Serum and cerebrospinal fluid host proteins indicate stroke in children with tuberculous meningitis

Introduction Stroke is a common complication in children with tuberculous meningitis (TBM). Host proteins may give us insight into the mechanisms of stroke in TBM and serve as biomarkers for detection of stroke, however, they have not been widely explored. In this study, we compared the concentrations of cerebrospinal fluid (CSF) and serum proteins between children who had TBM-related stroke and children with TBM without stroke. Methods We collected CSF and serum from 47 children consecutively admitted to the Tygerberg Academic Hospital in Cape Town, South Africa between November 2016, and November 2017, on suspicion of having TBM. A multiplex platform was used to measure the concentrations of 69 host proteins in CSF and serum from all study participants. Results After classification of study participants, 23 (48.9%) out of the 47 study participants were diagnosed with TBM, of which 14 (60.9%) demonstrated radiological arterial ischemic infarction. The levels of lipocalin-2, sRAGE, IP-10/ CXCL10, sVCAM-1, MMP-1, and PDGF-AA in CSF samples and the levels of D-dimer, ADAMTS13, SAA, ferritin, MCP-1/ CCL2, GDF-15 and IL-13 in serum samples were statistically different between children who had TBM-related stroke and children with TBM without stroke. After correcting for multiple testing, only the levels of sVCAM-1, MMP-1, sRAGE, and IP-10/ CXCL10 in CSF were statistically different between the two groups. CSF and serum protein biosignatures indicated stroke in children diagnosed with TBM with up to 100% sensitivity and 88.9% specificity. Conclusion Serum and CSF proteins may serve as biomarkers for identifying individuals with stroke amongst children diagnosed with TBM at admission and may guide us to understand the biology of stroke in TBM. This was a pilot study, and thus further investigations in larger studies are needed.

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OC 8277 IDENTIFICATION OF NEW CEREBROSPINAL FLUID AND BLOOD-BASED BIOMARKERS FOR THE DIAGNOSIS OF TUBERCULOUS MENINGITIS IN CHILDREN

BMJ Global Health ◽

10.1136/bmjgh-2019-edc.6 ◽

2019 ◽

Vol 4 (Suppl 3) ◽

pp. A3.2-A3

Author(s):

Masilo Charles Manyelo ◽

Regan S Solomons ◽

Gerhard Walzl ◽

Novel N Chegou

Keyword(s):

Cerebrospinal Fluid ◽

Tuberculous Meningitis ◽

Point Of Care ◽

Extrapulmonary Tuberculosis ◽

Diagnostic Delay ◽

Severe Form ◽

High Morbidity ◽

Serum Samples ◽

Meningitis In Children ◽

Study Participants

BackgroundTuberculous meningitis (TBM) is the most severe form of extrapulmonary tuberculosis (TB). It mostly affects young children and results in high morbidity and mortality, mainly due to diagnostic delay. There is an urgent need for new tests for the earlier and accurate diagnosis of the disease. We previously identified a 3-marker cerebrospinal fluid (CSF) biosignature (VEGF, IL-13, and LL-37) with potential to diagnose TBM. In the present study, we show that CSF and blood-based biosignatures may be useful in the diagnosis of TBM.MethodsCSF and serum samples were consecutively collected from 47 children that were admitted to the Tygerberg Academic Hospital in Cape Town, South Africa, on suspicion of having TBM. Using a multiplex platform, the concentrations of 69 host markers were evaluated in the CSF and serum samples from all the study participants, followed by statistical analysis to ascertain the usefulness of these biomarkers as diagnostic candidates for TBM disease.ResultsOut of the 47 study participants, 23 (48.9%) were finally diagnosed with TBM and 6 (12.8%) were infected with HIV. Several CSF and serum biomarkers showed potential individually as diagnostic candidates for TBM as ascertained by area under the receiver operator characteristics curve (AUC). However, the main findings of our study were the identification of a four-marker CSF biosignature which diagnosed TBM with an AUC of 0.97 (95% CI, 0.92–1.00), and a 3-marker serum biosignature which diagnosed TBM with an AUC of 0.84 (95% CI, 0.73–0.96). We also validated a previously identified 3-marker CSF biosignature (VEGF, IL13 and LL37) in the study.ConclusionCSF and serum biosignatures may be useful in the diagnosis of TBM in children. Our findings require further validation in larger, multi-site studies after which the biosignatures may be incorporated into point-of-care diagnostic tests for TBM.

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A unique protein in normal human cerebrospinal fluid.

Clinical Chemistry ◽

10.1093/clinchem/29.10.1842 ◽

1983 ◽

Vol 29 (10) ◽

pp. 1842-1844 ◽

Cited By ~ 4

Author(s):

N M Papadopoulos ◽

P A LeWitt ◽

R P Newman ◽

M I Raphaelson ◽

T N Chase

Keyword(s):

Cerebrospinal Fluid ◽

Serum Proteins ◽

Normal Volunteer ◽

Protein Band ◽

Serum Samples ◽

Immunofixation Electrophoresis ◽

Normal Human ◽

Monospecific Antibodies ◽

Immunoprecipitation Reaction ◽

Individual Human

Abstract On analysis of cerebrospinal fluid (CSF) samples from normal volunteer donors by high-resolution zone electrophoresis on agarose gel, an electrophoretically homogeneous protein band consistently appeared in the gamma-globulin region. Application of immunofixation electrophoresis in attempts to identify the band with use of monospecific antibodies against individual human serum proteins and against heavy- and light-chain immunoglobulins as well as polyvalent antisera did not produce a positive immunoprecipitation reaction with the protein band. The serum samples from these subjects did not show similar bands. Therefore, we conclude that this protein band is a normally occurring protein that is unique to CSF.

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SERUM-PROTEINS AND CEREBROSPINAL-FLUID PROTEIN IN TUBERCULOUS MENINGITIS

The Lancet ◽

10.1016/s0140-6736(57)91580-5 ◽

1957 ◽

Vol 270 (7008) ◽

pp. 1288

Author(s):

Z ERDOS

Keyword(s):

Cerebrospinal Fluid ◽

Tuberculous Meningitis ◽

Serum Proteins ◽

Cerebrospinal Fluid Protein

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Faculty Opinions recommendation of Rapid diagnosis of tuberculous meningitis by T cell-based assays on peripheral blood and cerebrospinal fluid mononuclear cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.3272966.2961056 ◽

2010 ◽

Author(s):

Phillip Peterson ◽

Bryan Rock

Keyword(s):

Cerebrospinal Fluid ◽

T Cell ◽

Tuberculous Meningitis ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Rapid Diagnosis

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Computer-supported Detection of M-Components and Evaluation of Immunoglobulins after Capillary Electrophoresis

Clinical Chemistry ◽

10.1093/clinchem/47.1.110 ◽

2001 ◽

Vol 47 (1) ◽

pp. 110-117 ◽

Cited By ~ 16

Author(s):

Magnus Jonsson ◽

Joyce Carlson ◽

Jan-Olof Jeppsson ◽

Per Simonsson

Keyword(s):

Capillary Electrophoresis ◽

Decision Support ◽

Protein Separation ◽

Serum Proteins ◽

Cost Effective ◽

Clinical Samples ◽

Serum Samples ◽

Computerized Decision Support ◽

Cost Effective Method ◽

Mathematical Algorithms

Abstract Background: Electrophoresis of serum samples allows detection of monoclonal gammopathies indicative of multiple myeloma, Waldenström macroglobulinemia, monoclonal gammopathy of undetermined significance, and amyloidosis. Present methods of high-resolution agarose gel electrophoresis (HRAGE) and immunofixation electrophoresis (IFE) are manual and labor-intensive. Capillary zone electrophoresis (CZE) allows rapid automated protein separation and produces digital absorbance data, appropriate as input for a computerized decision support system. Methods: Using the Beckman Paragon CZE 2000 instrument, we analyzed 711 routine clinical samples, including 95 monoclonal components (MCs) and 9 cases of Bence Jones myeloma, in both the CZE and HRAGE systems. Mathematical algorithms developed for the detection of monoclonal immunoglobulins (MCs) in the γ- and β-regions of the electropherogram were tested on the entire material. Additional algorithms evaluating oligoclonality and polyclonal concentrations of immunoglobulins were also tested. Results: CZE electropherograms corresponded well with HRAGE. Only one IgG MC of 1 g/L, visible on HRAGE, was not visible after CZE. Algorithms detected 94 of 95 MCs (98.9%) and 100% of those visible after CZE. Of 607 samples lacking an MC on HRAGE, only 3 were identified by the algorithms (specificity, 99%). Algorithms evaluating total gammaglobulinemia and oligoclonality also identified several cases of Bence Jones myeloma. Conclusions: The use of capillary electrophoresis provides a modern, rapid, and cost-effective method of analyzing serum proteins. The additional option of computerized decision support, which provides rapid and standardized interpretations, should increase the clinical availability and usefulness of protein analyses in the future.

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Comparison of plasma and cerebrospinal fluid proteomes identifies gene products guiding adult neurogenesis and neural differentiation in birds

Scientific Reports ◽

10.1038/s41598-021-84274-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Eleni Voukali ◽

Nithya Kuttiyarthu Veetil ◽

Pavel Němec ◽

Pavel Stopka ◽

Michal Vinkler

Keyword(s):

Cerebrospinal Fluid ◽

Adult Neurogenesis ◽

Neural Development ◽

Neural Differentiation ◽

Csf Proteins ◽

Nymphicus Hollandicus ◽

Liquid Chromatography Tandem Mass ◽

Genome Information ◽

Insight Into ◽

Brain Homeostasis

AbstractCerebrospinal fluid (CSF) proteins regulate neurogenesis, brain homeostasis and participate in signalling during neuroinflammation. Even though birds represent valuable models for constitutive adult neurogenesis, current proteomic studies of the avian CSF are limited to chicken embryos. Here we use liquid chromatography–tandem mass spectrometry (nLC-MS/MS) to explore the proteomic composition of CSF and plasma in adult chickens (Gallus gallus) and evolutionarily derived parrots: budgerigar (Melopsittacus undulatus) and cockatiel (Nymphicus hollandicus). Because cockatiel lacks a complete genome information, we compared the cross-species protein identifications using the reference proteomes of three model avian species: chicken, budgerigar and zebra finch (Taeniopygia guttata) and found the highest identification rates when mapping against the phylogenetically closest species, the budgerigar. In total, we identified 483, 641 and 458 unique proteins consistently represented in the CSF and plasma of all chicken, budgerigar and cockatiel conspecifics, respectively. Comparative pathways analyses of CSF and blood plasma then indicated clusters of proteins involved in neurogenesis, neural development and neural differentiation overrepresented in CSF in each species. This study provides the first insight into the proteomics of adult avian CSF and plasma and brings novel evidence supporting the adult neurogenesis in birds.

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COMPARATIVE EVALUATION OF BACTEC 460TB SYSTEM AND LOWENSTEIN-JENSEN MEDIUM FOR THE ISOLATION OF M. TUBERCULOSIS FROM CEREBROSPINAL FLUID SAMPLES OF TUBERCULOUS MENINGITIS PATIENTS

Indian Journal of Medical Microbiology ◽

10.1016/s0255-0857(21)02112-5 ◽

2007 ◽

Vol 25 (3) ◽

pp. 236-240

Author(s):

MM Venkataswamy ◽

W Rafi ◽

S Nagarathna ◽

V Ravi ◽

A Chandramuki

Keyword(s):

Cerebrospinal Fluid ◽

Tuberculous Meningitis ◽

Comparative Evaluation ◽

Lowenstein Jensen

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Weight changes in hypertensive patients with phlegm-dampness syndrome: an integrated proteomics and metabolomics approach

Chinese Medicine ◽

10.1186/s13020-021-00462-x ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Chi Zhang ◽

Li Li ◽

Shiping Cheng ◽

Debajyoti Chowdhury ◽

Yong Tan ◽

...

Keyword(s):

Pathway Analysis ◽

Complement C3 ◽

Integrative Approach ◽

Weight Changes ◽

Serum Samples ◽

Phosphorylated Proteins ◽

Circulating Markers ◽

One Year ◽

Study Participants

Abstract Background Hypertension (HTN) patients who have phlegm-dampness syndrome (PDS) tend to be obese and have worse outcomes. However, the association of body weight (BW) changes and mechanisms underlying the pathophysiology of HTN-PDS are not well elucidated. This study aims to identify the longitudinal observations associated with the circulating markers discriminating BW changes of individuals with HTN-PDS. Methods An integrative approach relying on metabolomics and proteomics was applied to serum samples from HTN-PDS patients in a prospective cohort to identify the plausible mechanistic pathways underpinning HTN-PDS pathophysiology. Study participants were determined to have experienced a weight change if they showed a 5%–15% increase/reduction in BW at the end of the follow-up period. The joint pathway analysis and network analysis were performed using Ingenuity Pathway Analysis (IPA®) on the serum samples obtained from the participants over the period. Results The study involved 22 HTN-PDS patients who were overweight initially and were able to lose enough weight and 24 HTN-PDS individuals who developed overweight from normal BMI during a one-year follow-up. Our analysis suggested three types of phosphatidylcholine (PC) were altered. PC (22:2(13Z,16Z)/24:1(15Z)) and LysoPC (16:1(9Z)) were decreased in Queryweight gain samples, whereas the levels of PC (14:0/16:0) were increased in weight loss samples. The metabolomic analysis suggested 24 metabolites associated with HTN-PDS. Of them, 13 were up-regulated and 11 were down-regulated. The two-dimensional difference gel electrophoresis (2D DIGE) identified 45 phosphorylated proteins got altered in the HTN-PDS patients, wherein 23 were up-regulated and 22 were down-regulated. Integrated proteomic and metabolomics analyse acknowledged biomarkers PC, Complement C3, C4a/C4b, A2M and SERPINF1 as strong predictors for BW changes in HTN-PDS patients. Conclusion The combined serum proteomic and metabolomic profiling reveals a link between BW change and the complement system activity, altered phosphatidylcholine metabolism in HTN-PDS patients. Future studies with larger cohorts are required to strengthen and validate these findings.

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