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1.
JCI Insight ; 1(10): e87919, 2016 07 07.
Article in English | MEDLINE | ID: mdl-27699221

ABSTRACT

BACKGROUND: Children treated with cerebrospinal fluid (CSF) shunts to manage hydrocephalus frequently develop shunt failure and/or infections, conditions that present with overlapping symptoms. The potential life-threatening nature of shunt infections requires rapid diagnosis; however, traditional microbiology is time consuming, expensive, and potentially unreliable. We set out to identify a biomarker that would identify shunt infection. METHODS: CSF was assayed for the soluble membrane attack complex (sMAC) by ELISA in patients with suspected shunt failure or infection. CSF was obtained at the time of initial surgical intervention. Statistical analysis was performed to assess the diagnostic potential of sMAC in pyogenic-infected versus noninfected patients. RESULTS: Children with pyogenic shunt infection had significantly increased sMAC levels compared with noninfected patients (3,211 ± 1,111 ng/ml vs. 26 ± 3.8 ng/ml, P = 0.0001). In infected patients undergoing serial CSF draws, sMAC levels were prognostic for both positive and negative clinical outcomes. Children with delayed, broth-only growth of commensal organisms (P. acnes, S. epidermidis, etc.) had the lowest sMAC levels (7.96 ± 1.7 ng/ml), suggesting contamination rather than shunt infection. CONCLUSION: Elevated CSF sMAC levels are both sensitive and specific for diagnosing pyogenic shunt infection and may serve as a useful prognostic biomarker during recovery from infection. FUNDING: This work was supported in part by the Impact Fund of Children's of Alabama.


Subject(s)
Cerebrospinal Fluid Shunts , Complement Membrane Attack Complex/cerebrospinal fluid , Surgical Wound Infection/diagnosis , Alabama , Child , Child, Preschool , Female , Humans , Hydrocephalus/surgery , Infant , Male , Surgical Wound Infection/microbiology
2.
J Thromb Haemost ; 13(11): 2076-86, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26340319

ABSTRACT

BACKGROUND: Mortality and morbidity in patients with bacterial meningitis result from the proinflammatory response and dysregulation of coagulation and fibrinolysis. Thrombin-activatable fibrinolysis inhibitor (TAFI) is activated by free thrombin or thrombin in complex with thrombomodulin, and plays an antifibrinolytic role during fibrin clot degradation, but also has an anti-inflammatory role by inactivating proinflammatory mediators, such as complement activation products. OBJECTIVE: To assess the role of TAFI in pneumococcal meningitis. METHODS: We performed a prospective nationwide genetic association study in patients with bacterial meningitis, determined TAFI and complement levels in cerebrospinal fluid (CSF), and assessed the function of TAFI in a pneumococcal meningitis mouse model by using Cpb2 (TAFI) knockout mice. RESULTS: Polymorphisms (reference sequences: rs1926447 and rs3742264) in the CPB2 gene, coding for TAFI, were related to the development of systemic complications in patients with pneumococcal meningitis. Higher protein levels of TAFI in CSF were significantly associated with CSF complement levels (C3a, iC3b, and C5b-9) and with more systemic complications in patients with bacterial meningitis. The risk allele of rs1926447 (TT) was associated with higher levels of TAFI in CSF. In the murine model, consistent with the human data, Cpb2-deficient mice had decreased disease severity, as reflected by lower mortality, and attenuated cytokine levels and bacterial outgrowth in the systemic compartment during disease, without differences in the brain compartment, as compared with wild-type mice. CONCLUSIONS: These findings suggest that TAFI plays an important role during pneumococcal meningitis, which is likely to be mediated through inhibition of the complement system, and influences the occurrence of systemic complications and inflammation.


Subject(s)
Carboxypeptidase B2/physiology , Meningitis, Meningococcal/cerebrospinal fluid , Meningitis, Pneumococcal/cerebrospinal fluid , Polymorphism, Single Nucleotide , Adult , Aged , Animals , Brain Damage, Chronic/etiology , Carboxypeptidase B2/cerebrospinal fluid , Carboxypeptidase B2/deficiency , Carboxypeptidase B2/genetics , Cerebral Hemorrhage/etiology , Community-Acquired Infections/blood , Community-Acquired Infections/cerebrospinal fluid , Community-Acquired Infections/complications , Community-Acquired Infections/genetics , Complement C3a/cerebrospinal fluid , Complement C3b/cerebrospinal fluid , Complement Membrane Attack Complex/cerebrospinal fluid , Cytokines/blood , Female , Fibrinolysis , Humans , Male , Meningitis, Meningococcal/blood , Meningitis, Meningococcal/complications , Meningitis, Meningococcal/genetics , Meningitis, Pneumococcal/blood , Meningitis, Pneumococcal/complications , Meningitis, Pneumococcal/genetics , Mice , Mice, Inbred C57BL , Middle Aged , Respiratory Insufficiency/etiology , Shock, Septic/etiology , Treatment Outcome
3.
Scand J Immunol ; 79(2): 127-30, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24313854

ABSTRACT

Neuromyelitis optica (NMO) and multiple sclerosis (MS) are two of the autoimmune inflammatory demyelinating diseases in the central nervous system. Complement is thought to have an important role in pathogenesis of these diseases, especially in NMO. However, the change of terminal complement complex (TCC, C5b-9) in patients with NMO is still unclear. Cerebrospinal fluid (CSF) C3a, C5a, sC5b-9 were measured by enzyme-linked immunosorbent assay in patients with NMO (n = 26), MS (n = 25) and other neurological disease (OND, n = 19). CSF levels of C5a in patients with NMO were higher than patients with OND (P = 0.006). Increased CSF sC5b-9 were found in the patients with NMO compared with patients with MS (P = 0.029) and OND (P = 0.0001). CSF sC5b-9 in patients with MS were also higher than patients with OND (P = 0.030). Patients with NMO revealed a trend to an increased disease disability with increased CSF sC5b-9 during relapse but not in MS (NMO: P = 0.006, MS: P = 0.097). CSF levels of sC5b-9 are increased in patients with NMO and reflect the activation of complement in NMO.


Subject(s)
Complement Membrane Attack Complex/cerebrospinal fluid , Neuromyelitis Optica/immunology , Adult , Complement C3a/cerebrospinal fluid , Complement C5a/cerebrospinal fluid , Disability Evaluation , Female , Humans , Male , Middle Aged , Neuromyelitis Optica/cerebrospinal fluid
4.
Acta Neurochir (Wien) ; 153(1): 90-100, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20686797

ABSTRACT

OBJECT: Complement activation has been suggested to play a role in the development of secondary injuries following traumatic brain injury (TBI). The present study was initiated in order to analyze complement activation in relation to the primary brain injury and to secondary insults, frequently occurring following TBI. METHODS: Twenty patients suffering from severe TBI (Glasgow coma score ≤ 8) were included in the study. The "membrane attack complex," C5b9, which is the cytolytic end product of the complement system was analyzed in cerebrospinal fluid (CSF). The degree of brain tissue damage was assessed using the release of S100B and neuron-specific enolase (NSE) to the CSF and blood. The blood-brain barrier was assessed using the CSF/serum quotient of albumin (Q (A)). RESULTS: Following impact, initial peaks (0-48 h) of C5b9, S100B, and NSE with a concomitant loss of integrity of the blood-brain barrier were observed. Secondary insults at the intensive care unit were monitored. Severe secondary insults were paralleled by a more pronounced complement activation (C5b9 in CSF) as well as increased levels of S100B (measured in CSF), but not with NSE. CONCLUSION: This human study indicates that complement activation in the brain is triggered not only by the impact of trauma per se but also by the amount of secondary insults that frequently occur at the scene of accident as well as during treatment in the neurointensive care unit. Complement activation and in particular the end product C5b9 may in turn contribute to additional secondary brain injuries by its membrane destructive properties.


Subject(s)
Brain Injuries/blood , Brain Injuries/cerebrospinal fluid , Complement Activation/physiology , Complement Membrane Attack Complex/metabolism , Nerve Growth Factors/metabolism , S100 Proteins/metabolism , Adult , Aged , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Brain Injuries/enzymology , Complement Membrane Attack Complex/cerebrospinal fluid , Female , Humans , Male , Middle Aged , Nerve Growth Factors/blood , Nerve Growth Factors/cerebrospinal fluid , Phosphopyruvate Hydratase/blood , Phosphopyruvate Hydratase/cerebrospinal fluid , Phosphopyruvate Hydratase/metabolism , S100 Calcium Binding Protein beta Subunit , S100 Proteins/blood , S100 Proteins/cerebrospinal fluid , Up-Regulation/physiology , Young Adult
5.
J Neurotrauma ; 24(1): 174-80, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17263681

ABSTRACT

Although coagulopathy is known to be the major contributor to a poor outcome of traumatic brain injury (TBI), the mechanisms that trigger coagulation abnormalities have not been studied in detail. We undertook a prospective observational study at a neurosurgical ICU (NICU) in a university hospital. We examined 11 patients with severe isolated TBI, at admittance to the hospital and during the next 3 days. We collected cerebrovenous blood samples from a jugular bulb catheter, arterial blood, and cerebrospinal fluid (CSF) samples. We measured concentrations of thrombin-antithrombin complex (TAT), fibrin D-dimer (DD), prothrombin fragment 1 + 2 (F1 + 2), interleukin-6 (IL-6), and complement complex (C5b-9). All patients had some degree of consumption coagulopathy at the study start and a tendency to thrombocytopenia during the next few days. Levels of DD (3.6 +/- 2.7 mg/L), TAT (86 +/- 72 microg/L) and F1 + 2 (5.9 +/- 6.8 nmol/L) were significantly increased shortly after the trauma compared to reference values, with considerable transcranial gradients for TAT (49 microg/L) and F1 + 2 (3.2 nmol/L). Compared to controls, IL-6 levels were increased more than a hundredfold in both blood (283 +/- 192 ng/L) and CSF (424 +/- 355 ng/L) samples, with a transcranial gradient at the study start (107 ng/L). C5b-9 levels were moderately increased in blood samples, 270 +/- 114 microg/L, versus controls, 184 +/- 39 (p < 0.05). We conclude that activation of the coagulation system takes place during the passage of blood through the damaged brain, and is already evident hours after the trauma. IL-6 and activation of the complement system (C5b-9) co-vary with hemostatic parameters in TBI patients.


Subject(s)
Blood Coagulation Disorders/blood , Blood Coagulation Disorders/etiology , Brain Injuries/blood , Brain Injuries/complications , Accidents , Adult , Antithrombins/chemistry , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Blood Coagulation Tests , Complement Membrane Attack Complex/cerebrospinal fluid , Complement Membrane Attack Complex/metabolism , Female , Fibrin/metabolism , Glasgow Coma Scale , Humans , Inflammation/blood , Interleukin-6/blood , Interleukin-6/cerebrospinal fluid , International Normalized Ratio , Male , Middle Aged , Peptide Fragments/blood , Prospective Studies , Prothrombin , Thrombin/chemistry
6.
Lupus ; 12(11): 846-50, 2003.
Article in English | MEDLINE | ID: mdl-14667101

ABSTRACT

The objective was to study the occurrence of autoantibodies and cytokines in serum and cerebrospinal fluid (CSF) in neuropsychiatric systemic lupus erythematosus (NPSLE). In total, 28 consecutive patients with NPSLE and 16 systemic lupus erythematosus (SLE) patients without neuropsychiatric involvement (non-NPSLE) were studied. IFN-alpha, IL-6, IL-10, soluble terminal complement complex (TCC), anti-ribosomal P protein antibodies (anti-P) and anti-cardiolipin antibodies (aCL) were measured in serum and CSF by immunoassays. Analyses of white blood cell differential count, CSF-albumin/serum-albumin ratio, IgG-index in CSF and isoelectric focusing in serum and CSF were also performed. CSF specimens from 23 healthy individuals were used as controls. IFN-alpha was elevated in the CSF of 5 of 28 NPSLE patients compared to three of 14 among the non-NPSLE patients. IL-6 was elevated in CSF in three of 26 NPSLE patients. Normal concentration of IL-10 was found in CSF in all 27 NPSLE-patients analysed. IFN-alpha in serum was elevated in 18 of 28 NPSLE patients. No distinct clinical phenotype was related to elevated cytokine concentration in serum or CSF. One patient with cerebral involvement complicated by progressive multifocal leukoencephalopathy displayed a very high IFN-alpha concentration in serum. High concentration of TCC was present in CSF from only one patient with systemic vasculitis and focal cerebral symptoms. In conclusion, the results of this study suggest that the diagnostic value of serum and CSF concentrations of IFN-alpha, IL-10, IL-6 and TCC is limited in unselected neuropsychiatric SLE, probably due to the heterogeneity of NPSLE pathogenesis.


Subject(s)
Cytokines/cerebrospinal fluid , Lupus Vasculitis, Central Nervous System/cerebrospinal fluid , Protozoan Proteins , Adolescent , Adult , Aged , Antibodies, Anticardiolipin/blood , Antibodies, Anticardiolipin/cerebrospinal fluid , Antibodies, Antinuclear/blood , Antibodies, Antinuclear/cerebrospinal fluid , Complement Membrane Attack Complex/analysis , Complement Membrane Attack Complex/cerebrospinal fluid , Humans , Interferon-alpha/blood , Interferon-alpha/cerebrospinal fluid , Interleukin-10/blood , Interleukin-10/cerebrospinal fluid , Interleukin-6/blood , Interleukin-6/cerebrospinal fluid , Lupus Erythematosus, Systemic/cerebrospinal fluid , Lupus Vasculitis, Central Nervous System/blood , Lupus Vasculitis, Central Nervous System/diagnosis , Middle Aged , Ribosomal Proteins/blood , Ribosomal Proteins/cerebrospinal fluid
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