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1.  Specific Investigation of Sample Handling Effects on Protease Activities and Absolute Serum Concentrations of Various Putative Peptidome Cancer Biomarkers 
Clinical Proteomics  2010;6(4):115-127.
Introduction
In the search for novel cancer biomarkers, various proteolytically derived peptides have been proposed to exhibit cancer or cancer-type specificity. As these peptides are presumably also generated after sample collection by tumor-specific proteases, extensive investigation of the involved proteolytic processes is crucial for further research.
Materials and Methods
Using two previously developed and fully validated liquid-chromatography coupled to tandem-mass spectrometry assays, absolute quantification of, in total, 13 proteolytically derived peptides in human serum was accomplished. The analytes included eight peptides derived from inter-α-trypsin inhibitor heavy chain-4 (ITIH4-30, ITIH4-29, ITIH4-28, ITIH4-27, ITIH4-26, ITIH4-25, ITIH4-22, and ITIH4-21), bradykinin, des-Arg9-bradykinin, Hyp3-bradykinin, and fragments from fibrinogen-α-chain (Fib-α [605–629]) and complement component 4a (C4a [1337–1350]). Samples were obtained from different healthy individuals and prepared with variable tube types, clotting times, and temperatures. Furthermore, stabilities in the serum fraction were assessed and compared to stabilities in serum from breast cancer patients.
Results and Discussion
The quantitative analyses showed either increasing or decreasing serum concentrations during blood coagulation, while comparable effects were observed in serum separated from the blood clot. Furthermore, comparisons of inter- and intra-individual variations suggested better reflection of an individual’s protease activity after prolonged ex vivo incubation. This was illustrated for the putative breast cancer marker ITIH4-22, revealing better differentiation after incubation of serum at ambient temperature for 24 h.
Conclusion
The presented study provides suggestions for more specific and optimized sample preparation, as well as extended knowledge necessary to further explore the opportunities of these proteolytic peptides as cancer biomarkers.
doi:10.1007/s12014-010-9054-z
PMCID: PMC2970821  PMID: 21124649
Biomarker; Cancer; Protease activity; LC-MS/MS; Peptide; Sample handling
2.  Frequent expression loss of Inter-alpha-trypsin inhibitor heavy chain (ITIH) genes in multiple human solid tumors: A systematic expression analysis 
BMC Cancer  2008;8:25.
Background
The inter-alpha-trypsin inhibitors (ITI) are a family of plasma protease inhibitors, assembled from a light chain – bikunin, encoded by AMBP – and five homologous heavy chains (encoded by ITIH1, ITIH2, ITIH3, ITIH4, and ITIH5), contributing to extracellular matrix stability by covalent linkage to hyaluronan. So far, ITIH molecules have been shown to play a particularly important role in inflammation and carcinogenesis.
Methods
We systematically investigated differential gene expression of the ITIH gene family, as well as AMBP and the interacting partner TNFAIP6 in 13 different human tumor entities (of breast, endometrium, ovary, cervix, stomach, small intestine, colon, rectum, lung, thyroid, prostate, kidney, and pancreas) using cDNA dot blot analysis (Cancer Profiling Array, CPA), semiquantitative RT-PCR and immunohistochemistry.
Results
We found that ITIH genes are clearly downregulated in multiple human solid tumors, including breast, colon and lung cancer. Thus, ITIH genes may represent a family of putative tumor suppressor genes that should be analyzed in greater detail in the future. For an initial detailed analysis we chose ITIH2 expression in human breast cancer. Loss of ITIH2 expression in 70% of cases (n = 50, CPA) could be confirmed by real-time PCR in an additional set of breast cancers (n = 36). Next we studied ITIH2 expression on the protein level by analyzing a comprehensive tissue micro array including 185 invasive breast cancer specimens. We found a strong correlation (p < 0.001) between ITIH2 expression and estrogen receptor (ER) expression indicating that ER may be involved in the regulation of this ECM molecule.
Conclusion
Altogether, this is the first systematic analysis on the differential expression of ITIH genes in human cancer, showing frequent downregulation that may be associated with initiation and/or progression of these malignancies.
doi:10.1186/1471-2407-8-25
PMCID: PMC2268946  PMID: 18226209
3.  Hyaluronan and Hyaluronan Binding Proteins Are Normal Components of Mouse Pancreatic Islets and Are Differentially Expressed by Islet Endocrine Cell Types 
The pancreatic islet comprises endocrine, vascular, and neuronal cells. Signaling among these cell types is critical for islet function. The extracellular matrix (ECM) is a key regulator of cell-cell signals, and while some islet ECM components have been identified, much remains unknown regarding its composition. We investigated whether hyaluronan, a common ECM component that may mediate inflammatory events, and molecules that bind hyaluronan such as versican, tumor necrosis factor–stimulated gene 6 (TSG-6), and components of inter-α-trypsin inhibitor (IαI), heavy chains 1 and 2 (ITIH1/ITIH2), and bikunin, are normally produced in the pancreatic islet. Mouse pancreata and isolated islets were obtained for microscopy (with both paraformaldehyde and Carnoy’s fixation) and mRNA. Hyaluronan was present predominantly in the peri-islet ECM, and hyaluronan synthase isoforms 1 and 3 were also expressed in islets. Versican was produced in α cells; TSG-6 in α and β cells; bikunin in α, β, and δ cells; and ITIH1/ITIH2 predominantly in β cells. Our findings demonstrate that hyaluronan, versican, TSG-6, and IαI are normal islet components and that different islet endocrine cell types contribute these ECM components. Thus, dysfunction of either α or β cells likely alters islet ECM composition and could thereby further disrupt islet function.
doi:10.1369/0022155412457048
PMCID: PMC3524560  PMID: 22821669
extracellular matrix; hyaluronan; islet; proteoglycan
4.  Hyaluronan and Hyaluronan Binding Proteins Are Normal Components of Mouse Pancreatic Islets and Are Differentially Expressed by Islet Endocrine Cell Types 
The pancreatic islet comprises endocrine, vascular, and neuronal cells. Signaling among these cell types is critical for islet function. The extracellular matrix (ECM) is a key regulator of cell-cell signals, and while some islet ECM components have been identified, much remains unknown regarding its composition. We investigated whether hyaluronan, a common ECM component that may mediate inflammatory events, and molecules that bind hyaluronan such as versican, tumor necrosis factor–stimulated gene 6 (TSG-6), and components of inter-α-trypsin inhibitor (IαI), heavy chains 1 and 2 (ITIH1/ITIH2), and bikunin, are normally produced in the pancreatic islet. Mouse pancreata and isolated islets were obtained for microscopy (with both paraformaldehyde and Carnoy’s fixation) and mRNA. Hyaluronan was present predominantly in the peri-islet ECM, and hyaluronan synthase isoforms 1 and 3 were also expressed in islets. Versican was produced in α cells; TSG-6 in α and β cells; bikunin in α, β, and δ cells; and ITIH1/ITIH2 predominantly in β cells. Our findings demonstrate that hyaluronan, versican, TSG-6, and IαI are normal islet components and that different islet endocrine cell types contribute these ECM components. Thus, dysfunction of either α or β cells likely alters islet ECM composition and could thereby further disrupt islet function.
doi:10.1369/0022155412457048
PMCID: PMC3524560  PMID: 22821669
extracellular matrix; hyaluronan; islet; proteoglycan
5.  Aberrant DNA hypermethylation of the ITIH5 tumor suppressor gene in acute myeloid leukemia 
Clinical Epigenetics  2011;2(2):419-423.
Epigenetic mechanisms such as DNA hypermethylation and modifications of histone amino acids are known to play an important role in the control of gene expression both in normal human development and tumorigenesis. Hypermethylation of CpG islands within promoter regions of tumor suppressor genes is associated with transcriptional inactivation and represents, in addition to genetic aberrations, an important mechanism of gene silencing in the pathogenesis of human cancer. Inter-α-trypsine inhibitors (ITIs) are a family of serine protease inhibitors consisting of one light chain (bikunin) and two heavy chains (ITI heavy chains, ITIHs). ITIHs stabilize the extracellular matrix (ECM) by interacting with hyaluronic acid, which is a major ECM component. Hypermethylation in the upstream region of the promoter-associated CpG island of ITIH5, the most recently described member of the ITIH family, has been previously detected in breast cancer and was associated with an adverse outcome. In this study, we determined the DNA methylation status of the promoter region near the transcription start site of the ITIH5 tumor suppressor gene in leukemia cell lines and primary samples from patients with acute myeloid leukemia (AML) as well as the potential use of demethylating agents to restore a demethylated state of the promoter. Aberrant ITIH5 promoter hypermethylation occurred in 15 of 104 (14.4%) diagnostic AML samples. There were no statistically significant correlations between the ITIH5 methylation status and clinical prognostic parameters. Our results indicate that aberrant ITIH5 promoter hypermethylation is a novel epigenetic event in AML.
doi:10.1007/s13148-011-0043-5
PMCID: PMC3365397  PMID: 22704354
DNA hypermethylation; Epigenetics; Acute myeloid leukemia; Inter-α-trypsine inhibitor; Tumor suppressor gene
6.  ITIH4 (Inter-Alpha-Trypsin Inhibitor Heavy Chain 4) Is a New Acute-Phase Protein Isolated from Cattle during Experimental Infection  
Infection and Immunity  2004;72(7):3777-3782.
We have isolated from calf serum a protein with an apparent Mr of 120,000. The protein was detected by using antibodies against major acute-phase protein in pigs with acute inflammation. The amino acid sequence of an internal fragment revealed that this protein is the bovine counterpart of ITIH4, the heavy chain 4 of the inter-alpha-trypsin inhibitor family. The response of this protein in the sera was determined for animals during experimental bacterial and viral infections. In the bacterial model, animals were inoculated with a mixture of Actinomyces pyogenes, Fusobacterium necrophorum, and Peptostreptococcus indolicus to induce an acute-phase reaction. All animals developed moderate to severe clinical mastitis and exhibited remarkable increases in ITIH4 concentration in serum (from 3 to 12 times the initial values, peaking at 48 to 72 h after infection) that correlated with the severity of the disease. Animals with experimental infections with bovine respiratory syncytial virus (BRSV) also showed increases in ITIH4 concentration (from two- to fivefold), which peaked at around 7 to 8 days after inoculation. Generally, no response was seen after a second infection of the same animals with the virus. Because of the significant induction of the protein in the animals in the mastitis and BRSV infection models, we can conclude that ITIH4 is a new positive acute-phase protein in cattle.
doi:10.1128/IAI.72.7.3777-3782.2004
PMCID: PMC427401  PMID: 15213118
7.  Isolation and Characterization of the Promoter and Partial Enhancer Region of the Porcine Inter-α-Trypsin Inhibitor Heavy Chain 4 Gene 
A porcine genomic library was screened for clones containing the promoter of the major acute-phase protein in pigs, inter-α-trypsin heavy chain 4 (ITIH4). Following isolation of the promoter, a functional analysis was performed with Hep3B cells. The promoter was induced by interleukin-6 (IL-6) but not by IL-1β. However, IL-1β was shown to inhibit the IL-6-induced activation of the porcine ITIH4 promoter.
doi:10.1128/CDLI.12.11.1336-1339.2005
PMCID: PMC1287766  PMID: 16275952
8.  Patients with ovarian carcinoma excrete different altered levels of urine CD59, kininogen-1 and fragments of inter-alpha-trypsin inhibitor heavy chain H4 and albumin 
Proteome Science  2010;8:58.
Background
Diagnosis of ovarian carcinoma is in urgent need for new complementary biomarkers for early stage detection. Proteins that are aberrantly excreted in the urine of cancer patients are excellent biomarker candidates for development of new noninvasive protocol for early diagnosis and screening purposes. In the present study, urine samples from patients with ovarian carcinoma were analysed by two-dimensional gel electrophoresis and the profiles generated were compared to those similarly obtained from age-matched cancer negative women.
Results
Significant reduced levels of CD59, kininogen-1 and a 39 kDa fragment of inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4), and enhanced excretion of a 19 kDa fragment of albumin, were detected in the urine of patients with ovarian carcinoma compared to the control subjects. The different altered levels of the proteins were confirmed by Western blotting using antisera and a lectin that bind to the respective proteins.
Conclusion
CD59, kininogen-1 and fragments of ITIH4 and albumin may be used as complementary biomarkers in the development of new noninvasive protocols for diagnosis and screening of ovarian carcinoma.
doi:10.1186/1477-5956-8-58
PMCID: PMC2998473  PMID: 21083881
9.  Clinical outcome following acute ischaemic stroke relates to both activation and autoregulatory inhibition of cytokine production 
BMC Neurology  2007;7:5.
Background
As critical mediators of local and systemic inflammatory responses, cytokines are produced in the brain following ischaemic stroke. Some have been detected in the circulation of stroke patients, but their role and source is unclear. Focusing primarily on interleukin(IL)-1-related mechanisms, we serially measured plasma inflammatory markers, and the production of cytokines by whole blood, from 36 patients recruited within 12 h and followed up to 1 year after acute ischaemic stroke (AIS).
Results
Admission plasma IL-1 receptor antagonist (IL-1ra) concentration was elevated, relative to age-, sex-, and atherosclerosis-matched controls. IL-1β, soluble IL-1 receptor type II, tumour necrosis factor (TNF)-α, TNF-RII, IL-10 and leptin concentrations did not significantly differ from controls, but peak soluble TNF receptor type I (sTNF-RI) in the first week correlated strongly with computed tomography infarct volume at 5–7 days, mRS and BI at 3 and 12 months. Neopterin was raised in patients at 5–7 d, relative to controls, and in subjects with significant atherosclerosis. Spontaneous IL-1β, TNF-α and IL-6 gene and protein expression by blood cells was minimal, and induction of these cytokines by lipopolysaccharide (LPS) was significantly lower in patients than in controls during the first week. Minimum LPS-induced cytokine production correlated strongly with mRS and BI, and also with plasma cortisol.
Conclusion
Absence of spontaneous whole blood gene activation or cytokine production suggests that peripheral blood cells are not the source of cytokines measured in plasma after AIS. Increased plasma IL-1ra within 12 h of AIS onset, the relationship between sTNF-RI and stroke severity, and suppressed cytokine induction suggests early activation of endogenous immunosuppressive mechanisms after AIS.
doi:10.1186/1471-2377-7-5
PMCID: PMC1810309  PMID: 17328808
10.  The Prognostic Values of Leukocyte Rho Kinase Activity in Acute Ischemic Stroke 
BioMed Research International  2014;2014:214587.
Objective. It has been reported that leukocyte ROCK activity is elevated in patients after ischemic stroke, but it is unclear whether leukocyte ROCK activity is associated with clinical outcomes following acute stroke events. The objective of this study is to investigate if leukocyte ROCK activity can predict the outcomes in patients with acute ischemic stroke. Materials and Methods. We enrolled 110 patients of acute ischemic stroke and measured the leukocyte ROCK activity and plasma level of inflammatory cytokines to correlate the clinical outcomes of these patients. Results. The leukocyte ROCK activity at 48 hours after admission in acute ischemic stroke patients was higher as compared to a risk-matched population. The leukocyte ROCK activity significantly correlated with National Institute of Health Stroke Scale (NIHSS) difference between admission and 90 days after stroke event. Kaplan-Meier survival estimates showed lower stroke-free survival during follow-up period in patients with high leukocyte ROCK activity or plasma hsCRP level. Leukocyte ROCK activity independently predicted the recurrent stroke in patients with atherosclerotic stroke. Conclusions. This study shows elevated leukocyte ROCK activity in patients with ischemic stroke as compared to risk-matched subjects and is an independent predictor for recurrent stroke.
doi:10.1155/2014/214587
PMCID: PMC3955656  PMID: 24716192
11.  Immune-inflammatory markers and arterial stiffness indexes in subjects with acute ischemic stroke with and without metabolic syndrome 
Objective
The aim of our study was to evaluate the associations between arterial stiffness indexes and immune-inflammatory markers in subjects with acute ischemic stroke with and without metabolic syndrome.
Materials/Methods
We enrolled 130 patients with acute ischemic stroke and metabolic syndrome, 127 patients with acute ischemic stroke without metabolic syndrome and 120 control subjects without acute stroke. Applanation tonometry was used to record the augmentation index (Aix) and pulse wave velocity (PWV). We also evaluated plasma levels of C-reactive protein (CRP), Interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), Interleukin-6 (IL-6) and Interleukin-10 (IL-10), E-selectin, P-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), von Willebrand Factor (vWF) plasma levels, tissue plasminogen activator (TPA) and plasminogen activator inhibitor-1 (PAI-1).
Results
In subjects with acute ischemic stroke and metabolic syndrome we observed higher median plasma values of immuno-inflammatory markers. In acute ischemic stroke patients and metabolic syndrome in relation of each TOAST subtype we observed a more significant positive correlation between PWV and immuno-inflammatory markers.
Conclusions
Stroke subjects with acute ischemic stroke and metabolic syndrome showed a higher degree of immuno-inflammatory and arterial stiffness indexes possibly due to metabolic background of these types of patients that trigger a more intense immune-inflammatory activation irrespective of stroke subtype, whereas being related to stroke subtype in subjects without metabolic syndrome.
doi:10.1186/1758-5996-6-28
PMCID: PMC3942622  PMID: 24571954
Stroke; Arterial stiffness; PWV; Aix; Cytokines
12.  Prolonged elevation of interleukin-8 and interleukin-6 concentrations in plasma and of leukocyte interleukin-8 mRNA levels during septicemic and localized Pseudomonas pseudomallei infection. 
Infection and Immunity  1992;60(6):2402-2408.
Patients suffering from serious bacterial infection present to the hospital after early inflammatory events, such as release of tumor necrosis factor (TNF), have been initiated. The role of other cytokines, such as interleukin-8 (IL-8), a neutrophil chemoattractant and activator, in the pathophysiology of human sepsis is not well characterized, and there are only limited data on IL-6. We studied serial concentrations of TNF, IL-6 (involved in the acute-phase response), and IL-8 in plasma and leukocyte levels of mRNA for these cytokines in patients with localized and septicemic Pseudomonas pseudomallei infection on admission to the hospital and during a prolonged recovery phase (up to 30 days). Of 18 patients, 8 had detectable plasma IL-8 and all had raised plasma IL-6 concentrations. In patients who died median initial concentration of IL-8 (167 pg/ml; range, 97 to 362 pg/ml) and IL-6 (4,800 pg/ml; range, 60 to 9,245 pg/ml) in plasma were higher than those in survivors (P less than 0.008 and P = 0.007, respectively). Septic patients who survived and patients with localized disease had similar cytokine levels. Plasma IL-8 and IL-6 concentrations were elevated throughout the inpatient period of recovery. Circulating leukocytes contained mRNA for IL-8 but not for IL-6 and TNF, and they may secrete IL-8. An elevated plasma IL-6 concentration (greater than 1,000 pg/ml) had 75% mortality) was the best predictor of mortality in P. pseudomallei sepsis. Fifty percent of patients with detectable plasma IL-8 concentrations died. In contrast, plasma TNF bioactivity did not relate to outcome; 75% of patients who did never had detectable plasma TNF activity.
Images
PMCID: PMC257173  PMID: 1375198
13.  Predicting the Long-Term Outcome after Subacute Stroke within the Middle Cerebral Artery Territory 
Background and Purpose
The National Institutes of Health Stroke Scale (NIHSS) score is known to be effective in predicting the likelihood of recovery after stroke. However, the baseline NIHSS score predicts long-term outcomes rather crudely because early changes in stroke scores may influence the stroke outcomes. Therefore, a precise prognostic algorithm or a cutoff point for predicting long-term outcomes based on data from serial NIHSS scores is needed.
Methods
We serially assessed 437 patients with acute symptomatic ischemic stroke within the middle cerebral artery territory who presented with nonlacunar stroke and were followed-up for at least 6 months after symptom onset. The NIHSS score was serially checked at 0, 1, 3, 7, and 14 days after admission. In all patients, the Barthel index (BI) and the modified Rankin Scale (mRS) score were checked, with a poor outcome defined as any of the following endpoints: death, modified mRS score of >3, or BI of <60.
Results
A marked neurological improvement or worsening (i.e., a change in the NIHSS score of at least 4) was seen in 13.5% or 5.5% of the patients, respectively, during the first 7 days after admission. About 25% of the 437 patients had poor long-term outcomes. Analysis of receiver operating characteristic curves showed that the NIHSS score at day 7 after admission was better for predicting poor long-term outcomes than was the baseline score (P=0.003). In addition, we analyzed the cutoff point of the 7th-day NIHSS score for predicting a poor outcome at 6 months after symptom onset. An NIHSS score of at least 6 at day 7 after admission predicted poor long-term outcomes with a sensitivity of 84% [95% confidence interval (CI), 76-90%], a specificity of 92% (95% CI, 88-94%), and positive and negative predictive values of 77% and 95%, respectively. A logistic regression analysis revealed that age, diffusion-weighted imaging lesion volume, stroke history, and 7th-day NIHSS score were independently associated with poor outcome. However, no score used in addition to the 7th-day NIHSS score improved the prediction of a poor outcome.
Conclusions
An NIHSS score of at least 6 on day 7 after admission accurately forecasts a poor long-term outcome after stroke. Our data may be helpful in predicting the long-term prognosis as well as in making decisions regarding novel therapeutic applications in subacute-stroke trials.
doi:10.3988/jcn.2005.1.2.148
PMCID: PMC2854920  PMID: 20396462
Ischemic stroke; Outcome; Stroke scale
14.  Cytokines and Inflammatory Mediators Do Not Indicate Acute Infection in Cystic Fibrosis 
Various treatment regimens and difficulties with research design are encountered with cystic fibrosis (CF) because no standard diagnostic criteria exist for defining acute respiratory exacerbations. This study evaluated the role of serial monitoring of concentrations of selected cytokines and inflammatory mediators in serum and sputum as predictors of respiratory exacerbation, as useful outcome measures for CF, and to guide therapy. Interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-α), neutrophil elastase-α-1-protease inhibitor complex (NE complex), protein, and α-1-protease inhibitor (α-1-PI) were measured in serum and sputum collected from CF patients during respiratory exacerbations and periods of well-being. Levels of NE complex, protein, and α-1-PI in sputum rose during respiratory exacerbations and fell after institution of antibiotic therapy (P = 0.078, 0.001, and 0.002, respectively). Mean (± standard error of the mean) levels of IL-8 and TNF-α were extremely high in sputum (13,780 ± 916 and 249.4 ± 23.5 ng/liter, respectively) but did not change significantly with clinical deterioration of the patient (P > 0.23). IL-8 and TNF-α were generally undetectable in serum, and therefore these measures were unhelpful. Drop in forced expiratory volume in 1 s was the only clinical or laboratory parameter that was close to being a determinant of respiratory exacerbation (P = 0.055). This study provides evidence of intense immunological activity occurring continually within the lungs of adult CF patients. Measurement of cytokines and inflammatory mediators in CF sputum is not helpful for identifying acute respiratory exacerbations.
PMCID: PMC95697  PMID: 10066664
15.  Proinflammatory cytokines in Egyptian elderly with chronic obstructive pulmonary disease 
Background:
The pulmonary component of chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases.
Hypothesis:
The levels of the proinflammatory cytokines, interleukin 1 beta (IL-1β), tumor necrosis factor alfa (TNF-α), and C-reactive protein (CRP), in elderly patients suffering from COPD are increased.
Settings and Design:
A case control study involving 90 elderly participants from the outpatient clinics of Ain Shams University hospitals.
Materials and Methods:
The 90 subjects were subdivided into three equal groups ’ group I (control), group II (patients with COPD), and group III (patients with COPD and cardiovascular complications). Comprehensive clinical assessment, pulmonary functions, and echocardiography were performed. The levels of IL-1β, TNF-α, and CRP were measured in the patients’ serum and compared.
Statistical analysis:
SPSS (Statistical Package for Social Science) version 10.
Results:
IL1-βand CRP were significantly higher in the third group than the first group (P <0.05). There was a similar significant difference between the second and third group as regards IL1-βand CRP (P < 0.05). Positive significant correlation between CRP and TNF-α with stage of COPD according to FEV1 (P <0.05) were found.
Conclusions:
Complicated cases of COPD had higher levels of IL1-β and CRP and the more severe the cases, the higher the levels of CRPand TNF-α.
doi:10.4103/0970-2113.71956
PMCID: PMC2988174  PMID: 21139720
Chronic obstructive pulmonary disease; C-reactive protein; interleukin-1 beta; cytokines; tumor necrosis factor-α
16.  Circulating CD133+CD34+ progenitor cells inversely correlate with soluble ICAM-1 in early ischemic stroke patients 
Background and Purpose
Both endothelial progenitor cells (EPC) and markers of neuroinflammation are candidate biomarkers for stroke severity and outcome prediction. A relationship between EPC and neuroinflammatory markers in early stroke is not fully elucidated. The objectives were to investigate correlations between EPC and neuroinflammation markers (adhesion molecules ICAM-1, VCAM-1, E-selectin, tumor necrosis factor (TNF)-α, interleukin (IL)-6, endothelin (ET)-1, markers of tissue injury (matrix metalloproteinases (MMP)-9 and tissue inhibitor of matrix metalloproteinases (TIMP)-1) in early stroke patients.
Methods
We prospectively recruited symptomatic patients with ischemic cerebrovascular disease. We assessed stroke severity by using of acute (diffusion-weighted imaging (DWI) and final lesion volumes (fluid attenuated inversion recovery (FLAIR). We measured serum soluble ICAM-1, VCAM-1, E-selectin, MMP-9, TIMP-1 and plasma TNF-α, IL-6, ET-1 by ELISA, and quantified EPC in mononuclear fraction of peripheral blood on days 1 and 3 in 17 patients (mean(SD) age 62(14), with admission National Institutes of Health Stroke Scale (NIHSS) 10(8)) selected from 175 patients with imaging confirmed ischemic stroke. Non-parametric statistics, univariate and multivariate analysis were used.
Results
Only ICAM-1 inversely correlated with EPC subset CD133+CD34+ on day 1 (Spearman r = -0.6, p < 0.01) and on day 3 (r = -0.967, p < 0.001). This correlation remained significant after adjustment for age and NIHSS (beta -0.992, p < 0.004), for glucose and systolic blood pressure (beta -0.86, p < 0.005), and for white blood cells and hematocrit (beta -1.057, p < 0.0001) on day 3. MMP-9 (r = 0.509, p < 0.04) and MMP-9/TIMP-1 (r = 0.59, p < 0.013) on day 1 correlated with acute lesion volume. Both IL-6 (r = 0.624, p < 0.01) and MMP-9/TIMP-1 (r = 0.56, p < 0.02) correlated with admission NIHSS.
Conclusion
Our study showed that high ICAM-1 is associated with low CD133+CD34+subset of EPC. Biomarkers of neuroinflammation may predict tissue injury and stroke severity in early ischemia.
doi:10.1186/1479-5876-9-145
PMCID: PMC3179728  PMID: 21871109
17.  Relevance of Distinct Monocyte Subsets to Clinical Course of Ischemic Stroke Patients 
PLoS ONE  2013;8(8):e69409.
Background and Purpose
The most common strategy for treating patients with acute ischemic stroke is thrombolytic therapy, though only a few patients receive benefits because of the narrow time window. Inflammation occurring in the central nervous system (CNS) in association with ischemia is caused by immune cells including monocytes and involved in lesion expansion. If the specific roles of monocyte subsets in stroke can be revealed, they may become an effective target for new treatment strategies.
Methods
We performed immunological examinations of 36 consecutive ischemic stroke patients within 2 days of onset and compared the results with 24 age-matched patients with degenerative disorders. The stroke patients were repeatedly tested for the proportions of monocyte subsets in blood, and serum levels of pro- and anti-inflammatory cytokines immediately after admission, on days 3-7 and 12-16 after stroke onset, and on the day of discharge. In addition, immunological measurements were analyzed for relationships to stroke subtypes and complications, including progressive infarction (PI) and stroke-associated infection (SAI).
Results
Monocyte count was significantly increased from 0–16 days after stroke as compared to the controls (p<0.05). CD14highCD16- classical and CD14highCD16+ intermediate monocytes were significantly increased from 0-7 and 3-16 days after stroke, respectively (p<0.05), whereas CD14 dimCD16high non-classical monocytes were decreased from 0–7 days (p<0.05). Cardioembolic infarction was associated with a persistent increase in intermediate monocytes. Furthermore, intermediate monocytes were significantly increased in patients with PI (p<0.05), while non-classical monocytes were decreased in those with SAI (p<0.05). IL-17A levels were positively correlated with monocyte count (r=0.485, p=0.012) as well as the percentage of non-classical monocytes (r=0.423, p=0.028), and negatively with that of classical monocytes (r=-0.51, p=0.007) during days 12-16.
Conclusions
Our findings suggest that CD14highCD16+ intermediate monocytes have a role in CNS tissue damage during acute and subacute phases in ischemic stroke especially in relation to cardioembolism.
doi:10.1371/journal.pone.0069409
PMCID: PMC3732285  PMID: 23936327
18.  Plasma Level of IL-6 and Its Relationship to Procoagulant and Fibrinolytic Markers in Acute Ischemic Stroke 
Yonsei Medical Journal  2006;47(2):201-206.
Procoagulant or impaired fibrinolytic states as well as inflammatory reactions mediated by cytokines are likely involved in the pathogenesis of acute ischemic stroke. We examined the potential relationship between interleukin 6 (IL-6) and hemostatic markers. The procoagulant and fibrinolytic states were assessed in 46 patients with acute stroke by measuring plasma levels of plasminogen activator inhibitor-1 (PAI-1), thrombin-antithrombin complex (TAT), and plasminogen-antiplasmin complex (PAP). Circulating IL-6 levels were measured using ELISA (Quantikine, R&D systems, MN, USA). Circulating IL-6 (mean, 26.5 pg/mL) and PAI-1 (mean, 19.9 ng/mL) levels were higher in patients with acute stroke than in healthy subjects (mean, 3.0 pg/mL, 10.4 ng/mL, respectively). TAT levels were statistically different according to the etiologic subtypes of stroke (atherogenic, 2.5 ng/mL; lacunar 3.2 ng/mL; cardiogenic 9.9 ng/mL, p = 0.021). Neither procoagulant levels nor fibrinolytic markers significantly correlated with circulating IL-6 levels. Our findings suggest that elevated proinflammatory cytokines during the initial hours of ischemic stroke may be an independent pathogenic factor or a consequence of the thrombotic event with no relationship to the procoagulant or fibrinolytic states.
doi:10.3349/ymj.2006.47.2.201
PMCID: PMC2687629  PMID: 16642549
Stroke; cytokine; procoagulant; fibrinolysis
19.  Prediction of severe acute pancreatitis: Current knowledge and novel insights 
Acute pancreatitis (AP) is a common and potentially lethal acute inflammatory process with a highly variable clinical course. It is still unclear why some patients progress to organ failure and others do not. Ability to predict which patients will develop severe disease is limited. Routine clinical and laboratory data and multi-factorial clinical scores measured on admission and during the first 48 h of hospitalization are currently the standards of care used to estimate the magnitude of the inflammatory response to injury. Current literature highlights several common environmental, metabolic and genetic factors that increase the risk of AP development and subsequent adverse sequelae. Several cytokines have been found to play a critical role in the pathogenesis of AP by driving the subsequent inflammatory response, to include tumor necrosis factor-α (TNF-α), Interleukin-1 (IL-1), IL-6 and monocyte chemotactic protein-1 (MCP-1). Large, prospective studies are still needed to address these questions by identifying AP risk factors and serum biomarkers of severe disease.
doi:10.3748/wjg.14.6273
PMCID: PMC2766104  PMID: 19009638
Acute pancreatitis; Prediction; Severity; Monocyte chemotactic protein-1
20.  Rising statin use and effect on ischemic stroke outcome 
BMC Medicine  2004;2:4.
Background
Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) have neuroprotective effects in experimental stroke models and are commonly prescribed in clinical practice. The aim of this study was to determine if patients taking statins before hospital admission for stroke had an improved clinical outcome.
Methods
This was an observational study of 436 patients admitted to the National Institutes of Health Suburban Hospital Stroke Program between July 2000 and December 2002. Self-reported risk factors for stroke were obtained on admission. Stroke severity was determined by the admission National Institutes of Health Stroke Scale score. Good outcome was defined as a Rankin score < 2 at discharge. Statistical analyses used univariate and multivariate logistic regression models.
Results
There were 436 patients with a final diagnosis of ischemic stroke; statin data were available for 433 of them. A total of 95/433 (22%) of patients were taking a statin when they were admitted, rising from 16% in 2000 to 26% in 2002. Fifty-one percent of patients taking statins had a good outcome compared to 38% of patients not taking statins (p = 0.03). After adjustment for confounding factors, statin pretreatment was associated with a 2.9 odds (95% CI: 1.2–6.7) of a good outcome at the time of hospital discharge.
Conclusions
The proportion of patients taking statins when they are admitted with stroke is rising rapidly. Statin pretreatment was significantly associated with an improved functional outcome at discharge. This finding could support the early initiation of statin therapy after stroke.
doi:10.1186/1741-7015-2-4
PMCID: PMC395844  PMID: 15035663
21.  Admission clinical characteristics and early clinical outcomes among acute ischemic stroke patients 
Journal of Biomedical Research  2012;26(3):152-158.
The purpose of the present study was to investigate the association between admission clinical characteristics and outcomes at discharge among acute ischemic stroke patients in the Chinese population. A total of 2,673 patients with acute ischemic stroke were included in the present study. The clinical characteristics at admission and other study variables were collected for all patients. The study outcome was defined as neurological deficiency (National Institute of Health Stroke Scale score ≥10) at discharge or in-hospital death. Compared with the subjects without neurological deficiency at discharge or in-hospital death, the subjects with neurological deficiency at discharge or in-hospital death had a significantly higher prevalence of hyperglycemia or history of atrial fibrillation at admission. Age ≥ 80 years, hyperglycemia, hypertension, and history of atrial fibrillation were significantly associated with neurological deficiency at discharge or in-hospital death after adjustment for other variables. It is concluded that old age (≥80 years), hyperglycemia, hypertension and history of atrial fibrillation are significantly associated with neurological deficiency at discharge or in-hospital death among patients with acute ischemic stroke.
doi:10.7555/JBR.26.20110129
PMCID: PMC3596064  PMID: 23554744
acute ischemic stroke; clinical characteristics; death; neurological deficiency; discharge outcome
22.  Selected acute phase CSF factors in ischemic stroke: findings and prognostic value 
BMC Neurology  2011;11:41.
Background
Study aimed at investigation of pathogenic role and prognostic value of several selected cerebrospinal fluid acute phase factors that can reflect the severity of ischemic brain damage.
Methods
Ninety five acute ischemic stroke patients were investigated. Ischemic region visualized at the twenty fourth hour by conventional Magnetic Resonance Imaging. Stroke severity evaluated by National Institute Health Stroke Scale. One month outcome of disease was assessed by Barthel Index. Cerebrospinal fluid was taken at the sixth hour of stroke onset. CSF pro- and anti-inflammatory cytokines were studied by Enzyme Linked Immunosorbent Assay. Nitric Oxide and Lipoperoxide radical were measured by Electron Paramagnetic Resonance. CSF Nitrate levels were detected using the Griess reagent. Statistics performed by SPSS-11.0.
Results
At the sixth hour of stroke onset, cerebrospinal fluid cytokine levels were elevated in patients against controls. Severe stroke patients had increased interleukin-6 content compared to less severe strokes (P < 0.05). Cerebrospinal fluid Electron Paramagnetic Resonance signal of nitric oxide was increased in patients against controls. Severe stroke group had an elevated Electron Paramagnetic Resonance signal of lipoperoxiradical compared to less severe stroke. Cerebrospinal fluid nitrate levels in less severe stroke patients were higher than those for severe stroke and control. Positive correlation was established between the initial interleukin-6 content and ischemic lesion size as well as with National Institute Health Stroke Scale score on the seventh day. Initial interleukin-6 and nitrate levels in cerebrospinal fluid found to be significant for functional outcome of stroke at one month.
Conclusion
According to present study the cerebrospinal fluid contents of interleukin-6 and nitrates seem to be the most reliable prognostic factors in acute phase of ischemic stroke.
doi:10.1186/1471-2377-11-41
PMCID: PMC3078848  PMID: 21450100
brain; ischemia; inflammation; oxidative stress
23.  Polymorphism of tumor necrosis factor alpha (TNF-alpha) gene promoter, circulating TNF-alpha level, and cardiovascular risk factor for ischemic stroke 
Background
Tumor necrosis factor-α (TNF-α) is one of the most typical pro-inflammatory cytokines with both beneficial and destructive properties for the central nervous system. Increasing evidences have demonstrated the important role of TNF-α in the development of ischemic stroke, but studies examining the possible association with stroke or direct functional effects of polymorphisms in TNF-α have been contradictory.
Findings
In this study, a 2-kb length of the proximal promoter of the TNF-α was screened and four polymorphisms were investigated in the case–control study. Our data confirmed the association between -308G/A variant with stroke in 1,388 stroke patients and 1,027 controls and replicated in an independent population of 961 stroke patients and 821 controls (odds ratio (OR) = 1.34, 95% confidence interval (CI) =1.02 to 1.77 and OR = 1.56, 95% CI = 1.09 to 2.23, respectively). To reconcile the association between polymorphisms and stroke and to give a comprehensive picture of the genetic architecture of this important gene, we performed a meta-analysis of 15 published studies in an Asian population. Our results demonstrated an association between rs1800629 and ischemic stroke (OR = 1.43, 95% CI = 1.21 to 1.69). Another meta-analysis results of 14 studies demonstrated that ischemic stroke patients have higher serum TNF-α level than the control subjects (standardized mean difference (SMD) = 2.33, 95% CI = 1.85 to 2.81). In vitro evaluation of potential interaction between variants of the TNF-α gene (−308G/A, -857C/T, and -1031T/C) demonstrated that these three polymorphisms could interact together to determine the overall activity of the TNF-α gene.
Conclusions
These findings strongly implicate the involvement of TNF-α in the pathogenesis of stroke.
doi:10.1186/1742-2094-9-235
PMCID: PMC3521196  PMID: 23050663
Tumor necrosis factor alpha (TNF-α); Genetics; Cardiovascular risk factors; Function study
24.  Growth-differentiation factor-15 and functional outcome after acute ischemic stroke 
Journal of Neurology  2012;259(8):1574-1579.
Blood biomarkers may improve the performance in predicting early stroke outcome beyond well-established clinical factors. We investigated the value of growth-differentiation factor-15 (GDF-15) to predict functional outcome after 90 days in a prospectively collected patient cohort with symptoms of acute ischemic stroke. Two hundred eighty-one patients with symptoms of acute ischemic stroke were prospectively investigated. Serial blood samples for GDF-15 analysis were obtained after the admission of the patient, after 6 and 24 h. Primary outcome was the dichotomized modified ranking scale (MRS) 90 days after the initial clinical event. Within the final study population (264 patients, mean age 70.3 ± 12.7 years, 55.3% male), National Institutes of Health Stroke Scale (NIH-SS) [odds ratio (OR) 1.269, 95% confidence interval (CI) 1.141–1.412, p < 0.001] and initial GDF-15 levels (OR 1.029, 95% CI 1.007–1.053, p = 0.011) were independently associated with a MRS ≥ 2 after day 90 after multiple regression analysis. Growth-differentiation factor-15 levels increase with higher NIH-SS-tertiles (p = 0.005). Receiver-operator characteristic curves demonstrated a discriminatory accuracy to predict unfavourable stroke outcome of 0.629 (95% CI 0.558–0.699), 0.753 (95% CI 0.693–812) and 0.774 (95% CI 0.717–0.832) for GDF-15, NIH-SS and the combination of these variables. The additional use of GDF-15 to NIH-SS ameliorates the model with a net reclassification index of 0.044 (p = 0.541) and integrated discrimination improvement of 0.034 (p = 0.443). Growth-differentiation factor-15 as an acute stroke biomarker independently predicts unfavourable functional 90 day stroke outcome. Discriminatory value in addition to NIH-SS is only modestly distinct.
doi:10.1007/s00415-011-6379-0
PMCID: PMC3410030  PMID: 22231869
GDF-15; Clinical trial; Ischemic stroke; TIA; Biomarker; Outcome
25.  Dopaminergic Mechanisms of Reduced Basal Ganglia Responses to Hedonic Reward During Interferon Alfa Administration 
Archives of general psychiatry  2012;69(10):1044-1053.
Context
Inflammatory cytokines or cytokine inducers can alter basal ganglia activity, including reducing responsiveness to rewarding stimuli that may be mediated by cytokine effects on dopamine function.
Objectives
To determine whether long-term administration of the inflammatory cytokine interferon alfa reduces the basal ganglia response to reward and whether such changes are associated with decreased presynaptic striatal dopamine function and altered behavior.
Design
Cross-sectional and longitudinal studies.
Setting
Outpatient research unit and neuroimaging facilities at Emory University, Atlanta, Georgia.
Patients
Medically stable adults with chronic hepatitis C virus (HCV) infection eligible for interferon alfa treatment.
Main Outcome Measures
Neural activity in the ventral striatum during a hedonic reward task as measured by functional magnetic resonance imaging, uptake and turnover of radiolabeled fluorodopa F 18 (18F-dopa) in caudate and putamen using positron emission tomography, and interferon alfa–induced depression, anhedonia, fatigue, and neurotoxicity.
Results
Patients with HCV receiving interferon alfa for 4 to 6 weeks (n=14) exhibited significantly reduced bilateral activation of the ventral striatum in the win vs lose condition of a gambling task compared with patients with HCV awaiting interferon alfa treatment (n=14). Reduced activation of the ventral striatum was, in turn, significantly correlated with anhedonia, depression, and fatigue. In a separate longitudinal study, patients with HCV treated with interferon alfa for 4 to 6 weeks (n=12) exhibited significantly increased 18F-dopa uptake and decreased 18F-dopa turnover in caudate and putamen and in the same ventral striatal regions identified in the functional magnetic resonance imaging study. Baseline and percentage change in 18F-dopa uptake and turnover were correlated with behavioral alterations, including depression, fatigue, and neurotoxicity, during interferon alfa administration.
Conclusions
These data replicate and extend findings that inflammatory stimuli, including inflammatory cytokines, such as interferon alfa, alter basal ganglia activity and behavior in association with significant changes in presynaptic striatal dopamine function consistent with decreased dopamine synthesis or release.
doi:10.1001/archgenpsychiatry.2011.2094
PMCID: PMC3640298  PMID: 23026954

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