167 cases; serogroup C, 304 cases) . Data were collected from medical files, postal questionnaires, and telephone interviews . Age groups having the most cases were the 10-19-year age group for serogroup C and the < 1-year age group for serogroup B . Fatality rates were 7% for serogroup B and 14% for serogroup C disease . Only 3% of survivors of serogroup B disease had physical sequelae, compared with 15% of survivors of serogroup C disease (skin scars, 12%; amputations, 5%; hearing loss, 2%; renal problems, 1%; and other sequelae, 4%) . These results confirm the gravity of disease caused by serogroup C, serotype 2a Neisseria meningitidis and justify liberal use of vaccination for outbreak control.

Croat Med J, 1998 Mar, 39(1), 62 - 5
Familial epidemic of meningococcal disease; Smilovic V et al.; Two closely related boys from the same house hold (Home 1), aged two and three, were affected with fulminant meningococcal sepsis known as Waterhouse-Friderichsen syndrome . Neisseria meningitidis serogorup B was isolated from their blood and cerebrospinal fluid . The two-year-old boy died one day after the onset of the disease . Epidemiological examination of contacts and pharyngeal swabs were performed in 14 persons from the household, all of them relatives of the affected children, as well as in a number of other contacts . Chemoprophylaxis with cotrimoxazole was simultaneously administered to all contacts . Family histories revealed that two contacts from the household where the patients did not live (Home 2) were inadvertently omitted . Subsequent examinations, following a report of another contagious disease (salmonelosis), revealed that these two persons were Neisseria meningitidis carriers, together with another one in the same household . The carriers most probably caused the infection of a third, five-year-old boy, the deceased boy's brother (Home 1) who also developed fulminant meningococcal sepsis . The failure to take the appropriate prophylaxis led to a prolonged carrier state in the carrier from the second household . Repeated pharyngeal swab sampling revealed two more carriers from both households that had previously been negative . Control of the epidemic was achieved after 5 weeks by repeated and controlled chemoprophylaxis with ciprofloxacin, and by repeated epidemiological examinations, disinfection, and daily health surveillance by the Sanitary Inspectorate . This extremely rare instance of a familial epidemic with three infected persons emphasizes the need for consistent chemoprophylaxis in meningococcal disease contacts.

Rev Saude Publica, 1997 Aug, 31(4), 402 - 16
{Immunologic behavior of meningococcal vaccines}; Requejo HI; Meningococcal disease continues to be a great health problem on all continents and the meningococcal vaccines have been proposed for their prevention and epidemic control . The polysaccharide A and C vaccines are relatively efficacious with distinct immunological behavior with regard to the different age groups, however, up to the present no highly efficacious vaccine for meningococcal B disease exists . The meningococcal B capsular polysaccharide is not immunogenic due to the structural mimicry of mammalian tissues and efforts to produce carrier proteins have been proposed in order to obtain an immunogenic vaccine for all age groups that would if possible, protect against all the meningococci . This review of the literature presents the study of the development of the immunological behavior of all the meningococcal vaccines undergoing development and reports on the efforts to obtain a safe and efficacious product for the control of meningococcal disease.

FEMS Microbiol Lett, 1998 May 1, 162(1), 25 - 30
Identification of a human cDNA clone that mediates adherence of pathogenic Neisseria to non-binding cells; Jonsson AB; Neisseria gonorrhoeae and Neisseria meningitidis are exclusively human pathogens . A crucial property of the pathogenicity of neisserial infection is the ability to adhere to human epithelial cells . Pili mediate adherence of these bacteria to target cells and thereby promote colonization and infection of mucosal surfaces . In order to identify and to learn more about the initial event during infection, a cDNA clone from a human cervical epithelial cell line was identified in a panning experiment using purified gonococcal pili as probe . Upon transfection of the cloned cDNA into COS-7 cells, both gonococci and meningococci adhered to these otherwise non-binding cells . The deduced amino acid sequence of the cDNA clone showed homology to a recently reported human cDNA, called WWP2, that encodes an N-terminal C2-like domain . The C2 domain has been shown to bind membrane phospholipids in a calcium-dependent manner and is thought to function in the intracellular compartmentalization of proteins . Antiserum raised against the product encoded by the cDNA did not inhibit bacterial adherence, indicating that the cloned gene is most likely involved in up-regulation of a surface receptor for pathogenic Neisseria.

J Infect Dis, 1998 May, 177(5), 1401 - 5
Posttranscriptional down-regulation of tumor necrosis factor-alpha and interleukin-1beta production in acute meningococcal infections; van Deuren M et al.; The regulation of tumor necrosis factor-alpha (TNF) and interleukin-1beta (IL-1beta) production was studied in patients with meningococcal disease . Circulating TNF and IL-1beta normalized within 1 day . TNF mRNA and IL-1beta mRNA in white blood cells decreased over 3-4 days . During the acute stage, TNF and IL-1beta production in stimulated whole blood cultures was down-regulated . After 4-5 days, this production was restored . The down-regulation was unlikely to be caused by circulating IL-6 and IL-10, as these cytokines normalized within 2-3 days . TNF mRNA in stimulated cultures during the acute stage, with down-regulated production, did not differ from that at recovery, with restored production . In contrast, the down-regulated production of IL-1beta was associated with significantly lower IL-1beta mRNA levels . Thus, TNF and IL-1beta production are differentially regulated . Whereas TNF production is regulated posttranscriptionally, IL-1beta production is also regulated at the mRNA level.

Crit Care Med, 1998 May, 26(5), 965 - 8
Protein C in the treatment of coagulopathy in meningococcal disease; Rintala E et al.; OBJECTIVE: To evaluate the clinical and laboratory effects of the substitution of protein C (PC) as an adjunct to conventional therapy in the treatment of purpura fulminans associated with meningococcal sepsis . DESIGN: case series . SETTING: Medical and medical-surgical intensive care units of two university hospitals . PATIENTS: Three patients with purpura fulminans and multiple organ failure caused by Neisseria meningitidis . INTERVENTION: Intravenous administration of PC concentrate (100 IU/kg every 6 to 8 hrs) . MEASUREMENTS AND MAIN RESULTS: The administration of PC resulted in normal or above normal levels of the plasma PC activity in all patients . The laboratory and clinical parameters reflecting the severity of coagulopathy improved during the treatment, as did peripheral ischemia and the clinical manifestations of multiple organ failure . No adverse events were noted . One patient died of cerebral edema . CONCLUSION: The administration of PC had a beneficial effect on coagulopathy and peripheral gangrene formation associated with meningococcal disease and showed no adverse effects.

J Immunol, 1998 May 15, 160(10), 5028 - 36
Bactericidal monoclonal antibodies that define unique meningococcal B polysaccharide epitopes that do not cross-react with human polysialic acid; Granoff DM et al.; The poor immunogenicity of the Neisseria meningitidis group B polysaccharide capsule, a homopolymer of alpha(2-->8) sialic acid, has been attributed to immunologic tolerance induced by prenatal exposure to host polysialyated glycoproteins . Substitution of N-propionyl (N-Pr) for N-acetyl groups on the meningococcal B polysaccharide, and conjugation of the resulting polysaccharide to a protein carrier, have been reported to yield a conjugate vaccine that elicits protective Abs with minimal autoantibody activity . To characterize the protective epitopes on the derivatized polysaccharide, we isolated 30 anti-N-Pr meningococcal B polysaccharide mAbs . These Abs were heterogeneous with respect to complement-mediated bactericidal activity, fine antigenic specificity, and autoantibody activity as defined by binding to the neuroblastoma cell line, CHP-134, which expresses long-chain a(2-->8)-linked polysialic acid . Eighteen of the Abs could activate complement-mediated bacteriolysis . Seven of these 18 Abs cross-reacted with N-acetyl meningococcal B polysaccharide by ELISA and had strong autoantibody activity . Thus, N-Pr meningococcal B polysaccharide conjugate vaccine has the potential to elicit autoantibodies . However, 7 of the 18 bactericidal mAbs had no detectable autoantibody activity . These Abs may be useful for the identification of molecular mimetics capable of eliciting protective Abs specific to the bacteria, without the risk of evoking autoimmune disease.

Electrophoresis, 1998 Apr, 19(4), 593 - 6
Microevolution during epidemic spread of Neisseria meningitidis; Achtman M; Similar to many other naturally transformable bacteria, Neisseria meningitidis has yielded many examples where horizontal genetic exchange has resulted in genetic variation of individual strains . Epidemic strains are purified of genetic variants due to bottlenecks during the spread from country to country, resulting in clonal descent . Occasionally, clonal replacement also occurs during epidemic spread . These processes occur rapidly in serogroup A meningococci; such that after their descent from a common ancestor, clonally related bacteria have diversified at numerous loci within the last decades.

Electrophoresis, 1998 Apr, 19(4), 577 - 81
Comparison of the genome organization of pathogenic neisseriae; Bautsch W; Current efforts to completely sequence the meningococcal and gonocococcal genomes raise the question whether the lessons learned from the sequenced strains may be safely extrapolated to other members of these species, or whether, in view of the fact that Neisseriae are highly recombinogenic and exhibit a high degree of horizontal intra- and interspecies genetic transfer, only clone-specific conclusions are valid . From the known physical and genetic maps of each of two gonococcal and meningococcal strains, it would appear that both species exhibit a species-specific conservation in their genetic organization while the interspecies comparison revealed several rearrangements, although still with a high overall similarity . However, these data contrast with other evidence suggesting intra-species rearrangements, such as the nonconserved I-CeuI macrorestriction patterns of different meningococcal and other neisserial strains . Since I-CeuI cuts within the 23S-rRNA sequence, the restriction pattern should give reliable information on the distribution of rrn loci in the neisserial genomes . Further studies are warranted to answer these questions.

An Esp Pediatr, 1997 Nov, 47(5), 466 - 72
{Multicenter prospective study on severe bacterial meningitis in children}; Casado Flores J et al.; We prospectively studied the epidemiologic, clinic signs and outcome of bacterial meningitis in 125 children who were admitted into a PICU (Pediatric Intensive Care Unit) of 11 hospitals of Spain and whose meningitis was diagnosed between May 1994 and April 1995 . RESULTS: The median age of the children was 3.55 +/- 3.32 years (range 1 month to 16.5 yrs) . Eighty-eight were bacterial meningitis, probably bacterial 30 and aseptic 7 . The most frequently isolated organisms were N . meningitidis (52), H . influenza type b (17) and S . pneumoniae (8) . Twenty-five percent of N . meningitidis had C serotype . Incidence rate of each germen was depending of age . All patients diagnosed of H . influenza type b meningitis were less than 3 years old . H . influenza type b and meningococcus had similar incidence rate during the first year of life (27% versus 31%) . During the first three years of life H . influenza type b produced one third of bacterial meningitis . A mortality rate of 5.6% (seven patients: 3 S . pneumoniae, 1 N . meningitidis, 1 H . influenza type b and 2 unknown germen) was observed . Patients who die had lower Glasgow coma score (p = 0.034) and seizures (p = 0.001) at admission . At discharge of PICU, 9 survivors (7.2%) had sequelae: mental retardation in 7 patients and hearing loss in two . One third of patients needed hemodynamic support and a 15% of them ventilatory support . CONCLUSIONS: Age is an important epidemiological factor in the etiology of pediatric acute meningitis . H . influenza type b and N . meningitidis had similar incidence rate during the first year of life . S . pneumoniae had the highest mortality rate (37.5%) . The presence of coma and seizures at admission were associated with mortality.

Dev Biol Stand, 1998, 92, 269 - 76
Influence of several adjuvants on the immune response against a recombinant meningococcal high molecular weight antigen; Gonzalez S et al.; Studying outer membrane proteins as vaccine candidates, our group has previously isolated, cloned, and expressed in Escherichia coli the gene encoding for a high molecular weight protein (P64k), common to many meningococcal strains . To continue the characterisation of this meningococcal antigen, we have evaluated its immunogenicity in mice alone or combined with several commercially-available adjuvants . We used as an adjuvant aluminium hydroxide (Alhydrogel and Rehydragel), aluminium phosphate, Algammulin, crude saponin, the saponin Quil A, dimethyl-dioctadecyl ammonium bromide (DDA), Freund's adjuvant, and Montanide 888 . The antibody titres against the recombinant protein and whole meningococci elicited with these adjuvants were compared . We found that Quil A produced the highest titres against the recombinant P64k . Algammulin and the quaternary ammonium compound DDA induced the highest levels of antibodies against meningococci . We analysed the recognition of a set of linear peptides by antisera prepared against the protein combined with some of the adjuvants . The responses depended on the adjuvant used and the results have been confirmed by epitope mapping using overlapping peptides synthesised on pins.

J Immunol, 1998 Feb 1, 160(3), 1509 - 13
A non-sense mutation at Arg95 is predominant in complement 9 deficiency in Japanese; Horiuchi T et al.; Deficiency of the ninth component of complement (C9D) is one of the most common genetic abnormalities in Japan, with an incidence of one homozygote in 1000 . Although C9D individuals are usually healthy, it has been shown that they have an significantly increased risk of developing meningococcal meningitis . In the present study we report the molecular bases for C9D in 10 unrelated Japanese subjects . As a screening step for mutations, exons 2 to 11 of the C9 gene were analyzed using exon-specific PCR/single-strand conformation polymorphism analysis, which demonstrated aberrantly migrating DNA bands in exon 4 in all the C9D subjects . Subsequent direct sequencing of exon 4 of the C9D subjects revealed that eight of the 10 C9D subjects were homozygous for a C to T transition at nucleotide 343, the first nucleotide of the codon CGA for Arg95, leading to a TGA stop codon (R95X) . R95X is a novel mutation different from those recently identified in a Swiss family with C9D . Cases 6 and 7 were heterozygous for the R95X mutation . Family study in case 10 confirmed the genetic nature of the defect . In case 6, the second mutation for C9D of the C9 gene was identified to be the substitution of Cys to Tyr at amino acid residue 507 (C507Y), while the genetic defect(s) in the other allele in case 7 remains unknown . Our results indicate that a novel mutation, R95X, is present in most cases of C9D in Japan.

Mol Microbiol, 1998 Mar, 27(6), 1203 - 12
Neisseria meningitidis producing the Opc adhesin binds epithelial cell proteoglycan receptors; de Vries FP et al.; Neisseria meningitidis possesses a repertoire of surface adhesins that promote bacterial adherence to and entry into mammalian cells . Here, we have identified heparan sulphate proteoglycans as epithelial cell receptors for the meningococcal Opc invasin . Binding studies with radiolabelled heparin and heparin affinity chromatography demonstrated that Opc is a heparin binding protein . Subsequent binding experiments with purified 35SO4-labelled epithelial cell proteoglycan receptors and infection assays with epithelial cells that had been treated with heparitinase to remove glycosaminoglycans confirmed that Opc-expressing meningococci exploit host cell-surface proteoglycans to gain access to the epithelial cell interior . Unexpectedly, Opa28-producing meningococci lacking Opc also bound proteoglycans . These bacteria also bound CEA receptors in contrast to the Opc-expressing phenotype, suggesting that Opa28 may possess domains with specificity for different receptors . Opa/Opc-negative meningococci did not bind either proteoglycan or CEA receptors . Using a set of genetically defined mutants with different lipopolysaccharide (LPS) and capsular phenotype, we were able to demonstrate that surface sialic acids interfere with the Opc-proteoglycan receptor interaction . This effect may provide the molecular basis for the reported modulatory effect of capsule and LPS on meningococcal adherence to and entry into various cell types.

J Accid Emerg Med, 1998 Mar, 15(2), 102 - 4
Notification of infectious diseases by junior doctors in accident and emergency departments; Spedding RL et al.; OBJECTIVE: To assess the knowledge about notifiable infectious diseases by accident and emergency (A&E) senior house officers . METHODS: A telephone questionnaire of senior house officers was carried out over a one week period at the end of their six month attachment in A&E departments in Northern Ireland . RESULTS: 81 (91%) of the senior house officers participated in the study; 23 (29%) realised that the doctor diagnosing the notifiable disease had a statutory duty to notify that disease; nine (11%) were aware there were three statutory lists in the United Kingdom . Knowledge about which infectious diseases require notification varied from 79/81 (98%) for meningococcal disease to 15/91 (19%) for methicillin resistant S aureus . Seventy nine (98%) of the doctors thought that a poster displayed in the A&E department would be helpful . There was no significant difference between duration of qualification and performance on the questionnaire (p = 0.2) . CONCLUSIONS: Despite varying experience, junior doctors in A&E do not know which infectious diseases are notifiable by statute . They felt that it would be helpful to have a poster in the A&E department listing the notifiable diseases of that region . To encourage accurate reporting, interregional variation between the statutory lists should be abolished and replaced by one nationally agreed list.

Vaccine, 1998 Apr, 16(6), 630 - 6
Pneumococcal conjugate vaccination in adults: circulating antibody secreting cell response and humoral antibody responses in saliva and in serum; Nieminen T et al.; The results from our previous study showed IgA dominated ASC responses to pneumococcal polysaccharide vaccine and to pneumococcal polysaccharide meningococcal outer membrane protein conjugate vaccine (PncOMPC) in adult volunteers . The results indicated that a high IgA ASC response is a useful indicator of a secretory IgA response in saliva . We believe that the mucosal immune responses is potentially an important characteristic of the pneumococcal vaccines and should thus be measured when the new pneumococcal conjugate vaccines are evaluated . In the present study, we studied two new tetravalent pneumococcal conjugate vaccines: the diphtheria toxoid and tetanus toxoid conjugates . In contrast to PncOMPC, these conjugates induced higher responses than the polysaccharide vaccine . Furthermore, the different structure of the two conjugate vaccines might affect the nature of the response . Thus a different vaccine may be optimal for induction of a mucosal response than is of systemic responses.

Dev Biol Stand, 1998, 92, 323 - 33
Effect of aluminium hydroxide and meningococcal serogroup C capsular polysaccharide on the immunogenicity and reactogenicity of a group B Neisseria meningitidis outer membrane vesicle vaccine; Rosenqvist E et al.; Three different formulations of an outer membrane vesicle (OMV) vaccine against group B meningococcal disease have been prepared and tested for immunogenicity and reactogenicity in adult volunteers . The vaccines were prepared with or without aluminium hydroxide and serogroup C-polysaccharide (C-ps) . Doses from 12.5 to 100 micrograms protein were given twice at a six weeks' interval . All three formulations were well tolerated and highly immunogenic, inducing bactericidal and opsonizing antibodies in humans . Adsorption of OMVs to aluminium hydroxide reduced the pyrogenicity in rabbits . The differences in immunogenicity between the formulations were relatively small, but after the second dose a stronger booster response was observed when the vaccines were adsorbed . Thus, a formulation with OMVs and C-ps represents a safe and highly immunogenic vaccine, even without aluminium hydroxide.

Dev Biol Stand, 1998, 92, 127 - 33
Towards a nasal vaccine against meningococcal disease, and prospects for its use as a mucosal adjuvant; Haneberg B et al.; A Norwegian outer membrane vesicle (OMV) vaccine against group B meningococcal disease proved to be strongly immunogenic when administered intranasally in mice . The OMV preparation, made from Neisseria meningitidis and intended for parenteral use, was therefore given without adjuvant to human volunteers (n = 12) in the form of nose drops or nasal spray . Such immunizations, which were carried out at weekly intervals during a three-week period, were able to induce systemic antibodies with bactericidal activity in more than half of the individuals . In addition, all vaccinees developed marked increases in OMV-specific IgA antibodies in nasal secretions . The potential of the OMV particles as carriers for other less immunogenic antigens were elucidated in mice with use of whole inactivated influenza virus . Even though influenza virus alone did induce some systemic and salivary antibody responses after being administered intranasally, these responses were greatly augmented when the virus was presented together with OMVs . Thus, it is possible that a nasal OMV vaccine may induce protection against invasive meningococcal disease, and also that it might be used as a vehicle for nasal vaccines against other diseases.

Pediatr Allergy Immunol, 1997 Nov, 8(4), 194 - 9
Lack of correlation between soluble CD14 and IL-6 in meningococcal septic shock; Arranz E et al.; Meningococcal sepsis is a good model to study the dynamic response of cytokines and other soluble factors in vivo in the early stages of the disease . Levels of soluble CD14, interleukin-6 (IL-6), IL-6 receptor (IL-6R), and C-reactive protein (CRP) have been measured in plasma from 26 children with septic shock (nine of whom had disseminated intravascular coagulation) and from ten control children . All samples were collected at the onset, before treatment, and, when possible, 24 and 48 hours later . At admission, patients had significantly higher levels of IL-6 (p < 0.001) and CRP (p < 0.001), and lower levels of IL-6R (p < 0.005) than normal controls . After 24 hours, there was a significant increase of sCD24 (p < 0.05) and CRP (p < 0.001) . Although IL-6 showed a progressive decline since the onset, its levels were always higher than controls . There was an inverse correlation between IL-6 and both IL-6R (p < 0.001) and CRP (p < 0.001), probably due to the later increase of CRP . Nevertheless, sCD14 did not correlate with IL-6 levels . We have confirmed the finding of IL-6 as a sensitive and reliable inflammatory marker in septic shock . Moreover, the ratio IL-6/IL-6R may have a prognostic value, given a putative role of IL-6R in modulating the effects of IL-6 in meningococcal sepsis.

Rev Esp Salud Publica, 1997 Mar-Apr, 71(2), 103 - 26
{Efficacy of the meningococcal vaccine from Group C capsular polysaccharide}; Gonzalez Enriquez J et al.; BACKGROUND: This report is a systematic review of the effect intensity and duration of the immune response to meningococcal serogroup C vaccine . The vaccine safety, efficacy and effectiveness are also analyzed . METHODS: MEDLINE literature search in the period 1970-1996 . Meningoccocal polysaccharide vaccine clinical trials and human prospective studies were specifically searched . Quality of the retrieved studies were analyzed . Information available was integrated . RESULTS: Group C meningoccal polysaccharide vaccine is a safe product . Its efficacy is over 85% among adults and children over 5 years old . 70% (CI 95%: 5-91%) under 5 years old, and 55% among children 2-3 years old . The vaccine is not effective under 2 years . The duration of protective antibody levels decrease with age . The proportion of vaccinated children effectively protected one year after vaccination is low . Vaccination does not affect the immune response to ulterior revaccination . CONCLUSIONS: Group C meningococcal polysaccharide vaccine is indicated in adults and children over 2 years old to protect them from meningococcal disease due to group C when exposed to high risk of infection . The outbreaks control is the main indication for the use of this vaccine . Routine immunization in not outbreak situation is not recommended due to the small vaccine protection in children under 2 years old, the limited efficacy in children under 5, and the short duration of the immunity in children.

Proc Natl Acad Sci U S A, 1998 Mar 17, 95(6), 3140 - 5
Multilocus sequence typing: a portable approach to the identification of clones within populations of pathogenic microorganisms; Maiden MC et al.; Traditional and molecular typing schemes for the characterization of pathogenic microorganisms are poorly portable because they index variation that is difficult to compare among laboratories . To overcome these problems, we propose multilocus sequence typing (MLST), which exploits the unambiguous nature and electronic portability of nucleotide sequence data for the characterization of microorganisms . To evaluate MLST, we determined the sequences of approximately 470-bp fragments from 11 housekeeping genes in a reference set of 107 isolates of Neisseria meningitidis from invasive disease and healthy carriers . For each locus, alleles were assigned arbitrary numbers and dendrograms were constructed from the pairwise differences in multilocus allelic profiles by cluster analysis . The strain associations obtained were consistent with clonal groupings previously determined by multilocus enzyme electrophoresis . A subset of six gene fragments was chosen that retained the resolution and congruence achieved by using all 11 loci . Most isolates from hyper-virulent lineages of serogroups A, B, and C meningococci were identical for all loci or differed from the majority type at only a single locus . MLST using six loci therefore reliably identified the major meningococcal lineages associated with invasive disease . MLST can be applied to almost all bacterial species and other haploid organisms, including those that are difficult to cultivate . The overwhelming advantage of MLST over other molecular typing methods is that sequence data are truly portable between laboratories, permitting one expanding global database per species to be placed on a World-Wide Web site, thus enabling exchange of molecular typing data for global epidemiology via the Internet.

Intensive Care Med, 1998 Feb, 24(2), 157 - 61
A normal platelet count at admission in acute meningococcal disease does not exclude a fulminant course; Van Deuren M et al.; OBJECTIVE: To determine the value of the platelet count at admission for the assessment of the severity of disease in acute meningococcal infections . DESIGN: Retrospective and prospective, descriptive patient study . SETTING: University Hospital Intensive Care Unit (ICU) . PATIENTS: All patients (n = 92) with acute meningococcal disease from 1985 to 1997, who arrived at the ICU within 12 h after hospital admission and had more than one platelet count during the first 12 h . MEASUREMENTS AND RESULTS: After admission, platelets dropped in 95% of the patients . At admission, 2/41 (5%) of the non-hypotensive patients and 13/51 (25%) of the hypotensive patients had platelets fewer than 100 x 10(9)/l . During the following 12 h, these percentages increased to 15% and 71%, respectively . Fatalities had, at admission, a median platelet count of 111 x 10(9)/l (range, 19-302 x 10(9)/l), whereas the nadir, occurring at median 7.0 h (range, 1.3-12 h), was 31 x 10(9)/l (range, 12-67 x 10(9)/l) . Plasma TNF, measured shortly after admission, correlated better with the platelet nadir (r = -0.65, p < 0.0001) than with the platelet count at admission . Similarly, serum lactate correlated better with the platelet nadir . CONCLUSIONS: As platelets drop after admission, the use of the platelet count at admission for the assessment of the prognosis in acute meningococcal disease may be misleading . Frequently repeated platelet counts are a better tool for evaluating the severity of disease.

Pathol Biol (Paris), 1997 Nov, 45(9), 729 - 36
Epidemiological survey of Neisseria meningitidis susceptibility to penicillin G in France; Guibourdenche M et al.; The susceptibility of 82 strains of Neisseria meningitidis to penicillin G and amoxicillin was evaluated with two media "gonococci-meningococci" medium (G medium) derived from Mueller Hinton and chocolate agar . Among these 82 strains 52 were isolated from CSF and/or blood and 30 from miscellaneous isolates . G medium was compared with chocolate agar using the correlation between diameters and MIC and the E-test . Routinely standardised antibiogram is still used but the authors added the following techniques 1) MIC of penicillin G is tested (0.06; 0.125; 0.250; 0.50 mg/l); 2) use of oxacillin disc charged with 5 micrograms . Penicillinase producing meningococci were not found . Standardised antibiogram on 4192 strains resulted in a modal distribution of diameters between 18 to 40 mm . Moderate meningococci susceptible strains to penicillin G are increasing in France: 1994: 4%; 1995: 11%; 1996: 18%.

Arch Dis Child, 1998 Jan, 78(1), 58 - 60
Preliminary clinical evaluation of meningococcal disease and bacterial meningitis by ultrasonic enhancement; Barnes RA et al.; Antigen detection in the urine and serum may be useful in the diagnosis of suspected meningococcal disease, especially after previous antibiotic treatment . Current test card procedures using commercial agglutination kits are often too insensitive to contribute to diagnosis . Diagnosis of meningococcal disease rose from 37% with the test card procedure to 74% following ultrasonic enhancement.

Infect Immun, 1998 Apr, 66(4), 1334 - 41
Intranasal administration of a meningococcal outer membrane vesicle vaccine induces persistent local mucosal antibodies and serum antibodies with strong bactericidal activity in humans; Haneberg B et al.; A nasal vaccine, consisting of outer membrane vesicles (OMVs) from group B Neisseria meningitidis, was given to 12 volunteers in the form of nose drops or nasal spray four times at weekly intervals, with a fifth dose 5 months later . Each nasal dose consisted of 250 microg of protein, equivalent to 10 times the intramuscular dose that was administered twice with a 6-week interval to 11 other volunteers . All individuals given the nasal vaccine developed immunoglobulin A (IgA) antibody responses to OMVs in nasal secretions, and eight developed salivary IgA antibodies which persisted for at least 5 months . Intramuscular immunizations did not lead to antibody responses in the secretions . Modest increases in serum IgG antibodies were obtained in 5 volunteers who had been immunized intranasally, while 10 individuals responded strongly to the intramuscular vaccine . Both the serum and secretory antibody responses reached a maximum after two to three doses of the nasal vaccine, with no significant booster effect of the fifth dose . The pattern of serum antibody specificities against the different OMV components after intranasal immunizations was largely similar to that obtained with the intramuscular vaccine . Five and eight vaccinees in the nasal group developed persistent increases in serum bactericidal titers to the homologous meningococcal vaccine strain expressing low and high levels, respectively, of the outer membrane protein Opc . Our results indicate that meningococcal OMVs possess the structures necessary to initiate systemic as well as local mucosal immune responses when presented as a nasal vaccine . Although the serum antibody levels were less conspicuous than those after intramuscular vaccinations, the demonstration of substantial bactericidal activity indicates that a nonproliferating nasal vaccine might induce antibodies of high functional quality.

Enferm Infecc Microbiol Clin, 1997 Nov, 15(9), 451 - 5
{Meningococcal meningitis:descriptive study of 76 cases in a pediatric hospital}; Muzzio de Califano G et al.; BACKGROUND: One of the principal causes of bacterial meningitis (BM) in children older than one month is Neisseria meningitidis (Nm) . A quick diagnosis and an immediate treatment are considered essential for a good outcome . We propose this study with the purpose of evaluating the clinical and epidemiological characteristics of the patients with BM caused by Nm and analyzing the effect on the presentation and incidence of sequelae and/or complications of the time elapsed since the starting of symptoms and the beginning of the treatment . METHODS: We performed a retrospective analysis of the clinical registers of 76 patients diagnosed as BM caused by Nm entered in the Hospital de Pediatria Pedro de Elizalde, Buenos Aires, Argentina, during the years 1992 and 1993 . We investigated age, sex, date of entrance, first symptoms, biochemistry of cerebrospinal fluid (CSF), nutritional status, convulsions and/or complications, length of internation and conditions at discharge . Processing was done with Epi-info 5.0 . Differences between qualitative variables were analyzed with chi 2 and differences between means with z-test . RESULTS: Boys were majority; fever was the most frequent initial symptom; petechiae were less frequently found, specially among infants . 79% of the patients had CSF of purulent characteristics; 32.9% of the patients had complications during their evolution; its incidence raised up to 48% in infants . Lethality was 1.3%, 6.5% of the children had sequelae at the moment of discharge . The average time of internment was 13 days . There were no significant differences when different groups were compared according to their prior evolution time . CONCLUSIONS: 1) Petechiae and vomits were significantly less frequent in infants; 2) the incidence of complications was significantly higher in this last group; 3) no greater incidence of complications or sequelae was observed in patients whose previous period of evolution was longer than 48 hours; 4) in all groups of age we found insidious forms of starting, and 5) there were patients with CSF of normal biochemical characteristics in all groups considered independently of the time of evolution elapsed.

Enferm Infecc Microbiol Clin, 1997 Dec, 15(10), 510 - 4
{Clinical and epidemiologic study of meningococcal meningitis in the health region of Santiago de Compostela (1990-1997)}; Juncal AR et al.; BACKGROUND: The aim of this study was to determine the clinico-epidemiologic characteristics of meningitis caused by Neisseria meningitidis . METHODS: A retrospective study was performed of the bacterial meningitis with LCR positive cultures for Neisseria meningitidis from January 1990 to 31 March, 1997 . To calculate the rate of incidence data from the 1990 population census were used corresponding to a population of 465,786 inhabitants per year attended in our hospital . RESULTS: A growth was observed in the strains of N . meningitidis in 61 LCR, representing 30% of all positive LCRs . Thirty-three strains belonged to serogroup B (54%) and 28 of serogroup C (46%) . Ninety-one point nine percent of the cases were found in patients under the age of 20 . The annual rates of incidence ranged from 2.3 cases/100,000 inhabitants in 1990 to 3.4 cases/100,000 inhabitants in 1996 with a slight decrease between these two dates . In patients under the age of 15 years, the rates of incidence ranged from 12.3/100,000 in 1990 to 13.4 per 100,000 inhabitants in 1996 . In the remaining years the rates decreased with a minimum of 2.2 cases/100,000 inhabitants . The incidence for N . meningitis serogroup C ranged from 0 to 0.9 cases/100,000 inhabitants between 1990 and 1995 . In 1996 the rate increased up to 2.6 cases/100,000 inhabitants . The rate of mortality was 6.6% and sequelae 8.7% . Since 1995 strains with decreased sensitivity to penicillin have been isolated, with percentages ranging from 20% to 56.25% . All strains remained sensitive to third generation cephalosporins and rifampicin . CONCLUSIONS: Neisseria meningitidis remains the most frequent etiologic agent of acute bacterial meningitis . The increase in serogroup C strains and the ever more frequent appearance of strains with decreased resistance to penicillin are confirmed, as is the persistence of high levels of endemia in our medium.

South Med J, 1998 Mar, 91(3), 287 - 8
Meningococcal cellulitis and sialadenitis; Gelfand MS et al.; Neisseria meningitidis is a rare cause of cellulitis . No cases of meningococcal sialadenitis have previously been reported . We recently successfully treated a patient who had meningococcal cellulitis and sialadenitis . We review previously reported cases of cellulitis due to N meningitidis and speculate on the role of underlying disease in the pathogenesis of this infection.

Postgrad Med, 1998 Mar, 103(3), 102 - 117
Bacterial meningitis in children and adults . Changes in community-acquired disease may affect patient care; Phillips EJ et al.; Despite improved understanding of how bacterial meningitis develops, the infection remains a potentially life-threatening emergency capable of causing significant morbidity and mortality . Since the introduction and widespread use of H influenzae type b vaccine in infancy and childhood in North America, the epidemiology of community-acquired bacterial meningitis has changed . S pneumoniae is now the most common cause in children and adults overall, although N meningitidis causes most disease in patients between ages 2 and 18 years . Broad-spectrum cephalosporins (eg, ceftriaxone, cefotaxime) are considered the agents of choice for empirical treatment of bacterial meningitis . However, use of these agents will have to be reconsidered if the incidence of invasive infection from drug-resistant S pneumoniae continues to increase . The role of adjunctive corticosteroid therapy needs to be better defined . Improved conjugate pneumococcal and meningococcal vaccines may soon make bacterial meningitis a preventable disease.

J Bacteriol, 1998 Mar, 180(6), 1533 - 9
Characterization of the gene cassette required for biosynthesis of the (alpha1-->6)-linked N-acetyl-D-mannosamine-1-phosphate capsule of serogroup A Neisseria meningitidis; Swartley JS et al.; The (alpha1-->6)-linked N-acetyl-D-mannosamine-1-phosphate meningococcal capsule of serogroup A Neisseria meningitidis is biochemically distinct from the sialic acid-containing capsules produced by other disease-associated meningococcal serogroups (e.g., B, C, Y, and W-135) . We defined the genetic cassette responsible for expression of the serogroup A capsule . The cassette comprised a 4,701-bp nucleotide sequence located between the outer membrane capsule transporter gene, ctrA, and galE, encoding the UDP-glucose-4-epimerase . Four open reading frames (ORFs) not found in the genomes of the other meningococcal serogroups were identified . The first serogroup A ORF was separated from ctrA by a 218-bp intergenic region . Reverse transcriptase (RT) PCR and primer extension studies of serogroup A mRNA showed that all four ORFs were cotranscribed in the opposite orientation to ctrA and that transcription of the ORFs was initiated from the intergenic region by a sigma-70-type promoter that overlapped the ctrA promoter . The first ORF exhibited 58% amino acid identity with the UDP-N-acetyl-D-glucosamine (UDP-GlcNAc) 2-epimerase of Escherichia coli, which is responsible for the conversion of UDP-GlcNAc into UDP-N-acetyl-D-mannosamine . Polar or nonpolar mutagenesis of each of the ORFs resulted in an abrogation of serogroup A capsule production as determined by colony immunoblots and enzyme-linked immunosorbent assay . Replacement of the serogroup A biosynthetic gene cassette with a serogroup B cassette by transformation resulted in capsule switching from a serogroup A capsule to a serogroup B capsule . These data indicate that assembly of the serogroup A capsule likely begins with monomeric UDP-GlcNAc and requires proteins encoded by three other genes found in the serogroup A N . meningitidis-specific operon located between ctrA and galE.

Mol Microbiol, 1998 Feb, 27(4), 705 - 15
Consequences of the loss of O-linked glycosylation of meningococcal type IV pilin on piliation and pilus-mediated adhesion; Marceau M et al.; Pili, which are assembled from protein subunits called pilin, are indispensable for the adhesion of capsulated Neisseria meningitidis (MC) to eukaryotic cells . Both MC and Neisseria gonorrhoeae (GC) pilins are glycosylated, but the effect of this modification is unknown . In GC, a galactose alpha-1,3-N-acetyl glucosamine is O-linked to Ser-63, whereas in MC, an O-linked trisaccharide is present between residues 45 and 73 of pilin . As Ser-63 was found to be conserved in pilin variants from different strains, it was replaced by Ala in two MC variants to test the possible role of this residue in pilin glycosylation and modulation of pili function . The mutated alleles were stably expressed in MC, and the proteins they encoded migrated more quickly than the normal protein during SDS-PAGE . As controls, neighbouring Asn-61 and Ser-62 were replaced by an Ala with no effect on electrophoretic mobility . Silver staining of purified pilin obtained from MC after oxidation with periodic acid confirmed the loss of glycosylation in the Ser-63-->Ala pilin variants . Mass spectrometry of HPLC-purified trypsin-digested peptides of pilin and Ser-63-->Ala pilin confirmed that peptide 45-73 has the molecular size of a glycopeptide in the wild type . In strains producing non-glycosylated pilin variants, we observed that (i) no truncated S pilin monomer was produced; (ii) piliation was slightly increased; and (iii) presumably as a consequence, adhesiveness for epithelial cells was increased 1.6- to twofold in these derivatives . In addition, pilin monomers and/or individual pilus fibres, obtained after solubilization of a crude pili preparation in a high pH buffer, were reassociated into insoluble aggregates of pili more completely with non-glycosylated variants than with the normal pilin . Taken together, these data eliminate a major role for pilin glycosylation in piliation and subsequent pilus-mediated adhesion, but they demonstrate that glycosylation facilitates solubilization of pilin monomers and/or individual pilus fibres.

Rev Saude Publica, 1997 Jun, 31(3), 254 - 62
{Epidemiological characterization of meningococcal disease in a metropolitan area in Southeastern Brazil, 1976-1994}; Gama SG et al.; INTRODUCTION: Meningococcal disease continues to warrant assessment as to its endemic and epidemic multicausality and temporal trends in various locations . MATERIAL AND METHOD: Based on a standardization of epidemiological investigation of meningococcal disease in the municipality of Rio de Janeiro county, Southeastern Brazil, as from epidemic of the 1970s a study to characterized the epidemiological characteristics of the disease, was realized . The total of 4,155 cases reported between 1976 and 1994 were analyzed in a retrospective, descriptive, and analytical study, using the epidemiological investigation forms issued by the Municipal Health Secretariat . Statistical analysis was performed using the chi 2, Wilcoxon-Mann-Whitney, and Kruskal-Wallis tests . RESULTS: The study resulted in the definition of three periods, classified as post-epidemic (1976-79), endemic (1980-86), and epidemic (1987-94), differentiated by the incidence rates and the predominant meningococcal serogroup . The mean incidence rates per period in the municipality were 3.51, 1.67, and 6.53 cases/ 100,000 inhabitants, respectively . Serogroups A and C predominated during the post-epidemic period, B and A in the endemic, and B in the epidemic . CONCLUSION: The mean case fatality rate remained virtually unchanged over time, but it varied by hospital, and during all three periods was lower in the State government reference hospital than in the other hospitals, whether public or private . The highest incidence and case fatality rates were associated with patients under one year of age, and the risk of acquiring the disease was greater among males . The highest incidence coefficients tended to occur in the same areas of the county during the three epidemiological periods, and the shanty-town population was at twice the risk of acquiring the disease.

FEMS Immunol Med Microbiol, 1998 Jan, 20(1), 79 - 86
Bactericidal activity of antibodies elicited against the Neisseria meningitidis 37-kDa ferric binding protein (FbpA) with different adjuvants; Gomez JA et al.; The 37-kDa ferric binding protein, FbpA, from three Neisseria meningitidis strains was purified to homogeneity with iron-affinity chromatography and used for immunisation of mice employing four different adjuvants: aluminium hydroxide, Freund's, the saponin Quil-A, and a Ribi adjuvant system (RAS) . Controls immunised without adjuvant were also included . All sera obtained were monospecific for the meningococcal FbpA, with antibody titres higher when RAS and Quil-A were used (256), PBS resulting in titres similar to those of Freund's (64), and, surprisingly, with no antibodies elicited when aluminium hydroxide, the only approved adjuvant for use in humans, was used . All anti-FbpA sera bound to intact meningococcal cells, showing a complete cross-reactivity, but the bactericidal activity of anti-FbpA antibodies, demonstrated for the first time in this work, was low (32% of killing with the homologous strain), and the analysis of immunoglobulin isotypes showed that the non-bactericidal IgG1 was predominant . The results confirm that the FbpA is surface-exposed, antigenic, and able to elicit bactericidal antibodies, although, in the conditions and with the adjuvants tested, killing efficacy was low and cross-killing was very variable, not supporting the inclusion of this protein in vaccine formulations . Nevertheless, given the high conservation of the FbpA in the genus Neisseria, its surface exposure and its antigenicity, studies on immunisation with peptides corresponding to the exposed epitopes and/or new adjuvant systems could improve the bactericidal response to this protein, making it suitable for vaccine development.

J Med Microbiol, 1998 Mar, 47(3), 257 - 64
Differential binding of apo and holo human transferrin to meningococci and co-localisation of the transferrin-binding proteins (TbpA and TbpB); Powell NB et al.; Apo-transferrin (apo-hTf) and holo-transferrin (holo-hTf) were separately conjugated to 15-nm colloidal gold . Iron-restricted Neisseria meningitidis strain SD (B:15:P1.16) bound up to three-fold more holo-hTf than apo-hTf (p <0.001) . The ability of meningococcal mutants lacking either transferrin-binding protein A (TbpA) or TbpB to discriminate between apo-hTf and holo-hTf was also investigated . There was no significant difference between the amount of gold-labelled apo-transferrin bound by the isogenic TbpA mutant (expressing TbpB) and the parent strain, whereas an isogenic TbpB mutant (expressing TbpA) bound significantly less gold-labelled apo-hTf . The isogenic TbpA and TbpB mutants and the parent strain all bound significantly more holo-hTf than apo-hTf, whereas the double 'knock-out' mutant failed to bind hTf irrespective of the iron-loading . In the isogenic mutants, TbpB was more effective in binding either apo- or holo-hTf than TbpA . Monoclonal antibodies against TbpA and TbpB were used to co-localise the transferrin-binding proteins on strain SD . The ratio of TbpA:TbpB was approximately 1:1 . TbpA and TbpB were occasionally observed in close proximity to each other, but the two proteins were generally quite separate, which may indicate that they do not usually form a complex to act as a transferrin receptor.

Am J Med Genet, 1998 Feb 26, 76(1), 67 - 70
Nevo syndrome; Dumic M et al.; We report on a patient with Nevo syndrome manifesting intrauterine and postpartum overgrowth, accelerated osseous maturation, dolichocephaly, highly arched palate, large, low-set ears, cryptorchidism, delayed neuropsychological development, hypotonia, adema, contractures of the hands and feet, a single a transverse palmar crease, and tapering digits . After meningococcal sepsis at age 6 months, he remained decerebrate . Thereafter, overgrowth and especially weight gain were extremely accelerated until his death at age 18 months, at which time his height was 103 cm and his weight was 23 kg . In addition to low plasma concentrations of growth hormone and insulin-like growth factor, severe insulin resistance was observed . It is presumed that a selective defect in insulin-stimulated glucose uptake, with preservation of anabolic effect, was one of the causes of his "overgrowth without growth hormone," at least in the last 12 months of life after severe brain damage.

Bull Soc Pathol Exot, 1997, 90(5), 299 - 302
{Chronical of a declared meningococcal meningitis epidemic (Goma, Zaire, August 1994)}; Niel L et al.; The authors relate their experience controlling an epidemic of meningitis which broke out in the refugee camps of the Goma region, in northern Zaire, after the dramatic events which had happened in Rwanda in April and June 1994 . Out of the 348 cases of purulent meningitis diagnosed by the Bioforce team, meningococcal etiology was confirmed 327 times . The isolated meningococci were all of the serogroup A, serotype A; 4; P 1,9 . They were resistant to streptomycin and to sulphamides . The epidemic lasted one month, touched people of all ages and spread progressively to all the camps . The epidemic surveillance set up meant that vaccination was carried out very quickly and the epidemic brought rapidly under control, even if other factors did intervene . All those called upon to intervene in such a context should be made aware of the interest of the basic triad to fight these epidemics: rapid vaccination, treatment of cases with oily chloramphenicol and bio-epidemiological surveillance.

J Pediatr Nurs, 1998 Feb, 13(1), 32 - 40
Sleep as an indicator for pain relief in an infant: a case study; Gedaly-Duff V et al.; Sleep was used as an indicator of pain relief for an 8-month-old female infant with meningococcemia who experienced nociceptive input from skin wounds and multiple noxious treatment procedures during her recovery . A sleep activity record documented total hours of sleep, awake/crying, awake/content, and longest hours of sleep after nonanalgesic and analgesic interventions to mediate the infant's pain . Sleep appears to be a useful indicator of the efficacy of pain treatment for infants.

FEMS Microbiol Lett, 1998 Feb 15, 159(2), 209 - 14
siaD PCR ELISA for confirmation and identification of serogroup Y and W135 meningococcal infections; Borrow R et al.; Non-culture diagnosis and serogroup determination of meningococcal infection is important in contact management where vaccination may be possible . A serogroup B and C PCR ELISA assay for the non-culture diagnosis and serogroup determination has proved invaluable for enhanced epidemiological surveillance and contact management . A polymerase chain reaction assay, based on a restriction fragment length polymorphism in the meningococcal serogroup Y and W135 sialyltransferase (siaD) gene, was developed to enhance the range of non-culture diagnosis of meningococcal infection from clinical samples . The PCR assay was adapted to an ELISA format incorporating hybridisation with serogroup-specific Y and W135 oligonucleotide probes . The serogroup-specific W135 and Y PCR ELISA is a useful addition to currently available serogroup B and C assay for non-culture diagnosis of meningococcal infection and outbreak investigation.

Sante, 1997 Nov-Dec, 7(6), 384 - 90
{An epidemic of meningococcal meningitis in the region of Savanes in Togo in 1997: research and control strategies}; Aplogan A et al.; Neisseria meningitidis is responsible for high levels of morbidity and mortality in the developing countries of the African meningitis belt . There are frequent meningococcal meningitis epidemics in this region affecting almost 1,000 people in every 100,000 (1%) . Epidemics generally occur during the dry season but the interval between epidemics is variable (between 2 and 25 years) . The reasons for these recurrent epidemics are unclear . There is a safe and effective polysaccharide vaccine against meningococci A and C . Unfortunately, the immunity it provides decreases with time, especially in young children (aged less than 5 years) and it is thus not included in the Expanded Program on Immunization (EPI) . WHO recommends mass vaccination using a threshold approach . This control strategy is effective if vaccination begins very soon after the threshold is crossed . There was an outbreak of group A meningococcal meningitis in the Savanes region of northern Togo in December 1996 . The national surveillance system put out an alert and control measures were implemented . These involved improvement of the surveillance system, and containment immunization in villages for early cases followed by a mass immunization campaign in the entire region, distribution of oily chloramphenicol and decentralized case management . The target population for mass vaccination included everyone older than 6 months of age living in the Savanes region . The aim was to vaccinate at least 80% of the target population . There were 2,992 cases of meningitis reported in the Savanes region between December 1996 and May 1997 (in a population of about 500,000) . This gives a cumulative incidence rate of 581 per 100,000 population . The epidemic was bimodal, with the first peak in the number of cases occurring at the end of January and the second peak in March . There were 60,700 vaccinations in two of the four districts of the region in December and January, as part of the containment strategy and 346,469 vaccinations in the four districts of the region during February, as part of the mass vaccination campaign . By the end of the mass campaign, 67.3% of the target population in the region as a whole had been vaccinated, with 61% vaccinated in the Kpendjal district and 78% in the Oti district . There was an increase in the number of cases 2 weeks after the end of the mass vaccination campaign . This was attributed to the inadequate level of vaccination achieved . Only 52% of the urban population of Dapaong were vaccinated . The national surveillance system put out an alert early in the epidemic . The intervention was planned and adapted according to the progression of the epidemic, and national and international efforts were well coordinated . This emphasizes the importance of a rapid reaction from the surveillance system and of the choice of strategy for dealing with meningitis epidemics in sub-Sahelian Africa.

J Infect Dis, 1998 Mar, 177(3), 683 - 91
Immunogenicity of two efficacious outer membrane protein-based serogroup B meningococcal vaccines among young adults in Iceland; Perkins BA et al.; Serum bactericidal activity (SBA) and ELISA antibody levels elicited by two efficacious serogroup B meningococcal vaccines were measured in a controlled trial involving 408 15- to 20-year-olds . Subjects were given two doses at a 6-week interval of a serogroup B or control vaccine . Response was defined as > or = 4-fold rise in antibody level . After two doses of the Finlay Institute (Havana) vaccine at 12 months, the proportions of SBA and ELISA responders were not different from those of the control group (15% and 17% {vaccine} vs . 13% and 9% {control}, P > .05) . After two doses of the National Institute of Public Health (Oslo) vaccine, there were more SBA and ELISA responders than in the control group (47% and 34% {vaccine} vs . 10% and 1% {control}) or the Finlay Institute vaccine group (P < .05 for both) . SBA and ELISA may be insensitive correlates for protective efficacy for some outer membrane protein-based serogroup B meningococcal vaccines.

Gac Sanit, 1997 Sep-Oct, 11(5), 242 - 51
{Analysis of the management of the vaccination campaign in 1996-1997 against meningococcus C in Galicia}; Farjas P et al.; This paper describes the process to design and plan a vaccination campaign against group C N . Meningitidis developed in the Autonomous Community of Galicia between December 9, 1996 and January 31, 1997 . We also analyse the results of this process in terms of management results, vaccine coverage and preliminary estimates of effectiveness . A Work group was established, made up of professionals in charge of different intervention areas . A person was designated in charge of the whole campaign and a follow-up and information system was created . The work plan consisted of daily meetings for follow-up, co-ordination and task distribution; and periodical meetings with primary health care and peripheral public health coordinators . Strategies of implantation--in order to make sure the campaign accessibility and acceptability; of budget and of communication with health workers, inhabitants and mass media were developed . Up to 100 tasks were identified to develop the technical information and logistic activities: mailings, meetings, leaflets, ...; purchasing of 584.980 doses of vaccine, supplying to 715 vaccination points (1040 deliveries); problem solving and intervention recording . A vaccination coverage of 85% was achieved, with notification of 8 adverse reactions and 6 errors in the administration of the vaccine (34 children affected) . The strategy chosen for the design and planning of the campaign has proven to be effective and valid and sufficient to achieve the final goals, in due time and without problems of misinformation, shortage of vaccine or lack of participation of professionals or people . Mistakes due to incorrect administration of the vaccine, management problems, rupture of the cold chain or recording failures were minimal and accidental.

East Afr Med J, 1997 Jul, 74(7), 423 - 6
Clinical predictors of epidemic outcome in meningococcal infection in Jos, Nigeria; Angyo IA et al.; The clinical predictors of outcome in children admitted into the Emergency Paediatric Unit at the Jos University Teaching Hospital with meningococcal infection during an out-break of the disease (between February-April 1996) were studied . Eighty seven children were admitted with meningococcal infection during the period . There were 60 males and 27 females (M:F = 2.2:1), aged between five weeks and 16 years (mean 7.7 +/- 4.9 years) . Overall mortality was 26.4 per cent . Eighty five per cent of the patients who presented in shock died, compared with nine per cent who presented without shock (p < 0.000001) . Similarly, 65% of the patients who presented in coma died, compared with 12.5% who did not present in coma (p < 0.000001) . Other factors associated with a poor outcome included age one year and below, petechial/purpuric rash on presentation and meningococcaemia . Complications were documented in 27 (31.0%) of the patients, consisting mainly of deafness, extensive vasculitis/ulceration of extremities, gangrene of legs hemiparesis and cranial nerve palsies.

Shock, 1998 Feb, 9(2), 138 - 42
Activated protein C concentrate for the treatment of meningococcal endotoxin shock in rabbits; Roback MG et al.; To evaluate the effects of activated protein C therapy in a rabbit model of meningococcal endotoxin-induced shock, we performed a prospective, blinded, placebo-controlled animal trial . Forty New Zealand White rabbits were challenged with intravenous meningococcal endotoxin (lipooligosaccharide) 100 microg/kg . Ten minutes before endotoxin challenge, animals were administered either activated protein C 1600 microg/mL (n = 20) or an equal volume of saline (n = 20) as an initial bolus . After endotoxin challenge, activated protein C treated animals were administered a continuous infusion of activated protein C 160 microg/kg/h and saline-treated animals were administered an equal volume infusion of saline . Both activated protein C treated and saline control animals demonstrated evidence of shock after endotoxin challenge; mean arterial pressure and serum bicarbonate significantly (p < .01) declined, and heart rate significantly (p < .01) increased from baseline . In activated protein C treated animals, mean plasma activated protein C activity was 5.69 microg/mL (+/- 3.2) 1 h after challenge, whereas plasma protein C activity was not detected in controls . Mean prothrombin and activated partial thromboplastin times were significantly (p < or = .01) prolonged compared with saline-treated controls . Other hematologic and chemical measurements did not differ between groups . Fifteen of 20 (75%) animals treated with activated protein C concentrate survived to 24 h, while 9 of 20 (45%) control animals survived to 24 h (p = .05) . Those animals treated with activated protein C had improved survival, which corroborates the findings of early clinical studies in which replacement of protein C improved outcome.

Infect Immun, 1998 Mar, 66(3), 1028 - 36
Nonopsonic phagocytosis of group C Neisseria meningitidis by human neutrophils; Estabrook MM et al.; Although complement-mediated bactericidal activity in serum has long been known to be very important in host defense against Neisseria meningitidis, recent studies have shown that opsonic phagocytosis by neutrophils is also important . The purpose of this study was to determine if endemic group C N . meningitidis strains were susceptible to nonopsonic (complement- and antibody-independent) phagocytosis by human neutrophils, which is a well-described phenomenon for Neisseria gonorrhoeae . Gonococci that possess one or more of a group of heat-modifiable outer membrane proteins (called opacity-associated {Opa} proteins) are phagocytosed by neutrophils in the absence of serum . We found that four serogroup C meningococcal strains bearing the lacto-N-neotetraose (LNnT) structure on lipooligosaccharide (LOS) were phagocytosed by neutrophils in the absence of antibody and active complement . Confocal microscopy confirmed that the organisms were internalized by neutrophils . This susceptibility was not restricted to carrier isolates, since two of the strains were cultured from blood or cerebrospinal fluid . All four strains expressed Opa protein and had relatively less endogenous LOS and capsule sialylation compared to six strains that were resistant to this type of phagocytosis . Nonopsonic phagocytosis of two of the four strains was inhibited by exogenous sialylation of LOS LNnT and the binding of monoclonal antibody to LNnT . However, an isogenic mutant that lacked the LNnT structure was fully susceptible to nonopsonic phagocytosis . We conclude that group C meningococci can be phagocytosed by neutrophils in the absence of antibody and active complement possibly by two different mechanisms . Expression of Opa protein and downregulation of endogenous surface sialic acids analogous to what is seen for N . gonorrhoeae might be necessary for N . meningitidis as well.

Infect Immun, 1998 Mar, 66(3), 959 - 65
Human T-cell responses after vaccination with the Norwegian group B meningococcal outer membrane vesicle vaccine; Naess LM et al.; We have analyzed human T-cell responses in parallel with serum immunoglobulin G (IgG) antibody levels after systemic vaccination with the Norwegian group B Neisseria meningitidis outer membrane vesicle (OMV) vaccine . Ten adult volunteers, with no or very low levels of serum IgG antibodies against meningococci, received three doses intramuscularly of the OMV vaccine (at weeks 0, 6, and 46) . T-cell proliferation against the OMV vaccine, purified outer membrane proteins (PorA and PorB), and control antigens (Mycobacterium bovis BCG vaccine and tetanus toxoid) was measured by thymidine incorporation of peripheral blood mononuclear cells before and after vaccination . The results showed that vaccination with OMV elicits strong primary and booster T-cell responses specific to OMV as well as the PorA (class 1) protein and significant, but markedly lower, responses against the PorB (class 3) protein . The median responses to OMV and PorA were 26 and 16 times the prevaccination levels, respectively . Most of the vaccinees showed low T-cell responses against OMV and PorA before vaccination, and the maximum T-cell responses to all vaccine antigens were usually obtained after the second vaccine dose . We found a positive correlation between T-cell responses and anti-OMV IgG antibody levels (r = 0.50, P < 0.0001, for OMV and PorA) . In addition, we observed a progressive increase in the percentage of CD45R0+ (memory) CD4-positive T cells (P = 0.002) . In conclusion, we have shown that the Norwegian OMV vaccine against meningococcal B disease induced antigen-specific T-cell responses, kinetically accompanied by serum IgG responses, and that vaccination increased the proportion of memory T-helper cells.

Med Sci Law, 1998 Jan, 38(1), 52 - 6
Digoxin-like immunoreactivity in early infantile death; Couper RT et al.; The aim of this study was to determine if the level of digoxin-like immunoreactivity in post-mortem sera obtained from infants differs according to the cause of death and if the level is related to age, post-mortem interval, cardiac pathology or adrenal weight . Twelve infants whose deaths were attributed to sudden infant death syndrome (SIDS), and 11 infants who died from other causes, had blood sampled between 3 to 53 hours post-mortem from their right atrial cavity . Digoxin-like immunoreactivity was measured, using a specific and sensitive digoxin radioimmunoassay, and was detected in 7 of the infants who died of SIDS and 7 of those who died from other causes . The highest levels were seen in two patients who died from meningococcal sepsis and haemorrhage, hyperpyrexia and encephalopathy syndrome, respectively . No correlation was detected between the digoxin-like immunoreactivity level, gender, age at death, post-mortem interval or cardiac pathology . Digoxin-like immunoreactivity levels correlated with adrenal weight . It is concluded that digoxin-like immunoreactivity is frequently found in infant sera, but levels are not specific to and are no higher in SIDS infants than infants dying of other conditions.

Immunol Res, 1998, 17(1-2), 95 - 108
Peptide mimotopes of carbohydrate antigens; Kieber-Emmons T; Carbohydrate structures have been identified as significant antigens for bacterial, viral, and fungal pathogens as well as targets on human tumor cells . Many of these antigens are poorly immunogenic in humans, requiring extensive adjuvant sublimation . Although conjugate carbohydrate vaccines appear promising, there are limitations of using carbohydrate formulations . An alternative approach is to use surrogate antigens for some carbohydrates . We are developing peptides that mimic carbohydrates which might be further manipulated to induce responses that target biologically important carbohydrates expressed on pathogens and on tumor cells . We have shown that peptide mimotopes of carbohydrates induce immune responses to carbohydrate structures with in vivo and vitro functionality . Model systems include the Neisseria group C meningococcal polysaccharide; the histo-blood group-related antigens expressed on tumor cells; and mannose, sialyl, and histo-blood group-related carbohydrate epitopes expressed on human immunodeficiency virus.

World Health Stat Q, 1997, 50(3-4), 170 - 7
Meningococcal disease: public health burden and control; Tikhomirov E et al.; Meningococcal disease which is increasing globally is still associated with a high mortality and persistent neurological defects, particularly among infants and young children . Sporadic meningococcal meningitis occurs throughout the world, with seasonal variations, and accounts for 10-40% of endemic bacterial meningitis . Epidemic meningitis occurs in any part of the world but the largest and most frequently recurring epidemics have been in the semi-arid area of sub-Saharan Africa where the current pandemic is associated with attack rates exceeding 500 per 100,000 population and thousands of deaths . In the Americas and Europe serogroup B is the predominant agent causing systemic disease, followed in frequency by serogroup C . Serogroup A meningococcus was historically the main cause of epidemic meningococcal disease globally and still predominates in Africa and Asia . A range of internal and external factors predispose for epidemics such as strain virulence, carriers, humoral immunity, co-infections, low humidity and drought, population movements and crowding . To respond to the current situation and the expected spread of the disease, WHO, in collaboration with its Member States and various governmental and non-governmental agencies, has developed a sustainable plan of action for preparedness and control of meningitis.

Int J Cardiol, 1997 Dec 19, 62(3), 277 - 8
Asymptomatic temporary atrioventricular dissociation complicating meningococcal meningitis; Shapira MY et al.; We present a case of a young man with meningococcal meningitis and various asymptomatic temporary ECG abnormalities, including sinus bradycardia, atrioventricular dissociation and non specific ST-T changes.

Immunopharmacology, 1997 Dec, 38(1-2), 93 - 9
The effect of mannan-binding lectin on opsonophagocytosis of Neisseria meningitidis; Drogari-Apiranthitou M et al.; Mannan-binding lectin (MBL), an acute phase protein with a structure and a function very similar to that of C1q, is known to act as an opsonin binding to a number of microorganisms . In order to investigate the effect of MBL on the phagocytic killing of meningococci, a serogroup B meningococcal strain (H44/76) and its unencapsulated variant v24, as well as a serogroup A meningococcal strain were opsonized with MBL (purified from normal human plasma at the State Serum Institute, Denmark) and used in a phagocytic killing assay at a density of 7 x 10(3) CFU/ml . Polymorphonuclear cells (PMNs) from one healthy donor were isolated by density gradient centrifugation over Percoll and added to the system (7 x 10(6) cells/ml) . In a first set of experiments without addition of serum or complement, no influence of MBL was observed on the killing of any of these strains . Addition of MBL to non-opsonized bacteria of the serogroup A strain did not result in enhanced killing either; on the contrary, the growth of this strain increased significantly when a high MBL concentration (40 micrograms/ml) was used in the presence of PMNs . Further investigations were performed using sera of five individuals with late complement component deficiency (LCCD) and a concomitant MBL deficiency, vaccinated with a tetra-valent (ACYW135) meningococcal capsular polysaccharide vaccine . Pre- and post-vaccination sera (50% final concentration) were tested against a group A strain opsonized or not with MBL . In only one patient was there a moderate increase of killing of the opsonized bacteria after vaccination compared to pre-vaccination serum . Our results suggest that MBL may not play a significant role in the opsonophagocytosis of meningococci, irrespective of its binding to unencapsulated and serogroup A strains.

Clin Exp Immunol, 1998 Jan, 111(1), 97 - 101
Meningococcal disease and polymorphism of FcgammaRIIa (CD32) in late complement component-deficient individuals; Platonov AE et al.; Late complement component-deficient (LCCD) individuals lack plasma bactericidal activity and are highly susceptible to meningococcal disease . Phagocytosis plays a significant role in immune defence against meningococci and involves FcgammaRIIa (CD32) on leucocytes . Two allotypic forms are currently recognized: FcgammaRIIa-R131 and RIIa-H131 . Neutrophils with the IIa-H/H131 allotype are more effective in phagocytosis than IIa-R/R131 . We studied the distributions of IIa-R131 and IIa-H131 allotypes among 29 Russian LCCD patients who had suffered from recurrent episodes of meningococcal disease . The distribution of IIa-R/R131 to heterozygous IIa-R/H131 to homozygous IIa-H/H131 genotypes was 0.14:0.29:0.57 for LCCD patients who developed the first episode of disease before 10 years of age . The distribution was 0.21:0.64:0.14 for patients who experienced meningococcal disease above the age of 10 years (chi2 = 6, P < 0.05, odds ratio for IIa H/H131 versus R/R131 = 8) . Meningococcal disease had a 'grave' course in 14 of 31 disease episodes in patients with IIa-R/R131 and IIa-R/H131 allotypes, in contrast to 1 of 18 episodes in patients with IIa-H/H131 allotype (chi2 = 7, P < 0.01, odds ratio = 14) . We conclude that IIa-H/H131 individuals appear to have a higher acquired antibody-mediated phagocytosis-dependent resistance to meningococcal disease above the age of 10 years . Additionally, effective CD32-mediated phagocytosis may restrict the severity of meningococcal disease in LCCD patients with IIa-H/H131 phenotype.

Clin Exp Immunol, 1998 Jan, 111(1), 91 - 6
Molecular defects leading to human complement component C6 deficiency in an African-American family; Zhu ZB et al.; Complement component C6 deficiency (C6D) was diagnosed in a 16-year-old African-American male with meningococcal meningitis . The patient's father and two brothers also had C6D, but gave no history of meningitis or other neisserial infection . By using exon-specific polymerase chain reaction (PCR)/single-strand conformation polymorphism as a screening step and nucleotide sequencing of target exons, we determined that the proband was a compound heterozygote for two C6 gene mutations . The first, 1195delC located in exon 7, is a novel mutation, while the second, 1936delG in exon 12, has been described before to cause C6D in an unrelated African-American individual . Both mutations result in premature termination codons and C6 null alleles . Allele-specific PCR indicated that the proband's two brothers also inherited the 1195delC mutation from their heterozygous mother and the 1936delG mutation from their homozygous father.

BMJ, 1998 Jan 24, 316(7127), 276 - 9
Recognising meningococcal disease in primary care: qualitative study of how general practitioners process clinical and contextual information; Granier S et al.; OBJECTIVES: To describe the presentation of meningococcal disease in primary care; to explore how general practitioners process clinical and contextual information in children with meningococcal disease; and to describe how this information affects management . DESIGN: Qualitative analysis of semistructured interviews . SETTING: General practices in South Glamorgan . SUBJECTS: 26 general practitioners who between January 1994 and December 1996 admitted 31 children (under 16 years of age) in whom meningococcal disease was diagnosed . MAIN OUTCOME MEASURES: Categories of clinical rules and techniques used by general practitioners in processing each case . RESULTS: 22 children had rashes; in 16 of them the rashes were non-blanching . When present, a haemorrhagic rash was the most important factor in the doctor's decision to admit a child . 22 children had clinical features not normally expected in children with acute self limiting illnesses--for example, lethargy, poor eye contact, altered mental states, pallor with a high temperature, and an abnormal cry . Contextual information, such as knowledge of parents' consultation patterns and their normal degree of anxiety, played an important part in the management decisions in 15 cases . Use of penicillin was associated with the certainty of diagnosis and the presence and type of haemorrhagic rash . CONCLUSION: The key clinical feature of meningococcal disease--a haemorrhagic rash--was present in only half of the study children . The general practitioners specifically hunted for the rash in some ill children, but doctors should not be deterred from diagnosing meningococcal disease and starting antibiotic treatment if the child is otherwise well, if the rash has an unusual or scanty distribution, or if the rash is non-haemorrhagic.

Epidemiol Mikrobiol Imunol, 1997 Dec, 46(4), 145 - 8
{Changes in clinical and epidemiologic characteristics in Western Bohemia of invasive meningococcal disease associated with the occurrence of an invasive clone of Neisseria meningitidis}; Struncova V et al.; The authors analyzed the incidence of meningococcal diseases in the West Bohemian region in 1982-1996 . The draw attention to changes of clinical and epidemiological characteristics of the disease which appeared in 1994 in conjunction with a new invasive clonus of Neisseria meningitidis C:2a:P1.2, P1.5, ET-15/37 . While in 1982-1993 invasive meningococcal diseases had in 75% the course of meningitis with a relatively low fatality (4%), during the subsequent period a marked change occurred . Since 1994 the disease took in the West Bohemian region in 58% the course of sepsis with a fatality of 16% . 25% cases of meningococcal meningitis were diagnosed combined sepsis and meningitis in 17% . The disease lost its seasonal character and the authors confirmed the highest incidence of the disease in the age group from 15-19 years and 0-4 years . Neisseria meningitidis group C was detected in 1994-1996 in 73% and the invasive clone C:2a:P1.2, P1.5, ET-15/37 in 62%.

Microbiology, 1998 Jan, 144 ( Pt 1), 157 - 66
Recombinational reassortment among opa genes from ET-37 complex Neisseria meningitidis isolates of diverse geographical origins; Hobbs MM et al.; Opacity (Opa) proteins are a family of antigenically variable outer-membrane proteins of Neisseria meningitidis . ET-37 complex meningococci, defined by multilocus enzyme electrophoresis, have been isolated on different continents . Twenty-six different Opa proteins have been observed within strains of the ET-37 complex isolated between the 1960s and the 1980s, although individual strains have only four opa genes per chromosome . In this work the opa genes of four closely related ET-37 complex N . meningitidis strains recently isolated from Mali, West Africa were characterized and compared with the opa genes of strain FAM18, an ET-37 complex isolate from the USA . DNA sequence analysis and Southern blot experiments indicated that recombinational reassortment, including gene duplication and import by horizontal genetic exchange, has occurred in the opa genes within the ET-37 complex, resulting in two partially different Opa repertoires being present in FAM18 and the Mali isolates . Using synthetic peptides derived from the hypervariable (HV) regions of opa genes, the epitopes for nine mAbs were mapped . These bacteria, isolated on different continents, contain both shared and unique opa HV regions encoding epitopes recognized by mAbs and show evidence of recombinational reassortment of the HV regions.

JAMA, 1998 Feb 11, 279(6), 435 - 9
Efficacy of meningococcal vaccine and barriers to vaccination; Rosenstein N et al.; CONTEXT: Use of the quadrivalent meningococcal vaccine for control of outbreaks has increased in recent years, but the efficacy of meningococcal vaccine during mass vaccination campaigns in US civilian populations has not been assessed . OBJECTIVES: To evaluate the efficacy of the quadrivalent meningococcal vaccine against serogroup C meningococcal disease in a community outbreak setting and to evaluate potentially modifiable barriers to vaccination in an area with persistent meningococcal disease following immunization . DESIGN: Matched case-control study of vaccine efficacy using cases of serogroup C meningococcal disease in persons eligible for vaccination during mass vaccination campaigns . Control patients were matched by neighborhood and age . The control group was used to identify possible barriers to vaccination . SETTING: Gregg County, Texas, population 106076, from 1993 to 1995 . PARTICIPANTS: A total of 17 case patients with serogroup C meningococcal disease eligible for vaccine and 84 control patients . MAIN OUTCOME MEASURES: Vaccine efficacy and risk factors associated with nonvaccination . RESULTS: Vaccine efficacy among 2- to 29-year-olds was 85% (95% confidence interval, 27%-97%) and did not change in bivariate analyses with other risk factors that were significant in univariate analysis . Among control patients, older age was strongly associated with nonvaccination; vaccination rates for 2- to 4-year-olds, 5- to 18-year-olds, and 19- to 29-year-olds were 67%, 48%, and 20%, respectively (chi2 for linear trend, P=.01) . CONCLUSIONS: The meningococcal polysaccharide vaccine was effective against serogroup C meningococcal disease in this community outbreak . Although specific barriers to vaccination were not identified, older age was a risk factor for nonvaccination in the target population of 2- to 29-year-olds . In future outbreaks, emphasis should be placed on achieving high vaccination coverage, with special efforts to vaccinate young adults.

J Infect Dis, 1998 Feb, 177(2), 497 - 500
New Zealand epidemic of meningococcal disease identified by a strain with phenotype B:4:P1.4; Martin DR et al.; New Zealand is experiencing an epidemic of serogroup B meningococcal disease, which has taken the rate of disease from an average of 1.5/100,000 population in the preepidemic years of 1989 and 1990 to 14.0/100,000 in 1996 . Sterile-site isolates of Neisseria meningitidis from cases of invasive disease have been phenotypically characterized by serogrouping, serotyping, and serosubtyping, revealing the involvement of a strain with phenotype B:4:P1.4 . Macrorestriction analysis using pulsed-field gel electrophoresis on 667 meningococci isolated from cases during the epidemic has identified the clonal relationship of meningococci expressing the PorA P1.4 antigen . Multilocus enzyme electrophoresis has shown the epidemic strain B:4:P1.4 to belong to lineage III . The recorded characteristics of New Zealand's epidemic are consistent with previous serogroup B epidemics in other parts of the world.

J Antimicrob Chemother, 1997 Dec, 40(6), 895 - 7
Meropenem susceptibility of Neisseria meningitidis and Streptococcus pneumoniae from meningitis patients in The Netherlands; van de Beek D et al.; In-vitro susceptibility of 299 Neisseria meningitidis and 157 Streptococcus pneumoniae strains from meningitis patients in The Netherlands in 1993 and 1994 to meropenem was determined using the Etest . Susceptibility to penicillin, ceftriaxone, and chloramphenicol was also determined . Rifampicin susceptibility was additionally tested for N . meningitidis . Of the meningococci, 4.3% were of intermediate resistance to penicillin and 0.3% were resistant to rifampicin . One pneumococcal isolate (0.6%) was of intermediate resistance to penicillin . All strains were susceptible to meropenem . We conclude that meropenem is in vitro highly active against N . meningitidis and S . pneumoniae.

Heart Lung, 1997 Nov-Dec, 26(6), 492 - 500
Case study of fulminant meningococcal septicemia diagnosed in a twenty-year-old woman with bulimia nervosa; Pierson DM; Fulminant meningococcal septicemia accounts for 5% to 10% of patients with meningococcemia; it is rapidly progressive and is associated with high morbidity and mortality rates . The highest meningococcal incidence is found in the 6- to 20-month-old age group; whereas immunoincompetence is suggested in adults with the condition . Coincidentally, eating disorders are purported to be the most prevalent psychiatric or behavioral disturbance affecting adolescents, and studies indicate that vulnerability to infectious disease may be present in this group as a result of a subclinical malnutrition state . I report a case of fulminant meningococcal septicemia in a patient with a comorbid eating disorder of bulimia nervosa, who had a tumultuous disease course, and with rapid and aggressive management of her condition--an impressive recovery.

Zh Mikrobiol Epidemiol Immunobiol, 1995 Jul-Aug, (4), 67 - 71
{The relationship between the immunological efficacy of a dried meningococcal group-A polysaccharide vaccine and the molecular parameters of the group-A polysaccharide}; Alliluev AP et al.; This work deals with the problem of relationship between the molecular parameters of group A meningococcal polysaccharide and its immunological effectiveness for laboratory animals and humans . The depolymerization of group A polysaccharide contained in the vaccine leads to a decrease in its capacity of inducing the production of hemagglutinating (19S and 7S) and bactericidal IgA antibodies in humans, as well as inducing an increase in the number of cells producing IgA antibodies in the spleen of immunized mice and the appearance of circulating IgA antibodies in their sera . As shown in this investigation, fully developed immune response to group A meningococcal vaccine may be achieved in humans only if the content of group A high-molecular polysaccharide in the vaccine is not less than 70% . Mice have been recommended as an experimental model for the prognostication of the effectiveness of meningococcal polysaccharide vaccines and for their control in the process of manufacture instead of currently used titration of bacteriolysins in the sera of immunized humans.

Zh Mikrobiol Epidemiol Immunobiol, 1995 Jul-Aug, (4), 17 - 9
{The range of individual sensitivity to adhesion by Neisseria meningitidis serogroup B in young men}; Rumiantsev SN et al.; 5,340 young adult males, including 5,149 healthy persons, 141 N . meningitidis carriers, 25 patients with generalized meningococcal infection and 6 patients with nasopharyngitis of meningococcal etiology, were examined . The study revealed that red blood cells of 17.4% of healthy persons were highly sensitive to N.meningitidis adhesion (adhesion indices equal to 0.25 and less), red blood cells of 20.4% of persons had low sensitivity to N.meningitidis adhesion (adhesion indices equal to 2 and greater) . All other persons with high sensitivity of their red blood cells proved to be patients with meningococcal infection or carriers of N.meningitidis of the same group.

Lik Sprava, 1996 May-Jun, (5-6), 136 - 41
{Oculomotor disorders in the clinical picture of bacterial meningoencephalitis}; Iarosh O et al.; The clinical study comprising 254 patients with bacterial meningoencephalitis (meningococcal, pneumococcal, staphylococcal, undefined, with n = 135, 76, 43, 120 respectively) permitted identifying a syndrome of oculomotor disturbances . It has been shown that assessment of changes in oculomotor disturbances enables the extent of inflammatory process, focal lesion as well as course and outcome of bacterial meningoencephalitis to be determined in a timely fashion.

Rev Neurol, 1997 Sep, 25(145), 1381 - 2
{Spontaneous intracranial hemorrhages in childhood}; Veira C et al.; INTRODUCTION: Spontaneous or non-traumatic intracranial haemorrhages seen in children of under 15 years old are most frequently due to cerebral vascular malformations, followed at a considerable distance by blood disorders, vasculopathies, tumours and the complications of radio-therapy . OBJECTIVE: To present the cases of spontaneous and non-traumatic cerebral haemorrhage seen at our hospital . MATERIAL AND METHODS: We reviewed all the paediatric cases of spontaneous cerebral haemorrhage diagnosed in our hospital over the previous sixteen years, excluding bleeding in the neonatal period . Computerized tomography was done in all cases, study of the cerebrospinal fluid, angiography and/or magnetic resonance in some cases . RESULTS: We selected 44 patients, of who the aetiology could be determined in 30 . Of these, 20 cases were due to vascular malformations, 7 were associated with haematological disorders, 2 with cerebral tumours and one case with meningococcal sepsis . The commonest form of presentation was that of an acute intracranial hypertension syndrome, also showing focal deficits, partial crises and meningism . CONCLUSIONS: The commonest cause of spontaneous intracranial haemorrhage in children is due to rupture of a vascular malformation, namely an arterio-venous malformation . Angiography and/or magnetic resonance are the techniques of choice for diagnosis . The various causes of disorders of haemostasia also are important in giving rise to intracranial bleeding.

Cent Eur J Public Health, 1997 Dec, 5(4), 214 - 8
Development of the epidemiological situation in invasive meningococcal disease in the Czech Republic caused by emerging Neisseria meningitidis clone ET-15/37; Krizova P et al.; Meningococcal clone ET-15/37, which appeared as a new one in the Czech Republic in 1993, caused an emergency epidemiological and clinical situation in invasive meningococcal disease, characterized by a high fatality rate (20%) compared to the "normal" fatality rate due to "non ET-15/37" strains . Morbidity rate increased since the first year of the new clone occurrence and reached the peak in 1995 . This clone has spread all over the country and investigation of the epidemiological markers of Neisseria meningitidis allowed to quickly recognize the emergency situation and subsequently to provide a targeted vaccination with A + C polysaccharide meningococcal vaccine which prevented the spread of the disease caused by Neisseria meningitidis C . The most frequent phenotype of ET-15/37 clone was C:2a:P1.2(P1.5) and its percentage achieved 80% of group C Neisseria meningitidis strains tested . This antigenic shift of Neisseria meningitidis was associated with the age shift in invasive meningococcal disease morbidity: teenagers started to be the most affected age group and later age group of 1-4 olds followed with high morbidity rates . In 1995 B variant of ET-15/37 clone, B:2a:P1.2(P1.5), appeared, causing a high fatality rate, too . Some data are indicative of a possible decrease in the invasive meningococcal disease incidence in the Czech Republic; nevertheless, the active surveillance and detailed investigation of meningococci have to be continued . After four years following the vaccination and chemoprophylaxis strategy recommended in the Guidelines, set up by the National Reference Laboratory for Meningococcal Infections in 1993, it is possible to conclude, that there have been practically no secondary cases of invasive meningococcal disease in the Czech Republic.

Commun Dis Rep CDR Rev, 1997 Dec 12, 7(13), R195 - 200
A retrospective survey of clusters of meningococcal disease in England and Wales, 1993 to 1995: estimated risks of further cases in household and educational settings; Hastings L et al.; Information about the epidemiology of meningococcal disease case clusters and the risk of further cases is sparse . Data on clusters in household and educational settings from 1 January 1993 to 31 March 1995 was requested from consultants in communicable disease control in England and Wales through a retrospective postal survey . Ninety-three per cent (122/131) responded . Of the 114 cases in 45 reported clusters, 77 (67.5%) were microbiologically confirmed . The case fatality rate in index cases was higher than in associated cases (18.2% vs 4.5%; p = 0.02) . Five out of 11 clusters in household settings consisted only of index and co-primary cases . No further cases occurred within two weeks after giving chemoprophylaxis to household contacts . The relative risks of further cases in the week after the index case arose were estimated to be 1200 for contacts in the household, 160 in secondary schools, 60 in primary schools, 1.8 in universities/colleges, and 0 in nurseries . Between seven and 30 days the relative risks were lower; 150 in households, and between 0 and 13 in all other settings . Beyond 30 days, the relative risk in the household setting was 8 and lower than this in all other settings . The absolute risk of further cases in the month following the index case was calculated as 210 per 100,000 in household members, 7-10/10(5) in pupils at the same school, and 0.6/10(5) in students at the same university or college . The current policy in England and Wales to recommend chemoprophylaxis for household members may prevent half of the further cases in this setting . Raised awareness may have contributed to the lower case fatality rate among household contacts who developed meningococcal disease, but the number of co-primary cases observed should prompt urgent enquiries about current illness in household contacts of index cases . The relative risk of further cases in preschool groups was low and apparently unaffected by changes in chemoprophylactic policy . The relative risk in school settings was raised in the month following a case, but the absolute risk was still low . Further study to quantify the risk in university settings is needed.

Arkh Patol, 1997 Sep-Oct, 59(5), 22 - 7
{Kidney morphology in children with meningococcal infection}; Khodasevich LS et al.; The kidneys of 30 children aged 1 month to 5 years who died of meningococcal infection were studied . Three variants of the kidney damage were distinguished on the basis of morphometric parameters . These variants corresponded to the stages of the infectious-toxic shock . The 1st variant observed in the reversible shock stages was characterized by arteriolar spasm and circulation shunts . The 2nd variant corresponded to initial manifestations of the disseminated vascular coagulation and was characterized by a combination of spasm and paralytic arteriola dilatation with a predominant thrombosis of the juxtamedullar glomeruli . The 3rd variant, the stage of the organ alterations, was followed by development of glomerular thrombotic microangiopathy with tubular epithelial necrosis in the proximal tubules this being the morphological counterpart of the hemolytico-uremic syndrome.

Klin Padiatr, 1997 Nov-Dec, 209(6), 380 - 3
{Recombinant tissue plasminogen activator in treatment of fulminant meningococcal infection}; Winter K et al.; This article reports about a young boy with fulminant meningococcal septicemia . Conventional treatment with antibiotics, intensive care and hemostatic drugs hold up vital functions . Because of extensive purpura fulminans with skin necrosis recombinant tissue plasminogen activator (rt-PA) was used . Under this therapy clinical improvement was observed.

Mol Gen Genet, 1997 Dec, 257(1), 28 - 34
Molecular divergence of the sia locus in different serogroups of Neisseria meningitidis expressing polysialic acid capsules; Claus H et al.; The serogroups B, C, W135 and Y of Neisseria meningitidis express chemically and immunologically distinct capsular polysaccharides containing sialic acid . In the case of serogroup B meningococci sialic acid is synthesized by the gene products of a locus termed sia and forms the homopolymers of the capsule . The organization of the genes required for sialic acid synthesis in serogroups B, C, W135 and Y was elucidated by PCR technology . Cloning, sequencing and the functional expression of the polysialyltransferase (PST) genes of serogroups B and C demonstrated that the difference in capsule composition derives from the presence of related, but distinct siaD genes coding for PSTs . Analysis of meningococci of serogroups W135 and Y expressing sialic acid heteropolymers revealed that the DNA sequences of the corresponding genetic loci in these serogroups were highly homologous, but differed completely from the siaD genes of serogroups B and C . This finding suggests that enzymes unrelated to those of serogroups B and C are required for the formation of sialic acid heteropolymers characteristic of the capsules of serogroups W135 and Y.

Curr Opin Hematol, 1995 Sep, 2(5), 402 - 6
Disseminated intravascular coagulation; Kitchens CS; Disseminated intravascular coagulation is the result of a severe underlying disorder that initiates massive activation of the coagulation system . It is always a symptom of the underlying disorder . These disorders may be as varied as meningococcemia and abdominal aortic aneurysm . Disseminated intravascular coagulation is a clinical diagnosis . Once the clinical impression has been considered, a small number of readily available tests will substantiate the diagnosis . Further testing is probably not necessary and certainly not cost-effective . Therapy for disseminated intravascular coagulation requires 1) the correction of the underlying problem, either by drainage of an abscess for sepsis, evacuation of the uterus in an obstetric catastrophe, or treatment of septicemia with antibiotics; and 2) the concomitant restoration of the circulatory system, perfusion, blood pressure, and electrolyte balance . Other forms of therapy are available but are quite secondary to these two . Success depends on the ability to recognize and correct the cause.

J Intern Med, 1997 Dec, 242(6), 519 - 20
The usefulness of skin culture in the diagnosis of chronic meningococcaemia; Texereau M et al.; We deal with the second reported case of chronic meningococcaemia in which the culture of skin biopsy led to the diagnosis . A 46-year-old man presented a history of recurrent fever and rash . Laboratory studies revealed an inflammatory syndrome . Serologic tests as well as blood culture tests were negative . The histological examination of skin lesions revealed a perivascular infiltrate in the dermis without any picture of leukocytoclastic vasculitis . A culture of skin specimen tested positive for Neisseria meningitidis (N . meningitidis) . After a week of antibiotic treatment, the patient recovered with no recurrence of either fever or rash over a two year period.

J Intern Med, 1997 Dec, 242(6), 455 - 64
Hypocomplementaemia caused by C3 nephritic factors (C3 NeF): clinical findings and the coincidence of C3 NeF type II with anti-C1q autoantibodies; Skattum L et al.; OBJECTIVES: The main purposes were to document manifestations associated with prolonged or clinically unexplained C3 deficiency and to approximate how often hypocomplementaemia of this kind is caused by C3 nephritic factors (C3 NeF), i.e . autoantibodies to alternative pathway C3 convertases . We also wished to distinguish between C3 NeF types I and II and to assess coincident autoantibody responses to the collagen-like region of C1q (C1qCLR) . SETTING: The investigation was based on serum samples referred to a specialized laboratory for complement analysis in the course of several years . SUBJECTS: Twenty-five persons with C3 concentrations lower than 0.43 g L-1, a third of the normal, were included in the study . RESULTS: Analysis using three methods provided evidence of C3 NeF in 20 persons with equal frequencies of C3 NeF types I and II . We also gave evidence of antibody specificity differences for the two types of C3 NeF . Six patients with C3 NeF type II showed antibodies to C1qCLR . Membranoproliferative glomerulonephritis was the predominant diagnosis and two patients had partial lipodystrophy reflecting the well-known association between these diseases and C3 NeF . Anaphylactoid purpura, systemic lupus erythematosus, and severe infection, mainly meningococcal disease, were also observed . CONCLUSIONS: The study group was probably fairly representative of C3 deficiency syndromes as encountered in clinical practice . The findings emphasize the heterogeneity of C3 NeF, and that acquired C3 deficiency syndromes caused by C3 NeF should perhaps be considered more often in diagnostic work.

Presse Med, 1997 Oct 25, 26(32), 1516 - 9
{Rapid epidemiological characterization of Neisseria meningitidis using polymerization chain reaction from biological samplings}; Giorgini D et al.; OBJECTIVES: Due to the spread of the meningococcal infections, a good epidemiological surveillance is needed . Prophylactic measures should be undertaken because of the high transmissibility of these bacteria . One problem which hinders the epidemiological characterization is that the responsible strain should be isolated . The aim of this work is to develop a rapid and non culture typing method of Neisseria meningitidis . METHODS: Six cerebrospinal fluids were obtained from 5 different patients with meningococcal meningitis . A specific locus, pil A, for N . meningitidis was amplified by polymerization chain reaction (PCR) . The polymorphism of this locus was then analyzed by digesting the PCR products with one of three different restriction enzymes . RESULTS: The polymorphism of this locus allowed us to establish the clonal relationships between the meningococcal strains involved in the infection . Three CSF corresponded to epidemiological strains . CONCLUSION: This typing method allows a rapid and less expensive epidemiological characterization of meningococcal infections . Moreover, it is a non culture typing method.

Scand J Infect Dis, 1997, 29(5), 479 - 83
Purpura fulminans in pneumococcal sepsis: case report and review; Carpenter CT et al.; Purpura fulminans is classically defined by ecchymotic skin lesions, fever, and hypotension . The majority of cases occur in association with bacterial sepsis, and disseminated intravascular coagulation (DIC) is usually present . Prompted by our experience with a patient with pneumococcal sepsis and purpura fulminans in whom hypotension was never observed, we evaluated the important parameters of sepsis in reports of this syndrome . 42 additional cases of pneumococcal bacteremia and purpura fulminans were identified . Hypotension was present in only 51% . Although DIC was present in 85% of patients, hypofibrinogenemia was documented in only 26% . By contrast, both hypotension and hypofibrinogenemia are present in the vast majority of patients described with purpura fulminans in association with meningococcal sepsis . These data confirm that hypotension is not a necessary feature of the syndrome of purpura fulminans associated with pneumococcal sepsis and suggest further that qualitative or quantitative differences exist in the DIC cascade of pneumococcal vs meningococcal sepsis.

J Laryngol Otol, 1997 Oct, 111(10), 913 - 6
Acute otitis media and otitis media with effusion in children with bacterial meningitis; Richardson MP et al.; Acute otitis media and otitis media with effusion (OME) have often been observed in children with bacterial meningitis . OME has also been proposed as the mechanism of reversible hearing loss after meningitis . In this controlled study, children with acute bacterial meningitis were studied using auditory brainstem responses (ABR), otoacoustic emissions, tympanometry and otoscopy . An age- and sex-matched control was recruited for each patient and the incidence of acute otitis media and OME was compared between the two groups . One hundred and twenty-four children with meningitis were studied . Ninety-two children (74 per cent) had meningococcal meningitis . Five patients (4 per cent) had conductive hearing loss (ABR threshold > or = 30 dB HL) at the time of discharge from hospital . None of the patients or controls had acute otitis media . Patients and controls were well matched for risk factors for OME and the prevalence of middle ear effusion in patients and controls was 7.2 per cent and 11.3 per cent respectively . The relative risk of OME in the children with meningitis was 0.64 (95 per cent confidence interval 0.29 to 1.42) . After nine months, three of the five children with meningitis and conductive hearing loss had regained normal hearing . In contrast to previous reports, there was no relationship between bacterial meningitis and acute otitis media or OME in this study . Nevertheless, coincidental conductive hearing defects were identified as the cause of reversible hearing loss in three patients.

Enferm Infecc Microbiol Clin, 1997 Oct, 15(8), 414 - 7
{A clone of Neisseria meningitidis serogroup C was responsible in 1994 of an unusual high rate of strains with a moderate resistance to penicillin in Caracas (Venezuela)}; Toro S et al.; BACKGROUND: The aim of the study was to analyse meningococcal strains isolated from patients in Caracas (Venezuela) with epidemiological markers and to determine their susceptibility to antimicrobial agents . METHODS: We analyzed 29 meningococcal clinical strains isolated during 1994 in Caracas by serogrouping, serotyping and subserotyping, multilocus enzyme analysis (MEE), ribotyping and pulse field electrophoresis (PFGE) profile . We also determined the Minimal Inhibitory Concentration (MIC) to 5 antimicrobial agents . RESULTS: Twenty four (82.7%) were group C meningococcal strains . All group C meningococci were characterized as C: 2b: P1.5, belonging to the same electrophoretic type (ET) by MEE and showing the same profile by PFGE by using Bg/II endonuclease restriction enzyme . These group C meningococci showed two different patterns by ribotyping, with only one band difference . All Group C and one group B N . meningitidis isolates were moderately resistant to penicillin (MIC > or = 0.12 mg/l) . CONCLUSIONS: During 1994 an unusual high incidence of meningococcal strains moderately resistant to penicillin (PenMR) was detected in Caracas (Venezuela) . A clone of C: 2b: P1.5 meningococci seem to be responsable for this high incidence of PenMR isolates.

Infect Immun, 1998 Jan, 66(1), 213 - 7
Periplasmic superoxide dismutase in meningococcal pathogenicity; Wilks KE et al.; Meningococcal sodC encodes periplasmic copper- and zinc-cofactored superoxide dismutase (Cu,Zn SOD) which catalyzes the conversion of the superoxide radical anion to hydrogen peroxide, preventing a sequence of reactions leading to production of toxic hydroxyl free radicals . From its periplasmic location, Cu,Zn SOD was inferred to acquire its substrate from outside the bacterial cell and was speculated to play a role in preserving meningococci from the action of microbicidal oxygen free radicals produced in the context of host defense . A sodC mutant was constructed by allelic exchange and was used to investigate the role of Cu,Zn SOD in pathogenicity . Wild-type and mutant meningococci grew at comparable rates and survived equally long in aerobic liquid culture . The mutant showed no increased sensitivity to paraquat, which generates superoxide within the cytosol, but was approximately 1,000-fold more sensitive to the toxicity of superoxide generated in solution by the xanthine/xanthine oxidase system . These data support a role for meningococcal Cu,Zn SOD in protection against exogenous superoxide . In experiments to translate this into a role in pathogenicity, wild-type and mutant organisms were used in an intraperitoneal mouse infection model . The sodC mutant was significantly less virulent . We conclude that periplasmic Cu,Zn SOD contributes to the virulence of Neisseria meningitidis, most likely by reducing the effectiveness of toxic oxygen host defenses.

Ren Fail, 1997 Nov, 19(6), 807 - 10
Outcome of acute renal failure in meningococcemia; Marotto MS et al.; We studied 28 consecutive patients (18 males and 10 females), 1-32 years of age, admitted to the intensive care unit from January 1989 to July 1995, with acute renal failure (ARF) due to meningococcal septicemia . All patients were treated with dexamethasone, penicillin, and/or chloramphenicol . Twenty-two patients presented septic shock and needed fluid replacement and vasoactive drugs . Acute renal failure was oliguric in 67.8% . Maximum levels of blood urea and serum creatinine were 210.3 +/- 26.6 mg/dL and 6.9 +/- 1.3 mg/dL, respectively . Metabolic acidosis was observed in 89.3% and hyperkalemia in 43% . The fractional excretion of sodium on day 1 was high (9.9 +/- 0.6%) . The urinalysis did not show trace protein, but hematuria was positive in 81% . The mortality rate was 63.3% . In the 10 survivors, oliguria was present for a period of 12.7 +/- 2.4 days, and the period to reach a normal serum creatinine level was 20.2 +/- 4.7 days, although in two female patients, 7 and 17 years old, the elevated serum creatinine persisted . Renal biopsy was performed in one of these patients which revealed bilateral cortical necrosis . These data show that acute renal failure in meningococcemia presents high mortality rate associated to shock; 80% of the survivors recover renal function; and bilateral cortical necrosis occurred in one patient in this series.

Enferm Infecc Microbiol Clin, 1997 Aug-Sep, 15(7), 369 - 72
{Meningococcal infection caused by Neisseria meningitidis serogroup C}; Ursua MI et al.; BACKGROUND: In recent years an increase has been observed in the prevalence of meningococcal infection by Neisseria meningitidis serogroup C and in the appearance of strains with moderate resistance to penicillin . PATIENTS AND METHODS: A microbiologic study of the cases of meningococcal infection of serogroup C treated from 1995 to 1996 in the health care area of Ferrol (La Coruna, Spain) was carried out . RESULTS AND CONCLUSIONS: Twenty-nine cases were detected in 1995 and 28 in 1996 . Meningococcal infection was observed in patients ranging from 8 months to 21 years of age (mean 5.7 years) . Distribution by sex was homogeneous . Two patients died . According to the clinical presentation, 11 were sepsis (38%), 4 meningitis (14%) and 14 both processes (48%) . In 4 LCR samples, the analytical study was normal with posterior positive culture results . The detection of bacterial antigen by latex agglutination in CSF only detected 32% of the cases . MIC study determined that 11 strains (38%) presented moderate resistance to penicillin, 9 with a MIC of 0.12 microgram/ml, one with a MIC of 0.25 microgram/ml and another with a MIC of 0.5 microgram/ml . In all the cases the strains were sensitive to cefotaxime (MIC < or = 0.06 microgram/ml) and rifampicin (MIC < or = 0.5 microgram/ml) . All the strains belonged to serogroup C serotype 2b, serosubtype P1.2,5 . During the study period 4 additional cases of meningococcal disease by serogroup B were observed.

Acad Emerg Med, 1997 Dec, 4(12), 1129 - 36
Adverse outcomes of managed care gatekeeping; Young GP et al.; OBJECTIVES: To determine whether telephone preauthorization for reimbursement of ED care (medical "gate-keeping") by managed care organizations (MCOs) is associated with adverse outcomes . METHODS: A structured review was performed of case reports solicited during 1994 and 1995 with possible adverse outcomes related to managed care gatekeeping . Gatekeeping was defined as the requirement imposed by an MCO that ED staff contact on-call gatekeepers (i.e., clinical or nonclinical MCO personnel) to request preauthorization for ED treatment (a requirement that such MCOs enforce by refusing payment for the ED care unless preauthorization is obtained) . Cases in which gatekeeper denial of preauthorization occurred were sought . Two physicians agreed on patient eligibility and classification criteria, then independently, retrospectively classified case reports identified as MCO ED payment denials into 1 of 4 categories: 1) adverse outcome; 2) patient placed at increased risk of death or disability; 3) "near miss" (emergency physicians prevented adverse outcome by caring for patient despite denial); and 4) none of the above . RESULTS: Of the 143 cases reviewed, 29 reports represented MCO ED payment denial . Of these 29 eligible cases, there were 4 (14%) patients with adverse outcomes, 4 (14%) patients placed at increased risk, and 21 (72%) near misses . All of the 29 cases came from different EDs, representing 9 different states, with the majority from California . Adverse outcomes included respiratory failure from fulminant meningococcemia, hypovolemic syncope from ruptured ectopic pregnancy, hypovolemic arrest from vascular fibroid hemorrhage necessitating emergency hysterectomy, and prolonged postoperative course following ruptured duodenal ulcer . Patients placed at increased risk were diagnosed as having epiglottitis, myocardial infarction, ruptured ectopic pregnancy, and delayed treatment of hip septic arthritis . Near misses included diagnoses of ectopic pregnancy (n = 2), pneumothorax (n = 2), alcohol withdrawal seizures and pancreatitis necessitating intensive care unit admission, appendicitis, bacterial meningitis, cerebrovascular accident, cryptococal meningitis in immuno comprised host, endocarditis, incarerated inguinal hernia, meningocococemia, meninoccocal meningitis, peritonsillar abscess, pneumococcal meningitis, ruptured abdominal aortic aneurysm, shock from gastrointestinal bleeding, small bowel obstruction, schizophrenic crisis resulting in psychiatric hospitalization, suicidal depression resulting in psychiatric hospitalization, and unstable angina . CONCLUSION: Adverse outcomes occur with MCO gatekeeping, Although the present study cannot ascertain whether this is a frequent event or a rare one, the safety of MCO gatekeeping deserves further study.

Thorax, 1997 Oct, 52(10), 927 - 9; discussion 926-7
Three cases of meningococcal pneumonia; Jones EM et al.; Three cases of pneumonia due to Neisseria meningitidis are described . In all three cases the organism was isolated only from blood cultures, but in the presence of good clinical and radiological evidence of pneumonia . The isolates belonged to three different serogroups: B type 2b, C, and Y . The cases illustrate the fact that N meningitidis can cause pneumonia and that culture of blood plays an important part in the diagnosis . Clinically there is nothing to differentiate meningococcal pneumonia from other causes of community acquired pneumonia . Predisposing factors include aspiration, immunosuppression, influenza, and adenovirus infections . When diagnosed, pneumonia due to N meningitidis should be notified and prophylaxis given as for meningitis or septicaemia.

Med Microbiol Immunol (Berl), 1997 Oct, 186(2-3), 159 - 66
Functional characterization of an isogenic meningococcal alpha-2,3-sialyltransferase mutant: the role of lipooligosaccharide sialylation for serum resistance in serogroup B meningococci; Vogel U et al.; The neisserial alpha-2,3-sialyltransferase, which is encoded by the lst gene, terminally links sialic acid to the lacto-N-neotetraose residue of neisserial lipooligosaccharide (LOS) . We used the recently published nucleotide sequence of the neisserial lst gene to construct an isogenic serogroup B meningococcal lst mutant by insertion of a kanamycin resistance gene . The resulting lst mutant expressed the unsialylated lacto-N-neotetraose structure . Using bactericidal assays and an infant rat model of meningococcal infection, we were able to demonstrate that lst mutation, in contrast to galE mutation, which results in a truncated LOS, or to siaD mutation, which results in loss of the capsule, neither had an effect on resistance to normal human serum, nor did it impair the ability of meningococci to spread systemically in the non-immune host . The lst mutant was serum resistant despite of the fact that the central factor of complement activation, C3b, was deposited on the lst mutant as efficiently as it was on the galE mutant . Thus, the terminal sialic acid residue linked to the wild-type LOS inhibited C3b deposition on the meningocuccus . However, in contrast to the galE mutant, where C3b deposition is promoted by IgM binding, the lst mutant's surface is not a target for IgM molecules . Thus, the lacto-N-neotetraose residue of neisserial LOS alone, without the presence of terminal sialic acid, is sufficient to block IgM epitopes either on the LOS itself, or on other surface molecules . Our data provide further insight into the complex interplay of capsular and LOS sialic acids in serogroup B meningococci with host effector mechanisms, and suggest that LOS sialylation in meningococci is of a less central importance as it is in gonococci.

Acta Paediatr, 1997 Nov, 86(11), 1263 - 6
Severe skin loss after meningococcal septicaemia: complications in treatment; Huang S et al.; Meningococcal septicaemia can lead to purpura fulminans with subsequent full thickness skin loss and deep muscle damage . The case reports on two infants who recovered from such a severe episode are used to describe post-septicaemic procedures and complications encountered in nursing care, psychological support and rehabilitation, with the main focus on surgery . Skin grafting is complicated by contaminated and contracting wound areas . Extensive tissue necrosis required leg amputations . Cultured keratinocytes in one of the patients were found to be too vulnerable . It has still to be proven whether more radical early-stage fasciotomies can limit skin and muscle necrosis . Patients with meningococcal septicaemia are subject to a high number of complications that are optimally treated in a burns unit . These patients require up-to-date knowledge of constantly evolving treatment possibilities and a high-level collaboration of all medical fields involved.

J Clin Microbiol, 1997 Dec, 35(12), 3215 - 9
Confirmation of suspicious cases of meningococcal meningitis by PCR and enzyme-linked immunosorbent assay; Saunders NB et al.; A significant problem in efficacy trials of meningococcal vaccines has been accurate identification of all cases of meningococcal disease that occur in study populations . The accuracy of case determination would be improved by utilizing methods which confirm or disprove suspicious cases of meningococcal disease that are culture negative . A collection of serum and cerebrospinal fluid (CSF) samples from a meningococcal vaccine field trial performed in Iquique, Chile, were utilized to assess the status of patients for whom cultures, Gram stains, and clinical evaluations for meningococcal disease were available . Nested PCRs (nPCRs) for amplification of Neisseria meningitidis DNA in CSF samples and enzyme-linked immunosorbent assays (ELISAs) for quantification of serum immunoglobulin G antibodies specific for N . meningitidis were used in combination to confirm or eliminate cases classified by physicians as suspicious for meningococcal disease . Samples from 12 of 79 patients suspected of having meningococcal meningitis tested positive by both methods; specimens from 61 of the 79 were negative by both methods; and samples from 6 patients yielded ambiguous results, and these cases remained unconfirmed . Direct sequence analysis of amplified DNA from patients suspected of having meningococcal disease confirmed that 2 of the 12 newly confirmed cases were not attributable to the typical epidemic strain (B:15:P1.{7},3) while the others were due to the epidemic strain . A combination of nPCR and ELISA reduced the number of suspicious cases in this study from 79 to 6, thereby improving the potential for assessment of vaccine efficacy . Molecular identification by nPCR in conjunction with immunological assessment of patient response could be considered diagnostic of disease in future testing of meningococcal vaccines to improve efficacy analyses.

FEBS Lett, 1997 Nov 10, 417(2), 253 - 9
Identification of potential ferric binding residues in the iron-binding protein of pathogenic Neisseria meningitidis through structure-based multiple sequence alignments; Gorinsky B et al.; The ferric iron-binding proteins of pathogenic Neisseria display structural and metal-binding properties characteristic of the transferrin family . In the absence of structural data for the ferric iron-binding proteins, spacial folding templates have been derived for the meningococcal protein from complete and partial structure-based multiple sequence alignments with structurally related proteins . The templates have been used to identify a number of potential iron-binding residues . These include four residues that are identical with the iron coordinating ligands of transferrin, but only two reside within equivalent structural elements.

FEMS Immunol Med Microbiol, 1997 Oct, 19(2), 159 - 67
Analysis of the human Ig isotype response to individual transferrin binding proteins A and B from Neisseria meningitidis; Johnson AS et al.; Subcapsular antigens, including transferrin binding proteins, are being considered as potential vaccines against serogroup B meningococci . This study examined the human isotype antibody responses in cases of meningococcal disease to meningococcal TbpA (transferrin binding protein A) and TbpB (transferrin binding protein B) from two strains (SD and B16B6) expressing high and low molecular mass TbpB respectively . TbpA isolated from both strains were recognised more frequently and higher durable ELISA absorbance values were detected than those detected against TbpB from either strain . These antibody responses to Tbps were independent of the infecting meningococcal strain type . The antibody response to the four proteins was highly variable between individuals and differed significantly against all four antigens . The variability of immune responses to each Tbp from the two strains suggests that a successful vaccine would need to include TbpA and TbpB from a number of strains.

Infect Immun, 1997 Dec, 65(12), 5184 - 90
Human B- and T-cell responses after immunization with a hexavalent PorA meningococcal outer membrane vesicle vaccine; van der Voort ER et al.; The PorA protein from Neisseria meningitidis, a potential vaccine candidate, induces human bactericidal antibodies which are serosubtype specific . We developed a hexavalent PorA outer membrane vesicle vaccine based on reference strain H44/76 . This vaccine contains the six most prevalent PorA serosubtypes as found in many countries . We previously reported on the immune responses of 20 adult volunteers after a single immunization with this vaccine . In this study, the B- and T-cell responses in three adult volunteers were studied after three consecutive immunizations (0, 2, and 11 months) . The first immunization induced a strong B-cell response resulting in high immunoglobulin G levels in an outer membrane vesicle enzyme-linked immunosorbent assay . At least a fourfold increase in bactericidal activity was observed against the majority (four to six) of the vaccine antigens compared to prevaccination titers . Immunodominance was observed for one or two of the PorAs in the bactericidal assay with a set of six isogenic H44/76-derived PorA target strains . These strains carry the individual PorAs as present in the vaccine . The second and third immunizations did not induce a further increase in the immune responses . A decline in time with respect to PorA-specific antibodies was observed after each immunization . These observations were reflected by the T-cell proliferation responses . Two additional sets of isogenic H44/76-derived mutant strains were used to study the specificity and/or cross-reactivity of the induced bactericidal antibodies . These target strains differ only in expressing mutant family variants of either PorA P1.7,16 or P1.5,10, both present in the PorA vesicle vaccine . The bactericidal antibody responses found were directed predominantly against the P1.7 (loop 1 of P1.7,16) and the P1.10 (loop 4 of P1.5,10) epitopes . This indicates that different portions of PorA were involved in the induction of bactericidal antibodies depending upon the PorA serosubtype.

Lancet, 1997 Nov 29, 350(9091), 1590 - 3
Use of protein-C concentrate, heparin, and haemodiafiltration in meningococcus-induced purpura fulminans; Smith OP et al.; BACKGROUND: Inflammatory and coagulation processes are both affected in meningococcaemia . Severe acquired protein-C deficiency in meningococcaemia is usually associated with substantial mortality: in survivors, skin grafts, amputation, and end-organ failure are not uncommon . Protein C is a natural anticoagulant and also has important anti-inflammatory activity . We assessed the effects of early replacement therapy with protein-C concentrate together with continuous veno-venous haemodiafiltration and conventional treatment in meningococcaemia . METHODS: 12 patients aged between 3 months and 27 years with meningococcaemia and severe acquired protein-C deficiency (mean 0.20 IU/mL) were studied . All patients had septic shock, widespread purpura, skin necrosis, and disseminated intravascular coagulopathy . After a test dose of protein-C concentrate, patients received a continuous infusion with the dose adjusted daily to keep the plasma concentration between 0.8 and 1.2 IU/mL . 11 patients were given unfractionated intravenous heparin (10-15 IU kg-1 h-1) . Nine patients had haemodiafiltration and one had peritoneal dialysis . The Glasgow meningococcal septicaemia prognostic score and the paediatric risk of mortality score predicted a minimum mortality of 80% and 57%, respectively . FINDINGS: No patient died . No adverse reactions to the treatment were seen . Two patients had lower-limb amputations, one of whom had a thrombotic cerebrovascular accident; both patients had received the protein-C concentrate and heparin later than the rest of the group (60 h {16.97} vs 12 h {3.13}) . One patient developed chronic renal failure despite receiving protein-C infusion 15 h after admission . INTERPRETATION: The acquired severe deficiency of protein C in meningococcaemia contributes to the pathogenesis of the thrombotic necrotic lesions in the skin and other organs and probably has an important role in the inflammatory response . Protein-C therapy is merely one approach to improve the host response in this syndrome . We suggest that a double-blind, randomised, controlled multicentre trial is needed to confirm our results.

Lancet, 1997 Nov 15, 350(9089), 1439 - 43
Preliminary evaluation of recombinant amino-terminal fragment of human bactericidal/permeability-increasing protein in children with severe meningococcal sepsis; Giroir BP et al.; BACKGROUND: Meningococcal sepsis remains an important cause of morbidity and mortality . We hypothesised that children with severe meningococcaemia might benefit from inhibition of the inflammatory processes thought responsible for fulminant disease . rBPI21 is a recombinant, N-terminal fragment of human bactericidal/permeability-increasing protein, which kills meningococci and binds to and clears bacterial endotoxin, these being the primary inducers of the systemic inflammation . The aim of this study was to determine the safety and kinetics of rBPI21 in children with severe meningococcaemia and to make a preliminary assessment of clinical outcome . METHODS: In this open-label, dose-escalation, phase I/II trial in severe meningococcaemia (Glasgow meningococcal prognostic septicaemia score {GMSPS} > or = 8), 26 patients aged 1-18 years, who had received their first dose of antibiotics no more than 8 hours earlier were given rBPI21 by infusion at total doses of 1.0, 2.0, and 4.0 mg/kg . FINDINGS: The patients had significantly raised plasma concentrations of bacterial endotoxin and cytokines . Peak and steady state BPI concentrations were comparable with pharmacokinetic data in healthy adults . All complications were compatible with the expected pattern for severe meningococcal sepsis . Only one patient died . This outcome was found to compare favourably with a predicted mortality of > or = 30% by GMSPS, > or = 15% by plasma endotoxin values, > or = 28% by plasma interleukin-6 concentrations, 29-49% by severity of coagulopathy, and 20% (11/54) by comparison with recent historical patients consecutively treated in participating centres before this study . INTERPRETATION: This, the first clinical trial or rBPI21, shows that rBPI21 can be safely administered to children with severe meningococcaemia and that the pharmacokinetics are consistent with patterns seen in healthy adults . Predicted mortality, on the basis of GMSPS, laboratory indices of inflammation and coagulopathy, and historical controls, was for between four and eight deaths . These findings have prompted a phase III randomised trial.

J Infect Dis, 1997 Nov, 176(5), 1285 - 92
Interaction of Neisseria maningitidis with the components of the blood-brain barrier correlates with an increased expression of PilC; Pron B et al.; A fatal untreated case of fulminant meningococcemia was examined to investigate the crossing of the blood-brain barrier (BBB) by Neisseria meningitidis . Microscopic examination showed bacteria in vivo adhering to the endothelium of both the choroid plexus and the meninges . Comparison of the isolates cultivated from the blood and the cerebrospinal fluid (CSF) revealed no antigenic variation of the pilin or the class 5 protein, whereas the expression of the PilC protein was greater in the CSF and the choroid plexus than in the blood . This was due to an increased activity of one of the pilC promotors . This higher expression of PilC correlated in vitro with greater adhesiveness to endothelial cells . A mutation in the single pilC locus of this strain abolished in vitro pilus-mediated adhesion to endothelial cells . These data suggest that PilC plays an important role in the crossing of the BBB, likely through pilus-mediated adhesion.

J Infect Dis, 1997 Nov, 176(5), 1277 - 84
Molecular epidemiology of sporadic (endemic) serogroup C meningococcal disease; Raymond NJ et al.; Understanding the basis of sporadic (endemic) meningococcal disease may be critical to prevention of meningococcal epidemic outbreaks and to understanding fluctuations in incidence . Active, prospective, population-based surveillance and molecular epidemiologic techniques were used to study sporadic serogroup C meningococcal disease in a population of 2.34 million persons (Atlanta area) . During 1988-1994, in which no outbreaks or case clusters were reported, 71 patients developed sporadic serogroup C meningococcal disease (annual incidence, 0.51/100,000) . Eighty-three percent of patients were >2 years old . By multilocus enzyme electrophoresis, pulsed-field gel electrophoresis, and serotyping, 84% (52/62) of the isolates available for study were identical or closely related members of the electrophoretic type 37 (ET 37) complex responsible for multiple serogroup C outbreaks in the United States in the 1990s . Sporadic disease caused by 9 clonal strains occurred over periods up to 4 years and accounted for 45% (28/62) of cases . Sporadic serogroup C meningococcal disease was most often due to a limited number of related strains that appear to slowly circulate in the population.

Mil Med, 1997 Nov, 162(11), 769 - 72
Primary meningococcal arthritis: case report and review of the literature; Wells M et al.; Meningococcal arthritis is a recognized manifestation of Neisseria meningitidis infection, the presentation of which may be confusing . Although arthritis occurs in the setting of meningococcal meningitis, it may also be seen as a primary event without neurological involvement and with or without cutaneous manifestations . We describe a patient with primary meningococcal arthritis and review the literature relating to the clinical types and pathogenic mechanisms . Comparisons of patient series from 1980 to the present with those reported before 1980 are described.

Microbiologia, 1997 Sep, 13(3), 337 - 42
Moderate resistance to penicillin in Neisseria meningitidis; Saez Nieto JA et al.; Meningococcal moderate resistance to penicillin (MICs 0.12 to 1 mg/l) was rarely reported before the 1980's in Spain . The frequency of isolation of resistant strains increased from 0.4% in 1985 to 42.6% in 1990 . In the last few years, these strains have been reported in several countries, which suggests a change in the meningococcal response to penicillin . The resistance is due, at least in part, to a decreased affinity of penicillin binding protein 2 (PBP2) for penicillin . This decreased affinity has also been found in commensal Neisseriae . Population genetic studies demonstrate that recombinational events, replacing parts of the PBP2 gene by the corresponding regions of commensal species, followed by a rapid spread of the clones could be the origin of such resistant strains.

Infect Immun, 1997 Nov, 65(11), 4836 - 42
Interaction of Neisseria meningitidis with a polarized monolayer of epithelial cells; Pujol C et al.; An important step in the pathogenesis of Neisseria meningitidis is the crossing of two cellular barriers, one in the nasopharynx and one in the brain . To approach the mechanisms by which this bacterium can achieve these goals, we studied the interactions between N . meningitidis and a monolayer of polarized tight junction-forming T84 cells grown on filter units . A capsulated, piliated, Opa-, and Opc- N . meningitidis strain is shown to be capable of adhering to and crossing this monolayer several orders of magnitude more efficiently than an isogenic nonpiliated derivative . This bacterial interaction does not affect the barrier function of tight junctions, as assessed by (i) the absence of modification of the transepithelial resistance, (ii) the lack of increase of {3H}inulin penetration across the monolayer, and (iii) the absence of delocalization of ZO-1, a tight junction protein . Electron microscopy studies and confocal examinations demonstrated that N . meningitidis (i) induces cytoskeletal rearrangements with actin polymerization beneath adherent bacteria, (ii) is intimately attached to the apical membrane of the cells, and (iii) can be internalized inside cells . Immunofluorescent staining with antipilus antibodies showed evidence that meningococcal piliation was dramatically reduced at later time points of bacterial cell interaction compared to the early phase of this interaction . In addition, adhesive bacteria recovered from an infected monolayer are piliated, capsulated, Opa-, and Opc-, a phenotype similar to that of the parental strain . Taken together, these data demonstrate that following pilus-mediated adhesion, N . meningitidis is involved in an intimate attachment which requires a bacterial component different from Opa and Opc and that meningococci cross a monolayer of tight-junction-forming epithelial cells by using a transcellular pathway rather than a paracellular route.

Infect Immun, 1997 Nov, 65(11), 4436 - 44
Sialylation of Neisseria meningitidis lipooligosaccharide inhibits serum bactericidal activity by masking lacto-N-neotetraose; Estabrook MM et al.; Exogenous sialylation of gonococcal lipooligosaccharide causes resistance to serum bactericidal activity . The aim of this study was to determine how lipooligosaccharide sialylation affects the serum sensitivities of group C Neisseria meningitidis strains . The relationship between the degree of sialylation or expression of the lipooligosaccharide sialic acid acceptor, lacto-N-neotetraose (LNnT), of nine meningococcal strains and their sensitivities to a pool of normal human sera was assessed . All strains expressed LNnT that was variously endogenously sialylated . Susceptibility to serum bactericidal activity ranged from extremely sensitive to resistant in 50% serum . For endogenously sialylated strains, the amount of killing correlated with the amount of free LNnT above a threshold of expression; strains that expressed less than the threshold survived in 25% serum . All strains added more sialic acid when they were grown in medium that contained cytidine monophospho-N-acetylneuraminic acid . Exogenous sialylation reduced the expression of free LNnT and significantly increased serum resistance . Exogenous sialylation affected killing through both classical and alternative complement pathways . The killing of exogenously sialylated strains also correlated with the amount of free LNnT . The amounts of endogenous, exogenous, and total sialic acid bound to LNnT did not correlate with the resistance of strains to serum bactericidal activity; rather, the loss of free LNnT expression by sialylation was associated with resistance . In conclusion, the expression of free LNnT by group C meningococcal strains is directly associated with the amount of killing of organisms in pooled human sera . Both endogenous and exogenous lipooligosaccharide sialylation are associated with increased serum resistance by masking LNnT.

Mol Microbiol, 1997 Sep, 25(6), 1047 - 64
Clonal descent and microevolution of Neisseria meningitidis during 30 years of epidemic spread; Morelli G et al.; Serogroup A meningococci of subgroups III, IV-1 and IV-2 are probably descended from a common ancestor that existed in the nineteenth century . The 10.5kb sequences spanning five distinct chromosomal loci, encoding cell-surface antigens, a secreted protease or housekeeping genes and intergenic regions, were almost identical in strains of those subgroups isolated in 1966, 1966 and 1917 respectively . During the subsequent two to three decades, all of these loci varied as a result of mutation, translocation or import of DNA from unrelated neisseriae . Thus, microevolution occurs frequently in naturally transformable bacteria . Many variants were isolated only once or within a single geographical location and disappeared thereafter . Other variants achieved genetic fixation within months or a few years . The speed with which sequence variation is either eliminated or fixed may reflect sequential bottlenecks associated with epidemic spread and contrasts with the results of phylogenetic analyses from bacteria that do not cause epidemics.

BMJ, 1997 Sep 27, 315(7111), 774 - 9
Epidemiology and clinical management of meningococcal disease in west Gloucestershire: retrospective, population based study; Wylie PA et al.; OBJECTIVE: To study changes in the epidemiology and management of meningococcal disease in one health district during a period of high local incidence of disease . DESIGN: Prospective case ascertainment and data collection over 14 years, with retrospective analysis of cases . SETTING: West Gloucestershire (population 320,000) . SUBJECTS: Residents developing meningococcal disease between 1 January 1982 and 31 December 1995 . RESULTS: 252 cases of invasive meningococcal disease were identified, of which 102 (40%) were officially notified and 191 (76%) were confirmed by culture from a deep site . The observed disease incidence of 5.6/100,000/year was about 2.7 times the national incidence (as measured by either statutory notifications or reference laboratory reports) . The period 1983-90 was characterised by a prolonged localised outbreak due to serogroup B serotype 15 sulphonamide resistant (B15R) strains . General practitioners gave benzylpenicillin before hospital admission to 18% of patients who presented with meningococcal disease in the first half of the study period and to 40% who presented in the second half . The overall case fatality rate was 6.7% (17/252) . Four deaths were directly or indirectly related to lumbar puncture . Of 120 patients whose lumbar puncture yielded meningococci, nine (8%) showed no abnormality on initial examination . CONCLUSIONS: Neither laboratory records nor formal notifications alone can give an accurate estimate of the incidence of meningococcal disease . Because of the dangers of lumbar puncture, the frequency of misleading negative initial findings, and the advent of new diagnostic techniques, the need for samples of cerebrospinal fluid should be critically questioned in each case of suspected meningococcal disease.

Pediatr Infect Dis J, 1997 Oct, 16(10), 979 - 83
Tobacco smoke as a risk factor for meningococcal disease; Fischer M et al.; BACKGROUND: Since 1992 the US Pacific Northwest has experienced a substantial increase in the incidence of serogroup B meningococcal disease . The current meningococcal polysaccharide vaccine is poorly immunogenic in young children and does not protect against N . meningitidis serogroup B . Defining alternative approaches to the prevention and control of meningococcal disease is of considerable public health importance . METHODS: We performed a case-control study comparing 129 patients in Oregon and southwest Washington with 274 age- and area-matched controls . We used conditional logistic regression analysis to determine which exposures remained associated with disease after adjusting for other risk factors and confounders and calculated the proportion of disease attributable to modifiable exposures . RESULTS: After adjustment for all other significant exposures identified, having a mother who smokes was the strongest independent risk factor for invasive meningococcal disease in children < 18 years of age {odds ratio (OR), 3.8; 95% confidence interval (CI) 1.6 to 8.9)}, with 37% (CI 15 to 65) of all cases in this age group potentially attributable to maternal smoking . Adult patients were more likely than controls to have a chronic underlying illness (OR 10.8, CI 2.7 to 43.3), passive tobacco smoke exposure (OR 2.5, CI 0.9 to 6.9) and to smoke tobacco (OR 2.4, CI 0.9 to 6.6) . Dose-response effects were seen for passive smoke exposure and risk of disease in all age groups . CONCLUSION: Tobacco smoke exposure independently increases the risk of developing meningococcal disease.

Biochemistry, 1997 Oct 14, 36(41), 12583 - 91
Thermodynamic analysis of the interaction between a bactericidal antibody and a PorA epitope of Neisseria meningitidis; van den Elsen JM et al.; An antibody-peptide model system was used to study the binding characteristics between a bactericidal antibody (MN12H2) and the P1 . 16 epitope of class 1 outer membrane protein PorA of Neisseria meningitidis by means of a thermodynamic approach . A series of four linear peptides and three "head-to-tail" cyclic peptides (with ring sizes of 9, 15 and 17 amino acids) were synthesized and evaluated as ligands . The peptides contain a fluorescein label and the core determinant amino acid sequence TKDTNNN (residues 180-186) of the PorA P1.16 epitope of meningococcal strain H44/76 . Thermodynamic data of the binding of the peptide homologs of the epitope by MN12H2 were assessed by measuring affinity constants (Ka) over a temperature range of 4-55 degrees C, using fluorescence spectroscopy . Curvilinear plots of ln Ka versus T (K) revealed strong temperature dependencies of enthalpy (DeltaH) and entropy (DeltaS) . The Gibbs free energy change (DeltaG) was only weakly temperature dependent . The large negative enthalpy value indicated the importance of polar interactions in the binding of both linear and cyclic peptides by MN12H2 . Sturtevant's analysis of the thermodynamic parameters showed large unfavorable vibrational contributions to the binding for all linear peptides {Sturtevant, J . M . (1977) Proc . Natl . Acad . Sci.U.S.A . 74, 2236-2240} . The large hydrophobic contribution compensating these vibrational modes was partially attributed to aspecific interaction of the fluorescein label with the antibody . Binding of MN12H2 to conformationally restricted epitope sequences was characterized by a dramatic reduction in the size of unfavorable vibrational components of the thermodynamic parameters . Substitution of individual charged amino acids of the P1.16 epitope sequence revealed that aspartate-182 was essential for the binding . The pH profile observed for the MN12H2-peptide complexes with a midpoint pH of approximately 8.5 suggests a positively charged histidine from the antibody binding site to be involved in a charge interaction with Asp-182 . These findings are consistent with the results from the crystal structure of the Fab fragment of MN12H2 in complex with a linear fluorescein-conjugated peptide homolog of the P1.16 epitope {van den Elsen et al . (1997) Proteins (in press)}, thereby identifying the basis of an increased incidence of endemic disease in England and Wales since 1981 caused by a mutant meningococcal strain.

Clin Immunol Immunopathol, 1997 Nov, 85(2), 134 - 42
T-Cell epitope mapping the PorB protein of serogroup B Neisseria meningitidis in B10 congenic strains of mice; Delvig AA et al.; T-cell epitope mapping the meningococcal serotype 15 PorB protein performed in this study in three congenic strains of mice with B10 genetic background revealed at least three murine T-cell epitopes (55-72, 163-180, and 226-261), located in the highly conserved putative transmembrane regions of Neisserial porins . Proliferation assays with popliteal lymph node cells derived from mice immunized with the PorB protein or with synthetic 18-mer peptides showed that epitope 163-180 immunized only in the H-2d haplotype, epitope 55-72 could be presented by both H-2f and H-2s molecules, while the 226-261 region covered by three overlapping peptides could be efficiently recognized in context of all three MHC class II haplotypes studied . Inhibition experiments with blocking I-Aalpha- and I-Ealpha-specific mAb showed that peptide 163-180 was presented by I-Ad and peptide 244-261 was presented by both I-Af and I-As . In addition, evidence was obtained that peptide 226-243 was presented in context of H-2d or I-As haplotypes and peptide 55-72 was presented in context of I-Af and I-As loci . Finally, the Norwegian outer membrane vesicle vaccine, but not the purified PorB protein, could recall responses in mice immunized with synthetic peptides corresponding to the 226-261 region . Altogether, these results suggest that T-cell epitopes identified on the serotype 15 PorB protein, particularly those presented by several MHC class II molecules (e.g., 226-261), could have important implications for the development of meningococcal vaccines .

J Pediatr, 1997 Sep, 131(3), 398 - 404
Incidence of bacteremia in infants and children with fever and petechiae; Mandl KD et al.; OBJECTIVE: We determined the incidence of serious invasive bacteremia caused by Neisseria meningitidis and other organisms in febrile infants and children with a petechial rash . Further, we studied the diagnostic value of laboratory and clinical finding in these patients . STUDY DESIGN: We conducted this prospective cohort study in the emergency department of an urban pediatric teaching hospital, during an 18-month period, and enrolled consecutive patients with temperature of 38 degrees C or higher and petechiae . Our measures included (1) laboratory tests (leukocyte count, coagulation profile, blood culture, and cerebrospinal fluid bacterial culture); (2) a questionnaire requesting clinical data including general appearance, number and location of petechiae, and presence or absence of purpura; and (3) a follow-up telephone survey documenting health status . RESULTS: A total of 411 patients were enrolled, with 57.7% between 3 and 36 months of age . Eight patients (1.9%) had bacteremia or clinical sepsis . Six had serious invasive bacteremia: N . meningitidis (two patients), group A streptococcus (one), or sepsis with negative culture results (three) . Two had occult bacteremia caused by Streptococcus pneumoniae and no evidence of sepsis . No patient had a positive cerebrospinal fluid culture result . None of the 357 well-appearing patients (95% confidence interval: 0.0%, 1.0%) had serious invasive bacteremia . Fifty-three patients appeared ill, including all six with serious invasive bacteremia . Ill appearance of the child had a sensitivity of 1.00 (95% confidence interval: 0.60, 1.00), and a leukocyte count of 15,000 or greater, or of less than 5000, had a sensitivity of 1.0 (95% confidence interval: 0.53, 1.00) for detecting serious invasive bacteremia . All children with meningococcemia had purpura . CONCLUSIONS: Invasive bacteremia occurred less frequently in our study than in previous series and was identified by clinical criteria . Our data support the treatment of selected well-appearing children with fever and petechiae as outpatients.

Eur J Obstet Gynecol Reprod Biol, 1997 Aug, 74(2), 145 - 7
Endocervical infection in a pregnant woman caused by Neisseria meningitidis: evidence of associated oropharyngeal colonization of the male partner; Harriau P et al.; A case of premature birth associated with an endocervical infection caused by Neisseria meningitidis is reported . Treatment of the mother with amoxycillin eradicated the bacteria from the endocervix and avoided newborn colonization or infection . Epidemiological investigation identified meningococcal oropharyngeal colonization of the male partner . The two strains were of the same antigenic formula B:4:P1.14 and exhibited identical rDNA restriction fragment patterns and outer membrane protein profiles . This phenotypic and genomic identity of strains is the first clear evidence for cross-colonization between sexual partners.

Acta Paediatr, 1997 Sep, 86(9), 1009 - 10
Screening for complement deficiency in bacterial meningitis; Ernst T et al.; Seventy-seven children with bacterial meningitis were screened for complement deficiency . Both the classical and the alternate pathways were normal in 75 patients . Transiently reduced total haemolytic activity of the classical pathway was documented in a boy with meningococcal meningitis . Total haemolytic activity of both the classical and the alternate pathways were reduced in another patient with pneumococcal meningitis: individual complement components determination indicated predominant activation of the alternate pathway.

J Acquir Immune Defic Syndr Hum Retrovirol, 1997 Aug 15, 15(5), 375 - 80
HIV-1 risk and vaccine acceptability in the Ugandan military; Hom DL et al.; Between July and October 1993, 570 19- to 22-year-old volunteers were screened for HIV-1, with a resulting seroprevalence rate of 18.3% (95% CI: 14.0%, 22.6%) . A cohort of 249 HIV-1-noninfected military recruits in the Ugandan Peoples' Defense Forces was followed prospectively for up to 18 months to document rates of HIV-1 seroprevalence, seroconversion, and knowledge and attitudes related to vaccine acceptability . The HIV-1 seroincidence rate was 3.56 per 100 person-years (95% CI: 1.49, 5.62) over 309 person-years of observation . At the 3- and 12-month visits, subjects were interviewed on issues of acceptance and knowledge about vaccines, including anti-HIV vaccines in particular . More than 90% believe that HIV vaccines will not cause HIV infection, and if offered, 88% report that they would take the vaccine if they were not already infected . Nonvaccine prevention methods were considered less reliable; monogamy and condom use were considered effective by only 33.5% and 69.3% of the cohort respectively . After completing the vaccine acceptability questionnaire at the 12-month visit, subjects were offered an approved polyvalent meningococcal vaccine as an indicator of general vaccine acceptance . All subjects reported receiving at least one previous vaccination, and 95% willingly accepted the meningococcal vaccination . The Ugandan military is a stable population at substantial risk for HIV-1 infection and may be a suitable population for vaccine efficacy trials.

Rev Prat, 1997 Sep 1, 47(13), 1428 - 32
{Febrile purpura in children}; Gillet Y et al.; The association of fever and purpura should first suggest the diagnosis of fulminant meningococcemia, owing to the severity of this condition . Compromise of peripheral circulation (cyanosis, prolonged refilling time) is important to consider, because normal blood pressure is usually observed at an early stage of a septic shock in children and particularly in young infants . When this hypothesis has been eliminated, other causes of febrile purpura can be considered: meningococcal meningitis; measles or other viral diseases; non infectious causes include mechanical purpura, Schonlein-Henoch's purpura and thrombocytopenia . In the frequent case where no cause has been found, the diagnosis of occult bacteriaemia should be considered, leading to parenteral administration of antibiotic following blood and cerebrospinal fluid cultures.

Clin Microbiol Rev, 1997 Oct, 10(4), 650 - 73
A week in the life of a travel clinic; Blair DC; International travel has increased enormously in recent years . With the greater movement of people have come increased encounters with a wide variety of diseases: malaria, dengue, cholera, typhoid fever, Ebola virus, and many more . The need for greater scope, consistency, and knowledgeability in pretravel health care to meet these challenges has been met by the emergence of the discipline of travel medicine . Travelers are well advised to become informed of the risks they face and to take steps to minimize those risks . After reviewing a traveler's medical history and a detailed itinerary, a travel medicine practitioner can offer expert advice on behavioral modifications, immunizations, and chemoprophylaxis regimens which will increase the traveler's margin of safety . The issues most frequently addressed in a travel clinic include treatment of traveler's diarrhea, malaria chemoprophylaxis, and immunizations, for hepatitis A, typhoid fever, tetanus/diphtheria, influenza, pneumococcus, hepatitis B, polio, meningococcus, measles, mumps, rubella, varicella, and rabies . Pretravel consultation must consider the age and underlying health problems of the traveler, the nature of the trip (wilderness, jungle, rural, urban, resort, or cruise), the duration of travel, and the latest available information on the site in terms of disease outbreaks, terrorism, and natural calamities.

J Bacteriol, 1997 Oct, 179(20), 6400 - 7
Identification of human transferrin-binding sites within meningococcal transferrin-binding protein B; Renauld-Mongenie G et al.; Transferrin-binding protein B (TbpB) from Neisseria meningitidis binds human transferrin (hTf) at the surface of the bacterial cell as part of the iron uptake process . To identify hTf binding sites within the meningococcal TbpB, defined regions of the molecule were produced in Escherichia coli by a translational fusion expression system and the ability of the recombinant proteins (rTbpB) to bind peroxidase-conjugated hTf was characterized by Western blot and dot blot assays . Both the N-terminal domain (amino acids {aa} 2 to 351) and the C-terminal domain (aa 352 to 691) were able to bind hTf, and by a peptide spot synthesis approach, two and five hTf binding sites were identified in the N- and C-terminal domains, respectively . The hTf binding activity of three rTbpB deletion variants constructed within the central region (aa 346 to 543) highlighted the importance of a specific peptide (aa 377 to 394) in the ligand interaction . Taken together, the results indicated that the N- and C-terminal domains bound hTf approximately 10 and 1000 times less, respectively, than the full-length rTbpB (aa 2 to 691), while the central region (aa 346 to 543) had a binding avidity in the same order of magnitude as the C-terminal domain . In contrast with the hTf binding in the N-terminal domain, which was mediated by conformational epitopes, linear determinants seemed to be involved in the hTf binding in the C-terminal domain . The host specificity for transferrin appeared to be mediated by the N-terminal domain of the meningococcal rTbpB rather than the C-terminal domain, since we report that murine Tf binds to the C-terminal domain . Antisera raised to both N- and C-terminal domains were bactericidal for the parent strain, indicating that both domains are accessible at the bacterial surface . We have thus identified hTf binding sites within each domain of the TbpB from N . meningitidis and propose that the N- and C-terminal domains together contribute to the efficient binding of TbpB to hTf with their respective affinities and specificities for determinants of their ligand.

FEMS Immunol Med Microbiol, 1997 Sep, 19(1), 1 - 5
Reactivity of the new monoclonal antibody '22' with meningococcal strains isolated from patients and carriers in Greece; Tzanakaki G et al.; Previous studies found that the majority of Neisseria meningitidis isolates from either patients or carriers in Greece do not react with the monoclonal antibodies used at present in the whole-cell ELISA (WCE) for determination of serotype and subtype antigens . A new monoclonal antibody designated '22' produced by the National Meningococcal Reference Laboratory in the Czech Republic was assessed in the whole-cell ELISA with 257 non-typable meningococcal strains from both patients (52) and carriers (205) . The carrier strains included 34 non-typable isolates from two immigrant populations: ethnic Greeks who have immigrated from Russia since 1989 (19/75) and Kurdish refugees (15/34) . Approximately 10% of the meningococcal strains isolated from patients and 11.7% of the carrier strains reacted with the reagent . Although the majority of meningococcal isolates from resident Greeks were not typable with the antibody, 11/19 (57.9%) of the carrier strains from Russian immigrants and 4/15 (20%) of those from the Kurdish refugees reacted with the new reagent.

Infect Immun, 1997 Oct, 65(10), 4341 - 9
Attachment of piliated, Opa- and Opc- gonococci and meningococci to epithelial cells elicits cortical actin rearrangements and clustering of tyrosine-phosphorylated proteins; Merz AJ et al.; Attachment of piliated Neisseria gonorrhoeae or Neisseria meningitidis cells to A431, Chang, HEC-1-B, or polarized T(84) cells triggers rearrangements of cortical microfilaments and the accumulation of phosphotyrosine-containing proteins at sites of bacterial contact . Actin stress fibers and the microtubule network remain unaltered in infected cells . The rearrangements reported here are triggered by piliated, Opa- and Opc- strains and also by nonpiliated gonococci (GC) that produce the invasion-associated OpaA protein . Thus, neisserial adhesion via either of at least two different adhesins can trigger cortical rearrangements . In contrast, these rearrangements are not triggered by nonadherent GC or meningococcal strains, by heat-killed or chloramphenicol-treated GC strains, or by Escherichia coli recombinants that adhere to cells via GC OpaA or Opal fusion proteins, suggesting that additional neisserial components are involved . Immunoblotting experiments did not detect consistent increases in the phosphorylation of specific proteins . Possible biological implications of these Neisseria-induced cortical rearrangements are discussed.

Infect Immun, 1997 Oct, 65(10), 4022 - 9
Complement factor C3 deposition and serum resistance in isogenic capsule and lipooligosaccharide sialic acid mutants of serogroup B Neisseria meningitidis; Vogel U et al.; Serogroup B meningococci express sialic acids on their surfaces as a modification of the lipooligosaccharide (LOS) and as capsular material consisting of alpha2,8-linked sialic acid homopolymers . The aim of this study was to elucidate the impact of each sialic acid component on the deposition of complement factor C3 and serum resistance . For this purpose, we used isogenic mutants deficient in capsule expression (a polysialyltransferase mutant) or sialylation of the LOS (a galE mutant) or both (a mutant with a deletion of the cps gene locus) . Bactericidal assays using 40% normal human serum (NHS) demonstrated that both the capsule and LOS sialic acid are indispensable for serum resistance . By immunoblotting with monoclonal antibody MAb755 that is specific for the C3 alpha-chain, we were able to demonstrate that C3 from 40% NHS was covalently linked to the surface structures of meningococci as C3b and iC3b, irrespective of the surface sialic acid compounds . However, C3b linkage was more pronounced and occurred on a larger number of target molecules in galE mutants with nonsialylated LOS than in meningococci with wild-type LOS, irrespective of the capsule phenotype . C3b deposition was caused by both the classical pathway (CP) and the alternative pathway of complement activation . Use of 10% NHS revealed that at low serum concentrations, C3 deposition occurred via the CP and was detected primarily on nonsialylated-LOS galE mutants, irrespective of the capsular phenotype . Accordingly, immunoglobulin M (IgM) binding to meningococci from heat-inactivated NHS was demonstrated only in both encapsulated and unencapsulated galE mutants . In contrast, inhibition of IgA binding required both encapsulation and LOS sialylation . We conclude that serum resistance in wild-type serogroup B meningococci can only be partly explained by an alteration of the C3b linkage pattern, which seems to depend primarily on the presence of wild-type LOS, since a serum-resistant phenotype also requires capsule expression.

FEBS Lett, 1997 Sep 8, 414(2), 409 - 13
Characterisation of the meningococcal transferrin binding protein complex by photon correlation spectroscopy; Boulton IC et al.; Photon correlation spectroscopy demonstrated for the first time that co-purified meningococcal TbpA+B form a complex in solution . This structure bound hTf and the resultant species underwent partial dissociation after exposure to additional hTf or following prolonged incubation . Purified TbpA and TbpB had similar apparent sizes but showed distinctive size profiles suggesting that TbpA forms a largely homogeneous population while TbpB may produce more variable particle sizes under these conditions.

Clin Infect Dis, 1997 Sep, 25(3), 640 - 6
Meningococcal septic shock in children: clinical and laboratory features, outcome, and development of a prognostic score; Kornelisse RF et al.; The clinical characteristics of and outcome for 75 children with meningococcal septic shock were studied . In addition, a new prognostic scoring system was developed . The median age of the patients was 3.2 years (range, 3 weeks to 17.9 years) . The most common phenotype of Neisseria meningitidis was B:4:P1.4 (27%) . A mortality rate of 21% was observed . Ten (17%) of the 59 survivors had serious sequelae . Calcium levels were significantly lower in patients with seizures . Disseminated intravascular coagulation occurred in 58% of the patients who were tested . Logistic regression analysis identified four laboratory features independently associated with mortality: serum C-reactive protein level, base excess, serum potassium level, and platelet count . These features were used to develop a novel scoring system with a predictive value for death and survival of 71% and 90%, respectively . The outcome was predicted correctly for 86% of the patients, which is higher than rates previously reported for scoring systems.

Lancet, 1997 Sep 20, 350(9081), 880 - 2
"Love's labours lost": failure to implement mass vaccination against group A meningococcal meningitis in sub-Saharan Africa; Robbins JB et al.; PIP: Despite the availability of a safe, effective polysaccharide vaccine, group A meningococcal meningitis epidemics persist in sub-Saharan Africa . In October 1996, there were almost 150,000 reported cases and 15,000 deaths, the majority of which involved children . At 3 months of age, induction of protective group A meningococcal antibody levels requires 2 injections at least 1 month apart . Reinjection of 5-year-old children increases group A antibodies to long-term protective levels . During meningitis epidemics in Nigeria, Mali, and Rwanda, fatality was significantly reduced in areas where scarce vaccine was administered selectively . Although effective on an individual basis, selective vaccination is unable to control meningitis epidemics . In Chad, mass vaccination of the entire population (excluding infants under 12 months) eliminated the disease . Successful mass vaccination against group A meningococcal epidemics also has been reported in Saudi Arabia, China, and refugee camps in Africa . Although cost is cited as an obstacle to routine mass vaccination to prevent meningococcal meningitis in South Africa, prevention is the least expensive approach to disease control . It is recommended that the entire population of Africa's meningitis belt receive group A meningococcal vaccine in accordance with the recommended age schedule in a mass vaccination program .

Pathol Biol (Paris), 1997 Apr, 45(4), 274 - 80
Neisseria meningitidis: fifteen cases of bronchopulmonary infections associated with septicaemia; Angelini S et al.; From 1989 to 1995, 4,053 meningococcal strains with a clinical information form were sent to the National Reference Center for Meningococci (NRCM) . Among these strains 569 meningococci (14.04%) were isolated from secretions of the bronchopulmonary tract by expectoration or fibroscopy protected or not from contamination by microflora . Fifteen observations associated an infection of bronchopulmonary syndrome and a meningococcemia without any other symptoms . These patients were in general elderly (mean = 71.3 years old) except for two cases: one of them presented sickle cell anemia and the other was very young (13 months) . In all cases, there were signs of clinical and X-ray pneumopathies . Among the fifteen cases described, eight cases occurred during the winter, and four during the spring . Twelve were described in countries north of the Loire . Serogroup Y was isolated six times, serogroup B four times and serogroup C three times . The small quantity of cases did not permit us to study the distribution of serotype and serosubtype . Three patients, aged 92, 86 and 74 years old, died from the meningococcal infection.

Proteins, 1997 Sep, 29(1), 113 - 25
Bactericidal antibody recognition of a PorA epitope of Neisseria meningitidis: crystal structure of a Fab fragment in complex with a fluorescein-conjugated peptide; van den Elsen JM et al.; Class 1 outer membrane protein PorA of Neisseria meningitidis is a vaccine candidate against bacterial meningitis . Antibodies against PorA are able to induce complement-mediated bacterial killing and thereby play an important role in protection against meningococcal disease . Bactericidal antibodies are all directed against variable regions VR1 and VR2 of the PorA sequence, corresponding to loops 1 and 4 of a two-dimensional topology model of the porin with eight extracellular loops . We have determined the crystal structure to 2.6 A resolution of the Fab fragment of bactericidal antibody MN12H2 against meningococcal PorA in complex with a linear fluorescein-conjugated peptide TKDTNNNL derived from the VR2 sequence of sero-subtype P1.7,16 (residues 180-187) from meningococcal strain H44/76 . The peptide folds deeply into the binding cavity of the Fab molecule in a type I beta-turn, with the minimal P1.16 epitope DTNNN virtually completely buried . The structure reveals H-bonds and van der Waals interactions with all minimal epitope residues and one essential salt bridge between Asp-182 of the peptide and His-31 of the MN12H2 light chain . The key components of the recognition of PorA epitope P1.16 by bactericidal antibody MN12H2 correspond well with available thermodynamic data from binding studies . Furthermore, they indicate the structural basis of an increased endemic incidence of infection by group B meningococci in England and Wales since 1981 associated with the occurrence of an Neisseria meningitidis escape mutant (strain-MC58) . The observed three-dimensional conformation of the peptide provides a rationale for the development of a synthetic peptide vaccine against meningococcal disease.

Microb Pathog, 1997 Sep, 23(3), 139 - 55
Lipopolysaccharide heterogeneity and escape mechanisms of Neisseria meningitidis: possible consequences for vaccine development; Rune Andersen S et al.; We wanted to compare the potential protective capacity of antibodies to meningococcal lipopolysaccharides (LPS) . The frequency of occurrence and degree of expression of the epitopes recognized by murine monoclonal antibodies (MAbs) to immunotypes L3,7,9 (9-2-L379) and L8 (2-1-L8) and to the LPS inner core (216-Lc and 217-Lc), were determined among 77 consecutive Norwegian meningococcal patient isolates from 1995 . The immunotype L3,7,9 was strongly expressed by 95% of the isolates, whereas L8 was weakly to moderately expressed by 9% . The inner core epitopes, were widely distributed among the serogroup B organisms, but were proved weakly expressed . The bactericidal activity of the four MAbs to various selected strains, was found to correlate positively with the quantity of the LPS epitopes recognized by these four MAbs in the bacteria . When tested in the serum bactericidal assay (SBA), often a few percent of the colonies of the inocula survived high concentrations of the MAbs . The results indicate that escape from the bactericidal action could be achieved through: (i) selection of variants not expressing the LPS-epitope of the actual MAb, (ii) a relative reduction in the density of the LPS-epitope achieved by dilution with another LPS structure or (iii) other factors, not yet understood . In conclusion, antibodies to the L3,7,9 epitope seem to be of importance for protection, whereas antibodies to the epitopes of the LPS inner core or immunotype L8, are not likely to offer protection alone . However, in order to prevent escape through alteration of the LPS pattern of the microbes, various LPS structures should probably be present in the OMV vaccine.

Commun Dis Intell, 1997 Aug 21, 21(17), 233 - 6
Meningococcal disease in Australia; looking at the past, thinking of the future; Patel M; In 1987 an unexpected change in the epidemiology of meningococcal disease began in Australia . The change was accompanied by an outbreak of serogroup A meningococcal disease among Aboriginal central Australians, and was followed by a progressive rise in notifications of disease caused by both serogroup B and C nationwide . Over the last 4 years, the notification rate has plateaued at 2.1-2.3 per 100,000 population . Virulent clonal groups of serogroup A and C meningococci that have caused outbreaks appear to be identical to strains that have caused large outbreaks in other countries . We cannot predict where and when the next outbreak will occur . However, we can plan to respond swiftly when it does . This report presents an overview of the observed trends, the association between the microbiology and epidemiology of meningococcal disease, and the relevance of this association to outbreaks, with recommendations for management.

FEBS Lett, 1997 Aug 18, 413(2), 364 - 70
Identification of potential ferric binding residues in the iron-binding protein of pathogenic Neisseria meningitidis through structure-based multiple sequence alignments; Gorinsky B et al.; The ferric iron-binding proteins of pathogenic Neisseria display structural and metal-binding properties characteristic of the transferrin family . In the absence of structural data for the ferric iron-binding proteins, spacial folding templates have been derived for the meningococcal protein from complete and partial structure-based multiple sequence alignments with structurally related proteins . The templates have been used to identify a number of potential iron-binding residues . These include four residues that are identical with the iron coordinating ligands of transferrin, but only two reside within equivalent structural elements.

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