Diss. (sammanfattning) Linköping : Univ., 2002. / Härtill 6 uppsatser.

No description available.

Thesis (PhD)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Tuberculous meningitis (TBM) continues to be an important cause of mortality and neurological disability in resource-limited countries. Many questions remain about the best approaches to prevent, diagnose, and treat TBM, and there are still too fewanswers. The aim of this dissertation was to challenge current management strategies in childhood TBM. Accurate prediction of outcome in TBM is of critical importance when assessing the efficacy of different interventions. I conducted a retrospective cohort study of 554 children with TBM less than 13 years of age admitted to Tygerberg Children’s Hospital over a 20 year period (1985-2005) and reclassified all patients according to the criteria of all the currently available staging systems in childhood TBM (chapter 4). In this study, I found that the “Refined Medical Research Council (MRC) staging system after 1 week” had the highest predictive value of all TBM staging systems. It is created by subdivision of stage 2 (2a and 2b) of the existing MRC staging system. Additionally, I proposed and validated a simplified TBM staging system which is less dependent on clinical ability and neurological expertise than current staging systems. The simplified staging system was termed the “Tygerberg Children’s Hospital Scale” (TCH) and relies solely on the patient’s ability to visually fixate and follow and the motor response to pain on both sides. It demonstrated excellent predictive power of outcome after 1 week and did not differ significantly from the “Refined MRC staging system” in this regard. The optimal anti-TB drug regimen and duration of treatment for TBM is unknown. It has been suggested that intensive short-course (6 months) anti-TB therapy may be sufficient and safe. I conducted a prospective descriptive study of 184 consecutively treated children with TBM and found that short-course intensified anti-TB therapy aimed at treating TBM patients (anti-TBM therapy) is sufficient and safe in both HIV-uninfected and HIVinfected children with drug susceptible TBM (chapter 5). The overall study mortality of 3.8% at completion of treatment compares favourably with the median mortality rate of 33% (range 5-65%) reported in a recent review describing outcome in TBM treatmentstudies. TB-immune reconstitution inflammatory syndrome (IRIS) is a potentially life-threatening complication in HIV-infected children with TB of the central nervous system. Little is known about the incidence, case fatality, underlying immunopathology and treatment approaches in HIV-infected children with neurological TB-IRIS. In a case series, I found that neurological TB-IRIS should be considered when new neurological signs develop after initiation of antiretroviral therapy (ART) in children with TBM (chapter 6.1). Manifestations of neurological TB-IRIS include headache, seizures, meningeal irritation, a decreased level of consciousness, ataxia and focal motor deficit. I also discussed the rational for using certain treatment modalities, includingthalidomide. Neurological tuberculous mass lesions (tuberculomas and pseudo-abscesses) may develop or enlarge in children on anti-TBM treatment. These lesions respond poorly to therapy, and may require surgical excision, but may be responsive to thalidomide, a potent inhibitor of tumour necrosis factor-alpha (TNF-alpha). The optimal dose and duration of thalidomide therapy and the correlation with magnetic resonance imaging (MRI) is yet to be explored. The primary objective of our next study was to investigate whether serial MRI is useful in evaluating treatment response and duration of thalidomide therapy (chapter 6.2). A secondary objective was to determine the value of thalidomide in the treatment of these lesions. In a prospective observational study over three years, serial MRI was performed in 16 consecutive children compromised by TB pseudo-abscesses who were treated with thalidomide. The rapid clinical response of most patients suggests that thalidomide provides substantial clinical benefit in this clinical context. I also identified a MRI marker of cure that is evolution of lesions from early stage “T2 bright” with edema to “T2 black.” This finding could be useful in the future management of these patients. Transcranial Doppler imaging (TCDI) is potentially a valuable investigational tool in children with TBM, a condition often complicated by pathology relevant to Doppler imaging such as raised intracranial pressure (ICP) and cerebral vasculopathies. Serial TCDI was performed on 20 TBM children with the aim of investigating cerebral haemodynamics and the relationship between pulsatility index (PI) and ICP (chapter 6.3). In this study, I found that TCDI-derived pulsatility index (PI) is not a reliable indicator of raised ICP in children with tuberculous hydrocephalus which I attributed this to individual variation of tuberculous vascular disease, possibly compromising cerebral vascular compliance and resistance. The study did confirm the efficacy of medical therapy in children with tuberculous communicating hydrocephalus. In all cases, the ICP normalized within 7 days after initiation of acetazolamide and furosemide. In the same cohort of children with TBM I also measured cerebral blood flow velocities (BFV) in the anterior cerebral artery (ACA), middle cerebral artery (MCA) and posterior cerebral artery (PCA) on admission and after day 3 and 7. I found persistent high BFV in all the basal cerebral arteries suggesting stenosis due to vasculitis rather than functional vasospasm. Additionally, I found that complete MCA occlusion, subnormal mean MCA velocities (less than 40 cm/s) and a reduced PI (less than 0.4) correlated with radiological proven large cerebral infarcts. No side-to-side differences in MCA BFV or subnormal PI’s were detected in four TBM children with territory infarcts on admission. I attributed this to the occlusion of a limited number (one or two) of the 9 MCA perforators which has been shown not to affect the hemodynamics of the MCA. I concluded by highlighting the many questions that remain about the best approaches to prevent, diagnose, and treat TBM (chapter 2). In a second literature review, aimed at clinicians working in resource-limited countries, I describe novel approaches to the management of childhood TBM, including a treatment algorithm for tuberculous hydrocephalus, the role for short-course intensified anti-TBM treatment and home-based anti-TBM treatment (chapter 3). Even with the best diagnostic and treatment modalities, outcome in childhood TBM will remain poor if diagnosis is delayed. Our efforts should be on increased awareness and earlier diagnosis. / AFRIKAANSE OPSOMMING: Tuberkuleuse meningitis (TBM) bly ‘n belangrike oorsaak van mortaliteit en neurologiese ongeskiktheid in lande met beperkte hulpbronne. Baie vrae oor die beste benaderings tot voorkoming, diagnose en behandeling van TBM bly bestaan en daar is steeds te min antwoorde. Die doel van die verhandeling was om huidige behandelingstrategieë van tuberkuleuse meningitis (TBM) in kinders uit te daag. Akkurate voorspelling oor die uitkoms van TBM is van kritieke belang wanneer doeltreffendheid van verskillende ingrypings beoordeel word. Ek het ‘n retrospektiewe kohort studie van 554 kinders jonger as 13 jaar met TBM wat in Tygerberg Kinderhospitaal toegelaat is oor `n tydperk van twintig jaar (1985 tot 2005) uitgevoer en al die pasiënte volgens die kriteria van al die huidig beskikbare stadiëringsisteme vir kinder TBM geherklassifiseer (hoofstuk 4). Die waarde van die verskillende stadiëringsisteme in die voorspelling van neurologiese uitkoms is toe bepaal. In hierdie studie het ek bevind dat die “Verfynde Mediese Navorsings Raad (MNR) stadiëringsisteem na 1 week” die TBM stadiëringsisteem met die hoogste voorspellende waarde was om neurolgiese uitkoms te voorspel. Dit is geskep deur onderverdeling van stadium 2 (2a en 2b) van die bestaande gemodifiseerde MNR stadiëringsisteem. Daarbenewens het ek ’n vereenvoudigde stadiëringsisteem vir TBM wat minder afhanklik van kliniese vermoëns en neurologiese kundigheid sal wees as die bestaande stadiëringsisteme daargestel en getoets. Die vereenvoudigde stadiëringsisteem is die “Tygerberg Kinderhospitaal Skaal (TKH)” genoem en dit is slegs gebaseer op `n pasiënt se vermoë om visueel te fikseer en te volg en die motoriese respons tot pyn aan beide kante van die ligaam. Dit het uitstekende voorspellingswaarde gehad vir uitkoms na die eerste week van siekte en het in hierdie verband nie betekenisvol verskil van die “Verfynde MNR stadiëringsisteem” nie. Die optimale anti-TB middel regimen en duurte van behandeling vir TBM is onbekend. Sommige kenners stel voor dat ‘n intensiewe kort-kursus (6 maande) van anti-TB behandeling veilig en voldoende mag wees. Ek het ‘n prospektiewe beskrywende studie op 184 opeenvolgende kinders met TBM uitgevoer en bevind dat intensiewe kort-kursus anti-TB behandeling gemik op die behandeling van kinders met TBM (anti-TBM behandeling) in beide menslike immuniteitgebrekvirus (MIV)-ongeïnfekteerde en MIV-geïnfekteerde kinders met middel-gevoelige TBM voldoende en veilig was (hoofstuk 5 ). Die mortaliteit in my studie met voltooing van behandeling vergelyk gunstig met die mediane mortaliteit van 33% (reikwydte 5-65%) wat onlangs in ‘n oorsig van uitkoms in TBM gerapporteer is. TB immuun rekonstitusie inflammatoriese sindrome (IRIS) is ‘n potensieël lewensbedreigende komplikasie in MIV-geïnfekteerde kinders met TB van die sentrale senuwee sisteem (SSS). Min is oor die voorkoms, mortaliteit, onderliggende immunopatologie en behandelingsbenaderings in MIV-geïnfekteerde kinders met neurologiese TB-IRIS bekend. In `n gevalle-reeks het ek gevind dat neurologiese TB-IRIS oorweeg moet word as nuwe neurologiese tekens na aanvang van antiretrovirale terapie (ART) in MIV-geïnfekteerde kinders met TBM ontwikkel (hoostuk 6.1). Simptome en tekens van neurologies TB-IRIS behels hoofpyn, konvulsies, meningiale prikkeling, ‘n verlaagde vlak van bewussyn, ataksie en fokale motoriese uitval. Ons bespreek ook die rasionaal vir die gebruik van sekere behandelingsmodaliteite, insluitende thalidomied. Neurologiese tuberkuleuse massaletsels (tuberkulome en pseudo-absesse) mag ontwikkel of vergroot in kinders op anti-TBM behandeling. Hierdie letsels reageer swak op terapie, vereis soms chirurgiese verwydering, maar kan op talidomied behandeling reageer, ‘n kragtige inhibeerder van tumor nekrose faktor-alfa (TNF-α). Die optimale dosis en duurte van thalidomide behandeling en die korrelasie met magnetiese resonansbeelding (MRB) moet nog ondersoek word. Die primêre doel van my volgende studie was om te bepaal of seriële MRB van waarde is om die respons op behandeling te evalueer asook die duurte van talidomied behandeling. Die sekondêre doelwit was om die waarde van talidomied in die behandeling van hierdie letsels te bepaal. In ‘n prospektiewe waarnemingstudie wat oor 3 jaar gestrek het is seriële MRB uitgevoer op 16 opeenvolgende kinders met TB pseudo-absesse wat behandel is met talidomied (hoofstuk 6.2). Die spoedige kliniese verbetering van die meeste pasiënte dui daarop dat thalidomied `n aansienlike kliniese voordeel bied in hierdie kliniese konteks. Verder het ek `n MRB merker van genesing geïdentifiseer naamlik evolusie van die letsel van vroeë stadium “T2 helder” met edeem na “T2 swart”. Hierdie bevinding is van groot waarde in die toekomstige behandeling van TBM pasiënte wat hierdie komplikasie ontwikkel. Transkraniale Doppler beelding (TKDB) is potensieël `n waardevolle ondersoekmetode in kinders met TBM, `n toestand wat dikwels gekompliseer word deur patologie verwant aan Doppler beelding soos verhoogde intrakraniale druk (IKP) en serebrale vaskulopatieë. Seriële TKBD is op 20 TBM kinders uitgevoer om serebrale hemodinamika en die verband tussen die pulsatiele indeks (PI) en IKP te ondersoek (hoofstuk 6.3). In hierdie studie het ek gevind dat TKDB-afgeleide PI nie `n betroubare aanduiding van verhoogde IKD in kinders met tuberkuleuse hidrokefalus is nie en dit aan individuele variasies van tuberkuleuse vaskulêre siekte toegeskryf, wat serebrale vaskulêre toegeeflikheid en weerstand benadeel. Die studie het die doeltreffendheid van mediese behandeling in kinders met kommunikerende tuberkuleuse hidrokefalus bevestig. In alle gevalle het die IKP binne 7 dae na aanvang van asetosoolamied en furosemied genormaliseer. In dieselfde groep TBM kinders het ek die serebrale bloedvloei-snelhede (BVS) in die anterior serebrale arterie (ASA), middel serebrale arterie (MSA) en posterior serebrale arterie (PSA) met toelating en na dag 3 en 7 gemeet. Ek het volgehoue hoё BVS in al die basale arteries gevind wat op stenose sekondêr tot vaskulitis eerder as funksionele vasospasma dui. Daarbenewens het ek gevind dat volledige MSA afsluiting, subnormale gemiddelde MSA snelhede (minder as 40 sentimeter per sekonde) en `n verminderde PI (minder as 0.4) met radiologies-bewysde groot serebrale infarksies gekorreleer het. Geen kant-tot-kant verskille in MSA BVS of subnormale PI’s is in vier TBM kinders met kleiner infarksies met toelating bespeur nie. Ek skryf dit toe aan die afsluiting van `n beperkte aantal (een of twee) van die nege MSA perforators wat nie nie die hemodinamika van die MSA beïnvloed nie. Ek het afgesluit om al die vrae wat nog bestaan oor die beste benadering ten opsigte van voorkoming, diagnose and behandeling van TBM uit te wys (hoofstuk 2). In die tweede literatuuroorsig, wat gemik is op dokters wat werk in hulpbron-beperkte lande, beskryf ek nuwe benaderings tot die hantering van pediatriese TBM, insluitend `n behandelingsalgoritme vir tuberkuleuse hidrokefalus, die rol van kort- kursus versterkte anti-TB behandeling vir TBM en tuis-gebaseerede anti-TBM behandeling (hoofstuk 3). Selfs met die beste diagnostiese en behandelingsmodaliteite, is die uitkoms van kinder TBM swak indien diagnose vertraag word. Ons pogings moet daarom op groter bewustheid en vroeёr diagnose berus.

Thesis (MMed)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: BACKGROUND: Tuberculous meningitis (TBM) research remains important but obtaining adequate sample sizes of microbiologically-confirmed TBM cases is difficult, therefore clinical cases of TBM need to be included. A uniform research case definition for TBM was developed to assist diagnostic standardization. METHODS: Our study evaluated the proposed uniform research case definition in a group of children diagnosed with TBM. A subgroup of 66 children with cultureconfirmed TBM was compared to culture-confirmed bacterial meningitis controls. RESULTS: The uniform case definition was applied to 554 TBM patients. Sixty-six (11.9%) patients had definite TBM, 408 (73.6%) had probable TBM and 72 (13.0%) had possible TBM. Symptom duration >5 days, weight loss or persistent cough >2 weeks, recent TB contact, focal neurological deficit, clear cerebrospinal fluid (CSF) appearance and basal meningeal enhancement predicted TBM when compared to definite bacterial meningitis with a sensitivity and specificity of 97.0% and 93.7%, respectively. When using a probable TBM score as the diagnostic measure, sensitivity was 86% and specificity was 100%. When using a possible TBM score as the diagnostic measure, sensitivity was 100% but specificity was 56%. CONCLUSION: The uniform research case definition for TBM performed well when using a probable TBM score as the diagnostic marker. A regression model also differentiated TBM from bacterial meningitis with good accuracy, but caution is needed in its application to early TBM.

Hintergrund: Die bakterielle Meningitis hat eine Letalität von 10-20%. Das Hirnödem stellt bei ca. 14 % der Erkrankten eine prognosebestimmende Komplikation dar. Ein aktueller Forschungsansatz umfasst die Bedeutung der Aquaporine für die Entwicklung, Aufrechterhaltung und Resorption der verschiedenen Hirnödemformen, insbesondere des zytotoxischen und des vasogenen Hirnödems. In dieser Arbeit wird untersucht, ob Aquaporin 1 und Aquaporin 4 im Liquor von Patienten mit bakterieller und viraler Meningitis, im Vergleich zu einer gesunden Kontrollgruppe, nachweisbar sind. Zudem sollte geklärt werden, ob sich hieraus eine differenzialdiagnostische Einordnung ergibt und sich Rückschlüsse auf das Ausmaß eines Hirnödems und das Outcome schließen lassen. Methode: Aquaporin 1 und 4 wurde im Liquor und im Serum von Patienten mit bakterieller (nCSF = 35 , nSerum = 20) und viraler  (nCSF = 22) Meningitis sowie in einer Kontrollgruppe (nCSF = 27 , nSerum = 12) mittels eines (kommerziell erhältlichen) ELISAs bestimmt. Klinische Daten und Routinelaborparameter wurden verglichen und in Korrelation zu den Aquaporinkonzentrationen gesetzt. Ergänzend wurde bei einer Untergruppe der Patienten mit bakterieller Meningitis (n = 8) eine neuropsychologische Testung durchgeführt. Ergebnisse: Aquaporin 1 und 4 ließen sich in allen Gruppen nachweisen, ca. 40% der Aquaporin 4 Konzentrationen lagen unterhalb der Nachweisgrenze des ELISAs. Im Gruppenvergleich aller drei Gruppen unterschieden sich die Aquaporin 1-Konzentrationen (p = 0,0001) und die Aquaporin 4-Konzentrationen (p = 0,035) im Liquor signifikant voneinander. In der Gruppe der Patienten mit bakterieller Meningitis ließ sich eine negative Korrelation zwischen Aquaporin 1 und 4 im Liquor feststellen (r = - 0,519, p = 0,002). Aussagekräftige Korrelationen der klinischen Daten, der liquor- und laborchemischen Parameter sowie der neuropsychologischen Testergebnisse zu den Aquaporin 1- und Aquaporin 4-Konzentrationen fanden sich nicht.  Diskussion: In dieser Arbeit konnte erstmalig gezeigt werden, dass Aquaporin 1 und Aquaporin 4 im Liquor (und Serum) von Patienten mit einer bakteriellen und viralen Meningitis sowie in einer Kontrollgruppe nachweisbar sind. Für Aquaporin 1 und Aquaporin 4 im Liquor fanden sich signifikante Unterschiede im Vergleich aller Gruppen im Kruskal-Wallis-Test. Rückschlüsse bezüglich einer differenzial-diagnostischen Einordnung zur viralen Meningitis konnten nicht gezogen werden. Aussagen zur Schwere eines Hirnödems und zur Prognose können mit den vorliegenden Daten nicht getroffen werden. Der Ursprung der gemessenen Aquaporine bei Patienten mit Meningitis lässt sich in dieser Arbeit nicht abschließend klären und bedarf weiterer Grundlagenforschung.

A model for meningitis is developed by adding a class of carriers to the basic SIR model. This model is used to analyze the impact a vaccination program can have on the health of the population of epidemic prone countries. Analysis of the model shows the local stability of the disease free equilibrium, the existence of an endemic equilibrium and computation of the reproduction number, ℜ0 . Using a MATLAB program we simulate a time course of the model using parameters gathered from the World Health Organization. The numerical solution demonstrates that our reproduction number was correct. We thenconcluded that a high infection transmission rate requires a high vaccine rate.

Antecedentes: La Meningitis tuberculosa es la causante de muerte y discapacidad en más de la mitad de las personas afectadas, a pesar de la quimioterapia antituberculosa. Es necesario desarrollar herramientas que permiten abordar el diagnostico clínico de maneras más eficientes. Objetivo: Evaluar el valor diagnóstico del Árbol de Clasificación y Regresión de Thwaites para diferenciar Meningitis Tuberculosa de Meningitis Bacteriana. Material y Métodos: Es un estudio observacional, transversal y retrospectivo de evaluación de test diagnóstico en los que se utilizó las historias clínicas de pacientes con diagnóstico de meningitis tuberculosa y meningitis bacteriana del Servicio de Medicina Interna del Hospital Nacional Hipólito Unanue entre los años 2003-2012 y se aplicó el Árbol de Clasificación y Regresión de Thwaites. Resultados: Se incluyeron 108 historias clínicas, de las cuales 77 (71.30%) presentaron diagnóstico de meningitis tuberculosa y 31 (28.7%) presentaron diagnóstico de meningitis bacteriana. El Árbol de clasificación y regresión presentó una Sensibilidad de 0.80 (IC 95% 0.71-0.87), Especificidad de 0.72 (IC 95% 0.49-0.88), Valor Predictivo Positivo de 0.94 (IC 95% 0.85-0.98),Valor Predictivo Negativo fue de 0.42 (IC 95% 0.25-0.61), exactitud diagnóstica de 0.79 (IC 95% 0.70-0.86). Likelihood ratio negativo de 0.28 (IC 95% 0.17-0.46) y Likelihood ratio positivo de 2.88 (IC 95% 1.36-6.11) Conclusiones: Nuestros resultados muestran que el árbol de clasificación y regresión de Twaithes es una herramienta con utilidad limitada para el diagnóstico diferencial de meningitis tuberculosa vs bacteriana. En escenarios de alta incidencia puede ser útil corroborar el diagnostico.

Infecções por Neisseria meningitidis estão associadas a altos índices de morbimortalidade no mundo. Na Região da Grande São Paulo a Doença Meningocócica (DM) causada por Neisseria meningitidis sorogrupo C começou a se tornar prevalente em 2001 , representando, em 2003, 62,7% de todos os casos de DM sorogrupados sendo que aproximadamente 88,5% dessas cepas eram não sorotipados e não sorosubtipados (C:NST:NSST). Estes dados sugeriam que um fenótipo, C: NST:NSST, tinha emergido na Grande São Paulo e, considerando-se a importância histórica da doença na região, iniciamos o presente estudo com o objetivo de esclarecer a mudança na dinâmica da DM pela determinação das características fenotípicas e genotípicas destas cepas. Para tanto, analisamos por sorotipagem, tipagem das regiões Variáveis da PorA e PorB e do gene 16S RNA ribossomal, 753 cepas de N. meningitidis C isoladas de casos de DM provenientes da Grande São Paulo, no período de 1990 a 2003. Dado a impossibilidade de caracterização do novo fenótipo pelos anticorpos monoclonais disponíveis mundialmente, objetivamos também a produção de hibridomas produtores desses anticorpos para caracterização do fenótipo C:NST:NSST. Foram selecionadas duas linhagens celulares híbridas, produtoras de anticorpos monoclonais que reconhecem as proteínas PorA e PorB deste novo fenótipo. Entre as 255 cepas de N. meningitidis C inicialmente caracterizadas como NST:NSST, 75% (n=191) tomaram-se completamente sorotipadas como 23:P1.14-6. A análise da similaridade do gene 16S RNA ribossomal das cepas analisadas demonstrou um único padrão genético, sugerindo a clonalidade deste novo fenótipo. Os dados obtidos neste trabalho, demonstram a introdução, na Região da Grande São Paulo, de um novo clone de Neisseria meningitidis C apresentando o fenótipo C:23:P1.14-6 e que está sendo responsável pelo aumento dos casos de DM causada por este sorogrupo. / Neisseria meningitidis (Men) is an important cause of morbidity and mortality and is a leading cause of bacterial meningitis and septicemia in children and young adults in Brazil. Meningococcal disease caused by MenC started becoming the most prevalent serogroup in 2001, representing 62.7% of all MD cases serogrouped in 2003 in Greater Sao Paulo and approximately 88.5% of MenC isolates were nonserotypeable and non-serosubtypeable (NST:NSST). This data suggested that a novel invasive isolate (C:NT:NSST) had emerged in GSP, and considering the historical importance of MenC disease in the region, we initiated this study to better understand the dynamics of MD looking at the phenotypic and molecular characteristics of these isolates. To accomplish this goal, we characterized 753 MenC isolates recovered during the period of 1990 to 2003 by serotyping, PorS and PorA VR typing, 16S rRNA gene typing and produced new serotyping monoclonal antibodies (MAbs) to characterize the C:NST:NSST isolates. We were able to select two hybridoma cells that recognizes PorB and PorA proteins. Among the 255 strains initially characterized as NST:NSST, 75% (n=191) of them became completely serotyped as 23:P1 .14-6. Sy 16S RNA ribossomal typing, these strains showed the same pattern suggesting strain clonality. Our data demonstrate the introduction of a new clone of Neisseria rneningitidis C presenting the phenotype C:23:P1.14-6 and that is being responsible for the increase of the cases of DM caused by this serogroup in Great Sao Paulo.

Das Opc-Protein ist ein Außenmembranprotein von Meningokokken, das über extrazelluläre Matrixproteine mit Integrinen der Wirtszelle interagiert. Opc ist in Menschen immunogen und induziert bakterizide Antikörper. Das Opc-Protein wurde daher als aussichtsreicher Impfstoff-Kandidat angesehen, da es außerdem relativ gut konserviert ist. Allerdings wird das Opc-Protein nicht von allen Meningokokkenstämmen exprimiert. Einerseits fehlt das opc-Gen in einigen klonalen Komplexen (z.B. ST-8, ST-11, ST-53), andererseits ist die Opc-Expression nicht konstitutiv wegen einer phasenvariablen Transkription, die auf einem Poly-Cytidin-Bereich im Promotor des opc-Gens beruht. In dieser Arbeit wurde die Präsenz des opc-Gens und die Opc-Expression in zwei großen Sammlungen deutscher Meningokokkenisolate von invasiven Erkrankungen (n=1141) und gesunden Trägern (n=792) untersucht. Das opc-Gen war bei 71% der invasiven und 77% der Trägerstämme nachweisbar. Der größte Teil der opc-Gen negativen Stämme gehörte zu den klonalen Komplexen ST-8, ST-11, ST-213, ST-231, ST-334 und ST-53. Der Anteil opc-positiver Stämme, die Opc in vitro exprimieren, war bei den invasiven Stämmen kleiner als bei den Trägerstämmen (13% vs. 29%, p<0,001, Chi-square-Test). Der größere Anteil Opc-exprimierender Trägerstämme ist u.a. am ehesten mit der Überrepräsentation von wenig pathogenen klonalen Komplexen (ST-23, ST-35, ST-198) mit einer hohen Opc-Expressionsrate zu erklären. 24 von den 176 invasiven Stämmen mit einer Anzahl von 11 - 14 Cs in der Promotor-Region, die die Opc-Expression begünstigt, zeigten weder im ELISA noch im Westernblot eine Opc-Expression. Bei 14 dieser 24 Stämme wurde als Ursache ein phasenvariabler, intragenischer Poly-Adenin-Bereich identifiziert, der zu einer Leserasterverschiebung führte. Die Vermutung mehrerer Autoren, dass die Opc-Expression mit dem klinischen Bild der Meningitis verknüpft ist, konnte mit der hier genutzten großen Stammsammlung nicht bestätigt werden. Invasive Stämme, die das Opc-Protein exprimierten, wurden genauso häufig von Patienten mit dem klinischen Bild der Meningitis isoliert wie Stämme, die das Opc-Protein nicht exprimierten (46% vs. 47%, Chi-square-Test: p<0,9). Allerdings gibt es eine starke Assoziation der Gegenwart des opc-Gens mit dem klinischen Merkmal Meningitis. Dieser Befund gibt Anlass zu der Hypothese, dass in vitro und in vivo Expression von Opc sich unterscheiden. Zusammenfassend lässt sich festhalten, dass das Opc-Protein nur in 19,8% aller Isolate (invasive und Trägerstämme zusammengenommen) exprimiert wurde. Es zeigte sich eine Tendenz zu häufigerer Opc-Expression in apathogenen Trägerisolaten. Das Vorhandensein des opc-Gens, nicht aber die in vitro Expression konnten mit dem klinischen Merkmal Meningitis assoziiert werden. Zusätzlich wurde ein weiterer Mechanismus der intragenischen Phasenvariation beschrieben. / Presence of opc was associated with meningitis, mostly because ST-11/ST-8 cc meningococci with low meningitis rates were consistently opc negative. On the other hand, lack of opc did not exclude meningitis. Opc was expressed in only 13% of all invasive isolates. In vitro Opc expression was not associated with meningitis. Limitation: Definite conclusion about expression in vivo is not possible with cultured isolates. Evidence for intragenic opc phase-variation was provided.

Thesis (M.Dip.Tech.-Medical Tech)--Cape Technikon, 1997. / Bibliography: leaf. 59-62. Also available online.