Granulocyte-colony–stimulating factor (G-CSF) signaling in spinal microglia drives visceral sensitization following colitis

PubMed Central

Basso, Lilian; Lapointe, Tamia K.; Iftinca, Mircea; Marsters, Candace; Hollenberg, Morley D.; Kurrasch, Deborah M.; Altier, Christophe

2017-01-01

Pain is a main symptom of inflammatory diseases and often persists beyond clinical remission. Although we have a good understanding of the mechanisms of sensitization at the periphery during inflammation, little is known about the mediators that drive central sensitization. Recent reports have identified hematopoietic colony-stimulating factors as important regulators of tumor- and nerve injury-associated pain. Using a mouse model of colitis, we identify the proinflammatory cytokine granulocyte-colony–stimulating factor (G-CSF or Csf-3) as a key mediator of visceral sensitization. We report that G-CSF is specifically up-regulated in the thoracolumbar spinal cord of colitis-affected mice. Our results show that resident spinal microglia express the G-CSF receptor and that G-CSF signaling mediates microglial activation following colitis. Furthermore, healthy mice subjected to intrathecal injection of G-CSF exhibit pronounced visceral hypersensitivity, an effect that is abolished by microglial depletion. Mechanistically, we demonstrate that G-CSF injection increases Cathepsin S activity in spinal cord tissues. When cocultured with microglia BV-2 cells exposed to G-CSF, dorsal root ganglion (DRG) nociceptors become hyperexcitable. Blocking CX3CR1 or nitric oxide production during G-CSF treatment reduces excitability and G-CSF–induced visceral pain in vivo. Finally, administration of G-CSF–neutralizing antibody can prevent the establishment of persistent visceral pain postcolitis. Overall, our work uncovers a DRG neuron–microglia interaction that responds to G-CSF by engaging Cathepsin S-CX3CR1-inducible NOS signaling. This interaction represents a central step in visceral sensitization following colonic inflammation, thereby identifying spinal G-CSF as a target for treating chronic abdominal pain. PMID:28973941

A Normative Data Set for the Clinical Assessment of Achromatic and Chromatic Contrast Sensitivity Using a qCSF Approach.

PubMed

Kim, Yeon Jin; Reynaud, Alexandre; Hess, Robert F; Mullen, Kathy T

2017-07-01

The measurement of achromatic sensitivity has been an important tool for monitoring subtle changes in vision as the result of disease or response to therapy. In this study, we aimed to provide a normative data set for achromatic and chromatic contrast sensitivity functions within a common cone contrast space using an abbreviated measurement approach suitable for clinical practice. In addition, we aimed to provide comparisons of achromatic and chromatic binocular summation across spatial frequency. We estimated monocular cone contrast sensitivity functions (CCSFs) using a quick Contrast Sensitivity Function (qCSF) approach for achromatic as well as isoluminant, L/M cone opponent, and S cone opponent stimuli in a healthy population of 51 subjects. We determined the binocular CCSFs for achromatic and chromatic vision to evaluate the degree of binocular summation across spatial frequency for these three different mechanisms in a subset of 20 subjects. Each data set shows consistent contrast sensitivity across the population. They highlight the extremely high cone contrast sensitivity of L/M cone opponency compared with the S-cone and achromatic responses. We also find that the two chromatic sensitivities are correlated across the healthy population. In addition, binocular summation for all mechanisms depends strongly on stimulus spatial frequency. This study, using an approach well suited to the clinic, is the first to provide a comparative normative data set for the chromatic and achromatic contrast sensitivity functions, yielding quantitative comparisons of achromatic, L/M cone opponent, and S cone opponent chromatic sensitivities as a function of spatial frequency.

Effect of aberrations in human eye on contrast sensitivity function

NASA Astrophysics Data System (ADS)

Quan, Wei; Wang, Feng-lin; Wang, Zhao-qi

2011-06-01

The quantitative analysis of the effect of aberrations in human eye on vision has important clinical value in the correction of aberrations. The wave-front aberrations of human eyes were measured with the Hartmann-Shack wave-front sensor and modulation transfer function (MTF) was computed from the wave-front aberrations. Contrast sensitivity function (CSF) was obtained from MTF and the retinal aerial image modulation (AIM). It is shown that the 2nd, 3rd, 4th, 5th, 6th Zernike aberrations deteriorate contrast sensitivity function. When the 2nd, 3rd, 4th, 5th, 6th Zernike aberrations are corrected high contrast sensitivity function can be obtained.

Repeatability Evaluation of a Contrast Sensitivity System for Transfer to the Eye Clinic

NASA Astrophysics Data System (ADS)

Alcalde, N. G.; Castillo, L. R.; Filgueira, C. Paz; Colombo, E. M.

2016-04-01

The Contrast Sensitivity Function (CSF) is a valuable tool which can be used to characterize functional vision and also for the diagnosis and management of patients with different eye diseases. In spite of its usefulness, the CSF is currently hardly ever used in clinical practice. The aim of this study was to validate the use of the system called FVC-100 (Tecnovinc-UNT-CONICET, Argentina), which calculates the CSF, in order to transfer this important tool to ophthalmological clinics. The validation was carried out through the design of a repeatability test and the subsequent analysis of the results. Furthermore, we evaluated the impact of different factors influencing the repeatability of the measurements such as age and previous training. The tests were based on the discrimination of sinusoidal gratings for different spatial frequencies (1, 4 and 12 c/°) in both eyes of 12 people, aged between 20 and 70. The results show that the calculated values of SC of each subject have a high repeatability and are not dependent on age or training. These results allow us to conclude positively regarding the effectiveness of the FVC-100, and to validate its use in clinics for the calculation of the FSC as a standard measure of functional vision quality.

Refractive index sensor based on lateral-offset of coreless silica interferometer

NASA Astrophysics Data System (ADS)

Baharin, Nur Faizzah; Azmi, Asrul Izam; Abdullah, Ahmad Sharmi; Mohd Noor, Muhammad Yusof

2018-02-01

A compact, cost-effective and high sensitivity fiber interferometer refractive index (RI) sensor based on symmetrical offset coreless silica fiber (CSF) configuration is proposed, optimized and demonstrated. The sensor is formed by splicing a section of CSF between two CSF sections in an offset manner. Thus, two distinct optical paths are created with large index difference, the first path through the connecting CSF sections and the second path is outside the CSF through the surrounding media. RI sensing is established from direct interaction of light with surrounding media, hence high sensitivity can be achieved with a relatively compact sensor length. In the experimental work, a 1.5 mm sensor demonstrates RI sensitivity of 750 nm/RIU for RI range between 1.33 and 1.345. With the main attributes of high sensitivity and compact size, the proposed sensor can be further developed for related applications including blood diagnosis, water quality control and food industries.

Stereo chromatic contrast sensitivity model to blue-yellow gratings.

PubMed

Yang, Jiachen; Lin, Yancong; Liu, Yun

2016-03-07

As a fundamental metric of human visual system (HVS), contrast sensitivity function (CSF) is typically measured by sinusoidal gratings at the detection of thresholds for psychophysically defined cardinal channels: luminance, red-green, and blue-yellow. Chromatic CSF, which is a quick and valid index to measure human visual performance and various retinal diseases in two-dimensional (2D) space, can not be directly applied into the measurement of human stereo visual performance. And no existing perception model considers the influence of chromatic CSF of inclined planes on depth perception in three-dimensional (3D) space. The main aim of this research is to extend traditional chromatic contrast sensitivity characteristics to 3D space and build a model applicable in 3D space, for example, strengthening stereo quality of 3D images. This research also attempts to build a vision model or method to check human visual characteristics of stereo blindness. In this paper, CRT screen was clockwise and anti-clockwise rotated respectively to form the inclined planes. Four inclined planes were selected to investigate human chromatic vision in 3D space and contrast threshold of each inclined plane was measured with 18 observers. Stimuli were isoluminant blue-yellow sinusoidal gratings. Horizontal spatial frequencies ranged from 0.05 to 5 c/d. Contrast sensitivity was calculated as the inverse function of the pooled cone contrast threshold. According to the relationship between spatial frequency of inclined plane and horizontal spatial frequency, the chromatic contrast sensitivity characteristics in 3D space have been modeled based on the experimental data. The results show that the proposed model can well predicted human chromatic contrast sensitivity characteristics in 3D space.

Targeting of colony-stimulating factor 1 receptor (CSF1R) in the CLL microenvironment yields antineoplastic activity in primary patient samples.

PubMed

Edwards V, David K; Sweeney, David Tyler; Ho, Hibery; Eide, Christopher A; Rofelty, Angela; Agarwal, Anupriya; Liu, Selina Qiuying; Danilov, Alexey V; Lee, Patrice; Chantry, David; McWeeney, Shannon K; Druker, Brian J; Tyner, Jeffrey W; Spurgeon, Stephen E; Loriaux, Marc M

2018-05-15

In many malignancies, the tumor microenvironment includes CSF1R-expressing supportive monocyte/macrophages that promote tumor cell survival. For chronic lymphocytic leukemia (CLL), these supportive monocyte/macrophages are known as nurse-like cells (NLCs), although the potential effectiveness of selective small-molecule inhibitors of CSF1R against CLL is understudied. Here, we demonstrate the preclinical activity of two inhibitors of CSF1R, GW-2580 and ARRY-382, in primary CLL patient samples. We observed at least 25% of CLL samples showed sub-micromolar sensitivity to CSF1R inhibitors. This sensitivity was observed in samples with varying genetic and clinical backgrounds, although higher white cell count and monocyte cell percentage was associated with increased sensitivity. Depleting CD14-expressing monocytes preferentially decreased viability in samples sensitive to CSF1R inhibitors, and treating samples with CSF1R inhibitors eliminated the presence of NLCs in long-term culture conditions. These results indicate that CSF1R small-molecule inhibitors target CD14-expressing monocytes in the CLL microenvironment, thereby depriving leukemia cells of extrinsic support signals. In addition, significant synergy was observed combining CSF1R inhibitors with idelalisib or ibrutinib, two current CLL therapies that disrupt tumor cell intrinsic B-cell receptor signaling. These findings support the concept of simultaneously targeting supportive NLCs and CLL cells and demonstrate the potential clinical utility of this combination.

Accurate antemortem diagnosis of equine protozoal myeloencephalitis (EPM) based on detecting intrathecal antibodies against Sarcocystis neurona using the SnSAG2 and SnSAG4/3 ELISAs.

PubMed

Reed, S M; Howe, D K; Morrow, J K; Graves, A; Yeargan, M R; Johnson, A L; MacKay, R J; Furr, M; Saville, W J A; Williams, N M

2013-01-01

Recent work demonstrated the value of antigen-specific antibody indices (AI and C-value) to detect intrathecal antibody production against Sarcocystis neurona for antemortem diagnosis of equine protozoal myeloencephalitis (EPM). The study was conducted to assess whether the antigen-specific antibody indices can be reduced to a simple serum : cerebrospinal fluid (CSF) titer ratio to achieve accurate EPM diagnosis. Paired serum and CSF samples from 128 horses diagnosed by postmortem examination. The sample set included 44 EPM cases, 35 cervical-vertebral malformation (CVM) cases, 39 neurologic cases other than EPM or CVM, and 10 non-neurologic cases. Antibodies against S. neurona were measured in serum and CSF pairs using the SnSAG2 and SnSAG4/3 (SnSAG2, 4/3) ELISAs, and the ratio of each respective serum titer to CSF titer was determined. Likelihood ratios and diagnostic sensitivity and specificity were calculated based on serum titers, CSF titers, and serum : CSF titer ratios. Excellent diagnostic sensitivity and specificity was obtained from the SnSAG2, 4/3 serum : CSF titer ratio. Sensitivity and specificity of 93.2 and 81.1%, respectively, were achieved using a ratio cutoff of ≤100, whereas sensitivity and specificity were 86.4 and 95.9%, respectively, if a more rigorous cutoff of ≤50 was used. Antibody titers in CSF also provided good diagnostic accuracy. Serum antibody titers alone yielded much lower sensitivity and specificity. The study confirms the value of detecting intrathecal antibody production for antemortem diagnosis of EPM, and they further show that the antigen-specific antibody indices can be reduced in practice to a simple serum : CSF titer ratio. Copyright © 2013 by the American College of Veterinary Internal Medicine.

First- and second-order contrast sensitivity functions reveal disrupted visual processing following mild traumatic brain injury.

PubMed

Spiegel, Daniel P; Reynaud, Alexandre; Ruiz, Tatiana; Laguë-Beauvais, Maude; Hess, Robert; Farivar, Reza

2016-05-01

Vision is disrupted by traumatic brain injury (TBI), with vision-related complaints being amongst the most common in this population. Based on the neural responses of early visual cortical areas, injury to the visual cortex would be predicted to affect both 1(st) order and 2(nd) order contrast sensitivity functions (CSFs)-the height and/or the cut-off of the CSF are expected to be affected by TBI. Previous studies have reported disruptions only in 2(nd) order contrast sensitivity, but using a narrow range of parameters and divergent methodologies-no study has characterized the effect of TBI on the full CSF for both 1(st) and 2(nd) order stimuli. Such information is needed to properly understand the effect of TBI on contrast perception, which underlies all visual processing. Using a unified framework based on the quick contrast sensitivity function, we measured full CSFs for static and dynamic 1(st) and 2(nd) order stimuli. Our results provide a unique dataset showing alterations in sensitivity for both 1(st) and 2(nd) order visual stimuli. In particular, we show that TBI patients have increased sensitivity for 1(st) order motion stimuli and decreased sensitivity to orientation-defined and contrast-defined 2(nd) order stimuli. In addition, our data suggest that TBI patients' sensitivity for both 1(st) order stimuli and 2(nd) order contrast-defined stimuli is shifted towards higher spatial frequencies. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Differential Effects of CSF-1R D802V and KIT D816V Homologous Mutations on Receptor Tertiary Structure and Allosteric Communication

PubMed Central

Da Silva Figueiredo Celestino Gomes, Priscila; Panel, Nicolas; Laine, Elodie; Pascutti, Pedro Geraldo; Solary, Eric; Tchertanov, Luba

2014-01-01

The colony stimulating factor-1 receptor (CSF-1R) and the stem cell factor receptor KIT, type III receptor tyrosine kinases (RTKs), are important mediators of signal transduction. The normal functions of these receptors can be compromised by gain-of-function mutations associated with different physiopatological impacts. Whereas KIT D816V/H mutation is a well-characterized oncogenic event and principal cause of systemic mastocytosis, the homologous CSF-1R D802V has not been identified in human cancers. The KIT D816V oncogenic mutation triggers resistance to the RTK inhibitor Imatinib used as first line treatment against chronic myeloid leukemia and gastrointestinal tumors. CSF-1R is also sensitive to Imatinib and this sensitivity is altered by mutation D802V. Previous in silico characterization of the D816V mutation in KIT evidenced that the mutation caused a structure reorganization of the juxtamembrane region (JMR) and facilitated its departure from the kinase domain (KD). In this study, we showed that the equivalent CSF-1R D802V mutation does not promote such structural effects on the JMR despite of a reduction on some key H-bonds interactions controlling the JMR binding to the KD. In addition, this mutation disrupts the allosteric communication between two essential regulatory fragments of the receptors, the JMR and the A-loop. Nevertheless, the mutation-induced shift towards an active conformation observed in KIT D816V is not observed in CSF-1R D802V. The distinct impact of equivalent mutation in two homologous RTKs could be associated with the sequence difference between both receptors in the native form, particularly in the JMR region. A local mutation-induced perturbation on the A-loop structure observed in both receptors indicates the stabilization of an inactive non-inhibited form, which Imatinib cannot bind. PMID:24828813

Does more favourable handling of the cerebrospinal fluid increase the diagnostic sensitivity of Borrelia burgdorferi sensu lato-specific PCR in Lyme neuroborreliosis?

PubMed

Forselv, Kristine J N; Lorentzen, Åslaug R; Ljøstad, Unn; Mygland, Åse; Eikeland, Randi; Kjelland, Vivian; Noraas, Sølvi; Quarsten, Hanne

2018-04-01

Tests for direct detection of Borrelia burgdorferi sensu lato (Bb) in Lyme neuroborreliosis (LNB) are needed. Detection of Bb DNA using PCR is promising, but clinical utility is hampered by low diagnostic sensitivity. We aimed to examine whether diagnostic sensitivity can be improved by the use of larger cerebrospinal fluid (CSF) volumes and faster handling of samples. Patients who underwent CSF examination for LNB were included. We collected two millilitres of CSF for PCR analysis, extracted DNA from the pellets within 24 h and analysed the eluate by two real-time PCR protocols (16S rRNA and OspA). Patients who fulfilled diagnostic criteria for LNB were classified as LNB cases and the rest as controls. Bb DNA in CSF was detected by PCR in seven of 28 adults with LNB. Two were Bb antibody negative. No Bb DNA was detected in CSF from 137 controls. Diagnostic sensitivity was 25% and specificity 100%. There was a non-significant trend towards larger CSF sample volume, faster handling of the sample, shorter duration of symptoms, and higher CSF cell count in the PCR-positive cases. We did not find that optimized handling of CSF increased diagnostic sensitivity of PCR in adults with LNB. However, our case series is small and we hypothesize that the importance of these factors will be clarified in further studies with larger case series and altered study design. PCR for diagnosis of LNB may be useful in cases without Bb antibodies due to short duration of symptoms.

Sensitivity and specificity of western blot testing of cerebrospinal fluid and serum for diagnosis of equine protozoal myeloencephalitis in horses with and without neurologic abnormalities.

PubMed

Daft, Barbara M; Barr, Bradd C; Gardner, Ian A; Read, Deryck; Bell, William; Peyser, Karen G; Ardans, Alex; Kinde, Hailu; Morrow, Jennifer K

2002-10-01

To determine sensitivity and specificity of western blot testing (WBT) of CSF and serum for diagnosis of equine protozoal myeloencephalitis (EPM) in horses with and without neurologic abnormalities. Prospective investigation. 65 horses with and 169 horses without neurologic abnormalities. CSF and serum from horses submitted for necropsy were tested for Sarcocystis neurona-specific antibody with a WBT. Results of postmortem examination were used as the gold standard against which results of the WBT were compared. Sensitivity of WBT of CSF was 87% for horses with and 88% for horses without neurologic abnormalities. Specificity of WBT of CSF was 44% for horses with and 60% for horses without neurologic abnormalities. Regardless of whether horses did or did not have neurologic abnormalities, sensitivity and specificity of WBT of serum were not significantly different from values for WBT of CSF. Ninety-four horses without EPM had histologic evidence of slight CNS inflammation. The low specificity of WBT of CSF indicated that it is inappropriate to diagnose EPM on the basis of a positive test result alone because of the possibility of false-positive test results. The high sensitivity, however, means that a negative result is useful in ruling out EPM. There was no advantage in testing CSF versus serum in horses without neurologic abnormalities. Slight CNS inflammation was common in horses with and without S neurona-specific antibodies in the CSF and should not be considered an indication of CNS infection with S neurona.

Comparison of the Cerebrospinal Fluid (CSF) Toluidine Red Unheated Serum Test and the CSF Rapid Plasma Reagin Test with the CSF Venereal Disease Research Laboratory Test for Diagnosis of Neurosyphilis among HIV-Negative Syphilis Patients in China

PubMed Central

Zhu, Lin; Gu, Xin; Peng, Rui-Rui; Wang, Cuini; Gao, Zixiao; Gao, Ying; Shi, Mei; Guan, Zhifang; Seña, Arlene C.

2014-01-01

In this study, we aimed to investigate the performance of nontreponemal antibody tests in cerebrospinal fluid (CSF) specimens from syphilis patients. From September 2009 to September 2012, CSF specimens were collected at the Shanghai Skin Disease Hospital in Shanghai, China, from 1,132 syphilis patients without HIV infection, including 154 with symptomatic and 56 with asymptomatic neurosyphilis. All of the CSF specimens underwent testing with a rapid plasma reagin (RPR) test, an RPR-V (commercial RPR antigen diluted 1:2 in 10% saline) test, the toluidine red unheated serum test (TRUST), and the Venereal Disease Research Laboratory (VDRL) test. Specificities, sensitivities, positive predictive values (PPVs), negative predictive values (NPVs), and kappa values were calculated to determine the performances of the tests. We compared results of the CSF-VDRL, CSF-RPR, CSF-RPR-V, and CSF-TRUST among patients with symptomatic and asymptomatic neurosyphilis who had reactive CSF-Treponema pallidum particle agglutination (TPPA) test results. Overall, the CSF-VDRL test was reactive in 261 patients (23.1%). There were no cases in which the CSF-VDRL was nonreactive and CSF-RPR, CSF-RPR-V, or CSF-TRUST was reactive. Agreement between the results of CSF-TRUST and CSF-RPR was almost perfect (κ = 0.861), with substantial agreement between the results of CSF-RPR and CSF-RPR-V (κ = 0.740). The sensitivities of CSF-VDRL, CSF-RPR, CSF-RPR-V, and CSF-TRUST were 81.4%, 76.2%, 79.5%, and 76.2%, respectively. Compared to CSF-VDRL, CSF-RPR, CSF-RPR-V, and CSF-TRUST had comparable PPVs and NPVs. However, the specificity of CSF-VDRL (90.3%) was significantly lower than those of the other tests (92.7 to 93.4%). Therefore, CSF-RPR, CSF-RPR-V, and CSF-TRUST can be considered alternative tests for neurosyphilis diagnosis in HIV-negative populations, particularly when the CSF-VDRL is not available. PMID:24335955

CSF inflammatory biomarkers responsive to treatment in progressive multiple sclerosis capture residual inflammation associated with axonal damage.

PubMed

Romme Christensen, Jeppe; Komori, Mika; von Essen, Marina Rode; Ratzer, Rikke; Börnsen, Lars; Bielekova, Bibi; Sellebjerg, Finn

2018-05-01

Development of treatments for progressive multiple sclerosis (MS) is challenged by the lack of sensitive and treatment-responsive biomarkers of intrathecal inflammation. To validate the responsiveness of cerebrospinal fluid (CSF) inflammatory biomarkers to treatment with natalizumab and methylprednisolone in progressive MS and to examine the relationship between CSF inflammatory and tissue damage biomarkers. CSF samples from two open-label phase II trials of natalizumab and methylprednisolone in primary and secondary progressive MS. CSF concentrations of 20 inflammatory biomarkers and CSF biomarkers of axonal damage (neurofilament light chain (NFL)) and demyelination were analysed using electrochemiluminescent assay and enzyme-linked immunosorbent assay (ELISA). In all, 17 natalizumab- and 23 methylprednisolone-treated patients had paired CSF samples. CSF sCD27 displayed superior standardised response means and highly significant decreases during both natalizumab and methylprednisolone treatment; however, post-treatment levels remained above healthy donor reference levels. Correlation analyses of CSF inflammatory biomarkers and NFL before, during and after treatment demonstrated that CSF sCD27 consistently correlates with NFL. These findings validate CSF sCD27 as a responsive and sensitive biomarker of intrathecal inflammation in progressive MS, capturing residual inflammation after treatment. Importantly, CSF sCD27 correlates with NFL, consistent with residual inflammation after anti-inflammatory treatment being associated with axonal damage.

Autocrine CSF-1R signaling drives mesothelioma chemoresistance via AKT activation

PubMed Central

Cioce, M; Canino, C; Goparaju, C; Yang, H; Carbone, M; Pass, H I

2014-01-01

Clinical management of malignant pleural mesothelioma (MPM) is very challenging because of the uncommon resistance of this tumor to chemotherapy. We report here increased expression of macrophage colony-stimulating-factor-1-receptor (M-CSF/CSF-1R) mRNA in mesothelioma versus normal tissue specimens and demonstrate that CSF-1R expression identifies chemoresistant cells of mesothelial nature in both primary cultures and mesothelioma cell lines. By using RNAi or ligand trapping, we demonstrate that the chemoresistance properties of those cells depend on autocrine CSF-1R signaling. At the single-cell level, the isolated CSF-1Rpos cells exhibit a complex repertoire of pluripotency, epithelial–mesenchymal transition and detoxifying factors, which define a clonogenic, chemoresistant, precursor-like cell sub-population. The simple activation of CSF-1R in untransformed mesothelial cells is sufficient to confer clonogenicity and resistance to pemetrexed, hallmarks of mesothelioma. In addition, this induced a gene expression profile highly mimicking that observed in the MPM cells endogenously expressing the receptor and the ligands, suggesting that CSF-1R expression is mainly responsible for the phenotype of the identified cell sub-populations. The survival of CSF1Rpos cells requires active AKT (v-akt murine thymoma viral oncogene homolog 1) signaling, which contributed to increased levels of nuclear, transcriptionally competent β-catenin. Inhibition of AKT reduced the transcriptional activity of β-catenin-dependent reporters and sensitized the cells to senescence-induced clonogenic death after pemetrexed treatment. This work expands what is known on the non-macrophage functions of CSF-1R and its role in solid tumors, and suggests that CSF-1R signaling may have a critical pathogenic role in a prototypical, inflammation-related cancer such as MPM and therefore may represent a promising target for therapeutic intervention. PMID:24722292

USE OF SCORE AND CEREBROSPINAL FLUID LACTATE DOSAGE IN DIFFERENTIAL DIAGNOSIS OF BACTERIAL AND ASEPTIC MENINGITIS.

PubMed

Pires, Frederico Ribeiro; Franco, Andréia Christine Bonotto Farias; Gilio, Alfredo Elias; Troster, Eduardo Juan

2017-01-01

To evaluate Bacterial Meningitis Score (BMS) on its own and in association with Cerebrospinal Fluid (CSF) lactate dosage in order to distinguish bacterial from aseptic meningitis. Children diagnosed with meningitis at a tertiary hospital between January/2011 and December/2014 were selected. All data were obtained upon admission. BMS was applied and included: CSF Gram staining (2 points); CSF neutrophil count ≥1,000 cells/mm3 (1 point); CSF protein ≥80 mg/dL (1 point); peripheral blood neutrophil count ≥10,000 cells/mm3 (1 point) and seizures upon/before arrival (1 point). Cutoff value for CSF lactate was ≥30 mg/dL. Sensitivity, specificity and negative predictive value of several BMS cutoffs and BMS associated with high CSF lactate were evaluated for prediction of bacterial meningitis. Among 439 eligible patients, 94 did not have all data available to complete the score, and 345 patients were included: 7 in bacterial meningitis group and 338 in aseptic meningitis group. As predictive factors of bacterial meningitis, BMS ≥1 had 100% sensitivity (95%CI 47.3-100), 64.2% specificity (58.8-100) and 100% negative predictive value (97.5-100); BMS ≥2 or BMS ≥1 associated with high CSF lactate also showed 100% sensitivity (47.3-100); but 98.5% specificity (96.6-99.5) and 100% negative predictive value (98.3-100). 2 point BMS in association with CSF lactate dosage had the same sensitivity and negative predictive value, with increased specificity for diagnosis of bacterial meningitis when compared with 1-point BMS.

Neurogranin, a synaptic protein, is associated with memory independent of Alzheimer biomarkers.

PubMed

Casaletto, Kaitlin B; Elahi, Fanny M; Bettcher, Brianne M; Neuhaus, John; Bendlin, Barbara B; Asthana, Sanjay; Johnson, Sterling C; Yaffe, Kristine; Carlsson, Cynthia; Blennow, Kaj; Zetterberg, Henrik; Kramer, Joel H

2017-10-24

To determine the association between synaptic functioning as measured via neurogranin in CSF and cognition relative to established Alzheimer disease (AD) biomarkers in neurologically healthy older adults. We analyzed CSF concentrations of neurogranin, β-amyloid (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau) among 132 neurologically normal older adults (mean 64.5, range 55-85), along with bilateral hippocampal volumes and a measure of episodic memory (Auditory Verbal Learning Test, delayed recall). Univariable analyses examined the relationship between neurogranin and the other AD-related biomarkers. Multivariable regression models examined the relationship between neurogranin and delayed recall, adjusting for age and sex, and interaction terms (neurogranin × AD biomarkers). Higher neurogranin concentrations were associated with older age (ρ = 0.20, p = 0.02), lower levels of p-tau and t-tau, and smaller hippocampal volumes ( p < 0.03), but not with CSF Aβ42 ( p = 0.18). In addition, CSF neurogranin demonstrated a significant relationship with memory performance independent of the AD-related biomarkers; individuals with the lowest CSF neurogranin concentrations performed better on delayed recall than those with medium or high CSF neurogranin concentrations ( p < 0.01). Notably, CSF p-tau, t-tau, and Aβ42 and hippocampal volumes were not significantly associated with delayed recall scores ( p > 0.40), and did not interact with neurogranin to predict memory ( p > 0.10). Synaptic dysfunction (assessed via neurogranin) may be an early pathologic process in age-related neurodegeneration, and a sensitive marker of age-related cognitive abilities, potentially preceding or even acting independently from AD pathogenesis. Synaptic functioning may be a useful early marker of cognitive aging and possibly a target for future brain aging interventions. © 2017 American Academy of Neurology.

Inhibition of the CSF-1 receptor sensitizes ovarian cancer cells to cisplatin.

PubMed

Yu, Rong; Jin, Hao; Jin, Congcong; Huang, Xuefeng; Lin, Jinju; Teng, Yili

2018-03-01

Ovarian cancer is one of the most common female malignancies, and cisplatin-based chemotherapy is routinely used in locally advanced ovarian cancer patients. Acquired or de novo cisplatin resistance remains the barrier to patient survival, and the mechanisms of cisplatin resistance are still not well understood. In the current study, we found that colony-stimulating-factor-1 receptor (CSF-1R) was upregulated in cisplatin-resistant SK-OV-3 and CaoV-3 cells. Colony-stimulating-factor-1 receptor knockdown suppressed proliferation and enhanced apoptosis in cisplatin-resistant SK-OV-3 and CaoV-3 cells. However, CSF-1R overexpression had inverse effects. While parental SK-OV-3 and CaoV-3 cells were more resistant to cisplatin after CSF-1R overexpression, CSF-1R knockdown in SK-OV-3 and CaoV-3 cells promoted cisplatin sensitivity. Overexpression and knockdown studies also showed that CSF-1R significantly promoted active AKT and ERK1/2 signalling pathways in cisplatin-resistant cells. Furthermore, a combination of cisplatin and CSF-1R inhibitor effectively inhibited tumour growth in xenografts. Taken together, our results provide the first evidence that CSF-1R inhibition can sensitize cisplatin-refractory ovarian cancer cells. This study may help to increase understanding of the molecular mechanisms underlying cisplatin resistance in tumours. Copyright © 2018 John Wiley & Sons, Ltd.

Perceptual color difference metric including a CSF based on the perception threshold

NASA Astrophysics Data System (ADS)

Rosselli, Vincent; Larabi, Mohamed-Chaker; Fernandez-Maloigne, Christine

2008-01-01

The study of the Human Visual System (HVS) is very interesting to quantify the quality of a picture, to predict which information will be perceived on it, to apply adapted tools ... The Contrast Sensitivity Function (CSF) is one of the major ways to integrate the HVS properties into an imaging system. It characterizes the sensitivity of the visual system to spatial and temporal frequencies and predicts the behavior for the three channels. Common constructions of the CSF have been performed by estimating the detection threshold beyond which it is possible to perceive a stimulus. In this work, we developed a novel approach for spatio-chromatic construction based on matching experiments to estimate the perception threshold. It consists in matching the contrast of a test stimulus with that of a reference one. The obtained results are quite different in comparison with the standard approaches as the chromatic CSFs have band-pass behavior and not low pass. The obtained model has been integrated in a perceptual color difference metric inspired by the s-CIELAB. The metric is then evaluated with both objective and subjective procedures.

Theoretical and experimental investigation of near-infrared light propagation in a model of the adult head.

PubMed

Okada, E; Firbank, M; Schweiger, M; Arridge, S R; Cope, M; Delpy, D T

1997-01-01

Near-infrared light propagation in various models of the adult head is analyzed by both time-of-flight measurements and mathematical prediction. The models consist of three- or four-layered slabs, the latter incorporating a clear cerebrospinal fluid (CSF) layer. The most sophisticated model also incorporates slots that imitate sulci on the brain surface. For each model, the experimentally measured mean optical path length as a function of source-detector spacing agrees well with predictions from either a Monte Carlo model or a finite-element method based on diffusion theory or a hybrid radiosity-diffusion theory. Light propagation in the adult head is shown to be highly affected by the presence of the clear CSF layer, and both the optical path length and the spatial sensitivity profile of the models with a CSF layer are quite different from those without the CSF layer. However, the geometry of the sulci and the boundary between the gray and the white matter have little effect on the detected light distribution.

Highly Expressed Granulocyte Colony-Stimulating Factor (G-CSF) and Granulocyte Colony-Stimulating Factor Receptor (G-CSFR) in Human Gastric Cancer Leads to Poor Survival.

PubMed

Fan, Zhisong; Li, Yong; Zhao, Qun; Fan, Liqiao; Tan, Bibo; Zuo, Jing; Hua, Kelei; Ji, Qiang

2018-03-23

BACKGROUND Chemotherapy for advanced gastric cancer (GC) patients has been the mainstay of therapy for many years. Although adding anti-angiogenic drugs to chemotherapy improves patient survival slightly, identifying anti-angiogenic therapy-sensitive patients remains challenging for oncologists. Granulocyte colony-stimulating factor (G-CSF) promotes tumor growth and angiogenesis, which can be minimized with the anti-G-CSF antibody. Thus, G-CSF might be a potential tumor marker. However, the effects of G-CSF and G-CSFR expression on GC patient survival remain unclear. MATERIAL AND METHODS Seventy GC tissue samples were collected for G-CSF and G-CSFR detection by immunohistochemistry. A total of 40 paired GC tissues and matched adjacent mucosa were used to measure the G-CSF and G-CSFR levels by ELISA. Correlations between G-CSF/G-CSFR and clinical characteristics, VEGF-A levels and overall survival were analyzed. Biological function and underlying mechanistic investigations were carried out using SGC7901 cell lines, and the effects of G-CSF on tumor proliferation, migration, and tube formation were examined. RESULTS The levels of G-CSFR were upregulated in GC tissues compared to normal mucosa tissues. Higher G-CSF expression was associated with later tumor stages and higher tumor VEGF-A and serum CA724 levels, whereas higher G-CSFR expression was associated with lymph node metastasis. Patients with higher G-CSF expression had shorter overall survival times. In vitro, G-CSF stimulated SGC7901 proliferation and migration through the JAK2/STAT3 pathway and accelerated HUVEC tube formation. CONCLUSIONS These data suggest that increased G-CSF and G-CSFR in tumors leads to unfavorable outcomes for GC patients by stimulating tumor proliferation, migration, and angiogenesis, indicating that these factors are potential tumor targets for cancer treatment.

CSF free light chain identification of demyelinating disease: comparison with oligoclonal banding and other CSF indexes.

PubMed

Gurtner, Kari M; Shosha, Eslam; Bryant, Sandra C; Andreguetto, Bruna D; Murray, David L; Pittock, Sean J; Willrich, Maria Alice V

2018-02-19

Cerebrospinal fluid (CSF) used in immunoglobulin gamma (IgG) index testing and oligoclonal bands (OCBs) are common laboratory tests used in the diagnosis of multiple sclerosis. The measurement of CSF free light chains (FLC) could pose as an alternative to the labor-intensive isoelectric-focusing (IEF) gels used for OCBs. A total of 325 residual paired CSF and serum specimens were obtained after physician-ordered OCB IEF testing. CSF kappa (cKFLC) and lambda FLC (cLFLC), albumin and total IgG were measured. Calculations were performed based on combinations of analytes: CSF sum of kappa and lambda ([cKFLC+cLFLC]), kappa-index (K-index) ([cKFLC/sKFLC]/[CSF albumin/serum albumin]), kappa intrathecal fraction (KFLCIF) {([cKFLC/sKFLC]-[0.9358×CSF albumin/serum albumin]^[0.6687×sKFLC]/cKFLC)} and IgG-index ([CSF IgG/CSF albumin]/[serum IgG/serum albumin]). Patients were categorized as: demyelination (n=67), autoimmunity (n=53), non-inflammatory (n=50), inflammation (n=38), degeneration (n=28), peripheral neuropathy (n=24), infection (n=13), cancer (n=11), neuromyelitis optica (n=10) and others (n=31). cKFLC measurement used alone at a cutoff of 0.0611 mg/dL showed >90% agreement to OCBs, similar or better performance than all other calculations, reducing the number of analytes and variables. When cases of demyelinating disease were reviewed, cKFLC measurements showed 86% clinical sensitivity/77% specificity. cKFLC alone demonstrates comparable performance to OCBs along with increased sensitivity for demyelinating diseases. Replacing OCB with cKFLC would alleviate the need for serum and CSF IgG and albumin and calculated conversions. cKFLC can overcome challenges associated with performance, interpretation, and cost of traditional OCBs, reducing costs and maintaining sensitivity and specificity supporting MS diagnosis.

Cerebrospinal Fluid B-lymphocyte Chemoattractant CXCL13 in the Diagnosis of Acute Lyme Neuroborreliosis in Children.

PubMed

Barstad, Bjørn; Tveitnes, Dag; Noraas, Sølvi; Selvik Ask, Ingvild; Saeed, Maryam; Bosse, Franziskus; Vigemyr, Grete; Huber, Ilka; Øymar, Knut

2017-12-01

Current markers of Lyme neuroborreliosis (LNB) in children have insufficient sensitivity in the early stage of disease. The B-lymphocyte chemoattractant CXCL13 in the cerebrospinal fluid (CSF) may be useful in diagnosing LNB, but its specificity has not been evaluated in studies including children with clinically relevant differential diagnoses. The aim of this study was to elucidate the diagnostic value of CSF CXCL13 in children with symptoms suggestive of LNB. Children with symptoms suggestive of LNB were included prospectively into predefined groups with a high or low likelihood of LNB based on CSF pleocytosis and the detection of Borrelia antibodies or other causative agents. CSF CXCL13 levels were compared between the groups, and receiver-operating characteristic analyses were performed to indicate optimal cutoff levels to discriminate LNB from non-LNB conditions. Two hundred and ten children were included. Children with confirmed LNB (n=59) and probable LNB (n=18) had higher CSF CXCL13 levels than children with possible LNB (n=7), possible peripheral LNB (n=7), non-Lyme aseptic meningitis (n=12), non-meningitis (n=91) and negative controls (n=16). Using 18 pg/mL as a cutoff level, both the sensitivity and specificity of CSF CXCL13 for LNB (confirmed and probable) were 97%. Comparing only children with LNB and non-Lyme aseptic meningitis, the sensitivity and specificity with the same cutoff level were 97% and 83%, respectively. CSF CXCL13 is a sensitive marker of LNB in children. The specificity to discriminate LNB from non-Lyme aseptic meningitis may be more moderate, suggesting that CSF CXCL13 should be used together with other variables in diagnosing LNB in children.

USE OF SCORE AND CEREBROSPINAL FLUID LACTATE DOSAGE IN DIFFERENTIAL DIAGNOSIS OF BACTERIAL AND ASEPTIC MENINGITIS

PubMed Central

Pires, Frederico Ribeiro; Franco, Andréia Christine Bonotto Farias; Gilio, Alfredo Elias; Troster, Eduardo Juan

2017-01-01

ABSTRACT Objective: To evaluate Bacterial Meningitis Score (BMS) on its own and in association with Cerebrospinal Fluid (CSF) lactate dosage in order to distinguish bacterial from aseptic meningitis. Methods: Children diagnosed with meningitis at a tertiary hospital between January/2011 and December/2014 were selected. All data were obtained upon admission. BMS was applied and included: CSF Gram staining (2 points); CSF neutrophil count ≥1,000 cells/mm3 (1 point); CSF protein ≥80 mg/dL (1 point); peripheral blood neutrophil count ≥10,000 cells/mm3 (1 point) and seizures upon/before arrival (1 point). Cutoff value for CSF lactate was ≥30 mg/dL. Sensitivity, specificity and negative predictive value of several BMS cutoffs and BMS associated with high CSF lactate were evaluated for prediction of bacterial meningitis. Results: Among 439 eligible patients, 94 did not have all data available to complete the score, and 345 patients were included: 7 in bacterial meningitis group and 338 in aseptic meningitis group. As predictive factors of bacterial meningitis, BMS ≥1 had 100% sensitivity (95%CI 47.3-100), 64.2% specificity (58.8-100) and 100% negative predictive value (97.5-100); BMS ≥2 or BMS ≥1 associated with high CSF lactate also showed 100% sensitivity (47.3-100); but 98.5% specificity (96.6-99.5) and 100% negative predictive value (98.3-100). Conclusions: 2 point BMS in association with CSF lactate dosage had the same sensitivity and negative predictive value, with increased specificity for diagnosis of bacterial meningitis when compared with 1-point BMS. PMID:29185620

A Simulation Model to Determine Sensitivity and Timeliness of Surveillance Strategies.

PubMed

Schulz, J; Staubach, C; Conraths, F J; Schulz, K

2017-12-01

Animal surveillance systems need regular evaluation. We developed an easily applicable simulation model of the German wild boar population to investigate two evaluation attributes: the sensitivity and timeliness (i.e. the ability to detect a disease outbreak rapidly) of a surveillance system. Classical swine fever (CSF) was used as an example for the model. CSF is an infectious disease that may lead to massive economic losses. It can affect wild boar as well as domestic pigs, and CSF outbreaks in domestic pigs have been linked to infections in wild boar. Awareness of the CSF status in wild boar is therefore vital. Our non-epidemic simulation model is based on real data and evaluates the currently implemented German surveillance system for CSF in wild boar. The results show that active surveillance for CSF fulfils the requirements of detecting an outbreak with 95% confidence within one year after the introduction of CSF into the wild boar population. Nevertheless, there is room for improved performance and efficiency by more homogeneous (active and passive) sampling of wild boar over the year. Passive surveillance alone is not sufficient to meet the requirements for detecting the infection. Although CSF was used as example to develop the model, it may also be applied to the evaluation of other surveillance systems for viral diseases in wild boar. It is also possible to compare sensitivity and timeliness across hypothetical alternative or risk-based surveillance strategies. © 2016 Blackwell Verlag GmbH.

Cerebrospinal fluid lactate: a differential biomarker for bacterial and viral meningitis in children.

PubMed

Nazir, Mudasir; Wani, Wasim Ahmad; Malik, Muzaffar Ahmad; Mir, Mohd Rafiq; Ashraf, Younis; Kawoosa, Khalid; Ali, Syed Wajid

To assess the performance of cerebrospinal fluid (CSF) lactate as a biomarker to differentiate bacterial meningitis from viral meningitis in children, and to define an optimal CSF lactate concentration that can be called significant for the differentiation. Children with clinical findings compatible with meningitis were studied. CSF lactate and other conventional CSF parameters were recorded. At a cut-off value of 3mmol/L, CSF lactate had a sensitivity of 0.90, specificity of 1.0, positive predictive value of 1.0, and negative predictive value of 0.963, with an accuracy of 0.972. The positive and negative likelihood ratios were 23.6 and 0.1, respectively. When comparing between bacterial and viral meningitis, the area under the curve for CSF lactate was 0.979. The authors concluded that CSF lactate has high sensitivity and specificity in differentiating bacterial from viral meningitis. While at a cut-off value of 3mmol/L, CSF lactate has high diagnostic accuracy for bacterial meningitis, mean levels in viral meningitis remain essentially below 2mmol/L. Copyright © 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Biological role of granulocyte macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) on cells of the myeloid lineage

PubMed Central

Ushach, Irina; Zlotnik, Albert

2016-01-01

M-CSF and GM-CSF are 2 important cytokines that regulate macrophage numbers and function. Here, we review their known effects on cells of the macrophage-monocyte lineage. Important clues to their function come from their expression patterns. M-CSF exhibits a mostly homeostatic expression pattern, whereas GM-CSF is a product of cells activated during inflammatory or pathologic conditions. Accordingly, M-CSF regulates the numbers of various tissue macrophage and monocyte populations without altering their "activation" status. Conversely, GM-CSF induces activation of monocytes/macrophages and also mediates differentiation to other states that participate in immune responses [i.e., dendritic cells (DCs)]. Further insights into their function have come from analyses of mice deficient in either cytokine. M-CSF signals through its receptor (CSF-1R). Interestingly, mice deficient in CSF-1R expression exhibit a more significant phenotype than mice deficient in M-CSF. This observation was explained by the discovery of a novel cytokine (IL-34) that represents a second ligand of CSF-1R. Information about the function of these ligands/receptor system is still developing, but its complexity is intriguing and strongly suggests that more interesting biology remains to be elucidated. Based on our current knowledge, several therapeutic molecules targeting either the M-CSF or the GM-CSF pathways have been developed and are currently being tested in clinical trials targeting either autoimmune diseases or cancer. It is intriguing to consider how evolution has directed these pathways to develop; their complexity likely mirrors the multiple functions in which cells of the monocyte/macrophage system are involved. PMID:27354413

Association between Plasma Homocysteine Levels and Neuronal Injury in HIV Infection

PubMed Central

Ahlgren, Erika; Hagberg, Lars; Fuchs, Dietmar; Andersson, Lars-Magnus; Nilsson, Staffan; Zetterberg, Henrik; Gisslén, Magnus

2016-01-01

Objective To investigate the role of homocysteine in neuronal injury in HIV infection. Methods Using a cross-sectional design and archived samples, we compared concentrations of plasma homocysteine and cerebrospinal fluid (CSF) neurofilament light protein (NFL), a sensitive marker of neuronal injury, in 83 HIV-1-infected subjects without antiretroviral treatment. We also analyzed plasma vitamin B12, serum folate, CSF, and plasma HIV RNA, the immune activation marker neopterin in CSF and serum, and albumin ratio as a marker of blood-brain barrier integrity. Twenty-two subjects provided a second sample median of 12.5 months after antiretroviral treatment initiation. Results A significant correlation was found between plasma homocysteine and CSF NFL concentrations in untreated individuals (r = 0.52, p < 0.0001). As expected, there was a significant inverse correlation between homocysteine and B12 (r = –0.41, p < 0.001) and folate (r = –0.40, p = < 0.001) levels. In a multiple linear regression analysis homocysteine stood out as an independent predictor of CSF NFL in HIV-1-infected individuals. The correlation of plasma homocysteine and CSF NFL was also present in the group receiving antiretroviral therapy (r = 0.51, p = 0.016). Conclusion A correlation between plasma homocysteine and axonal injury, as measured by CSF NFL, was found in both untreated and treated HIV. While this study is not able to prove a causal link, homocysteine and functional B12/folate deficiency appear to play a role in neural injury in HIV-infected individuals. PMID:27441551

Association between Plasma Homocysteine Levels and Neuronal Injury in HIV Infection.

PubMed

Ahlgren, Erika; Hagberg, Lars; Fuchs, Dietmar; Andersson, Lars-Magnus; Nilsson, Staffan; Zetterberg, Henrik; Gisslén, Magnus

2016-01-01

To investigate the role of homocysteine in neuronal injury in HIV infection. Using a cross-sectional design and archived samples, we compared concentrations of plasma homocysteine and cerebrospinal fluid (CSF) neurofilament light protein (NFL), a sensitive marker of neuronal injury, in 83 HIV-1-infected subjects without antiretroviral treatment. We also analyzed plasma vitamin B12, serum folate, CSF, and plasma HIV RNA, the immune activation marker neopterin in CSF and serum, and albumin ratio as a marker of blood-brain barrier integrity. Twenty-two subjects provided a second sample median of 12.5 months after antiretroviral treatment initiation. A significant correlation was found between plasma homocysteine and CSF NFL concentrations in untreated individuals (r = 0.52, p < 0.0001). As expected, there was a significant inverse correlation between homocysteine and B12 (r = -0.41, p < 0.001) and folate (r = -0.40, p = < 0.001) levels. In a multiple linear regression analysis homocysteine stood out as an independent predictor of CSF NFL in HIV-1-infected individuals. The correlation of plasma homocysteine and CSF NFL was also present in the group receiving antiretroviral therapy (r = 0.51, p = 0.016). A correlation between plasma homocysteine and axonal injury, as measured by CSF NFL, was found in both untreated and treated HIV. While this study is not able to prove a causal link, homocysteine and functional B12/folate deficiency appear to play a role in neural injury in HIV-infected individuals.

Nontransformed, GM-CSF-dependent macrophage lines are a unique model to study tissue macrophage functions.

PubMed

Fejer, György; Wegner, Mareike Dorothee; Györy, Ildiko; Cohen, Idan; Engelhard, Peggy; Voronov, Elena; Manke, Thomas; Ruzsics, Zsolt; Dölken, Lars; Prazeres da Costa, Olivia; Branzk, Nora; Huber, Michael; Prasse, Antje; Schneider, Robert; Apte, Ron N; Galanos, Chris; Freudenberg, Marina A

2013-06-11

Macrophages are diverse cell types in the first line of antimicrobial defense. Only a limited number of primary mouse models exist to study their function. Bone marrow-derived, macrophage-CSF-induced cells with a limited life span are the most common source. We report here a simple method yielding self-renewing, nontransformed, GM-CSF/signal transducer and activator of transcription 5-dependent macrophages (Max Planck Institute cells) from mouse fetal liver, which reflect the innate immune characteristics of alveolar macrophages. Max Planck Institute cells are exquisitely sensitive to selected microbial agents, including bacterial LPS, lipopeptide, Mycobacterium tuberculosis, cord factor, and adenovirus and mount highly proinflammatory but no anti-inflammatory IL-10 responses. They show a unique pattern of innate responses not yet observed in other mononuclear phagocytes. This includes differential LPS sensing and an unprecedented regulation of IL-1α production upon LPS exposure, which likely plays a key role in lung inflammation in vivo. In conclusion, Max Planck Institute cells offer an useful tool to study macrophage biology and for biomedical science.

Human chorionic gonadotropin detection in cerebrospinal fluid of patients with a germinoma and its prognostic significance: assessment by using a highly sensitive enzyme immunoassay.

PubMed

Fukuoka, Kohei; Yanagisawa, Takaaki; Suzuki, Tomonari; Shirahata, Mitsuaki; Adachi, Jun-Ichi; Mishima, Kazuhiko; Fujimaki, Takamitsu; Katakami, Hideki; Matsutani, Masao; Nishikawa, Ryo

2016-11-01

OBJECTIVE Human chorionic gonadotropin (HCG) can be detected in a certain population of patients with a germinoma, but the frequency of germinoma HCG secretion and the prognostic value of HCG in the CSF are unknown. METHODS The authors measured HCG levels in sera and CSF in patients with a histologically confirmed germinoma by using a highly sensitive assay known as an immune complex transfer enzyme immunoassay (EIA), which is more than 100 times as sensitive as the conventional method, and they analyzed the correlation between HCG levels and the prognoses of patients with a germinoma. RESULTS HCG levels in sera and CSF of 35 patients with a germinoma were examined with the immune complex transfer EIA. The median CSF HCG levels in patients with a germinoma during the pretreatment and posttreatment evaluations were 192.5 pg/ml (range 1.2-13,116.5 pg/ml) and 18.7 pg/ml (1.2-283.9 pg/ml), respectively. Before treatment, the CSF HCG level was greater than the cutoff value in 85.7% of the patients with a germinoma. The authors compared survival rates among the patients by using a CSF HCG cutoff level of 1000 pg/ml, and the difference was statistically significant between the groups (p = 0.029, log-rank test). CONCLUSIONS Results of this study demonstrate that most germinomas secrete HCG. Patients with a germinoma that secretes higher amounts of HCG in their CSF experienced recurrence more frequently than those with lower CSF HCG levels.

Utility of (1-3)-β-D-glucan testing for diagnostics and monitoring response to treatment during the multistate outbreak of fungal meningitis and other infections.

PubMed

Litvintseva, Anastasia P; Lindsley, Mark D; Gade, Lalitha; Smith, Rachel; Chiller, Tom; Lyons, Jennifer L; Thakur, Kiran T; Zhang, Sean X; Grgurich, Dale E; Kerkering, Thomas M; Brandt, Mary E; Park, Benjamin J

2014-03-01

 The 2012 outbreak of fungal meningitis associated with contaminated methylprednisolone produced by a compounding pharmacy has resulted in >750 infections. An important question facing patients and clinicians is the duration of antifungal therapy. We evaluated (1-3)-β-d-glucan (BDG) as a marker for monitoring response to treatment.  We determined sensitivity and specificity of BDG testing using the Fungitell assay, by testing 41 cerebrospinal fluid (CSF) specimens from confirmed cases of fungal meningitis and 66 negative control CSF specimens. We also assessed whether BDG levels correlate with clinical status by using incident samples from 108 case patients with meningitis and 20 patients with serially collected CSF.  A cutoff value of 138 pg/mL provided 100% sensitivity and 98% specificity for diagnosis of fungal meningitis in this outbreak. Patients with serially collected CSF were divided into 2 groups: those in whom BDG levels declined with treatment and those in whom BDG remained elevated. Whereas most patients with a decline in CSF BDG had clinical improvement, all 3 patients with continually elevated BDG had poor clinical outcomes (stroke, meningitis relapse, or development of new disease).  Our data suggest that measuring BDG in CSF is a highly sensitive test for diagnosis of fungal meningitis in this outbreak. Analysis of BDG levels in serially collected CSF demonstrated that BDG may correlate with clinical response. Routine measurement of BDG in CSF may provide useful adjunctive data for the clinical management of patients with outbreak-associated meningitis.

A balanced view of the cerebrospinal fluid composition and functions: Focus on adult humans.

PubMed

Spector, Reynold; Robert Snodgrass, S; Johanson, Conrad E

2015-11-01

In this review, a companion piece to our recent examination of choroid plexus (CP), the organ that secretes the cerebrospinal fluid (CSF), we focus on recent information in the context of reliable older data concerning the composition and functions of adult human CSF. To accomplish this, we define CSF, examine the methodology employed in studying the CSF focusing on ideal or near ideal experiments and discuss the pros and cons of several widely used analogical descriptions of the CSF including: the CSF as the "third circulation," the CSF as a "nourishing liquor," the similarities of the CSF/choroid plexus to the glomerular filtrate/kidney and finally the CSF circulation as part of the "glymphatic system." We also consider the close interrelationship between the CSF and extracellular space of brain through gap junctions and the paucity of data suggesting that the cerebral capillaries secrete a CSF-like fluid. Recently human CSF has been shown to be in dynamic flux with heart-beat, posture and especially respiration. Functionally, the CSF provides buoyancy, nourishment (e.g., vitamins) and endogenous waste product removal for the brain by bulk flow into the venous (arachnoid villi and nerve roots) and lymphatic (nasal) systems, and by carrier-mediated reabsorptive transport systems in CP. The CSF also presents many exogenous compounds to CP for metabolism or removal, indirectly cleansing the extracellular space of brain (e.g., of xenobiotics like penicillin). The CSF also carries hormones (e.g., leptin) from blood via CP or synthesized in CP (e.g., IGF-2) to the brain. In summary the CP/CSF, the third circulation, performs many functions comparable to the kidney including nourishing the brain and contributing to a stable internal milieu for the brain. These tasks are essential to normal adult brain functioning. Copyright © 2015. Published by Elsevier Inc.

Cross-media color reproduction using the frequency-based spatial gamut mapping algorithm based on human color vision

NASA Astrophysics Data System (ADS)

Wu, Guangyuan; Niu, Shijun; Li, Xiaozhou; Hu, Guichun

2018-04-01

Due to the increasing globalization of printing industry, remoting proofing will become the inevitable development trend. Cross-media color reproduction will occur in different color gamuts using remote proofing technologies, which usually leads to the problem of incompatible color gamut. In this paper, to achieve equivalent color reproduction between a monitor and a printer, a frequency-based spatial gamut mapping algorithm is proposed for decreasing the loss of visual color information. The design of algorithm is based on the contrast sensitivity functions (CSF), which exploited CSF spatial filter to preserve luminance of the high spatial frequencies and chrominance of the low frequencies. First we show a general framework for how to apply CSF spatial filter in retention of relevant visual information. Then we compare the proposed framework with HPMINDE, CUSP, Bala's algorithm. The psychophysical experimental results indicated the good performance of the proposed algorithm.

Detection by PCR of Enteroviruses in Cerebrospinal Fluid during a Summer Outbreak of Aseptic Meningitis in Switzerland

PubMed Central

Gorgievski-Hrisoho, Meri; Schumacher, Jean-Daniel; Vilimonovic, Nevenka; Germann, Daniel; Matter, Lukas

1998-01-01

Enteroviruses (EV) are among the most common causes of aseptic meningitis. Standard diagnostic techniques are often too slow and lack sensitivity to be of clinical relevance. EV RNA can be detected within 5 h by a commercially available reverse transcription-PCR (RT-PCR) test kit. Cerebrospinal fluid (CSF) samples from 68 patients presenting with aseptic meningitis during a summer outbreak in Switzerland were examined in parallel with cell culture and commercial RT-PCR. RT-PCR was positive in all 16 CSF specimens positive by cell culture (100%). In addition, 42 of 52 (80%) CSF samples negative by cell culture were PCR positive. In 26 of these 42 (62%) patients, viral culture from other sites (throat swab or stool) was also positive. The CSF virus culture took 3 to 7 days to become positive. Echovirus 30 was the type most often isolated in this outbreak. The sensitivity of CSF RT-PCR based on clinical diagnosis during this aseptic meningitis outbreak in patients with negative bacterial culture results was 85%, i.e., considerably higher than the sensitivity of CSF virus culture (24%). We conclude that this commercial RT-PCR assay allows a positive diagnosis with minimal delay and may thus influence clinical decisions. PMID:9705364

[Endoscopic endonasal detection of cerebrospinal fluid leakage with topical fluorescein].

PubMed

Sato, Taku; Kishida, Yugo; Watanabe, Tadashi; Tani, Akiko; Tada, Yasuhiro; Tamura, Takamitsu; Ichikawa, Masahiro; Sakuma, Jun; Omori, Koichi; Saito, Kiyoshi

2013-08-01

We evaluated the effectiveness of intraoperative topical application of fluorescein to detect the leakage point of cerebrospinal fluid(CSF)rhinorrhea. Three patients with CSF rhinorrhea were treated with an endoscopic endonasal technique. Ten percent fluorescein was topically used for intraoperative localization of the leak site. A change of the fluorescein color from brown to green due to dilation of CSF were recognized as evidence of CSF rhinorrhea. We repeated the procedure to detect any small defects. All CSF rhinorrheas were successfully repaired by this endoscopic endonasal approach. Topical application of fluorescein is simple and sensitive for identifying intraoperative CSF rhinorrhea.

The use of dried cerebrospinal fluid filter paper spots as a substrate for PCR diagnosis of the aetiology of bacterial meningitis in the Lao PDR

PubMed Central

Elliott, I; Dittrich, S; Paris, D; Sengduanphachanh, A; Phoumin, P; Newton, P N

2013-01-01

We investigated whether dried cerebrospinal fluid (CSF) conserved on filter paper can be used as a substrate for accurate PCR diagnosis of important causes of bacterial meningitis in the Lao PDR. Using mock CSF, we investigated and optimized filter paper varieties, paper punch sizes, elution volumes and quantities of DNA template to achieve sensitive and reliable detection of bacterial DNA from filter paper specimens. FTA Elute Micro Card™ (Whatman, Maidstone, UK) was the most sensitive, consistent and practical variety of filter paper. Following optimization, the lower limit of detection for Streptococcus pneumoniae from dried mock CSF spots was 14 genomic equivalents (GE)/μL (interquartile range 5.5 GE/μL) or 230 (IQR 65) colony forming units/mL. A prospective clinical evaluation for S. pneumoniae, S. suis and Neisseria meningitidis was performed. Culture and PCR performed on fresh liquid CSF from patients admitted with a clinical diagnosis of meningitis (n = 73) were compared with results derived from dried CSF spots. Four of five fresh PCR-positive CSF samples also tested PCR positive from dried CSF spots, with one patient under the limit of detection. In a retrospective study of S. pneumoniae samples (n = 20), the median (IQR; range) CSF S. pneumoniae bacterial load was 1.1 × 104 GE/μL (1.2 × 105; 1 to 6.1 × 106 DNA GE/μL). Utilizing the optimized methodology, we estimate an extrapolated sensitivity of 90%, based on the range of CSF genome counts found in Laos. Dried CSF filter paper spots could potentially help us to better understand the epidemiology of bacterial meningitis in resource-poor settings and guide empirical treatments and vaccination policies. PMID:23738720

Antimicrobial sensitivity patterns of cerebrospinal fluid (CSF) isolates in Namibia: implications for empirical antibiotic treatment of meningitis.

PubMed

Mengistu, Assegid; Gaeseb, Johannes; Uaaka, Gottfried; Ndjavera, Christophine; Kambyambya, Kennedy; Indongo, Lazarus; Kalemeera, Francis; Ntege, Christopher; Mabirizi, David; Joshi, Mohan P; Sagwa, Evans

2013-01-01

Bacterial meningitis is a medical emergency associated with high mortality rates. Cerebrospinal fluid (CSF) culture is the "gold standard" for diagnosis of meningitis and it is important to establish the susceptibility of the causative microorganism to rationalize treatment. The Namibia Standard Treatment Guidelines (STGs) recommends initiation of empirical antibiotic treatment in patients with signs and symptoms of meningitis after taking a CSF sample for culture and sensitivity. The objective of this study was to assess the antimicrobial sensitivity patterns of microorganisms isolated from CSF to antibiotics commonly used in the empirical treatment of suspected bacterial meningitis in Namibia. This was a cross-sectional descriptive study of routinely collected antibiotic susceptibility data from the Namibia Institute of Pathology (NIP) database. Results of CSF culture and sensitivity from January 1, 2009 to May 31, 2012, from 33 state hospitals throughout Namibia were analysed. The most common pathogens isolated were Streptococcus species, Neisseria meningitidis, Haemophilus influenzae, Staphylococcus, and Escherichia coli. The common isolates from CSF showed high resistance (34.3% -73.5%) to penicillin. Over one third (34.3%) of Streptococcus were resistance to penicillin which was higher than 24.8% resistance in the United States. Meningococci were susceptible to several antimicrobial agents including penicillin. The sensitivity to cephalosporins remained high for Streptococcus, Neisseria, E. coli and Haemophilus. The highest percentage of resistance to cephalosporins was seen among ESBL K. pneumoniae (n = 7, 71%-100%), other Klebsiella species (n = 7, 28%-80%), and Staphylococcus (n = 36, 25%-40%). The common organisms isolated from CSF were Streptococcus Pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Staphylococcus, and E. coli. All common organisms isolated from CSF showed high sensitivity to cephalosporins used in the empirical treatment of meningitis. The resistance of the common isolates to penicillin is high. Most ESBL K. pneumoniae were isolated from CSF samples drawn from neonates and were found to be resistant to the antibiotics recommended in the Namibia STGs. Based on the above findings, it is recommended to use a combination of aminoglycoside and third-generation cephalosporin to treat non-ESBL Klebsiella isolates. Carbapenems (e.g., meropenem) and piperacillin/tazobactam should be considered for treating severely ill patients with suspected ESBL Klebsiella infection. Namibia should have a national antimicrobial resistance surveillance system for early detection of antibiotics that may no longer be effective in treating meningitis and other life-threatening infections due to resistance.

Risk score for identifying adults with CSF pleocytosis and negative CSF Gram stain at low risk for an urgent treatable cause.

PubMed

Hasbun, Rodrigo; Bijlsma, Merijn; Brouwer, Matthijs C; Khoury, Nabil; Hadi, Christiane M; van der Ende, Arie; Wootton, Susan H; Salazar, Lucrecia; Hossain, Md Monir; Beilke, Mark; van de Beek, Diederik

2013-08-01

We aimed to derive and validate a risk score that identifies adults with cerebrospinal fluid (CSF) pleocytosis and a negative CSF Gram stain at low risk for an urgent treatable cause. Patients with CSF pleocytosis and a negative CSF Gram stain were stratified into a prospective derivation (n = 193) and a retrospective validation (n = 567) cohort. Clinically related baseline characteristics were grouped into three composite variables, each independently associated with a set of predefined urgent treatable causes. We subsequently derived a risk score classifying patients into low (0 composite variables present) or high (≥ 1 composite variables present) risk for an urgent treatable cause. The sensitivity of the risk score was determined in the validation cohort and in a prospective case series of 214 adults with CSF-culture proven bacterial meningitis, CSF pleocytosis and a negative Gram stain. A total of 41 of 193 patients (21%) in the derivation cohort and 71 of 567 (13%) in the validation cohort had an urgent treatable cause. Sensitivity of the dichotomized risk score to detect an urgent treatable cause was 100.0% (95% CI 93.9-100.0%) in the validation cohort and 100.0% (95% CI 97.8-100.0%) in bacterial meningitis patients. The risk score can be used to identify adults with CSF pleocytosis and a negative CSF Gram stain at low risk for an urgent treatable cause. Copyright © 2013 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

RISK SCORE FOR IDENTIFYING ADULTS WITH CSF PLEOCYTOSIS AND NEGATIVE CSF GRAM STAIN AT LOW RISK FOR AN URGENT TREATABLE CAUSE

PubMed Central

Hasbun, Rodrigo; Bijlsma, Merijn; Brouwer, Matthijs C; Khoury, Nabil; Hadi, Christiane M; van der Ende, Arie; Wootton, Susan H.; Salazar, Lucrecia; Hossain, Md Monir; Beilke, Mark; van de Beek, Diederik

2013-01-01

Background We aimed to derive and validate a risk score that identifies adults with cerebrospinal fluid (CSF) pleocytosis and a negative CSF Gram stain at low risk for an urgent treatable cause. Methods Patients with CSF pleocytosis and a negative CSF Gram stain were stratified into a prospective derivation (n=193) and a retrospective validation (n=567) cohort. Clinically related baseline characteristics were grouped into three composite variables, each independently associated with a set of predefined urgent treatable causes. We subsequently derived a risk score classifying patients into low (0 composite variables present) or high ( ≥ 1 composite variables present) risk for an urgent treatable cause. The sensitivity of the risk score was determined in the validation cohort and in a prospective case series of 214 adults with CSF-culture proven bacterial meningitis, CSF pleocytosis and a negative Gram stain. Findings A total of 41 of 193 patients (21%) in the derivation cohort and 71 of 567 (13%) in the validation cohort had an urgent treatable cause. Sensitivity of the dichotomized risk score to detect an urgent treatable cause was 100.0% (95%CI 93.9-100.0%) in the validation cohort and 100.0% (95%CI 97.8-100.0%) in bacterial meningitis patients. Interpretation The risk score can be used to identify adults with CSF pleocytosis and a negative CSF Gram stain at low risk for an urgent treatable cause. PMID:23619080

Embryonic blood-cerebrospinal fluid barrier formation and function

PubMed Central

Bueno, David; Parvas, Maryam; Hermelo, Ismaïl; Garcia-Fernàndez, Jordi

2014-01-01

During embryonic development and adult life, brain cavities and ventricles are filled with cerebrospinal fluid (CSF). CSF has attracted interest as an active signaling medium that regulates brain development, homeostasis and disease. CSF is a complex protein-rich fluid containing growth factors and signaling molecules that regulate multiple cell functions in the central nervous system (CNS). The composition and substance concentrations of CSF are tightly controlled. In recent years, it has been demonstrated that embryonic CSF (eCSF) has a key function as a fluid pathway for delivering diffusible signals to the developing brain, thus contributing to the proliferation, differentiation and survival of neural progenitor cells, and to the expansion and patterning of the brain. From fetal stages through to adult life, CSF is primarily produced by the choroid plexus. The development and functional activities of the choroid plexus and other blood–brain barrier (BBB) systems in adults and fetuses have been extensively analyzed. However, eCSF production and control of its homeostasis in embryos, from the closure of the anterior neuropore when the brain cavities become physiologically sealed, to the formation of the functional fetal choroid plexus, has not been studied in as much depth and remains open to debate. This review brings together the existing literature, some of which is based on experiments conducted by our research group, concerning the formation and function of a temporary embryonic blood–CSF barrier in the context of the crucial roles played by the molecules in eCSF. PMID:25389383

Sustained choroid plexus function in human elderly and Alzheimer's disease patients.

PubMed

Spector, Reynold; Johanson, Conrad E

2013-09-24

We and other investigators have postulated deterioration of essential choroid plexus (CP) functions in some elderly and especially Alzheimer's disease patients based on apparent anatomical, histological and pathological changes in CP. We have termed this putative phenomenon CP failure. By focusing on four essential energy-requiring CP functions, specifically ascorbic acid (AA) and folate transport from blood into CSF, transthyretin synthesis and secretion into CSF, and electrolyte/acid-base balance in CSF, we were able to evaluate the hypothesis of CP failure by reviewing definitive human data. In both healthy elderly and Alzheimer's disease patients, the CP functions normally to transport AA and folates actively from blood into CSF, synthesize and secrete transthyretin into CSF, and maintain CSF acid-base balance and ion concentrations. These human CSF compositional data provide no support for the notion of CP failure in elderly humans and Alzheimer's disease patients.

Photoacoustic and photothermal detection of circulating tumor cells, bacteria and nanoparticles in cerebrospinal fluid in vivo and ex vivo.

PubMed

Nedosekin, Dmitry A; Juratli, Mazen A; Sarimollaoglu, Mustafa; Moore, Christopher L; Rusch, Nancy J; Smeltzer, Mark S; Zharov, Vladimir P; Galanzha, Ekaterina I

2013-06-01

Circulating cells, bacteria, proteins, microparticles, and DNA in cerebrospinal fluid (CSF) are excellent biomarkers of many diseases, including cancer and infections. However, the sensitivity of existing methods is limited in their ability to detect rare CSF biomarkers at the treatable, early-stage of diseases. Here, we introduce novel CSF tests based on in vivo photoacoustic flow cytometry (PAFC) and ex vivo photothermal scanning cytometry. In the CSF of tumor-bearing mice, we molecularly detected in vivo circulating tumor cells (CTCs) before the development of breast cancer brain metastasis with 20-times higher sensitivity than with current assays. For the first time, we demonstrated assessing three pathways (i.e., blood, lymphatic, and CSF) of CTC dissemination, tracking nanoparticles in CSF in vivo and their imaging ex vivo. In label-free CSF samples, we counted leukocytes, erythrocytes, melanoma cells, and bacteria and imaged intracellular cytochromes, hemoglobin, melanin, and carotenoids, respectively. Taking into account the safety of PAFC, its translation for use in humans is expected to improve disease diagnosis beyond conventional detection limits. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Human Cerebrospinal Fluid Promotes Neuronal Viability and Activity of Hippocampal Neuronal Circuits In Vitro

PubMed Central

Perez-Alcazar, Marta; Culley, Georgia; Lyckenvik, Tim; Mobarrez, Kristoffer; Bjorefeldt, Andreas; Wasling, Pontus; Seth, Henrik; Asztely, Frederik; Harrer, Andrea; Iglseder, Bernhard; Aigner, Ludwig; Hanse, Eric; Illes, Sebastian

2016-01-01

For decades it has been hypothesized that molecules within the cerebrospinal fluid (CSF) diffuse into the brain parenchyma and influence the function of neurons. However, the functional consequences of CSF on neuronal circuits are largely unexplored and unknown. A major reason for this is the absence of appropriate neuronal in vitro model systems, and it is uncertain if neurons cultured in pure CSF survive and preserve electrophysiological functionality in vitro. In this article, we present an approach to address how human CSF (hCSF) influences neuronal circuits in vitro. We validate our approach by comparing the morphology, viability, and electrophysiological function of single neurons and at the network level in rat organotypic slice and primary neuronal cultures cultivated either in hCSF or in defined standard culture media. Our results demonstrate that rodent hippocampal slices and primary neurons cultured in hCSF maintain neuronal morphology and preserve synaptic transmission. Importantly, we show that hCSF increases neuronal viability and the number of electrophysiologically active neurons in comparison to the culture media. In summary, our data indicate that hCSF represents a physiological environment for neurons in vitro and a superior culture condition compared to the defined standard media. Moreover, this experimental approach paves the way to assess the functional consequences of CSF on neuronal circuits as well as suggesting a novel strategy for central nervous system (CNS) disease modeling. PMID:26973467

Label-Free LC-MS/MS Proteomic Analysis of Cerebrospinal Fluid Identifies Protein/Pathway Alterations and Candidate Biomarkers for Amyotrophic Lateral Sclerosis.

PubMed

Collins, Mahlon A; An, Jiyan; Hood, Brian L; Conrads, Thomas P; Bowser, Robert P

2015-11-06

Analysis of the cerebrospinal fluid (CSF) proteome has proven valuable to the study of neurodegenerative disorders. To identify new protein/pathway alterations and candidate biomarkers for amyotrophic lateral sclerosis (ALS), we performed comparative proteomic profiling of CSF from sporadic ALS (sALS), healthy control (HC), and other neurological disease (OND) subjects using label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 1712 CSF proteins were detected and relatively quantified by spectral counting. Levels of several proteins with diverse biological functions were significantly altered in sALS samples. Enrichment analysis was used to link these alterations to biological pathways, which were predominantly related to inflammation, neuronal activity, and extracellular matrix regulation. We then used our CSF proteomic profiles to create a support vector machines classifier capable of discriminating training set ALS from non-ALS (HC and OND) samples. Four classifier proteins, WD repeat-containing protein 63, amyloid-like protein 1, SPARC-like protein 1, and cell adhesion molecule 3, were identified by feature selection and externally validated. The resultant classifier distinguished ALS from non-ALS samples with 83% sensitivity and 100% specificity in an independent test set. Collectively, our results illustrate the utility of CSF proteomic profiling for identifying ALS protein/pathway alterations and candidate disease biomarkers.

Diagnostic Value of Cerebrospinal Fluid T-SPOT.TB for Tuberculousis Meningitis in China.

PubMed

Li, Xue Lian; Xie, Na; Wang, Song Wang; Wu, Qian Hong; Ma, Yan; Shu, Wei; Chen, Hong Mei; Zhang, Li Qun; Wu, Xiao Guang; Ma, Li Ping; Che, Nan Ying; Gao, Meng Qiu

2017-09-01

The aim of this study was to evaluate the diagnostic value of the cerebrospinal fluid (CSF) T-SPOT.TB test for the diagnosis of TB meningitis (TBM). A retrospective analysis of 96 patients with manifested meningitis was conducted; T-SPOT.TB test was performed for diagnosing TBM to determine the diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). A receiver operating characteristic (ROC) curve was also drawn to assess the diagnostic accuracy. The sensitivity, specificity, PPV, and NPV of CSF T-SPOT.TB test were 97.8%, 78.0%, 80.3%, and 97.5%, respectively, for 52 patients (54.2%) of the 96 enrolled patients. The area under the curve (AUC) was 0.910, and the sensitivities of CSF T-SPOT.TB for patients with stages I, II, and III of TBM were 96.7%, 97.2%, and 98.9%, respectively. CSF T-SPOT.TB test is a rapid and accurate diagnostic method with higher sensitivity and specificity for diagnosing TBM. Copyright © 2017 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

More than a drainage fluid: the role of CSF in signaling in the brain and other effects on brain tissue.

PubMed

Illes, Sebastian

2017-01-01

Current progress in neuroscience demonstrates that the brain is not an isolated organ and is influenced by the systemic environment and extracerebral processes within the body. In view of this new concept, blood and cerebrospinal fluid (CSF) are important body fluids linking extracerebral and intracerebral processes. For decades, substantial evidence has been accumulated indicating that CSF modulates brain states and influences behavior as well as cognition. This chapter provides an overview of how CSF directly modulates the function of different types of brain cells, such as neurons, neural stem cells, and CSF-contacting cells. Alterations in CSF content occur in most pathologic central nervous system (CNS) conditions. In a classic view, the function of CSF is to drain waste products and detrimental factors derived from diseased brain parenchyma. This chapter presents examples for how intra- and extracerebral pathologic processes lead to alterations in the CSF content. Current knowledge about how pathologically altered CSF influences the functionality of brain cells will be presented. Thereby, it becomes evident that CSF has more than a drainage function and has a causal role for the etiology and pathogenesis of different CNS diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

CSF soluble amyloid precursor proteins in the diagnosis of incipient Alzheimer disease.

PubMed

Perneczky, R; Tsolakidou, A; Arnold, A; Diehl-Schmid, J; Grimmer, T; Förstl, H; Kurz, A; Alexopoulos, P

2011-07-05

To explore if soluble amyloid precursor proteins (sAPP) in CSF improve the identification of patients with incipient Alzheimer disease (AD) in a group of patients with mild cognitive impairment (MCI). A cohort study with follow-up assessments of 58 patients with MCI with baseline CSF sampling was conducted: 21 patients had progressed to probable AD (MCI-AD), 27 still had MCI, 8 had reverted to normal (MCI-NAD), and 2 patients with frontotemporal dementia (FTD) were excluded. Sixteen additional patients with FTD were included to explore the specificity of the CSF markers. CSF concentrations of sAPPα, sAPPβ, tau, and Aβ(1-42) were measured with sensitive and specific ELISAs. Associations between diagnostic status, CSF protein concentrations, and other patient characteristics were explored using multiple logistic regression analyses with stepwise variable selection. The optimal sensitivity and specificity of the best models were derived from receiver operating characteristic curves. The MCI-AD group had significantly higher sAPPβ concentrations than the MCI-NAD and the FTD groups. A combination of sAPPβ, tau, and age differentiated the MCI-AD and the MCI-NAD groups with a sensitivity of 80.00% and a specificity of 81.00%. The best model for the differentiation of the MCI-AD and the FTD groups included sAPPβ and tau, and showed a sensitivity of 95.20% and a specificity of 81.20%. Aβ(1-42) and sAPPα did not significantly contribute to the models. These findings suggest that sAPPβ may be clinically useful, and superior to Aβ(1-42), in the early and differential diagnosis of incipient AD.

Delivery of CSF-1R to the lumen of macropinosomes promotes its destruction in macrophages

PubMed Central

Lou, Jieqiong; Low-Nam, Shalini T.; Kerkvliet, Jason G.; Hoppe, Adam D.

2014-01-01

ABSTRACT Activation of the macrophage colony stimulating factor-1 receptor (CSF-1R) by CSF-1 stimulates pronounced macropinocytosis and drives proliferation of macrophages. Although the role of macropinocytosis in CSF-1R signaling remains unknown, we show here that, despite internalizing large quantities of plasma membrane, macropinosomes contribute little to the internalization of the CSF-1–CSF-1R complex. Rather, internalization of the CSF-1R in small endocytic vesicles that are sensitive to clathrin disruption, outcompetes macropinosomes for CSF-1R endocytosis. Following internalization, small vesicles carrying the CSF-1R underwent homotypic fusion and then trafficked to newly formed macropinosomes bearing Rab5. As these macropinosomes matured, acquiring Rab7, the CSF-1R was transported into their lumen and degraded. Inhibition of macropinocytosis delayed receptor degradation despite no disruption to CSF-1R endocytosis. These data indicate that CSF-1-stimulated macropinosomes are sites of multivesicular body formation and accelerate CSF-1R degradation. Furthermore, we demonstrate that macropinocytosis and cell growth have a matching dose dependence on CSF-1, suggesting that macropinosomes might be a central mechanism coupling CSF-1R signaling and macrophage growth. PMID:25335894

A sensitive WST-8-based bioassay for PEGylated granulocyte colony stimulating factor using the NFS-60 cell line.

PubMed

Tiwari, Krishna; Wavdhane, Madan; Haque, Shafiul; Govender, Thavendran; Kruger, Hendrik G; Mishra, Maheshwari K; Chandra, Ramesh; Tiwari, Dileep

2015-06-01

Granulocyte colony stimulating factor (G-CSF) has been commonly used to treat neutropenia caused by chemotherapy, radiotherapy, and organ transplants. Improved in vitro efficacy of G-CSF has already been observed by conjugating it to polyethylene glycol (PEG). The in vivo bioassay using tetrazolium dye with the NFS-60 cell line has been recommended for G-CSF but no such monographs are available for PEGylated G-CSF in pharmacopeias. In the present study, the assay recommended for G-CSF was evaluated for its suitability to PEGylated G-CSF. The generally used MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium]-based assay was compared with a bioassay employing a water-soluble tetrazolium dye, WST-8 [2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium], using NFS-60 cells at a concentration of 7 × 10(5) cells/ml against 800 IU/ml of PEGylated G-CSF at 24, 48, 72, and 72 h time points to determine the efficacy of PEGylated G-CSF. Further, the optimized WST-8 dye-based assay was used to test the potency of various commercially available PEGylated G-CSF preparations. The results demonstrated enhanced sensitivity of the WST-8-based assay over the conventional MTS-based assay for determining the potency of PEGylated G-CSF using the NFS-60 cell line. Our study demonstrates the potential application of WST-8-based bioassays for other biotherapeutic proteins of human and veterinary interest.

The Colony-Stimulating Factor 3 Receptor T640N Mutation Is Oncogenic, Sensitive to JAK Inhibition, and Mimics T618I.

PubMed

Maxson, Julia E; Luty, Samuel B; MacManiman, Jason D; Paik, Jason C; Gotlib, Jason; Greenberg, Peter; Bahamadi, Swaleh; Savage, Samantha L; Abel, Melissa L; Eide, Christopher A; Loriaux, Marc M; Stevens, Emily A; Tyner, Jeffrey W

2016-02-01

Colony-stimulating factor 3 receptor (CSF3R) mutations have been identified in the majority of chronic neutrophilic leukemia (CNL) and a smaller percentage of atypical chronic myeloid leukemia (aCML) cases. Although CSF3R point mutations (e.g., T618I) are emerging as key players in CNL/aCML, the significance of rarer CSF3R mutations is unknown. In this study, we assess the importance of the CSF3R T640N mutation as a marker of CNL/aCML and potential therapeutic target. Sanger sequencing of leukemia samples was performed to identify CSF3R mutations in CNL and aCML. The oncogenicity of the CSF3R T640N mutation relative to the T618I mutation was assessed by cytokine independent growth assays and by mouse bone marrow transplant. Receptor dimerization and O-glycosylation of the mutants was assessed by Western blot, and JAK inhibitor sensitivity was assessed by colony assay. Here, we identify a CSF3R T640N mutation in two patients with CNL/aCML, one of whom was originally diagnosed with MDS and acquired the T640N mutation upon evolution of disease to aCML. The T640N mutation is oncogenic in cellular transformation assays and an in vivo mouse bone marrow transplantation model. It exhibits many similar phenotypic features to T618I, including ligand independence and altered patterns of O-glycosylation--despite the transmembrane location of T640 preventing access by GalNAc transferase enzymes. Cells transformed by the T640N mutation are sensitive to JAK kinase inhibition to a similar degree as cells transformed by CSF3R T618I. Because of its similarities to CSF3R T618I, the T640N mutation likely has diagnostic and therapeutic relevance in CNL/aCML. ©2015 American Association for Cancer Research.

Initial CSF total tau correlates with 1-year outcome in patients with traumatic brain injury.

PubMed

Ost, M; Nylén, K; Csajbok, L; Ohrfelt, A Olsson; Tullberg, M; Wikkelsö, C; Nellgård, P; Rosengren, L; Blennow, K; Nellgård, B

2006-11-14

We investigated if tau, microtubular binding protein, in serum and ventricular CSF (vCSF) in patients with severe traumatic brain injury (TBI) during the initial posttraumatic days correlated to 1-year outcome. Patients with severe TBI (n = 39, Glasgow Coma Scale score 2,126 pg/mL on days 2 to 3 discriminated between dead and alive (sensitivity of 100% and a specificity of 81%). A vCSF total tau level of >702 pg/mL on days 2 to 3 discriminated between bad (GOSE 1 to 4) and good (GOSE 5 to 8) outcome (sensitivity of 83% and a specificity of 69%). Patients with GOSE 1 (dead) had higher vCSF total tau levels on days 2 to 3 (p < 0.001) vs both surviving patients (GOSE 2 to 8) and those with NPH. Total tau was not detected in serum throughout the study. The increase in ventricular CSF (vCSF) total tau probably reflects axonal damage, known to be a central pathologic mechanism in traumatic brain injury (TBI). These results suggest that vCSF total tau may be an important early biochemical neuromarker for predicting long-term outcome in patients with a severe TBI.

The Human Face: A View From the Infant's Eye.

ERIC Educational Resources Information Center

Souther, Arthur F.; Banks, Martin S.

This study explores the reason why very young infants are unable to respond differentially to faces and the cause for developmental changes in infant face perception by age 3 months. Linear systems analysis (LSA) and the contrast sensitivity function (CSF) were used to estimate the facial pattern information available to 1- and 3-month-old…

Regulation of Embryonic and Postnatal Development by the CSF-1 Receptor

PubMed Central

Chitu, Violeta; Stanley, E. Richard

2017-01-01

Macrophages are found in all tissues and regulate tissue morphogenesis during development through trophic and scavenger functions. The colony stimulating factor-1 (CSF-1) receptor (CSF-1R) is the major regulator of tissue macrophage development and maintenance. In combination with receptor activator of nuclear factor κB (RANK), the CSF-1R also regulates the differentiation of the bone-resorbing osteoclast and controls bone remodeling during embryonic and early postnatal development. CSF-1R-regulated macrophages play trophic and remodeling roles in development. Outside the mononuclear phagocytic system, the CSF-1R directly regulates neuronal survival and differentiation, the development of intestinal Paneth cells and of preimplantation embryos, as well as trophoblast innate immune function. Consistent with the pleiotropic roles of the receptor during development, CSF-1R deficiency in most mouse strains causes embryonic or perinatal death and the surviving mice exhibit multiple developmental and functional deficits. The CSF-1R is activated by two dimeric glycoprotein ligands, CSF-1, and interleukin-34 (IL-34). Homozygous Csf1-null mutations phenocopy most of the deficits of Csf1r-null mice. In contrast, Il34-null mice have no gross phenotype, except for decreased numbers of Langerhans cells and microglia, indicating that CSF-1 plays the major developmental role. Homozygous inactivating mutations of the Csf1r or its ligands have not been reported in man. However, heterozygous inactivating mutations in the Csf1r lead to a dominantly inherited adult-onset progressive dementia, highlighting the importance of CSF-1R signaling in the brain. PMID:28236968

Regulation of Embryonic and Postnatal Development by the CSF-1 Receptor.

PubMed

Chitu, Violeta; Stanley, E Richard

2017-01-01

Macrophages are found in all tissues and regulate tissue morphogenesis during development through trophic and scavenger functions. The colony stimulating factor-1 (CSF-1) receptor (CSF-1R) is the major regulator of tissue macrophage development and maintenance. In combination with receptor activator of nuclear factor κB (RANK), the CSF-1R also regulates the differentiation of the bone-resorbing osteoclast and controls bone remodeling during embryonic and early postnatal development. CSF-1R-regulated macrophages play trophic and remodeling roles in development. Outside the mononuclear phagocytic system, the CSF-1R directly regulates neuronal survival and differentiation, the development of intestinal Paneth cells and of preimplantation embryos, as well as trophoblast innate immune function. Consistent with the pleiotropic roles of the receptor during development, CSF-1R deficiency in most mouse strains causes embryonic or perinatal death and the surviving mice exhibit multiple developmental and functional deficits. The CSF-1R is activated by two dimeric glycoprotein ligands, CSF-1, and interleukin-34 (IL-34). Homozygous Csf1-null mutations phenocopy most of the deficits of Csf1r-null mice. In contrast, Il34-null mice have no gross phenotype, except for decreased numbers of Langerhans cells and microglia, indicating that CSF-1 plays the major developmental role. Homozygous inactivating mutations of the Csf1r or its ligands have not been reported in man. However, heterozygous inactivating mutations in the Csf1r lead to a dominantly inherited adult-onset progressive dementia, highlighting the importance of CSF-1R signaling in the brain. © 2017 Elsevier Inc. All rights reserved.

T-Lymphocytes Traffic into the Brain across the Blood-CSF Barrier: Evidence Using a Reconstituted Choroid Plexus Epithelium

PubMed Central

Strazielle, Nathalie; Creidy, Rita; Malcus, Christophe; Boucraut, José; Ghersi-Egea, Jean-François

2016-01-01

An emerging concept of normal brain immune surveillance proposes that recently and moderately activated central memory T lymphocytes enter the central nervous system (CNS) directly into the cerebrospinal fluid (CSF) via the choroid plexus. Within the CSF space, T cells inspect the CNS environment for cognate antigens. This gate of entry into the CNS could also prevail at the initial stage of neuroinflammatory processes. To actually demonstrate T cell migration across the choroidal epithelium forming the blood-CSF barrier, an in vitro model of the rat blood-CSF barrier was established in an “inverse” configuration that enables cell transmigration studies in the basolateral to apical, i.e. blood/stroma to CSF direction. Structural barrier features were evaluated by immunocytochemical analysis of tight junction proteins, functional barrier properties were assessed by measuring the monolayer permeability to sucrose and the active efflux transport of organic anions. The migratory behaviour of activated T cells across the choroidal epithelium was analysed in the presence and absence of chemokines. The migration pathway was examined by confocal microscopy. The inverse rat BCSFB model reproduces the continuous distribution of tight junction proteins at cell margins, the restricted paracellular permeability, and polarized active transport mechanisms, which all contribute to the barrier phenotype in vivo. Using this model, we present experimental evidence of T cell migration across the choroidal epithelium. Cell migration appears to occur via a paracellular route without disrupting the restrictive barrier properties of the epithelial interface. Apical chemokine addition strongly stimulates T cell migration across the choroidal epithelium. The present data provide evidence for the controlled migration of T cells across the blood-CSF barrier into brain. They further indicate that this recruitment route is sensitive to CSF-borne chemokines, extending the relevance of this migration pathway to neuroinflammatory and neuroinfectious disorders which are typified by elevated chemokine levels in CSF. PMID:26942913

T-Lymphocytes Traffic into the Brain across the Blood-CSF Barrier: Evidence Using a Reconstituted Choroid Plexus Epithelium.

PubMed

Strazielle, Nathalie; Creidy, Rita; Malcus, Christophe; Boucraut, José; Ghersi-Egea, Jean-François

2016-01-01

An emerging concept of normal brain immune surveillance proposes that recently and moderately activated central memory T lymphocytes enter the central nervous system (CNS) directly into the cerebrospinal fluid (CSF) via the choroid plexus. Within the CSF space, T cells inspect the CNS environment for cognate antigens. This gate of entry into the CNS could also prevail at the initial stage of neuroinflammatory processes. To actually demonstrate T cell migration across the choroidal epithelium forming the blood-CSF barrier, an in vitro model of the rat blood-CSF barrier was established in an "inverse" configuration that enables cell transmigration studies in the basolateral to apical, i.e. blood/stroma to CSF direction. Structural barrier features were evaluated by immunocytochemical analysis of tight junction proteins, functional barrier properties were assessed by measuring the monolayer permeability to sucrose and the active efflux transport of organic anions. The migratory behaviour of activated T cells across the choroidal epithelium was analysed in the presence and absence of chemokines. The migration pathway was examined by confocal microscopy. The inverse rat BCSFB model reproduces the continuous distribution of tight junction proteins at cell margins, the restricted paracellular permeability, and polarized active transport mechanisms, which all contribute to the barrier phenotype in vivo. Using this model, we present experimental evidence of T cell migration across the choroidal epithelium. Cell migration appears to occur via a paracellular route without disrupting the restrictive barrier properties of the epithelial interface. Apical chemokine addition strongly stimulates T cell migration across the choroidal epithelium. The present data provide evidence for the controlled migration of T cells across the blood-CSF barrier into brain. They further indicate that this recruitment route is sensitive to CSF-borne chemokines, extending the relevance of this migration pathway to neuroinflammatory and neuroinfectious disorders which are typified by elevated chemokine levels in CSF.

Accuracy of real-time PCR, Gram stain and culture for Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae meningitis diagnosis.

PubMed

Wu, Henry M; Cordeiro, Soraia M; Harcourt, Brian H; Carvalho, Mariadaglorias; Azevedo, Jailton; Oliveira, Tainara Q; Leite, Mariela C; Salgado, Katia; Reis, Mitermayer G; Plikaytis, Brian D; Clark, Thomas A; Mayer, Leonard W; Ko, Albert I; Martin, Stacey W; Reis, Joice N

2013-01-22

Although cerebrospinal fluid (CSF) culture is the diagnostic reference standard for bacterial meningitis, its sensitivity is limited, particularly when antibiotics were previously administered. CSF Gram staining and real-time PCR are theoretically less affected by antibiotics; however, it is difficult to evaluate these tests with an imperfect reference standard. CSF from patients with suspected meningitis from Salvador, Brazil were tested with culture, Gram stain, and real-time PCR using S. pneumoniae, N. meningitidis, and H. influenzae specific primers and probes. An antibiotic detection disk bioassay was used to test for the presence of antibiotic activity in CSF. The diagnostic accuracy of tests were evaluated using multiple methods, including direct evaluation of Gram stain and real-time PCR against CSF culture, evaluation of real-time PCR against a composite reference standard, and latent class analysis modeling to evaluate all three tests simultaneously. Among 451 CSF specimens, 80 (17.7%) had culture isolation of one of the three pathogens (40 S. pneumoniae, 36 N. meningitidis, and 4 H. influenzae), and 113 (25.1%) were real-time PCR positive (51 S. pneumoniae, 57 N. meningitidis, and 5 H. influenzae). Compared to culture, real-time PCR sensitivity and specificity were 95.0% and 90.0%, respectively. In a latent class analysis model, the sensitivity and specificity estimates were: culture, 81.3% and 99.7%; Gram stain, 98.2% and 98.7%; and real-time PCR, 95.7% and 94.3%, respectively. Gram stain and real-time PCR sensitivity did not change significantly when there was antibiotic activity in the CSF. Real-time PCR and Gram stain were highly accurate in diagnosing meningitis caused by S. pneumoniae, N. meningitidis, and H. influenzae, though there were few cases of H. influenzae. Furthermore, real-time PCR and Gram staining were less affected by antibiotic presence and might be useful when antibiotics were previously administered. Gram staining, which is inexpensive and commonly available, should be encouraged in all clinical settings.

The concentration of CYFRA 21-1, NSE and CEA in cerebro-spinal fluid can be useful indicators for diagnosis of meningeal carcinomatosis of lung cancer.

PubMed

Wang, Peng; Piao, Yingzhe; Zhang, Xiaohui; Li, Wenliang; Hao, Xishan

2013-01-01

We aimed to investigate the concentration of CYFRA 21-1, NSE and CEA in cerebro-spinal fluid (CSF) and to explore their clinical value in the meningeal carcinomatosis (MC) of lung cancer. So that, sensitive and specificity of CSF examination can be improved in the initial diagnosis of MC. A total of 35 lung cancer patients and 35 patients with benign brain tumor in the same period enrolled in this study. The concentrations of tumor markers CEA, CYFRA 21-1 and NSE in CSF and peripheral blood were examined. The concentrations of three tumor markers of CYFRA 21-1, NSE and CEA in blood serum and CSF were obviously higher than that of benign disease group. In MC patients, the concentrations of three tumor markers of CYFRA 21-1, NSE and CEA in blood serum were significant lower than that in CSF. The maximum of Youden's index was identified as the cutoff value of indicator of MC in three tumor markers in CSF which were CEA > 4.7 μg/L, NSE > 14.6 μg/L and CYFRA21-1 > 5.5 μg/L respectively. Based on the cutoff values, the CEA had the highest sensitivity while the CYFRA21-1 had the highest specificitiy. Three tumor markers in the CSF had higher positive rate than those in blood serum. We combined the levels of CEA, NSE and CYFRA21-1 in CSF to diagnosis of MC. Positive of CEA or CYFRA21-1 had the greatest sensitivity of 100% while the specificity of 91.4%; the positive of both CEA and CYFRA21-1 had the highest specificity of 100% while the sensitivity of 74.3%. Both positive predictive value and negative predictive value were 100% when combination positive were confirmed when the all three markers were positive. The combination of CEA and CYFRA21-1 can be recommended in early screening of meningeal carcinoma. Especially, for the patient who was difficult to be diagnosed by CSF histology and MRI, it will be a useful auxiliary marker in diagnosis of MC. The combination of CEA, NSE and CYFRA21-1 can be an effective clinically confirmation and exclusively diagnose indictor of MC.

Diagnostic value of cerebrospinal fluid Aβ ratios in preclinical Alzheimer's disease.

PubMed

Adamczuk, Katarzyna; Schaeverbeke, Jolien; Vanderstichele, Hugo M J; Lilja, Johan; Nelissen, Natalie; Van Laere, Koen; Dupont, Patrick; Hilven, Kelly; Poesen, Koen; Vandenberghe, Rik

2015-12-18

In this study of preclinical Alzheimer's disease (AD) we assessed the added diagnostic value of using cerebrospinal fluid (CSF) Aβ ratios rather than Aβ42 in isolation for detecting individuals who are positive on amyloid positron emission tomography (PET). Thirty-eight community-recruited cognitively intact older adults (mean age 73, range 65-80 years) underwent (18)F-flutemetamol PET and CSF measurement of Aβ1-42, Aβ1-40, Aβ1-38, and total tau (ttau). (18)F-flutemetamol retention was quantified using standardized uptake value ratios in a composite cortical region (SUVRcomp) with reference to cerebellar grey matter. Based on a prior autopsy validation study, the SUVRcomp cut-off was 1.57. Sensitivities, specificities and cut-offs were defined based on receiver operating characteristic analysis with CSF analytes as variables of interest and (18)F-flutemetamol positivity as the classifier. We also determined sensitivities and CSF cut-off values at fixed specificities of 90 % and 95 %. Seven out of 38 subjects (18 %) were positive on amyloid PET. Aβ42/ttau, Aβ42/Aβ40, Aβ42/Aβ38, and Aβ42 had the highest accuracy to identify amyloid-positive subjects (area under the curve (AUC) ≥ 0.908). Aβ40 and Aβ38 had significantly lower discriminative power (AUC = 0.571). When specificity was fixed at 90 % and 95 %, Aβ42/ttau had the highest sensitivity among the different CSF markers (85.71 % and 71.43 %, respectively). Sensitivity of Aβ42 alone was significantly lower under these conditions (57.14 % and 42.86 %, respectively). For the CSF-based definition of preclinical AD, if a high specificity is required, our data support the use of Aβ42/ttau rather than using Aβ42 in isolation.

Predictive value of cerebrospinal fluid parameters in neonates with intraventricular drainage devices.

PubMed

Lenfestey, Robert W; Smith, P Brian; Moody, M Anthony; Clark, Reese H; Cotten, C Michael; Seed, Patrick C; Benjamin, Daniel K

2007-09-01

Infection is a common and potentially devastating complication following placement of ventriculoperitoneal (VP) shunts and cerebrospinal fluid (CSF) reservoirs in neonates. The goal of this study was to determine the normal ranges for cell count parameters in neonates with VP shunts and CSF reservoirs, as well as to determine the predictive value of CSF parameters as markers of infection. The authors evaluated neonates from 150 different neonatal intensive care units of the Pediatrix Medical Group who had undergone a lumbar puncture, VP shunt insertion, or CSF reservoir placement between 1997 and 2004. Data were collected from 9704 neonates with a mean birthweight of 2573 g and a mean gestational age of 35 weeks. Of these neonates, 181 had VP shunt insertions or CSF reservoir placements. In neonates with negative CSF cultures, significant differences were found between those with and without VP shunts or CSF reservoirs when comparing red blood cell (RBC) count (620/mm' compared with 155/mm3, p < 0.05), absolute eosinophil count (4/mm3 compared with 2/mm3, p < 0.001), protein levels (179 mg/dl compared with 115 mg/dl, p < 0.001), and glucose levels (27.5 mg/dl compared with 49 mg/dl, p < 0.001). No significant difference was found between white blood cell (WBC) counts in neonates with or without VP shunts who had negative CSF cultures. The sensitivity and specificity of a cutoff value of 20 WBCs/mm3 for diagnosing meningitis in neonates with positive cultures and intraventricular drainage devices were 67% and 62%, respectively. Although differences exist between CSF parameters found in neonates with or without VP shunts or CSF reservoirs, only the difference in RBC count is large enough to be clinically significant. The authors found that the utility of CSF parameters in neonates with VP shunts or CSF reservoirs was limited due to poor diagnostic sensitivity and specificity.

G-CSF suppresses allergic pulmonary inflammation, downmodulating cytokine, chemokine and eosinophil production.

PubMed

Queto, Túlio; Vasconcelos, Zilton F M; Luz, Ricardo Alves; Anselmo, Carina; Guiné, Ana Amélia A; e Silva, Patricia Machado R; Farache, Júlia; Cunha, José Marcos T; Bonomo, Adriana C; Gaspar-Elsas, Maria Ignez C; Xavier-Elsas, Pedro

2011-05-09

Granulocyte Colony-Stimulating Factor (G-CSF), which mobilizes hemopoietic stem cells (HSC), is believed to protect HSC graft recipients from graft-versus-host disease by enhancing Th2 cytokine secretion. Accordingly, G-CSF should aggravate Th2-dependent allergic pulmonary inflammation and the associated eosinophilia. We evaluated the effects of G-CSF in a model of allergic pulmonary inflammation. Allergic pulmonary inflammation was induced by repeated aerosol allergen challenge in ovalbumin-sensitized C57BL/6J mice. The effects of allergen challenge and of G-CSF pretreatment were evaluated by monitoring: a) eosinophilia and cytokine/chemokine content of bronchoalveolar lavage fluid, pulmonary interstitium, and blood; b) changes in airway resistance; and c) changes in bone-marrow eosinophil production. Contrary to expectations, G-CSF pretreatment neither induced nor enhanced allergic pulmonary inflammation. Instead, G-CSF: a) suppressed accumulation of infiltrating eosinophils in bronchoalveolar, peribronchial and perivascular spaces of challenged lungs; and b) prevented ovalbumin challenge-induced rises in airway resistance. G-CSF had multiple regulatory effects on cytokine and chemokine production: in bronchoalveolar lavage fluid, levels of IL-1 and IL-12 (p40), eotaxin and MIP-1a were decreased; in plasma, KC, a neutrophil chemoattractant, was increased, while IL-5 was decreased and eotaxin was unaffected. In bone-marrow, G-CSF: a) prevented the increase in bone-marrow eosinophil production induced by ovalbumin challenge of sensitized mice; and b) selectively stimulated neutrophil colony formation. These observations challenge the view that G-CSF deviates cytokine production towards a Th2 profile in vivo, and suggest that this neutrophil-selective hemopoietin affects eosinophilic inflammation by a combination of effects on lung cytokine production and bone-marrow hemopoiesis. Copyright © 2011 Elsevier Inc. All rights reserved.

A standardized blood test for the routine clinical diagnosis of impaired GM-CSF signaling using flow cytometry.

PubMed

Kusakabe, Yoshiomi; Uchida, Kanji; Hiruma, Takahiro; Suzuki, Yoko; Totsu, Tokie; Suzuki, Takuji; Carey, Brenna C; Yamada, Yoshitsugu; Trapnell, Bruce C

2014-11-01

Impaired signaling by granulocyte/macrophage-colony stimulating factor (GM-CSF) drives the pathogenesis of two diseases (autoimmune and hereditary pulmonary alveolar proteinosis (PAP)) representing over ninety percent of patients who develop PAP syndrome but not a broad spectrum of diseases that cause PAP by other mechanisms. We previously exploited the ability of GM-CSF to rapidly increase cell-surface CD11b levels on neutrophils (CD11bSurface) to establish the CD11b stimulation index (CD11b-SI), a test enabling the clinical research diagnosis of impaired GM-CSF signaling based on measuring CD11bSurface by flow cytometry using fresh, heparinized blood. (CD11b-SI is defined as GM-CSF-stimulated- CD11bSurface minus unstimulated CD11bSurface divided by un-stimulated CD11bSurface multiplied by 100.) Notwithstanding important and unique diagnostic utility, the test is sensitive to experimental conditions that can affect test performance. The present study was undertaken to optimize and standardize CD11b-SI test for detecting impaired GM-CSF signaling in heparinized human blood specimens from PAP patients. Results demonstrated the test was sensitive to choice of anticoagulant, pretesting incubation on ice, a delay between phlebotomy and test performance of more than one hour, and the concentration GM-CSF used to stimulate blood. The standardized CD11b-SI test reliably distinguished blood specimens from autoimmune PAP patients with impaired GM-CSF signaling from those of health people with normal signaling. Intra-subject differences were smaller than inter-subject differences in repeated measures. Receiver operating characteristic curve analysis identified a CD11b-SI test result of 112 as the optimal cut off threshold for diagnosis of impaired GM-CSF signaling in autoimmune PAP for which the sensitivity and specificity were both 100%. These results support the use of this standardized CD11b-SI for routine clinical identification of impaired GM-CSF signaling in patients with autoimmune PAP. The CD11b-SI may also have utility in clinical trials of novel therapeutic strategies targeting reduction in GM-CSF bioactivity now under evaluation for multiple common autoimmune and inflammatory disorders. Copyright © 2014 Elsevier B.V. All rights reserved.

Feasibility of using diffuse reflectance spectroscopy for the quantification of brain edema

NASA Astrophysics Data System (ADS)

Rodriguez, Juan G.; Sisson, Cynthia; Hendricks, Chad; Pattillo, Chris; McWaters, Megan; Hardjasudarma, Mardjohan; Quarles, Chad; Yaroslavsky, Anna N.; Yaroslavsky, Ilya V.; Battarbee, Harold

2001-05-01

Many diseased states of the brain can result in the displacement of brain tissues and restrict cerebral blood flow, disrupting function in a life-threatening manner. Clinical examples where displacements are observed include venous thromboses, hematomas, strokes, tumors, abscesses, and, particularly, brain edema. For the latter, the brain tissue swells, displacing the cerebral spinal fluid (CSF) layer that surrounds it, eventually pressing itself against the skull. Under such conditions, catheters are often inserted into the brain's ventricles or the subarachnoid space to monitor increased pressure. These are invasive procedures that incur increased risk of infection and consequently are used reluctantly by clinicians. Recent studies in the field of biomedical optics have suggested that the presence or absence of the CSF layer can lead to dramatic changes in NIR signals obtained from diffuse reflectance measurements around the head. In this study, we consider how this sensitivity of NIR signals to CSF might be exploited to non-invasively monitor the onset and resolution of brain edema.

Analysis of light emitting diode array lighting system based on human vision: normal and abnormal uniformity condition.

PubMed

Qin, Zong; Ji, Chuangang; Wang, Kai; Liu, Sheng

2012-10-08

In this paper, condition for uniform lighting generated by light emitting diode (LED) array was systematically studied. To take human vision effect into consideration, contrast sensitivity function (CSF) was novelly adopted as critical criterion for uniform lighting instead of conventionally used Sparrow's Criterion (SC). Through CSF method, design parameters including system thickness, LED pitch, LED's spatial radiation distribution and viewing condition can be analytically combined. In a specific LED array lighting system (LALS) with foursquare LED arrangement, different types of LEDs (Lambertian and Batwing type) and given viewing condition, optimum system thicknesses and LED pitches were calculated and compared with those got through SC method. Results show that CSF method can achieve more appropriate optimum parameters than SC method. Additionally, an abnormal phenomenon that uniformity varies with structural parameters non-monotonically in LALS with non-Lambertian LEDs was found and analyzed. Based on the analysis, a design method of LALS that can bring about better practicability, lower cost and more attractive appearance was summarized.

Validity of a PCR assay in CSF for the diagnosis of neurocysticercosis.

PubMed

Carpio, Arturo; Campoverde, Alfredo; Romo, Matthew L; García, Lorena; Piedra, Luis M; Pacurucu, Mónica; López, Nelson; Aguilar, Jenner; López, Sebastian; Vintimilla, Luis C; Toral, Ana M; Peña-Tapia, Pablo

2017-03-01

To prospectively evaluate the validity of a PCR assay in CSF for the diagnosis of neurocysticercosis (NC). We conducted a multicenter, prospective case-control study, recruiting participants from 5 hospitals in Cuenca, Ecuador, from January 2015 to February 2016. Cases fulfilled validated diagnostic criteria for NC. For each case, a neurosurgical patient who did not fulfill the diagnostic criteria for NC was selected as a control. CT and MRI, as well as a CSF sample, were collected from both cases and controls. The diagnostic criteria to identify cases were used as a reference standard. Overall, 36 case and 36 control participants were enrolled. PCR had a sensitivity of 72.2% (95% confidence interval [CI] 54.8%-85.8%) and a specificity of 100.0% (95% CI 90.3%-100.0%). For parenchymal NC, PCR had a sensitivity of 42.9% (95% CI 17.7%-71.1%), and for extraparenchymal NC, PCR had a sensitivity of 90.9% (95% CI 70.8%-98.9%). This study demonstrated the usefulness of this PCR assay in CSF for the diagnosis of NC. PCR may be particularly helpful for diagnosing extraparenchymal NC when neuroimaging techniques have failed. This study provides Class III evidence that CSF PCR can accurately identify patients with extraparenchymal NC.

The use of droplet digital PCR in liquid biopsies: A highly sensitive technique for MYD88 p.(L265P) detection in cerebrospinal fluid.

PubMed

Hiemcke-Jiwa, Laura S; Minnema, Monique C; Radersma-van Loon, Joyce H; Jiwa, N Mehdi; de Boer, Mirthe; Leguit, Roos J; de Weger, Roel A; Huibers, Manon M H

2018-04-01

The gold standard for diagnosis of central nervous system lymphomas still regards a stereotactic brain biopsy, with the risk of major complications for the patient. As tumor cells can be detected in cerebrospinal fluid (CSF), CSF analysis can be used as an alternative. In this respect, mutation analysis in CSF can be of added value to other diagnostic parameters such a cytomorphology and clonality analysis. A well-known example of targeted mutation analysis entails MYD88 p.(L265P) detection, which is present in the majority of Bing Neel syndrome and primary central nervous system lymphoma (PCNSL) patients. Unfortunately, tumor yield in CSF can be very low. Therefore, use of the highly sensitive droplet digital PCR (ddPCR) might be a suitable analysis strategy for targeted mutation detection. We analyzed 26 formalin fixed paraffin embedded (FFPE) samples (8 positive and 18 negative for MYD88 p.(L265P) mutation) by ddPCR, of which the results were compared with next generation sequencing (NGS). Subsequently, 32 CSF samples were analyzed by ddPCR. ddPCR and NGS results on FFPE material showed 100% concordance. Among the 32 CSF samples, 9 belonged to patients with lymphoplasmacytic lymphoma (LPL) and clinical suspicion of Bing Neel syndrome, and 3 belonged to patients with PCNSL. Nine of these samples tested positive for MYD88 p.(L265P) (8 LPL and 1 PCNSL). This study shows that sensitive MYD88 mutation analysis by ddPCR in CSF is highly reliable and can be applied even when DNA input is low. Therefore, ddPCR is of added value to current diagnostic parameters, especially when the available amount of DNA is limited. Copyright © 2017 John Wiley & Sons, Ltd.

Volume transmission-mediated encephalopathies: a possible new concept?

PubMed

Hartung, Hans-Peter; Dihné, Marcel

2012-03-01

There is strong evidence that the composition of cerebrospinal fluid (CSF) influences brain development, neurogenesis, and behavior. The bidirectional exchange of CSF and interstitial fluid (ISF) across the ependymal and pia-glial membranes is required for these phenomena to occur. Because ISF surrounds the parenchymal compartment, neuroactive substances in the CSF and ISF can influence neuronal activity. Functionally important neuroactive substances are distributed to distant sites of the central nervous system by the convection and diffusion of CSF and ISF, a process known as volume transmission. It has recently been shown that pathologically altered CSF from patients with acute traumatic brain injury suppresses in vitro neuronal network activity (ivNNA) recorded by multielectrode arrays measuring synchronously bursting neural populations. Functionally relevant substances in pathologically altered CSF have been biochemically identified, and ivNNA has been partially recovered by pharmacologic intervention. It remains unclear whether the in vivo parenchymal compartment remains unaffected by pathologically altered CSF that significantly impairs ivNNA. We hypothesize that pathologic CSF alterations are not just passive indicators of brain diseases but that they actively and directly evoke functional disturbances in global brain activity through the distribution of neuroactive substances, for instance, secondary to focal neurologic disease. For this mechanism, we propose the new term volume transmission-mediated encephalopathies (VTE). Recording ivNNA in the presence of pure human CSF could help to identify and monitor functionally relevant CSF alterations that directly result in VTEs, and the collected data might point to therapeutic ways to antagonize these alterations.

Cerebrospinal fluid biomarkers of simian immunodeficiency virus encephalitis

PubMed Central

Bissel, Stephanie J.; Kofler, Julia; Nyaundi, Julia; Murphey-Corb, Michael; Wisniewski, Stephen R.; Wiley, Clayton A.

2016-01-01

Antiretroviral therapy has led to increased survival of HIV-infected patients but also increased prevalence of HIV-associated neurocognitive disorders. We previously identified YKL40 as a potential cerebrospinal fluid (CSF) biomarker of lentiviral central nervous system (CNS) disease in HIV-infected patients and in the macaque model of HIV encephalitis. The aim of this study was to define the specificity and sensitivity along with the predictive value of YKL40 as a biomarker of encephalitis and to assess its relationship to CSF viral load. CSF YKL40 and SIV RNA concentrations were analyzed over the course of infection in 19 SIV-infected pigtailed macaques and statistical analyses were performed to evaluate the relationship to encephalitis. Using these relationships, CSF alterations of 31 neuroimmune markers were studied pre-infection, during acute and asymptomatic infection, at the onset of encephalitis, and at necropsy. YKL40 CSF concentrations above 1122 ng/ml were found to be a specific and sensitive biomarker for the presence of encephalitis and were highly correlated with CSF viral load. Macaques that developed encephalitis had evidence of chronic CNS immune activation during early, asymptomatic, and end stages of infection. At the onset of encephalitis, CSF demonstrated a rise of neuroimmune markers associated with macrophage recruitment, activation and interferon response. CSF YKL40 concentration and viral load are valuable biomarkers to define the onset of encephalitis. Chronic CNS immune activation precedes the development of encephalitis while some responses suggest protection from CNS lentiviral disease. PMID:27059917

Macrophage Colony-Stimulating Factor Improves Cardiac Function after Ischemic Injury by Inducing Vascular Endothelial Growth Factor Production and Survival of Cardiomyocytes

PubMed Central

Okazaki, Tatsuma; Ebihara, Satoru; Asada, Masanori; Yamanda, Shinsuke; Saijo, Yoshifumi; Shiraishi, Yasuyuki; Ebihara, Takae; Niu, Kaijun; Mei, He; Arai, Hiroyuki; Yambe, Tomoyuki

2007-01-01

Macrophage colony-stimulating factor (M-CSF), known as a hematopoietic growth factor, induces vascular endothelial growth factor (VEGF) production from skeletal muscles. However, the effects of M-CSF on cardiomyocytes have not been reported. Here, we show M-CSF increases VEGF production from cardiomyocytes, protects cardiomyocytes and myotubes from cell death, and improves cardiac function after ischemic injury. In mice, M-CSF increased VEGF production in hearts and in freshly isolated cardiomyocytes, which showed M-CSF receptor expression. In rat cell line H9c2 cardiomyocytes and myotubes, M-CSF induced VEGF production via the Akt signaling pathway, and M-CSF pretreatment protected these cells from H2O2-induced cell death. M-CSF activated Akt and extracellular signal-regulated kinase signaling pathways and up-regulated downstream anti-apoptotic Bcl-xL expression in these cells. Using goats as a large animal model of myocardial infarction, we found that M-CSF treatment after the onset of myocardial infarction by permanent coronary artery ligation promoted angiogenesis in ischemic hearts but did not reduce the infarct area. M-CSF pretreatment of the goat myocardial infarction model by coronary artery occlusion-reperfusion improved cardiac function, as assessed by hemodynamic parameters and echocardiography. These results suggest M-CSF might be a novel therapeutic agent for ischemic heart disease. PMID:17717142

Trifluoromethylation of ketones and aldehydes with Bu₃SnCF₃.

PubMed

Sanhueza, Italo A; Bonney, Karl J; Nielsen, Mads C; Schoenebeck, Franziska

2013-08-02

The (trifluoromethyl)stannane reagent, Bu3SnCF3, was found to react under CsF activation with ketones and aldehydes to the corresponding trifluoromethylated stannane ether intermediates at room temperature in high yield. Only a mildly acidic extraction (aqueous NH4Cl) is required to release the corresponding trifluoromethyl alcohol products. The protocol is compatible with acid-sensitive functional groups.

Alzheimer's Disease Normative Cerebrospinal Fluid Biomarkers Validated in PET Amyloid-β Characterized Subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.

PubMed

Li, Qiao-Xin; Villemagne, Victor L; Doecke, James D; Rembach, Alan; Sarros, Shannon; Varghese, Shiji; McGlade, Amelia; Laughton, Katrina M; Pertile, Kelly K; Fowler, Christopher J; Rumble, Rebecca L; Trounson, Brett O; Taddei, Kevin; Rainey-Smith, Stephanie R; Laws, Simon M; Robertson, Joanne S; Evered, Lisbeth A; Silbert, Brendan; Ellis, Kathryn A; Rowe, Christopher C; Macaulay, S Lance; Darby, David; Martins, Ralph N; Ames, David; Masters, Colin L; Collins, Steven

2015-01-01

The cerebrospinal fluid (CSF) amyloid-β (Aβ)(1-42), total-tau (T-tau), and phosphorylated-tau (P-tau181P) profile has been established as a valuable biomarker for Alzheimer's disease (AD). The current study aimed to determine CSF biomarker cut-points using positron emission tomography (PET) Aβ imaging screened subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, as well as correlate CSF analyte cut-points across a range of PET Aβ amyloid ligands. Aβ pathology was determined by PET imaging, utilizing ¹¹C-Pittsburgh Compound B, ¹⁸F-flutemetamol, or ¹⁸F-florbetapir, in 157 AIBL participants who also underwent CSF collection. Using an INNOTEST assay, cut-points were established (Aβ(1-42) >544 ng/L, T-tau <407 ng/L, and P-tau181P <78 ng/L) employing a rank based method to define a "positive" CSF in the sub-cohort of amyloid-PET negative healthy participants (n = 97), and compared with the presence of PET demonstrated AD pathology. CSF Aβ(1-42) was the strongest individual biomarker, detecting cognitively impaired PET positive mild cognitive impairment (MCI)/AD with 85% sensitivity and 91% specificity. The ratio of P-tau181P or T-tau to Aβ(1-42) provided greater accuracy, predicting MCI/AD with Aβ pathology with ≥92% sensitivity and specificity. Cross-validated accuracy, using all three biomarkers or the ratio of P-tau or T-tau to Aβ(1-42) to predict MCI/AD, reached ≥92% sensitivity and specificity. CSF Aβ(1-42) levels and analyte combination ratios demonstrated very high correlation with PET Aβ imaging. Our study offers additional support for CSF biomarkers in the early and accurate detection of AD pathology, including enrichment of patient cohorts for treatment trials even at the pre-symptomatic stage.

The effect of CSF-1 administration on lung maturation in a mouse model of neonatal hyperoxia exposure.

PubMed

Jones, Christina V; Alikhan, Maliha A; O'Reilly, Megan; Sozo, Foula; Williams, Timothy M; Harding, Richard; Jenkin, Graham; Ricardo, Sharon D

2014-09-06

Lung immaturity due to preterm birth is a significant complication affecting neonatal health. Despite the detrimental effects of supplemental oxygen on alveolar formation, it remains an important treatment for infants with respiratory distress. Macrophages are traditionally associated with the propagation of inflammatory insults, however increased appreciation of their diversity has revealed essential functions in development and regeneration. Macrophage regulatory cytokine Colony-Stimulating Factor-1 (CSF-1) was investigated in a model of neonatal hyperoxia exposure, with the aim of promoting macrophages associated with alveologenesis to protect/rescue lung development and function. Neonatal mice were exposed to normoxia (21% oxygen) or hyperoxia (Hyp; 65% oxygen); and administered CSF-1 (0.5 μg/g, daily × 5) or vehicle (PBS) in two treatment regimes; 1) after hyperoxia from postnatal day (P)7-11, or 2) concurrently with five days of hyperoxia from P1-5. Lung structure, function and macrophages were assessed using alveolar morphometry, barometric whole-body plethysmography and flow cytometry. Seven days of hyperoxia resulted in an 18% decrease in body weight and perturbation of lung structure and function. In regime 1, growth restriction persisted in the Hyp + PBS and Hyp + CSF-1 groups, although perturbations in respiratory function were resolved by P35. CSF-1 increased CSF-1R+/F4/80+ macrophage number by 34% at P11 compared to Hyp + PBS, but was not associated with growth or lung structural rescue. In regime 2, five days of hyperoxia did not cause initial growth restriction in the Hyp + PBS and Hyp + CSF-1 groups, although body weight was decreased at P35 with CSF-1. CSF-1 was not associated with increased macrophages, or with functional perturbation in the adult. Overall, CSF-1 did not rescue the growth and lung defects associated with hyperoxia in this model; however, an increase in CSF-1R+ macrophages was not associated with an exacerbation of lung injury. The trophic functions of macrophages in lung development requires further elucidation in order to explore macrophage modulation as a strategy for promoting lung maturation.

In enterovirus 71 encephalitis with cardio-respiratory compromise, elevated interleukin 1β, interleukin 1 receptor antagonist, and granulocyte colony-stimulating factor levels are markers of poor prognosis.

PubMed

Griffiths, Michael J; Ooi, Mong H; Wong, See C; Mohan, Anand; Podin, Yuwana; Perera, David; Chieng, Chae H; Tio, Phaik H; Cardosa, Mary J; Solomon, Tom

2012-09-15

Enterovirus 71 (EV71) causes large outbreaks of hand, foot, and mouth disease (HFMD), with severe neurological complications and cardio-respiratory compromise, but the pathogenesis is poorly understood. We measured levels of 30 chemokines and cytokines in serum and cerebrospinal fluid (CSF) samples from Malaysian children hospitalized with EV71 infection (n = 88), comprising uncomplicated HFMD (n = 47), meningitis (n = 8), acute flaccid paralysis (n = 1), encephalitis (n = 21), and encephalitis with cardiorespiratory compromise (n = 11). Four of the latter patients died. Both pro-inflammatory and anti-inflammatory mediator levels were elevated, with different patterns of mediator abundance in the CSF and vascular compartments. Serum concentrations of interleukin 1β (IL-1β), interleukin 1 receptor antagonist (IL-1Ra), and granulocyte colony-stimulating factor (G-CSF) were raised significantly in patients who developed cardio-respiratory compromise (P = .013, P = .004, and P < .001, respectively). Serum IL-1Ra and G-CSF levels were also significantly elevated in patients who died, with a serum G-CSF to interleukin 5 ratio of >100 at admission being the most accurate prognostic marker for death (P < .001; accuracy, 85.5%; sensitivity, 100%; specificity, 84.7%). Given that IL-1β has a negative inotropic action on the heart, and that both its natural antagonist, IL-1Ra, and G-CSF are being assessed as treatments for acute cardiac impairment, the findings suggest we have identified functional markers of EV71-related cardiac dysfunction and potential treatment options.

European Mitochondrial DNA Haplogroups are Associated with Cerebrospinal Fluid Biomarkers of Inflammation in HIV Infection

PubMed Central

Samuels, David C.; Kallianpur, Asha R.; Ellis, Ronald J.; Bush, William S.; Letendre, Scott; Franklin, Donald; Grant, Igor; Hulgan, Todd

2017-01-01

Background Mitochondrial DNA (mtDNA) haplogroups are ancestry-related patterns of single-nucleotide polymorphisms that are associated with differential mitochondrial function in model systems, neurodegenerative diseases in HIV-negative populations, and chronic complications of HIV infection, including neurocognitive impairment. We hypothesized that mtDNA haplogroups are associated with neuroinflammation in HIV-infected adults. Methods CNS HIV Antiretroviral Therapy Effects Research (CHARTER) is a US-based observational study of HIV-infected adults who underwent standardized neurocognitive assessments. Participants who consented to DNA collection underwent whole blood mtDNA sequencing, and a subset also underwent lumbar puncture. IL-6, IL-8, TNF-α (high-sensitivity), and IP-10 were measured in cerebrospinal fluid (CSF) by immunoassay. Multivariable regression of mtDNA haplogroups and log-transformed CSF biomarkers were stratified by genetic ancestry using whole-genome nuclear DNA genotyping (European [EA], African [AA], or Hispanic ancestry [HA]), and adjusted for age, sex, antiretroviral therapy (ART), detectable CSF HIV RNA, and CD4 nadir. A total of 384 participants had both CSF cytokine measures and genetic data (45% EA, 44% AA, 11% HA, 22% female, median age 43 years, 74% on ART). Results In analyses stratified by the 3 continental ancestry groups, no haplogroups were significantly associated with the 4 biomarkers. In the subgroup of participants with undetectable plasma HIV RNA on ART, European haplogroup H participants had significantly lower CSF TNF-α (P = 0.001). Conclusions Lower CSF TNF-α may indicate lower neuroinflammation in the haplogroup H participants with well-controlled HIV on ART. PMID:28317034

A Low-Molecular-Weight Ferroxidase Is Increased in the CSF of sCJD Cases: CSF Ferroxidase and Transferrin as Diagnostic Biomarkers for sCJD

PubMed Central

Haldar, Swati; Beveridge, ’Alim J.; Wong, Joseph; Singh, Ajay; Galimberti, Daniela; Borroni, Barbara; Zhu, Xiongwei; Blevins, Janis; Greenlee, Justin; Perry, George; Mukhopadhyay, Chinmay K.; Schmotzer, Christine

2013-01-01

Abstract Aims: Most biomarkers used for the premortem diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) are surrogate in nature, and provide suboptimal sensitivity and specificity. Results: We report that CJD-associated brain iron dyshomeostasis is reflected in the cerebrospinal fluid (CSF), providing disease-specific diagnostic biomarkers. Analysis of 290 premortem CSF samples from confirmed cases of CJD, Alzheimer's disease, and other dementias (DMs), and 52 non-DM (ND) controls revealed a significant difference in ferroxidase (Frx) activity and transferrin (Tf) levels in sporadic Creutzfeldt-Jakob disease (sCJD) relative to other DM and ND controls. A combination of CSF Frx and Tf discriminated sCJD from other DMs with a sensitivity of 86.8%, specificity of 92.5%, accuracy of 88.9%, and area-under-the receiver-operating-characteristic (ROC) curve of 0.94. This combination provided a similar diagnostic accuracy in discriminating CJD from rapidly progressing cases who died within 6 months of sample collection. Surprisingly, ceruloplasmin and amyloid precursor protein, the major brain Frxs, displayed minimal activity in the CSF. Most of the Frx activity was concentrated in the <3-kDa fraction in normal and diseased CSF, and resisted heat and proteinase-K treatment. Innovation: (i) A combination of CSF Frx and Tf provides disease-specific premortem diagnostic biomarkers for sCJD. (ii) A novel, nonenzymatic, nonprotein Frx predominates in human CSF that is distinct from the currently known CSF Frxs. Conclusion: The underlying cause of iron imbalance is distinct in sCJD relative to other DMs associated with the brain iron imbalance. Thus, change in the CSF levels of iron-management proteins can provide disease-specific biomarkers and insight into the cause of iron imbalance in neurodegenerative conditions. Antioxid. Redox Signal. 19, 1662–1675. PMID:23379482

Rapid spontaneous cerebrospinal fluid leak detected in the gastrointestinal tract.

PubMed

Ma, Hong Yun; Sen, Papia; Stein, Evan G; Freeman, Leonard M

2014-02-01

There are many causes of cerebrospinal (CSF) leaks. Most cases are secondary to blunt trauma and iatrogenic trauma caused by postoperative sequelae. Occasionally, CSF leakage may occur from nontraumatic or "spontaneous" causes, such as benign intracranial hypertension and "empty sella syndrome." Mass effect due to an encephalocele or meningocele may also be seen. Radionuclide cisternography is a sensitive method of determining CSF leak when combined with intranasal cotton pledget placement and analysis. We present a spontaneous CSF fluid leak that was detected when scintigraphic activity appeared first in the gastrointestinal tract.

3D fluid-attenuated inversion recovery imaging: reduced CSF artifacts and enhanced sensitivity and specificity for subarachnoid hemorrhage.

PubMed

Lummel, N; Schoepf, V; Burke, M; Brueckmann, H; Linn, J

2011-12-01

FLAIR images are highly sensitive for SAH. However, CSF flow artifacts caused by conventional FLAIR can produce false-positive results. Here, we compare 3D and 3D FLAIR sequences, focusing on their potential for containing these artifacts and their sensitivity and specificity for detection of SAHs. We evaluated the following 4 FLAIR sequences: 1) 2D FLAIR at 1.5T, 2) 2D FLAIR, 3) 2D PROPELLER-FLAIR, and 4) 3D Cube-FLAIR at 3T. All sequences were performed in 5 healthy volunteers; sequences 2 and 4 were also performed under routine conditions in 10 patients with focal epilepsy and in 10 patients with SAH. Two neuroradiologists independently conducted the analysis. The presence of flow artifacts in the ventricles and cisterns of healthy volunteers and patients with epilepsy was evaluated and scored on a 4-point scale. Mean values were calculated and compared by using paired t tests. Sensitivity and specificity for SAH detection in sequences 2 and 4 were determined. Cube-FLAIR showed almost no CSF artifacts in the volunteers and the patients with epilepsy; therefore, it was superior to any other FLAIR (P < .001). Sensitivity and specificity of SAH detection by 3T FLAIR were 58.3% and 89.4%, respectively, whereas Cube-FLAIR had a sensitivity of 95% and a specificity of 100%. Cube-FLAIR allows FLAIR imaging with almost no CSF artifacts and is, thus, particularly useful for SAH detection.

Quantification of vitamin B6 vitamers in human cerebrospinal fluid by ultra performance liquid chromatography-tandem mass spectrometry.

PubMed

van der Ham, M; Albersen, M; de Koning, T J; Visser, G; Middendorp, A; Bosma, M; Verhoeven-Duif, N M; de Sain-van der Velden, M G M

2012-01-27

Since vitamin B6 is essential for normal functioning of the central nervous system, there is growing need for sensitive analysis of B6 vitamers in cerebrospinal fluid (CSF). This manuscript describes the development and validation of a rapid, sensitive and accurate method for quantification of the vitamin B6 vitamers pyridoxal (PL), pyridoxamine (PM), pyridoxine (PN), pyridoxic acid (PA), pyridoxal 5'-phosphate (PLP), pyridoxamine 5'-phosphate (PMP) and pyridoxine 5'-phosphate (PNP) in human CSF. The method is based on ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) with a simple sample preparation procedure of protein precipitation using 50 g L(-1) trichloroacetic acid containing stable isotope labeled internal standards: PL-D(3) for PL and PM, PN-(13)C(4) for PN, PA-D(2) for PA and PLP-D(3) for the phosphorylated vitamers. B6 vitamers were separated (Acquity HSS-T3 UPLC column) with a buffer containing acetic acid, heptafluorobutyric acid and acetonitrile. Positive electrospray ionization was used to monitor transitions m/z 168.1→150.1 (PL), 169.1→134.1 (PM), 170.1→134.1 (PN), 184.1→148.1 (PA), 248.1→150.1 (PLP), 249.1→232.1 (PMP) and 250.1→134.1 (PNP). The method was validated at three concentration levels for each B6 vitamer in CSF. Recoveries of the internal standards were between 93% and 96%. Intra- and inter-assay variations were below 20%. Accuracy tests showed deviations from 3% (PN) to 39% (PMP). Limits of quantification were in the range of 0.03-5.37 nM. Poor results were obtained for quantification of PNP. The method was applied to CSF samples of 20 subjects and two patients on pyridoxine supplementation. Using minimal CSF volumes this method is suitable for implementation in a routine diagnostic setting. Copyright © 2011 Elsevier B.V. All rights reserved.

CSF ADA Determination in Early Diagnosis of Tuberculous Meningitis in HIV-Infected Patients.

PubMed

Ghosh, Gopal Chandra; Sharma, Brijesh; Gupta, B B

2016-01-01

Tuberculous and Cryptococcal meningitis are common in HIV patients. A highly specific and sensitive rapid test for diagnosis of Tuberculous meningitis especially in setting of HIV is not available in developing countries where the burden of disease is high. We measured ADA (adenosine deaminase) levels using spectrophotometric method in the CSF of HIV patients with meningitis to differentiate Tuberculous meningitis from meningitis due to other causes. Kruskal-Wallis test was used to compare ADA values between tuberculous meningitis (TBM) and nontuberculous (non-TB) meningitis patients and a receiver-operating characteristic (ROC) analysis curve was drawn from these values. Levels of ADA in the CSF of patients with TBM were significantly higher than those in patients with meningitis due to other causes. CSF ADA level determination with a cut-off value of 6 IU/L was found to be highly specific and fairly sensitive test for the diagnosis of TBM in HIV positive patients.

Pleocytosis is not fully responsible for low CSF glucose in meningitis.

PubMed

Baud, Maxime O; Vitt, Jeffrey R; Robbins, Nathaniel M; Wabl, Rafael; Wilson, Michael R; Chow, Felicia C; Gelfand, Jeffrey M; Josephson, S Andrew; Miller, Steve

2018-01-01

The mechanism of hypoglycorrhachia-low CSF glucose-in meningitis remains unknown. We sought to evaluate the relative contribution of CSF inflammation vs microorganisms (bacteria and fungi) in lowering CSF glucose levels. We retrospectively categorized CSF profiles into microbial and aseptic meningitis and analyzed CSF leukocyte count, glucose, and protein concentrations. We assessed the relationship between these markers using multivariate and stratified linear regression analysis for initial and repeated CSF sampling. We also calculated the receiver operating characteristics of CSF glucose and CSF-to-serum glucose ratios to presumptively diagnose microbial meningitis. We found that increasing levels of CSF inflammation were associated with decreased CSF glucose levels in the microbial but not aseptic category. Moreover, elevated CSF protein levels correlated more strongly than the leukocyte count with low CSF glucose levels on initial ( R 2 = 36%, p < 0.001) and repeated CSF sampling ( R 2 = 46%, p < 0.001). Hypoglycorrhachia (<40 mg/dL) was observed in 50.1% of microbial cases, but only 9.6% of aseptic cases, most of which were neurosarcoidosis. Absolute CSF glucose and CSF-to-serum glucose ratios had similar low sensitivity and moderate-to-high specificity in diagnosing microbial meningitis at thresholds commonly used. The main driver of hypoglycorrhachia appears to be a combination of microbial meningitis with moderate to high degrees of CSF inflammation and proteins, suggesting that the presence of microorganisms capable of catabolizing glucose is a determinant of hypoglycorrhachia in meningitis. A major notable exception is neurosarcoidosis. Low CSF glucose and CSF-to-serum glucose ratios are useful markers for the diagnosis of microbial meningitis.

Increased cerebrospinal fluid albumin and immunoglobulin A fractions forecast cortical atrophy and longitudinal functional deterioration in relapsing-remitting multiple sclerosis.

PubMed

Kroth, Julia; Ciolac, Dumitru; Fleischer, Vinzenz; Koirala, Nabin; Krämer, Julia; Muthuraman, Muthuraman; Luessi, Felix; Bittner, Stefan; Gonzalez-Escamilla, Gabriel; Zipp, Frauke; Meuth, Sven G; Groppa, Sergiu

2017-12-01

Currently, no unequivocal predictors of disease evolution exist in patients with multiple sclerosis (MS). Cortical atrophy measurements are, however, closely associated with cumulative disability. Here, we aim to forecast longitudinal magnetic resonance imaging (MRI)-driven cortical atrophy and clinical disability from cerebrospinal fluid (CSF) markers. We analyzed CSF fractions of albumin and immunoglobulins (Ig) A, G, and M and their CSF to serum quotients. Widespread atrophy was highly associated with increased baseline CSF concentrations and quotients of albumin and IgA. Patients with increased CSF IgA and CSF IgM showed higher functional disability at follow-up. CSF markers of blood-brain barrier integrity and specific immune response forecast emerging gray matter pathology and disease progression in MS.

CSF-1R regulates non-small cell lung cancer cells dissemination through Wnt3a signaling.

PubMed

Yu, Yan Xia; Wu, Hai Jian; Tan, Bing Xu; Qiu, Chen; Liu, Hui Zhong

2017-01-01

Therapeutic antibodies targeting colony stimulating factor 1 receptor (CSF-1R) to block colony stimulating factor-1/colony stimulating factor 1 receptor (CSF-1/CSF-R) signaling axis have exhibit remarkable efficacy in the treatment of malignant tumor. Yet, little is known about the effects of intrinsic CSF-1R in human non-small-cell carcinoma (NSCLC). Here we demonstrated that NSCLC cell-intrinsic CSF-1R promoted cells growth and metastasis both in vitro and in vivo. CSF-1R knocked-down by transfecting with shRNA target CSF-1R suppressed NSCLC cells proliferation and tumor growth in nude mice. Conversely, ectopic expression of CSF-1R promoted cells proliferation and accelerated tumor growth. Mechanistically, the NSCLC CSF-1R modulated downstream effectors of phosphatidylinositol 3-kinase (PI3K) signaling. In addition, CSF-1R overexpression significantly enhanced NSCLC cells mobility, invasion and epithelial-mesenchymal transition (EMT) process, whereas silencing CSF-1R inhibits these phenotypes. Microarray analysis suggested that Wnt family member 3a (Wnt3a) function as a downstream factor of CSF-1R. On account of this, we future identified CSF-1R/Wnt3a a signaling pathway sustained NSCLC cells metastasis. Finally, in patients, CSF-1R and Wnt3a expression positively correlated with the of NSCLC patients. Our results identify NSCLC cell intrinsic functions of CSF-1R/Wnt3a axis in dissemination of NSCLC.

CSF-1R regulates non-small cell lung cancer cells dissemination through Wnt3a signaling

PubMed Central

Yu, Yan Xia; Wu, Hai Jian; Tan, Bing Xu; Qiu, Chen; Liu, Hui Zhong

2017-01-01

Therapeutic antibodies targeting colony stimulating factor 1 receptor (CSF-1R) to block colony stimulating factor-1/colony stimulating factor 1 receptor (CSF-1/CSF-R) signaling axis have exhibit remarkable efficacy in the treatment of malignant tumor. Yet, little is known about the effects of intrinsic CSF-1R in human non-small-cell carcinoma (NSCLC). Here we demonstrated that NSCLC cell-intrinsic CSF-1R promoted cells growth and metastasis both in vitro and in vivo. CSF-1R knocked-down by transfecting with shRNA target CSF-1R suppressed NSCLC cells proliferation and tumor growth in nude mice. Conversely, ectopic expression of CSF-1R promoted cells proliferation and accelerated tumor growth. Mechanistically, the NSCLC CSF-1R modulated downstream effectors of phosphatidylinositol 3-kinase (PI3K) signaling. In addition, CSF-1R overexpression significantly enhanced NSCLC cells mobility, invasion and epithelial-mesenchymal transition (EMT) process, whereas silencing CSF-1R inhibits these phenotypes. Microarray analysis suggested that Wnt family member 3a (Wnt3a) function as a downstream factor of CSF-1R. On account of this, we future identified CSF-1R/Wnt3a a signaling pathway sustained NSCLC cells metastasis. Finally, in patients, CSF-1R and Wnt3a expression positively correlated with the of NSCLC patients. Our results identify NSCLC cell intrinsic functions of CSF-1R/Wnt3a axis in dissemination of NSCLC. PMID:29218239

Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study.

PubMed

Gresa-Arribas, Nuria; Titulaer, Maarten J; Torrents, Abiguei; Aguilar, Esther; McCracken, Lindsey; Leypoldt, Frank; Gleichman, Amy J; Balice-Gordon, Rita; Rosenfeld, Myrna R; Lynch, David; Graus, Francesc; Dalmau, Josep

2014-02-01

Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is a severe but treatable autoimmune disorder which diagnosis depends on sensitive and specific antibody testing. We aimed to assess the sensitivity and specificity of serum and CSF antibody testing in patients with anti-NMDA receptor encephalitis, and the relation between titres, relapses, outcome, and epitope repertoire. In this observational study, we used rat brain immunohistochemistry and cell-based assays (CBA) with fixed or live NMDA receptor-expressing cells to determine the sensitivity and specificity of antibody testing in paired serum and CSF samples. Samples were obtained at diagnosis from patients with anti-NMDA receptor encephalitis and from control participants worldwide. We deemed a patient to be antibody positive if their serum, their CSF, or both tested positive with both immunohistochemistry and CBA techniques; we determined titres with serial sample dilution using brain immunohistochemistry. We examined samples from 45 patients (25 with good outcome [modified Rankin Scale, mRS 0-2], ten with poor outcome [mRS 3-6], and ten with relapses) at three or more timepoints. We determined the epitope repertoire in the samples of 23 patients with CBA expressing GluN1-NMDA receptor mutants. We analysed samples from 250 patients with anti-NMDA receptor encephalitis and 100 control participants. All 250 patients had NMDA receptor antibodies in CSF but only 214 had antibodies in serum (sensitivity 100.0% [98.5-1000%] vs 85.6% [80.7-89.4%], p<0.0001). Serum immunohistochemistry testing was more often in agreement with CBA with fixed cells (77 [71%] of 108) than with CBA with live cells (63 [58%] of 108, p=0.0056). In multivariable analysis, CSF and serum titres were higher in patients with poor outcome than in those with good outcome (CSF dilution 340 vs 129, difference 211, [95% CI 1-421], p=0.049; serum dilution 7370 vs 1243, difference 6127 [2369-9885], p=0.0025), and in patients with teratoma than in those without teratoma (CSF 395 vs 110, difference 285 [134-437], p=0.0079; serum 5515 vs 1644, difference 3870 [548-7193], p=0.024). Over time there was a decrease of antibody titres in the 35 patients with good or poor outcome and samples followed at three timepoints regardless of outcome (from diagnosis to last follow-up: CSF 614 to 76, difference 538 [288-788]; serum 5460 to 1564, difference 3896 [2428-5362]; both p<0.0001). Relapses were associated with a change in titre more often in CSF than in serum (14 of 19 vs seven of 16, p=0.037). After recovery, 24 of 28 CSF samples and 17 of 23 serum samples from patients remained antibody positive. Patients' antibodies targeted a main epitope region at GluN1 aminoacid 369; the epitope repertoire did not differ between patients with different outcomes, and did not change during relapses. The sensitivity of NMDA receptor antibody testing is higher in CSF than in serum. Antibody titres in CSF and serum were higher in patients with poor outcome or teratoma than in patients with good outcome or no tumour. The titre change in CSF was more closely related with relapses than was that in serum. These findings emphasise the importance of including CSF in antibody studies, and that antibody titres can complement clinical assessments. Dutch Cancer Society, National Institutes of Health, McKnight Neuroscience of Brain Disorders award, the Fondo de Investigaciones Sanitarias, ErasmusMC fellowship, and Fundació la Marató de TV3. Copyright © 2014 Elsevier Ltd. All rights reserved.

Crystallization of M-CSF.alpha.

DOEpatents

Pandit, Jayvardhan; Jancarik, Jarmila; Kim, Sung-Hou; Koths, Kirston; Halenbeck, Robert; Fear, Anna Lisa; Taylor, Eric; Yamamoto, Ralph; Bohm, Andrew

1999-01-01

The present invention is directed to methods for crystallizing macrophage colony stimulating factor (M-CSF) and to a crystalline M-CSF produced thereby. The present invention is also directed to methods for designing and producing M-CSF agonists and antagonists using information derived from the crystallographic structure of M-CSF. The invention is also directed to methods for screening M-CSF agonists and antagonists. In addition, the present invention is directed to an isolated, purified, soluble and functional M-CSF receptor.

CSF levels of oligomeric alpha-synuclein and beta-amyloid as biomarkers for neurodegenerative disease

PubMed Central

Chatterjee, Gaurav; McGraw, Claire; Kasturirangan, Srinath; Schulz, Philip

2012-01-01

Protein misfolding and aggregation is a critically important feature in many devastating neurodegenerative diseases, therefore characterization of the CSF concentration profiles of selected key forms and morphologies of proteins involved in these diseases, including β-amyloid (Aβ) and α-synuclein (a-syn), can be an effective diagnostic assay for these diseases. CSF levels of tau and Aβ have been shown to have great promise as biomarkers for Alzheimer’s disease. However since the onset and progression of many neurodegenerative diseases have been strongly correlated with the presence of soluble oligomeric aggregates of proteins including various Aβ and a-syn aggregate species, specific detection and quantification of levels of each of these different toxic protein species in CSF may provide a simple and accurate means to presymptomatically diagnose and distinguish between these diseases. Here we show that the presence of different protein morphologies in human CSF samples can be readily detected using highly selective morphology specific reagents in conjunction with a sensitive electronic biosensor. We further show that these morphology specific reagents can readily distinguish between post-mortem CSF samples from AD, PD and cognitively normal sources. These studies suggest that detection of specific oligomeric aggregate species holds great promise as sensitive biomarkers for neurodegenerative disease. PMID:22076255

Validity of a PCR assay in CSF for the diagnosis of neurocysticercosis

PubMed Central

Campoverde, Alfredo; Romo, Matthew L.; García, Lorena; Piedra, Luis M.; Pacurucu, Mónica; López, Nelson; Aguilar, Jenner; López, Sebastian; Vintimilla, Luis C.; Toral, Ana M.; Peña-Tapia, Pablo

2017-01-01

Objective: To prospectively evaluate the validity of a PCR assay in CSF for the diagnosis of neurocysticercosis (NC). Methods: We conducted a multicenter, prospective case-control study, recruiting participants from 5 hospitals in Cuenca, Ecuador, from January 2015 to February 2016. Cases fulfilled validated diagnostic criteria for NC. For each case, a neurosurgical patient who did not fulfill the diagnostic criteria for NC was selected as a control. CT and MRI, as well as a CSF sample, were collected from both cases and controls. The diagnostic criteria to identify cases were used as a reference standard. Results: Overall, 36 case and 36 control participants were enrolled. PCR had a sensitivity of 72.2% (95% confidence interval [CI] 54.8%–85.8%) and a specificity of 100.0% (95% CI 90.3%–100.0%). For parenchymal NC, PCR had a sensitivity of 42.9% (95% CI 17.7%–71.1%), and for extraparenchymal NC, PCR had a sensitivity of 90.9% (95% CI 70.8%–98.9%). Conclusions: This study demonstrated the usefulness of this PCR assay in CSF for the diagnosis of NC. PCR may be particularly helpful for diagnosing extraparenchymal NC when neuroimaging techniques have failed. Classification of evidence: This study provides Class III evidence that CSF PCR can accurately identify patients with extraparenchymal NC. PMID:28105460

The Neuroimaging Studies in Children with Ventriculoperitoneal Shunt Complications: A 10 Years Descriptive Sudy in Tehran.

PubMed

Shahi, Mohammad Vafaee; Noorbakhsh, Samileh; Zarrabi, Vida; Nourozi, Banafsheh; Tahernia, Leila

2018-01-01

Any mismatch between the production and absorption of CSF results in hydrocephalus. In most cases, the selected choice of treatment is the ventriculoperitoneal shunt insertion. Although, the surgery could have complications such as infection, shunt malfunction, subdural hematoma, seizure and Shunt immigration; so, the early and proper detection of these complications could result in better prognosis. The aim of this study was to evaluate and compare the efficacy of CT scan, CSF analysis and X-ray radiography in detection of shunt complications and problems in shunt placement and further follow-up in hospitalized children. The medical records of children in Rasul Akram hospital in Tehran were reviewed retrospectively in the last 10 years, from 2006 to 2016. All data were recorded in the prepared form including the age, sex, shunt complication, CT scan and CSF characteristics. The total number of 95 patients were interfered in this study including 56 males (58.9%) and 39 females (41.1%). The mean age at the onset of complications were 2.8±2.2 years-old. The shunt obstruction (60%) and infection (25.3%) were the most common complications. The CT scan was able to detect 36.5% of shunt complications. The CT scan had the sensitivity and specificity of 50 and 87%, respectively in detection of shunt obstruction. The all cases of brain hematoma and hemorrhage were revealed by CT scan. On the other hand, the CT scan had 20% of sensitivity and 60% of specificity in the detection of shunt infection. The CSF evaluation in shunt infection revealed 92% hypoglycemia, 87.5% pleocytosis, and 62.5% positive CSF culture. CSF had the sensitivity, specificity, positive predictive value and negative predictive value of 92, 82, 63 and 97%, respectively. The patient's symptoms and signs were helpful in obtaining higher test accuracy. The CT scan was not a good sensitive and specific study in the detection of shunt obstruction and infection, but it was very accurate in detection of hemorrhage and hematoma. On the other hand, CSF evaluation was a reliable test in shunt infection disclosure.

Clinical evaluation of a loop-mediated isothermal amplification (LAMP) assay for rapid detection of Neisseria meningitidis in cerebrospinal fluid.

PubMed

Lee, DoKyung; Kim, Eun Jin; Kilgore, Paul E; Kim, Soon Ae; Takahashi, Hideyuki; Ohnishi, Makoto; Anh, Dang Duc; Dong, Bai Qing; Kim, Jung Soo; Tomono, Jun; Miyamoto, Shigehiko; Notomi, Tsugunori; Kim, Dong Wook; Seki, Mitsuko

2015-01-01

Neisseria meningitidis (Nm) is a leading causative agent of bacterial meningitis in humans. Traditionally, meningococcal meningitis has been diagnosed by bacterial culture. However, isolation of bacteria from patients' cerebrospinal fluid (CSF) is time consuming and sometimes yields negative results. Recently, polymerase chain reaction (PCR)-based diagnostic methods of detecting Nm have been considered the gold standard because of their superior sensitivity and specificity compared with culture. In this study, we developed a loop-mediated isothermal amplification (LAMP) method and evaluated its ability to detect Nm in cerebrospinal fluid (CSF). We developed a meningococcal LAMP assay (Nm LAMP) that targets the ctrA gene. The primer specificity was validated using 16 strains of N. meningitidis (serogroup A, B, C, D, 29-E, W-135, X, Y, and Z) and 19 non-N. meningitidis species. Within 60 min, the Nm LAMP detected down to ten copies per reaction with sensitivity 1000-fold more than that of conventional PCR. The LAMP assays were evaluated using a set of 1574 randomly selected CSF specimens from children with suspected meningitis collected between 1998 and 2002 in Vietnam, China, and Korea. The LAMP method was shown to be more sensitive than PCR methods for CSF samples (31 CSF samples were positive by LAMP vs. 25 by PCR). The detection rate of the LAMP method was substantially higher than that of the PCR method. In a comparative analysis of the PCR and LAMP assays, the clinical sensitivity, specificity, positive predictive value, and negative predictive value of the LAMP assay were 100%, 99.6%, 80.6%, and 100%, respectively. Compared to PCR, LAMP detected Nm with higher analytical and clinical sensitivity. This sensitive and specific LAMP method offers significant advantages for screening patients on a population basis and for diagnosis in clinical settings.

Noise Enhanced Sensory Signal Processing

DTIC Science & Technology

2012-01-31

Moreover, a contrast sensitivity function (CSF), as an object feature enhancer , was employed for further improving the segmentation performance, which...Digital mammography work appeared in ACM Tech News on Feb. 3, 2010. 8. Interactions/Transitions Invited talks: • P.K. Varshney, “Noise Enhanced ... mammography machines with regard to our work on image enhancement based on SR. • Lectures at Lockheed Martin in Syracuse and SRC that included discussion

Hypertension from chronic central sodium chloride in mice is mediated by the ouabain-binding site on the Na,K-ATPase α2-isoform

PubMed Central

Dostanic, Iva; Lingrel, Jerry B.; Hou, Xiaohong; Wu, Hengwei

2011-01-01

A chronic increase in the concentration of sodium chloride in the cerebrospinal fluid (CSF) (↑CSF [NaCl]) appears to be critically important for the development of salt-dependent hypertension. In agreement with this concept, increasing CSF [NaCl] chronically by intracerebroventricular (icv) infusion of NaCl-rich artificial CSF (aCSF-HiNaCl) in rats produces hypertension by the same mechanisms (i.e., aldosterone-ouabain pathway in the brain) as that produced by dietary sodium in salt-sensitive strains. We first demonstrate here that icv aCSF-HiNaCl for 10 days also causes hypertension in wild-type (WT) mice. We then used both WT and gene-targeted mice to explore the mechanisms. In WT mice with a ouabain-sensitive Na,K-ATPase α2-isoform (α2S/S), mean arterial pressure rose by ∼25 mmHg within 2 days of starting aCSF-HiNaCl (0.6 nmol Na/min) and remained elevated throughout the study. Ouabain (171 pmol/day icv) increased blood pressure to a similar extent. aCSF-HiNaCl or ouabain given at the same rates subcutaneously instead of intracerebroventricularly had no effect on blood pressure. The pressor response to icv aCSF-HiNaCl was abolished by an anti-ouabain antibody given intracerebroventricularly but not subcutaneously, indicating that it is mediated by an endogenous ouabain-like substance in the brain. We compared the effects of icv aCSF-HiNaCl or icv ouabain on blood pressure in α2S/S versus knockout/knockin mice with a ouabain-resistant endogenous α2-subunit (α2R/R). In α2R/R, there was no pressor response to icv aCSF-HiNaCl in contrast to WT mice. The α2R/R genotype also lacked a pressor response to icv ouabain. These data demonstrate that chronic ↑CSF [NaCl] causes hypertension in mice and that the blood pressure response is mediated by the ouabain-like substance in the brain, specifically by its binding to the α2-isoform of the Na,K-ATPase. PMID:21856907

Nicorandil improves myocardial function by regulating plasma nitric oxide and endothelin-1 in coronary slow flow

PubMed Central

Chen, Xiuhua; Li, Shan; Huo, Xuezhen; Fu, Xiuxiu; Dong, Xiaonan

2015-01-01

Background Coronary slow flow (CSF) is a special coronary microvascular disorder. The pathogenesis and effective therapeutics of CSF remain unclear. This study aimed to evaluate the global and regional functions of the left ventricle (LV) and investigate the efficacy of nicorandil in patients with CSF. Patients and methods Thirty-six patients with CSF in the left anterior descending (LAD) branch and 20 patients with normal coronary arteries were included. Global and regional functions of the LV supplied by LAD were measured using conventional Doppler echocardiography and two-dimensional speckle tracking echocardiography, respectively, within 24 h after coronary angiography. Concentrations of plasma nitric oxide (NO) and endothelin-1 (ET-1) were detected using colorimetry and radioimmunoassay, respectively. The function of the LV and the levels of NO and ET-1 were also investigated before and 90 days after treatment with 15 mg/day of nicorandil. Results Compared with the control group, the early diastolic peak velocity (E), E/A ratio, and plasma NO levels were lower, whereas the late diastolic peak flow velocity (A) and plasma ET-1 levels were significantly higher in the CSF group (P<0.05). The longitudinal strain rate peak of the LV was reduced significantly in CSF patients (P<0.001). After treatment, 75% (27/36) of CSF patients were free of chest pain. The values of E peak, E/A ratio, longitudinal strain rate peak, and plasma NO level were increased (P<0.001), whereas the ET-1 level was decreased in CSF patients (P<0.001). Conclusion Nicorandil may improve chest pain symptoms and the impaired function of the LV, possibly by increasing plasma NO and reducing ET-1 in CSF. PMID:25325437

An integrated mechanism of pediatric pseudotumor cerebri syndrome: evidence of bioenergetic and hormonal regulation of cerebrospinal fluid dynamics

PubMed Central

Sheldon, Claire A.; Kwon, Young Joon; Liu, Grant T.; McCormack, Shana E.

2015-01-01

Pseudotumor cerebri syndrome (PTCS) is defined by the presence of elevated intracranial pressure (ICP) in the setting of normal brain parenchyma and cerebrospinal fluid (CSF). Headache, vision changes, and papilledema are common presenting features. Up to 10% of appropriately treated patients may experience permanent visual loss. The mechanism(s) underlying PTCS is unknown. PTCS occurs in association with a variety of conditions, including kidney disease, obesity, and adrenal insufficiency, suggesting endocrine and/or metabolic derangements may occur. Recent studies suggest that fluid and electrolyte balance in renal epithelia is regulated by a complex interaction of metabolic and hormonal factors; these cells share many of the same features as the choroid plexus cells in the central nervous system (CNS) responsible for regulation of CSF dynamics. Thus, we posit that similar factors may influence CSF dynamics in both types of fluid-sensitive tissues. Specifically, we hypothesize that, in patients with PTCS, mitochondrial metabolites (glutamate, succinate) and steroid hormones (cortisol, aldosterone) regulate CSF production and/or absorption. In this integrated mechanism review, we consider the clinical and molecular evidence for each metabolite and hormone in turn. We illustrate how related intracellular signaling cascades may converge in the choroid plexus, drawing on evidence from functionally similar tissues. PMID:25420176

Potential clinical applications of rhGM-CSF in acute myeloid leukemia based on its biologic activity and receptor interaction.

PubMed

Lanza, F; Rigolin, G M; Castagnari, B; Moretti, S; Castoldi, G

1997-01-01

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multilineage hemopoietic growth factor that stimulates proliferation, differentiation, and survival of progenitor cells, enhances the functional activities of mature myeloid effector cells, and plays a key role in host defense and the inflammatory process. Although the clinical use of rhGM-CSF in patients affected by lymphoid malignancies is widely accepted, its utility and safety in the management of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) is still controversial. The three main schedules adopted for clinical application of GM-CSF in AML are as follows: A) post-chemotherapy, in order to shorten the duration of neutropenia and/or monocytopenia; B) prechemotherapy to recruit blast cells into active cell cycle phases, and to increase their sensitivity to cell cycle-dependent cytotoxic drugs; C) as a mobilizing agent to induce the release of progenitor cells from bone marrow into circulation (peripheral blood progenitor cell transplantation-PBPC). The objective of this paper is to analyze the potential clinical applications of rhGM-CSF in AML. The material examined in the present review includes several personal papers in this field and articles and abstracts published in journals covered by the Science Citation Index. Based on current knowledge, it may be argued that rhGM-CSF should be used only in a subset of AML patients at high risk of infection mortality, including elderly subjects, and/or in those AML patients who relapse or are resistant to induction treatment. However, the risk of stimulating the leukemic clone following GM-CSF therapy should be kept in mind when using this growth factor in the clinical setting, even though the great majority of the reported papers on this subject have shown that GM-CSF therapy does not affect relapse rates, frequency of remissions or patient life expectancy. It is likely that new data from controlled clinical trials will clarify the therapeutic role of GM-CSF in myeloid-derived malignancies, allowing the establishment of consensus guidelines for its use.

Csf2 null mutation alters placental gene expression and trophoblast glycogen cell and giant cell abundance in mice.

PubMed

Sferruzzi-Perri, Amanda N; Macpherson, Anne M; Roberts, Claire T; Robertson, Sarah A

2009-07-01

Genetic deficiency in granulocyte-macrophage colony-stimulating factor (CSF2, GM-CSF) results in altered placental structure in mice. To investigate the mechanism of action of CSF2 in placental morphogenesis, the placental gene expression and cell composition were examined in Csf2 null mutant and wild-type mice. Microarray and quantitative RT-PCR analyses on Embryonic Day (E) 13 placentae revealed that the Csf2 null mutation caused altered expression of 17 genes not previously known to be associated with placental development, including Mid1, Cd24a, Tnfrsf11b, and Wdfy1. Genes controlling trophoblast differentiation (Ascl2, Tcfeb, Itgav, and Socs3) were also differentially expressed. The CSF2 ligand and the CSF2 receptor alpha subunit were predominantly synthesized in the placental junctional zone. Altered placental structure in Csf2 null mice at E15 was characterized by an expanded junctional zone and by increased Cx31(+) glycogen cells and cyclin-dependent kinase inhibitor 1C (CDKN1C(+), P57(Kip2+)) giant cells, accompanied by elevated junctional zone transcription of genes controlling spongiotrophoblast and giant cell differentiation and secretory function (Ascl2, Hand1, Prl3d1, and Prl2c2). Granzyme genes implicated in tissue remodeling and potentially in trophoblast invasion (Gzmc, Gzme, and Gzmf) were downregulated in the junctional zone of Csf2 null mutant placentae. These data demonstrate aberrant placental gene expression in Csf2 null mutant mice that is associated with altered differentiation and/or functional maturation of junctional zone trophoblast lineages, glycogen cells, and giant cells. We conclude that CSF2 is a regulator of trophoblast differentiation and placental development, which potentially influences the functional capacity of the placenta to support optimal fetal growth in pregnancy.

Biological false-positive venereal disease research laboratory test in cerebrospinal fluid in the diagnosis of neurosyphilis - a case-control study.

PubMed

Zheng, S; Lin, R J; Chan, Y H; Ngan, C C L

2018-03-01

There is no clear consensus on the diagnosis of neurosyphilis. The Venereal Disease Research Laboratory (VDRL) test from cerebrospinal fluid (CSF) has traditionally been considered the gold standard for diagnosing neurosyphilis but is widely known to be insensitive. In this study, we compared the clinical and laboratory characteristics of true-positive VDRL-CSF cases with biological false-positive VDRL-CSF cases. We retrospectively identified cases of true and false-positive VDRL-CSF across a 3-year period received by the Immunology and Serology Laboratory, Singapore General Hospital. A biological false-positive VDRL-CSF is defined as a reactive VDRL-CSF with a non-reactive Treponema pallidum particle agglutination (TPPA)-CSF and/or negative Line Immuno Assay (LIA)-CSF IgG. A true-positive VDRL-CSF is a reactive VDRL-CSF with a concordant reactive TPPA-CSF and/or positive LIA-CSF IgG. During the study period, a total of 1254 specimens underwent VDRL-CSF examination. Amongst these, 60 specimens from 53 patients tested positive for VDRL-CSF. Of the 53 patients, 42 (79.2%) were true-positive cases and 11 (20.8%) were false-positive cases. In our setting, a positive non-treponemal serology has 97.6% sensitivity, 100% specificity, 100% positive predictive value and 91.7% negative predictive value for a true-positive VDRL-CSF based on our laboratory definition. HIV seropositivity was an independent predictor of a true-positive VDRL-CSF. Biological false-positive VDRL-CSF is common in a setting where patients are tested without first establishing a serological diagnosis of syphilis. Serological testing should be performed prior to CSF evaluation for neurosyphilis. © 2017 European Academy of Dermatology and Venereology.

Computational modeling of epidural cortical stimulation

NASA Astrophysics Data System (ADS)

Wongsarnpigoon, Amorn; Grill, Warren M.

2008-12-01

Epidural cortical stimulation (ECS) is a developing therapy to treat neurological disorders. However, it is not clear how the cortical anatomy or the polarity and position of the electrode affects current flow and neural activation in the cortex. We developed a 3D computational model simulating ECS over the precentral gyrus. With the electrode placed directly above the gyrus, about half of the stimulus current flowed through the crown of the gyrus while current density was low along the banks deep in the sulci. Beneath the electrode, neurons oriented perpendicular to the cortical surface were depolarized by anodic stimulation, and neurons oriented parallel to the boundary were depolarized by cathodic stimulation. Activation was localized to the crown of the gyrus, and neurons on the banks deep in the sulci were not polarized. During regulated voltage stimulation, the magnitude of the activating function was inversely proportional to the thickness of the CSF and dura. During regulated current stimulation, the activating function was not sensitive to the thickness of the dura but was slightly more sensitive than during regulated voltage stimulation to the thickness of the CSF. Varying the width of the gyrus and the position of the electrode altered the distribution of the activating function due to changes in the orientation of the neurons beneath the electrode. Bipolar stimulation, although often used in clinical practice, reduced spatial selectivity as well as selectivity for neuron orientation.

CEREBROSPINAL FLUID STASIS AND ITS CLINICAL SIGNIFICANCE

PubMed Central

Whedon, James M.; Glassey, Donald

2010-01-01

We hypothesize that stasis of the cerebrospinal fluid (CSF) occurs commonly and is detrimental to health. Physiologic factors affecting the normal circulation of CSF include cardiovascular, respiratory, and vasomotor influences. The CSF maintains the electrolytic environment of the central nervous system (CNS), influences systemic acid-base balance, serves as a medium for the supply of nutrients to neuronal and glial cells, functions as a lymphatic system for the CNS by removing the waste products of cellular metabolism, and transports hormones, neurotransmitters, releasing factors, and other neuropeptides throughout the CNS. Physiologic impedance or cessation of CSF flow may occur commonly in the absence of degenerative changes or pathology and may compromise the normal physiologic functions of the CSF. CSF appears to be particularly prone to stasis within the spinal canal. CSF stasis may be associated with adverse mechanical cord tension, vertebral subluxation syndrome, reduced cranial rhythmic impulse, and restricted respiratory function. Increased sympathetic tone, facilitated spinal segments, dural tension, and decreased CSF flow have been described as closely related aspects of an overall pattern of structural and energetic dysfunction in the axial skeleton and CNS. Therapies directed at affecting CSF flow include osteopathic care (especially cranial manipulation), craniosacral therapy, chiropractic adjustment of the spine and cranium, Network Care (formerly Network Chiropractic), massage therapy (including lymphatic drainage techniques), yoga, therapeutic breathwork, and cerebrospinal fluid technique. Further investigation into the nature and causation of CSF stasis, its potential effects upon human health, and effective therapies for its correction is warranted. PMID:19472865

Neurogranin as a predictor of memory and executive function decline in MCI patients.

PubMed

Headley, Alison; De Leon-Benedetti, Andres; Dong, Chuanhui; Levin, Bonnie; Loewenstein, David; Camargo, Christian; Rundek, Tatjana; Zetterberg, Henrik; Blennow, Kaj; Wright, Clinton B; Sun, Xiaoyan

2018-03-06

To determine whether high CSF levels of neurogranin (Ng) predict longitudinal decline in memory and executive function during early-stage Alzheimer disease (AD). Baseline levels of CSF Ng were studied in relation to cross-sectional and longitudinal cognitive performance over 8 years. Data were obtained from the Alzheimer's Disease Neuroimaging Initiative database, and participants with normal cognition (n = 111) and mild cognitive impairment (MCI) (n = 193) were included. High levels of CSF Ng were associated with poor baseline memory scores (β = -0.21, p < 0.0001). CSF Ng predicted both memory and executive function decline over time (β = -0.0313, p = 0.0068 and β = -0.0346, p = 0.0169, respectively) independently of age, sex, education, and APOE ε4 status. When the rate of decline by tertiles was examined, CSF Ng was a level-dependent predictor of memory function, whereby the group with highest levels of Ng showed the fastest rates of decline in both memory and executive function. When examined separately, elevated Ng was associated with cognitive decline in participants with MCI but not in those with normal cognition. The levels of CSF Ng were not associated with cognitive measures when tau and amyloid 42 (Aβ 42 ) were controlled for in these analyses. High CSF Ng associates with poor memory scores in participants with MCI cross-sectionally and with poor memory and executive function longitudinally. The association of Ng with cognitive measures disappears when tau and Aβ 42 are included in the statistical models. Our findings suggest that CSF Ng may serve as a biomarker of cognition. Synaptic dysfunction contributes to cognitive impairment in early-stage AD. © 2018 American Academy of Neurology.

Plasma Concentration of the Neurofilament Light Protein (NFL) is a Biomarker of CNS Injury in HIV Infection: A Cross-Sectional Study.

PubMed

Gisslén, Magnus; Price, Richard W; Andreasson, Ulf; Norgren, Niklas; Nilsson, Staffan; Hagberg, Lars; Fuchs, Dietmar; Spudich, Serena; Blennow, Kaj; Zetterberg, Henrik

2016-01-01

Cerebrospinal fluid (CSF) neurofilament light chain protein (NFL) is a sensitive marker of neuronal injury in a variety of neurodegenerative conditions, including the CNS dysfunction injury that is common in untreated HIV infection. However, an important limitation is the requirement for lumbar puncture. For this reason, a sensitive and reliable blood biomarker of CNS injury would represent a welcome advance in both clinical and research settings. To explore whether plasma concentrations of NFL might be used to detect CNS injury in HIV infection, an ultrasensitive Single molecule array (Simoa) immunoassay was developed. Using a cross-sectional design, we measured NFL in paired CSF and plasma samples from 121 HIV-infected subjects divided into groups according to stage of their systemic disease, presence of overt HIV-associated dementia (HAD), and after antiretroviral treatment (ART)-induced viral suppression. HIV-negative controls were also examined. Plasma and CSF NFL concentrations were very highly correlated (r = 0.89, P < 0.0001). While NFL was more than 50-fold lower plasma than CSF it was within the quantifiable range of the new plasma assay in all subjects, including the HIV negatives and the HIV positives with normal CSF NFL concentrations. The pattern of NFL changes were almost identical in plasma and CSF, both exhibiting similar age-related increases in concentrations along with highest values in HAD and substantial elevations in ART-naïve neuroasymptomatic subjects with low blood CD4(+) T cells. These results show that plasma NFL may prove a valuable tool to evaluate ongoing CNS injury in HIV infection that may be applied in the clinic and in research settings to assess the presence if active CNS injury. Because CSF NFL is also elevated in a variety of other CNS disorders, sensitive measures of plasma NFL may similarly prove useful in other settings.

Plasma Concentration of the Neurofilament Light Protein (NFL) is a Biomarker of CNS Injury in HIV Infection: A Cross-Sectional Study

PubMed Central

Gisslén, Magnus; Price, Richard W.; Andreasson, Ulf; Norgren, Niklas; Nilsson, Staffan; Hagberg, Lars; Fuchs, Dietmar; Spudich, Serena; Blennow, Kaj; Zetterberg, Henrik

2015-01-01

Background Cerebrospinal fluid (CSF) neurofilament light chain protein (NFL) is a sensitive marker of neuronal injury in a variety of neurodegenerative conditions, including the CNS dysfunction injury that is common in untreated HIV infection. However, an important limitation is the requirement for lumbar puncture. For this reason, a sensitive and reliable blood biomarker of CNS injury would represent a welcome advance in both clinical and research settings. Methods To explore whether plasma concentrations of NFL might be used to detect CNS injury in HIV infection, an ultrasensitive Single molecule array (Simoa) immunoassay was developed. Using a cross-sectional design, we measured NFL in paired CSF and plasma samples from 121 HIV-infected subjects divided into groups according to stage of their systemic disease, presence of overt HIV-associated dementia (HAD), and after antiretroviral treatment (ART)-induced viral suppression. HIV-negative controls were also examined. Findings Plasma and CSF NFL concentrations were very highly correlated (r = 0.89, P < 0.0001). While NFL was more than 50-fold lower plasma than CSF it was within the quantifiable range of the new plasma assay in all subjects, including the HIV negatives and the HIV positives with normal CSF NFL concentrations. The pattern of NFL changes were almost identical in plasma and CSF, both exhibiting similar age-related increases in concentrations along with highest values in HAD and substantial elevations in ART-naïve neuroasymptomatic subjects with low blood CD4+ T cells. Interpretation These results show that plasma NFL may prove a valuable tool to evaluate ongoing CNS injury in HIV infection that may be applied in the clinic and in research settings to assess the presence if active CNS injury. Because CSF NFL is also elevated in a variety of other CNS disorders, sensitive measures of plasma NFL may similarly prove useful in other settings. PMID:26870824

Neurodegenerative cerebrospinal fluid biomarkers tau and amyloid beta predict functional, quality of life, and neuropsychological outcomes after aneurysmal subarachnoid hemorrhage.

PubMed

Joswig, Holger; Korte, Wolfgang; Früh, Severin; Epprecht, Lorenz; Hildebrandt, Gerhard; Fournier, Jean-Yves; Stienen, Martin Nikolaus

2018-04-01

Cerebrospinal fluid (CSF) biomarkers might be useful in predicting outcome after aneurysmal subarachnoid hemorrhage (aSAH). It was the aim to determine whether tau and amyloid beta CSF concentrations predict functional, health-related quality of life (hrQoL), and neuropsychological outcomes after aSAH. Ventricular CSF was obtained from n = 24 aSAH patients at admission (D0), day 2 (D2), and day 6 (D6). CSF total (t)Tau, phosphorylated (p)Tau (181P) , and amyloid beta (1-40 and 1-42) (Aβ40/Aβ42) levels were compared between patients with favorable and unfavorable functional (modified Rankin Scale (mRS)), hrQoL (Euro-Qol (EQ-5D)), and neuropsychological outcomes at 3 (3 m) and 12 months (12 m). Patients with unfavorable functional (mRS 4-6) and hrQoL outcome (EQ-5D z-score ≤ - 1.0) at 3 and 12 m had higher CSF tTau/pTau and lower Aβ40/Aβ42 at D0, D2, and D6 with varying degrees of statistical significance. In terms of predicting neuropsychological outcome, CSF pTau showed a statistically significant correlation with the z-scores of executive function (r = - 0.7486, p = 0.008), verbal memory (r = - 0.8101, p = 0.002), attention (r = - 0.6498, p = 0.030), and visuospatial functioning (r = - 0.6944, p = 0.017) at 3 m. At 12 m, CSF pTau had statistically significant correlations with the z-scores of verbal memory (r = - 0.7473, p = 0.008) and visuospatial functioning (r = - 0.6678, p = 0.024). In conclusion, higher tTau/pTau and lower Aβ40/Aβ42 CSF levels predict unfavorable long-term functional and hrQoL outcomes. Neuropsychological deficits correlate with increased CSF tTau and pTau concentrations.

Development of a new LAMP assay for the detection of CSFV strains from Cuba: a proof-of-concept study.

PubMed

Postel, Alexander; Pérez, Lester J; Perera, Carmen L; Schmeiser, Stefanie; Meyer, Denise; Meindl-Boehmer, Alexandra; Rios, Liliam; Austermann-Busch, Sophia; Frias-Lepoureau, Maria T; Becher, Paul

2015-06-01

Classical swine fever (CSF) is a devastating animal disease of great economic impact worldwide. In many countries, CSF has been endemic for decades, and vaccination of domestic pigs is one of the measures to control the disease. Consequently, differentiating infected from vaccinated animals by antibody ELISA screening is not applicable. In some countries, such as Cuba, lack of molecular techniques for sensitive, rapid and reliable detection of virus genomes is a critical point. To overcome this problem, an easy-to-use one-tube assay based on the loop-mediated isothermal amplification (LAMP) principle has been developed for detection of the genome of CSF virus (CSFV) of endemic Cuban genotype 1.4 isolates. The assay reliably detected recent isolates from three different regions of Cuba with an analytical sensitivity 10-100 times lower than that of quantitative reverse transcription RT-qPCR. Diagnostic test sensitivity was examined using reference sera from two groups of pigs experimentally infected with Cuban virulent strain CSF0705 "Margarita" and the recent field isolate CSF1058 "Pinar del Rio". Differences in pathogenicity of the two viruses were reflected in the clinical course of disease as well as in virus loads of blood samples. Low viral RNA loads in samples from pigs infected with the field isolate caused serious detection problems in RT-LAMP as well as in RT-qPCR. Thus, it will be necessary in future research to focus on targeted sampling of diseased animals and to restrict diagnosis to the herd level in order to establish LAMP as an efficient tool for diagnosing CSF under field conditions.

Application of κ free light chains in cerebrospinal fluid as a biomarker in multiple sclerosis diagnosis: development of a diagnosis algorithm.

PubMed

Valencia-Vera, Estefania; Martinez-Escribano Garcia-Ripoll, Ana; Enguix, Alfredo; Abalos-Garcia, Carmen; Segovia-Cuevas, Maria Jesus

2018-03-28

The determination of κ free light chains (KFLC) in cerebrospinal fluid (CSF) by nephelometry is a feasible alternative to immunoglobulin G oligoclonal bands (OCB) in the evaluation of intrathecal synthesis of immunoglobulin in multiple sclerosis (MS) and other demyelinating diseases. The aim of this study was to assess the diagnostic value of KFLC and its inclusion in a procedure algorithm along with OCB interpretation. A cross-sectional study, which included 123 patients with a CSF OCB request, was carried out. Isoelectric focusing followed by immunofixation was used to detect OCB, and nephelometry was used to analyze KFLC. The KFLC index was calculated using CSF/serum quotient of KFLC and albumin. The KFLC index was compared with MS diagnosis to find the optimal cutoff. It was obtained from the receiver operating characteristic (ROC) curves and the Youden method. The CSF KFLC median was 1.66 mg/L in the MS group, whereas in other central nervous system diseases, KFLC showed generally no or only moderate increase in CSF (median 0.10 mg/L). KFLC index showed a significant difference between groups. ROC analysis for CSF KFLC concentration, and KFLC indexes were 91.88% and 93.94%, respectively. The best cutoff for the KFLC index was 2.91 for MS diagnosis (sensitivity: 83.78%; specificity: 85.88%). The proposed algorithm showed high sensitivity (89.19%) and specificity (84.71%). KFLC determination is rapid and automatized, but it has no higher sensitivity and specificity than OCB in MS diagnosis. Nevertheless, when used in screening, it could reduce the number of manual OCB tests.

Diagnostic and prognostic value of human prion detection in cerebrospinal fluid.

PubMed

Foutz, Aaron; Appleby, Brian S; Hamlin, Clive; Liu, Xiaoqin; Yang, Sheng; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Fausett, Cameron; Wang, Han; Gambetti, Pierluigi; Zhang, Shulin; Hughson, Andrew; Tatsuoka, Curtis; Schonberger, Lawrence B; Cohen, Mark L; Caughey, Byron; Safar, Jiri G

2017-01-01

Several prion amplification systems have been proposed for detection of prions in cerebrospinal fluid (CSF), most recently, the measurements of prion seeding activity with second-generation real-time quaking-induced conversion (RT-QuIC). The objective of this study was to investigate the diagnostic performance of the RT-QuIC prion test in the broad phenotypic spectrum of prion diseases. We performed CSF RT-QuIC testing in 2,141 patients who had rapidly progressive neurological disorders, determined diagnostic sensitivity and specificity in 272 cases that were autopsied, and evaluated the impact of mutations and polymorphisms in the PRNP gene, and type 1 or type 2 human prions on diagnostic performance. The 98.5% diagnostic specificity and 92% sensitivity of CSF RT-QuIC in a blinded retrospective analysis matched the 100% specificity and 95% sensitivity of a blind prospective study. The CSF RT-QuIC differentiated 94% of cases of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 from the sCJD MM2 phenotype, and 80% of sCJD VV2 from sCJD VV1. The mixed prion type 1-2 and cases heterozygous for codon 129 generated intermediate CSF RT-QuIC patterns, whereas genetic prion diseases revealed distinct profiles for each PRNP gene mutation. The diagnostic performance of the improved CSF RT-QuIC is superior to surrogate marker tests for prion diseases such as 14-3-3 and tau proteins, and together with PRNP gene sequencing the test allows the major prion subtypes to be differentiated in vivo. This differentiation facilitates prediction of the clinicopathological phenotype and duration of the disease-two important considerations for envisioned therapeutic interventions. ANN NEUROL 2017;81:79-92. © 2016 American Neurological Association.

Diagnostic and Prognostic Value of Human Prion Detection in Cerebrospinal Fluid

PubMed Central

Foutz, Aaron; Appleby, Brian S.; Hamlin, Clive; Liu, Xiaoqin; Yang, Sheng; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Fausett, Cameron; Wang, Han; Gambetti, Pierluigi; Zhang, Shulin; Hughson, Andrew; Tatsuoka, Curtis; Schonberger, Lawrence B.; Cohen, Mark L.; Caughey, Byron; Safar, Jiri G.

2016-01-01

Objective Several prion amplification systems have been proposed for detection of prions in cerebrospinal fluid (CSF), most recently, the measurements of prion seeding activity with second-generation real-time quaking-induced conversion (RT-QuIC). The objective of this study was to investigate the diagnostic performance of the RT-QuIC prion test in the broad phenotypic spectrum of prion diseases. Methods We performed CSF RT-QuIC testing in 2,141 patients who had rapidly progressive neurological disorders, determined diagnostic sensitivity and specificity in 272 cases which were autopsied, and evaluated the impact of mutations and polymorphisms in the PRNP gene, and Type 1 or Type 2 of human prions on diagnostic performance. Results The 98.5% diagnostic specificity and 92% sensitivity of CSF RT-QuIC in a blinded retrospective analysis matched the 100% specificity and 95% sensitivity of a blind prospective study. The CSF RT-QuIC differentiated 94% of cases of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 from the sCJD MM2 phenotype, and 80% of sCJD VV2 from sCJD VV1. The mixed prion type 1–2 and cases heterozygous for codon 129 generated intermediate CSF RT-QuIC patterns, while genetic prion diseases revealed distinct profiles for each PRNP gene mutation. Interpretation The diagnostic performance of the improved CSF RT-QuIC is superior to surrogate marker tests for prion diseases such as 14-3-3 and Tau proteins and together with PRNP gene sequencing, the test allows the major prion subtypes to be differentiated in vivo. This differentiation facilitates prediction of the clinicopathological phenotype and duration of the disease—two important considerations for envisioned therapeutic interventions. PMID:27893164

Role of Clinical Presentations and Routine CSF Analysis in the Rapid Diagnosis of Acute Bacterial Meningitis in Cases of Negative Gram Stained Smears

PubMed Central

Fouad, Rabab; El-Kholy, Badawy; Yosry, Ayman

2014-01-01

Background and Aim. Bacterial meningitis is a lethal, disabling endemic disease needing prompt antibiotic management. Gram stained smears is rapid accurate method for diagnosis of bacterial meningitis. In cases of negative gram stained smears diagnosis is delayed till culture results. We aim to assess the role of clinical presentations and routine CSF analysis in the cost-effective rapid diagnosis of negative gram stained smears bacterial meningitis. Methods. Cross sectional study including 623 acute meningitis patients divided into two groups: bacterial meningitis and nonbacterial meningitis groups. The clinical presentations, systemic inflammatory parameters, and CSF analysis were evaluated and compared in both groups. Results. Altered conscious level, localizing neurological signs, Kernig's and Brudzinski's signs together with peripheral leucocytosis (>10.000/mm3), high CRP (>6) together with high CSF protein (>50 gl/dL), CSF neutrophilic count (≥50% of total CSF leucocytic count), and low CSF glucose level (<45 gm/dL) and CSF/serum glucose ≤0.6 were significantly diagnostic in bacterial meningitis patients. From the significant CSF analysis variables CSF protein carried the higher accuracy of diagnosis 78% with sensitivity 88% and specificity 72%. Conclusions. High CSF protein (>50 mg/dL) together with plasma inflammatory markers and CSF cytochemical parameters can diagnose bacterial meningitis in gram stain negative smear till culture results. PMID:24803939

CXCL13 as a Cerebrospinal Fluid Marker for Neurosyphilis in HIV-infected Patients with Syphilis

PubMed Central

Marra, Christina M.; Tantalo, Lauren C.; Sahi, Sharon K.; Maxwell, Clare L.; Lukehart, Sheila A.

2010-01-01

Background Asymptomatic neurosyphilis is more difficult to diagnose in HIV-infected patients because HIV itself can cause cerebrospinal fluid (CSF) pleocytosis. The proportion of CSF lymphocytes that are B cells is elevated in neurosyphilis, suggesting that the CSF concentration of the B cell chemoattractant, chemokine (C-X-C motif) ligand 13 (CXCL13) concentration may also be elevated. Methods CSF and blood were collected from 199 HIV-infected patients with syphilis and neurosyphilis. Serum and CSF CXCL13 concentrations were determined. Results Patients with neurosyphilis had higher CSF and serum CXCL13 concentrations compared to patients with syphilis but not neurosyphilis. The odds of having symptomatic neurosyphilis were increased by 2.23 fold for every log increase in CSF CXCL13 concentration and were independent of CSF WBC and plasma HIV RNA concentrations, peripheral blood CD4+ T cell count and use of antiretroviral medications. A cut-off of 10 pg/mL CSF CXCL13 had high sensitivity and a cut-off of 250 pg/mL or evidence of intrathecal synthesis of CXCL13 had high specificity for diagnosis of both symptomatic and asymptomatic neurosyphilis. CSF concentrations of CXCL13 declined after treatment for neurosyphilis. Conclusions CSF CXCL13 concentration may be particularly useful for diagnosis of neurosyphilis in HIV-infected patients because it is independent of CSF pleocytosis and markers of HIV disease. PMID:20393380

Meningitis in adult patients with a negative direct cerebrospinal fluid examination: value of cytochemical markers for differential diagnosis

PubMed Central

2011-01-01

Introduction The objective of this study was to determine the ability of various parameters commonly used for the diagnosis of acute meningitis to differentiate between bacterial and viral meningitis, in adult patients with a negative direct cerebrospinal fluid (CSF) examination. Methods This was a prospective study, started in 1997, including all patients admitted to the emergency unit with acute meningitis and a negative direct CSF examination. Serum and CSF samples were taken immediately on admission. The patients were divided into two groups according to the type of meningitis: bacterial (BM; group I) or viral (VM; group II). The CSF parameters investigated were cytology, protein, glucose, and lactate; the serum parameters evaluated were C-reactive protein and procalcitonin. CSF/serum glucose and lactate ratios were also assessed. Results Of the 254 patients with meningitis with a negative direct CSF examination, 35 had BM and 181, VM. The most highly discriminative parameters for the differential diagnosis of BM proved to be CSF lactate, with a sensitivity of 94%, a specificity of 92%, a negative predictive value of 99%, a positive predictive value of 82% at a diagnostic cut-off level of 3.8 mmol/L (area under the curve (AUC), 0.96; 95% confidence interval (CI), 0.95 to 1), and serum procalcitonin, with a sensitivity of 95%, a specificity of 100%, a negative predictive value of 100%, and a positive predictive value of 97% at a diagnostic cut-off level of 0.28 ng/ml (AUC, 0.99; 95% CI, 0.99 to 1). Conclusions Serum procalcitonin and CSF lactate concentrations appear to be the most highly discriminative parameters for the differential diagnosis of BM and VM. PMID:21645387

Is Cerebrospinal Fluid C-reactive Protein a Better Tool than Blood C-reactive Protein in Laboratory Diagnosis of Meningitis in Children?

PubMed Central

Malla, Kalpana K.; Malla, Tejesh; Rao, K. Seshagiri; Basnet, Sahisnuta; Shah, Ravi

2013-01-01

Objectives: This study aimed to test whether C-reactive protein (CRP) measurement could differentiate between different types of meningitis and become a routine test. Methods: A prospective study included 140 children admitted to Manipal Teaching Hospital, Pokhara, Nepal, between July 2009 and June 2011. The subjects had a blood test and detailed cerebrospinal fluid (CSF) analysis, including blood and CSF CRP levels. Results: Of those admitted, 31.1% had pyogenic meningitis (PM), 26.2% partially treated meningitis (PPM), 33% viral meningitis (VM), and 9.7% tubercular meningitis (TBM), with 26.4% controls. Organisms were isolated in 12.5% of the cases by blood culture and 25% of cases through CSF culture. Blood CRP was positive in all groups, with the highest values in PM (53.12 ± 28.88 mg/dl) and PPM (47.55 ± 34.34 mg/dl); this was not statistically significant (P = 0.08). The CSF CRP levels were significantly higher (P <0.001) in PM (45.75 ± 28.50 mg/dl) and PPM (23.11 ± 23.98 mg/dl). The sensitivity and specificity of blood CRP was 90.62%, 88.88%, 64.7%, 70% and 32.4%, 30.97%, 24.52%, 26.12% and that of CSF CRP was 96.87%, 66.66%, 20.58%, 10% and 74.73%, 63.71%, 50.94%, 55.35% for PM, PPM, VM and TBM, respectively. Conclusion: Because of its high sensitivity, both CSF CRP and blood CRP can be used to screen for bacterial meningitis (both PM and PPM). CSF CRP screening yielded results with a higher specificity than blood CRP; hence, it can be a supportive test along with CSF cytology, biochemistry, and microbiology for diagnosing meningitis. PMID:23573388

Validation of α-Synuclein as a CSF Biomarker for Sporadic Creutzfeldt-Jakob Disease.

PubMed

Llorens, Franc; Kruse, Niels; Karch, André; Schmitz, Matthias; Zafar, Saima; Gotzmann, Nadine; Sun, Ting; Köchy, Silja; Knipper, Tobias; Cramm, Maria; Golanska, Ewa; Sikorska, Beata; Liberski, Pawel P; Sánchez-Valle, Raquel; Fischer, Andre; Mollenhauer, Brit; Zerr, Inga

2018-03-01

The analysis of cerebrospinal fluid (CSF) biomarkers gains importance in the differential diagnosis of prion diseases. However, no single diagnostic tool or combination of them can unequivocally confirm prion disease diagnosis. Electrochemiluminescence (ECL)-based immunoassays have demonstrated to achieve high diagnostic accuracy in a variety of sample types due to their high sensitivity and dynamic range. Quantification of CSF α-synuclein (a-syn) by an in-house ECL-based ELISA assay has been recently reported as an excellent approach for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD), the most prevalent form of human prion disease. In the present study, we validated a commercially available ECL-based a-syn ELISA platform as a diagnostic test for correct classification of sCJD cases. CSF a-syn was analysed in 203 sCJD cases with definite diagnosis and in 445 non-CJD cases. We investigated reproducibility and stability of CSF a-syn and made recommendations for its analysis in the sCJD diagnostic workup. A sensitivity of 98% and a specificity of 97% were achieved when using an optimal cut-off of 820 pg/mL a-syn. Moreover, we were able to show a negative correlation between a-syn levels and disease duration suggesting that CSF a-syn may be a good prognostic marker for sCJD patients. The present study validates the use of a-syn as a CSF biomarker of sCJD and establishes the clinical and pre-analytical parameters for its use in differential diagnosis in clinical routine. Additionally, the current test presents some advantages compared to other diagnostic approaches: it is fast, economic, requires minimal amount of CSF and a-syn levels are stable along disease progression.

Association between CSF biomarkers, hippocampal volume and cognitive function in patients with amnestic mild cognitive impairment (MCI).

PubMed

Nathan, Pradeep J; Lim, Yen Ying; Abbott, Rosemary; Galluzzi, Samantha; Marizzoni, Moira; Babiloni, Claudio; Albani, Diego; Bartres-Faz, David; Didic, Mira; Farotti, Lucia; Parnetti, Lucilla; Salvadori, Nicola; Müller, Bernhard W; Forloni, Gianluigi; Girtler, Nicola; Hensch, Tilman; Jovicich, Jorge; Leeuwis, Annebet; Marra, Camillo; Molinuevo, José Luis; Nobili, Flavio; Pariente, Jeremie; Payoux, Pierre; Ranjeva, Jean-Philippe; Rolandi, Elena; Rossini, Paolo Maria; Schönknecht, Peter; Soricelli, Andrea; Tsolaki, Magda; Visser, Pieter Jelle; Wiltfang, Jens; Richardson, Jill C; Bordet, Régis; Blin, Olivier; Frisoni, Giovanni B

2017-05-01

Few studies have examined the relationship between CSF and structural biomarkers, and cognitive function in MCI. We examined the relationship between cognitive function, hippocampal volume and cerebrospinal fluid (CSF) Aβ 42 and tau in 145 patients with MCI. Patients were assessed on cognitive tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB), the Geriatric Depression Scale and the Functional Activities Questionnaire. Hippocampal volume was measured using magnetic resonance imaging (MRI), and CSF markers of Aβ 42 , tau and p-tau 181 were also measured. Worse performance on a wide range of memory and sustained attention tasks were associated with reduced hippocampal volume, higher CSF tau and p-tau 181 and increased tau/Aβ 42 ratio. Memory tasks were also associated with lower ability to conduct functional activities of daily living, providing a link between AD biomarkers, memory performance and functional outcome. These results suggest that biomarkers of Aβ and tau are strongly related to cognitive performance as assessed by the CANTAB, and have implications for the early detection and characterization of incipient AD. Copyright © 2017 Elsevier Inc. All rights reserved.

Granulocyte-macrophage and macrophage colony-stimulating factors differentially regulate alpha v integrin expression on cultured human macrophages.

PubMed

De Nichilo, M O; Burns, G F

1993-03-15

The colony-stimulating factors (CSFs) greatly influence mature macrophage function in vitro: macrophage (M)-CSF induces maturation of monocytes and enhances differentiated cell function; granulocyte-macrophage (GM)-CSF stimulates a variety of antimicrobial functions. In vivo M-CSF is thought to promote differentiation, and GM-CSF is thought to potentiate the inflammatory response. One mechanism by which these differential effects may be achieved is through the receptor-mediated interaction of macrophages with their extracellular matrix. Here we show that M-CSF induces specifically the expression of the alpha v beta 5 integrin receptor, whereas GM-CSF rapidly induces mRNA and surface expression of the alpha v beta 3 integrin. The M-CSF-treated cells acquire a flattened epitheloid phenotype, and on vitronectin the alpha v beta 5 is located in adhesion plaques. These cells do not bind collagen or laminin. In contrast, cells treated with GM-CSF adopt an elongated phenotype on a number of substrates, including collagen and laminin, and express alpha v beta 3 at the leading edge of cells on vitronectin. These results suggest that a primary means by which the CSFs exert their individual effects on mature cells may be through regulating integrin expression.

ROS is Required for Alternatively Activated Macrophage Differentiation | Center for Cancer Research

Cancer.gov

Macrophages are key regulators in host inflammatory responses. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) are responsible for inducing macrophage differentiation from monocytes. GM-CSF or M-CSF-differentiated macrophages can be further differentiated, or polarized, to more specialized cells. Classically activated, or M1, macrophages have immune-stimulatory properties and cytotoxic function against tumor cells. Alternatively activated, or M2, macrophages have low cytotoxic function but high tissue-remodeling activity. There are also M2-like cells called tumor-associated macrophages (TAMs) that are responsible for many tumor-promoting activities. Blocking the function of TAMs inhibits tumorigenesis.

CSF 5-HIAA and exposure to and expression of interpersonal violence in suicide attempters.

PubMed

Moberg, T; Nordström, P; Forslund, K; Kristiansson, M; Asberg, M; Jokinen, J

2011-07-01

Serotonin is implicated in impaired impulse control, aggression and suicidal behaviour. Low cerebrospinal fluid (CSF) concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) have been found in violent suicide attempters, suicide victims and in violent offenders. CSF 5-HIAA concentrations have both genetic and environmental determinants. Childhood trauma may have an effect on central monoamine function as an adult. The aim of this study was to assess the relationship of CSF 5-HIAA and the exposure to and the expression of violence in childhood and during adult life measured with the Karolinska Interpersonal Violence Scale (KIVS). 42 medication free suicide attempters underwent lumbar puncture and were assessed with the Karolinska Interpersonal Violence Scale (KIVS) to assess history of childhood exposure to violence and lifetime expressed violent behaviour. In women, but not in men, CSF 5-HIAA showed a significant negative correlation to exposure to violence during childhood. Furthermore, suicide attempters with low CSF 5-HIAA were more prone to commit violent acts as an adult if exposed to violence as a child compared to suicide attempters with high CSF 5-HIAA. In the non-traumatized group, CSF 5-HIAA showed a significant negative correlation to expressed violent behaviour in childhood. Although central serotonergic function has important genetic determinants, exposure to childhood trauma may also affect serotonergic function. Low serotonergic function may facilitate impaired aggression control in traumatized suicide attempters. Copyright © 2011 Elsevier B.V. All rights reserved.

FSI simulation of CSF hydrodynamic changes in a large population of non-communicating hydrocephalus patients during treatment process with regard to their clinical symptoms

PubMed Central

2018-01-01

3D fluid-structure interaction modelling was utilized for simulation of 13 normal subjects, 11 non-communicating hydrocephalus (NCH) patients at pre-treatment phase, and 3 patients at five post-treatment phases. Evaluation of ventricles volume and maximum CSF pressure (before shunting) following results validation indicated that these parameters were the most proper hydrodynamic indices and the NCH type doesn’t have any significant effect on changes in two indices. The results confirmed an appropriate correlation between these indices although the correlation decreased slightly after the occurrence of disease. NCH raises the intensity of vortex and pulsatility (2.4 times) of CSF flow while the flow remains laminar. On day 18 after shunting, the CSF pressure decreased 81.0% and all clinical symptoms of patients vanished except for headache. Continuing this investigation during the treatment process showed that maximum CSF pressure is the most sensitive parameter to patients’ clinical symptoms. Maximum CSF pressure has decreased proportional to the level of decrease in clinical symptoms and has returned close to the pressure range in normal subjects faster than other parameters and simultaneous with disappearance of patients’ clinical symptoms (from day 81 after shunting). However, phase lag between flow rate and pressure gradient functions and the degree of CSF pulsatility haven’t returned to normal subjects’ conditions even 981 days after shunting and NCH has also caused a permanent volume change (of 20.1%) in ventricles. Therefore, patients have experienced a new healthy state in new hydrodynamic conditions after shunting and healing. Increase in patients’ intracranial compliance was predicted with a more accurate non-invasive method than previous experimental methods up to more than 981 days after shunting. The changes in hydrodynamic parameters along with clinical reports of patients can help to gain more insight into the pathophysiology of NCH patients. PMID:29708982

Effects of granulocyte colony-stimulating factor (G-CSF) treatment on granulocyte function and receptor expression in patients with ventilator-dependent pneumonia

PubMed Central

Hustinx, W N M; Van Kessel, C P M; Heezius, E; Burgers, S; Lammers, J-W; Hoepelman, I M

1998-01-01

Considerable experimental evidence in animals suggests that treatment with G-CSF may have a beneficial effect in the management of severe infections in non-neutropenic hosts. This beneficial effect is attributed to an enhancement of granulopoiesis and neutrophil function, the latter possibly involving up-regulation of receptors on neutrophils that are involved in antibody-mediated cytotoxicity and killing of microorganisms. We compared neutrophil function and phenotype in blood and bronchoalveolar lavage fluid (BALF) of 10 patients with severe ventilator-dependent pneumonia, at baseline and following initiation of G-CSF treatment as adjunct to standard therapy. G-CSF treatment was associated with three-fold increased blood neutrophil counts at day 3 of treatment compared with baseline counts. Mean serum G-CSF concentration increased from 313 to 2007 pg/ml. After correction for lavage dilution effects, BALF G-CSF levels did not differ significantly from baseline, nor did neutrophil receptor expression (FcγRI, FcγRII, FcγRIII, CR3, and l-selectin) or indicators of neutrophil function such as respiratory burst activity, phagocytosis and killing of Candida albicans in BALF or blood. The mortality in this group of patients was 30% and compared favourably to the APACHE II-derived predicted mortality of 60%. We conclude that the possible therapeutic benefit of G-CSF administration in the early phase of severe bacterial pneumonia is not readily explained by its effect on baseline indicators of neutrophil function or receptor expression. PMID:9649199

Identification of M-CSF agonists and antagonists

DOEpatents

Pandit, Jayvardhan [Mystic, CT; Jancarik, Jarmila [Walnut Creek, CA; Kim, Sung-Hou [Moraga, CA; Koths, Kirston [El Cerrito, CA; Halenbeck, Robert [San Rafael, CA; Fear, Anna Lisa [Oakland, CA; Taylor, Eric [Oakland, CA; Yamamoto, Ralph [Martinez, CA; Bohm, Andrew [Armonk, NY

2000-02-15

The present invention is directed to methods for crystallizing macrophage colony stimulating factor. The present invention is also directed to methods for designing and producing M-CSF agonists and antagonists using information derived from the crystallographic structure of M-CSF. The invention is also directed to methods for screening M-CSF agonists and antagonists. In addition, the present invention is directed to an isolated, purified, soluble and functional M-CSF receptor.

Role of Granulocyte-Macrophage Colony-Stimulating Factor Production by T Cells during Mycobacterium tuberculosis Infection.

PubMed

Rothchild, Alissa C; Stowell, Britni; Goyal, Girija; Nunes-Alves, Cláudio; Yang, Qianting; Papavinasasundaram, Kadamba; Sassetti, Christopher M; Dranoff, Glenn; Chen, Xinchun; Lee, Jinhee; Behar, Samuel M

2017-10-24

Mice deficient for granulocyte-macrophage colony-stimulating factor (GM-CSF -/- ) are highly susceptible to infection with Mycobacterium tuberculosis , and clinical data have shown that anti-GM-CSF neutralizing antibodies can lead to increased susceptibility to tuberculosis in otherwise healthy people. GM-CSF activates human and murine macrophages to inhibit intracellular M. tuberculosis growth. We have previously shown that GM-CSF produced by iNKT cells inhibits growth of M. tuberculosis However, the more general role of T cell-derived GM-CSF during infection has not been defined and how GM-CSF activates macrophages to inhibit bacterial growth is unknown. Here we demonstrate that, in addition to nonconventional T cells, conventional T cells also produce GM-CSF during M. tuberculosis infection. Early during infection, nonconventional iNKT cells and γδ T cells are the main source of GM-CSF, a role subsequently assumed by conventional CD4 + T cells as the infection progresses. M. tuberculosis -specific T cells producing GM-CSF are also detected in the peripheral blood of infected people. Under conditions where nonhematopoietic production of GM-CSF is deficient, T cell production of GM-CSF is protective and required for control of M. tuberculosis infection. However, GM-CSF is not required for T cell-mediated protection in settings where GM-CSF is produced by other cell types. Finally, using an in vitro macrophage infection model, we demonstrate that GM-CSF inhibition of M. tuberculosis growth requires the expression of peroxisome proliferator-activated receptor gamma (PPARγ). Thus, we identified GM-CSF production as a novel T cell effector function. These findings suggest that a strategy augmenting T cell production of GM-CSF could enhance host resistance against M. tuberculosis IMPORTANCE Mycobacterium tuberculosis is the bacterium that causes tuberculosis, the leading cause of death by any infection worldwide. T cells are critical components of the immune response to Mycobacterium tuberculosis While gamma interferon (IFN-γ) is a key effector function of T cells during infection, a failed phase IIb clinical trial and other studies have revealed that IFN-γ production alone is not sufficient to control M. tuberculosis In this study, we demonstrate that CD4 + , CD8 + , and nonconventional T cells produce GM-CSF during Mycobacterium tuberculosis infection in mice and in the peripheral blood of infected humans. Under conditions where other sources of GM-CSF are absent, T cell production of GM-CSF is protective and is required for control of infection. GM-CSF activation of macrophages to limit bacterial growth requires host expression of the transcription factor PPARγ. The identification of GM-CSF production as a T cell effector function may inform future host-directed therapy or vaccine designs. Copyright © 2017 Rothchild et al.

EGFR mutation status of paired cerebrospinal fluid and plasma samples in EGFR mutant non-small cell lung cancer with leptomeningeal metastases.

PubMed

Zhao, Jing; Ye, Xin; Xu, Yan; Chen, Minjiang; Zhong, Wei; Sun, Yun; Yang, Zhenfan; Zhu, Guanshan; Gu, Yi; Wang, Mengzhao

2016-12-01

Central nervous system (CNS) is the prevalent site for metastases in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-relapsed NSCLC patients. To understand the EGFR mutation status in paired cerebrospinal fluid (CSF) and plasma samples after EGFR-TKI treatment failure might be useful to guide the treatment of intra- and extracranial tumors in those patients. Paired CSF and plasma samples were collected from seven NSCLC patients with CNS metastases after EGFR-TKI failure. EGFR mutations were tested by amplification refractory mutation system (ARMS) and droplet digital PCR (ddPCR) methods. Gefitinib concentrations were evaluated by high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS). EGFR mutations were detected in all seven CSF samples, including three of E19-Del, three of L858R and one of E19-Del&T790M by both methods. On the other hand, majority of the matched plasma samples (5/7) were negative for EGFR mutations by both methods. The other two plasma samples were positive for E19-Del&T790M by ddPCR, and one of them had undetectable T790M by ARMS. Gefitinib concentration in CSF was much lower than that in plasma (mean CSF/plasma ratio: 1.8 %). After EGFR-TKI failure, majority of the NSCLC patients with CNS metastases remained positive detection of EGFR sensitive mutations in CSF, but much less detection in the matched plasma. Significantly low exposure of gefitinib in CSF might explain the intracranial protection of the EGFR sensitive mutation positive tumor cells.

Cost-benefit analysis of prophylactic granulocyte colony-stimulating factor during CHOP antineoplastic therapy for non-Hodgkin's lymphoma.

PubMed

Dranitsaris, G; Altmayer, C; Quirt, I

1997-06-01

Several randomised comparative trials have shown that granulocyte colony-stimulating factor (G-CSF) reduces the duration of neutropenia, hospitalisation and intravenous antibacterial use in patients with cancer who are receiving high-dosage antineoplastic therapy. However, one area that has received less attention is the role of G-CSF in standard-dosage antineoplastic regimens. One such treatment that is considered to have a low potential for inducing fever and neutropenia is the CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) for non-Hodgkin's lymphoma. We conducted a cost-benefit analysis from a societal perspective in order to estimate the net cost or benefit of prophylactic G-CSF in this patient population. This included direct costs for hospitalisation with antibacterial support, as well as indirect societal costs, such as time off work and antineoplastic therapy delays secondary to neutropenia. The findings were then tested by a comprehensive sensitivity analysis. The administration of G-CSF at a dosage of 5 micrograms/kg/day for 11 doses following CHOP resulted in an overall net cost of $Can1257. In the sensitivity analysis, lowering the G-CSF dosage to 2 micrograms/kg/day generated a net benefit of $Can6564, indicating a situation that was cost saving to society. The results of the current study suggest that the use of G-CSF in patients receiving CHOP antineoplastic therapy produces a situation that is close to achieving cost neutrality. However, low-dosage (2 micrograms/kg/day) G-CSF is an economically attractive treatment strategy because it may result in overall savings to society.

M-CSF increases proliferation and phagocytosis while modulating receptor and transcription factor expression in adult human microglia

PubMed Central

2013-01-01

Background Microglia are the primary immune cells of the brain whose phenotype largely depends on their surrounding micro-environment. Microglia respond to a multitude of soluble molecules produced by a variety of brain cells. Macrophage colony-stimulating factor (M-CSF) is a cytokine found in the brain whose receptor is expressed by microglia. Previous studies suggest a critical role for M-CSF in brain development and normal functioning as well as in several disease processes involving neuroinflammation. Methods Using biopsy tissue from patients with intractable temporal epilepsy and autopsy tissue, we cultured primary adult human microglia to investigate their response to M-CSF. Mixed glial cultures were treated with 25 ng/ml M-CSF for 96 hours. Proliferation and phagocytosis assays, and high through-put immunocytochemistry, microscopy and image analysis were performed to investigate microglial phenotype and function. Results We found that the phenotype of primary adult human microglia was markedly changed following exposure to M-CSF. A greater number of microglia were present in the M-CSF- treated cultures as the percentage of proliferating (BrdU and Ki67-positive) microglia was greatly increased. A number of changes in protein expression occurred following M-CSF treatment, including increased transcription factors PU.1 and C/EBPβ, increased DAP12 adaptor protein, increased M-CSF receptor (CSF-1R) and IGF-1 receptor, and reduced HLA-DP, DQ, DR antigen presentation protein. Furthermore, a distinct morphological change was observed with elongation of microglial processes. These changes in phenotype were accompanied by a functional increase in phagocytosis of Aβ1-42 peptide. Conclusions We show here that the cytokine M-CSF dramatically influences the phenotype of adult human microglia. These results pave the way for future investigation of M-CSF-related targets for human therapeutic benefit. PMID:23866312

The Connected Steady State Model and the Interdependence of the CSF Proteome and CSF Flow Characteristics.

PubMed

Metzger, Fabian; Mischek, Daniel; Stoffers, Frédéric

2017-01-01

Here we show that the hydrodynamic radii-dependent entry of blood proteins into cerebrospinal fluid (CSF) can best be modeled with a diffusional system of consecutive interdependent steady states between barrier-restricted molecular flux and bulk flow of CSF. The connected steady state model fits precisely to experimental results and provides the theoretical backbone to calculate the in-vivo hydrodynamic radii of blood-derived proteins as well as individual barrier characteristics. As the experimental reference set we used a previously published large-scale patient cohort of CSF to serum quotient ratios of immunoglobulins in relation to the respective albumin quotients. We related the inter-individual variances of these quotient relationships to the individual CSF flow time and barrier characteristics. We claim that this new concept allows the diagnosis of inflammatory processes with Reibergrams derived from population-based thresholds to be shifted to individualized judgment, thereby improving diagnostic sensitivity. We further use the source-dependent gradient patterns of proteins in CSF as intrinsic tracers for CSF flow characteristics. We assume that the rostrocaudal gradient of blood-derived proteins is a consequence of CSF bulk flow, whereas the slope of the gradient is a consequence of the unidirectional bulk flow and bidirectional pulsatile flow of CSF. Unlike blood-derived proteins, the influence of CSF flow characteristics on brain-derived proteins in CSF has been insufficiently discussed to date. By critically reviewing existing experimental data and by reassessing their conformity to CSF flow assumptions we conclude that the biomarker potential of brain-derived proteins in CSF can be improved by considering individual subproteomic dynamics of the CSF system.

Research into the Physiology of Cerebrospinal Fluid Reaches a New Horizon: Intimate Exchange between Cerebrospinal Fluid and Interstitial Fluid May Contribute to Maintenance of Homeostasis in the Central Nervous System

PubMed Central

MATSUMAE, Mitsunori; SATO, Osamu; HIRAYAMA, Akihiro; HAYASHI, Naokazu; TAKIZAWA, Ken; ATSUMI, Hideki; SORIMACHI, Takatoshi

2016-01-01

Cerebrospinal fluid (CSF) plays an essential role in maintaining the homeostasis of the central nervous system. The functions of CSF include: (1) buoyancy of the brain, spinal cord, and nerves; (2) volume adjustment in the cranial cavity; (3) nutrient transport; (4) protein or peptide transport; (5) brain volume regulation through osmoregulation; (6) buffering effect against external forces; (7) signal transduction; (8) drug transport; (9) immune system control; (10) elimination of metabolites and unnecessary substances; and finally (11) cooling of heat generated by neural activity. For CSF to fully mediate these functions, fluid-like movement in the ventricles and subarachnoid space is necessary. Furthermore, the relationship between the behaviors of CSF and interstitial fluid in the brain and spinal cord is important. In this review, we will present classical studies on CSF circulation from its discovery over 2,000 years ago, and will subsequently introduce functions that were recently discovered such as CSF production and absorption, water molecule movement in the interstitial space, exchange between interstitial fluid and CSF, and drainage of CSF and interstitial fluid into both the venous and the lymphatic systems. Finally, we will summarize future challenges in research. This review includes articles published up to February 2016. PMID:27245177

Colour vision and contrast sensitivity losses of mercury intoxicated industry workers in Brazil.

PubMed

Ventura, D F; Simões, A L; Tomaz, S; Costa, M F; Lago, M; Costa, M T V; Canto-Pereira, L H M; de Souza, J M; Faria, M A M; Silveira, L C L

2005-05-01

We evaluated vision loss in workers from fluorescent lamp industries (n=39) who had retired due to intoxication with mercury vapour and had been away from the work situation for several years (mean=6.32 years). An age-matched control group was submitted to the same tests for comparison. The luminance contrast sensitivity (CSF) was measured psychophysically and with the sweep visual evoked potential (sVEP) method. Chromatic red-green and blue-yellow CSFs were measured psychophysically. Colour discrimination was assessed with the Farnsworth-Munsell 100-hue test, Lanthony D-15d test and Cambridge Colour Vision Test. Patient data showed significantly lower scores in all colour tests compared to controls (p<.001). The behavioural luminance CSF of the patients was lower than that of controls (p<.001 at all frequencies tested). This result was confirmed by the electrophysiologically measured sweep VEP luminance CSF except at the highest frequencies-a difference that might be related to stimulus differences in the two situations. Chromatic CSFs were also statistically significantly lower for the patients than for the controls, for both chromatic equiluminant stimuli: red-green (p<.005) and blue-yellow (p<.04 for all frequencies, except 2 cycles per degree (cpd), the highest spatial frequency tested) spatial gratings. We conclude that exposure to elemental mercury vapour is associated with profound and lasting losses in achromatic and chromatic visual functions, affecting the magno-, parvo- and koniocellular visual pathways.

CSF tau and β-amyloid predict cerebral synucleinopathy in autopsied Lewy body disorders.

PubMed

Irwin, David J; Xie, Sharon X; Coughlin, David; Nevler, Naomi; Akhtar, Rizwan S; McMillan, Corey T; Lee, Edward B; Wolk, David A; Weintraub, Daniel; Chen-Plotkin, Alice; Duda, John E; Spindler, Meredith; Siderowf, Andrew; Hurtig, Howard I; Shaw, Leslie M; Grossman, Murray; Trojanowski, John Q

2018-03-20

To test the association of antemortem CSF biomarkers with postmortem pathology in Lewy body disorders (LBD). Patients with autopsy-confirmed LBD (n = 24) and autopsy-confirmed Alzheimer disease (AD) (n = 23) and cognitively normal (n = 36) controls were studied. In LBD, neuropathologic criteria defined Lewy body α-synuclein (SYN) stages with medium/high AD copathology (SYN + AD = 10) and low/no AD copathology (SYN - AD = 14). Ordinal pathology scores for tau, β-amyloid (Aβ), and SYN pathology were averaged across 7 cortical regions to obtain a global cerebral score for each pathology. CSF total tau (t-tau), phosphorylated tau at threonine 181 , and Aβ 1-42 levels were compared between LBD and control groups and correlated with global cerebral pathology scores in LBD with linear regression. Diagnostic accuracy for postmortem categorization of LBD into SYN + AD vs SYN - AD or neocortical vs brainstem/limbic SYN stage was tested with receiver operating curves. SYN + AD had higher CSF t-tau (mean difference 27.0 ± 8.6 pg/mL) and lower Aβ 1-42 (mean difference -84.0 ± 22.9 g/mL) compared to SYN - AD ( p < 0.01, both). Increasing global cerebral tau and plaque scores were associated with higher CSF t-tau ( R 2 = 0.15-0.16, p < 0.05, both) and lower Aβ 1-42 ( R 2 = 0.43-0.49, p < 0.001, both), while increasing cerebral SYN scores were associated with lower CSF Aβ 1-42 ( R 2 = 0.31, p < 0.001) and higher CSF t-tau/Aβ 1-42 ratio ( R 2 = 0.27, p = 0.01). CSF t-tau/Aβ 1-42 ratio had 100% specificity and 90% sensitivity for SYN + AD, and CSF Aβ 1-42 had 77% specificity and 82% sensitivity for neocortical SYN stage. Higher antemortem CSF t-tau/Aβ 1-42 and lower Aβ 1-42 levels are predictive of increasing cerebral AD and SYN pathology. These biomarkers may identify patients with LBD vulnerable to cortical SYN pathology who may benefit from both SYN and AD-targeted disease-modifying therapies. © 2018 American Academy of Neurology.

Comparison of colony stimulation factors on in vitro rat and human neutrophil function.

PubMed

Wheeler, J G; Huffine, M E; Childress, S; Sikes, J

1994-01-01

The effects of rhCSFs on in vitro polymorphonuclear leukocyte (PMN) function were studied in Sprague-Dawley neonatal and adult rats and adult and umbilical cord derived human PMN to compare species response. Following in vitro exposure to buffer or rhCSFs (50-100 micrograms/ml), PMN oxidative burst, chemotactic activity and adherence protein expression were measured. RhG-CSF increased the oxidative burst of adult rat PMN as measured by chemiluminescence and altered CD11b/CD18 in resting neonatal rat but not adult rat cells. RhGM-CSF had no effect on adult rat PMN function in vitro, but led to modest changes in adult rat PMN diapedesis across rat peritoneum. No responses were noted to rhM-CSF. Human PMN responded best to GM-CSF (particularly in the neonate), intermediately to G-CSF and none to M-CSF. These experiments show that the profile of cytokine effects is not similar in adult and neonatal rat PMN when compared to human cells. The diversity of actions in other species must be considered when using rhCSFs in animal models.

Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease

PubMed Central

Simon, Matthew J.; Iliff, Jeffrey J.

2015-01-01

Cerebrospinal fluid (CSF) circulation and turnover provides a sink for the elimination of solutes from the brain interstitium, serving an important homeostatic role for the function of the central nervous system. Disruption of normal CSF circulation and turnover is believed to contribute to the development of many diseases, including neurodegenerative conditions such as Alzheimer’s disease, ischemic and traumatic brain injury, and neuroinflammatory conditions such as multiple sclerosis. Recent insights into CSF biology suggesting that CSF and interstitial fluid exchange along a brain-wide network of perivascular spaces termed the ‘glymphatic’ system suggest that CSF circulation may interact intimately with glial and vascular function to regulate basic aspects of brain function. Dysfunction within this glial vascular network, which is a feature of the aging and injured brain, is a potentially critical link between brain injury, neuroinflammation and the development of chronic neurodegeneration. Ongoing research within this field may provide a powerful new framework for understanding the common links between neurodegenerative, neurovascular and neuroinflammatory disease, in addition to providing potentially novel therapeutic targets for these conditions. PMID:26499397

Knowledge-base for interpretation of cerebrospinal fluid data patterns. Essentials in neurology and psychiatry.

PubMed

Reiber, Hansotto

2016-06-01

The physiological and biophysical knowledge base for interpretations of cerebrospinal fluid (CSF) data and reference ranges are essential for the clinical pathologist and neurochemist. With the popular description of the CSF flow dependent barrier function, the dynamics and concentration gradients of blood-derived, brain-derived and leptomeningeal proteins in CSF or the specificity-independent functions of B-lymphocytes in brain also the neurologist, psychiatrist, neurosurgeon as well as the neuropharmacologist may find essentials for diagnosis, research or development of therapies. This review may help to replace the outdated ideas like "leakage" models of the barriers, linear immunoglobulin Index Interpretations or CSF electrophoresis. Calculations, Interpretations and analytical pitfalls are described for albumin quotients, quantitation of immunoglobulin synthesis in Reibergrams, oligoclonal IgG, IgM analysis, the polyspecific ( MRZ- ) antibody reaction, the statistical treatment of CSF data and general quality assessment in the CSF laboratory. The diagnostic relevance is documented in an accompaning review.

Blood-cerebrospinal fluid barrier permeability in Alzheimer's disease.

PubMed

Chalbot, Sonia; Zetterberg, Henrik; Blennow, Kaj; Fladby, Tormod; Andreasen, Niels; Grundke-Iqbal, Inge; Iqbal, Khalid

2011-01-01

The role of blood-cerebrospinal fluid barrier (BCB) dysfunction in Alzheimer's disease (AD) has been addressed but not yet established. We evaluated the BCB integrity in 179 samples of cerebrospinal fluid (CSF) retrospectively collected from AD patients and control cases using both CSF/serum albumin ratio (QAlb) and CSF secretory Ca2+-dependent phospholipase A2 (sPLA2) activity. These analyses were supplemented with the measurement of total tau, amyloid-β1-42 (Aβ1-42), and ubiquitin CSF levels. We found that due to its higher sensitivity, CSF sPLA2 activity could 1) discriminate AD from healthy controls and 2) showed BCB impairment in neurological control cases while QAlb could not. Moreover, the CSF sPLA2 activity measurement showed that around half of the AD patients were characterized by a BCB impairment. The BCB dysfunction observed in AD was independent from Mini-Mental State Examination score as well as CSF levels of total tau, Aβ1-42, and ubiquitin. Finally, the BCB dysfunction was not limited to any of the CSF biomarkers-based previously identified subgroups of AD. These results suggest that the BCB damage occurs independent of and probably precedes both Aβ and tau pathologies in a restricted subgroup of AD patients.

Cerebrospinal fluid lactate level as a diagnostic biomarker for bacterial meningitis in children

PubMed Central

2014-01-01

Background Cerebrospinal fluid (CSF) lactate is a potential biomarker for bacterial meningitis in children. To this end, we performed a single-center retrospective cohort study of children from Sao Paulo, Brazil, with CSF pleocytosis to evaluate the ability of CSF lactate to distinguish between children with bacterial and aseptic meningitis. We determined the optimum cutoff point for CSF lactate using receiver-operator curve (ROC) analysis. Findings We identified 451 children of whom 40 (9%) had bacterial meningitis. Children with bacterial meningitis had a higher median CSF lactate level [9.6 mmol/l, interquartile range (IQR) 3.2-38.5 mmol/l bacterial meningitis vs. 2.0 mmol/l, IQR 1.2-2.8 mmol/l aseptic meningitis]. A CSF lactate cutoff point of 3.0 mmol/l had a sensitivity of 95% [95% confidence interval (CI) 83-99%), specificity of 94% (95% CI 90-96%) and negative predictive value of 99.3% (95% CI 97.7-99.9%) for bacterial meningitis. Conclusions In combination with a validated meningitis clinical prediction rule, the CSF lactate level can be used to distinguish between bacterial and aseptic meningitis in children with CSF pleocytosis. PMID:24576334

Cerebrospinal fluid lactate level as a diagnostic biomarker for bacterial meningitis in children.

PubMed

Mekitarian Filho, Eduardo; Horita, Sérgio Massaru; Gilio, Alfredo Elias; Nigrovic, Lise E

2014-02-27

Cerebrospinal fluid (CSF) lactate is a potential biomarker for bacterial meningitis in children. To this end, we performed a single-center retrospective cohort study of children from Sao Paulo, Brazil, with CSF pleocytosis to evaluate the ability of CSF lactate to distinguish between children with bacterial and aseptic meningitis. We determined the optimum cutoff point for CSF lactate using receiver-operator curve (ROC) analysis. We identified 451 children of whom 40 (9%) had bacterial meningitis. Children with bacterial meningitis had a higher median CSF lactate level [9.6 mmol/l, interquartile range (IQR) 3.2-38.5 mmol/l bacterial meningitis vs. 2.0 mmol/l, IQR 1.2-2.8 mmol/l aseptic meningitis]. A CSF lactate cutoff point of 3.0 mmol/l had a sensitivity of 95% [95% confidence interval (CI) 83-99%), specificity of 94% (95% CI 90-96%) and negative predictive value of 99.3% (95% CI 97.7-99.9%) for bacterial meningitis. In combination with a validated meningitis clinical prediction rule, the CSF lactate level can be used to distinguish between bacterial and aseptic meningitis in children with CSF pleocytosis.

Standard-dose osimertinib for refractory leptomeningeal metastases in T790M-positive EGFR-mutant non-small cell lung cancer.

PubMed

Nanjo, Shigeki; Hata, Akito; Okuda, Chiyuki; Kaji, Reiko; Okada, Hideaki; Tamura, Daisuke; Irie, Kei; Okada, Hiroshi; Fukushima, Shoji; Katakami, Nobuyuki

2018-01-01

Osimertinib demonstrated promising efficacy for refractory leptomeningeal metastases (LM) in preclinical data and a clinical study at 160 mg, but there is limited data for the standard 80 mg dose. T790M-positive patients with suspected LM after classical epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) failure were enroled. We investigated 13 patients (5 definitive and 8 possible LM cases). In two of the five definitive cases with T790M in and outside the central nervous system (CNS), osimertinib was effective for both lesions, with cerebrospinal fluid (CSF) clearance of cancer cells and sensitive/T790M mutations. In three definitive cases with extra-CNS T790M without CSF T790M, cancer cells and sensitive mutations in the CSF persisted after osimertinib initiation. The median progression-free survival of all 13 patients was 7.2 months. Osimertinib was generally well-tolerated despite poor performance status, but interstitial lung disease (grade 2) was confirmed in one patient. Based on 25 samples from 13 patients, the osimertinib CSF penetration rate was 2.5±0.3%. Osimertinib 80 mg is a useful therapeutic option for refractory LM after classical EGFR-TKI failure. It appears more effective in CSF T790M-positive cases.

Advantages of flow cytometry immunophenotyping for the diagnosis of central nervous system non-Hodgkin's lymphoma in AIDS patients.

PubMed

Subirá, D; Górgolas, M; Castañón, S; Serrano, C; Román, A; Rivas, F; Tomás, J F

2005-01-01

Neurological disorders are common in HIV-infected patients. Central nervous system (CNS) lymphoma should always be considered because it is an important cause of morbidity and mortality. To investigate the clinical utility of flow cytometry immunophenotyping (FCI) in diagnosing or discarding leptomeningeal involvement in HIV-infected patients and to compare its sensitivity with that of conventional cytological methods. Fifty-six cerebrospinal fluid (CSF) samples from 29 HIV-infected patients were independently evaluated by flow cytometry and cytology. The description of an aberrant immunophenotype was the criterion used to define the malignant nature of any CSF cell population. FCI and cytology gave concordant results for 48 of the 56 CSF samples studied: 37 were negative for malignancy and 11 had evidence of CNS lymphoma. Discordant results were obtained for eight CSF samples, and the accuracy of the FCI findings could be demonstrated for four CSF samples described as positive for malignancy according to the FCI criteria. A high level of agreement was found between the results obtained using the two methods, but FCI gave at least 25% higher sensitivity than conventional cytomorphological methods for the detection of malignant cells. This advantage suggests that, in case of negative flow cytometry results, disorders other than non-Hodgkin's lymphoma should be strongly considered.

The significance of G-CSF expression and myeloid-derived suppressor cells in the chemoresistance of uterine cervical cancer.

PubMed

Kawano, Mahiru; Mabuchi, Seiji; Matsumoto, Yuri; Sasano, Tomoyuki; Takahashi, Ryoko; Kuroda, Hiromasa; Kozasa, Katsumi; Hashimoto, Kae; Isobe, Aki; Sawada, Kenjiro; Hamasaki, Toshimitsu; Morii, Eiichi; Kimura, Tadashi

2015-12-15

Granulocyte-colony stimulating factor (G-CSF) producing malignant tumor has been reported to occur in various organs, and has been associated with poor clinical outcome. The aim of this study is to investigate the significance of tumor G-CSF expression in the chemosensitivity of uterine cervical cancer. The clinical data of recurrent or advanced cervical cancer patients who were treated with platinum-based chemotherapy were analyzed. Clinical samples, cervical cancer cell lines, and a mouse model of cervical cancer were employed to examine the mechanisms responsible for the development of chemoresistance in G-CSF-producing cervical cancer, focusing on myeloid-derived suppressor cells (MDSC). As a result, the tumor G-CSF expression was significantly associated with increased MDSC frequencies and compromised survival. In vitro and in vivo experiments demonstrated that the increased MDSC induced by tumor-derived G-CSF is involved in the development of chemoresistance. The depletion of MDSC via splenectomy or the administration of anti-Gr-1 antibody sensitized G-CSF-producing cervical cancer to cisplatin. In conclusion, tumor G-CSF expression is an indicator of an extremely poor prognosis in cervical cancer patients that are treated with chemotherapy. Combining MDSC-targeting treatments with current standard chemotherapies might have therapeutic efficacy as a treatment for G-CSF-producing cervical cancer.

Beneficial effect of bilingualism on Alzheimer's disease CSF biomarkers and cognition.

PubMed

Estanga, Ainara; Ecay-Torres, Mirian; Ibañez, Almudena; Izagirre, Andrea; Villanua, Jorge; Garcia-Sebastian, Maite; Iglesias Gaspar, M Teresa; Otaegui-Arrazola, Ane; Iriondo, Ane; Clerigue, Monserrat; Martinez-Lage, Pablo

2017-02-01

Bilingualism as a component of cognitive reserve has been claimed to delay the onset of Alzheimer's disease (AD). However, its effect on cerebrospinal fluid (CSF) AD-biomarkers has not been investigated. We assessed cognitive performance and CSF AD-biomarkers, and potential moderation effect of bilingualism on the association between age, CSF AD-biomarkers, and cognition. Cognitively healthy middle-aged participants classified as monolinguals (n = 100, n CSF  = 59), early (n = 81, n CSF  = 55) and late bilinguals (n = 97, n CSF  = 52) were evaluated. Models adjusted for confounders showed that bilinguals performed better than monolinguals on digits backwards (early-bilinguals p = 0.003), Judgment of Line Orientation (JLO) (early-bilinguals p = 0.018; late-bilinguals p = 0.004), and Trail Making Test-B (late-bilinguals p = 0.047). Early bilingualism was associated with lower CSF total-tau (p = 0.019) and lower prevalence of preclinical AD (NIA-AA classification) (p = 0.02). Bilingualism showed a moderation effect on the relationship between age and CSF AD-biomarkers and the relationship between age and executive function. We conclude that bilingualism contributes to cognitive reserve enhancing executive and visual-spatial functions. For the first time, this study reveals that early bilingualism is associated with more favorable CSF AD-biomarker profile. Copyright © 2016 Elsevier Inc. All rights reserved.

[Effects of cell-mediated immunity induced by intramuscular chitosan-pJME/ GM-CSF nano-DNA vaccine in BAlb/c mice].

PubMed

Zhai, Yong-Zhen; Zhou, Yan; Ma, Li; Feng, Guo-He

2014-07-01

This study aimed to investigate the immune adjuvant effect and mechanism induced by chitosan nanoparticles carrying pJME/GM-CSF. In this study, plasmid DNA (pJME/GM-CSF) was encapsulated in chitosan to prepare chitosan-pJME/GM-CSF nanoparticles using a complex coacervation process. Immunohistochemistry was used to detect the type of infiltrating cells at the site of intramuscular injection. The phenotype and functional changes of splenic DCs were measured by flow cytometry after different immunogens were injected intramuscularly. The killing activity of CTLs was assessed using the lactate dehydrogenase (LDH) release assay. The preparation of chitosan-pJME/GM-CSF nanoparticles matched the expected theoretical results. Our results also found that, after pJME/GM-CSF injection, the incoming cells were a mixture of macrophages, neutrophils, and immature DCs. Meanwhile, pJME/GM-CSF increased the expression of MHC class II molecules on splenic DCs, and enhanced their Ag capture and presentation functions. Cell-mediated immunity was induced by the vaccine. Furthermore, chitosan-pJME/GM-CSF nanoparticles outperformed the administration of standard pJME/GM-CSF in terms of DC recruitment, antigen processing and presentation, and vaccine enhancement. These findings reveal that chitosan could be used as delivery vector for DNA vaccine intramuscular immunizations, and enhance pJME/GM-CSF-induced cellular immune responses.

G-CSF loaded nanofiber/nanoparticle composite coated with collagen promotes wound healing in vivo.

PubMed

Tanha, Shima; Rafiee-Tehrani, Morteza; Abdollahi, Mohamad; Vakilian, Saeid; Esmaili, Zahra; Naraghi, Zahra Safaei; Seyedjafari, Ehsan; Javar, Hamid Akbari

2017-10-01

Sustained release of functional growth factors can be considered as a beneficial methodology for wound healing. In this study, recombinant human granulocyte colony-stimulating factor (G-CSF)-loaded chitosan nanoparticles were incorporated in Poly(ε-caprolactone) (PCL) nanofibers, followed by surface coating with collagen type I. Physical and mechanical properties of the PCL nanofibers containing G-CSF loaded chitosan nanoparticles PCL/NP(G-CSF) and in vivo performance for wound healing were investigated. G-CSF structural stability was evaluated through SDS_PAGE, reversed phase (RP) HPLC and size-exclusion chromatography, as well as circular dichroism. Nanofiber/nanoparticle composite scaffold was demonstrated to have appropriate mechanical properties as a wound dresser and a sustained release of functional G-CSF. The PCL/NP(G-CSF) scaffold showed a suitable proliferation and well-adherent morphology of stem cells. In vivo study and histopathological evaluation outcome revealed that skin regeneration was dramatically accelerated under PCL/NP(G-CSF) as compared with control groups. Superior fibroblast maturation, enhanced collagen deposition and minimum inflammatory cells were also the beneficial properties of PCL/NP(G-CSF) over the commercial dressing. The synergistic effect of extracellular matrix-mimicking nanofibrous membrane and G-CSF could develop a suitable supportive substrate in order to extensive utilization for the healing of skin wounds. © 2017 Wiley Periodicals Inc. J Biomed Mater Res Part A: 105A: 2830-2842, 2017. © 2017 Wiley Periodicals, Inc.

Diagnostic and prognostic value of procalcitonin for early intracranial infection after craniotomy

PubMed Central

Yu, Y.; Li, H.J.

2017-01-01

Intracranial infection is a common clinical complication after craniotomy. We aimed to explore the diagnostic and prognostic value of dynamic changing procalcitonin (PCT) in early intracranial infection after craniotomy. A prospective study was performed on 93 patients suspected of intracranial infection after craniotomy. Routine peripheral venous blood was collected on the day of admission, and C reactive protein (CRP) and PCT levels were measured. Cerebrospinal fluid (CSF) was collected for routine biochemical, PCT and culture assessment. Serum and CSF analysis continued on days 1, 2, 3, 5, 7, 9, and 11. The patients were divided into intracranial infection group and non-intracranial infection group; intracranial infection group was further divided into infection controlled group and infection uncontrolled group. Thirty-five patients were confirmed with intracranial infection after craniotomy according to the diagnostic criteria. The serum and cerebrospinal fluid PCT levels in the infected group were significantly higher than the non-infected group on day 1 (P<0.05, P<0.01). The area under curve of receiver operating characteristics was 0.803 for CSF PCT in diagnosing intracranial infection. The diagnostic sensitivity and specificity of CSF PCT was superior to other indicators. The serum and CSF PCT levels have potential value in the early diagnosis of intracranial infection after craniotomy. Since CSF PCT levels have higher sensitivity and specificity, dynamic changes in this parameter could be used for early detection of intracranial infection after craniotomy, combined with other biochemical indicators. PMID:28443989

Evidence that the granulocyte colony-stimulating factor (G-CSF) receptor plays a role in the pharmacokinetics of G-CSF and PegG-CSF using a G-CSF-R KO model.

PubMed

Kotto-Kome, Anne C; Fox, Samuel E; Lu, Wenge; Yang, Bing-Bing; Christensen, Robert D; Calhoun, Darlene A

2004-07-01

The covalent attachment of polyethylene glycol to filgrastim results in a new molecule pegfilgrastim, which has a significantly longer half-life than filgrastim. It is likely that the clearance of both filgrastim and pegfilgrastim involves granulocyte colony simulating factor (G-CSF) receptor binding, but the pharmacokinetics of these drugs have not been compared in mice with and without a functional G-CSF receptor. We sought to clarify the role of receptor-mediated clearance of filgrastim and pegfilgrastim using wild-type (WT) mice or mice with a non-functional G-CSF-R (knockout, KO). We administered single doses of filgrastim or pegfilgrastim (10 or 100 microg kg(-1)) intravenously to WT and KO mice. Plasma levels of protein were measured by enzyme-linked immunosorbent assay (ELISA) at preset time points, and AUC, MRT, CL, V(d), and T(1/2) were calculated. When compared with WT mice, the G-CSF-R KO mice had significantly greater AUC, longer MRT, longer T(1/2), and lower clearance. This was the case whether animals received 10 or 100 microg kg(-1) and whether they received filgrastim or pegfilgrastim. The volume of protein distribution was identical among WT and KO mice. However, the V(d) was larger after pegfilgrastim dosing than after filgrastim dosing. In both WT and KO mice, increasing the dose of figrastim or pegfilgrastim resulted in a proportional increase in the AUC. A functional G-CSF-R is an important mechanism in the plasma clearance of both filgrastim and pegfilgrastim.

A study of structural differences between TBM patients' and non-TBM persons' CSF using UV-Vis absorption spectroscopy

NASA Astrophysics Data System (ADS)

Xu, Fangcheng; Wang, Xin; Xu, Huajia; Wang, Kai

2016-01-01

Tuberculous meningitis (TBM) is a very common infectious disease in the central nervous system. The delay of diagnosing and treating TBM will lead to high disability and mortality of TBM. Hence, it is very important to promptly diagnose TBM early. In this work, we proposed a new method for diagnosing TBM with CSF samples by using UV-Vis absorption spectroscopy. CSF samples from TBM patients and non-TBM persons were compared, and the sensitivity, specificity, accuracy, positive predictive value reached 83.6%, 69.8%, 77.2%, 76.1% respectively. Our work indicated investigation of CSF using UV-Vis absorption spectroscopy might become a potentially useful method for TBM diagnosis.

CSF profile in primary progressive multiple sclerosis: Re-exploring the basics.

PubMed

Abdelhak, Ahmed; Hottenrott, Tilman; Mayer, Christoph; Hintereder, Gudrun; Zettl, Uwe K; Stich, Oliver; Tumani, Hayrettin

2017-01-01

The aim of this study was to report the basic cerebrospinal fluid (CSF) profile in patients with primary progressive multiple sclerosis (PPMS). The results of CSF analysis from 254 patients with PPMS were collected at four university hospitals in Germany. Routine CSF parameters and different indices of intrathecal immunoglobulin synthesis were evaluated. We assessed possible correlations between the various CSF parameters and the expanded disability status scale (EDSS) both at the time of lumbar puncture and during the course of the disease. The median cell count and albumin concentration in the CSF did not deviate from normal values. The CSF-serum albumin-quotient (QALB) was elevated in 29.6% of the patients, while intrathecal immunoglobulin G (IgG) oligoclonal bands (OCBs) were detected in 91.1% of the patients. CSF-lactate levels as well as local IgM- and IgA-synthesis were correlated with the yearly disease progression rate, as assessed by EDSS. We present the results of the hitherto largest and most detailed CSF biomarker profile in a cohort of 254 patients with PPMS. As reported previously, OCBs are the most sensitive marker for intrathecal IgG synthesis. CSF-lactate concentrations are positively correlated with the progression rate, which might suggest that mitochondrial dysfunction plays a relevant role in PPMS. The negative correlation between intrathecally produced IgM and IgA and disease progression may indicate their hitherto unexplored protective role.

Effects and safety of granulocyte colony-stimulating factor in healthy volunteers

PubMed Central

Anderlini, Paolo

2015-01-01

Purpose of Review Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is now widely used in normal donors for collection of peripheral blood progenitor cells (PBPCs) for allogeneic transplantation and granulocytes for transfusion. Currently available data on biologic and molecular effects, and safety of rhG-CSF in normal healthy volunteers are reviewed. Recent Findings In addition to its known activating role on neutrophil kinetics and functional status, rhG-CSF administration can affect monocytes, lymphocytes and the hemostatic system. G-CSF receptors were identified in a variety of non-myeloid tissues, although their role and functional activity have not always been well defined. Moreover, rhG-CSF is capable of modulating complex cytokine networks and can impact the inflammatory response. In addition to its known mobilizing role for PBPCs, rhG-CSF can mobilize dendritic and endothelial progenitor cells as well. On a clinical level, serious rhG-CSF-related adverse events are well described (e.g. splenic rupture) but remain rare. Summary rhG-CSF effects in healthy volunteers, while normally transient and self-limiting, are now believed to be more complex and heterogeneous that previously thought. While rhG-CSF administration to healthy volunteers continues to have a favorable risk-benefit profile, these new findings have implications for safeguarding the safety of normal individuals. PMID:19057203

Use of Fetal Magnetic Resonance Image Analysis and Machine Learning to Predict the Need for Postnatal Cerebrospinal Fluid Diversion in Fetal Ventriculomegaly.

PubMed

Pisapia, Jared M; Akbari, Hamed; Rozycki, Martin; Goldstein, Hannah; Bakas, Spyridon; Rathore, Saima; Moldenhauer, Julie S; Storm, Phillip B; Zarnow, Deborah M; Anderson, Richard C E; Heuer, Gregory G; Davatzikos, Christos

2018-02-01

Which children with fetal ventriculomegaly, or enlargement of the cerebral ventricles in utero, will develop hydrocephalus requiring treatment after birth is unclear. To determine whether extraction of multiple imaging features from fetal magnetic resonance imaging (MRI) and integration using machine learning techniques can predict which patients require postnatal cerebrospinal fluid (CSF) diversion after birth. This retrospective case-control study used an institutional database of 253 patients with fetal ventriculomegaly from January 1, 2008, through December 31, 2014, to generate a predictive model. Data were analyzed from January 1, 2008, through December 31, 2015. All 25 patients who required postnatal CSF diversion were selected and matched by gestational age with 25 patients with fetal ventriculomegaly who did not require CSF diversion (discovery cohort). The model was applied to a sample of 24 consecutive patients with fetal ventriculomegaly who underwent evaluation at a separate institution (replication cohort) from January 1, 1998, through December 31, 2007. Data were analyzed from January 1, 1998, through December 31, 2009. To generate the model, linear measurements, area, volume, and morphologic features were extracted from the fetal MRI, and a machine learning algorithm analyzed multiple features simultaneously to find the combination that was most predictive of the need for postnatal CSF diversion. Accuracy, sensitivity, and specificity of the model in correctly classifying patients requiring postnatal CSF diversion. A total of 74 patients (41 girls [55%] and 33 boys [45%]; mean [SD] gestational age, 27.0 [5.6] months) were included from both cohorts. In the discovery cohort, median time to CSF diversion was 6 days (interquartile range [IQR], 2-51 days), and patients with fetal ventriculomegaly who did not develop symptoms were followed up for a median of 29 months (IQR, 9-46 months). The model correctly classified patients who required CSF diversion with 82% accuracy, 80% sensitivity, and 84% specificity. In the replication cohort, the model achieved 91% accuracy, 75% sensitivity, and 95% specificity. Image analysis and machine learning can be applied to fetal MRI findings to predict the need for postnatal CSF diversion. The model provides prognostic information that may guide clinical management and select candidates for potential fetal surgical intervention.

Qualitative metabolome analysis of human cerebrospinal fluid by 13C-/12C-isotope dansylation labeling combined with liquid chromatography Fourier transform ion cyclotron resonance mass spectrometry.

PubMed

Guo, Kevin; Bamforth, Fiona; Li, Liang

2011-02-01

Metabolome analysis of human cerebrospinal fluid (CSF) is challenging because of low abundance of metabolites present in a small volume of sample. We describe and apply a sensitive isotope labeling LC-MS technique for qualitative analysis of the CSF metabolome. After a CSF sample is divided into two aliquots, they are labeled by (13)C-dansyl and (12)C-dansyl chloride, respectively. The differentially labeled aliquots are then mixed and subjected to LC-MS using Fourier-transform ion cyclotron resonance mass spectrometry (FTICR MS). Dansylation offers significant improvement in the performance of chromatography separation and detection sensitivity. Moreover, peaks detected in the mass spectra can be readily analyzed for ion pair recognition and database search based on accurate mass and/or retention time information. It is shown that about 14,000 features can be detected in a 25-min LC-FTICR MS run of a dansyl-labeled CSF sample, from which about 500 metabolites can be profiled. Results from four CSF samples are compared to gauge the detectability of metabolites by this method. About 261 metabolites are commonly detected in replicate runs of four samples. In total, 1132 unique metabolite ion pairs are detected and 347 pairs (31%) matched with at least one metabolite in the Human Metabolome Database. We also report a dansylation library of 220 standard compounds and, using this library, about 85 metabolites can be positively identified. Among them, 21 metabolites have never been reported to be associated with CSF. These results illustrate that the dansylation LC-FTICR MS method can be used to analyze the CSF metabolome in a more comprehensive manner. © American Society for Mass Spectrometry, 2011

Qualitative Metabolome Analysis of Human Cerebrospinal Fluid by 13C-/12C-Isotope Dansylation Labeling Combined with Liquid Chromatography Fourier Transform Ion Cyclotron Resonance Mass Spectrometry

NASA Astrophysics Data System (ADS)

Guo, Kevin; Bamforth, Fiona; Li, Liang

2011-02-01

Metabolome analysis of human cerebrospinal fluid (CSF) is challenging because of low abundance of metabolites present in a small volume of sample. We describe and apply a sensitive isotope labeling LC-MS technique for qualitative analysis of the CSF metabolome. After a CSF sample is divided into two aliquots, they are labeled by 13C-dansyl and 12C-dansyl chloride, respectively. The differentially labeled aliquots are then mixed and subjected to LC-MS using Fourier-transform ion cyclotron resonance mass spectrometry (FTICR MS). Dansylation offers significant improvement in the performance of chromatography separation and detection sensitivity. Moreover, peaks detected in the mass spectra can be readily analyzed for ion pair recognition and database search based on accurate mass and/or retention time information. It is shown that about 14,000 features can be detected in a 25-min LC-FTICR MS run of a dansyl-labeled CSF sample, from which about 500 metabolites can be profiled. Results from four CSF samples are compared to gauge the detectability of metabolites by this method. About 261 metabolites are commonly detected in replicate runs of four samples. In total, 1132 unique metabolite ion pairs are detected and 347 pairs (31%) matched with at least one metabolite in the Human Metabolome Database. We also report a dansylation library of 220 standard compounds and, using this library, about 85 metabolites can be positively identified. Among them, 21 metabolites have never been reported to be associated with CSF. These results illustrate that the dansylation LC-FTICR MS method can be used to analyze the CSF metabolome in a more comprehensive manner.

Biomarker evidence of axonal injury in neuroasymptomatic HIV-1 patients.

PubMed

Jessen Krut, Jan; Mellberg, Tomas; Price, Richard W; Hagberg, Lars; Fuchs, Dietmar; Rosengren, Lars; Nilsson, Staffan; Zetterberg, Henrik; Gisslén, Magnus

2014-01-01

Prevalence of neurocognitive impairment in HIV-1 infected patients is reported to be high. Whether this is a result of active HIV-related neurodegeneration is unclear. We examined axonal injury in HIV-1 patients by measuring the light subunit of neurofilament protein (NFL) in CSF with a novel, sensitive method. With a cross-sectional design, CSF concentrations of neurofilament protein light (NFL) (marker of neuronal injury), neopterin (intrathecal immunoactivation) and CSF/Plasma albumin ratio (blood-brain barrier integrity) were analyzed on CSF from 252 HIV-infected patients, subdivided into untreated neuroasymptomatics (n = 200), HIV-associated dementia (HAD) (n = 14) and on combinations antiretroviral treatment (cART) (n = 85), and healthy controls (n = 204). 46 HIV-infected patients were included in both treated and untreated groups, but sampled at different timepoints. Furthermore, 78 neuroasymptomatic patients were analyzed before and after treatment initiation. While HAD patients had the highest NFL concentrations, elevated CSF NFL was also found in 33% of untreated neuroasymptomatic patients, mainly in those with blood CD4+ cell counts below 250 cells/μL. CSF NFL concentrations in the untreated neuroasymptomatics and treated groups were equivalent to controls 18.5 and 3.9 years older, respectively. Neopterin correlated with NFL levels in untreated groups while the albumin ratio correlated with NFL in both untreated and treated groups. Increased CSF NFL indicates ongoing axonal injury in many neuroasymptomatic patients. Treatment decreases NFL, but treated patients retain higher levels than controls, indicating either continued virus-related injury or an aging-like effect of HIV infection. NFL correlates with neopterin and albumin ratio, suggesting an association between axonal injury, neuroinflammation and blood-brain barrier permeability. NFL appears to be a sensitive biomarker of subclinical and clinical brain injury in HIV and warrants further assessment for broader clinical use.

Efficacy of gene-therapy based on adenovirus encoding granulocyte-macrophage colony-stimulating factor in drug-sensitive and drug-resistant experimental pulmonary tuberculosis.

PubMed

Francisco-Cruz, Alejandro; Mata-Espinosa, Dulce; Ramos-Espinosa, Octavio; Marquina-Castillo, Brenda; Estrada-Parra, Sergio; Xing, Zhou; Hernández-Pando, Rogelio

2016-09-01

Tuberculosis (TB), although a curable disease, remains a major cause of morbidity and mortality worldwide. It is necessary to develop a short-term therapy with reduced drug toxicity in order to improve adherence rate and control disease burden. Granulocyte-macrophage colony-stimulating factor (GM-CSF) may be a key cytokine in the treatment of pulmonary TB since it primes the activation and differentiation of myeloid and non-myeloid precursor cells, inducing the release of protective Th1 cytokines. In this work, we administrated by intratracheal route recombinant adenoviruses encoding GM-CSF (AdGM-CSF). This treatment produced significant bacterial elimination when administered in a single dose at 60 days of infection with drug sensitive or drug resistant Mtb strains in a murine model of progressive disease. Moreover, AdGM-CSF combined with primary antibiotics produced more rapid elimination of pulmonary bacterial burdens than conventional chemotherapy suggesting that this form of treatment could shorten the conventional treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy

PubMed Central

Holmgaard, Rikke B.; Brachfeld, Alexandra; Gasmi, Billel; Jones, David R.; Mattar, Marissa; Doman, Thompson; Murphy, Mary; Schaer, David; Wolchok, Jedd D.; Merghoub, Taha

2016-01-01

ABSTRACT Colony stimulating factor-1 (CSF-1) is produced by a variety of cancers and recruits myeloid cells that suppress antitumor immunity, including myeloid-derived suppressor cells (MDSCs.) Here, we show that both CSF-1 and its receptor (CSF-1R) are frequently expressed in tumors from cancer patients, and that this expression correlates with tumor-infiltration of MDSCs. Furthermore, we demonstrate that these tumor-infiltrating MDSCs are highly immunosuppressive but can be reprogrammed toward an antitumor phenotype in vitro upon CSF-1/CSF-1R signaling blockade. Supporting these findings, we show that inhibition of CSF-1/CSF-1R signaling using an anti-CSF-1R antibody can regulate both the number and the function of MDSCs in murine tumors in vivo. We further find that treatment with anti-CSF-1R antibody induces antitumor T-cell responses and tumor regression in multiple tumor models when combined with CTLA-4 blockade therapy. However, this occurs only when administered after or concurrent with CTLA-4 blockade, indicating that timing of each therapeutic intervention is critical for optimal antitumor responses. Importantly, MDSCs present within murine tumors after CTLA-4 blockade showed increased expression of CSF-1R and were capable of suppressing T cell proliferation, and CSF-1/CSF-1R expression in the human tumors was not reduced after treatment with CTLA-4 blockade immunotherapy. Taken together, our findings suggest that CSF-1R-expressing MDSCs can be targeted to modulate the tumor microenvironment and that timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to checkpoint based immunotherapy. Significance: Infiltration by immunosuppressive myeloid cells contributes to tumor immune escape and can render patients resistant or less responsive to therapeutic intervention with checkpoint blocking antibodies. Our data demonstrate that blocking CSF-1/CSF-1R signaling using a monoclonal antibody directed to CSF-1R can regulate both the number and function of tumor-infiltrating immunosuppressive myeloid cells. In addition, our findings suggest that reprogramming myeloid responses may be a key in effectively enhancing cancer immunotherapy, offering several new potential combination therapies for future clinical testing. More importantly for clinical trial design, the timing of these interventions is critical to achieving improved tumor protection. PMID:27622016

Granulocyte colony-stimulating factor (G-CSF) positive effects on muscle fiber degeneration and gait recovery after nerve lesion in MDX mice

PubMed Central

Simões, Gustavo F; Benitez, Suzana U; Oliveira, Alexandre L R

2014-01-01

Background G-CSF has been shown to decrease inflammatory processes and to act positively on the process of peripheral nerve regeneration during the course of muscular dystrophy. Aims The aims of this study were to investigate the effects of treatment of G-CSF during sciatic nerve regeneration and histological analysis in the soleus muscle in MDX mice. Methods Six-week-old male MDX mice underwent left sciatic nerve crush and were G-CSF treated at 7 days prior to and 21 days after crush. Ten and twenty-one days after surgery, the mice were euthanized, and the sciatic nerves were processed for immunohistochemistry (anti-p75NTR and anti-neurofilament) and transmission electron microscopy. The soleus muscles were dissected out and processed for H&E staining and subsequent morphologic analysis. Motor function analyses were performed at 7 days prior to and 21 days after sciatic crush using the CatWalk system and the sciatic nerve index. Results Both groups treated with G-CSF showed increased p75NTR and neurofilament expression after sciatic crush. G-CSF treatment decreased the number of degenerated and regenerated muscle fibers, thereby increasing the number of normal muscle fibers. Conclusions The reduction in p75NTR and neurofilament indicates a decreased regenerative capacity in MDX mice following a lesion to a peripheral nerve. The reduction in motor function in the crushed group compared with the control groups may reflect the cycles of muscle degeneration/regeneration that occur postnatally. Thus, G-CSF treatment increases motor function in MDX mice. Nevertheless, the decrease in baseline motor function in these mice is not reversed completely by G-CSF. PMID:25328849

Using detergent to enhance detection sensitivity of African trypanosomes in human CSF and blood by loop-mediated isothermal amplification (LAMP).

PubMed

Grab, Dennis J; Nikolskaia, Olga V; Inoue, Noboru; Thekisoe, Oriel M M; Morrison, Liam J; Gibson, Wendy; Dumler, J Stephen

2011-08-01

The loop-mediated isothermal amplification (LAMP) assay, with its advantages of simplicity, rapidity and cost effectiveness, has evolved as one of the most sensitive and specific methods for the detection of a broad range of pathogenic microorganisms including African trypanosomes. While many LAMP-based assays are sufficiently sensitive to detect DNA well below the amount present in a single parasite, the detection limit of the assay is restricted by the number of parasites present in the volume of sample assayed; i.e. 1 per µL or 10(3) per mL. We hypothesized that clinical sensitivities that mimic analytical limits based on parasite DNA could be approached or even obtained by simply adding detergent to the samples prior to LAMP assay. For proof of principle we used two different LAMP assays capable of detecting 0.1 fg genomic DNA (0.001 parasite). The assay was tested on dilution series of intact bloodstream form Trypanosoma brucei rhodesiense in human cerebrospinal fluid (CSF) or blood with or without the addition of the detergent Triton X-100 and 60 min incubation at ambient temperature. With human CSF and in the absence of detergent, the LAMP detection limit for live intact parasites using 1 µL of CSF as the source of template was at best 10(3) parasites/mL. Remarkably, detergent enhanced LAMP assay reaches sensitivity about 100 to 1000-fold lower; i.e. 10 to 1 parasite/mL. Similar detergent-mediated increases in LAMP assay analytical sensitivity were also found using DNA extracted from filter paper cards containing blood pretreated with detergent before card spotting or blood samples spotted on detergent pretreated cards. This simple procedure for the enhanced detection of live African trypanosomes in biological fluids by LAMP paves the way for the adaptation of LAMP for the economical and sensitive diagnosis of other protozoan parasites and microorganisms that cause diseases that plague the developing world.

The recomBead Borrelia antibody index, CXCL13 and total IgM index for laboratory diagnosis of Lyme neuroborreliosis in children.

PubMed

Skogman, B H; Lager, M; Henningsson, A J; Tjernberg, I

2017-11-01

For laboratory diagnostics of Lyme neuroborreliosis (LNB), the recomBead Borrelia antibody index (AI) assay has shown promising results in a mixed age population, but has not previously been evaluated with specific focus on paediatric patients. The aim of the study was to evaluate the recomBead Borrelia AI assay in cerebrospinal fluid (CSF) for the laboratory diagnosis of LNB in children. We also wanted to explore whether early markers, such as CXCL13 in CSF and/or total IgM index could be useful as complementary diagnostic tools. Children being evaluated for LNB in a Swedish Lyme endemic area were included in the study (n = 146). Serum and CSF were collected on admission. Patients with other specific diagnoses were controls (n = 15). The recomBead Borrelia AI assay and the recomBead CXCL13 assay (Mikrogen) were applied together with total IgM index. The overall sensitivity for recomBead Borrelia AI (IgM and IgG together) was 74% and the specificity was 97%. However, the highest sensitivity (91%) at an acceptable level of specificity (90%) was obtained by recomBead Borrelia AI together with CXCL13 and total IgM index, showing a positive predictive value of 84% and a negative predictive value of 95%. Thus, the recomBead Borrelia AI assay performs with moderate sensitivity and high specificity in paediatric LNB patients. The major advantage seems to be increased sensitivity in the possible LNB group compared to the IDEIA assay. The diagnostic sensitivity may be further increased by using a combination of early markers, such as CXCL13 in CSF and total IgM index.

Spatial-frequency cutoff requirements for pattern recognition in central and peripheral vision

PubMed Central

Kwon, MiYoung; Legge, Gordon E.

2011-01-01

It is well known that object recognition requires spatial frequencies exceeding some critical cutoff value. People with central scotomas who rely on peripheral vision have substantial difficulty with reading and face recognition. Deficiencies of pattern recognition in peripheral vision, might result in higher cutoff requirements, and may contribute to the functional problems of people with central-field loss. Here we asked about differences in spatial-cutoff requirements in central and peripheral vision for letter and face recognition. The stimuli were the 26 letters of the English alphabet and 26 celebrity faces. Each image was blurred using a low-pass filter in the spatial frequency domain. Critical cutoffs (defined as the minimum low-pass filter cutoff yielding 80% accuracy) were obtained by measuring recognition accuracy as a function of cutoff (in cycles per object). Our data showed that critical cutoffs increased from central to peripheral vision by 20% for letter recognition and by 50% for face recognition. We asked whether these differences could be accounted for by central/peripheral differences in the contrast sensitivity function (CSF). We addressed this question by implementing an ideal-observer model which incorporates empirical CSF measurements and tested the model on letter and face recognition. The success of the model indicates that central/peripheral differences in the cutoff requirements for letter and face recognition can be accounted for by the information content of the stimulus limited by the shape of the human CSF, combined with a source of internal noise and followed by an optimal decision rule. PMID:21854800

Quantification and regulation of the adipokines resistin and progranulin in human cerebrospinal fluid.

PubMed

Berghoff, Martin; Hochberg, Alexandra; Schmid, Andreas; Schlegel, Jutta; Karrasch, Thomas; Kaps, Manfred; Schäffler, Andreas

2016-01-01

Adipokines bearing the potential to cross the blood-brain barrier (BBB) are promising candidates for the endocrine regulation of central nervous processes and of a postulated fat-brain axis. Resistin and progranulin concentrations in paired serum and cerebrospinal fluid (CSF) samples of patients undergoing neurological evaluation and spinal puncture were investigated. Samples of n = 270 consecutive patients with various neurological diseases were collected without prior selection. Adipokine serum and CSF concentrations were measured by enzyme-linked immunosorbent assay and serum and CSF routine parameters by standard procedures. Anthropometric data, medication and patient history were available. Serum levels of resistin and progranulin were positively correlated among each other, with respective CSF levels, low-density lipoprotein cholesterol levels and markers of systemic inflammation. CSF resistin concentrations were generally low. Progranulin CSF concentrations and CSF/serum progranulin ratio were significantly higher in patients with infectious diseases, with disturbed BBB function and with elevated CSF cell count and presence of oligoclonal bands. Both adipokines are able to cross the BBB depending on a differing patency that increases with increasing grade of barrier dysfunction. Whereas resistin represents a systemic marker of inflammation, CSF progranulin levels strongly depend on the underlying disease and dysfunction of blood-CSF barrier. Resistin and progranulin represent novel and putative regulators of the fat-brain axis by their ability to cross the BBB under physiological and pathophysiological conditions. The presented data provide insight into the characteristics of BBB function regarding progranulin and resistin and the basis for future establishment of normal values for CSF concentrations and CSF/serum ratios. © 2015 Stichting European Society for Clinical Investigation Journal Foundation.

Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease.

PubMed

Simon, Matthew J; Iliff, Jeffrey J

2016-03-01

Cerebrospinal fluid (CSF) circulation and turnover provides a sink for the elimination of solutes from the brain interstitium, serving an important homeostatic role for the function of the central nervous system. Disruption of normal CSF circulation and turnover is believed to contribute to the development of many diseases, including neurodegenerative conditions such as Alzheimer's disease, ischemic and traumatic brain injury, and neuroinflammatory conditions such as multiple sclerosis. Recent insights into CSF biology suggesting that CSF and interstitial fluid exchange along a brain-wide network of perivascular spaces termed the 'glymphatic' system suggest that CSF circulation may interact intimately with glial and vascular function to regulate basic aspects of brain function. Dysfunction within this glial vascular network, which is a feature of the aging and injured brain, is a potentially critical link between brain injury, neuroinflammation and the development of chronic neurodegeneration. Ongoing research within this field may provide a powerful new framework for understanding the common links between neurodegenerative, neurovascular and neuroinflammatory disease, in addition to providing potentially novel therapeutic targets for these conditions. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger. Copyright © 2015 Elsevier B.V. All rights reserved.

The Activin A-Peroxisome Proliferator-Activated Receptor Gamma Axis Contributes to the Transcriptome of GM-CSF-Conditioned Human Macrophages.

PubMed

Nieto, Concha; Bragado, Rafael; Municio, Cristina; Sierra-Filardi, Elena; Alonso, Bárbara; Escribese, María M; Domínguez-Andrés, Jorge; Ardavín, Carlos; Castrillo, Antonio; Vega, Miguel A; Puig-Kröger, Amaya; Corbí, Angel L

2018-01-01

GM-CSF promotes the functional maturation of lung alveolar macrophages (A-MØ), whose differentiation is dependent on the peroxisome proliferator-activated receptor gamma (PPARγ) transcription factor. In fact, blockade of GM-CSF-initiated signaling or deletion of the PPARγ-encoding gene PPARG leads to functionally defective A-MØ and the onset of pulmonary alveolar proteinosis. In vitro , macrophages generated in the presence of GM-CSF display potent proinflammatory, immunogenic and tumor growth-limiting activities. Since GM-CSF upregulates PPARγ expression, we hypothesized that PPARγ might contribute to the gene signature and functional profile of human GM-CSF-conditioned macrophages. To verify this hypothesis, PPARγ expression and activity was assessed in human monocyte-derived macrophages generated in the presence of GM-CSF [proinflammatory GM-CSF-conditioned human monocyte-derived macrophages (GM-MØ)] or M-CSF (anti-inflammatory M-MØ), as well as in ex vivo isolated human A-MØ. GM-MØ showed higher PPARγ expression than M-MØ, and the expression of PPARγ in GM-MØ was found to largely depend on activin A. Ligand-induced activation of PPARγ also resulted in distinct transcriptional and functional outcomes in GM-MØ and M-MØ. Moreover, and in the absence of exogenous activating ligands, PPARγ knockdown significantly altered the GM-MØ transcriptome, causing a global upregulation of proinflammatory genes and significantly modulating the expression of genes involved in cell proliferation and migration. Similar effects were observed in ex vivo isolated human A-MØ, where PPARγ silencing led to enhanced expression of genes coding for growth factors and chemokines and downregulation of cell surface pathogen receptors. Therefore, PPARγ shapes the transcriptome of GM-CSF-dependent human macrophages ( in vitro derived GM-MØ and ex vivo isolated A-MØ) in the absence of exogenous activating ligands, and its expression is primarily regulated by activin A. These results suggest that activin A, through enhancement of PPARγ expression, help macrophages to switch from a proinflammatory to an anti-inflammatory polarization state, thus contributing to limit tissue damage and restore homeostasis.

Intra-articular administration of an antibody against CSF-1 receptor reduces pain-related behaviors and inflammation in CFA-induced knee arthritis.

PubMed

Alvarado-Vazquez, P A; Morado-Urbina, C E; Castañeda-Corral, G; Acosta-Gonzalez, R I; Kitaura, H; Kimura, K; Takano-Yamamoto, T; Jiménez-Andrade, J M

2015-01-01

Several studies have shown that blockade of colony stimulating factor-1 (CSF-1) or its receptor (CSF-1R) inhibits disease progression in rodent models of rheumatoid arthritis (RA); however, the role of the CSF-1/CSF-1R pathway in RA-induced pain and functional deficits has not been studied. Thus, we examined the effect of chronic intra-articular administration of a monoclonal anti-CSF-1R antibody (AFS98) on spontaneous pain, knee edema and functional disabilities in mice with arthritis. Unilateral arthritis was produced by multiple injections of complete Freund's adjuvant (CFA) into the right knee joint of adult male ICR mice. CFA-injected mice were then treated twice weekly from day 10 until day 25 with anti-CSF-1R antibody (3 and 10 μg/5 μL per joint), isotype control (rat IgG 10 μg/5 μL per joint) or PBS (5 μl/joint). Knee edema, spontaneous flinching, vertical rearing and horizontal exploratory activity were assessed at different days. Additionally, counts of peripheral leukocytes and body weight were measured to evaluate general health status. Intra-articular treatment with anti-CSF-1R antibody significantly increased horizontal exploratory activity and vertical rearing as well as reduced spontaneous flinching behavior and knee edema as compared to CFA-induced arthritis mice treated with PBS. Treatment with this antibody neither significantly affect mouse body weight nor the number of peripheral leukocytes. These results suggest that blockade of CSF-1R at the initial injury site (joint) could represent a therapeutic alternative for improving the functional disabilities and attenuating pain and inflammation in patients with RA. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

False-positive cerebrospinal fluid cryptococcus antigen in Libman-Sacks endocarditis.

PubMed

Isseh, Iyad N; Bourgi, Kassem; Nakhle, Asaad; Ali, Mahmoud; Zervos, Marcus J

2016-12-01

Cryptococcus meningoencephalitis is a serious opportunistic infection associated with high morbidity and mortality in immunocompromised hosts, particularly patients with advanced AIDS disease. The diagnosis is established through cerebrospinal fluid (CSF) cryptococcus antigen detection and cultures. Cryptococcus antigen testing is usually the initial test of choice due its high sensitivity and specificity along with the quick availability of the results. We hereby report a case of a false-positive CSF cryptococcus antigen assay in a patient with systemic lupus erythematosus presenting with acute confusion. While initial CSF evaluation revealed a positive cryptococcus antigen assay, the patient's symptoms were inconsistent with cryptococcus meningoencephalitis. A repeat CSF evaluation, done 3 days later, revealed a negative CSF cryptococcus antigen assay. Given the patient's active lupus disease and the elevated antinuclear antibody titers, we believe that the initial positive result was a false positive caused by interference from autoantibodies.

Emerging Roles for CSF-1 Receptor and its Ligands in the Nervous System

PubMed Central

Chitu, Violeta; Gokhan, Solen; Nandi, Sayan; Mehler, Mark F.; Stanley, E. Richard

2016-01-01

The colony stimulating factor-1 receptor (CSF-1R) kinase regulates tissue macrophage homeostasis, osteoclastogenesis, and Paneth cell development. However, recent studies in mice have revealed that CSF-1R signaling directly controls the development and maintenance of microglia, and cell autonomously regulates neuronal differentiation and survival. While the CSF-1R-cognate ligands, CSF-1 and interleukin-34 (IL-34), compete for binding to the CSF-1R, they are expressed in a largely non-overlapping manner by mature neurons. The recent identification of a dominantly inherited, adult-onset, progressive dementia associated with inactivating mutations in the CSF-1R highlights the importance of CSF-1R signaling in the brain. We review the roles of the CSF-1R and its ligands in microglial and neural development and function, and their relevance to our understanding of neurodegenerative disease. PMID:27083478

CSF-1R Inhibitor Development: Current Clinical Status.

PubMed

Peyraud, Florent; Cousin, Sophie; Italiano, Antoine

2017-09-05

Colony-stimulating factor 1 receptor (CSF-1R) and its ligands, CSF-1 and interleukin 34 (IL-34), regulate the function and survival of tumor-associated macrophages, which are involved in tumorigenesis and in the suppression of antitumor immunity. Moreover, the CSF-1R/CSF-1 axis has been implicated in the pathogenesis of pigmented villonodular synovitis (PVNS), a benign tumor of the synovium. As advanced or metastatic malignant solid tumors and relapsed/refractory PVNS remain unresolved therapeutic problems, new approaches are needed to improve the outcome of patients with these conditions. In solid tumors, targeting CSF-1R via either small molecules or antibodies has shown interesting results in vitro but limited antitumor activity in vivo. Concerning PVNS, clinical trials assessing CSF-1R inhibitors have revealed promising initial outcomes. Blocking CSF-1/CSF-1R signaling represents a promising immunotherapy approach and several new potential combination therapies for future clinical testing.

Dihydroxyphenylglycol as a Biomarker of Norepinephrine Transporter Inhibition by Atomoxetine: Human Model to Assess Central and Peripheral Effects of Dosing.

PubMed

Bieck, Peter R; Leibowitz, Mark; Lachno, D Richard; Ledent, Edouard; Padich, Robert; Jhee, Stan

2016-12-01

To assess the primary metabolite of norepinephrine, 3,4-dihydroxyphenylglycol (DHPG), as a sensitive biomarker for norepinephrine transporter (NET) function and the relationship of DHPG measured peripherally and centrally, NET was antagonized with 80 mg/d atomoxetine for 18 days. Twelve healthy subjects were treated with atomoxetine in an open-label, multiple-dose exploratory study. Plasma atomoxetine reached steady state by day 6, and the pharmacokinetic results demonstrated availability of atomoxetine to the central nervous system. The cerebrospinal fluid (CSF)/plasma ratios of atomoxetine based on area under concentration-time curve from 0 to 12 hours postdose (AUC0-12), maximum concentration (Cmax), and predose were 0.3%, 0.2%, and 11%, respectively. Plasma from atomoxetine-treated subjects (ex vivo) significantly inhibited radioligand binding to human NET (P < 0.001) only 1 hour after dosing. Plasma DHPG and DHPG/norepinephrine (ratio) during repeated posture tests were reduced significantly (P < 0.001) on day 5 and stayed significantly reduced up to 1 day after treatment. In CSF, both DHPG and the ratio were significantly reduced (P < 0.001) on day 18. Urine results showed significant decreases for both DHPG and the ratio (P = 0.010 to P < 0.001). Brain-derived neurotrophic factor in CSF was lesser than the limits of detection. The findings suggest that NET blockade can be assessed with DHPG concentration or with the ratio in plasma, CSF, and urine. The data suggest that DHPG is a useful biomarker to proactively assess the pharmacological activity of compounds intended to inhibit NET activity within the brain. The study shows that CSF is a medium for early identification and quantification of biomarkers useful in assessing novel neuroscience targets.

The two-pore domain K+ channel TASK-1 is closely associated with brain barriers and meninges.

PubMed

Kanjhan, Refik; Pow, David V; Noakes, Peter G; Bellingham, Mark C

2010-12-01

Impairment of the blood-brain barrier (BBB), the blood-cerebrospinal fluid (CSF) barrier and brain-CSF barrier has been implicated in neuropathology of several brain disorders, such as amyotrophic lateral sclerosis, cerebral edema, multiple sclerosis, neural inflammation, ischemia and stroke. Two-pore domain weakly inward rectifying K+ channel (TWIK)-related acid-sensitive potassium (TASK)-1 channels (K2p3.1; KCNK3) are among the targets that contribute to the development of these pathologies. For example TASK-1 activity is inhibited by acidification, ischemia, hypoxia and several signaling molecules released under pathologic conditions. We have used immuno-histochemistry to examine the distribution of the TASK-1 protein in structures associated with the BBB, blood-CSF barrier, brain-CSF barrier, and in the meninges of adult rat. Dense TASK-1 immuno-reactivity (TASK-1-IR) was observed in ependymal cells lining the fourth ventricle at the brain-CSF interface, in glial cells that ensheath the walls of blood vessels at the glio-vascular interface, and in the meninges. In these structures, TASK-1-IR often co-localized with glial fibrillary associated protein (GFAP) or vimentin. This study provides anatomical evidence for localization of TASK-1 K+ channels in cells that segregate distinct fluid compartments within and surrounding the brain. We suggest that TASK-1 channels, in coordination with other ion channels (e.g., aquaporins and chloride channels) and transporters (e.g., Na+-K+-ATPase and Na+-K+-2Cl⁻ and by virtue of its heterogeneous distribution, may differentially contribute to the varying levels of K+ vital for cellular function in these compartments. Our findings are likely to be relevant to recently reported roles of TASK-1 in cerebral ischemia, stroke and inflammatory brain disorders.

Identification and in vitro characterization of novel nanobodies against human granulocyte colony-stimulating factor receptor to provide inhibition of G-CSF function.

PubMed

Bakherad, Hamid; Gargari, Seyed Latif Mousavi; Sepehrizadeh, Zargham; Aghamollaei, Hossein; Taheri, Ramezan Ali; Torshabi, Maryam; Yazdi, Mojtaba Tabatabaei; Ebrahimizadeh, Walead; Setayesh, Neda

2017-09-01

It has been shown that Granulocyte colony-stimulating factor (G-CSF) has a higher expression in malignant tumors, and anti-G-CSF therapy considerably decreases tumor growth, tumor vascularization and metastasis. Thus, blocking the signaling pathway of G-CSF could be beneficial in cancer therapy. This study is aimed at designing and producing a monoclonal nanobody that could act as an antagonist of G-CSF receptor. Nanobodies are the antigen binding fragments of camelid single-chain antibodies, also known as VHH. These fragments have exceptional properties which makes them ideal for tumor imaging and therapeutic applications. We have used our previously built nanobody phage libraries to isolate specific nanobodies to the G-CSF receptor. After a series of cross-reactivity and affinity experiments, two unique nanobodies were selected for functional analysis. Proliferation assay, real-time PCR and immunofluorescence assays were used to characterize these nanobodies. Finally, VHH26 nanobody that was able to specifically bind G-CSF receptor (G-CSF-R) on the surface of NFS60 cells and efficiently block G-CSF-R downstream signaling pathway in a dose-dependent manner was selected. This nanobody could be further developed into a valuable tool in tumor therapy and it forms a basis for additional studies in preclinical animal models. Copyright © 2017. Published by Elsevier Masson SAS.

M-CSF Mediates Host Defense during Bacterial Pneumonia by Promoting the Survival of Lung and Liver Mononuclear Phagocytes.

PubMed

Bettina, Alexandra; Zhang, Zhimin; Michels, Kathryn; Cagnina, R Elaine; Vincent, Isaah S; Burdick, Marie D; Kadl, Alexandra; Mehrad, Borna

2016-06-15

Gram-negative bacterial pneumonia is a common and dangerous infection with diminishing treatment options due to increasing antibiotic resistance among causal pathogens. The mononuclear phagocyte system is a heterogeneous group of leukocytes composed of tissue-resident macrophages, dendritic cells, and monocyte-derived cells that are critical in defense against pneumonia, but mechanisms that regulate their maintenance and function during infection are poorly defined. M-CSF has myriad effects on mononuclear phagocytes but its role in pneumonia is unknown. We therefore tested the hypothesis that M-CSF is required for mononuclear phagocyte-mediated host defenses during bacterial pneumonia in a murine model of infection. Genetic deletion or immunoneutralization of M-CSF resulted in reduced survival, increased bacterial burden, and greater lung injury. M-CSF was necessary for the expansion of lung mononuclear phagocytes during infection but did not affect the number of bone marrow or blood monocytes, proliferation of precursors, or recruitment of leukocytes to the lungs. In contrast, M-CSF was essential to survival and antimicrobial functions of both lung and liver mononuclear phagocytes during pneumonia, and its absence resulted in bacterial dissemination to the liver and hepatic necrosis. We conclude that M-CSF is critical to host defenses against bacterial pneumonia by mediating survival and antimicrobial functions of mononuclear phagocytes in the lungs and liver. Copyright © 2016 by The American Association of Immunologists, Inc.

M-CSF mediates host defense during bacterial pneumonia by promoting the survival of lung and liver mononuclear phagocytes

PubMed Central

Bettina, Alexandra; Zhang, Zhimin; Michels, Kathryn; Cagnina, R. Elaine; Vincent, Isaah S.; Burdick, Marie D.; Kadl, Alexandra; Mehrad, Borna

2016-01-01

Gram-negative bacterial pneumonia is a common and dangerous infection with diminishing treatment options due to increasing antibiotic resistance among causal pathogens. The mononuclear phagocyte system is a heterogeneous group of leukocytes composed of tissue-resident macrophages, dendritic cells and monocyte-derived cells that are critical in defense against pneumonia, but mechanisms that regulate their maintenance and function during infection are poorly defined. Macrophage-colony stimulating factor (M-CSF) has myriad effects on mononuclear phagocytes but its role in pneumonia is unknown. We therefore tested the hypothesis that M-CSF is required for mononuclear phagocyte-mediated host defenses during bacterial pneumonia in a murine model of infection. Genetic deletion or immunoneutralization of M-CSF resulted in reduced survival, increased bacterial burden and greater lung injury. M-CSF was necessary for the expansion of lung mononuclear phagocytes during infection but did not affect the number of bone marrow or blood monocytes, the proliferation of precursors or the recruitment of leukocytes to the lungs. In contrast, M-CSF was essential to survival and anti-microbial functions of both lung and liver mononuclear phagocytes during pneumonia and its absence resulted in bacterial dissemination to the liver and hepatic necrosis. We conclude that M-CSF is critical to host defenses against bacterial pneumonia by mediating survival and anti-microbial functions of mononuclear phagocytes in the lungs and liver. PMID:27183631

Dysregulation of the Cytokine GM-CSF Induces Spontaneous Phagocyte Invasion and Immunopathology in the Central Nervous System.

PubMed

Spath, Sabine; Komuczki, Juliana; Hermann, Mario; Pelczar, Pawel; Mair, Florian; Schreiner, Bettina; Becher, Burkhard

2017-02-21

Chronic inflammatory diseases are influenced by dysregulation of cytokines. Among them, granulocyte macrophage colony stimulating factor (GM-CSF) is crucial for the pathogenic function of T cells in preclinical models of autoimmunity. To study the impact of dysregulated GM-CSF expression in vivo, we generated a transgenic mouse line allowing the induction of GM-CSF expression in mature, peripheral helper T (Th) cells. Antigen-independent GM-CSF release led to the invasion of inflammatory myeloid cells into the central nervous system (CNS), which was accompanied by the spontaneous development of severe neurological deficits. CNS-invading phagocytes produced reactive oxygen species and exhibited a distinct genetic signature compared to myeloid cells invading other organs. We propose that the CNS is particularly vulnerable to the attack of monocyte-derived phagocytes and that the effector functions of GM-CSF-expanded myeloid cells are in turn guided by the tissue microenvironment. Copyright © 2017 Elsevier Inc. All rights reserved.

CSF lactate for accurate diagnosis of community-acquired bacterial meningitis.

PubMed

Giulieri, S; Chapuis-Taillard, C; Jaton, K; Cometta, A; Chuard, C; Hugli, O; Du Pasquier, R; Bille, J; Meylan, P; Manuel, O; Marchetti, O

2015-10-01

CSF lactate measurement is recommended when nosocomial meningitis is suspected, but its value in community-acquired bacterial meningitis is controversial. We evaluated the diagnostic performance of lactate and other CSF parameters in a prospective cohort of adult patients with acute meningitis. Diagnostic accuracy of lactate and other CSF parameters in patients with microbiologically documented episodes was assessed by receiver operating characteristic (ROC) curves. The cut-offs with the best diagnostic performance were determined. Forty-five of 61 patients (74%) had a documented bacterial (n = 18; S. pneumoniae, 11; N. meningitidis, 5; other, 2) or viral (n = 27 enterovirus, 21; VZV, 3; other, 3) etiology. CSF parameters were significantly different in bacterial vs. viral meningitis, respectively (p < 0.001 for all comparisons): white cell count (median 1333 vs. 143/mm(3)), proteins (median 4115 vs. 829 mg/l), CSF/blood glucose ratio (median 0.1 vs. 0.52), lactate (median 13 vs. 2.3 mmol/l). ROC curve analysis showed that CSF lactate had the highest accuracy for discriminating bacterial from viral meningitis, with a cutoff set at 3.5 mmol/l providing 100% sensitivity, specificity, PPV, NPV, and efficiency. CSF lactate had the best accuracy for discriminating bacterial from viral meningitis and should be included in the initial diagnostic workup of this condition.

Differential allelic expression of IL13 and CSF2 genes associated with asthma.

PubMed

Burkhardt, Jana; Kirsten, Holger; Wolfram, Grit; Quente, Elfi; Ahnert, Peter

2012-07-01

An important area of genetic research is the identification of functional mechanisms in polymorphisms associated with diseases. A highly relevant functional mechanism is the influence of polymorphisms on gene expression levels (differential allelic expression, DAE). The coding single nucleotide polymorphisms (SNPs) CSF2(rs25882) and IL13(rs20541) have been associated with asthma. In this work, we investigated whether the mRNA expression levels of CSF2 or IL13 were correlated with these SNPs. Samples were analyzed by mass spectrometry-based quantification of gene expression. Both SNPs influenced gene expression levels (CSF2(rs25882): p(overall) = 0.008 and p(DAE samples) = 0.00006; IL13(rs20541): p(overall) = 0.059 and p(DAE samples) = 0.036). For CSF2, the expression level was increased by 27.4% (95% CI: 18.5%-35.4%) in samples with significant DAE in the presence of one copy of risk variant CSF2(rs25882-T). The average expression level of IL13 was increased by 29.8% (95% CI: 3.1%-63.4%) in samples with significant DAE in the presence of one copy of risk variant IL13(rs20541-A). Enhanced expression of CSF2 could stimulate macrophages and neutrophils during inflammation and may be related to the etiology of asthma. For IL-13, higher expression could enhance the functional activity of the asthma-associated isoform. Overall, the analysis of DAE provides an efficient approach for identifying possible functional mechanisms that link disease-associated variants with altered gene expression levels.

Is febrile neutropenia prophylaxis with granulocyte-colony stimulating factors economically justified for adjuvant TC chemotherapy in breast cancer?

PubMed

Skedgel, Chris; Rayson, Daniel; Younis, Tallal

2016-01-01

Febrile neutropenia (FN) during adjuvant chemotherapy is associated with morbidity, mortality risk, and substantial cost, and subsequent chemotherapy dose reductions may result in poorer outcomes. Patients at high risk of, or who develop FN, often receive prophylaxis with granulocyte colony-stimulating factors (G-CSF). We investigated whether different prophylaxis strategies with G-CSF offered favorable value-for-money. We developed a decision model to estimate the short- and long-term costs and outcomes of a hypothetical cohort of women with breast cancer receiving adjuvant taxotere + cyclophosphamide (TC) chemotherapy. The short-term phase estimated upfront costs and FN risks with adjuvant TC chemotherapy without G-CSF prophylaxis (i.e., chemotherapy dose reductions) as well as with secondary and primary G-CSF prophylaxis strategies. The long-term phase estimated the expected costs and quality-adjusted life years (QALYs) for patients who completed adjuvant TC chemotherapy with or without one or more episodes of FN. Secondary G-CSF was associated with lower costs and greater QALY gains than a no G-CSF strategy. Primary G-CSF appears likely to be cost-effective relative to secondary G-CSF at FN rates greater than 28%, assuming some loss of chemotherapy efficacy at lower dose intensities. The cost-effectiveness of primary vs. secondary G-CSF was sensitive to FN risk and mortality, and loss of chemotherapy efficacy following FN. Secondary G-CSF is more effective and less costly than a no G-CSF strategy. Primary G-CSF may be justified at higher willingness-to-pay thresholds and/or higher FN risks, but this threshold FN risk appears to be higher than the 20% rate recommended by current clinical guidelines.

Granulocyte colony-stimulating factor improves host defense to resuscitated shock and polymicrobial sepsis without provoking generalized neutrophil-mediated damage.

PubMed

Patton, J H; Lyden, S P; Ragsdale, D N; Croce, M A; Fabian, T C; Proctor, K G

1998-05-01

Granulocyte colony-stimulating factor (G-CSF) increases production and release of neutrophil precursors and activates multiple functions of circulating polymorphonuclear neutrophils (PMNs). G-CSF has therapeutic effects in many experimental models of sepsis; its actions with superimposed reperfusion insults are unknown. In traumatic conditions, G-CSF could exacerbate unregulated, PMN-dependent injury to otherwise normal host tissue or, it could partially reverse trauma-induced immune suppression, which may improve long-term outcome. This study tested whether stimulating PMN proliferation and function with G-CSF during recovery from trauma+sepsis potentiated reperfusion injury or whether it improved host defense. Anesthetized swine were subjected to cecal ligation and incision, 35% hemorrhage, and 1 hr of hypotension. Resuscitation consisted of intravenous G-CSF (5 microg/kg) or placebo followed by shed blood and 40 mL/kg of lactated Ringer's solution. The control group received laparotomy only. G-CSF or placebo was given daily. Animals were killed at 4 days. Observers, blind to the protocol, graded autopsy samples for localization of infection and quality of abscess wall formation. Data included complete blood count, granulocyte oxidative burst after phorbol myristate acetate stimulation in vitro (GO2B), bronchoalveolar lavage (BAL) cell count, BAL noncellular protein, lipopolysaccharide-stimulated tumor necrosis factor production in whole blood in vitro (lipopolysaccharide-tumor necrosis factor), and lung tissue myeloperoxidase (MPO). Neutrophilia and localization of infection, were significantly improved by G-CSF. Variables altered by G-CSF, though not significantly, showed GO2B potential increased by 50%, lipopolysaccharide-tumor necrosis factor decreased by 50%, and improved survival versus placebo (100% vs. 70%). G-CSF did not increase lung MPO, BAL cell count, or BAL protein. Both arterial and venous O2 saturations were unaltered. Our data show that G-CSF initiated at the time of resuscitation reduced the sequelae of posttrauma sepsis by increasing PMN proliferation and function without potentiating PMN-mediated lung reperfusion injury.

EEG and Neuronal Activity Topography analysis can predict effectiveness of shunt operation in idiopathic normal pressure hydrocephalus patients☆

PubMed Central

Aoki, Yasunori; Kazui, Hiroaki; Tanaka, Toshihisa; Ishii, Ryouhei; Wada, Tamiki; Ikeda, Shunichiro; Hata, Masahiro; Canuet, Leonides; Musha, Toshimitsu; Matsuzaki, Haruyasu; Imajo, Kaoru; Yoshiyama, Kenji; Yoshida, Tetsuhiko; Shimizu, Yoshiro; Nomura, Keiko; Iwase, Masao; Takeda, Masatoshi

2013-01-01

Idiopathic normal pressure hydrocephalus (iNPH) is a neuropsychiatric syndrome characterized by gait disturbance, cognitive impairment and urinary incontinence that affect elderly individuals. These symptoms can potentially be reversed by cerebrospinal fluid (CSF) drainage or shunt operation. Prior to shunt operation, drainage of a small amount of CSF or “CSF tapping” is usually performed to ascertain the effect of the operation. Unfortunately, conventional neuroimaging methods such as single photon emission computed tomography (SPECT) and functional magnetic resonance imaging (fMRI), as well as electroencephalogram (EEG) power analysis seem to have failed to detect the effect of CSF tapping on brain function. In this work, we propose the use of Neuronal Activity Topography (NAT) analysis, which calculates normalized power variance (NPV) of EEG waves, to detect cortical functional changes induced by CSF tapping in iNPH. Based on clinical improvement by CSF tapping and shunt operation, we classified 24 iNPH patients into responders (N = 11) and nonresponders (N = 13), and performed both EEG power analysis and NAT analysis. We also assessed correlations between changes in NPV and changes in functional scores on gait and cognition scales before and after CSF tapping. NAT analysis showed that after CSF tapping there was a significant decrease in alpha NPV at the medial frontal cortex (FC) (Fz) in responders, while nonresponders exhibited an increase in alpha NPV at the right dorsolateral prefrontal cortex (DLPFC) (F8). Furthermore, we found correlations between cortical functional changes and clinical symptoms. In particular, delta and alpha NPV changes in the left-dorsal FC (F3) correlated with changes in gait status, while alpha and beta NPV changes in the right anterior prefrontal cortex (PFC) (Fp2) and left DLPFC (F7) as well as alpha NPV changes in the medial FC (Fz) correlated with changes in gait velocity. In addition, alpha NPV changes in the right DLPFC (F8) correlated with changes in WMS-R Mental Control scores in iNPH patients. An additional analysis combining the changes in values of alpha NPV over the left-dorsal FC (∆alpha-F3-NPV) and the medial FC (∆alpha-Fz-NPV) induced by CSF tapping (cut-off value of ∆alpha-F3-NPV + ∆alpha-Fz-NPV = 0), could correctly identified “shunt responders” and “shunt nonresponders” with a positive predictive value of 100% (10/10) and a negative predictive value of 66% (2/3). In contrast, EEG power spectral analysis showed no function related changes in cortical activity at the frontal cortex before and after CSF tapping. These results indicate that the clinical changes in gait and response suppression induced by CSF tapping in iNPH patients manifest as NPV changes, particularly in the alpha band, rather than as EEG power changes. Our findings suggest that NAT analysis can detect CSF tapping-induced functional changes in cortical activity, in a way that no other neuroimaging methods have been able to do so far, and can predict clinical response to shunt operation in patients with iNPH. PMID:24273735

EEG and Neuronal Activity Topography analysis can predict effectiveness of shunt operation in idiopathic normal pressure hydrocephalus patients.

PubMed

Aoki, Yasunori; Kazui, Hiroaki; Tanaka, Toshihisa; Ishii, Ryouhei; Wada, Tamiki; Ikeda, Shunichiro; Hata, Masahiro; Canuet, Leonides; Musha, Toshimitsu; Matsuzaki, Haruyasu; Imajo, Kaoru; Yoshiyama, Kenji; Yoshida, Tetsuhiko; Shimizu, Yoshiro; Nomura, Keiko; Iwase, Masao; Takeda, Masatoshi

2013-01-01

Idiopathic normal pressure hydrocephalus (iNPH) is a neuropsychiatric syndrome characterized by gait disturbance, cognitive impairment and urinary incontinence that affect elderly individuals. These symptoms can potentially be reversed by cerebrospinal fluid (CSF) drainage or shunt operation. Prior to shunt operation, drainage of a small amount of CSF or "CSF tapping" is usually performed to ascertain the effect of the operation. Unfortunately, conventional neuroimaging methods such as single photon emission computed tomography (SPECT) and functional magnetic resonance imaging (fMRI), as well as electroencephalogram (EEG) power analysis seem to have failed to detect the effect of CSF tapping on brain function. In this work, we propose the use of Neuronal Activity Topography (NAT) analysis, which calculates normalized power variance (NPV) of EEG waves, to detect cortical functional changes induced by CSF tapping in iNPH. Based on clinical improvement by CSF tapping and shunt operation, we classified 24 iNPH patients into responders (N = 11) and nonresponders (N = 13), and performed both EEG power analysis and NAT analysis. We also assessed correlations between changes in NPV and changes in functional scores on gait and cognition scales before and after CSF tapping. NAT analysis showed that after CSF tapping there was a significant decrease in alpha NPV at the medial frontal cortex (FC) (Fz) in responders, while nonresponders exhibited an increase in alpha NPV at the right dorsolateral prefrontal cortex (DLPFC) (F8). Furthermore, we found correlations between cortical functional changes and clinical symptoms. In particular, delta and alpha NPV changes in the left-dorsal FC (F3) correlated with changes in gait status, while alpha and beta NPV changes in the right anterior prefrontal cortex (PFC) (Fp2) and left DLPFC (F7) as well as alpha NPV changes in the medial FC (Fz) correlated with changes in gait velocity. In addition, alpha NPV changes in the right DLPFC (F8) correlated with changes in WMS-R Mental Control scores in iNPH patients. An additional analysis combining the changes in values of alpha NPV over the left-dorsal FC (∆alpha-F3-NPV) and the medial FC (∆alpha-Fz-NPV) induced by CSF tapping (cut-off value of ∆alpha-F3-NPV + ∆alpha-Fz-NPV = 0), could correctly identified "shunt responders" and "shunt nonresponders" with a positive predictive value of 100% (10/10) and a negative predictive value of 66% (2/3). In contrast, EEG power spectral analysis showed no function related changes in cortical activity at the frontal cortex before and after CSF tapping. These results indicate that the clinical changes in gait and response suppression induced by CSF tapping in iNPH patients manifest as NPV changes, particularly in the alpha band, rather than as EEG power changes. Our findings suggest that NAT analysis can detect CSF tapping-induced functional changes in cortical activity, in a way that no other neuroimaging methods have been able to do so far, and can predict clinical response to shunt operation in patients with iNPH.

Validation of two commercial real-time RT-PCR kits for rapid and specific diagnosis of classical swine fever virus.

PubMed

Le Dimna, M; Vrancken, R; Koenen, F; Bougeard, S; Mesplède, A; Hutet, E; Kuntz-Simon, G; Le Potier, M F

2008-01-01

Two real-time RT-PCR kits, developed by LSI (TaqVet CSF) and ADIAGENE (Adiavet CSF), obtained an agreement to be commercialised in France, subject to conditions, defined by the French Classical Swine Fever (CSF) National Reference Laboratory. The producers were asked to introduce an internal control to check the RNA extraction efficacy. The different criteria assessed were sensitivity, "pestivirus specificity", reproducibility and ease of handling, using 189 different samples. These samples were either CSFV inactivated strains or blood/serum/organs collected from CSFV experimentally infected pigs or naturally infected wild boars. The reproducibility of the assays was confirmed by the analysis of a batch-to-batch panel control that was used for inter-laboratory tests involving nine laboratories. The two kits were also tested for the use in mass diagnostics and the results proved the kits to be suited using pools of blood, serum and tonsils. Moreover, a field evaluation, carried out on spleen samples collected from the CSF surveillance of wild boars in an area known to be infected and from domestic pigs at a slaughterhouse, confirmed the high sensitivity and specificity of the two kits. This step-by-step evaluation procedure confirmed that the two commercial CSF real-time RT-PCR kits have a higher predictive value than the current diagnostic standard, Virus Isolation.

Evaluation of trypan blue stain in a haemocytometer for rapid detection of cerebrospinal fluid sterility in HIV patients with cryptococcal meningitis.

PubMed

Kwizera, Richard; Akampurira, Andrew; Kandole, Tadeo K; Nielsen, Kirsten; Kambugu, Andrew; Meya, David B; Boulware, David R; Rhein, Joshua

2017-08-22

Quantitative culture is the most common method to determine the fungal burden and sterility of cerebrospinal fluid (CSF) among persons with cryptococcal meningitis. A major drawback of cultures is a long turnaround-time. Recent evidence demonstrates that live and dead Cryptococcus yeasts can be distinguished using trypan blue staining. We hypothesized that trypan blue staining combined with haemocytometer counting may provide a rapid estimation of quantitative culture count and detection of CSF sterility. To test this, we evaluated 194 CSF specimens from 96 HIV-infected participants with cryptococcal meningitis in Kampala, Uganda. Cryptococcal meningitis was diagnosed by CSF cryptococcal antigen (CRAG). We stained CSF with trypan blue and quantified yeasts using a haemocytometer. We compared the haemocytometer readings versus quantitative Cryptococcus CSF cultures. Haemocytometer counting with trypan blue staining had a sensitivity of 98% (64/65), while CSF cultures had a sensitivity of 95% (62/65) with reference to CSF CRAG for diagnostic CSF specimens. For samples that were positive in both tests, the haemocytometer had higher readings compared to culture. For diagnostic specimens, the median of log 10 transformed counts were 5.59 (n = 64, IQR = 5.09 to 6.05) for haemocytometer and 4.98 (n = 62, IQR = 3.75 to 5.79) for culture; while the overall median counts were 5.35 (n = 189, IQR = 4.78-5.84) for haemocytometer and 3.99 (n = 151, IQR = 2.59-5.14) for cultures. The percentage agreement with culture sterility was 2.4% (1/42). Counts among non-sterile follow-up specimens had a median of 5.38 (n = 86, IQR = 4.74 to 6.03) for haemocytometer and 2.89 (n = 89, IQR = 2.11 to 4.38) for culture. At diagnosis, CSF quantitative cultures correlated with haemocytometer counts (R 2  = 0.59, P < 0.001). At 7-14 days, quantitative cultures did not correlate with haemocytometer counts (R 2  = 0.43, P = 0.4). Despite a positive correlation, the haemocytometer counts with trypan blue staining did not predict the outcome of quantitative cultures in patients receiving antifungal therapy.

Quantification of rifampicin in human plasma and cerebrospinal fluid by a highly sensitive and rapid liquid chromatographic-tandem mass spectrometric method.

PubMed

Srivastava, Abhishek; Waterhouse, David; Ardrey, Alison; Ward, Stephen A

2012-11-01

A highly sensitive and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been developed to measure the levels of the antitubercular drug rifampicin (RIF) in human plasma and cerebrospinal fluid (CSF). The analyte and internal standard (IS) were isolated from plasma and CSF by a simple organic solvent based precipitation of proteins followed by centrifugation. Detection was carried out by electrospray positive ionization mass spectrometry in the multiple-reaction monitoring (MRM) mode. The assay was linear in the concentration range 25-6400 ng/mL with intra- and inter-day precision of <7% and <8%, respectively. The validated method was applied to the study of RIF pharmacokinetics in human CSF and plasma over 25 h period after a 10 mg/kg oral dose. Copyright © 2012 Elsevier B.V. All rights reserved.

Na-coupled bicarbonate transporters of the Slc4 family in the nervous system: function, localization, and relevance to neurologic function

PubMed Central

Majumdar, Debeshi; Bevensee, Mark O.

2010-01-01

Many cellular processes including neuronal activity are sensitive to changes in intracellular and/or extracellular pH— both of which are regulated by acid-base transporter activity. HCO3−-dependent transporters are particularly potent regulators of intracellular pH in neurons and astrocytes, and also contribute to the composition of the cerebrospinal fluid (CSF). The molecular physiology of HCO3− transporters has advanced considerably over the past ~14 years as investigators have cloned and characterized the function and localization of many Na-Coupled Bicarbonate Transporters of the Slc4 family (NCBTs). In this review, we provide an updated overview of the function and localization of NCBTs in the nervous system. Multiple NCBTs are expressed in neurons and astrocytes in various brain regions, as well as in epithelial cells of the choroid plexus. Characteristics of human patients with SLC4 gene mutations/deletions and results from recent studies on mice with Slc4 gene disruptions highlight the functional importance of NCBTs in neuronal activity, somatosensory function, and CSF production. Furthermore, energy-deficient states (e.g., hypoxia and ischemia) lead to altered expression and activity of NCBTs. Thus, recent studies expand our understanding of the role of NCBTs in regulating the pH and ionic composition of the nervous system that can modulate neuronal activity. PMID:20884330

Detailed comparison of amyloid PET and CSF biomarkers for identifying early Alzheimer disease

PubMed Central

Zetterberg, Henrik; Mattsson, Niklas; Johansson, Per; Minthon, Lennart; Blennow, Kaj; Olsson, Mattias

2015-01-01

Objective: To compare the diagnostic accuracy of CSF biomarkers and amyloid PET for diagnosing early-stage Alzheimer disease (AD). Methods: From the prospective, longitudinal BioFINDER study, we included 122 healthy elderly and 34 patients with mild cognitive impairment who developed AD dementia within 3 years (MCI-AD). β-Amyloid (Aβ) deposition in 9 brain regions was examined with [18F]-flutemetamol PET. CSF was analyzed with INNOTEST and EUROIMMUN ELISAs. The results were replicated in 146 controls and 64 patients with MCI-AD from the Alzheimer's Disease Neuroimaging Initiative study. Results: The best CSF measures for identifying MCI-AD were Aβ42/total tau (t-tau) and Aβ42/hyperphosphorylated tau (p-tau) (area under the curve [AUC] 0.93–0.94). The best PET measures performed similarly (AUC 0.92–0.93; anterior cingulate, posterior cingulate/precuneus, and global neocortical uptake). CSF Aβ42/t-tau and Aβ42/p-tau performed better than CSF Aβ42 and Aβ42/40 (AUC difference 0.03–0.12, p < 0.05). Using nonoptimized cutoffs, CSF Aβ42/t-tau had the highest accuracy of all CSF/PET biomarkers (sensitivity 97%, specificity 83%). The combination of CSF and PET was not better than using either biomarker separately. Conclusions: Amyloid PET and CSF biomarkers can identify early AD with high accuracy. There were no differences between the best CSF and PET measures and no improvement when combining them. Regional PET measures were not better than assessing the global Aβ deposition. The results were replicated in an independent cohort using another CSF assay and PET tracer. The choice between CSF and amyloid PET biomarkers for identifying early AD can be based on availability, costs, and doctor/patient preferences since both have equally high diagnostic accuracy. Classification of evidence: This study provides Class III evidence that amyloid PET and CSF biomarkers identify early-stage AD equally accurately. PMID:26354982

CSF1 Restores Innate Immunity After Liver Injury in Mice and Serum Levels Indicate Outcomes of Patients With Acute Liver Failure

PubMed Central

Stutchfield, Benjamin M.; Antoine, Daniel J.; Mackinnon, Alison C.; Gow, Deborah J.; Bain, Calum C.; Hawley, Catherine A.; Hughes, Michael J.; Francis, Benjamin; Wojtacha, Davina; Man, Tak Y.; Dear, James W.; Devey, Luke R.; Mowat, Alan M.; Pollard, Jeffrey W.; Park, B. Kevin; Jenkins, Stephen J.; Simpson, Kenneth J.; Hume, David A.; Wigmore, Stephen J.; Forbes, Stuart J.

2015-01-01

Background & Aims Liver regeneration requires functional liver macrophages, which provide an immune barrier that is compromised after liver injury. The numbers of liver macrophages are controlled by macrophage colony-stimulating factor (CSF1). We examined the prognostic significance of the serum level of CSF1 in patients with acute liver injury and studied its effects in mice. Methods We measured levels of CSF1 in serum samples collected from 55 patients who underwent partial hepatectomy at the Royal Infirmary Edinburgh between December 2012 and October 2013, as well as from 78 patients with acetaminophen-induced acute liver failure admitted to the Royal Infirmary Edinburgh or the University of Kansas Medical Centre. We studied the effects of increased levels of CSF1 in uninjured mice that express wild-type CSF1 receptor or a constitutive or inducible CSF1-receptor reporter, as well as in chemokine receptor 2 (Ccr2)-/- mice; we performed fate-tracing experiments using bone marrow chimeras. We administered CSF1-Fc (fragment, crystallizable) to mice after partial hepatectomy and acetaminophen intoxication, and measured regenerative parameters and innate immunity by clearance of fluorescent microbeads and bacterial particles. Results Serum levels of CSF1 increased in patients undergoing liver surgery in proportion to the extent of liver resected. In patients with acetaminophen-induced acute liver failure, a low serum level of CSF1 was associated with increased mortality. In mice, administration of CSF1-Fc promoted hepatic macrophage accumulation via proliferation of resident macrophages and recruitment of monocytes. CSF1-Fc also promoted transdifferentiation of infiltrating monocytes into cells with a hepatic macrophage phenotype. CSF1-Fc increased innate immunity in mice after partial hepatectomy or acetaminophen-induced injury, with resident hepatic macrophage as the main effector cells. Conclusions Serum CSF1 appears to be a prognostic marker for patients with acute liver injury. CSF1 might be developed as a therapeutic agent to restore innate immune function after liver injury. PMID:26344055

Absence of Colony Stimulation Factor-1 Receptor Results in Loss of Microglia, Disrupted Brain Development and Olfactory Deficits

PubMed Central

Etgen, Anne M.; Dobrenis, Kostantin; Pollard, Jeffrey W.

2011-01-01

The brain contains numerous mononuclear phagocytes called microglia. These cells express the transmembrane tyrosine kinase receptor for the macrophage growth factor colony stimulating factor-1 (CSF-1R). Using a CSF-1R-GFP reporter mouse strain combined with lineage defining antibody staining we show in the postnatal mouse brain that CSF-1R is expressed only in microglia and not neurons, astrocytes or glial cells. To study CSF-1R function we used mice homozygous for a null mutation in the Csflr gene. In these mice microglia are >99% depleted at embryonic day 16 and day 1 post-partum brain. At three weeks of age this microglial depletion continues in most regions of the brain although some contain clusters of rounded microglia. Despite the loss of microglia, embryonic brain development appears normal but during the post-natal period the brain architecture becomes perturbed with enlarged ventricles and regionally compressed parenchyma, phenotypes most prominent in the olfactory bulb and cortex. In the cortex there is increased neuronal density, elevated numbers of astrocytes but reduced numbers of oligodendrocytes. Csf1r nulls rarely survive to adulthood and therefore to study the role of CSF-1R in olfaction we used the viable null mutants in the Csf1 (Csf1op) gene that encodes one of the two known CSF-1R ligands. Food-finding experiments indicate that olfactory capacity is significantly impaired in the absence of CSF-1. CSF-1R is therefore required for the development of microglia, for a fully functional olfactory system and the maintenance of normal brain structure. PMID:22046273

Heterogeneous effects of M-CSF isoforms on the progression of MLL-AF9 leukemia.

PubMed

Wang, Rong; Feng, Wenli; Yang, Feifei; Yang, Xiao; Wang, Lina; Chen, Chong; Hu, Yuting; Ren, Qian; Zheng, Guoguang

2018-02-01

Macrophage colony-stimulating factor (M-CSF) regulates both malignant cells and microenvironmental cells. Its splicing isoforms show functional heterogeneity. However, their roles on leukemia have not been well established. Here, the expression of total M-CSF in patients with hematopoietic malignancies was analyzed. The roles of M-CSF isoforms on the progression of acute myeloid leukemia (AML) were studied by establishing MLL-AF9-induced mouse AML models with high level membrane-bound M-CSF (mM-CSF) or soluble M-CSF (sM-CSF). Total M-CSF was highly expressed in myeloid leukemia patients. Furthermore, mM-CSF but not sM-CSF prolonged the survival of leukemia mice. While sM-CSF was more potent to promote proliferation and self-renew, mM-CSF was more potent to promote differentiation. Moreover, isoforms had different effects on leukemia-associated macrophages (LAMs) though they both increase monocytes/macrophages by growth-promoting and recruitment effects. In addition, mM-CSF promoted specific phagocytosis of leukemia cells by LAMs. RNA-seq analysis revealed that mM-CSF enhanced phagocytosis-associated genes and activated oxidative phosphorylation and metabolism pathway. These results highlight heterogeneous effects of M-CSF isoforms on AML progression and the mechanisms of mM-CSF, that is, intrinsically promoting AML cell differentiation and extrinsically enhancing infiltration of macrophages and phagocytosis by macrophages, which may provide potential clues for clinical diagnosis and therapy. © 2017 Australasian Society for Immunology Inc.

Contamination control concepts for space station customer servicing

NASA Technical Reports Server (NTRS)

Maruya, K. A.; Ryan, L. E.; Rosales, L. A.; Medler, E. H.

1986-01-01

The customer servicing operations envisioned for the space station, which include instrument repair, orbital replacement unit (ORU) changeout, and fluid replenishment for free-flying and attached payloads, are expected to create requirements for a unique contamination control subsystem for the customer servicing facility (CSF). Both the core space station and the CSF users present unique requirements/sensitivities, not all of which are currently defined with common criteria. Preliminary results from an assessment of the effects of the CSF-induced contamination environment are reported. Strategies for a comprehensive contamination control approach and a description of specific hardware devices and their applicability are discussed.

G-CSF and GM-CSF in Neutropenia

PubMed Central

Mehta, Hrishikesh M.; Malandra, Michael; Corey, Seth J.

2015-01-01

Granulocyte Colony Stimulating Factor (G-CSF) and Granulocyte/Macrophage Colony Stimulating Factor (GM-CSF) are used widely to promote the production of granulocytes or antigen presenting cells (APC). The Food and Drug Administration approved G-CSF (filgrastim) for the treatment of congenital and acquired neutropenias and for mobilization of peripheral hematopoietic progenitor cells for stem cell transplantation. A polyethylene glycol modified (PEGylated) form of G-CSF is approved for the treatment of neutropenias. Clinically significant neutropenia, rendering an individual immunocompromised, occurs when their number is less than 1500/µl. Current guidelines recommend their use when the risk of febrile neutropenia is greater than 20%. GM-CSF (sargramostim) is approved for neutropenia associated with stem cell transplantation. Because of its promotion of APC function, GM-CSF is being evaluated as an immunostimulatory adjuvant in a number of clinical trials. More than 20 million persons have benefited worldwide, and more than $5 billion sales occur annually in the United States. PMID:26254266

Brain-wide pathway for waste clearance captured by contrast-enhanced MRI.

PubMed

Iliff, Jeffrey J; Lee, Hedok; Yu, Mei; Feng, Tian; Logan, Jean; Nedergaard, Maiken; Benveniste, Helene

2013-03-01

The glymphatic system is a recently defined brain-wide paravascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange that facilitates efficient clearance of solutes and waste from the brain. CSF enters the brain along para-arterial channels to exchange with ISF, which is in turn cleared from the brain along para-venous pathways. Because soluble amyloid β clearance depends on glymphatic pathway function, we proposed that failure of this clearance system contributes to amyloid plaque deposition and Alzheimer's disease progression. Here we provide proof of concept that glymphatic pathway function can be measured using a clinically relevant imaging technique. Dynamic contrast-enhanced MRI was used to visualize CSF-ISF exchange across the rat brain following intrathecal paramagnetic contrast agent administration. Key features of glymphatic pathway function were confirmed, including visualization of para-arterial CSF influx and molecular size-dependent CSF-ISF exchange. Whole-brain imaging allowed the identification of two key influx nodes at the pituitary and pineal gland recesses, while dynamic MRI permitted the definition of simple kinetic parameters to characterize glymphatic CSF-ISF exchange and solute clearance from the brain. We propose that this MRI approach may provide the basis for a wholly new strategy to evaluate Alzheimer's disease susceptibility and progression in the live human brain.

Brain-wide pathway for waste clearance captured by contrast-enhanced MRI

PubMed Central

Iliff, Jeffrey J.; Lee, Hedok; Yu, Mei; Feng, Tian; Logan, Jean; Nedergaard, Maiken; Benveniste, Helene

2013-01-01

The glymphatic system is a recently defined brain-wide paravascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange that facilitates efficient clearance of solutes and waste from the brain. CSF enters the brain along para-arterial channels to exchange with ISF, which is in turn cleared from the brain along para-venous pathways. Because soluble amyloid β clearance depends on glymphatic pathway function, we proposed that failure of this clearance system contributes to amyloid plaque deposition and Alzheimer’s disease progression. Here we provide proof of concept that glymphatic pathway function can be measured using a clinically relevant imaging technique. Dynamic contrast-enhanced MRI was used to visualize CSF-ISF exchange across the rat brain following intrathecal paramagnetic contrast agent administration. Key features of glymphatic pathway function were confirmed, including visualization of para-arterial CSF influx and molecular size-dependent CSF-ISF exchange. Whole-brain imaging allowed the identification of two key influx nodes at the pituitary and pineal gland recesses, while dynamic MRI permitted the definition of simple kinetic parameters to characterize glymphatic CSF-ISF exchange and solute clearance from the brain. We propose that this MRI approach may provide the basis for a wholly new strategy to evaluate Alzheimer’s disease susceptibility and progression in the live human brain. PMID:23434588

High-throughput analysis of sulfatides in cerebrospinal fluid using automated extraction and UPLC-MS/MS.

PubMed

Blomqvist, Maria; Borén, Jan; Zetterberg, Henrik; Blennow, Kaj; Månsson, Jan-Eric; Ståhlman, Marcus

2017-07-01

Sulfatides (STs) are a group of glycosphingolipids that are highly expressed in brain. Due to their importance for normal brain function and their potential involvement in neurological diseases, development of accurate and sensitive methods for their determination is needed. Here we describe a high-throughput oriented and quantitative method for the determination of STs in cerebrospinal fluid (CSF). The STs were extracted using a fully automated liquid/liquid extraction method and quantified using ultra-performance liquid chromatography coupled to tandem mass spectrometry. With the high sensitivity of the developed method, quantification of 20 ST species from only 100 μl of CSF was performed. Validation of the method showed that the STs were extracted with high recovery (90%) and could be determined with low inter- and intra-day variation. Our method was applied to a patient cohort of subjects with an Alzheimer's disease biomarker profile. Although the total ST levels were unaltered compared with an age-matched control group, we show that the ratio of hydroxylated/nonhydroxylated STs was increased in the patient cohort. In conclusion, we believe that the fast, sensitive, and accurate method described in this study is a powerful new tool for the determination of STs in clinical as well as preclinical settings. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis

PubMed Central

Piccoli, Luca; Campo, Ilaria; Fregni, Chiara Silacci; Rodriguez, Blanca Maria Fernandez; Minola, Andrea; Sallusto, Federica; Luisetti, Maurizio; Corti, Davide; Lanzavecchia, Antonio

2015-01-01

Pulmonary alveolar proteinosis (PAP) is a severe autoimmune disease caused by autoantibodies that neutralize GM-CSF resulting in impaired function of alveolar macrophages. In this study, we characterize 21 GM-CSF autoantibodies from PAP patients and find that somatic mutations critically determine their specificity for the self-antigen. Individual antibodies only partially neutralize GM-CSF activity using an in vitro bioassay, depending on the experimental conditions, while, when injected in mice together with human GM-CSF, they lead to the accumulation of a large pool of circulating GM-CSF that remains partially bioavailable. In contrast, a combination of three non-cross-competing antibodies completely neutralizes GM-CSF activity in vitro by sequestering the cytokine in high-molecular-weight complexes, and in vivo promotes the rapid degradation of GM-CSF-containing immune complexes in an Fc-dependent manner. Taken together, these findings provide a plausible explanation for the severe phenotype of PAP patients and for the safety of treatments based on single anti-GM-CSF monoclonal antibodies. PMID:26077231

TALEN-mediated functional correction of human iPSC-derived macrophages in context of hereditary pulmonary alveolar proteinosis.

PubMed

Kuhn, Alexandra; Ackermann, Mania; Mussolino, Claudio; Cathomen, Toni; Lachmann, Nico; Moritz, Thomas

2017-11-09

Hereditary pulmonary alveolar proteinosis (herPAP) constitutes a rare, life threatening lung disease characterized by the inability of alveolar macrophages to clear the alveolar airspaces from surfactant phospholipids. On a molecular level, the disorder is defined by a defect in the CSF2RA gene coding for the GM-CSF receptor alpha-chain (CD116). As therapeutic options are limited, we currently pursue a cell and gene therapy approach aiming for the intrapulmonary transplantation of gene-corrected macrophages derived from herPAP-specific induced pluripotent stem cells (herPAP-iPSC) employing transcriptional activator-like effector nucleases (TALENs). Targeted insertion of a codon-optimized CSF2RA-cDNA driven by the hybrid cytomegalovirus (CMV) early enhancer/chicken beta actin (CAG) promoter into the AAVS1 locus resulted in robust expression of the CSF2RA gene in gene-edited herPAP-iPSCs as well as thereof derived macrophages. These macrophages displayed typical morphology, surface phenotype, phagocytic and secretory activity, as well as functional CSF2RA expression verified by STAT5 phosphorylation and GM-CSF uptake studies. Thus, our study provides a proof-of-concept, that TALEN-mediated integration of the CSF2RA gene into the AAVS1 safe harbor locus in patient-specific iPSCs represents an efficient strategy to generate functionally corrected monocytes/macrophages, which in the future may serve as a source for an autologous cell-based gene therapy for the treatment of herPAP.

CSF tau and the CSF tau/ABeta ratio for the diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI).

PubMed

Ritchie, Craig; Smailagic, Nadja; Noel-Storr, Anna H; Ukoumunne, Obioha; Ladds, Emma C; Martin, Steven

2017-03-22

Research suggests that measurable change in cerebrospinal fluid (CSF) biomarkers occurs years in advance of the onset of clinical symptoms (Beckett 2010). In this review, we aimed to assess the ability of CSF tau biomarkers (t-tau and p-tau) and the CSF tau (t-tau or p-tau)/ABeta ratio to enable the detection of Alzheimer's disease pathology in patients with mild cognitive impairment (MCI). These biomarkers have been proposed as important in new criteria for Alzheimer's disease dementia that incorporate biomarker abnormalities. To determine the diagnostic accuracy of 1) CSF t-tau, 2) CSF p-tau, 3) the CSF t-tau/ABeta ratio and 4) the CSF p-tau/ABeta ratio index tests for detecting people with MCI at baseline who would clinically convert to Alzheimer's disease dementia or other forms of dementia at follow-up. The most recent search for this review was performed in January 2013. We searched MEDLINE (OvidSP), Embase (OvidSP), BIOSIS Previews (Thomson Reuters Web of Science), Web of Science Core Collection, including Conference Proceedings Citation Index (Thomson Reuters Web of Science), PsycINFO (OvidSP), and LILACS (BIREME). We searched specialized sources of diagnostic test accuracy studies and reviews. We checked reference lists of relevant studies and reviews for additional studies. We contacted researchers for possible relevant but unpublished data. We did not apply any language or data restriction to the electronic searches. We did not use any methodological filters as a method to restrict the search overall. We selected those studies that had prospectively well-defined cohorts with any accepted definition of MCI and with CSF t-tau or p-tau and CSF tau (t-tau or p-tau)/ABeta ratio values, documented at or around the time the MCI diagnosis was made. We also included studies which looked at data from those cohorts retrospectively, and which contained sufficient data to construct two by two tables expressing those biomarker results by disease status. Moreover, studies were only selected if they applied a reference standard for Alzheimer's disease dementia diagnosis, for example, the NINCDS-ADRDA or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. We screened all titles generated by the electronic database searches. Two review authors independently assessed the abstracts of all potentially relevant studies, and the full papers for eligibility. Two independent assessors performed data extraction and quality assessment. Where data allowed, we derived estimates of sensitivity at fixed values of specificity from the model we fitted to produce the summary receiver operating characteristic (ROC) curve. In total, 1282 participants with MCI at baseline were identified in the 15 included studies of which 1172 had analysable data; 430 participants converted to Alzheimer's disease dementia and 130 participants to other forms of dementia. Follow-up ranged from less than one year to over four years for some participants, but in the majority of studies was in the range one to three years. Conversion to Alzheimer's disease dementia The accuracy of the CSF t-tau was evaluated in seven studies (291 cases and 418 non-cases).The sensitivity values ranged from 51% to 90% while the specificity values ranged from 48% to 88%. At the median specificity of 72%, the estimated sensitivity was 75% (95% CI 67 to 85), the positive likelihood ratio was 2.72 (95% CI 2.43 to 3.04), and the negative likelihood ratio was 0.32 (95% CI 0.22 to 0.47).Six studies (164 cases and 328 non-cases) evaluated the accuracy of the CSF p-tau. The sensitivities were between 40% and 100% while the specificities were between 22% and 86%. At the median specificity of 47.5%, the estimated sensitivity was 81% (95% CI: 64 to 91), the positive likelihood ratio was 1.55 (CI 1.31 to 1.84), and the negative likelihood ratio was 0.39 (CI: 0.19 to 0.82).Five studies (140 cases and 293 non-cases) evaluated the accuracy of the CSF p-tau/ABeta ratio. The sensitivities were between 80% and 96% while the specificities were between 33% and 95%. We did not conduct a meta-analysis because the studies were few and small. Only one study reported the accuracy of CSF t-tau/ABeta ratio.Our findings are based on studies with poor reporting. A significant number of studies had unclear risk of bias for the reference standard, participant selection and flow and timing domains. According to the assessment of index test domain, eight of 15 studies were of poor methodological quality.The accuracy of these CSF biomarkers for 'other dementias' had not been investigated in the included primary studies. Investigation of heterogeneity The main sources of heterogeneity were thought likely to be reference standards used for the target disorders, sources of recruitment, participant sampling, index test methodology and aspects of study quality (particularly, inadequate blinding).We were not able to formally assess the effect of each potential source of heterogeneity as planned, due to the small number of studies available to be included. The insufficiency and heterogeneity of research to date primarily leads to a state of uncertainty regarding the value of CSF testing of t-tau, p-tau or p-tau/ABeta ratio for the diagnosis of Alzheimer's disease in current clinical practice. Particular attention should be paid to the risk of misdiagnosis and overdiagnosis of dementia (and therefore over-treatment) in clinical practice. These tests, like other biomarker tests which have been subject to Cochrane DTA reviews, appear to have better sensitivity than specificity and therefore might have greater utility in ruling out Alzheimer's disease as the aetiology to the individual's evident cognitive impairment, as opposed to ruling it in. The heterogeneity observed in the few studies awaiting classification suggests our initial summary will remain valid. However, these tests may have limited clinical value until uncertainties have been addressed. Future studies with more uniformed approaches to thresholds, analysis and study conduct may provide a more homogenous estimate than the one that has been available from the included studies we have identified.

Which AML subsets benefit from leukemic cell priming during chemotherapy? Long-term analysis of the ALFA-9802 GM-CSF study.

PubMed

Thomas, Xavier; Raffoux, Emmanuel; Renneville, Aline; Pautas, Cecile; de Botton, Stephane; Terre, Christine; Gardin, Claude; Hayette, Sandrine; Preudhomme, Claude; Dombret, Herve

2010-04-01

: Priming with granulocytic hematopoietic growth factors may modulate cell cycle kinetics of leukemic cells and render them more susceptible to phase-specific chemotherapeutic agents. In a first report, we have shown that priming with granulocyte-macrophage colony-stimulating factor (GM-CSF) may enhance complete remission (CR) rate and event-free survival (EFS) in younger adults with acute myeloid leukemia (AML). : In this randomized trial, 259 patients with AML were randomized at baseline to receive or not receive GM-CSF concurrently with all cycles of chemotherapy. The effects of GM-CSF on survival were reported herein with a long-term follow-up and studied according to distinct biological subgroups defined on cytogenetics and molecular markers. : The EFS rate was better in the GM-CSF group (43% vs 34%; P = .04). GM-CSF did not improve the outcome in patients from good risk subgroups, while patients from poor risk subgroups benefited from GM-CSF therapy. In this population, the difference in terms of EFS probability was mainly observed in patients with high initial white blood cell count and in those with FLT3-ITD or MLL rearrangement. When combining these 2 molecular abnormalities for comparison of the effect of GM-CSF priming, the difference in terms of EFS was highly significant (5-year EFS, 39% with GM-CSF vs 8% without GM-CSF; P = .007). : Sensitization of leukemic cells and their progenitors by GM-CSF appears as a plausible strategy for improving the outcome of patients with newly diagnosed AML. Patients with poor-prognosis FLT3-ITD or MLL rearrangement might be a good target population to further investigate priming strategies. Cancer 2010. (c) 2010 American Cancer Society.

Measurement of peak CSF flow velocity at cerebral aqueduct, before and after lumbar CSF drainage, by use of phase-contrast MRI: utility in the management of idiopathic normal pressure hydrocephalus.

PubMed

Sharma, Ashwani Kumar; Gaikwad, Shailesh; Gupta, Vipul; Garg, Ajay; Mishra, Nalini K

2008-04-01

Since it was first described, normal pressure hydrocephalus (NPH) and its treatment by means of cerebrospinal fluid (CSF) shunting have been the focus of much investigation. Whatever be the cause of NPH, it has been hypothesized that in this disease there occurs decreased arterial expansion and an increased brain expansion leading to increased transmantle pressure. We cannot measure the latter, but fortunately the effect of these changes (increased peak flow velocity through the aqueduct) can be quantified with cine phase-contrast magnetic resonance imaging (MRI). This investigation was thus undertaken to characterize and measure CSF peak flow velocity at the level of the aqueduct, before and after lumbar CSF drainage, by means of a phase-contrast cine MRI and determine its role in selecting cases for shunt surgery. 37 patients with clinically suspected NPH were included in the study. Changes in the hyperdynamic peak CSF flow velocity with 50 ml lumbar CSF drainage (mimicking shunt) were evaluated in them for considering shunt surgery. 14 out of 15 patients who were recommended for shunt surgery, based on changes peak flow velocity after lumbar CSF drainage, improved after shunt surgery. None of the cases which were not recommended for shunt surgery, based on changes in CSF peak flow velocity after lumbar CSF drainage, improved after shunt surgery (2 out of 22 cases). The study concluded that the phase-contrast MR imaging, done before and after CSF drainage, is a sensitive method to support the clinical diagnosis of normal pressure hydrocephalus, selecting patients of NPH who are likely to benefit from shunt surgery, and to select patients of NPH who are not likely to benefit from shunt surgery.

Multimodal Classification of Alzheimer’s Disease and Mild Cognitive Impairment

PubMed Central

Zhang, Daoqiang; Wang, Yaping; Zhou, Luping; Yuan, Hong; Shen, Dinggang

2011-01-01

Effective and accurate diagnosis of Alzheimer’s disease (AD), as well as its prodromal stage (i.e., mild cognitive impairment (MCI)), has attracted more and more attentions recently. So far, multiple biomarkers have been shown sensitive to the diagnosis of AD and MCI, i.e., structural MR imaging (MRI) for brain atrophy measurement, functional imaging (e.g., FDG-PET) for hypometabolism quantification, and cerebrospinal fluid (CSF) for quantification of specific proteins. However, most existing research focuses on only a single modality of biomarkers for diagnosis of AD and MCI, although recent studies have shown that different biomarkers may provide complementary information for diagnosis of AD and MCI. In this paper, we propose to combine three modalities of biomarkers, i.e., MRI, FDG-PET, and CSF biomarkers, to discriminate between AD (or MCI) and healthy controls, using a kernel combination method. Specifically, ADNI baseline MRI, FDG-PET, and CSF data from 51 AD patients, 99 MCI patients (including 43 MCI converters who had converted to AD within 18 months and 56 MCI non-converters who had not converted to AD within 18 months), and 52 healthy controls are used for development and validation of our proposed multimodal classification method. In particular, for each MR or FDG-PET image, 93 volumetric features are extracted from the 93 regions of interest (ROIs), automatically labeled by an atlas warping algorithm. For CSF biomarkers, their original values are directly used as features. Then, a linear support vector machine (SVM) is adopted to evaluate the classification accuracy, using a 10-fold cross-validation. As a result, for classifying AD from healthy controls, we achieve a classification accuracy of 93.2% (with a sensitivity of 93% and a specificity of 93.3%) when combining all three modalities of biomarkers, and only 86.5% when using even the best individual modality of biomarkers. Similarly, for classifying MCI from healthy controls, we achieve a classification accuracy of 76.4% (with a sensitivity of 81.8% and a specificity of 66%) for our combined method, and only 72% even using the best individual modality of biomarkers. Further analysis on MCI sensitivity of our combined method indicates that 91.5% of MCI converters and 73.4% of MCI non-converters are correctly classified. Moreover, we also evaluate the classification performance when employing a feature selection method to select the most discriminative MR and FDG-PET features. Again, our combined method shows considerably better performance, compared to the case of using an individual modality of biomarkers. PMID:21236349

Evaluation and comparison of an indirect fluorescent antibody test for detection of antibodies to Sarcocystis neurona, using serum and cerebrospinal fluid of naturally and experimentally infected, and vaccinated horses.

PubMed

Duarte, Paulo C; Daft, Barbara M; Conrad, Patricia A; Packham, Andrea E; Saville, William J; MacKay, Robert J; Barr, Bradd C; Wilson, W David; Ng, Terry; Reed, Stephen M; Gardner, Ian A

2004-04-01

The objectives of this study were to evaluate the accuracy of the indirect fluorescent antibody test (IFAT) using serum and cerebrospinal fluid (CSF) of horses naturally and experimentally infected with Sarcocystis neurona, to assess the correlation between serum and CSF titers, and to determine the effect of S. neurona vaccination on the diagnosis of infection. Using receiver-operating characteristic analysis, the areas under the curve for the IFAT were 0.97 (serum) and 0.99 (CSF). Sensitivity and specificity were 83.3 and 96.9% (serum, cutoff 80) and 100 and 99% (CSF, cutoff 5), respectively. Titer-specific likelihood ratios (LRs) ranged from 0.03 to 187.8 for titers between <10 and 640. Median time to conversion was 22-26 days postinfection (DPI) (serum) and 30 DPI (CSF). The correlation between serum and CSF titers was moderately strong (r = 0.6) at 30 DPI. Percentage of vaccinated antibody-positive horses ranged from 0 to 95% between 0 and 112 days after the second vaccination. Thus, the IFAT was reliable and accurate using serum and CSF. Use of LRs potentially improves clinical decision making. Correlation between serum and CSF titers affects the joint accuracy of the IFAT; therefore, the ratio of serum to CSF titers has potential diagnostic value. The S. neurona vaccine could possibly interfere with equine protozoal myeloencephalitis diagnosis.

Utility of CSF Cytokine/Chemokines as Markers of Active Intrathecal Inflammation: Comparison of Demyelinating, Anti-NMDAR and Enteroviral Encephalitis

PubMed Central

Kothur, Kavitha; Wienholt, Louise; Mohammad, Shekeeb S.; Tantsis, Esther M.; Pillai, Sekhar; Britton, Philip N.; Jones, Cheryl A.; Angiti, Rajeshwar R.; Barnes, Elizabeth H.; Schlub, Timothy; Bandodkar, Sushil; Brilot, Fabienne; Dale, Russell C.

2016-01-01

Background Despite the discovery of CSF and serum diagnostic autoantibodies in autoimmune encephalitis, there are still very limited CSF biomarkers for diagnostic and monitoring purposes in children with inflammatory or autoimmune brain disease. The cause of encephalitis is unknown in up to a third of encephalitis cohorts, and it is important to differentiate infective from autoimmune encephalitis given the therapeutic implications. Aim To study CSF cytokines and chemokines as diagnostic biomarkers of active neuroinflammation, and assess their role in differentiating demyelinating, autoimmune, and viral encephalitis. Methods We measured and compared 32 cytokine/chemokines using multiplex immunoassay and APRIL and BAFF using ELISA in CSF collected prior to commencing treatment from paediatric patients with confirmed acute disseminated encephalomyelitis (ADEM, n = 16), anti-NMDAR encephalitis (anti-NMDAR E, n = 11), and enteroviral encephalitis (EVE, n = 16). We generated normative data using CSF from 20 non-inflammatory neurological controls. The sensitivity of CSF cytokine/chemokines to diagnose encephalitis cases was calculated using 95th centile of control values as cut off. We correlated CSF cytokine/chemokines with disease severity and follow up outcome based on modified Rankin scale. One-way hierarchical correlational cluster analysis of molecules was performed in different encephalitis and outcome groups. Results In descending order, CSF TNF-α, IL-10, IFN-α, IL-6, CXCL13 and CXCL10 had the best sensitivity (>79.1%) when all encephalitis patients were included. The combination of IL-6 and IFN-α was most predictive of inflammation on multiple logistic regression with area under the ROC curve 0.99 (CI 0.97–1.00). There were no differences in CSF cytokine concentrations between EVE and anti-NMDAR E, whereas ADEM showed more pronounced elevation of Th17 related (IL-17, IL-21) and Th2 (IL-4, CCL17) related cytokine/chemokines. Unlike EVE, heat map analysis showed similar clustering of cytokine/chemokine molecules in immune mediated encephalitis (ADEM and anti-NMDAR E). Th1 and B cell (CXCL13 and CXCL10) molecules clustered together in patients with severe encephalopathy at admission and worse disability at follow up in all encephalitis. There was no correlation between CSF neopterin and IFN-γ or IFN-α. Conclusion A combination panel of cytokine/chemokines consisting of CSF TNF-α, IL-10, IFN-α, IL-6, CXCL13 and CXCL10 measured using multiplex immunoassay may be used to diagnose and monitor intrathecal inflammation in the brain. Given their association with worse outcome, certain key chemokines (CXCL13, CXCL10) could represent potential therapeutic targets in encephalitis. PMID:27575749

Low levels of HIV-1 RNA detected in the cerebrospinal fluid after up to 10 years of suppressive therapy are associated with local immune activation

PubMed Central

Dahl, Viktor; Peterson, Julia; Fuchs, Dietmar; Gisslen, Magnus; Palmer, Sarah; Price, Richard W.

2015-01-01

Objective and design Though combination antiretroviral therapy reduces the concentration of HIV-1 RNA in both plasma and cerebrospinal fluid (CSF) below the detection limit of clinical assays, low levels of HIV-1 RNA are frequently detectable in plasma using more sensitive assays. We examined the frequency and magnitude of persistent low-level HIV-1 RNA in CSF and its relation to the central nervous system (CNS) immune activation. Methods CSF and plasma HIV-1 RNA were measured using the single-copy assay with a detection limit of 0.3 copies/ml in 70 CSF and 68 plasma samples from 45 treated HIV-1-infected patients with less than 40 copies/ml of HIV-1 RNA in both fluids by standard clinical assays. We also measured CSF neopterin to assess intrathecal immune activation. Theoretical drug exposure was estimated using the CNS penetration-efficacy score of treatment regimens. Results CSF HIV-1 RNA was detected in 12 of the 70 CSF samples (17%) taken after up to 10 years of suppressive therapy, compared to 39 of the 68 plasma samples (57%) with a median concentration of less than 0.3 copies/ml in CSF compared to 0.3 copies/ml in plasma (P <0.0001). CSF samples with detectable HIV-1 RNA had higher CSF neopterin levels (mean 8.2 compared to 5.7 nmol/l; P =0.0085). Patients with detectable HIV-1 RNA in CSF did not differ in pretreatment plasma HIV-1 RNA levels, nadir CD4+ cell count or CNS penetration-efficacy score. Conclusion Low-level CSF HIV-1 RNA and its association with elevated CSF neopterin highlight the potential for the CNS to serve as a viral reservoir and for persistent infection to cause subclinical CNS injury. PMID:25022595

Low levels of HIV-1 RNA detected in the cerebrospinal fluid after up to 10 years of suppressive therapy are associated with local immune activation.

PubMed

Dahl, Viktor; Peterson, Julia; Fuchs, Dietmar; Gisslen, Magnus; Palmer, Sarah; Price, Richard W

2014-09-24

Though combination antiretroviral therapy reduces the concentration of HIV-1 RNA in both plasma and cerebrospinal fluid (CSF) below the detection limit of clinical assays, low levels of HIV-1 RNA are frequently detectable in plasma using more sensitive assays. We examined the frequency and magnitude of persistent low-level HIV-1 RNA in CSF and its relation to the central nervous system (CNS) immune activation. CSF and plasma HIV-1 RNA were measured using the single-copy assay with a detection limit of 0.3 copies/ml in 70 CSF and 68 plasma samples from 45 treated HIV-1-infected patients with less than 40 copies/ml of HIV-1 RNA in both fluids by standard clinical assays. We also measured CSF neopterin to assess intrathecal immune activation. Theoretical drug exposure was estimated using the CNS penetration-efficacy score of treatment regimens. CSF HIV-1 RNA was detected in 12 of the 70 CSF samples (17%) taken after up to 10 years of suppressive therapy, compared to 39 of the 68 plasma samples (57%) with a median concentration of less than 0.3 copies/ml in CSF compared to 0.3 copies/ml in plasma (P < 0.0001). CSF samples with detectable HIV-1 RNA had higher CSF neopterin levels (mean 8.2 compared to 5.7 nmol/l; P = 0.0085). Patients with detectable HIV-1 RNA in CSF did not differ in pretreatment plasma HIV-1 RNA levels, nadir CD4 cell count or CNS penetration-efficacy score. Low-level CSF HIV-1 RNA and its association with elevated CSF neopterin highlight the potential for the CNS to serve as a viral reservoir and for persistent infection to cause subclinical CNS injury.

Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung

PubMed Central

Willinger, Tim; Rongvaux, Anthony; Takizawa, Hitoshi; Yancopoulos, George D.; Valenzuela, David M.; Murphy, Andrew J.; Auerbach, Wojtek; Eynon, Elizabeth E.; Stevens, Sean; Manz, Markus G.; Flavell, Richard A.

2011-01-01

Mice with a functional human immune system have the potential to allow in vivo studies of human infectious diseases and to enable vaccine testing. To this end, mice need to fully support the development of human immune cells, allow infection with human pathogens, and be capable of mounting effective human immune responses. A major limitation of humanized mice is the poor development and function of human myeloid cells and the absence of human immune responses at mucosal surfaces, such as the lung. To overcome this, we generated human IL-3/GM-CSF knock-in (hIL-3/GM-CSF KI) mice. These mice faithfully expressed human GM-CSF and IL-3 and developed pulmonary alveolar proteinosis because of elimination of mouse GM-CSF. We demonstrate that hIL-3/GM-CSF KI mice engrafted with human CD34+ hematopoietic cells had improved human myeloid cell reconstitution in the lung. In particular, hIL-3/GM-CSF KI mice supported the development of human alveolar macrophages that partially rescued the pulmonary alveolar proteinosis syndrome. Moreover, human alveolar macrophages mounted correlates of a human innate immune response against influenza virus. The hIL-3/GM-CSF KI mice represent a unique mouse model that permits the study of human mucosal immune responses to lung pathogens. PMID:21262803

Cortisol inhibits CSF2 and CSF3 via DNA methylation and inhibits invasion in first-trimester trophoblast cells

PubMed Central

Smith, Arianna; Witte, Elizabeth; McGee, Devin; Knott, Jason; Narang, Kavita; Racicot, Karen

2018-01-01

Problem Heightened maternal stress affects trophoblast function and increases risk for adverse pregnancy outcomes. Methods of Study Studies were performed using the first-trimester trophoblast cell line, Sw.71. Cytokines were quantified using qPCR and ELISA. Epigenetic regulation of cytokines was characterized by inhibiting histone deacetylation (1 μmol/L suberoylanilide hydroxamic acid [SAHA]) or methylation (5 μmol/L 5-azacytidine), or with chromatin immunoprecipitation (ChIP) with a pan-acetyl histone-3 antibody. Invasion assays used Matrigel chambers. Results Cortisol inhibited expression of CSF2 (GM-CSF) and CSF3 (G-CSF) in trophoblast cells. Cortisol-associated inhibition was dependent on DNA methylation and was not affected by acetylation. There was also a modest decrease in trophoblast invasion, not dependent on loss of CSFs. Conclusion In first-trimester trophoblast cells, the physiological glucocorticoid, cortisol, inhibited two cytokines with roles in placental development and decreased trophoblast invasion. Cortisol-associated changes in trophoblast function could increase the risk for immune-mediated abortion or other adverse pregnancy outcomes. PMID:28846166

Flutamide and biomarkers in women at high risk for ovarian cancer: preclinical and clinical evidence.

PubMed

Gruessner, Christine; Gruessner, Angelika; Glaser, Katherine; AbuShahin, Nisreen; Zhou, Yi; Laughren, Cynthia; Wright, Heather; Pinkerton, Samantha; Yi, Xiaofang; Stoffer, Jha'nae; Azodi, Masoud; Zheng, Wenxin; Chambers, Setsuko K

2014-09-01

We hypothesized that (i) preclinical biologic evidence exists for the role of androgens in ovarian cancer development and (ii) flutamide treatment of women at high risk for ovarian cancer may identify meaningful tissue biomarkers of androgen action and of ovarian cancer initiation. We showed that androgen ablation of male mice led to a 24-fold decrease in tumor burden from serous ovarian cells. In a phase II study, we studied the effect of preoperative flutamide treatment (125 mg/day × 6 weeks) in 12 women versus 47 controls, 47% with BRCA mutation. We analyzed immunohistochemical scores of candidate proteins CSF-1, CSF-1R, and ErbB4 in the epithelium and stroma of fallopian tube, ovary, and ovarian endosalpingiosis. Flutamide decreased the levels, notably, of CSF-1 and ErbB4 in ovarian stroma (P ≤ 0.0006) and ovarian endosalpingiosis (P ≤ 0.01), ErbB4 in ovarian epithelium (P = 0.006), and CSF-1R in ovarian endosalpingiosis (P = 0.009). Our logistic regression model clearly distinguished the flutamide patients from controls (P ≤ 0.0001). Our analysis of the precision of this model of CSF-1 and ErbB4 expression in ovarian stroma achieved 100% sensitivity and 97% specificity (AUC = 0.99). Thus, our data suggest that a short 6-week exposure of flutamide reversed elevated levels of CSF-1 and ErbB4 (both of which we had previously found correlated with high risk status). CSF-1 and ErbB4 in ovarian stroma led to a model with high predictive value for flutamide sensitivity. The effect of flutamide on marker expression in ovarian endosalpingiosis, previously associated with BRCA carrier status, suggests that ovarian endosalpingiosis may be a latent precursor to pelvic serous cancers. ©2014 American Association for Cancer Research.

Biomarker Evidence of Axonal Injury in Neuroasymptomatic HIV-1 Patients

PubMed Central

Price, Richard W.; Hagberg, Lars; Fuchs, Dietmar; Rosengren, Lars; Nilsson, Staffan; Zetterberg, Henrik; Gisslén, Magnus

2014-01-01

Background Prevalence of neurocognitive impairment in HIV-1 infected patients is reported to be high. Whether this is a result of active HIV-related neurodegeneration is unclear. We examined axonal injury in HIV-1 patients by measuring the light subunit of neurofilament protein (NFL) in CSF with a novel, sensitive method. Methods With a cross-sectional design, CSF concentrations of neurofilament protein light (NFL) (marker of neuronal injury), neopterin (intrathecal immunoactivation) and CSF/Plasma albumin ratio (blood-brain barrier integrity) were analyzed on CSF from 252 HIV-infected patients, subdivided into untreated neuroasymptomatics (n = 200), HIV-associated dementia (HAD) (n = 14) and on combinations antiretroviral treatment (cART) (n = 85), and healthy controls (n = 204). 46 HIV-infected patients were included in both treated and untreated groups, but sampled at different timepoints. Furthermore, 78 neuroasymptomatic patients were analyzed before and after treatment initiation. Results While HAD patients had the highest NFL concentrations, elevated CSF NFL was also found in 33% of untreated neuroasymptomatic patients, mainly in those with blood CD4+ cell counts below 250 cells/μL. CSF NFL concentrations in the untreated neuroasymptomatics and treated groups were equivalent to controls 18.5 and 3.9 years older, respectively. Neopterin correlated with NFL levels in untreated groups while the albumin ratio correlated with NFL in both untreated and treated groups. Conclusions Increased CSF NFL indicates ongoing axonal injury in many neuroasymptomatic patients. Treatment decreases NFL, but treated patients retain higher levels than controls, indicating either continued virus-related injury or an aging-like effect of HIV infection. NFL correlates with neopterin and albumin ratio, suggesting an association between axonal injury, neuroinflammation and blood-brain barrier permeability. NFL appears to be a sensitive biomarker of subclinical and clinical brain injury in HIV and warrants further assessment for broader clinical use. PMID:24523921

Development and validation of sensitive LC-MS/MS assays for quantification of HP-β-CD in human plasma and CSF

PubMed Central

Jiang, Hui; Sidhu, Rohini; Fujiwara, Hideji; De Meulder, Marc; de Vries, Ronald; Gong, Yong; Kao, Mark; Porter, Forbes D.; Yanjanin, Nicole M.; Carillo-Carasco, Nuria; Xu, Xin; Ottinger, Elizabeth; Woolery, Myra; Ory, Daniel S.; Jiang, Xuntian

2014-01-01

2-Hydroxypropyl-β-cyclodextrin (HP-β-CD), a widely used excipient for drug formulation, has emerged as an investigational new drug for the treatment of Niemann-Pick type C1 (NPC1) disease, a neurodegenerative cholesterol storage disorder. Development of a sensitive quantitative LC-MS/MS assay to monitor the pharmacokinetics (PKs) of HP-β-CD required for clinical trials has been challenging owing to the dispersity of the HP-β-CD. To support a phase 1 clinical trial for ICV delivery of HP-β-CD in NPC1 patients, novel methods for quantification of HP-β-CD in human plasma and cerebrospinal fluid (CSF) using LC-MS/MS were developed and validated: a 2D-LC-in-source fragmentation-MS/MS (2D-LC-IF-MS/MS) assay and a reversed phase ultra performance LC-MS/MS (RP-UPLC-MS/MS) assay. In both assays, protein precipitation and “dilute and shoot” procedures were used to process plasma and CSF, respectively. The assays were fully validated and in close agreement, and allowed determination of PK parameters for HP-β-CD. The LC-MS/MS methods are ∼100-fold more sensitive than the current HPLC assay, and were successfully employed to analyze HP-β-CD in human plasma and CSF samples to support the phase 1 clinical trial of HP-β-CD in NPC1 patients. PMID:24868096

Development and validation of sensitive LC-MS/MS assays for quantification of HP-β-CD in human plasma and CSF.

PubMed

Jiang, Hui; Sidhu, Rohini; Fujiwara, Hideji; De Meulder, Marc; de Vries, Ronald; Gong, Yong; Kao, Mark; Porter, Forbes D; Yanjanin, Nicole M; Carillo-Carasco, Nuria; Xu, Xin; Ottinger, Elizabeth; Woolery, Myra; Ory, Daniel S; Jiang, Xuntian

2014-07-01

2-Hydroxypropyl-β-cyclodextrin (HP-β-CD), a widely used excipient for drug formulation, has emerged as an investigational new drug for the treatment of Niemann-Pick type C1 (NPC1) disease, a neurodegenerative cholesterol storage disorder. Development of a sensitive quantitative LC-MS/MS assay to monitor the pharmacokinetics (PKs) of HP-β-CD required for clinical trials has been challenging owing to the dispersity of the HP-β-CD. To support a phase 1 clinical trial for ICV delivery of HP-β-CD in NPC1 patients, novel methods for quantification of HP-β-CD in human plasma and cerebrospinal fluid (CSF) using LC-MS/MS were developed and validated: a 2D-LC-in-source fragmentation-MS/MS (2D-LC-IF-MS/MS) assay and a reversed phase ultra performance LC-MS/MS (RP-UPLC-MS/MS) assay. In both assays, protein precipitation and "dilute and shoot" procedures were used to process plasma and CSF, respectively. The assays were fully validated and in close agreement, and allowed determination of PK parameters for HP-β-CD. The LC-MS/MS methods are ∼100-fold more sensitive than the current HPLC assay, and were successfully employed to analyze HP-β-CD in human plasma and CSF samples to support the phase 1 clinical trial of HP-β-CD in NPC1 patients. Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.

MRI-based noninvasive measurement of intracranial compliance derived from the relationship between transcranial blood and cerebrospinal fluid flows: modeling vs. direct approach

NASA Astrophysics Data System (ADS)

Tain, Rong-Wen; Alperin, Noam

2008-03-01

Intracranial compliance (ICC) determines the ability of the intracranial space to accommodate increase in volume (e.g., brain swelling) without a large increase in intracranial pressure (ICP). Therefore, measurement of ICC is potentially important for diagnosis and guiding treatment of related neurological problems. Modeling based approach uses an assumed lumped-parameter model of the craniospinal system (CSS) (e.g., RCL circuit), with either the arterial or the net transcranial blood flow (arterial inflow minus venous outflow) as input and the cranio-spinal cerebrospinal fluid (CSF) flow as output. The phase difference between the output and input is then often used as a measure of ICC However, it is not clear whether there is a predetermined relationship between ICC and the phase difference between these waveforms. A different approach for estimation of ICC has been recently proposed. This approach estimates ICC from the ratio of the intracranial volume and pressure changes that occur naturally with each heartbeat. The current study evaluates the sensitivity of the phase-based and the direct approach to changes in ICC. An RLC circuit model of the cranio-spinal system is used to simulate the cranio-spinal CSF flow for 3 different ICC states using the transcranial blood flows measured by MRI phase contrast from healthy human subjects. The effect of the increase in the ICC on the magnitude and phase response is calculated from the system's transfer function. We observed that within the heart rate frequency range, changes in ICC predominantly affected the amplitude of CSF pulsation and less so the phases. The compliance is then obtained for the different ICC states using the direct approach. The measures of compliance calculated using the direct approach demonstrated the highest sensitivity for changes in ICC. This work explains why phase shift based measure of ICC is less sensitive than amplitude based measures such as the direct approach method.

A novel Bayesian approach to accounting for uncertainty in fMRI-derived estimates of cerebral oxygen metabolism fluctuations

PubMed Central

Simon, Aaron B.; Dubowitz, David J.; Blockley, Nicholas P.; Buxton, Richard B.

2016-01-01

Calibrated blood oxygenation level dependent (BOLD) imaging is a multimodal functional MRI technique designed to estimate changes in cerebral oxygen metabolism from measured changes in cerebral blood flow and the BOLD signal. This technique addresses fundamental ambiguities associated with quantitative BOLD signal analysis; however, its dependence on biophysical modeling creates uncertainty in the resulting oxygen metabolism estimates. In this work, we developed a Bayesian approach to estimating the oxygen metabolism response to a neural stimulus and used it to examine the uncertainty that arises in calibrated BOLD estimation due to the presence of unmeasured model parameters. We applied our approach to estimate the CMRO2 response to a visual task using the traditional hypercapnia calibration experiment as well as to estimate the metabolic response to both a visual task and hypercapnia using the measurement of baseline apparent R2′ as a calibration technique. Further, in order to examine the effects of cerebral spinal fluid (CSF) signal contamination on the measurement of apparent R2′, we examined the effects of measuring this parameter with and without CSF-nulling. We found that the two calibration techniques provided consistent estimates of the metabolic response on average, with a median R2′-based estimate of the metabolic response to CO2 of 1.4%, and R2′- and hypercapnia-calibrated estimates of the visual response of 27% and 24%, respectively. However, these estimates were sensitive to different sources of estimation uncertainty. The R2′-calibrated estimate was highly sensitive to CSF contamination and to uncertainty in unmeasured model parameters describing flow-volume coupling, capillary bed characteristics, and the iso-susceptibility saturation of blood. The hypercapnia-calibrated estimate was relatively insensitive to these parameters but highly sensitive to the assumed metabolic response to CO2. PMID:26790354

A novel Bayesian approach to accounting for uncertainty in fMRI-derived estimates of cerebral oxygen metabolism fluctuations.

PubMed

Simon, Aaron B; Dubowitz, David J; Blockley, Nicholas P; Buxton, Richard B

2016-04-01

Calibrated blood oxygenation level dependent (BOLD) imaging is a multimodal functional MRI technique designed to estimate changes in cerebral oxygen metabolism from measured changes in cerebral blood flow and the BOLD signal. This technique addresses fundamental ambiguities associated with quantitative BOLD signal analysis; however, its dependence on biophysical modeling creates uncertainty in the resulting oxygen metabolism estimates. In this work, we developed a Bayesian approach to estimating the oxygen metabolism response to a neural stimulus and used it to examine the uncertainty that arises in calibrated BOLD estimation due to the presence of unmeasured model parameters. We applied our approach to estimate the CMRO2 response to a visual task using the traditional hypercapnia calibration experiment as well as to estimate the metabolic response to both a visual task and hypercapnia using the measurement of baseline apparent R2' as a calibration technique. Further, in order to examine the effects of cerebral spinal fluid (CSF) signal contamination on the measurement of apparent R2', we examined the effects of measuring this parameter with and without CSF-nulling. We found that the two calibration techniques provided consistent estimates of the metabolic response on average, with a median R2'-based estimate of the metabolic response to CO2 of 1.4%, and R2'- and hypercapnia-calibrated estimates of the visual response of 27% and 24%, respectively. However, these estimates were sensitive to different sources of estimation uncertainty. The R2'-calibrated estimate was highly sensitive to CSF contamination and to uncertainty in unmeasured model parameters describing flow-volume coupling, capillary bed characteristics, and the iso-susceptibility saturation of blood. The hypercapnia-calibrated estimate was relatively insensitive to these parameters but highly sensitive to the assumed metabolic response to CO2. Copyright © 2016 Elsevier Inc. All rights reserved.

Pivotal Roles of GM-CSF in Autoimmunity and Inflammation

PubMed Central

Shiomi, Aoi; Usui, Takashi

2015-01-01

Granulocyte macrophage-colony stimulating factor (GM-CSF) is a hematopoietic growth factor, which stimulates the proliferation of granulocytes and macrophages from bone marrow precursor cells. In autoimmune and inflammatory diseases, Th17 cells have been considered as strong inducers of tissue inflammation. However, recent evidence indicates that GM-CSF has prominent proinflammatory functions and that this growth factor (not IL-17) is critical for the pathogenicity of CD4+ T cells. Therefore, the mechanism of GM-CSF-producing CD4+ T cell differentiation and the role of GM-CSF in the development of autoimmune and inflammatory diseases are gaining increasing attention. This review summarizes the latest knowledge of GM-CSF and its relationship with autoimmune and inflammatory diseases. The potential therapies targeting GM-CSF as well as their possible side effects have also been addressed in this review. PMID:25838639

Optimized Standard Operating Procedures for the Analysis of Cerebrospinal Fluid Aβ42 and the Ratios of Aβ Isoforms Using Low Protein Binding Tubes.

PubMed

Vanderstichele, Hugo Marcel Johan; Janelidze, Shorena; Demeyer, Leentje; Coart, Els; Stoops, Erik; Herbst, Victor; Mauroo, Kimberley; Brix, Britta; Hansson, Oskar

2016-05-31

Reduced cerebrospinal fluid (CSF) concentration of amyloid-β1-42 (Aβ1-42) reflects the presence of amyloidopathy in brains of subjects with Alzheimer's disease (AD). To qualify the use of Aβ1-42/Aβ1-40 for improvement of standard operating procedures (SOP) for measurement of CSF Aβ with a focus on CSF collection, storage, and analysis. Euroimmun ELISAs for CSF Aβ isoforms were used to set up a SOP with respect to recipient properties (low binding, polypropylene), volume of tubes, freeze/thaw cycles, addition of detergents (Triton X-100, Tween-20) in collection or storage tubes or during CSF analysis. Data were analyzed with linear repeated measures and mixed effects models. Optimization of CSF analysis included a pre-wash of recipients (e.g., tubes, 96-well plates) before sample analysis. Using the Aβ1-42/Aβ1-40 ratio, in contrast to Aβ1-42, eliminated effects of tube type, additional freeze/thaw cycles, or effect of CSF volumes for polypropylene storage tubes. 'Low binding' tubes reduced the loss of Aβ when aliquoting CSF or in function of additional freeze/thaw cycles. Addition of detergent in CSF collection tubes resulted in an almost complete absence of variation in function of collection procedures, but affected the concentration of Aβ isoforms in the immunoassay. The ratio of Aβ1-42/Aβ1-40 is a more robust biomarker than Aβ1-42 toward (pre-) analytical interfering factors. Further, 'low binding' recipients and addition of detergent in collection tubes are able to remove effects of SOP-related confounding factors. Integration of the Aβ1-42/Aβ1-40 ratio and 'low-binding tubes' into guidance criteria may speed up worldwide standardization of CSF biomarker analysis.

Effects of macrophage colony-stimulating factor on macrophages and their related cell populations in the osteopetrosis mouse defective in production of functional macrophage colony-stimulating factor protein.

PubMed Central

Umeda, S.; Takahashi, K.; Shultz, L. D.; Naito, M.; Takagi, K.

1996-01-01

The development of macrophage populations in osteopetrosis (op) mutant mice defective in production of functional macrophage colony-stimulating factor (M-CSF) and the response of these cell populations to exogenous M-CSF were used to classify macrophages into four groups: 1) monocytes, monocyte-derived macrophages, and osteoclasts, 2) MOMA-1-positive macrophages, 3) ER-TR9-positive macrophages, and 4) immature tissue macrophages. Monocytes, monocyte-derived macrophages, osteoclasts in bone, microglia in brain, synovial A cells, and MOMA-1- or ER-TR9-positive macrophages were deficient in op/op mice. The former three populations expanded to normal levels in op/op mice after daily M-CSF administration, indicating that they are developed and differentiated due to the effect of M-CSF supplied humorally. In contrast, the other cells did not respond or very slightly responded to M-CSF, and their development seems due to either M-CSF produced in situ or expression of receptor for M-CSF. Macrophages present in tissues of the mutant mice were immature and appear to be regulated by either granulocyte/macrophage colony-stimulating factor and/or interleukin-3 produced in situ or receptor expression. Northern blot analysis revealed different expressions of GM-CSF and IL-3 mRNA in various tissues of the op/op mice. However, granulocyte/macrophage colony-stimulating factor and interleukin-3 in serum were not detected by enzyme-linked immunosorbent assay. The immature macrophages differentiated and matured into resident macrophages after M-CSF administration, and some of these cells proliferated in response to M-CSF. Images Figure 4 Figure 6 Figure 8 Figure 10 Figure 11 PMID:8701995

A WAVE2-Abi1 complex mediates CSF-1-induced F-actin-rich membrane protrusions and migration in macrophages.

PubMed

Kheir, Wassim Abou; Gevrey, Jean-Claude; Yamaguchi, Hideki; Isaac, Beth; Cox, Dianne

2005-11-15

Colony-stimulating factor 1 (CSF-1) is an important physiological chemoattractant for macrophages. The mechanisms by which CSF-1 elicits the formation of filamentous actin (F-actin)-rich membrane protrusions and induces macrophage migration are not fully understood. In particular, very little is known regarding the contribution of the different members of the Wiskott-Aldrich Syndrome protein (WASP) family of actin regulators in response to CSF-1. Although a role for WASP itself in macrophage chemotaxis has been previously identified, no data was available regarding the function of WASP family verprolin-homologous (WAVE) proteins in this cell type. We found that WAVE2 was the predominant isoform to be expressed in primary macrophages and in cells derived from the murine monocyte/macrophage RAW264.7 cell line (RAW/LR5). CSF-1 treatment of macrophages resulted in WAVE2 accumulation in F-actin-rich protrusions induced by CSF-1. Inhibition of WAVE2 function by expressing a dominant-negative mutant or introducing anti-WAVE2 antibodies in RAW/LR5 cells, as well as reduction of endogenous WAVE2 expression by RNA-mediated interference (RNAi), resulted in a significant reduction of CSF-1-elicited F-actin protrusions. WAVE2 was found in a protein complex together with Abelson kinase interactor 1 (Abi1) in resting or stimulated cells. Both WAVE2 and Abi1 were recruited to and necessary for the formation of F-actin protrusions in response to CSF-1. Reducing the levels of WAVE2, directly or by targeting Abi1, resulted in an impaired cell migration to CSF-1. Altogether these data identify a WAVE2-Abi1 complex crucial for the normal actin cytoskeleton reorganization and migration of macrophages in response to CSF-1.

Combination of neurofilament heavy chain and complement c3 as CSF biomarkers for ALS

PubMed Central

Ganesalingam, Jeban; An, Jiyan; Shaw, Christopher E; Shaw, Gerry; Lacomis, David; Bowser, Robert

2011-01-01

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disease with an average survival of 3 years from symptom onset. Rapid and conclusive early diagnosis is essential if interventions with disease-modifying therapies are to be successful. Cytoskeletal modification and inflammation are known to occur during the pathogenesis of ALS. We measured levels of cytoskeletal proteins and inflammatory markers in the cerebrospinal fluid (CSF) of ALS, disease controls and healthy subjects. We determined threshold values for each protein that provided the optimal sensitivity and specificity for ALS within a training set, as determined by receiver operating characteristic (ROC) analysis. Interestingly, the optimal assay was a ratio of the levels for phosphorylated neurofilament heavy chain and complement C3 (pNFH/C3). We next applied this assay to a separate test set of CSF samples to verify our results. Overall, the predictive pNFH/C3 ratio identified ALS with 87.3% sensitivity and 94.6% specificity in a total of 71 ALS subjects, 52 disease control subjects and 40 healthy subjects. In addition, the level of CSF pNFH correlated with survival of ALS patients. We also detected increased pNFH in the plasma of ALS patients and observed a correlation between CSF and plasma pNFH levels within the same subjects. These findings support large-scale prospective biomarker studies to determine the clinical utility of diagnostic and prognostic signatures in ALS. PMID:21418221

A pilot study on the use of cerebrospinal fluid cell-free DNA in intramedullary spinal ependymoma.

PubMed

Connolly, Ian David; Li, Yingmei; Pan, Wenying; Johnson, Eli; You, Linya; Vogel, Hannes; Ratliff, John; Hayden Gephart, Melanie

2017-10-01

Cerebrospinal fluid (CSF) represents a promising source of cell-free DNA (cfDNA) for tumors of the central nervous system. A CSF-based liquid biopsy may obviate the need for riskier tissue biopsies and serve as a means for monitoring tumor recurrence or response to therapy. Spinal ependymomas most commonly occur in adults, and aggressive resection must be delicately balanced with the risk of injury to adjacent normal tissue. In patients with subtotal resection, recurrence commonly occurs. A CSF-based liquid biopsy matched to the patient's spinal ependymoma mutation profile has potential to be more sensitive then surveillance MRI, but the utility has not been well characterized for tumors of the spinal cord. In this study, we collected matched blood, tumor, and CSF samples from three adult patients with WHO grade II intramedullary spinal ependymoma. We performed whole exome sequencing on matched tumor and normal DNA to design Droplet Digital™ PCR (ddPCR) probes for tumor and wild-type mutations. We then interrogated CSF samples for tumor-derived cfDNA by performing ddPCR on extracted cfDNA. Tumor cfDNA was not reliably detected in the CSF of our cohort. Anatomic sequestration and low grade of intramedullary spinal cord tumors likely limits the role of CSF liquid biopsy.

Impact of round-the-clock CSF Gram stain on empirical therapy for suspected central nervous system infections.

PubMed

Tissot, F; Prod'hom, G; Manuel, O; Greub, G

2015-09-01

The impact of round-the-clock cerebrospinal fluid (CSF) Gram stain on overnight empirical therapy for suspected central nervous system (CNS) infections was investigated. All consecutive overnight CSF Gram stains between 2006 and 2011 were included. The impact of a positive or a negative test on empirical therapy was evaluated and compared to other clinical and biological indications based on institutional guidelines. Bacterial CNS infection was documented in 51/241 suspected cases. Overnight CSF Gram stain was positive in 24/51. Upon validation, there were two false-positive and one false-negative results. The sensitivity and specificity were 41 and 99 %, respectively. All patients but one had other indications for empirical therapy than Gram stain alone. Upon obtaining the Gram result, empirical therapy was modified in 7/24, including the addition of an appropriate agent (1), addition of unnecessary agents (3) and simplification of unnecessary combination therapy (3/11). Among 74 cases with a negative CSF Gram stain and without formal indication for empirical therapy, antibiotics were withheld in only 29. Round-the-clock CSF Gram stain had a low impact on overnight empirical therapy for suspected CNS infections and was associated with several misinterpretation errors. Clinicians showed little confidence in CSF direct examination for simplifying or withholding therapy before definite microbiological results.

Functional characterization of muscle fibres from patients with chronic fatigue syndrome: case-control study.

PubMed

Pietrangelo, T; Toniolo, L; Paoli, A; Fulle, S; Puglielli, C; Fanò, G; Reggiani, C

2009-01-01

Chronic fatigue syndrome (CFS) is a disabling condition characterized by unexplained chronic fatigue that impairs normal activities. Although immunological and psychological aspects are present, symptoms related to skeletal muscles, such as muscle soreness, fatigability and increased lactate accumulation, are prominent in CFS patients. In this case-control study, the phenotype of the same biopsy samples was analyzed by determining i) fibre-type proportion using myosin isoforms as fibre type molecular marker and gel electrophoresis as a tool to separate and quantify myosin isoforms, and ii) contractile properties of manually dissected, chemically made permeable and calcium-activated single muscle fibres. The results showed that fibre-type proportion was significantly altered in CSF samples, which showed a shift from the slow- to the fast-twitch phenotype. Cross sectional area, force, maximum shortening velocity and calcium sensitivity were not significantly changed in single muscle fibres from CSF samples. Thus, the contractile properties of muscle fibres were preserved but their proportion was changed, with an increase in the more fatigue-prone, energetically expensive fast fibre type. Taken together, these results support the view that muscle tissue is directly involved in the pathogenesis of CSF and it might contribute to the early onset of fatigue typical of the skeletal muscles of CFS patients.

Involvement of suppressors of cytokine signaling in toll-like receptor-mediated block of dendritic cell differentiation.

PubMed

Bartz, Holger; Avalos, Nicole M; Baetz, Andrea; Heeg, Klaus; Dalpke, Alexander H

2006-12-15

Dendritic cells (DCs) are important sentinels within innate immunity, monitoring the presence of infectious microorganisms. They operate in 2 different maturation stages, with transition from immature to mature DCs being induced by activation of toll-like receptors (TLRs). However, TLRs are also expressed on precursor cells of DCs. Here we analyzed the effects of TLR stimulation during the process of granulocyte-macrophage-colony-stimulating factor (GM-CSF)-mediated in vitro generation of immature DCs from precursor cells. We show that TLR triggering deviated phenotypic and functional differentiation from CD14+ monocytes to CD1a+ DCs. Similar results were obtained when differentiation of murine myeloid DCs from bone marrow cells was analyzed. The inhibitory effects were independent of soluble factors. TLR stimulation in DC precursor cells induced proteins of the suppressor of cytokine signaling family (SOCS), which correlated with loss of sensitivity to GM-CSF. Overexpression of SOCS-1 abolished GM-CSF signal transduction. Moreover, forced SOCS-1 expression in DC precursors mimicked the inhibitory effects on DC generation observed for TLR stimulation. The results indicate that TLR stimulation during the period of DC generation interferes with and deviates DC differentiation and that these effects are mediated particularly by SOCS-1.

Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status.

PubMed

Piccio, Laura; Deming, Yuetiva; Del-Águila, Jorge L; Ghezzi, Laura; Holtzman, David M; Fagan, Anne M; Fenoglio, Chiara; Galimberti, Daniela; Borroni, Barbara; Cruchaga, Carlos

2016-06-01

Low frequency coding variants in TREM2 are associated with increased Alzheimer disease (AD) risk, while loss of functions mutations in the gene lead to an autosomal recessive early-onset dementia, named Nasu-Hakola disease (NHD). TREM2 can be detected as a soluble protein in cerebrospinal fluid (CSF) and plasma, and its CSF levels are elevated in inflammatory CNS diseases. We measured soluble TREM2 (sTREM2) in the CSF of a large AD case-control dataset (n = 180) and 40 TREM2 risk variant carriers to determine whether CSF sTREM2 levels are associated with AD status or mutation status. We also performed genetic studies to identify genetic variants associated with CSF sTREM2 levels. CSF, but not plasma, sTREM2 was highly correlated with CSF total tau and phosphorylated-tau levels (r = 0.35, P < 1×10(-4); r = 0.40, P < 1×10(-4), respectively), but not with CSF Aβ42. AD cases presented higher CSF sTREM2 levels than controls (P = 0.01). Carriers of NHD-associated TREM2 variants presented significantly lower CSF sTREM2 levels, supporting the hypothesis that these mutations lead to reduced protein production/function (R136Q, D87N, Q33X or T66M; P = 1×10(-3)). In contrast, CSF sTREM2 levels were significantly higher in R47H carriers compared to non-carriers (P = 6×10(-3)), suggesting that this variant does not impact protein expression and increases AD risk through a different pathogenic mechanism than NHD variants. In GWAS analyses for CSF sTREM2 levels the most significant signal was located on the MS4A gene locus (P = 5.45 × 10(-07)) corresponding to one of the SNPs reported to be associated with AD risk in this locus. Furthermore, SNPs involved in pathways related to virus cellular entry and vesicular trafficking were overrepresented, suggesting that CSF sTREM2 levels could be an informative phenotype for AD.

Spectrophotometry of cerebrospinal fluid in subacute and chronic subdural haematomas

PubMed Central

Kjellin, K. G.; Steiner, L.

1974-01-01

Spectrophotometric examinations were performed on cerebrospinal and subdural fluids in subacute (five patients) and chronic (20 patients) subdural haematomas, with special reference to the diagnostic aid of CSF spectrophotometry. Spectrophotometric xanthochromia of haemorrhagic origin was found in all CSFs examined, while definite visible xanthochromia was observed in only 28% and the CSF was judged as colourless in 52% of those cases. Characteristic bleeding patterns were found spectrophotometrically in all the 20 CSFs examined within 24 hours after lumbar puncture, haematoma patterns being detected in 90-95% of the cases. In many cases the electrophoretically separated protein fractions of CSF and subdural fluids were spectrophotometrically examined. In conclusion, CSF spectrophotometry is a simple, fast, and extremely sensitive method, which in our opinion should be used routinely in the diagnosis of suspected subdural haematomas, if lumbar puncture is not contraindicated. PMID:4140892

Cerebrospinal Fluid Peptides as Potential Parkinson Disease Biomarkers: A Staged Pipeline for Discovery and Validation*

PubMed Central

Shi, Min; Movius, James; Dator, Romel; Aro, Patrick; Zhao, Yanchun; Pan, Catherine; Lin, Xiangmin; Bammler, Theo K.; Stewart, Tessandra; Zabetian, Cyrus P.; Peskind, Elaine R.; Hu, Shu-Ching; Quinn, Joseph F.; Galasko, Douglas R.; Zhang, Jing

2015-01-01

Finding robust biomarkers for Parkinson disease (PD) is currently hampered by inherent technical limitations associated with imaging or antibody-based protein assays. To circumvent the challenges, we adapted a staged pipeline, starting from our previous proteomic profiling followed by high-throughput targeted mass spectrometry (MS), to identify peptides in human cerebrospinal fluid (CSF) for PD diagnosis and disease severity correlation. In this multicenter study consisting of training and validation sets, a total of 178 subjects were randomly selected from a retrospective cohort, matching age and sex between PD patients, healthy controls, and neurological controls with Alzheimer disease (AD). From ∼14,000 unique peptides displaying differences between PD and healthy control in proteomic investigations, 126 peptides were selected based on relevance and observability in CSF using bioinformatic analysis and MS screening, and then quantified by highly accurate and sensitive selected reaction monitoring (SRM) in the CSF of 30 PD patients versus 30 healthy controls (training set), followed by diagnostic (receiver operating characteristics) and disease severity correlation analyses. The most promising candidates were further tested in an independent cohort of 40 PD patients, 38 AD patients, and 40 healthy controls (validation set). A panel of five peptides (derived from SPP1, LRP1, CSF1R, EPHA4, and TIMP1) was identified to provide an area under curve (AUC) of 0.873 (sensitivity = 76.7%, specificity = 80.0%) for PD versus healthy controls in the training set. The performance was essentially confirmed in the validation set (AUC = 0.853, sensitivity = 82.5%, specificity = 82.5%). Additionally, this panel could also differentiate the PD and AD groups (AUC = 0.990, sensitivity = 95.0%, specificity = 97.4%). Furthermore, a combination of two peptides belonging to proteins TIMP1 and APLP1 significantly correlated with disease severity as determined by the Unified Parkinson's Disease Rating Scale motor scores in both the training (r = 0.381, p = 0.038)j and the validation (r = 0.339, p = 0.032) sets. The novel panel of CSF peptides, if validated in independent cohorts, could be used to assist in clinical diagnosis of PD and has the potential to help monitoring or predicting disease progression. PMID:25556233

Assessment of the effector function of CMV-specific CTLs isolated using MHC-multimers from granulocyte-colony stimulating factor mobilized peripheral blood.

PubMed

Beloki, Lorea; Ciaurriz, Miriam; Mansilla, Cristina; Zabalza, Amaya; Perez-Valderrama, Estela; Samuel, Edward R; Lowdell, Mark W; Ramirez, Natalia; Olavarria, Eduardo

2015-05-20

Adoptive transfer of CMV-specific T cells has shown promising results in preventing pathological effects caused by opportunistic CMV infection in immunocompromised patients following allogeneic hematopoietic stem cell transplantation. The majority of studies have used steady-state leukapheresis for CMV-reactive product manufacture, a collection obtained prior to or months after G-CSF mobilization, but the procurement of this additional sample is often not available in the unrelated donor setting. If the cellular product for adoptive immunotherapy could be generated from the same G-CSF mobilized collection, the problems associated with the additional harvest could be overcome. Despite the tolerogenic effects associated with G-CSF mobilization, recent studies described that CMV-primed T cells generated from mobilized donors remain functional. MHC-multimers are potent tools that allow the rapid production of antigen-specific CTLs. Therefore, in the present study we have assessed the feasibility and efficacy of CMV-specific CTL manufacture from G-CSF mobilized apheresis using MHC-multimers. CMV-specific CTLs can be efficiently isolated from G-CSF mobilized samples with Streptamers and are able to express activation markers and produce cytokines in response to antigenic stimulation. However, this anti-viral functionality is moderately reduced when compared to non-mobilized products. The translation of Streptamer technology for the isolation of anti-viral CTLs from G-CSF mobilized PBMCs into clinical practice would widen the number of patients that could benefit from this therapeutic strategy, although our results need to be taken into consideration before the infusion of antigen-specific T cells obtained from G-CSF mobilized samples.

GM-CSF modulates autoantibody production and skin blistering in experimental epidermolysis bullosa acquisita.

PubMed

Samavedam, Unni Krishna S R L; Iwata, Hiroaki; Müller, Susen; Schulze, Franziska S; Recke, Andreas; Schmidt, Enno; Zillikens, Detlef; Ludwig, Ralf J

2014-01-15

GM-CSF activates hematopoietic cells and recruits neutrophils and macrophages to sites of inflammation. Inhibition of GM-CSF attenuates disease activity in models of chronic inflammatory disease. Effects of GM-CSF blockade were linked to modulation of the effector phase, whereas effects on early pathogenic events, for example, Ab production, have not been identified. To evaluate yet uncharacterized effects of GM-CSF on early pathogenic events in chronic inflammation, we employed immunization-induced epidermolysis bullosa acquisita (EBA), an autoimmune bullous disease caused by autoantibodies to type VII collagen. Compared to wild-type mice, upon immunization, GM-CSF(-/-) mice produced lower serum autoantibody titers, which were associated with reduced neutrophil numbers in draining lymph nodes. The same effect was observed in neutrophil-depleted wild-type mice. Neutrophil depletion in GM-CSF(-/-) mice led to a stronger inhibition, indicating that GM-CSF and neutrophils have additive functions. To characterize the contribution of GM-CSF specifically in the effector phase of EBA, disease was induced by transfer of anti-type VII collagen IgG into mice. We observed an increased GM-CSF expression, and GM-CSF blockade reduced skin blistering. Additionally, GM-CSF enhanced reactive oxygen species release and neutrophil migration in vitro. In immunization-induced murine EBA, treatment with anti-GM-CSF had a beneficial effect on established disease. We demonstrate that GM-CSF modulates both autoantibody production and skin blistering in a prototypical organ-specific autoimmune disease.

Evaluation of BioFM liquid medium for culture of cerebrospinal fluid in tuberculous meningitis to identify Mycobacterium tuberculosis.

PubMed

Kashyap, R S; Ramteke, S S; Gaherwar, H M; Deshpande, P S; Purohit, H J; Taori, G M; Daginawala, H

2010-01-01

The present study was designed to evaluate the sensitivity and specificity of liquid culture medium (BioFM broth) for the diagnosis of tuberculous meningitis (TBM) in cerebrospinal fluid (CSF). CSF samples from 200 patients (TBM group = 150 and non-TBM group = 50) were tested for culture of Mycobacterium tuberculosis in BioFM liquid culture medium. Out of 150 TBM cases, 120 were found to be culture positive, indicating a sensitivity of 80% in BioFM broth within 2-3 weeks of inoculation. Positive cultures were also observed for CSF from 32 (64%) out of 50 non-TBM patients in BioFM liquid culture medium within 4 days of sample inoculation. Therefore, according to our study, BioFM broth system yielded 80% sensitivity [95% confidence interval (CI): 67-93%] and 36% specificity (95% CI: 57-98%) for TBM diagnosis. Our results indicate that although BioFM broth allows the detection of positive cultures within a shorter time, it has a high potential for contamination or for the coexistence of M. tuberculosis and non-tuberculous meningitis (NTM). This coexistence may go undetected or potentially lead to erroneous reporting of results.

Use of granulocyte colony-stimulating factor: a survey among Italian medical oncologists.

PubMed

Danova, Marco; Rosti, Giovanni; De Placido, Sabino; Bencardino, Katia; Venturini, Marco

2005-12-01

In October 2003, the Italian Association of Medical Oncology (AIOM) published its own guidelines on the use of granulocyte colony-stimulating factor (G-CSF). The present survey was conducted during the same period with the aim of collecting data on the current use of G-CSF to provide a starting point for future evaluations of the implementation of AIOM guidelines. From October 2003 to January 2004, 1591 AIOM members were asked to complete a questionnaire based on specific clinical scenarios, regarding the use of G-CSF for primary and secondary prophylaxis and treatment of neutropenia. The rate of response was 22%. For primary prophylaxis, the majority of physicians avoid using G-CSF, with no difference in cases of adjuvant, curative or palliative chemotherapy (CT). In fact, 67.2% to 74.9% would 'rarely or never' use G-CSF in the proposed clinical scenarios. In chemosensitive tumors, rather than reducing CT doses, 55.7% would use G-CSF as a secondary prophylaxis after afebrile neutropenia (AN), and 68.8% after febrile neutropenia (FN). In elderly patients experiencing FN, 35.7% would reduce the adjuvant CT doses and 23.1% would change the regimen. Most oncologists would use G-CSF to treat neutropenia, and the median duration of G-CSF treatment is less than 1 week and would depend on neutrophil count. Our survey shows that Italian oncologists are particularly oriented towards the use of G-CSF in clinical practice to maintain the CT dose intensity, and are sensitive to the prevention and treatment of not only FN, but also AN. Finally, Italian medical oncologists appear to be very cautious in introducing G-CSF when treating elderly patients.

UPLC-MS/MS assay of riluzole in human plasma and cerebrospinal fluid (CSF): Application in samples from spinal cord injured patients.

PubMed

Sarkar, Mahua; Grossman, Robert G; Toups, Elizabeth G; Chow, Diana S-L

2017-11-30

In the present study, a sensitive and robust LC-MS/MS method has been developed and validated for the quantification of riluzole in human plasma and cerebrospinal fluid (CSF) in clinical samples from patients with spinal cord injury (SCI). Riluzole and its labeled internal standard (IS) were isolated from plasma and CSF by liquid-liquid extraction using ethyl acetate. Riluzole (m/z 235→166) and IS (m/z 238→169) were detected by electrospray ionization (ESI) using multiple reaction monitoring (MRM) in a positive mode. The assay was linear in the concentration range of 0.5 (LLOQ, signal/noise ratio>10)-800ng/ml in plasma, and 1.0 (LLOQ)-800ng/ml in CSF samples. The intra- and inter-day accuracy in plasma were 94.2-110.0% and 97.8-102.0%, respectively, and those in CSF were 87.6-105.1% and 91.9-98.8%, respectively. The intra- and inter-day precision were 2.2-7.2% and 4.0-9.1%, respectively, in plasma, and 1.4-14.1% and 2.6-11.5%, respectively in CSF. Matrix effect was negligible from both matrices with signal percentages of 97.6-100.6% in plasma and 99.4-106.4% in CSF. The recoveries were >75% in plasma, >84% in CSF with low protein (53.9mg/dl), and >68% in CSF with high protein (348.2mg/dl). This method was successfully applied to quantify riluzole concentrations in plasma and CSF from patients with SCI. Copyright © 2017 Elsevier B.V. All rights reserved.

A Customized Quantitative PCR MicroRNA Panel Provides a Technically Robust Context for Studying Neurodegenerative Disease Biomarkers and Indicates a High Correlation Between Cerebrospinal Fluid and Choroid Plexus MicroRNA Expression.

PubMed

Wang, Wang-Xia; Fardo, David W; Jicha, Gregory A; Nelson, Peter T

2017-12-01

MicroRNA (miRNA) expression varies in association with different tissue types and in diseases. Having been found in body fluids including blood and cerebrospinal fluid (CSF), miRNAs constitute potential biomarkers. CSF miRNAs have been proposed as biomarkers for neurodegenerative diseases; however, there is a lack of consensus about the best candidate miRNA biomarkers and there has been variability in results from different research centers, perhaps due to technical factors. Here, we sought to optimize technical parameters for CSF miRNA studies. We examined different RNA isolation methods and performed miRNA expression profiling with TaqMan® miRNA Arrays. More specifically, we developed a customized CSF-miRNA low-density array (TLDA) panel that contains 47 targets: miRNAs shown previously to be relevant to neurodegenerative disease, miRNAs that are abundant in CSF, data normalizers, and controls for potential blood and tissue contamination. The advantages of using this CSF-miRNA TLDA panel include specificity, sensitivity, fast processing and data analysis, and cost effectiveness. We optimized technical parameters for this assay. Further, the TLDA panel can be tailored to other specific purposes. We tested whether the profile of miRNAs in the CSF resembled miRNAs isolated from brain tissue (hippocampus or cerebellum), blood, or the choroid plexus. We found that the CSF miRNA expression profile most closely resembles that of choroid plexus tissue, underscoring the potential importance of choroid plexus-derived signaling through CSF miRNAs. In summary, the TLDA miRNA array panel will enable evaluation and discovery of CSF miRNA biomarkers and can potentially be utilized in clinical diagnosis and disease stage monitoring.

CSF-1 Receptor Signaling in Myeloid Cells

PubMed Central

Stanley, E. Richard; Chitu, Violeta

2014-01-01

The CSF-1 receptor (CSF-1R) is activated by the homodimeric growth factors colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34). It plays important roles in development and in innate immunity by regulating the development of most tissue macrophages and osteoclasts, of Langerhans cells of the skin, of Paneth cells of the small intestine, and of brain microglia. It also regulates the differentiation of neural progenitor cells and controls functions of oocytes and trophoblastic cells in the female reproductive tract. Owing to this broad tissue expression pattern, it plays a central role in neoplastic, inflammatory, and neurological diseases. In this review we summarize the evolution, structure, and regulation of expression of the CSF-1R gene. We review, the structures of CSF-1, IL-34, and the CSF-1R and the mechanism of ligand binding to and activation of the receptor. We further describe the pathways regulating macrophage survival, proliferation, differentiation, and chemotaxis downstream from the CSF-1R. PMID:24890514

Csf3r mutations in mice confer a strong clonal HSC advantage via activation of Stat5

PubMed Central

Liu, Fulu; Kunter, Ghada; Krem, Maxwell M.; Eades, William C.; Cain, Jennifer A.; Tomasson, Michael H.; Hennighausen, Lothar; Link, Daniel C.

2008-01-01

A fundamental property of leukemic stem cells is clonal dominance of the bone marrow microenvironment. Truncation mutations of CSF3R, which encodes the G-CSF receptor (G-CSFR), are implicated in leukemic progression in patients with severe congenital neutropenia. Here we show that expression of a truncated mutant Csf3r in mice confers a strong clonal advantage at the HSC level that is dependent upon exogenous G-CSF. G-CSF–induced proliferation, phosphorylation of Stat5, and transcription of Stat5 target genes were increased in HSCs isolated from mice expressing the mutant Csf3r. Conversely, the proliferative advantage conferred by the mutant Csf3r was abrogated in myeloid progenitors lacking both Stat5A and Stat5B, and HSC function was reduced in mice expressing a truncated mutant Csf3r engineered to have impaired Stat5 activation. These data indicate that in mice, inappropriate Stat5 activation plays a key role in establishing clonal dominance by stem cells expressing mutant Csf3r. PMID:18292815

CSF1R mutations in hereditary diffuse leukoencephalopathy with spheroids are loss of function

NASA Astrophysics Data System (ADS)

Pridans, Clare; Sauter, Kristin A.; Baer, Kristin; Kissel, Holger; Hume, David A.

2013-10-01

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) in humans is a rare autosomal dominant disease characterized by giant neuroaxonal swellings (spheroids) within the CNS white matter. Symptoms are variable and can include personality and behavioural changes. Patients with this disease have mutations in the protein kinase domain of the colony-stimulating factor 1 receptor (CSF1R) which is a tyrosine kinase receptor essential for microglia development. We investigated the effects of these mutations on Csf1r signalling using a factor dependent cell line. Corresponding mutant forms of murine Csf1r were expressed on the cell surface at normal levels, and bound CSF1, but were not able to sustain cell proliferation. Since Csf1r signaling requires receptor dimerization initiated by CSF1 binding, the data suggest a mechanism for phenotypic dominance of the mutant allele in HDLS.

Usefulness of interleukin 6 levels in the cerebrospinal fluid for the diagnosis of bacterial meningitis.

PubMed

Takahashi, Waka; Nakada, Taka-aki; Abe, Ryuzo; Tanaka, Kumiko; Matsumura, Yosuke; Oda, Shigeto

2014-08-01

Interleukin 6 (IL-6) is a proinflammatory cytokine produced during infections. We hypothesized that IL-6 levels in the cerebrospinal fluid (CSF) would be elevated in bacterial meningitis and useful for diagnosing and predicting neurologic outcomes. For the differentiation of bacterial meningitis, serum and CSF samples were obtained from patients with an altered level of consciousness. Patients were classified into 3 groups: bacterial meningitis, nonbacterial central nervous system disease, and other site sepsis. Of the 70 patients included in this study, there were 13 in the bacterial meningitis group, 21 in the nonbacterial central nervous system disease group, and 36 in the other site sepsis group. The CSF IL-6 level was significantly higher in the bacterial meningitis group than in the other 2 groups (P<.0001). Of the 5 CSF parameters assessed, CSF IL-6 level exhibited the largest area under the receiver operating characteristic curve (0.962), with a cut-off value of 644 pg/mL (sensitivity, 92.3%; specificity, 89.5%). To examine a potential association between a high CSF level and neurologic outcome, CSF IL-6 levels were divided into 4 quartiles, and each level was compared with the frequency of a good neurologic outcome. The frequency of a good neurologic outcome was significantly lower in the highest CSF IL-6 quartile than in the other 3 quartiles (odds ratio, 0.18; 95% confidence interval, 0.05-0.69; P=.013). Measurement of the CSF IL-6 level is useful for diagnosing bacterial meningitis. Copyright © 2014 Elsevier Inc. All rights reserved.

Flow cytometric characterization of cerebrospinal fluid cells.

PubMed

de Graaf, Marieke T; de Jongste, Arjen H C; Kraan, Jaco; Boonstra, Joke G; Sillevis Smitt, Peter A E; Gratama, Jan W

2011-09-01

Flow cytometry facilitates the detection of a large spectrum of cellular characteristics on a per cell basis, determination of absolute cell numbers and detection of rare events with high sensitivity and specificity. White blood cell (WBC) counts in cerebrospinal fluid (CSF) are important for the diagnosis of many neurological disorders. WBC counting and differential can be performed by microscopy, hematology analyzers, or flow cytometry. Flow cytometry of CSF is increasingly being considered as the method of choice in patients suspected of leptomeningeal localization of hematological malignancies. Additionally, in several neuroinflammatory diseases such as multiple sclerosis and paraneoplastic neurological syndromes, flow cytometry is commonly performed to obtain insight into the immunopathogenesis of these diseases. Technically, the low cellularity of CSF samples, combined with the rapidly declining WBC viability, makes CSF flow cytometry challenging. Comparison of flow cytometry with microscopic and molecular techniques shows that each technique has its own advantages and is ideally combined. We expect that increasing the number of flow cytometric parameters that can be simultaneously studied within one sample, will further refine the information on CSF cell subsets in low-cellular CSF samples and enable to define cell populations more accurately. Copyright © 2011 International Clinical Cytometry Society.

Effects of spatial variation of skull and cerebrospinal fluid layers on optical mapping of brain activities

NASA Astrophysics Data System (ADS)

Wang, Shuping; Shibahara, Nanae; Kuramashi, Daishi; Okawa, Shinpei; Kakuta, Naoto; Okada, Eiji; Maki, Atsushi; Yamada, Yukio

2010-07-01

In order to investigate the effects of anatomical variation in human heads on the optical mapping of brain activity, we perform simulations of optical mapping by solving the photon diffusion equation for layered-models simulating human heads using the finite element method (FEM). Particularly, the effects of the spatial variations in the thicknesses of the skull and cerebrospinal fluid (CSF) layers on mapping images are investigated. Mapping images of single active regions in the gray matter layer are affected by the spatial variations in the skull and CSF layer thicknesses, although the effects are smaller than those of the positions of the active region relative to the data points. The increase in the skull thickness decreases the sensitivity of the images to active regions, while the increase in the CSF layer thickness increases the sensitivity in general. The images of multiple active regions are also influenced by their positions relative to the data points and by their depths from the skin surface.

The Structure of the GM-CSF Receptor Complex Reveals a Distinct Mode of Cytokine Receptor Activation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hansen, Guido; Hercus, Timothy R.; McClure, Barbara J.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that controls the production and function of blood cells, is deregulated in clinical conditions such as rheumatoid arthritis and leukemia, yet offers therapeutic value for other diseases. Its receptors are heterodimers consisting of a ligand-specific {alpha} subunit and a {beta}c subunit that is shared with the interleukin (IL)-3 and IL-5 receptors. How signaling is initiated remains an enigma. We report here the crystal structure of the human GM-CSF/GM-CSF receptor ternary complex and its assembly into an unexpected dodecamer or higher-order complex. Importantly, mutagenesis of the GM-CSF receptor at the dodecamer interface andmore » functional studies reveal that dodecamer formation is required for receptor activation and signaling. This unusual form of receptor assembly likely applies also to IL-3 and IL-5 receptors, providing a structural basis for understanding their mechanism of activation and for the development of therapeutics.« less

[Laboratory diagnosis of bacterial meningitis: usefulness of various tests for the determination of the etiological agent].

PubMed

Carbonnelle, E

2009-01-01

Despite breakthroughs in the diagnosis and treatment of infectious diseases, meningitis still remains an important cause of mortality and morbidity. An accurate and rapid diagnosis of acute bacterial meningitis is essential for a good outcome. The gold-standard test for diagnosis is CSF analysis. Gram staining of CSF reveals bacteria in about 50 to 80 % of cases and cultures are positive in at best 80 % of cases. However, the sensitivity of both tests is less than 50 % in patients who are already on antibiotic treatment. CSF leukocyte count and concentration of protein and glucose lack specificity and sensitivity for the diagnosis of meningitis. Other biological tests are available for the diagnosis. Latex agglutination test were adapted for rapid and direct detection of soluble bacterial antigens in CSF of patients suspected with bacterial meningitis. This test is efficient in detecting antigens of most common central nervous system bateria but lacks sensibility. Furthermore, in the early phases of acute bacterial and viral meningitis, signs and symptoms are often non specific and it is not always possible to make a differential diagnosis. Markers like CRP, procalcitonin, or sTREM-1 may be very useful for the diagnosis and to differentiate between viral and bacterial meningitis. Bacterial meningitis diagnosis and management require various biological tests and a multidisciplinary approach.

The Dynamic Gait Index in Evaluating Patients with Normal Pressure Hydrocephalus for Cerebrospinal Fluid Diversion.

PubMed

Chivukula, Srinivas; Tempel, Zachary J; Zwagerman, Nathan T; Newman, W Christopher; Shin, Samuel S; Chen, Ching-Jen; Gardner, Paul A; McDade, Eric M; Ducruet, Andrew F

2015-12-01

Diagnosing normal pressure hydrocephalus (NPH) remains challenging. Most clinical tests currently used to evaluate suspected NPH patients for shunt surgery are invasive, require inpatient admission, and are not without complications. An objective, noninvasive, and low-cost alternative would be ideal. A retrospective review was performed of prospectively collected dynamic gait index (DGI) scores, obtained at baseline and on every day of a 3- to 5-day lumbar cerebrospinal fluid (CSF) drainage trial on patients with suspected NPH at our institution. Between 2003 and 2014, 170 patients were suspected to have primary NPH (166, 97.6%) or secondary NPH (4, 2.4%). Using responsiveness to lumbar CSF drainage and subsequent shunting as the reference standard, we found that a baseline DGI ≥ 7 was found to have significant ability in selecting patients for permanent CSF diverting shunt surgery: sensitivity of 84.2% (95% confidence interval [95% CI]: 75.6%-90.2%), specificity of 80.6% (95% CI 70.0%-88.0%), and diagnostic odds ratio of 22.1 (95% CI 9.9-49.3). A baseline DGI ≥ 7 appears to provide an objective, low-cost, noninvasive measure to select patients with suspected NPH for a positive response to CSF diversion with high sensitivity, specificity and diagnostic odds ratio. Copyright © 2015 Elsevier Inc. All rights reserved.

Vitamin B6 in plasma and cerebrospinal fluid of children.

PubMed

Albersen, Monique; Bosma, Marjolein; Jans, Judith J M; Hofstede, Floris C; van Hasselt, Peter M; de Sain-van der Velden, Monique G M; Visser, Gepke; Verhoeven-Duif, Nanda M

2015-01-01

Over the past years, the essential role of vitamin B6 in brain development and functioning has been recognized and genetic metabolic disorders resulting in functional vitamin B6 deficiency have been identified. However, data on B6 vitamers in children are scarce. B6 vitamer concentrations in simultaneously sampled plasma and cerebrospinal fluid (CSF) of 70 children with intellectual disability were determined by ultra performance liquid chromatography-tandem mass spectrometry. For ethical reasons, CSF samples could not be obtained from healthy children. The influence of sex, age, epilepsy and treatment with anti-epileptic drugs, were investigated. The B6 vitamer composition of plasma (pyridoxal phosphate (PLP) > pyridoxic acid > pyridoxal (PL)) differed from that of CSF (PL > PLP > pyridoxic acid > pyridoxamine). Strong correlations were found for B6 vitamers in and between plasma and CSF. Treatment with anti-epileptic drugs resulted in decreased concentrations of PL and PLP in CSF. We provide concentrations of all B6 vitamers in plasma and CSF of children with intellectual disability (±epilepsy), which can be used in the investigation of known and novel disorders associated with vitamin B6 metabolism as well as in monitoring of the biochemical effects of treatment with vitamin B6.

Specific Contributions of CSF-1 and GM-CSF to the Dynamics of the Mononuclear Phagocyte System.

PubMed

Louis, Cynthia; Cook, Andrew D; Lacey, Derek; Fleetwood, Andrew J; Vlahos, Ross; Anderson, Gary P; Hamilton, John A

2015-07-01

M-CSF (or CSF-1) and GM-CSF can regulate the development and function of the mononuclear phagocyte system (MPS). To address some of the outstanding and sometimes conflicting issues surrounding this biology, we undertook a comparative analysis of the effects of neutralizing mAbs to these CSFs on murine MPS populations in the steady-state and during acute inflammatory reactions. CSF-1 neutralization, but not of GM-CSF, in normal mice rapidly reduced the numbers of more mature Ly6C(-) monocytes in blood and bone marrow, without any effect on proliferating precursors, and also the numbers of the resident peritoneal macrophages, observations consistent with CSF-1 signaling being essential only at a relatively late state in steady-state MPS development; in contrast, GM-CSF neutralization had no effect on the numbers of these particular populations. In Ag-induced peritonitis (AIP), thioglycolate-induced peritonitis, and LPS-induced lung inflammation, CSF-1 neutralization lowered inflammatory macrophage number; in the AIP model, this reduced number was not due to suppressed proliferation. More detailed studies with the convenient AIP model indicated that CSF-1 neutralization led to a relatively uniform reduction in all inflammatory cell populations; GM-CSF neutralization, in contrast, was more selective, resulting in the preferential loss among the MPS populations of a cycling, monocyte-derived inflammatory dendritic cell population. Some mechanistic options for the specific CSF-dependent biologies enumerated are discussed. Copyright © 2015 by The American Association of Immunologists, Inc.

Lentivirus-ABCG1 instillation reduces lipid accumulation and improves lung compliance in GM-CSF knock-out mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Malur, Anagha; Huizar, Isham; Wells, Greg

2011-11-18

Highlights: Black-Right-Pointing-Pointer Lentivirus-ABCG1 reduces lipid accumulation in lungs of GM-CSF knock-out mice. Black-Right-Pointing-Pointer Up-regulation of ABCG1 improves lung function. Black-Right-Pointing-Pointer Upregulation of ABCG1 improves surfactant metabolism. -- Abstract: We have shown decreased expression of the nuclear transcription factor, peroxisome proliferator-activated receptor-gamma (PPAR{gamma}) and the PPAR{gamma}-regulated ATP-binding cassette transporter G1 (ABCG1) in alveolar macrophages from patients with pulmonary alveolar proteinosis (PAP). PAP patients also exhibit neutralizing antibodies to granulocyte-macrophage colony stimulating factor (GM-CSF), an upregulator of PPAR{gamma}. In association with functional GM-CSF deficiency, PAP lung is characterized by surfactant-filled alveolar spaces and lipid-filled alveolar macrophages. Similar pathology characterizes GM-CSF knock-out (KO)more » mice. We reported previously that intratracheal instillation of a lentivirus (lenti)-PPAR{gamma} plasmid into GM-CSF KO animals elevated ABCG1 and reduced alveolar macrophage lipid accumulation. Here, we hypothesized that instillation of lenti-ABCG1 might be sufficient to decrease lipid accumulation and improve pulmonary function in GM-CSF KO mice. Animals received intratracheal instillation of lenti-ABCG1 or control lenti-enhanced Green Fluorescent Protein (eGFP) plasmids and alveolar macrophages were harvested 10 days later. Alveolar macrophage transduction efficiency was 79% as shown by lenti-eGFP fluorescence. Quantitative PCR analyses indicated a threefold (p = 0.0005) increase in ABCG1 expression with no change of PPAR{gamma} or ABCA1 in alveolar macrophages of lenti-ABCG1 treated mice. ABCG1 was unchanged in control lenti-eGFP and PBS-instilled groups. Oil Red O staining detected reduced intracellular neutral lipid in alveolar macrophages from lenti-ABCG1 treated mice. Extracellular cholesterol and phospholipids were also decreased as shown by analysis of bronchoalveolar lavage fluid. Lung compliance was diminished in untreated GMCSF KO mice but improved significantly after lenti-ABCG1 treatment. Data demonstrate that in vivo instillation of lenti-ABCG1 in GM-CSF KO mice is sufficient to restore pulmonary homeostasis by: (1) upregulating ABCG1; (2) reducing intra and extracellular lipids; and (3) improving lung function. Results suggest that the ABCG1 lipid transporter is the key downstream target of GM-CSF-induced PPAR{gamma} necessary for surfactant catabolism.« less

Sensitive biomarkers of alcoholism's effect on brain macrostructure: similarities and differences between France and the United States

PubMed Central

Le Berre, Anne-Pascale; Pitel, Anne-Lise; Chanraud, Sandra; Beaunieux, Hélène; Eustache, Francis; Martinot, Jean-Luc; Reynaud, Michel; Martelli, Catherine; Rohlfing, Torsten; Pfefferbaum, Adolf; Sullivan, Edith V.

2015-01-01

Alcohol consumption patterns and recognition of health outcomes related to hazardous drinking vary widely internationally, raising the question whether these national differences are reflected in brain damage observed in alcoholism. This retrospective analysis assessed variability of alcoholism's effects on brain cerebrospinal fluid (CSF) and white matter volumes between France and the United States (U.S.). MRI data from two French sites (Caen and Orsay) and a U.S. laboratory (SRI/Stanford University) were acquired on 1.5T imaging systems in 287 controls, 165 uncomplicated alcoholics (ALC), and 26 alcoholics with Korsakoff's Syndrome (KS). All data were analyzed at the U.S. site using atlas-based parcellation. Results revealed graded CSF volume enlargement from ALC to KS and white matter volume deficits in KS only. In ALC from France but not the U.S., CSF and white matter volumes correlated with lifetime alcohol consumption, alcoholism duration, and length of sobriety. MRI highlighted CSF volume enlargement in both ALC and KS, serving as a basis for an ex vacuo process to explain correlated gray matter shrinkage. By contrast, MRI provided a sensitive in vivo biomarker of white matter volume shrinkage in KS only, suggesting a specific process sensitive to mechanisms contributing to Wernicke's encephalopathy, the precursor of KS. Identified structural brain abnormalities may provide biomarkers underlying alcoholism's heterogeneity in and among nations and suggest a substrate of gray matter tissue shrinkage. Proposed are hypotheses for national differences in interpreting whether the severity of sequelae observe a graded phenomenon or a continuum from uncomplicated alcoholism to alcoholism complicated by KS. PMID:26157376

Blood-CSF-barrier dysfunction is a marker for encephalitic involvement in patients with aseptic meningitis/meningoencephalitis.

PubMed

Hoyer, C; Eisele, P; Ebert, A D; Schneider, S; Gass, A; Fatar, M; Szabo, K; Alonso, A

2016-11-01

The term "aseptic meningitis" encompasses cases of meningitis with negative bacterial CSF culture, which predominantly are of viral etiology. While the clinical course is usually benign, complications such as encephalitic involvement resulting in a more severe clinical course may occur. Dysfunction of the blood-brain-barrier (BBB), which is a prerequisite for viral entry into the brain parenchyma, can be approximated using the CSF/serum albumin ratio, readily obtainable in routine CSF analysis. Analysis of CSF patterns in patients with aseptic meningitis/meningoencephalitis with a focus on BBB dysfunction as a marker for encephalitic involvement. Retrospective chart review of patients admitted to our hospital between 2004 and 2016 with a diagnosis of aseptic meningitis/meningoencephalitis. Patients with aseptic meningitis displaying clinical, MR-tomographic or electroencephalographic signs of encephalitic involvement were significantly older than patients without these features (47.4 vs. 35.5 yrs., p=0.002). In patients with meningoencephalitis, CSF analysis revealed a more severe disruption of BBB, approximated by the CSF/serum albumin ratio (p=0.002). Compromised BBB function correlated positively with length of hospitalization (p=0.007), indicative of a more severe clinical course. The number of CSF lymphocytes was found to predict the severity of the BBB disruption, which additionally was more frequently observed when herpesviridae were identified as infectious agents. We suggest that the CSF/serum albumin ratio as an estimate for BBB function should be attended to in the evaluation of patients with aseptic meningitis. Severe BBB dysfunction, older age and infection with herpesviridae appear to raise the risk for encephalitic involvement. Copyright © 2016 Elsevier B.V. All rights reserved.

Interaction of RNA-binding protein HuR and miR-466i regulates GM-CSF expression.

PubMed

Chen, Jing; Adamiak, William; Huang, Ganlei; Atasoy, Ulus; Rostami, Abdolmohamad; Yu, Shiguang

2017-12-08

Granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by T helper 17 (Th17) cells plays an essential role in autoimmune diseases. Transcriptional regulation of Th17 cell differentiation has been extensively studied, but post-transcriptional regulation of Th17 cell differentiation has remained less well characterized. The RNA-binding protein HuR functions to promote the stability of target mRNAs via binding the AU-rich elements of the 3' untranslated region (3'UTR) of numerous pro-inflammatory cytokines including IL-4, IL-13, IL-17 and TNF-α. However, whether HuR regulates GM-CSF expression in Th17 cells has not been fully investigated. Here we showed that HuR conditional knockout (KO) Th17 cells have decreased GM-CSF mRNA in comparison with wild-type (WT) Th17 cells, and that HuR binds directly to GM-CSF mRNA 3'UTR. Interestingly, HuR deficiency increased the levels of certain microRNA expression in Th17 cells; for example, miR-466i functioned to mediate GM-CSF and IL-17 mRNA decay, which was confirmed by in vitro luciferase assay. Furthermore, we found that HuR promoted Mxi1 expression to inhibit certain miRNA expression. Taken together, these findings indicate that interaction of HuR and miR-466i orchestrates GM-CSF expression in Th17 cells.

Detection of wild-type EGFR amplification and EGFRvIII mutation in CSF-derived extracellular vesicles of glioblastoma patients.

PubMed

Figueroa, Javier M; Skog, Johan; Akers, Johnny; Li, Hongying; Komotar, Ricardo; Jensen, Randy; Ringel, Florian; Yang, Isaac; Kalkanis, Steven; Thompson, Reid; LoGuidice, Lori; Berghoff, Emily; Parsa, Andrew; Liau, Linda; Curry, William; Cahill, Daniel; Bettegowda, Chetan; Lang, Frederick F; Chiocca, E Antonio; Henson, John; Kim, Ryan; Breakefield, Xandra; Chen, Clark; Messer, Karen; Hochberg, Fred; Carter, Bob S

2017-10-19

RNAs within extracellular vesicles (EVs) have potential as diagnostic biomarkers for patients with cancer and are identified in a variety of biofluids. Glioblastomas (GBMs) release EVs containing RNA into cerebrospinal fluid (CSF). Here we describe a multi-institutional study of RNA extracted from CSF-derived EVs of GBM patients to detect the presence of tumor-associated amplifications and mutations in epidermal growth factor receptor (EGFR). CSF and matching tumor tissue were obtained from patients undergoing resection of GBMs. We determined wild-type (wt)EGFR DNA copy number amplification, as well as wtEGFR and EGFR variant (v)III RNA expression in tumor samples. We also characterized wtEGFR and EGFRvIII RNA expression in CSF-derived EVs. EGFRvIII-positive tumors had significantly greater wtEGFR DNA amplification (P = 0.02) and RNA expression (P = 0.03), and EGFRvIII-positive CSF-derived EVs had significantly more wtEGFR RNA expression (P = 0.004). EGFRvIII was detected in CSF-derived EVs for 14 of the 23 EGFRvIII tissue-positive GBM patients. Conversely, only one of the 48 EGFRvIII tissue-negative patients had the EGFRvIII mutation detected in their CSF-derived EVs. These results yield a sensitivity of 61% and a specificity of 98% for the utility of CSF-derived EVs to detect an EGFRvIII-positive GBM. Our results demonstrate CSF-derived EVs contain RNA signatures reflective of the underlying molecular genetic status of GBMs in terms of wtEGFR expression and EGFRvIII status. The high specificity of the CSF-derived EV diagnostic test gives us an accurate determination of positive EGFRvIII tumor status and is essentially a less invasive "liquid biopsy" that might direct mutation-specific therapies for GBMs. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Therapeutic effects of CSF1R-blocking antibodies in multiple myeloma.

PubMed

Wang, Q; Lu, Y; Li, R; Jiang, Y; Zheng, Y; Qian, J; Bi, E; Zheng, C; Hou, J; Wang, S; Yi, Q

2018-01-01

Our previous studies showed that macrophages (MФs), especially myeloma-associated MФs (MAMs), induce chemoresistance in human myeloma. Here we explored the potential of targeting MФs, by using colony-stimulating factor 1 receptor (CSF1R)-blocking mAbs, to treat myeloma. Our results showed that CSF1R blockade specifically inhibited the differentiation, proliferation and survival of murine M2 MФs and MAMs, and repolarized MAMs towards M1-like MФs in vitro. CSF1R blockade alone inhibited myeloma growth in vivo, by partially depleting MAMs, polarizing MAMs to the M1 phenotype, and inducing a tumor-specific cytotoxic CD4 + T-cell response. Similarly, genetically depleting MФs in myeloma-bearing MM DTR mice retarded myeloma growth in vivo. Furthermore, the combination of CSF1R blockade and chemotherapy such as bortezomib or melphalan displayed an additive therapeutic efficacy against established myeloma. Finally, a fully human CSF1R blocking mAb, similar to its murine counterpart, was able to inhibit the differentiation, proliferation and survival of human MФs. Thus, this study provides the first direct in vivo evidence that MΦs and MAMs are indeed important for myeloma development and progression. Our results also suggest that targeting MAMs by CSF1R blocking mAbs may be promising methods to (re)sensitize myeloma cells to chemotherapy and promote anti-myeloma immune responses in patients.

Network Disruption and Cerebrospinal Fluid Amyloid-Beta and Phospho-Tau Levels in Mild Cognitive Impairment.

PubMed

Canuet, Leonides; Pusil, Sandra; López, María Eugenia; Bajo, Ricardo; Pineda-Pardo, José Ángel; Cuesta, Pablo; Gálvez, Gerardo; Gaztelu, José María; Lourido, Daniel; García-Ribas, Guillermo; Maestú, Fernando

2015-07-15

Synaptic dysfunction is a core deficit in Alzheimer's disease, preceding hallmark pathological abnormalities. Resting-state magnetoencephalography (MEG) was used to assess whether functional connectivity patterns, as an index of synaptic dysfunction, are associated with CSF biomarkers [i.e., phospho-tau (p-tau) and amyloid beta (Aβ42) levels]. We studied 12 human subjects diagnosed with mild cognitive impairment due to Alzheimer's disease, comparing those with normal and abnormal CSF levels of the biomarkers. We also evaluated the association between aberrant functional connections and structural connectivity abnormalities, measured with diffusion tensor imaging, as well as the convergent impact of cognitive deficits and CSF variables on network disorganization. One-third of the patients converted to Alzheimer's disease during a follow-up period of 2.5 years. Patients with abnomal CSF p-tau and Aβ42 levels exhibited both reduced and increased functional connectivity affecting limbic structures such as the anterior/posterior cingulate cortex, orbitofrontal cortex, and medial temporal areas in different frequency bands. A reduction in posterior cingulate functional connectivity mediated by p-tau was associated with impaired axonal integrity of the hippocampal cingulum. We noted that several connectivity abnormalities were predicted by CSF biomarkers and cognitive scores. These preliminary results indicate that CSF markers of amyloid deposition and neuronal injury in early Alzheimer's disease associate with a dual pattern of cortical network disruption, affecting key regions of the default mode network and the temporal cortex. MEG is useful to detect early synaptic dysfunction associated with Alzheimer's disease brain pathology in terms of functional network organization. In this preliminary study, we used magnetoencephalography and an integrative approach to explore the impact of CSF biomarkers, neuropsychological scores, and white matter structural abnormalities on neural function in mild cognitive impairment. Disruption in functional connectivity between several pairs of cortical regions associated with abnormal levels of biomarkers, cognitive deficits, or with impaired axonal integrity of hippocampal tracts. Amyloid deposition and tau protein-related neuronal injury in early Alzheimer's disease are associated with synaptic dysfunction and a dual pattern of cortical network disorganization (i.e., desynchronization and hypersynchronization) that affects key regions of the default mode network and temporal areas. Copyright © 2015 the authors 0270-6474/15/3510326-06$15.00/0.

The diagnostic value of cytokine and nitric oxide concentrations in cerebrospinal fluid for the differential diagnosis of meningitis.

PubMed

Bociąga-Jasik, M; Garlicki, A; Cieśla, A; Kalinowska-Nowak, A; Sobczyk-Krupiarz, I; Mach, T

2012-06-01

In several cases of meningitis routinely used diagnostic procedures are unable to identify the cause of this disease. The objective of the present study was to determine whether proinflammatory cytokine (tumour necrosis factor (TNF-α), interleukin-1β (IL-1β), interleukin-8 (IL-8)) and nitric oxide (NO) concentrations in the CSF are useful markers for the differential diagnosis of meningitis. Sixty-seven patients (42 patients with bacterial meningitis and 25 patients with viral meningitis) were included in the present study. In the investigated group, the TNF-α, IL-1β and IL-8 concentrations in the CSF samples collected on the day of admission were assessed. Furthermore, the NO concentrations were assessed in 23 patients. The results revealed that the measurement of proinflammatory cytokines in CSF can aid in a differential diagnosis. In particular, a high concentration of TNF-α may be a sensitive and specific marker of a bacterial aetiology of the neuroinfection. In the present study, TNF-α concentrations greater than 75.8 pg/ml differentiated between bacterial and viral meningitis with 100% sensitivity and specificity. The NO concentration in the CSF was also significantly greater in patients with bacterial meningitis than in those with viral meningitis. The assessment of TNF-α, IL-1β and IL-8 concentrations in the CSF is useful in the differential diagnosis of neuroinfection. Because many factors may influence NO production in the central nervous system (CNS), it is not clear whether NO values can be used for the differential diagnosis of meningitis, and further studies are required.

Translating G-CSF as an adjunct therapy to stem cell transplantation for stroke

PubMed Central

dela Peña, Ike; Borlongan, Cesar V.

2015-01-01

Among recently investigated stroke therapies, stem cell treatment holds great promise by virtue of their putative ability to replace lost cells, promote endogenous neurogenesis and produce behavioral and functional improvement through their “bystander effects.” Translating stem cell in the clinic, however, presents a number of technical difficulties. A strategy suggested to enhance therapeutic utility of stem cells is combination therapy, i.e., cotransplantation of stem cells or adjunct treatment with pharmacological agents and substrates, which is assumed to produce more profound therapeutic benefits by circumventing limitations of individual treatments, and facilitating complementary brain repair processes. We previously demonstrated enhanced functional effects of co-treatment with granulocyte-colony stimulating factor (G-CSF) and human umbilical cord blood cell (hUCB) transplantation in animal models of traumatic brain injury (TBI). Here, we suggest that the aforementioned combination therapy may also produce synergistic effects in stroke. Accordingly, G-CSF treatment may reduce expression of pro-inflammatory cytokines and enhance neurogenesis rendering a receptive microenvironment for hUCB engraftment. Adjunct treatment of G-CSF with hUCB may facilitate stemness maintenance and guide neural lineage commitment of hUCB cells. Moreover, regenerative mechanisms afforded by G-CSF-mobilized endogenous stem cells, secretion of growth factors by hUCB grafts and G-CSF-recruited endothelial progenitor cells (EPCs) , as well as the potential graft–host integration that may promote synaptic circuitry re-establishment could altogether produce more pronounced functional improvement in stroked rats subjected to a combination G-CSF treatment and hUCB transplantation. Nevertheless, differences in pathology and repair processes underlying TBI and stroke deserve consideration when testing effects of combinatorial G-CSF and hUCB cell transplantation for stroke treatment. Further studies are also required to determine safety and efficacy of this intervention in both preclinical and clinical stroke studies. PMID:26482176

Serial MRI and CSF biomarkers in normal aging, MCI, and AD

PubMed Central

Vemuri, P.; Wiste, H.J.; Weigand, S.D.; Knopman, D.S.; Trojanowski, J.Q.; Shaw, L.M.; Bernstein, M.A.; Aisen, P.S.; Weiner, M.; Petersen, R.C; Jack, C.R

2010-01-01

Objective: To compare the annual change in MRI and CSF biomarkers in cognitively normal (CN), amnestic mild cognitive impairment (aMCI), and Alzheimer disease (AD). Comparisons were based on intergroup discrimination, correlation with concurrent cognitive/functional changes, relationships to APOE genotype, and sample sizes for clinical trials. Methods: We used data from the Alzheimer's Disease Neuroimaging Initiative study consisting of CN, aMCI, and AD cohorts with both baseline and 12-month follow-up CSF and MRI. The annual change in CSF (total-tau [t-tau], Aβ1-42) and MRI (change in ventricular volume) was obtained in 312 subjects (92 CN, 149 aMCI, 71 AD). Results: There was no significant average annual change in either CSF biomarker in any clinical group except t-tau in CN; moreover, the annual change did not differ by clinical group in pairwise comparisons. In contrast, annual increase in ventricular volume increased in the following order, AD > aMCI > CN, and differences were significant between all clinical groups in pairwise comparisons. Ventricular volume increase correlated with concurrent worsening on cognitive/functional indices in aMCI and AD whereas evidence of a similar correlation with change in CSF measures was unclear. The annual changes in MRI differed by APOE ε4 status overall and among aMCI while annual changes in CSF biomarkers did not. Estimated sample sizes for clinical trials are notably less for MRI than the CSF or clinical measures. Conclusions: Unlike the CSF biomarkers evaluated, changes in serial structural MRI are correlated with concurrent change on general cognitive and functional indices in impaired subjects, track with clinical disease stage, and are influenced by APOE genotype. GLOSSARY AD = Alzheimer disease; ADAS-Cog = Alzheimer's Disease Assessment Scale–cognitive subscale; ADNI = Alzheimer's Disease Neuroimaging Initiative; aMCI = amnestic mild cognitive impairment; AUROC = area under the receiver operator characteristic curve; BSI = boundary shift integral; CDR-SB = Clinical Dementia Rating–sum of boxes; CN = cognitively normal; MMSE = Mini-Mental State Examination; NFT = neurofibrillary tangle; NT = neuropil thread; PiB = Pittsburgh compound B; t-tau = total-tau. PMID:20625167

Polyoma virus JC DNA detection by polymerase chain reaction in CSF of HIV infected patients with suspected progressive multifocal leukoencephalopathy.

PubMed

Giri, J A; Gregoresky, J; Silguero, P; García Messina, O; Planes, N

2001-01-01

Several studies had previously demonstrated the high sensitivity and specificity of JCV DNA detection in CSF by PCR. This paper reported the implementation of a simple PCR procedure to detect JCV in the CSF in a cohort of HIV-1 infected patients from Argentina. Years ago, the confirmatory diagnosis of this disease was made by in-situ hybridization or immunohistochemistry techniques on brain biopsies. The PCR procedure described here improves the diagnosis of PML because it is simple and noninvasive, and allows the differential diagnosis of PML from other neurological syndromes associated with AIDS. Many recent studies report a significant benefit of combined antiretroviral therapy on the survival of HIV patients without clear neurological improvements. A negative correlation has been described between the concentration of JCV in the CSF and survival time in HIV-1 infected patients, and the level of immune depression may influence JCV replication. This suggests that a single CSF JCV viral load determination during the course of PML disease progression may be of prognostic value for managing HIV patients.

MDSCs are involved in the protumorigenic potentials of GM-CSF in colitis-associated cancer.

PubMed

Ma, Ning; Liu, Qilin; Hou, Lin; Wang, Yalin; Liu, Ziling

2017-06-01

Chronic inflammation is thought to be a major driving force for the development of colitis-associated colorectal cancer (CAC). As one member of proinflammatory cytokine family, granulocyte macrophage colony-stimulating factor (GM-CSF) has been identified to play a key role in CAC pathogenesis recently. The underlying mechanisms, however, remain largely unknown. In this study, we found that myeloid-derived suppressor cells (MDSCs) accumulated increasingly in the lesions during the progression from colitis to cancer, which was critical for CAC formation. Importantly, this MDSC accumulation was controlled by GM-CSF. MDSC number decreased significantly in GM-CSF-deficient mice suffering from CAC induction, and transfusion of MDSCs from wild-type CAC-bearing mice into GM-CSF-deficient counterparts led to recurrence of CAC. Furthermore, the supernatants of CAC lesions or GM-CSF alone was sufficient to differentiate hematopoietic precursors into MDSCs. Addition of neutralizing anti-GM-CSF antibody impaired the MDSC-differentiating effects of the supernatants of CAC lesions. Overall, these findings shed new insights into the mechanisms of GM-CSF underlying CAC development, by inducing/recruiting CAC-promoting MDSCs. Blocking GM-CSF activity or MDSC function may represent new therapeutic strategies for CAC in clinic.

A new look at cerebrospinal fluid circulation

PubMed Central

2014-01-01

According to the traditional understanding of cerebrospinal fluid (CSF) physiology, the majority of CSF is produced by the choroid plexus, circulates through the ventricles, the cisterns, and the subarachnoid space to be absorbed into the blood by the arachnoid villi. This review surveys key developments leading to the traditional concept. Challenging this concept are novel insights utilizing molecular and cellular biology as well as neuroimaging, which indicate that CSF physiology may be much more complex than previously believed. The CSF circulation comprises not only a directed flow of CSF, but in addition a pulsatile to and fro movement throughout the entire brain with local fluid exchange between blood, interstitial fluid, and CSF. Astrocytes, aquaporins, and other membrane transporters are key elements in brain water and CSF homeostasis. A continuous bidirectional fluid exchange at the blood brain barrier produces flow rates, which exceed the choroidal CSF production rate by far. The CSF circulation around blood vessels penetrating from the subarachnoid space into the Virchow Robin spaces provides both a drainage pathway for the clearance of waste molecules from the brain and a site for the interaction of the systemic immune system with that of the brain. Important physiological functions, for example the regeneration of the brain during sleep, may depend on CSF circulation. PMID:24817998

Therapy with granulocyte colony-stimulating factor in the chronic stage, but not in the acute stage, improves experimental autoimmune myocarditis in rats via nitric oxide.

PubMed

Shimada, Kana; Okabe, Taka-aki; Mikami, Yu; Hattori, Miki; Fujita, Masatoshi; Kishimoto, Chiharu

2010-09-01

We systematically investigated serial efficacy of granulocyte colony-stimulating factor (G-CSF) therapy upon experimental autoimmune myocarditis (EAM) in rats treated with and without the inhibition of nitric oxide (NO) with the analyses of tissue regeneration. G-CSF could mobilize multipotent progenitor cells of bone marrow into the peripheral blood and may improve ventricular function. A rat model of porcine myosin-induced EAM was used. After the immunization of myosin, G-CSF (10 microg/kg/day) or saline was injected intraperitoneally on days 0-21 in experiment 1 and on days 21-42 in experiment 2. Additional myosin-immunized rats were orally given 25 mg/kg/day of N(G)-nitro-L-arginine methylester (L-NAME), an inhibitor of nitric oxide synthase (NOS), in each experiment (each group; n=8-21). Serum cytokines and peripheral blood cell counts were measured in each group. In experiment 1, G-CSF treatment aggravated cardiac pathology associated with increased macrophage inflammatory protein-2 (MIP-2) and interleukin-6 (IL-6) levels and enhanced superoxide production. In experiment 2, G-CSF treatment reduced the severity of myocarditis with increased capillary density and improved left ventricular ejection fraction. In the rats with EAM treated with G-CSF associated with oral L-NAME treatment in experiment 2, the severity of myocarditis was not reduced. Myocardial c-kit(+) cells were demonstrated only in G-CSF-treated group in experiment 2 but not in other groups. G-CSF has differential effects on EAM in rats associated with the modulation of cytokine network. The overwhelming superoxide production by G-CSF administration in the acute stage may worsen the disease. G-CSF therapy improved cardiac function via NO system in a rat model of myocarditis in the chronic stage, but not in the acute stage, possibly through the myocardial regeneration and acceleration of healing process. Copyright 2010 Elsevier Ltd. All rights reserved.

Increased cortisol in the cerebrospinal fluid of women with functional hypothalamic amenorrhea.

PubMed

Brundu, Benedetta; Loucks, Tammy L; Adler, Lauri J; Cameron, Judy L; Berga, Sarah L

2006-04-01

The proximate cause of functional hypothalamic amenorrhea (FHA) is reduced GnRH drive. The concomitant increase in circulating cortisol suggests that psychogenic stress plays an etiologic role, but others have argued for a strictly metabolic cause, such as undernutrition or excessive exercise. Indeed, our finding that the cerebrospinal fluid (CSF) concentration of CRH was not elevated in FHA cast doubt about the extent of hypothalamic-pituitary-adrenal activation in FHA and, therefore, we wondered whether central cortisol levels were elevated. We tested the null hypothesis that CSF cortisol levels would be comparable in FHA and eumenorrheic women (EW). The study is a cross-sectional comparison. The study was set in a general clinical research center at an academic medical center. Fifteen women with FHA who were of normal body weight and 14 EW participated. Blood samples were collected at 15-min intervals for 24 h, followed by procurement of 25 ml CSF. Cortisol, cortisol-binding globulin (CBG), and SHBG levels in blood and CSF were the main outcome measures. CSF cortisol concentrations were 30% greater when serum cortisol was 16% higher in FHA compared with EW. Circulating CBG, but not SHBG, was increased in FHA and, thus, the circulating free cortisol index was similar in FHA and EW. Because CBG and SHBG were nil in CSF, the increase in CSF cortisol in FHA was unbound. The hypothalamic-pituitary-adrenal axis is activated in FHA. The maintenance of CRH drive despite increased CSF cortisol indicates resistance to cortisol feedback inhibition. The mechanisms mediating feedback resistance likely involve altered hippocampal corticosteroid reception and serotonergic and GABAergic neuromodulation.

Development of a cerebrospinal fluid lateral reservoir model in rhesus monkeys (Macaca mulatta).

PubMed

Lester McCully, Cynthia M; Bacher, John; MacAllister, Rhonda P; Steffen-Smith, Emilie A; Saleem, Kadharbatcha; Thomas, Marvin L; Cruz, Rafael; Warren, Katherine E

2015-02-01

Rapid, serial, and humane collection of cerebrospinal fluid (CSF) in nonhuman primates (NHP) is an essential element of numerous research studies and is currently accomplished via two different models. The CSF reservoir model (FR) combines a catheter in the 4th ventricle with a flexible silastic reservoir to permit circulating CSF flow. The CSF lateral port model (LP) consists of a lateral ventricular catheter and an IV port that provides static access to CSF and volume restrictions on sample collection. The FR model is associated with an intensive, prolonged recovery and frequent postsurgical hydrocephalus and nonpatency, whereas the LP model is associated with an easier recovery. To maximize the advantages of both systems, we developed the CSF lateral reservoir model (LR), which combines the beneficial features of the 2 previous models but avoids their limitations by using a reservoir for circulating CSF flow combined with catheter placement in the lateral ventricle. Nine adult male rhesus monkeys were utilized in this study. Pre-surgical MRI was performed to determine the coordinates of the lateral ventricle and location of choroid plexus (CP). The coordinates were determined to avoid the CP and major blood vessels. The predetermined coordinates were 100% accurate, according to MRI validation. The LR system functioned successfully in 67% of cases for 221 d, and 44% remain functional at 426 to 510 d postoperatively. Compared with established models, our LR model markedly reduced postoperative complications and recovery time. Development of the LR model was successful in rhesus macaques and is a useful alternative to the FR and LP methods of CSF collection from nonhuman primates.

Validated age-specific reference values for CSF total protein levels in children.

PubMed

Kahlmann, V; Roodbol, J; van Leeuwen, N; Ramakers, C R B; van Pelt, D; Neuteboom, R F; Catsman-Berrevoets, C E; de Wit, M C Y; Jacobs, B C

2017-07-01

To define age-specific reference values for cerebrospinal fluid (CSF) total protein levels for children and validate these values in children with Guillain-Barré syndrome (GBS), acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS). Reference values for CSF total protein levels were determined in an extensive cohort of diagnostic samples from children (<18 year) evaluated at Erasmus Medical Center/Sophia Children's Hospital. These reference values were confirmed in children diagnosed with disorders unrelated to raised CSF total protein level and validated in children with GBS, ADEM and MS. The test results of 6145 diagnostic CSF samples from 3623 children were used to define reference values. The reference values based on the upper limit of the 95% CI (i.e. upper limit of normal) were for 6 months-2 years 0.25 g/L, 2-6 years 0.25 g/L, 6-12 years 0.28 g/L, 12-18 years 0.34 g/L. These reference values were confirmed in a subgroup of 378 children diagnosed with disorders that are not typically associated with increased CSF total protein. In addition, the CSF total protein levels in these children in the first 6 months after birth were highly variable (median 0.47 g/L, IQR 0.26-0.65). According to these new reference values, CSF total protein level was elevated in 85% of children with GBS, 66% with ADEM and 23% with MS. More accurate age-specific reference values for CSF total protein levels in children were determined. These new reference values are more sensitive than currently used values for diagnosing GBS and ADEM in children. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

[Severe clinical problems lasting several weeks on a multiplier pig farm: what if it had been classical swine fever?].

PubMed

Backer, Jantien; Spierenburg, Marcel; van der Spek, Arco; Elbers, Armin

2010-10-15

In the Spring of 2009, a veterinarian reported suspected classical swine fever (CSF) on a multiplier pig farm in the southern part of The Netherlands (close to the Belgian border). Over a 5-week period there had been a number of sick sows and an excessively high percentage of stillborn and preterm piglets. Sick animals were treated with anti-inflammatory drugs and antibiotics, but did not respond as well as anticipated. A visiting specialist team from the Food Safety Authority could not exclude CSF as the cause of the clinical problems and sent blood samples to the reference laboratory in Lelystad for a PCR test on CSF antigen. Fortunately, test results obtained 6 hours later were negative for CSF, and the disease control measures were lifted. It later appeared that porcine reproductive and respiratory syndrome (PRRSV) might have been responsible for the problems. But what if CSF had caused the clinical problems? A CSF-transmission model was used to simulate CSF outbreaks dependent on the duration of the high-risk period (HRP). As the duration of the HRP increased, there was an exponential growth in the number of pig farms infected during this period. Simulations also showed that with a longer HRP, the virus spread over greater distances from the source herd. It was also investigated whether a possible CSF outbreak could be detected on the basis of an increased mortality and hence increased number of cadavers sent to a rendering plant. However, the calculated mortality incidence was not sensitive enough to serve as an alarm signal. It is recommended that CSF-exclusion diagnostics be used much earlier in similar clinical situations on pig farms.

Imaging review of cerebrospinal fluid leaks

PubMed Central

Vemuri, Naga V; Karanam, Lakshmi S P; Manchikanti, Venkatesh; Dandamudi, Srinivas; Puvvada, Sampath K; Vemuri, Vineet K

2017-01-01

Cerebrospinal fluid (CSF) leak occurs due to a defect in the dura and skull base. Trauma remains the most common cause of CSF leak; however, a significant number of cases are iatrogenic, and result from a complication of functional endoscopic sinus surgery (FESS). Early diagnosis of CSF leak is of paramount importance to prevent life-threatening complications such as brain abscess and meningitis. Imaging plays a crucial role in the detection and characterization of CSF leaks. Three-dimensional, isotropic, high resolution computed tomography (HRCT) accurately detects the site and size of the bony defect. CT cisternography, though invasive, helps accurately identify the site of CSF leak, especially in the presence of multiple bony defects. Magnetic resonance imaging (MRI) accurately detects CSF leaks and associated complications such as the encephaloceles and meningoceles. In this review, we emphasize the importance and usefulness of 3D T2 DRIVE MR cisternography in localizing CSF leaks. This sequence has the advantages of effective bone and fat suppression, decreased artefacts, faster acquisition times, three-dimensional capability, y and high spatial resolution in addition to providing very bright signal from the CSF. PMID:29379240

Imaging review of cerebrospinal fluid leaks.

PubMed

Vemuri, Naga V; Karanam, Lakshmi S P; Manchikanti, Venkatesh; Dandamudi, Srinivas; Puvvada, Sampath K; Vemuri, Vineet K

2017-01-01

Cerebrospinal fluid (CSF) leak occurs due to a defect in the dura and skull base. Trauma remains the most common cause of CSF leak; however, a significant number of cases are iatrogenic, and result from a complication of functional endoscopic sinus surgery (FESS). Early diagnosis of CSF leak is of paramount importance to prevent life-threatening complications such as brain abscess and meningitis. Imaging plays a crucial role in the detection and characterization of CSF leaks. Three-dimensional, isotropic, high resolution computed tomography (HRCT) accurately detects the site and size of the bony defect. CT cisternography, though invasive, helps accurately identify the site of CSF leak, especially in the presence of multiple bony defects. Magnetic resonance imaging (MRI) accurately detects CSF leaks and associated complications such as the encephaloceles and meningoceles. In this review, we emphasize the importance and usefulness of 3D T2 DRIVE MR cisternography in localizing CSF leaks. This sequence has the advantages of effective bone and fat suppression, decreased artefacts, faster acquisition times, three-dimensional capability, y and high spatial resolution in addition to providing very bright signal from the CSF.

Beyond CD34+ cell dose: impact of method of peripheral blood hematopoietic stem cell mobilization (granulocyte-colony-stimulating factor [G-CSF], G-CSF plus plerixafor, or cyclophosphamide G-CSF/granulocyte-macrophage [GM]-CSF) on number of colony-forming unit-GM, engraftment, and Day +100 hematopoietic graft function.

PubMed

Alexander, Erin T; Towery, Jeanne A; Miller, Ashley N; Kramer, Cindy; Hogan, Kathy R; Squires, Jerry E; Stuart, Robert K; Costa, Luciano J

2011-09-01

The dose of CD34+ cells/kg in the mobilized peripheral blood product is the main determinant of neutrophil and platelet (PLT) engraftment after autologous hematopoietic stem cell transplantation (AHSCT). Whether the method of mobilization, namely, granulocyte-colony-stimulating factor (G-CSF) alone (G), G-CSF plus plerixafor (G+P), or cyclophosphamide + G/granulocyte-macrophage (GM)-CSF (Cy+G/GM), independently affects number of colony-forming unit (CFU)-GM, engraftment, and hematopoietic graft function is unknown. We used a database of AHSCT patients with multiple myeloma or lymphoma to identify three groups with different mobilization strategies receiving transplantation with similar CD34+ cell doses. Groups were compared in terms of CFU-GM, ratio of CFU-GM/CD34+, engraftment of neutrophils and PLTs, and hematopoietic graft function on Day +100. Ninety-six patients were included in the analysis, 26 G, 32 G+P, and 38 Cy+G/GM, with median cell doses of 4.21 × 10(6) , 4.11 × 10(6) , and 4.67 × 10(6) CD34+/kg, respectively (p = 0.433). There was no significant difference in number of CFU-GM between the three groups; however, the ratio of CFU-GM/CD34+ was significantly lower for G+P (p = 0.008). Median time for neutrophil engraftment was 13 days in G+P and 12 days in G and Cy+G/GM (p = 0.028), while PLT engraftment happened at a median of 14.5 days in G+P versus 12 days in G and 11 days in Cy+G/GM (p = 0.012). There was no difference in hematopoietic graft function at Day +100. Plerixafor-based mobilization is associated with slightly reduced number of CFU-GM and minimal delay in engraftment that is independent of CD34+ cell dose. Hematopoietic graft function on Day 100 is not affected by mobilization strategy. © 2011 American Association of Blood Banks.

Determination and Validation of a Lower Cut Off Value of Cerebrospinal Fluid Adenosine Deaminase (CSF-ADA) Activity in Diagnosis of Tuberculous Meningitis.

PubMed

Raviraj; Henry, Renoy A; Rao, G Ganapathi

2017-04-01

Tuberculous meningitis is an infection of the meninges caused by Mycobacterium tuberculosis . It is one of the most common infectious diseases of the Central Nervous System (CNS) and a major health problem in developing countries like India. If there is delay in diagnosis and initiation of specific treatment, it causes significant morbidity and mortality. CSF-ADA 10 U/l is the standard cut off value that is used for differentiation between Tuberculous (TBM) and Non-Tuberculous Meningitis (non-TBM). To determine and validate a lower cut off value for CSF-ADA for diagnosing TBM in an Indian setting. This was a prospective study involving 85 cases of meningitis whose CSF were analysed and ADA estimated using an enzymatic deamination assay kit. Diagnosis of various types of meningitis was made based on specified diagnostic criteria. The comparison of mean value of CSF- ADA activity of the two types of meningitis was done using two Sample t-test. A p-value of <0.05 was considered as significant. Cut off value to differentiate between TBM and non-TBM meningitis was determined using ROC curve analysis. The CSF-ADA activity of TBM and non-TBM cases was compared. The mean CSF-ADA activity was found to be significantly higher in TBM patients (10.97±4.43; Mean±SD) than in non-TBM patients (5.09±1.53) which was statistically significant with a p-value of <0.001. A cut off value of 6.65 was calculated using ROC curve for the diagnosis of TBM which gave a sensitivity of 85.3% and a specificity of 84.3% for differentiating TBM from non-TBM. The positive predictive value was 78.3% and negative predictive value of 89.5% using the above cut off. The positive likelihood ratio was 5.44 and negative likelihood ratio of 0.17 when this lower cut off value was applied. This study has demonstrated that CSF-ADA can be used as an important diagnostic tool in early diagnosis of TBM using a cut off value of 6.65. This cut off value gave a good sensitivity and specificity in differentiating it from non-TBM.

Disturbed Glucose Metabolism in Rat Neurons Exposed to Cerebrospinal Fluid Obtained from Multiple Sclerosis Subjects

PubMed Central

Mathur, Deepali; María-Lafuente, Eva; Ureña-Peralta, Juan R.; Sorribes, Lucas; Hernández, Alberto; Casanova, Bonaventura; López-Rodas, Gerardo; Coret-Ferrer, Francisco; Burgal-Marti, Maria

2017-01-01

Axonal damage is widely accepted as a major cause of permanent functional disability in Multiple Sclerosis (MS). In relapsing-remitting MS, there is a possibility of remyelination by myelin producing cells and restoration of neurological function. The purpose of this study was to delineate the pathophysiological mechanisms underpinning axonal injury through hitherto unknown factors present in cerebrospinal fluid (CSF) that may regulate axonal damage, remyelinate the axon and make functional recovery possible. We employed primary cultures of rat unmyelinated cerebellar granule neurons and treated them with CSF obtained from MS and Neuromyelitis optica (NMO) patients. We performed microarray gene expression profiling to study changes in gene expression in treated neurons as compared to controls. Additionally, we determined the influence of gene-gene interaction upon the whole metabolic network in our experimental conditions using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) program. Our findings revealed the downregulated expression of genes involved in glucose metabolism in MS-derived CSF-treated neurons and upregulated expression of genes in NMO-derived CSF-treated neurons. We conclude that factors in the CSF of these patients caused a perturbation in metabolic gene(s) expression and suggest that MS appears to be linked with metabolic deformity. PMID:29267205

Analytical variables affecting analysis of F2-isoprostanes and F4-neuroprostanes in human cerebrospinal fluid by gas chromatography/mass spectrometry.

PubMed

Yen, Hsiu-Chuan; Wei, Hsing-Ju; Chen, Ting-Wei

2013-01-01

F2-isoprostanes (F2-IsoPs) are a gold marker of lipid peroxidation in vivo, whereas F4-neuroprostanes (F4-NPs) measured in cerebrospinal fluid (CSF) or brain tissue selectively indicate neuronal oxidative damage. Gas chromatography/negative-ion chemical-ionization mass spectrometry (GC/NICI-MS) is the most sensitive and robust method for quantifying these compounds, which is essential for CSF samples because abundance of these compounds in CSF is very low. The present study revealed potential interferences on the analysis of F2-IsoPs and F4-NPs in CSF by GC/NICI-MS due to the use of improper analytical methods that have been employed in the literature. First, simultaneous quantification of F2-IsoPs and F4-NPs in CSF samples processed for F4-NPs analysis could cause poor chromatographic separation and falsely higher F2-IsoPs values for CSF samples with high levels of F2-IsoPs and F4-NPs. Second, retention of unknown substances in GC columns from CSF samples during F4-NPs analysis and from plasma samples during F2-IsoPs analysis might interfere with F4-NPs analysis of subsequent runs, which could be solved by holding columns at a high temperature for a period of time after data acquisition. Therefore, these special issues should be taken into consideration when performing analysis of F2-IsoPs and F4-NPs in CSF to avoid misleading results.

Analytical Variables Affecting Analysis of F2-Isoprostanes and F4-Neuroprostanes in Human Cerebrospinal Fluid by Gas Chromatography/Mass Spectrometry

PubMed Central

Yen, Hsiu-Chuan; Wei, Hsing-Ju; Chen, Ting-Wei

2013-01-01

F2-isoprostanes (F2-IsoPs) are a gold marker of lipid peroxidation in vivo, whereas F4-neuroprostanes (F4-NPs) measured in cerebrospinal fluid (CSF) or brain tissue selectively indicate neuronal oxidative damage. Gas chromatography/negative-ion chemical-ionization mass spectrometry (GC/NICI-MS) is the most sensitive and robust method for quantifying these compounds, which is essential for CSF samples because abundance of these compounds in CSF is very low. The present study revealed potential interferences on the analysis of F2-IsoPs and F4-NPs in CSF by GC/NICI-MS due to the use of improper analytical methods that have been employed in the literature. First, simultaneous quantification of F2-IsoPs and F4-NPs in CSF samples processed for F4-NPs analysis could cause poor chromatographic separation and falsely higher F2-IsoPs values for CSF samples with high levels of F2-IsoPs and F4-NPs. Second, retention of unknown substances in GC columns from CSF samples during F4-NPs analysis and from plasma samples during F2-IsoPs analysis might interfere with F4-NPs analysis of subsequent runs, which could be solved by holding columns at a high temperature for a period of time after data acquisition. Therefore, these special issues should be taken into consideration when performing analysis of F2-IsoPs and F4-NPs in CSF to avoid misleading results. PMID:23957004

CSF Hypocretin-1 Levels and Clinical Profiles in Narcolepsy and Idiopathic CNS Hypersomnia in Norway

PubMed Central

Heier, Mona Skard; Evsiukova, Tatiana; Vilming, Steinar; Gjerstad, Michaela D.; Schrader, Harald; Gautvik, Kaare

2007-01-01

Objective: To evaluate the relationship between CSF hypocretin-1 levels and clinical profiles in narcolepsy and CNS hypersomnia in Norwegian patients. Method: CSF hypocretin-1 was measured by a sensitive radioimmunoassay in 47 patients with narcolepsy with cataplexy, 7 with narcolepsy without cataplexy, 10 with idiopathic CNS hypersomnia, and a control group. Results: Low hypocretin-1 values were found in 72% of the HLA DQB1*0602 positive patients with narcolepsy and cataplexy. Patients with low CSF hypocretin-1 levels reported more extensive muscular involvement during cataplectic attacks than patients with normal levels. Hypnagogic hallucinations and sleep paralysis occurred more frequently in patients with cataplexy than in the other patient groups, but with no correlation to hypocretin-1 levels. Conclusion: About three quarters of the HLA DQB1*0602 positive patients with narcolepsy and cataplexy had low CSF hypocretin-1 values, and appear to form a distinct clinical entity. Narcolepsy without cataplexy could not be distinguished from idiopathic CNS hypersomnia by clinical symptoms or biochemical findings. Citation: Heier MS; Evsiukova T; Vilming S; Gjerstad MD; Schrader H; Gautvik K. CSF hypocretin-1 levels and clinical profiles in narcolepsy and idiopathic CNS hypersomnia in norway. SLEEP 2007;30(8):969-973. PMID:17702265

Relationship between serum visfatin levels and coronary slow-flow phenomenon.

PubMed

Cakmak, Huseyin Altug; Aslan, Serkan; Yalcin, Ahmet Arif; Akturk, Ibrahim Faruk; Yalcin, Burce; Uzun, Fatih; Ozturk, Derya; Erturk, Mehmet; Gul, Mehmet

2015-09-01

Increased levels of visfatin, a novel adipocytokine, are reported in atherosclerosis, obesity, and type 2 diabetes. The aim of the present study was to investigate the relationship between coronary slow flow (CSF) and visfatin in patients undergoing elective coronary angiography for suspected coronary artery disease. A total of 140 recruited participants (90 patients with CSF and 50 controls) were divided into two groups according to their coronary flow rates. Coronary flow was quantified by thrombolysis in myocardial infarction (TIMI) frame count (TFC). Serum visfatin levels were higher in the CSF group than in the control group (3.29 ± 1.11 vs. 2.70 ± 1.08 ng/ml, p = 0.003). A significant correlation was found between TFC and visfatin (r = 0.535, p < 0.001). The area under the receiver operating characteristic curve was 0.720 (95 % confidence interval, 0.622-0.817, p < 0.001) for visfatin in the diagnosis of CSF. If a cut-off value of 2.59 ng/ml was used, higher levels of visfatin could predict the presence of CSF with 78.9 % sensitivity and 64.0 % specificity. Visfatin levels might be a useful biomarker for predicting CSF in patients undergoing diagnostic coronary angiography.

Granulocyte Macrophage-Colony Stimulating Factor-induced Zn Sequestration Enhances Macrophage Superoxide and Limits Intracellular Pathogen Survival

PubMed Central

Vignesh, Kavitha Subramanian; Landero Figueroa, Julio A.; Porollo, Aleksey; Caruso, Joseph A.; Deepe, George S.

2013-01-01

SUMMARY Macrophages possess numerous mechanisms to combat microbial invasion, including sequestration of essential nutrients, like Zn. The pleiotropic cytokine granulocyte macrophage-colony stimulating factor (GM-CSF) enhances antimicrobial defenses against intracellular pathogens such as Histoplasma capsulatum, but its mode of action remains elusive. We have found that GM-CSF activated infected macrophages sequestered labile Zn by inducing binding to metallothioneins (MTs) in a STAT3 and STAT5 transcription factor-dependent manner. GM-CSF upregulated expression of Zn exporters, Slc30a4 and Slc30a7 and the metal was shuttled away from phagosomes and into the Golgi apparatus. This distinctive Zn sequestration strategy elevated phagosomal H+ channel function and triggered reactive oxygen species (ROS) generation by NADPH oxidase. Consequently, H. capsulatum was selectively deprived of Zn, thereby halting replication and fostering fungal clearance. GM-CSF mediated Zn sequestration via MTs in vitro and in vivo in mice and in human macrophages. These findings illuminate a GM-CSF-induced Zn-sequestration network that drives phagocyte antimicrobial effector function. PMID:24138881

Identification of the soluble form of tyrosine kinase receptor Axl as a potential biomarker for intracranial aneurysm rupture.

PubMed

Xu, Jing; Ma, Feiqiang; Yan, Wei; Qiao, Sen; Xu, Shengquan; Li, Yi; Luo, Jianhong; Zhang, Jianmin; Jin, Jinghua

2015-03-05

Subarachnoid hemorrhage caused by a ruptured intracranial aneurysm (RIA) is a devastating condition with significant morbidity and mortality. Despite the fact that RIAs can be prevented by microsurgical clipping or endovascular coiling, there are no reliable means of effectively predicting IA patients at risk for rupture. The purpose of our study was to discover differentially-expressed glycoproteins in IAs with or without rupture as potential biomarkers to predict rupture. Forty age/gender-matched patients with RIA, unruptured IA (UIA), healthy controls (HCs) and disease controls (DCs) (discovery cohort, n = 10 per group) were recruited and a multiplex quantitative proteomic method, iTRAQ (isobaric Tagging for Relative and Absolute protein Quantification), was used to quantify relative changes in the lectin-purified glycoproteins in CSF from RIAs and UIAs compared to HCs and DCs. Then we verified the proteomic results in an independent set of samples (validation cohort, n = 20 per group) by enzyme-linked immunosorbent assay. Finally, we evaluated the specificity and sensitivity of the candidate marker with receiver operating characteristic (ROC) curve methods. The proteomic findings identified 294 proteins, 40 of which displayed quantitative changes unique to RIA, 13 to UIA, and 20 to IA. One of these proteins, receptor tyrosine kinase Axl, was significantly increased in RIA, as confirmed in CSF from the discovery cohort as well as in CSF and plasma from the validation cohort (p <0.05). Spearman's correlation analysis revealed that the CSF and plasma Axl levels were strongly correlated (r = 0.93, p <0.0001). The ROC curve indicated an optimal CSF Axl threshold of 0.12 nM for discriminating RIA from UIA with corresponding sensitivity/specificity of 73.33%/90% and an area under the curve (AUC) of 0.89 (95% CI: 0.80-0.97, p < 0.0001). The optimal threshold for plasma Axl was 1.7 nM with corresponding sensitivity/specificity of 50%/80% and an AUC of 0.71 (95% CI: 0.54-0.87, p = 0.027). Both CSF and plasma Axl levels are significantly elevated in RIA patients. Axl might serve as a promising biomarker to predict the rupture of IA.

Direct Molecular Detection and Genotyping of Borrelia burgdorferi Sensu Lato in Cerebrospinal Fluid of Children with Lyme Neuroborreliosis.

PubMed

Barstad, Bjørn; Quarsten, Hanne; Tveitnes, Dag; Noraas, Sølvi; Ask, Ingvild S; Saeed, Maryam; Bosse, Franziskus; Vigemyr, Grete; Huber, Ilka; Øymar, Knut

2018-05-01

The current diagnostic marker of Lyme neuroborreliosis (LNB), the Borrelia burgdorferi sensu lato antibody index (AI) in the cerebrospinal fluid (CSF), has insufficient sensitivity in the early phase of LNB. We aimed to elucidate the diagnostic value of PCR for B. burgdorferi sensu lato in CSF from children with symptoms suggestive of LNB and to explore B. burgdorferi sensu lato genotypes associated with LNB in children. Children were prospectively included in predefined groups with a high or low likelihood of LNB based on diagnostic guidelines (LNB symptoms, CSF pleocytosis, and B. burgdorferi sensu lato antibodies) or the detection of other causative agents. CSF samples were analyzed by two B. burgdorferi sensu lato -specific real-time PCR assays and, if B. burgdorferi sensu lato DNA was detected, were further analyzed by five singleplex real-time PCR assays for genotype determination. For children diagnosed as LNB patients (58 confirmed and 18 probable) ( n = 76) or non-LNB controls ( n = 28), the sensitivity and specificity of PCR for B. burgdorferi sensu lato in CSF were 46% and 100%, respectively. B. burgdorferi sensu lato DNA was detected in 26/58 (45%) children with AI-positive LNB and in 7/12 (58%) children with AI-negative LNB and symptoms of short duration. Among 36 children with detectable B. burgdorferi sensu lato DNA, genotyping indicated Borrelia garinii ( n = 27) and non- B. garinii ( n = 1) genotypes, while 8 samples remained untyped. Children with LNB caused by B. garinii did not have a distinct clinical picture. The rate of detection of B. burgdorferi sensu lato DNA in the CSF of children with LNB was higher than that reported previously. PCR for B. burgdorferi sensu lato could be a useful supplemental diagnostic tool in unconfirmed LNB cases with symptoms of short duration. B. garinii was the predominant genotype in children with LNB. Copyright © 2018 American Society for Microbiology.

Cerebrospinal Fluid (CSF) Neuronal Biomarkers across the Spectrum of HIV Infection: Hierarchy of Injury and Detection

PubMed Central

Peterson, Julia; Gisslen, Magnus; Zetterberg, Henrik; Fuchs, Dietmar; Shacklett, Barbara L.; Hagberg, Lars; Yiannoutsos, Constantin T.; Spudich, Serena S.; Price, Richard W.

2014-01-01

The character of central nervous system (CNS) HIV infection and its effects on neuronal integrity vary with evolving systemic infection. Using a cross-sectional design and archived samples, we compared concentrations of cerebrospinal fluid (CSF) neuronal biomarkers in 143 samples from 8 HIV-infected subject groups representing a spectrum of untreated systemic HIV progression and viral suppression: primary infection; four groups of chronic HIV infection neuroasymptomatic (NA) subjects defined by blood CD4+ T cells of >350, 200–349, 50–199, and <50 cells/µL; HAD; treatment-induced viral suppression; and ‘elite’ controllers. Samples from 20 HIV-uninfected controls were also examined. The neuronal biomarkers included neurofilament light chain protein (NFL), total and phosphorylated tau (t-tau, p-tau), soluble amyloid precursor proteins alpha and beta (sAPPα, sAPPβ) and amyloid beta (Aβ) fragments 1–42, 1–40 and 1–38. Comparison of the biomarker changes showed a hierarchy of sensitivity in detection and suggested evolving mechanisms with progressive injury. NFL was the most sensitive neuronal biomarker. Its CSF concentration exceeded age-adjusted norms in all HAD patients, 75% of NA CD4<50, 40% of NA CD4 50–199, and 42% of primary infection, indicating common neuronal injury with untreated systemic HIV disease progression as well as transiently during early infection. By contrast, only 75% of HAD subjects had abnormal CSF t-tau levels, and there were no significant differences in t-tau levels among the remaining groups. sAPPα and β were also abnormal (decreased) in HAD, showed less marked change than NFL with CD4 decline in the absence of HAD, and were not decreased in PHI. The CSF Aβ peptides and p-tau concentrations did not differ among the groups, distinguishing the HIV CNS injury profile from Alzheimer's disease. These CSF biomarkers can serve as useful tools in selected research and clinical settings for patient classification, pathogenetic analysis, diagnosis and management. PMID:25541953

Cerebrospinal fluid (CSF) neuronal biomarkers across the spectrum of HIV infection: hierarchy of injury and detection.

PubMed

Peterson, Julia; Gisslen, Magnus; Zetterberg, Henrik; Fuchs, Dietmar; Shacklett, Barbara L; Hagberg, Lars; Yiannoutsos, Constantin T; Spudich, Serena S; Price, Richard W

2014-01-01

The character of central nervous system (CNS) HIV infection and its effects on neuronal integrity vary with evolving systemic infection. Using a cross-sectional design and archived samples, we compared concentrations of cerebrospinal fluid (CSF) neuronal biomarkers in 143 samples from 8 HIV-infected subject groups representing a spectrum of untreated systemic HIV progression and viral suppression: primary infection; four groups of chronic HIV infection neuroasymptomatic (NA) subjects defined by blood CD4+ T cells of >350, 200-349, 50-199, and <50 cells/µL; HAD; treatment-induced viral suppression; and 'elite' controllers. Samples from 20 HIV-uninfected controls were also examined. The neuronal biomarkers included neurofilament light chain protein (NFL), total and phosphorylated tau (t-tau, p-tau), soluble amyloid precursor proteins alpha and beta (sAPPα, sAPPβ) and amyloid beta (Aβ) fragments 1-42, 1-40 and 1-38. Comparison of the biomarker changes showed a hierarchy of sensitivity in detection and suggested evolving mechanisms with progressive injury. NFL was the most sensitive neuronal biomarker. Its CSF concentration exceeded age-adjusted norms in all HAD patients, 75% of NA CD4<50, 40% of NA CD4 50-199, and 42% of primary infection, indicating common neuronal injury with untreated systemic HIV disease progression as well as transiently during early infection. By contrast, only 75% of HAD subjects had abnormal CSF t-tau levels, and there were no significant differences in t-tau levels among the remaining groups. sAPPα and β were also abnormal (decreased) in HAD, showed less marked change than NFL with CD4 decline in the absence of HAD, and were not decreased in PHI. The CSF Aβ peptides and p-tau concentrations did not differ among the groups, distinguishing the HIV CNS injury profile from Alzheimer's disease. These CSF biomarkers can serve as useful tools in selected research and clinical settings for patient classification, pathogenetic analysis, diagnosis and management.

Early applications of granulocyte colony-stimulating factor (G-CSF) can stabilize the blood-optic-nerve barrier and ameliorate inflammation in a rat model of anterior ischemic optic neuropathy (rAION).

PubMed

Wen, Yao-Tseng; Huang, Tzu-Lun; Huang, Sung-Ping; Chang, Chung-Hsing; Tsai, Rong-Kung

2016-10-01

Granulocyte colony-stimulating factor (G-CSF) was reported to have a neuroprotective effect in a rat model of anterior ischemic optic neuropathy (rAION model). However, the therapeutic window and anti-inflammatory effects of G-CSF in a rAION model have yet to be elucidated. Thus, this study aimed to determine the therapeutic window of G-CSF and investigate the mechanisms of G-CSF via regulation of optic nerve (ON) inflammation in a rAION model. Rats were treated with G-CSF on day 0, 1, 2 or 7 post-rAION induction for 5 consecutive days, and a control group were treated with phosphate-buffered saline (PBS). Visual function was assessed by flash visual evoked potentials at 4 weeks post-rAION induction. The survival rate and apoptosis of retinal ganglion cells were determined by FluoroGold labeling and TUNEL assay, respectively. ON inflammation was evaluated by staining of ED1 and Iba1, and ON vascular permeability was determined by Evans Blue extravasation. The type of macrophage polarization was evaluated using quantitative real-time PCR (qRT-PCR). The protein levels of TNF-α and IL-1β were analyzed by western blotting. A therapeutic window during which G-CSF could rescue visual function and retinal ganglion cell survival was demonstrated at day 0 and day 1 post-infarct. Macrophage infiltration was reduced by 3.1- and 1.6-fold by G-CSF treatment starting on day 0 and 1 post-rAION induction, respectively, compared with the PBS-treated group (P<0.05). This was compatible with 3.3- and 1.7-fold reductions in ON vascular permeability after G-CSF treatment compared with PBS treatment (P<0.05). Microglial activation was increased by 3.8- and 3.2-fold in the early (beginning treatment at day 0 or 1) G-CSF-treated group compared with the PBS-treated group (P<0.05). Immediate (within 30 mins of infarct) treatment with G-CSF also induced M2 microglia/macrophage activation. The cytokine levels were lower in the group that received immediate G-CSF treatment compared to those in the later G-CSF treatment group (P<0.05). Early treatment with G-CSF stabilized the blood-ON barrier to reduce macrophage infiltration and induced M2 microglia/macrophage polarization to decrease the expressions of pro-inflammatory cytokines in this rAION model. © 2016. Published by The Company of Biologists Ltd.

Sex-Related Differences in Rat Choroid Plexus and Cerebrospinal Fluid: A cDNA Microarray and Proteomic Analysis.

PubMed

Quintela, T; Marcelino, H; Deery, M J; Feret, R; Howard, J; Lilley, K S; Albuquerque, T; Gonçalves, I; Duarte, A C; Santos, C R A

2016-01-01

The choroid plexus (CP) epithelium is a unique structure in the brain that forms an interface between the peripheral blood and the cerebrospinal fluid (CSF), which is mostly produced by the CP itself. Because the CP transcriptome is regulated by the sex hormone background, the present study compared gene/protein expression profiles in the CP and CSF from male and female rats aiming to better understand sex-related differences in CP functions and brain physiology. We used data previously obtained by cDNA microarrays to compare the CP transcriptome between male and female rats, and complemented these data with the proteomic analysis of the CSF of castrated and sham-operated males and females. Microarray analysis showed that 17 128 and 17 002 genes are expressed in the male and female CP, which allowed the functional annotation of 141 and 134 pathways, respectively. Among the most expressed genes, canonical pathways associated with mitochondrial dysfunctions and oxidative phosphorylation were the most prominent, whereas the most relevant molecular and cellular functions annotated were protein synthesis, cellular growth and proliferation, cell death and survival, molecular transport, and protein trafficking. No significant differences were found between males and females regarding these pathways. Seminal functions of the CP differentially regulated between sexes were circadian rhythm signalling, as well as several canonical pathways related to stem cell differentiation, metabolism and the barrier function of the CP. The proteomic analysis identified five down-regulated proteins in the CSF samples from male rats compared to females and seven proteins exhibiting marked variation in the CSF of gonadectomised males compared to sham animals, whereas no differences were found between sham and ovariectomised females. These data clearly show sex-related differences in CP gene expression and CSF protein composition that may impact upon neurological diseases. © 2015 British Society for Neuroendocrinology.

Multipronged attenuation of macrophage-colony stimulating factor signaling by Epstein-Barr virus BARF1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shim, Ann Hye-Ryong; Chang, Rhoda Ahn; Chen, Xiaoyan

The ubiquitous EBV causes infectious mononucleosis and is associated with several types of cancers. The EBV genome encodes an early gene product, BARF1, which contributes to pathogenesis, potentially through growth-altering and immune-modulating activities, but the mechanisms for such activities are poorly understood. We have determined the crystal structure of BARF1 in complex with human macrophage-colony stimulating factor (M-CSF), a hematopoietic cytokine with pleiotropic functions in development and immune response. BARF1 and M-CSF form a high-affinity, stable, ring-like complex in both solution and the crystal, with a BARF1 hexameric ring surrounded by three M-CSF dimers in triangular array. The binding ofmore » BARF1 to M-CSF dramatically reduces but does not completely abolish M-CSF binding and signaling through its cognate receptor FMS. A three-pronged down-regulation mechanism is proposed to explain the biological effect of BARF1 on M-CSF:FMS signaling. These prongs entail control of the circulating and effective local M-CSF concentration, perturbation of the receptor-binding surface of M-CSF, and imposition of an unfavorable global orientation of the M-CSF dimer. Each prong may reduce M-CSF:FMS signaling to a limited extent but in combination may alter M-CSF:FMS signaling dramatically. The downregulating mechanism of BARF1 underlines a viral modulation strategy, and provides a basis for understanding EBV pathogenesis.« less

Pten Cell Autonomously Modulates the Hematopoietic Stem Cell Response to Inflammatory Cytokines.

PubMed

Porter, Shaina N; Cluster, Andrew S; Signer, Robert A J; Voigtmann, Jenna; Monlish, Darlene A; Schuettpelz, Laura G; Magee, Jeffrey A

2016-06-14

Pten negatively regulates the phosphatidylinositol 3-kinase (PI3K) pathway and is required to maintain quiescent adult hematopoietic stem cells (HSCs). Pten has been proposed to regulate HSCs cell autonomously and non-cell autonomously, but the relative importance of each mechanism has not been directly tested. Furthermore, the cytokines that activate the PI3K pathway upstream of Pten are not well defined. We sought to clarify whether Pten cell autonomously or non-cell autonomously regulates HSC mobilization. We also tested whether Pten deficiency affects the HSC response to granulocyte colony-stimulating factor (G-CSF) and interferon-α (IFNα) since these cytokines induce HSC mobilization or proliferation, respectively. We show that Pten regulates HSC mobilization and expansion in the spleen primarily via cell-autonomous mechanisms. Pten-deficient HSCs do not require G-CSF to mobilize, although they are hyper-sensitized to even low doses of exogenous G-CSF. Pten-deficient HSCs are similarly sensitized to IFNα. Pten therefore modulates the HSC response to inflammatory cytokines. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Correlation between decreased CSF α-synuclein and Aβ₁₋₄₂ in Parkinson disease.

PubMed

Buddhala, Chandana; Campbell, Meghan C; Perlmutter, Joel S; Kotzbauer, Paul T

2015-01-01

Accumulation of misfolded α-synuclein (α-syn) protein in Lewy bodies and neurites is the cardinal pathologic feature of Parkinson disease (PD), but abnormal deposition of other proteins may also play a role. Cerebrospinal fluid (CSF) levels of proteins known to accumulate in PD may provide insight into disease-associated changes in protein metabolism and their relationship to disease progression. We measured CSF α-syn, amyloid β₁₋₄₂ (Aβ₁₋₄₂), and tau from 77 nondemented PD and 30 control participants. CSF α-syn and Aβ₁₋₄₂ were significantly lower in PD compared with controls. In contrast with increased CSF tau in Alzheimer disease, CSF tau did not significantly differ between PD and controls. CSF protein levels did not significantly correlate with ratings of motor function or performance on neuropsychological testing. As expected, CSF Aβ₁₋₄₂ inversely correlated with [(11)C]-Pittsburgh compound B (PiB) mean cortical binding potential, with PiB(+) PD participants having lower CSF Aβ₁₋₄₂ compared with PiB(-) PD participants. Furthermore, CSF α-syn positively correlated with Aβ₁₋₄₂ in PD participants but not in controls, suggesting a pathophysiologic connection between the metabolisms of these proteins in PD. Copyright © 2015 Elsevier Inc. All rights reserved.

Immune-enhancing effect of nano-DNA vaccine encoding a gene of the prME protein of Japanese encephalitis virus and BALB/c mouse granulocyte-macrophage colony-stimulating factor

PubMed Central

ZHAI, YONGZHEN; ZHOU, YAN; LI, XIMEI; FENG, GUOHE

2015-01-01

Plasmid-encoded granulocyte-macrophage colony-stimulating factor (GM-CSF) is an adjuvant for genetic vaccines; however, how GM-CSF enhances immunogenicity remains to be elucidated. In the present study, it was demonstrated that injection of a plasmid encoding the premembrane (prM) and envelope (E) protein of Japanese encephalitis virus and mouse GM-CSF (pJME/GM-CSF) into mouse muscle recruited large and multifocal conglomerates of macrophages and granulocytes, predominantly neutrophils. During the peak of the infiltration, an appreciable number of immature dendritic cells (DCs) appeared, although no T and B-cells was detected. pJME/GM-CSF increased the number of splenic DCs and the expression of major histocompatibility complex class II (MHCII) on splenic DC, and enhanced the antigenic capture, processing and presentation functions of splenic DCs, and the cell-mediated immunity induced by the vaccine. These findings suggested that the immune-enhancing effect by pJME/GM-CSF was associated with infiltrate size and the appearance of integrin αx (CD11c)+cells. Chitosan-pJME/GM-CSF nanoparticles, prepared by coacervation via intramuscular injection, outperformed standard pJME/GM-CSF administrations in DC recruitment, antigen processing and presentation, and vaccine enhancement. This revealed that muscular injection of chitosan-pJME/GM-CSF nanoparticles may enhance the immunoadjuvant properties of GM-CSF. PMID:25738258

Immune-enhancing effect of nano-DNA vaccine encoding a gene of the prME protein of Japanese encephalitis virus and BALB/c mouse granulocyte-macrophage colony-stimulating factor.

PubMed

Zhai, Yongzhen; Zhou, Yan; Li, Ximei; Feng, Guohe

2015-07-01

Plasmid-encoded granulocyte-macrophage colony-stimulating factor (GM‑CSF) is an adjuvant for genetic vaccines; however, how GM-CSF enhances immunogenicity remains to be elucidated. In the present study, it was demonstrated that injection of a plasmid encoding the premembrane (prM) and envelope (E) protein of Japanese encephalitis virus and mouse GM-CSF (pJME/GM-CSF) into mouse muscle recruited large and multifocal conglomerates of macrophages and granulocytes, predominantly neutrophils. During the peak of the infiltration, an appreciable number of immature dendritic cells (DCs) appeared, although no T and B-cells was detected. pJME/GM-CSF increased the number of splenic DCs and the expression of major histocompatibility complex class II (MHCII) on splenic DC, and enhanced the antigenic capture, processing and presentation functions of splenic DCs, and the cell-mediated immunity induced by the vaccine. These findings suggested that the immune-enhancing effect by pJME/GM-CSF was associated with infiltrate size and the appearance of integrin αx (CD11c)+cells. Chitosan-pJME/GM-CSF nanoparticles, prepared by coacervation via intramuscular injection, outperformed standard pJME/GM-CSF administrations in DC recruitment, antigen processing and presentation, and vaccine enhancement. This revealed that muscular injection of chitosan‑pJME/GM-CSF nanoparticles may enhance the immunoadjuvant properties of GM-CSF.

Neutrophil-to-lymphocyte ratio in the differential diagnosis of acute bacterial meningitis.

PubMed

Mentis, A-F A; Kyprianou, M A; Xirogianni, A; Kesanopoulos, K; Tzanakaki, G

2016-03-01

The differential diagnosis of acute community-acquired meningitis is of paramount importance in both therapeutic and healthcare-related economic terms. Despite the routinely used markers, novel, easily calculated, and rapidly available biomarkers are needed particularly in resource-poor settings. A promising, exponentially studied inflammatory marker is the neutrophil-to-lymphocyte ratio (NLR), albeit not assessed in meningitis. The aim of this study was to investigate the utility of the NLR in the differential diagnosis of acute meningitis. Data on cerebrospinal fluid (CSF) and blood leukocyte parameters from more than 4,000 patients diagnosed with either bacterial or viral meningitis in Greece during the period 2006-2013 were retrospectively examined. The diagnostic accuracy of the NLR and neutrophil counts in CSF and blood were evaluated by receiver operating characteristic curves. The discrimination ability of both the NLR and neutrophil counts was significantly higher in CSF than in blood. The optimal cutoff values of the NLR and neutrophil counts were 2 in CSF vs 8 in blood, and 287 cells in CSF vs 12,100 cells in blood, respectively. For these values, sensitivity, negative predictive value, and odds ratio were statistically significantly higher in CSF than blood for both markers. Logistic regression analysis showed that the CSF NLR carries independent and additive information to neutrophil counts in the differential diagnosis of acute meningitis. This study is the first one to assess NLR in acute meningitis, providing promising results for its differential diagnosis.

Clinical Prognosis in Neonatal Bacterial Meningitis: The Role of Cerebrospinal Fluid Protein.

PubMed

Tan, Jintong; Kan, Juan; Qiu, Gang; Zhao, Dongying; Ren, Fang; Luo, Zhongcheng; Zhang, Yongjun

2015-01-01

Neonates are at high risk of meningitis and of resulting neurologic complications. Early recognition of neonates at risk of poor prognosis would be helpful in providing timely management. From January 2008 to June 2014, we enrolled 232 term neonates with bacterial meningitis admitted to 3 neonatology departments in Shanghai, China. The clinical status on the day of discharge from these hospitals or at a postnatal age of 2.5 to 3 months was evaluated using the Glasgow Outcome Scale (GOS). Patients were classified into two outcome groups: good (167 cases, 72.0%, GOS = 5) or poor (65 cases, 28.0%, GOS = 1-4). Neonates with good outcome had less frequent apnea, drowsiness, poor feeding, bulging fontanelle, irritability and more severe jaundice compared to neonates with poor outcome. The good outcome group also had less pneumonia than the poor outcome group. Besides, there were statistically significant differences in hemoglobin, mean platelet volume, platelet distribution width, C-reaction protein, procalcitonin, cerebrospinal fluid (CSF) glucose and CSF protein. Multivariate logistic regression analyses suggested that poor feeding, pneumonia and CSF protein were the predictors of poor outcome. CSF protein content was significantly higher in patients with poor outcome. The best cut-offs for predicting poor outcome were 1,880 mg/L in CSF protein concentration (sensitivity 70.8%, specificity 86.2%). After 2 weeks of treatment, CSF protein remained higher in the poor outcome group. High CSF protein concentration may prognosticate poor outcome in neonates with bacterial meningitis.

Effects of Granulocyte-Macrophage Colony-Stimulating (GM-CSF) Factor on Corneal Epithelial Cells in Corneal Wound Healing Model

PubMed Central

Rho, Chang Rae; Park, Mi-young; Kang, Seungbum

2015-01-01

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that activates granulocyte and macrophage cell lineages. It is also known to have an important function in wound healing. This study investigated the effect of GM-CSF in wound healing of human corneal epithelial cells (HCECs). We used human GM-CSF derived from rice cells (rice cell-derived recombinant human GM-CSF; rhGM-CSF). An in vitro migration assay was performed to investigate the migration rate of HCECs treated with various concentrations of rhGM-CSF (0.1, 1.0, and 10.0 μg/ml). MTT assay and flow cytometric analysis were used to evaluate the proliferative effect of rhGM-CSF. The protein level of p38MAPK was analyzed by western blotting. For in vivo analysis, 100 golden Syrian hamsters were divided into four groups, and their corneas were de-epithelialized with alcohol and a blade. The experimental groups were treated with 10, 20, or 50 μg/ml rhGM-CSF four times daily, and the control group was treated with phosphate-buffered saline. The corneal wound-healing rate was evaluated by fluorescein staining at the initial wounding and 12, 24, 36, and 48 hours after epithelial debridement. rhGM-CSF accelerated corneal epithelial wound healing both in vitro and in vivo. MTT assay and flow cytometric analysis revealed that rhGM-CSF treatment had no effects on HCEC proliferation. Western blot analysis demonstrated that the expression level of phosphorylated p38MAPK increased with rhGM-CSF treatment. These findings indicate that rhGM-CSF enhances corneal wound healing by accelerating cell migration. PMID:26376304

Effects of Granulocyte-Macrophage Colony-Stimulating (GM-CSF) Factor on Corneal Epithelial Cells in Corneal Wound Healing Model.

PubMed

Rho, Chang Rae; Park, Mi-young; Kang, Seungbum

2015-01-01

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that activates granulocyte and macrophage cell lineages. It is also known to have an important function in wound healing. This study investigated the effect of GM-CSF in wound healing of human corneal epithelial cells (HCECs). We used human GM-CSF derived from rice cells (rice cell-derived recombinant human GM-CSF; rhGM-CSF). An in vitro migration assay was performed to investigate the migration rate of HCECs treated with various concentrations of rhGM-CSF (0.1, 1.0, and 10.0 μg/ml). MTT assay and flow cytometric analysis were used to evaluate the proliferative effect of rhGM-CSF. The protein level of p38MAPK was analyzed by western blotting. For in vivo analysis, 100 golden Syrian hamsters were divided into four groups, and their corneas were de-epithelialized with alcohol and a blade. The experimental groups were treated with 10, 20, or 50 μg/ml rhGM-CSF four times daily, and the control group was treated with phosphate-buffered saline. The corneal wound-healing rate was evaluated by fluorescein staining at the initial wounding and 12, 24, 36, and 48 hours after epithelial debridement. rhGM-CSF accelerated corneal epithelial wound healing both in vitro and in vivo. MTT assay and flow cytometric analysis revealed that rhGM-CSF treatment had no effects on HCEC proliferation. Western blot analysis demonstrated that the expression level of phosphorylated p38MAPK increased with rhGM-CSF treatment. These findings indicate that rhGM-CSF enhances corneal wound healing by accelerating cell migration.

GM-CSF and IL-3 Modulate Human Monocyte TNF-α Production and Renewal in In Vitro Models of Trained Immunity.

PubMed

Borriello, Francesco; Iannone, Raffaella; Di Somma, Sarah; Loffredo, Stefania; Scamardella, Eloise; Galdiero, Maria Rosaria; Varricchi, Gilda; Granata, Francescopaolo; Portella, Giuseppe; Marone, Gianni

2016-01-01

GM-CSF and IL-3 are hematopoietic cytokines that also modulate the effector functions of several immune cell subsets. In particular, GM-CSF and IL-3 exert a significant control on monocyte and macrophage effector functions, as assessed in experimental models of inflammatory and autoimmune diseases and also in human studies. Here, we sought to investigate the mechanisms and the extent to which GM-CSF and IL-3 modulate the pro-inflammatory, LPS-mediated, activation of human CD14 + monocytes taking into account the new concept of trained immunity (i.e., the priming stimulus modulates the response to subsequent stimuli mainly by inducing chromatin remodeling and increased transcription at relevant genetic loci). We demonstrate that GM-CSF and IL-3 priming enhances TNF-α production upon subsequent LPS stimulation (short-term model of trained immunity) in a p38- and SIRT2-dependent manner without increasing TNF primary transcript levels (a more direct measure of transcription), thus supporting a posttranscriptional regulation of TNF-α in primed monocytes. GM-CSF and IL-3 priming followed by 6 days of resting also results in increased TNF-α production upon LPS stimulation (long-term model of trained immunity). In this case, however, GM-CSF and IL-3 priming induces a c-Myc-dependent monocyte renewal and increase in cell number that is in turn responsible for heightened TNF-α production. Overall, our results provide insights to understand the biology of monocytes in health and disease conditions in which the hematopoietic cytokines GM-CSF and IL-3 play a role and also extend our knowledge of the cellular and molecular mechanisms of trained immunity.

Roles of Stat3 and ERK in G-CSF signaling.

PubMed

Kamezaki, Kenjirou; Shimoda, Kazuya; Numata, Akihiko; Haro, Takashi; Kakumitsu, Haruko; Yoshie, Masumi; Yamamoto, Masahiro; Takeda, Kiyoshi; Matsuda, Tadashi; Akira, Shizuo; Ogawa, Katsuhiro; Harada, Mine

2005-02-01

G-CSF specifically stimulates the proliferation and differentiation of cells that are committed to the neutrophil-granulocyte lineage. Although Stat3 was thought to be essential for the transduction of G-CSF-induced cell proliferation and differentiation signals, mice deficient for Stat3 in hematopoietic cells show neutrocytosis and infiltration of cells into the digestive tract. The number of progenitor cells in the neutrophil lineage is not changed, and G-CSF-induced proliferation of progenitor cells and prolonged neutrophil survival were observed in Stat3-deficient mice. In hematopoietic cells from Stat3-deficient mice, trace levels of SOCS3, a negative regulator of granulopoiesis, were observed, and SOCS3 expression was not induced by G-CSF stimulation. Stat3-null bone marrow cells displayed a significant activation of extra-cellular regulated kinase 1 (ERK1)/ERK2 under basal conditions, and the activation of ERK was enhanced and sustained by G-CSF stimulation. Furthermore, the augmented proliferation of Stat3-deficient bone marrow cells in response to G-CSF was dramatically decreased by addition of a MEK1 inhibitor. These results indicate that Stat3 functions as a negative regulator of G-CSF signaling by inducing SOCS3 expression and that ERK activation is the major factor responsible for inducing the proliferation of hematopoietic cells in response to G-CSF.

Numerical evaluation of moiré pattern in touch sensor module with electrode mesh structure in oblique view

NASA Astrophysics Data System (ADS)

Pournoury, M.; Zamiri, A.; Kim, T. Y.; Yurlov, V.; Oh, K.

2016-03-01

Capacitive touch sensor screen with the metal materials has recently become qualified for substitution of ITO; however several obstacles still have to be solved. One of the most important issues is moiré phenomenon. The visibility problem of the metal-mesh, in touch sensor module (TSM) is numerically considered in this paper. Based on human eye contract sensitivity function (CSF), moiré pattern of TSM electrode mesh structure is simulated with MATLAB software for 8 inch screen display in oblique view. Standard deviation of the generated moiré by the superposition of electrode mesh and screen image is calculated to find the optimal parameters which provide the minimum moiré visibility. To create the screen pixel array and mesh electrode, rectangular function is used. The filtered image, in frequency domain, is obtained by multiplication of Fourier transform of the finite mesh pattern (product of screen pixel and mesh electrode) with the calculated CSF function for three different observer distances (L=200, 300 and 400 mm). It is observed that the discrepancy between analytical and numerical results is less than 0.6% for 400 mm viewer distance. Moreover, in the case of oblique view due to considering the thickness of the finite film between mesh electrodes and screen, different points of minimum standard deviation of moiré pattern are predicted compared to normal view.

Two signs indicative of successful access in nuclear medicine cerebrospinal fluid diversionary shunt studies.

PubMed

Bermo, Mohammed S; Khalatbari, Hedieh; Parisi, Marguerite T

2018-05-08

Successful shunt access is the first step in a properly performed nuclear medicine cerebrospinal fluid (CSF) shunt study. To determine the significance of the radiotracer configuration at the injection site during initial nuclear medicine CSF shunt imaging and the lack of early systemic radiotracer activity as predictors of successful shunt access. With Institutional Review Board approval, three nuclear medicine physicians performed a retrospective review of all consecutive CSF shunt studies performed in children at our institution in 2015. Antecedent nuclear medicine CSF shunt studies in these patients were also assessed and included in the review. The appearance of the reservoir site immediately after radiotracer injection was classified as either figure-of-eight or round/ovoid configuration. The presence or absence of early systemic distribution of the tracer on the 5-min static images was noted and separately evaluated. A total of 98 nuclear medicine ventriculoperitoneal CSF shunt studies were evaluated. Figure-of-eight configuration was identified in 87% of studies and, when present, had 93% sensitivity, 78% specificity, 92% accuracy, 98% positive predictive value (PPV) and 54% negative predictive value (NPV) as a predictor of successful shunt access. Early systemic activity was absent in 89 of 98 studies. Lack of early systemic distribution of the radiotracer had 98% sensitivity, 78% specificity, 96% accuracy, 98% PPV and 78% NPV as a predictor of successful shunt access. Figure-of-eight configuration in conjunction with the absence of early systemic tracer activity had 99% PPV for successful shunt access. Figure-of-eight configuration at the injection site or lack of early systemic radiotracer activity had moderate specificity for successful shunt access. Specificity and PPV significantly improved when both signs were combined in assessment.

High-performance liquid chromatographic determination of histamine in biological samples: the cerebrospinal fluid challenge--a review.

PubMed

Wang, Zhaopin; Wu, Juanli; Wu, Shihua; Bao, Aimin

2013-04-24

Histamine, a neurotransmitter crucially involved in a number of basic physiological functions, undergoes changes in neuropsychiatric disorders. Detection of histamine in biological samples such as cerebrospinal fluid (CSF) is thus of clinical importance. The most commonly used method for measuring histamine levels is high performance liquid chromatography (HPLC). However, factors such as very low levels of histamine, the even lower CSF-histamine and CSF-histamine metabolite levels, especially in certain neuropsychiatric diseases, rapid formation of histamine metabolites, and other confounding elements during sample collection, make analysis of CSF-histamine and CSF-histamine metabolites a challenging task. Nonetheless, this challenge can be met, not only with respect to HPLC separation column, derivative reagent, and detector, but also in terms of optimizing the CSF sample collection. This review aims to provide a general insight into the quantitative analyses of histamine in biological samples, with an emphasis on HPLC instruments, methods, and hyphenated techniques, with the aim of promoting the development of an optimal and practical protocol for the determination of CSF-histamine and/or CSF-histamine metabolites. Copyright © 2013 Elsevier B.V. All rights reserved.

Dual Role of GM-CSF as a Pro-Inflammatory and a Regulatory Cytokine: Implications for Immune Therapy

PubMed Central

Bhattacharya, Palash; Budnick, Isadore; Singh, Medha; Thiruppathi, Muthusamy; Alharshawi, Khaled; Elshabrawy, Hatem; Holterman, Mark J.

2015-01-01

Granulocyte macrophage colony stimulating factor (GM-CSF) is generally recognized as an inflammatory cytokine. Its inflammatory activity is primarily due its role as a growth and differentiation factor for granulocyte and macrophage populations. In this capacity, among other clinical applications, it has been used to bolster anti-tumor immune responses. GM-CSF-mediated inflammation has also been implicated in certain types of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. Thus, agents that can block GM-CSF or its receptor have been used as anti-inflammatory therapies. However, a review of literature reveals that in many situations GM-CSF can act as an anti-inflammatory/regulatory cytokine. We and others have shown that GM-CSF can modulate dendritic cell differentiation to render them “tolerogenic,” which, in turn, can increase regulatory T-cell numbers and function. Therefore, the pro-inflammatory and regulatory effects of GM-CSF appear to depend on the dose and the presence of other relevant cytokines in the context of an immune response. A thorough understanding of the various immunomodulatory effects of GM-CSF will facilitate more appropriate use and thus further enhance its clinical utility. PMID:25803788

Stimulatory versus suppressive effects of GM-CSF on tumor progression in multiple cancer types

PubMed Central

Hong, In-Sun

2016-01-01

Granulocyte-macrophage colony-stimulating factor (GM-CSF, also called CSF-2) is best known for its critical role in immune modulation and hematopoiesis. A large body of experimental evidence indicates that GM-CSF, which is frequently upregulated in multiple types of human cancers, effectively marks cancer cells with a ‘danger flag' for the immune system. In this context, most studies have focused on its function as an immunomodulator, namely its ability to stimulate dendritic cell (DC) maturation and monocyte/macrophage activity. However, recent studies have suggested that GM-CSF also promotes immune-independent tumor progression by supporting tumor microenvironments and stimulating tumor growth and metastasis. Although some studies have suggested that GM-CSF has inhibitory effects on tumor growth and metastasis, an even greater number of studies show that GM-CSF exerts stimulatory effects on tumor progression. In this review, we summarize a number of findings to provide the currently available information regarding the anticancer immune response of GM-CSG. We then discuss the potential roles of GM-CSF in the progression of multiple types of cancer to provide insights into some of the complexities of its clinical applications. PMID:27364892

The choroid plexus: function, pathology and therapeutic potential of its transplantation.

PubMed

Emerich, Dwaine F; Vasconcellos, Alfred V; Elliott, Robert B; Skinner, Stephen J M; Borlongan, Cesario V

2004-08-01

The choroid plexus (CP) produces cerebrospinal fluid (CSF) and forms the blood-CSF barrier. However, the CP may have additional functions in the CNS beyond these traditional roles. Preclinical and clinical studies in ageing and neurodegeneration demonstrate anatomical and physiological changes in CP, suggesting roles in normal and pathological conditions and potentially endogenous repair processes following trauma. One of the broadest functions of the CP is establishing and maintaining the extracellular milieu throughout the brain and spinal cord, in part by secreting numerous growth factors into the CSF. The endogenous secretion of growth factors raises the possibility that transplantable CP might enable delivery of these molecules to the brain, while avoiding the conventional molecular and genetic alterations associated with modifying cells to secrete selected products. This review describes some of the anatomical and functional changes of CP in ageing and neurodegeneration, and recent demonstrations of the therapeutic potential of transplanted CP for neural trauma.

Cerebrospinal fluid as a reflector of central cholinergic and amino acid neurotransmitter activity in cerebellar ataxia.

PubMed

Manyam, B V; Giacobini, E; Ferraro, T N; Hare, T A

1990-11-01

Cerebrospinal fluid (CSF) amino acid neurotransmitters, related compounds, and their precursors, choline levels, and acetylcholinesterase activity were measured in the CSF of patients with cerebellar ataxia during a randomized, double-blind, crossover, placebo-controlled clinical trial of physostigmine salicylate. The CSF gamma-aminobutyric acid, methionine, and choline levels, adjusted for age, were significantly lower in patients with cerebellar ataxia compared with controls. Physostigmine selectively reduced the level of CSF isoleucine and elevated the levels of phosphoethanolamine. No change occurred in CSF acetylcholinesterase activity and in the levels of plasma amino compounds in patients with cerebellar ataxia when compared with controls. Median ataxia scores did not statistically differ between placebo and physostigmine nor did functional improvement occur in any of the patients.

Direct anti-inflammatory effects of granulocyte colony-stimulating factor (G-CSF) on activation and functional properties of human T cell subpopulations in vitro.

PubMed

Malashchenko, Vladimir Vladimirovich; Meniailo, Maxsim Evgenievich; Shmarov, Viacheslav Anatolievich; Gazatova, Natalia Dinislamovna; Melashchenko, Olga Borisovna; Goncharov, Andrei Gennadievich; Seledtsova, Galina Victorovna; Seledtsov, Victor Ivanovich

2018-03-01

We investigated the direct effects of human granulocyte colony-stimulating factor (G-CSF) on functionality of human T-cell subsets. CD3 + T-lymphocytes were isolated from blood of healthy donors by positive magnetic separation. T cell activation with particles conjugated with antibodies (Abs) to human CD3, CD28 and CD2 molecules increased the proportion of cells expressing G-CSF receptor (G-CSFR, CD114) in all T cell subpopulations studied (CD45RA + /CD197 + naive T cells, CD45RA - /CD197 + central memory T cells, CD45RA - /CD197 - effector memory T cells and CD45RA + /CD197 - terminally differentiated effector T cells). Upon T-cell activation in vitro, G-CSF (10.0 ng/ml) significantly and specifically enhanced the proportion of CD114 + T cells in central memory CD4 + T cell compartment. A dilution series of G-CSF (range, 0.1-10.0 ng/ml) was tested, with no effect on the expression of CD25 (interleukin-2 receptor α-chain) on activated T cells. Meanwhile, G-CSF treatment enhanced the proportion of CD38 + T cells in CD4 + naïve T cell, effector memory T cell and terminally differentiated effector T cell subsets, as well as in CD4 - central memory T cells and terminally differentiated effector T cells. G-CSF did not affect IL-2 production by T cells; relatively low concentrations of G-CSF down-regulated INF-γ production, while high concentrations of this cytokine up-regulated IL-4 production in activated T cells. The data obtained suggests that G-CSF could play a significant role both in preventing the development of excessive and potentially damaging inflammatory reactivity, and in constraining the expansion of potentially cytodestructive T cells. Copyright © 2018 Elsevier Inc. All rights reserved.

Effect of outpatient treatment of febrile neutropenia on the risk threshold for the use of CSF in patients with cancer treated with chemotherapy.

PubMed

Cosler, Leon E; Sivasubramaniam, Visaharan; Agboola, Olayemi; Crawford, Jeffrey; Dale, David; Lyman, Gary H

2005-01-01

Febrile neutropenia (FN) in patients with cancer treated with chemotherapy has traditionally been managed with inpatient broad-spectrum antibiotics until the infection and neutropenia have resolved. A newer strategy is outpatient oral or intravenous antibiotics in selected patients after an initial hospitalization. We sought to determine these costs, both overall and relative to those of traditional management, and the optimal role of prophylactic colony-stimulating factor (CSF) in patients at greatest risk for FN. Existing economic decision models were modified by incorporating a treatment strategy for FN in which patients are classified as high- and low-risk according to criteria described by Talcott. Low-risk patients were assumed to be treated as outpatients. Overall costs with the revised economic model were assessed and sensitivity analyses were performed. The costs of an episode of FN were estimated as 1) no CSF: dollar 13,355; 2) CSF with hospitalization for FN: dollar 8677; and 3) CSF with risk stratification and outpatient management in low-risk patients: dollar 8188. The risk threshold for the cost-effective use of CSF was only slightly lower with outpatient treatment. When all patients with FN are treated as inpatients and the cost of hospitalization is dollar 1750/day the risk threshold for FN at which prophylactic CSF becomes cost-effective is 16%. It is 15% when low-risk patients are treated as outpatients. Outpatient treatment slightly decreases the risk threshold for FN at which prophylactic CSF becomes cost-effective. The limited economic effect of this strategy may be because the patients who were at greatest risk of complications had significantly longer lengths of stay and accounted for most of the hospitalization costs.

T Cell Intrinsic Function of the Noncanonical NF-κB Pathway in the Regulation of GM-CSF Expression and EAE Pathogenesis

PubMed Central

Yu, Jiayi; Zhou, Xiaofei; Nakaya, Mako; Jin, Wei; Cheng, Xuhong; Sun, Shao-Cong

2014-01-01

The Noncanonical NF-κB pathway induces processing of the NF-κB2 precursor protein p100 and, thereby, mediates activation of p52-containing NF-κB complexes. This pathway is crucial for B-cell maturation and humoral immunity, but its role in regulating T-cell function is less clear. Using mutant mice that express a non-processible p100, NF-κB2lym1, we show that the noncanonical NF-κB pathway has a T cell-intrinsic role in regulating the pathogenesis of a T cell-mediated autoimmunity, experimental autoimmune encephalomyelitis (EAE). Although the lym1 mutation does not interfere with naïve T-cell activation, it renders the Th17 cells defective in the production of inflammatory effector molecules, particularly the cytokine GM-CSF. We provide evidence that p52 binds to the promoter of the GM-CSF-encoding gene (Csf2) and cooperates with c-Rel in the transactivation of this target gene. Introduction of exogenous p52 or GM-CSF to the NF-κB2lym1 mutant T cells partially restores their ability to induce EAE. These results suggest that the noncanonical NF-κB pathway mediates induction of EAE by regulating the effector function of inflammatory T cells. PMID:24899500

Evaluation of blood-brain barrier function by quotient alpha2 macroglobulin and its relationship with interleukin-6 and complement component 3 levels in neuropsychiatric systemic lupus erythematosus

PubMed Central

Asano, Tomoyuki; Ito, Hiromi; Kariya, Yoshinobu; Hoshi, Kyoka; Yoshihara, Akioh; Ugawa, Yoshikazu; Sekine, Hideharu; Hirohata, Shunsei; Yamaguchi, Yoshiki; Sato, Shuzo; Kobayashi, Hiroko; Migita, Kiyoshi; Ohira, Hiromasa; Hashimoto, Yasuhiro

2017-01-01

Although quotient of alpha2 macroglobulin (Qα2MG) was previously reported to be useful for the evaluation of blood–brain barrier (BBB) function, it is not commonly used. We therefore evaluated BBB function among the various subsets of neuropsychiatric systemic lupus erythematosus (NPSLE) using quotient Q α2MG. Furthermore, we determined the correlation between Q α2MG and cerebrospinal (CSF) interleukin (IL)-6 level and quotient complement component 3 (Q C3). To determine intrathecal production of C3, the C3 index (Q C3/Q α2MG) was also calculated. Fifty-six patients with SLE were included in this study. Of these, 48 were diagnosed with NPSLE, consisting of 30 diffuse NPSLE patients (acute confusional state (ACS): n = 14, non-ACS: n = 16) and 18 patients with focal NPSLE. CSF IL-6 concentration, and paired serum and CSF levels of α2MG and C3, were measured by enzyme-linked immuno solvent assay (ELISA). The Q α2MG, Q C3, and C3 index were then calculated. Q α2MG, Q C3, and IL-6 concentrations in the CSF were significantly elevated in NPSLE compared with non-NPSLE. Among the subsets of NPSLE, significant increases in Q α2MG, CSF IL-6, and Q C3 were observed in ACS compared with non-ACS or focal NPSLE. There was a positive correlation between CSF IL-6 level and Q α2MG, as well as between Q C3 and Q α2MG, in diffuse NPSLE. There were no significant differences in C3 index between NPSLE and non-NPSLE, as well as among the subgroups of NPSLE. Our study suggests that BBB disruption is present in ACS, and elevated levels of IL-6 and C3 in CSF in diffuse NPSLE, especially in ACS, might result from their entry to the CSF from the systemic circulation through the damaged BBB, as well as increased intrathecal production. Furthermore, Q α2MG might be useful for the evaluation of BBB integrity. PMID:29036223

Central nervous system antiretroviral efficacy in HIV infection: a qualitative and quantitative review and implications for future research.

PubMed

Cysique, Lucette A; Waters, Edward K; Brew, Bruce J

2011-11-22

There is conflicting information as to whether antiretroviral drugs with better central nervous system (CNS) penetration (neuroHAART) assist in improving neurocognitive function and suppressing cerebrospinal fluid (CSF) HIV RNA. The current review aims to better synthesise existing literature by using an innovative two-phase review approach (qualitative and quantitative) to overcome methodological differences between studies. Sixteen studies, all observational, were identified using a standard citation search. They fulfilled the following inclusion criteria: conducted in the HAART era; sample size > 10; treatment effect involved more than one antiretroviral and none had a retrospective design. The qualitative phase of review of these studies consisted of (i) a blind assessment rating studies on features such as sample size, statistical methods and definitions of neuroHAART, and (ii) a non-blind assessment of the sensitivity of the neuropsychological methods to HIV-associated neurocognitive disorder (HAND). During quantitative evaluation we assessed the statistical power of studies, which achieved a high rating in the qualitative analysis. The objective of the power analysis was to determine the studies ability to assess their proposed research aims. After studies with at least three limitations were excluded in the qualitative phase, six studies remained. All six found a positive effect of neuroHAART on neurocognitive function or CSF HIV suppression. Of these six studies, only two had statistical power of at least 80%. Studies assessed as using more rigorous methods found that neuroHAART was effective in improving neurocognitive function and decreasing CSF viral load, but only two of those studies were adequately statistically powered. Because all of these studies were observational, they represent a less compelling evidence base than randomised control trials for assessing treatment effect. Therefore, large randomised trials are needed to determine the robustness of any neuroHAART effect. However, such trials must be longitudinal, include the full spectrum of HAND, ideally carefully control for co-morbidities, and be based on optimal neuropsychology methods.

MafB antagonizes phenotypic alteration induced by GM-CSF in microglia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koshida, Ryusuke, E-mail: rkoshida-myz@umin.ac.jp; Oishi, Hisashi, E-mail: hoishi@md.tsukuba.ac.jp; Hamada, Michito

2015-07-17

Microglia are tissue-resident macrophages which are distributed throughout the central nervous system (CNS). Recent studies suggest that microglia are a unique myeloid population distinct from peripheral macrophages in terms of origin and gene expression signature. Granulocyte-macrophage colony-stimulating factor (GM-CSF), a pleiotropic cytokine regulating myeloid development, has been shown to stimulate proliferation and alter phenotype of microglia in vitro. However, how its signaling is modulated in microglia is poorly characterized. MafB, a bZip transcriptional factor, is highly expressed in monocyte-macrophage lineage cells including microglia, although its role in microglia is largely unknown. We investigated the crosstalk between GM-CSF signaling and MafB bymore » analyzing primary microglia. We found that Mafb-deficient microglia grew more rapidly than wild-type microglia in response to GM-CSF. Moreover, the expression of genes associated with microglial differentiation was more downregulated in Mafb-deficient microglia cultured with GM-CSF. Notably, such differences between the genotypes were not observed in the presence of M-CSF. In addition, we found that Mafb-deficient microglia cultured with GM-CSF barely extended their membrane protrusions, probably due to abnormal activation of RhoA, a key regulator of cytoskeletal remodeling. Altogether, our study reveals that MafB is a negative regulator of GM-CSF signaling in microglia. These findings could provide new insight into the modulation of cytokine signaling by transcription factors in microglia. - Highlights: • GM-CSF alters the phenotype of microglia in vitro more potently than M-CSF. • Transcription factor MafB antagonizes the effect of GM-CSF on microglia in vitro. • MafB deficiency leads to RhoA activation in microglia in response to GM-CSF. • We show for the first time the function of MafB in microglia.« less

Granulocyte-macrophage colony-stimulating factor induces the differentiation of murine erythroleukaemia cells into dendritic cells.

PubMed Central

Cao, X; Zhao, Y; Yu, Y; Wang, Y; Zhang, M; Zhang, W; Wang, J

1998-01-01

Dendritic cells (DC) are professional antigen-presenting cells (APC) within the immune system and antigen-pulsed DC can be used as an effective vaccine for active immunotherapy of cancer. Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays an important role in the generation of DC. We previously showed that GM-CSF can induce murine erythroleukaemia cells (FBL-3) to differentiate into monocyte-like cells. To develop a new vaccinating method to stimulate the host immune response to leukaemia, we further investigate whether FBL-3 cells induced by GM-CSF can differentiate into DC in the present study. After being treated with GM-CSF, FBL-3 cells expressed high levels of 33D1 and NLDC-145, which are the specific markers of DC. The expression of MHC-II, B7-1, B7-2 and vascular cell adhesion molecule-1 (VCAM-1) was up-regulated markedly; the typical morphology of DC were also observed by electron microscopy. Functionally, the GM-CSF-induced FBL-3 cells could apparently stimulate the proliferation of naive allogeneic and autologous T lymphocytes and induce the generation of specific CTL more efficiently than the wild-type FBL-3 cells. Mice immunized with GM-CSF-induced FBL-3 cells could resist the subsequent challenge with the wild-type FBL-3 cells. Collectively, these data indicate that GM-CSF differentiates murine erythroleukaemia cells into DC phenotypically, morphologically and functionally. FBL-3-derived DC can be used as a new type of vaccine. Our results may have important implications for the immunotherapy of leukaemia. Images Figure 3 Figure 4 PMID:9767469

Sinus anatomy associated with inadvertent cerebrospinal fluid leak during functional endoscopic sinus surgery.

PubMed

Heaton, Chase M; Goldberg, Andrew N; Pletcher, Steven D; Glastonbury, Christine M

2012-07-01

Anatomic variations in skull base anatomy may predispose the surgeon to inadvertent skull base injury with resultant cerebrospinal fluid (CSF) leak during functional endoscopic sinus surgery (ESS). Our objective was to compare preoperative sinus imaging of patients who underwent FESS with and without CSF leak to elucidate these variations. In this retrospective case-control study, 18 patients with CSF leak following FESS for chronic rhinosinusitis (CRS) from 2000 to 2011 were compared to 18 randomly selected patients who underwent preoperative imaging for FESS for CRS. Measurements were obtained from preoperative computed tomography images with specific attention to anatomic differences in cribriform plate and ethmoid roof heights in the coronal plane, and the skull base angle in the sagittal plane. Mean values of measured variables were compared using a nonparametric Mann-Whitney test. When compared to controls, patients with CSF leak demonstrated a greater angle of the skull base in the sagittal plane (P < .001) and a greater slope of the skull base in the coronal plane (P < .006). A lower cribriform height relative to ethmoid roof height was also noted in cases of CSF leak as compared to controls (P < .04). A steep skull base angle in the sagittal plane, a greater slope of the skull base in the coronal plane, and a low cribriform height relative to the ethmoid roof predispose the patient to CSF leak during FESS. Preoperative review of imaging with specific attention paid to these anatomic variations may help to prevent iatrogenic CSF leak. Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.

IFNγ inhibits G-CSF induced neutrophil expansion and invasion of the CNS to prevent viral encephalitis.

PubMed

Ramakrishna, Chandran; Cantin, Edouard M

2018-01-01

Emergency hematopoiesis facilitates the rapid expansion of inflammatory immune cells in response to infections by pathogens, a process that must be carefully regulated to prevent potentially life threatening inflammatory responses. Here, we describe a novel regulatory role for the cytokine IFNγ that is critical for preventing fatal encephalitis after viral infection. HSV1 encephalitis (HSE) is triggered by the invasion of the brainstem by inflammatory monocytes and neutrophils. In mice lacking IFNγ (GKO), we observed unrestrained increases in G-CSF levels but not in GM-CSF or IL-17. This resulted in uncontrolled expansion and infiltration of apoptosis-resistant, degranulating neutrophils into the brainstem, causing fatal HSE in GKO but not WT mice. Excessive G-CSF in GKO mice also induced granulocyte derived suppressor cells, which inhibited T-cell proliferation and function, including production of the anti-inflammatory cytokine IL-10. Unexpectedly, we found that IFNγ suppressed G-CSF signaling by increasing SOCS3 expression in neutrophils, resulting in apoptosis. Depletion of G-CSF, but not GM-CSF, in GKO mice induced neutrophil apoptosis and reinstated IL-10 secretion by T cells, which restored their ability to limit innate inflammatory responses resulting in protection from HSE. Our studies reveals a novel, complex interplay among IFNγ, G-CSF and IL-10, which highlights the opposing roles of G-CSF and IFNγ in regulation of innate inflammatory responses in a murine viral encephalitis model and reveals G-CSF as a potential therapeutic target. Thus, the antagonistic G-CSF-IFNγ interactions emerge as a key regulatory node in control of CNS inflammatory responses to virus infection.

Effect of cerebral spinal fluid suppression for diffusional kurtosis imaging.

PubMed

Yang, Alicia W; Jensen, Jens H; Hu, Caixia C; Tabesh, Ali; Falangola, Maria F; Helpern, Joseph A

2013-02-01

To evaluate the cerebral spinal fluid (CSF) partial volume effect on diffusional kurtosis imaging (DKI) metrics in white matter and cortical gray matter. Four healthy volunteers participated in this study. Standard DKI and fluid-attenuated inversion recovery (FLAIR) DKI experiments were performed using a twice-refocused-spin-echo diffusion sequence. The conventional diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA), mean, axial, and radial diffusivity (MD, D[symbol in text], D[symbol in text] together with DKI metrics of mean, axial, and radial kurtosis (MK, K[symbol in text], K[symbol in text], were measured and compared. Single image slices located above the lateral ventricles, with similar anatomical features for each subject, were selected to minimize the effect of CSF from the ventricles. In white matter, differences of less than 10% were observed between diffusion metrics measured with standard DKI and FLAIR-DKI sequences, suggesting minimal CSF contamination. For gray matter, conventional DTI metrics differed by 19% to 52%, reflecting significant CSF partial volume effects. Kurtosis metrics, however, changed by 11% or less, indicating greater robustness with respect to CSF contamination. Kurtosis metrics are less sensitive to CSF partial voluming in cortical gray matter than conventional diffusion metrics. The kurtosis metrics may then be more specific indicators of changes in tissue microstructure, provided the effect sizes for the changes are comparable. Copyright © 2012 Wiley Periodicals, Inc.

Predictive value of decoy receptor 3 in postoperative nosocomial bacterial meningitis.

PubMed

Liu, Yong-Juan; Shao, Li-Hua; Wang, Qian; Zhang, Jian; Ma, Rui-Ping; Liu, Hai-Hong; Dong, Xiao-Meng; Ma, Li-Xian

2014-11-03

Nosocomial bacterial meningitis requires timely treatment, but what is difficult is the prompt and accurate diagnosis of this disease. The aim of this study was to assess the potential role of decoy receptor 3 (DcR3) levels in the differentiation of bacterial meningitis from non-bacterial meningitis. A total of 123 patients were recruited in this study, among them 80 patients being with bacterial meningitis and 43 patients with non-bacterial meningitis. Bacterial meningitis was confirmed by bacterial culture of cerebrospinal fluid (CSF) culture and enzyme-linked immunosorbent assay (ELISA) was used to detect the level of DcR3 in CSF. CSF levels of DcR3 were statistically significant between patients with bacterial meningitis and those with non-bacterial meningitis (p<0.001). A total of 48.75% of patients with bacterial meningitis received antibiotic>24 h before CSF sampling, which was much higher than that of non-bacterial meningitis. CSF leucocyte count yielded the highest diagnostic value, with an area under the receiver operating characteristic curve (ROC) of 0.928, followed by DcR3. At a critical value of 0.201 ng/mL for DcR3, the sensitivity and specificity were 78.75% and 81.40% respectively. DcR3 in CSF may be a valuable predictor for differentiating patients with bacterial meningitis from those with non-bacterial meningitis. Further studies are needed for the validation of this study.

Multiplicity of cerebrospinal fluid functions: New challenges in health and disease

PubMed Central

Johanson, Conrad E; Duncan, John A; Klinge, Petra M; Brinker, Thomas; Stopa, Edward G; Silverberg, Gerald D

2008-01-01

This review integrates eight aspects of cerebrospinal fluid (CSF) circulatory dynamics: formation rate, pressure, flow, volume, turnover rate, composition, recycling and reabsorption. Novel ways to modulate CSF formation emanate from recent analyses of choroid plexus transcription factors (E2F5), ion transporters (NaHCO3 cotransport), transport enzymes (isoforms of carbonic anhydrase), aquaporin 1 regulation, and plasticity of receptors for fluid-regulating neuropeptides. A greater appreciation of CSF pressure (CSFP) is being generated by fresh insights on peptidergic regulatory servomechanisms, the role of dysfunctional ependyma and circumventricular organs in causing congenital hydrocephalus, and the clinical use of algorithms to delineate CSFP waveforms for diagnostic and prognostic utility. Increasing attention focuses on CSF flow: how it impacts cerebral metabolism and hemodynamics, neural stem cell progression in the subventricular zone, and catabolite/peptide clearance from the CNS. The pathophysiological significance of changes in CSF volume is assessed from the respective viewpoints of hemodynamics (choroid plexus blood flow and pulsatility), hydrodynamics (choroidal hypo- and hypersecretion) and neuroendocrine factors (i.e., coordinated regulation by atrial natriuretic peptide, arginine vasopressin and basic fibroblast growth factor). In aging, normal pressure hydrocephalus and Alzheimer's disease, the expanding CSF space reduces the CSF turnover rate, thus compromising the CSF sink action to clear harmful metabolites (e.g., amyloid) from the CNS. Dwindling CSF dynamics greatly harms the interstitial environment of neurons. Accordingly the altered CSF composition in neurodegenerative diseases and senescence, because of adverse effects on neural processes and cognition, needs more effective clinical management. CSF recycling between subarachnoid space, brain and ventricles promotes interstitial fluid (ISF) convection with both trophic and excretory benefits. Finally, CSF reabsorption via multiple pathways (olfactory and spinal arachnoidal bulk flow) is likely complemented by fluid clearance across capillary walls (aquaporin 4) and arachnoid villi when CSFP and fluid retention are markedly elevated. A model is presented that links CSF and ISF homeostasis to coordinated fluxes of water and solutes at both the blood-CSF and blood-brain transport interfaces. Outline 1 Overview 2 CSF formation 2.1 Transcription factors 2.2 Ion transporters 2.3 Enzymes that modulate transport 2.4 Aquaporins or water channels 2.5 Receptors for neuropeptides 3 CSF pressure 3.1 Servomechanism regulatory hypothesis 3.2 Ontogeny of CSF pressure generation 3.3 Congenital hydrocephalus and periventricular regions 3.4 Brain response to elevated CSF pressure 3.5 Advances in measuring CSF waveforms 4 CSF flow 4.1 CSF flow and brain metabolism 4.2 Flow effects on fetal germinal matrix 4.3 Decreasing CSF flow in aging CNS 4.4 Refinement of non-invasive flow measurements 5 CSF volume 5.1 Hemodynamic factors 5.2 Hydrodynamic factors 5.3 Neuroendocrine factors 6 CSF turnover rate 6.1 Adverse effect of ventriculomegaly 6.2 Attenuated CSF sink action 7 CSF composition 7.1 Kidney-like action of CP-CSF system 7.2 Altered CSF biochemistry in aging and disease 7.3 Importance of clearance transport 7.4 Therapeutic manipulation of composition 8 CSF recycling in relation to ISF dynamics 8.1 CSF exchange with brain interstitium 8.2 Components of ISF movement in brain 8.3 Compromised ISF/CSF dynamics and amyloid retention 9 CSF reabsorption 9.1 Arachnoidal outflow resistance 9.2 Arachnoid villi vs. olfactory drainage routes 9.3 Fluid reabsorption along spinal nerves 9.4 Reabsorption across capillary aquaporin channels 10 Developing translationally effective models for restoring CSF balance 11 Conclusion PMID:18479516

Inherited biallelic CSF3R mutations in severe congenital neutropenia.

PubMed

Triot, Alexa; Järvinen, Päivi M; Arostegui, Juan I; Murugan, Dhaarini; Kohistani, Naschla; Dapena Díaz, José Luis; Racek, Tomas; Puchałka, Jacek; Gertz, E Michael; Schäffer, Alejandro A; Kotlarz, Daniel; Pfeifer, Dietmar; Díaz de Heredia Rubio, Cristina; Ozdemir, Mehmet Akif; Patiroglu, Turkan; Karakukcu, Musa; Sánchez de Toledo Codina, José; Yagüe, Jordi; Touw, Ivo P; Unal, Ekrem; Klein, Christoph

2014-06-12

Severe congenital neutropenia (SCN) is characterized by low numbers of peripheral neutrophil granulocytes and a predisposition to life-threatening bacterial infections. We describe a novel genetic SCN type in 2 unrelated families associated with recessively inherited loss-of-function mutations in CSF3R, encoding the granulocyte colony-stimulating factor (G-CSF) receptor. Family A, with 3 affected children, carried a homozygous missense mutation (NM_000760.3:c.922C>T, NP_000751.1:p.Arg308Cys), which resulted in perturbed N-glycosylation and aberrant localization to the cell surface. Family B, with 1 affected infant, carried compound heterozygous deletions provoking frameshifts and premature stop codons (NM_000760.3:c.948_963del, NP_000751.1:p.Gly316fsTer322 and NM_000760.3:c.1245del, NP_000751.1:p.Gly415fsTer432). Despite peripheral SCN, all patients had morphologic evidence of full myeloid cell maturation in bone marrow. None of the patients responded to treatment with recombinant human G-CSF. Our study highlights the genetic and morphologic SCN variability and provides evidence both for functional importance and redundancy of G-CSF receptor-mediated signaling in human granulopoiesis. © 2014 by The American Society of Hematology.

Inherited biallelic CSF3R mutations in severe congenital neutropenia

PubMed Central

Triot, Alexa; Järvinen, Päivi M.; Arostegui, Juan I.; Murugan, Dhaarini; Kohistani, Naschla; Dapena Díaz, José Luis; Racek, Tomas; Puchałka, Jacek; Gertz, E. Michael; Schäffer, Alejandro A.; Kotlarz, Daniel; Pfeifer, Dietmar; Díaz de Heredia Rubio, Cristina; Ozdemir, Mehmet Akif; Patiroglu, Turkan; Karakukcu, Musa; Sánchez de Toledo Codina, José; Yagüe, Jordi; Touw, Ivo P.; Unal, Ekrem

2014-01-01

Severe congenital neutropenia (SCN) is characterized by low numbers of peripheral neutrophil granulocytes and a predisposition to life-threatening bacterial infections. We describe a novel genetic SCN type in 2 unrelated families associated with recessively inherited loss-of-function mutations in CSF3R, encoding the granulocyte colony-stimulating factor (G-CSF) receptor. Family A, with 3 affected children, carried a homozygous missense mutation (NM_000760.3:c.922C>T, NP_000751.1:p.Arg308Cys), which resulted in perturbed N-glycosylation and aberrant localization to the cell surface. Family B, with 1 affected infant, carried compound heterozygous deletions provoking frameshifts and premature stop codons (NM_000760.3:c.948_963del, NP_000751.1:p.Gly316fsTer322 and NM_000760.3:c.1245del, NP_000751.1:p.Gly415fsTer432). Despite peripheral SCN, all patients had morphologic evidence of full myeloid cell maturation in bone marrow. None of the patients responded to treatment with recombinant human G-CSF. Our study highlights the genetic and morphologic SCN variability and provides evidence both for functional importance and redundancy of G-CSF receptor-mediated signaling in human granulopoiesis. PMID:24753537

Reversible CSF cyst related to a functioning ventriculo-peritoneal shunt.

PubMed

Vajramani, G V; Fugleholm, K

2005-11-01

Although the occurrence of CSF oedema and cyst has been described in presence of a blocked ventriculoperitoneal shunt, especially distal end block, its occurrence in presence of a well functioning shunt has not been described so far. We report a case where a 51-year old lady developed an insidious onset and gradually progressive CSF cyst without any clinical or radiological feature of shunt block over a period of about 2 years. The changes started about 6 months after a course of radiation therapy for an extensive residual supra and infratentorial meningioma. Following surgery, where the cyst was punctured and a new ventricular catheter was inserted, despite well functioning upper and lower end, the cyst gradually disappeared. We review the literature and hypothesize that the radiation-induced changes were responsible for initiation and progression of the cyst.

GM-CSF-Producing Th Cells in Rats Sensitive and Resistant to Experimental Autoimmune Encephalomyelitis.

PubMed

Stojić-Vukanić, Zorica; Pilipović, Ivan; Vujnović, Ivana; Nacka-Aleksić, Mirjana; Petrović, Raisa; Arsenović-Ranin, Nevena; Dimitrijević, Mirjana; Leposavić, Gordana

2016-01-01

Given that granulocyte macrophage colony-stimulating factor (GM-CSF) is identified as the key factor to endow auto-reactive Th cells with the potential to induce neuroinflammation in experimental autoimmune encephalomyelitis (EAE) models, the frequency and phenotype of GM-CSF-producing (GM-CSF+) Th cells in draining lymph nodes (dLNs) and spinal cord (SC) of Albino Oxford (AO) and Dark Agouti (DA) rats immunized for EAE were examined. The generation of neuroantigen-specific GM-CSF+ Th lymphocytes was impaired in dLNs of AO rats (relatively resistant to EAE induction) compared with their DA counterparts (susceptible to EAE) reflecting impaired CD4+ lymphocyte proliferation and less supportive of GM-CSF+ Th cell differentiation dLN cytokine microenvironment. Immunophenotyping of GM-CSF+ Th cells showed their phenotypic heterogeneity in both strains and revealed lower frequency of IL-17+IFN-γ+, IL-17+IFN-γ-, and IL-17-IFN-γ+ cells accompanied by higher frequency of IL-17-IFN-γ- cells among them in AO than in DA rats. Compared with DA, in AO rats was also found (i) slightly lower surface density of CCR2 (drives accumulation of highly pathogenic GM-CSF+IFN-γ+ Th17 cells in SC) on GM-CSF+IFN-γ+ Th17 lymphocytes from dLNs, and (ii) diminished CCL2 mRNA expression in SC tissue, suggesting their impaired migration into the SC. Moreover, dLN and SC cytokine environments in AO rats were shown to be less supportive of GM-CSF+IFN-γ+ Th17 cell differentiation (judging by lower expression of mRNAs for IL-1β, IL-6 and IL-23/p19). In accordance with the (i) lower frequency of GM-CSF+ Th cells in dLNs and SC of AO rats and their lower GM-CSF production, and (ii) impaired CCL2 expression in the SC tissue, the proportion of proinflammatory monocytes among peripheral blood cells and their progeny (CD45hi cells) among the SC CD11b+ cells were reduced in AO compared with DA rats. Collectively, the results indicate that the strain specificities in efficacy of several mechanisms controlling (auto)reactive CD4+ lymphocyte expansion/differentiation into the cells with pathogenic phenotype and migration of the latter to the SC contribute to AO rat resistance to EAE.

MicroRNA-Mediated Down-Regulation of M-CSF Receptor Contributes to Maturation of Mouse Monocyte-Derived Dendritic Cells

PubMed Central

Riepsaame, Joey; van Oudenaren, Adri; den Broeder, Berlinda J. H.; van IJcken, Wilfred F. J.; Pothof, Joris; Leenen, Pieter J. M.

2013-01-01

Dendritic cell (DC) maturation is a tightly regulated process that requires coordinated and timed developmental cues. Here we investigate whether microRNAs are involved in this process. We identify microRNAs in mouse GM-CSF-generated, monocyte-related DC (GM-DC) that are differentially expressed during both spontaneous and LPS-induced maturation and characterize M-CSF receptor (M-CSFR), encoded by the Csf1r gene, as a key target for microRNA-mediated regulation in the final step toward mature DC. MicroRNA-22, -34a, and -155 are up-regulated in mature MHCIIhi CD86hi DC and mediate Csf1r mRNA and protein down-regulation. Experimental inhibition of Csf1r-targeting microRNAs in vitro results not only in sustained high level M-CSFR protein expression but also in impaired DC maturation upon stimulation by LPS. Accordingly, over-expression of Csf1r in GM-DC inhibits terminal differentiation. Taken together, these results show that developmentally regulated microRNAs control Csf1r expression, supplementing previously identified mechanisms that regulate its transcription and protein surface expression. Furthermore, our data indicate a novel function for Csf1r in mouse monocyte-derived DC, showing that down-regulation of M-CSFR expression is essential for final DC maturation. PMID:24198819

Translating G-CSF as an Adjunct Therapy to Stem Cell Transplantation for Stroke.

PubMed

Peña, Ike dela; Borlongan, Cesar V

2015-12-01

Among recently investigated stroke therapies, stem cell treatment holds great promise by virtue of their putative ability to replace lost cells, promote endogenous neurogenesis,and produce behavioral and functional improvement through their "bystander effects." Translating stem cell in the clinic, however, presents a number of technical difficulties. A strategy suggested to enhance therapeutic utility of stem cells is combination therapy, i.e., co-transplantation of stem cells or adjunct treatment with pharmacological agents and substrates,which is assumed to produce more profound therapeutic benefits by circumventing limitations of individual treatments and facilitating complementary brain repair processes. We previously demonstrated enhanced functional effects of cotreatment with granulocyte-colony stimulating factor (GCSF)and human umbilical cord blood cell (hUCB) transplantation in animal models of traumatic brain injury (TBI). Here,we suggest that the aforementioned combination therapy may also produce synergistic effects in stroke. Accordingly, G-CSF treatment may reduce expression of pro-inflammatory cytokines and enhance neurogenesis rendering a receptive microenvironment for hUCB engraftment. Adjunct treatment of GCSF with hUCB may facilitate stemness maintenance and guide neural lineage commitment of hUCB cells. Moreover, regenerative mechanisms afforded by G-CSF-mobilized endogenous stem cells, secretion of growth factors by hUCB grafts and G-CSF-recruited endothelial progenitor cells(EPCs), as well as the potential graft–host integration that may promote synaptic circuitry re-establishment could altogether produce more pronounced functional improvement in stroked rats subjected to a combination G-CSF treatment and hUCB transplantation. Nevertheless, differences in pathology and repair processes underlying TBI and stroke deserve consideration when testing the effects of combinatorial G-CSF and hUCB cell transplantation for stroke treatment. Further studies are also required to determine the safety and efficacy of this intervention in both preclinical and clinical stroke studies.

GM-CSF production by glioblastoma cells has a functional role in eosinophil survival, activation and growth factor production for enhanced tumor cell proliferation

PubMed Central

Curran, Colleen S.; Evans, Michael D.; Bertics, Paul J.

2011-01-01

Medicinal interventions of limited efficacy are currently available for the treatment of glioblastoma multiforme (GBM), the most common and lethal primary brain tumor in adults. The eosinophil is a pivotal immune cell in the pathobiology of atopic disease that is also found to accumulate in certain tumor tissues. Inverse associations between atopy and GBM risk suggest that the eosinophil may play a functional role in certain tumor immune responses. To assess the potential interactions between eosinophils and GBM, human primary blood eosinophils were cultured with two separate human GBM-derived cell lines (A172, U87-MG) or conditioned media generated in the presence or absence of TNF-α. Results revealed differential eosinophil adhesion and increased survival in response to co-culture with GBM cell lines. Eosinophil responses to GBM cell line-conditioned media included increased survival, activation, CD11b expression and S100A9 release. Addition of GM-CSF neutralizing antibodies to GBM cell cultures or conditioned media reduced eosinophil adhesion, survival and activation, linking tumor cell-derived GM-CSF to the functions of eosinophils in the tumor microenvironment. Dexamethasone, which has been reported to inhibit eosinophil recruitment and shrink GBM lesions on contrast enhanced scans, reduced the production of tumor cell-derived GM-CSF. Furthermore, culture of GBM cells in eosinophil-conditioned media increased tumor cell viability, and generation of eosinophil-conditioned media in the presence of GM-CSF enhanced the effect. These data support the idea of a paracrine loop between GM-CSF producing tumors and eosinophil-derived growth factors in tumor promotion/progression. PMID:21705618

IFN Regulatory Factor 8 Represses GM-CSF Expression in T cells to Affect Myeloid Cell Lineage Differentiation

PubMed Central

Paschall, Amy V.; Zhang, Ruihua; Qi, Chen-Feng; Bardhan, Kankana; Peng, Liang; Lu, Geming; Yang, Jianjun; Merad, Miriam; McGaha, Tracy; Zhou, Gang; Mellor, Andrew; Abrams, Scott I.; Morse, Herbert C.; Ozato, Keiko; Xiong, Huabao; Liu, Kebin

2015-01-01

During hematopoiesis, hematopoietic stem cells constantly differentiate into granulocytes and macrophages via a distinct differentiation program that is tightly controlled by myeloid lineage-specific transcription factors. Mice with a null mutation of IFN Regulatory Factor 8 (IRF8) accumulate CD11b+Gr1+ myeloid cells that phenotypically and functionally resemble tumor-induced myeloid-derived suppressor cells (MDSCs), indicating an essential role of IRF8 in myeloid cell lineage differentiation. However, IRF8 is expressed in various types of immune cells and whether IRF8 functions intrinsically or extrinsically in regulation of myeloid cell lineage differentiation is not fully understood. Here we report an intriguing finding that although IRF8-deficient mice exhibit deregulated myeloid cell differentiation and resultant accumulation of CD11b+Gr1+ MDSCs, surprisingly, mice with IRF8 deficiency only in myeloid cells exhibit no abnormal myeloid cell lineage differentiation. Instead, mice with IRF8 deficiency only in T cells exhibited deregulated myeloid cell differentiation and MDSC accumulation. We further demonstrated that IRF8-deficient T cells exhibit elevated GM-CSF expression and secretion. Treatment of mice with GM-CSF increased MDSC accumulation, and adoptive transfer of IRF8-deficient T cells, but not GM-CSF-deficient T cells, increased MDSC accumulation in the recipient chimeric mice. Moreover, overexpression of IRF8 decreased GM-CSF expression in T cells. Our data determine that in addition to its intrinsic function as an apoptosis regulator in myeloid cells, IRF8 also acts extrinsically to represses GM-CSF expression in T cells to control myeloid cell lineage differentiation, revealing a novel mechanism that the adaptive immune component of the immune system regulates the innate immune cell myelopoiesis in vivo. PMID:25646302

Deficiency of Kruppel-like factor KLF4 in mammary tumor cells inhibits tumor growth and pulmonary metastasis and is accompanied by compromised recruitment of myeloid-derived suppressor cells

PubMed Central

Yu, Fang; Shi, Ying; Wang, Junfeng; Li, Juan; Fan, Daping; Ai, Walden

2013-01-01

Increasing evidence indicates that myeloid-derived suppressor cells (MDSCs) negatively regulate immune responses during tumor progression, inflammation and infection. However, the underlying molecular mechanisms of their development and mobilization remain to be fully delineated. Kruppel-like factor KLF4 is a transcription factor that has an oncogenic function in breast cancer development, but its function in tumor microenvironment, a critical component for tumorigenesis, has not been examined. By using a spontaneously metastatic 4T1 breast cancer mouse model and an immunodeficient NOD/SCID mouse model, we demonstrated that KLF4 knockdown delayed tumor development and inhibited pulmonary metastasis, which was accompanied by decreased accumulation of MDSCs in bone marrow, spleens and primary tumors. Mechanistically, we found that KLF4 knockdown resulted in a significant decrease of circulating GM-CSF, an important cytokine for MDSC biology. Consistently, recombinant GM-CSF restored the frequency of MDSCs in purified bone marrow cells incubated with conditioned medium from KLF4 deficient cells. In addition, we identified CXCL5 as a critical mediator to enhance the expression and function of GM-CSF. Reduced CXCL5 expression by KLF4 knockdown in primary tumors and breast cancer cells was correlated with a decreased GM-CSF expression in our mouse models. Finally, we found that CXCL5/CXCR2 axis facilitated MDSC migration and that anti-GM-CSF antibodies neutralized CXCL5-induced accumulation of MDSCs. Taken together, our data suggest that KLF4 modulates maintenance of MDSCs in bone marrow by inducing GM-CSF production via CXCL5 and regulates recruitment of MDSCs into the primary tumors through the CXCL5/CXCR2 axis, both of which contribute to KLF4-mediated mammary tumor development. PMID:23737434

IL-3 Maintains Activation of the p90S6K/RPS6 Pathway and Increases Translation in Human Eosinophils.

PubMed

Esnault, Stephane; Kelly, Elizabeth A B; Shen, Zhong-Jian; Johansson, Mats W; Malter, James S; Jarjour, Nizar N

2015-09-15

IL-5 is a major therapeutic target to reduce eosinophilia. However, all of the eosinophil-activating cytokines, such as IL-5, IL-3, and GM-CSF, are typically present in atopic diseases, including allergic asthma. As a result of the functional redundancy of these three cytokines on eosinophils and the loss of IL-5R on airway eosinophils, it is important to take IL-3 and GM-CSF into account to efficiently reduce tissue eosinophil functions. Moreover, these three cytokines signal through a common β-chain receptor but yet differentially affect protein production in eosinophils. Notably, the increased ability of IL-3 to induce the production of proteins, such as semaphorin-7A, without affecting mRNA levels suggests a unique influence of IL-3 on translation. The purpose of this study was to identify the mechanisms by which IL-3 distinctively affects eosinophil function compared with IL-5 and GM-CSF, with a focus on protein translation. Peripheral blood eosinophils were used to study intracellular signaling and protein translation in cells activated with IL-3, GM-CSF, or IL-5. We establish that, unlike GM-CSF or IL-5, IL-3 triggers prolonged signaling through activation of ribosomal protein S6 (RPS6) and the upstream kinase 90-kDa ribosomal S6 kinase (p90S6K). Blockade of p90S6K activation inhibited phosphorylation of RPS6 and IL-3-enhanced semaphorin-7A translation. Furthermore, in an allergen-challenged environment, in vivo phosphorylation of RPS6 and p90S6K was enhanced in human airway compared with circulating eosinophils. Our findings provide new insights into the mechanisms underlying differential activation of eosinophils by IL-3, GM-CSF, and IL-5. These observations identify IL-3 and its downstream intracellular signals as novel targets that should be considered to modulate eosinophil functions. Copyright © 2015 by The American Association of Immunologists, Inc.

IL-3 maintains activation of the P90S6K/RPS6 pathway and increases translation in human eosinophils1

PubMed Central

Esnault, Stephane; Kelly, Elizabeth A.B.; Shen, Zhong-Jian; Johansson, Mats W.; Malter, James S.; Jarjour, Nizar N.

2015-01-01

IL-5 is a major therapeutic target to reduce eosinophilia. However, all of the eosinophil-activating cytokines IL-5, IL-3, and GM-CSF are typically present in atopic diseases including allergic asthma. Due to the functional redundancy of these 3 cytokines on eosinophils and the loss of IL-5 receptor on airway eosinophils, it is important to take IL-3 and GM-CSF into account to efficiently reduce tissue eosinophil functions. Moreover, these 3 cytokines signal through a common β-chain receptor, and yet differentially affect protein production in eosinophils. Notably, the increased ability of IL-3 to induce production of proteins such as semaphorin-7A without affecting mRNA level suggests a unique influence by IL-3 on translation. The purpose of this study is to identify the mechanisms by which IL-3 distinctively affects eosinophil function compared to IL-5 and GM-CSF, with a focus on protein translation. Peripheral blood eosinophils were used to study intracellular signaling and protein translation in cells activated with IL-3, GM-CSF or IL-5. We establish that, unlike GM-CSF or IL-5, IL-3 triggers prolonged signaling through activation of ribosomal protein (RP) S6 and the upstream kinase, p90S6K. Blockade of p90S6K activation inhibited phosphorylation of RPS6 and IL-3-enhanced semaphorin-7A translation. Furthermore, in an allergen-challenged environment, in vivo phosphorylation of RPS6 and p90S6K was enhanced in human airway compared to circulating eosinophils. Our findings provide new insights into the mechanisms underlying differential activation of eosinophils by IL-3, GM-CSF, and IL-5. These observations place IL-3 and its downstream intracellular signals as novel targets that should be considered to modulate eosinophil functions. PMID:26276876

Transplanted Peripheral Blood Stem Cells Mobilized by Granulocyte Colony-Stimulating Factor Promoted Hindlimb Functional Recovery After Spinal Cord Injury in Mice.

PubMed

Takahashi, Hiroshi; Koda, Masao; Hashimoto, Masayuki; Furuya, Takeo; Sakuma, Tsuyoshi; Kato, Kei; Okawa, Akihiko; Inada, Taigo; Kamiya, Koshiro; Ota, Mitsutoshi; Maki, Satoshi; Takahashi, Kazuhisa; Yamazaki, Masashi; Mannoji, Chikato

2016-01-01

Granulocyte colony-stimulating factor (G-CSF) mobilizes peripheral blood stem cells (PBSCs) derived from bone marrow. We hypothesized that intraspinal transplantation of PBSCs mobilized by G-CSF could promote functional recovery after spinal cord injury. Spinal cords of adult nonobese diabetes/severe immunodeficiency mice were injured using an Infinite Horizon impactor (60 kdyn). One week after the injury, 3.0 µl of G-CSF-mobilized human mononuclear cells (MNCs; 0.5 × 10(5)/µl), G-CSF-mobilized human CD34-positive PBSCs (CD34; 0.5 × 10(5)/µl), or normal saline was injected to the lesion epicenter. We performed immunohistochemistry. Locomotor recovery was assessed by Basso Mouse Scale. The number of transplanted human cells decreased according to the time course. The CD31-positive area was significantly larger in the MNC and CD34 groups compared with the vehicle group. The number of serotonin-positive fibers was significantly larger in the MNC and CD34 groups than in the vehicle group. Immunohistochemistry revealed that the number of apoptotic oligodendrocytes was significantly smaller in cell-transplanted groups, and the areas of demyelination in the MNC- and CD34-transplanted mice were smaller than that in the vehicle group, indicating that cell transplantation suppressed oligodendrocyte apoptosis and demyelination. Both the MNC and CD34 groups showed significantly better hindlimb functional recovery compared with the vehicle group. There was no significant difference between the two types of transplanted cells. Intraspinal transplantation of G-CSF-mobilized MNCs or CD34-positive cells promoted angiogenesis, serotonergic fiber regeneration/sparing, and preservation of myelin, resulting in improved hindlimb function after spinal cord injury in comparison with vehicle-treated control mice. Transplantation of G-CSF-mobilized PBSCs has advantages for treatment of spinal cord injury in the ethical and immunological viewpoints, although further exploration is needed to move forward to clinical application.

Granulocyte-colony stimulating factor therapy to induce neovascularization in ischemic heart disease.

PubMed

Ripa, Rasmus Sejersten

2012-03-01

Cell based therapy for ischemic heart disease has the potential to reduce post infarct heart failure and chronic ischemia. Treatment with granulocyte-colony stimulating factor (G-CSF) mobilizes cells from the bone marrow to the peripheral blood. Some of these cells are putative stem or progenitor cells. G-CSF is injected subcutaneously. This therapy is intuitively attractive compared to other cell based techniques since repeated catheterizations and ex vivo cell purification and expansion are avoided. Previous preclinical and early clinical trials have indicated that treatment with G-CSF leads to improved myocardial perfusion and function in acute or chronic ischemic heart disease. The hypothesis of this thesis is that patient with ischemic heart disease will benefit from G-CSF therapy. We examined this hypothesis in two clinical trials with G-CSF treatment to patients with either acute myocardial infarction or severe chronic ischemic heart disease. In addition, we assed a number of factors that could potentially affect the effect of cell based therapy. Finally, we intended to develop a method for in vivo cell tracking in the heart. Our research showed that subcutaneous G-CSF along with gene therapy do not improve myocardial function in patients with chronic ischemia despite a large increase in circulation bone marrow-derived cells. Also, neither angina pectoris nor exercise capacity was improved compared to placebo treatment. We could not identify differences in angiogenic factors or bone marrow-derived cells in the blood that could explain the neutral effect of G-CSF. Next, we examined G-CSF as adjunctive therapy following ST segment elevation myocardial infarction. We did not find any effect of G-CSF neither on the primary endpoint--regional myocardial function--nor on left ventricular ejection fraction (secondary endpoint) compared to placebo treatment. In subsequent analyses, we found significant differences in the types of cells mobilized from the bone marrow by G-CSF. This could explain why intracoronary injections of unfractionated bone marrow-derived cells have more effect that mobilization with G-CSF. A number of other factors could explain the neutral effect of G-CSF in our trial compared to previous studies. These factors include timing of the treatment, G-CSF dose, and study population. It is however, remarkable that the changes in our G-CSF group are comparable to the results of previous non-blinded studies, whereas the major differences are in the control/placebo groups. We found that ejection fraction, wall motion, edema, perfusion, and infarct size all improve significantly in the first month following ST-segment myocardial infarction with standard guideline treatment (including acute mechanical revascularization), but without cell therapy. This is an important factor to take into account when assessing the results of non-controlled trials. Finally, we found that ex vivo labeling of cells with indium-111 for in vivo cell tracking after intramyocardial injection is problematic. In our hand, a significant amount of indium-111 remained in the myocardium despite cell death. It is difficult to determine viability of the cells after injection in human trials, and it is thus complicated to determine if the activity in the myocardium tracks viable cells. Cell based therapy is still in the explorative phase, but based on the intense research within this field it is our hope that the clinical relevance of the therapy can be determined in the foreseeable future. Ultimately, this will require large randomized, double-blind and placebo-controlled trials with "hard" clinical endpoints like mortality and morbidity.

Evaluation of new monoclonal antibody-based latex agglutination test for detection of cryptococcal polysaccharide antigen in serum and cerebrospinal fluid.

PubMed Central

Kiska, D L; Orkiszewski, D R; Howell, D; Gilligan, P H

1994-01-01

We evaluated the performance of CRYPTO-LEX (Trinity Laboratories, Inc., Raleigh, N. C.), a new mouse immunoglobulin M monoclonal antibody latex agglutination reagent which reacts with the capsular polysaccharide of the four serogroups of Cryptococcus neoformans. This test was compared with CALAS (Meridian Diagnostics, Cincinnati, Ohio) for the ability to detect cryptococcal antigen in serum and cerebrospinal fluid (CSF). A total of 580 clinical specimens (327 serum and 253 CSF samples), primarily from human immunodeficiency virus-infected patients, were tested in this study. Sixty-seven specimens (44 serum and 23 CSF samples) were positive for cryptococcal antigen with both tests, and 511 (282 serum and 229 CSF samples) were negative. The two latex reagents agreed for 326 of 327 serum specimens (44 positives and 282 negatives). One serum specimen with a titer of 1:2 was CALAS positive but CRYPTO-LEX negative. The titer correlation coefficient for the two tests was 0.884 when two highly discordant serum specimens were eliminated from analysis of the data. The two latex tests agreed for 252 of 253 CSF specimens (23 positives and 229 negatives). One specimen with a titer of 1:2 was positive with CALAS and negative by CRYPTO-LEX. The correlation coefficient of the two tests for CSF titers was 0.886. The sensitivity and specificity of CRYPTO-LEX were 97 and 100%, respectively, with a 99.6% correlation with CALAS. These data show that the performance of CRYPTO-LEX is comparable to that of CALAS for detection of cryptococcal antigen in serum and CSF. PMID:7814566

Characterization of Acid Sphingomyelinase Activity in Human Cerebrospinal Fluid

PubMed Central

Mühle, Christiane; Huttner, Hagen B.; Walter, Silke; Reichel, Martin; Canneva, Fabio; Lewczuk, Piotr; Gulbins, Erich; Kornhuber, Johannes

2013-01-01

Background As a key enzyme in sphingolipid metabolism, acid sphingomyelinase (ASM) is involved in the regulation of cell fate and signaling via hydrolysis of sphingomyelin to form ceramide. While increased activity of the lysosomal form has been associated with various pathological conditions, there are few studies on secretory ASM limited only to cell models, plasma or serum. Methods An optimized assay based on a fluorescent substrate was applied to measure the ASM activity in cerebrospinal fluid (CSF) collected from mice and from 42 patients who were classified as controls based on normal routine CSF values. Results We have detected ASM activity in human CSF, established a sensitive quantitative assay and characterized the enzyme’s properties. The enzyme resembles plasmatic ASM including protein stability and Zn2+-dependence but the assays differ considerably in the optimal detergent concentration. Significantly increased activities in the CSF of ASM transgenic mice and undetectable levels in ASM knock-out mice prove that the measured ASM activity originates from the ASM-encoding gene SMPD1. CSF localized ASM activities were comparable to corresponding serum ASM levels at their respective optimal reaction conditions, but no correlation was observed. The large variance in ASM activity was independent of sex, age or analyzed routine CSF parameters. Conclusions Human and mouse CSF contain detectable levels of secretory ASM, which are unrelated to serum ASM activities. Further investigations in humans and in animal models will help to elucidate the role of this enzyme in human disease and to assess its value as a potential biomarker for disease type, severity, progress or therapeutic success. PMID:23658784

Cost-effectiveness of granulocyte colony-stimulating factor prophylaxis in chemotherapy-induced febrile neutropenia among breast cancer and Non-Hodgkin's lymphoma patients under Taiwan's national health insurance system.

PubMed

Wen, Tsun-Jen; Wen, Yu-Wen; Chien, Chun-Ru; Chiang, Shao-Chin; Hsu, William Wei-Yuan; Shen, Li-Jiuan; Hsiao, Fei-Yuan

2017-04-01

The beneficial effects of granulocyte colony-stimulating factor (G-CSF) prophylaxis on reducing the risk of chemotherapy-induced febrile neutropenia (CIFN) were well documented throughout the literature. However, existing data regarding its cost-effectiveness were conflicting. We estimated the cost-effectiveness of G-CSF prophylaxis in CIFN under Taiwan's National Health Insurance (NHI) system. Data on clinical outcomes and direct medical costs were derived for 5179 newly diagnosed breast cancer and 629 non-Hodgkin's lymphoma (NHL) patients from the NHI claims database. Patients were further categorized into three subgroups as "primary-", "secondary-" and "no -" prophylaxis based on their patterns of G-CSF use. Generalized estimating equations were applied to estimate the impact of G-CSF use on the incidence of CIFN. The incremental cost-effectiveness ratios of primary and secondary prophylactic G-CSF use were calculated and sensitivity analyses were performed. Primary prophylaxis of G-CSF decreased the incidence of CIFN by 27% and 83%, while secondary prophylaxis by 34% and 22% in breast cancer and NHL patients, respectively. Compared with those with no prophylaxis, the incremental cost per CIFN reduced in primary prophylaxis is $931 and $52 among patients with breast cancer and NHL, respectively. In contrast, secondary prophylaxis is dominated by no prophylaxis and primary prophylaxis in both cancer patients. Primary but not secondary prophylactic use of G-CSF was cost-effective in CIFN in breast cancer and NHL patients under Taiwan's NHI system. © 2016 John Wiley & Sons, Ltd.

Performance of Aspergillus PCR in cerebrospinal fluid for the diagnosis of cerebral aspergillosis.

PubMed

Imbert, S; Brossas, J-Y; Palous, M; Joly, I; Meyer, I; Fekkar, A

2017-11-01

Cerebral aspergillosis is a rare but often fatal form of invasive aspergillosis that remains difficult to diagnose. The literature has shown the value of Aspergillus PCR in blood-derived samples for the diagnosis of invasive aspergillosis but provides far less information for cerebrospinal fluid (CSF) in cerebral aspergillosis. Here, we evaluated the usefulness of an Aspergillus PCR assay performed on CSF for the diagnosis of cerebral aspergillosis. This retrospective study involved 72 patients with suspected cerebral aspergillosis for a total of 88 CSF samples in whom CSF Aspergillus PCR was performed. Seventeen patients had proven/probable invasive aspergillosis according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria, including 12 cases of proven/probable cerebral aspergillosis. Aspergillus PCR in CSF was positive in nine of the twelve patients with cerebral aspergillosis, i.e. 75% sensitivity. In contrast, CSF culture was positive for Aspergillus in only two patients. In the non-cerebral aspergillosis group (60 patients), PCR was positive in one patient, i.e. 98.3% specificity. In this particular population of high-risk patients with suspicion of cerebral aspergillosis, the disease incidence was 16.7%. Therefore, the positive and negative predictive values of PCR were 90% and 95.2%, respectively. The results of this study indicate that Aspergillus PCR in CSF is an interesting tool that may eliminate the need for cerebral biopsy in patients with suspected cerebral aspergillosis. Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Simplified Large-Scale Refolding, Purification, and Characterization of Recombinant Human Granulocyte-Colony Stimulating Factor in Escherichia coli

PubMed Central

Kim, Chang Kyu; Lee, Chi Ho; Lee, Seung-Bae; Oh, Jae-Wook

2013-01-01

Granulocyte-colony stimulating factor (G-CSF) is a pleiotropic cytokine that stimulates the development of committed hematopoietic progenitor cells and enhances the functional activity of mature cells. Here, we report a simplified method for fed-batch culture as well as the purification of recombinant human (rh) G-CSF. The new system for rhG-CSF purification was performed using not only temperature shift strategy without isopropyl-l-thio-β-d-galactoside (IPTG) induction but also the purification method by a single step of prep-HPLC after the pH precipitation of the refolded samples. Through these processes, the final cell density and overall yield of homogenous rhG-CSF were obtained 42.8 g as dry cell weights, 1.75 g as purified active proteins, from 1 L culture broth, respectively. The purity of rhG-CSF was finally 99% since the isoforms of rhG-CSF could be separated through the prep-HPLC step. The result of biological activity indicated that purified rhG-CSF has a similar profile to the World Health Organization (WHO) 2nd International Standard for G-CSF. Taken together, our results demonstrate that the simple purification through a single step of prep-HPLC may be valuable for the industrial-scale production of biologically active proteins. PMID:24224041

Intranasal Delivery of Granulocyte Colony-Stimulating Factor Enhances Its Neuroprotective Effects Against Ischemic Brain Injury in Rats.

PubMed

Sun, Bao-Liang; He, Mei-Qing; Han, Xiang-Yu; Sun, Jing-Yi; Yang, Ming-Feng; Yuan, Hui; Fan, Cun-Dong; Zhang, Shuai; Mao, Lei-Lei; Li, Da-Wei; Zhang, Zong-Yong; Zheng, Cheng-Bi; Yang, Xiao-Yi; Li, Yang V; Stetler, R Anne; Chen, Jun; Zhang, Feng

2016-01-01

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor with strong neuroprotective properties. However, it has limited capacity to cross the blood-brain barrier and thus potentially limiting its protective capacity. Recent studies demonstrated that intranasal drug administration is a promising way in delivering neuroprotective agents to the central nervous system. The current study therefore aimed at determining whether intranasal administration of G-CSF increases its delivery to the brain and its neuroprotective effect against ischemic brain injury. Transient focal cerebral ischemia in rat was induced with middle cerebral artery occlusion. Our resulted showed that intranasal administration is 8-12 times more effective than subcutaneous injection in delivering G-CSF to cerebrospinal fluid and brain parenchyma. Intranasal delivery enhanced the protective effects of G-CSF against ischemic injury in rats, indicated by decreased infarct volume and increased recovery of neurological function. The neuroprotective mechanisms of G-CSF involved enhanced upregulation of HO-1 and reduced calcium overload following ischemia. Intranasal G-CSF application also promoted angiogenesis and neurogenesis following brain ischemia. Taken together, G-CSF is a legitimate neuroprotective agent and intranasal administration of G-CSF is more effective in delivery and neuroprotection and could be a practical approach in clinic.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is released by female mouse bladder urothelial cells and expressed by the urothelium as an early response to lipopolysaccharides (LPS).

PubMed

Li, Yan; Lu, Ming; Alvarez-Lugo, Lery; Chen, Gang; Chai, Toby C

2017-04-01

We studied in vitro and in vivo response of primary mouse bladder urothelial cells (mBUC) and bladder urothelium to lipopolysaccharides (LPS), focusing on granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling. Female C57BL/6 mBUC were exposed for 12 hr to differing concentrations of LPS (100 ng/ml to 10 µg/ml). mBUC were also exposed to a single dose of LPS (1 µg/ml) for 3, 6, 12 hr. Neutralizing GM-CSF antibody (0.1 μg/ml) was used block GM-CSF activity in vitro. In vivo experiments were performed, whereby, LPS (1 mg/ml) was instilled intravesically and left to dwell for 30 min followed by harvest of bladder urothelium 3 to 18 hr later. ELISA measured GM-CSF. qPCR quantitated mRNA for GM-CSF, vascular endothelial growth factor-A (VEGF-A), cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), and tumor necrosis factor α (TNF-α). RT-PCR was used to detect mRNA for GM-CSF, GM-CSFRα, and β in bladder tissues. Immunohistofluorescence and Western blots for GM-CSFRα were performed on bladder tissues. LPS induced a dose-dependent release of GM-CSF by mBUC. Mouse bladder urothelium did not express GM-CSF mRNA at baseline, but expressed GM-CSF mRNA 3 hr after in vivo LPS exposure, with GM-CSF mRNA expression disappearing 18 hr later. GM-CSFRα expression was confirmed in bladder urothelium. GM-CSF neutralizing antibody significantly diminished LPS-induced increases of VEGF and COX-2 mRNA expression. Urothelium and mBUC secreted GM-CSF as an early response to LPS. GM-CSF mediated downstream expression of VEGF and COX-2. Urothelial GM-CSF may function as a signaling mediator for both inflammation and pain transduction. Neurourol. Urodynam. 36:1020-1025, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Interactions of phosphatidylinositol kinase, GTPase-activating protein (GAP), and GAP-associated proteins with the colony-stimulating factor 1 receptor.

PubMed Central

Reedijk, M; Liu, X Q; Pawson, T

1990-01-01

The interactions of the macrophage colony-stimulating factor 1 (CSF-1) receptor with potential targets were investigated after ligand stimulation either of mouse macrophages or of fibroblasts that ectopically express mouse CSF-1 receptors. In Rat-2 cells expressing the mouse CSF-1 receptor, full activation of the receptor and cellular transformation require exogenous CSF-1, whereas NIH 3T3 cells expressing mouse c-fms are transformed by autocrine stimulation. Activated CSF-1 receptors physically associate with a phosphatidylinositol (PI) 3'-kinase. A mutant CSF-1 receptor with a deletion of the kinase insert region was deficient in its ability to bind functional PI 3'-kinase and to induce PI 3'-kinase activity precipitable with antiphosphotyrosine antibodies. In fibroblasts, CSF-1 stimulation also induced the phosphorylation of the GTPase-activating protein (GAP)-associated protein p62 on tyrosine, although GAP itself was a relatively poor substrate. In contrast to PI 3'-kinase association, phosphorylation of p62 and GAP was not markedly affected by deletion of the kinase insert region. These results indicate that the kinase insert region selectively enhances the CSF-1-dependent association of the CSF-1 receptor with active PI 3'-kinase. The insert deletion mutant retains considerable transforming activity in NIH 3T3 cells (G. Taylor, M. Reedijk, V. Rothwell, L. Rohrschneider, and T. Pawson, EMBO J. 8:2029-2037, 1989). This mutant was more seriously impaired in Rat-2 cell transformation, although mutant-expressing Rat-2 cells still formed small colonies in soft agar in the presence of CSF-1. Therefore, phosphorylation of GAP and p62 through activation of the CSF-1 receptor does not result in full fibroblast transformation. The interaction between the CSF-1 receptor and PI 3'-kinase may contribute to c-fms fibroblast transformation and play a role in CSF-1-stimulated macrophages. Images PMID:2172781

Artifact Suppression in Imaging of Myocardial Infarction Using B1-Weighted Phased-Array Combined Phase-Sensitive Inversion Recovery

PubMed Central

Kellman, Peter; Dyke, Christopher K.; Aletras, Anthony H.; McVeigh, Elliot R.; Arai, Andrew E.

2007-01-01

Regions of the body with long T1, such as cerebrospinal fluid (CSF), may create ghost artifacts on gadolinium-hyperenhanced images of myocardial infarction when inversion recovery (IR) sequences are used with a segmented acquisition. Oscillations in the transient approach to steady state for regions with long T1 may cause ghosts, with the number of ghosts being equal to the number of segments. B1-weighted phased-array combining provides an inherent degree of ghost artifact suppression because the ghost artifact is weighted less than the desired signal intensity by the coil sensitivity profiles. Example images are shown that illustrate the suppression of CSF ghost artifacts by the use of B1-weighted phased-array combining of multiple receiver coils. PMID:14755669

CSF-1R as an inhibitor of apoptosis and promoter of proliferation, migration and invasion of canine mammary cancer cells

PubMed Central

2013-01-01

Background Tumor-associated macrophages (TAMs) have high impact on the cancer development because they can facilitate matrix invasion, angiogenesis, and tumor cell motility. It gives cancer cells the capacity to invade normal tissues and metastasize. The signaling of colony-stimulating factor-1 receptor (CSF-1R) which is an important regulator of proliferation and differentiation of monocytes and macrophages regulates most of the tissue macrophages. However, CSF-1R is expressed also in breast epithelial tissue during some physiological stages i.g.: pregnancy and lactation. Its expression has been also detected in various cancers. Our previous study has showed the expression of CSF-1R in all examined canine mammary tumors. Moreover, it strongly correlated with grade of malignancy and ability to metastasis. This study was therefore designed to characterize the role of CSF-1R in canine mammary cancer cells proliferation, apoptosis, migration, and invasion. As far as we know, the study presented hereby is a pioneering experiment in this field of veterinary medicine. Results We showed that csf-1r silencing significantly increased apoptosis (Annexin V test), decreased proliferation (measured as Ki67 expression) and decreased migration (“wound healing” assay) of canine mammary cancer cells. Treatment of these cells with CSF-1 caused opposite effect. Moreover, csf-1r knock-down changed growth characteristics of highly invasive cell lines on Matrigel matrix, and significantly decreased the ability of these cells to invade matrix. CSF-1 treatment increased invasion of cancer cells. Conclusion The evidence of the expression and functional role of the CSF-1R in canine mammary cancer cells indicate that CSF-1R targeting may be a good therapeutic approach. PMID:23561040

IFNγ inhibits G-CSF induced neutrophil expansion and invasion of the CNS to prevent viral encephalitis

PubMed Central

Ramakrishna, Chandran

2018-01-01

Emergency hematopoiesis facilitates the rapid expansion of inflammatory immune cells in response to infections by pathogens, a process that must be carefully regulated to prevent potentially life threatening inflammatory responses. Here, we describe a novel regulatory role for the cytokine IFNγ that is critical for preventing fatal encephalitis after viral infection. HSV1 encephalitis (HSE) is triggered by the invasion of the brainstem by inflammatory monocytes and neutrophils. In mice lacking IFNγ (GKO), we observed unrestrained increases in G-CSF levels but not in GM-CSF or IL-17. This resulted in uncontrolled expansion and infiltration of apoptosis-resistant, degranulating neutrophils into the brainstem, causing fatal HSE in GKO but not WT mice. Excessive G-CSF in GKO mice also induced granulocyte derived suppressor cells, which inhibited T-cell proliferation and function, including production of the anti-inflammatory cytokine IL-10. Unexpectedly, we found that IFNγ suppressed G-CSF signaling by increasing SOCS3 expression in neutrophils, resulting in apoptosis. Depletion of G-CSF, but not GM-CSF, in GKO mice induced neutrophil apoptosis and reinstated IL-10 secretion by T cells, which restored their ability to limit innate inflammatory responses resulting in protection from HSE. Our studies reveals a novel, complex interplay among IFNγ, G-CSF and IL-10, which highlights the opposing roles of G-CSF and IFNγ in regulation of innate inflammatory responses in a murine viral encephalitis model and reveals G-CSF as a potential therapeutic target. Thus, the antagonistic G-CSF-IFNγ interactions emerge as a key regulatory node in control of CNS inflammatory responses to virus infection. PMID:29352287

Lower CSF Aβ is Associated with HAND in HIV-Infected Adults with a Family History of Dementia

PubMed Central

Fazeli, Pariya. L.; Moore, David J.; Franklin, Donald R.; Umlauf, Anya; Heaton, Robert K.; Collier, Ann C.; Marra, Christina M.; Clifford, David B.; Gelman, Benjamin B.; Sacktor, Ned C.; Morgello, Susan; Simpson, David M.; McCutchan, John A.; Grant, Igor; Letendre, Scott L.

2015-01-01

Background Both family history of dementia (FHD) and lower levels of Aβ-42 are indepentently associated with worse neurocognitive functioning in HIV-infected patients. Objective To examine the relationships between cerebrospinal fluid (CSF) Aβ-42 and FHD with HIV-associated neurocognitive disorders (HAND). Methods One hundred eighty-three HIV+ adults underwent neuropsychological and neuromedical assessments, and determination of CSF Aβ-42 concentration and FHD (defined as a self-reported first or second-degree relative with a dementia diagnosis). Univariate analyses and multivariable logistic regressions were used. Results FHD was not associated with HAND (p = 0.24); however, CSF Aβ-42 levels were lower (p = 0.03) in the HAND group, but were not associated with FHD (p = 0.89). Multivariable models showed a main effect of CSF Aβ-42 (p = 0.03) and a trend-level (p = 0.06) interaction between FHD and CSF Aβ-42, such that lower CSF Aβ-42 was associated with HAND in those with FHD (p < 0.01) compared to those without FHD (p = 0.83). An analysis in those with follow-up data showed that higher baseline CSF Aβ-42 was associated with lower risk of neurocognitive decline (p = 0.02). While we did not find an FHD X CSF Aβ-42 interaction (p = 0.83), when analyses were stratified by FHD, lower CSF Aβ-42 was associated at the trend-level with neurocognitive decline in the FHD group (p = 0.08) compared to the no FHD group (p = 0.15). Conclusions FHD moderates the relationship between of CSF Aβ-42 and HAND. The findings highlight the complexities in interpreting the relationships between biomarkers of age-related neurodegeneration and HAND. PMID:26673902

Optimal-mass-transfer-based estimation of glymphatic transport in living brain.

PubMed

Ratner, Vadim; Zhu, Liangjia; Kolesov, Ivan; Nedergaard, Maiken; Benveniste, Helene; Tannenbaum, Allen

2015-02-21

It was recently shown that the brain-wide cerebrospinal fluid (CSF) and interstitial fluid exchange system designated the 'glymphatic pathway' plays a key role in removing waste products from the brain, similarly to the lymphatic system in other body organs 1,2 . It is therefore important to study the flow patterns of glymphatic transport through the live brain in order to better understand its functionality in normal and pathological states. Unlike blood, the CSF does not flow rapidly through a network of dedicated vessels, but rather through para-vascular channels and brain parenchyma in a slower time-domain, and thus conventional fMRI or other blood-flow sensitive MRI sequences do not provide much useful information about the desired flow patterns. We have accordingly analyzed a series of MRI images, taken at different times, of the brain of a live rat, which was injected with a paramagnetic tracer into the CSF via the lumbar intrathecal space of the spine. Our goal is twofold: (a) find glymphatic (tracer) flow directions in the live rodent brain; and (b) provide a model of a (healthy) brain that will allow the prediction of tracer concentrations given initial conditions. We model the liquid flow through the brain by the diffusion equation. We then use the Optimal Mass Transfer (OMT) approach 3 to derive the glymphatic flow vector field, and estimate the diffusion tensors by analyzing the (changes in the) flow. Simulations show that the resulting model successfully reproduces the dominant features of the experimental data.

Neuroimaging in normal pressure hydrocephalus

PubMed Central

Damasceno, Benito Pereira

2015-01-01

Normal pressure hydrocephalus (NPH) is a syndrome characterized by the triad of gait disturbance, mental deterioration and urinary incontinence, associated with ventriculomegaly and normal cerebrospinal fluid (CSF) pressure. The clinical presentation (triad) may be atypical or incomplete, or mimicked by other diseases, hence the need for supplementary tests, particularly to predict postsurgical outcome, such as CSF tap-tests and computed tomography (CT) or magnetic resonance imaging (MRI). The CSF tap-test, especially the 3 to 5 days continuous external lumbar drainage of at least 150 ml/day, is the only procedure that simulates the effect of definitive shunt surgery, with high sensitivity (50-100%) and high positive predictive value (80-100%). According to international guidelines, the following are CT or MRI signs decisive for NPH diagnosis and selection of shunt-responsive patients: ventricular enlargement disproportionate to cerebral atrophy (Evans index >0.3), and associated ballooning of frontal horns; periventricular hyperintensities; corpus callosum thinning and elevation, with callosal angle between 40º and 90º; widening of temporal horns not fully explained by hippocampal atrophy; and aqueductal or fourth ventricular flow void; enlarged Sylvian fissures and basal cistern, and narrowing of sulci and subarachnoid spaces over the high convexity and midline surface of the brain. On the other hand, other imaging methods such as radionuclide cisternography, SPECT, PET, and also DTI or resting-state functional MRI, although suitable for NPH diagnosis, do not yet provide improved accuracy for identifying shunt-responsive cases. PMID:29213984

mCSF1, a nucleus-encoded CRM protein required for the processing of many mitochondrial introns, is involved in the biogenesis of respiratory complexes I and IV in Arabidopsis.

PubMed

Zmudjak, Michal; Colas des Francs-Small, Catherine; Keren, Ido; Shaya, Felix; Belausov, Eduard; Small, Ian; Ostersetzer-Biran, Oren

2013-07-01

The coding regions of many mitochondrial genes in plants are interrupted by intervening sequences that are classified as group II introns. Their splicing is essential for the expression of the genes they interrupt and hence for respiratory function, and is facilitated by various protein cofactors. Despite the importance of these cofactors, only a few of them have been characterized. CRS1-YhbY domain (CRM) is a recently recognized RNA-binding domain that is present in several characterized splicing factors in plant chloroplasts. The Arabidopsis genome encodes 16 CRM proteins, but these are largely uncharacterized. Here, we analyzed the intracellular location of one of these hypothetical proteins in Arabidopsis, mitochondrial CAF-like splicing factor 1 (mCSF1; At4 g31010), and analyzed the growth phenotypes and organellar activities associated with mcsf1 mutants in plants. Our data indicated that mCSF1 resides within mitochondria and its functions are essential during embryogenesis. Mutant plants with reduced mCSF1 displayed inhibited germination and retarded growth phenotypes that were tightly associated with reduced complex I and IV activities. Analogously to the functions of plastid-localized CRM proteins, analysis of the RNA profiles in wildtype and mcsf1 plants showed that mCSF1 acts in the splicing of many of the group II intron RNAs in Arabidopsis mitochondria. © 2013 The Authors. New Phytologist © 2013 New Phytologist Trust.

The diagnostic value of cerebrospinal fluid lactate for post-neurosurgical bacterial meningitis: a meta-analysis.

PubMed

Xiao, Xiong; Zhang, Yang; Zhang, Liwei; Kang, Peng; Ji, Nan

2016-09-13

Bacterial meningitis is not rare in post-neurosurgical patients. If patients are not treated promptly, the mortality rate can reach 20 to 50 %. The concentration of cerebrospinal fluid (CSF) lactate has been reported to be helpful in the diagnosis of bacterial meningitis; however, no systematic evaluations have investigated CSF from a postoperative perspective. In this study, we performed a systematic evaluation and meta-analysis of the efficacy of using CSF lactate concentrations in the diagnosis of post-neurosurgical bacterial meningitis. We retrieved studies that investigated the diagnostic value of CSF lactate for the diagnosis of post-neurosurgical bacterial meningitis by searching PubMed, EBSCO, the Cochrane Library and ClinicalTrials.gov. All these databases were searched from inception to November 2015. We used Quality Assessment of Diagnostic Accuracy Studies (QUADAS), a tool for the quality assessment of diagnostic accuracy, to evaluate the quality of the included studies. The Meta-DiSc 1.4 and Review Manager 5.3 software programs were used to analyze the included studies. Forest plots and summary receiver operating characteristics (SROC) curves were also drawn. Five studies, involving a total of 404 post-neurosurgical patients, were selected from 1,672 articles according to the inclusion criteria. The quality of the five included studies was assessed using QUADAS, and the related results are presented in tables. The meta-analysis revealed the following diagnostic values regarding CSF lactate for post-neurosurgical bacterial meningitis: a pooled sensitivity of 0.92 (95 % CI 0.85-0.96), a pooled specificity of 0.88 (95 % CI 0.84-0.92 with significant heterogeneity), a diagnostic odds ratio of 83.09 (95 % CI 36.83-187.46), an area under the curve (AUCSROC) of 0.9601, an SE(AUC) of 0.0122, a Q* of 0.9046 and an SE(Q*) of 0.0179. The meta-analysis indicated that the CSF lactate concentration has relatively high sensitivity and specificity for the diagnosis of post-neurosurgical bacterial meningitis and thus has relatively good efficacy.

A new LC-MS based method to quantitate exogenous recombinant transferrin in cerebrospinal fluid: a potential approach for pharmacokinetic studies of transferrin-based therapeutics in the central nervous system

PubMed Central

Wang, Shunhai; Bobst, Cedric E.; Kaltashov, Igor A.

2018-01-01

Transferrin (Tf) is an 80 kDa iron-binding protein which is viewed as a promising drug carrier to target the central nervous system due to its ability to penetrate the blood-brain barrier (BBB). Among the many challenges during the development of Tf-based therapeutics, sensitive and accurate quantitation of the administered Tf in cerebrospinal fluid (CSF) remains particularly difficult due to the presence of abundant endogenous Tf. Herein, we describe the development of a new LC-MS based method for sensitive and accurate quantitation of exogenous recombinant human Tf in rat CSF. By taking advantage of a His-tag present in recombinant Tf and applying Ni affinity purification, the exogenous hTf can be greatly enriched from rat CSF, despite the presence of the abundant endogenous protein. Additionally, we applied a newly developed O18-labeling technique that can generate internal standards at the protein level, which greatly improved the accuracy and robustness of quantitation. The developed method was investigated for linearity, accuracy, precision and lower limit of quantitation, all of which met the commonly accepted criteria for bioanalytical method validation. PMID:26307718

CSF Flow in the Brain in the Context of Normal Pressure Hydrocephalus.

PubMed

Bradley, W G

2015-05-01

CSF normally flows back and forth through the aqueduct during the cardiac cycle. During systole, the brain and intracranial vasculature expand and compress the lateral and third ventricles, forcing CSF craniocaudad. During diastole, they contract and flow through the aqueduct reverses. Hyperdynamic CSF flow through the aqueduct is seen when there is ventricular enlargement without cerebral atrophy. Therefore, patients presenting with clinical normal pressure hydrocephalus who have hyperdynamic CSF flow have been found to respond better to ventriculoperitoneal shunting than those with normal or decreased CSF flow. Patients with normal pressure hydrocephalus have also been found to have larger intracranial volumes than sex-matched controls, suggesting that they may have had benign external hydrocephalus as infants. While their arachnoidal granulations clearly have decreased CSF resorptive capacity, it now appears that this is fixed and that the arachnoidal granulations are not merely immature. Such patients appear to develop a parallel pathway for CSF to exit the ventricles through the extracellular space of the brain and the venous side of the glymphatic system. This pathway remains functional until late adulthood when the patient develops deep white matter ischemia, which is characterized histologically by myelin pallor (ie, loss of lipid). The attraction between the bare myelin protein and the CSF increases resistance to the extracellular outflow of CSF, causing it to back up, resulting in hydrocephalus. Thus idiopathic normal pressure hydrocephalus appears to be a "2 hit" disease: benign external hydrocephalus in infancy followed by deep white matter ischemia in late adulthood. © 2015 by American Journal of Neuroradiology.

iRhom2 regulates cell surface expression of CSF1R and non-steady state myelopoiesis in mice

PubMed Central

Qing, Xiaoping; Lavin, Yonit; Redecha, Patricia; Issuree, Priya D.; Maretzky, Thorsten; Merad, Miriam; McIlwain, David; Mak, Tak W.; Overall, Christopher M.

2016-01-01

The colony stimulating factor 1 receptor (CSF1R) functions as the major receptor for macrophage colony stimulating factor (CSF1) with crucial roles in regulating myelopoeisis. CSF1R can be proteolytically released from the cell surface by A disintegrin and metalloprotease 17 (ADAM17). Here we identified CSF1R as a major substrate of ADAM17 in an unbiased degradomics screen. We explored the impact of CSF1R shedding by ADAM17 and its upstream regulator, inactive rhomboid protein 2 (iRhom2, gene name Rhbdf2), on homeostatic development of mouse myeloid cells. In iRhom2−/− mice, we found constitutive accumulation of membrane-bound CSF1R on myeloid cells at steady state, although cell numbers of these populations were not altered. However, in the context of mixed bone marrow (BM) chimera, under competitive pressure, iRhom2−/− BM progenitor-derived monocytes, tissue macrophages and lung DCs showed a repopulation advantage over those derived from wild type (WT) BM progenitors, suggesting enhanced CSF1R signaling in the absence of iRhom2. In vitro experiments indicate that iRhom2−/− Lin−SCA-1+c-Kit+ (LSKs) cells, but not granulocyte-macrophage progenitors (GMPs), had faster growth rates than WT cells in response to CSF1. Our results shed light on an important role of iRhom2/ADAM17 pathway in regulation of CSF1R shedding and repopulation of monocytes, macrophages and DCs. PMID:27601030

The effect of recombinant GM-CSF on the recovery of monkeys transplanted with autologous bone marrow.

PubMed

Monroy, R L; Skelly, R R; MacVittie, T J; Davis, T A; Sauber, J J; Clark, S C; Donahue, R E

1987-11-01

The regulatory function of recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) on granulocyte production in vivo was evaluated in an autologous bone marrow transplantation model using rhesus monkeys. Monkeys were exposed to 9.0 Gy total body irradiation and then transplanted with 5.0 x 10(7) low-density bone marrow cells/kg. Alzet miniosmotic pumps were subcutaneously implanted to deliver rhGM-CSF at a rate of 50,400 U/kg/d. Minipumps, containing either rhGM-CSF or saline, were implanted between zero and five days after transplantation for seven days. Kinetic recoveries of peripheral blood cells after either saline or rhGM-CSF treatment were compared. Treatment with rhGM-CSF accelerated the recovery of neutrophils. Neutrophils in rhGM-CSF-treated animals recovered to 80% (3.4 x 10(3)/mm3) pre-irradiation control levels by day 20, in comparison with only 33% (0.9 x 10(3)/mm3) recovery for saline control monkeys. In addition, the recovery of neutrophils was enhanced over that of the controls, reaching 140% v 70% on day 30. Another prominent feature of rhGM-CSF-treated monkeys was the accelerated recovery of platelets, reaching near 50% normal levels by day 24 in comparison with 20% of normal levels for controls. The infusion of rhGM-CSF was shown to be an effective regulator of early hematopoietic regeneration, leading to the accelerated recovery of both neutrophils and platelets and then providing a consistent sustained increase of neutrophils even in the absence of rhGM-CSF.

Therapeutic trial of granulocyte-colony stimulating factor for dilated cardiomyopathy in three dogs.

PubMed

Park, Chul; Yoo, Jong-Hyun; Jeon, Hyo-Won; Kang, Byeong-Teck; Kim, Jung-Hyun; Jung, Dong-In; Lim, Chae-Young; Lee, Hye-Jung; Hahm, Dae-Hyun; Woo, Eung-Je; Park, Hee-Myung

2007-09-01

Three dogs were presented to us for evaluation of cardiac problems. Electrocardiographic recordings revealed severe tachyarrhythmia and atrial fibrillation with ventricular tachycardia in 2 of the 3 dogs. The echocardiographic findings of the 3 dogs revealed markedly decreased fractional shortening and a marked increase in E-point septal separation. Based on the results of electrocardiographic and echocardiographic evaluation, the 3 dogs were diagnosed as dilated cardiomyopathy (DCM). The dogs were treated with conventional cardiac medication, but cardiac function did not improve and the clinical signs remained. We subsequently attempted treatment with granulocyte-colony stimulating factor (G-CSF; 10 microg/kg, subcutaneously). The specific purpose of G-CSF therapy for DCM was to improve cardiac function and a significant improvement in cardiac function was confirmed. The three dogs had no treatment side effects. This case report suggests that G-CSF might have therapeutic effects for medically refractory DCM in dogs.

Clinical assessment of cerebrospinal fluid dynamics in hydrocephalus. Guide to interpretation based on observational study.

PubMed

Weerakkody, R A; Czosnyka, M; Schuhmann, M U; Schmidt, E; Keong, N; Santarius, T; Pickard, J D; Czosnyka, Z

2011-08-01

The term hydrocephalus encompasses a range of disorders characterised by clinical symptoms, abnormal brain imaging and derangement of cerebrospinal fluid (CSF) dynamics. The ability to elucidate which patients would benefit from CSF diversion (a shunt or third ventriculostomy) is often unclear. Similar difficulties are often encountered in shunted patients to predict the scope for improvement by shunt re-adjustment or revision. In this study we aimed to update our knowledge of how key quantitative parameters describing CSF dynamics may be used in diagnosis of shunt-responsive hydrocephalus and in the assessment of shunt function. A number of quantitative parameters [including resistance to CSF outflow (Rcsf), pulse amplitude of intracranial pressure waveform (AMP), RAP index and slow vasogenic waves] were studies in 1423 patients with 2665 CSF infusion tests and 305 overnight intracranial pressure (ICP)-monitoring sessions over a 17 year period. We demonstrate our observations for typical values of Pb, Rcsf, AMP, slow vasogenic waves derived from infusion studies or overnight ICP monitoring in differentiating atrophy from shunt-responsive normal pressure hydrocephalus or acute hydrocephalus. From the same variables tested on shunted patients we demonstrate a standardised approach to help differentiate a properly-functioning shunt from underdrainage or overdrainage. Quantitative variables derived from CSF dynamics allow differentiation between clinically overlapping entities such as shunt-responsive normal pressure hydrocephalus and brain atrophy (not shunt responsive) as well as allowing the detection of shunt malfunction (partial or complete blockage) or overdrainage. This observational study is intended to serve as an update for our understanding of quantitative testing of CSF dynamics. © 2011 John Wiley & Sons A/S.

Comparison of parathyroid hormone and G-CSF treatment after myocardial infarction on perfusion and stem cell homing.

PubMed

Huber, Bruno C; Fischer, Rebekka; Brunner, Stefan; Groebner, Michael; Rischpler, Christoph; Segeth, Alexander; Zaruba, Marc M; Wollenweber, Tim; Hacker, Marcus; Franz, Wolfgang-Michael

2010-05-01

Mobilization of stem cells by granulocyte colony-stimulating factor (G-CSF) was shown to have protective effects after myocardial infarction (MI); however, clinical trials failed to be effective. In search for alternative cytokines, parathyroid hormone (PTH) was recently shown to promote cardiac repair by enhanced neovascularization and cell survival. To compare the impact of the two cytokines G-CSF and PTH on myocardial perfusion, mice were noninvasively and repetitively investigated by pinhole single-photon emission computed tomography (SPECT) after MI. Mobilization and homing of bone marrow-derived stem cells (BMCs) was analyzed by fluorescence-activated cell sorter (FACS) analysis. Mice (C57BL/6J) were infarcted by left anterior descending artery ligation. PTH (80 mug/kg) and G-CSF (100 mug/kg) were injected for 5 days. Perfusion defects were determined by (99m)Tc-sestamibi SPECT at days 6 and 30 after MI. The number of BMCs characterized by Lin(-)/Sca-1(+)/c-kit(+) cells in peripheral blood and heart was analyzed by FACS. Both G-CSF and PTH treatment resulted in an augmented mobilization of BMCs in the peripheral blood. Contrary to G-CSF and controls, PTH and the combination showed significant migration of BMCs in ischemic myocardium associated with a significant reduction of perfusion defects from day 6 to day 30. A combination of both cytokines had no additional effects on migration and perfusion. In our preclinical model, SPECT analyses revealed the functional potential of PTH reducing size of infarction together with an enhanced homing of BMCs to the myocardium in contrast to G-CSF. A combination of both cytokines did not improve the functional outcome, suggesting clinical applications of PTH in ischemic heart diseases.

Differentiating between Alzheimer's Disease and Vascular Cognitive Impairment: Is the "Memory Versus Executive Function" Contrast Still Relevant?

PubMed

Andriuta, Daniela; Roussel, Martine; Barbay, Mélanie; Despretz-Wannepain, Sandrine; Godefroy, Olivier

2018-01-01

The contrast between memory versus executive function impairments is commonly used to differentiate between neurocognitive disorders (NCDs) due to Alzheimer's disease (AD) and vascular cognitive impairment (VCI). We reconsidered this question because of the current use of AD biomarkers and the recent revision of the criteria for AD, VCI, and dysexecutive syndrome. To establish and compare the neuropsychological profiles in AD (i.e., with positive CSF biomarkers) and in VCI. We included 62 patients with mild or major NCDs due to pure AD (with positive CSF biomarker assays), and 174 patients (from the GRECogVASC cohort) with pure VCI. The neuropsychological profiles were compared after stratification for disease severity (mild or major NCD). We defined a memory-executive function index (the mean z score for the third free recall and the delayed free recall in the Free and Cued Selective Reminding Test minus the mean z score for category fluency and the completion time in the Trail Making Test part B) and determined its diagnostic accuracy. Compared with VCI patients, patients with AD had significantly greater memory impairments (p = 0.001). Executive function was impaired to a similar extent in the two groups (p = 0.11). Behavioral executive disorders were more prominent in the AD group (p = 0.001). Although the two groups differed significant with regard to the memory-executive function index (p < 0.001), the latter's diagnostic accuracy was only moderate (sensitivity: 63%, specificity: 87%). Although the contrast between memory and executive function impairments was supported at the group level it does not reliably discriminate between AD and VCI at the individual level.

Leukocyte attraction by CCL20 and its receptor CCR6 in humans and mice with pneumococcal meningitis.

PubMed

Klein, Matthias; Brouwer, Matthijs C; Angele, Barbara; Geldhoff, Madelijn; Marquez, Gabriel; Varona, Rosa; Häcker, Georg; Schmetzer, Helga; Häcker, Hans; Hammerschmidt, Sven; van der Ende, Arie; Pfister, Hans-Walter; van de Beek, Diederik; Koedel, Uwe

2014-01-01

We previously identified CCL20 as an early chemokine in the cerebrospinal fluid (CSF) of patients with pneumococcal meningitis but its functional relevance was unknown. Here we studied the role of CCL20 and its receptor CCR6 in pneumococcal meningitis. In a prospective nationwide study, CCL20 levels were significantly elevated in the CSF of patients with pneumococcal meningitis and correlated with CSF leukocyte counts. CCR6-deficient mice with pneumococcal meningitis and WT mice with pneumococcal meningitis treated with anti-CCL20 antibodies both had reduced CSF white blood cell counts. The reduction in CSF pleocytosis was also accompanied by an increase in brain bacterial titers. Additional in vitro experiments showed direct chemoattractant activity of CCL20 for granulocytes. In summary, our results identify the CCL20-CCR6 axis as an essential component of the innate immune defense against pneumococcal meningitis, controlling granulocyte recruitment.

Direct observation of cerebrospinal fluid bulk flow in the brain

NASA Astrophysics Data System (ADS)

Mestre, Humberto; Tithof, Jeffrey; Thomas, John; Kelley, Douglas; Nedergaard, Maiken

2017-11-01

Cerebrospinal fluid (CSF) serves a vital role in normal brain function. Its adequate flow and exchange with interstitial fluid through perivascular spaces (PVS) has been shown to be important in the clearance of toxic metabolites like amyloid- β, and its disturbance can cause severe neurological diseases. It has long been suspected that bulk flow may transport CSF, but limitations in imaging techniques have prevented direct observation of such flows in the PVS. In this talk, we describe a novel approach using high speed two photon laser scanning microscopy which has allowed for the first ever direct observation of CSF flow in the PVS of a mouse brain. By performing particle tracking velocimetry, we quantify the CSF bulk flow speeds and PVS geometry. This technique enables future studies of CSF flow disturbances on a new scale and will pave the way for evaluating the role of these fluxes in neurodegenerative disease. R01NS100366 (to M.N.).

Use of G-CSF-stimulated marrow in allogeneic hematopoietic stem cell transplantation settings: a comprehensive review.

PubMed

Chang, Ying-Jun; Huang, Xiao-Jun

2011-01-01

In recent years, several researchers have unraveled the previously unrecognized effects of granulocyte colony-stimulating factor (G-CSF) on hematopoiesis and the immune cell functions of bone marrow in healthy donors. In human leukocyte antigen-matched or haploidentical transplant settings, available data have established the safety of using G-CSF-stimulated bone marrow grafts, as well as the ability of this source to produce rapid and sustained engraftment. Interestingly, G-CSF-primed bone marrow transplants could capture the advantages of blood stem cell transplants, without the increased risk of chronic graft-versus-host disease that is associated with blood stem cell transplants. This review summarizes the growing body of evidence that supports the use of G-CSF-stimulated bone marrow grafts as an alternative stem cell source in allogeneic hematopoietic stem cell transplantation. © 2010 John Wiley & Sons A/S.

Leukocyte Attraction by CCL20 and Its Receptor CCR6 in Humans and Mice with Pneumococcal Meningitis

PubMed Central

Angele, Barbara; Geldhoff, Madelijn; Marquez, Gabriel; Varona, Rosa; Häcker, Georg; Schmetzer, Helga; Häcker, Hans; Hammerschmidt, Sven; van der Ende, Arie; Pfister, Hans-Walter

2014-01-01

We previously identified CCL20 as an early chemokine in the cerebrospinal fluid (CSF) of patients with pneumococcal meningitis but its functional relevance was unknown. Here we studied the role of CCL20 and its receptor CCR6 in pneumococcal meningitis. In a prospective nationwide study, CCL20 levels were significantly elevated in the CSF of patients with pneumococcal meningitis and correlated with CSF leukocyte counts. CCR6-deficient mice with pneumococcal meningitis and WT mice with pneumococcal meningitis treated with anti-CCL20 antibodies both had reduced CSF white blood cell counts. The reduction in CSF pleocytosis was also accompanied by an increase in brain bacterial titers. Additional in vitro experiments showed direct chemoattractant activity of CCL20 for granulocytes. In summary, our results identify the CCL20-CCR6 axis as an essential component of the innate immune defense against pneumococcal meningitis, controlling granulocyte recruitment. PMID:24699535

Monoamines and neurosteroids in sexual function during induced hypogonadism in healthy men.

PubMed

Bloch, Miki; Rubinow, David R; Berlin, Kate; Kevala, Karl R; Kim, Hee-Yong; Schmidt, Peter J

2006-04-01

Although the behavioral effects of high-dose androgen administration may involve alterations in serotonergic activity, few studies have investigated the impact of androgen withdrawal on the central nervous system in humans. To examine the effects of pharmacologically induced hypogonadism on several cerebrospinal fluid (CSF) systems that could mediate the behavioral concomitants of hypogonadism. Double-blind assessment of the effects of the short-term induction of hypogonadism and subsequent replacement with testosterone and placebo in a crossover design. National Institutes of Health, Bethesda, Md. Twelve healthy male volunteers. We administered the gonadotropin-releasing hormone agonist leuprolide acetate (7.5 mg intramuscularly every 4 weeks) to the healthy male volunteers, creating a hypogonadal state, and then either replaced testosterone (200 mg intramuscularly) or administered a placebo every 2 weeks for 1 month. Mood and behavioral symptoms were monitored with daily self-ratings, and lumbar punctures were performed during both hypogonadal (placebo) and testosterone-replaced conditions for CSF levels of steroids and monoamine metabolites. The CSF testosterone, dihydrotestosterone, and androsterone levels were significantly lower during hypogonadism (P=.002, .04, and .046, respectively), but no significant changes were observed in CSF measures of 5-hydroxyindoleacetic acid, homovanillic acid, dehydroepiandrosterone, or pregnenolone. Decreased sexual interest was observed during the hypogonadal state compared with both baseline and testosterone replacement (P=.009) and correlated significantly with CSF measures of androsterone during both hypogonadism and testosterone replacement (r = -0.76 and -0.81, respectively; P<.01). Moreover, the change in severity of decreased sexual interest correlated significantly with the change in CSF androsterone levels between testosterone replacement and hypogonadism (r = -0.68; P<.05). The CSF 5-hydroxyindoleacetic acid and homovanillic acid levels did not correlate significantly with any behavioral or CSF measure. These data suggest that the neurosteroid androsterone contributes to the regulation of sexual function in men.

Cerebrospinal Fluid Lumbar Tapping Utilization for Suspected Ventriculoperitoneal Shunt Under-Drainage Malfunctions.

PubMed

Lee, Jong-Beom; Ahn, Ho-Young; Lee, Hong-Jae; Yang, Ji-Ho; Yi, Jin-Seok; Lee, Il-Woo

2017-01-01

The diagnosis of shunt malfunction can be challenging since neuroimaging results are not always correlated with clinical outcomes. The purpose of this study was to evaluate the efficacy of a simple, minimally invasive cerebrospinal fluid (CSF) lumbar tapping test that predicts shunt under-drainage in hydrocephalus patients. We retrospectively reviewed the clinical and radiological features of 48 patients who underwent routine CSF lumbar tapping after ventriculoperitoneal shunt (VPS) operation using a programmable shunting device. We compared shunt valve opening pressure and CSF lumbar tapping pressure to check under-drainage. The mean pressure difference between valve opening pressure and CSF lumbar tapping pressure of all patients were 2.21±24.57 mmH 2 O. The frequency of CSF lumbar tapping was 2.06±1.26 times. Eighty five times lumbar tapping of 41 patients showed that their VPS function was normal which was consistent with clinical improvement and decreased ventricle size on computed tomography scan. The mean pressure difference in these patients was -3.69±19.20 mmH 2 O. The mean frequency of CSF lumbar tapping was 2.07±1.25 times. Fourteen cases of 10 patients revealed suspected VPS malfunction which were consistent with radiological results and clinical symptoms, defined as changes in ventricle size and no clinical improvement. The mean pressure difference was 38.07±23.58 mmH 2 O. The mean frequency of CSF lumbar tapping was 1.44±1.01 times. Pressure difference greater than 35 mmH 2 O was shown in 2.35% of the normal VPS function group (2 of 85) whereas it was shown in 64.29% of the suspected VPS malfunction group (9 of 14). The difference was statistically significant ( p =0.000001). Among 10 patients with under-drainage, 5 patients underwent shunt revision. The causes of the shunt malfunction included 3 cases of proximal occlusion and 2 cases of distal obstruction and valve malfunction. Under-drainage of CSF should be suspected if CSF lumbar tapping pressure is 35 mmH 2 O higher than the valve opening pressure and shunt malfunction evaluation or adjustment of the valve opening pressure should be made.

Pre-cut Filter Paper for Detecting Anti-Japanese Encephalitis Virus IgM from Dried Cerebrospinal Fluid Spots

PubMed Central

Bharucha, Tehmina; Chanthongthip, Anisone; Phuangpanom, Soumphou; Phonemixay, Ooyanong; Sengvilaipaseuth, Onanong; Vongsouvath, Manivanh; Lee, Sue; Newton, Paul N.; Dubot-Pérès, Audrey

2016-01-01

Background The use of filter paper as a simple, inexpensive tool for storage and transportation of blood, ‘Dried Blood Spots’ or Guthrie cards, for diagnostic assays is well-established. In contrast, there are a paucity of diagnostic evaluations of dried cerebrospinal fluid (CSF) spots. These have potential applications in low-resource settings, such as Laos, where laboratory facilities for central nervous system (CNS) diagnostics are only available in Vientiane. In Laos, a major cause of CNS infection is Japanese encephalitis virus (JEV). We aimed to develop a dried CSF spot protocol and to evaluate its diagnostic performance using the World Health Organisation recommended anti-JEV IgM antibody capture enzyme-linked immunosorbent assay (JEV MAC-ELISA). Methodology and Principal Findings Sample volumes, spotting techniques and filter paper type were evaluated using a CSF-substitute of anti-JEV IgM positive serum diluted in Phosphate Buffer Solution (PBS) to end-limits of detection by JEV MAC-ELISA. A conventional protocol, involving eluting one paper punch in 200μl PBS, did not detect the end-dilution, nor did multiple punches utilising diverse spotting techniques. However, pre-cut filter paper enabled saturation with five times the volume of CSF-substitute, sufficiently improving sensitivity to detect the end-dilution. The diagnostic accuracy of this optimised protocol was compared with routine, neat CSF in a pilot, retrospective study of JEV MAC-ELISA on consecutive CSF samples, collected 2009–15, from three Lao hospitals. In comparison to neat CSF, 132 CSF samples stored as dried CSF spots for one month at 25–30°C showed 81.6% (65.7–92.3 95%CI) positive agreement, 96.8% (91.0–99.3 95%CI) negative agreement, with a kappa coefficient of 0.81 (0.70–0.92 95%CI). Conclusions/Significance The novel design of pre-cut filter paper saturated with CSF could provide a useful tool for JEV diagnostics in settings with limited laboratory access. It has the potential to improve national JEV surveillance and inform vaccination policies. The saturation of filter paper has potential use in the wider context of pathogen detection, including dried spots for detecting other analytes in CSF, and other body fluids. PMID:26986061

High diagnostic yield by CSF-PCR for entero- and herpes simplex viruses and TBEV serology in adults with acute aseptic meningitis in Stockholm.

PubMed

Franzen-Rohl, Elisabeth; Larsson, Kenny; Skoog, Eva; Tiveljung-Lindell, Annika; Grillner, Lena; Aurelius, Elisabeth; Glimåker, Martin

2008-01-01

Acute aseptic meningitis (AAM) affects 10-20/100,000 inhabitants per years in Sweden. Up to the beginning of the 1980s the diagnoses were made by virus isolation and/or determination of viral antibodies in serum. The development of PCR for detection of viruses in CSF samples has increased the sensitivity and diagnostic efficiency considerably. We investigated the aetiology of AAM and the diagnostic efficiency in an adult population in Stockholm, using a limited first-line combination of microbiological assays. CSF and serum samples, consecutively collected in 419 patients with clinical symptoms of AAM in northern Stockholm during 1999-2004, were included. PCR assays for herpes simplex virus (HSV) DNA and enterovirus (EV) RNA in the CSF as well as ELISA for IgM in serum to tick-borne encephalitis virus (TBEV) were performed routinely. A viral diagnosis was obtained in 255 of the 419 cases (62%) with these routinely performed assays. Clinical findings in combination with additional diagnostic tests resulted in an overall aetiological yield of 72%. EV was the major causative agent (27%) followed by TBEV (21%) and HSV-2 (19%). We conclude that consistent use of CSF-PCR for EV and HSV and TBEV serology established a diagnosis in the majority of AAM patients.

M-CSF in a new biomarker panel with HE4 and CA 125 in the diagnostics of epithelial ovarian cancer patients.

PubMed

Będkowska, Grażyna Ewa; Ławicki, Sławomir; Gacuta, Ewa; Pawłowski, Przemysław; Szmitkowski, Maciej

2015-05-03

We investigated plasma levels of M-CSF and conventional tumor markers (HE4 and CA 125) in epithelial ovarian cancer patients as compared to control groups: benign ovarian tumor patients (cysts) and healthy subjects. M-CSF levels were determined by ELISA, HE4 and CA 125 levels - by CMIA method. Our results have demonstrated significant differences in the concentration levels of M-CSF, CA 125 and HE4 between the groups of ovarian cancer patients, cysts patients and the healthy controls. In the groups tested M-CSF demonstrated equal to or higher values than both CA 125 and HE4 in diagnostic sensitivity (SE), positive and negative predictive values (PPV, NPV), and in the area under the ROC curve (AUC), particularly in the group with the serous epithelial sub-type of OC. Moreover, CA 125 showed better results of the aforementioned diagnostic criteria than HE4. The combined use of the parameters studied resulted in a further, significant increase in the value of the diagnostic indicators and in the value of the diagnostic power (AUC), especially in the early stages of ovarian cancer. These findings suggest a high usefulness of M-CSF in diagnosing the serous sub-type of epithelial ovarian cancer and in discriminating between cancer and non-carcinoma lesions, particularly in new diagnostic panels in combination with CA 125 and HE4 for the detection of EOC in the early stages.

Predictive Value of Decoy Receptor 3 in Postoperative Nosocomial Bacterial Meningitis

PubMed Central

Liu, Yong-Juan; Shao, Li-Hua; Wang, Qian; Zhang, Jian; Ma, Rui-Ping; Liu, Hai-Hong; Dong, Xiao-Meng; Ma, Li-Xian

2014-01-01

Nosocomial bacterial meningitis requires timely treatment, but what is difficult is the prompt and accurate diagnosis of this disease. The aim of this study was to assess the potential role of decoy receptor 3 (DcR3) levels in the differentiation of bacterial meningitis from non-bacterial meningitis. A total of 123 patients were recruited in this study, among them 80 patients being with bacterial meningitis and 43 patients with non-bacterial meningitis. Bacterial meningitis was confirmed by bacterial culture of cerebrospinal fluid (CSF) culture and enzyme-linked immunosorbent assay (ELISA) was used to detect the level of DcR3 in CSF. CSF levels of DcR3 were statistically significant between patients with bacterial meningitis and those with non-bacterial meningitis (p < 0.001). A total of 48.75% of patients with bacterial meningitis received antibiotic >24 h before CSF sampling, which was much higher than that of non-bacterial meningitis. CSF leucocyte count yielded the highest diagnostic value, with an area under the receiver operating characteristic curve (ROC) of 0.928, followed by DcR3. At a critical value of 0.201 ng/mL for DcR3, the sensitivity and specificity were 78.75% and 81.40% respectively. DcR3 in CSF may be a valuable predictor for differentiating patients with bacterial meningitis from those with non-bacterial meningitis. Further studies are needed for the validation of this study. PMID:25372942

Normal pressure hydrocephalus: Diagnostic and predictive evaluationon

PubMed Central

Damasceno, Benito Pereira

2009-01-01

In typical cases, normal pressure hydrocephalus (NPH) manifests itself with the triad of gait disturbance, which begins first, followed by mental deterioration and urinary incontinence associated with ventriculomegaly (on CT or MRI) and normal cerebrospinal fluid (CSF) pressure. These cases present minor diagnostic difficulties and are the most likely to improve after shunting. Problems arise when NPH shows atypical or incomplete clinical manifestations (25–50% of cases) or is mimicked by other diseases. In this scenario, other complementary tests have to be used, preferentially those that can best predict surgical outcome. Radionuclide cisternography, intracranial pressure monitoring (ICP) and lumbar infusion tests can show CSF dynamics malfunction, but none are able to confirm whether the patient will benefit from surgery. The CSF tap test (CSF-TT) is the only procedure that can temporarily simulate the effect of definitive shunt. Since the one tap CSF-TT has low sensitivity, it cannot be used to exclude patients from surgery. In such cases, we have to resort to a repeated CSF-TT (RTT) or continuous lumbar external drainage (LED). The most reliable prediction would be achieved if RTT or LED proved positive, in addition to the occurrence of B-waves during more than 50% of ICP recording time. This review was based on a PubMed literature search from 1966 to date. It focuses on clinical presentation, neuroimaging, complementary prognostic tests, and differential diagnosis of NPH, particularly on the problem of selecting appropriate candidates for shunt. PMID:29213603

A whole-brain computational modeling approach to explain the alterations in resting-state functional connectivity during progression of Alzheimer's disease.

PubMed

Demirtaş, Murat; Falcon, Carles; Tucholka, Alan; Gispert, Juan Domingo; Molinuevo, José Luis; Deco, Gustavo

2017-01-01

Alzheimer's disease (AD) is the most common dementia with dramatic consequences. The research in structural and functional neuroimaging showed altered brain connectivity in AD. In this study, we investigated the whole-brain resting state functional connectivity (FC) of the subjects with preclinical Alzheimer's disease (PAD), mild cognitive impairment due to AD (MCI) and mild dementia due to Alzheimer's disease (AD), the impact of APOE4 carriership, as well as in relation to variations in core AD CSF biomarkers. The synchronization in the whole-brain was monotonously decreasing during the course of the disease progression. Furthermore, in AD patients we found widespread significant decreases in functional connectivity (FC) strengths particularly in the brain regions with high global connectivity. We employed a whole-brain computational modeling approach to study the mechanisms underlying these alterations. To characterize the causal interactions between brain regions, we estimated the effective connectivity (EC) in the model. We found that the significant EC differences in AD were primarily located in left temporal lobe. Then, we systematically manipulated the underlying dynamics of the model to investigate simulated changes in FC based on the healthy control subjects. Furthermore, we found distinct patterns involving CSF biomarkers of amyloid-beta (Aβ1 - 42) total tau (t-tau) and phosphorylated tau (p-tau). CSF Aβ1 - 42 was associated to the contrast between healthy control subjects and clinical groups. Nevertheless, tau CSF biomarkers were associated to the variability in whole-brain synchronization and sensory integration regions. These associations were robust across clinical groups, unlike the associations that were found for CSF Aβ1 - 42. APOE4 carriership showed no significant correlations with the connectivity measures.

The functional and structural borders between the CSF- and blood-dominated milieus in the choroid plexuses and the area postrema of the rat.

PubMed

Krisch, B

1986-01-01

In the borderline area between the hemal milieu of the choroid plexuses (PC) and the interstitial cerebrospinal-fluid (CSF) compartment, ground substances displaying increased amounts of basal lamina-like material and containing negatively charged sulfated glycosaminoglycans appear to be endowed with selective properties. They may function as a sieve or filtration barrier gradually controlling the passage of substances between the two milieus, depending on their charge and molecular weight. Special structural features and functional properties of ependymal cells are associated with such bordering structures. These ependymal cells are transitional elements between choroid epithelium and ciliated ependymal cells. As judged from experiments with horseradish peroxidase and conventional electron microscopy, occluding junctions at the basal pole of these cells prevent a rapid alteration in the milieu conditions, enabling gradual change from hemal to CSF composition near the bases of these transitional ependymal cells. The borderline structures between the hemal milieu of the PC and the area postrema are established by leptomeningeal cells which face a hemal milieu, are endowed with conspicuous tight junctions, and produce a flocculent substance, the light-microscopic equivalent of which is PAS positive. These structures probably establish an effective barrier between the two milieus of different composition. The functional characteristics and the morphology of the meningeal cells facing the hemal milieu of neurohemal regions resemble closely the neurothelial cells, which are interposed between the CSF milieu and the hemal milieu in the dura mater. The present results suggest that the location between the hemal and the CSF milieu is decisive for the transformation of leptomeningeal cells into "neurothelial" elements.

Intranetwork and internetwork connectivity in patients with Alzheimer disease and the association with cerebrospinal fluid biomarker levels.

PubMed

Weiler, Marina; de Campos, Brunno Machado; Teixeira, Camila Vieira de Ligo; Casseb, Raphael Fernandes; Carletti-Cassani, Ana Flávia Mac Knight; Vicentini, Jéssica Elias; Magalhães, Thamires Naela Cardoso; Talib, Leda Leme; Forlenza, Orestes Vicente; Balthazar, Marcio Luiz Figueredo

2017-11-01

In the last decade, many studies have reported abnormal connectivity within the default mode network (DMN) in patients with Alzheimer disease. Few studies, however, have investigated other networks and their association with pathophysiological proteins obtained from cerebrospinal fluid (CSF). We performed 3 T imaging in patients with mild Alzheimer disease, patients with amnestic mild cognitive impairment (aMCI) and healthy controls, and we collected CSF samples from the patients with aMCI and mild Alzheimer disease. We analyzed 57 regions from 8 networks. Additionally, we performed correlation tests to investigate possible associations between the networks' functional connectivity and the protein levels obtained from the CSF of patients with aMCI and Alzheimer disease. Our sample included 41 patients with Alzheimer disease, 35 with aMCI and 48 controls. We found that the main connectivity abnormalities in those with Alzheimer disease occurred between the DMN and task-positive networks: these patients presented not only a decreased anticorrelation between some regions, but also an inversion of the correlation signal (positive correlation instead of anticorrelation). Those with aMCI did not present statistically different connectivity from patients with Alzheimer disease or controls. Abnormal levels of CSF proteins were associated with functional disconnectivity between several regions in both the aMCI and mild Alzheimer disease groups, extending well beyond the DMN or temporal areas. The presented data are cross-sectional in nature, and our findings are dependent on the choice of seed regions used. We found that the main functional connectivity abnormalities occur between the DMN and task-positive networks and that the pathological levels of CSF biomarkers correlate with functional connectivity disruption in patients with Alzheimer disease.

Intranetwork and internetwork connectivity in patients with Alzheimer disease and the association with cerebrospinal fluid biomarker levels

PubMed Central

Weiler, Marina; de Campos, Brunno Machado; de Ligo Teixeira, Camila Vieira; Casseb, Raphael Fernandes; Mac Knight Carletti-Cassani, Ana Flávia; Vicentini, Jéssica Elias; Magalhães, Thamires Naela Cardoso; Talib, Leda Leme; Forlenza, Orestes Vicente; Balthazar, Marcio Luiz Figueredo

2017-01-01

Background In the last decade, many studies have reported abnormal connectivity within the default mode network (DMN) in patients with Alzheimer disease. Few studies, however, have investigated other networks and their association with pathophysiological proteins obtained from cerebrospinal fluid (CSF). Methods We performed 3 T imaging in patients with mild Alzheimer disease, patients with amnestic mild cognitive impairment (aMCI) and healthy controls, and we collected CSF samples from the patients with aMCI and mild Alzheimer disease. We analyzed 57 regions from 8 networks. Additionally, we performed correlation tests to investigate possible associations between the networks’ functional connectivity and the protein levels obtained from the CSF of patients with aMCI and Alzheimer disease. Results Our sample included 41 patients with Alzheimer disease, 35 with aMCI and 48 controls. We found that the main connectivity abnormalities in those with Alzheimer disease occurred between the DMN and task-positive networks: these patients presented not only a decreased anticorrelation between some regions, but also an inversion of the correlation signal (positive correlation instead of anti-correlation). Those with aMCI did not present statistically different connectivity from patients with Alzheimer disease or controls. Abnormal levels of CSF proteins were associated with functional disconnectivity between several regions in both the aMCI and mild Alzheimer disease groups, extending well beyond the DMN or temporal areas. Limitations The presented data are cross-sectional in nature, and our findings are dependent on the choice of seed regions used. Conclusion We found that the main functional connectivity abnormalities occur between the DMN and task-positive networks and that the pathological levels of CSF biomarkers correlate with functional connectivity disruption in patients with Alzheimer disease. PMID:28375076

Petrous bone fractures violating otic capsule.

PubMed

Magliulo, Giuseppe; Ciniglio Appiani, Mario; Iannella, Giannicola; Artico, Marco

2012-12-01

This study presents our experience with a series of patients suffering from petrous bone fractures violating the otic capsule who underwent subtotal petrosectomy combined with eustachian tube, middle ear, and mastoid obliteration, with the goal of preventing cerebrospinal fluid (CSF) leak and meningitis. This study enrolled 26 patients between 1997 and 2011. The clinical symptoms, otoscopy, and preoperative and postoperative audiometry and facial function, as well as CSF leak or meningitis, were evaluated in each patient. The entire group underwent a subtotal petrosectomy using the technique described in detail by Fisch. In addition, each patient was interviewed using a questionnaire to evaluate the impact on quality of life. Intraoperatively, we found significant CSF leaks in 14 patients (42.5%). No patient reported other episodes of CSF leak or meningitis after the surgery. The patients' responses of facial nerve function were slightly worse than the House-Brackmann evaluation (50% versus 42.3%; p < 0.05). The vast majority (88.5%) of the patients experienced no social impact. Our findings suggest the importance of not underestimating the risk for CSF leak in the petrous bone fractures violating the otic capsule. Preoperative counseling regarding the various troublesome complications must adequately motivate candidates to undergo surgery by pointing out the positive impact of the proposed treatment.

Focal Solute Trapping and Global Glymphatic Pathway Impairment in a Murine Model of Multiple Microinfarcts

PubMed Central

Wang, Minghuan; Ding, Fengfei; Deng, SaiYue; Guo, Xuequn; Wang, Wei

2017-01-01

Microinfarcts occur commonly in the aging brain as a consequence of diffuse embolic events and are associated with the development of vascular dementia and Alzheimer's disease. However, the manner in which disperse microscopic lesions reduce global cognitive function and increase the risk for Alzheimer's disease is unclear. The glymphatic system, which is a brain-wide perivascular network that supports the recirculation of CSF through the brain parenchyma, facilitates the clearance of interstitial solutes including amyloid β and tau. We investigated whether glymphatic pathway function is impaired in a murine model of multiple microinfarcts induced by intraarterial injection of cholesterol crystals. The analysis showed that multiple microinfarcts markedly impaired global influx of CSF along the glymphatic pathway. Although suppression of global glymphatic function was transient, resolving within 2 weeks of injury, CSF tracers also accumulated within tissue associated with microinfarcts. The effect of diffuse microinfarcts on global glymphatic pathway function was exacerbated in the mice aged 12 months compared with the 2- to 3-month-old mice. These findings indicate that glymphatic function is focally disrupted around microinfarcts and that the aging brain is more vulnerable to this disruption than the young brain. These observations suggest that microlesions may trap proteins and other interstitial solutes within the brain parenchyma, increasing the risk of amyloid plaque formation. SIGNIFICANCE STATEMENT Microinfarcts, small (<1 mm) ischemic lesions, are strongly associated with age-related dementia. However, how these microscopic lesions affect global cognitive function and predispose to Alzheimer's disease is unclear. The glymphatic system is a brain-wide network of channels surrounding brain blood vessels that allows CSF to exchange with interstitial fluid, clearing away cellular wastes such as amyloid β. We observed that, in mice, microinfarcts impaired global glymphatic function and solutes from the CSF became trapped in tissue associated with microinfarcts. These data suggest that small, disperse ischemic lesions can impair glymphatic function across the brain and trapping of solutes in these lesions may promote protein aggregation and neuroinflammation and eventually lead to neurodegeneration, especially in the aging brain. PMID:28188218

Focal Solute Trapping and Global Glymphatic Pathway Impairment in a Murine Model of Multiple Microinfarcts.

PubMed

Wang, Minghuan; Ding, Fengfei; Deng, SaiYue; Guo, Xuequn; Wang, Wei; Iliff, Jeffrey J; Nedergaard, Maiken

2017-03-15

Microinfarcts occur commonly in the aging brain as a consequence of diffuse embolic events and are associated with the development of vascular dementia and Alzheimer's disease. However, the manner in which disperse microscopic lesions reduce global cognitive function and increase the risk for Alzheimer's disease is unclear. The glymphatic system, which is a brain-wide perivascular network that supports the recirculation of CSF through the brain parenchyma, facilitates the clearance of interstitial solutes including amyloid β and tau. We investigated whether glymphatic pathway function is impaired in a murine model of multiple microinfarcts induced by intraarterial injection of cholesterol crystals. The analysis showed that multiple microinfarcts markedly impaired global influx of CSF along the glymphatic pathway. Although suppression of global glymphatic function was transient, resolving within 2 weeks of injury, CSF tracers also accumulated within tissue associated with microinfarcts. The effect of diffuse microinfarcts on global glymphatic pathway function was exacerbated in the mice aged 12 months compared with the 2- to 3-month-old mice. These findings indicate that glymphatic function is focally disrupted around microinfarcts and that the aging brain is more vulnerable to this disruption than the young brain. These observations suggest that microlesions may trap proteins and other interstitial solutes within the brain parenchyma, increasing the risk of amyloid plaque formation. SIGNIFICANCE STATEMENT Microinfarcts, small (<1 mm) ischemic lesions, are strongly associated with age-related dementia. However, how these microscopic lesions affect global cognitive function and predispose to Alzheimer's disease is unclear. The glymphatic system is a brain-wide network of channels surrounding brain blood vessels that allows CSF to exchange with interstitial fluid, clearing away cellular wastes such as amyloid β. We observed that, in mice, microinfarcts impaired global glymphatic function and solutes from the CSF became trapped in tissue associated with microinfarcts. These data suggest that small, disperse ischemic lesions can impair glymphatic function across the brain and trapping of solutes in these lesions may promote protein aggregation and neuroinflammation and eventually lead to neurodegeneration, especially in the aging brain. Copyright © 2017 the authors 0270-6474/17/372870-08$15.00/0.

The mediational effects of FDG hypometabolism on the association between cerebrospinal fluid biomarkers and neurocognitive function.

PubMed

Dowling, N Maritza; Johnson, Sterling C; Gleason, Carey E; Jagust, William J

2015-01-15

Positive cerebrospinal fluid (CSF) biomarkers of tau and amyloid beta42 suggest possible active underlying Alzheimer's disease (AD) including neurometabolic dysfunction and neurodegeneration leading to eventual cognitive decline. But the temporal relationship between CSF, imaging markers of neural function, and cognition has not been described. Using a statistical mediation model, we examined relationships between cerebrospinal fluid (CSF) analytes (hyperphosphorylated tau (p-Tau(181p)), β-amyloid peptides 1-42 (Aβ(1-42)), total tau (t-Tau), and their ratios); change in cognitive function; and change in [18F]fluorodeoxyglucose (FDG) uptake using positron emission tomography (PET). We hypothesized that a) abnormal CSF protein values at baseline, result in cognitive declines by decreasing neuronal glucose metabolism across time, and b) the role of altered glucose metabolism in the assumed causal chain varies by brain region and the nature of CSF protein alteration. Data from 412 individuals participating in Alzheimer's Disease Neuroimaging (ADNI) cohort studies were included in analyses. At baseline, individuals were cognitively normal (N = 82), or impaired: 241 with mild cognitive impairment, and 89 with Alzheimer's disease. A parallel-process latent growth curve model was used to test mediational effects of changes in regional FDG-PET uptake over time in relation to baseline CSF biomarkers and changes in cognition, measured with the 13-item Alzheimer Disease's Assessment Scale-cognitive subscale (ADAS-Cog). Findings suggested a causal sequence of events; specifically, FDG hypometabolism acted as a mediator between antecedent CSF biomarker alterations and subsequent cognitive impairment. Higher baseline concentrations of t-Tau, and p-Tau(181p) were more predictive of decline in cerebral glucose metabolism than lower baseline concentrations of Aβ(1-42). FDG-PET changes appeared to mediate t-Tau or t-Tau/Aβ(1-42)-associated cognitive change across all brain regions examined. Significant direct effects of alterations in Aβ(1-42) levels on hypometabolism were observed in a single brain region: middle/inferior temporal gyrus. Results support a temporal framework model in which reduced CSF amyloid-related biomarkers occur earlier in the pathogenic pathway, ultimately leading to detrimental cognitive effects. Also consistent with this temporal framework model, baseline markers of neurofibrillary degeneration predicted changes in brain glucose metabolism in turn causing longitudinal cognitive changes, suggesting that tau-related burden precedes neurometabolic dysfunction. While intriguing, the hypothesized mediational relationships require further validation. Published by Elsevier Inc.

Prolonged effect of stress at weaning on the brain serotonin metabolism and sexuality of female rats.

PubMed

Tekes, K; Hantos, M; Gyenge, M; Karabélyos, Cs; Csaba, G

2006-12-01

Weanling female rats were stressed (by water and food deprivation for two days) and three months later the following indexes were studied: 5-HT and 5-HIAA levels in five brain regions, blood plasma and cerebrospinal fluid (CSF), sexual activity and nocistatin level of the plasma and CSF. The 5-HIAA content of hypothalamus and brainstem was significantly decreased (in the brainstem with one third) and in the striatum significantly increased. Plasma nocistatin level was significantly increased. Meyerson index and lordosis quotient were similar to control, but the estrus frequency almost doubled in the stressed animals. Much more defense reactions were observed in the stressed females during trials of mating. The results demonstrate that, 1) the perinatal period is not only sensitive to the remote-effects of stress but later could also be stress-sensitive critical periods, and 2) the continuously differentiating (e.g. bone marrow) cells are sensitive to late imprinting by stress, as well as to the brain and the sexual system.

The effect of gas physics on the halo mass function

NASA Astrophysics Data System (ADS)

Stanek, R.; Rudd, D.; Evrard, A. E.

2009-03-01

Cosmological tests based on cluster counts require accurate calibration of the space density of massive haloes, but most calibrations to date have ignored complex gas physics associated with halo baryons. We explore the sensitivity of the halo mass function to baryon physics using two pairs of gas-dynamic simulations that are likely to bracket the true behaviour. Each pair consists of a baseline model involving only gravity and shock heating, and a refined physics model aimed at reproducing the observed scaling of the hot, intracluster gas phase. One pair consists of billion-particle resimulations of the original 500h-1Mpc Millennium Simulation of Springel et al., run with the smoothed particle hydrodynamics (SPH) code GADGET-2 and using a refined physics treatment approximated by pre-heating (PH) at high redshift. The other pair are high-resolution simulations from the adaptive-mesh refinement code ART, for which the refined treatment includes cooling, star formation and supernova feedback (CSF). We find that, although the mass functions of the gravity-only (GO) treatments are consistent with the recent calibration of Tinker et al. (2008), both pairs of simulations with refined baryon physics show significant deviations. Relative to the GO case, the masses of ~1014h-1Msolar haloes in the PH and CSF treatments are shifted by the averages of -15 +/- 1 and +16 +/- 2 per cent, respectively. These mass shifts cause ~30 per cent deviations in number density relative to the Tinker function, significantly larger than the 5 per cent statistical uncertainty of that calibration.

Cerebrospinal Fluid proNGF: A Putative Biomarker for Early Alzheimer’s Disease

PubMed Central

Counts, Scott E.; He, Bin; Prout, John G.; Michalski, Bernadeta; Farotti, Lucia; Fahnestock, Margaret; Mufson, Elliott J.

2018-01-01

The discovery of biomarkers for the onset of Alzheimer’s disease (AD) is essential for disease modification strategies. To date, AD biomarker studies have focused on brain imaging and cerebrospinal fluid (CSF) changes in amyloid-β (Aβ) peptide and tau proteins. While reliable to an extent, this panel could be improved by the inclusion of novel biomarkers that optimize sensitivity and specificity. In this study, we determined whether CSF levels of the nerve growth factor (NGF) precursor protein, proNGF, increased during the progression of AD, mirroring its up regulation in postmortem brain samples of people who died with a clinical diagnosis of mild cognitive impairment (MCI) or AD. Immunoblot analysis was performed on ventricular CSF harvested from participants in the Rush Religious Orders Study with an antemortem clinical diagnosis of no cognitive impairment (NCI), amnestic MCI (aMCI, a putative prodromal AD stage), or mild/moderate AD. ProNGF levels were increased 55% in aMCI and 70% in AD compared to NCI. Increasing CSF proNGF levels correlated with impairment on cognitive test scores. In a complementary study, we found that proNGF was significantly increased by 30% in lumbar CSF samples derived from patients with a clinical dementia rating (CDR) of 0.5 or 1 compared to those with a CDR = 0. Notably, proNGF/Aβ1-42 levels were 50% higher in CDR 0.5 and CDR 1 compared to CDR 0 controls. By contrast, ELISA measurements of CSF brain-derived neurotrophic factor (BDNF) did not distinguish aMCI from NCI. Taken together, these results suggest that proNGF protein levels may augment the diagnostic accuracy of currently used CSF biomarker panels. PMID:26825093

Predictive factors of bacterial meningitis in the patients seen in emergency departments.

PubMed

Morales-Casado, María Isabel; Julián-Jiménez, Agustín; Lobato-Casado, Paula; Cámara-Marín, Belén; Pérez-Matos, Julio Alberto; Martínez-Maroto, Tamara

2017-04-01

To analyse and compare predictive factors of bacterial meningitis in the patients seen in the Emergency Departments (ED) due to an episode of acute meningitis (AM). A prospective, observational study was carried out in patients aged 15 years and older seen in ED due to AM between August 2009 and November 2015. Thirty-two variables for predicting bacterial meningitis were assessed. They covered epidemiological, comorbidity, clinical and analytical factors. Multivariate logistic regression analysis was performed. The study included 154 patients. The diagnosis was bacterial meningitis in 53 (34.4%) patients. Four variables were significantly associated with bacterial aetiology: cerebrospinal fluid (CSF) lactate concentration ≥33mg/dl (odds ratio [OR] 50.84; 95% confidence interval [CI]: 21.63-119.47, P<.001), serum procalcitonin (PCT) ≥0.8ng/ml (OR 46.34; 95%CI: 19.71-108.89; P<.001), CSF glucose <60% of blood value (OR 20.82; 95%CI: 8.86-48.96; P=.001), CSF polymorphonuclears greater than 50% (OR 20.19; 95%CI: 8.31-49.09; P=.002]. The area under the curve for the model serum PCT≥0.8ng/ml plus CSF lactate ≥33mg/dl was 0.992 (95%CI: 0.979-1; P<.001), and achieved 99% sensitivity and 98% specificity for predicting bacterial meningitis. Serum PCT with CSF lactate, CSF glucose and CSF polymorphonuclears evaluated in an initial assessment in the ED for patients with AM, achieved an excellent diagnostic usefulness for predicting bacterial meningitis. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

[Intracranial pressure monitoring and CSF dynamics in patients with neurological disorders: indications and practical considerations].

PubMed

Poca, M; Sahuquillo, J

2001-01-01

The study of cerebrospinal fluid (CSF) dynamics is central to the diagnosis of adult chronic hydrocephalus (ACH). At present, many neurology and neurosurgery departments use one or more tests to guide diagnosis of this syndrome and to predict patient response to shunting. In specialised centres, the study of CSF dynamics is combined with continuous intracranial pressure (ICP) monitoring. Determination of several variables of CSF dynamics and definitions of qualitative and quantitative characteristics of ICP can be used to establish whether the hydrocephalus is active, compensated or arrested. CSF dynamics and ICP monitoring can also be used to check the correct functioning of the shunt and can be of use in the clinical management of patients with pseudotumor cerebri. Moreover, ICP monitoring is used to guide the treatment of several acute neurological processes. The aim of this review is to describe the fundamentals of CSF dynamics studies and the bases of continuous ICP monitoring. The advantages and disadvantages of several hydrodynamic tests that can be performed by lumbar puncture, as well as the normal and abnormal characteristics of an ICP recording, are discussed.

Hematopoietic Effects of Paeoniflorin and Albiflorin on Radiotherapy-Induced Myelosuppression Mice

PubMed Central

Zhu, Yingli; Wang, Linyuan; Yang, Zhihui; Wang, Jingxia; Li, Wei; Zhou, Jianyu; Zhang, Jianjun

2016-01-01

Paeonia lactiflora root (baishao in Chinese) is a commonly used herb in traditional Chinese medicine (TCM). Paeoniflorin (PF) and albiflorin (AF) are two major active constituents of P. lactiflora. In this paper, we aimed to investigate the hematopoietic effects of PF and AF on myelosuppression mice induced by radiotherapy and to explore the underlying mechanism. The finding indicated that PF and AF significantly increased the numbers of white blood cells (WBC) and reversed the atrophy of thymus. Furthermore, PF and AF increased the levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) and reduced the levels of tumor necrosis factor-α (TNF-α) in serum and increased the level of colony-stimulating factor (G-CSF) in plasma. Lastly, PF and AF not only enhanced the mRNA levels of GM-CSF and G-CSF in the spleens, but also increased the protein levels of G-CSF and GM-CSF in bone marrow. Our results suggest that PF and AF may promote the recovery of bone marrow hemopoietic function in a myelosuppressed mouse model. PMID:27313650

Soluble sortilin is present in excess and positively correlates with progranulin in CSF of aging individuals.

PubMed

Molgaard, Simon; Demontis, Ditte; Nicholson, Alexandra M; Finch, Nicole A; Petersen, Ronald C; Petersen, Claus M; Rademakers, Rosa; Nykjaer, Anders; Glerup, Simon

2016-11-01

Mutations in progranulin are a major cause of frontotemporal lobe degeneration (FTLD). Hence, plasma progranulin is an attractive biomarker in FTLD but poorly reflects levels in cerebrospinal fluid (CSF), suggesting tissue-specific regulation of progranulin levels. Sortilin was recently identified as a progranulin scavenger receptor that destines it for lysosomal degradation. Proteolysis or alternative splicing generates soluble sortilin variants that retain progranulin binding and potentially functions as a decoy receptor. In the present study, we analyzed soluble sortilin and progranulin in plasma and CSF in 341 aging individuals. We found that soluble sortilin exists in CSF in ten-fold molar excess compared to progranulin and observed a highly significant positive correlation between soluble sortilin and progranulin levels in CSF but not in plasma. However, carriers of the minor allele of SNP rs646776 in SORT1 encoding sortilin displayed significantly increased soluble sortilin and reduced progranulin specifically in plasma but not in CSF. Taken together, our findings suggest that soluble sortilin may affect progranulin levels in both a tissue-specific and genotype-dependent manner. Copyright © 2016 Elsevier Inc. All rights reserved.

Diagnostic Performance of a Multiplex PCR assay for meningitis in an HIV-infected population in Uganda

PubMed Central

Rhein, Joshua; Bahr, Nathan C; Hemmert, Andrew C; Cloud, Joann L; Bellamkonda, Satya; Oswald, Cody; Lo, Eric; Nabeta, Henry; Kiggundu, Reuben; Akampurira, Andrew; Musubire, Abdu; Williams, Darlisha; Meya, David B; Boulware, David R

2015-01-01

Meningitis remains a worldwide problem, and rapid diagnosis is essential to optimize survival. We evaluated the utility of a multiplex PCR test in differentiating possible etiologies of meningitis. Cerebrospinal fluid (CSF) from 69 HIV-infected Ugandan adults with meningitis was collected at diagnosis (n=51) and among persons with cryptococcal meningitis during therapeutic lumbar punctures (n=68). Cryopreserved CSF specimens were analyzed with BioFire FilmArray® Meningitis/Encephalitis panel, which targets 17 pathogens. The panel detected Cryptococcus in the CSF of patients diagnosed with a first-episode of cryptococcal meningitis by fungal culture with 100% sensitivity and specificity, and differentiated between fungal relapse and paradoxical immune reconstitution inflammatory syndrome in recurrent episodes. A negative FilmArray result was predictive of CSF sterility on follow-up lumbar punctures for cryptococcal meningitis. EBV was frequently detected in this immunosuppressed population (n=45). Other pathogens detected included: CMV (n=2), VZV (n=2), HHV-6 (n=1), and Streptococcus pneumoniae (n=1). The FilmArray Meningitis/Encephalitis panel offers a promising platform for rapid meningitis diagnosis. PMID:26711635

Diagnostic function of the neuroinflammatory biomarker YKL-40 in Alzheimer's disease and other neurodegenerative diseases.

PubMed

Baldacci, Filippo; Lista, Simone; Cavedo, Enrica; Bonuccelli, Ubaldo; Hampel, Harald

2017-04-01

Neuroinflammation is a crucial mechanism in the pathophysiology of neurodegenerative diseases pathophysiology. Cerebrospinal fluid (CSF) YKL-40 - an indicator of microglial activation - has recently been identified by proteomic studies as a candidate biomarker for Alzheimer's disease (AD). Areas covered: We review the impact of CSF YKL-40 as a pathophysiological biomarker for AD and other neurodegenerative diseases. CSF YKL-40 concentrations have been shown to predict progression from prodromal mild cognitive impairment to AD dementia. Moreover, a positive association between CSF YKL-40 and other biomarkers of neurodegeneration - particularly total tau protein - has been reported during the asymptomatic preclinical stage of AD and other neurodegenerative diseases. Albeit preliminary, current data do not support an association between APOE-ε4 status and CSF YKL-40 concentrations. When interpreting the diagnostic/prognostic significance of CSF YKL-40 concentrations in neurodegenerative diseases, potential confounders - including age, metabolic and cardiovascular risk factors, diagnostic criteria for selecting cases/controls - need to be considered. Expert opinion/commentary: CSF YKL-40 represents a pathophysiological biomarker reflecting immune/inflammatory mechanisms in neurodegenerative diseases, associated with tau protein pathology. Besides being associated with tau pathology, CSF YKL-40 adds to the growing array of biomarkers reflecting distinct molecular brain mechanisms potentially useful for stratifying individuals for biomarker-guided, targeted anti-inflammatory therapies emerging from precision medicine.

[Cytokines in cancer chemotherapy: present state and problems in use of G- and GM-CSF for solid tumors in Japan].

PubMed

Ogawara, M

1998-01-01

The present state and the problems of G and GM-CSF in cancer chemotherapy, especially for solid tumors in Japan, were reviewed. One of the problems is that adaptation is restricted to several tumors, and the other that recommended doses are about half or one-fourth as much as in North America or Europe. With G-CSF after dose-intensive chemotherapy in small-cell lung cancer, three studies showed G-CSF shortened the duration of neutropenia, and reduced the incidence of neutropenic fever, use of antibiotics and hospitalization, while they showed no advantages in terms of response rate and the incidence of infection-related death. Moreover, the effect on survival has not been proved. In afebrile neutropenic patients, G-CSF could accelerate recovery from neutropenia, but did not reduce the incidence of neutropenic fever. In febrile neutropenic patients with antibiotics, it could also accelerate recovery from neutropenia, but did not reduce neutropenic fever compared with no CSF except in some subsets. Our retrospective study showed the effects of G-CSF in grade 4 neutropenia were comparable with grade 3 neutropenia. The functions of neutrophils with G-CSF after chemotherapy were reported to be increased or maintained. Clinical benefits were only obtained in certain dose-intensive chemotherapy or in limited subsets. Additional clinical trials and a guideline like ASCO's should be planned.

Rhythmic control of endocannabinoids in the rat pineal gland.

PubMed

Koch, Marco; Ferreirós, Nerea; Geisslinger, Gerd; Dehghani, Faramarz; Korf, Horst-Werner

2015-01-01

Endocannabinoids modulate neuroendocrine networks by directly targeting cannabinoid receptors. The time-hormone melatonin synchronizes these networks with external light condition and guarantees time-sensitive and ecologically well-adapted behaviors. Here, the endocannabinoid arachidonoyl ethanolamide (AEA) showed rhythmic changes in rat pineal glands with higher levels during the light-period and reduced amounts at the onset of darkness. Norepinephrine, the essential stimulus for nocturnal melatonin biosynthesis, acutely down-regulated AEA and other endocannabinoids in cultured pineal glands. These temporal dynamics suggest that AEA exerts time-dependent autocrine and/or paracrine functions within the pineal. Moreover, endocananbinoids may be released from the pineal into the CSF or blood stream.

Annual patient and caregiver burden of oncology clinic visits for granulocyte-colony stimulating factor therapy in the US.

PubMed

Stephens, J Mark; Li, Xiaoyan; Reiner, Maureen; Tzivelekis, Spiros

2016-01-01

Prophylactic treatment with granulocyte-colony stimulating factors (G-CSFs) is indicated for chemotherapy patients with a significant risk of febrile neutropenia. This study estimates the annual economic burden on patients and caregivers of clinic visits for prophylactic G-CSF injections in the US. Annual clinic visits for prophylactic G-CSF injections (all cancers) were estimated from national cancer incidence, chemotherapy treatment and G-CSF utilization data, and G-CSF sales and pricing information. Patient travel times, plus time spent in the clinic, were estimated from patient survey responses collected during a large prospective cohort study (the Prospective Study of the Relationship between Chemotherapy Dose Intensity and Mortality in Early-Stage (I-III) Breast Cancer Patients). Economic models were created to estimate travel costs, patient co-pays and the economic value of time spent by patients and caregivers in G-CSF clinic visits. Estimated total clinic visits for prophylactic G-CSF injections in the US were 1.713 million for 2015. Mean (SD) travel time per visit was 62 (50) min; mean (SD) time in the clinic was 41 (68) min. Total annual time for travel to and from the clinic, plus time at the clinic, is estimated at 4.9 million hours, with patient and caregiver time valued at $91.8 million ($228 per patient). The estimated cumulative annual travel distance for G-CSF visits is 60.2 million miles, with a total transportation cost of $28.9 million ($72 per patient). Estimated patient co-pays were $61.1 million, ∼$36 per visit, $152 per patient. The total yearly economic impact on patients and caregivers is $182 million, ∼$450 per patient. Data to support model parameters were limited. Study estimates are sensitive to the assumptions used. The burden of clinic visits for G-CSF therapy is a significant addition to the total economic burden borne by cancer patients and their families.

Stage progression and neurological symptoms in Trypanosoma brucei rhodesiense sleeping sickness: role of the CNS inflammatory response.

PubMed

MacLean, Lorna; Reiber, Hansotto; Kennedy, Peter G E; Sternberg, Jeremy M

2012-01-01

Human African trypanosomiasis progresses from an early (hemolymphatic) stage, through CNS invasion to the late (meningoencephalitic) stage. In experimental infections disease progression is associated with neuroinflammatory responses and neurological symptoms, but this concept requires evaluation in African trypanosomiasis patients, where correct diagnosis of the disease stage is of critical therapeutic importance. This was a retrospective study on a cohort of 115 T.b.rhodesiense HAT patients recruited in Eastern Uganda. Paired plasma and CSF samples allowed the measurement of peripheral and CNS immunoglobulin and of CSF cytokine synthesis. Cytokine and immunoglobulin expression were evaluated in relation to disease duration, stage progression and neurological symptoms. Neurological symptoms were not related to stage progression (with the exception of moderate coma). Increases in CNS immunoglobulin, IL-10 and TNF-α synthesis were associated with stage progression and were mirrored by a reduction in TGF-β levels in the CSF. There were no significant associations between CNS immunoglobulin and cytokine production and neurological signs of disease with the exception of moderate coma cases. Within the study group we identified diagnostically early stage cases with no CSF pleocytosis but intrathecal immunoglobulin synthesis and diagnostically late stage cases with marginal CSF pleocytosis and no detectable trypanosomes in the CSF. Our results demonstrate that there is not a direct linkage between stage progression, neurological signs of infection and neuroinflammatory responses in rhodesiense HAT. Neurological signs are observed in both early and late stages, and while intrathecal immunoglobulin synthesis is associated with neurological signs, these are also observed in cases lacking a CNS inflammatory response. While there is an increase in inflammatory cytokine production with stage progression, this is paralleled by increases in CSF IL-10. As stage diagnostics, the CSF immunoglobulins and cytokines studied do not have sufficient sensitivity to be of clinical value.

A novel Aβ isoform pattern in CSF reflects γ-secretase inhibition in Alzheimer disease

PubMed Central

2010-01-01

Introduction LY450139 (semagacestat) inhibits γ-secretase, a key enzyme for generation of amyloid β (Aβ), the peptide deposited in plaques in Alzheimer disease (AD). Previous data have shown that LY450139 lowers plasma Aβ, but has no clear effect on Aβ1-40 or Aβ1-42 levels in cerebrospinal fluid (CSF). By using targeted proteomics techniques, we recently identified several shorter Aβ isoforms, such as Aβ1-16, that in experimental settings increase during γ-secretase inhibitor treatment, and thus may serve as sensitive biochemical indices of the treatment effect. Here, we test the hypothesis that these shorter Aβ isoforms may be biomarkers of γ-secretase inhibitor treatment in clinical trials. Methods In a phase II clinical trial, 35 individuals with mild to moderate AD were randomized to placebo (n = 10) or LY450139 (100 mg (n = 15) or 140 mg (n = 10)) and underwent lumbar puncture at baseline and after 14 weeks of treatment. The CSF Aβ isoform pattern was analyzed with immunoprecipitation combined with MALDI-TOF mass spectrometry. Results The CSF levels of Aβ1-14, Aβ1-15, and Aβ1-16 showed a dose-dependent increase by 57% and 74%, 21% and 35%, and 30% and 67%, respectively in the 100-mg and 140-mg treatment groups. Aβ1-40 and Aβ1-42 were unaffected by treatment. Conclusions CSF Aβ1-14, Aβ1-15, and Aβ1-16 increase during γ-secretase inhibitor treatment in AD, even at doses that do not affect Aβ1-42 or Aβ1-40, probably because of increased substrate availability of the C99 APP stub (APP β-CTF) induced by γ-secretase inhibition. These Aβ isoforms may be novel sensitive biomarkers to monitor the biochemical effect in clinical trials. Trial registration Clinical Trials.gov NCT00244322 PMID:20350302

Rapid diagnosis of cryptococcal meningitis by use of lateral flow assay on cerebrospinal fluid samples: influence of the high-dose "hook" effect.

PubMed

Lourens, Adré; Jarvis, Joseph N; Meintjes, Graeme; Samuel, Catherine M

2014-12-01

Cryptococcal meningitis is the most frequent cause of meningitis and a major cause of mortality in HIV-infected adults in Africa. This study evaluated the performance of the lateral flow assay (LFA) on cerebrospinal fluid (CSF) samples for the diagnosis of cryptococcal meningitis against that of existing diagnostic tests. LFA performed on 465 undiluted CSF samples had a sensitivity of 91%. When the LFA was paired with Gram staining, a sensitivity of 100% was achieved after implementation of a dilution step for samples with negative LFA results and the presence of yeasts on microscopy. Microscopy is essential for preventing the reporting of false-negative results due to the high-dose "hook" effect. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

[Gene expression in murine splenocytes induced by soluble beta-glucan].

PubMed

Hida, Toshie; Kawaminami, Hiromi; Ishibashi, Ken-ichi; Miura, Noriko; Adachi, Yoshiyuki; Ohno, Naohito

2010-01-01

SCG is a 6-branched 1,3-β-D-glucan, and is a major cell wall structural component in fungi. The leukocytes from DBA/1 and DBA/2 mice are highly sensitive to SCG, producing cytokines, such as GM-CSF, IFN-γ and TNF-α. GM-CSF plays a key biological role in this activity. We analyzed factors induced by SCG in splenocytes from DBA/2 mice by DNA microarray analysis on the condition of high sensitivity to β-glucan. Splenocytes were stimulated with SCG at 0, 24 or 30 h, and then supernatant was collected at 48 h to measure cytokines. SCG stimulated splenocytes to produce GM-CSF, IFN-γ and TNF-α in all the supernatants of 0, 24, and 30 h. The amount of IFN-γ production thus stimulated at 24 h was comparable to that at 0 h. Cytokine induction was observed at 4 h after SCG-stimulation even in the splenocytes pre-cultured for 36 h. The gene expression induced by SCG was analyzed with DNA microarray in the splenocytes in this condition. SCG up-regulated the expression of genes including Edn1 and Ptgs2 as well as genes associated with cytokine and chemokine. PGE(2) was detected in the medium of splenocytes stimulated with SCG. Taken together, these results indicated that splenocytes enhanced the sensitivity to SCG in earlier culture periods, and then responded to SCG to induce not only the cytokines but also various other factors.

Human enteroviruses in cerebrospinal fluid of children with suspected aseptic meningitis: A study in northern Iran.

PubMed

Sadeghi, Farzin; Talebi-Nesami, Masoumeh; Barari-Savadkouhi, Rahim; Bijani, Ali; Ferdosi-Shahandashti, Elahe; Yahyapour, Yousef

2017-01-01

Enterovirus (EV) infections are one of the most common causes of aseptic meningitis in pediatrics. To diagnose EV meningitis, virus isolation in cell cultures is often time consuming and lacks sensitivity to be of clinical relevance. This makes the virus culture results difficult to interpret. The rapid detection of EVs in cerebrospinal fluid (CSF) by molecular diagnostic techniques may improve the management of patients with aseptic meningitis. The purpose of the present study was to develop a more convenient and sensitive alternative technique to viral culture. The current investigation aimed to explore the prevalence of EVs in CSF of children with suspected aseptic meningitis in northern Iran, between June 2014 and March 2015 via the one-step real-time RT-PCR technique. A single center cross-sectional study was carried out on 50 children suspected with aseptic meningitis, aged 6 months to 13 years. The presence of EV RNA in CSF samples was screened by the use of qualitative one-step real-time RT-PCR. Enteroviral RNA was detected in 9 (18%) subjects using the one-step real-time RT-PCR assay. There was significant difference between EV positive and negative subjects regarding mean age (P=0.023), mean lymphocyte percentage (P=0.001) and mean glucose levels in CSF (P=0.037). The disease onset data indicate that the majority of EV meningitis occurred in the summer. This study provides the first data on the prevalence and epidemiology of EV infections in children with suspected aseptic meningitis in northern Iran.

A review of the relationship between proinflammatory cytokines and major depressive disorder.

PubMed

Young, Juan Joseph; Bruno, Davide; Pomara, Nunzio

2014-12-01

Determining etiological factors and reviewing advances in diagnostic modalities sensitive and specific to Major Depressive Disorder (MDD) is of importance in its evaluation and treatment. The inflammatory hypothesis is one of the most prevalent topics concerning MDD and may provide insight into the pathogenesis of depression, development of biomarkers, and ultimately production of more effective depression therapies. We reviewed several studies to evaluate contemporary concepts concerning proinflammatory cytokines and their relationship to various depressive disorders, the use of anti-inflammatory therapies in MDD treatment, and the application of neuroimaging in conjunction with cytokine profiles from both plasma and CSF as possible diagnostic tools. Proinflammatory cytokines in both plasma and CSF have been found to influence the progression and severity of depressive disorders in different populations. Studies have shown elevated serum levels of IL-1, IL-6, TNF-α, CRP, and MCP-1 in depressed patients, but have presented mixed results with IL-8 serum levels, and with IL-6 and MCP-1 CSF levels. Anti-inflammatory treatment of MDD may have adjuvant properties with current depression medications. MRI and NIRS neuroimaging confirm neurological abnormalities in the presence of elevated proinflammatory cytokines in depressed or stressed patients. Heterogeneity of MDD and limited CSF cytokine research complicate the study of MDD pathogenesis. There is significant evidence that inflammatory processes influence the development and progression of MDD. Future studies with larger arrays of cytokine profiles aided by neuroimaging may provide more sensitive and specific modes of diagnostics in determining MDD etiology and provide guidance in individual therapies. Copyright © 2014 Elsevier B.V. All rights reserved.

Childhood Acute Bacterial Meningitis: Clinical Spectrum, Bacteriological Profile and Outcome.

PubMed

Bari, Attia; Zeeshan, Fatima; Zafar, Aiza; Ejaz, Hassan; Iftikhar, Aisha; Rathore, Ahsan Waheed

2016-10-01

To determine the disease pattern, etiological agents and outcome of childhood acute bacterial meningitis. Adescriptive study. Department of Paediatric Medicine, The Children's Hospital, Lahore, from January to December 2012. Atotal of 199 children between the ages of 1 month and 5 years, admitted with the diagnosis of meningitis on the basis of clinical findings and positive cerebrospinal fluid (CSF), were included. In all patients, complete blood count (CBC), CSF culture sensitivity, and blood culture sensitivity were performed. Data was analysed using SPSS version 20. Out of 199 children, 127 (63.8%) were males with M:F ratio of 1.7:1. Mean age was 11.33 ±12 months. Maximum numbers of children were < 1 year of age, 136 (68.3%). Only 90 (45.2%) children were fully vaccinated according to Expanded Program of Immunisation (EPI) schedule. Presentations with refusal to take feed (p=0.008) and with impaired conscious state were independent predictors of death (p=0.002). Complications were noted in 34 (17%) and were significantly associated with severe malnutrition (p=0.006) and altered conscious level at presentation (p < 0.001). The common pathogens identified on CSF culture were coagulase negative staphylococci (CoNS) in 11 (5.5%) and streptococcus pneumoniaein 5 (2.5%). Overall mortality was 10.1%. The commonest pathogen isolated from children who died was streptococcus pneumoniae(p=0.039). Acute bacterial meningitis mostly affected children under the age of 1 year. CSF culture revealed both Grampositive and Gram-negative bacteria. The most common pathogen in children who died was streptococcus pneumoniae.

[Concentration of proinflammatory cytokines (TNF-alpha, IL-8) in the cerebrospinal fluid and the course of bacterial meningitis].

PubMed

Bociaga-Jasik, Monika; Garlicki, Aleksander; Kalinowska-Nowak, Anna; Mach, Tomasz

2004-01-01

Bacterial meningitis is still associated with high mortality rate and severe neurological sequels. The aim of the study was to assess correlation between concentration of proinflammatory cytokines (TNF-alpha, IL-1 beta, IL-8) in the cerebrospinal fluid (CSF) and patient condition described on the basis of Glasgow Coma Scale (GCS), changes in the CSF (pleocytosis, protein and glucose level), mortality rate and occurrence of neurological complications. 42 patients with bacterial meningitis have been analysed. Control group consisted of 25 patients with viral meningitis and 23 patients without meningitis. In analysed group with bacterial meningitis the correlation between number of scores aggregated by patients in GCS and outcome has been observed. Concentration of TNF-alpha, IL-1 beta, IL-8 in CSF of patient with bacterial meningitis was significantly higher (mean value; 705.2 pg/ml, 401.1 pg/ml and 1696.0 pg/ml) than in control group (viral meningitis: 7.93 pg/ml, 31.89 pg/ml, 405.28 pg/ml, without meningitis: 0.38 pg/ml, 2.55 pg/ml, 32.56 pg/ml). Negative correlation between concentration of investigated cytokines in the CSF of patient with bacterial meningitis and GCS has been observed. Furthermore TNF-alpha and IL-8 levels correlated with pleocytosis, and protein and glucose levels, whereas IL-1 beta correlated with pleocytosis and protein level in CSF. Connection between TNF-alpha and IL-1 beta but not IL-8 level and outcome of bacterial meningitis has been observed. High TNF-alpha in the CSF (median value 953 pg/ml) was associated with significant risk of patient death. IL-1 beta has been better prognostic indicator. Patients who developed neurological sequels had median value of IL-1 beta level 401.3 pg/ml, and those who died had 585.9 pg/ml vs 244.7 pg/ml in the group who survived without any complications. Analysis of the ROC curve-revealed, that concentration of IL-1 beta > or = 289.9 pg/ml with 88.9% sensitivity and 67.7% specifity differentiate cases who at risk for death. For TNF-alpha the cut-off was > or = 538.9 pg/ml. The sensitivity for determined critical point was 77%, and specificity was 68.7%. Our investigation confirm that TNF alpha, IL-1 beta, IL-8 are useful in differential diagnosis of neuroinfections. Assessment of patients with bacterial meningitis on the basis of GCS is helpful to establish prognosis, and CGS seems to correlate with the intensity of inflammation in the CSF. High concentration of TNF-alpha, and IL-1 beta in the CSF are associated with the risk of patient death during the course of bacterial meningitis, but IL-1 beta has been the better prognostic marker.

Simulation of Two-Fluid Flows by the Least-Squares Finite Element Method Using a Continuum Surface Tension Model

NASA Technical Reports Server (NTRS)

Wu, Jie; Yu, Sheng-Tao; Jiang, Bo-nan

1996-01-01

In this paper a numerical procedure for simulating two-fluid flows is presented. This procedure is based on the Volume of Fluid (VOF) method proposed by Hirt and Nichols and the continuum surface force (CSF) model developed by Brackbill, et al. In the VOF method fluids of different properties are identified through the use of a continuous field variable (color function). The color function assigns a unique constant (color) to each fluid. The interfaces between different fluids are distinct due to sharp gradients of the color function. The evolution of the interfaces is captured by solving the convective equation of the color function. The CSF model is used as a means to treat surface tension effect at the interfaces. Here a modified version of the CSF model, proposed by Jacqmin, is used to calculate the tension force. In the modified version, the force term is obtained by calculating the divergence of a stress tensor defined by the gradient of the color function. In its analytical form, this stress formulation is equivalent to the original CSF model. Numerically, however, the use of the stress formulation has some advantages over the original CSF model, as it bypasses the difficulty in approximating the curvatures of the interfaces. The least-squares finite element method (LSFEM) is used to discretize the governing equation systems. The LSFEM has proven to be effective in solving incompressible Navier-Stokes equations and pure convection equations, making it an ideal candidate for the present applications. The LSFEM handles all the equations in a unified manner without any additional special treatment such as upwinding or artificial dissipation. Various bench mark tests have been carried out for both two dimensional planar and axisymmetric flows, including a dam breaking, oscillating and stationary bubbles and a conical liquid sheet in a pressure swirl atomizer.

Granulocyte colony-stimulating factor (G-CSF) plays an important role in immune complex-mediated arthritis.

PubMed

Christensen, Anne D; Haase, Claus; Cook, Andrew D; Hamilton, John A

2016-05-01

Neutrophils are an abundant cell type in many chronic inflammatory diseases such as rheumatoid arthritis (RA); however, their contribution to the pathology of RA has not been widely studied. A key cytokine involved in neutrophil development and function is granulocyte-colony stimulating factor (G-CSF). In this study we used the K/BxN serum-transfer arthritis (STA) model, mimicking the effector phase of RA, to investigate the importance of G-CSF in arthritis development and its relation to neutrophils. Here, we show for the first time in this model that G-CSF levels are increased both in the serum and in inflamed paws of arthritic mice and importantly that G-CSF blockade leads to a profound reduction in arthritis severity, as well as reduced numbers of neutrophils in blood. Moreover, CXCL1 and CXCL2 levels in the arthritic joints were also lowered. Our data demonstrate that G-CSF is a pivotal driver of the disease progression in the K/BxN STA model and possibly acts in part by regulating neutrophil numbers in the circulation. Therefore, our findings suggest that G-CSF might be a suitable target in RA, and perhaps in other immune complex-driven pathologies. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

White matter lesion severity is associated with reduced cognitive performances in patients with normal CSF Abeta42 levels.

PubMed

Stenset, V; Hofoss, D; Johnsen, L; Skinningsrud, A; Berstad, A E; Negaard, A; Reinvang, I; Gjerstad, L; Fladby, T

2008-12-01

To identify possible associations between white matter lesions (WML) and cognition in patients with memory complaints, stratified in groups with normal and low cerebrospinal fluid (CSF) Abeta42 values. 215 consecutive patients with subjective memory complaints were retrospectively included. Patients were stratified into two groups with normal (n = 127) or low (n = 88) CSF Abeta42 levels (cut-off is 450 ng/l). Cognitive scores from the Mini-Mental State Examination (MMSE) and the Neurobehavioral Cognitive Status Examination (Cognistat) were used as continuous dependent variables in linear regression. WML load was used as a continuous independent variable and was scored with a visual rating scale. The regression model was corrected for possible confounding factors. WML were significantly associated with MMSE and all Cognistat subscores except language (repetition and naming) and attention in patients with normal CSF Abeta42 levels. No significant associations were observed in patients with low CSF Abeta42. WML were associated with affection of multiple cognitive domains, including delayed recall and executive functions, in patients with normal CSF Abeta42 levels. The lack of such associations for patients with low CSF Abeta42 (i.e. with evidence for amyloid deposition), suggests that amyloid pathology may obscure cognitive effects of WML.

What is the risk of infecting a cerebrospinal fluid-diverting shunt with percutaneous tapping?

PubMed

Spiegelman, Lindsey; Asija, Richa; Da Silva, Stephanie L; Krieger, Mark D; McComb, J Gordon

2014-10-01

Most CSF-diverting shunt systems have an access port that can be percutaneously tapped. Tapping the shunt can yield valuable information as to its function and whether an infection is present. The fear of causing a shunt infection by tapping may limit the physician's willingness to do so. The authors of this study investigate the risk of infecting a shunt secondary to percutaneous tapping. Following institutional review board approval, CSF specimens obtained from tapping an indwelling CSF-diverting shunt during the 2011 and 2012 calendar years were identified and matched with clinical information. A culture-positive CSF sample was defined as an infection. If results were equivocal, such as a broth-only-positive culture, a repeat CSF specimen was examined. The CSF was obtained by tapping the shunt access port with a 25-gauge butterfly needle after prepping the unshaven skin with chlorhexidine. During the study period, 266 children underwent 542 shunt taps. With 541 taps, no clinical evidence of a subsequent shunt infection was found. One child's CSF went from sterile to infected 11 days later; however, this patient had redness along the shunt tract at the time of the initial sterile tap. The risk of infection from tapping a shunt is remote if the procedure is done correctly.

Cerebrospinal fluid and plasma oxytocin concentrations are positively correlated and negatively predict anxiety in children.

PubMed

Carson, D S; Berquist, S W; Trujillo, T H; Garner, J P; Hannah, S L; Hyde, S A; Sumiyoshi, R D; Jackson, L P; Moss, J K; Strehlow, M C; Cheshier, S H; Partap, S; Hardan, A Y; Parker, K J

2015-09-01

The neuropeptide oxytocin (OXT) exerts anxiolytic and prosocial effects in the central nervous system of rodents. A number of recent studies have attempted to translate these findings by investigating the relationships between peripheral (e.g., blood, urinary and salivary) OXT concentrations and behavioral functioning in humans. Although peripheral samples are easy to obtain in humans, whether peripheral OXT measures are functionally related to central OXT activity remains unclear. To investigate a possible relationship, we quantified OXT concentrations in concomitantly collected cerebrospinal fluid (CSF) and blood samples from child and adult patients undergoing clinically indicated lumbar punctures or other CSF-related procedures. Anxiety scores were obtained in a subset of child participants whose parents completed psychometric assessments. Findings from this study indicate that plasma OXT concentrations significantly and positively predict CSF OXT concentrations (r=0.56, P=0.0064, N=27). Moreover, both plasma (r=-0.92, P=0.0262, N=10) and CSF (r=-0.91, P=0.0335, N=10) OXT concentrations significantly and negatively predicted trait anxiety scores, consistent with the preclinical literature. Importantly, plasma OXT concentrations significantly and positively (r=0.96, P=0.0115, N=10) predicted CSF OXT concentrations in the subset of child participants who provided behavioral data. This study provides the first empirical support for the use of blood measures of OXT as a surrogate for central OXT activity, validated in the context of behavioral functioning. These preliminary findings also suggest that impaired OXT signaling may be a biomarker of anxiety in humans, and a potential target for therapeutic development in individuals with anxiety disorders.

Cerebrospinal fluid biomarkers of infantile congenital hydrocephalus

PubMed Central

Limbrick, David D.; Baksh, Brandon; Morgan, Clinton D.; Habiyaremye, Gakwaya; McAllister, James P.; Inder, Terrie E.; Mercer, Deanna; Holtzman, David M.; Strahle, Jennifer; Wallendorf, Michael J.; Morales, Diego M.

2017-01-01

Introduction Hydrocephalus is a complex neurological disorder with a pervasive impact on the central nervous system. Previous work has demonstrated derangements in the biochemical profile of cerebrospinal fluid (CSF) in hydrocephalus, particularly in infants and children, in whom neurodevelopment is progressing in parallel with concomitant neurological injury. The objective of this study was to examine the CSF of children with congenital hydrocephalus (CHC) to gain insight into the pathophysiology of hydrocephalus and identify candidate biomarkers of CHC with potential diagnostic and therapeutic value. Methods CSF levels of amyloid precursor protein (APP) and derivative isoforms (sAPPα, sAPPβ, Aβ42), tau, phosphorylated tau (pTau), L1CAM, NCAM-1, aquaporin 4 (AQP4), and total protein (TP) were measured by ELISA in 20 children with CHC. Two comparative groups were included: age-matched controls and children with other neurological diseases. Demographic parameters, ventricular frontal-occipital horn ratio, associated brain malformations, genetic alterations, and surgical treatments were recorded. Logistic regression analysis and receiver operating characteristic curves were used to examine the association of each CSF protein with CHC. Results CSF levels of APP, sAPPα, sAPPβ, Aβ42, tau, pTau, L1CAM, and NCAM-1 but not AQP4 or TP were increased in untreated CHC. CSF TP and normalized L1CAM levels were associated with FOR in CHC subjects, while normalized CSF tau levels were associated with FOR in control subjects. Predictive ability for CHC was strongest for sAPPα, especially in subjects ≤12 months of age (p<0.0001 and AUC = 0.99), followed by normalized sAPPβ (p = 0.0001, AUC = 0.95), tau, APP, and L1CAM. Among subjects ≤12 months, a normalized CSF sAPPα cut-point of 0.41 provided the best prediction of CHC (odds ratio = 528, sensitivity = 0.94, specificity = 0.97); these infants were 32 times more likely to have CHC. Conclusions CSF proteins such as sAPPα and related proteins hold promise as biomarkers of CHC in infants and young children, and provide insight into the pathophysiology of CHC during this critical period in neurodevelopment. PMID:28212403

Supraorbital Versus Endoscopic Endonasal Approaches for Olfactory Groove Meningiomas: A Cost-Minimization Study.

PubMed

Gandhoke, Gurpreet S; Pease, Matthew; Smith, Kenneth J; Sekula, Raymond F

2017-09-01

To perform a cost-minimization study comparing the supraorbital and endoscopic endonasal (EEA) approach with or without craniotomy for the resection of olfactory groove meningiomas (OGMs). We built a decision tree using probabilities of gross total resection (GTR) and cerebrospinal fluid (CSF) leak rates with the supraorbital approach versus EEA with and without additional craniotomy. The cost (not charge or reimbursement) at each "stem" of this decision tree for both surgical options was obtained from our hospital's finance department. After a base case calculation, we applied plausible ranges to all parameters and carried out multiple 1-way sensitivity analyses. Probabilistic sensitivity analyses confirmed our results. The probabilities of GTR (0.8) and CSF leak (0.2) for the supraorbital craniotomy were obtained from our series of 5 patients who underwent a supraorbital approach for the resection of an OGM. The mean tumor volume was 54.6 cm 3 (range, 17-94.2 cm 3 ). Literature-reported rates of GTR (0.6) and CSF leak (0.3) with EEA were applied to our economic analysis. Supraorbital craniotomy was the preferred strategy, with an expected value of $29,423, compared with an EEA cost of $83,838. On multiple 1-way sensitivity analyses, supraorbital craniotomy remained the preferred strategy, with a minimum cost savings of $46,000 and a maximum savings of $64,000. Probabilistic sensitivity analysis found the lowest cost difference between the 2 surgical options to be $37,431. Compared with EEA, supraorbital craniotomy provides substantial cost savings in the treatment of OGMs. Given the potential differences in effectiveness between approaches, a cost-effectiveness analysis should be undertaken. Copyright © 2017 Elsevier Inc. All rights reserved.

Gene expression changes in spinal motoneurons of the SOD1(G93A) transgenic model for ALS after treatment with G-CSF.

PubMed

Henriques, Alexandre; Kastner, Stefan; Chatzikonstantinou, Eva; Pitzer, Claudia; Plaas, Christian; Kirsch, Friederike; Wafzig, Oliver; Krüger, Carola; Spoelgen, Robert; Gonzalez De Aguilar, Jose-Luis; Gretz, Norbert; Schneider, Armin

2014-01-01

Amyotrophic lateral sclerosis (ALS) is an incurable fatal motoneuron disease with a lifetime risk of approximately 1:400. It is characterized by progressive weakness, muscle wasting, and death ensuing 3-5 years after diagnosis. Granulocyte-colony stimulating factor (G-CSF) is a drug candidate for ALS, with evidence for efficacy from animal studies and interesting data from pilot clinical trials. To gain insight into the disease mechanisms and mode of action of G-CSF, we performed gene expression profiling on isolated lumbar motoneurons from SOD1(G93A) mice, the most frequently studied animal model for ALS, with and without G-CSF treatment. Motoneurons from SOD1(G93A) mice present a distinct gene expression profile in comparison to controls already at an early disease stage (11 weeks of age), when treatment was initiated. The degree of deregulation increases at a time where motor symptoms are obvious (15 weeks of age). Upon G-CSF treatment, transcriptomic deregulations of SOD1(G93A) motoneurons were notably restored. Discriminant analysis revealed that SOD1 mice treated with G-CSF has a transcriptom close to presymptomatic SOD1 mice or wild type mice. Some interesting genes modulated by G-CSF treatment relate to neuromuscular function such as CCR4-NOT or Prss12. Our data suggest that G-CSF is able to re-adjust gene expression in symptomatic SOD1(G93A) motoneurons. This provides further arguments for G-CSF as a promising drug candidate for ALS.

Mobilization of hematopoietic stem cells with highest self-renewal by G-CSF precedes clonogenic cell mobilization peak.

PubMed

Winkler, Ingrid G; Wiercinska, Eliza; Barbier, Valerie; Nowlan, Bianca; Bonig, Halvard; Levesque, Jean-Pierre

2016-04-01

Harvest of granulocyte colony-stimulating factor (G-CSF)-mobilized hematopoietic stem cells (HSCs) begins at day 5 of G-CSF administration, when most donors have achieved maximal mobilization. This is based on surrogate markers for HSC mobilization, such as CD34(+) cells and colony-forming activity in blood. However, CD34(+) cells or colony-forming units in culture (CFU-C) are heterogeneous cell populations with hugely divergent long-term repopulation potential on transplantation. HSC behavior is influenced by the vascular bed in the vicinity of which they reside. We hypothesized that G-CSF may mobilize sequentially cells proximal and more distal to bone marrow venous sinuses where HSCs enter the blood. We addressed this question with functional serial transplantation assays using blood and bone marrow after specific time points of G-CSF treatment in mice. We found that in mice, blood collected after only 48 hours of G-CSF administration was as enriched in serially reconstituting HSCs as blood collected at 5 days of G-CSF treatment. Similarly, mobilized Lin(-)CD34(+) cells were relatively enriched in more primitive Lin(-)CD34(+)CD38(-) cells at day 2 of G-CSF treatment compared with later points in half of human donors tested (n = 6). This suggests that in both humans and mice, hematopoietic progenitor and stem cells do not mobilize uniformly according to their maturation stage, with most potent HSCs mobilizing as early as day 2 of G-CSF. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

Gene expression changes in spinal motoneurons of the SOD1G93A transgenic model for ALS after treatment with G-CSF

PubMed Central

Henriques, Alexandre; Kastner, Stefan; Chatzikonstantinou, Eva; Pitzer, Claudia; Plaas, Christian; Kirsch, Friederike; Wafzig, Oliver; Krüger, Carola; Spoelgen, Robert; Gonzalez De Aguilar, Jose-Luis; Gretz, Norbert; Schneider, Armin

2015-01-01

Background: Amyotrophic lateral sclerosis (ALS) is an incurable fatal motoneuron disease with a lifetime risk of approximately 1:400. It is characterized by progressive weakness, muscle wasting, and death ensuing 3–5 years after diagnosis. Granulocyte-colony stimulating factor (G-CSF) is a drug candidate for ALS, with evidence for efficacy from animal studies and interesting data from pilot clinical trials. To gain insight into the disease mechanisms and mode of action of G-CSF, we performed gene expression profiling on isolated lumbar motoneurons from SOD1G93A mice, the most frequently studied animal model for ALS, with and without G-CSF treatment. Results: Motoneurons from SOD1G93A mice present a distinct gene expression profile in comparison to controls already at an early disease stage (11 weeks of age), when treatment was initiated. The degree of deregulation increases at a time where motor symptoms are obvious (15 weeks of age). Upon G-CSF treatment, transcriptomic deregulations of SOD1G93A motoneurons were notably restored. Discriminant analysis revealed that SOD1 mice treated with G-CSF has a transcriptom close to presymptomatic SOD1 mice or wild type mice. Some interesting genes modulated by G-CSF treatment relate to neuromuscular function such as CCR4-NOT or Prss12. Conclusions: Our data suggest that G-CSF is able to re-adjust gene expression in symptomatic SOD1G93A motoneurons. This provides further arguments for G-CSF as a promising drug candidate for ALS. PMID:25653590

Quantitative SERS Detection of Dopamine in Cerebrospinal Fluid by Dual-Recognition-Induced Hot Spot Generation.

PubMed

Zhang, Kun; Liu, Yu; Wang, Yuning; Zhang, Ren; Liu, Jiangang; Wei, Jia; Qian, Hufei; Qian, Kun; Chen, Ruoping; Liu, Baohong

2018-05-09

Reliable profiling of the extracellular dopamine (DA) concentration in the central nervous system is essential for a deep understanding of its biological and pathological functions. However, quantitative determination of this neurotransmitter remains a challenge because of the extremely low concentration of DA in the cerebrospinal fluid (CSF) of patients. Herein, on the basis of the specific recognition of boronate toward diol and N-hydroxysuccinimide ester toward the amine group, a simple and highly sensitive strategy was presented for DA detection by using surface-enhanced Raman scattering (SERS) spectroscopy as a signal readout. This was realized by first immobilizing 3,3'-dithiodipropionic acid di( N-hydroxysuccinimide ester) on gold thin film surfaces to capture DA, followed by introducing 3-mercaptophenylboronic acid (3-MPBA)-functionalized silver nanoparticles to generate numerous plasmonic "hot spots" with the nanoparticle-on-mirror geometry. Such a dual-recognition mechanism not only avoids complicated bioelement-based manipulations but also efficiently decreases the background signal. With the direct use of the recognition probe 3-MPBA as a Raman reporter, the "signal-on" SERS method was employed to quantify the concentration of DA from 1 pM to 1 μM with a detection limit of 0.3 pM. Moreover, our dual-recognition-directed SERS assay exhibited a high resistance to cerebral interference and was successfully applied to monitoring of DA in CSF samples of patients.

Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone.

PubMed

Wong, M L; Kling, M A; Munson, P J; Listwak, S; Licinio, J; Prolo, P; Karp, B; McCutcheon, I E; Geracioti, T D; DeBellis, M D; Rice, K C; Goldstein, D S; Veldhuis, J D; Chrousos, G P; Oldfield, E H; McCann, S M; Gold, P W

2000-01-04

Both stress-system activation and melancholic depression are characterized by fear, constricted affect, stereotyped thinking, and similar changes in autonomic and neuroendocrine function. Because norepinephrine (NE) and corticotropin-releasing hormone (CRH) can produce these physiological and behavioral changes, we measured the cerebrospinal fluid (CSF) levels each hour for 30 consecutive hours in controls and in patients with melancholic depression. Plasma adrenocorticotropic hormone (ACTH) and cortisol levels were obtained every 30 min. Depressed patients had significantly higher CSF NE and plasma cortisol levels that were increased around the clock. Diurnal variations in CSF NE and plasma cortisol levels were virtually superimposable and positively correlated with each other in both patients and controls. Despite their hypercortisolism, depressed patients had normal levels of plasma ACTH and CSF CRH. However, plasma ACTH and CSF CRH levels in depressed patients were inappropriately high, considering the degree of their hypercortisolism. In contrast to the significant negative correlation between plasma cortisol and CSF CRH levels seen in controls, patients with depression showed no statistical relationship between these parameters. These data indicate that persistent stress-system dysfunction in melancholic depression is independent of the conscious stress of the disorder. These data also suggest mutually reinforcing bidirectional links between a central hypernoradrenergic state and the hyperfunctioning of specific central CRH pathways that each are driven and sustained by hypercortisolism. We postulate that alpha-noradrenergic blockade, CRH antagonists, and treatment with antiglucocorticoids may act at different loci, alone or in combination, in the treatment of major depression with melancholic features.

Minimally Invasive Lumbar Port System for the Collection of Cerebrospinal Fluid from Rhesus Macaques (Macaca mulatta)

PubMed Central

MacAllister, Rhonda Pung; Lester McCully, Cynthia M; Bacher, John; Thomas, Marvin L; Cruz, Rafael; Wangari, Solomon; Warren, Katherine E

2016-01-01

Biomedical translational research frequently incorporates collection of CSF from NHP, because CSF drug levels are used as a surrogate for CNS tissue penetration in pharmacokinetic and dynamic studies. Surgical placement of a CNS ventricular catheter reservoir for CSF collection is an intensive model to create and maintain and thus may not be feasible or practical for short-term studies. Furthermore, previous NHP lumbar port models require laminectomy for catheter placement. The new model uses a minimally invasive technique for percutaneous placement of a lumbar catheter to create a closed, subcutaneous system for effective, repeated CSF sample collection. None of the rhesus macaques (Macaca mulatta; n = 10) implanted with our minimally invasive lumbar port (MILP) system experienced neurologic deficits, postoperative infection of the surgical site, or skin erosion around the port throughout the 21.7-mo study. Functional MILP systems were maintained in 70% of the macaques, with multiple, high-quality, 0.5- to 1.0-mL samples of CSF collected for an average of 3 mo by using aspiration or gravitational flow. Among these macaques, 57% had continuous functionality for a mean of 19.2 mo; 50% of the cohort required surgical repair for port repositioning and replacement during the study. The MILP was unsuccessful in 2 macaques, at an average of 9.5 d after surgery. Nonpatency in these animals was attributed to the position of the lumbar catheter. The MILP system is an appropriate replacement for temporary catheterization and previous models requiring laminectomy and is a short-term alternative for ventricular CSF collection systems in NHP. PMID:27538866

5-AED enhances survival of irradiated mice in a G-CSF-dependent manner, stimulates innate immune cell function, reduces radiation-induced DNA damage and induces genes that modulate cell cycle progression and apoptosis

PubMed Central

Grace, Marcy B.; Singh, Vijay K.; Rhee, Juong G.; Jackson, William E.; Kao, Tzu-Cheg; Whitnall, Mark H.

2012-01-01

The steroid androst-5-ene-3ß,17ß-diol (5-androstenediol, 5-AED) elevates circulating granulocytes and platelets in animals and humans, and enhances survival during the acute radiation syndrome (ARS) in mice and non-human primates. 5-AED promotes survival of irradiated human hematopoietic progenitors in vitro through induction of Nuclear Factor-κB (NFκB)-dependent Granulocyte Colony-Stimulating Factor (G-CSF) expression, and causes elevations of circulating G-CSF and interleukin-6 (IL-6). However, the in vivo cellular and molecular effects of 5-AED are not well understood. The aim of this study was to investigate the mechanisms of action of 5-AED administered subcutaneously (s.c.) to mice 24 h before total body γ- or X-irradiation (TBI). We used neutralizing antibodies, flow cytometric functional assays of circulating innate immune cells, analysis of expression of genes related to cell cycle progression, DNA repair and apoptosis, and assessment of DNA strand breaks with halo-comet assays. Neutralization experiments indicated endogenous G-CSF but not IL-6 was involved in survival enhancement by 5-AED. In keeping with known effects of G-CSF on the innate immune system, s.c. 5-AED stimulated phagocytosis in circulating granulocytes and oxidative burst in monocytes. 5-AED induced expression of both bax and bcl-2 in irradiated animals. Cdkn1a and ddb1, but not gadd45a expression, were upregulated by 5-AED in irradiated mice. S.c. 5-AED administration caused decreased DNA strand breaks in splenocytes from irradiated mice. Our results suggest 5-AED survival enhancement is G-CSF-dependent, and that it stimulates innate immune cell function and reduces radiation-induced DNA damage via induction of genes that modulate cell cycle progression and apoptosis. PMID:22843381

5-AED enhances survival of irradiated mice in a G-CSF-dependent manner, stimulates innate immune cell function, reduces radiation-induced DNA damage and induces genes that modulate cell cycle progression and apoptosis.

PubMed

Grace, Marcy B; Singh, Vijay K; Rhee, Juong G; Jackson, William E; Kao, Tzu-Cheg; Whitnall, Mark H

2012-11-01

The steroid androst-5-ene-3ß,17ß-diol (5-androstenediol, 5-AED) elevates circulating granulocytes and platelets in animals and humans, and enhances survival during the acute radiation syndrome (ARS) in mice and non-human primates. 5-AED promotes survival of irradiated human hematopoietic progenitors in vitro through induction of Nuclear Factor-κB (NFκB)-dependent Granulocyte Colony-Stimulating Factor (G-CSF) expression, and causes elevations of circulating G-CSF and interleukin-6 (IL-6). However, the in vivo cellular and molecular effects of 5-AED are not well understood. The aim of this study was to investigate the mechanisms of action of 5-AED administered subcutaneously (s.c.) to mice 24 h before total body γ- or X-irradiation (TBI). We used neutralizing antibodies, flow cytometric functional assays of circulating innate immune cells, analysis of expression of genes related to cell cycle progression, DNA repair and apoptosis, and assessment of DNA strand breaks with halo-comet assays. Neutralization experiments indicated endogenous G-CSF but not IL-6 was involved in survival enhancement by 5-AED. In keeping with known effects of G-CSF on the innate immune system, s.c. 5-AED stimulated phagocytosis in circulating granulocytes and oxidative burst in monocytes. 5-AED induced expression of both bax and bcl-2 in irradiated animals. Cdkn1a and ddb1, but not gadd45a expression, were upregulated by 5-AED in irradiated mice. S.c. 5-AED administration caused decreased DNA strand breaks in splenocytes from irradiated mice. Our results suggest 5-AED survival enhancement is G-CSF-dependent, and that it stimulates innate immune cell function and reduces radiation-induced DNA damage via induction of genes that modulate cell cycle progression and apoptosis.

Cross-sectional and longitudinal relationships between cerebrospinal fluid biomarkers and cognitive function in people without cognitive impairment from across the adult life span.

PubMed

Li, Ge; Millard, Steven P; Peskind, Elaine R; Zhang, Jing; Yu, Chang-En; Leverenz, James B; Mayer, Cynthia; Shofer, Jane S; Raskind, Murray A; Quinn, Joseph F; Galasko, Douglas R; Montine, Thomas J

2014-06-01

Age-related cognitive decline among older individuals with normal cognition is a complex trait that potentially derives from processes of aging, inherited vulnerabilities, environmental factors, and common latent diseases that can progress to cause dementia, such as Alzheimer disease and vascular brain injury. To use cerebrospinal fluid (CSF) biomarkers to gain insight into this complex trait. Secondary analyses of an academic multicenter cross-sectional (n = 315) and longitudinal (n = 158) study of 5 neuropsychological tests (Immediate Recall, Delayed Recall, Trail Making Test Parts A and B, and Category Fluency) in cognitively normal individuals aged 21 to 100 years. To investigate the association of these cognitive function test results with age, sex, educational level, inheritance of the ε4 allele of the apolipoprotein E gene, and CSF concentrations of β-amyloid 42 (Aβ42) and tau (biomarkers of Alzheimer disease) as well as F2-isoprostanes (measures of free radical injury). Age and educational level were broadly predictive of cross-sectional cognitive performance; of the genetic and CSF measures, only greater CSF F2-isoprostane concentration was significantly associated with poorer executive function (adjusted R2 ≤0.31). Longitudinal measures of cognitive abilities, except Category Fluency, also were associated broadly with age; of the genetic and CSF measures, only lower baseline CSF Aβ42 concentration was associated with longitudinal measures of immediate and delayed recall (marginal R2 ≤0.31). Our results suggest that age and educational level accounted for a substantial minority of variance in cross-sectional or longitudinal cognitive test performance in this large group of cognitively normal adults. Latent Alzheimer disease and other diseases that produce free radical injury, such as vascular brain injury, accounted for a small amount of variation in cognitive test performance across the adult human life span. Additional genetic and environmental factors likely contribute substantially to age-related cognitive decline.

Neuropeptide Y - an early biomarker for cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

PubMed

Schebesch, Karl-Michael; Brawanski, Alexander; Bele, Sylvia; Schödel, Petra; Herbst, Andreas; Bründl, Elisabeth; Kagerbauer, Simone Maria; Martin, Jan; Lohmeier, Anette; Stoerr, Eva-Maria; Proescholdt, Martin

2013-12-01

In the human brain, the potent vasoconstrictive neuropeptide Y (NPY) is abundantly expressed. Neuropeptide Y, which is stored in perivascular nerve fibers of the cerebral arteries, regulates the cerebral vascular diameter as well as cerebral blood flow. However, the role of NPY in the pathogenesis of cerebral vasospasm (CV) related to subarachnoid hemorrhage (SAH) is unclear. We prospectively analyzed and compared the release of endogenous NPY in the cerebrospinal fluid (CSF) of 66 patients with SAH to NPY release in a control group. Additionally, we correlated the levels of NPY with CV and consecutive ischemic stroke. Sixty-six consecutive patients (40 women, 26 men; mean age 53·1 years) with aneurysmal SAH were included. In the SAH group, CSF was drawn daily from day 1 to day 10 after the onset of SAH. The CSF of 29 patients undergoing spinal anesthesia for orthopedic surgery served as control samples. The NPY levels were determined in duplicate CSF samples by means of a competitive enzyme immunoassay (EIA). The levels of NPY in CSF were correlated with the development of CV over the 10-day period after the onset of SAH and to the occurrence of consecutive ischemic stroke. To evaluate CSF NPY levels as a predictive biomarker for vasospasm, we calculated the sensitivity and specificity as well as the positive and negative predictive values. The NPY levels were significantly higher in the SAH group than in the control group (p < 0·001). The treatment modality (clip versus coil) did not influence the level of NPY in CSF (p > 0·05). Patients with CV showed significantly higher NPY levels than patients without CV during the entire observation period. The NPY levels of the non-CV group dissipated over time, whereas the CV group showed continuously increasing values. The NPY levels from day 4 to 10 were significantly higher in patients with CV-related stroke than in non-stroke patients. Using 0·3 ng/ml as a cut-off value, NPY levels on day 3 predicted the occurrence of CV with a sensitivity and specificity of 82% and 72%, respectively. High NPY levels, starting on day 4, significantly correlated with poor Glasgow Outcome Score grading at the follow-up (p < 0·05). Our data indicate that NPY is involved in the pathogenesis of SAH-related CV and ischemia. Neuropeptide Y represents an early and reliable biomarker for the prediction of CV and consecutive stroke due to aneurysmal SAH.

Granulocyte Macrophage Colony-Stimulating Factor-Activated Eosinophils Promote Interleukin-23 Driven Chronic Colitis

PubMed Central

Griseri, Thibault; Arnold, Isabelle C.; Pearson, Claire; Krausgruber, Thomas; Schiering, Chris; Franchini, Fanny; Schulthess, Julie; McKenzie, Brent S.; Crocker, Paul R.; Powrie, Fiona

2015-01-01

Summary The role of intestinal eosinophils in immune homeostasis is enigmatic and the molecular signals that drive them from protective to tissue damaging are unknown. Most commonly associated with Th2 cell-mediated diseases, we describe a role for eosinophils as crucial effectors of the interleukin-23 (IL-23)-granulocyte macrophage colony-stimulating factor (GM-CSF) axis in colitis. Chronic intestinal inflammation was characterized by increased bone marrow eosinopoiesis and accumulation of activated intestinal eosinophils. IL-5 blockade or eosinophil depletion ameliorated colitis, implicating eosinophils in disease pathogenesis. GM-CSF was a potent activator of eosinophil effector functions and intestinal accumulation, and GM-CSF blockade inhibited chronic colitis. By contrast neutrophil accumulation was GM-CSF independent and dispensable for colitis. In addition to TNF secretion, release of eosinophil peroxidase promoted colitis identifying direct tissue-toxic mechanisms. Thus, eosinophils are key perpetrators of chronic inflammation and tissue damage in IL-23-mediated immune diseases and it suggests the GM-CSF-eosinophil axis as an attractive therapeutic target. PMID:26200014

Timing and Predictors of Fever and Infection after Craniotomy for Epilepsy in Children

PubMed Central

Phung, Jennifer; Mathern, Gary W.; Krogstad, Paul

2013-01-01

Background Fevers and leukocytosis after pediatric craniotomy trigger diagnostic evaluation and antimicrobial therapy for possible brain infection. This study determined the incidence and predictors of infection in infants and children undergoing epilepsy neurosurgery. Methods We reviewed the postoperative course of 100 consecutive surgeries for pediatric epilepsy, comparing those with and without infections for clinical variables and daily maximum temperatures, blood WBC and differential, and cerebrospinal fluid (CSF) studies. Results Infections were the most common adverse events following these surgeries. Four patients (4%) had CSF infections and 12 had non-CSF infections (including one with distinct CSF and bloodstream infections). Most (88%) infections occurred before postoperative day 12 and were associated with larger resections involving ventriculostomies. Fevers (T ≥38.5°C) were observed in the first 12-days postsurgery in 43 % of cases, and were associated with patients undergoing hemispherectomy and multilobar resections. Fevers in the first three days postsurgery identified infections with 73% sensitivity, 69% specificity, and 70% accuracy; two (13%) patients with infections never developed fevers. Peripheral blood WBC >15,000 was found in 49% of patients and 5 cases of infections never had elevated WBC counts. WBC differential, CSF protein, RBC, WBC, and RBC/WBC ratios were poor predictors of infections. Longer hospital stays were associated with infections and hemispherectomy and multilobar resections. Patients with and without infections were equally likely to be seizure free after surgery. Conclusions Fevers and elevated blood WBC counts were common after pediatric epilepsy surgery, but CSF infections were uncommon. Positive cultures and other confirmatory microbiologic tests should drive changes in antimicrobial therapy after surgery. PMID:23348815

Proteomic analysis of cerebrospinal fluid from children with central nervous system tumors identifies candidate proteins relating to tumor metastatic spread.

PubMed

Spreafico, Filippo; Bongarzone, Italia; Pizzamiglio, Sara; Magni, Ruben; Taverna, Elena; De Bortoli, Maida; Ciniselli, Chiara M; Barzanò, Elena; Biassoni, Veronica; Luchini, Alessandra; Liotta, Lance A; Zhou, Weidong; Signore, Michele; Verderio, Paolo; Massimino, Maura

2017-07-11

Central nervous system (CNS) tumors are the most common solid tumors in childhood. Since the sensitivity of combined cerebrospinal fluid (CSF) cytology and radiological neuroimaging in detecting meningeal metastases remains relatively low, we sought to characterize the CSF proteome of patients with CSF tumors to identify biomarkers predictive of metastatic spread. CSF samples from 27 children with brain tumors and 13 controls (extra-CNS non-Hodgkin lymphoma) were processed using core-shell hydrogel nanoparticles, and analyzed with reverse-phase liquid chromatography/electrospray tandem mass spectrometry (LC-MS/MS). Candidate proteins were identified with Fisher's exact test and/or a univariate logistic regression model. Reverse phase protein array (RPPA), Western blot (WB), and ELISA were used in the training set and in an independent set of CFS samples (60 cases, 14 controls) to validate our discovery findings. Among the 558 non-redundant proteins identified by LC-MS/MS, 147 were missing from the CSF database at http://www.biosino.org. Fourteen of the 26 final top-candidate proteins were chosen for validation with WB, RPPA and ELISA methods. Six proteins (type 1 collagen, insulin-like growth factor binding protein 4, procollagen C-endopeptidase enhancer 1, glial cell-line derived neurotrophic factor receptor α2, inter-alpha-trypsin inhibitor heavy chain 4, neural proliferation and differentiation control protein-1) revealed the ability to discriminate metastatic cases from controls. Combining a unique dataset of CSFs from pediatric CNS tumors with a novel enabling nanotechnology led us to identify CSF proteins potentially related to metastatic status.

Detection of antibodies against classical swine fever virus in fecal samples from wild boar.

PubMed

Seo, Sang won; Sunwoo, Sun young; Hyun, Bang hoon; Lyoo, Young S

2012-12-28

Classical swine fever (CSF) is a contagious viral disease that affects pigs. Wild boars can play an important epidemiological role in CSF outbreaks. In the past decades, studies conducted in many countries have reported that the CSF virus (CSFV) may persist in wild boar populations. The existence of CSFV in the free-ranging wild boar populations was indirectly confirmed by determining the prevalence of antibodies against CSFV in the serum of hunted wild boars. However, analyzing sero-prevalence in hunted wild boars to study the risk of CSF outbreaks is difficult due to insufficient number of samples, limitation of hunting area and biased age distribution of hunted wild boars. To improve this survey method, we collected feces of wild boars from their habitat and tested them using CSFV antibody enzyme-linked immunosorbent assay (ELISA) and CSF virus neutralization (VN) test. In this study, ELISA was found to be highly sensitive for detecting antibodies against CSFV in fecal samples. Most of doubtful or positive results obtained in CSFV ELISA were confirmed by VN tests. Despite the high coincidence rate of antibody-positive samples between CSFV ELISA and VN test, the possibility of false positive reaction should be considered. In the regional distribution, a fact that antibody-positive fecal and serum samples were found in geographically close area was shown. Hence, presence of antibodies in fecal samples may provide vital information regarding the risk of CSF outbreaks in wild boar groups in geographical proximity. Copyright © 2012 Elsevier B.V. All rights reserved.

Effect of GM-CSF on cytokine induction by soluble beta-glucan SCG in vitro in beta-glucan-treated mice.

PubMed

Hida, Toshie H; Kawaminami, Hiromi; Ishibashi, Ken-Ichi; Miura, Noriko N; Adachi, Yoshiyuki; Yadomae, Toshiro; Ohno, Naohito

2009-07-01

SCG is a 6-branched 1,3-beta-D-glucan, which are major cell wall structural components in fungi. Leukocytes from DBA/1 and DBA/2 mice are highly sensitive to SCG, producing cytokines such as GM-CSF, IFN-gamma, TNF-alpha and IL-12p70, but not IL-6. GM-CSF plays a key biological role in this activity. In the present study, we examined the effect of giving i.p. SCG to DBA/2 mice on cytokine production in vitro. SCG was given i.p. to DBA/2 mice on day 0. Splenocytes were prepared on day 7 and cultured in the presence of SCG in vitro. The levels of cytokine production induced by SCG in vitro were lower in the cells from SCG-treated mice than in control mice. Expression of the beta-glucan receptor, dectin-1, in SCG-treated mice was comparable with that shown in control mice. However, the consumption of exogenously added rmGM-CSF in vitro was observed in SCG-treated mice. The addition of a large amount of rmGM-CSF to the culture medium resulted in larger amounts of TNF-alpha and IL-6 in SCG-treated mice than in normal mice. These results suggested that GM-CSF was closely related with the reactivity of beta-glucan. Giving SCG increased the number of macrophages and granulocytes in the spleen. These results suggested that in SCG-treated mice, a change of cell population would be related to modulation of the profile of cytokine production induced by SCG in vitro.

Cerebrospinal fluid ferritin in children with viral and bacterial meningitis.

PubMed

Rezaei, M; Mamishi, S; Mahmoudi, S; Pourakbari, B; Khotaei, G; Daneshjou, K; Hashemi, N

2013-01-01

Despite the fact that the prognosis of bacterial meningitis has been improved by the influence of antibiotics, this disease is still one of the significant causes of morbidity and mortality in children. Rapid differentiation between bacterial and aseptic meningitis, and the need for immediate antibiotic treatment in the former, is crucial in the prognosis of these patients. Ferritin is one of the most sensitive biochemical markers investigated in cerebrospinal fluid (CSF) for the early diagnosis of bacterial meningitis. The present study aims to evaluate the diagnostic capability of CSF ferritin in differentiating bacterial and viral meningitis in the paediatric setting. A cross-sectional study was carried out in the referral Children's Medical Center Hospital, Tehran, during 2008 and 2009. According to the inclusion criteria, CSF samples from 42 patients with suspected meningitis were obtained and divided into two meningitis groups, bacterial (n = 18) and viral (n = 24). Ferritin and other routine determinants (i.e., leucocytes, protein and glucose) were compared between the two groups. Ferritin concentration in the bacterial meningitis group was 106.39 +/- 86.96 ng/dL, which was considerably higher than in the viral meningitis group (10.17 +/- 14.09, P < 0.001). Mean CSF protein concentration and cell count were significantly higher in the bacterial meningitis group and showed a positive correlation with CSF ferritin. In conclusion, this study suggests that CSF ferritin concentration is an accurate test for the early differentiation of bacterial and aseptic meningitis; however, further investigation on a larger cohort of patients is required to confirm this finding.

Alzheimer's disease cerebrospinal fluid biomarkers are not influenced by gravity drip or aspiration extraction methodology.

PubMed

Rembach, Alan; Evered, Lisbeth A; Li, Qiao-Xin; Nash, Tabitha; Vidaurre, Lesley; Fowler, Christopher J; Pertile, Kelly K; Rumble, Rebecca L; Trounson, Brett O; Maher, Sarah; Mooney, Francis; Farrow, Maree; Taddei, Kevin; Rainey-Smith, Stephanie; Laws, Simon M; Macaulay, S Lance; Wilson, William; Darby, David G; Martins, Ralph N; Ames, David; Collins, Steven; Silbert, Brendan; Masters, Colin L; Doecke, James D

2015-11-19

Cerebrospinal fluid (CSF) biomarkers, although of established utility in the diagnostic evaluation of Alzheimer's disease (AD), are known to be sensitive to variation based on pre-analytical sample processing. We assessed whether gravity droplet collection versus syringe aspiration was another factor influencing CSF biomarker analyte concentrations and reproducibility. Standardized lumbar puncture using small calibre atraumatic spinal needles and CSF collection using gravity fed collection followed by syringe aspirated extraction was performed in a sample of elderly individuals participating in a large long-term observational research trial. Analyte assay concentrations were compared. For the 44 total paired samples of gravity collection and aspiration, reproducibility was high for biomarker CSF analyte assay concentrations (concordance correlation [95%CI]: beta-amyloid1-42 (Aβ42) 0.83 [0.71 - 0.90]), t-tau 0.99 [0.98 - 0.99], and phosphorylated tau (p-tau) 0.82 [95 % CI 0.71 - 0.89]) and Bonferroni corrected paired sample t-tests showed no significant differences (group means (SD): Aβ42 366.5 (86.8) vs 354.3 (82.6), p = 0.10; t-tau 83.9 (46.6) vs 84.7 (47.4) p = 0.49; p-tau 43.5 (22.8) vs 40.0 (17.7), p = 0.05). The mean duration of collection was 10.9 minutes for gravity collection and <1 minute for aspiration. Our results demonstrate that aspiration of CSF is comparable to gravity droplet collection for AD biomarker analyses but could considerably accelerate throughput and improve the procedural tolerability for assessment of CSF biomarkers.

Phenotype of postural instability/gait difficulty in Parkinson disease: relevance to cognitive impairment and mechanism relating pathological proteins and neurotransmitters

PubMed Central

Zuo, Li-Jun; Piao, Ying-Shan; Li, Li-Xia; Yu, Shu-Yang; Guo, Peng; Hu, Yang; Lian, Teng-Hong; Wang, Rui-Dan; Yu, Qiu-Jin; Jin, Zhao; Wang, Ya-Jie; Wang, Xiao-Min; Chan, Piu; Chen, Sheng-Di; Wang, Yong-Jun; Zhang, Wei

2017-01-01

Parkinson disease (PD) is identified as tremor-dominant (TD) and postural instability and gait difficulty (PIGD) phenotypes. The relationships between motor phenotypes and cognitive impairment and the underlying mechanisms relating pathological proteins and neurotransmitters in cerebrospinal fluid (CSF) are unknown. We evaluated the motor symptoms and cognitive function by scales, and detected the levels of pathological proteins and neurotransmitters in CSF. TD group and PIGD group had significantly higher levels of total tau, tau phosphorylated at the position of threonine 181(P-tau181t), threonine 231, serine 396, serine 199 and lower β amyloid (Aβ)1–42 level in CSF than those in control group; PIGD group had significantly higher P-tau181t level and lower Aβ1–42 level than those in TD group. In PD group, PIGD severity was negatively correlated with MoCA score and Aβ1–42 level in CSF, and positively correlated with Hoehn-Yahr stage and P-tau181t level in CSF. In PIGD group, PIGD severity was negatively correlated with homovanillic acid (HVA) level in CSF, and HVA level was positively correlated with Aβ1–42 level in CSF. PIGD was significantly correlated with cognitive impairment, which underlying mechanism might be involved in Aβ1–42 aggregation in brain and relevant neurochemical disturbance featured by the depletion of HVA in CSF. PMID:28332604

Tyr721 regulates specific binding of the CSF-1 receptor kinase insert to PI 3'-kinase SH2 domains: a model for SH2-mediated receptor-target interactions.

PubMed Central

Reedijk, M; Liu, X; van der Geer, P; Letwin, K; Waterfield, M D; Hunter, T; Pawson, T

1992-01-01

Efficient binding of active phosphatidylinositol (PI) 3'-kinase to the autophosphorylated macrophage colony stimulating factor receptor (CSF-1R) requires the noncatalytic kinase insert (KI) region of the receptor. To test whether this region could function independently to bind PI 3'-kinase, the isolated CSF-1R KI was expressed in Escherichia coli, and was inducibly phosphorylated on tyrosine. The tyrosine phosphorylated form of the CSF-1R KI bound PI 3'-kinase in vitro, whereas the unphosphorylated form had no binding activity. The p85 alpha subunit of PI 3'-kinase contains two Src homology (SH)2 domains, which are implicated in the interactions of signalling proteins with activated receptors. Bacterially expressed p85 alpha SH2 domains complexed in vitro with the tyrosine phosphorylated CSF-1R KI. Binding of the CSF-1R KI to PI 3'-kinase activity, and to the p85 alpha SH2 domains, required phosphorylation of Tyr721 within the KI domain, but was independent of phosphorylation at Tyr697 and Tyr706. Tyr721 was also critical for the association of activated CSF-1R with PI 3'-kinase in mammalian cells. Complex formation between the CSF-1R and PI 3'-kinase can therefore be reconstructed in vitro in a specific interaction involving the phosphorylated receptor KI and the SH2 domains of p85 alpha. Images PMID:1314163

[The role of computerized rheoencephalography in the assessment of normal pressure hydrocephalus. Preliminary report].

PubMed

Traczewski, Wojciech; Moskała, Marek; Szwabowska, Dorota; Gościński, Igor; Krupa, Mariusz; Polak, Jarosław

2005-01-01

It is generally agreed that the positive result of lumbar cerebrospinal fluid (CSF) withdrawal offers a reliable means for selection of patients likely to respond to shunting in normal pressure hydrocephalus (NPH). However the studies of cerebral hemodynamics in NPH are performed Routinely only in few neurosurgical centers. We therefore studied the effect of CSF withdrawal on cerebrovascular autoregulation (CVA) in this condition by means of computerized rheoencephalography [REG]. The study group consisted of 27 patients with presumed posttraumatic NPH. In each patient both the tap test and infusion test were performed. Psychometric tests and rheoencephalographic examinations were made twice: before and after CSF withdrawal. The obvious restoration of the functional state of CVA after CSF withdrawal was considered as a positive result of the tap test. Fourteen patients with a positive tap test and/or with resistance to CSF outflow (Rout) of more than 11 mmHg/ml/min were shunted. The improvement was obtained in 10 of them. Only one patient with a positive tap test did not improve. Our study suggests that restoration of CVA after CSF withdrawal is associated with high likelihood of shunt success, but not vice versa. Evaluation of CVA using REG seems to offer a new diagnostic tool in selecting patients likely to respond to shunting. Further studies are necessary to optimize the amount of CSF withdrawal, the delay between CSF withdrawal and control examinations and methodology of neuropsychological examinations.

Essential mechanisms of differential activation of eosinophils by IL-3 compared to GM-CSF and IL-5

PubMed Central

Esnault, Stephane; Kelly, Elizabeth A.

2017-01-01

There is compelling evidence that the eosinophils bring negative biological outcomes in several diseases, including eosinophilic asthma and hypereosinophilic syndromes. Eosinophils produce and store a broad range of toxic proteins and other mediators that enhance the inflammatory response and lead to tissue damage. For instance, in asthma, there is a close relationship between increased lung eosinophilia, asthma exacerbation, and loss of lung function. The use of an anti-IL-5 therapy in severe eosinophilic asthmatic patients is efficient to reduce exacerbations. However, anti-IL-5-treated patients still display a relatively high amount of functional lung tissue eosinophils, indicating that supplemental therapies are required to damper the eosinophil functions. Our recent published works, suggest that compared to IL-5, IL-3 can more strongly and differentially affect eosinophil functions. In this review, we will summarize our and other investigations that have compared the effects of the three β-chain receptor cytokines (IL-5, GM-CSF and IL-3) on eosinophil biology. We will focus on how IL-3 differentially activates eosinophils compared to IL-5 or GM-CSF. PMID:28605348

A new liquid chromatography-mass spectrometry-based method to quantitate exogenous recombinant transferrin in cerebrospinal fluid: a potential approach for pharmacokinetic studies of transferrin-based therapeutics in the central nervous systems.

PubMed

Wang, Shunhai; Bobst, Cedric E; Kaltashov, Igor A

2015-01-01

Transferrin (Tf) is an 80 kDa iron-binding protein that is viewed as a promising drug carrier to target the central nervous system as a result of its ability to penetrate the blood-brain barrier. Among the many challenges during the development of Tf-based therapeutics, the sensitive and accurate quantitation of the administered Tf in cerebrospinal fluid (CSF) remains particularly difficult because of the presence of abundant endogenous Tf. Herein, we describe the development of a new liquid chromatography-mass spectrometry-based method for the sensitive and accurate quantitation of exogenous recombinant human Tf in rat CSF. By taking advantage of a His-tag present in recombinant Tf and applying Ni affinity purification, the exogenous human serum Tf can be greatly enriched from rat CSF, despite the presence of the abundant endogenous protein. Additionally, we applied a newly developed (18)O-labeling technique that can generate internal standards at the protein level, which greatly improved the accuracy and robustness of quantitation. The developed method was investigated for linearity, accuracy, precision, and lower limit of quantitation, all of which met the commonly accepted criteria for bioanalytical method validation.

Optimal-mass-transfer-based estimation of glymphatic transport in living brain

PubMed Central

Zhu, Liangjia; Kolesov, Ivan; Nedergaard, Maiken; Benveniste, Helene; Tannenbaum, Allen

2016-01-01

It was recently shown that the brain-wide cerebrospinal fluid (CSF) and interstitial fluid exchange system designated the ‘glymphatic pathway’ plays a key role in removing waste products from the brain, similarly to the lymphatic system in other body organs1,2. It is therefore important to study the flow patterns of glymphatic transport through the live brain in order to better understand its functionality in normal and pathological states. Unlike blood, the CSF does not flow rapidly through a network of dedicated vessels, but rather through para-vascular channels and brain parenchyma in a slower time-domain, and thus conventional fMRI or other blood-flow sensitive MRI sequences do not provide much useful information about the desired flow patterns. We have accordingly analyzed a series of MRI images, taken at different times, of the brain of a live rat, which was injected with a paramagnetic tracer into the CSF via the lumbar intrathecal space of the spine. Our goal is twofold: (a) find glymphatic (tracer) flow directions in the live rodent brain; and (b) provide a model of a (healthy) brain that will allow the prediction of tracer concentrations given initial conditions. We model the liquid flow through the brain by the diffusion equation. We then use the Optimal Mass Transfer (OMT) approach3 to derive the glymphatic flow vector field, and estimate the diffusion tensors by analyzing the (changes in the) flow. Simulations show that the resulting model successfully reproduces the dominant features of the experimental data. PMID:26877579

Cerebrospinal fluid biochemical studies in patients with Parkinson's disease: toward a potential search for biomarkers for this disease

PubMed Central

Jiménez-Jiménez, Félix J.; Alonso-Navarro, Hortensia; García-Martín, Elena; Agúndez, José A. G.

2014-01-01

The blood-brain barrier supplies brain tissues with nutrients and filters certain compounds from the brain back to the bloodstream. In several neurodegenerative diseases, including Parkinson's disease (PD), there are disruptions of the blood-brain barrier. Cerebrospinal fluid (CSF) has been widely investigated in PD and in other parkinsonian syndromes with the aim of establishing useful biomarkers for an accurate differential diagnosis among these syndromes. This review article summarizes the studies reported on CSF levels of many potential biomarkers of PD. The most consistent findings are: (a) the possible role of CSF urate on the progression of the disease; (b) the possible relations of CSF total tau and phosphotau protein with the progression of PD and with the preservation of cognitive function in PD patients; (c) the possible value of CSF beta-amyloid 1-42 as a useful marker of further cognitive decline in PD patients, and (d) the potential usefulness of CSF neurofilament (NFL) protein levels in the differential diagnosis between PD and other parkinsonian syndromes. Future multicentric, longitudinal, prospective studies with long-term follow-up and neuropathological confirmation would be useful in establishing appropriate biomarkers for PD. PMID:25426023

Therapeutic use of recombinant human G-CSF (RHG-CSF) in a canine model of sublethal and lethal whole-body irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Macvittie, T.J.; Monroy, R.L.; Patchen, M.L.

The short biologic half-life of the peripheral neutrophil (PMN) requires an active granulopoietic response to replenish functional PMSs and to remain a competent host defence in irradiated animals. Recombinant human G-CSF (rhG-CSF) was studied for its ability to modulate hemopoiesis in normal dogs as well as to decrease therapeutically the severity and duration of neutropenia in sublethally and lethally irradiated dogs. For the normal dog, subcutaneous administration of rhG-CSF induced neutrophilia within hours after the first injection; total PMSs continued to increase (with plateau phases) to mean peak values of 1000 per cent of baseline at the end of themore » treatment period (12-14 days). Bone-marrow-derived granulocyte-macrophage colony-forming cells (GM-CFC) increased significantly during treatment. For a sublethal 200 cGy dose, treatment with rhG-CSF for 14 consecutive days decreased the severity and shortened the duration of neutropenia and thrombocytopenia. The radiation-induced lethality of 60 per cent after a dose of 350 cGy was associated with marrow-derived GM-CFC survival of 1 per cent.« less

Cerebrospinal fluid hypersecretion in pediatric hydrocephalus.

PubMed

Karimy, Jason K; Duran, Daniel; Hu, Jamie K; Gavankar, Charuta; Gaillard, Jonathan R; Bayri, Yasar; Rice, Hunter; DiLuna, Michael L; Gerzanich, Volodymyr; Marc Simard, J; Kahle, Kristopher T

2016-11-01

Hydrocephalus, despite its heterogeneous causes, is ultimately a disease of disordered CSF homeostasis that results in pathological expansion of the cerebral ventricles. Our current understanding of the pathophysiology of hydrocephalus is inadequate but evolving. Over this past century, the majority of hydrocephalus cases has been explained by functional or anatomical obstructions to bulk CSF flow. More recently, hydrodynamic models of hydrocephalus have emphasized the role of abnormal intracranial pulsations in disease pathogenesis. Here, the authors review the molecular mechanisms of CSF secretion by the choroid plexus epithelium, the most efficient and actively secreting epithelium in the human body, and provide experimental and clinical evidence for the role of increased CSF production in hydrocephalus. Although the choroid plexus epithelium might have only an indirect influence on the pathogenesis of many types of pediatric hydrocephalus, the ability to modify CSF secretion with drugs newer than acetazolamide or furosemide would be an invaluable component of future therapies to alleviate permanent shunt dependence. Investigation into the human genetics of developmental hydrocephalus and choroid plexus hyperplasia, and the molecular physiology of the ion channels and transporters responsible for CSF secretion, might yield novel targets that could be exploited for pharmacotherapeutic intervention.

Cerebrospinal Fluid Lumbar Tapping Utilization for Suspected Ventriculoperitoneal Shunt Under-Drainage Malfunctions

PubMed Central

Lee, Jong-Beom; Ahn, Ho-Young; Lee, Hong-Jae; Yang, Ji-Ho; Yi, Jin-Seok; Lee, Il-Woo

2017-01-01

Objective The diagnosis of shunt malfunction can be challenging since neuroimaging results are not always correlated with clinical outcomes. The purpose of this study was to evaluate the efficacy of a simple, minimally invasive cerebrospinal fluid (CSF) lumbar tapping test that predicts shunt under-drainage in hydrocephalus patients. Methods We retrospectively reviewed the clinical and radiological features of 48 patients who underwent routine CSF lumbar tapping after ventriculoperitoneal shunt (VPS) operation using a programmable shunting device. We compared shunt valve opening pressure and CSF lumbar tapping pressure to check under-drainage. Results The mean pressure difference between valve opening pressure and CSF lumbar tapping pressure of all patients were 2.21±24.57 mmH2O. The frequency of CSF lumbar tapping was 2.06±1.26 times. Eighty five times lumbar tapping of 41 patients showed that their VPS function was normal which was consistent with clinical improvement and decreased ventricle size on computed tomography scan. The mean pressure difference in these patients was −3.69±19.20 mmH2O. The mean frequency of CSF lumbar tapping was 2.07±1.25 times. Fourteen cases of 10 patients revealed suspected VPS malfunction which were consistent with radiological results and clinical symptoms, defined as changes in ventricle size and no clinical improvement. The mean pressure difference was 38.07±23.58 mmH2O. The mean frequency of CSF lumbar tapping was 1.44±1.01 times. Pressure difference greater than 35 mmH2O was shown in 2.35% of the normal VPS function group (2 of 85) whereas it was shown in 64.29% of the suspected VPS malfunction group (9 of 14). The difference was statistically significant (p=0.000001). Among 10 patients with under-drainage, 5 patients underwent shunt revision. The causes of the shunt malfunction included 3 cases of proximal occlusion and 2 cases of distal obstruction and valve malfunction. Conclusion Under-drainage of CSF should be suspected if CSF lumbar tapping pressure is 35 mmH2O higher than the valve opening pressure and shunt malfunction evaluation or adjustment of the valve opening pressure should be made. PMID:28061484

Application of Targeted Mass Spectrometry for the Quantification of Sirtuins in the Central Nervous System

NASA Astrophysics Data System (ADS)

Jayasena, T.; Poljak, A.; Braidy, N.; Zhong, L.; Rowlands, B.; Muenchhoff, J.; Grant, R.; Smythe, G.; Teo, C.; Raftery, M.; Sachdev, P.

2016-10-01

Sirtuin proteins have a variety of intracellular targets, thereby regulating multiple biological pathways including neurodegeneration. However, relatively little is currently known about the role or expression of the 7 mammalian sirtuins in the central nervous system. Western blotting, PCR and ELISA are the main techniques currently used to measure sirtuin levels. To achieve sufficient sensitivity and selectivity in a multiplex-format, a targeted mass spectrometric assay was developed and validated for the quantification of all seven mammalian sirtuins (SIRT1-7). Quantification of all peptides was by multiple reaction monitoring (MRM) using three mass transitions per protein-specific peptide, two specific peptides for each sirtuin and a stable isotope labelled internal standard. The assay was applied to a variety of samples including cultured brain cells, mammalian brain tissue, CSF and plasma. All sirtuin peptides were detected in the human brain, with SIRT2 being the most abundant. Sirtuins were also detected in human CSF and plasma, and guinea pig and mouse tissues. In conclusion, we have successfully applied MRM mass spectrometry for the detection and quantification of sirtuin proteins in the central nervous system, paving the way for more quantitative and functional studies.

Development of an adaptive bilateral filter for evaluating color image difference

NASA Astrophysics Data System (ADS)

Wang, Zhaohui; Hardeberg, Jon Yngve

2012-04-01

Spatial filtering, which aims to mimic the contrast sensitivity function (CSF) of the human visual system (HVS), has previously been combined with color difference formulae for measuring color image reproduction errors. These spatial filters attenuate imperceptible information in images, unfortunately including high frequency edges, which are believed to be crucial in the process of scene analysis by the HVS. The adaptive bilateral filter represents a novel approach, which avoids the undesirable loss of edge information introduced by CSF-based filtering. The bilateral filter employs two Gaussian smoothing filters in different domains, i.e., spatial domain and intensity domain. We propose a method to decide the parameters, which are designed to be adaptive to the corresponding viewing conditions, and the quantity and homogeneity of information contained in an image. Experiments and discussions are given to support the proposal. A series of perceptual experiments were conducted to evaluate the performance of our approach. The experimental sample images were reproduced with variations in six image attributes: lightness, chroma, hue, compression, noise, and sharpness/blurriness. The Pearson's correlation values between the model-predicted image difference and the observed difference were employed to evaluate the performance, and compare it with that of spatial CIELAB and image appearance model.

Proteomic Analysis Reveals Distinct Metabolic Differences Between Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and Macrophage Colony Stimulating Factor (M-CSF) Grown Macrophages Derived from Murine Bone Marrow Cells.

PubMed

Na, Yi Rang; Hong, Ji Hye; Lee, Min Yong; Jung, Jae Hun; Jung, Daun; Kim, Young Won; Son, Dain; Choi, Murim; Kim, Kwang Pyo; Seok, Seung Hyeok

2015-10-01

Macrophages are crucial in controlling infectious agents and tissue homeostasis. Macrophages require a wide range of functional capabilities in order to fulfill distinct roles in our body, one being rapid and robust immune responses. To gain insight into macrophage plasticity and the key regulatory protein networks governing their specific functions, we performed quantitative analyses of the proteome and phosphoproteome of murine primary GM-CSF and M-CSF grown bone marrow derived macrophages (GM-BMMs and M-BMMs, respectively) using the latest isobaric tag based tandem mass tag (TMT) labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Strikingly, metabolic processes emerged as a major difference between these macrophages. Specifically, GM-BMMs show significant enrichment of proteins involving glycolysis, the mevalonate pathway, and nitrogen compound biosynthesis. This evidence of enhanced glycolytic capability in GM-BMMs is particularly significant regarding their pro-inflammatory responses, because increased production of cytokines upon LPS stimulation in GM-BMMs depends on their acute glycolytic capacity. In contrast, M-BMMs up-regulate proteins involved in endocytosis, which correlates with a tendency toward homeostatic functions such as scavenging cellular debris. Together, our data describes a proteomic network that underlies the pro-inflammatory actions of GM-BMMs as well as the homeostatic functions of M-BMMs. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Myo-inositol changes precede amyloid pathology and relate to APOE genotype in Alzheimer disease

PubMed Central

Sundgren, Pia C.; Strandberg, Olof; Zetterberg, Henrik; Minthon, Lennart; Blennow, Kaj; Wahlund, Lars-Olof; Westman, Eric

2016-01-01

Objective: We aimed to test whether in vivo levels of magnetic resonance spectroscopy (MRS) metabolites myo-inositol (mI), N-acetylaspartate (NAA), and choline are abnormal already during preclinical Alzheimer disease (AD), relating these changes to amyloid or tau pathology, and functional connectivity. Methods: In this cross-sectional multicenter study (a subset of the prospective Swedish BioFINDER study), we included 4 groups, representing the different stages of predementia AD: (1) cognitively healthy elderly with normal CSF β-amyloid 42 (Aβ42), (2) cognitively healthy elderly with abnormal CSF Aβ42, (3) patients with subjective cognitive decline and abnormal CSF Aβ42, (4) patients with mild cognitive decline and abnormal CSF Aβ42 (Ntotal = 352). Spectroscopic markers measured in the posterior cingulate/precuneus were considered alongside known disease biomarkers: CSF Aβ42, phosphorylated tau, total tau, [18F]-flutemetamol PET, f-MRI, and the genetic risk factor APOE. Results: Amyloid-positive cognitively healthy participants showed a significant increase in mI/creatine and mI/NAA levels compared to amyloid-negative healthy elderly (p < 0.05). In amyloid-positive healthy elderly, mI/creatine and mI/NAA correlated with cortical retention of [18F] flutemetamol tracer ( = 0.44, p = 0.02 and = 0.51, p = 0.01, respectively). Healthy elderly APOE ε4 carriers with normal CSF Aβ42 levels had significantly higher mI/creatine levels (p < 0.001) than ε4 noncarriers. Finally, elevated mI/creatine was associated with decreased functional connectivity within the default mode network (rpearson = −0.16, p = 0.02), independently of amyloid pathology. Conclusions: mI levels are elevated already at asymptomatic stages of AD. Moreover, mI/creatine concentrations were increased in healthy APOE ε4 carriers with normal CSF Aβ42 levels, suggesting that mI levels may reveal regional brain consequences of APOE ε4 before detectable amyloid pathology. PMID:27164711

Myo-inositol changes precede amyloid pathology and relate to APOE genotype in Alzheimer disease.

PubMed

Voevodskaya, Olga; Sundgren, Pia C; Strandberg, Olof; Zetterberg, Henrik; Minthon, Lennart; Blennow, Kaj; Wahlund, Lars-Olof; Westman, Eric; Hansson, Oskar

2016-05-10

We aimed to test whether in vivo levels of magnetic resonance spectroscopy (MRS) metabolites myo-inositol (mI), N-acetylaspartate (NAA), and choline are abnormal already during preclinical Alzheimer disease (AD), relating these changes to amyloid or tau pathology, and functional connectivity. In this cross-sectional multicenter study (a subset of the prospective Swedish BioFINDER study), we included 4 groups, representing the different stages of predementia AD: (1) cognitively healthy elderly with normal CSF β-amyloid 42 (Aβ42), (2) cognitively healthy elderly with abnormal CSF Aβ42, (3) patients with subjective cognitive decline and abnormal CSF Aβ42, (4) patients with mild cognitive decline and abnormal CSF Aβ42 (Ntotal = 352). Spectroscopic markers measured in the posterior cingulate/precuneus were considered alongside known disease biomarkers: CSF Aβ42, phosphorylated tau, total tau, [(18)F]-flutemetamol PET, f-MRI, and the genetic risk factor APOE. Amyloid-positive cognitively healthy participants showed a significant increase in mI/creatine and mI/NAA levels compared to amyloid-negative healthy elderly (p < 0.05). In amyloid-positive healthy elderly, mI/creatine and mI/NAA correlated with cortical retention of [(18)F] flutemetamol tracer ([Formula: see text] = 0.44, p = 0.02 and [Formula: see text] = 0.51, p = 0.01, respectively). Healthy elderly APOE ε4 carriers with normal CSF Aβ42 levels had significantly higher mI/creatine levels (p < 0.001) than ε4 noncarriers. Finally, elevated mI/creatine was associated with decreased functional connectivity within the default mode network (rpearson = -0.16, p = 0.02), independently of amyloid pathology. mI levels are elevated already at asymptomatic stages of AD. Moreover, mI/creatine concentrations were increased in healthy APOE ε4 carriers with normal CSF Aβ42 levels, suggesting that mI levels may reveal regional brain consequences of APOE ε4 before detectable amyloid pathology. © 2016 American Academy of Neurology.

Mobilisation of Hematopoietic CD34+ Precursor Cells in Patients with Acute Stroke Is Safe - Results of an Open-Labeled Non Randomized Phase I/II Trial

PubMed Central

Kraemer, Mathias; Schormann, Thorsten; Schlachetzki, Felix; Schuierer, Gerhard; Luerding, Ralph; Hennemann, Burkhard; Orso, Evelyn; Dabringhaus, Andreas; Winkler, Jürgen; Bogdahn, Ulrich

2011-01-01

Background Regenerative strategies in the treatment of acute stroke may have great potential. Hematopoietic growth factors mobilize hematopoietic stem cells and may convey neuroprotective effects. We examined the safety, potential functional and structural changes, and CD34+ cell–mobilization characteristics of G-CSF treatment in patients with acute ischemic stroke. Methods and Results Three cohorts of patients (8, 6, and 6 patients per cohort) were treated subcutaneously with 2.5, 5, or 10 µg/kg body weight rhG-CSF for 5 consecutive days within 12 hrs of onset of acute stroke. Standard treatment included IV thrombolysis. Safety monitoring consisted of obtaining standardized clinical assessment scores, monitoring of CD34+ stem cells, blood chemistry, serial neuroradiology, and neuropsychology. Voxel-guided morphometry (VGM) enabled an assessment of changes in the patients' structural parenchyma. 20 patients (mean age 55 yrs) were enrolled in this study, 5 of whom received routine thrombolytic therapy with r-tPA. G-CSF treatment was discontinued in 4 patients because of unrelated adverse events. Mobilization of CD34+ cells was observed with no concomitant changes in blood chemistry, except for an increase in the leukocyte count up to 75,500/µl. Neuroradiological and neuropsychological follow-up studies did not disclose any specific G-CSF toxicity. VGM findings indicated substantial atrophy of related hemispheres, a substantial increase in the CSF space, and a localized increase in parenchyma within the ischemic area in 2 patients. Conclusions We demonstrate a good safety profile for daily administration of G-CSF when begun within 12 hours after onset of ischemic stroke and, in part in combination with routine IV thrombolysis. Additional analyses using VGM and a battery of neuropsychological tests indicated a positive functional and potentially structural effect of G-CSF treatment in some of our patients. Trial Registration German Clinical Trial Register DRKS 00000723 PMID:21887230

Outer brain barriers in rat and human development

PubMed Central

Brøchner, Christian B.; Holst, Camilla B.; Møllgård, Kjeld

2015-01-01

Complex barriers at the brain's surface, particularly in development, are poorly defined. In the adult, arachnoid blood-cerebrospinal fluid (CSF) barrier separates the fenestrated dural vessels from the CSF by means of a cell layer joined by tight junctions. Outer CSF-brain barrier provides diffusion restriction between brain and subarachnoid CSF through an initial radial glial end feet layer covered with a pial surface layer. To further characterize these interfaces we examined embryonic rat brains from E10 to P0 and forebrains from human embryos and fetuses (6–21st weeks post-conception) and adults using immunohistochemistry and confocal microscopy. Antibodies against claudin-11, BLBP, collagen 1, SSEA-4, MAP2, YKL-40, and its receptor IL-13Rα2 and EAAT1 were used to describe morphological characteristics and functional aspects of the outer brain barriers. Claudin-11 was a reliable marker of the arachnoid blood-CSF barrier. Collagen 1 delineated the subarachnoid space and stained pial surface layer. BLBP defined radial glial end feet layer and SSEA-4 and YKL-40 were present in both leptomeningeal cells and end feet layer, which transformed into glial limitans. IL-13Rα2 and EAAT1 were present in the end feet layer illustrating transporter/receptor presence in the outer CSF-brain barrier. MAP2 immunostaining in adult brain outlined the lower border of glia limitans; remnants of end feet were YKL-40 positive in some areas. We propose that outer brain barriers are composed of at least 3 interfaces: blood-CSF barrier across arachnoid barrier cell layer, blood-CSF barrier across pial microvessels, and outer CSF-brain barrier comprising glial end feet layer/pial surface layer. PMID:25852456

Outer brain barriers in rat and human development.

PubMed

Brøchner, Christian B; Holst, Camilla B; Møllgård, Kjeld

2015-01-01

Complex barriers at the brain's surface, particularly in development, are poorly defined. In the adult, arachnoid blood-cerebrospinal fluid (CSF) barrier separates the fenestrated dural vessels from the CSF by means of a cell layer joined by tight junctions. Outer CSF-brain barrier provides diffusion restriction between brain and subarachnoid CSF through an initial radial glial end feet layer covered with a pial surface layer. To further characterize these interfaces we examined embryonic rat brains from E10 to P0 and forebrains from human embryos and fetuses (6-21st weeks post-conception) and adults using immunohistochemistry and confocal microscopy. Antibodies against claudin-11, BLBP, collagen 1, SSEA-4, MAP2, YKL-40, and its receptor IL-13Rα2 and EAAT1 were used to describe morphological characteristics and functional aspects of the outer brain barriers. Claudin-11 was a reliable marker of the arachnoid blood-CSF barrier. Collagen 1 delineated the subarachnoid space and stained pial surface layer. BLBP defined radial glial end feet layer and SSEA-4 and YKL-40 were present in both leptomeningeal cells and end feet layer, which transformed into glial limitans. IL-13Rα2 and EAAT1 were present in the end feet layer illustrating transporter/receptor presence in the outer CSF-brain barrier. MAP2 immunostaining in adult brain outlined the lower border of glia limitans; remnants of end feet were YKL-40 positive in some areas. We propose that outer brain barriers are composed of at least 3 interfaces: blood-CSF barrier across arachnoid barrier cell layer, blood-CSF barrier across pial microvessels, and outer CSF-brain barrier comprising glial end feet layer/pial surface layer.

Impact of Aromatase Genetic Variation on Hormone Levels and Global Outcome after Severe TBI

PubMed Central

Garringer, Julie A.; Niyonkuru, Christian; McCullough, Emily H.; Loucks, Tammy; Dixon, C. Edward; Conley, Yvette P.; Berga, Sarah

2013-01-01

Abstract Although experimental traumatic brain injury (TBI) studies support estradiol as a neuroprotectant and potent stimulator of neuroplasticity, clinical studies suggest a negative association between endogenous estradiol profiles and mortality/poor outcomes. However, no studies have evaluated associations with cerebral spinal fluid (CSF) hormone profiles and aromatase gene (cytochrome P450 [CYP]19A1) variability on clinical TBI outcomes. We evaluated 110 adults with severe TBI. Average and daily estradiol, testosterone, and estradiol/testosterone ratios (E2:T) were measured using CSF and serum samples and compared to healthy controls. Eighteen tagging and four functional single-nucleotide polymorphisms (SNPs) for CYP19A1 were genotyped and compared to hormones, acute mortality, and Glasgow Outcome Scale (GOS) scores 6 months post-TBI. TBI subjects had lower CSF estradiol over time versus controls. CSF testosterone was initially high, but declined over time. E2/T ratios were initially low, compared to controls, but rose over time. Higher mean E2/T ratio in bivariate analysis was associated with lower mortality (p=0.019) and better GOS-6 scores (p=0.030). rs2470152 influenced CSF E2/T ratio and also serum and CSF testosterone (p≤0.05 all comparisons). Multiple-risk SNPs rs2470152, rs4646, and rs2470144 were associated with worse GOS-6 scores (p≤0.05, all comparisons), and those with>1 risk SNP variant had a higher risk for poor outcome, compared with those with ≤1 risk variant. TBI results in low CSF estradiol and dynamic CSF testosterone and E2/T ratio. In contrast to clinical serum hormone studies, higher CSF E2/T ratio was associated with better outcome. Further, genetic variation in CYP19A1 influences both hormone dynamics and outcome post-TBI. PMID:23540392

Granulocyte-Colony Stimulating Factor (G-CSF) Accelerates Wound Healing in Hemorrhagic Shock Rats by Enhancing Angiogenesis and Attenuating Apoptosis

PubMed Central

Huang, Hong; Zhang, Qi; Liu, Jiejie; Hao, Haojie; Jiang, Chaoguang; Han, Weidong

2017-01-01

Background Following severe trauma, treatment of cutaneous injuries is often delayed by inadequate blood supply. The aim of the present study was to determine whether granulocyte-colony stimulating factor (G-CSF) protects endothelial cells (ECs) and enhances angiogenesis in a rat model of hemorrhagic shock (HS) combined with cutaneous injury after resuscitation. Material/Methods The HS rats with full-thickness defects were resuscitated and randomly divided into a G-CSF group (200 μg/kg body weight), a normal saline group, and a blank control group. Histological staining was to used estimate the recovery and apoptosis of skin. Apoptosis- and angiogenesis-related factors were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot (WB). Scratch assay, tube formation, and WB experiments were performed to verify the functional effects of G-CSF on HUVECs in vitro. Results H&E staining and Masson trichrome staining showed earlier inflammation resolution and collagen synthesis in the G-CSF-treated group. Angiogenesis-related factors were elevated at mRNA and protein levels. TUNEL staining suggested fewer apoptotic cells in the G-CSF group. The apoptotic-related factors were down-regulated and anti-apoptotic factors were up-regulated in the G-CSF-treated group. Scratch assay and tube formation experiments revealed that G-CSF facilitated migration ability and angiogenic potential of HUVECs. The angiogenic and anti-apoptotic effects were also enhanced in vitro. Conclusions Our results suggest that G-CSF after resuscitation attenuates local apoptosis and accelerates angiogenesis. These findings hold great promise for improving therapy for cutaneous injury in severe trauma and ischemia diseases. PMID:28559534

Tumor-Derived G-CSF Facilitates Neoplastic Growth through a Granulocytic Myeloid-Derived Suppressor Cell-Dependent Mechanism

PubMed Central

Waight, Jeremy D.; Hu, Qiang; Miller, Austin; Liu, Song; Abrams, Scott I.

2011-01-01

Myeloid-derived suppressor cells (MDSC) are induced under diverse pathologic conditions, including neoplasia, and suppress innate and adaptive immunity. While the mechanisms by which MDSC mediate immunosuppression are well-characterized, details on how they develop remain less understood. This is complicated further by the fact that MDSC comprise multiple myeloid cell types, namely monocytes and granulocytes, reflecting diverse stages of differentiation and the proportion of these subpopulations vary among different neoplastic models. Thus, it is thought that the type and quantities of inflammatory mediators generated during neoplasia dictate the composition of the resultant MDSC response. Although much interest has been devoted to monocytic MDSC biology, a fundamental gap remains in our understanding of the derivation of granulocytic MDSC. In settings of heightened granulocytic MDSC responses, we hypothesized that inappropriate production of G-CSF is a key initiator of granulocytic MDSC accumulation. We observed abundant amounts of G-CSF in vivo, which correlated with robust granulocytic MDSC responses in multiple tumor models. Using G-CSF loss- and gain-of-function approaches, we demonstrated for the first time that: 1) abrogating G-CSF production significantly diminished granulocytic MDSC accumulation and tumor growth; 2) ectopically over-expressing G-CSF in G-CSF-negative tumors significantly augmented granulocytic MDSC accumulation and tumor growth; and 3) treatment of naïve healthy mice with recombinant G-CSF protein elicited granulocytic-like MDSC remarkably similar to those induced under tumor-bearing conditions. Collectively, we demonstrated that tumor-derived G-CSF enhances tumor growth through granulocytic MDSC-dependent mechanisms. These findings provide us with novel insights into MDSC subset development and potentially new biomarkers or targets for cancer therapy. PMID:22110722

GM-CSF produced by non-hematopoietic cells is required for early epithelial cell proliferation and repair of injured colonic mucosa1,2

PubMed Central

Egea, Laia; McAllister, Christopher S.; Lakhdari, Omar; Minev, Ivelina; Shenouda, Steve; Kagnoff, Martin F.

2012-01-01

GM-CSF is a growth factor that promotes the survival and activation of macrophages and granulocytes, and dendritic cell (DC) differentiation and survival in vitro. The mechanism by which exogenous GM-CSF ameliorates the severity of Crohn’s disease in humans and colitis in murine models has been considered mainly to reflect its activity on myeloid cells. We used GM-CSF deficient (GM-CSF−/−) mice to probe the functional role of endogenous host-produced GM-CSF in a colitis model induced after injury to the colon epithelium. Dextran sodium sulfate (DSS) at doses that resulted in little epithelial damage and mucosal ulceration in wild type (WT) mice resulted in marked colon ulceration and delayed ulcer healing in GM-CSF−/− mice. Colon crypt epithelial cell proliferation in vivo was significantly decreased in GM-CSF−/− mice at early times after DSS injury. This was paralleled by decreased expression of crypt epithelial cell genes involved in cell cycle, proliferation, and wound healing. Decreased crypt cell proliferation and delayed ulcer healing in GM-CSF−/− mice were rescued by exogenous GM-CSF, indicating the lack of a developmental abnormality in the epithelial cell proliferative response in those mice. Non-hematopoietic cells and not myeloid cells produced the GM-CSF important for colon epithelial proliferation after DSS-induced injury as revealed by bone marrow chimera and DC depletion experiments, with colon epithelial cells being the cellular source of GM-CSF. Endogenous epithelial cell produced GM-CSF has a novel non-redundant role in facilitating epithelial cell proliferation and ulcer healing in response to injury of the colon crypt epithelium. PMID:23325885

Identification and validation of clinical predictors for the risk of neurological involvement in children with hand, foot, and mouth disease in Sarawak

PubMed Central

2009-01-01

Background Human enterovirus 71 (HEV71) can cause Hand, foot, and mouth disease (HFMD) with neurological complications, which may rapidly progress to fulminant cardiorespiratory failure, and death. Early recognition of children at risk is the key to reduce acute mortality and morbidity. Methods We examined data collected through a prospective clinical study of HFMD conducted between 2000 and 2006 that included 3 distinct outbreaks of HEV71 to identify risk factors associated with neurological involvement in children with HFMD. Results Total duration of fever ≥ 3 days, peak temperature ≥ 38.5°C and history of lethargy were identified as independent risk factors for neurological involvement (evident by CSF pleocytosis) in the analysis of 725 children admitted during the first phase of the study. When they were validated in the second phase of the study, two or more (≥ 2) risk factors were present in 162 (65%) of 250 children with CSF pleocytosis compared with 56 (30%) of 186 children with no CSF pleocytosis (OR 4.27, 95% CI2.79–6.56, p < 0.0001). The usefulness of the three risk factors in identifying children with CSF pleocytosis on hospital admission during the second phase of the study was also tested. Peak temperature ≥ 38.5°C and history of lethargy had the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 28%(48/174), 89%(125/140), 76%(48/63) and 50%(125/251), respectively in predicting CSF pleocytosis in children that were seen within the first 2 days of febrile illness. For those presented on the 3rd or later day of febrile illness, the sensitivity, specificity, PPV and NPV of ≥ 2 risk factors predictive of CSF pleocytosis were 75%(57/76), 59%(27/46), 75%(57/76) and 59%(27/46), respectively. Conclusion Three readily elicited clinical risk factors were identified to help detect children at risk of neurological involvement. These risk factors may serve as a guide to clinicians to decide the need for hospitalization and further investigation, including cerebrospinal fluid examination, and close monitoring for disease progression in children with HFMD. PMID:19152683

CSF generation by pineal gland results in a robust melatonin circadian rhythm in the third ventricle as an unique light/dark signal.

PubMed

Tan, Dun-Xian; Manchester, Lucien C; Reiter, Russel J

2016-01-01

Pineal gland is an important organ for the regulation of the bio-clock in all vertebrate species. Its major secretory product is melatonin which is considered as the chemical expression of darkness due to its circadian peak exclusively at night. Pineal melatonin can be either released into the blood stream or directly enter into the CSF of the third ventricle via the pineal recess. We have hypothesized that rather than the peripheral circulatory melatonin circadian rhythm serving as the light/dark signal, it is the melatonin rhythm in CSF of the third ventricle that serves this purpose. This is due to the fact that melatonin circadian rhythm in the CSF is more robust in terms of its extremely high concentration and its precise on/off peaks. Thus, extrapineal-generated melatonin or diet-derived melatonin which enters blood would not interfere with the bio-clock function of vertebrates. In addition, based on the relationship of the pineal gland to the CSF and the vascular structure of this gland, we also hypothesize that pineal gland is an essential player for CSF production. We feel it participates in both the formation and reabsorption of CSF. The mechanisms associated with these processes are reviewed and discussed in this brief review. Copyright © 2015 Elsevier Ltd. All rights reserved.

Prototype of an opto-capacitive probe for non-invasive sensing cerebrospinal fluid circulation

NASA Astrophysics Data System (ADS)

Myllylä, Teemu; Vihriälä, Erkki; Pedone, Matteo; Korhonen, Vesa; Surazynski, Lukasz; Wróbel, Maciej; Zienkiewicz, Aleksandra; Hakala, Jaakko; Sorvoja, Hannu; Lauri, Janne; Fabritius, Tapio; Jedrzejewska-Szczerska, Małgorzata; Kiviniemi, Vesa; Meglinski, Igor

2017-03-01

In brain studies, the function of the cerebrospinal fluid (CSF) awakes growing interest, particularly related to studies of the glymphatic system in the brain, which is connected with the complex system of lymphatic vessels responsible for cleaning the tissues. The CSF is a clear, colourless liquid including water (H2O) approximately with a concentration of 99 %. In addition, it contains electrolytes, amino acids, glucose, and other small molecules found in plasma. The CSF acts as a cushion behind the skull, providing basic mechanical as well as immunological protection to the brain. Disturbances of the CSF circulation have been linked to several brain related medical disorders, such as dementia. Our goal is to develop an in vivo method for the non-invasive measurement of cerebral blood flow and CSF circulation by exploiting optical and capacitive sensing techniques simultaneously. We introduce a prototype of a wearable probe that is aimed to be used for long-term brain monitoring purposes, especially focusing on studies of the glymphatic system. In this method, changes in cerebral blood flow, particularly oxy- and deoxyhaemoglobin, are measured simultaneously and analysed with the response gathered by the capacitive sensor in order to distinct the dynamics of the CSF circulation behind the skull. Presented prototype probe is tested by measuring liquid flows inside phantoms mimicking the CSF circulation.

CSF N-glycan profile reveals sialylation deficiency in a patient with GM2 gangliosidosis presenting as childhood disintegrative disorder.

PubMed

Barone, Rita; Sturiale, Luisella; Fiumara, Agata; Palmigiano, Angelo; Bua, Rosaria O; Rizzo, Renata; Zappia, Mario; Garozzo, Domenico

2016-04-01

Protein N-glycosylation consists in the synthesis and processing of the oligosaccharide moiety (N-glycan) linked to a protein and it serves several functions for the proper central nervous system (CNS) development and function. Previous experimental and clinical studies have shown the importance of proper glycoprotein sialylation for the synaptic function and the occurrence of autism spectrum disorders (ASD) in the presence of sialylation deficiency in the CNS. Late-onset Tay Sachs disease (LOTSD) is a lysosomal disorder caused by mutations in the HEXA gene resulting in GM2-ganglioside storage in the CNS. It is characterized by progressive neurological impairment and high co-occurrence of psychiatric disturbances. We studied the N-glycome profile of the cerebrospinal fluid (CSF) in a 14 year-old patient with GM2-gangliosidosis (LOTSD). At the age of 4, the patient presented regressive autism fulfilling criteria for childhood disintegrative disorder (CDD). A CSF sample was obtained in the course of diagnostic work-up for the suspicion of an underlying neurodegenerative disorder. We found definite changes of CSF N-glycans due to a dramatic decrease of sialylated biantennary and triantennary structures and an increase of asialo-core fucosylated bisected N-glycans. No changes of total plasma N-glycans were found. Herein findings highlight possible relationships between the early onset psychiatric disturbance featuring CDD in the patient and defective protein sialylation in the CNS. In conclusion, the study first shows aberrant N-glycan structures of CSF proteins in LOTSD; unveils possible pathomechanisms of GM2-gangliosidosis; supports existing relationships between neuropsychiatric disorders and unproper protein glycosylation in the CNS. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

Association of MAOA gene functional promoter polymorphism with CSF dopamine turnover and atypical depression.

PubMed

Aklillu, Eleni; Karlsson, Sara; Zachrisson, Olof O; Ozdemir, Vural; Agren, Hans

2009-04-01

Monoamine oxidase-A (MAO-A) is a key mitochondrial enzyme that metabolizes biogenic amine neurotransmitters such as dopamine and serotonin. Individuals with atypical depression (AD) are particularly responsive to treatment with MAO inhibitors (MAOIs). Biomarker tests are essential for prompt diagnosis of AD, and to identify those with an altered brain neurotransmitter metabolism who may selectively respond to MAOI therapy. In a sample of 118 Scandinavian patients with treatment-resistant depression who are naive to MAOI therapy, we investigated the associations between a common MAOA functional promoter polymorphism (MAOA-uVNTR), cerebrospinal fluid (CSF) neurotransmitter metabolites, and AD susceptibility. The metabolites for dopamine (homovanillic acid, HVA), serotonin (5-hydroxyindoleacetic acid) and noradrenaline (3-methoxy-4-hydroxyphenylglycol) were measured in the CSF. AD was associated with the female sex and a higher HVA in CSF (P=0.008). The carriers of the MAOA-uVNTR short allele were significantly overrepresented among women with AD (P=0.005; odds ratio=4.76; 95% confidence interval=1.5-13.1; statistical power=80.0%). Moreover, the MAOA-uVNTR genotype significantly influenced the HVA concentration (P=0.01) and showed a strong trend in relation to 5-hydroxyindoleacetic acid concentration (P=0.057) in women. The mediational statistical analyses showed the CSF-HVA concentration as a key driver of the relationship between MAOA-uVNTR genotype and AD. The association of the MAOA-uVNTR with both susceptibility to AD and dopamine metabolite (HVA) concentration lends further biological plausibility for high MAO-A enzyme activity as a mechanistic factor for genetic predisposition to AD through altered dopamine turnover. Our observations provide new evidence on the in-vivo functional significance of the MAOA-uVNTR short allele as a high activity variant.

Practical and adequate approach to modeling light propagation in an adult head with low-scattering regions by use of diffusion theory.

PubMed

Koyama, Tatsuya; Iwasaki, Atsushi; Ogoshi, Yosuke; Okada, Eiji

2005-04-10

A practical and adequate approach to modeling light propagation in an adult head with a low-scattering cerebrospinal fluid (CSF) region by use of diffusion theory was investigated. The diffusion approximation does not hold in a nonscattering or low-scattering regions. The hybrid radiosity-diffusion method was adopted to model the light propagation in the head with a nonscattering region. In the hybrid method the geometry of the nonscattering region is acquired as a priori information. In reality, low-level scattering occurs in the CSF region and may reduce the error caused by the diffusion approximation. The partial optical path length and the spatial sensitivity profile calculated by the finite-element method agree well with those calculated by the Monte Carlo method in the case in which the transport scattering coefficient of the CSF layer is greater than 0.3 mm(-1). Because it is feasible to assume that the transport scattering coefficient of a CSF layer is 0.3 mm(-1), it is practical to adopt diffusion theory to the modeling of light propagation in an adult head as an alternative to the hybrid method.

Practical and adequate approach to modeling light propagation in an adult head with low-scattering regions by use of diffusion theory

NASA Astrophysics Data System (ADS)

Koyama, Tatsuya; Iwasaki, Atsushi; Ogoshi, Yosuke; Okada, Eiji

2005-04-01

A practical and adequate approach to modeling light propagation in an adult head with a low-scattering cerebrospinal fluid (CSF) region by use of diffusion theory was investigated. The diffusion approximation does not hold in a nonscattering or low-scattering regions. The hybrid radiosity-diffusion method was adopted to model the light propagation in the head with a nonscattering region. In the hybrid method the geometry of the nonscattering region is acquired as a priori information. In reality, low-level scattering occurs in the CSF region and may reduce the error caused by the diffusion approximation. The partial optical path length and the spatial sensitivity profile calculated by the finite-element method agree well with those calculated by the Monte Carlo method in the case in which the transport scattering coefficient of the CSF layer is greater than 0.3 mm^-1. Because it is feasible to assume that the transport scattering coefficient of a CSF layer is 0.3 mm^-1, it is practical to adopt diffusion theory to the modeling of light propagation in an adult head as an alternative to the hybrid method.

Neurofilament light chain protein as a marker of neuronal injury: review of its use in HIV-1 infection and reference values for HIV-negative controls.

PubMed

Yilmaz, Aylin; Blennow, Kaj; Hagberg, Lars; Nilsson, Staffan; Price, Richard W; Schouten, Judith; Spudich, Serena; Underwood, Jonathan; Zetterberg, Henrik; Gisslén, Magnus

2017-08-01

Several CSF biomarkers of neuronal injury have been studied in people living with HIV. At this time, the most useful is the light subunit of the neurofilament protein (NFL). This major structural component of myelinated axons is essential to maintain axonal caliber and to facilitate effective nerve conduction. CSF concentrations of NFL provide a sensitive marker of CNS injury in a number of neurological diseases, including HIV-related neuronal injury. Areas Covered: In this review, the authors describe CSF NFL concentrations across the spectrum of HIV-infection, from its early acute phase to severe immunosuppression, with and without neurological conditions, and with and without antiretroviral treatment (n = 516). Furthermore, in order to provide more precise estimates of age-related upper limits of CSF NFL concentrations, the authors present data from a large number (n = 359) of HIV-negative controls. Expert Commentary: Recently a new ultrasensitive diagnostic assay for quantification of NFL in plasma has been developed, providing a convenient way to assess neuronal damage without having to perform a lumbar puncture. This review also considers our current knowledge of plasma NFL in HIV CNS infection.

6-Mercaptopurine modifies cerebrospinal fluid T cell abnormalities in paediatric opsoclonus-myoclonus as steroid sparer.

PubMed

Pranzatelli, M R; Tate, E D; Allison, T J

2017-11-01

The purpose of this study was to evaluate the capacity of 6-mercaptopurine (6-MP), a known immunosuppressant, to normalize cerebrospinal fluid (CSF) lymphocyte frequencies in opsoclonus-myoclonus syndrome (OMS) and function as a steroid sparer. CSF and blood lymphocytes were immunophenotyped in 11 children with OMS (without CSF B cell expansion) using a comprehensive panel of cell surface adhesion, activation and maturation markers by flow cytometry, and referenced to 18 paediatric controls. Drug metabolites, lymphocyte counts and liver function tests were used clinically to monitoring therapeutic range and toxicity. In CSF, adjunctive oral 6-MP was associated with a 21% increase in the low percentage of CD4 + T cells in OMS, restoring the CD4/CD8 ratio. The percentage of CD4 + T cells that were interferon (IFN)-γ + was reduced by 66%, shifting the cytokine balance away from T helper type 1 (Th1) (proinflammatory) predominance. The percentage of natural killer (NK) cells decreased significantly in CSF (-32%) and blood (-67 to -82%). Low blood absolute lymphocyte count was more predictive of improvement in CSF lymphocyte proportions (correlated with % CD4 + T cells) than the 6-thioguanine level (no correlation). 6-MP was difficult to titrate: 50% achieved the target absolute lymphocyte count (< 1·5 K/mm); 20%, the 'therapeutic' 6-thioguanine level; and 40% the non-toxic 6-methylmercaptopurine level. Side effects and transaminase elevation were mild and reversible. Clinical steroid-sparing properties and lowered relapse frequency were demonstrated. 6-MP displayed unique pharmacodynamic properties that may be useful in OMS and other autoimmune disorders. Its steroid sparer capacity is limited to children in whom the therapeutic window can be reached without limiting pharmacokinetic factors or side effects. © 2017 British Society for Immunology.

Macrophage Phenotype Modulation by CXCL4 in Atherosclerosis.

PubMed

Gleissner, Christian A

2012-01-01

During atherogenesis, blood monocytes transmigrate into the subendothelial space and differentiate toward macrophages and foam cells. The major driver of monocyte-macrophage differentiation is macrophage colony-stimulating factor (M-CSF). M-CSF-induced macrophages are important promoters of atherogenesis as demonstrated in M-CSF and M-CSF receptor knock out mice. However, M-CSF is not the only relevant promoter of macrophage differentiation. The platelet chemokine CXCL4 also prevents monocyte apoptosis and promotes macrophage differentiation in vitro. It is secreted from activated platelets and has effects on various cell types relevant in atherogenesis. Knocking out the Pf4 gene coding for CXCL4 in Apoe(-/-) mice leads to reduced atherogenesis. Thus, it seems likely that CXC4-induced macrophages may have specific pro-atherogenic capacities. We have studied CXC4-induced differentiation of human macrophages using gene chips, systems biology, and functional in vitro and ex vivo experiments. Our data indicate that CXCL4-induced macrophages are distinct from both their M-CSF-induced counterparts and other known macrophage polarizations like M1 macrophages (induced by lipopolysaccharide and interferon-gamma) or M2 macrophages (induced by interleukin-4). CXCL4-induced macrophages have distinct phenotypic and functional characteristics, e.g., the complete loss of the hemoglobin-haptoglobin (Hb-Hp) scavenger receptor CD163 which is necessary for effective hemoglobin clearance after plaque hemorrhage. Lack of CD163 is accompanied by the inability to upregulate the atheroprotective enzyme heme oxygenase-1 in response to Hb-Hp complexes. This review covers the current knowledge about CXCL4-induced macrophages. Based on their unique properties, we have suggested to call these macrophages "M4." CXCL4 may represent an important orchestrator of macrophage heterogeneity within atherosclerotic lesions. Further dissecting its effects on macrophage differentiation may help to identify novel therapeutic targets in atherogenesis.

Implementation and Evaluation of a Fully Automated Multiplex Real-Time PCR Assay on the BD Max Platform to Detect and Differentiate Herpesviridae from Cerebrospinal Fluids

PubMed Central

Köller, Thomas; Kurze, Daniel; Lange, Mirjam; Scherdin, Martin; Podbielski, Andreas; Warnke, Philipp

2016-01-01

A fully automated multiplex real-time PCR assay—including a sample process control and a plasmid based positive control—for the detection and differentiation of herpes simplex virus 1 (HSV1), herpes simplex virus 2 (HSV2) and varicella-zoster virus (VZV) from cerebrospinal fluids (CSF) was developed on the BD Max platform. Performance was compared to an established accredited multiplex real time PCR protocol utilizing the easyMAG and the LightCycler 480/II, both very common devices in viral molecular diagnostics. For clinical validation, 123 CSF specimens and 40 reference samples from national interlaboratory comparisons were examined with both methods, resulting in 97.6% and 100% concordance for CSF and reference samples, respectively. Utilizing the BD Max platform revealed sensitivities of 173 (CI 95%, 88–258) copies/ml for HSV1, 171 (CI 95%, 148–194) copies/ml for HSV2 and 84 (CI 95%, 5–163) copies/ml for VZV. Cross reactivity could be excluded by checking 25 common viral, bacterial and fungal human pathogens. Workflow analyses displayed shorter test duration as well as remarkable fewer and easier preparation steps with the potential to reduce error rates occurring when manually assessing patient samples. This protocol allows for a fully automated PCR assay on the BD Max platform for the simultaneously detection of herpesviridae from CSF specimens. Singular or multiple infections due to HSV1, HSV2 and VZV can reliably be differentiated with good sensitivities. Control parameters are included within the assay, thereby rendering its suitability for current quality management requirements. PMID:27092772

Real-time polymerase chain reaction and culture in the diagnosis of invasive group B streptococcal disease in infants: a retrospective study.

PubMed

Meehan, M; Cafferkey, M; Corcoran, S; Foran, A; Hapnes, N; LeBlanc, D; McGuinness, C; Nusgen, U; O'Sullivan, N; Cunney, R; Drew, R

2015-12-01

Group B streptococcus (GBS) is a leading cause of invasive disease in infants. Accurate and rapid diagnosis is crucial to reduce morbidity and mortality. Real-time polymerase chain reaction (PCR) targeting the dltR gene was utilised for the direct detection of GBS DNA in blood and cerebrospinal fluid (CSF) from infants at an Irish maternity hospital. A retrospective review of laboratory and patient records during the period 2011-2013 was performed in order to evaluate PCR and culture for the diagnosis of invasive GBS disease. A total of 3570 blood and 189 CSF samples from 3510 infants had corresponding culture and PCR results. Culture and PCR exhibited concordance in 3526 GBS-negative samples and 13 (25%) GBS-positive samples (n = 53). Six (11%) and 34 (64%) GBS-positive samples were positive only in culture or PCR, respectively. Culture and PCR identified more GBS-positive infants (n = 47) than PCR (n = 43) or culture (n = 16) alone. Using culture as the reference standard, the sensitivity, specificity, and positive and negative predictive values for PCR on blood samples were 71.4%, 99.2%, 25% and 99.9%, and for CSF samples, they were 60%, 97.8%, 42.9% and 98.9%, respectively. The sensitivity and positive predictive values were improved (blood: 84.6% and 55%; CSF: 77.8% and 100%, respectively) when maternal risk factors and other laboratory test results were considered. The findings in this study recommend the use of direct GBS real-time PCR for the diagnosis of GBS infection in infants with a clinical suspicion of invasive disease and as a complement to culture, but should be interpreted in the light of other laboratory and clinical findings.

Reduced Levels of Nitric Oxide Metabolites in Cerebrospinal Fluid Are Associated with Equine Protozoal Myeloencephalitis

PubMed Central

Njoku, Chinedu J.; Saville, William J. A.; Reed, Stephen M.; Oglesbee, Michael J.; Rajala-Schultz, Päivi J.; Stich, Roger W.

2002-01-01

Equine protozoal myeloencephalitis (EPM) is a disease of horses that is primarily associated with infection with the apicomplexan Sarcocystis neurona. Infection with this parasite alone is not sufficient to induce the disease, and the mechanism of neuropathogenesis associated with EPM has not been reported. Nitric oxide (NO) functions as a neurotransmitter, a vasodilator, and an immune effector and is produced in response to several parasitic protozoa. The purpose of this work was to determine if the concentration of NO metabolites (NOx−) in the cerebrospinal fluid (CSF) is correlated with the development of EPM. CSF NOx− levels were measured before and after transport-stressed, acclimated, or dexamethasone-treated horses (n = 3 per group) were experimentally infected with S. neurona sporocysts. CSF NOx− levels were also compared between horses that were diagnosed with EPM after natural infection with S. neurona and horses that did not have clinical signs of disease or that showed no evidence of infection with the parasite (n = 105). Among the experimentally infected animals, the mean CSF NOx− levels of the transport-stressed group, which had the most severe clinical signs, was reduced after infection, while these values were found to increase after infection in the remaining groups that had less severe signs of EPM. Under natural conditions, horses with EPM (n = 65) had a lower mean CSF NOx− concentration than clinically normal horses with antibodies (Abs) against S. neurona (n = 15) in CSF, and horses that developed ataxia (n = 81) had a significantly lower mean CSF NOx− concentration than horses that did not have neurologic signs (n = 24). In conclusion, lower CSF NOx− levels were associated with clinical EPM, suggesting that measurement of CSF NOx− levels could improve the accuracy of diagnostic tests that are based upon detection of S. neurona-specific Abs in CSF alone and that reduced NO levels could be causatively related to the development of EPM. PMID:11986267

Acute radiation syndrome (ARS) - treatment of the reduced host defense.

PubMed

Heslet, Lars; Bay, Christiane; Nepper-Christensen, Steen

2012-01-01

The current radiation threat from the Fukushima power plant accident has prompted rethinking of the contingency plan for prophylaxis and treatment of the acute radiation syndrome (ARS). The well-documented effect of the growth factors (granulocyte colony-stimulating factor [G-CSF] and granulocyte-macrophage colony-stimulating factor [GM-CSF]) in acute radiation injury has become standard treatment for ARS in the United States, based on the fact that growth factors increase number and functions of both macrophages and granulocytes. Review of the current literature. The lungs have their own host defense system, based on alveolar macrophages. After radiation exposure to the lungs, resting macrophages can no longer be transformed, not even during systemic administration of growth factors because G-CSF/GM-CSF does not penetrate the alveoli. Under normal circumstances, locally-produced GM-CSF receptors transform resting macrophages into fully immunocompetent dendritic cells in the sealed-off pulmonary compartment. However, GM-CSF is not expressed in radiation injured tissue due to defervescence of the macrophages. In order to maintain the macrophage's important role in host defense after radiation exposure, it is hypothesized that it is necessary to administer the drug exogenously in order to uphold the barrier against exogenous and endogenous infections and possibly prevent the potentially lethal systemic infection, which is the main cause of death in ARS. Preemptive treatment should be initiated after suspected exposure of a radiation dose of at least <2 Gy by prompt dosing of 250-400 μg GM-CSF/m(2) or 5 μg/kg G-CSF administered systemically and concomitant inhalation of GM-CSF < 300 mcg per day for at least 14-21 days. The present United States standard for prevention and treatment of ARS standard intervention should consequently be modified into the combined systemic administration of growth factors and inhaled GM-CSF to ensure the sustained systemic and pulmonary host defense and thus prevent pulmonary dysfunction.

Synovial CD4+ T-cell-derived GM-CSF supports the differentiation of an inflammatory dendritic cell population in rheumatoid arthritis

PubMed Central

Reynolds, G; Gibbon, J R; Pratt, A G; Wood, M J; Coady, D; Raftery, G; Lorenzi, A R; Gray, A; Filer, A; Buckley, C D; Haniffa, M A; Isaacs, J D; Hilkens, C M U

2016-01-01

Objective A population of synovial inflammatory dendritic cells (infDCs) has recently been identified in rheumatoid arthritis (RA) and is thought to be monocyte-derived. Here, we investigated the role and source of granulocyte macrophage-colony-stimulating factor (GM-CSF) in the differentiation of synovial infDC in RA. Methods Production of GM-CSF by peripheral blood (PB) and synovial fluid (SF) CD4+ T cells was assessed by ELISA and flow cytometry. In vitro CD4+ T-cell polarisation experiments were performed with T-cell activating CD2/CD3/CD28-coated beads in the absence or presence of pro-Th1 or pro-Th17 cytokines. CD1c+ DC and CD16+ macrophage subsets were flow-sorted and analysed morphologically and functionally (T-cell stimulatory/polarising capacity). Results RA-SF CD4+ T cells produced abundant GM-CSF upon stimulation and significantly more than RA-SF mononuclear cells depleted of CD4+ T cells. GM-CSF-producing T cells were significantly increased in RA-SF compared with non-RA inflammatory arthritis SF, active RA PB and healthy donor PB. GM-CSF-producing CD4+ T cells were expanded by Th1-promoting but not Th17-promoting conditions. Following coculture with RA-SF CD4+ T cells, but not healthy donor PB CD4+ T cells, a subpopulation of monocytes differentiated into CD1c+ infDC; a process dependent on GM-CSF. These infDC displayed potent alloproliferative capacity and enhanced GM-CSF, interleukin-17 and interferon-γ production by CD4+ T cells. InfDC with an identical phenotype to in vitro generated cells were significantly enriched in RA-SF compared with non-RA-SF/tissue/PB. Conclusions We demonstrate a therapeutically tractable feedback loop of GM-CSF secreted by RA synovial CD4+ T cells promoting the differentiation of infDC with potent capacity to induce GM-CSF-producing CD4+ T cells. PMID:25923217

Impact of donor hematopoietic cells mobilized with G-CSF and plerixafor on murine acute graft-versus-host-disease.

PubMed

Arbez, Jessy; Saas, Philippe; Lamarthée, Baptiste; Malard, Florent; Couturier, Mélanie; Mohty, Mohamad; Gaugler, Béatrice

2015-07-01

This study aimed to characterize the immune effectors contained in the grafts from donor mice mobilized by granulocyte colony-stimulating factor (G-CSF) and plerixafor and to evaluate their impact on the development of acute graft-versus-host-disease (aGVHD). Mobilization was done with G-CSF alone or G-CSF plus plerixafor (G+P). In grafts collected after G+P mobilization, we observed a significantly higher proportion of c-kit(+)Sca-1(+) hematopoietic stem cells compared with G-CSF. A significant increase in the percentage of plasmacytoid dendritic cells was detected in the G+P graft compared with G-CSF graft. We also studied the ability of stem cell grafts mobilized with G+P to induce GVHD in a mouse model. We observed higher mortality (P < 0.001) associated with increased aGVHD clinical score (P < 0.0001) as well as higher pathology score in the intestine of mice receiving G+P as compared with G-CSF grafts (P < 0.001). Moreover, the exacerbated aGVHD severity was associated with upregulation of CCR6 expression on both CD4(+) and CD8(+) T cells from the G+P grafts, as well as on T cells from mice transplanted with G+P grafts. In conclusion, we showed that grafts mobilized with G+P exhibited functional features different from those mobilized with G-CSF alone, which increase the severity of aGVHD in the recipients. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Targeting cFMS signaling to restore immune function and eradicate HIV reservoirs

NASA Astrophysics Data System (ADS)

Gerngross, Lindsey

While combination anti-retroviral therapy (cART) has improved the length and quality of life of individuals living with HIV-1 infection, the prevalence of HIV-associated neurocognitive disorders (HAND) has increased and remains a significant clinical concern. The neuropathogenesis of HAND is not completely understood, however, latent HIV infection in the central nervous system (CNS) and chronic neuroinflammation are believed to play a prominent role. CNS-associated macrophages and resident microglia are significant contributors to CNS inflammation and constitute the chief reservoir of HIV-1 infection in the CNS. Previous studies from our lab suggest monocyte/macrophage invasion of the CNS in HIV may be driven by altered monocyte/macrophage homeostasis. We have reported expansion of a monocyte subset (CD14+CD16 +CD163+) in peripheral blood of HIV+ patients that is phenotypically similar to macrophages/microglia that accumulate in the CNS as seen in post-mortem tissue. The factors driving the expansion of this monocyte subset are unknown, however, signaling through cFMS, a type III receptor tyrosine kinase (RTK), may play a role. Macrophage-colony stimulating factor (M-CSF), a ligand of cFMS, has been shown to be elevated in the cerebral spinal fluid (CSF) of individuals with the most severe form of HAND, HIV-associated dementia (HAD). M-CSF promotes a Macrophage-2-like phenotype and increases CD16 and CD163 expression in cultured monocytes. M-CSF has also been shown to increase the susceptibility of macrophages to HIV infection and enhance virus production. These findings, in addition to the known function of M-CSF in promoting macrophage survival, supports a role for M-CSF in the development and maintenance of macrophage viral reservoirs in tissues where these cells accumulate, including the CNS. Interestingly, a second ligand for cFMS, IL-34, was recently identified and reported to share some functions with M-CSF, suggesting that both ligands may contribute to HIV-associated CNS injury and AIDS pathogenesis. Through immunohistochemical studies using a relevant animal model of HIV infection, SIV infected rhesus macaques, we reported the presence of M-CSF and IL-34 in the brains of seronegative and SIV+ animals, for the first time, and identified spatial differences in the expression of these ligands. Important to our interest in viral persistence in the CNS, we observed the predominance of M-CSF expression in brain to be by cells that comprise perivascular cuffs and nodular lesions, which contain monocytes/ macrophages that have migrated into the CNS. IL-34 appeared to be a tissue-specific ligand expressed by resident microglia. Like M-CSF, we found that IL-34 also increased the frequency of CD16 +CD163+ monocytes in vitro. We further investigated the potential of cFMS inhibition as a means to abrogate macrophage-2-like immune polarization using the small molecule tyrosine kinase inhibitor (TKI), GW2580. The addition of GW2580 abolished cFMS ligand-mediated increases in CD16+CD163+ monocyte frequency in human peripheral blood mononuclear cells (PBMC) as well as virus production in HIV infected primary human microglia. Furthermore, we found cFMS-mediated upregulation of CD16 and CD163 to be relevant to an additional disease process, high-grade astrocytomas, suggesting that M-CSF and IL-34 may be mediators of other neuroinflammatory diseases, as well. We hope these findings will provide insight into the role of altered monocyte/macrophage homeostasis in HIV disease and identify a novel strategy for targeting long-lived cellular reservoirs of HIV infection through restored immune homeostasis.

Marker vaccines and companion diagnostic tests for classical swine fever.

PubMed

Floegel-Niesmann, G

2003-01-01

For Classical Swine Fever (CSF) a subunit vaccine consisting of the E2 protein is commercially available. The discriminatory ELISAs detect antibodies against another viral protein, the E(rns). As CSF has already been eradicated from many countries the use of a marker vaccine in these regions can only be contemplated as emergency vaccination after a new introduction of virus. Therefore, a Large Scale Marker Vaccine Trial was financed by the EU Commission and organised by the EU Reference Laboratory for CSF in 1999. When tested under the conditions of emergency vaccination, e.g. challenge before full immunity had developed, it was shown, that most CSF challenge infections took a subclinical course with reduced virus shedding. Transplacental transmission in pregnant sows could not be prevented after an application of a single vaccine dose. The most serious deficiencies have been found in the discriminatory ELISAs. Both available tests have shown deficiencies in sensitivity and specificity compared to conventional CSF antibody ELISAs. At the time, when the trial was performed, no confirmatory test was available to verify the results of the discriminatory ELISAs. Currently two new developments of marker vaccines for CSF are in progress. A chimaeric vaccine is based on infectious clones of the conventional live vaccine (C-strain) where a gene is replaced with the corresponding gene of the closely related pestivirus Bovine Viral Diarrhoea (BVD) virus. Conversely, the E2 gene of a BVD virus can be replaced by the E2 of a virulent CSF virus. The other principle is the construction of a DNA vaccine, expressing the E2 gene after entering the host cell. Deletion mutants of the E2 gene have also been constructed and tested for their induction of immunity. Both new developments are based on the same discriminatory tests as mentioned previously and developments of other principles for discrimination are rare.

A Hospital Based Study on Estimation of Adenosine Deaminase Activity (ADA) in Cerebrospinal Fluid (CSF) in Various Types of Meningitis.

PubMed

Agarwal, Ashok Kumar; Bansal, Sonia; Nand, Vidya

2014-02-01

Tuberculosis kills 3.70 lakh patients in India every year,out of which 7-12 % are meningeal involvement. Delay in its diagnosis and initiation of treatment results in poor prognosis and squeal in up to 25% of cases. The aim of the present study is to look for a simple, rapid, cost effective, and fairly specific test in differentiating tubercular aetiology from other causes of meningitis. In the present study we measured the adenosine deaminase activity (ADA) in Cerebrospinal Fluid (CSF) of Tubercular Meningitis (TBM) and non-TBM patients. Fifty six patients attending hospital with symptoms and signs of meningitis were selected and divided into three groups: tubercular, pyogenic, and aseptic meningitis, depending upon the accepted criteria. CSF was drawn and ADA estimated. Out of 32 tubercular patients, 28 had CSF-ADA at or above the cut-off value while four had below. Out of 24 non-tuberculous patients (pyogenic and aseptic meningitis), two aseptic meningitis (AM) patient had ADA levels at or above the cut-off value while 22 had below this value. RESULTS of our study indicate that ADA level estimation in CSF is not only of considerable value in the diagnosis of TBM, CSF, and ADA level 10 U/L as a cut-off value with sensitivity 87.5% and specificity 83.33% and positive predictive value of the test was 87.5%.and 83.3% negative predictive value. It can be concluded that ADA estimation in CSF is not only simple, inexpensive and rapid but also fairly specific method for making a diagnosis of tuberculous aetiology in TBM, especially when there is a dilemma of differentiating the tuberculous aetiology from non-tuberculous ones. For this reason ADA estimation in TBM may find a place as a routine investigation.

Normal cerebrospinal fluid histamine and tele-methylhistamine levels in hypersomnia conditions.

PubMed

Dauvilliers, Yves; Delallée, Nathalie; Jaussent, Isabelle; Scholz, Sabine; Bayard, Sophie; Croyal, Mickael; Schwartz, Jean-Charles; Robert, Philippe

2012-10-01

To determine the activity of cerebral histaminergic system evaluated by CSF levels of histamine (HA) and tele-methylhistamine (t-MHA), its major metabolite, and their relationships with hypocretin-1 levels in a large population of patients with hypersomnia and neurological conditions. sensitive liquid chromatographic-electrospray/tandem mass spectrometric assay was developed for the simultaneous quantification of CSF HA and t-MHA. ata were collected and CSF hypocretin-1 levels were measured using radioimmunoassay at the Sleep Disorders Center, Montpellier, France. CSF HA and t-MHA were measured in Bioprojet-Biotech, France One hundred fourteen unrelated patients with a suspicion of central hypersomnia underwent one night of polysomnography followed by the multiple sleep latency test. Sleep disorders were diagnosed clinically and using sleep studies: narcolepsy-cataplexy NC (n = 56), narcolepsy without cataplexy NwC (n = 27), idiopathic hypersomnia IH (n = 11), secondary narcolepsy (n = 3), and unspecified hypersomnia Uns EDS (n = 17). Fifty neurological patients without daytime sleepiness were included as controls. No between-hypersomnia group differences were found for CSF HA levels (median 708.62 pM extreme range [55.92-3335.50] in NC; 781.34 [174.08-4391.50] in NwC; 489.42 [177.45-906.70] in IH, and 1155.40 [134.80-2736.59] in Uns EDS) or for t-MHA levels. No association was found between CSF HA, t-MHA, or HA + t-MHA, sleepiness, treatment intake, and frequency of cataplexy. A slight negative correlation was found between age and HA levels. Further adjustment for the age revealed no significant HA levels difference between hypersomnia patients and controls. CSF histamine and tele-methylhistamine did not significantly differ between patients with narcolepsy-cataplexy and other etiologies of non-hypocretin-1 deficient central hypersomnias; these measurements, therefore, are not useful in assessing the etiology or severity of centrally mediated hypersomnia.

Relationship between Cough-Associated Changes in CSF Flow and Disease Severity in Chiari I Malformation: An Exploratory Study Using Real-Time MRI.

PubMed

Bezuidenhout, A F; Khatami, D; Heilman, C B; Kasper, E M; Patz, S; Madan, N; Zhao, Y; Bhadelia, R A

2018-05-10

Currently no quantitative objective test exists to determine disease severity in a patient with Chiari I malformation. Our aim was to correlate disease severity in symptomatic patients with Chiari I malformation with cough-associated changes in CSF flow as measured with real-time MR imaging. Thirteen symptomatic patients with Chiari I malformation (tonsillar herniation of ≥5 mm) were prospectively studied. A real-time, flow-sensitized pencil-beam MR imaging scan was used to measure CSF stroke volume during rest and immediately following coughing and relaxation periods (total scan time, 90 seconds). Multiple posterior fossa and craniocervical anatomic measurements were also obtained. Patients were classified into 2 groups by neurosurgeons blinded to MR imaging measurements: 1) nonspecific Chiari I malformation (5/13)-Chiari I malformation with nonspecific symptoms like non-cough-related or mild occasional cough-related headache, neck pain, dizziness, paresthesias, and/or trouble swallowing; 2) specific Chiari I malformation (8/13)-patients with Chiari I malformation with specific symptoms and/or objective findings like severe cough-related headache, myelopathy, syringomyelia, and muscle atrophy. The Spearman correlation was used to determine correlations between MR imaging measurements and disease severity, and both groups were also compared using a Mann-Whitney U test. There was a significant negative correlation between the percentage change in CSF stroke volume (resting to postcoughing) and Chiari I malformation disease severity ( R = 0.59; P = .03). Mann-Whitney comparisons showed the percentage change in CSF stroke volume (resting to postcoughing) to be significantly different between patient groups ( P = .04). No other CSF flow measurement or anatomic measure was significantly different between the groups. Our exploratory study suggests that assessment of CSF flow response to a coughing challenge has the potential to become a valuable objective noninvasive test for clinical assessment of disease severity in patients with Chiari I malformation. © 2018 by American Journal of Neuroradiology.

Procalcitonin in cerebrospinal fluid in meningitis: a prospective diagnostic study.

PubMed

Alons, Imanda M E; Verheul, Rolf J; Kuipers, Irma; Jellema, Korné; Wermer, Marieke J H; Algra, Ale; Ponjee, Gabriëlle

2016-11-01

Bacterial meningitis is a severe but treatable condition. Clinical symptoms may be ambiguous and current diagnostics lack sensitivity and specificity, complicating diagnosis. Procalcitonin (PCT) is a protein that is elevated in serum in bacterial infection. We aimed to assess the value of PCT in cerebrospinal fluid (CSF) in the diagnosis of bacterial meningitis. We included patients with bacterial meningitis, both community acquired and post neurosurgery. We included two comparison groups: patients with viral meningitis and patients who underwent lumbar punctures for noninfectious indications. We calculated mean differences and 95% confidence intervals of procalcitonin in CSF and plasma in patients with and without bacterial meningitis. Average PCT concentrations in CSF were 0.60 ng mL -1 (95% CI: 0.29-0.92) in the bacterial meningitis group ( n  = 26), 0.81 (95% CI: 0.33-1.28) in community-acquired meningitis ( n  = 16) and 0.28 (95% CI: 0.10-0.45) in postneurosurgical meningitis ( n  = 10), 0.10 ng mL -1 (95% CI: 0.08-0.12) in the viral meningitis group ( n  = 14) and 0.08 ng mL -1 (95% CI: 0.06-0.09) in the noninfectious group ( n  = 14). Mean difference of PCT-CSF between patients with community-acquired bacterial meningitis and with viral meningitis was 0.71 ng mL -1 (95% CI: 0.17-1.25) and 0.73 ng mL -1 (95% CI: 0.19-1.27) for community-acquired bacterial meningitis versus the noninfectious group. The median PCT CSF: plasma ratio was 5.18 in postneurosurgical and 0.18 in community-acquired meningitis (IQR 4.69 vs. 0.28). Procalcitonin in CSF was significantly higher in patients with bacterial meningitis when compared with patients with viral or no meningitis. PCT in CSF may be a valuable marker in diagnosing bacterial meningitis, and could become especially useful in patients after neurosurgery.

Reciprocal contribution of clinical studies and the HP10 antigen ELISA for the diagnosis of extraparenchymal neurocysticercosis.

PubMed

Parkhouse, R Michael E; Carpio, Arturo; Campoverde, Alfredo; Sastre, Patricia; Rojas, Glenda; Cortez, María Milagros

2018-02-01

To evaluate diagnosis of active neurocysticercosis, paired cerebral spinal fluid (CSF) and serum samples from 24 neurocysticercosis (NCC) patients and 17 control neurological patients were assayed in the HP10 Taenia antigen (Ag) ELISA. The CSF samples were also tested with an HP10 Lateral Flow Assay (LFA). The HP10 Ag was detected by ELISA in the CSF of 5/5 patients with Definitive extraparenchymal NCC, and in 4/5 of the corresponding sera. In the Definitive parenchymal group, on the other hand, the HP10 Ag was absent in 2/3 CSF (with a very low value in the one positive sample) and all the corresponding serum samples. Samples of CSF from 4/7 patients in the Probable parenchymal group, were also significantly HP10 Ag positive, suggesting the presence of extraparenchymal cysts not identified by the imaging studies. With the possible exception of one patient, the corresponding serum samples of the Probable parenchymal NCC group, were all HP10 Ag negative. Samples of CSF from 9 NCC patients diagnosed with Mixed parenchymal and extraparenchymal NCC were all significantly HP10 Ag positive, confirming the presence of extraparenchymal cysts, with only 7/9 of the corresponding serum samples being HP10 positive. Thus detection of the HP10 Ag indicates extraparenchymal and not parenchymal cyst localization and is more sensitive with CSF than serum. Three neurological patients clinically diagnosed as subarachnoid cyst, hydrocephalus and tuberculoma, respectively, were clearly positive for HP10 Ag. Of these, two were confirmed as NCC by subsequent imaging; the third died prior to further examination. Thus, a total of 8 patients had their clinical diagnosis questioned. Finally, there was good agreement between the HP10 Ag ELISA and LFA with CSF samples giving an optical density ≥0.4 in the ELISA assay. In conclusion, the HP10 Ag assay should provide a valuable and reciprocal tool in the clinical diagnosis and follow up of extraparenchymal NCC. Copyright © 2017 Elsevier B.V. All rights reserved.

Neuroimmunomodulators in neuroborreliosis and Lyme encephalopathy.

PubMed

Eckman, Elizabeth A; Pacheco-Quinto, Javier; Herdt, Aimee R; Halperin, John J

2018-01-11

Lyme encephalopathy, characterized by non-specific neurobehavioral symptoms including mild cognitive difficulties, may occur in patients with systemic Lyme disease and is often mistakenly attributed to CNS infection. Identical symptoms occur in innumerable other inflammatory states and may reflect the effect of systemic immune mediators on the CNS. Multiplex immunoassays were used to characterize the inflammatory profile in serum and CSF from Lyme and non-Lyme patients with a range of symptoms to determine if there are specific markers of active CNS infection (neuroborreliosis), or systemic inflammatory mediators associated with neurobehavioral syndromes. CSF CXCL13 was elevated dramatically in confirmed neuroborreliosis (n=8) and to a lesser extent in possible neuroborreliosis (n=11) and other neuroinflammatory conditions (n=44). Patients with Lyme (n=63) or non-Lyme (n=8) encephalopathy had normal CSF findings, but had elevated serum levels of IL-7, TSLP, IL-17A, IL-17F, and MIP-1α/CCL3. CSF CXCL13 is a sensitive and specific marker of neuroborreliosis in individuals with Borrelia-specific intrathecal antibody (ITAb) production. However, CXCL13 does not distinguish individuals strongly suspected of having neuroborreliosis, but lacking confirmatory ITAb, from those with other neuroinflammatory conditions. Patients with mild cognitive symptoms occurring during acute Lyme disease, and/or following appropriate treatment, have normal CSF but elevated serum levels of T-helper 17 markers and T-cell growth factors. These markers are also elevated in non-Lyme disease patients experiencing similar symptoms. Our results support that in the absence of CSF abnormalities, neurobehavioral symptoms are associated with systemic inflammation, not CNS infection or inflammation, and are not specific to Lyme disease. © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Salt-Induced Hypertension in a Mouse Model of Liddle's Syndrome is Mediated by Epithelial Sodium Channels in the Brain

PubMed Central

Van Huysse, James W.; Amin, Md. Shahrier; Yang, Baoli; Leenen, Frans H. H.

2012-01-01

Neural precursor cell expressed and developmentally downregulated 4-2 protein (Nedd4-2) facilitates the endocytosis of epithelial Na channels (ENaC). Both mice and humans with a loss of regulation of ENaC by Nedd4-2 have salt-induced hypertension. ENaC is also expressed in the brain, where it is critical for hypertension on high salt diet in salt-sensitive rats. In the present studies we assessed whether Nedd4-2 knockout (−/−) mice have: 1) increased brain ENaC; 2) elevated CSF sodium on high salt diet; and 3) enhanced pressor responses to CSF sodium and hypertension on high salt diet, both mediated by brain ENaC. Prominent choroid plexus and neuronal ENaC staining was present in −/− but not in wild-type (W/T) mice. In chronically instrumented mice, intracerebroventricular (icv) infusion of Na-rich aCSF increased MAP 3-fold higher in −/− than W/T. Icv infusion of the ENaC blocker benzamil abolished this enhancement. In telemetered −/− mice on high salt diet (8% NaCl), CSF [Na+], MAP and HR increased significantly, MAP by 30-35 mmHg. These MAP and HR responses were largely prevented by icv benzamil, but only to a minor extent by sc benzamil at the icv rate. We conclude that increased ENaC expression in the brain of Nedd 4-2 −/− mice mediates their hypertensive response to high salt diet, by causing increased sodium levels in the CSF as well as hyper-responsiveness to CSF sodium. These findings highlight the possible causative contribution of CNS ENaC in the etiology of salt-induced hypertension. PMID:22802227

A potential endophenotype for Alzheimer's disease: cerebrospinal fluid clusterin.

PubMed

Deming, Yuetiva; Xia, Jian; Cai, Yefei; Lord, Jenny; Holmans, Peter; Bertelsen, Sarah; Holtzman, David; Morris, John C; Bales, Kelly; Pickering, Eve H; Kauwe, John; Goate, Alison; Cruchaga, Carlos

2016-01-01

Genome-wide association studies have associated clusterin (CLU) variants with Alzheimer's disease (AD). However, the role of CLU on AD pathogenesis is not totally understood. We used cerebrospinal fluid (CSF) and plasma CLU levels as endophenotypes for genetic studies to understand the role of CLU in AD. CSF, but not plasma, CLU levels were significantly associated with AD status and CSF tau/amyloid-beta ratio, and highly correlated with CSF apolipoprotein E (APOE) levels. Several loci showed almost genome-wide significant associations including LINC00917 (p = 3.98 × 10(-7)) and interleukin 6 (IL6, p = 9.94 × 10(-6), in the entire data set and in the APOE ε4- individuals p = 7.40 × 10(-8)). Gene ontology analyses suggest that CSF CLU levels may be associated with wound healing and immune response which supports previous functional studies that demonstrated an association between CLU and IL6. CLU may play a role in AD by influencing immune system changes that have been observed in AD or by disrupting healing after neurodegeneration. Copyright © 2016 Elsevier Inc. All rights reserved.

A potential endophenotype for Alzheimer’s disease: cerebrospinal fluid clusterin

PubMed Central

Deming, Yuetiva; Xia, Jian; Cai, Yefei; Lord, Jenny; Holmans, Peter; Bertelsen, Sarah; Holtzman, David; Morris, John C; Bales, Kelly; Pickering, Eve H; Kauwe, John; Goate, Alison; Cruchaga, Carlos

2016-01-01

Genome-wide association studies have associated clusterin (CLU) variants with Alzheimer’s disease (AD). However the role of CLU on AD pathogenesis is not totally understood. We used CSF and plasma CLU levels as endophenotypes for genetic studies to understand the role of CLU in AD. CSF, but not plasma, CLU levels were significantly associated with AD status and CSF tau/Aβ ratio, and highly correlated with CSF apolipoprotein E (APOE) levels. Several loci showed almost genome-wide significant associations including LINC00917 (p=3.98×10−7) and interleukin 6 (IL6, p=9.94×10−6, in the entire dataset and in the APOE ε4- individuals p=7.40×10−8). Gene-ontology analyses suggest that CSF CLU levels may be associated with wound healing and immune response which supports previous functional studies that demonstrated an association between CLU and IL6. CLU may play a role in AD by influencing immune system changes that have been observed in AD or by disrupting healing after neurodegeneration. PMID:26545630

Disease progression model in subjects with mild cognitive impairment from the Alzheimer's disease neuroimaging initiative: CSF biomarkers predict population subtypes

PubMed Central

Samtani, Mahesh N; Raghavan, Nandini; Shi, Yingqi; Novak, Gerald; Farnum, Michael; Lobanov, Victor; Schultz, Tim; Yang, Eric; DiBernardo, Allitia; Narayan, Vaibhav A

2013-01-01

AIM The objective is to develop a semi-mechanistic disease progression model for mild cognitive impairment (MCI) subjects. The model aims to describe the longitudinal progression of ADAS-cog scores from the Alzheimer's disease neuroimaging initiative trial that had data from 198 MCI subjects with cerebrospinal fluid (CSF) information who were followed for 3 years. METHOD Various covariates were tested on disease progression parameters and these variables fell into six categories: imaging volumetrics, biochemical, genetic, demographic, cognitive tests and CSF biomarkers. RESULTS CSF biomarkers were associated with both baseline disease score and disease progression rate in subjects with MCI. Baseline disease score was also correlated with atrophy measured using hippocampal volume. Progression rate was also predicted by executive functioning as measured by the Trail B-test. CONCLUSION CSF biomarkers have the ability to discriminate MCI subjects into sub-populations that exhibit markedly different rates of disease progression on the ADAS-cog scale. These biomarkers can therefore be utilized for designing clinical trials enriched with subjects that carry the underlying disease pathology. PMID:22534009

Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer.

PubMed

Yang, Lijun; Kress, Benjamin T; Weber, Harris J; Thiyagarajan, Meenakshisundaram; Wang, Baozhi; Deane, Rashid; Benveniste, Helene; Iliff, Jeffrey J; Nedergaard, Maiken

2013-05-01

Neurodegenerative diseases such as Alzheimer's are associated with the aggregation of endogenous peptides and proteins that contribute to neuronal dysfunction and loss. The glymphatic system, a brain-wide perivascular pathway along which cerebrospinal fluid (CSF) and interstitial fluid (ISF) rapidly exchange, has recently been identified as a key contributor to the clearance of interstitial solutes from the brain, including amyloid β. These findings suggest that measuring changes in glymphatic pathway function may be an important prognostic for evaluating neurodegenerative disease susceptibility or progression. However, no clinically acceptable approach to evaluate glymphatic pathway function in humans has yet been developed. Time-sequenced ex vivo fluorescence imaging of coronal rat and mouse brain slices was performed at 30-180 min following intrathecal infusion of CSF tracer (Texas Red- dextran-3, MW 3 kD; FITC- dextran-500, MW 500 kD) into the cisterna magna or lumbar spine. Tracer influx into different brain regions (cortex, white matter, subcortical structures, and hippocampus) in rat was quantified to map the movement of CSF tracer following infusion along both routes, and to determine whether glymphatic pathway function could be evaluated after lumbar intrathecal infusion. Following lumbar intrathecal infusions, small molecular weight TR-d3 entered the brain along perivascular pathways and exchanged broadly with the brain ISF, consistent with the initial characterization of the glymphatic pathway in mice. Large molecular weight FITC-d500 remained confined to the perivascular spaces. Lumbar intrathecal infusions exhibited a reduced and delayed peak parenchymal fluorescence intensity compared to intracisternal infusions. Lumbar intrathecal contrast delivery is a clinically useful approach that could be used in conjunction with dynamic contrast enhanced MRI nuclear imaging to assess glymphatic pathway function in humans.

Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer

PubMed Central

2013-01-01

Background Neurodegenerative diseases such as Alzheimer’s are associated with the aggregation of endogenous peptides and proteins that contribute to neuronal dysfunction and loss. The glymphatic system, a brain-wide perivascular pathway along which cerebrospinal fluid (CSF) and interstitial fluid (ISF) rapidly exchange, has recently been identified as a key contributor to the clearance of interstitial solutes from the brain, including amyloid β. These findings suggest that measuring changes in glymphatic pathway function may be an important prognostic for evaluating neurodegenerative disease susceptibility or progression. However, no clinically acceptable approach to evaluate glymphatic pathway function in humans has yet been developed. Methods Time-sequenced ex vivo fluorescence imaging of coronal rat and mouse brain slices was performed at 30–180 min following intrathecal infusion of CSF tracer (Texas Red- dextran-3, MW 3 kD; FITC- dextran-500, MW 500 kD) into the cisterna magna or lumbar spine. Tracer influx into different brain regions (cortex, white matter, subcortical structures, and hippocampus) in rat was quantified to map the movement of CSF tracer following infusion along both routes, and to determine whether glymphatic pathway function could be evaluated after lumbar intrathecal infusion. Results Following lumbar intrathecal infusions, small molecular weight TR-d3 entered the brain along perivascular pathways and exchanged broadly with the brain ISF, consistent with the initial characterization of the glymphatic pathway in mice. Large molecular weight FITC-d500 remained confined to the perivascular spaces. Lumbar intrathecal infusions exhibited a reduced and delayed peak parenchymal fluorescence intensity compared to intracisternal infusions. Conclusion Lumbar intrathecal contrast delivery is a clinically useful approach that could be used in conjunction with dynamic contrast enhanced MRI nuclear imaging to assess glymphatic pathway function in humans. PMID:23635358

The Relationship Between Monthdisease Incidence Rate and Climatic Factor of Classical Swine Fever

NASA Astrophysics Data System (ADS)

Wang, Hongbin; Xu, Danning; Xiao, Jianhua; Zhang, Ru; Dong, Jing

The Swine Fever is a kind of acute, highly infective epidemic disease of animals; it is name as Classical Swine Fever (CSF) by World animal Health organization. Meteorological factors such as temperature, air pressure and rainfall affect the epidemic of CSF significantly through intermediary agent and CSF viral directly. However there is significant difference among different region for mode of effects. Accordingly, the analyze must adopt different methods. The dependability between incidence rate each month of CSF and meteorological factors from 1999 to 2004 was analyzed in this paper. The function of meteorological factors on CSF was explored and internal law was expected to be discovered. The correlation between the incidence rate of Swine Fever and meteorological factors, thus the foundation analysis of the early warning and the decision-making was made, the result indicated that the incidence rate of CSF has negative correlation with temperature, rainfall, cloudage; relative humidity has positive correlation with disease; for air pressure, except average air pressure of one month, other air pressure factors have positive correlation with disease; for wind speed, except Difference among moths of wind speed and average temperature of one month. have positive correlation with disease, other wind speed factors has negative correlation with disease.

Development of a diagnostic system for bilirubin detection in cerebral spinal fluid

NASA Astrophysics Data System (ADS)

Bhadri, Prashant R.; Salgaonkar, Vasant A.; Majumdar, Anindya; Morgan, Chad J.; Zuccarello, Mario; Pyne, Gail J.; Dulaney, Elizabeth; Caffery, James, Jr.; Shukla, Rakesh; Beyette, Fred R., Jr.

2004-11-01

A weakened portion of an artery in the brain leads to a medical condition known as a cerebral aneurysm. A subarachnoid hemorrhage (SAH) occurs when an aneurysm ruptures. For those individuals suspected of having a SAH, a computerized tomography (CT) scan of the brain usually demonstrates evidence of the bleeding. However, in a considerable portion of people, the CT scan is unable to detect the blood that has escaped from the blood vessel. Recent studies have indicated nearly 30% of patients with a SAH are initially misdiagnosed. For circumstances when a SAH is suspected despite a normal CT scan, physicians make the diagnosis of SAH by performing a spinal tap. A spinal tap uses a needle to sample the cerebrospinal fluid (CSF) collected from the patient"s lumbar spine. However, it is also possible for blood to be introduced into the CSF as a result of the spinal tap procedure. Therefore, an effective solution is required to help medical personnel differentiate between the blood that results from a tap and that from a ruptured aneurysm. In this paper, the development of a prototype is described which is sensitive and specific for measuring bilirubin in CSF, hemorrhagic-CSF and CSF-like solutions. To develop this instrument a combination of spectrophotometric analysis, custom data analysis software and other hardware interfaces are assembled that lay the foundation for the development of portable and user-friendly equipment suitable for assisting trained medical personnel with the diagnosis of a ruptured cerebral aneurysm.

Absence of LTB4/BLT1 axis facilitates generation of mouse GM-CSF-induced long-lasting antitumor immunologic memory by enhancing innate and adaptive immune systems.

PubMed

Yokota, Yosuke; Inoue, Hiroyuki; Matsumura, Yumiko; Nabeta, Haruka; Narusawa, Megumi; Watanabe, Ayumi; Sakamoto, Chika; Hijikata, Yasuki; Iga-Murahashi, Mutsunori; Takayama, Koichi; Sasaki, Fumiyuki; Nakanishi, Yoichi; Yokomizo, Takehiko; Tani, Kenzaburo

2012-10-25

BLT1 is a high-affinity receptor for leukotriene B4 (LTB4) that is a potent lipid chemoattractant for myeloid leukocytes. The role of LTB4/BLT1 axis in tumor immunology, including cytokine-based tumor vaccine, however, remains unknown. We here demonstrated that BLT1-deficient mice rejected subcutaneous tumor challenge of GM-CSF gene-transduced WEHI3B (WGM) leukemia cells (KO/WGM) and elicited robust antitumor responses against second tumor challenge with WEHI3B cells. During GM-CSF-induced tumor regression, the defective LTB4/BLT1 signaling significantly reduced tumor-infiltrating myeloid-derived suppressor cells, increased the maturation status of dendritic cells in tumor tissues, enhanced their CD4(+) T-cell stimulation capacity and migration rate of dendritic cells that had phagocytosed tumor-associated antigens into tumor-draining lymph nodes, suggesting a positive impact on GM-CSF-sensitized innate immunity. Furthermore, KO/WGM mice displayed activated adaptive immunity by attenuating regulatory CD4(+) T subsets and increasing numbers of Th17 and memory CD44(hi)CD4(+) T subsets, both of which elicited superior antitumor effects as evidenced by adoptive cell transfer. In vivo depletion assays also revealed that CD4(+) T cells were the main effectors of the persistent antitumor immunity. Our data collectively underscore a negative role of LTB4/BLT1 signaling in effective generation and maintenance of GM-CSF-induced antitumor memory CD4(+) T cells.

Validation of the bacterial meningitis score in adults presenting to the ED with meningitis.

PubMed

McArthur, Robert; Edlow, Jonathan A; Nigrovic, Lise E

2016-07-01

The Bacterial Meningitis Score classifies children with meningitis and none of the following high-risk predictors at very low risk for bacterial meningitis: positive cerebrospinal fluid (CSF) Gram stain, CSF protein ≥80mg/dL, CSF absolute neutrophil count (ANC) ≥1000 cells/mm(3), peripheral ANC ≥10,000 cells/mm(3), and seizure at or prior to presentation. Although extensively validated in children, the Bacterial Meningitis Score has not been rigorously evaluated in adults. We performed a single-center cross-sectional retrospective study of adults presenting to the emergency department between 2003 and 2013 with meningitis (defined by CSF white blood cell count ≥10 cells/mm(3)). We defined a case of bacterial meningitis with either a positive CSF or blood culture. We report the performance of the Bacterial Meningitis Score in the study population. We identified 441 eligible patients of which, 4 (1%) had bacterial meningitis. The Bacterial Meningitis Score had a sensitivity of 100% [95% confidence interval (CI) 40%-100%], specificity 51% (95% CI, 46%-56%) and negative predictive value of 100% (95% CI, 98%-100%). None of the low risk adults had bacterial meningitis. If Bacterial Meningitis Score had been applied prospectively, the hospital admission rate would have dropped from 84% to 49% without missing any patients with bacterial meningitis. The Bacterial Meningitis Score accurately identified patients at low risk for bacterial meningitis and could assist clinical decision-making for adults with meningitis. Copyright © 2016 Elsevier Inc. All rights reserved.

Proteinase-activated receptor 2 and disease biomarkers in cerebrospinal fluid in cases with autopsy-confirmed prion diseases and other neurodegenerative diseases.

PubMed

Rohan, Zdenek; Smetakova, Magdalena; Kukal, Jaromir; Rusina, Robert; Matej, Radoslav

2015-03-31

Proteinase-activated receptor 2 (PAR-2) has been shown to promote both neurotoxic and neuroprotective effects. Similarly, other routinely used nonspecific markers of neuronal damage can be found in cerebrospinal fluid (CSF) and can be used as biomarkers for different neurodegenerative disorders. Using enzyme-linked immunosorbent assays and western blotting we assessed PAR-2, total-tau, phospho-tau, beta-amyloid levels, and protein 14-3-3 in the CSF of former patients who had undergone a neuropathological autopsy after death and who had been definitively diagnosed with a prion or other neurodegenerative disease. We did not find any significant correlation between levels of PAR-2 and other biomarkers, nor did we find any differences in PAR-2 levels between prion diseases and other neurodegenerative conditions. However, we confirmed that very high total-tau levels were significantly associated with definitive prion diagnoses and exhibited greater sensitivity and specificity than protein 14-3-3, which is routinely used as a marker. Our study showed that PAR-2, in CSF, was not specifically altered in prion diseases compared to other neurodegenerative conditions. Our results also confirmed that very high total-tau protein CSF levels were significantly associated with a definitive Creutzfeldt-Jakob disease (CJD) diagnosis and should be routinely tested as a diagnostic marker. Observed individual variability in CSF biomarkers provide invaluable feedback from neuropathological examinations even in "clinically certain" cases.

CSF GABA is reduced in first-episode psychosis and associates to symptom severity

PubMed Central

Orhan, F; Fatouros-Bergman, H; Goiny, M; Malmqvist, A; Piehl, F; Engberg, Göran; Erhardt, Sophie; Schwieler, Lilly; Orhan, Funda; Malmqvist, Anna; Hedberg, Mikael; Farde, Lars; Cervenka, Simon; Flyckt, Lena; Collste, Karin; Ikonen, Pauliina; Piehl, Fredrik; Agartz, Ingrid; Cervenka, S; Collste, K; Victorsson, P; Sellgren, C M; Flyckt, L; Erhardt, S; Engberg, G

2018-01-01

Schizophrenia is characterized by a multiplicity of symptoms arising from almost all domains of mental function. γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain and is increasingly recognized to have a significant role in the pathophysiology of the disorder. In the present study, cerebrospinal fluid (CSF) concentrations of GABA were analyzed in 41 first-episode psychosis (FEP) patients and 21 age- and sex-matched healthy volunteers by high-performance liquid chromatography. We found lower CSF GABA concentration in FEP patients compared with that in the healthy volunteers, a condition that was unrelated to antipsychotic and/or anxiolytic medication. Moreover, lower CSF GABA levels were associated with total and general score of Positive and Negative Syndrome Scale, illness severity and probably with a poor performance in a test of attention. This study offers clinical in vivo evidence for a potential role of GABA in early-stage schizophrenia. PMID:28289277

Colony-stimulating factors: clinical evidence for treatment and prophylaxis of chemotherapy-induced febrile neutropenia.

PubMed

Gómez Raposo, César; Pinto Marín, Alvaro; González Barón, Manuel

2006-10-01

The hematopoietic growth factors (HGFs) are a family of glycoproteins which plays a major role in the proliferation, differentiation, and survival of primitive hematopoietic stem and progenitor cells, and in the functions of some mature cells. More than 20 different molecules of HGF have been identified. Among them, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been demostrated to be effective in reducing the incidence of febrile neutropenia when administered inmediately after chemotherapy and as supportive therapy in patients undergoing bone marrow transplantation. Chemotherapy used for treatment of cancer often causes neutropenia, which may be profound, requiring hospitalization, and leading to potentially fatal infection. The uses of the recombinant human hematopoietic colony-stimulating factors G-CSF and GM-CSF for treatment and prophylaxis of chemotherapy-induced febrile neutropenia will be reviewed here.

The predictive value of cerebrospinal fluid tap-test in normal pressure hydrocephalus.

PubMed

Damasceno, B P; Carelli, E F; Honorato, D C; Facure, J J

1997-06-01

Eighteen patients (mean age of 66.5 years) with normal pressure hydrocephalus (NPH) underwent a ventriculo-peritoneal shunt surgery. Prior to operation a cerebrospinal fluid tap-test (CSF-TT) was performed with measurements of gait pattern and psychometric functions (memory, visuo-motor speed and visuo-constructive skills) before and after the removal of 50 ml CSF by lumbar puncture (LP). Fifteen patients improved and 3 were unchanged after surgery. Short duration of disease, gait disturbance preceding mental deterioration, wide temporal horns and small sulci on CT-scan were associated with good outcome after shunting. There was a good correlation between the results of CSF-TT and shunt surgery (chi 2 = 4.11, phi = 0.48, p < 0.05), with gait test showing highest correlation (r = 0.99, p = 0.01). In conclusion, this version of CSF-TT proved to be an effective test to predict improvement after shunting in patients with NPH.

The subcommissural organ of the rat secretes Reissner's fiber glycoproteins and CSF-soluble proteins reaching the internal and external CSF compartments

PubMed Central

Vio, Karin; Rodríguez, Sara; Yulis, Carlos R; Oliver, Cristian; Rodríguez, Esteban M

2008-01-01

Background The subcommissural organ (SCO) is a highly conserved brain gland present throughout the vertebrate phylum; it secretes glycoproteins into the cerebrospinal fluid (CSF), where they aggregate to form Reissner's fiber (RF). SCO-spondin is the major constituent protein of RF. Evidence exists that the SCO also secretes proteins that remain soluble in the CSF. The aims of the present investigation were: (i) to identify and partially characterize the SCO-secretory compounds present in the SCO gland itself and in the RF of the Sprague-Dawley rat and non-hydrocephalic hyh mouse, and in the CSF of rat; (ii) to make a comparative analysis of the proteins present in these three compartments; (iii) to identify the proteins secreted by the SCO into the CSF at different developmental periods. Methods The proteins of the SCO secreted into the CSF were studied (i) by injecting specific antibodies into ventricular CSF in vivo; (ii) by immunoblots of SCO, RF and CSF samples, using specific antibodies against the SCO secretory proteins (AFRU and anti-P15). In addition, the glycosylated nature of SCO-compounds was analysed by concanavalin A and wheat germ agglutinin binding. To analyse RF-glycoproteins, RF was extracted from the central canal of juvenile rats and mice; to investigate the CSF-soluble proteins secreted by the SCO, CSF samples were collected from the cisterna magna of rats at different stages of development (from E18 to PN30). Results Five glycoproteins were identified in the rat SCO with apparent molecular weights of 630, 450, 390, 320 and 200 kDa. With the exception of the 200-kDa compound, all other compounds present in the rat SCO were also present in the mouse SCO. The 630 and 390 kDa compounds of the rat SCO have affinity for concanavalin A but not for wheat germ agglutinin, suggesting that they correspond to precursor forms. Four of the AFRU-immunoreactive compounds present in the SCO (630, 450, 390, 320 kDa) were absent from the RF and CSF. These may be precursor and/or partially processed forms. Two other compounds (200, 63 kDa) were present in SCO, RF and CSF and may be processed forms. The presence of these proteins in both, RF and CSF suggests a steady-state RF/CSF equilibrium for these compounds. Eight AFRU-immunoreactive bands were consistently found in CSF samples from rats at E18, E20 and PN1. Only four of these compounds were detected in the cisternal CSF of PN30 rats. The 200 kDa compound appears to be a key compound in rats since it was consistently found in all samples of SCO, RF and embryonic and juvenile CSF. Conclusion It is concluded that (i) during the late embryonic life, the rat SCO secretes compounds that remain soluble in the CSF and reach the subarachnoid space; (ii) during postnatal life, there is a reduction in the number and concentration of CSF-soluble proteins secreted by the SCO. The molecular structure and functional significance of these proteins remain to be elucidated. The possibility they are involved in brain development has been discussed. PMID:18218138

An update on the clinical diagnostic value of β-hCG and αFP for intracranial germ cell tumors.

PubMed

Hu, Mingming; Guan, Hongzhi; Lau, Ching C; Terashima, Keita; Jin, Zimeng; Cui, Liying; Wang, Yuzhou; Li, Guilin; Yao, Yong; Guo, Yi; Li, Yan Michael; Zhong, Dingrong; Xiao, Juan; Wan, Xirun; Lian, Xin; Feng, Feng; Ren, Haitao; Zhao, Yanhuan; Cheng, Xinqi; Gu, Feng

2016-03-12

Pathological examination combined with tumor markers has become a standard for the diagnosis of intracranial germ cell tumors (ICGCTs), but the current concept of 'secreting germ cell tumors' and three empirically highly specific diagnostic criteria (β-hCG ≥ 50 IU/L or αFP ≥ 10 ng/mL; β-hCG ≥ 100 IU/L or αFP ≥ 50 ng/mL; β-hCG > 50 IU/L or αFP > 25 ng/mL) are not based upon pathology examination or CSF cytology. Further investigation is needed to re-evaluate their value. A multidisciplinary diagnostic team was created. Valid β-hCG/αFP data were collected from cases of ICGCTs confirmed by pathology and CSF cytology (n = 58) between 1991 and 2012, and from suspected ICGCTs cases (n = 17) between 2011 and 2012 as controls [Langerhans cell histiocytosis (LCH), n = 12; and other intracranial tumor (ICT), n = 5]. The cut-off points for β-hCG and αFP were calculated using receiver operating characteristic (ROC) curves. This study clarifies the relative rationality of one criteria (β-hCG > 50 IU/L and αFP > 25 ng/mL); confirms new β-hCG diagnostic cut-off points: CSF β-hCG ≥ 8.2 IU/L and serum β-hCG ≥ 2.5 IU/L (sensitivity of 47 and 34%, respectively, specificity of 100%, both; P < 0.05); and empirically adjusts the criteria for αFP to ≥ 3.8 ng/mL in CSF and to ≥ 25 ng/mL in serum. The total diagnostic sensitivity for ICGCTs finally increased from 34.6 to 65.4% (P < 0.05, diagnostic value of CSF β-hCG exceeds 90%). Subtype diagnosis improved with αFP in 16.7% of non-geminomatous germ cell tumor cases. New evidence-based criteria of β-hCG and αFP can help improving early and formal diagnosis of ICGCTs, and is of great clinical significance.

Specific serum and CSF microRNA profiles distinguish sporadic behavioural variant of frontotemporal dementia compared with Alzheimer patients and cognitively healthy controls

PubMed Central

Oberhauser, Felix; Kornhuber, Johannes; Wiltfang, Jens; Fassbender, Klaus; Schroeter, Matthias L.; Volk, Alexander E.; Diehl-Schmid, Janine; Prudlo, Johannes; Danek, Adrian; Landwehrmeyer, Bernhard; Lauer, Martin; Otto, Markus; Jahn, Holger

2018-01-01

Information on circulating miRNAs in frontotemporal lobar degeneration is very limited and conflicting results have complicated an interpretation in Alzheimer’s disease thus far. In the present study we I) collected samples from multiple clinical centers across Germany, II) defined 3 homogenous patient groups with high sample sizes (bvFTD n = 48, AD n = 48 and cognitively healthy controls n = 44), III) compared expression levels in both CSF and serum samples and IV) detected a limited set of miRNAs by using a MIQE compliant protocol based on SYBR-green miRCURY assays that have proven reliable to generate reproducible results. We included several quality controls that identified and reduced technical variation to increase the reliability of our data. We showed that the expression levels of circulating miRNAs measured in CSF did not correlate with levels in serum. Using cluster analysis we found expression pattern in serum that, in part, reflects the genomic organization and affiliation to a specific miRNA family and that were specifically altered in bvFTD, AD, and control groups. Applying factor analysis we identified a 3-factor model characterized by a miRNA signature that explained 80% of the variance classifying healthy controls with 97%, bvFTD with 77% and AD with 72% accuracy. MANOVA confirmed signals like miR-320a and miR-26b-5p at BH corrected significance that contributed most to discriminate bvFTD cases with 96% sensitivity and 90% specificity and AD cases with 89% sensitivity and specificity compared to healthy controls, respectively. Correlation analysis revealed that miRNAs from the 3-factor model also correlated with levels of protein biomarker amyloid-beta1-42 and phosphorylated neurofilament heavy chain, indicating their potential role in the monitoring of progressive neuronal degeneration. Our data show that miRNAs can be reproducibly measured in serum and CSF without pre-amplification and that serum includes higher expressed signals that demonstrate an overall better ability to classify bvFTD, AD and healthy controls compared to signals detected in CSF. PMID:29746584

Enhanced cloning efficiency of mouse bone marrow macrophage progenitors correlates with increased content of CSF-1 receptor of their progeny at low oxygen tension.

PubMed

Flamant, Stéphane; Lebastard, Maï; Pescher, Pascale; Besmond, Claude; Milon, Geneviève; Marchal, Gilles

2003-10-01

Mononuclear phagocytes are located in every tissue of metazoan organisms. In this extravascular space, they are designated as macrophages and are known to sense and process many signals including the local oxygen tension (PO2), which ranges from 150 mmHg at the lung apices to around 40 mmHg in mixed venous blood and most organs, and to less than 10 mmHg in tissues where long-term and dynamic remodeling processes occur. Most tissue macrophages survive and maintain their differentiated status within an environment bathed by colony-stimulating factor (CSF)-1 through the CSF-1 receptor, encoded by the Csf1r gene. In order to investigate the mRNA expression profile of macrophages as a function of PO2, we developed an in vitro model in which monocyte-derived macrophages were generated from mouse bone marrow progenitor cells grown and maintained under low (36 mmHg) or atmospheric (142 mmHg) PO2, in the presence of L929-conditioned medium (L-CM) as a source of CSF-1. We show that CSF-1-reactive C57BL/6 bone marrow cells displayed an increased cloning efficiency under a PO2 of 36, compared with 142 mmHg. Furthermore, we provide evidence of the overexpression of both CSF-1 receptor protein and mRNA by mouse monocyte-derived macrophages generated from bone marrow under low PO2.

[Use of the methods of mathematical modeling for evaluation of the data of cerebrospinal fluid examination in patients with bacterial meningoencephalitis].

PubMed

Iarosh, O A; Iarosh, A A

1991-01-01

As many as 300 patients of different age groups underwent a probability statistical analysis of cytosis and CSF protein depending on the outcome of bacterial meningoencephalitis. The clinical and CSF interrelations discovered reflect the function of the blood-brain barrier and can be used as an additional test for predicting the disease outcome.

The Characterization and Treatment of Aggressive Breast Cancer

DTIC Science & Technology

2007-05-01

of febrile neutropenia , G- CSF should be given with the next cycle. For an episode of febrile neutropenia despite dose reduction and G-CSF, protocol...permitted, and should be documented. 5.2.3 The use of granulocyte colony stimulating agents should only be used if there is persistent neutropenia ... neutropenia , leukopenia, more pronounced in patients with compromised renal function Gastrointestinal: nausea and vomiting, treatable with moderate doses

Evaluation of the IS6110 PCR assay for the rapid diagnosis of tuberculous meningitis

PubMed Central

Deshpande, Poonam S; Kashyap, Rajpal S; Ramteke, Sonali S; Nagdev, Khushboo J; Purohit, Hemant J; Taori, Girdhar M; Daginawala, Hatim F

2007-01-01

Background Tuberculous meningitis (TBM) is one of the common clinical manifestations of extra-pulmonary tuberculosis. It is difficult to diagnose due to a lack of rapid, sensitive, and specific tests. Newer methods, which are easy and reliable, are required to diagnose TBM at an early stage. Thus our aim was to evaluate the polymerase chain reaction (PCR) technique, using primers directed against the IS6110 gene, for the detection of Mycobacterium tuberculosis in the CSF, for the diagnosis of TBM patients. Methods An in-house IS6110 PCR method using a specific pair of primers designed to amplify the insertion sequence, IS6110, in the M. tuberculosis genome was used to analyze CSF. A total of 80 CSF samples from different groups of patients were studied (confirmed TBM n = 35, clinically suspected TBM n = 16, non-TBM infectious meningitis n = 12, non infectious neurological diseases n = 17). Results PCR gave a sensitivity of 91.4% and specificity of 75.9% for the diagnosis of TBM in patients with TBM confirmed by culture. In 16 clinically diagnosed, but unconfirmed, TBM cases PCR was positive in 10 (62.5%) cases. There were seven (24.1%) PCR-positive cases among the 29 patients with non-TBM and non-infectious neurological disease. Conclusion We conclude that the performance of an in-house IS6110 PCR assay is valuable in the rapid diagnosis of tuberculous meningitis. PMID:17976247

Neuroprotective effects of recombinant human granulocyte colony-stimulating factor (G-CSF) in a rat model of anterior ischemic optic neuropathy (rAION).

PubMed

Chang, Chung-Hsing; Huang, Tzu-Lun; Huang, Shun-Ping; Tsai, Rong-Kung

2014-01-01

The purpose of this study was to investigate the neuroprotective effects of recombinant human granulocyte colony stimulating factor (G-CSF), as administered in a rat model of anterior ischemic optic neuropathy (rAION). Using laser-induced photoactivation of intravenously administered Rose Bengal in the optic nerve head of 60 adult male Wistar rats, an anterior ischemic optic neuropathy (rAION) was inducted. Rats either immediately received G-CSF (subcutaneous injections) or phosphate buffered saline (PBS) for 5 consecutive days. Rats were euthanized at 4 weeks post infarct. Density of retinal ganglion cells (RGCs) was counted using retrograde labeling of Fluoro-gold. Visual function was assessed by flash visual-evoked potentials (FVEP) at 4 weeks. TUNEL assay in the retinal sections and immunohistochemical staining of ED1 (marker of macrophage/microglia) were investigated in the optic nerve (ON) specimens. The RGC densities in the central and mid-peripheral retinas in the G-CSF treated rats were significantly higher than those of the PBS-treated rats (survival rate was 71.4% vs. 33.2% in the central retina; 61.8% vs. 22.7% in the mid-peripheral retina, respectively; both p < 0.05). FVEP measurements showed a significantly better preserved latency and amplitude of the p1 wave in the G-CSF-treated rats than that of the PBS-treated rats (latency120 ± 11 ms vs. 142 ± 12 ms, p = 0.03; amplitude 50 ± 11 μv vs. 31 ± 13 μv, p = 0.04). TUNEL assays showed fewer apoptotic cells in the retinal ganglion cell layers of G-CSF treated rats [2.1 ± 1.0 cells/high power field (HPF) vs. 8.0 ± 1.5/HPF; p = 0.0001]. In addition, the number of ED1 positive cells was attenuated at the optic nerve sections of G-CSF-treated rats (16 ± 6/HPF vs. 35 ± 10/HPF; p = 0.016). In conclusion, administration of G-CSF is neuroprotective in the rat model of anterior ischemic optic neuropathy, as demonstrated both structurally by RGC density and functionally by FVEP. G-CSF may work via the dual actions of anti-apoptosis for RGC surviving as well as anti-inflammation in the optic nerves as evidenced by less infiltration of ED1-povitive cells. Copyright © 2013 Elsevier Ltd. All rights reserved.

Fibronectin induces macrophage migration through a SFK-FAK/CSF-1R pathway.

PubMed

Digiacomo, Graziana; Tusa, Ignazia; Bacci, Marina; Cipolleschi, Maria Grazia; Dello Sbarba, Persio; Rovida, Elisabetta

2017-07-04

Integrins, following binding to proteins of the extracellular matrix (ECM) including collagen, laminin and fibronectin (FN), are able to transduce molecular signals inside the cells and to regulate several biological functions such as migration, proliferation and differentiation. Besides activation of adaptor molecules and kinases, integrins transactivate Receptor Tyrosine Kinases (RTK). In particular, adhesion to the ECM may promote RTK activation in the absence of growth factors. The Colony-Stimulating Factor-1 Receptor (CSF-1R) is a RTK that supports the survival, proliferation, and motility of monocytes/macrophages, which are essential components of innate immunity and cancer development. Macrophage interaction with FN is recognized as an important aspect of host defense and wound repair. The aim of the present study was to investigate on a possible cross-talk between FN-elicited signals and CSF-1R in macrophages. FN induced migration in BAC1.2F5 and J774 murine macrophage cell lines and in human primary macrophages. Adhesion to FN determined phosphorylation of the Focal Adhesion Kinase (FAK) and Src Family Kinases (SFK) and activation of the SFK/FAK complex, as witnessed by paxillin phosphorylation. SFK activity was necessary for FAK activation and macrophage migration. Moreover, FN-induced migration was dependent on FAK in either murine macrophage cell lines or human primary macrophages. FN also induced FAK-dependent/ligand-independent CSF-1R phosphorylation, as well as the interaction between CSF-1R and β1. CSF-1R activity was necessary for FN-induced macrophage migration. Indeed, genetic or pharmacological inhibition of CSF-1R prevented FN-induced macrophage migration. Our results identified a new SFK-FAK/CSF-1R signaling pathway that mediates FN-induced migration of macrophages.

G-CSF treatment after myocardial infarction: impact on bone marrow-derived vs cardiac progenitor cells.

PubMed

Brunner, Stefan; Huber, Bruno C; Fischer, Rebekka; Groebner, Michael; Hacker, Marcus; David, Robert; Zaruba, Marc-Michael; Vallaster, Marcus; Rischpler, Christoph; Wilke, Andrea; Gerbitz, Armin; Franz, Wolfgang-Michael

2008-06-01

Besides its classical function in the field of autologous and allogenic stem cell transplantation, granulocyte colony-stimulating factor (G-CSF) was shown to have protective effects after myocardial infarction (MI) by mobilization of bone marrow-derived progenitor cells (BMCs) and in addition by activation of multiple signaling pathways. In the present study, we focused on the impact of G-CSF on migration of BMCs and the impact on resident cardiac cells after MI. Mice (C57BL/6J) were sublethally irradiated, and BM from green fluorescent protein (GFP)-transgenic mice was transplanted. Coronary artery ligation was performed 10 weeks later. G-CSF (100 microg/kg) was daily injected for 6 days. Subpopulations of enhanced GFP(+) cells in peripheral blood, bone marrow, and heart were characterized by flow cytometry. Growth factor expression in the heart was analyzed by quantitative real-time polymerase chain reaction. Perfusion was investigated in vivo by gated single photon emission computed tomography (SPECT). G-CSF-treated animals revealed a reduced migration of c-kit(+) and CXCR-4(+) BMCs associated with decreased expression levels of the corresponding growth factors, namely stem cell factor and stromal-derived factor-1 alpha in ischemic myocardium. In contrast, the number of resident cardiac Sca-1(+) cells was significantly increased. However, SPECT-perfusion showed no differences in infarct size between G-CSF-treated and control animals 6 days after MI. Our study shows that G-CSF treatment after MI reduces migration capacity of BMCs into ischemic tissue, but increases the number of resident cardiac cells. To optimize homing capacity a combination of G-CSF with other agents may optimize cytokine therapy after MI.

Cell to cell contact through ICAM-1-LFA-1 and TNF-alpha synergistically contributes to GM-CSF and subsequent cytokine synthesis in DBA/2 mice induced by 1,3-beta-D-Glucan SCG.

PubMed

Harada, Toshie; Kawaminami, Hiromi; Miura, Noriko N; Adachi, Yoshiyuki; Nakajima, Mitsuhiro; Yadomae, Toshiro; Ohno, Naohito

2006-04-01

SCG is a major 6-branched 1,3-beta-D-glucan in Sparassis crispa Fr. showing antitumor activity. We recently found that the splenocytes from naive DBA/1 and DBA/2 mice are potently induced by SCG to produce interferon- gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-12p70 (IL-12p70), and that GM-CSF plays a key biologic role among these cytokines. In this study, we investigated the contribution of cell-cell contact and soluble factors to cytokine induction by SCG in DBA/2 mice. Cell-cell contact involving intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) was an essential step for the induction of GM-CSF and IFN-gamma by SCG but not for the induction of TNF-alpha or IL-12p70 by SCG. SCG directly induced adherent splenocytes to produce TNF-alpha and IL-12p70. GM-CSF was required for the induction of TNF-alpha by SCG, and in turn, TNF-alpha enhanced the release of GM-CSF and thereby augmented the induction of IL-12p70 and IFN-gamma by SCG. Neutralization of IL-12 significantly inhibited the induction of IFN-gamma by SCG. We concluded that induction of GM-CSF production by SCG was mediated through ICAM-1 and LFA-1 interaction, GM-CSF subsequently contributed to further cytokine induction by SCG, and reciprocal actions of the cytokines were essential for enhancement of the overall response to SCG in DBA/2 mice.

Validity and Normative Data for the Biber Figure Learning Test: A Visual Supraspan Memory Measure.

PubMed

Gifford, Katherine A; Liu, Dandan; Neal, Jacquelyn E; Acosta, Lealani Mae Y; Bell, Susan P; Wiggins, Margaret E; Wisniewski, Kristi M; Godfrey, Mary; Logan, Laura A; Hohman, Timothy J; Pechman, Kimberly R; Libon, David J; Blennow, Kaj; Zetterberg, Henrik; Jefferson, Angela L

2018-05-01

The Biber Figure Learning Test (BFLT), a visuospatial serial figure learning test, was evaluated for biological correlates and psychometric properties, and normative data were generated. Nondemented individuals ( n = 332, 73 ± 7, 41% female) from the Vanderbilt Memory & Aging Project completed a comprehensive neuropsychological protocol. Adjusted regression models related BFLT indices to structural brain magnetic resonance imaging and cerebrospinal fluid (CSF) markers of brain health. Regression-based normative data were generated. Lower BFLT performances (Total Learning, Delayed Recall, Recognition) related to smaller medial temporal lobe volumes and higher CSF tau concentrations but not CSF amyloid. BFLT indices were most strongly correlated with other measures of verbal and nonverbal memory and visuospatial skills. The BFLT provides a comprehensive assessment of all aspects of visuospatial learning and memory and is sensitive to biomarkers of unhealthy brain aging. Enhanced normative data enriches the clinical utility of this visual serial figure learning test for use with older adults.

Detection and genotyping of enteroviruses in cerebrospinal fluid in patients in Victoria, Australia, 2007-2013.

PubMed

Papadakis, Georgina; Chibo, Doris; Druce, Julian; Catton, Michael; Birch, Chris

2014-09-01

Genotyping by VP1 fragment polymerase chain reaction (PCR) and nucleic acid sequencing to detect enterovirus (EV) genotypes was performed directly on 729 EV PCR positive cerebrospinal fluid (CSF) samples collected between 2007 and 2012 from Victorian hospital inpatients. The overall genotype identification rate from CSF-positive material was 43%. The four most common genotypes identified were Echovirus 6 (24%), Echovirus 30 (17%), Echovirus 25 (10%), and Coxsackievirus A9 (10%), together comprising 61% of all EVs typed. The seasonal distribution of all EVs identified followed the recognized pattern of mainly summer epidemics. Three of the four predominant genotypes were present in each of the 6 years in which the study was conducted, with 20 other EV genotypes also detected, often in only a single year. Genotyping of EVs directly in CSF is faster, simpler and more sensitive than traditional virus neutralization assays performed on EV positive samples. © 2014 Wiley Periodicals, Inc.

A novel and highly sensitive real-time nested RT-PCR assay in a single closed tube for detection of enterovirus.

PubMed

Shen, Xin-Xin; Qiu, Fang-Zhou; Zhao, Huai-Long; Yang, Meng-Jie; Hong, Liu; Xu, Song-Tao; Zhou, Shuai-Feng; Li, Gui-Xia; Feng, Zhi-Shan; Ma, Xue-Jun

2018-03-01

The sensitivity of qRT-PCR assay is not adequate for the detection of the samples with lower viral load, particularly in the cerebrospinal fluid (CSF) of patients. Here, we present the development of a highly sensitive real-time nested RT-PCR (RTN RT-PCR) assay in a single closed tube for detection of human enterovirus (HEV). The clinical performance of both RTN RT-PCR and qRT-PCR was also tested and compared using 140 CSF and fecal specimens. The sensitivities of RTN RT-PCR assay for EV71, Coxsackievirus A (CVA)16, CVA6 and CVA10 achieved 10 -8 dilution with a corresponding Ct value of 38.20, 36.45, 36.75, and 36.45, respectively, which is equal to traditional two-step nested RT-PCR assay and approximately 2-10-fold lower than that of qRT-PCR assay. The specificity of RTN RT-PCR assay was extensively analyzed insilico and subsequently verified using the reference isolates and clinical samples. Sixteen qRT-PCR-negative samples were detected by RTN RT-PCR and a variety of enterovirus serotypes was identified by sequencing of inner PCR products. We conclude RTN RT-PCR is more sensitive than qRT-PCR for the detection of HEV in clinical samples. Copyright © 2017 Elsevier Inc. All rights reserved.

Statistically Derived Subtypes and Associations with Cerebrospinal Fluid and Genetic Biomarkers in Mild Cognitive Impairment: A Latent Profile Analysis.

PubMed

Eppig, Joel S; Edmonds, Emily C; Campbell, Laura; Sanderson-Cimino, Mark; Delano-Wood, Lisa; Bondi, Mark W

2017-08-01

Research demonstrates heterogeneous neuropsychological profiles among individuals with mild cognitive impairment (MCI). However, few studies have included visuoconstructional ability or used latent mixture modeling to statistically identify MCI subtypes. Therefore, we examined whether unique neuropsychological MCI profiles could be ascertained using latent profile analysis (LPA), and subsequently investigated cerebrospinal fluid (CSF) biomarkers, genotype, and longitudinal clinical outcomes between the empirically derived classes. A total of 806 participants diagnosed by means of the Alzheimer's Disease Neuroimaging Initiative (ADNI) MCI criteria received a comprehensive neuropsychological battery assessing visuoconstructional ability, language, attention/executive function, and episodic memory. Test scores were adjusted for demographic characteristics using standardized regression coefficients based on "robust" normal control performance (n=260). Calculated Z-scores were subsequently used in the LPA, and CSF-derived biomarkers, genotype, and longitudinal clinical outcome were evaluated between the LPA-derived MCI classes. Statistical fit indices suggested a 3-class model was the optimal LPA solution. The three-class LPA consisted of a mixed impairment MCI class (n=106), an amnestic MCI class (n=455), and an LPA-derived normal class (n=245). Additionally, the amnestic and mixed classes were more likely to be apolipoprotein e4+ and have worse Alzheimer's disease CSF biomarkers than LPA-derived normal subjects. Our study supports significant heterogeneity in MCI neuropsychological profiles using LPA and extends prior work (Edmonds et al., 2015) by demonstrating a lower rate of progression in the approximately one-third of ADNI MCI individuals who may represent "false-positive" diagnoses. Our results underscore the importance of using sensitive, actuarial methods for diagnosing MCI, as current diagnostic methods may be over-inclusive. (JINS, 2017, 23, 564-576).

Peripheral myopization and visual performance with experimental rigid gas permeable and soft contact lens design.

PubMed

Pauné, J; Queiros, A; Quevedo, L; Neves, H; Lopes-Ferreira, D; González-Méijome, J M

2014-12-01

To evaluate the performance of two experimental contact lenses (CL) designed to induce relative peripheral myopic defocus in myopic eyes. Ten right eyes of 10 subjects were fitted with three different CL: a soft experimental lens (ExpSCL), a rigid gas permeable experimental lens (ExpRGP) and a standard RGP lens made of the same material (StdRGP). Central and peripheral refraction was measured using a Grand Seiko open-field autorefractometer across the central 60° of the horizontal visual field. Ocular aberrations were measured with a Hartman-Shack aberrometer, and monocular contrast sensitivity function (CSF) was measured with a VCTS6500 without and with the three contact lenses. Both experimental lenses were able to increase significantly the relative peripheral myopic defocus up to -0.50 D in the nasal field and -1.00 D in the temporal field (p<0.05). The ExpRGP induced a significantly higher myopic defocus in the temporal field compared to the ExpSCL. ExpSCL induced significantly lower levels of Spherical-like HOA than ExpRGP for the 5mm pupil size (p<0.05). Both experimental lenses kept CSF within normal limits without any statistically significant change from baseline (p>0.05). RGP lens design seems to be more effective to induce a significant myopic change in the relative peripheral refractive error. Both lenses preserve a good visual performance. The worsened optical quality observed in ExpRGP was due to an increased coma-like and spherical-like HOA. However, no impact on the visual quality as measured by CSF was observed. Copyright © 2014 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

Optimal-mass-transfer-based estimation of glymphatic transport in living brain

NASA Astrophysics Data System (ADS)

Ratner, Vadim; Zhu, Liangjia; Kolesov, Ivan; Nedergaard, Maiken; Benveniste, Helene; Tannenbaum, Allen

2015-03-01

It was recently shown that the brain-wide cerebrospinal fluid (CSF) and interstitial fluid exchange system designated the `glymphatic pathway' plays a key role in removing waste products from the brain, similarly to the lymphatic system in other body organs . It is therefore important to study the flow patterns of glymphatic transport through the live brain in order to better understand its functionality in normal and pathological states. Unlike blood, the CSF does not flow rapidly through a network of dedicated vessels, but rather through para-vascular channels and brain parenchyma in a slower time-domain, and thus conventional fMRI or other blood-flow sensitive MRI sequences do not provide much useful information about the desired flow patterns. We have accordingly analyzed a series of MRI images, taken at different times, of the brain of a live rat, which was injected with a paramagnetic tracer into the CSF via the lumbar intrathecal space of the spine. Our goal is twofold: (a) find glymphatic (tracer) flow directions in the live rodent brain; and (b) provide a model of a (healthy) brain that will allow the prediction of tracer concentrations given initial conditions. We model the liquid flow through the brain by the diffusion equation. We then use the Optimal Mass Transfer (OMT) approach to derive the glymphatic flow vector field, and estimate the diffusion tensors by analyzing the (changes in the) flow. Simulations show that the resulting model successfully reproduces the dominant features of the experimental data. Keywords: inverse problem, optimal mass transport, diffusion equation, cerebrospinal fluid flow in brain, optical flow, liquid flow modeling, Monge Kantorovich problem, diffusion tensor estimation

The Closely Related CD103+ Dendritic Cells (DCs) and Lymphoid-Resident CD8+ DCs Differ in Their Inflammatory Functions

PubMed Central

Jiao, Zhijun; Bedoui, Sammy; Brady, Jamie L.; Walter, Anne; Chopin, Michael; Carrington, Emma M.; Sutherland, Robyn M.; Nutt, Stephen L.; Zhang, Yuxia; Ko, Hyun-Ja; Wu, Li

2014-01-01

Migratory CD103+ and lymphoid-resident CD8+ dendritic cells (DCs) share many attributes, such as dependence on the same transcription factors, cross-presenting ability and expression of certain surface molecules, such that it has been proposed they belong to a common sub-lineage. The functional diversity of the two DC types is nevertheless incompletely understood. Here we reveal that upon skin infection with herpes simplex virus, migratory CD103+ DCs from draining lymph nodes were more potent at inducing Th17 cytokine production by CD4+ T cells than CD8+ DCs. This superior capacity to drive Th17 responses was also evident in CD103+ DCs from uninfected mice. Their differential potency to induce Th17 differentiation was reflected by higher production of IL-1β and IL-6 by CD103+ DCs compared with CD8+ DCs upon stimulation. The two types of DCs from isolated lymph nodes also differ in expression of certain pattern recognition receptors. Furthermore, elevated levels of GM-CSF, typical of those found in inflammation, substantially increased the pool size of CD103+ DCs in lymph nodes and skin. We argue that varied levels of GM-CSF may explain the contrasting reports regarding the positive role of GM-CSF in regulating development of CD103+ DCs. Together, we find that these two developmentally closely-related DC subsets display functional differences and that GM-CSF has differential effect on the two types of DCs. PMID:24637385

Oxidation-induced Structural Changes of Ceruloplasmin Foster NGR Motif Deamidation That Promotes Integrin Binding and Signaling

PubMed Central

Barbariga, Marco; Curnis, Flavio; Spitaleri, Andrea; Andolfo, Annapaola; Zucchelli, Chiara; Lazzaro, Massimo; Magnani, Giuseppe; Musco, Giovanna; Corti, Angelo; Alessio, Massimo

2014-01-01

Asparagine deamidation occurs spontaneously in proteins during aging; deamidation of Asn-Gly-Arg (NGR) sites can lead to the formation of isoAsp-Gly-Arg (isoDGR), a motif that can recognize the RGD-binding site of integrins. Ceruloplasmin (Cp), a ferroxidase present in the cerebrospinal fluid (CSF), contains two NGR sites in its sequence: one exposed on the protein surface (568NGR) and the other buried in the tertiary structure (962NGR). Considering that Cp can undergo oxidative modifications in the CSF of neurodegenerative diseases, we investigated the effect of oxidation on the deamidation of both NGR motifs and, consequently, on the acquisition of integrin binding properties. We observed that the exposed 568NGR site can deamidate under conditions mimicking accelerated Asn aging. In contrast, the hidden 962NGR site can deamidate exclusively when aging occurs under oxidative conditions, suggesting that oxidation-induced structural changes foster deamidation at this site. NGR deamidation in Cp was associated with gain of integrin-binding function, intracellular signaling, and cell pro-adhesive activity. Finally, Cp aging in the CSF from Alzheimer disease patients, but not in control CSF, causes Cp deamidation with gain of integrin-binding function, suggesting that this transition might also occur in pathological conditions. In conclusion, both Cp NGR sites can deamidate during aging under oxidative conditions, likely as a consequence of oxidative-induced structural changes, thereby promoting a gain of function in integrin binding, signaling, and cell adhesion. PMID:24366863

Macrophage colony-stimulating factor accelerates wound healing and upregulates TGF-beta1 mRNA levels through tissue macrophages.

PubMed

Wu, L; Yu, Y L; Galiano, R D; Roth, S I; Mustoe, T A

1997-10-01

Macrophage colony-stimulating factor (M-CSF) is produced by many cell types involved in wound repair, yet it acts specifically on monocytes and macrophages. The monocyte-derived cell is thought to be important in wound healing, but the importance of the role of tissue macrophages in wound healing has not been well defined. Dermal ulcers were created in normal and ischemic ears of young rabbits. Either rhM-CSF (17 microg/wound) or buffer was applied to each wound. Wounds were bisected and analyzed histologically at Days 7 and 10 postwounding. The amounts of epithelial growth and granulation tissue deposition were measured in all wounds. The level of increase of TGF-beta1 mRNA level in M-CSF-treated wounds was examined using competitive RT-PCR. M-CSF increased new granulation tissue formation by 37% (N = 21, P < 0.01) and 50% (P < 0.01) after single and multiple treatments, respectively, in nonischemic wounds. TGF-beta1 mRNA levels in rhM-CSF-treated wounds increased 5.01-fold (N = 8) over vehicle-treated wounds under nonischemic conditions. In contrast, no effect could be detected in ischemic wounds treated with rhM-CSF, and these wounds only showed a 1.66-fold increase in TGF-beta1 mRNA levels when compared to ischemic wounds treated with vehicle alone. GAPDH, a housekeeping gene, showed no change. As mesenchymal cells lack receptors for M-CSF, the improved healing of wounds treated with topical rhM-CSF must reflect a generalized enhancement of activation and function of tissue macrophages, as demonstrated by upregulation of TGF-beta. The lack of effect under ischemic conditions suggests that either macrophage activity and/or response to M-CSF is adversely affected under those conditions; this may suggest the pathogenesis of impaired wound healing at the cellular level. Copyright 1997 Academic Press.

Peptide fingerprinting of Alzheimer's disease in cerebrospinal fluid: identification and prospective evaluation of new synaptic biomarkers.

PubMed

Jahn, Holger; Wittke, Stefan; Zürbig, Petra; Raedler, Thomas J; Arlt, Sönke; Kellmann, Markus; Mullen, William; Eichenlaub, Martin; Mischak, Harald; Wiedemann, Klaus

2011-01-01

Today, dementias are diagnosed late in the course of disease. Future treatments have to start earlier in the disease process to avoid disability requiring new diagnostic tools. The objective of this study is to develop a new method for the differential diagnosis and identification of new biomarkers of Alzheimer's disease (AD) using capillary-electrophoresis coupled to mass-spectrometry (CE-MS) and to assess the potential of early diagnosis of AD. Cerebrospinal fluid (CSF) of 159 out-patients of a memory-clinic at a University Hospital suffering from neurodegenerative disorders and 17 cognitively-healthy controls was used to create differential peptide pattern for dementias and prospective blinded-comparison of sensitivity and specificity for AD diagnosis against the Criterion standard in a naturalistic prospective sample of patients. Sensitivity and specificity of the new method compared to standard diagnostic procedures and identification of new putative biomarkers for AD was the main outcome measure. CE-MS was used to reliably detect 1104 low-molecular-weight peptides in CSF. Training-sets of patients with clinically secured sporadic Alzheimer's disease, frontotemporal dementia, and cognitively healthy controls allowed establishing discriminative biomarker pattern for diagnosis of AD. This pattern was already detectable in patients with mild cognitive impairment (MCI). The AD-pattern was tested in a prospective sample of patients (n = 100) and AD was diagnosed with a sensitivity of 87% and a specificity of 83%. Using CSF measurements of beta-amyloid1-42, total-tau, and phospho(181)-tau, AD-diagnosis had a sensitivity of 88% and a specificity of 67% in the same sample. Sequence analysis of the discriminating biomarkers identified fragments of synaptic proteins like proSAAS, apolipoprotein J, neurosecretory protein VGF, phospholemman, and chromogranin A. The method may allow early differential diagnosis of various dementias using specific peptide fingerprints and identification of incipient AD in patients suffering from MCI. Identified biomarkers facilitate face validity for the use in AD diagnosis.

A specific, nonproliferative role for E2F-5 in choroid plexus function revealed by gene targeting

PubMed Central

Lindeman, Geoffrey J.; Dagnino, Lina; Gaubatz, Stefan; Xu, Yuhui; Bronson, Roderick T.; Warren, Henry B.; Livingston, David M.

1998-01-01

Homozygous E2F-5 knockout embryos and mice have been generated. Although embryonic development appeared normal, newborn mice developed nonobstructive hydrocephalus, suggesting excessive cerebrospinal fluid (CSF) production. Although the CSF-producing choroid plexus displayed normal cellular organization, it contained abundant electron-lucent epithelial cells, consistent with excessive CSF secretory activity. Moreover, E2F-5 CNS expression in normal animals was largely confined to the choroid plexus. Cell cycle kinetics were not perturbed in homozygous knockout embryo fibroblasts. Thus, E2F-5 is not essential for cell proliferation. Rather, it affects the secretory behavior of a differentiated neural tissue. PMID:9553039