Meningococcus

Pediatr Dermatol, 2003 Mar-Apr, 20(2), 169 - 72
Tissue-engineered skin in the healing of wound stumps from limb amputations secondary to purpura fulminans; Greenberg JE et al.; Currently wound treatment options of amputation stumps due to purpura fulminans include healing by secondary intention from wound debridement, split-thickness skin grafting, tissue and muscle flaps, plantar skin free transfer, skin expansion, artificial skin, and hyperbaric oxygen therapy . We saw a 6-month-old girl with purpura fulminans as a complication of meningococcemia . She developed necrosis of the distal extremities resulting in bilateral amputation of the lower limbs . Shortly thereafter the leg stumps also became necrosed and she underwent unsuccessful split-thickness grafts of lower limb ulcers . The patient's difficult-to-heal wounds made her an excellent candidate for treatment with tissue-engineered skin . At 10 months of age, this was applied to her previously nonhealing wounds . The tissue-engineered skin induced rapid healing of the patient's chronic amputation stump ulcers and provided her with substantial pain relief . In conclusion, tissue-engineered skin appears to be a potential beneficial treatment for chronic wounds in children with nonhealing amputation stumps.

Infect Immun, 2003 Apr, 71(4), 1849 - 55
Development and evaluation of an improved mouse model of meningococcal colonization; Yi K et al.; Studies of meningococcal pathogenesis have been severely restricted due to the absence of an adequate animal model . Given the significance of iron in meningococcal pathogenesis, we developed a model of Neisseria meningitidis colonization in outbred adult mice that included daily administration of iron dextran . While receiving iron, the animals were inoculated intranasally with the initial doses of bacterial suspension . Meningococci were recovered from the animals by nasopharyngeal washes . Approximately half of the animals inoculated with 10(7) CFU remained colonized 13 days after the initial bacterial inoculation . The model was further evaluated with genetically defined isogenic serogroup B mutant strains, and the colonization capabilities of the mutants were compared to that of the wild-type parent . A mutant that produces truncated lipooligosaccharide (KDO(2)-lipid A) and a mutant defective in capsule transport were dramatically impaired in colonization . A mutant defective in pilus transport (pilQ) showed moderately impaired colonization . The immunological aspect of the model was also evaluated by challenging mice after immunization with homologous whole-cell meningococci . The immunized mice were protected from colonization of the homologous strain . In this model, long-term meningococcal colonization was maintained, allowing us to study the effects of specific genetic mutation on colonization . In addition, this model allows investigation of the role of active immune response against meningococci.

Infect Immun, 2003 Apr, 71(4), 1650 - 5
Cross-reactivity of antibodies against PorA after vaccination with a meningococcal B outer membrane vesicle vaccine; Vermont CL et al.; The cross-reactivity of PorA-specific antibodies induced by a monovalent P1.7-2,4 (MonoMen) and/or a hexavalent (HexaMen) meningococcal B outer membrane vesicle vaccine (OMV) in toddlers and school children was studied by serum bactericidal assays (SBA) . First, isogenic vaccine strains and PorA-identical patient isolates were compared as a target in SBA, to ensure that the vaccine strains are representative for patient isolates . Geometric mean titers (GMTs) in SBA against patient isolates with subtypes P1.5-2,10 and P1.5-1,2-2 after vaccination with HexaMen were generally lower than those against vaccine strains with the same subtype, although the percentage of vaccine responders (> or =4-fold increase in SBA after vaccination) was not affected . Using various P1.7-2,4 patient isolates, GMTs as well as the number of vaccine responders were higher than for the P1.7-2,4 vaccine strain, indicating that the use of the P1.7-2,4 vaccine strain may have underestimated the immunogenicity of this subtype in HexaMen . Secondly, the cross-reactivity of antibodies induced by MonoMen and HexaMen was studied using several patient isolates that differed from the vaccine subtypes by having minor antigenic variants of one variable region (VR), by having a completely different VR or by having a different combination of VRs . MonoMen induced P1.4-specific antibodies that were cross-reactive with P1.4 variants P1.4-1 and P1.4-3 . HexaMen induced a broader cross-reactive antibody response against various patient isolates with one VR identical to a vaccine subtype or a combination of VRs included in HexaMen . Cross-reactivity, measured by a fourfold increase in SBA after vaccination, against these strains ranged from 23 to 92% depending on the subtype of the tested strain and was directed against both VR1 and VR2 . The extended cross-reactivity of vaccinee sera induced by HexaMen against antigenic variants has important favorable implications for meningococcal B OMV vaccine coverage.

Emerg Infect Dis, 2003 Mar, 9(3), 355 - 61
Epidemiology of meningococcal disease, New York City, 1989-2000; Moura AS et al.; Study of the epidemiologic trends in meningococcal disease is important in understanding infection dynamics and developing timely and appropriate public health interventions . We studied surveillance data from the New York City Department of Health and Mental Hygiene, which showed that during 1989-2000 a decrease occurred in both the proportion of patients with serogroup B infection (from 28% to 13% of reported cases; p<0.01) and the rate of serogroup B infection (from 0.25/100,000 to 0.08/100,000; p<0.01) . We also noted an increased proportion (from 3% to 39%; p<0.01) and rate of serogroup Y infection (from 0.02/100,000 to 0.23/100,000; p<0.01) . Median patient age increased (from 15 to 30 years; p<0.01) . The case-fatality rate for the period was 17% . As more effective meningococcal vaccines become available, recommendations for their use in nonepidemic settings should consider current epidemiologic trends, particularly changes in age and serogroup distribution of meningococcal infections.

J Exp Med, 2003 Mar 17, 197(6), 789 - 99
Vaccination against Neisseria meningitidis using three variants of the lipoprotein GNA1870; Masignani V et al.; Sepsis and meningitis caused by serogroup B meningococcus are devastating diseases of infants and young adults, which cannot yet be prevented by vaccination . By genome mining, we discovered GNA1870, a new surface-exposed lipoprotein of Neisseria meningitidis that induces high levels of bactericidal antibodies . The antigen is expressed by all strains of N . meningitidis tested . Sequencing of the gene in 71 strains representative of the genetic and geographic diversity of the N . meningitidis population, showed that the protein can be divided into three variants . Conservation within each variant ranges between 91.6 to 100%, while between the variants the conservation can be as low as 62.8% . The level of expression varies between strains, which can be classified as high, intermediate, and low expressors . Antibodies against a recombinant form of the protein elicit complement-mediated killing of the strains that carry the same variant and induce passive protection in the infant rat model . Bactericidal titers are highest against those strains expressing high yields of the protein; however, even the very low expressors are efficiently killed . The novel antigen is a top candidate for the development of a new vaccine against meningococcus.

East Afr Med J, 2002 Aug, 79(8), 405 - 7
Platelet functions in patients with meningococcal meningitis at the Kenyatta National Hospital, Nairobi; Amayo EO et al.; OBJECTIVE: To determine platelet abnormalities in patients with menigococcal meningitis . DESIGN: Case control study . SUBJECTS: Fifty seven cases of mennigococcal meningitis based on a cerebrospinal fluid gram stain for gram negative diplococcus or positive culture were recruited . Fifty-seven controls matched for age and sex were also recruited . The following platelet functions tests were performed; platelet counts, platelet adhesiveness, platelet aggregation and clot retraction . RESULTS: Fifty seven patients (41 males and 16 females) with meningococcal meningitis were studied . Their mean age was 25.5 +/- 8.32 years with a range of 15 to 45 years . Five patients had purpura, four peripheral gangrene, eight conjunctival haemorrhages and one was in shock . There was a statistical significant difference in the platelet aggregation and clot retraction between the patients and controls at p-values of 0.0001 and 0.0002 respectively . There was no significant difference in the platelet count and adhesiveness between the patients and the controls at a p-value of 0.203 and 0.22 respectively . No association was found between the platelet functions and the clinical presentations . CONCLUSION: Patients with meningococcal meningitis have abnormalities in the platelet functions mainly in aggregation and adhesiveness.

Ned Tijdschr Geneeskd, 2003 Jan 25, 147(4), 167 - 8
{Primary meningococcal-monoarthritis (Neisseria meningitidis serotype C) in a child}; te Poele EM et al.; A 26-month-old girl had a painful, swollen right knee, accompanied by fever and vomiting . She had had an upper respiratory tract infection for a number of days . Following a positive culture of synovial fluid, monoarthritis caused by Neisseria meningitidis serotype C without other signs of illness was diagnosed . She recovered completely after one joint aspiration and intravenous and oral antibiotic therapy . N . meningitidis serotype C infections without meningitis or septicaemia are rare, but should form part of the differential diagnosis of septic monoarthritis.

Euro Surveill, 2002 May, 7(5), 74 - 6
Vaccination campaign following an increase in incidence of serogroup C meningococcal diseases in the department of Puy-de-Dôme (France); Levy-Bruhl D et al.; In the department of Puy-de-Dome, France, 17 cases of invasive meningococcal disease C were notified between March 2001 and the first week of 2002 . Among the 15 confirmed cases, 11 (73%) were serogroup C, 2 (13%) serogroup B, and 2 could not be identified . The rapid increase in the number of cases in a period of low endemicity for the rest of the country and the severity of the disease (case fatality ratio 27%, purpura fulminans 64%) led the health authorities to initiate a vaccination campaign targeting children and young adults from 2 months up to 20 years living in a limited area of the department . Around 80,000 people were immunised between 16/01/02 and 09/02/02 . More than half of the 1390 immediate side effects were headache and dizziness . As of mid-March, no further case of meningococcal disease has been notified since 6 January.

Euro Surveill, 1999 Feb, 4(2), 18 - 21
Vaccination campaign for meningococcal disease in a rural area in the Netherlands - January 1998; Van Steenbergen JE et al.; Neisseria meningitidis group C regularly causes epidemics in schools, universities, and army units, and in the past decade community outbreaks have been reported . Since a safe and effective polysaccharide vaccine is available the issue arises repeatedly

Euro Surveill, 1996 Jun, 1(6), 45 - 46
Bacterial meningitis in Europe for 1994; Comite Editorial / Editorial Committee; Thirty-five European countries contributed surveillance data to the fourth annual report of the King's European Meningococcal Surveillance Unit in London, which gathers and shares information about the epidemiology of meningococcal disease to inform publi

Euro Surveill . 1997 Oct;2(10):80.
New epidemiological features of meningococcal disease in Belgium; Carion F et al.; SCIENTIFIC EDITOR In Belgium, after the epidemic of the early 1970s caused by Neisseria meningitidis B:2b:P1.2 (highest incidences in 1971 and 1972 with 5 cases per 100 000 population per year), the incidence of meningococcal disease fell to normal inter

Euro Surveill, 1997 Oct, 2(10), 78 - 79
Surveillance of meningococcal disease in France, 1990-1997; Hubert B et al.; The surveillance of meningococcal disease in France is based on four complementary sources of data . 1 . Meningococcal disease has been a notifiable disease since 1902 . A case definition for surveillance was introduced in 1985, based on the isolation of Ne

Euro Surveill . 1997 Oct;2(10):78.
Cases of Neisseria meningitidis in Greece; Kremastinou J et al.; In Greece, Neisseria meningitidis appears as sporadic cases with some seasonal local outbreaks . The notification of meningococcal disease to the local health authorities and the Ministry of Health is mandatory . In 1994, the National Reference Centre for M

Euro Surveill, 1997 Oct, 2(10), 76 - 77
Meningococcal infection in Scotland, 1995 to 1997; O Brien SJ et al.; The incidence of meningococcal infection in Scotland was 4.1 cases per 100 000 population in 1996 compared with 3.8/100 000 in 1995 (210 cases reported in 1996 compared with 193 in 1995) . There were 14 deaths, representing a crude case fatality rate of 6.

Euro Surveill, 1997 Oct, 2(10), 75 - 76
Trends in serogroup C meningococcal disease in the Republic of Ireland; Fogarty J; A national laboratory surveillance system for meningococcal disease was established in the Republic of Ireland (ROI) in November 1994 . Data collection forms are returned centrally each month whether or not cases have occurred, containing a minimum data se

Euro Surveill, 1997 Oct, 2(10), 74 - 75
The epidemiology of meningococcal disease in England and Wales, 1996 and 1997; Ramsay ME et al.; Surveillance of meningococcal infection in England and Wales relies on three sources of data . Doctors are required by statute to notify clinically diagnosed cases of meningococcal meningitis and, since 1989, cases of meningococcal septicaemia (in the abse

Euro Surveill, 1997 Oct, 2(10), 71 - 74
Changing epidemiology of meningococcal disease in Spain, 1989-1997; Mateo S et al.; In the 1980s, the presentation of meningococcal disease in Spain was closely linked to the predominance of serotype B . Since the early 1990s however, an increasing number of serotype C strains have been isolated from a number of localities in the west of

Euro Surveill, 1997 Oct, 2(10), 69 - 71
Recent changes in meningococcal disease in Europe; Hubert B et al.; Few infections can cause the social stress that occurs when meningococcal disease enters a community . The ability of Neisseria meningitidisto kill a healthy child within a few hours is one reason for this fear . It is also clear that preventive measures ag

Zh Mikrobiol Epidemiol Immunobiol, 2003 Jan-Feb, (1), 68 - 70
{Antibodies to meningococcal iron regulated protein FbpA and minor proteins in the sera of patients with meningococcal meningitis}; Gamzulina LN et al.; Altogether 7 blood serum specimens taken from 3 patients with meningococcal meningitis were studied by the method of immunoblotting . The study revealed that on day 7 and especially on day 10 from the onset of the disease antibodies to periplasmatic iron-regulated protein FbpA with a molecular weight of 34 kD appeared in the serum of one patient . In the sera of two other patients the appearance of antibodies to minor iron-regulated proteins with molecular weights of 43 kD and 46 kD, absent at the acute stage of the disease, were detected on day 7 . As the process of convalescence was progressing, in all patients under observation an increase in the specific immune response to proteins of class 5 with molecular weights of 20-14 kD was observed.

Clin Infect Dis, 2003 Mar 15, 36(6), 679 - 83 Epub 2003 Mar 03.
Hajj-associated outbreak strain of Neisseria meningitidis serogroup W135: estimates of the attack rate in a defined population and the risk of invasive disease developing in carriers; Wilder-Smith A et al.; An outbreak of disease due to Neisseria meningitidis serogroup W135 (W135) occurred in 2000 and 2001 among pilgrims returning from the annual Islamic pilgrimage to Saudi Arabia (the Hajj) and in their contacts . For the Hajj in 2000, the attack rate of W135 disease was 25 cases per 100,000 pilgrims . After the introduction of quadrivalent meningococcal vaccine for the Hajj in 2001, no pilgrim developed W135 disease . The estimated attack rates for household contacts of returning pilgrims were 18 cases and 28 cases per 100,000 contacts for the years 2000 and 2001, respectively . On the basis of rates of transmission of W135 carriage and national epidemiological data, the risk that an unvaccinated household contact who had acquired W135 carriage would develop invasive meningococcal disease was estimated to be 1 case per 70 acquisitions . Public health policies to protect household contacts of Hajj pilgrims need to be implemented.

East Afr Med J, 2002 Apr, 79(4), 214 - 6
Rheumatic disorders in Sub-saharan Africa; McGill PE et al.; OBJECTIVE: To review prevalence of rheumatic disorders in Sub-saharan Africa and in the context of current medical practice in the region assess the need for service and educational provision . DATA SOURCES: Medline, (English, French) . Pre-Medline literature review from the 1950's (Current contents) . Various conference reports including attendance at all three AFLAR (African League Against Rheumatism) congresses in the 1990's . Author's personal database . All cited references read in full . CONCLUSIONS: The evidence shows rheumatoid arthritis and systemic lupus erythematosus to be increasing in frequency in the indigenous populations of East, Central and South Africa but remaining rare in West Africans . Gout is now more prevalent than ever throughout the subcontinent . HIV has spawned a variety of previously rare spondyloarthropathies (reactive arthritis, psoriatic arthritis, enthesopathy) and changed the epidemiology of pyomyositis and osteomyelitis . Osteoarthritis is a universal problem . Juvenile chronic arthritis is not rare and rheumatic fever is common . Acute and chronic locomotor problems associated with diverse entities such as leprosy, brucellosis, meningococcus, alpha viruses, parasites, fluorosis, rickets and haemoglobinopathies enhance diagnostic diversity and therapeutic and educational requirements . Suggestions made to address the challenge posed by the burden of rheumatic disorders.

Genome Res, 2003 Mar, 13(3), 391 - 8
Large-scale analysis of the meningococcus genome by gene disruption: resistance to complement-mediated lysis; Geoffroy MC et al.; The biologic role of a majority of the Neisseria meningitidis 2100 predicted coding regions is still to be assigned or experimentally confirmed . Determining the phenotypic effect of gene disruption being a fundamental approach to understanding gene function, we used high-density signature-tagged transposon mutagenesis, followed by a large-scale sequencing of the transposon insertion sites, to construct a genome-wide collection of mutants . The sequencing results for the first half of the 4548 mutants composing the library suggested that we have mutations in 80%-90% of N . meningitidis nonessential genes . This was confirmed by a whole-genome identification of the genes required for resistance to complement-mediated lysis, a key to meningococcal virulence . We show that all the genes we identified, including four previously uncharacterized, were important for the synthesis of the polysialic acid capsule or the lipooligosaccharide (LOS), suggesting that these are likely to be the only meningococcal attributes necessary for serum resistance . Our work provides a valuable and lasting resource that may lead to a global map of gene function in N . meningitidis.

J Am Chem Soc, 2003 Mar 12, 125(10), 2930 - 9
Conformational flexibility of the group B meningococcal polysaccharide in solution; Henderson TJ et al.; To elucidate the role of secondary structure in the immune response against alpha(2-->8)-linked polysialic acid, the capsular polysaccharide of Group B meningococci, we have investigated its solution dynamics by using specific models of molecular motion and hydrodynamic modeling to interpret experimental NMR data . (13)C-{(1)H} NMR relaxation times and steady-state NOE enhancements were measured for two aqueous solutions of alpha(2-->8)-linked sialic acid polysaccharides . Each contained a unique distribution of polysaccharide chain lengths, with average lengths estimated at 40 or 400 residues . Models for rigid molecule tumbling, including two based on helical conformations proposed for the polysaccharide,(31) could not explain the NMR measurements . In general for these helices, the correlation times for their overall tumbling that best account for the NMR data correspond to polysaccharide chains between 9 and 18 residues in length, far short of the average lengths estimated for either solution . The effects of internal motions incorporated into these helices was modeled with an effective correlation time representing helix tumbling as well as internal motion . This modeling demonstrated that even with extreme amounts of internal motion, "flexible helices" of 25 residues or more still could not produce the NMR measurements . All data are consistent with internal and segmental motions dominating the nuclear magnetic relaxation of the polysaccharide and not molecular tumbling . Statistical distributions of correlation times have been found specifically for the pyranose rings, linkage groups, and methoxy groups that can account for the measured relaxation times and NOE enhancements . The distributions suggest that considerable flexibility attends the polysaccharide in solution, and the ranges of motional frequencies for the linkage groups and pyranose rings are comparable . We conclude that the Group B meningococcal polysaccharide is a random coil chain in solution, and therefore, does not have antigenic epitopes dependent upon a rigid, ordered conformation.

Int J Antimicrob Agents, 2003 Feb, 21(2), 189 - 92
Neurological disorders and travel; Awada A et al.; Travel is associated with a number of neurological disorders that can be divided into two categories: (1) Neurological infections including encephalitides, neurotuberculosis, neurobrucellosis, cysticercosis and trichinosis . Some of these disorders can be prevented by vaccinations, such as Japanese B encephalitis and rabies, some by the use of insect repellents and some by avoiding raw milk products and undercooked meat . (2) Non-infective neurological disorders, such as acute mountain sickness and high altitude cerebral oedema, problems occurring during air travel such as syncope, seizures, strokes, nerve compression, barotrauma and vertigo, motion sickness and foodborne neurotoxic disorders such as ciguatera, shellfish poisoning and intoxication by cassava . This group of diseases and disorders could be prevented if the traveller knows about them, applies simple physiological rules, takes some specific medications and knows how to avoid intoxications in certain geographical areas . Meningococcal meningitis, malaria and jet lag syndrome are extensively discussed in other articles of this issue . The discussion in this paper will be limited to the other disorders.

Int J Antimicrob Agents, 2003 Feb, 21(2), 175 - 80
Vaccination priorities; Steffen R et al.; Selection of immunizations should be based on requirements and on risk of infection . According to the International Health Regulations, many countries require yellow fever vaccination and proof thereof as the International Certificate of vaccination . Additionally selected countries require proof of vaccination against cholera and meningococcal disease . A consultation for travel health advice is always an opportunity to ascertain that routine immunizations have been performed . Recommended immunizations often are more important for traveller's health than the required or routine ones . The most frequent vaccine preventable infection in non-immune travellers to developing countries is hepatitis A with an average incidence rate of 0.3% per month; in high risk backpackers or foreign-aid-volunteers this rate is 2.0% . Many immunizations are recommended for special risk groups only: there is a growing tendency in many countries to immunize all young travellers to developing countries against hepatitis B, as it is uncertain who will voluntarily or involuntarily get exposed . The attack rate of influenza in intercontinental travel is estimated to be 1% . Immunity against poliomyelitis remains essential for travel to Africa and parts of Asia . Many of the 0.2-0.4% who experience an animal bite are at risk of rabies . Typhoid fever is diagnosed with an incidence rate of 0.03% per month among travellers to the Indian subcontinent, North and West Africa (except Tunisia), and Peru, elsewhere this rate is 10-fold lower . Meningococcal disease, Japanese encephalitis, cholera and tuberculosis have been reported in travellers, but these infections are rare in this population . Although no travel health vaccine is cost beneficial, most professionals will offer protection against the frequent risks, while most would find it ridiculous to use all available vaccines in every traveller . It is essentially an arbitrary decision made on the risk level one wishes to recommend protection--but the priorities need to be set correctly.

Int J Antimicrob Agents, 2003 Feb, 21(2), 112 - 5
W135 meningococcal carriage in association with the Hajj pilgrimage 2001: the Singapore experience; Wilder-Smith A; An international outbreak among pilgrims returning from the Hajj (pilgrimage to Mecca) and their close contacts was caused by W135 Neisseria meningitidis . In Singapore, this strain is a new emerging problem, clearly associated with this outbreak . We investigated the extent of transmission of N . meningitidis in Hajj pilgrims and their contacts, in order to provide evidence for developing a rational public health policy . We found a high acquisition rate of W135 N . meningitidis in Singaporean pilgrims during the Hajj with substantial transmission to their household contacts . These findings would support a policy of eradication of pharyngeal carriage in returning pilgrims to prevent introduction and dissemination of meningococci.

Int J Antimicrob Agents, 2003 Feb, 21(2), 107 - 11
Meningococcal carriage among local inhabitants during the pilgrimage 2000-2001; Balkhy HH et al.; The first international outbreak of Neisseria meningitidis serogroup W135 occurred in 2000, in direct association with the annual Hajj in Saudi Arabia . In anticipation of the following Hajj, we conducted a survey of oropharyngeal carriage rates of N . meningitidis both pre- and post-pilgrimage in the King Khalid National Guard Hospital (KKNGH) employees preparing to attend the Hajj . These KKNGH employees were native to the Mecca-Jeddah area . Pre-Hajj throat cultures were obtained 1 week prior to Hajj, and post-Hajj cultures within 10 days after completing the Hajj pilgrimage . A total of 327 throat culture samples were collected from 218 persons . Overall meningococcal carriage rate was found to be 4.7% . Serogroup W135 accounted for 40% of all recovered pre-Hajj strains of N . meningitidis . Only one post-Hajj sample was positive for N . meningitidis W135 . This high rate of colonization with N . meningitidis serogroup W135 indicates this strain predominates amongst the population indigenous to the Mecca-Jeddah area . This 'nidus' of N . meningitidis W135 is a potential reservoir for future outbreaks . More worrying, there is real risk of future W135 endemicity in this vulnerable local population . These preliminary findings warrant larger surveillance studies examining both transmission and carrier rate acquisition of N . meningitidis in the Mecca-Jeddah area . These vital data are needed to curb further epidemic outbreaks during future Hajj pilgrimages.

Int J Antimicrob Agents, 2003 Feb, 21(2), 102 - 6
Meningococcal disease and travel; Wilder-Smith A et al.; Meningococcal disease continues to be a worldwide problem . This review examines the impact meningococcal disease has on international travel and vice versa the impact international travel has on the intercontinental spread of meningococci . The risk of meningococcal disease to the endemic population differs from that of travellers . The best documented risk of meningococcal disease among travellers has been in Hajj pilgrims for Mecca and Madina in Saudi Arabia . In response to the recent Hajj associated outbreak of W135 meningococcal disease, quadrivalent meningococcal vaccine (against serogroups A/C/Y/W135) became a visa requirement . In view of increasing worldwide reports of Y and W135 meningococcal disease, there should be a switch in recommendation from the bivalent (against A& C) to the quadrivalent vaccine for all travellers.

Int J Antimicrob Agents, 2003 Feb, 21(2), 96 - 101
Travel epidemiology: the Saudi perspective; Memish ZA et al.; The Kingdom of Saudi Arabia occupies four-fifths of the Arabian Peninsula, with a land area of 2 million square kilometres . Saudi Arabia holds a unique position in the Islamic world, as the custodian of the two holiest places of Islam, in Mecca and Medina . Annually, some 2 million Muslims from over 140 countries embark on Hajj . This extraordinary en masse migration is a unique forum for the study of travel epidemiology since the Hajj carries various health risks, both communicable and non-communicable, often on a colossal scale . Non-communicable hazards of the Hajj include stampede and motor vehicle trauma, fire-related burn injuries and accidental hand injury during animal slaughter . Communicable hazards in the form of outbreaks of multiple infectious diseases have been reported repeatedly, during and following the Hajj . Meningococcal meningitis, gastroenteritis, hepatitis A, B and C, and various zoonotic diseases comprise some of the possible infectious hazards at the Hajj . Many of these infectious and non-infectious hazards can be avoided or averted by adopting appropriate prophylactic measures . Physicians and health personnel must be aware of these risks to appropriately educate, immunize and prepare these travellers facing the unique epidemiological challenges of Hajj in an effort to minimize untoward effects.Travel epidemiology related to the Hajj is a new and exciting area, which offers valuable insights to the travel specialist . The sheer scale of numbers affords a rare view of migration medicine in action . As data is continually gathered and both national and international policy making is tailored to vital insights gained through travel epidemiology, the Hajj will be continually safeguarded . Practitioners will gain from findings of travel related epidemiological changes in evolution at the Hajj: the impact of vaccinating policies, infection control policies and public health are afforded a real-world laboratory setting at each annual Hajj, allowing us to learn from this unique phenomenon of migration medicine.

Epidemiol Infect, 2003 Feb, 130(1), 59 - 70
Genetic analysis of capsular status of meningococcal carrier isolates; Sadler F et al.; The meningococcal capsule is the primary virulence factor with systemic isolates requiring full expression of the capsule but with capability to down-regulate the capsule in order to invade . The meningococcal capsular operon is composed of a number of genes that are involved in capsular synthesis and transport . Differences in capsular synthesis genes may allow discrimination between meningococcal serogroups whereas absence of genes for either synthesis or transport imply that the meningococcus is unencapsulated . Although mechanisms such as slipped-strand mispairing and acquisition of insertion sequences have been demonstrated to be involved in regulation of capsular expression, few studies have addressed the mechanisms of capsular expression in carrier isolates . Following a community-based intervention programme for an outbreak of meningococcal disease, we collected meningococcal carrier isolates from the intervention area and control areas . We undertook genetic analysis of the capsular operon and the mechanisms of capsular regulation, together with an investigation of the potential of capsular genes to identify the genogroup of non-serogroupable isolates . Use of the siaD gene allowed the discrimination of 30/89 (34%) non-serogroupable isolates into B, C, W135 and Y with a siaA gene PCR permitting the characterization of a further 6 isolates whose capsules contained sialic acid . Slipped-strand mispairing was evident in only 4 of 13 genogroupable B isolates and the insertion sequence IS1301 was found in 2 of 36 siaA-positive isolates . Of 51 non-genogroupable isolates 25 (49%) were shown to be ctrA negative . There was a higher percentage of ctrA-positive isolates (P<0.001) amongst meningococcal strains obtained from those sampled in non-intervention schools than those sampled at intervention schools . The ctrA-negative isolates warrant further investigation of their genotypic organization since such avirulent strains may be important in conferring natural protection against invasive disease . We found that after mass antibiotic prophylaxis, recolonization occurs preferentially with non-pathogenic meningococcal strains . This as implications for assessment of the benefits of mass antibiotic and vaccination programmes for outbreak control . Previously expressed concerns of increased risk due to removal of protective ora may have been overstated.

Epidemiol Infect, 2003 Feb, 130(1), 53 - 8
Meningococcal disease and social deprivation: a small area geographical study in Gwent, UK; Fone DL et al.; Although meningococcal disease is known to be linked to characteristics of individuals associated with social deprivation, there is only limited evidence of a relation with area-based measures of deprivation . In a small area geographical study, we ascertained 295 confirmed or probable cases occurring between 1996 and 1999 in the socially diverse resident population of Gwent Health Authority, equating to an average annual rate of 13.2 per 100,000 . Incidence rates of meningococcal disease increased from 8.1 per 100,000 in the least deprived fifth of enumeration districts to 19.8 per 100,000 in the most deprived fifth, a relative risk of 2.4 (95% CI 1.7-3.6) . In Poisson regression, the percentage change in the incidence rate arising from a unit change in the enumeration district Townsend score, was 9.4% (95% CI 6.2-12.6%) . Strongest associations were found for the under 5 age group, serogroup B disease and with the overcrowding variable component of the Townsend index . Our study quantifies the strength of the relation between meningococcal disease and social deprivation at small area level and provides further evidence of the need for action to reduce health inequalities.

Arq Gastroenterol, 2002 Apr-Jun, 39(2), 126 - 31 Epub 2003 Feb 19.
{Reflux esophagitis in children: histological and morphometric study}; Mader AM et al.; BACKGROUND: Gastroesophageal reflux disease is a frequent cause of morbidity in childhood, including esophagitis and recurrent respiratory symptoms; however histological and morphometric studies in esophageal biopsies of children are scarce . AIM: To study histological and morphometric findings in children with reflux esophagitis . PATIENTS AND METHODS: We studied 26 esophageal biopsies of children (mean age: 4.1 years +/- 3.4) with reflux esophagitis, which prevailed in boys (84.6%); post-prandial vomiting (76.9%) and repetitive bronchopneumonia (38.5%) were the most frequent symptoms . The diagnosis was made by X-ray in 18, by pH evaluation in 5 and by scintilography in 3 patients . The control group was formed by seven children without reflux symptoms who died from meningococcemia or congenital heart malformation (mean age: 2.5 years +/- 2.3) . Histological variables were studied by hematoxylin-eosin and periodic acid of Schiff stain, inflammatory infiltrate, epithelial and basal layer thickness, papillary length and its ratio with the thickness of the epithelium . Morphometry was performed at a digital system connected to pro-image software . Student's t test, Mann-Whitney test, Fisher and Pearson's correlation methods were used for the statistical analysis . RESULTS: Epithelial and basal zone thickness, papillary length and its rate with thickness of epithelium, among the reflux group patients were higher than the control group . Eosinophils, neutrophils and "balloon cells" were not observed in the control group . Intraepithelial capillaries occurred in 11 cases in the reflux group (mean diameter: 59 mum) . CONCLUSION: Epithelial and basal zone thickness, papillary length and its ratio with thickness of epithelium, resulted greater in the gastroesophageal reflux group than in the control group . There was a direct correlation between thickness of epithelium, basal zone thickness and papillary length, showing increased epithelial cell turnover . Eosinophils, neutrophils and "balloon cells" were observed only in patients with gastroesophageal reflux, thus serving as specific markers of this disease.

Lancet, 2003 Feb 22, 361(9358), 675 - 6
Effectiveness of meningococcal C conjugate vaccine in teenagers in England; Bose A et al.; Meningococcal C conjugate vaccine was introduced into clinical practice in the UK before phase 3 trials had been undertaken . We therefore did a case-control study in teenagers to assess vaccine effectiveness . All cases (n=31) enrolled had laboratory confirmed meningococcal C disease . We also enrolled between one and three controls (n=65) per case, matched by age, sex, and general practitioner . Three patients and 23 controls had been vaccinated . The protective effectiveness of the vaccine, estimated by conditional logistic regression, was 93% (95% CI 39-99), which is similar to screening method estimates . The estimated protective effectiveness varied little when potential confounding risk factors were taken into account . Our findings indicate that the vaccine is highly protective against invasive meningococcal C disease.

J Infect Dis, 2003 Mar 1, 187(5), 869 - 71 Epub 2003 Feb 18.
Outbreak of meningococcal disease caused by PorA-deficient meningococci; van der Ende A et al.; An outbreak of 7 cases of group C meningococcal disease occurred during the last week of July and the first week of August 2001 in the southwestern part of The Netherlands . Characterization of the 7 patients' isolates by various typing methods showed that the isolates were identical, except for the expression of PorA . Isolates from 5 patients were PorA deficient . These results show that transmission of PorA-deficient meningococci occurs and that PorA-deficient meningococci can cause invasive disease . PorA-based meningococcal vaccines may provide limited protection.

J Pharm Belg, 2002 Nov-Dec, 57(6), 130 - 4
{Vaccinations for the traveler}; Van Laethem Y; Long distance journeys are more and more frequent . Beside malaria prophylaxis, the general practitioner shall consider several points . Vaccinations against tetanus, diphtheria and (for a few years at least) polio should be done every ten years . Hepatitis A vaccine shall often be done (with > 20 years protection) but typhoid fever vaccine shall be limited to advanturous and/or long stays . Yellow fever vaccine (10 years validity) is only administrated in specialised centers; this is the only mandatory vaccine for certain african or south american countries . In certains instances, one shall consider vaccination against hepatitis B, meningococcal meningitis or, less often, against rabies, central european or japanese encephalitis . The vaccine against cholera (numerous side effects and poor efficacy) is no more available.

Hum Genet, 2003 Mar, 112(3), 244 - 8 Epub 2003 Jan 09.
Founder effect of the C9 R95X mutation in Orientals; Khajoee V et al.; A nonsense mutation at codon 95 (R95X) in the C9 gene is responsible for most Japanese C9 deficiency (C9D) cases, with a carrier frequency of 6.7% . Upon analysis of microsatellite markers and newly identified dinucleotide repeat number polymorphisms in the 3' flanking region of the C9 gene, a founder effect was demonstrated for the R95X mutation of the C9 gene in Japanese . Screening for the R95X mutation in Korean and Chinese individuals showed that the R95X carrier frequencies in Koreans and Chinese were 2.0% and 1.0%, respectively . Although homozygotes for the R95X mutation were not found in Korea or China, the shared haplotype of the dinucleotide repeat number polymorphisms appeared to be associated with the R95X mutation in the heterozygotes in Korea and China . The founder effect found in East Asians (Japanese, Koreans and Chinese) but not in Caucasians, as well as the haplotype sharing in only a small chromosomal interval, suggested that the R95X mutation of C9 gene was ancient and had occurred after the divergence of East Asians and Caucasians, and before migration of the Yayoi people to Japan . Since the mortality of meningococcal infections in complement-deficient patients is lower than that in normal individuals, a founder effect and a selective advantage in isolation might be the main reasons for the high frequency of the R95X mutation in Japan.

Cell Microbiol, 2003 Feb, 5(2), 99 - 109
Neisserial PorB is translocated to the mitochondria of HeLa cells infected with Neisseria meningitidis and protects cells from apoptosis; Massari P et al.; We have previously shown that purified meningococcal porin PorB associates with mitochondria and prevents apoptosis of B cells, Jurkat cells and HeLa cells (Massari et al., 2000, Proc Natl Acad Sci USA 97: 9070-9075) . This work examines if intact meningococci have a similar effect as purified porins . It was first determined that intact live meningococci do not induce apoptosis of HeLa cells and do not perturb mitochondrial physiology . This latter consideration is important as Neisserial porins affect the susceptibility of cells to apoptosis by preventing mitochondrial depolarization and cytochrome c release, events involved in the apoptosis cascade . Purified PorB or PorB from live bacteria were found to translocate into and interact with mitochondria . It was then determined whether treatment of HeLa cells with meningococci could prevent staurosporine-mediated apoptosis due to an effect of PorB on the mitochondrial parameters . Incubation of HeLa cells with live meningococci prevented staurosporine-induced apoptosis, as ascertained by measurements of mitochondrial potential, translocation of mitochondrial cytochrome c to the cytosol, caspases activation, and nuclear DNA degradation . These data are consistent with our previous findings that purified PorB associates with mitochondria and prevents apoptosis, and demonstrates that the mechanism by which whole meningococci protects cells from apoptosis is a result of direct interaction of neisserial porin with mitochondria.

Scand J Infect Dis, 2002, 34(11), 804 - 7
Molecular characteristics of Neisseria meningitidis strains isolated in Burkina Faso in 2001; Ouedraogo-Traore R et al.; In the course of an epidemic of meningitis in Burkina Faso in 2001, 27 cerebrospinal fluid samples from patients in 7 districts were forwarded to Norway for isolation and characterization of the causative agents . Neisseria meningitidis was isolated from 13 (48%) samples . The isolates were analysed using serological and genetic methods . Of the 13 strains, 4 were serogroup A, serotype 21:P1.9, sequence type (ST)-5 and belonged to clonal subgroup III, while the remaining 9 strains were serogroup W135, serotype 2a:P1.5,2, ST-11 and belonged to the electrophoretic type-37 complex . PCR analyses revealed meningococcal DNA in 13/14 culture-negative samples . Sequence analysis of the PCR products demonstrated that at least 3 different meningococcal strains were responsible for these 13 cases . Our results show that the W135 strain associated with the 2000 hajj (Muslim pilgrimage) outbreak was a significant cause of disease in Burkina Faso in 2001 . Further studies are warranted to determine whether W135 is about to replace serogroup A in sub-Saharan Africa.

Clin Infect Dis, 2003 Feb 15, 36(4), 422 - 8 Epub 2003 Jan 30.
Serotype distribution, antibiotic susceptibility, and genetic relatedness of Neisseria meningitidis strains recently isolated in Italy; Mastrantonio P et al.; The availability of new polysaccharide-protein conjugate vaccines against Neisseria meningitidis serogroup C prompted European National Health authorities to carefully monitor isolate characteristics . In Italy, during 1999-2001, the average incidence was 0.4 cases per 100,000 inhabitants . Serogroup B was predominant and accounted for 75% of the isolates, followed by serogroup C with 24% . Serogroup C was isolated almost twice as frequently in cases of septicemia than in cases of meningitis, and the most common phenotypes were C:2a:P1.5 and C:2b:P1.5 . Among serogroup B meningococci, the trend of predominant phenotypes has changed from year to year, with a recent increase in the frequency of B:15:P1.4 . Only a few meningococci had decreased susceptibility to penicillin, and, in the penA gene, all of these strains had exogenous DNA blocks deriving from the DNA of commensal Neisseria flavescens, Neisseria cinerea, and Neisseria perflava/sicca . Fluorescent amplified fragment-length polymorphism analysis revealed the nonclonal nature of the strains with decreased susceptibility to penicillin.

Commun Dis Public Health, 2002 Dec, 5(4), 329 - 32
PCR and the notification of meningococcal disease; Pitches D et al.; The polymerase chain reaction (PCR) can be used to investigate suspected meningococcal infection, with rapid results . We became aware that Birmingham Health Authority was not being informed about certain patients on whom meningococcal PCR had been performed . To establish whether notification was overlooked in some patients with suspected meningococcal disease, or whether PCR was performed on patients in whom it was thought meningococcal disease was unlikely, we compared numbers of patients notified to us over six months who had PCR with numbers of patients not notified who had PCR . Between 1st August 1999 and 31st January 2000, 54 PCR requests were made on seventy-seven notified patients; 51 PCR requests were made on non-notified patients and none were positive . Median age and length of stay were shorter in the non-notified patients . We conclude: (i) PCR may be being used inappropriately on younger patients who have shorter admissions and are unlikely to have meningococcal disease; (ii) in a number of patients initially admitted and notified with meningococcal disease the diagnosis is subsequently reconsidered . A 'denotification' procedure for such patients could make information on meningococcal disease more reliable.

Commun Dis Public Health, 2002 Dec, 5(4), 327 - 8
Socioeconomic inequality and meningococcal disease; Stuart JM et al.; Incidence of meningococcal disease was associated with socioeconomic deprivation across a rural English region . In young children the incidence was twice as high in the most deprived compared with the least deprived electoral wards . By addressing social inequalities the incidence of this serious infection could be reduced.

Vaccine, 2003 Mar 7, 21(11-12), 1094 - 8
Seroprevalence of meningococcal serogroup C bactericidal antibody in England and Wales in the pre-vaccination era; Trotter C et al.; Sera from an age-stratified sample of 1689 individuals, submitted to the PHLS Seroepidemiology Unit between 1996 and 1999 were tested for serum bactericidal antibodies to serogroup C meningococci . Titres decreased during infancy, presumably as maternal antibody waned, and increased in older teenagers, the peak age of meningococcal carriage . The prevalence of antibody titres greater than or equal to 8 was highest in adults, with an average of 25% of adults 25 years old or above with titres above this putative protective level . In the absence of vaccination, antibody may be generated from periods of carriage of serogroup C meningococci, from other meningococcal strains sharing non-capsular antigens, and other cross-reactive organisms . The inverse relationship between disease incidence and the prevalence of 'protective' antibody titres as described by Goldschneider et al . appears more consistent with a titre of > or =8 rather than > or =128, although the proportions 'protected' are much lower here than in Goldschneider's study . This study provides baseline antibody levels which will facilitate the evaluation of the meningococcal serogroup C conjugate vaccination programme .

Med J Aust, 2003 Feb 3, 178(3), 134 - 7
Early clinical clues to meningococcaemia; Yung AP et al.; Meningococcal septicaemia has high mortality, especially when the diagnosis is delayed or missed . Early recognition is not always straightforward, as classic clinical features may be absent or overlooked at initial presentation . Septicaemia without focal infection accounts for 15%-20% of cases of meningococcal disease and is the most worrisome manifestation in terms of diagnosis and outcome; in contrast, meningococcal meningitis is usually straightforward to diagnose, with a relatively good prognosis . Useful early clinical clues to meningococcaemia include: - a haemorrhagic (petechial or purpuric) rash; - blanching macular or maculopapular rash that appears in first 24 hours of illness; - true rigors; - severe pain in extremities, neck or back; vomiting, especially in association with headache or abdominal pain; rapid evolution of the illness; - concern of parents, relatives or friends; - patient age (highest incidence at age 3-12 months, followed by 1-4 and then 15-19 years); and - contact with a patient with meningococcal disease . In addition to specific clues, clinicians should look at the whole pattern of the illness . Timely clinical review is essential if there is doubt about the diagnosis . In any acutely febrile patient, it is prudent to ask "Why is this patient seeking help now?", then "Could this patient have meningococcaemia?".

Epidemiol Infect, 2002 Dec, 129(3), 459 - 70
National enhanced surveillance of meningococcal disease in England, Wales and Northern Ireland, January 1999-June 2001; Shigematsu M et al.; Enhanced surveillance of meningococcal disease (ESMD) was implemented nationally across ten regions of England, Wales and Northern Ireland from 1 January 1999 . It aims to deliver more sensitive surveillance than laboratory reporting by including clinically diagnosed but laboratory unconfirmed cases . Consultants in Communicable Disease Control (CsCDC) report all clinically diagnosed cases of meningococcal disease (MD) to the Regional Epidemiologist in the relevant regional unit of the Public Health Laboratory Service (PHLS) Communicable Disease Surveillance Centre (CDSC) . These reports are reconciled with laboratory data from the PHLS Meningococcal Reference Unit and then forwarded to the national CDSC where further reconciliation with laboratory data takes place . In addition, CsCDC are asked to report any clusters of MD that occur . Between 1 January 1999 and 30 June 2001, 12,074 cases of MD were ascertained through ESMD . The majority (57%) were laboratory confirmed . The estimated incidence of MD fell between 1999 and 2001 from 9.2 to 8.0 per 100,000 population . Of laboratory confirmed cases, the number of cases of serogroups B and W135 increased and of serogroup C and of ungrouped meningococcal infection decreased . Variation between regions was considerable and deserves further investigation . Of 11,522 cases with a reported clinical diagnosis, 53.6% were diagnosed as septicaemia, 32.6% as meningitis, 12.5% as both septicaemia and meningitis, and 13% had other invasive MD . Between 1 January 1999 and 30 June 2001 698 deaths were reported, an overall case fatality rate (CFR) of 5.8%; 567 deaths were in confirmed cases and 131 probable (CFR 8.2% and 2.5%, respectively) . CFR was higher in serogroup C (13.5%) than B (5.8%) . No peak in serogroup C meningococcal infection occurred in the winter of 2000/1 and no clusters of serogroup C meningococcal infection were reported in the first half of 2001 . ESMD provides information about the epidemiology of MD that is more complete than statutory notification and laboratory surveillance and is useful for evaluating the impact of the meningococcal serogroup C vaccination programme and of the other non-vaccine preventable serogroups.

Ann Med, 2002, 34(7-8), 624 - 34
Meningococcal disease: treatment and prevention; Wall RA; Many countries have been experiencing a significant increase in meningococcal disease . With the strains currently circulating, septicaemia is now a more frequent manifestation than meningitis and early recognition of disease manifestations by patient, parent or physician as well as early recognition of disease severity are the most important factors in attempting to reduce mortality and morbidity . Ceftriaxone is the treatment of choice but must be accompanied by aggressive supportive therapy in those with severe disease . The role of steroids is unknown . The evidence to support their use in both meningitis and severe systemic sepsis is discussed . The purified polysaccharide vaccines that have been available for some years may play a limited role in disease prevention . The recently introduced conjugate vaccine for preventing serogroup C disease represents a major advance but no vaccine is currently available to prevent serogroup B disease, cases of which will continue to challenge clinical practice.

Commun Dis Intell, 2002, 26(4), 592 - 5
Refining the public health response to primary meningococcal conjunctivitis; Poulos RG et al.; Primary meningococcal conjunctivitis (PMC) is accepted as an uncommon condition . This report describes two recent cases of PMC in newborn infants in a hospital nursery . In both cases the organisms identified were non-groupable strains of N . meningiditis, considered to be of low pathogenic potential . Both infants received systemic therapy and recovered without sequelae . The Guidelines for the early clinical and public health management of meningococcal disease in Australia recommend the notification of PMC to public health authorities and chemoprophylaxis of contacts . However, our 2 cases suggest that the guidelines should allow for an assessment of risk in determining the public health response . This assessment should include the severity of the conjunctivitis and the serogroup of the N . meningitidis isolate.

Vaccine, 2003 Feb 14, 21(9-10), 950 - 60
Restored functional immunogenicity of purified meningococcal PorA by incorporation into liposomes; Arigita C et al.; The impact of the conformation, lipooligosaccharide (LOS)-depletion and the presentation form of outer membrane protein PorA from Neisseria meningitidis (PorA) subtype P1.7-2,4 on the immune response in mice was studied . Native PorA was purified from outer membrane vesicles (OMVs) derived from meningococci and reconstituted into liposomes . The conformation of PorA after purification from OMVs and reconstitution in liposomes was monitored by use of electrophoretic and spectroscopic techniques and compared with the conformation of PorA in outer membrane complexes (OMCs) and heat-denatured PorA . The antigenicity of the PorA formulations was measured by ELISA by using a bactericidal anti-P1.4 monoclonal antibody . Immunogenicity was determined in Balb/c mice . PorA-specific IgG, isotype distribution and bactericidal activity were measured after subcutaneous immunization . In all formulations except in heat-denatured OMVs, PorA was present as trimers . The lipooligosaccharide (LOS) content was reduced by 96% in the purified protein with respect to the original OMVs . The antigenicity of purified PorA (i.e . ELISA response) was substantially higher as compared to PorA in liposomes, OMVs or OMCs . The results of the immunogenicity studies showed that all formulations were able to induce comparable IgG titers . However, whereas the antibodies raised by OMVs were bactericidal, the antibodies elicited by immunization with purified PorA were unable to kill meningococci . Remarkably, the ability to induce bactericidal antibodies was fully recovered by incorporation of the purified PorA into liposomes, in the absence of other adjuvants, as compared to LOS-containing OMVs.

J Med Microbiol, 2003 Feb, 52(Pt 2), 173 - 9
Neisseria meningitidis phenotypic markers and septicaemia, disease progress and case-fatality rate of meningococcal disease: a 20-year population-based historical follow-up study in a Danish county; Jensen ES et al.; The incidence rate (IR) and case-fatality rate (CFR) of meningococcal disease increased during the late 1980s and early 1990s in North Jutland County, Denmark . We examined the hypothesis that phenotypic markers of Neisseria meningitidis are predictors of septicaemia with or without meningitis, rapid disease progress and fatal outcome of meningococcal disease and we studied whether changes in IR and CFR over time might be related to emergence or spread of certain phenotypes . This follow-up study was based on a complete registration of 413 cases of meningococcal disease in North Jutland County during 1980-99 . Phenotypic markers included serogroup, serotype and serosubtype . A complete phenotype was available for 315 cases (76 %); 100 (32 %) strains were phenotype B : 15 : P1.7,16 and 31 (10 %) were C : 2a : P1.2,5 . Septicaemia without meningitis was less common in cases with B : 15 : P1.7,16 and C : 2a : P1.2,5 strains . No association was found between phenotype and rapid disease progress . The overall CFR was 12 % . An increased CFR was associated with phenotypes B : 15 : P1.7,16 {odds ratio (OR) 2.8, 95 % confidence interval (CI) 1.2-18.5} and C : 2a : P1.2,5 (OR 5.2, 95 % CI 1.6-16.4) when compared with other phenotypes . The prevalence of B : 15 : P1.7,16 strains increased gradually during the study period and the CFR increased from 8 % during 1980-89 to 19 % during 1990-99, although the CFR for other phenotypes also increased . The CFR for C : 2a : P1.2,5 remained high ( approximately 20 %), but the contribution of this phenotype to the overall CFR decreased during the study period . In conclusion, phenotypes B : 15 : P1.7,16 and C : 2a : P1.2,5 were predictors of an increased CFR . The high prevalence of phenotype B : 15 : P1.7,16 contributed to increased overall IR and CFR during 1990-99.

J Bacteriol, 2003 Feb, 185(3), 1101 - 6
The NorM efflux pump of Neisseria gonorrhoeae and Neisseria meningitidis recognizes antimicrobial cationic compounds; Rouquette-Loughlin C et al.; In Neisseria gonorrhoeae and Neisseria meningitidis, we identified a gene that would encode a protein highly similar to NorM of Vibrio parahaemolyticus (Y . Morita et al., Antimicrob . Agents Chemother . 42:1778-1782, 1998) . A nonpolar insertional mutation in either the gonococcal or meningococcal norM gene resulted in increased bacterial sensitivity to compounds harboring a quaternary ammonium on an aromatic ring (e.g., ethidium bromide, acriflavine hydrochloride, 2-N-methylellipticinium, and berberine) . The presence of point mutations within the -35 region of a putative norM promoter or a likely ribosome binding site resulted in an increased resistance of gonococci and meningococci to the same compounds, as well as to norfloxacin and ciprofloxacin . Structure-activity relationship studies with putative NorM substrates have found that a cationic moiety is essential for NorM recognition.

Emerg Infect Dis, 2003 Jan, 9(1), 123 - 6
Persistence of W135 Neisseria meningitidis carriage in returning Hajj pilgrims: risk for early and late transmission to household contacts; Wilder-Smith A et al.; After an outbreak of meningococcal disease caused by Neisseria meningitidis W135, associated with the Hajj pilgrimage in 2001, 15% of returning vaccinated pilgrims carried a single W135 clone, and 55% were still carriers 6 months later . Transmission to 8% of their unvaccinated household contacts occurred within the first few weeks, but no late transmission took place . Public health interventions are needed to protect household contacts.

Vaccine, 2003 Jan 30, 21(7-8), 768 - 75
Transcriptome-based antigen identification for Neisseria meningitidis; Kurz S et al.; The identification of suitable antigens is crucial to successful vaccine development based on subunit approaches . While many methods exist for the identification of vaccine candidates which are surface-exposed or secreted, immunogenic and conserved, contain B and T cell epitopes, most of these have a major drawback: they do not yield any information on whether the antigen is indeed expressed by the pathogen during infection . However, DNA microarrays offer a novel tool for the investigation of the transcriptional activity of all genes of a pathogenic microorganism under in vivo conditions . Employing whole genome DNA microarrays, we have analyzed the transcriptome of Neisseria meningitidis serogroup B bacteria during different stages of infection, i.e . exposure to human serum and the interaction with human epithelial and endothelial cells . Combined with data derived from genome-based approaches (such as reverse vaccinology) and immunogenicity studies, this novel transcriptome-based antigen identification should reveal ideal vaccine candidates against serogroup B meningococcal infection.

Vaccine, 2003 Jan 30, 21(7-8), 729 - 33
Dramatic decline of serogroup C meningococcal disease in Catalonia (Spain) after a mass vaccination campaign with meningococcal C conjugated vaccine; Salleras L et al.; In the last quarter of the year 2000, the meningococcal C conjugated vaccine was incorporated into the routine vaccination schedule in Catalonia (at 2, 4 and 6 months) . In addition a vaccination campaign was carried out in children <6 years of age, with a coverage of 96.2% . The effectiveness of the vaccination in this age group during 2001 and the first 28 weeks of 2002 was 100% (94.27-100%) . A vaccination campaign has been carried out in 6-19-year olds during 2001 and 2002, with a coverage rate of 23.5% in the year 2001 . In this age group a reduction in disease incidence was seen in the 2000-2001 season, but not in the following one.

Vaccine, 2003 Jan 30, 21(7-8), 725 - 8
Impact of mass vaccination with polysaccharide conjugate vaccine against serogroup C meningococcal disease in Spain; Salleras L et al.; During the fourth quarter of 1997, a vaccination campaign using the meningococcal C polysaccharide vaccine was carried out in 14 autonomous regions of Spain . The remaining three regions did not participate . In the last quarter of the year 2000, a mass vaccination campaign using the meningococcal C conjugated vaccine was carried out in all regions . In the year 2001 the incidence decreased in all regions, although the decrease was greater in regions that did not vaccinate in 1997 . In contrast, case fatality rates did not decrease . During 2001, the incidence rate of meningococcal C disease was still lower (0.32 per 100000 persons-year) in the regions that vaccinated in 1997 with the polysaccharide vaccine than in those that did not (0.64 per 100000 persons-year).

Carbohydr Res, 2003 Jan 20, 338(2), 167 - 75
Conjugation of meningococcal lipooligosaccharides through their lipid A terminus conserves their inner epitopes and results in conjugate vaccines having improved immunological properties; Mieszala M et al.; The importance of conserved inner saccharide epitopes to the immune performance of meningococcal lipooligosaccharide-protein conjugate vaccines was demonstrated in the following experiments . Two different oligosaccharides were obtained by chemical degradations of the same L7 lipooligosaccharide, and both were linked terminally to tetanus toxoid . One was a truncated oligosaccharide in which the inner epitopes were incomplete and was obtained by mild acid hydrolysis of the L7 lipooligosaccharide . This oligosaccharide was conjugated by direct reductive amination through its newly exposed terminal Kdo residue . The second, a full-length oligosaccharide, was obtained by O-deacylation of the L7 lipooligosaccharide, with subsequent removal of phosphate substituents from its lipid A moiety using alkaline phosphatase . This permitted the full-length oligosaccharide to be conjugated directly to tetanus toxoid by reductive amination through its newly exposed terminal 2-N-acyl-2-deoxy-D-glucopyranose residue . Comparison of the immune performance of the two conjugates in mice revealed, that while both were able to induce significant levels of L7-lipooligosaccharide-specific IgG antibody, the conjugate made with the full-length saccharide was able to induce antibodies with increased bactericidal activity against homologous meningococci.

Science, 2003 Jan 10, 299(5604), 262 - 5
Role of a highly conserved bacterial protein in outer membrane protein assembly; Voulhoux R et al.; After transport across the cytoplasmic membrane, bacterial outer membrane proteins are assembled into the outer membrane . Meningococcal Omp85 is a highly conserved protein in Gram-negative bacteria, and its homolog Toc75 is a component of the chloroplast protein-import machinery . Omp85 appeared to be essential for viability, and unassembled forms of various outer membrane proteins accumulated upon Omp85 depletion . Immunofluorescence microscopy revealed decreased surface exposure of outer membrane proteins, which was particularly apparent at the cell-division planes . Thus, Omp85 is likely to play a role in outer membrane protein assembly.

J Clin Microbiol, 2003 Jan, 41(1), 273 - 8
Nonencapsulated Neisseria meningitidis strain produces amylopectin from sucrose: altering the concept for differentiation between N . meningitidis and N . polysaccharea; Zhu P et al.; Neisseria meningitidis is the causative agent of meningococcal sepsis and meningitis . Neisseria polysaccharea is a nonpathogenic species . N . polysaccharea is able to use sucrose to produce amylopectin, a starch-like polysaccharide, which distinguishes it biochemically from the pathogenic species N . meningitidis . The data presented here indicate that this may be an insufficient criterion to distinguish between these two species . The nonencapsulated Neisseria strain 93246 expressed a phenotype of amylopectin production similar to that of N . polysaccharea . However, strain 93246 reacted with N . meningitidis serotype 4 and serosubtype P1.14 monoclonal antibodies and showed the N . meningitidis L1(8) lipo-oligosaccharide immunotype . Further analyses were performed on four genetic loci in strain 93246, and the results were compared with 7 N . meningitidis strains, 13 N . polysaccharea strains, and 2 N . gonorrhoeae strains . Three genetic loci, opcA, siaD, and lgt-1 in strain 93246, were the same as in N . meningitidis . Particularly, the siaD gene encoding polysialyltransferase responsible for biosynthesis of N . meningitidis group B capsule was detected in strain 93246 . This siaD gene was inactivated by a frameshift mutation at the poly(C) tract, which makes strain 93246 identical to other nonencapsulated N . meningitidis strains . As expected, the ams gene encoding amylosucrase, responsible for production of amylopectin from sucrose, was detected in strain 93246 and all 13 N . polysaccharea strains but not in N . meningitidis and N . gonorrhoeae strains . These data suggest that strain 93246 is nonencapsulated N . meningitidis but has the ability to produce extracellular amylopectin from sucrose . The gene for amylopectin production in strain 93246 was likely imported from N . polysaccharea by horizontal genetic exchange . Therefore, we conclude that genetic analysis is required to complement the traditional phenotypic classification for the nonencapsulated Neisseria strains.

Eur Cytokine Netw, 2002 Oct-Dec, 13(4), 411 - 7
Neisseria meningitidis can induce pro-inflammatory cytokine production via pathways independent from CD14 and toll-like receptor 4; Sprong T et al.; Fulminant meningococcal sepsis (FMS) is considered the prototypical Gram-negative sepsis . Lipopolysaccharide (LPS) is thought to be the main toxic element that induces pro-inflammatory cytokine production after interaction with CD14 and toll-like receptor 4 (TLR4) . However, there is increasing evidence that LPS is not the sole toxic element of meningococci . The aim of the present study was to determine the role of CD14 and TLR4 in pro-inflammatory cytokine induction by meningococci . To this end, cytokine induction by isolated meningoccal LPS, wild-type N . meningitidis H44/76 (LPS+-meningococci) matched for concentrations of LPS and LPS-deficient N . meningitidis H44/76lpxA (LPS - -meningococci) was studied in human PBMCs and murine peritoneal macrophages (PMs) . Pre-incubation of PBMCs with WT14, a monoclonal antibody against CD14, abolished TNF-alpha and IL-1beta induction by E . coli LPS, while cytokine induction by meningococcal LPS was only partially inhibited . When LPS+- and LPS - -meningococci at higher concentrations were used as stimuli, anti-CD14 had a minimal effect . In C3H/HeJ murine PMs, devoid of a functional TLR4, minimal IL-1alpha, IL-6 and TNF-alpha production was seen after stimulation with 10 ng/mL E . coli or meningococcal LPS . However, at higher concentrations (1000 ng LPS/mL) the production of TNF-alpha, but not IL-1alpha or IL-6, occurred also independently of TLR4 . The expression of a functional TLR4 in murine PMs had no effect on the cytokine induction by LPS+- or LPS - -meningococci . It is concluded that pro-inflammatory cytokine induction by N . meningitidis can occur independently of CD14 and TLR4.

Expert Opin Biol Ther, 2002 Dec, 2(8), 895 - 905
Reverse vaccinology: a genome-based approach for vaccine development; Masignani V et al.; During the last century several approaches have been followed for the development of vaccines . These include live-attenuated viruses and bacteria, killed microorganisms and the subunit vaccines {1} . With the introduction of recombinant DNA technologies, new approaches have been exploited for vaccine manufacturing . However, the major problem remains the rapid identification of highly immunogenic and protective antigens suitable for vaccine development, which still relies on standard biochemical and microbiological techniques . The advent of genomics has greatly contributed to providing a new impulse to the microbial field . The complete genomic sequence of a human pathogen represents a new unexploited field, to be used for the design of novel vaccines and antimicrobial drugs . In the case of meningococcus B, four decades of continuous efforts, using conventional technologies of purifying antigens from the microorganism, had not been sufficient to deliver an effective and universal vaccine . It was therefore decided to obtain the genomic sequence of serogroup B Neisseria meningitidis (MenB) and use this information to identify vaccine candidates . This approach was named "reverse vaccinology"{2}.

Pathol Biol (Paris), 2002 Dec, 50(10), 613 - 9
{Physiopathology and curative treatment of meningococcal diseases: current aspects}; Senneville E et al.; Early administration of antibiotics as soon as the diagnosis of meningococcemia has been evoked is a significant therapeutic advance . However, the poor outcome of these diseases whose mortality remains high despite the current techniques of reanimation shows that improving the vaccination against meningococci is still of actuality . Diagnosing rapidly severe meningococcal disease is also a means for acting against the pathological activation of the inflammatory and coagulation pathways . Significant advances have been made in understanding the physiopathology of the meningococcal purpura fulminans especially about the deleterious role of the deficiency of the protein C and the antithrombin III . It is too soon to advance that the prognosis of these diseases has been improved by these new therapeutic approaches but the results of preliminary clinical studies are encouraging . However, informing parents about the first skin abnormalities seen in infants with purpura fulminans is essential in attempt to improve the efficiency of these new therapeutic strategies.

Emerg Infect Dis, 2002 Dec, 8(12), 1512 - 4
Capsule switching among C:2b:P1.2,5 meningococcal epidemic strains after mass immunization campaign, Spain; Alcala B et al.; A mass immunization campaign for 18-month to 19-year-olds was undertaken in Spain in 1996-1997 because of an epidemic of serogroup C meningococcal disease associated with a C:2b:P1.2,5 strain belonging to the A4 lineage . Surveillance for the "capsule-switching" phenomenon producing B:2b:P1.2,5 isolates was undertaken . Of 2,975 meningococci characterized, B:2b:P1.2,5 and B:2b:P1.2 antigenic combinations were found in 18 isolates; 15 meningococci were defined as serogroup B belonging to the A4 lineage.

Emerg Infect Dis, 2002 Dec, 8(12), 1398 - 403
Mass vaccination campaign following community outbreak of meningococcal disease; Krause G et al.; During December 12-29, 1998, seven patients ages 2-18 years were diagnosed with serogroup C meningococcal disease in two neighboring Florida towns with 33,000 residents . We evaluated a mass vaccination campaign implemented to control the outbreak . We maintained vaccination logs and recorded the resources used in the campaign that targeted 2- to 22-year-old residents of the two towns . A total of 13,148 persons received the vaccinations in 3 days . Vaccination coverage in the target population was estimated to be 86% to 99% . Five additional cases of serogroup C meningococcal disease occurred in the community during the year after the campaign began, four in patients who had not received the vaccine . The cost of control efforts was approximately $370,000 . Although cases continued to occur, the vaccination campaign appeared to control the outbreak . Rapid implementation, a targeted approach, and high coverage were important to the campaign's success.

Infect Immun, 2003 Jan, 71(1), 275 - 86
Age-related disparity in functional activities of human group C serum anticapsular antibodies elicited by meningococcal polysaccharide vaccine; Harris SL et al.; Serum bactericidal activity confers protection against meningococcal disease, but it is not known whether vaccine-induced anticapsular antibodies that lack bactericidal activity are protective . We developed an infant rat challenge model using a naturally occurring O-acetylated strain of Neisseria meningitidis group C and a strain that was negative for O acetylation (OAc) . Rats 4 to 7 days of age inoculated intraperitoneally (i.p.) with approximately 10(3) CFU of either strain developed >5 x 10(5) CFU/ml of blood obtained 18 h later . Dilutions of preimmunization sera given i.p . 2 h before the bacterial challenge had no effect on bacteremia, whereas group C anticapsular antibody in sera from adults immunized with meningococcal polysaccharide vaccine conferred complete or partial (>99% decrease in CFU per milliliter of blood) protection against the OAc-positive or OAc-negative strain, respectively, at antibody doses as low as 0.04 micro g/rat . Anticapsular antibody at doses fivefold higher (0.18 to 0.2 micro g/rat) in pooled sera from children immunized at a mean age of 2.6 years failed to protect rats, but antibody at the same or fivefold-lower dose in a serum pool from a group of children immunized at 4 years of age gave complete or partial protection . Protective activity was observed with some serum pools that lacked detectable complement-mediated bactericidal activity (titers < 1:4) and correlated with increasing antibody avidity . Thus, not only does the magnitude of the group C antibody response to meningococcal polysaccharide vaccine increase with increasing age but there are also age-related affects on antibody functional activity such that higher serum concentrations of vaccine-induced antibody are required for protection of immunized children than for immunized adults.

Eur J Pediatr, 2002 Dec, 161 Suppl 2, S127 - 31 Epub 2002 Nov 09.
Safety and efficacy of the seven-valent pneumococcal conjugate vaccine: evidence from Northern California; Black S et al.; Pneumococcal disease remains a significant cause of morbidity among young children . A large-scale efficacy trial in the Northern California Kaiser Permanente system (the KP trial) demonstrated that a seven-valent conjugate vaccine (PCV) is safe and immunogenic in young children and effective in preventing both invasive pneumococcal disease caused by vaccine serotypes (97.4% efficacy) and episodes of otitis media (7.0% efficacy) . Since the publication of the results of the KP trial in 2000, we have performed an additional analysis on the safety, immunogenicity, and efficacy of the vaccine in low birth weight (LBW) and preterm (PT) infants, and have examined the efficacy of the vaccine during 1 year of wide-scale post-licensure use . The vaccine was at least as immunogenic in LBW and PT infants as in normal-weight, full-term infants and was 100% effective, although the LBW and PT infants had higher rates of adverse events such as redness and swelling . LBW and PT infants receiving pneumococcal vaccine also had higher rates of adverse events, such as hives, than those receiving control meningococcal vaccine, but these reactions were not severe . When the PCV was used in the general population, the efficacy remained high and there was no corresponding increase in disease caused by nonvaccine serotypes . There was also evidence that vaccine administration led to herd immunity . Febrile illness was the only adverse event seen more frequently after vaccine administration than during a control period . CONCLUSION: the seven-valent conjugate vaccine is safe and effective for use in the general population.

Mol Microbiol, 2003 Jan, 47(1), 135 - 43
The Neisseria meningitidis adhesion regulatory protein CrgA acts through oligomerization and interaction with RNA polymerase; Deghmane AE et al.; CrgA is a LysR-type transcriptional regulator involved in the intimate adhesion of Neisseria meningitidis to target human epithelial cells . It is negatively autoregulated, and its expression is transiently induced upon contact with target cells . We analysed the functional organization of CrgA using in frame deleted proteins . Four truncated proteins were constructed and purified . They were deleted between residues 20 and 40, 121 and 154, 111 and 181 and 268 and 291 . Meningococcal mutants harbouring the corresponding deleted crgA alleles were also constructed . All mutants showed a reduced ability to adhere to epithelial cells . beta-Galactosidase activity assays using a crgA-lacZ transcriptional fusion showed that all the mutations except the 268-291 deletion resulted in loss of induction upon contact with target cells . Gel mobility shift assays and cross-linking assays showed that the oligomerization of CrgA is required for DNA binding and that the N-terminal part of CrgA is directly involved in DNA binding through a helix-turn-helix motif . The C-terminal region is also involved in DNA binding, probably by permitting the oligomerization of CrgA . The C-terminal region also seemed to interact with RNA polymerase . Therefore, the binding of CrgA and its interaction with RNA polymerase may inhibit the clearance of meningococcal promoters that are repressed by CrgA during the intimate adhesion of N . meningitidis to target cells.

J Med Microbiol, 2003 Jan, 52(Pt 1), 75 - 7
Impact of meningococcal vaccination with combined serogroups A and C polysaccharide vaccine on carriage of Neisseria meningitidis C; Fernandez S et al.; Two studies of meningococcal carriage state were carried out in Galicia (Spain) before and after a mass vaccination campaign between December 1996 and January 1997 against Neisseria meningitidis serogroup C with meningococcal serogroups A and C polysaccharide vaccine . The studies covered two areas with different incidence rates of meningococcal disease in 1996 (high and low incidence) . Carriage rates of serogroup C showed a decrease in both areas, 47 and 65 % respectively, before and after the vaccination . Results showed a decrease in carrier state in the age groups 10-14- and 15-19-year-olds, but not in the 5-9-year-olds . These results demonstrate the effect of immunization on the reduction of the carriage state.

J Med Microbiol, 2003 Jan, 52(Pt 1), 51 - 7
Detection and genotyping of meningococci using a nested PCR approach; Diggle MA et al.; An effective vaccine against Neisseria meningitidis serogroup B is required . Outer-membrane protein vaccines have been developed, which may provide protection against common circulating serotypes and serosubtypes in some countries . However, limited genosubtyping data are available because most laboratories use mAbs directed against a limited number of specific serotypes and serosubtypes and laboratories do not genosubtype directly from body fluids due to the lack of a sensitive PCR method . A nested PCR was therefore developed that enables the amplification of the porA gene directly from clinical samples and has the required sensitivity for nucleotide sequencing of the three main variable regions, VR1, VR2 and VR3 . Data were compared with those from culture-based nucleotide sequencing, and the use of this method increased the availability of genosubtype information by 45 %, thereby indicating the impact that this methodology has on the data provided and the implications for vaccine design.

Br J Anaesth, 2003 Jan, 90(1), 72 - 83
Severe meningococcal disease in childhood; Baines PB et al.; Meningococcal disease remains an important cause of illness in the UK (Commun Dis Rep CDR Suppl 1999; 9: S5), and is the commonest infective cause of death in children outwith the neonatal period . Although most common in children, adults are also affected . Meningococcal vaccines offer long-term protection only against Group C disease, which causes less than half of invasive meningococcal disease (Commun Dis Rep CDR Wkly 1998; 8: 2) in the UK.

J Bacteriol, 2003 Jan, 185(1), 155 - 64
Transcriptome analysis of Neisseria meningitidis during infection; Dietrich G et al.; Neisseria meningitidis is the cause of septicemia and meningococcal meningitis . During the course of infection, N . meningitidis encounters multiple environments within its host, which makes rapid adaptation to environmental changes a crucial factor for neisserial pathogenicity . Employing oligonucleotide-based DNA microarrays, we analyzed the transcriptome of N . meningitidis during two key steps of meningococcal infection, i.e., the interaction with epithelial cells (HeLa cells) and endothelial cells (human brain microvascular endothelial cells) . Seventy-two genes were differentially regulated after contact with epithelial cells, and 48 genes were differentially regulated after contact with endothelial cells, including a considerable proportion of well-known virulence genes . While a considerable number of genes were in concordance between bacteria adherent to both cell types, we identified several open reading frames that were differentially regulated in only one system . The data obtained with this novel approach may provide insight into the pathogenicity mechanisms of N . meningitidis and could demonstrate the importance of gene regulation on the transcriptional level during different stages of meningococcal infection.

Crit Care Med, 2002 Dec, 30(12), 2757 - 61
Calciphylaxis, proteases, and purpura: an alternative hypothesis for the severe shock, rash, and hypocalcemia associated with meningococcal septicemia; Holland PC et al.; The hallmarks of severe meningococcal sepsis include the rapid onset of shock, purpuric rash, and metabolic derangement, in particular, hypocalcemia . The severe ecchymoses and purpura associated with meningococcal sepsis are usually attributed to acute thrombotic episodes, attributable to the associated procoagulation disorder . An alternative explanation for the rash is a sudden extravasation of calcium from the intravascular space into the tissues . We will argue that in meningococcal sepsis, cleavage of albumin into fragments by protease(s) occurs and these fragments, along with calcium, cross the endothelium into the interstitium . The fragmentation of albumin and its loss through the endothelium would also provide a more rational explanation for the rapidity of the shock and the hypocalcemia that is so characteristic of the disease.

Mycoses, 2002 Dec, 45(11-12), 504 - 11
Case Reports . Chronic and acute Aspergillus meningitis; Moling O et al.; Cerebral aspergillosis usually occurs in severely immunocompromized hosts, is difficult to diagnose, and has a poor prognosis . After 14 months of chronic meningitis, ventriculitis, choroid plexitis, and lumbar arachnoiditis, which was complicated by acute hydrocephalus, Aspergillus, suspected to be from the candidus group, was isolated from the cerebrospinal fluid (CSF) of a previously healthy man . Thereafter Aspergillus antigen was found in stored plasma and CSF samples . He was treated with voriconazole and itraconazole . In a haemodialysis patient affected by an acute meningococcal meningitis, following a 3-day symptom-free interval, symptoms and signs of acute meningitis had reappeared and were unresponsive to a broad antimicrobial coverage . However, they resolved within 5 days after liposomal amphotericin B treatment had been started . From his CSF Aspergillus-DNA was identified and Aspergillus fumigatus isolated by culture . These two different clinical cases show that Aspergillus-DNA and antigen detection tests represent an advance in the diagnosis and liposomal amphotericin B, voriconazole, and itraconazole are an advance in the treatment of Aspergillus meningitis.

Lancet Infect Dis, 2002 Dec, 2(12), 763 - 5
Chronicle of an outbreak foretold: meningococcal meningitis W135 in Burkina Faso; Decosas J et al.; Burkina Faso lies within the African meningitis belt . Until recently, serogroup A of Neisseria meningitidis was the most common cause of epidemic meningitis in Burkina Faso . However, during the epidemic that started in January 2002, W135 was the predominant serogroup of meningococcus . Vaccine against the W135 serogroup is expensive and in short supply . Strategies to react to a future African epidemic of W135 meningococcal meningitis with a sufficient and affordable supply of vaccine must be put into place now.

J Med Microbiol, 2002 Dec, 51(12), 1102 - 6
The epidemic wave of meningococcal disease in Spain in 1996-1997: probably a consequence of strain displacement; Alcala B et al.; During 1996 and 1997 an epidemic wave of meningococcal disease took place in Spain . Initial studies described the antigenic expression of the epidemic strain as C:2b:P1.2,5 and proposed that it was a variant of the previously identified Spanish C:2b:non-subtypable epidemic strain . To clarify this hypothesis, 1036 C:2b:P1.2(5) and 76 C:2b:NST isolates obtained during 1992-1999 were analysed by pulsed-field gel electrophoresis . The majority of the C:2b:P1.2,5 and C:2b:P1.2 isolates showed one of two very closely related profiles . During the epidemic period, 80% of the C:2b:NST strains showed these two pulsotypes . However, before the epidemic wave, most of these C:2b:NST strains (60%) showed a profile that was found infrequently among C:2b:P1.2,5 and C:2b:P1.2 isolates . A similar evolution was observed in C:2b:P1.5 isolates . Thirty-four C:2b:P1.2(5) and 10 C:2b:NST isolates, exhibiting representative pulsotypes, were subjected to multi-locus sequence typing . Isolates belonging to both A4 and ET-37 lineages were identified . These data point to the possibility that the A4 cluster has displaced the ET-37 complex among serogroup C meningococci in Spain.

Front Biosci, 2003 Jan 01, 8, e14 - 22
Molecular epidemiology of Neisseria meningitidis; Vogel U et al.; Neisseria meningitidis poses a major disease burden on human beings . Meningococcal typing has a longstanding tradition for epidemiological surveillance of the disease . Genetic and antigenetic variability resulting from horizontal genetic exchange has been exploited for this purpose . Neisseria meningitidis served as the bacterial prototype organism for the development of multi locus sequence typing, which has replaced multi locus enzyme electrophoresis as the gold standard for meningococcal typing . Due to the rapid emergence of new porin variants serotyping by monoclonal antibodies is currently being replaced by DNA sequencing of variable regions of the porA gene . Sequence data were used to characterize the population structure of meningococci in carriage and disease . The advances in molecular epidemiology of meningococcal disease, and the rapid exchange of DNA sequence data via curated internet websites have resulted in an interactive international network, which is capable of identifying newly emerging clones within weeks.

J Clin Microbiol, 2002 Dec, 40(12), 4531 - 5
Direct and rapid identification and genogrouping of meningococci and porA amplification by LightCycler PCR; Molling P et al.; Invasive meningococcal infections are usually diagnosed by culture . This approach is far from optimal due to, e.g., treatment with precollection antibiotics . Molecular-genetics methods are therefore recognized as important tools for optimal laboratory confirmation of meningococcal infections as well as characterization of meningococci (Mc) . The aims of the present study were to develop real-time PCRs for identification and genogrouping (A, B, C, Y, and W-135) of Mc and porA amplification that further can be used for subsequent genosubtyping . In a first run Mc were identified . In a second run they were genogrouped and porA genes were amplified . All the Mc isolates (n = 71) but one and cerebrospinal fluid samples (n = 11) tested gave the expected positive results . The specificity, inter- and intra-assay variations, and effects of different amounts of DNA on the melting temperatures were also explored . The LightCycler PCR system was found to effectively detect and characterize Mc in a few hours . This testing, including the DNA sequencing of the porA gene to reveal the genosubtype, does not take more than a working day, and the results can be compared to those from culturing with phenotypic analysis, which takes at least a few days.

Biotechnol Appl Biochem, 2002 Dec, 36(Pt 3), 219 - 26
Evaluation of meningococcal C oligosaccharide conjugate vaccines by size-exclusion chromatography/multi-angle laser light scattering; Jumel K et al.; The mean molecular masses of three different meningococcal C saccharide (MenC)-protein conjugate vaccines and their constituent proteins were estimated using HPLC size-exclusion chromatography (SEC) with multi-angle laser light scattering (MALLS) and refractive-index (RI) detection (SEC/MALLS) . Chromatography of two CRM(197) conjugates (MenC-CRM(197)-A and MenC-CRM(197)-B) and one tetanus toxoid (TT) conjugate (MenC-TT) was performed in PBS, pH 7.4, on TSK-Gel (TosoHaas) analytical columns {CRM(197) is a non-catalytic cross-reacting mutant (CRM) of diphtheria toxin} . Analysis of the light-scattering signal measured at 18 angles simultaneously, using the RI signal as a measure of concentration, gave absolute weight-average-molecular-mass (M(w)) values for the CRM(197) conjugates as follows: MenC-CRM(197)-A, approximately 75,000 g x mol(-1) and MenC-CRM(197)-B, approximately 350,000 g x mol(-1), suggesting that MenC-CRM(197)-A is a monomer (one carrier protein per conjugate molecule), while MenC-CRM(197)-B is largely composed of conjugates containing three or four CRM(197) molecules . The MenC-TT conjugate eluted as a two-component system with (M(w)) of 1.63 x 10(6) and 395,000 g x mol(-1), suggesting that some cross-linked complexes contain up to six TT molecules . Comparison of results from MALLS/RI with those obtained using UV detection highlights the differences in size and relative composition of the various subpopulations of the MenC conjugates that can be obtained using different detection systems.

Clin Med, 2002 Sep-Oct, 2(5), 440 - 3
Update of guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen; Davies JM et al.; Guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen were first published by the British Committee for Standards in Haematology in 1996 . Key aspects of these guidelines related to anti-infective prophylaxis, immunisation schedules and treatment of proven or suspected infection . A recent review of the guidelines was undertaken, with a view to updating the recommendations where necessary The guideline review process did not reveal any major change in patient groups considered at risk . Occupational exposure to certain pathogens may, however, be a new risk factor for some infections . The recommendations for anti-infective prophylaxis remain unchanged . New recommendations for vaccination include the use of meningococcal group C vaccine in previously non-immunised hyposplenic patients and a need to consider the use of seven-valent pneumococcal vaccine . Recommendations for treatment of suspected or proven infection have not been significantly amended, but a local protocol should take into account relevant resistance patterns . There is an identified urgent need for further research into the effectiveness of varying vaccination strategies in the hyposplenic patient, and audit of infective episodes in this patient group should continue long term . Key guidelines are summarised below, together with grades of recommendation.

J Infect Dis, 2002 Dec 15, 186(12), 1848 - 51 Epub 2002 Nov 14.
Safety, reactogenicity, and immunogenicity of a tetravalent meningococcal polysaccharide-diphtheria toxoid conjugate vaccine given to healthy adults; Campbell JD et al.; Healthy adults, 18-55 years old, were immunized once with a tetravalent (serogroups A, C, Y, and W-135) meningococcal vaccine conjugated to diphtheria toxoid at 1 of 3 doses and were monitored for safety, reactogenicity, and immunogenicity . No immediate reactions were observed . Only 1 of 89 subjects reported fever; only 1 reported any severe reactogenicity (local pain/soreness, chills, arthralgia, anorexia, and malaise) . For each serogroup and in each dose group, the geometric mean serum bactericidal antibody (SBA) titer and immunoglobulin G concentration increased after immunization . In the 4- and 10-microg-dose groups, all subjects had SBA titers >/=8 against serogroups A and C, and 89% and 93% of subjects had SBA titers >/=8 against serogroups Y and W-135, respectively . The A, C, Y, and W-135 Neisseria meningitidis-diphtheria toxoid conjugate vaccine, when given to healthy adults as a single intramuscular injection of 1, 4, or 10 microg/serogroup, is acceptably tolerated and immunogenic and deserves further development.

FEMS Immunol Med Microbiol, 2002 Dec 13, 34(4), 267 - 75
Phase variation in meningococcal lipooligosaccharide biosynthesis genes; Berrington AW et al.; Neisseria meningitidis expresses a range of lipooligosaccharide (LOS) structures, comprising of at least 13 immunotypes (ITs) . Meningococcal LOS is subject to phase variation of its terminal structures allowing switching between ITs, which is proposed to have functional significance in disease . The objectives of this study were to investigate the repertoire of structures that can be expressed in clinical isolates, and to examine the role of phase-variable expression of LOS genes during invasive disease . Southern blotting was used to detect the presence of LOS biosynthetic genes in two collections of meningococci, a global set of strains previously assigned to lineages of greater or lesser virulence, and a collection of local clinical isolates which included paired throat and blood isolates from individual patients . Where the phase-variable genes lgtA, lgtC or lgtG were identified, they were amplified by PCR and the homopolymeric tracts, responsible for their phase-variable expression, were sequenced . The results revealed great potential for variation between alternate LOS structures in the isolates studied, with most strains capable of expressing several alternative terminal structures . The structures predicted to be currently expressed by the genotype of the strains agreed well with conventional immunotyping . No correlation was observed between the structural repertoire and virulence of the isolate . Based on the potential for LOS phase variation in the clinical collection and observations with the paired patient isolates, our data suggest that phase variation of LOS structures is not required for translocation between distinct compartments in the host.

Glycoconj J, 2001 Oct, 18(10), 751 - 8
Mutant bacteriophage with non-catalytic endosialidase binds to both bacterial and eukaryotic polysialic acid and can be used as probe for its detection; Aalto J et al.; There is a molecular mimicry between the polysialic acid polysaccharide of bacterial pathogens causing sepsis and meningitis, and the carbohydrate units of the neural cell adhesion molecule NCAM . We investigated whether bacteriophage mutants with catalytically disabled endosialidase, which bind but do not cleave polysialic acid, could recognise and bind to bacterial and eukaryotic polysialic acid . In nitrocellulose dot blot assay the mutant bacteriophages, but not the wild-type phages, remained specifically bound to polysialic acid-containing bacteria including Escherichia coli K1 and K92, group B meningococci, Mannheimia (Pasteurella) haemolytica A2, and Moraxella nonliquefaciens . A minimum binding requirement was determined to be 10 sialyl residues in the polysialic acid chain . In Western blots the mutant phages specifically bound to the embryonic polysialylated form of NCAM, but not to the adult less sialylated form of the molecule . The mutant phages together with secondary anti-phage antibodies were subsequently successfully used in fluorescence microscopy of cultured cells and light microscopy of paraffin-embedded tissue sections as a probe for the eukaryotic polysialic acid . Thus, mutant bacteriophages of meningitis causing bacteria bind to and detect the molecularly mimicked polysialic acid of the neural cell adhesion molecule in host tissues.

Clin Infect Dis, 2002 Dec 1, 35(11), 1376 - 81 Epub 2002 Nov 05.
Meningococcal disease among United States military service members in relation to routine uses of vaccines with different serogroup-specific components, 1964-1998; Brundage JF et al.; Historically, military recruits have been at high risk of acquiring meningococcal disease . Beginning in the 1940s, the US military relied on mass treatment with sulfadiazine to control outbreaks in training camps . In the 1960s, a vaccine was developed in response to the emergence of sulfadiazine-resistant strains . Since 1971, all new recruits in the US military have been immunized against Neisseria meningitidis during their first days of service . Serogroups represented in vaccines given to service members have changed over time: the quadrivalent (A, C, Y, W135) vaccine has been given since 1982 . In the US military, meningococcal disease rates decreased by approximately 94% from 1964 to 1998 . After initiating routine immunization in 1971, crude rates decreased sharply and have remained low; in addition, there have been few cases of disease caused by serogroups represented in contemporaneously administered vaccines . In the US military, immunizations have been effective for the prevention of disease caused by vaccine-homologous serogroups of N . meningitidis.

Infect Immun, 2002 Dec, 70(12), 7063 - 72
Comparative genomics identifies the genetic islands that distinguish Neisseria meningitidis, the agent of cerebrospinal meningitis, from other Neisseria species; Perrin A et al.; Neisseria meningitidis colonizes the nasopharynx and, unlike commensal Neisseria species, is capable of entering the bloodstream, crossing the blood-brain barrier, and invading the meninges . The other pathogenic Neisseria species, Neisseria gonorrhoeae, generally causes an infection which is localized to the genitourinary tract . In order to investigate the genetic basis of this difference in disease profiles, we used a strategy of genomic comparison . We used DNA arrays to compare the genome of N . meningitidis with those of N . gonorrhoeae and Neisseria lactamica, a commensal of the nasopharynx . We thus identified sequences conserved among a representative set of virulent strains which are either specific to N . meningitidis or shared with N . gonorrhoeae but absent from N . lactamica . Though these bacteria express dramatically different pathogenicities, these meningococcal sequences were limited and, in contrast to what has been found in other pathogenic bacterial species, they are not organized in large chromosomal islands.

Infect Immun, 2002 Dec, 70(12), 6576 - 82
A glycoconjugate vaccine for Neisseria meningitidis induces antibodies in human infants that afford protection against meningococcal bacteremia in a neonate rat challenge model; Mountzouros KT et al.; The functional activities of serum samples from human infants immunized with a glycoconjugate vaccine for Neisseria meningitidis serogroup C were assessed in a complement-mediated antibody-dependent serum bactericidal assay (SBA) and in a neonate rat model of protection from bacteremia . Selective serum samples from individual human infants were combined to make a panel of 11 serum pools to obtain a sufficient volume for testing . Each pool was assayed (i) for the anti-N . meningitidis serogroup C capsular polysaccharide (PS) immunoglobulin G (IgG) concentration as determined by reactivity in a direct-binding enzyme-linked immunosorbent assay, (ii) for bactericidal activity against N . meningitidis serogroup C strain C11, and (iii) for the ability to reduce bacteremia after passive transfer into a neonate rat model . Representative serum samples from infants who were not previously immunized with any N . meningitidis serogroup C vaccine served as a negative control . The prepared serum pools ranged in antibody concentration from 0.18 to 17.31 micro g of IgG specific for N . meningitidis serogroup C PS per ml . For this serum panel, a direct relationship between concentrations of anti-N . meningitidis serogroup C PS-specific IgG and serum SBA titers (r = 0.9960) was observed . Passive transfer to neonate rats demonstrated the ability of postimmunization serum samples to significantly reduce (> or =2-log(10) reduction compared to control animals) the level of bacteremia following a challenge . Of 79 neonate rats that received > or =0.031 micro g of human infant anti-N . meningitidis serogroup C PS IgG, 75 (94.9%) had a > or =2-log(10) reduction in bacteremia, whereas of the animals that received <0.031 micro g of antigen-specific IgG, 10.3% (4 of 39 rats) showed a > or =2-log(10) reduction in bacteremia . It was concluded that the anti-N . meningitidis serogroup C PS IgG antibody induced by this glycoconjugate vaccine had in vitro functional activity (as determined by a SBA) and also afforded protection against meningococcal bacteremia in an animal model.

J Med Microbiol, 2002 Oct, 51(10), 855 - 60
Fatal outcome from meningococcal disease--an association with meningococcal phenotype but not with reduced susceptibility to benzylpenicillin; Trotter CL et al.; Penicillin has been the mainstay of treatment for meningococcal disease . Isolates of Neisseria meningitidis that are less susceptible to penicillin have been reported in several countries and in recent years have become more common . The clinical significance of this reduced susceptibility has not been investigated on a large scale . Hence, N . meningitidis isolates from culture-confirmed cases of meningococcal disease in England and Wales, between 1993 and 2000, were routinely serogrouped, serotyped and tested for susceptibility to penicillin . These data were linked to death registrations and analysed retrospectively . The changing trends in susceptibility were described and multivariate logistic regression was used to examine associations between strain characteristics and fatal outcome . The frequency of N . meningitidis isolates less susceptible to penicillin increased from < 6% in 1993 to > 18% in 2000 . In particular, isolates expressing serogroup C with serotype 2b and serogroup W135 had a higher frequency of reduced penicillin susceptibility (49% and 55%, respectively) . There was no evidence of an association between fatal outcome and infection with a less penicillin-susceptible isolate . Fatal outcome was associated with serogroup and serotype, with the odds of death for cases infected with C:2a and B:2a strains three-fold higher when compared with the baseline . For this large dataset the serogroup and serotype of the infecting strain influenced mortality from meningococcal disease and may be markers for hypervirulence . No association was found between reduced penicillin susceptibility and fatal outcome, but the increasing frequency of isolates less susceptible to penicillin highlights the need for continued surveillance.

Commun Dis Public Health, 2002 Sep, 5(3), 220 - 5
Meningococcal serogroup C conjugate vaccination in England and Wales: coverage and initial impact of the campaign; Trotter CL et al.; The UK was the first country to introduce meningococcal serogroup C conjugate vaccination . The vaccine was incorporated into the routine infant immunisation schedule and was offered to all under 18 year olds in a catch-up campaign . The vaccine has been well accepted in infants receiving routine vaccination, with coverage around 89% . Coverage in older children targeted in the catch-up campaign was above 85% up to the age of 14, and was lowest (43%) in 15-17 year olds not in education . The winter of 2000-01 was the first meningococcal season following the offer of the vaccination to all children and adolescents . The incidence of serogroup C disease in the targeted age groups fell by 80%, and the number of deaths in laboratory confirmed cases in 0-19 year olds decreased from 78 to 8 between 1998-99 and 2000-01 . The incidence of serogroup B disease in all age groups was slightly higher in 2000-01 than previous years, and there was an increase in the incidence of serogroup C disease in those aged over 20 during the study period, leading to the extension of the vaccination campaign to 20-24 year olds.

Commun Dis Public Health, 2002 Sep, 5(3), 213 - 9
Estimating the burden of serogroup C meningococcal disease in England and Wales; Davison KL et al.; In 1999 a new conjugate vaccine for serogroup C meningococcal disease was licensed for use in the UK . In order for an appropriate vaccination strategy to be developed the burden of serogroup C disease in England and Wales needed to be established . This was done using data from an enhanced surveillance scheme alongside routine laboratory reports and a total of 5,052 cases of serogroup C disease in England and Wales between 1993 and 1998 were estimated . Among these, an estimated 398 died and 1,767 were admitted to intensive care units (ITUs) . The greatest burden of disease was in young children and teenagers . The current literature identified four studies reporting sequelae following serogroup C meningococcal disease . These provided estimates of sequelae in the range of 6.5% and 45% and presented some evidence of higher levels than occur following serogroup B meningococcal disease . This information was provided to the Joint Committee on Vaccination and Immunisation to inform policy to implement a serogroup C conjugate vaccination programme in the UK . The vaccination programme has since been justified by the dramatic reduction in serogroup C meningococcal cases.

Commun Dis Public Health, 2002 Sep, 5(3), 205 - 12
Enhanced surveillance scheme for suspected meningococcal disease in five regional health authorities in England: 1998; Davison KL et al.; Enhanced surveillance of meningococcal disease (ESMD) began in five English regions on 1st January 1998 . The aims of the scheme were to obtain accurate incidence data and develop a robust surveillance system with which to monitor the impact of a new meningococcal serogroup C conjugate vaccine . During 1998, 2,314 suspected cases of meningococcal disease were identified . The majority (84%) was classified as invasive meningococcal disease, with infection of N . meningitidis confirmed in 66% . Sixteen per cent of suspected cases were subsequently given an alternative diagnosis . Age differences between those classified as meningococcal disease and those not, implied a higher index of suspicion of meningococcal disease in younger children . Regions with high rates of meningococcal disease were due to a higher rate of serogroup C . ESMD increased ascertainment of meningococcal disease and deaths . Cases were 34% greater than identified through statutory notifications, an additional 6.8% confirmed infections were identified than were reported to the PHLS Meningococcal Reference Unit (MRU) and deaths were 24% greater than death registrations . These data were used to inform the national meningococcal serogroup C conjugate vaccination programme in England and Wales . In 1999 ESMD was extended to all regions of England, Wales and Northern Ireland.

Commun Dis Public Health, 2002 Sep, 5(3), 187 - 204
Guidelines for public health management of meningococcal disease in the UK; Public Health Laboratory Service;; Public Health Medicine Environmental Group;; Scottish Centre for Infection and Environmental Health; Following changes in the epidemiology of meningococcal disease, the advent of new vaccines, and with new evidence on risk and control measures, the Public Health Laboratory Service Meningococcus Forum set up a Working Group to review the guidance for control measures in the UK . This review is based on available evidence, and recommendations are graded according to the level of evidence on which they are based . These guidelines cover pre-admission management, investigation of suspected cases, the role of public health, public health action after a single case, prophylaxis in healthcare settings, and management of clusters . Detailed revised recommendations are presented on the use of antibiotics before admission to hospital, the rationale and indications for chemoprophylaxis, and the use of new vaccines . Links to relevant websites are included.

Rev Med Brux, 2002 Sep, 23(4), A251 - 5
{Vaccinations for the traveller}; Van Laethem Y; Long distance journeys are more and more frequent . Beside malaria prophylaxis, the general practitioner shall consider several points . Vaccinations against tetanus, diphtheria and (for a few years at least) polio should be done every ten years . Hepatitis A vaccine shall often be done (with > 20 years protection) but typhoid fever vaccine shall be limited to adventurous and/or long stays . Yellow fever vaccine (10 years validity) is only administrated in specialised centers; this is the only mandatory vaccine for certain african or south american countries . In certain instances, one shall consider vaccination against hepatitis B, meningococcal meningitis or, less often, against rabies, central european or japanese encephalitis . The vaccine against cholera (numerous side effects and poor efficacy) is no more available.

Mol Microbiol, 2002 Nov, 46(4), 933 - 46
Fibronectin mediates Opc-dependent internalization of Neisseria meningitidis in human brain microvascular endothelial cells; Unkmeir A et al.; A central step in the pathogenesis of bacterial meningitis caused by Neisseria meningitidis (the meningococcus) is the interaction of the bacteria with cells of the blood-brain barrier . In the present study, we analysed the invasive potential of two strains representing hypervirulent meningococcal lineages of the ET-5 and ET-37 complex in human brain-derived endothelial cells (HBEMCs) . In contrast to previous observations made with epithelial cells and human umbilical vein-derived endothelial cells (HUVECs), significant internalization of encapsulated meningococci by HBMECs was observed . However, this uptake was found only for the ET-5 complex isolate MC 58, and not for an ET-37 complex strain . Furthermore, the uptake of meningococci by HBMECs depended on the presence of human serum, whereas serum of bovine origin did not promote the internalization of meningococci in HBMECs . By mutagenesis experiments, we demonstrate that internalization depended on the expression of the opc gene, which is present in meningococci of the ET-5 complex, but absent in ET-37 complex meningococci . Chromatographic separation of human serum proteins revealed fibronectin as the uptake-promoting serum factor, which binds to HBMECs via alpha 5 beta 1 integrin receptors . These data provide evidence for unique molecular mechanisms of the interaction of meningococci with endothelial cells of the blood-brain barrier and contribute to our understanding of the pathogenesis of meningitis caused by meningococci of different clonal lineages.

Commun Dis Intell, 2002, 26(3), 407 - 18
Annual report of the Australian Meningococcal Surveillance Programme, 2001; Procalcitonin as a prognostic marker in meningococcal disease; Department of Paediatrics, Division of Paediatric Intensive Care, Erasmus Medical Center/Sophia Children's Hospital, Dr Molewaterplein 60, 3015 GJ Rotterdam, The NetherlandsOBJECTIVE: To assess the prognostic value of procalcitonin levels during the clinical course of meningococcal disease in children . DESIGN: A retrospective, descriptive study . SETTING: University paediatric intensive care unit . PATIENTS: Nine patients with meningococcal sepsis and 55 patients with meningococcal septic shock were included in the study, giving a total of 64 . MEASUREMENTS AND RESULTS: Procalcitonin (PCT), C-reactive protein (CRP), cytokines (IL-6, IL-8 and TNF-alpha), plasminogen activator inhibitor-1 (PAI-1) and several routine laboratory parameters were determined and expressed as medians (ranges) . PCT levels on hospitalisation were elevated in all children as compared to normal values . Median PCT levels on admission were significantly higher in children with septic shock than in children with sepsis (270 ng/ml (5.7-672.3) versus 64.4 (20.6-283.7); p<0.01) . When the patients were categorised to severity using the Pediatric Risk of Mortality (PRISM) score (group 1: <15 points, group 2: 16-30, group 3: >30), the PCT levels were significantly different in the three groups . All markers, with the exception of PCT (p=0.056), were significantly different between survivors and non-survivors . When the duration of petechiae was taken into account, the difference in PCT levels became significant (p=0.04) . CONCLUSIONS: Procalcitonin levels on admission are related to severity . In the case of a short disease history (duration of petechiae), PCT levels are also related to mortality . Although PCT levels are elevated in all patients, the levels per se do not allow a prediction about survival versus non-survival, this is in contrast to other markers and scores (PRISM).

J Clin Microbiol, 2002 Nov, 40(11), 4325 - 8
5' exonuclease assay for detection of serogroup Y Neisseria meningitidis; Probert WS et al.; The incidence of serogroup Y meningococcal disease has increased recently in the United States . Here, we describe the development of a 5' exonuclease assay for the detection of serogroup Y Neisseria meningitidis and demonstrate the usefulness of this assay for resolving serogroup identification of strains that are resistant to conventional serogrouping and for the nonculture identification of serogroup Y meningococcal disease.

J Clin Microbiol, 2002 Nov, 40(11), 3917 - 21
Rates of detection of Neisseria meningitidis in tonsils differ in relation to local incidence of invasive disease; Greiner O et al.; Nasopharyngeal swabbing substantially underestimates carriage of Neisseria meningitidis . Real-time PCR assays were employed to examine the presence of a broad range of bacteria and of N . meningitidis groups B and C, respectively, in tonsils from 26 individuals from Oxford, England, and 72 individuals from Zurich, Switzerland . The detection limit of each PCR system was DNA from one bacterial cell per reaction mixture . Tonsillar DNA did not inhibit amplification of meningococcal gene sequences, and N . meningitidis was detected in tonsils exposed to the bacterium . Whereas in both sets of patients other bacteria were detected, N . meningitidis group B and group C were only found in tonsils from Oxford where the incidence of invasive meningococcal disease is much higher than in Zurich . These observations suggest that PCR-based methods could be used for the detection of meningococcal carriage and that difference in disease incidence could be explained by different transmission rates in the community rather than host genetics or coexisting infections.

J Pharm Biomed Anal, 2002 Nov 7, 30(4), 1233 - 47
Use and validation of NMR assays for the identity and O-acetyl content of capsular polysaccharides from Neisseria meningitidis used in vaccine manufacture; Jones C et al.; We describe a validated NMR (nuclear magnetic resonance) spectroscopic assay for the identity of the capsular polysaccharides (CPSs) from Neisseria meningitidis Groups A, C, W135 and Y used in vaccine manufacture, and to determine the proportion of residues carrying an O-acetyl substituent . Proof of structural identity and quantitation of the O-acetyl content are key control parameters for these vaccines . The meningococcal CPSs have variable levels of O-acetylation, present at multiple sites in the repeat unit, leading to complex NMR spectra . Base-catalysed de-O-acetylation of the Groups A, C, W135 and Y CPSs yields simplified and reproducible spectra suitable for comparison with reference data . The degree of O-acetylation of the original CPS can be determined by integration of the acetate anion resonance and a suitable resonance from the saccharide moiety . The assay was validated using 46 independent samples from five manufacturers, and is shown to be robust and reproducible.

BioDrugs, 2002, 16(5), 321 - 9
Meningococcal vaccines: a progress report; Wildes SS et al.; Neisseria meningitidis causes a wide range of human disease and remains a common cause of septicaemia and meningitis . Meningococcal serogroups A, B, C and Y cause the majority of cases of invasive disease in the US and throughout the world, with epidemics usually caused by serogroups A and C . Most patients with meningococcaemia, with or without meningitis, respond to standard antimicrobial therapy with either penicillin or ampicillin, but the recent emergence of meningococcal strains that are intermediately resistant to penicillin may alter these recommendations in the future . Given the devastating nature of meningococcal disease and emergence of these resistant strains, prevention (specifically through vaccination) remains the best approach to control this serious infection . A polysaccharide meningococcal vaccine is efficacious against disease caused by serogroups A, C, Y and W135, but is not effective in infants and children aged <2 years, and the duration of efficacy decreases markedly during the first 3 years after a single dose of the vaccine . Conjugate meningococcal vaccines have been developed to address these concerns . Initial studies with the meningococcal C conjugate vaccine have shown that the vaccine is safe and immunogenic and provides a T cell-dependent antigen that can be boosted by further doses of vaccine, or following exposure to the homologous organism or cross-reacting antigens . The UK recently implemented routine vaccination with the meningococcal C conjugate vaccine to all infants, and to all persons aged >1 year in a catch-up programme to immunise all school-aged children and young adults up to 20 years of age . Early postlicensure data indicate that this vaccine has shown significant efficacy in reduction of invasive meningococcal disease in these age groups . The full impact of vaccination will be determined once all age groups are immunised.

Protein Expr Purif, 2002 Nov, 26(2), 243 - 8
Expression of the class 1 outer-membrane protein of Neisseria meningitidis in Escherichia coli and purification using a self-cleavable affinity tag; Humphries HE et al.; The class 1 protein (PorA) is a major component of the outer membrane of Neisseria meningitidis and functions as a cationic porin . The protein is particularly effective in generating a bactericidal immune response following infection and is therefore under investigation as a potential antigen for inclusion in new meningococcal vaccines . Studies on the vaccine potential of PorA would be facilitated by the production of pure protein, free from other components of the meningococcal outer membrane . In the current study, PorA was expressed from the heterologous host Escherichia coli as a C-terminal fusion to an inducible protein-splicing element (intein) with an N-terminal chitin-binding domain (CBD) (IMPACT-TWIN system) . The CBD acted as an affinity tag and allowed binding of the fusion protein to a chitin bead column, after which self-cleavage of the intein at its C-terminus was induced, resulting in the release of mature PorA . Cleavage of the fusion protein was temperature- and time-dependent, and was optimal at pH 7.0 after 5 days of storage at 4 degrees C . Efficient cleavage was also dependent on the addition of a minimal amino acid sequence (Gly-Arg-Ala) to the N-terminus of the mature PorA protein . This represented a significant improvement on the large N-terminal sequences introduced by other expression systems previously used to prepare recombinant PorA, and the yields of PorA purified with the IMPACT-TWIN system were similar . Thus, the IMPACT-TWIN system provides a facile method for producing recombinant PorA and may also be useful for the production of other bacterial outer-membrane proteins for vaccine studies.

J Infect Dis, 2002 Nov 1, 186(9), 1353 - 7 Epub 2002 Oct 08.
Antibody persistence and immunological memory at age 4 years after meningococcal group C conjugate vaccination in children in the United kingdom; Borrow R et al.; Antibody persistence and immunological priming for 2 formulations of a meningococcal group C (menC) conjugate (MCC) vaccine (containing 2 or 10 microg of menC polysaccharide) administered at 2, 3, and 4 months of age was investigated by boosting vaccine recipients at age 13-16 months or 4 years with 10 microg of unconjugated menC polysaccharide . At age 4 years, geometric mean titers (GMTs) and concentrations of menC-specific immunoglobulin G and serum bactericidal antibody (SBA) had decreased to prevaccination levels . Geometric mean avidity indices increased after the primary vaccination until age 13-16 months and then remained constant until age 4 years . One month after boosting at age 4 years, menC immunoglobulin G and SBA levels increased significantly . The postbooster SBA GMT for the 2-microg vaccination (2181.2; 95% confidence interval {CI}, 975.9-4875.1) was 2-fold higher than that for the 10-microg vaccination (931.6; 95% CI, 338.0-2568.1) . This is the first demonstration of immunological memory at 4 years of age in children receiving MCC vaccine on the United Kingdom's 2/3/4-month immunization schedule.

Pediatr Infect Dis J, 2002 Oct, 21(10), 978 - 9
Dose escalation, safety and immunogenicity study of a tetravalent meninogococcal polysaccharide diphtheria conjugate vaccine in toddlers; Rennels M et al.; Two injections of tetravalent (Groups A, C, Y and W-135) meningococcal polysaccharide vaccine conjugated to diphtheria were given to 30 toddlers at dosages of 1, 4 and 10 microg/ml polysaccharide of each serogroup . Reactogenicity was acceptable at all dosages . The 4-microg/ml dose appears to be immunologically optimal.

Vaccine, 2002 Nov 1, 20(31-32), 3778 - 82
Prior meningococcal A/C polysaccharide vaccine does not reduce immune responses to conjugate vaccine in young adults; Lakshman R et al.; The immune responses induced in young adults by a meningococcal A/C polysaccharide-diphtheria toxoid conjugate vaccine (Mcj) and a meningococcal A/C plain polysaccharide vaccine (Mps) were evaluated in unvaccinated subjects and those who had received either vaccine previously . 195 subjects aged 17-30 years received either Mps or Mcj . After 12 months, they were randomised again to receive a second dose of either vaccine . Serogroup specific serum bactericidal assay (SBA) titers and IgG antibody responses were assayed before and 4-8 weeks after primary and booster immunisation . Both vaccines were immunogenic in previously unvaccinated subjects . Administration of a dose of Mps after previous Mps or Mcj induced lower bactericidal titers to group C Neisseria meningitidis than those seen after a single dose of Mps . Bactericidal antibody responses to Mcj were not reduced in subjects who had previously received Mps.

Ann Pharmacother, 2002 Nov, 36(11), 1776 - 84
Meningococcal vaccine use in college students; Kelleher JA et al.; OBJECTIVE: To discuss the role of meningococcal vaccine in prevention of meningococcal disease . DATA SOURCES: A MEDLINE search (1966-June 2001) was performed to identify key literature . Search terms included, but were not limited to, meningococcal vaccines, meningococcal meningitis, meningococcal infection, and meningococcus . The search was limited to English-language literature and references dealing with humans . The MEDLINE search was supplemented by a hand search of various bibliographies . DATA SYNTHESIS: The impact of meningococcal disease has caused national and regional organizations to develop recommendations for use of meningococcal vaccine . Even though the meningococcal vaccine can provide benefit, limitations exist . The available vaccine does not cover all meningococcal strains and is not useful in all age groups . The appropriate target groups for prevention of disease through vaccination have been difficult to determine; vaccine use in college students is especially controversial . CONCLUSIONS: Although a meningococcal vaccine is available, meningococcus causes significant morbidity and mortality . Controversy exists over the meningococcal vaccine and its use . Students entering college who will be living in dormitories should be informed of the increased risk of meningococcal disease and be offered vaccination.

Crit Care Med, 2002 Oct, 30(10), 2191 - 8
Characterization of a myocardial depressant factor in meningococcal septicemia; Pathan N et al.; OBJECTIVE: Identification and characterization of myocardial depressant factors present in meningococcal septicemia . DESIGN: Laboratory investigation of myocardial depression that used isolated cardiac myocytes as an model of cardiac contractile function . SETTING: University hospital and laboratories . PATIENTS: Children with severe meningococcal septic shock requiring intensive care . ANIMALS: Myocytes obtained from adult male Sprague-Dawley rats . INTERVENTIONS: Serum samples obtained from the acute phase of sepsis were evaluated for the presence of myocardial depressant activity . Further characterization of the myocardial depressant factor was undertaken by using cell culture supernatants from whole blood and peripheral blood mononuclear cells that had been exposed to heat-killed meningococci . MEASUREMENTS AND MAIN RESULTS: Myocardial depressant activity was measured by using isolated rat left-ventricular myocytes . Changes in amplitude of contraction and in the speed of contraction and relaxation were determined after cells were exposed to various stimuli . Serum from patients with meningococcal disease had myocardial depressant activity . This activity was also present in whole blood and peripheral blood mononuclear cells exposed to meningococci . Myocardial depressant activity was found to be heat stable, proteinaceous, and of a molecular weight range of 10-25 kDa . The activity did not elevate concentrations of cyclic guanylic acid . Lipopolysaccharide-binding protein augmented the release of myocardial depressant factor by peripheral blood mononuclear cells exposed to meningococci . CONCLUSIONS: Myocardial depression in meningococcal sepsis is mediated in part by circulating myocardial depressant factors . Myocardial depressant factors are also released when whole blood or peripheral blood mononuclear cells of healthy donors are exposed to heat-killed meningococci . Release of the factors appears to be mediated through endotoxin-induced activation of peripheral blood mononuclear cells, since lipopolysaccharide-binding protein augments release in a dose-responsive manner . Partial physicochemical characterization of the factors has been achieved.

Cell Microbiol, 2002 Sep, 4(9), 599 - 611
Expression of foreign LpxA acyltransferases in Neisseria meningitidis results in modified lipid A with reduced toxicity and retained adjuvant activity; Steeghs L et al.; A major problem in the development of vaccines against Gram-negative bacteria is the endotoxic -activity of lipopolysaccharide (LPS), which is determined by its lipid A moiety . Nevertheless, LPS would be an interesting vaccine component because of its immune-stimulating properties . In the present study, we have changed the fatty acid composition of Neisseria meningitidis LPS by replacing the lpxA gene of strain H44/76 with the Escherichia coli or Pseudomonas aeruginosa homologue . The majority of the O-linked 3-OH C12 in N . meningitidis lipid A was replaced by 3-OH C14 (strain HA01E) and 3-OH C10 (strain HA25P) respectively . Both strains, but most notably strain HA01E, had reduced amounts of LPS compared with the wild-type strain . In addition, growth was severely impaired for HA01E . The major outer membrane proteins were expressed normally . Outer membrane complexes of both strains normalized on their LPS content showed a 10-fold reduction in their ability to induce tumour necrosis factor (TNF)-alpha . Immunogenicity studies in BALB/c mice revealed that the adjuvant activity of the LPS was not affected . Thus, the replacement of the O-linked fatty acids in meningococcal lipid A results in immunogenic outer membranes with reduced endotoxic activity, more suitable for use in outer membrane vesicle vaccines.

J Infect, 2002 Oct, 45(3), 144 - 51
Pre-hospital parenteral antibiotic treatment of meningococcal disease and case fatality: a Danish population-based cohort study; Norgard B et al.; OBJECTIVES: Studies about the efficiency of pre-hospital antibiotic treatment of meningococcal disease are conflicting . We examined the case fatality rate in patients with meningococcal disease treated with pre-hospital antibiotics . METHODS: A cohort study of 534 patients hospitalized with meningococcal disease from two Danish counties . Clinical data were obtained from referral letters from general practitioners and hospital records . Complete follow-up for all patient until death or discharge . RESULTS: Seventy-seven patients (16% of the patients seen by a general practitioner) received parenteral antibiotics before hospital admission; 9 (12%) of them died . Of 402 patients who did not receive pre-hospital parenteral antibiotics, 26 (7%) died . The overall risk of case fatality among antibiotic-treated patients was increased with adjusted odds ratio (OR) = 2.4 (95% CI, 1.0-5.6) . Meningococcus serogroup B was associated with increased case fatality in patients who received pre-hospital parenteral antibiotics (OR = 2.6; 95% CI, 0.8-8.3) in contrast to other serogroups . In Aarhus County there were no deaths in patients who received pre-hospital parenteral antibiotics, but in North Jutland County the case fatality was high (OR = 2.9; 95% CI, 1.2-6.8) . CONCLUSIONS: The efficiency of pre-hospital parenteral antibiotic treatment seems to be dependent on hospital care and may vary with the serogroup.

FEMS Immunol Med Microbiol, 2002 Oct 11, 34(2), 89 - 96
Neisseria meningitidis serogroup B: laboratory correlates of protection; Vermont C et al.; Meningococcal disease in the Western countries is frequently caused by Neisseria meningitidis serogroup B . Major efforts have been made to develop a safe and efficacious vaccine against this serogroup which is suitable for use in infants and young children . To assess the quality of the immune response after vaccination with candidate vaccines, laboratory correlates of protection are needed . For serogroups A and C, serum bactericidal activity (SBA) is a well established predictor for protection, but for serogroup B other mechanisms besides SBA may also be involved in conferring protection from disease . Several laboratory methods for identification and evaluation of the immunogenicity of possible vaccine antigens are described in this review.

Infect Immun, 2002 Nov, 70(11), 6021 - 31
Sequential immunization with vesicles prepared from heterologous Neisseria meningitidis strains elicits broadly protective serum antibodies to group B strains; Moe GR et al.; The capsular polysaccharide of Neisseria meningitidis group B is an autoantigen, whereas noncapsular antigens are highly variable . These factors present formidable challenges for development of a broadly protective and safe group B vaccine . Mice and guinea pigs were sequentially immunized with three doses of micovesicles or outer membrane vesicles prepared from three meningococcal strains that were each antigenically heterologous with respect to the two major porin proteins, PorA and PorB, and the group capsular polysaccharide . The resulting antisera conferred passive protection against meningococcal group B bacteremia in infant rats and elicited complement-mediated bactericidal activity against genetically diverse group B strains that were either homologous or heterologous with respect to PorA of the strains used to prepare the vaccine . By using knockout strains, a portion of the bactericidal antibody was directed against the highly conserved protein, neisserial surface protein A (NspA) . Further, an anti-NspA monoclonal antibody elicited by the sequential immunization was highly bactericidal against strains that were previously shown to be resistant to bacteriolysis by anti-NspA antibodies produced by immunization with recombinant NspA . Sequential immunization with heterologous vesicle preparations offers a novel approach to eliciting broadly protective immunity against N . meningitidis strains . An NspA-based vaccine prepared from protein expressed by Neisseria also may be more effective than the corresponding recombinant protein made in Escherichia coli.

Br J Biomed Sci, 2002, 59(3), 137 - 40
Semi-automation of the polymerase chain reaction for laboratory confirmation of meningococcal disease; Diggle MA et al.; Demand for accurate high-throughput detection and characterisation of medically important bacteria has increased dramatically within research and clinical laboratories . Liquid-handling robots have been developed to achieve high levels of accuracy and reproducibility . Assay automation can play a key role in the modern diagnostic laboratory and the data presented here shows that automated PCR is comparable with manual methods . Importantly, automation is preferred when high-quality results cannot be guaranteed using manual methods . This is particularly important when results are required quickly for public health management.

J Med Microbiol, 2002 Sep, 51(9), 717 - 22
Impact of meningococcal C conjugate vaccine in the UK; Balmer P et al.; This review details the impact of the introduction of meningococcal serogroup C conjugate (MCC) vaccines in the UK . An overall reduction of 86.7% in the incidence of serogroup C infection in the targeted age groups has been observed from 1999 to 2001, with a concomitant decrease in deaths, from 67 in 1999 to 5 in 2001 . The enhanced surveillance programme initiated to complement the introduction of MCC vaccines has been essential in generating data relating to vaccine coverage, vaccine failures and efficacy estimates . Vaccine coverage has exceeded 80% in all age groups targeted and up to the end of 2001, 25 confirmed and 1 probable vaccine failure have been observed in England and Wales . Efficacy estimates for England up to September 2001 were 91.5% in infants receiving three doses of MCC vaccine and 89.3% in toddlers receiving one dose of MCC vaccine (England) . There is some evidence of herd immunity in unvaccinated cohorts of the target age groups, ranging from a reduction in disease incidence of 34% in 9-14 year olds to 61% in 15-17 year olds . Surveillance of the genotypic and phenotypic characteristics of invasive and carriage isolates has shown no evidence to date of capsular switching from serogroup C to serogroup B.

Chemistry, 2002 Oct 4, 8(19), 4424 - 33
Towards a synthetic glycoconjugate vaccine against Neisseria meningitidis A; Berkin A et al.; Albumin conjugates of synthetic fragments of the capsular polysaccharide of the Gram-negative bacterium Neisseria meningitidis serogroup A were prepared . The fragments include monosaccharides 1 {alpha-D-ManpNAc-(1-->O)-(CH(2))(2)NH(2)} and 2 {6-O-P(O)(O(-))(2)-alpha-D-ManpNAc-(1-->O)-(CH(2))(2)NH(2)}, disaccharide 3 {alpha-D-ManpNAc-{1-->O-P(O)(O(-))-->6}-alpha-D-ManpNAc-(1-->O)-(CH(2))(2)NH(2)}, and trisaccharide 4 {alpha-D-ManpNAc-{1-->O-P(O)(O(-))-->6}-alpha-D-ManpNAc-{1-->O-P(O)(O(-))-->6}-alpha-D-ManpNAc-(1-->O)-(CH(2))(2)NH(2)} . Two monosaccharide blocks were employed as key intermediates . The reducing-end mannose unit featured the NHAc group at C-2, and contained the aminoethyl spacer as the aglycon for the final bioconjugation . The interresidual phosphodiester linkages were fashioned from an anomerically positioned H-phosphonate group in a 2-azido-mannose building block . The spacer-linked saccharides 1-4 were N-acylated with hepta-4,6-dienoic acid and the resulting conjugated diene-equipped saccharides were subjected to Diels-Alder-type addition with maleimidobutyryl-group functionalized human serum albumin to form covalent conjugates containing up to 26 saccharide haptens per albumin molecule . Complete (1)H, (13)C, and (31)P NMR assignments for 1-4 are given . Antigenicity of the neoglycoconjugates containing 1-4 was demonstrated by a double immunodiffusion assay which indicated that a fragment as small as a monosaccharide is recognized by a polyclonal meningococcus group A antiserum and that the O-acetyl group(s) present in the natural capsular material is not essential for antigenicity.

J Clin Microbiol, 2002 Oct, 40(10), 3565 - 71
Molecular epidemiological analysis of the changing nature of a meningococcal outbreak following a vaccination campaign; Shlush LI et al.; A serogroup C meningococcal outbreak that occurred in an Israeli Arab village led to a massive vaccination campaign . During the subsequent 18 months, new cases of type B Neisseria meningitidis infection were revealed . To investigate the influence of vaccination on bacteriological epidemiology, bacteria were isolated from individuals at the outbreak location, patients with several additional other sporadic cases, and patients involved in another outbreak . Haploid bacterial genomic DNA was mixed with a consensus PCR product to form a heteroduplex state that enabled multilocus sequence typing (MLST) to be combined with denaturing high-performance liquid chromatography (DHPLC) for a novel high-throughput molecular typing method called MLST-DHPLC . A 100% correlation was found to exist between the sequencing by MLST alone and the MLST-DHPLC method . Independent molecular typing by repetitive extragenic palindromic PCR discriminated the neisserial clones as well as the MLST-DHPLC method did . The occurrence of type B N . meningitidis in the postvaccination period might be attributed to the selection pressure applied to the bacteria by vaccination, suggesting a possible unwarranted outcome of vaccination with the quadrivalent vaccine for control of a serogroup C meningococcal outbreak . This is the first time that DHPLC has been applied to the genotyping of bacteria, and it proved to be more efficient than MLST alone.

Pediatr Infect Dis J, 2002 Sep, 21(9), 810 - 5
Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia; Black SB et al.; OBJECTIVE: To determine the effectiveness of the Wyeth heptavalent pneumococcal conjugate vaccine against clinical and radiograph-confirmed pneumonia in children . METHODS: The heptavalent CRM(197) pneumococcal conjugate vaccine (PCV) was given to infants at 2, 4, 6 and 12 to 15 months of age in a randomized, double blind trial . Children were randomized to receive either the CRM(197) PCV (vaccine group) or the meningococcal type C CRM(197) conjugate vaccine (control group) . The primary outcome of this trial was invasive pneumococcal disease . In addition children with the clinical diagnosis of pneumonia in the study population were identified through review of automated inpatient, emergency and outpatient databases . The subset of the cohort of these children who had chest radiographs obtained at the time of diagnosis was identified, and the original reading of their radiographs by the radiologist was obtained from automated databases . Rates of clinically diagnosed pneumonia, of pneumonia with a radiograph obtained regardless of result, of pneumonia with positive radiograph (consolidation, empyema or parenchymal infiltrate) and of pneumonia with only perihilar infiltrates were compared between vaccinated and nonvaccinated groups . In addition risk of disease pneumonia was evaluated by race and ethnicity . RESULTS: The incidence of a first pneumonia episode in the control group was 55.9 per 1000 person-years . A radiograph was obtained in 61% of episodes, a positive radiograph in 21% and perihilar findings in an additional 5% . In per protocol follow-up of children given PCV, first episodes of all clinically diagnosed pneumonia were reduced by 4.3% {95% confidence interval (CI), -3.5, 11.5%, = 0.27}, episodes with a radiograph were reduced by 9.8% (CI 0.1, 18.5%, < 0.05) and episodes with a positive radiograph were reduced by 20.5% (CI 4.4, 34.0, = 0.02) . In the intent to treat analysis including all episodes after randomization, episodes with a positive radiograph were reduced by 17.7%, =.01) . The greatest impact was in the first year of life with a 32.2% reduction and a 23.4% reduction in the first 2 years, but only a 9.1% reduction in children >2 years of age . Asians, blacks and Hispanics were at higher risk of pneumonia than were whites, but there was no evidence of ethnic variation in PCV effectiveness . Ten of the 11 cases of pneumococcal pneumonia with a positive blood culture were in the control group . CONCLUSION: The pneumococcal conjugate vaccine tested was effective in reducing the risk of pneumonia in young children.

J Burn Care Rehabil, 2002 Sep-Oct, 23(5), 333 - 40
Differential effects of two different routes of immunization on protection against gram-negative sepsis by a detoxified Escherichia coli J5 lipopolysaccharide group B meningococcal outer membrane protein complex vaccine in a burned mouse model; Neely AN et al.; Gram-negative sepsis causes morbidity and mortality in burned patients . To determine whether immunization with core endotoxin (lipopolysaccharide) via one of two routes could protect burned mice from septic death, mice were immunized either three times subcutaneously (SC) or one time intramuscularly (IM) then two times intraperitoneally (IP) with a core-lipopolysaccharide vaccine . Control mice were immunized with either saline or an irrelevant antigen . Postimmunization, mice were immunocompromised with a 15% TBSA flame burn and challenged subeschar with Klebsiella pneumoniae or Escherichia coli . Vaccine immunization improved the survival of both E . coli- and K . pneumoniae-challenged mice when given SC but not when given IM, IP . Postimmunization, total immunoglobulin titers were elevated over preimmune titers, but titers in IM, IP-immunized mice were higher than those in SC-immunized mice . Both isotyping and flow cytometry studies indicated that sera from mice immunized via IM, IP opsonized better than sera from mice immunized via SC . Hence, this vaccine provided route-specific protection of burned mice against gram-negative sepsis; its mechanism of action was not solely dependent upon increased immunoglobulin titers or phagocytosis.

BMC Pediatr . 2002 Sep 02;2(1):8.
The role of lumbar puncture in children with suspected central nervous system infection; Kneen R et al.; BACKGROUND: The use of the lumbar puncture in the diagnosis of central nervous system infection in acutely ill children is controversial . Recommendations have been published but it is unclear whether they are being followed . METHODS: The medical case notes of 415 acute medical admissions in a children's hospital were examined to identify children with suspected central nervous system infection and suspected meningococcal septicaemia . We determined whether lumbar punctures were indicated or contraindicated, whether they had been performed, and whether the results contributed to the patients' management . RESULTS: Fifty-two children with suspected central nervous system infections, and 43 with suspected meningococcal septicaemia were identified . No lumbar punctures were performed in patients with contraindications, but only 25 (53%) of 47 children with suspected central nervous system infection and no contraindications received a lumbar puncture . Lumbar puncture findings contributed to the management in 18 (72%) of these patients, by identifying a causative organism or excluding bacterial meningitis . CONCLUSION: The recommendations for undertaking lumbar punctures in children with suspected central nervous system infection are not being followed because many children that should receive lumbar punctures are not getting them . When they are performed, lumbar puncture findings make a useful contribution to the patients' management.

Health Millions . 1997 Mar-Apr;23(2):19.
Emerging infectious disease: global response, global alert; Nakajima H; PIP: Despite spectacular progress in the eradication of infectious diseases, malaria and tuberculosis are making a comeback in many parts of the world . After years of decline, plague, diphtheria, dengue, meningococcal meningitis, yellow fever, and cholera have reappeared as public health threats . In the last 20 years {before 1997} more than 30 new and highly infectious diseases have been identified, including Ebola-type hemorrhagic fever, HIV/AIDs, and hepatitis C . Antibiotic resistance has also emerged during this period, and fewer new antibiotics are being produced because of high development costs and licensing . Drugs no longer offer protection or cure for many infectious diseases, and consequently more people need hospitalization with higher treatment costs . The causes of the appearance of new diseases and the resurgence of old ones include the rapid increase in international travel, the growth of mega-cities with high population densities, inadequate safe water and sanitation, food-borne diseases by the globalization of trade, and human penetration into remote animal and insect habitats . Meanwhile, resources for public health are being reduced, with the result that either the appearance of new diseases or resistance to drugs go unnoticed . A recent example is the human immunodeficiency virus, which went unrecognized until a large number of people got infected . For this very reason the 1997 World Health Day featured the theme of emerging infectious diseases and global response . Such forums are held to help countries rebuild the foundations of disease surveillance and control, while the public and private sectors may be encouraged to develop better techniques for surveillance to confront a common global threat .

QJM, 2002 Oct, 95(10), 663 - 70
The impact of new diagnostic methodologies in the management of meningitis in adults at a teaching hospital; Chadwick DR et al.; BACKGROUND:Suspected meningitis is a frequent reason for admission to hospital in the UK . While bacterial meningitis requires prompt antibiotic therapy to reduce mortality and morbidity, enteroviral meningitis, the most frequent viral cause, is almost invariably a benign disease . Aim: To determine the clinical presentation, laboratory findings and outcome of meningitis by microbiological aetiology and patient age, and to assess the clinical management of adults presenting with meningitis, with reference to national guidelines . DESIGN:Retrospective case-note review . METHODS:Adult (>14 years) admissions to Addenbrooke's Hospital with meningitis or meningococcal septicaemia March 1996-September 2001 were audited retrospectively . The case definition was: symptoms compatible with meningitis, and either abnormal CSF (leukocytes >5x10(9)/ml) or meningococcal disease . The only exclusion criterion was the presence of a ventricular shunt . RESULTS:Only 30% of patients seen by a General Practitioner were given pre-admission antibiotics . In a substantial number of cases, including those with bacterial meningitis, antibiotic administration was delayed either because patients were sent for CT head scans (delaying a lumbar puncture) or because the diagnosis was not considered, especially in elderly patients with reduced conscious levels . There were no confirmed cases of H . influenzae meningitis . Overall outcomes in terms of mortality and disability were similar to UK national data . A surprising number of patients (40%) were afebrile on admission . DISCUSSION:The proportion of patients with meningitis given pre-hospital antibiotics by GPs is still worryingly low, although early hospital management has improved . Improved diagnostic facilities, particularly viral PCR assays, reduce antibiotic usage and hospital stay, with considerable financial savings.

Med Trop (Mars), 2002, 62(3), 301 - 4
{First major epidemic caused by Neisseria meningitidis serogroup W135 in Africa?}; Bertherat E et al.; Neisseria meningitidis serogroup W 135 (N.m . W 135) has caused sporadic infections and small epidemics such as those that occurred during religious pilgrimages in Saudi Arabia in 2000 and in 2001 . It is routinely isolated from specimens coming from African countries . The first major epidemic involving N.m . W 135 occurred in Burkina Faso between January and May 1992 . There were more than 1300 cases including 1500 deaths . Enhanced surveillance of circulating strains showed that N.m . W 135 accounted for 83% of the 203 positive cerebrospinal fluid specimen cultures . The offending organism was identical to the strain that caused the smaller epidemic in Saudi Arabia in 2000 . Due to the shortage of tetravalent meningococcal vaccine against N.m . W 135, the Health Ministry based its response to the epidemic on treatment of symptomatic patients using chloramphenicol and ampicillian.These drugs were distributed free . The emergence of N.m . W135 has impacted public health in Africa . Repeated identification of this serogroup in Burkina Faso during 2002 raises the risk that similar outbreak will occur in the meningitis belt during the next epidemic season . The high cost of tetravalent meningococcal vaccine compounded with the only progressive increase in production capacity underline the need to reinforce surveillance of circulating strains and available treatment facilities . Control strategy for epidemic meningitis is currently the focus of close collaboration between the WHO and the health authorities and corresponding institutions in the countries involved.

Eur J Pediatr, 2002 Oct, 161(10), 531 - 7 Epub 2002 Aug 17.
Prospective validation of the Glasgow Meningococcal Septicaemia Prognostic Score . Comparison with other scoring methods; Riordan FA et al.; A prospective observational study was done to derive performance characteristics for the Glasgow Meningococcal Septicaemia Prognostic Score (GMSPS) and compare it with nine other severity scores (Stokland, Stiehm and Damrosch, Ansari, Niklasson, Leclerc, Kahn and Blum, Lewis, Istanbul and Bjark) and laboratory markers of disease severity . In the paediatric departments of six hospitals in Merseyside, UK, 278 children with confirmed or probable meningococcal disease were admitted between November 1988 and August 1990 ( n=152) and between September 1992 and April 1994 ( n=126); 26 of whom died . GMSPS was recorded on admission and again if there was clinical deterioration . Laboratory markers of disease severity (including endotoxin and cytokine levels) were measured on admission . The nine other scores were recorded on the first cohort . "Maximum" GMSPS (before referral to the paediatric intensive care unit) was achieved within 12 h of arrival in 97% of children . A GMSPS > or =8 had sensitivity 100%, specificity 75% and positive predictive value for death of 29%, GMSPS > or =10 had 100%, 88% and 46% respectively . All 26 who died scored >10, before referral to the paediatric intensive care unit . GMSPSs calculated by other medical staff had similar characteristics to those calculated by research fellows . All scores correlated significantly with white cell count, coagulopathy, endotoxin and cytokine levels . However, the predominantly clinical scores were the most robust . GMSPS had amongst the best performance characteristics of all scores and was more sensitive than laboratory markers . CONCLUSION: the Glasgow Meningococcal Septicaemia Prognostic Score is an easily performed, repeatable, clinical score that can rapidly identify children with fulminant meningococcal disease . When performed prospectively, a score > or =8 had a positive predictive value for death of 29% . This score can identify those children who should be offered intensive care and can select those who may benefit from novel therapies.

Arch Pathol Lab Med, 2002 Oct, 126(10), 1209 - 15
Evaluation of a diagnostic polymerase chain reaction assay for Neisseria meningitidis in North America and field experience during an outbreak; Pollard AJ et al.; CONTEXT: Meningococcal infection has a high public profile because of its dramatic presentation, high fatality rate, and propensity to occur in outbreaks and clusters of cases . Use of a diagnostic polymerase chain reaction (PCR) assay could enhance laboratory confirmation of cases and guide the public health response in North America . OBJECTIVE: To assess the performance of a PCR assay for the diagnosis of meningococcal disease after its implementation in a North American setting and to evaluate sensitivity and specificity of the assay for the detection of prevalent bacterial isolates . DESIGN: Laboratory evaluation of the sensitivity and specificity of a PCR assay for Neisseria meningitidis and observational study of a series of cases comparing molecular diagnosis against the criterion standard of conventional laboratory diagnostic tests . SETTING: A Canadian province with a population of 4 million people . PATIENTS: Children and adults presenting with suspected meningococcal disease in British Columbia . MAIN OUTCOME MEASURES: The sensitivity and specificity of the PCR assay when compared against standard laboratory methods . RESULTS: The PCR assay correctly identified all of 38 Canadian isolates of Neisseria meningitidis and correctly assigned the serogroup to each isolate . None of 57 other gram-positive or gram-negative bacteria or yeasts were detected by the PCR assay . In a clinical evaluation, for diagnosis of meningococcal disease, the PCR assay had a sensitivity and specificity of 91% and 76%, respectively, against conventional methods of diagnosis . Use of the PCR assay increased the laboratory confirmation of clinically suspected cases by 36% . During an outbreak, the PCR assay allowed serogroup determination in 3 of 7 cases, aiding in the public health decision to launch an immunization campaign . CONCLUSIONS: The PCR assay is more sensitive than conventional methods for the diagnosis of meningococcal disease, and enhanced surveillance may help direct the public health response to the changing epidemiology of disease in North America.

Mol Biol Evol, 2002 Oct, 19(10), 1686 - 94
Phylogenetic evidence for frequent positive selection and recombination in the meningococcal surface antigen PorB; Urwin R et al.; Previous estimates of rates of synonymous (d(S)) and nonsynonymous (d(N)) substitution among Neisseria meningitidis gene sequences suggested that the surface loops of the variable outer membrane protein PorB were under only weak selection pressure from the host immune response . These findings were consistent with studies indicating that PorB variants were not always protective in immunological and microbiological assays and questioned the suitability of this protein as a vaccine component . PorB, which is expressed at high levels on the surface of the meningococcus, has been implicated in mechanisms of pathogenesis and has also been used as a typing target in epidemiological investigations . In this work, using more precise estimates of selection pressures and recombination rates, we have shown that some residues in the surface loops of PorB are under very strong positive selection, as great as that observed in human immunodeficiency virus-1 surface glycoproteins, whereas amino acids within the loops and the membrane-spanning regions of the protein are under purifying selection, presumably because of structural constraints . Congruence tests showed that recombination occurred at a rate that was not sufficient to erase all phylogenetic similarity and did not greatly bias selection analysis . Homology models of PorB structure indicated that many strongly selected sites encoded residues that were predicted to be exposed to host immune responses, implying that this protein is under strong immune selection and requires further examination as a potential vaccine candidate . These data show that phylogenetic inference can be used to complement immunological and biochemical data in the choice of vaccine candidates.

Enferm Infecc Microbiol Clin, 2002 Aug-Sep, 20(7), 316 - 20
{Influence of adjuvants on the ability of anti-Tbp antibodies to block transferrin binding, iron uptake and growth of Neisseria meningitis}; Ferreiros C et al.; OBJECTIVE: To evaluate the effect of five adjuvants on the ability of specific anti-TbpA/B to block iron uptake in Neisseria meningitidis . MATERIALS AND METHODS: Transferrin binding complexes (TbpA/B) purified from a TbpB isotype II Neisseria meningitidis strain were used to obtain sera with five different adjuvant formulations in mice in order to test the effect of the adjuvant on the ability of specific anti-TbpA/B antibodies to block transferrin binding, iron uptake and growth by meningococci . RESULTS: Levels of anti-TbpA/B antibodies were relatively low (1:125 in most cases), the highest being obtained with the RAS adjuvant (1:3125) . Despite the relatively low responses, all sera were able to significantly inhibit transferrin binding, iron uptake and growth in the homologous strain . Nevertheless, the effect on a strain with a TbpB isotype different from that of the immunizing strain was almost nil, a result in keeping with the described division of the meningococci into at least two TbpB groups (isotypes I and II) . CONCLUSIONS: In contrast to previous results for another important meningococcal protein, FbpA, the use of various adjuvants in the immunization of mice with TbpA/B complexes did not produce differences in the immune responses elicited, except in relation to antibody titers.

Infection, 2002 Aug, 30(4), 216 - 24
A critical review of control strategies against meningococcal meningitis epidemics in sub-Saharan African countries; Chippaux JP et al.; The control strategy of meningitis epidemics in sub-Saharan countries, although reexamined regularly, is based on epidemiological, immunological and logistical considerations put forward at the end of the 1970s . It comprises organizing large-scale vaccinations in the event of a declared epidemic . The obvious failure of this strategy recommended by the World Health Organization (WHO) necessitates evaluation of the emergency vaccination criteria . Despite current controversy on the immunogenicity of the polysaccharide vaccine, its safety, effectiveness in the field and low cost could justify the reopening of a debate on its use in routine vaccination . Routine--or preventive--vaccination could significantly reduce the incidence of meningococcal meningitis and its severity . The conjugate vaccine, when available, will constitute an additional advantage in the prevention of meningococcal meningitis . A strategy combining both polysaccharide and conjugate vaccines according to the population targets and possibilities for funding remain to be defined.

J Infect Dis, 2002 Oct 1, 186(7), 1047 - 52 Epub 2002 Sep 13.
Cognitive impairment in adults with good recovery after bacterial meningitis; van de Beek D et al.; Adults without neurologic sequelae after bacterial meningitis are supposed to live without restrictions . Neuropsychological outcome was assessed in 51 adults from a prospective cohort with good recovery, defined as Glasgow Outcome Scale score 5, after pneumococcal or meningococcal meningitis . Patients who recovered well after pneumococcal meningitis showed cognitive slowness (P=.001) . A cognitive disorder was found in 27% of these patients . Patients who previously had meningococcal meningitis were not significantly different from control subjects . Scores on general health and quality of life questionnaires revealed lower scores for patients with meningitis, which were related to cognitive slowing (R, -0.46 to -0.38) . In conclusion, adults surviving pneumococcal meningitis were at significant risk of neuropsychological abnormalities, even if they were clinically well recovered.

Infect Immun, 2002 Oct, 70(10), 5479 - 84
Influence of intravenous anesthesia on mucosal and systemic antibody responses to nasal vaccines; Janakova L et al.; Inhalation of antigens may stimulate the immune system by way of the upper as well as the lower airways . We have shown that at least 1,000 times more live pneumococci were recovered from pulmonary tissue after being presented as drops of a liquid suspension onto the nares of anesthetized mice compared to the number of bacteria recovered from animals that were not anesthetized in the course of the challenge . Mice that were similarly immunized intranasally by inhalation of three different nonreplicating particulate vaccine formulations, i.e., a meningococcal outer membrane vesicle (OMV) vaccine, a formalin-inactivated whole-virus influenza (INV) vaccine, and the INV vaccine with OMVs as a mucosal adjuvant, during general intravenous anesthesia developed concentrations of vaccine-specific serum immunoglobulin G (IgG) antibodies that were four to nine times higher than in mice that were fully awake during immunizations . The concentrations of IgA antibodies in serum were also higher in anesthetized than in nonanesthetized mice and correlated positively with the corresponding levels of serum IgG antibodies in the anesthetized but not in the nonanesthetized mice . In saliva and feces, however, the concentrations of IgA antibodies were equally high whether or not the animals were dormant during immunizations . The results indicate that intrapulmonary antigen presentation, as a part of an intranasal immunization strategy, is of importance for systemic but not for mucosal antibody responses . A major portion of IgA antibodies in serum may thus be derived from nonmucosal sites.

Infect Immun, 2002 Oct, 70(10), 5346 - 54
The class A macrophage scavenger receptor is a major pattern recognition receptor for Neisseria meningitidis which is independent of lipopolysaccharide and not required for secretory responses; Peiser L et al.; Macrophages (Mphi) play a key role in the pathogenesis of invasive meningococcal infections . The roles of two pattern recognition molecules, the Mphi scavenger receptor (SR-A) and Toll-like receptor 4 (TLR-4), have been investigated using bone marrow culture-derived Mphi (BMMphi) . Surprisingly, a comparison of BMMphi from wild-type and SR-A knockout (SR-A(-/-)) mice showed that nonopsonic phagocytosis of meningococci was mediated almost exclusively via SR-A . Previous studies have demonstrated only a partial involvement of the receptor in the uptake of other bacteria, such as Escherichia coli . Interestingly, we also show that lipopolysaccharide (LPS) was not the ligand for the receptor on these organisms . Further study of the downstream events of SR-A-mediated ingestion of Neisseria meningitidis demonstrated that SR-A was not required for cytokine production . To determine the bacterial and host factors required to stimulate Mphi activation, we examined TLR-4-deficient Mphi from C3H/HeJ mice and LPS-deficient meningococci . TLR-4-deficient cells elaborated reduced amounts of tumor necrosis factor alpha, interleukin-12 (IL-12), and IL-10, even though ingestion via SR-A was unaffected in these cells . Similarly, although there was no change in SR-A-mediated ingestion of LPS-deficient meningococci, the mutant failed to stimulate a Mphi-dependent cytokine response . Thus, we show that Mphi SR-A mediates opsonin-independent uptake of N . meningitidis independently of lipid A and that this activity is uncoupled from the Mphi secretion of proinflammatory cytokines, which provides a basis for further investigation of the role of this receptor in meningococcal disease in humans.

Curr Infect Dis Rep, 2002 Oct, 4(5), 377 - 386
Pathogenesis, Therapy, and Prevention of Meningococcal Sepsis; Stephens DS et al.; Neisseria meningitidis (meningococcus), an exclusive pathogen of humans, is the cause of sepsis (meningococcemia) and meningitis, often in otherwise healthy individuals . Several hundred thousand cases of meningococcal disease occur worldwide each year, a number that is frequently accentuated by epidemic outbreaks . In recent years, significant advances, fueled by new molecular approaches and genome sequencing projects, have improved our understanding of the pathogenesis of meningococcal disease and have led to progress in the development of the next generation of meningococcal vaccines . However, the mortality of meningococcal disease remains 10% to 15% for all cases, and is up to 40% in patients with severe sepsis . This review summarizes current knowledge of the pathogenesis, therapy, and prevention of meningococcal disease with emphasis on meningococcal sepsis.

Rev Esp Salud Publica, 2002 Jul-Aug, 76(4), 347 - 57
{The Madrid autonomous community epidemiological bulletin . A survey on its dissemination and opinion thereof on among primary care physicians for the year 2000}; Fernandez Rodriguez S et al.; BACKGROUND: The Autonomous Community of Madrid Epidemiological Bulletin is the main communications link between epidemiological monitoring system and health care professionals . The purpose of this study is that of ascertaining the dissemination and opinion of this Autonomous Community of Madrid Epidemiological Bulletin among primary care physicians for the purpose of adapting this publication to its readers' interests . METHOD: A telephone survey among primary care physicians in the Autonomous Community of Madrid, asking how often they read the Bulletin, the interest and usefulness of the information included in it . The sample size was estimated at 346 physicians . A two-stage sampling process was carried out-by cluster sampling in the first stage, randomly selecting 125 health care centers and 2.7 physicians per center, 17% being primary care team coordinators . A comparison is made of the results among physicians and coordinators by means of the Chi-square and Fisher's Exact Test method, with Epi-Info v.6 . RESULTS: A total of 305 surveys were conducted (245 physicians and 60 coordinators) . There was an awareness of the existence of the Autonomous Community of Madrid Epidemiological Bulletin on the part of 91.5% (CI 95%: 88.1-94.8), and 27.2% (CI 95%: 21.9-32.5) were familiar with more than 50% of the last issues published . A total of 92.4% (CI 95%: 89.4-95.8) considered the Bulletin to be interesting or highly interesting, grading its usefulness an average of 3.5 on a maximum scale of 5 . Of the permanent sections, the most highly-valued was Epidemic Outbreaks, those reports related to meningococcal infection, tuberculosis and HIV/AIDS being the most highly-valued . CONCLUSIONS: The Autonomous Community of Madrid Epidemiological Bulletin is a publication which, although not widely-known by the primary care physicians in the Community, is well-valued when it is read, thus being a useful feedback tool within the Epidemiological Monitoring System.

Ned Tijdschr Geneeskd, 2002 Aug 17, 146(33), 1532 - 7
{Clinical reasoning and decision making in practice . Fever, purpura and hemiparesis in a 29-year old female}; van den Born BJ et al.; A 29-year-old female was admitted with fever, purpura and hemiparesis . She was treated for meningococcal sepsis after a Gram stain of a purpuric lesion showed Gram-negative diplococci . CT scan of the brain revealed multiple haemorrhagic lesions with obliteration of the sulci and basal cisterns . In the course of the disease she developed an acute myocardial infarction . Besides wall motion abnormalities, echocardiography revealed a bicuspid aortic valve with a vegetation on one of its cusps . Despite these findings, both the doctors who were involved in the treatment of this patient and the consulted physician in this article failed to reject the diagnosis 'meningococcal sepsis' and to replace it with a more likely diagnosis, namely Staphylococcus aureus endocarditis . The patient died one day after admission due to transtentorial herniation . Although purpuric lesions are common in meningococcal sepsis, they are not specific for this disease . The false-positive result of the Gram stain resulted in a process known as 'premature closure': the diagnosis of meningococcal sepsis was accepted before it was fully verified . In this case, the consequence was that other diagnostic tests and symptoms were misinterpreted with the result that inappropriate antibiotic therapy was instituted.

FEMS Immunol Med Microbiol, 2002 Sep 6, 34(1), 9 - 15
Analysis of Neisseria lactamica antigens putatively implicated in acquisition of natural immunity to Neisseria meningitidis; Troncoso G et al.; Sera from healthy human volunteers, patients convalescent from meningococcal meningitis, and mice immunized with outer membrane proteins from Neisseria meningitidis and Neisseria lactamica strains were used to analyze and identify antigens cross-reactive to both neisserial species . All classes of meningococcal proteins except class 1 (PorA) and class 5 cross-reacted with N . lactamica proteins and two other proteins of 65 and 55 kDa (an iron-regulated protein) . Results obtained with the mouse sera demonstrate that cross-reactive antibodies can be elicited by either N . meningitidis or N . lactamica . These results support the suggestion that N . lactamica contributes to the development of natural immunity against N . meningitidis during the first years of life . The use of vaccines containing proteins other than PorA could interfere in colonization of mucosal surfaces by N . lactamica, hampering the natural mechanisms of immunity acquisition in humans . Only convalescent sera reacted with the 55 and 65 kDa proteins, which suggests that they might be relevant for pathogenicity .

Pediatrics, 2002 Sep, 110(3), 563 - 9
Assessment of adrenal function in the initial phase of meningococcal disease; Bone M et al.; OBJECTIVE: To determine the status of the hypothalamic-pituitary-adrenal axis in children who had meningococcal disease and were admitted to 2 regional pediatric intensive care units . METHODS: Sixty-five children (34 boys; median age: 2.5 years; range: 0.2-15 years) had cortisol and adrenocorticotropic hormone (ACTH) levels measured on admission, then at 8 AM and 8 PM during the next 48 hours . At 48 hours, a low-dose short Synacthen test (LDST) (500 ng of 1-24 corticotropin/m2) was performed in 42 patients (19 boys) . Normal ranges for 8 AM cortisol and ACTH levels in unstressed children were 140 to 500 nmol/L and 2 to 11.3 pmol/L, respectively . Adrenal insufficiency (AI) was defined as a peak cortisol <500 nmol/L on the LDST or an 8 AM cortisol value <140 nmol/L . RESULTS: Five (7.7%) of the 65 children died, including 1 with primary AI . Cortisol levels were elevated on admission (median: 1122 mmol/L; range: 65-2110 nmol/L) with 81% of values more than the 8 AM normal range . The median ACTH level on admission was within the 8 AM normal range, but 40% of values were more than the 8 AM normal range . However, 7% and 8% of cortisol and ACTH values, respectively, were less than the normal range . Both cortisol and ACTH levels fell thereafter and showed no diurnal variation during the 48-hour profile . Six (14%) of the 42 failed the LDST . These patients had significantly lower mean 8 AM cortisol values than those with a normal peak value on the LDST . Five additional patients who did not have the LDST had 8 AM cortisol values <140 nmol/L . In the diagnosis of AI, the sensitivity of the 8 AM mean cortisol value at a cutoff of 400 nmol/L, judged against the LDST, was 83%; the specificity was 81% . CONCLUSIONS: During the initial phase of meningococcal disease, raised cortisol and ACTH levels indicate an appropriate stress response within the hypothalamic-pituitary-adrenal axis . However, a substantial subpopulation (11 {16.9%} of 65) has evidence of adrenal dysfunction during this period . Morning cortisol values in the initial phase of meningococcal disease could be used as a potential early index of AI.

Carbohydr Res, 2002 Sep 9, 337(16), 1435 - 44
Structural analysis of the lipopolysaccharide from Neisseria meningitidis strain BZ157 galE: localisation of two phosphoethanolamine residues in the inner core oligosaccharide; Cox AD et al.; The structure of the phase-variable lipopolysaccharide (LPS) from the group B Neisseria meningitidis strain BZ157 galE was elucidated . The structural basis for the LPS's variation in reactivity with a monoclonal antibody (MAb) B5 that has specificity for the presence of phosphoethanolamine (PEtn) at the 3-position of the distal heptose residue (HepII) was established . The structure of the O-deacylated LPS was deduced by a combination of monosaccharide analyses, nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry . These analyses revealed the presence of a novel inner core oligosaccharide (OS) structure in the MAb B5 reactive (B5+) LPS that contained two PEtn residues simultaneously substituting the 3- and 6-positions of the HepII residue . The determination of this structure has identified a further degree of variability within the inner core OS of meningococcal LPS that could contribute to the interaction of meningococcal strains with their host.

Eur J Biochem, 2002 Sep, 269(17), 4169 - 75
Identification and localization of glycine in the inner core lipopolysaccharide of Neisseria meningitidis; Cox AD et al.; The amino acid glycine is identified as a component of the inner core oligosaccharide in meningococcal lipopolysaccharide (LPS) . Ester-linked glycine residues were consistently found by mass spectrometry experiments to be located on the distal heptose residue (HepII) in LPS from several strains of Neisseria meningitidis . Nuclear magnetic resonance studies confirmed and extended this observation locating the glycine residue at the 7-position of the HepII molecule in L3 and L4 immunotype strains.

Bioorg Khim, 2002 Jul-Aug, 28(4), 291 - 7
{Induction of the anti-meningitis immunity with synthetic peptides . III . Immunoactive synthetic fragments of NspA protein from Neisseria meningitidis}; Koroev DO et al.; Four potentially immunoactive peptide fragments of the NspA protein from the outer membrane of the bacterium Neisseria meningitidis were synthesized in order to create a synthetic vaccine against the meningococcal infection by the serogroup B bacterium . Mice of various lines were immunized with the free peptides nonconjugated with a protein carrier . All the synthetic peptides were shown to induce the production of the antipeptide antibodies in mice . A peptide capable of inducing a decrease in the number of bacteria in blood and the protection of infected animals from death was found in the experiments on the protection of the animals infected with two strains of the Neisseria meningitidis serogroup B . The English version of the paper: Russian Journal of Bioorganic Chemistry, 2002, vol . 28, no . 4; see also http://www.maik.ru.

Biochem Soc Trans, 2002 Aug, 30(4), 705 - 7
Transferrin-mediated iron acquisition by pathogenic Neisseria; Evans RW et al.; The pathogenic Neisseria have a siderophore-independent iron-uptake system reliant on a direct interaction between the bacterial cell and transferrin . In the meningococcus this uptake system is dependent on two surface-exposed transferrin-binding proteins . This short account will review our current knowledge of the transferrin-mediated iron-acquisition system of pathogenic Neisseria.

Med Trop (Mars), 2002, 62(2), 137 - 40
{Clinical, bacteriological and therapeutic aspects of meningococcal meningitis in Dakar in 1999}; Seydi M et al.; Two major outbreaks of meningitis due Neisseria meningitidis serogroup A occurred in Senegal in 1998 and 1999 . The purpose of this report is to describe clinical, bacteriological and therapeutic findings in 70 patients admitted for cerebrospinal meningitis to the Infectious Disease Clinic at the Fann University Teaching Hospital in Dakar in 1999 . Diagnosis was based on direct microscopic examination after Gram staining in 71% of the cases, culture in 76%, and detection of soluble antigens in cerebrospinal fluid in 24% . Median patient age was 20 years . The highest incidence, i.e . 66% of cases, was recorded during February, March and April . Meningitic syndrome and fever were observed with 86% of the cases . The average duration of antibiotic therapy was 8 days . Chloramphenicol was the most commonly used drug (84% of cases) . All strains identified in cultures were sensitive to chloramphenicol, ceftriaxone and cefotaxime but resistant to cotrimoxazole . Outcome was favorable in 93% of the cases . Three patients (4%) died and two (3%) developed hearing loss . Despite the low death rate in this series of patients treated in a hospital setting, mass vaccination is still the most effective mean of controlling meningococcal meningitis.

Pediatr Infect Dis J, 2002 Aug, 21(8), 747 - 53
Safety and immunogenicity of meningococcus serogroup C conjugate vaccine administered as a primary or booster vaccination to healthy four-year-old children; McVernon J et al.; BACKGROUND: Meningococcal C conjugate (Men C) vaccines have been routinely used in the UK since November, 1999 . Little information exists regarding antibody persistence or immunologic memory after infant vaccination or response to a first dose at 4 years . METHODS: Ninety-five children immunized at 2, 3 and 4 months of age with 0 or 3 doses of Men C vaccine, boosted with Men C or meningococcal A/C polysaccharide vaccine at 12 months, received a single dose of Men C vaccine at 4 years; 103 age-matched controls were recruited . Pre- and postvaccination Men C IgG (enzyme-linked immunosorbent assay) antibody titers and serum bactericidal activity (SBA) were measured . Safety data were also collected . RESULTS: Baseline SBA titers of > or =1/4 were observed in 87% of children after at least 3 doses of Men C vaccine in infancy compared with 21% of controls . Reciprocals of postvaccination SBA geometric mean titers in those with four prior doses {3803 (95% confidence interval 3489, 4146)} were significantly higher than controls {33 (95% confidence interval 20, 55)} ( < 0.001) . Memory was attenuated by the 12-month meningococcal A/C polysaccharide booster {734 (95% confidence interval 484, 1115)} ( < 0.001) . All children had IgG responses to a first dose of Men C vaccine, 80% achieving SBA titers of > or =1/4 (77% > or =1/8) . The vaccine was safe and well-tolerated . CONCLUSION: Infant immunization with Men C produced persistent antibody and immunologic memory at 4 years . All children made IgG antibodies after a first dose at this age, with 80% showing bactericidal activity . Clarification of the best measures of Men C vaccine-induced protection is needed, through correlation of immunogenicity data such as this with UK vaccine efficacy estimates.

Ophthalmic Epidemiol, 2002 Oct, 9(4), 271 - 81
Prevalence and causes of severe visual impairment and blindness in children in Mongolia; Bulgan T et al.; BACKGROUND: Reliable epidemiological data on the prevalence and causes of visual loss in children are difficult to obtain, but are essential for planning . No such data are available from Mongolia . AIM: To determine the prevalence and causes of severe visual impairment and blindness (SVI/BL) in children from a defined area of Mongolia, using several methods of identification . METHODS: Children with presenting visual acuities of <6/60 in the better eye who lived in 10 of the 18 provinces (Aimaks) were identified 1) by family doctors 2) in the school for the blind 3) by visiting eye departments in the capital . All eligible children were examined (or data extracted from hospital records) and the cause of visual loss determined using the WHO classification system . RESULTS: Sixty-four children with SVI/BL before refraction were identified who lived in the 10 study Aimaks . They were recruited by family doctors (52); by home visits (3); from hospital records (4); or from the school for the blind (5) . The prevalence of SVI/BL before refraction was 0.19/1,000 children (95% CI 0.16-0.22), decreasing to 0.16/1,000 after refraction (95% CI 0.13-0.19) but there was considerable variation from Aimak to Aimak . The major causes of SVI/BL were lesions of the lens (34%), central nervous system disorders (19%), lesions of the whole globe (e.g . microphthalmos) (14%), and retinal conditions (12.5%) . Hereditary factors were responsible for 27% of causes, and 17% of children were blind following acquired conditions of childhood . The underlying cause could not be determined in 48% . The causes of SVI/BL was analysed in a further 16 children who lived outside the study Aimaks to compare the causes in children in special education with those not in schooling, and by age . CONCLUSION: The prevalence estimate obtained was lower than anticipated, and possible reasons are discussed . The pattern of causes of SVI/BL is similar to that in children in schools for the blind in China, but is very different from other Asian countries . Meningococcal meningitis was the most common preventable cause of SVI/BL, and immunisation is being considered . Other preventable causes were rare, and the majority of children needing surgical intervention had already been identified and referred for treatment . The control of blindness in children could possibly be improved by better management of conditions requiring surgery, and by the provision of low vision devices.

Curr Opin Investig Drugs, 2002 Jul, 3(7), 975 - 9
Meningococcal vaccines; Collins CL et al.; Neisseria meningitidis is one of the leading infectious causes of death in children under five years old in industrialized countries, and most cases can be attributed to five disease-causing serogroups: A, B, C, Y and W135 . Meningococcal vaccine development began in the 1930s with killed whole-cell and exotoxin vaccines, but widespread use of polysaccharide vaccines did not begin until the 1970s . Serogroup A, C, Y and W135 polysaccharides are all included in vaccines for travellers, other high risk groups and control of outbreaks, but have limited immunogenicity and effficacy in childhood . Protein-polysaccharide conjugate vaccines overcome this problem and offer the possibility of protection in early childhoodfrom serogroup A, C, Y and W135 . An effective serogroup B vaccine remains elusive and the greatest challengefor vaccine developers.

J AAPOS, 2002 Aug, 6(4), 259 - 60
Giant retinal tear and meningococcus endogenous endophthalmitis; Jain K et al.; Giant retinal tear is seen in association with Stickler's syndrome, Marfan syndrome, homocystinurea and after ocular trauma . Although bacterial meningitis(1) is not common since the advent of various antibiotics, meningococcus is the second most common cause of bacterial meningitis . Endogenous endophthalmitis(2) remains a challenge to clinicians despite the success of antibiotics in reducing its frequency and severity . The association of giant retinal tear and meningococcal endogenous endophthalmitis is not yet reported in the literature . We report here on a 14-year-old girl who developed a giant retinal tear after meningococcal meningitis and endogenous endophthalmitis, and we discuss the possible factors of its cause.

J AAPOS, 2002 Aug, 6(4), 221 - 3
Retinal hemorrhages in meningococcal septicemia; Dinakaran S et al.; PURPOSE: Meningococcal septicemia is associated with coagulopathy and hemorrhagic tendency . We carried out this study to determine the incidence of retinal hemorrhages in meningococcal septicemia . METHODS: This was a prospective study involving all children admitted to the Sheffield Children's Hospital, Sheffield, England, with a diagnosis of meningococcal septicemia . Confirmation of meningococcal infection was by blood culture or DNA analysis using polymerase chain reaction . The children underwent ocular examination including dilated fundus examination by direct and indirect ophthalmoscopy . Details of their coagulation status were also obtained . RESULTS: Twelve children (mean age, 4.5 years) with a confirmed diagnosis of meningococcal septicemia were included . All children had coagulopathy . Retinal hemorrhages were found in 5 children (42%) . The disease was fatal in 3 children . Group C meningococcus was responsible for the infection in all those with retinal hemorrhages and those with fatal outcome . CONCLUSIONS: Retinal hemorrhage is a common feature in meningococcal septicemia . Ophthalmic evaluation should be part of the assessment of children with meningococcal septicemia . Future studies on meningococcal disease should include retinal hemorrhage as another parameter in the assessment . This should help us to understand the role of retinal hemorrhage in the prognosis of this serious disease.

Infect Immun, 2002 Sep, 70(9), 5193 - 201
Analysis of pathogen-host cell interactions in purpura fulminans: expression of capsule, type IV pili, and PorA by Neisseria meningitidis in vivo; Harrison OB et al.; The pattern of meningococcal surface structure expression in different microenvironments following bloodstream invasion in vivo is not known . We used immunohistochemistry to determine the expression of capsule, type IV pili, and PorA by meningococci residing in the skin lesions of children with purpura fulminans . All the skin biopsy samples showed evidence of thrombosis and, frequently, a perivascular inflammatory cell infiltrate consisting of neutrophils (elastase positive) and monocytes/macrophages (CD68 positive) . Modified Gram staining revealed 20 to over 100 gram-negative diplococci in each 4-microm-thick section, usually grouped into microcolonies . Immunoperoxidase staining demonstrated that the invading meningococci expressed PorA, capsule, and type IV pilin . Expression of these antigens was not restricted to any particular environment and was found in association with meningococci located in leukocytes, small blood vessels, and the dermal interstitium . Confocal laser scanning microscopy demonstrated coexpression of pilin and capsule by numerous microcolonies . However, there was some discordance in capsule and pilin expression within the microcolonies, suggesting phase variation . The strategy employed in this study will be helpful in investigating invasive bacterial diseases where antigenic and phase variation has a significant impact on virulence and on vaccine design.

Infect Immun, 2002 Sep, 70(9), 4946 - 54
Effect of vaccination with carrier protein on response to meningococcal C conjugate vaccines and value of different immunoassays as predictors of protection; Burrage M et al.; In order to plan for the wide-scale introduction of meningococcal C conjugate (MCC) vaccine for United Kingdom children up to 18 years old, phase II trials were undertaken to investigate whether there was any interaction between MCC vaccines conjugated to tetanus toxoid (TT) or a derivative of diphtheria toxin (CRM(197)) and diphtheria-tetanus vaccines given for boosting at school entry or leaving . Children (n = 1,766) received a diphtheria-tetanus booster either 1 month before, 1 month after, or concurrently with one of three MCC vaccines conjugated to CRM(197) or TT . All of the MCC vaccines induced high antibody responses to the serogroup C polysaccharide that were indicative of protection . The immune response to the MCC-TT vaccine was reduced as a result of prior immunization with a tetanus-containing vaccine, but antibody levels were still well above the lower threshold for protection . Prior or simultaneous administration of a diphtheria-containing vaccine did not affect the response to MCC-CRM(197) vaccines . The immune responses to the carrier proteins were similar to those induced by a comparable dose of diphtheria or tetanus vaccine . The results also demonstrate that, for these conjugate vaccines in these age groups, both standard enzyme-linked immunosorbent assays and those that measure high-avidity antibodies to meningococcal C polysaccharide correlated equally well with assays that measure serum bactericidal antibodies, the established serological correlate of protection for MCC vaccines.

Infect Immun, 2002 Sep, 70(9), 4785 - 90
Enhancement of protective efficacy following intranasal immunization with vaccine plus a nontoxic LTK63 mutant delivered with nanoparticles; Baudner BC et al.; Most vaccines are still given parenterally . Mucosal vaccination would offer different advantages over parenteral immunization, including blocking of the pathogens at the portal of entry . In this paper, nontoxic Escherichia coli heat-labile enterotoxin (LT) mutants and Supramolecular Biovector systems (SMBV) were evaluated in mice as mucosal adjuvants and delivery systems, respectively, for intranasal immunization with the conjugated group C meningococcal vaccine . The conjugated vaccine formulated together with the LT mutants and the SMBV induced very high titers of serum and mucosal antibodies specific for the group C meningococcal polysaccharide . This vaccination strategy also induced high titers of antibodies with bactericidal activity, which is known to correlate with efficacy . Importantly, the mucosal vaccination, but not the conventional parenteral vaccination, induced bactericidal antibodies at the mucosal level . These data strongly support the feasibility of development of intranasal vaccines with an enhanced protective efficacy against meningococci and possibly against other encapsulated bacteria.

Vaccine Immun News, 1996 Jun, (1), 1, 3 - 4
Upcoming vaccines should fill gaps in meningitis control; Primary meningococcal arthritis: case report and review; 4th Department of Internal Medicine, University of Athens, Medical School, Greece . giamarel@internet.gr

A rare case of primary meningococcal arthritis of a 16-year-old female patient is described . Arthritis involved her left knee and Neisseria meningitidis was isolated from blood and from the synovial fluid . Successful treatment was achieved by the intravenous administration of penicillin G.

Trans R Soc Trop Med Hyg, 2002 May-Jun, 96(3), 242 - 9
Where is the meningitis belt? Defining an area at risk of epidemic meningitis in Africa; Molesworth AM et al.; Mapping an area at risk of epidemics of meningococcal meningitis in Africa has significant implications for their prevention and case treatment, through the targeted development of improved surveillance systems and control policies . Such an area was described using information obtained from published and unpublished reports of meningitis epidemics between 1980 and 1999 and cases of meningococcal disease reported by surveillance systems to WHO . The Sahel bore the greatest epidemic burden, with over two-thirds of documented outbreaks and high attack rates . In addition to those already in the Meningitis Belt, countries affected included Guinea-Bissau, Guinea, Cote d'Ivoire, Togo, the Central African Republic and Eritrea . Elsewhere epidemics were reported from a band of countries around the Rift Valley and Great Lakes regions extending as far south as Mozambique and from here west to Angola and Namibia in southern Africa . The cumulative pan-continental analysis provided evidence of an epidemic-susceptible area which extends beyond the region accepted as the Meningitis Belt and which, moreover, may be partially determined by the physical environment, as shown by a striking correspondence to the 300-1100-mm mean annual rainfall isohyets.

Saudi Med J, 2002 Jul, 23(7), 797 - 801
Meningococcal meningitis epidemic . A new role for single-dose oily chloramphenicol; Hussein AA et al.; OBJECTIVE: To compare the orthodox use of 5 days crystalline penicillin and an alternate regime of single intramuscular injection of long acting oily chloramphenicol during the 1999 cerebrospinal meningitis epidemic that occurred in Abu Jubeha, South Kordofan, Sudan . METHODS: All 793 patients with meningococcal meningitis admitted to Abu Jubeha hospital in the eastern parts of South Kordofan State, were investigated . Through a quasi-experimental design some 140 patients were treated with crystalline penicillin for 5 days while the remaining majority, after the exhaustion of penicillin stocks, were put on single-dose intramuscular injections of oily long-acting chloramphenicol . RESULTS: Males were slightly more affected than females (1.3:1), mean age affected was 17.2 years, the majority being below 20 years of age (68%) while 27.3% were below 10 years . The peak of the epidemic was during late March and early April namely 9th and 10th epidemic weeks . In the penicillin group 87.1% recovered uneventfully, 6.4% died, 2.1% developed blindness and 1.5% partial deafness . In the chloramphenicol group, full recovery was reported in 92.8%, 5% fatalities, blindness in 0.5%, partial deafness in 0.3% and skin necrosis in 0.1% . CONCLUSION: The study suggests the use of single-dose intramuscular injections of oily chloramphenicol as a nationwide antibiotic of choice for future meningitis epidemics in view of not only its efficacy, but also its low cost, easiness of use, stability and safety.

Saudi Med J, 2002 Jul, 23(7), 789 - 92
Epidemiology of neonatal meningitis in Qatar; El-Said MF et al.; OBJECTIVE: Neonatal meningitis is responsible for thousands of neonatal deaths annually all over the world . Our study was conducted to determine the epidemiology, management and best preventive measures for neonatal meningitis in Qatar . METHODS: A retrospective study reviewed the records of bacterial meningitis patients under the age of one month . The study was carried out at Hamad Medical Hospital, the only hospital that provides health care at Qatar and the study period was between January 1998 to December 2000 . RESULTS: Thirteen patients were included . Sixty percent of patients had early onset meningitis . Causative organisms were group B Streptococcus pneumoniae, Klebsiella pneumonia, Pseudomonas species, Neisseria meningitidis, Staphylococcus epidermidis and Flavibacterium meningococcus septicum . A bacterial resistance to the usual combination of ampicillin and gentamicin were noticed (as initial treatment before culture sensitivity results), which affected negatively on some patients . Complications of cerebral palsy, mental retardation and epilepsy occurred in 3 patients (23%) . None of the patients died during the study period . CONCLUSION: Emphasis is placed on the importance of correct early diagnosis and appropriate antibiotic therapy . It is suggested that the identification and appropriate treatment of any maternal bacterial infection is an important measure in preventing neonatal sepsis and meningitis.

Eur J Clin Microbiol Infect Dis, 2002 Jul, 21(7), 506 - 12 Epub 2002 Jun 28.
Period prevalence and case-fatality rate associated with distinctive clone complexes of Neisseria meningitidis serogroups B and C; Jensen ES et al.; In a recent 20-year Danish survey, Neisseria meningitidis phenotypes B:15:P1.7,16 and C:2a:P1.2,5 were associated with an increased case-fatality rate of meningococcal disease - 15% and 23% - compared to the case-fatality rate of 8% for any other strain . The aim of the present study was to investigate (i) the mutual genetic relatedness of strains with phenotype B:15:P1.7,16, phenotype C:2a:P1.2,5 or serologically related phenotypes; (ii) the changes in the prevalence of distinctive clone complexes over time; and (iii) whether distinctive clone complexes are associated with an increased case-fatality rate . During the period 1980-1999, 181 of a total of 315 invasive strains obtained in North Jutland County, Denmark, were chosen on the basis of serological characteristics for characterization by multilocus enzyme electrophoresis and ribotyping . Two major complexes were identified on the basis of electrophoretic type (ET): the ET-4/23 complex ( n=111), which included all B:15:P1.7,16 strains ( n=100), and the ET-15/25 complex ( n=44), which included all C:2a:P1.2,5 strains ( n=31) . Two ribotype complexes were identified within the ET-4/23 complex and one within the ET-15/25 complex, all of which were designated clone complexes . All three clone complexes were associated with an increased case-fatality rate (13-20%) . The results show that, among invasive Neisseria meningitidis B:15:P1.7,16, C:2a:P1.2,5 and phenotypically related strains, three distinctive clone complexes are more virulent than any other ET/ribotype combination.

Nat Biotechnol, 2002 Sep, 20(9), 914 - 21 Epub 2002 Aug 12.
Previously unrecognized vaccine candidates against group B meningococcus identified by DNA microarrays; Grifantini R et al.; We have used DNA microarrays to follow Neisseria meningitidis serogroup B (MenB) gene regulation during interaction with human epithelial cells . Host-cell contact induced changes in the expression of 347 genes, more than 30% of which encode proteins with unknown function . The upregulated genes included transporters of iron, chloride, amino acids, and sulfate, many virulence factors, and the entire pathway of sulfur-containing amino acids . Approximately 40% of the 189 upregulated genes coded for peripherally located proteins, suggesting that cell contact promoted a substantial reorganization of the cell membrane . This was confirmed by fluorescence activated cell sorting (FACS) analysis on adhering bacteria using mouse sera against twelve adhesion-induced proteins . Of the 12 adhesion-induced surface antigens, 5 were able to induce bactericidal antibodies in mice, demonstrating that microarray technology is a valid approach for identifying new vaccine candidates and nicely complements other genome mining strategies used for vaccine discovery.

Nurs Times, 2002 Jun 18-24, 98(25), 40 - 2
Travel vaccines: a guide to appropriate use; Hainsworth T; As greater numbers of people travel to exotic locations, vaccine technology is becoming increasingly important . Deciding on appropriate immunisation can be complex: it involves assessment of the traveller's risk, an awareness of the potential diseases at a particular destination and knowledge of the vaccines available . This article focuses on nine diseases that can be prevented through vaccination: hepatitis A; typhoid; yellow fever; hepatitis B; tick-borne encephalitis; rabies; meningococcal meningitis; Japanese encephalitis; and cholera . In each case the indications for immunisation are discussed as well as any contraindications and adverse reactions to the vaccines.

Acta Paediatr, 2002, 91(6), 626 - 31
Influence of leptin levels and body weight in survival of children with sepsis; Blanco-Quiros A et al.; High levels of serum leptin (LPT) were reported in adult patients with sepsis and a protective role was suggested . LPT was determined in sera from 55 children with severe sepsis at admission (0 h), 6, 24 and 48 h . LPT levels were higher at 0 h than at 24 h (2.80 vs 1.61 ng/ml; p = 0.009) and a negative correlation was found with IL-13 (p = 0.009), and granulocyte counts (p = 0.035), but not with other factors . Infants younger than 12 mo of age had higher LPT levels than older infants (5.88 vs 2.38 ng/ml; p = 0.0005) . The increase in LPT levels was higher in non-survivor patients than in survivors, with a maximum difference at 24 h (5.30 vs 1.45 ng/ml; p = 0.0042) . However, LPT levels were not associated with shock, multiorgan failure or the severity score . Children who died showed higher percentiles of weight than survivors (p = 0.025) . A subgroup with higher LPT (> Pc75) included mainly patients with weight > Pc50 (p = 0.0065), low IL-13 levels (p = 0.007) and low granulocyte counts (p = 0.013), Neisseria meningitidis B being the most frequently isolated germ (p = 0.022) . CONCLUSION: Using a model of severe infection, mainly meningococcal, in young children (median 3 y 6 mo old), it was not possible to confirm previous results in adults . A general protective role for LPT in sepsis seems unlikely.

J Clin Epidemiol, 2002 Jul, 55(7), 687 - 95
Comparison of prediction models for adverse outcome in pediatric meningococcal disease using artificial neural network and logistic regression analyses; Nguyen T et al.; The objective of this study was to compare artificial neural network (ANN) and multivariable logistic regression analyses for prediction modeling of adverse outcome in pediatric meningococcal disease . We analyzed a previously constructed database of children younger than 20 years of age with meningococcal disease at four pediatric referral hospitals from 1985-1996 . Patients were randomly divided into derivation and validation datasets . Adverse outcome was defined as death or limb amputation . ANN and multivariable logistic regression models were developed using the derivation set, and were tested on the validation set . Eight variables associated with adverse outcome in previous studies of meningococcal disease were considered in both the ANN and logistic regression analyses . Accuracies of these models were then compared . There were 381 patients with meningococcal disease in the database, of whom 50 had adverse outcomes . When applied to the validation data set, the sensitivities for both the ANN and logistic regressions models were 75% and the specificities were both 91% . There were no significant differences in any of the performance parameters between the two models . ANN analysis is an effective tool for developing prediction models for adverse outcome of meningococcal disease in children, and has similar accuracy as logistic regression modeling . With larger, more complete databases, and with advanced ANN algorithms, this technology may become increasingly useful for real-time prediction of patient outcome.

Trends Microbiol, 2002 Aug, 10(8), 376 - 82
The duality of virulence and transmissibility in Neisseria meningitidis; Taha MK et al.; Neisseria meningitidis is a commensal bacterium of the human nasopharynx that occasionally provokes invasive disease . Carriage strains of N . meningitidis are heterogeneous, more frequent in nature and are transmitted among carriers . Disease is not a part of this transmission cycle and is caused by virulent strains . N . meningitidis is highly variable and variants that are modified in their virulence and/or transmissibility are continually generated . These events probably occur frequently, thus explaining not only the heterogeneous nature of meningococcal populations in carriers but probably also the evolutionary success of this human-restricted bacterium.

Scand J Infect Dis, 2002, 34(6), 417 - 20
The effect of subcapsular meningococcal B + C vaccine on the prognosis of patients with meningococcal disease; Barroso DE et al.; The effectiveness of the meningococcal Cuban vaccine (VaMengoc B + C) was examined in terms of the prognosis of patients who develop disease . All cases in the vaccinee age category admitted to the Meningococcal Disease Reference Centre, Rio de Janeiro between August 1990 and December 1993 were enrolled . Vaccine effectiveness (VE) was estimated from the relationship 1-OR, where the OR (odds ratio) was the exponential of the logistic regression coefficient for the association between death from meningococcal disease and previous vaccination . The case fatality rate for vaccinees was 6.1% and that for non-vaccinees was 10.6% (relative risk 0.58; 95% confidence interval {CI} 0.33-1.01) . An overall protective effect of the vaccine against a fatal outcome was identified (VE 53%; 95% CI 12-75%) controlling for sex, age at time of immunization, elapsed time since vaccination and time between onset of disease and hospital admission . This study suggests that, for some people, even if the vaccine does not protect against the development of disease it may have a beneficial effect in terms of preventing a fatal outcome . This protective effect needs to be further investigated in a prospective cohort study specifically designed to evaluate the new generation of meningococcal vaccines.

Eur J Biochem, 2002 Aug, 269(15), 3722 - 31
GNA33 from Neisseria meningitidis serogroup B encodes a membrane-bound lytic transglycosylase (MltA); Jennings GT et al.; In a previous study, we used the genome of serogroup B Meningococcus to identify novel vaccine candidates . One of these molecules, GNA33, is well conserved among Meningococcus B strains, other Meningococcus serogroups and Gonococcus and induces bactericidal antibodies as a result of being a mimetic antigen of the PorA epitope P1.2 . GNA33 encodes a 48-kDa lipoprotein that is 34.5% identical with membrane-bound lytic transglycosylase A (MltA) from Escherichia coli . In this study, we expressed GNA33, i.e . Meningococcus MltA, as a lipoprotein in E . coli . The lipoprotein nature of recombinant MltA was demonstrated by incorporation of {3H}palmitate . MltA lipoprotein was purified to homogeneity from E . coli membranes by cation-exchange chromatography . Muramidase activity was confirmed when MltA was shown to degrade insoluble murein sacculi and unsubstituted glycan strands . HPLC analysis demonstrated the formation of 1,6-anhydrodisaccharide tripeptide and tetrapeptide reaction products, confirming that the protein is a lytic transglycosylase . Optimal muramidase activity was observed at pH 5.5 and 37 degrees C and enhanced by Mg2+, Mn2+ and Ca2+ . The addition of Ni2+ and EDTA had no significant effect on activity, whereas Zn2+ inhibited activity . Triton X-100 stimulated activity 5.1-fold . Affinity chromatography indicated that MltA interacts with penicillin-binding protein 2 from Meningococcus B, and, like MltA from E . coli, may form part of a multienzyme complex.

Pediatr Infect Dis J, 2002 May, 21(5), 366 - 70
Meningococcal infections in children from Arkansas; Stovall SH et al.; BACKGROUND: Infections with Neisseria meningitidis are an important cause of morbidity and mortality in children of all ages . With wide-spread use of the heptavalent pneumococcal conjugate vaccine, this organism might become the prominent pathogen for invasive disease in children . METHODS: Retrospective reviews of medical and microbiologic records from Arkansas Children's Hospital were done to identify patients with invasive N . meningitidis infections from January, 1988, through December, 2000 . Basic demographic and clinical data were gathered and reviewed . Data on invasive meningococcal infections were obtained from the Arkansas Department of Health . RESULTS: Three hundred ninety-four cases of invasive meningococcal infection were reported to the Arkansas Department of Health during the study period . Two hundred ninety-six cases were in patients <21 years of age . The estimated annual incidence of meningococcal disease for the State of Arkansas was calculated to be 1.2-cases/100000 population during the study period . The annual incidence of meningococcal disease in patients <21 years of age was estimated at 2.9 and 21.7 cases/100000 population for children < 1 year of age . One hundred fifty patients (51%) <21 years of age with 151 episodes of invasive meningococcal infections were treated at our institution . Eighty percent of the patients were Caucasian, 55% were male, 31% live in a rural area and the median age at presentation was 30 months (range, 2 weeks to 21 years) . The most common signs and symptoms at admission included fever (95%), petechial/purpuric rash (62%), nuchal rigidity (41%) and hypotension (41%) . Thirty-eight patients (26%) required both inotropic support and mechanical ventilation during hospitalization, 15 patients died and 18 patients had long term sequelae . Eighty-three of the isolates were serogrouped and included the following: A (2); B (38); C (33); and Y (10) . Eighty-four of the index cases were treated with parenteral cephalosporin therapy alone and did not receive additional chemoprophylaxis . CONCLUSIONS: Many infections in the general pediatric population are a result of N . meningitidis . Although most patients do well and recover without sequelae, there are a significant number who experience major morbidity and mortality as a result of this infection.

Emerg Infect Dis, 2002 Aug, 8(8), 761 - 7
Outbreak of serogroup W135 meningococcal disease after the Hajj pilgrimage, Europe, 2000; Aguilera JF et al.; The 2000 Hajj (March 15-18) was followed by an outbreak of Neisseria meningitidis W135 2a: P1.2,5 in Europe . From March 18 to July 31, 2000, some 90 cases of meningococcal infection were reported from nine countries, mostly the United Kingdom (UK) and France; 14 cases were fatal . Although most early cases were in pilgrims, the outbreak spread to their contacts and then to those with no known pilgrim contact . In France and the UK, the outbreak case-fatality rate was compared with the rate reported from national surveillance . The risk of dying during this outbreak was higher in France and the UK, although the difference was not statistically significant . Prophylaxis for all pilgrims and their household contacts was offered in France; in the UK and other European countries, prophylaxis was recommended only for close contacts . No difference in transmission rates following intervention was detected between France and the UK.

Aust N Z J Public Health, 2002, 26(3), 212 - 8
Meningococcal disease and meteorological conditions in Auckland, New Zealand; Lindsay AP et al.; OBJECTIVE: The purpose of the study was to explore and model the relationship between meteorological variables and meningococcal disease notifications in Auckland during an ongoing group B meningococcal disease epidemic . METHODS: An ecological study design was used to investigate the relationship between 1,097 notified cases of meningococcal disease from January 1992 to December 1998 among residents of Auckland's three health districts and various meteorological variables . Descriptive epidemiology and Poisson regression modelling were used to describe this relationship . FINDINGS: The study found that the occurrence of meningococcal disease varied with season, increased with high humidity and cooler temperatures and appeared to decline with prolonged periods of heavy rain . Poisson regression analysis showed a significant relationship between the expected number of cases developing meningococcal disease on a given day and season and temperature . DISCUSSION: The results of the modelling analysis provide the initial work for the future development of a predictive tool to forecast the magnitude and duration of the annual peak in meningococcal disease incidence using routine notification data and meteorological recordings, thus allowing for better management of the public health workload and interventions, and the appropriate timing of media campaigns.

Med Microbiol Immunol (Berl), 2002 May, 191(1), 41 - 7
Immunogenicity of recombinant L7/L12 ribosomal protein of Neisseria meningitidis--high prevalence of specific antibodies in humans but limited immunogenicity for T cells; Nolte O et al.; The rplL gene, coding for ribosomal protein L7/L12 of Neisseria meningitidis was cloned and expressed as a fusion protein . The recombinant protein was used in Western blots and lymphocyte proliferation assays to study the prevalence of specific antibodies in human sera and the immunogenicity for the cellular immune system . Most of the serum samples studied were found to be positive for L7/L12-specific antibodies . A number of peripheral blood mononuclear cell preparations tested displayed activation in lymphocyte proliferation assays . The magnitude of activation (stimulation index) was moderate, and there was no correlation with a history of meningococcal disease . The high prevalence of specific antibodies is explained by the high carriage rate of meningococci in the normal population or cross-reactivity to ribosomal proteins of other bacteria, thus indicating immunogenicity . However, meningococcal L7/L12 does not seem to be a potential T cell antigen.

J Pediatr Orthop, 2002 Jul-Aug, 22(4), 511 - 6
Osteochondral sequelae of meningococcemia: radiographic aspects; Appel M et al.; The authors retrospectively analyzed the files of 11 patients with osteochondral sequelae of meningococcemia, which were referred to this service between 1988 and 1996 . The purpose of this study was to radiographically evaluate bone and physeal injuries observed in these patients, deformities caused by them and correlate these findings with the current literature . During radiographic evaluation of patients with sequelae of meningococcemia, two distinct parameters should be observed: bone injury and physeal plate injury patterns . The most frequent bone injury pattern was lytic lesion and the most common physeal plate injury pattern was peripheral asymmetric physis destruction . The most frequent deformities were lower limb length discrepancy, angular deformities and digital amputations . Based upon the findings of the present research, a descriptive radiographic classification was proposed.

Crit Care Med, 2002 Jul, 30(7), 1623 - 9
Antioxidant protection against iron in children with meningococcal sepsis; Festa M et al.; OBJECTIVE: To assess antioxidant protection against iron-catalyzed reactive oxygen species in meningococcal sepsis and to establish whether severity of illness is related to deficiencies in these antioxidant systems . DESIGN: Prospective, controlled study . SETTING: Pediatric intensive care unit of a postgraduate teaching hospital . PATIENTS: Twenty children aged 6 months to 15 yrs (median, 5 yrs) with meningococcal septic shock were studied . Paired convalescent samples taken 8-10 wks after discharge were available in nine children . INTERVENTIONS: Routine management for meningococcal sepsis . MEASUREMENTS AND MAIN RESULTS: Patients were classified for disease severity using the Glasgow Meningococcal Septicaemia Prognostic Score . Paired acute and convalescent samples were compared . Transferrin level (1.77 +/- 0.08 g/L) and total iron-binding capacity (46.2 +/- 2.0 microM) were significantly decreased in acute patients compared with paired convalescent samples (2.85 +/- 0.10 g/L and 74.4 +/- 2.5 microM, respectively; p <.0001) . The iron saturation of transferrin was significantly increased in acute disease (36.9% +/- 2.5%) compared with convalescence (18.8% +/- 1.5%; p =.0003) . Iron-binding antioxidant protection was not significantly different in acute (81.4% +/- 1.7%) and paired convalescent samples (85.6% +/- 2.5%; p =.54) . However, patients with more severe meningococcal septicemia (GMSPS, >10; n = 12) had significantly diminished protection (77.5% +/- 2.4%) compared with less severe disease (87.1% +/- 1.6%; p =.0028), and there was a significant correlation between disease severity and iron-binding antioxidant protection (R =.48; p =.00067) in acute disease . Paired ceruloplasmin levels were available in six patients and were decreased in acute disease (0.29 +/- 0.02 g/L) compared with convalescence (0.40 +/- 0.04 g/L), although not statistically significant (p =.076) . However, there was a significant correlation between plasma ceruloplasmin and disease severity (Pearson product moment correlation, p =.038) in the acute patients . Iron-oxidizing antioxidant assays were performed in four paired samples and were diminished in acute patients (53.3 +/- 4.4%) compared with convalescence (67.8 +/- 3.2%; p =.015) . Acute samples demonstrated a significant relationship between iron-oxidizing antioxidant protection and both disease severity (r =.30; p =.012) and plasma ceruloplasmin levels (r =.48; p =.00067) . CONCLUSIONS: Children with meningococcal septicemia exhibit abnormal plasma iron chemistry and decreased protection against iron-catalyzed oxidative damage . Such deficiencies correlate with disease severity.

Vaccine, 2002 Jul 26, 20(23-24), 2957 - 63
In vitro induction of memory-driven responses against Neisseria meningitidis by priming with Neisseria lactamica; Sanchez S et al.; Natural immunity against Neisseria meningitidis is acquired during childhood and youth through successive colonizations by commensal Neisseria, carrier N . meningitidis, and other bacterial genera sharing cross-reactive antigens with the meningococci . We have analyzed in mice the ability of Neisseria lactamica strains to induce immunological memory so that, upon a later contact with N . meningitidis, quickly raise protective responses against antigens that show cross-reactivity with meningococcal surface proteins . Sera obtained from mice immunized with N . lactamica and boosted with N . meningitidis were able to kill meningococci, with bactericidal activities variable depending on the immunizing strains used in the assays . Different mixtures of those sera resulted in higher killing activities, which agrees with the idea that successive colonizations by N . lactamica enhance the anti-meningococcal response . The existence of such outer membrane cross-reactive antigens has to be kept in mind when using outer membrane vesicle (OMV)-based anti-meningococcal vaccines because their use can affect colonization by N . lactamica and other species, hampering the natural mechanisms of acquisition of immunity to the meningococci, and leaving its ecological niche free for colonization by undesirable microorganisms.

Vaccine, 2002 Jul 26, 20(23-24), 2851 - 6
Anticapsular polysaccharide meningococcal antibodies in Israeli military recruits: immune status and the effect of simultaneous administration of immune globulin on the response to polysaccharide vaccine; Shapira-Nahor O et al.; The effect of the administration of immune globulin (Ig), given during summer months to prevent hepatitis A, on the immune response to a simultaneously administered quadrivalent meningococcal polysaccharide vaccine (QMPV) was studied in Israeli military recruits . Data were obtained for the first time regarding the immune status of an Israeli population . Anticapsular polysaccharide antibodies were determined using a standardized ELISA assay before, 2 weeks and 3 months after QMPV immunization with or without Ig in two groups of recruits chosen to span the date determining seasonal administration or non-administration of Ig . Pre-vaccination antibody concentrations were > or = 2 microg/ml in 98.4 and 38.9% of subjects against serogroups A and C meningococci, respectively . These levels are consistent with the extremely low incidence of disease due to serogroup A in Israel, and with the previously documented occurrence of serogroup C disease in servicemen and women . Co-administration of Ig was associated with some reduction in antibody concentrations 3 months after vaccination, especially against serogroup A meningococci (P<0.05), but not to an extent likely to be of clinical significance.

Am J Prev Med, 2002 Aug, 23(2), 98 - 105
Vaccinating first-year college students living in dormitories for Meningococcal disease: an economic analysis; Scott RD 2nd et al.; BACKGROUND: Surveillance of meningococcal disease among U.S . college students found an elevated rate of this disease among first-year students living in dormitories . OBJECTIVE: This study examines the economics of routinely vaccinating a cohort of 591,587 incoming first-year students who will live in dormitories for > or =1 years . METHODS: A cost-benefit model (societal perspective) was constructed to measure the net present value (NPV) of various vaccination scenarios, as well as the cost/case and cost/death averted . Input values included hospitalization costs from $10,924 to $24,030 per hospitalization; immunization costs (vaccine plus administration costs) from $54 to $88 per vaccine; 30 nonfatal, vaccine-preventable cases over a 4-year period (includes 3 with sequelae); 3 premature deaths; value of human life from $1.2 million to $4.8 million; and long-run sequelae costs from $1298 to $14,600 . Sensitivity analyses were also conducted on vaccine efficacy (80% to 90%); discount rate (0% to 5%); and coverage (60% to 100%) . RESULTS: The costs of vaccination outweighed the benefits gained with NPVs ranging from -$11 million to -$49 million . The net cost per case averted ranged from $0.6 million to $1.9 million . The net cost per death averted ranged from $7 million to $20 million . The break-even costs of vaccination (when NPV=$0) at 60% coverage ranged from $23 (90% vaccine efficacy) to $5 (80% efficacy) . CONCLUSIONS: The model showed that the vaccination program is not cost-saving . Key variables influencing the results were the low number of vaccine-preventable cases and the high cost of vaccination . However, from the perspective of students and parents, the cost of vaccination might be worth the real or perceived benefit of reducing the risk to an individual student of developing meningococcal disease.

Int J Paediatr Dent, 2002 Jul, 12(4), 277 - 80
Teeth grinding, tongue and lip biting in a 24-month-old boy with meningococcal septicaemia . Report of a case; Coyne BM et al.; This paper describes the management of a 24-month-old boy who presented with self-inflicted trauma to his lower lip and tongue, and teeth grinding, 21 days after developing meningococcal septicaemia . A decision to observe and prescribe palliative therapy was made . Extraction of the lower right deciduous canine, which had become non-vital, possibly due to bruxism, was carried out.

Infect Immun, 2002 Aug, 70(8), 4447 - 61
Autotransported serine protease A of Neisseria meningitidis: an immunogenic, surface-exposed outer membrane, and secreted protein; Turner DP et al.; Several autotransporter proteins have previously been identified in Neisseria meningitidis . Using molecular features common to most members of the autotransporter family of proteins, we have identified an additional novel ca . 112-kDa autotransporter protein in the meningococcal genomic sequence data . This protein, designated autotransported serine protease A (AspA), has significant N-terminal homology to the secreted serine proteases (subtilases) from several organisms and contains a serine protease catalytic triad . The amino acid sequence of AspA is well-conserved in serogroup A, B, and C meningococci . In Neisseria gonorrhoeae, the AspA homologue appears to be a pseudogene . The gene encoding AspA was cloned and expressed from meningococcal strain MC58 (B15:P1.16b) . Anti-AspA antibodies were detected in patients' convalescent-phase sera, suggesting that AspA is expressed in vivo during infection and is immunogenic and cross-reactive . Rabbit polyclonal monospecific anti-AspA serum was used to probe whole-cell proteins from a panel of wild-type meningococcal strains and two AspA mutant strains . Expression of the ca . 112-kDa precursor polypeptide was detected in 12 of 20 wild-type meningococcal strains examined, suggesting that AspA expression is phase variable . Immunogold electron microscopy and cellular fractionation studies showed that the AspA precursor is transported to the outer membrane and remains surface exposed . Western blot experiments confirmed that smaller, ca . 68- or 70-kDa components of AspA (AspA68 and AspA70, respectively) are then secreted into the meningococcal culture supernatant . Site-directed mutagenesis of S426 abolished secretion of both rAspA68 and rAspA70 in Escherichia coli, confirming that AspA is an autocleaved autotransporter protein . In conclusion, we characterized a novel, surface-exposed and secreted, immunogenic, meningococcal autotransporter protein.

Infect Immun, 2002 Aug, 70(8), 4185 - 95
Phenotypes of a naturally defective recB allele in Neisseria meningitidis clinical isolates; Salvatore P et al.; Neisseria meningitidis strains belonging to the hypervirulent lineage ET-37 and several unrelated strains are extremely UV sensitive . The phenotype is consequent to the presence of a nonfunctional recB(ET-37) allele carrying multiple missense mutations . Phenotypic analysis has been performed with congenic meningococcal strains harboring either the wild-type recB allele or the recB(ET-37) allele . Congenic recB(ET-37) meningococci, in addition to being sensitive to UV, were defective both in repair of DNA lesions induced by UV treatment and, partially, in recombination-mediated transformation . Consistently, the wild-type, but not the recB(ET-37), allele was able to complement the Escherichia coli recB21 mutation to UV resistance and proficiency in recombination . recB(ET-37) meningococci did not exhibit higher frequencies of spontaneous mutation to rifampin resistance than recB-proficient strains . However, mutation rates were enhanced following UV treatment, a phenomenon not observed in the recB-proficient counterpart . Interestingly, the results of PCR-based assays demonstrated that the presence of the recB(ET-37) allele considerably increased the frequency of recombination at the pilin loci . The main conclusion that can be drawn is that the presence of the defective recB(ET-37) allele in N . meningitidis isolates causes an increase in genetic diversity, due to an ineffective RecBCD-dependent DNA repair and recombination pathway, and an increase in pilin antigenic variation.

Infect Immun, 2002 Aug, 70(8), 4035 - 44
Interaction of Neisseria meningitidis with human meningeal cells induces the secretion of a distinct group of chemotactic, proinflammatory, and growth-factor cytokines; Christodoulides M et al.; The interactions of Neisseria meningitidis with cells of the leptomeninges are pivotal events in the progression of bacterial leptomeningitis . An in vitro model based on the culture of human meningioma cells was used to investigate the role of the leptomeninges in the inflammatory response . Following challenge with meningococci, meningioma cells secreted specifically the proinflammatory cytokine interleukin-6 (IL-6), the CXC chemokine IL-8, the CC chemokines monocyte chemoattractant protein 1 (MCP-1) and regulated-upon-activation, normal-T-cell expressed and secreted protein (RANTES), and the cytokine growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) . A temporal pattern of cytokine production was observed, with early secretion of IL-6, IL-8, and MCP-1 followed by later increases in RANTES and GM-CSF levels . IL-6 was induced equally by the interactions of piliated and nonpiliated meningococci, whereas lipopolysaccharide (LPS) had a minimal effect, suggesting that other, possibly secreted, bacterial components were responsible . Induction of IL-8 and MCP-1 also did not require adherence of bacteria to meningeal cells, but LPS was implicated . In contrast, efficient stimulation of RANTES by intact meningococci required pilus-mediated adherence, which served to deliver increased local concentrations of LPS onto the surface of meningeal cells . Secretion of GM-CSF was induced by pilus-mediated interactions but did not involve LPS . In addition, capsule expression had a specific inhibitory effect on GM-CSF secretion, which was not observed with IL-6, IL-8, MCP-1, or RANTES . Thus, the data demonstrate that cells of the leptomeninges are not inert but are active participants in the innate host response during leptomeningitis and that there is a complex relationship between expression of meningococcal components and cytokine induction.

Infect Immun, 2002 Aug, 70(8), 4028 - 34
Immunization with the recombinant PorB outer membrane protein induces a bactericidal immune response against Neisseria meningitidis; Wright JC et al.; Infections with Neisseria meningitidis are characterized by life-threatening meningitis and septicemia . The meningococcal porin proteins from serogroup B meningococci have been identified as candidates for inclusion in vaccines to prevent such infections . In this study, we investigated the vaccine potential of the PorB porin protein free of other meningococcal components . The porB gene from a strain of Neisseria meningitidis expressing the class 3 outer membrane porin protein (PorB3) was cloned into the pRSETB vector, and the protein was expressed at high levels in a heterologous host Escherichia coli . The recombinant protein was purified to homogeneity by affinity chromatography and used for immunization after incorporation into liposomes and into micelles composed either of zwitterionic detergent or nondetergent sulfobetaine . The immunogenicity of these preparations was compared to recombinant PorB protein adsorbed to Al(OH)(3) adjuvant as a control . Although sera raised against the protein adsorbed to Al(OH)(3) reacted with the purified recombinant protein, sera raised against liposomes and micelles showed greater activity with native protein, as measured by enzyme immunoassay with outer membranes and by whole-cell immunofluorescence . Reactivity with native protein was considerably enhanced by incorporation of the adjuvant monophosphoryl lipid A into the liposome or micelle preparations . Recognition of the native protein was in a serotype-specific manner and was associated with the ability of the antisera to promote high levels of serotype-specific complement-mediated killing of meningococci . These results demonstrate that the PorB protein should be considered as a component of a vaccine designed to prevent serogroup B meningococcal infection.

N Z Med J, 2002 May 24, 115(1154), 247 - 51
Bioterrorism in the Northern Hemisphere and potential impact on New Zealand; Wilson N et al.; Given the historical evidence, and the characteristics of biological weapons, it appears unlikely that terrorists will use these weapons to produce mass casualties . Yet this terrorist threat will continue to be a concern while many countries still have bioweapon programmes, with advances in genetic engineering, and while determinants of terrorism persist around the world (eg, unresolved conflicts, poverty, inequality and environmental degradation) . Terrorist use of smallpox, pneumonic plague and genetically engineered pathogens in the Northern Hemisphere could lead to imported cases reaching New Zealand and some risk of ongoing disease outbreaks . However, a range of disease control measures are available that could substantially limit the size of any resulting outbreaks . The risk of terrorist use of bioweapons needs to be considered in the context of the more important risk of pandemic influenza on New Zealand, the many thousands of preventable deaths in each year in this country (eg, from smoking and physical inactivity), and the current epidemic of meningococcal disease . Nevertheless, attention needs to be given to the primary prevention of terrorism and to preparatory measures that improve the country's public health infrastructure.

J Med Virol, 2002 Aug, 67(4), 555 - 62
Development and evaluation of a 'real-time' RT-PCR for the detection of enterovirus and parechovirus RNA in CSF and throat swab samples; Corless CE et al.; A two-step reverse transcriptase TaqMantrade mark duplex PCR (RT-PCR) assay was developed using the ABI 7700 Sequence Detection System for the detection of enterovirus (EV) and parechovirus type 1 and 2 (PEV) RNA from samples of cerebrospinal fluid (CSF) and throat swabs . Using sequence-specific fluorescent dye labeled probes and continuous 'real-time' monitoring, PCR amplified product accumulation was measured . Based on limiting dilutions, the TaqMantrade mark enterovirus and parechovirus RT-PCR showed an increase of two orders of magnitude compared to cell culture with sensitivity of 100% (7/7) when assessed using enterovirus cell culture positive samples (CSF, TS) . The assays were specific for enterovirus and parechovirus and did not amplify a wide selection of virus and bacterial isolates . RNA was amplified from 22 enterovirus serotypes: coxsackie A7, A9, A21; coxsackie B2, B3, B4, B5; echovirus 2, 4, 6, 7, 9, 11, 13, 17, 18, 19, 30, 31; poliovirus types 1, 2, and 3, and parechovirus types 1 and 2 . The assay was used to assess the incidence of enterovirus and parechovirus RNA in cell culture negative CSF and throat swab samples (n = 200) . An additional 33 (15.9%) enterovirus and 2 (1%) parechovirus were identified as positive by RT-PCR . Also, of 100 CSF samples from suspected cases of meningococcal meningitis submitted for meningococcal PCR testing, 59 (59%) were enterovirus and 2 (2%) parechovirus 1 and 2 were positive by RT-PCR . The TaqMantrade mark duplex assay offers a more rapid and sensitive alternative to conventional cell culture for the diagnosis of enterovirus and parechovirus infection . Closed tube real-time detection using the ABI Sequence Detection System obviates the need for post-PCR manipulation, which reduces hands on time and eliminates the risk of contamination from amplified PCR product .

Commun Dis Public Health, 2001 Dec, 4(4), 316 - 8
Cluster of meningococcal disease in rugby match spectators; Orr H et al.; Four adults among three unconnected groups of spectators at a rugby match developed invasive meningococcal disease four to five days after the match . Two died . All four cases were caused by serogroup C serotype 2a strains, genotype P1.5, P1.2 . Although the route of transmission remains uncertain, the most likely explanation is that an asymptomatic carrier disseminated meningococci to at least four others in the course of an afternoon . Clusters among spectators at an event without other links between cases are very unusual.

Commun Dis Public Health, 2001 Dec, 4(4), 268 - 72
Improving the quality of communicable disease control: the example of meningococcal disease; Fischbacher CM et al.; Improving the quality of health services is central to current attempts to reform the National Health Service . The main approaches to quality improvement in communicable disease control to date have been the development of practice guidelines and audit projects . Descriptions of the impact of quality initiatives in public health generally and communicable disease in particular have been limited, objective measures of quality are rare and few reports outline improvements that have been achieved in practice . We describe a project to develop a set of quality indicators for meningococcal disease control . A set of candidate indicators was developed and screened using standard approaches based on local consensus . We outline how they could be further tested and used to promote quality improvement.

J Clin Endocrinol Metab, 2002 Jul, 87(7), 3118 - 24
Acute stress response in children with meningococcal sepsis: important differences in the growth hormone/insulin-like growth factor I axis between nonsurvivors and survivors; de Groof F et al.; Septic shock is the most severe clinical manifestation of meningococcal disease and is predominantly seen in children under 5 yr of age . Very limited research has been performed to elucidate the alterations of the GH/IGF-I axis in critically ill children . We evaluated the GH/IGF-I axis and the levels of IGF-binding proteins (IGFBPs), IGFBP-3 protease, glucose, insulin, and cytokines in 27 children with severe septic shock due to meningococcal sepsis during the first 3 d after admission . The median age was 22 months (range, 4-185 months) . Eight patients died . Nonsurvivors had extremely high GH levels that were significant different compared with mean GH levels in survivors during a 6-h GH profile (131 vs . 7 mU/liter; P < 0.01) . Significant differences were found between nonsurvivors and survivors for the levels of total IGF-I (2.6 vs . 5.6 nmol/liter), free IGF-I (0.003 vs . 0.012 nmol/liter), IGFBP-1 (44.3 vs . 8.9 nmol/liter), IGFBP-3 protease activity (61 vs . 32%), IL-6 (1200 vs . 50 ng/ml), and TNFalpha (34 vs . 5.3 pg/ml; P < 0.01) . The pediatric risk of mortality score correlated significantly with levels of IGFBP-1, IGFBP-3 protease activity, IL-6, and TNFalpha (r = +0.45 to +0.69) and with levels of total IGF-I and free IGF-I (r = -0.44 and -0.55, respectively) . Follow-up after 48 h in survivors showed an increased number of GH peaks, increased free IGF-I and IGFBP-3 levels, and lower IGFBP-1 levels compared with admission values . GH levels and IGFBP-1 levels were extremely elevated in nonsurvivors, whereas total and free IGF-I levels were markedly decreased and were accompanied by high levels of the cytokines IL-6 and TNFalpha . These values were different from those for the survivors . Based on these findings and literature data a hypothetical model was constructed summarizing our current knowledge and understanding of the various mechanisms.

Vaccine, 2002 Jun 21, 20(21-22), 2840 - 4
Economic analysis of the 1992-1993 mass immunization campaign against serogroup C meningococcal disease in Quebec; De Wals P et al.; The objective of the study was to evaluate the cost-effectiveness and utility of the mass immunization campaign performed in the province of Quebec in 1992-1993, following an outbreak of serogroup C meningococcal disease (CMD) . Effectiveness data were extracted from a population-based cohort study, and cost estimates were obtained from surveys . Costs of the campaign to the health system were $ 26 million (1993 Canadian dollars) . Between 48 and 74 CMD cases, and between 7 and 11 deaths were prevented in the following 5 years . Net societal costs were between $ 18 and 21 million (using a 3% discount rate), net costs per death averted were between $ 1.7 and 3.0 million, between $ 58,000 and 105,000 per life-year gained, and between $ 49,000 and 87,000 per quality-adjusted life-year gained . These economic indices are less favorable than those for current routine immunization programs in Canada, but within the range of those for other common health interventions.

Cent Eur J Public Health, 2002 Jun, 10(1-2), 60 - 5
MLEE and PFGE characterization of Neisseria meningitidis serogroup C and B isolated in the Slovak Republic in 1998; Karelova E et al.; In the Slovak Republic the incidence and mortality of invasive meningococcal disease increased after 1995 when the new meningococcal clone of Neisseria meningitidis C:2a:P1.2,P1.5, ET-1.5/37 emerged . The new clone spread between 1995 and 1998 throughout the whole country . Morbidity of invasive meningococcal disease was 1.6/100,000 of the population and fatality reached the highest level of 23% in the Slovak Republic in 1998 . The new clone caused a new emergent epidemiological and clinical situation . The occurrence of invasive meningococcal disease caused by this clone has continually risen since 1995 . In 1998 72% of all diseases in Slovakia were caused by serogroup C . The emerging clone C:2a:Pl.2,P1.5 represented 74% of the serogroup C isolates . Clonality and genetic diversity of 15 selected meningococcal strains causing invasive meningococcal disease was compared by multilocus enzyme electrophoresis (MLEE) and DNA macrorestriction analysis by pulsed-field gel electrophoresis (PFGE) . The strains of serogroup C and B were isolated in all regions of Slovakia in 1998 . The majority of isolates belong to hypervirulent clone ET-15 as determined by MLEE . By PFGE a higher degree of diversity was observed.

Pediatrics . 2002 Jul;110(1 Pt 1):e3.
Extremity pain and refusal to walk in children with invasive meningococcal disease; Inkelis SH et al.; OBJECTIVE: Early recognition of invasive meningococcal disease in children may be difficult . Extremity pain and refusal to walk (extremity symptoms) are uncommonly mentioned as clinical findings in children who present with this disease . We sought to determine 1) the frequency of extremity symptoms as part of the clinical presentation in children with invasive meningococcal disease and 2) whether these symptoms help identify children with otherwise unsuspected meningococcal disease . METHODS: We reviewed the medical records of patients who were younger than 20 years and had invasive meningococcal disease from 1985 to 1996 at 3 pediatric referral centers . Children with extremity symptoms were identified and described . We compared clinical and laboratory findings and frequency of adverse outcomes between these children and those with invasive meningococcal disease without extremity symptoms . RESULTS: We identified 274 children with invasive meningococcal disease, 45 (16%) of whom had either history or physical examination evidence of extremity pain (31) or refusal to walk (14) as part of their clinical presentations . Five of the 45 patients had arthritis at the time of presentation . Patients with extremity symptoms at presentation were significantly older (77.9 +/- 62.2 vs 44.0 +/- 56.9 months), had lower temperatures (38.8 +/- 1.2 degrees C vs 39.2 +/- 1.2 degrees C), and had higher band counts (28.2 +/- 15.2% vs 18.1 +/- 12.4%) than did patients without extremity symptoms . There were no significant differences, however, between groups with regard to rash, white blood cell counts, coagulation parameters, prevalence of meningitis, or adverse outcomes . Seventy-three (27%) of the 274 patients had unsuspected disease, and 5 (7%) of these had extremity symptoms at the time of diagnosis . CONCLUSIONS: Sixteen percent of children with invasive meningococcal disease have extremity symptoms at the time of diagnosis . These symptoms may help to identify some patients with otherwise unsuspected invasive meningococcal disease.

J Infect Dis, 2002 Jul 1, 186(1), 40 - 8 Epub 2002 Jun 07.
Genotype-specific carriage of Neisseria meningitidis in Georgia counties with hyper- and hyposporadic rates of meningococcal disease; Kellerman SE et al.; Carriage of Neisseria meningitidis in a Georgia county with hypersporadic incidence of meningococcal disease ("hypersporadic county") and in a county with no cases of meningococcal disease was determined by a cross-sectional pharyngeal culture study of high school students . Among 2730 students from whom culture samples were obtained, meningococcal carriage was 7.7% (140/1818) in the hypersporadic county and 6.1% (56/912) in the comparison county . Carriage rates by serogroup and genetic type (i.e., electrophoretic type {ET}) did not differ significantly between counties, but apartment or mobile home residency was a risk factor for carriage in the hypersporadic county . Although most cases of meningococcal disease in the hypersporadic county were caused by members of the serogroup C ET-37 clonal group, no ET-37 meningococcal isolates were recovered from carriers in this county . However, 38% of all meningococcal isolates recovered from carriers in both counties were members of the serogroup Y ET-508 clonal group, an emerging cause of meningococcal disease in Georgia and throughout the United States during 1996-2001 . Shifts in carriage and transmission of meningococcal strains with different pathogenic potential are important determinants of meningococcal disease incidence.

Arch Dis Child, 2002 Jul, 87(1), 13 - 7
The meningococcus tamed?
Pollard AJ, Moxon ER.
Serogroup B Neisseria meningitidis is a frequent cause of invasive meningococcal disease, yet there are no effective vaccines suitable for routine immunisation . Limited efficacy has been shown with meningococcal outer membrane vacccines in children 4 years and older . Here we review the status of current research and consider new approaches to development of meningococcal serogroup B vaccines.

J Dermatol, 2002 May, 29(5), 290 - 5
Report of eight infants with acute infantile hemorrhagic edema and review of the literature; Caksen H et al.; Acute infantile hemorrhagic edema (AIHE) is a cutaneous leukocytoclastic vasculitis, clinically characterized by the symptom triad of fever, large purpuric skin lesions, and edema . The clinical picture has a violent onset, a short benign course, and spontaneous complete recovery . In this article, we present eight patients who were admitted with rashes on the skin and edema on the eyelids and extremities, and were diagnosed with AIHE according to their clinical and histopathological features (immunohistological study was also performed in three of them) . Our purpose was to emphasize that, aside from Henoch-Schonlein purpura, meningococcemia, septicemia, and purpura fulminans, AIHE benign disorder should also be considered in the differential diagnosis to determine the clinical course and treatment protocol in patients with purpuric rashes.

Eur J Epidemiol, 2001, 17(9), 877 - 84
Carriers of Neisseria meningitidis in household contacts of meningococcal disease cases in Catalonia (Spain); Cardenosa N et al.; A population-based study was carried out in Catalonia (Spain) from May 1998 to April 1999 to determine the prevalence of Neisseria meningitidis strains in meningococcal disease (MD) cases and their contacts, as well as the prevalence of meningococci in close contacts of patients with MD, and risk factors for its carriage . A total of 364 close contacts of 87 patients with MD were studied . Throat samples were collected by hospital staff before rifampicin chemoprophylaxis was begun . For each contact, a questionnaire was completed for sociodemographic and epidemiological data . A total of 61 contacts (an overall prevalence of 16.8%) were carriers of meningococcal strains (40 B, 10 C, 1 Z and 10 non-groupable isolates) . This prevalence is two to three times higher than in the general population (5-10%) . In 33/61 microbiologically confirmed cases (54%) and in 9/26 probable cases (35%), contacts carrying N . meningitidis were found . In 22/33 confirmed cases with carrier contacts, it was possible to study the phenotype of the carrier and patient strains (sero-group, serotype and serosubtype) . In 14 cases (64%), both strains were identical, in four cases, only a minor change was observed, in three cases, some strain (from the case or from his contact) was non-serotypable and non-serosubtypable, and in one case, both isolates were completely different . Bivariate analysis identified five statistically significant risk factors for meningococcal carriage: age (5-9 years old), meningococcal A+C vaccination, severe household overcrowding, social class and heavy active smoking (>20 cigarettes a day) . Multivariate analysis revealed that of these five variables, only heavy active smoking remained statistically significant when the other factors were controlled.

Bull World Health Organ, 2002, 80(5), 342 - 9
Early detection and response to meningococcal disease epidemics in sub-Saharan Africa: appraisal of the WHO strategy; Leake JA et al.; OBJECTIVE: To assess the sensitivity, specificity and predictive value positive of the WHO threshold strategy for detecting meningococcal disease epidemics in sub-Saharan Africa and to estimate the impact of the strategy on an epidemic at district level . METHODS: Data on meningitis cases at the district level were collected weekly from health ministries, WHO country and regional offices, and nongovernmental organizations in countries where there were epidemics of meningococcal disease in 1997 . An epidemic was defined as a cumulative district attack rate of at least 100 cases per 100,000 population from January to May, the period of epidemic risk . The sensitivity, specificity and predictive value positive of the WHO threshold rate were calculated, and curves of sensitivity against (1 - specificity) were compared with alternatively defined threshold rates and epidemic sizes . The impact of the WHO strategy on a district epidemic was estimated by comparing the numbers of epidemic cases with cases estimated to have been prevented by vaccination . FINDINGS: An analysis was made of 48 198 cases reported in 174 districts in Benin, Burkina Faso, the Gambia, Ghana, Mali, Niger, and Togo . These cases were 80.3% of those reported from Africa to WHO during the 1997 epidemic period . District populations ranged from 10,298 to 573,908 . The threshold rate was crossed during two consecutive weeks in 69 districts (39.7%) and there were epidemics in 66 districts (37.9%) . Overall, the sensitivity of the threshold rate for predicting epidemics was 97%, the specificity was 95%, and the predictive value positive was 93% . Taken together, these values were equivalent or better than the sensitivity, specificity and predictive value positive of alternatively defined threshold rates and epidemics, and remained high regardless of district size . The estimated number of potential epidemic cases decreased by nearly 60% in the age group targeted for vaccination in one district where the guidelines were followed in a timely manner . CONCLUSION: The use of the WHO strategy was sensitive and specific for the early detection of meningococcal disease epidemics in countries of sub-Saharan Africa during 1997 and had a substantial impact on a district epidemic . Nevertheless, the burden of meningococcal disease in these countries remains formidable and additional control measures are needed.

APMIS, 2002 Mar, 110(3), 193 - 204
Outer membrane vesicles from Neisseria meningitidis; Mirlashari MR et al.; Flow cytometry was used to study the expression of leukocyte adhesion molecules CD11a, CD11b, CD11c, CD14, and CD62L (L-selectin) and production of reactive oxygen species (ROS) in an ex vivo human whole-blood system stimulated with lipopolysaccharide-containing outer membrane vesicles (LPS-OMV) from N . meningitidis . Results demonstrated a dose-dependent increase in surface expression of CD11a, CD11b, CD11c and CD14 in granulocytes and monocytes (maximal at 30-120 min) upon OMV-LPS challenge, whereas CD62L expression was heavily downregulated (maximal at 30-120 min) . The OMV-associated LPS was almost as potent (on a weight basis) as purified LPS from E . coli in inducing adhesion molecule modulation but the response was delayed . Upon stimulation with OMV-LPS or E . coli-LPS, the production of intracellular ROS increased in both granulocytes and monocytes when dihydroethidium (DHE, mainly reflecting superoxide anion) was used as a probe, whereas peroxynitrite production monitored with dihydrorhodamine 123 (DHR) was not significantly changed . The OMV-mediated modulation of leukocyte adhesion molecule expression and increased ROS production may certainly lead to increased entrapment of leukocytes in the microcirculation and contribute to untoward inflammatory reactions as seen in systemic meningococcal disease.

J Infect, 2002 Feb, 44(2), 94 - 5
Meningococcal disease presenting as bronchiolitis; Hameed R et al.; Meningococcal disease is the leading infective cause of mortality in children . Bronchiolitis and meningococcal disease share some common features . Both are seasonal diseases with epidemics in winter . A preceding history of upper respiratory tract infection is commonly present in both . We report two cases of meningococcal disease in infants whose initial presentation was suggestive of bronchiolitis . We draw attention to tachypnoea as an important but overlooked early sign of meningococcal septicaemia .

Pediatr Infect Dis J, 2002 Apr, 21(4), 330 - 6
Low serum cortisol in combination with high adrenocorticotrophic hormone concentrations are associated with poor outcome in children with severe meningococcal disease; De Kleijn ED et al.; OBJECTIVES: To study the correlation between serum concentrations of adrenocorticotrophic hormone (ACTH) and cortisol in relation to severity of disease in children with meningococcal sepsis . METHODS: Subjects were children with meningococcal sepsis, admitted to the pediatric intensive care unit . Clinical data, laboratory values and blood samples were selected . Arterial cortisol, ACTH, interleukin 6 and tumor necrosis factor alpha concentrations were measured on admission and studied for their relation to severity of disease (sepsis, septic shock/survivors, septic shock/nonsurvivors) . RESULTS: Seventy-two patients fulfilled the criteria for meningococcal sepsis . Sixty-two of these children with positive blood cultures of Neisseria meningitidis, who were not treated with corticosteroids before admission, were included . Fifty of the 62 patients had septic shock . Twelve of those children (24%) died . The median age of the subjects was 2.6 years (range, 0.3 to 16.1 years) . Cortisol values were significantly lower in non-survivors (median, 654 nmol/l) than in survivors (median, 2184 nmol/l) (P < 0.01) . ACTH values were significantly higher in children who died (median, 1271 ng/l) than in survivors (85 ng/l) (P < 0.01) . The median cortisol:ACTH ratio decreased significantly depending on the disease severity categories . CONCLUSIONS: Low serum cortisol concentrations in combination with high ACTH concentrations are associated with poor outcome in children with severe meningococcal disease.

Commun Dis Public Health, 2002 Mar, 5(1), 27 - 32
Audit of suspected meningitis in a district in 1996-1997 and in 1999; Ejidokun OO et al.; The Public Health Laboratory Service has published guidance outlining appropriate investigations and public health action to control the spread of meningococcal disease . We investigated compliance with this guidance in audits of suspected meningitis cases in our district notified to the public health department between January 1996 and December 1997, and in 1999 . The total number of suspected meningitis cases in 1996-7 and in 1999 were 58 and 34 respectively . Meningococcal disease was suspected in 49 and 28 patients respectively, and for 58 (75.3%) of these case notes were found . Rash was more often a presenting sign in 1999 . The second audit also showed a non-significant reduction in the proportion of patients given penicillin before hospital admission (22.4% vs . 7.1%, p = 0.12), and in CSF microscopy requests (31% vs . 17.6%, p < 0.5) . Requests for meningococcal investigation by blood culture (77.5% vs . 79.4%, p < 0.5) blood PCR (34.5% vs . 64.7%, p < 0.001) and throat swab (25.9% vs . 55.9%, p < 0.005) were increased . Notifications of cases to the public health department within 24 hours of admission were also increased slightly (42.8% vs . 52.9%; p < 0.5) . Changes in clinical practice can be achieved through guidelines, audit and feedback . The importance of parenteral penicillin administration prior to hospital admission, appropriate investigations and prompt public health notification should be re-emphasised.

Int J Hyg Environ Health, 2002 May, 205(4), 291 - 6
Detection and response to a meningococcal disease outbreak following a youth football tournament with teams from four European countries; Reintjes R et al.; An outbreak of meningococcal disease, caused by Neisseria meningitidis, occurred following an international youth football tournament in the summer of 1997, affecting individuals from four European countries . This paper describes the outbreak, focusing on international co-operation in detection, investigation, control and follow-up, identifying weaknesses and exploring opportunities for improved co-operation . Data came from interviews, reports and related documents . The detection and management of the outbreak in each country is analysed . Eleven cases were linked to this outbreak and serotyped as C:2a:P1.5 . Control measures varied in each country, reflecting different national guidelines . The outbreak illustrated deficiencies in management of international outbreaks but also demonstrated benefits of international co-operation.

Hosp Med, 2002 May, 63(5), 274 - 7
Long-term outcomes of childhood meningitis; Fellick JM et al.; Meningitis and meningococcal disease remain a major source of anxiety to paediatricians and parents alike . Survival rates have improved with rapid diagnosis and appropriate management . However, survivors remain at risk of long-term neurodevelopmental sequelae.

Hosp Med, 2002 May, 63(5), 268 - 73
Treating meningococcal infections in children; Welch SB et al.; Aggressive early treatment of meningococcal disease in children can reduce mortality . This relies on prompt recognition of septicaemia and meningitis, and treatment of the complications of shock and raised intracranial pressure.

Hosp Med, 2002 May, 63(5), 264 - 7
Epidemiology of meningococcal disease; Cartwright KA; In the UK, serogroup A strains disappeared 50 years ago, but in the 1990s, numbers of cases rose again to a 50-year high . Following the very successful introduction of conjugated meningitis C vaccines, effective meningitis B vaccines are now the highest priority.

Infect Immun, 2002 Jul, 70(7), 3752 - 8
Complement activation and formation of the membrane attack complex on serogroup B Neisseria meningitidis in the presence or absence of serum bactericidal activity; Drogari-Apiranthitou M et al.; Encapsulated meningococci are complement sensitive only in the presence of bactericidal antibodies by yet-unexplored mechanisms . The objective of this study was to investigate the involvement of major bacterial surface constituents on complement activation and membrane attack complex (MAC) formation on serogroup B meningococci in the presence or absence of antibody-dependent serum bactericidal activity (SBA) . The strains used were the encapsulated H44/76, five of its variants differing in capsulation and expression of the class 1 porin (PorA), and its lipopolysaccharide (LPS)-deficient isogenic mutant (LPS(-)) pLAK33 . Two normal sera, one with high SBA (SBA(+)) and one with no bactericidal activity (SBA(-)) against H44/76 as well as an a-gamma-globulinemic serum were used for sensibilization of the bacteria . C3b and iC3b deposition on H44/76, its unencapsulated variant v24, and pLAK33 was similar in SBA(+) and SBA(-) serum, and no difference was present between the strains . MAC deposition on H44/76 was higher in SBA(+) serum than in SBA(-) serum and the a-gamma-globulinemic serum . The amounts of C3b on H44/76, v24, and pLAK33 in the a-gamma-globulinemic serum were also not different, indicating immunoglobulin G (IgG)- and LPS-independent complement activation . H44/76 PorA(+) and its PorA(-) variant and the v24 PorA(+) and its PorA(-) variant incubated in SBA(-) serum induced comparable amounts of MAC, despite their different serum sensitivities . Complement formation on the surface of the bacteria occurred almost exclusively via the classical pathway, but the considerable amounts of Bb measured in the serum indicated alternative pathway activation in the fluid phase . We conclude that complement deposition on meningococci is, for the most part, independent of classical pathway IgG and is not influenced by the presence of PorA or LPS on the meningococcal surface . Addition of an anti-PorA chimeric antibody to the nonbactericidal normal serum, while promoting a dose-related bacterial lysis, did not influence the amounts of C3b, iC3b, and MAC formed on the bacterial surface . These findings support the hypothesis that proper MAC insertion rather than the quantity of MAC formed on the bacterial surface is of importance for efficient lysis of meningococci.

Infect Immun, 2002 Jul, 70(7), 3621 - 6
Neisseria lactamica protects against experimental meningococcal infection; Oliver KJ et al.; Immunological and epidemiological evidence suggests that the development of natural immunity to meningococcal disease results from colonization of the nasopharynx by commensal Neisseria spp., particularly with N . lactamica . We report here that immunization with N . lactamica killed whole cells, outer membrane vesicles, or outer membrane protein (OMP) pools and protected mice against lethal challenge by a number of diverse serogroup B and C meningococcal isolates in a model of bacteremic infection . Sera raised to N . lactamica killed whole cells, OMPs, or protein pools were found to cross-react with meningococcal isolates of a diverse range of genotypes and phenotypes . The results confirm the potential of N . lactamica to form the basis of a vaccine against meningococcal disease.

J Neurochem, 2002 Apr, 81(2), 270 - 6
Transcriptional activation of nitric oxide synthase-2, and NO-induced cell death, in mouse cerebrovascular endothelium exposed to Neisseria meningitidis; Constantin D et al.; The site and mechanisms by which meningococci gain access to the CNS are unclear . In this study we determined whether production of nitric oxide (NO) is part of the host (endothelial cell) response to meningococcal cell lysate, and the consequences for endothelial cell viability . Expression of NO synthase type II (NOS-2) mRNA, protein and enzyme activity were investigated in mouse cerebrovascular endothelial cells exposed to sonicated Neisseria meningitidis . The production of nitrite peaked after 48 h of incubation, and this reflected transcriptional activation of the NOS-2 gene and increased expression of the NOS-2 protein . This endothelial response was independent of meningococcal lipopolysaccharide production . Endothelial cell death occurred as a result of NO production, and addition of a NOS inhibitor prevented cell death, but the cells did not exhibit features of apoptosis . However, inhibition of poly (ADP-ribose) polymerase (PARP) decreased the rate of cell death by more than 40% . These data indicate that N . meningitidis increases expression of NOS-2 in endothelial cells and causes cell death . Such an effect could contribute to meningococcal entry into the CNS in situ.

Gesundheitswesen, 2002 Jun, 64(6), 336 - 43
{Surveillance system for assessing central nervous infections in Lower Saxony 1998-2000}; Beyrer K et al.; OBJECTIVE AND METHOD: In cooperation with the district public health authorities in Lower Saxony a surveillance system for infections of the central nervous system was established from 1998 to 2000 . Reporting was based on special questionnaires . It was the objective of this system to obtain information on the pathogens responsible for these infections and the corresponding age distribution . RESULTS: An increased risk was found for children under the age of 15 . About two-thirds of all reported central nervous infections were observed in this age group . The most frequent bacteria identified had been Meningococci, Pneumococci and Borrellia burgdorferi . They accounted for about 56 % of the reported bacterial infections . With respect to viral meningitis/encephalitis, enteroviruses were isolated in about 66 % of these cases . Twenty-five of all 628 reported cases had a lethal outcome which was more often associated with bacterial than viral infections . CONCLUSIONS: Infections of the central nervous system still play an important role in clinical and public health medicine . For the future an intensive and ongoing surveillance of these infectious diseases is required and should exceed the regulations of the official notification system . To this end, a prospective register for meningitis and encephalitis cases will be set up in Lower Saxony in cooperation with hospitals and laboratories.

Clin Cardiol, 2002 Jun, 25(6), 305 - 7
Primary (isolated) meningococcal pericarditis; Morgan DR et al.; A 19-year-old man was admitted with a history and examination findings of probable bacterial pericarditis . Blood cultures produced Neisseria meningitidis Group C, sensitive to penicillin . The patient was initially treated with intravenous benzylpenicillin . Echocardiogram demonstrated the development of a pericardial effusion which was tapped, and benzylpenicillin was instilled into the pericardial space . Because of failure of clinical resolution, cefotaxime was substituted for benzylpenicillin . Rapid clinical improvement then ensued . Repeat echocardiogram showed evidence of neither reaccumulation nor constrictive pericarditis . Primary (isolated) meningococcal pericarditis is a recognized though rare manifestation of meningococcal disease . It is most common in young adults and is associated with a good prognosis.

Vaccine, 2002 Jun 7, 20(19-20), 2592 - 6
Avidity maturation following vaccination with a meningococcal recombinant hexavalent PorA OMV vaccine in UK infants; Longworth E et al.; To date, there are no data assessing the utility of avidity indices as a surrogate marker for the induction of immunological memory following meningococcal serogroup B outer membrane vesicle (OMV) vaccination . We studied infants who had been immunized with three doses of a recombinant hexavalent PorA OMV vaccine at ages 2-4 months, together with a fourth dose at age 12-18 months . A control group had received a single dose of the same vaccine at age 12-18 months . As previously reported, serum bactericidal antibody (SBA) titres increased after each of the first three doses, with a significant increase observed from 6 months post third dose to 1 month post fourth dose . The geometric mean avidity indices (GMAI), against strain H44/76 OMVs, increased from 1 month post first dose to 1 month post third dose . Significant increases in GMAI were observed at 6 months post third dose and again following the fourth dose . At 32-42 months of age, though the SBA titres had returned to post first dose levels, the GMAI remained elevated . No increase in avidity was observed in the control group . Antibody avidity indices are useful laboratory markers for the priming of immunological memory following vaccination with meningococcal serogroup B OMV vaccines.

Vaccine, 2002 Jun 7, 20(19-20), 2533 - 6
The effectiveness of serogroup C meningococcal vaccine estimated from routine surveillance data; Rivest P et al.; Serogroup C meningococcal vaccine effectiveness was estimated from routine surveillance data, based on a comparison of the proportion of vaccine and non-vaccine serogroups in vaccinated and unvaccinated reported cases . Between 1 April 1993 and 31 March 1998, 109 eligible cases were reported . Among the 54 cases caused by serogroup C, 38 had been vaccinated . Among the 55 cases caused by non-vaccine serogroups, 49 had been vaccinated . Vaccine effectiveness was estimated at 71% (95% CI: 21-89%), a value similar to that obtained in the same population by a cohort study . Effectiveness was lower in children immunized before the age of 10 . This demonstrates that meningococcal vaccine effectiveness can be estimated from information obtained routinely from cases only, as an alternative to the more expensive cohort or case-control designs.

Microbiology, 2002 Jun, 148(Pt 6), 1813 - 9
Many carried meningococci lack the genes required for capsule synthesis and transport; Claus H et al.; Of 830 Neisseria meningitidis isolates obtained from healthy carriers in Bavaria, Germany, 136 (16.4%) lacked the operons necessary for the synthesis, lipid modification, and transport of capsular polysaccharide . These operons were replaced by a non-coding intergenic region either 113 or 114 bp in length, termed here the capsule null locus (cnl) . Comparisons of the nucleotide sequence of this region in the meningococcus and its acapsulate relatives, Neisseria gonorrhoeae and Neisseria lactamica, revealed six distinct sequence variants (cnl-1 to cnl-6), with a total of 10 nucleotide substitutions and three indels . With the exception of one 4 bp insertion, which was unique to a gonococcal isolate, all of the individual sequence changes were present in the N . lactamica isolates examined . The meningococcal isolates with a cnl belonged to one of four otherwise genetically diverse genetic groupings: the ST-53 and ST-1117 complexes (75 isolates); the ST-845 complex (12 isolates); the ST-198 and 1136 complexes (46 isolates), and the ST-44 complex (one isolate) . These data demonstrated that a substantial proportion of carried meningococci were incapable of capsule production, that the cnl circulated within Neisseria populations by horizontal genetic exchange, and that the expression of a polysaccharide capsule was not a requirement for person-to-person transmission of certain meningococcal lineages.

J Immunol, 2002 Jun 15, 168(12), 6273 - 8
Peptide mimotopes of pneumococcal capsular polysaccharide of 6B serotype: a peptide mimotope can bind to two unrelated antibodies; Shin JS et al.; Two groups of bacteriophage clones displaying the antigenic properties of serotype 6B pneumococcal capsular polysaccharide (PS) were obtained from different phage libraries expressing random heptameric peptides . One group, biopanned with a mouse mAb (Hyp6BM1), is comprised of 17 phage clones expressing 10 unique sequences of linear peptides . The other group, selected with another mAb (Hyp6BM8), contained six clones, all of which expressed the identical circular peptide . Phage clones expressing the linear peptides (e.g., PhaM1L3) bound only to Hyp6BM1, but not other 6B PS-specific mAb, and their binding could be inhibited with pneumococcal capsular type 6B PS only . In contrast, a phage clone expressing the circular peptide (PhaM8C1) cross-reacted with several other 6B PS-specific mAbs, and their binding could be inhibited with pneumococcal capsular PS of 6A and 6B serotypes . Two short peptides, PepM1L3 and PepM8C1, reflecting the peptide inserts of the corresponding phage clones, could inhibit the binding of the two clones to their respective mAb . Interestingly, the peptide insert in PhaM8C1 was identical to that in PhaB3C4, a previously reported mimotope of alpha(2-->8) polysialic acid, Neisseria meningitidis group B PS . Indeed, PhaM8C1 bound to HmenB3 (a meningococcal Ab), and their association could be inhibited with alpha(2-8) polysialic acid, but not with 6B PS . Conversely, alpha(2-8) polysialic acid could not inhibit the binding of PhaM8C1 to Hyp6BM8 . The two-dimensional nuclear magnetic resonance studies indicate that PepM8C1 peptide can assume several conformations in solution . The ability of this peptide to assume multiple conformations might account for its ability to mimic more than one Ag type.

Curr Opin Investig Drugs, 2002 Jan, 3(1), 51 - 3
Meningitis C vaccine (North American vaccine); Lattanzi M et al.; North American Vaccine Inc (NAVI) has launched a conjugate polysaccharide vaccinefor the prevention of meningitis caused by group C meningococcal bacteria {433475} . The vaccine is based upon conjugate technology, incorporating the serogroup C polysaccharide (CPS) of all three major serogroups . Antibody-dependent, complement-mediated activity was demonstrated in mice and non-human primates, with no detectable adverse effects {277193} . Approval was filed for in the UK in January 2000 {353305} . In July 2000, Baxter received approval for NeisVac-C in the UK, and by September 2000 the vaccine was expected to be incorporated into the NHS's immunization campaign against meningitis C {381225} . NeisVac-C will initially appear labeled from NAVI; Baxter completed its acquisition of NAVI in June 2000 {375389} . Baxter estimates the worldwide global market for the vaccine at US $600 million per year {376204}.

Nephron, 2002 Jun, 91(2), 336 - 8
Membranous glomerulonephritis, antiphospholipid syndrome, and persistent low C3 levels associated with meningococcal disease; Bulucu F et al.; A young male patient with a recent history of meningococcemia was referred to our hospital in his recovery period . He had signs suggesting deep venous thrombosis in the legs but no other abnormalities on physical examination at admission . Laboratory results showed proteinuria (3.1 g/day), prolonged activated partial thromboplastin time (56.3 s), low level of C3c (0.19 g/l), high titers of both IgM (27.04 MPLU/ml) and IgG (74.88 GPLU/ml) anticardiolipin antibodies and recanalized thrombotic changes in the deep veins of the lower extremities on venography . Histopathological diagnosis of the kidney disease was membranous glomerulonephritis . He was started on an angiotensin-converting enzyme inhibitor to reduce proteinuria and an oral anticoagulant to prevent thromboembolic events . Since no reduction in proteinuria was observed at the 10th month of therapy, the angiotensin-converting enzyme inhibitor was discontinued . On his last follow-up, approximately 1.5 years after meningococcemia, he had no complaints and no abnormal findings on physical examination . While both IgM and IgG anticardiolipin antibody titers returned to the normal range, he still had persistent proteinuria and hypocomplementemia .

Ned Tijdschr Geneeskd, 2002 May 18, 146(20), 932 - 3
{Universal vaccination against group C meningococci and pneumococci; advice from the Health Council of the Netherlands}; van Furth AM et al.; A committee of the Health Council of the Netherlands recently advised the Minister of Health on nationwide vaccination against group-C meningococci and pneumococci . They recommended the introduction of both vaccines into the national vaccination programme . The meningococcal C vaccine should be introduced as soon as possible, and the pneumococcal vaccine should be introduced as soon as a combined vaccine against diphtheria, tetanus, pertussis and polio and H . influenzae type B is available . In the meantime, due to various clusters of meningococcal disease caused by Neisseria meningitidis C in the Netherlands, parents have started to have their children vaccinated by buying vaccines and asking their general practitioners to perform the vaccination . This unfavourable situation must be controlled by the government through clear publicity to parents and healthcare workers.

J Paediatr Child Health, 2002 Jun, 38(3), 241 - 5
Improvement in resuscitation knowledge after a one-day paediatric life-support course; Durojaiye L et al.; OBJECTIVE: To assess the effect of a one-day paediatric life-support course on the knowledge of paediatric trainees . METHODS: A telephone survey was performed prior to and at set intervals following the course . Responses to individual questions before and after the course were analysed and an overall test score was calculated . The acquisition and retention of knowledge was measured by comparing test scores for the same group of trainees at time intervals after the course . RESULTS: All candidates were surveyed . The median duration of paediatric training prior to the course was 3 years . Eighteen candidates (78%) had previously intubated a child and 13 (57%) had previously used an intraosseous needle . Prior to the course, few of the 23 candidates had adequate knowledge of either the management of the cervical spine in the seriously injured child (17%), fluid resuscitation in meningococcal septicemia (52%), shock dose in ventricular fibrillation (61%), or the management of anaphylactic shock (35%) . There was a significant improvement in the knowledge of the group after the course, with median test scores increasing from 19 to a maximum of 22 (P < 0.001) . This knowledge was retained at 4 months after the course . CONCLUSION: Despite a high level of experience and previous training in paediatric resuscitation, many candidates lacked the basic knowledge necessary for the resuscitation of seriously ill or injured children . There was a significant improvement in this knowledge after the course, and this was maintained for 4 months . The paediatric life-support course is an important means of resuscitation training for junior doctors.

J Exp Med, 2002 Jun 3, 195(11), 1445 - 54
NadA, a novel vaccine candidate of Neisseria meningitidis; Comanducci M et al.; Neisseria meningitidis is a human pathogen, which, in spite of antibiotic therapy, is still a major cause of mortality due to sepsis and meningitis . Here we describe NadA, a novel surface antigen of N . meningitidis that is present in 52 out of 53 strains of hypervirulent lineages electrophoretic types (ET) ET37, ET5, and cluster A4 . The gene is absent in the hypervirulent lineage III, in N . gonorrhoeae and in the commensal species N . lactamica and N . cinerea . The guanine/cytosine content, lower than the chromosome, suggests acquisition by horizontal gene transfer and subsequent limited evolution to generate three well-conserved alleles . NadA has a predicted molecular structure strikingly similar to a novel class of adhesins (YadA and UspA2), forms high molecular weight oligomers, and binds to epithelial cells in vitro supporting the hypothesis that NadA is important for host cell interaction . NadA induces strong bactericidal antibodies and is protective in the infant rat model suggesting that this protein may represent a novel antigen for a vaccine able to control meningococcal disease caused by three hypervirulent lineages.

Lancet, 2002 May 25, 359(9320), 1829 - 31
Carriage of serogroup C meningococci 1 year after meningococcal C conjugate polysaccharide vaccination; Maiden MC et al.; The UK was the first place to introduce meningococcal serogroup C conjugate (MCC) vaccines . From November, 1999, all people younger than 18 years, about 14 million individuals, were offered MCC immunisation . The uptake rate was more than 70% by November, 2000 . We compared the carriage of meningococci in isolates we obtained from 14,064 students aged 15-17 years during vaccination in 1999, with those from 16,583 students of the same age surveyed 1 year later . Carriage of serogroup C meningococci was reduced by 66% (p=0.004) . Our results show that MCC vaccines protect against carriage of meningococci that express serogroup C polysaccharide capsules.

Ugeskr Laeger, 2002 May 13, 164(20), 2617 - 23
{Fever and skin hemorrhages in children--is it meningococcal disease?}; Nielsen HE et al.; INTRODUCTION: Our main aims were to establish criteria for early distinction between meningococcal disease and other conditions with similar clinical features, and to identify other causes of haemorrhagic rashes accompanied by fever . MATERIALS AND METHODS: This prospective study comprised 264 infants and children hospitalised with fever and skin haemorrhages . RESULTS: We identified an aetiological agent in 28%: 15% had meningococcal disease, 2% another invasive bacterial infection, 7% enterovirus infection, and 4% adenovirus infection . Five clinical variables discriminated meningococcal disease from other conditions on admission: skin haemorrhages of (1) characteristic appearance; (2) universal distribution and (3) a maximum diameter of > 2 mm; (4) poor general condition; and (5) nuchal rigidity . DISCUSSION: If any two or more of these clinical variables were present, the probability of identifying a patient with meningococcal disease was 97% and the false-positive rate was only 12% . This diagnostic algorithm did not identify children in whom septicaemia was caused by other bacterial species.

Zh Mikrobiol Epidemiol Immunobiol, 2002 Mar-Apr, (2), 33 - 7
{Evaluation of the immunological activity and safety of group B meningococcal vaccine prepared from a natural complex of specific polysaccharide and outer membrane proteins}; Kuvakina VI et al.; Immunological activity and safety of group B meningococcal vaccine prepared from a natural complex of specific polysaccharide and outer membrane proteins were under study . The immunological safety of the vaccine was evaluated by the absence of antibodies to denaturated and native DNA (d-DNA and n-DNA) . As shown with the use of the enzyme immunoassay (EIA), the administration of the vaccine did not induce antibody formation to d-DNA and n-DNA during the observation period . The titer of bactericidal antibodies in the immune bacteriolysis assay (IBA) to the vaccine strain B:2b:P1.2 after immunization increased four-fold and greater in 80% of the vaccinated persons . The significant increase of bactericidal antibodies to heterologous strains B:2a:P1.2 and B:15:P1.7 was registered in 20-30% of the vaccinees, respectively . A month after the repeated vaccination an increase in specific IgG antibodies to the complex antigen was found to occur according to EIA results . The use of RIB made it possible to evaluate the preventive activity of group B meningococcal vaccine as a whole and to suppose that the vaccine induced mainly type-specific response.

Intensive Care Med, 2002 May, 28(5), 648 - 50 Epub 2002 Mar 27.
Psychiatric adjustment following meningococcal disease treated on a PICU; Judge D et al.; OBJECTIVE: To describe the psychiatric status of child survivors of meningococcal disease and their mothers.DESIGN AND SETTING: Home interviews with 3-12 month follow-up.PATIENTS . 29 children aged 2-15 years admitted to a Paediatric Intensive Care Unit (PICU) with meningococcal disease.MEASUREMENTS AND RESULTS: Questionnaires to assess psychiatric risk in children and parents . We found an overall risk for child psychiatric disorder in 20% . Symptoms of post-traumatic stress disorder (PTSD) were present in 62% of children, and 10% had the features of a stress disorder . In 40% of mothers there was an increased risk for psychiatric disorder, 48% experienced clinically significant PTSD symptoms, and 29% were seeking psychological help . Maternal stress symptoms were significantly associated with severity of their child's illness.CONCLUSIONS: A significant proportion of children surviving meningococcal disease and their parents are likely to suffer psychological stress symptoms to a degree that warrants attention.

Paediatr Nurs, 2001 Feb, 13(1), 23 - 6
Group C meningococcal vaccine trial: safety, immunogenicity and parents' views of participation; Jonas C; In 1995, the Oxford Vaccine Group evaluated the safety and immunogenicity of a Group C meningococcal conjugate vaccine in 182 infants using the UK vaccination schedule . During and after the study we sought the views of parents about the vaccine and about their participation in the trial . The vaccine was well tolerated and resulted in fewer local reactions than the routine vaccinations, with no increase in systemic reactions . Post-vaccination antibody levels increased progressively after each dose of conjugate vaccine . We concluded that this meningococcal C conjugate vaccine is safe and immunogenic . The research process and the views of parents provide important lessons for researchers undertaking trials on infants.

J Infect Dis, 2002 Jun 1, 185(11), 1596 - 605 Epub 2002 May 17.
Outbreak of W135 meningococcal disease in 2000: not emergence of a new W135 strain but clonal expansion within the electophoretic type-37 complex; Mayer LW et al.; In 2000, >400 cases of disease caused by Neisseria meningitidis serogroup W135 (MenW135), the largest MenW135 outbreak reported to date, occurred worldwide among Hajj pilgrims and their contacts . To elucidate the origin of the outbreak strains and to investigate their relatedness to major clonal groups, genotypic and phenotypic subtyping was performed on 26 MenW135 outbreak-associated isolates and 50 MenW135 isolates collected worldwide from 1970 through 2000 . All outbreak-associated isolates were members of a single clone of the hypervirulent electrophoretic type (ET)-37 complex, designated the "(W)ET-37 clone"; 19 additional MenW135 strains were also members of this clone, and the remaining 31 MenW135 strains were clearly distinct . The 2000 MenW135 outbreak was not caused by emergence of a new MenW135 strain but rather by expansion of the (W)ET-37 clone that has been in circulation at least since 1970; the strains most closely related to those causing the 2000 outbreak have been isolated in Algeria, Mali, and The Gambia in the 1990s.

Arch Dis Child, 2002 Jun, 86(6), 449 - 52
Improved case confirmation in meningococcal disease with whole blood Taqman PCR; Hackett SJ et al.; BACKGROUND: The clinical diagnosis of meningococcal disease (MCD) can be difficult . Non-culture methods like the previous ELISA meningococcal PCR improved case confirmation rates, but were not ideal . A Taqman meningococcal PCR, using DNA extracted from serum (S-Taqman), which has an improved sensitivity compared to the ELISA method in vitro, was introduced into clinical practice in July 1997 . A new whole blood DNA extraction method for Taqman (WB-Taqman) was introduced in September 1999 . AIMS: To determine the degree of improvement in the confirmation rate in clinically diagnosed MCD, following the introduction of WB-Taqman . METHODS: A total of 192 patients (WB-Taqman) with possible or probable MCD, including those admitted to our paediatric intensive care unit, were studied . Admission EDTA samples obtained were sent for bacterial DNA detection at the Meningococcal Reference Unit (MRU), Manchester . These patients were compared to 319 patients with possible and probable MCD, seen at the same hospital prior to the introduction of WB-Taqman . RESULTS: Following the introduction of WB-Taqman, 82 of the 95 probable cases (88%) had a positive meningococcal PCR result . This gives a diagnostic sensitivity and specificity for WB-Taqman of 87% and 100% respectively . Following WB-Taqman all blood culture positive patients were also PCR positive . Confirmation of cases by PCR rose from 47% (S-Taqman, n = 166) to 88% (WB-Taqman) . When all confirmatory tests were included, case confirmation increased from 72% (S-Taqman) to 94% (WB-Taqman) . CONCLUSION: The sensitivity of PCR in confirming clinical MCD has improved significantly with this new method . The gold standard for confirming cases of MCD is now the WB-Taqman PCR.

Am J Med Sci, 2002 May, 323(5), 263 - 5
Thoracic myelopathy complicating acute meningococcal meningitis: MRI findings; Bhojo AK et al.; Spinal cord dysfunction is a rare complication of Neisseria meningitidis (meningococcal) meningitis . We report a 17-year-old patient who had a 3-day history of fever, headache and vomiting, agitation, and unresponsiveness . Cerebrospinal fluid showed a marked polymorphonuclear pleocytosis . Latex particle agglutination was positive for meningococci . The patient was given intravenous antibiotics and intravenous dexamethasone . Over the next 4 days, he developed weakness of the lower extremities, with areflexia and extensor plantar responses . MRI revealed contiguous hyperintensities on T2-weighted images involving the thoracic spinal cord from T4 to T9 and 4 brain abscesses . Five months later, he recovered brain function, but the paraparesis remained . This case illustrates that myelopathy may complicate acute meningococcal meningitis, possibly due to a vasculitis, stroke, autoimmune myelopathy, or direct infection of the spinal cord . Patients with myelopathy associated with acute meningitis should receive spinal MRI . In addition, meningitis should be considered in patients presenting with acute myelopathy.

J Pediatr Health Care, 2002 May-Jun, 16(3), 119 - 24
Neisseria meningitidis: presentation, treatment, and prevention; Ferguson LE et al.; Neisseria meningitidis is a leading cause of meningitis and septicemia in children and young adults in the United States . Highly publicized outbreaks of disease caused by this organism in communities and on college campuses have resulted in a heightened public awareness of its potentially devastating effects . The rapid progression of signs and symptoms of meningococcemia necessitate early recognition and institution of appropriate therapeutic measures . Identifying contacts of index cases who are at high risk of acquiring the disease allows health care providers to institute appropriate chemoprophylaxis . During community outbreaks, health care providers play an equally important role in calming the fears of low-risk contacts and their families . Familiarity with the risks and benefits of the meningococcal vaccine allows health care providers to offer this immunization to appropriate patients.

Curr Opin Infect Dis, 2002 Jun, 15(3), 275 - 81
Meningococcal disease: how to prevent and how to manage; Balmer P et al.; Meningococcal disease is a significant problem in the paediatric population . The diagnosis of meningococcal disease can be problematic and progression of the disease can rapidly lead to a life-threatening illness . Despite the success of antibiotic treatment, mortality rates remain high . The development of protein-polysaccharide conjugate vaccines has significantly improved the success of vaccination in reducing the incidence of meningococcal disease . However, a comprehensive vaccine conferring protection against disease-associated serogroups remains elusive . The aim of this review is to highlight recent significant improvements in the prevention and management of meningococcal disease.

Curr Opin Infect Dis, 2002 Jun, 15(3), 247 - 52
Current concepts in the role of the host response in Neisseria meningitidis septic shock; Brandtzaeg P et al.; Lipopolysaccharides in the outer membrane of Neisseria meningitidis are key molecules that induce inflammation and cause meningitis and shock . Mutant strains, with altered lipid A, the toxic moiety of lipopolysaccharide, or completely lacking lipopolysaccharide, induce significantly less inflammation than wild-type strains . Polymorphism of the Fc gamma receptors and interleukin-10 gene but not of the Toll-like receptor 4 may influence the development of meningococcal infection . Mannan-binding lectin is involved in complement activation, the regulation of adhesion molecules and cytokine production induced by meningococci . The activation of protein C by the thrombomodulin protein C receptor complex on the endothelial cell surface appears to be reduced in meningococcal sepsis but is still sufficient to convert protein C to activated protein C in patients treated with concentrated protein C.

Bull Soc Pathol Exot, 2002 Mar, 95(1), 37 - 44
{Critical review of control strategies for meningococcal meningitis epidemics in Sub-Saharan Africa}; Chippaux JP et al.; Strategies for controlling meningitis epidemics in Sub-Saharan countries, although regularly re-examined, are based on epidemiological, immunological and logistical considerations dating from the 1970s . The strategy recommended by WHO consists in organising large-scale vaccinations in the event of declared epidemic . However, the obvious failure of this strategy has meant that a review and evaluation of the emergency vaccination criteria is necessary . In spite of the current controversy regarding the immunogenicity of the polysaccharide vaccine, its safety, effectiveness in the field and low cost should justify the renewal of a debate on its use in routine vaccination . Routine--or preventive--vaccination could significantly reduce the incidence of meningococcal meningitis as well as its severity . The conjugate vaccine, when available, will constitute an additional advantage in the prevention of meningococcal meningitis . The organisation of a strategy combining both polysaccharide and conjugate vaccines according to the population targets and possibilities of funding remains to be defined.

Vaccine, 2002 May 22, 20(17-18), 2404 - 9
Placental and breast transfer of antibodies after maternal immunization with polysaccharide meningococcal vaccine: a randomized, controlled evaluation; Shahid NS et al.; We evaluated the strategy of maternal immunization with Neisseria meningitidis (Nm) vaccine in Asian mothers, to assess potential protection of infants, including by breast milk . One hundred and fifty-seven women in the third trimester were randomized to receive a single dose of the polysaccharide Nm (n=75) or a control vaccine (n=82) . Group A Nm IgG levels were measured in maternal and infant sera, and specific IgA in breast milk . A 5.6-fold rise of Nm IgG antibody was observed among the Nm vaccinees . At delivery, geometric mean titres (GMTs) of Nm IgG antibody in Nm mothers was 12.5 microg/ml versus 4.97 microg/ml, with a mean infant/maternal antibody ratio of 0.56 . Infants of Nm vaccinees had mean IgG levels of 6.9, 2.3, 1.2 and 0.6 microg/ml at 0, 6, 14 and 22 weeks, significantly higher than in control children up to 14 weeks . Anti-Nm IgA levels in milk were 6.8 to 2.0 microg/ml, significantly higher in Nm vaccinees till 6 months . Immunization during pregnancy is safe for both mothers and infants, and provides infants with significantly increased levels of specific IgG for 2-3 months and oral IgA for 6 months.

Pediatr Infect Dis J, 2002 Mar, 21(3), 209 - 13
Mucosal immune responses to meningococcal conjugate polysaccharide vaccines in infants; Zhang Q et al.; BACKGROUND: Serogroup C meningococcal conjugate polysaccharide vaccines have been reported to induce significant serum IgG antibodies and immunologic memory in infants . Because meningococcus is a mucosal pathogen colonizing the nasopharynx, local mucosal immune responses may play an important role in host defense against infection and carriage . We have investigated the mucosal IgA and IgG antibody responses to two meningococcal C conjugate vaccines in the saliva of healthy infants . METHODS: Specific salivary IgA and IgG antibodies to two meningococcal C polysaccharide conjugate vaccines (Menjugate from Chiron Corp., n = 46; and Meningitec from Wyeth Lederle, n = 54) were investigated by immunoassay in infants after parenteral vaccinations at the ages of 2, 3 and 4 months . Unstimulated saliva samples were collected immediately before the first immunization and 1 month after the third immunizations . Forty healthy infants receiving the same routine vaccines but no meningococcal C vaccine were recruited as controls . RESULTS: There were significant increases in meningococcal C polysaccharide-specific IgG antibody concentrations postvaccination compared with prevaccination concentrations in both vaccinated groups (both P < 0.001), but no change in the control group . There were no significant increases in specific IgA postvaccination geometric mean concentrations in either the vaccine or the control groups . The number of IgA positives postvaccination increased slightly in the Wyeth vaccine group vs . controls (P < 0.05) . CONCLUSIONS: Significant salivary IgG antibodies to meningococcal C polysaccharide were observed after parenteral immunization with two meningococcal C conjugate vaccines, whereas there was no significant increase in specific IgA antibody levels for these two vaccines.

Pediatr Infect Dis J, 2002 Mar, 21(3), 182 - 6
Efficacy, immunogenicity and safety of heptavalent pneumococcal conjugate vaccine in low birth weight and preterm infants; Shinefield H et al.; OBJECTIVE: To determine the efficacy, immunogenicity and safety of the heptavalent CRM197 pneumococcal conjugate vaccine (PCV) in low birth weight (LBW) and preterm (PT) infants against invasive pneumococcal disease caused by vaccine types . METHODS: In a randomized double blind trial of 37,868 infants given either PCV or meningococcal type C conjugate vaccine (MCV), 1756 infants <750 g <2500 g (LBW) and 4340 infants from 32 to <38 weeks old (PT) were identified . Risk of invasive pneumococcal disease in LBW and PT infants was compared with risk in normal birth weight (NBW) and full term (FT) infants . Local and systemic events observed within 48 h of recent vaccine were assessed by telephone interviews and similar comparisons made . Premature infant Emergency Department visits and hospitalization were also identified and compared with FT and NBW infants . RESULTS: Initiation of immunization and intervals between doses were similar for all groups . The risk ratio for invasive pneumococcal diseases for LBW infants compared with NBW infants was 2.6 (P = 0.03), and for PT compared with FT infants the risk ratio was 1.6 (P = 0.06) . Vaccine efficacy for both groups was 100% . PCV was as immunogenic in LBW and PT as in NBW and FT infants . Fever and local events after PCV vaccination were similar when adjusted for clustering among multiple doses per child . When stratified for individual doses there was more redness and swelling for LBW infants and more swelling for PT infants after Dose 3 . Isolated local and systemic reactions were more commonly seen with PCV than with MCV, a pattern similar to that in NBW and FT infants . Hospitalization rates were similar for PCV and MCV recipients . CONCLUSION: These data support the use of PCV in LBW infants and PT infants.

Crit Care Med, 2002 May, 30(5 Suppl), S318 - 24
Soluble thrombomodulin, plasma-derived unactivated protein C, and recombinant human activated protein C in sepsis; Dhainaut JF et al.; OBJECTIVE: To review the physiologic and biochemical mechanisms and the rationale for the use of soluble thrombomodulin, plasma-derived protein C, and recombinant human activated protein C in sepsis . DATA SOURCES AND STUDY SELECTION: Research and review articles related to the protein C pathway published in English from 1960 to present . DATA EXTRACTION AND SYNTHESIS: The protein C anticoagulant pathway plays a major role in controlling microvascular coagulation and inflammation . Protein C is the zymogen of the vitamin K-dependent serine protease activated protein C . Protein C is converted to activated protein C when thrombin complexes with thrombomodulin, an endothelial surface transmembrane glycoprotein . Activated protein C inactivates factors Va and VIIIa and effectively limits further thrombin generation . This protein also enhances endogenous fibrinolytic activity and modulates the inflammatory response . A rapid depletion of protein C occurs in sepsis, which contributes to sepsis-induced coagulopathy and correlates with a poor prognosis . The decrease in tissue levels of thrombomodulin in patients with meningococcemia suggests that the ability to convert protein C to activated protein C may also be compromised . The ability of soluble thrombomodulin to block fibrinogen clotting and cell activation, to activate protein C, and to promote thrombin inhibition in different animal models suggests that soluble thrombomodulin could be a useful therapeutic agent in sepsis . However, soluble thrombomodulin is less effective in blocking fibrinogen and platelet activation and in promoting thrombin inhibition than endothelial surface membrane-bound thrombomodulin . Only activated protein C, and not protein C, has clearly shown a reduction in mortality in experimental animal models of sepsis and in humans . CONCLUSIONS: The multipotent pharmacodynamic effects (antithrombotic, profibrinolytic, and anti-inflammatory) of activated protein C may explain why recombinantly derived human activated protein C is the first experimental agent to demonstrate a significant survival benefit in patients with severe sepsis.

Epidemiol Infect, 2002 Apr, 128(2), 157 - 60
Multilocus sequence typing of Neisseria meningitidis directly from cerebrospinal fluid; Kriz P et al.; MLST typing of Neisseria meningitidis directly from clinical material was introduced in the National Reference Laboratory for Meningococcal Infections in Prague . Four cerebrospinal fluid samples were obtained from patients with suspected meningococcal invasive disease . In all samples, all classical laboratory methods gave negative results and the only positive method was PCR, which revealed Neisseria meningitidis group C (two specimens) and group B (two specimens), respectively . MLST performed directly from cerebrospinal fluid revealed that the strains causing the two group C infections were of sequence type (ST) 11, while the two group B infections were characterized as ST-32 and ST-33 respectively . Multi-locus sequence typing of meningococci directly from clinical material offers the opportunity to improve further the surveillance of meningococcal disease and has now been introduced into the routine portfolio of tests employed at the national reference laboratory of the Czech Republic.

Epidemiol Infect, 2002 Apr, 128(2), 149 - 56
Prevalence of moderate penicillin resistant invasive Neisseria meningitidis infection in Scotland, 1994-9; Kyaw MH et al.; We examined the serological characteristics of 774 invasive meningococcal isolates collected through an active laboratory-based surveillance system in Scotland from 1994 to 1999 . Of these, 72-73% of isolates were tested for susceptibility to several antimicrobial agents . Meningococci with high-level resistance to sulphadiazine had a prevalence of 10% and incidence of 0.22 per 100,000 population . High-level resistance to penicillin and other antibiotics was not detected . The prevalence of moderate penicillin resistant meningococci was 8.3% . There was no increase in moderate penicillin resistant meningococcal isolates during the study period, but there were temporal and geographic variations . The estimated incidence of moderate penicillin resistant meningococci was 0.15 per 100,000 population . High and low incidence of moderate penicillin resistant meningococci appeared to correlate with the number of doses of penicillin prescribed in some geographic locations . The majority of moderate penicillin resistant isolates belonged to serogroups B (52.2%) and C (39.2%) . However, the prevalence of moderate penicillin resistance in serogroup W135 was substantially higher (51.7%) than serogroups B (7.8%) and C (7.6%) . Serogroup W135 accounted for a higher proportion of moderate penicillin resistance (8.7%) than disease (1%) . There was no predominant penicillin resistant serotype/subtype within any serogroup . Constant surveillance is necessary to monitor the emergence and spread of resistance and to guide appropriate public health interventions in preventing drug resistant meningococci.

Eur Respir J, 2002 Apr, 19(4), 776 - 9
Inhibition of granulocyte activation by surfactant in a 2-yr-old female with meningococcus-induced ARDS; Tegtmeyer FK et al.; Activated polymorphonuclear neutrophils (PMNs) play a crucial role in acute respiratory distress syndrome (ARDS) via extracellular release of reactive cell products such as elastase . Surfactant has proved valuable in restoring lung function in ARDS . The significance of its immunomodulatory properties with respect to this effect has not yet been clarified . The aim of the present study was to determine the anti-inflammatory effects of surfactant administration in an infant with ARDS . During the acute phase of ARDS in a 2-yr-old female, levels of PMN-derived elastase complexed with alpha1-protease inhibitor (E-alpha1PI) were measured in both arterial and central venous blood samples obtained simultaneously . The results were correlated with oxygen demand and plasma concentrations of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) after endotracheal administration of surfactant (Alveofact 60 mg x kg x body weight(-1)) . In the present case, for the first time, a higher E-alpha1PI concentration was detected in arterial blood (4.51 mg x L(-1)) than in central venous blood (2.28 mg x L(-1)) . After administration of surfactant, these concentrations and the arteriovenous difference decreased, indicating that during ARDS, most PMN degranulation takes place in the pulmonary vascular bed and is inhibited by surfactant administration . Simultaneously, TNF-alpha and IL-6 plasma concentrations decreased within hours and lung function was restored . This local inhibition of polymorphonuclear neutrophil activation by exogenous surfactant may play a key role in the early improvement in lung function after surfactant administration.

Emerg Infect Dis, 2002 May, 8(5), 519 - 21
Outbreak of Neisseria meningitidis, Edmonton, Alberta, Canada; Tyrrell GJ et al.; From December 1999 to April 2001, the greater Edmonton region had 61 cases of invasive meningococcal infection, two fatal . The outbreak was due to Neisseria meningitidis serogroup C, electrophoretic type 15, serotype 2a . Analysis of the strains showed that 50 of 56 culture-confirmed cases were due to a single clone and close relatives of this clone . This strain had not been previously identified in the province of Alberta dating back to January 1997.

J Infect Dis, 2002 May 15, 185(10), 1431 - 8 Epub 2002 Apr 30.
Proinflammatory responses to lipo-oligosaccharide of Neisseria meningitidis immunotype strains in relation to virulence and disease; Braun JM et al.; Inflammatory responses to lipo-oligosaccharide (LOS) contribute to the severity of meningococcal disease . Strains that express the L(3,7,9) LOS immunotypes are isolated from the majority of patients, but other immunotypes are isolated predominantly from carriers . Inflammatory responses elicited from a human monocytic cell line (THP-1) that had been pretreated with vitamin D3 (VD3) were compared after stimulation with purified LOSs from standard immunotype strains . The neutralizing effects of normal human serum and serum from mice immunized with strain B:2a:P1.5,2:L3 were compared . LOSs of immunotypes L3, L7, L8, and L9 induced significantly higher levels of tumor necrosis factor-alpha and interleukin-6, compared with other immunotypes . Normal human serum neutralized the proinflammatory responses to LOSs of all immunotypes tested . Immune mouse serum neutralized inflammatory responses against LOSs from immunotypes with epitopes cross-reactive with L(3,7,9) moieties . Antibodies found in normal human serum and immune mouse serum to the oligosaccharide, core, and lipid A moieties of meningococcal endotoxin contribute to neutralizing activity.

Microbiology, 2002 May, 148(Pt 5), 1467 - 74
Invasion by Neisseria meningitidis varies widely between clones and among nasopharyngeal mucosae derived from adult human hosts; Townsend R et al.; Colonization of the human nasopharynx is a feature of some species of Neisseria, and is a prerequisite of invasive meningococcal disease . The likelihood of colonization by Neisseria meningitidis varies widely between humans, and very few develop invasive disease . Explants of nasal mucosa derived from adult patients with non-allergic nasal obstruction were infected experimentally with Neisseria spp . At intervals over 18 h incubation, washed explants were homogenized, and viable bacteria were counted . To estimate bacterial invasion of mucosa, explants were exposed to 0.25% sodium taurocholate for 30 s prior to homogenization . N . meningitidis was recovered from the mucosa and the organism invaded and replicated within the tissue, in contrast to N . lactamica and N . animalis (n=9, P<0.008) . N . meningitidis isolates of clones ET-5, ET-37 and lineage III were recovered from and invaded tissue, but strains of clones A4, A:subgroup I, A:subgroup III and A:subgroup IV-1 did not invade (n=6) . To measure host variation, survival of N . meningitidis within nasal mucosa of 40 different human donors was measured . Intra-class correlation of replicates was 0.97, but the coefficient of variation of recovered viable counts was 1335% after 4 h and 77% after 18 h incubation . It is concluded that the distinctive colonization and disease potential of Neisseria spp . may be partly a consequence of their ability to invade and survive within human nasopharyngeal mucosa, but that this is influenced greatly by genetic or environmental factors operating on the host mucosa . This is consistent with the unpredictable epidemiology of meningococcal disease.

Lancet, 2002 Apr 27, 359(9316), 1499 - 508
Development of vaccines against meningococcal disease; Jodar L et al.; Neisseria meningitidis is a major cause of bacterial meningitis and sepsis . Polysaccharide-protein conjugate vaccines for prevention of group C disease have been licensed in Europe . Such vaccines for prevention of disease caused by groups A (which is associated with the greatest disease burden worldwide), Y, and W135 are being developed . However, conventional approaches to develop a vaccine for group B strains, which are responsible for most cases in Europe and the USA, have been largely unsuccessful . Capsular polysaccharide-based vaccines can elicit autoantibodies to host polysialic acid, whereas the ability of most non-capsular antigens to elicit broad-based immunity is limited by their antigenic diversity . Many new membrane proteins have been discovered during analyses of genomic sequencing data . These antigens are highly conserved and, in mice, elicit serum bactericidal antibodies, which are the serological hallmark of protective immunity in man . Therefore, there are many promising new vaccine candidates, and improved prospects for development of a broadly protective vaccine for group B disease, and for control of all meningococcal disease.

Prescrire Int, 2002 Apr, 11(58), 35 - 8
Meningococcal vaccine against serogroups A, C, Y and W-135: new preparation . Encouraging immunogenicity studies; Assignment of additional anticapsular antibody concentrations to the Neisseria meningitidis group A et al.; Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA . celie@cdc.gov

We assigned additional enzyme-linked immunosorbent assay antibody concentrations (immunoglobulin G {IgG}, IgM, and IgA, and total) to the Neisseria meningitidis standard reference serum CDC1992 for groups Y and W-135 to 12 Centers for Disease Control and Prevention quality control sera . These assignments will supplement previous assignments and will aid in the evaluation of present and developing vaccines.

Mol Microbiol, 2002 Jan, 43(2), 335 - 54
Interactions of haemoglobin with the Neisseria meningitidis receptor HpuAB: the role of TonB and an intact proton motive force; Rohde KH et al.; We have characterized the interaction of the Neisseria meningitidis TonB-dependent receptor HpuAB with haemoglobin (Hb) . Protease accessibility assays indicated that HpuA and HpuB are surface exposed, HpuB interacts physically with HpuA, and TonB energization affects the conformation of HpuAB . Binding assays using {125I}-Hb revealed that the bipartite receptor has a single binding site for Hb (Kd 150 nM) . Competitive binding assays using heterologous Hbs revealed that HpuAB Hb recognition was not species specific . The binding kinetics of Hb to HpuAB were dramatically altered in a TonB- mutant and in wild-type meningococci treated with the protonophore carbonylcyanide m-chlorophenylhydrazone (CCCP), indicating that TonB and an intact proton motive force are required for normal Hb binding and release from HpuAB . Our results support a model in which both HpuA and HpuB are required to form a receptor complex in the outer membrane with a single binding site, whose structure and ligand interactions are significantly affected by the TonB-mediated energy state of the receptor.

Clin Infect Dis, 2002 May 15, 34(10), 1323 - 30 Epub 2002 Apr 17.
Influence of serogroup on the presentation, course, and outcome of invasive meningococcal disease in children in the Republic of Ireland, 1995-2000; Healy CM et al.; To test the hypothesis that the infecting meningococcal serogroup modulates the presentation, course, and outcome of invasive meningococcal disease (IMD), we performed a retrospective review of cases of IMD in 407 children from 2 tertiary referral centers and 2 regional centers in Ireland . Patients infected with serogroup C meningococci (n=104) were older than those infected with serogroup B (n=303; median, 2.5 vs . 1.5 years; P=.04); all other demographic and clinical parameters were similar for the 2 groups . Among serogroup B patients, mortality was 3.6% and morbidity was 10%; for serogroup C patients, mortality was 4.8% and morbidity was 12.5% (P=.81 and P=.76, respectively) . Serogroup C-associated sequelae more often were multiple (P=.003) . Despite the introduction of serogroup C conjugate vaccine into the routine immunization schedule of some countries, ongoing morbidity from IMD is anticipated, because group B disease was very similar to group C disease in this pediatric population.

J Clin Microbiol, 2002 May, 40(5), 1834 - 7
Invasive meningococcal disease in Scotland, 1994 to 1999, with emphasis on group B meningococcal disease; Kyaw MH et al.; A review was carried out on 774 invasive meningococcal isolates reported to the active meningococcal surveillance system in Scotland from 1994 to 1999 . This showed that serogroups B (51.7%) and C (39.2%) caused the majority of disease . The six common PorB proteins (4, 1, 15, 2B, 12, and 21) and PorA proteins (serosubtypes) (P1.4, P1.15, P1.9, P1.14, P1.7, and P1.16) accounted for 50 and 51% of all group B isolates, respectively, during the study period.

Braz J Infect Dis, 2001 Dec, 5(6), 324 - 31 Epub 2003 Feb 21.
Effectiveness of a mass immunization campaign against serogroup C meningococci in children in the federal state of Santa Catarina, Brazil; Kupek E et al.; In addition to vaccine efficacy studies, there is a pressing need to evaluate vaccine effectiveness in a way that takes into account the limitations of health care systems in certain settings . An attempt to reach this objective was exemplified by a vaccination campaign against serogroup C meningococci in the federal state of Santa Catarina, in Brazil . A polysaccharide vaccine against serogroup C meningococci was administered to all individuals between 6 months and 14 years of age in March, 1996, in the municipalities that had the highest incidence of meningococcal disease in the previous year . All cases of the disease due to this serogroup observed in Santa Catarina during a 1-year period before and after the vaccination were included in the analysis . The cumulative incidence rate ratio was calculated for the unvaccinated compared to the vaccinated area . As a second step, the ratio of this quantity for the period before and after the vaccination, i.e . the ratio of the rate ratios (RRR), was calculated . One minus RRR was used to estimate the vaccine effectiveness . In the general population, the vaccine effectiveness was 74.3% (95% confidence intervals 52.7% to 99.6%) . In children 6 months to 14 years, vaccine effectiveness was 93.1% (85.2% to 100%) . Vaccine effectiveness could not be confirmed within more specific age bands, probably due to the lack of statistical power . It is concluded that group C meningococcal vaccine is effective in reducing the occurrence of meningococcal disease in children 6 months to 14 years of age, and that the ratio of rate ratios (RRR) in a useful method to evaluate vaccine effectiveness.

World Health Organ Tech Rep Ser, 2002, 904, i - vi, 1-107
WHO Expert Committee on Biological Standardization; Meningococcal infection; Scottish Centre for Infection and Environmental Health (SCIEH), GlasgowMeningococcal disease is an important medical emergency demanding early diagnosis and prompt treatment . This article provides an overview of meningococcal infection and discusses mode of transmission, risk factors, prevention of spread, vaccination and current recommendations for treatment.

Biochem J, 2002 Jun 15, 364(Pt 3), 613 - 6
Expression and purification of functional recombinant meningococcal transferrin-binding protein A; Oakhill JS et al.; Pathogenic bacteria of the genus Neisseria have a siderophore-independent iron-uptake system reliant on a direct interaction between the bacterial cell and human transferrin (hTf), a serum protein . In the meningococcus, this uptake system is dependent on two surface-exposed, transferrin-binding proteins (Tbps), TbpA and TbpB . TbpA is highly conserved among meningococcal strains, and is thought to be a porin-like integral protein that functions as a gated channel for the passage of iron into the periplasm . TbpB is more variable in size, lipidated and fully surface-exposed . Given its location on the cell surface, its role in pathogenicity and interstrain sequence conservation, TbpA is currently being regarded for inclusion in a meningococcal vaccine effective against all serogroups . This requires gaining knowledge of the ligand-receptor interactions . In the present study we have optimized a procedure for obtaining purified, functionally active recombinant TbpA at a level and stability necessary for the initiation of such studies.

J Infect, 2002 Jan, 44(1), 17 - 21
Myositis in children with meningococcal disease: a role for tumour necrosis factor-alpha and interleukin-8?
Carrol ED, Thomson AP, Mobbs KJ, Fraser WD, Sills JA, Hart CA.
OBJECTIVES: Myalgia is under-recognized in meningococcal disease (MCD) . In septic shock, myositis is thought to be mediated by pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8) and interleukin-6 (IL-6) but this has never previously been studied in MCD . We aimed to demonstrate whether muscle damage mediated via TNF-alpha and other pro-inflammatory cytokines occurs in MCD, as estimated by creatine kinase skeletal muscle isoenzyme (CK-MM) and cardiac isoenzyme (CK-MB) concentrations . METHODS: A total of 68 children, median age 2.7 years, with a diagnosis of MCD were prospectively studied . Severity of disease was measured using the Glasgow Meningococcal Septicaemia Prognostic Score (GMSPS) . Severe disease was defined as a GMSPS of > or =8 . TNF-alpha, IL-8, IL-6 and IL-1Ra concentrations were determined on samples taken on admission . RESULTS: CK-MM correlated significantly with TNF-alpha, IL-8 and GMSPS . There was no significant correlation between CK-MB and TNF-alpha or IL-6, but CK-MB correlated with GMSPS and IL-8 . Fifty-six percent of children with MCD had evidence of muscle damage as manifested by elevated CK-MM . CONCLUSIONS: TNF-alpha and IL-8 may be potential mediators in the pathophysiology of skeletal muscle damage in MCD .

Nurs Stand . 2000 Nov 8-14;15(8):33.
Meningococcal C conjugate vaccines: UK campaign; Improving the outcome of septic shock in children; aDepartment of Pediatrics,Wilford Hall Medical Center, Lackland AFB, Texas, USA and bDepartment of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USASepsis is an important cause of pediatric morbidity and mortality . Improving the outcome of pediatric sepsis requires diverse efforts, including prevention, early recognition, improvements in early management and transport, and physiology-directed care . Awareness that septic shock represents a pathophysiologic host response to infection has prompted investigation of immune mediators and coagulation factors as potential targets for anti-sepsis therapies . Advancements thus far include: the potential prevention of neonatal sepsis with granulocyte colony-stimulating factor; recognition of clindamycin as a potential inhibitor of endotoxin release; improved outcome from meningococcal disease in children treated with bactericidal/permeability-increasing protein (rBPI21); and improved outcome from sepsis in premature infants treated with pentoxifylline . Further randomized controlled studies of immunomodulatory agents are indicated and a few are in progress . Current studies on genetic propensities in cytokine and coagulation protein expression may explain variability in patient outcomes and eventually lead to genomics-based therapeutics.

Expert Rev Mol Diagn, 2002 Mar, 2(2), 143 - 50
Molecular detection and characterization of Neisseria meningitidis; Taha MK; Immediate management of meningococcal infections is a medical emergency that requires rapid identification and typing of bacterial strains . Isolation of Neisseria meningitidis is hindered by early antibiotic treatment . Molecular (nonculture) methods of diagnosis and characterization of N . meningitidis permit to overcome this failure . This bacterium is highly variable due to frequent horizontal DNA exchange between strains . Molecular approaches of typing allow a reliable tracking of meningococcal strains and a powerful epidemiological analysis.

J Biol Chem, 2002 Jul 5, 277(27), 24103 - 13 Epub 2002 Apr 15.
KpsF is the arabinose-5-phosphate isomerase required for 3-deoxy-D-manno-octulosonic acid biosynthesis and for both lipooligosaccharide assembly and capsular polysaccharide expression in Neisseria meningitidis; Tzeng YL et al.; We have identified and defined the function of kpsF of Neisseria meningitidis and the homologues of kpsF in encapsulated K1 and K5 Escherichia coli . KpsF was shown to be the arabinose-5-phosphate isomerase, an enzyme not previously identified in prokaryotes, that mediates the interconversion of ribulose 5-phosphate and arabinose 5-phosphate . KpsF is required for 3-deoxy-d-manno-octulosonic acid (Kdo) biosynthesis in N . meningitidis . Mutation of kpsF or the gene encoding the CMP-Kdo synthetase (kpsU/kdsB) in N . meningitidis resulted in expression of a lipooligosaccharide (LOS) structure that contained only lipid A and reduced capsule expression in the five invasive disease-associated meningococcal serogroups (A, B, C, Y, and W-135) . The step linking meningococcal capsule and LOS biosynthesis was shown to be Kdo production as the expression of capsule was wild type in a Kdo transferase (kdtA) mutant . Thus, in addition to lipooligosaccharide assembly, Kdo is required for meningococcal capsular polysaccharide expression . Furthermore, N . meningitidis, unlike enteric Gram-negative bacteria, can survive and synthesize only unglycosylated lipid A.

Am J Respir Crit Care Med, 2002 Apr 15, 165(8), 1103 - 6
Severity of meningococcal disease in children and the angiotensin-converting enzyme insertion/deletion polymorphism; Harding D et al.; Critical illness outcome may be causally related to inflammatory response severity . Given that tissue angiotensin-converting-enzyme (ACE) regulates such responses and that the deletion (D) {rather than insertion (I)} variant of the ACE gene is associated with higher tissue ACE levels, DD genotype might be associated with a poorer outcome in a uniform infectious disease state . Illness severity (Pediatric RIsk of Mortality score, the Glasgow Meningococcal Septicaemia Prognostic Score {GMSPS}, and clinical course) was recorded for consecutive white patients with meningococcal disease (n = 110, 34 DD genotype, 61 male, aged 49.4 +/- 5.4 months) referred to the Royal Liverpool Children's Hospital, UK . Compared with children with > or = I allele, DD genotype was associated with 14% higher predicted risk of mortality (p = 0.038), higher GMSPS (DD 9.4 +/- 0.5, ID/II 7.7+/- 0.4 {mean +/- SEM}, p = 0.013), greater prevalence of inotropic support (76% versus 55%, p = 0.03) and ventilation (82% versus 63%, p = 0.04), and longer Pediatric Intensive Care Unit (PICU) stay (5.8 versus 3.9, p = 0.02) . DD genotype frequency was 6% (1 case) for the 18 children who did not require PICU care, 33% for the 84 PICU survivors, and 45% for those who died (p = 0.01) . ACE DD is associated with increased illness severity in meningococcal disease.

Infect Immun, 2002 May, 70(5), 2454 - 62
Lipooligosaccharide and polysaccharide capsule: virulence factors of Neisseria meningitidis that determine meningococcal interaction with human dendritic cells; Unkmeir A et al.; In this work we analyzed the roles of meningococcal lipooligosaccharide (LOS) and capsule expression in the interaction of Neisseria meningitidis with human dendritic cells (DC) . Infection of DC with serogroup B wild-type meningococci induced a strong burst of the proinflammatory cytokines and chemokines tumor necrosis factor alpha, interleukin-6 (IL-6), and IL-8 . In contrast, a serogroup B mutant strain lacking LOS expression barely led to cytokine induction, demonstrating that meningococcal LOS is the main mediator of the proinflammatory response in human DC . Sialylation of meningococcal LOS did not influence cytokine secretion by DC . However, we found the phagocytosis of N . meningitidis by human DC to be inhibited by LOS sialylation . In addition, the expression of the meningococcal serogroup A, B, and C capsules dramatically reduced DC adherence of N . meningitidis and phagocytosis to some extent . Hence, LOS sialylation and capsule expression are independent mechanisms protecting N . meningitidis from the phagocytic activity of human DC.

J Travel Med, 2002 Jan-Feb, 9(1), 20 - 3
Crossover vaccination with quadrivalent meningococcal vaccine (against A/C/Y/W-135) following recent application of bivalent meningococcal vaccine (against A/C): assessment of safety and side effect profile; Wilder-Smith A et al.; BACKGROUND: Until May 2000, bivalent A/C meningococcal vaccine was the only available vaccine in Singapore for hajj travelers to Saudi Arabia . Recent worldwide reports of serogroup W-135 meningococcal meningitis associated with hajj returnees necessitated switching to quadrivalent A/C/Y/W-135 vaccine and crossover vaccination of travelers to Saudi Arabia . No safety data are available for quadrivalent vaccine following recent vaccination with bivalent vaccine . We assessed the safety and side effect profile of bivalent, quadrivalent, and quadrivalent meningococcal vaccine after recent vaccination with bivalent vaccine . METHODS: A postvaccination telephone questionnaire survey was performed for all travelers who received either bivalent (B), quadrivalent (Q), or quadrivalent with recent (as defined by less than 6 months before) bivalent meningococcal vaccine (BQ) between 22 May and 8 June 2000 in preparation for the umrah (minor pilgrimage) . Patients were asked about local reactions (pain, erythema, swelling at injection site graded in mild, moderate, and severe) and systemic reactions (fever, headache, graded in mild and severe) . RESULTS: Of 546 persons vaccinated, 323 were interviewed . Median time interval between interview and vaccination was 10 days . Of those interviewed, 64 patients received bivalent (B), 213 quadrivalent (Q), and 46 quadrivalent after recent bivalent vaccine (BQ) . The median interval time between previous bivalent and quadrivalent vaccine was 5 weeks . There was no statistically significant difference in the prevalence of side effects between the three groups . Mild pain at injection site was recorded in B as 21.8%, Q as 23%, BQ as 21.7%; low grade fever in B as 7.8%, Q as 9.8%, and BQ as 15.2% . CONCLUSIONS: Bivalent and quadrivalent meningococcal vaccine are well tolerated . Crossover vaccination of quadrivalent meningococcal vaccine after recent vaccination with bivalent vaccine does not increase the prevalence of adverse reactions and is therefore safe.

Mol Microbiol, 2002 Mar, 43(6), 1555 - 64
Down-regulation of pili and capsule of Neisseria meningitidis upon contact with epithelial cells is mediated by CrgA regulatory protein; Deghmane AE et al.; The initial attachment of Neisseria meningitidis to the target cell surface appears to be largely pilus depend-ent in capsulated bacteria . Intimate adhesion subsequently occurs to permit colonization . We recently reported that insertional inactivation of the crgA gene, which encodes a transcriptional regulator belonging to the LysR family, decreased meningococcal adhesion to epithelial cells and abolished intimate adhesion . In this report, we analyse expression of the pilE and sia genes, which are involved in the biosynthesis of pili and capsule respectively, during bacteria-host cell interactions . Western blotting, transcriptional fusion and reverse transcriptase polymerase chain reaction (RT-PCR) analysis showed that the expression of these genes was downregulated during intimate adhesion . DNA-binding assays, footprinting and RT-PCR analysis indicated that this downregulation was directly mediated by the CrgA protein . The pilE and sia promoters were found to have a CrgA binding motif in common . These results strongly suggest that N . meningitidis displays an adaptive response upon cell contact . CrgA may play a central regulatory role in meningococcal adhesion, particularly in switching from initial to intimate adhesion by downregulating the bacterial surface structures that hinder this adhesion.

Commun Dis Intell, 2002, 26(1), 44 - 50
Epidemiology of invasive meningococcal disease in north Queensland, 1995 to 1999; Harley D et al.; This study describes all episodes of invasive meningococcal disease (n=120) acquired in north Queensland over the 5 year period 1995 to 1999 . Indigenous people had a 3-fold greater risk than others of acquiring invasive meningococcal disease . There were 7 deaths, six in non-indigenous people . The majority (72.4%) of identified isolates were serogroup B . We found no evidence of significant resistance to the antibiotics recommended for treatment or chemoprophylaxis . Two outbreaks of disease were identified, one serogroup B and one serogroup C . Compared to the previous 5 years (1990 to 1994) there were far fewer cases of serogroup C disease and a lower incidence and risk of invasive meningococcal disease among indigenous people.

J Bacteriol, 2002 May, 184(9), 2546 - 51
Analysis of the heat shock response of Neisseria meningitidis with cDNA- and oligonucleotide-based DNA microarrays; Guckenberger M et al.; Oligonucleotide- and cDNA-based microarrays comprising a subset of Neisseria meningitidis genes were assessed for study of the meningococcal heat shock response and found to be highly suitable for transcriptional profiling of N . meningitidis . Employing oligonucleotide arrays encompassing the entire genome of N . meningitidis, we analyzed the meningococcal heat shock response on a global scale and identified 55 heat shock-deregulated open reading frames (34 induced and 21 repressed).

J Bacteriol, 2002 May, 184(9), 2379 - 88
Endotoxin of Neisseria meningitidis composed only of intact lipid A: inactivation of the meningococcal 3-deoxy-D-manno-octulosonic acid transferase; Tzeng YL et al.; Lipopolysaccharide, lipooligosaccharide (LOS), or endotoxin is important in bacterial survival and the pathogenesis of gram-negative bacteria . A necessary step in endotoxin biosynthesis is 3-deoxy-D-manno-octulosonic acid (Kdo) glycosylation of lipid A, catalyzed by the Kdo transferase KdtA (WaaA) . In enteric gram-negative bacteria, this step is essential for survival . A nonpolar kdtA::aphA-3 mutation was created in Neisseria meningitidis via allelic exchange, and the mutant was viable . Detailed structural analysis demonstrated that the endotoxin of the kdtA::aphA-3 mutant was composed of fully acylated lipid A with variable phosphorylation but without Kdo glycosylation . In contrast to what happens in other gram-negative bacteria, tetra-acylated lipid IV(A) did not accumulate . The LOS structure of the kdtA::aphA-3 mutant was restored to the wild-type structure by complementation with kdtA from N . meningitidis or Escherichia coli . The expression of a fully acylated, unglycosylated lipid A indicates that lipid A biosynthesis in N . meningitidis can proceed without the addition of Kdo and that KdtA is not essential for survival of the meningococcus.

Crit Care, 2002 Feb, 6(1), 60 - 5 Epub 2001 Nov 26.
Bench-to-bedside review: genetic influences on meningococcal disease; Vermont CL et al.; This review discusses the possible involvement of a variety of genetic polymorphisms on the course of meningococcal disease . It has been shown that several common genetic polymorphisms can either influence the susceptibility to meningococcal disease or can account for a higher mortality rate in patients . Gene polymorphisms concerning antibody receptors, lipopolysaccharide (LPS) binding receptors or proteins, innate complement proteins as well as cytokines and hemostatic proteins are described . The study of genetic polymorphisms might provide important insights in the pathogenesis of meningococcal disease and could make it possible to identify individuals who are at risk of either contracting or dying from meningococcal disease.

Wei Sheng Yan Jiu, 1999 Mar 30, 28(2), 79 - 80
{Study on the risk factors influencing the epidemicity of epidemic cerebrospinal meningitis}; Jin X et al.; Based on a 8-year surveillance data, a factor analysis theory was used to analyze the 12 risk factors influencing the epidemicity of epidemic cerebrospinal meningitis . The results showed that the first sixth risk factors were the rate of carrying meningococci A and B in the population, relative air humidity in January, morbidity rate in January, vaccination rate before epidemic, and the titre of antibody . Although the incidences of epidemic cerebrospinal meningitis are scattered, the risk factors influencing the epidemicity did not disappear . It is important to use meningococci A vaccine continuously and widely to strengthen the surveillance among migrated population and population at high risk.

Saudi Med J, 2002 Mar, 23(3), 259 - 64
Meningococcal disease; Memish ZA et al.; Meningococcal disease occurs as both endemic and epidemic disease in most parts of the world with significant morbidity and mortality . Among the different serogroups of Neisseria meningitidis, serogroups A, B, C account for 90% of the disease . In the last few years there has been a change in the epidemiology of the disease with an increase in the prevalence of serogroup C in Europe and North America, serogroup Y in the United States of America and Sweden, and W135 in the Kingdom of Saudi Arabia . The emergence of Neisseria meningitidis serogroup W135 in the Kingdom of Saudi Arabia has lead to 2 major outbreaks mainly among Pilgrims during the Hajj season of 2000 and 2001 . This has lead the health officials in the Kingdom of Saudi Arabia to change their vaccine requirements for the Umra and Hajj to include the quadrivalent meningococcal vaccine (A, C, Y, W135) instead of the bivalent one (A, C) . Despite all the advances in prevention, diagnosis and treatment, the disease continues to have high mortality (5-10%) . Prompt empirical treatment for suspected cases should include penicillin or a 3rd generation cephalosporin . A new conjugate vaccine against Neisseria meningitidis serogroup C has been recently licensed, while quadrivalent conjugate vaccine against serogroup A, C, Y and W135 is in early development . Meanwhile targeted vaccination with the available vaccines according to the epidemiology of the disease and rapid chemoprophylaxis for the close contacts of active cases are the most effective preventive strategies.

BMJ . 2002 Apr 6;324(7341):809.
Modelling cost effectiveness of meningococcal serogroup C conjugate vaccination campaign in England and Wales; Trotter CL et al.; OBJECTIVES: To assess the cost effectiveness of a meningococcal serogroup C conjugate vaccination campaign in 0-17 year olds . DESIGN: Cost effectiveness analysis from the perspective of the healthcare provider . Setting: England and Wales . MAIN OUTCOME MEASURE: Cost per life year saved . RESULTS: In 1998-9, immediately before the introduction of meningococcal C vaccination, the burden of serogroup C disease was considerable, with an estimated 1137 cases in people aged 0-17 years and at least 72 deaths . The vaccination campaign is estimated to have cost between 126m pound sterling ($180m, 207m) and 241 pound sterling 3m, 395m), depending on the price of the vaccine . Under base case assumptions the cost per life year saved from the vaccination campaign is estimated to be 6259 pound sterling . School based vaccination was more cost effective than general practice based vaccination because of lower delivery costs . Immunisation of infants aged under 1 year was the least cost effective component of the campaign because, although this maximises the life years gained, the three dose schedule required is more expensive than other methods of delivery . Estimates of the cost per life year saved were sensitive to assumptions on the future incidence of disease and the case fatality ratio . CONCLUSIONS: Meningococcal C vaccination is likely to be more cost effective in all age groups when the incidence of disease is high . It is also more cost effective when given to children aged 1-4 (by general practitioners) and to children and young people aged 5-17 years at school than when administered to infants under 12 months of age or young people aged 16-17 years who are not at school.

Mol Microbiol, 2002 Feb, 43(4), 931 - 43
Identification of a gene (lpt-3) required for the addition of phosphoethanolamine to the lipopolysaccharide inner core of Neisseria meningitidis and its role in mediating susceptibility to bactericidal killing and opsonophagocytosis; Mackinnon FG et al.; We have identified a gene, lpt-3, that is required for the addition of phosphoethanolamine to the 3-position (PEtn-3) on the beta-chain heptose (HepII) of the inner core lipopolysaccharide (LPS) of Neisseria meningitidis (Nm) . The presence of this PEtn-3 substituent is characteristic of the LPS of a majority ( approximately 70%) of hypervirulent Nm strains, irrespective of capsular serogroup, and is required for the binding of a previously described monoclonal antibody (mAb B5) to a surface-accessible epitope . All strains of Nm that have PEtn-3 possess the lpt-3 gene . In some lpt-3-containing strains, the 3-position on HepII is preferentially substituted by glucose instead of PEtn, the result of lgtG phase variation mediated by slippage of a homopolymeric tract of cytidines . Inactivation of lpt-3 resulted in loss of PEtn-3, lack of reactivity with mAb B5 and conferred relative resistance to bactericidal killing and opsonophagocytosis by mAb B5 in vitro . Thus, the identification of lpt-3 has facilitated rigorous genetic, structural and immunobiological definition of an immunodominant epitope that is a candidate immunogen for inclusion in an LPS-based vaccine to protect against invasive meningococcal disease.

Emerg Infect Dis, 2002 Mar, 8(3), 332 - 4
Hajj-related Neisseria meningitidis serogroup w135 in Mauritius; Issack MI et al.; Meningococcal disease is rare in Mauritius; only one case was reported from 1992 to 1999 . However, since June 2000, four cases have occurred . Epidemiologic information and typing results indicate that these recent cases probably followed the introduction of Neisseria meningitidis W135 in Mauritius by pilgrims returning from the Hajj in 2000 and 2001.

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