Browsing by Author "Solomons, Regan"
Now showing 1 - 13 of 13
Results Per Page
- ItemApplication of cerebrospinal fluid host protein biosignatures in the diagnosis of tuberculous meningitis in children from a high burden setting(Hindawi, 2019-04) Manyelo, Charles M.; Solomons, Regan; Snyders, Candice I.; Manngo, Portia M.; Mutavhatsindi, Hygon; Kriel, Belinda; Stanley, Kim; Walzl, Gerhard; Chegou, Novel N.Background. The diagnosis of tuberculous meningitis (TBM) especially in children is challenging. New tests are urgently needed for the diagnosis of the disease, especially in resource-limited settings. Methods. We collected cerebrospinal fluid (CSF) samples from children presenting with symptoms requiring investigation for meningitis at a tertiary hospital in Cape Town, South Africa. Children were later classified as TBM or no TBM using published case definitions. Using a multiplex platform, we investigated the concentrations of biomarkers comprising a previously established 3-marker biosignature (VEGF, IL-13, and LL-37) and other potentially useful host biomarkers as diagnostic candidates for TBM. Findings. Out of 47 children, age, 3 months to 13 years, 23 were diagnosed with TBM and six (16%) were HIV-infected. We validated the previously identified CSF biosignature (sensitivity of 95.7% (95% CI, 79.0-99.2%) and specificity of 37.5% (95% CI, 21.2-57.3%)). However, substitution of IL-13 and LL-37 with IFN-γ and MPO, respectively, resulted in improved accuracy (area under the ROC curve (AUC) = 0 97, 95% CI, 0.92-1.00, up to 91.3% (21/23) sensitivity and up to 100% (24/24) specificity). An alternative four-marker biosignature (sICAM-1, MPO, CXCL8, and IFN-γ) also showed potential, with an AUC of 0.97. Conclusion. We validated a previously identified CSF biosignature and showed that refinement of this biosignature by incorporation of other biomarkers diagnosed TBM with high accuracy. Incorporation of these biomarkers into a point-of-care or bedside diagnostic test platform may result in the improved management of TBM in children.
- ItemApproach to headaches in children(Health & Medical Publishing Group, 2011) Solomons, Regan; Schoeman, Johan; Van Toorn, RonaldHeadache is a common problem in childhood – up to 25% of schoolchildren suffer from chronic, recurrent headaches. Although primary headaches are far more common than those with a secondary cause, it is the latter that result in the most anxiety for families.1 A logical approach to investigating and managing headaches is needed.
- ItemCerebrospinal fluid amino acid profiling of pediatric cases with tuberculous meningitis(Frontiers Media, 2017) Mason, Shayne; Reinecke, Carolus J.; Solomons, ReganBackground: In Africa, tuberculosis is generally regarded as persisting as one of the most devastating infectious diseases. The pediatric population is particularly vulnerable, with infection of the brain in the form of tuberculous meningitis (TBM) being the most severe manifestation. TBM is often difficult to diagnose in its early stages because of its non-specific clinical presentation. Of particular concern is that late diagnosis, and subsequent delayed treatment, leads to high risk of long-term neurological sequelae, and even death. Using advanced technology and scientific expertise, we are intent on further describing the biochemistry behind this devastating neuroinflammatory disease, with the goal of improving upon its early diagnosis. Method: We used the highly sensitive analytical platform of gas chromatography-mass spectrometry (GC-MS) to analyze amino acid profiles of cerebrospinal fluid (CSF) collected from a cohort of 33 South African pediatric TBM cases, compared to 34 controls. Results: Through the use of a stringent quality assurance procedure and various statistical techniques, we were able to confidently identify five amino acids as being significantly elevated in TBM cases, namely, alanine, asparagine, glycine, lysine, and proline. We found also in an earlier untargeted metabolomics investigation that alanine can be attributed to increased CSF lactate levels, and lysine as a marker of lipid peroxidation. Alanine, like glycine, is an inhibitory neurotransmitter in the brain. Asparagine, as with proline, is linked to the glutamate-glutamine cycle. Asparagine is associated with the removal of increased nitrites in the brain, whereas elevated proline coincides with the classic biochemical marker of increased CSF protein in TBM. All five discriminatory amino acids are linked to ammonia due to increased nitrites in TBM. Conclusion: A large amount of untapped biochemical information is present in CSF of TBM cases, of which amino acid profiling through GC-MS has potential in aiding in earlier diagnosis, and hence crucial earlier treatment.
- ItemCerebrospinal fluid in tuberculous meningitis exhibits only the L-enantiomer of lactic acid(BioMed Central, 2016) Mason, Shayne; Reinecke, Carolus J.; Kulik, Willem; Van Cruchten, Arno; Solomons, ReganBackground: The defining feature of the cerebrospinal fluid (CSF) collected from infants and children with tuberculous meningitis (TBM), derived from an earlier untargeted nuclear magnetic resonance (NMR) metabolomics study, was highly elevated lactic acid. Undetermined was the contribution from host response (L-lactic acid) or of microbial origin (D-lactic acid), which was set out to be determined in this study. Methods: In this follow-up study, we used targeted ultra-performance liquid chromatography–electrospray ionization–tandem mass spectrometry (UPLC–ESI–MS/MS) to determine the ratio of the L and D enantiomers of lactic acid in these CSF samples. Results: Here we report for the first time that the lactic acid observed in the CSF of confirmed TBM cases was in the L-form and solely a response from the host to the infection, with no contribution from any bacteria. The significance of elevated lactic acid in TBM appears to be that it is a crucial energy substrate, used preferentially over glucose by microglia, and exhibits neuroprotective capabilities. Conclusion: These results provide experimental evidence to support our conceptual astrocyte–microglia lactate shuttle model formulated from our previous NMR-based metabolomics study — highlighting the fact that lactic acid plays an important role in neuroinflammatory diseases such as TBM. Furthermore, this study reinforces our belief that the determination of enantiomers of metabolites corresponding to infectious diseases is of critical importance in substantiating the clinical significance of disease markers.
- ItemChild with tuberculous meningitis and COVID-19 coinfection complicated by extensive cerebral sinus venous thrombosis(BMJ Publishing Group, 2020) Essajee, Farida; Solomons, Regan; Goussard, Pierre; Van Toorn, RonaldWe herein report a case of a child with tuberculous meningitis and COVID-19 coinfection complicated by hydrocephalus, arterial ischaemic stroke and extensive cerebral sinus venous thrombosis. Both conditions induce a proinflammatory cytokine drive resulting, among others, in a prothrombotic state. The disruption of the coagulation system in this case was supported by elevated D-dimers, fibrinogen and ferritin levels, consistent with thrombotic complications reported in some adult patients infected with COVID-19. The child also exhibited prolonged viral shedding that suggests severe disease.
- ItemComplementary surveillance strategies are needed to better characterise the epidemiology, care pathways and treatment outcomes of tuberculosis in children(BioMed Central, 2018-03-23) Du Preez, Karen; Schaaf, H. Simon; Dunbar, Rory; Walters, Elisabetta; Swartz, Alvera; Solomons, Regan; Hesseling, Anneke C.Background: Tuberculosis (TB) in young and HIV-infected children is frequently diagnosed at hospital level. In settings where general hospitals do not function as TB reporting units, the burden and severity of childhood TB may not be accurately reflected in routine TB surveillance data. Given the paucibacillary nature of childhood TB, microbiological surveillance alone will miss the majority of hospital-managed children. The study objective was to combine complementary hospital-based surveillance strategies to accurately report the burden, spectrum and outcomes of childhood TB managed at referral hospital-level in a high TB burden setting. Methods: We conducted a prospective cohort study including all children (< 13 years) managed for TB at a large referral hospital in Cape Town, South Africa during 2012. Children were identified through newly implemented clinical surveillance in addition to existing laboratory surveillance. Data were collected from clinical patient records, the National Health Laboratory Service database, and provincial electronic TB registers. Descriptive statistics were used to report overall TB disease burden, spectrum, care pathways and treatment outcomes. Univariate analysis compared characteristics between children identified through the two hospital-based surveillance strategies to characterise the group of children missed by existing laboratory surveillance. Results: During 2012, 395 children (180 [45.6%] < 2 years) were managed for TB. Clinical surveillance identified 237 (60%) children in addition to laboratory surveillance. Ninety (24.3%) children were HIV co-infected; 113 (29.5%) had weight-for-age z-scores <− 3. Extra-pulmonary TB (EPTB) was diagnosed in 188 (47.6%); 77 (19.5%) with disseminated TB. Favourable TB treatment outcomes were reported in 300/344 (87.2%) children with drugsusceptible and 50/51 (98.0%) children with drug-resistant TB. Older children (OR 1.7; 95% CI 1.0–2.8), children with EPTB (OR 2.3; 95% CI 1.5–3.6) and in-hospital deaths (OR 5.4; 95% CI 1.1–26.9) were more frequently detected by laboratory surveillance. TB/HIV co-infected children were less likely to be identified through laboratory surveillance (OR 0.3; 95% CI 0.2–0.5). Conclusions: The burden and spectrum of childhood TB disease managed at referral hospital level in high burden settings is substantial. Hospital-based surveillance in addition to routine TB surveillance is essential to provide a complete picture of the burden, spectrum and impact of childhood TB in settings where hospitals are not TB reporting units.
- ItemThe current global situation for tuberculous meningitis : epidemiology, diagnostics, treatment and outcomes [version 1; peer review: 2 approved](F1000Research, 2019) Seddon, James A.; Tugume, Lillian; Solomons, Regan; Prasad, Kameshwar; Bahr, Nathan C.ENGLISH ABSTRACT: Tuberculous meningitis (TBM) results from dissemination of M. tuberculosis to the cerebrospinal fluid (CSF) and meninges. Ischaemia, hydrocephalus and raised intracranial pressure frequently result, leading to extensive brain injury and neurodisability. The global burden of TBM is unclear and it is likely that many cases are undiagnosed, with many treated cases unreported. Untreated, TBM is uniformly fatal, and even if treated, mortality and morbidity are high. Young age and human immunodeficiency virus (HIV) infection are potent risk factors for TBM, while Bacillus Calmette–Guérin (BCG) vaccination is protective, particularly in young children. Diagnosis of TBM usually relies on characteristic clinical symptoms and signs, together with consistent neuroimaging and CSF parameters. The ability to confirm the TBM diagnosis via CSF isolation of M. tuberculosis depends on the type of diagnostic tests available. In most cases, the diagnosis remains unconfirmed. GeneXpert MTB/RIF and the next generation Xpert Ultra offer improved sensitivity and rapid turnaround times, and while roll-out has scaled up, availability remains limited. Many locations rely only on acid fast bacilli smear, which is insensitive. Treatment regimens for TBM are based on evidence for pulmonary tuberculosis treatment, with little consideration to CSF penetration or mode of drug action required. The World Health Organization recommends a 12-month treatment course, although data on which to base this duration is lacking. New treatment regimens and drug dosages are under evaluation, with much higher dosages of rifampicin and the inclusion of fluoroquinolones and linezolid identified as promising innovations. The inclusion of corticosteroids at the start of treatment has been demonstrated to reduce mortality in HIV-negative individuals but whether they are universally beneficial is unclear. Other host-directed therapies show promise but evidence for widespread use is lacking. Finally, the management of TBM within health systems is sub-optimal, with drop-offs at every stage in the care cascade.
- ItemImproving early diagnosis of tuberculous meningitis in children(Stellenbosch : Stellenbosch University, 2015-12) Solomons, Regan; Schoeman, J. F.; Van Furth, A. M.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Paediatrics and Child Health.ENGLISH SUMMARY: Due to the sub-optimal performance of definite diagnostic tests, the early identification of paediatric TBM suspects relies on a thorough assessment of all the evidence derived from a careful history, clinical examination and relevant investigations. Rapid diagnosis is needed for early treatment initiation but microbiological confirmation is difficult at stage 1 disease because a lumbar puncture is generally only done once signs of meningitis have developed (stage 2 and 3 TBM). With this thesis, I aim to investigate mechanisms of improving the early and/or more accurate diagnosis of childhood TBM. PART I In chapter 2 I provide an update on the diagnosis and management of TBM in children, based on local experience, which can be transposed to similar settings. Highlights include firstly that short (6 months) intensified therapy in children with drug susceptible TBM is safe and effective, with a good outcome and low mortality. Secondly, home-based TBM treatment after initial in-hospital stabilization is feasible in carefully selected patients under close supervision. Thirdly, treatment of tuberculous hydrocephalus depends on the level of cerebrospinal fluid (CSF) obstruction. Communicating hydrocephalus can be successfully treated with medical therapy with normalization of intracranial pressure occurring within days in the majority children and non-communicating hydrocephalus requires neurosurgical intervention. Fourthly, thalidomide is the local drug of choice in children who develop life-threatening TB mass lesions (IRIS) despite corticosteroids. PART II In clinical practice, TBM diagnosis is most often based on a combination of clinical, laboratory and radiological findings. A uniform research case definition utilizing these criteria was proposed by an international panel of experts as a means of improving diagnostic standardization in order to answer critical research questions, categorizing patients as definite, probable, or possible TBM. Part 2 of my thesis focuses on the diagnostic utility of the uniform research case definition criteria for TBM. In chapter 3.1 I retrospectively evaluate the diagnostic performance of probable and possible TBM criteria in children with culture-confirmed TBM and culture-confirmed bacterial meningitis. The proposed uniform research case definition provided excellent diagnostic accuracy compared to microbiologically-confirmed TBM, when a ‘probable’ TBM score was used. When a ‘possible’ TBM score was used, not a single TBM case would have been missed, but clinical utility was minimal given the low specificity achieved. In order to strengthen my findings I prospectively assessed the diagnostic accuracy of the uniform TBM research case definition (see chapter 3.2). Excellent diagnostic accuracy was obtained for a diagnosis of TBM when compared to bacterial and viral meningitis controls. The high specificity of a probable TBM score justifies its use as an alternative reference standard to microbiological confirmation in future studies. In both studies poor sensitivity was obtained when a probable TBM score was used to diagnose early (stage 1) TBM, emphasizing a very high clinical index of suspicion of TBM in young children with recent TB exposure and persistent non-specific signs. CSF findings are essential to early diagnosis of TBM. Cut-off values for CSF glucose in TBM lack evidence. A CSF protein cut-off of >1g/L (100mg/dL) differentiated between cases of TBM and other forms of meningitis. My study on the diagnostic value of cerebrospinal fluid chemistry results in childhood TBM found that the optimal lower limit of CSF glucose concentration as a diagnostic aid for TBM was 2.2 mmol/L (see chapter 3.3). Absolute CSF glucose differentiated non-TBM from TBM cases with sensitivity of 68% and specificity of 96%, excluding its use as a ‘rule-out’ test. Simultaneous determination of serum and CSF glucose was seldom performed but my findings suggest that the CSF:serum glucose ratio may further improve diagnostic sensitivity.. CSF protein cut-off of >1g/L as well as CSF macroscopic appearance, cell counts and the presence of lymphocyte predominance are required to assist the distinction between TBM and bacterial meningitis. Previous studies suggest that chest X-ray findings consistent with active pulmonary TB are observed in 70% to 84% of children with TBM. In my study (chapter 3.4) only 46% of cases with TBM had chest radiograph findings highly suggestive of pulmonary TB. A need to treat calculation showed that only 1 in 4.39 children ≤3 years of age with TBM are likely to have ‘certain TB’ on chest X-ray. PART III Microbiological confirmation of TBM remains the gold-standard of diagnosis, but is challenging in young children due to the paucibacillary nature of disease, low CSF volumes available for diagnostic analysis and sub-optimal sensitivity of direct microscopy for acid-fast bacilli and M.tuberculosis culture on CSF. Several new commercially available NAA tests have been developed for the rapid diagnosis of TB. In part III of the thesis my meta-analysis of newer commercial NAA tests found a summary sensitivity of 64% and specificity of 98%. Summary sensitivity of commercial NAA tests remains suboptimal and is unlikely to greatly enhance early accurate diagnosis. However, the excellent specificity suggests that commercial NAA tests may be regarded as definitive in the correct clinical setting. In 2013, the WHO recommended Xpert MTB/RIF® as the preferential initial investigation in all adults and pediatric TBM suspects. My sub-analysis of 5 studies reporting Xpert MTB/RIF® on CSF, found summary sensitivity of 70% and specificity of 97%. In chapter 4.2 I aim to assess the utility of MTBDRplus® and Xpert MTB/RIF® to diagnose TBM in a clinical setting, alone and/or in combination. The main finding was the incremental increase in diagnostic accuracy achieved with combined use of these commercial NAA tests performed on CSF. Although both NAA tests were superior to liquid culture, sensitivity remained low compared to a rigorous predefined clinical case definition. The MTBDRplus® assay performed with sensitivity of 33% (98% specificity), Xpert MTB/RIF® was 26% sensitive (100% specificity) and combining positive results from both these tests provided a sensitivity of 49% (98% specificity) against a TBM case definition. This is insufficient to serve as a rule-out test and provides limited clinical guidance. However, microbiological confirmation provided by a positive test prevents unnecessary treatment delay and potential life-threatening consequences. The additional advantage of a positive NAA test is that of early detection of mycobacterial resistance. A major limitation of this study was the failure to improve diagnosis of stage 1 childhood TBM, mainly because it was hospital-based. Good surveillance at primary healthcare level, identifying children with poor weight-gain (or weight loss) and persistent non-remitting cough for longer than 2 weeks, could improve the detection of both childhood TB and early TBM. IMCI is potentially a valuable tool to increase awareness of TBM among healthcare workers, and in detecting early TB and TBM, as it is practiced at the healthcare level of first contact. Household contact tracing and prophylaxis with isoniazid therapy, as well as more general measures such as improving nutrition, housing and poverty relief, are valuable measures in preventing TBM in young children.
- ItemNeurocognitive and functional impairment in adult and paediatric tuberculous meningitis [version 1; peer review: 2 approved](F1000Research, 2019) Davis, Angharad G.; Nightingale, Sam; Springer, Priscilla E.; Solomons, Regan; Arenivas, Ana; Wilkinson, Robert J.; Anderson, Suzanne T.; Chow, Felicia C.ENGLISH ABSTRACT: In those who survive tuberculous meningitis (TBM), the long-term outcome is uncertain; individuals may suffer neurocognitive, functional and psychiatric impairment, which may significantly affect their ability to lead their lives as they did prior to their diagnosis of TBM. In children who survive, severe illness has occurred at a crucial timepoint in their development, which can lead to behavioural and cognitive delay. The extent and nature of this impairment is poorly understood, particularly in adults. This is in part due to a lack of observational studies in this area but also inconsistent inclusion of outcome measures which can quantify these deficits in clinical studies. This leads to a paucity of appropriate rehabilitative therapies available for these individuals and their caregivers, as well as burden at a socioeconomic level. In this review, we discuss what is known about neurocognitive impairment in TBM, draw on lessons learnt from other neurological infections and discuss currently available and emerging tools to evaluate function and cognition and their value in TBM. We make recommendations on which measures should be used at what timepoints to assess for impairment, with a view to optimising and standardising assessment of neurocognitive and functional impairment in TBM research.
- ItemPotential of host serum protein biomarkers in the diagnosis of tuberculous meningitis in children(Frontiers Media, 2019) Manyelo, Charles M.; Solomons, Regan; Snyders, Candice I.; Mutavhatsindi, Hygon; Manngo, Portia M.; Stanley, Kim; Walzl, Gerhard; Chegou, Novel N.Background: Tuberculous meningitis (TBM) is the most severe form of tuberculosis and results in high morbidity and mortality in children. Diagnostic delay contributes to the poor outcome. There is an urgent need for new tools for the rapid diagnosis of TBM, especially in children. Methods: We collected serum samples from children in whom TBM was suspected at a tertiary hospital in Cape Town, South Africa. Children were subsequently classified as having TBM or no TBM using a published uniform research case-definition. Using a multiplex cytokine array platform, we investigated the concentrations of serum biomarkers comprising biomarkers that were previously found to be of value in the diagnosis of adult pulmonary TB (CRP, SAA, CFH, IFN-γ, IP-10, Apo-AI, and transthyretin) plus other potentially useful host biomarkers as diagnostic candidates for TBM. Findings: Out of 47 children included in the study, 23 (48.9%) had a final diagnosis of TBM and six were HIV infected. A modified version of the adult 7-marker biosignature in which transthyretin was replaced by NCAM1, diagnosed TBM in children with AUC of 0.80 (95% CI, 0.67–0.92), sensitivity of 73.9% (95% CI, 51.6–89.8%) and specificity of 66.7% (95% CI, 44.7–84.4%), with the other six proteins in the signature (CRP, IFN-γ, IP-10, CFH, Apo-A1, and SAA) only achieving and AUC of 0.75 (95% CI, 0.61–0.90) when used in combination. A new childhood TBM specific 3-marker biosignature (adipsin, Aβ42, and IL-10) showed potential in the diagnosis of TBM, with AUC of 0.84 (95% CI, 0.73–0.96), sensitivity of 82.6% (95 CI, 61.2–95.0%) and specificity of 75.0% (95% CI, 53.3–90.2%) after leave-one-out cross validation. Conclusion: A previously described adult 7-marker serum protein biosignature showed potential in the diagnosis of TBM in children. However, a smaller childhood TBM-specific 3-marker signature demonstrated improved performance characteristics. Our data indicates that blood-based biomarkers may be useful in the diagnosis of childhood TBM and requires further validation in larger cohort studies.
- ItemRecent Developments in Tuberculous Meningitis Pathogenesis and Diagnostics [version 3; peer review: 3 approved](F1000Research, 2019) Cresswell, Fiona V.; Davis, Angharad G.; Sharma, Kusum; Roy, Robindra Basu; Ganiem, Ahmad Rizal; Kagimu, Enock; Solomons, Regan; Wilkinson, Robert J.; Bahr, Nathan C.; Thuong, Nguyen Thuy Thuong; Tuberculous Meningitis International Research ConsortiumENGLISH ABSTRACT: The pathogenesis of Tuberculous meningitis (TBM) is poorly understood, but contemporary molecular biology technologies have allowed for recent improvements in our understanding of TBM. For instance, neutrophils appear to play a significant role in the immunopathogenesis of TBM, and either a paucity or an excess of inflammation can be detrimental in TBM. Further, severity of HIV-associated immunosuppression is an important determinant of inflammatory response; patients with the advanced immunosuppression (CD4+ T-cell count of <150 cells/μL) having higher CSF neutrophils, greater CSF cytokine concentrations and higher mortality than those with CD4+ T-cell counts > 150 cells/μL. Host genetics may also influence outcomes with LT4AH genotype predicting inflammatory phenotype, steroid responsiveness and survival in Vietnamese adults with TBM. Whist in Indonesia, CSF tryptophan level was a predictor of survival, suggesting tryptophan metabolism may be important in TBM pathogenesis. These varying responses mean that we must consider whether a “one-size-fits-all” approach to anti-bacillary or immunomodulatory treatment in TBM is truly the best way forward. Of course, to allow for proper treatment, early and rapid diagnosis of TBM must occur. Diagnosis has always been a challenge but the field of TB diagnosis is evolving, with sensitivities of at least 70% now possible in less than two hours with GeneXpert MTB/Rif Ultra. In addition, advanced molecular techniques such as CRISPR-MTB and metagenomic next generation sequencing may hold promise for TBM diagnosis. Host-based biomarkers and signatures are being further evaluated in childhood and adult TBM as adjunctive biomarkers as even with improved molecular assays, cases are still missed. A better grasp of host and pathogen behaviour may lead to improved diagnostics, targeted immunotherapy, and possibly biomarker-based, patient-specific treatment regimens.
- ItemTuberculous meningitis in children is characterized by compartmentalized immune responses and neural excitotoxicity(Nature Research (part of Springer Nature), 2019) Rohlwink, Ursula K.; Figaji, Anthony; Wilkinson, Katalin A.; Horswell, Stuart; Sesay, Abdul K.; Deffur, Armin; Enslin, Nico; Solomons, Regan; Van Toorn, Ronald; Eley, Brian; Levin, Michael; Wilkinson, Robert J.; Lai, Rachel P. J.ENGLISH ABSTRACT: Tuberculous meningitis (TBM) is the most severe form of TB with high rates of mortality and morbidity. Here we conduct RNA-sequencing on whole blood as well as on ventricular and lumbar cerebrospinal fluid (CSF) of pediatric patients treated for TBM. Differential transcript expression of TBM cases are compared with healthy controls in whole blood and with non-TB cerebral infection controls in CSF. Whole blood RNA-Seq analysis demonstrates a distinct immune response pattern in TBM, with significant increase in both canonical and non-canonical inflammasome activation and decrease in T-cell activation. In ventricular CSF, a significant enrichment associated with neuronal excitotoxicity and cerebral damage is detected in TBM. Finally, compartmental comparison in TBM indicates that the ventricular profile represents brain injury whereas the lumbar profile represents protein translation and cytokine signaling. Together, transcriptomic analysis shows that disease processes differ between the periphery and the central nervous system, and within brain compartments.
- ItemTuberculous meningitis in infants and children : insights from nuclear magnetic resonance metabolomics(Academy of Science of South Africa, 2016-03) Mason, Shayne; Reinecke, Carolus J.; Solomons, Regan; Van Furth, A. MarcelineTuberculous meningitis (TBM) is a prevalent form of central nervous system tuberculosis (CNS-TB) and the most severe common form of bacterial meningitis in infants and children below the age of 13 years, especially in the Western Cape Province of South Africa. Research to identify markers for timely and accurate diagnosis and treatment outcomes remains high on the agenda for TBM, in respect of which the field of metabolomics is as yet largely unexploited. However, the national Department of Science and Technology (DST) recently established several biotechnology platforms at South African institutions, including one for metabolomics hosted at North-West University. We introduce this national platform for nuclear magnetic resonance (NMR) metabolomics by providing an overview of work on TBM. We focus on selected collaborative multidisciplinary approaches to this disease and conclude with the outcomes of an untargeted NMR metabolomics study of cerebrospinal fluid from TBM patients. This study enabled the formulation of a conceptual shuttle representing the unique metabolic plasticity of CNS metabolism towards the energy requirements for the microglia-driven neuroinflammatory responses, of which TBM is one example. From insights generated by this explorative NMR metabolomics investigation, we propose directions for future in-depth research strategies to address this devastating disease. In our view, the timely initiative of the DST, the operational expertise in metabolomics now available and the potential for involving national and international networks in this field of research offers remarkable opportunities for the future of metabolomics in South Africa and for an ever greater understanding of disease mechanisms.