Irregularities of Coagulation in Hypertension.

PURPOSE OF REVIEW: This review article summarizes the role of coagulation in the pathogenesis of hypertension. It specifically focuses on significant factors and markers associated with coagulation, including D-dimer, fibrinogen and fibrin, prothrombin, P-selectin, soluble urokinase plasminogen activator receptor, thrombomodulin, tissue factor, tissue plasminogen activator, von Willebrand factor, ß-thromboglobulin, and Stuart-Prower factor. RECENT FINDINGS: D-dimer levels were elevated in hypertensive individuals compared to healthy controls, and the levels increased with the severity of hypertension. These findings indicate that increased coagulation activity of fibrin plays a role in the development of thromboembolic complications in hypertensive patients. Additionally, both fibrinogen levels and D-dimer levels displayed a positive correlation with the duration of hypertension, suggesting that these biomarkers were positively associated with the length of time an individual had been hypertensive. Increased systolic and diastolic blood pressures have been linked to higher levels of prothrombin time and activated partial thromboplastin time in individuals with hypertension as well as those with normal blood pressure. Also, the presence of P-selectin, produced by activated platelets and endothelial cells during angiotensin II stimulation, played a role in the development of cardiac inflammation and fibrosis associated with hypertension. Moreover, the change in systolic blood pressure was associated with baseline soluble urokinase plasminogen activator receptor (suPAR) in hypertensive participants, and the change in suPAR levels was associated with the development of hypertension. Moreover, it was observed a decrease in thrombomodulin expression in the placenta of preeclamptic patients, suggesting its potential involvement in placental dysfunction, possibly driven by an imbalance in angiogenic factors. Tissue factors and autophagy might have significant implications in the pathogenesis of chronic thromboembolic pulmonary hypertension, particularly in the context of vascular remodelling. Likewise, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) might be a promising biomarker for the early detection of pulmonary arterial hypertension and the von Willebrand factor is a candidate prognostic biomarker. The arterial ß-thromboglobulin levels were significantly lower than venous levels. This article concludes that D-dimer, fibrinogen and fibrin, prothrombin, P-selectin, soluble urokinase plasminogen activator receptor, thrombomodulin, tissue factor, tissue plasminogen activator, von Willebrand factor, and ß-thromboglobulin are important factors involved in the pathogenesis of hypertension.

An Evaluation of Platelet Factor 4, Beta-Thromboglobulin and Mean Platelet Volume in the Assessment of Thrombotic Risks in Subjects with Diabetes Mellitus at Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria.

BACKGROUND: Beta-thromboglobulin and platelet factor 4 are known platelet-specific proteins that are stored in the platelet alpha-granules and released during platelet activation. The measurement of these proteins can reflect the degree of platelet activation and indirectly suggest a pro-thrombotic state. This study aimed at determining serum levels of Betathromboglobulin, mean platelet volume, and platelet factor 4 in diabetes mellitus and control subjects in Lagos, Nigeria. MATERIALS AND METHODS: Using enzyme-linked immunosorbent assay at Lagos State University Teaching Hospital, Ikeja, this study evaluated serum concentrations of Beta-thromboglobulin, and platelet factor 4, the mean platelet volume was also determined from a Full Blood Count of all participants. Data were analyzed using Statistical Package for Social Sciences, Inc., Chicago, Ill; version 26.0. The continuous variables were given as mean ± standard deviation. The P-value was considered to be statistically significant when ≤0.05. RESULTS: Beta-thromboglobulin concentration was higher and statistically significant (7.82 ± 1.54ng/ml and 6.70 ± 2.23 ng/ml; P = 0.01), platelet factor 4 (39.86 ± 11.25 ng/ml and 47.73 ± 21.73ng/ml, P = 0.06) and mean platelet volume (10.26± 1.06fl and 10.29 ± 1.02fl P = 0.89) were not statistically significant in the diabetes mellitus group compared with non-diabetic participants, platelet factor 4 was higher in the older than younger diabetes mellitus participants. CONCLUSION: Elevated Beta-thromboglobulin may suggest a possible increase in thrombotic risks among diabetes mellitus.

CONTEXTE: La bêta-thromboglobuline et le facteur plaquettaire 4 sont des protéines spécifiques des plaquettes qui sont stockées dans les alpha-granules plaquettaires et libérées lors de l'activation des plaquettes. La mesure de ces protéines peut refléter le degré d'activation des plaquettes et suggérer indirectement un état prothrombotique. Cette étude visait à déterminer les taux sériques de bêta-thromboglobuline, le volume plaquettaire moyen et le facteur plaquettaire 4 chez des sujets atteints de diabète sucré et des sujets témoins à Lagos, au Nigéria. MATÉRIEL ET MÉTHODES: En utilisant le dosage immunoenzymatique au Lagos State University Teaching Hospital, Ikeja, cette étude a évalué les concentrations sériques de bêtathromboglobuline et de facteur plaquettaire 4, le volume plaquettaire moyen a également été déterminé à partir d'une numération globulaire complète de tous les participants. Les données ont été analysées à l'aide du logiciel Statistical Package for Social Sciences, Inc, Chicago,Ill ; version 26.0. Les variables continues ont été exprimées en moyen ± écart-type. La valeur P a été considérée comme statistiquement significative lorsqu'elle était inférieure à ≤0,05. RÉSULTATS: La concentration de bêta-thromboglobuline était plus élevée et statistiquement significative (7,82±1,54ng/ml et 6,70±2,23 ng/ml ; P=0,01), le facteur plaquettaire 4 (39,86±11,25 ng/ml et 47,73±21,73 ng/ml, P=0,06) et le volume plaquettaire moyen (10. 26± 1.06fl et 10.29±1.02fl P= 0.89) n'étaient pas statistiquement significatifs dans le groupe diabète sucré par rapport aux participants non-diabétiques, le facteur plaquettaire 4 était plus élevé chez les participants diabétiques plus âgés que chez les plus jeunes. CONCLUSION: Un taux élevé de bêta-thromboglobuline peutsuggérer une augmentation possible des risques thrombotiques chez les personnes atteintes de diabète sucré. Mots-clés: Bêta-thromboglobuline, facteur plaquettaire 4, volume plaquettaire moyen.

Assessment of coagulation markers, serum zinc and copper in children with beta-thalassemia major in Egypt.

BACKGROUND: Thalassemia is one of the commonest single gene disorders usually associated with many complications. Coagulation changes as well as trace elements levels alterations have been described in children with ß thalassemia. Activation of coagulation can be assessed by measuring thrombin-antithrombin (TAT) complex, plasmin-antiplasmin (PAP) complex and ß-thromboglobulin (ß-TG). METHODS: A total of 200 children and adolescents were enrolled in the study; 100 were from the Al-Azhar University hospital's pediatric hematology clinic diagnosed as thalassemia major, while the other 100 were apparently healthy volunteers who acted as the control group. Complete blood count, liver function test, kidney function tests, TAT complex, PAP complex, ß-TG as indicators of coagulation changes, serum zinc and copper were performed on all participants. RESULTS: Significantly higher levels of TAT complex, PAP complex and ß-TG in thalassemia children than the controls. Decreased serum zinc and increased serum copper levels in thalassemia children compared to the controls. A negative correlation was observed between the serum level of TAT and hemoglobin level, besides the negative correlation of TAT complex and ß-TG with the serum zinc. CONCLUSION: Thalassemia major was associated with increased serum level of coagulation activation markers, increased serum copper while decreased serum zinc.

Exploring the changes of brain immune microenvironment in Alzheimer's disease based on PANDA algorithm combined with blood brain barrier injury-related genes.

Studies have shown that the specific entry of peripheral cells into the brain parenchyma caused by BBB injury and the imbalance of the immune microenvironment in the brain are closely related to the pathogenesis of Alzheimer's disease (AD). Because of the difficulty of obtaining data inside the brain, it is urgent to find out the relationship between the peripheral and intracerebral data and their influence on the development of AD by machine learning methods. However, in the actual algorithm design, it is still a challenge to extract relevant information from a variety of data to establish a complete and accurate regulatory network. In order to overcome the above difficulties, we presented a method based on a message passing model (Passing Attributes between Networks for Data Assimilation, PANDA) to discover the correlation between internal and external brain by the BBB injury-related genes, and further explore their regulatory mechanism of the brain immune environment for AD pathology. The Biological analysis of the results showed that pathways such as immune response pathway, inflammatory response pathway and chemokine signaling pathway are closely related to the pathogenesis of AD. Especially, some significant genes such as RELA, LAMA4, PPBP were found play certain roles in the injury of BBB and the change of permeability in AD patients, thus leading to the change of immune microenvironment in AD brain.

Platelet factor 4 and ß-thromboglobulin mRNAs in circulating microparticles of trauma patients as diagnostic markers for deep vein thrombosis.

Deep vein thrombosis (DVT) is a common complication after trauma. The development of markers to predict DVT in trauma patients is needed, and circulating microparticles (MPs) and their contents are possible candidates. In this study, we aimed to identify platelet factor 4 (PF4) and ß-thromboglobulin (ß-TG) mRNAs in circulating MPs as potential markers for DVT diagnosis in trauma patients. Fifteen trauma patients diagnosed with DVT and fifteen matched patients without DVT were included in this study. Fifteen healthy volunteers also were included as controls. Circulating MPs were obtained from the plasma of all study subjects. Annexin V+ MPs and platelet-derived MPs (PMPs) were quantified using flow cytometry. PF4 and ß-TG mRNAs in MPs were determined by qPCR, and the common logarithm of relative quantitation (RQ) was calculated using the comparative Ct method. Receiver-operating characteristic (ROC) curves were performed to analyze the diagnostic value of PF4 and ß-TG mRNAs. No significant differences were found in Annexin V+ MPs and PMPs levels between trauma patients with and without DVT. However, both PF4 and ß-TG mRNAs in MPs from the DVT group were significantly higher than the non-DVT group and healthy controls (P = 0.014 for PF4, P = 0.010 for ß-TG). The ROC curve analysis showed that both the PF4 mRNA (area-under curve (AUC) 0.756, P = 0.017) and the ß-TG mRNA (AUC 0.751, P = 0.019) had a positive predictive value for DVT. This finding indicates that the PF4 and ß-TG mRNAs in MPs may be used as potential biomarkers for DVT diagnosis in trauma patients.

Increased CCL24 and CXCL7 levels in the cerebrospinal fluid of patients with neurosyphilis.

BACKGROUND: Monocytes are recruited into the cerebrospinal fluid (CSF) of patients with neurosyphilis, suggesting abnormal chemokine expression. We aimed to investigate the aberrant expression of chemokines in the CSF of these patients. METHODS: CSF and serum samples were collected from patients with neurosyphilis between July 2017 and June 2019 in the Dermatology Department, Second Affiliated Hospital of Zhejiang University. Differences in the expression of 38 chemokines between patients with and without neurosyphilis were detected using RayBio® Human Chemokine Antibody Array C1. CCL24 and CXCL7 levels in the patients' CSF and serum were further measured using RayBio® CCL24 and CXCL7 ELISA kits. RESULTS: Ninety-three CSF and serum samples of patients with syphilis were collected. Antibody array analysis showed that the CSF levels of CCL24 (P = .0185), CXCL7 (P < .0001), CXCL13 (P < .0001), CXCL10 (P < .0001), and CXCL8 (P < .0001) were significantly higher in patients with than without neurosyphilis. ELISA confirmed significantly higher CCL24 and CXCL7 levels in the CSF of patients with than without neurosyphilis (CCL24: 6.082 ± 1.137 pg/mL vs 1.773 ± 0.4565 pg/mL, P = .0037; CXCL7: 664.3 ± 73.19 pg/mL vs 431.1 ± 90.54 pg/mL, P = .0118). Increased CCL24 and CXCL7 expression was seen throughout all neurosyphilis stages, had moderate diagnostic efficiency for neurosyphilis, and correlated poorly with CSF cell count and Venereal Disease Research Laboratory titer. CSF CCL24 levels also correlated poorly with CSF protein concentration. CONCLUSION: Abnormally high CSF chemokines levels may play a role in the pathogenesis of neurosyphilis.

Increased Plasma Levels of Platelet Factor 4 and ß-thromboglobulin in Women with Recurrent Pregnancy Loss.

Thrombosis in decidual vessels is one of the mechanisms of pregnancy loss. However, few studies have assessed the relation between platelet activation, which is known to cause of thrombosis, and recurrent pregnancy loss (RPL). We investigated platelet activation in women with RPL compared to controls by measuring plasma levels of platelet factor 4 (PF4) and ß-thromboglobulin (ßTG), and assessed correlations between PF4/ßTG and coagulative risk factors associated with RPL. The study group included 135 women who had experienced two or more consecutive pregnancy losses. The control group included 28 age-matched healthy women who had never experienced pregnancy loss. PF4 and ßTG plasma levels were significantly higher in the women with RPL than controls (PF4: 14.0 [8.0-20.0] vs. 9.0 [6.0-12.0] ng/ml, p=0.043; ßTG: 42.0 [24.3-59.8] vs. 31.5 [26.6-36.4] ng/ml, p=0.002). There was a significant association between ßTG and anti-phosphatidylethanolamine antibody immunoglobulin M (aPE IgM) (p=0.048). Among the women with RPL, 18 of those who were positive for PF4 (45%) and 18 of those who were positive for ßTG (37%) were negative for all known coagulative risk factors associated with RPL. Measurements of PF4 and ßTG may be important because they help identify women who are at risk of RPL.

Inflammatory expression profile in peripheral blood mononuclear cells from patients with Nasu-Hakola Disease.

Homozygous mutations in Triggering Receptor Expressed on Myeloid cells 2 gene (TREM2) are one of the major causes of Nasu Hakola Disease (NHD). We analysed Peripheral Blood Mononuclear Cells (PBMC) profile of 164 inflammatory factors in patients with NHD carrying the TREM2 Q33X mutation as compared with heterozygous and wild type individuals. Several molecules related to bone formation and angiogenesis were altered in NHD compared to non-carriers: Bone Morphogenetic Protein (BMP)-1 mRNA levels were significantly increased in PBMC (2.32 fold-increase; P = 0.01), as were Transforming Growth Factor Beta (TGFB)3 levels (1.51 fold-increase; P = 0.02). Conversely, CXCL5 and Pro Platelet Basic Protein (PPBP) were strongly downregulated (-28.26, -9.85 fold-decrease over non-carriers, respectively, P = 0.01), as well as Platelet Factor 4 Variant 1 (PF4V1; -41.44, P = 0.03). Among other inflammatory factors evaluated, Interleukin (IL)-15 and Tumor Necrosis Factor Superfamily Member (TNFSF)4 mRNA levels were decreased in NHD as compared with non-carriers (-2.25 and -3.87 fold-decrease, P = 0.01 and 0.001, respectively). In heterozygous individuals, no significant differences were observed, apart from IL-15 mRNA levels, that were decreased at the same extent as NHD (-2.05 fold-decrease over non-carriers, P = 0.002). We identified a signature in PBMC from patients with NHD consisting of strongly decreased mRNA levels of CXCL5, PPBP, PF4V1, mildly decreased IL-15 and TNFSF4 and mildly increased BMP-1 and TGFB3.

Bioinformatics analysis on differentially expressed genes of alveolar macrophage in IPF.

Objective: This study aimed to explore the differentially expressed genes (DEGs) of pulmonary macrophages in human idiopathic pulmonary fibrosis (IPF) by bioinformatics, and elaborate on IPF on the gene level. Methods: The gene expression profile GSE49072 was downloaded from the gene expression omnibus (GEO) database. Genes of alveolar macrophages between normal volunteers and patients diagnosed as IPF were analyzed by GEO2R tools. Gene ontology (GO) and pathway enrichment analyses of genes were performed in the database for annotation, visualization and integrated discovery (DAVID) database, followed by functional annotation and protein-protein interaction (PPI) network construction in String website. Finally, the results were analyzed in a comprehensive way. Results: A total of 551 DEGs, including 205 down-regulated and 346 up-regulated were identified. The expression of 209875_s_at (secreted phosphoprotein 1, SPP1) and 214146_s_at (pro-platelet basic protein, PPBP) genes are the most significant in upregulated genes. DEGs in the MAPK（mitogen-activated protein kinase） signaling pathway and chemokine signaling pathway play important roles in the development of IPF. Conclusions: The up-regulation of genes such as SPP1 and PPBP affect the secretion of alveolar macrophages, thereby speeding up the process of fibrosis.

Analysis by proteomics reveals unique circulatory proteins in idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease that has a poor 3-year median survival rate with unclear pathophysiology. Radiological features include bibasal, subpleural fibrosis and honeycombing while its pathology is characterized by fibroblastic foci and honeycombing. Proteomic analysis of circulating molecules in plasma may identify factors that characterize IPF and may assist in the diagnosis, prognostication and determination of pathogenic pathways in this condition. METHODS: Two independent quantitative proteomic techniques were used, isobaric tags for relative and absolute quantitation (iTRAQ) and multiple reaction monitoring (MRM), to identify differentially expressed plasma proteins in a group of IPF patients in comparison to healthy controls with normal lung function matched for age and gender. RESULTS: Five proteins were identified to be differentially expressed in IPF compared to healthy controls (upregulation of platelet basic protein and downregulation of actin, cytoplasmic 2, antithrombin-III, extracellular matrix protein-1 and fibronectin). CONCLUSION: This study further validates the combinational use of non-targeted discovery proteomics (iTRAQ) with targeted quantitation by mass spectrometry (MRM) of soluble biomarkers to identify potentially important molecules and pathways for pulmonary diseases such as IPF.

Comprehensive lipidomic, metabolomic and proteomic profiling reveals the role of immune system in vitiligo.

BACKGROUND: Vitiligo is a common depigmentation disorder resulting from destruction of melanocytes, and has both genetic and environmental influences. Although genomic analyses have been performed to investigate the pathogenesis of vitiligo, the lipidomics, metabolomics and proteomics of serum have not been reported, and the role of small molecules and serum proteins in vitiligo remains unknown. AIM: To study the metabolite and protein profiles in patients with vitiligo and healthy controls (HCs). METHODS: Plasma samples from 60 participants (29 patients with vitiligo and 31 HCs) were analysed. Untargeted lipidomics, metabolomics and isobaric tags for relative and absolute quantification-based proteomics were performed using high performance liquid chromatography-tandem mass spectrometry. In addition, to validate differentially expressed metabolites in patients with vitiligo, plasma enzyme-linked immunosorbent assay was performed. RESULTS: We identified differential expression of several metabolites and proteins involved in the immune system. Among these metabolites and proteins, lysophosphatidylcholine, platelet-activating factor, sn-glycerol-3-phosphocholine, succinic acid, CXCL4 and CXCL7 were significantly elevated in the plasma of patients with vitiligo, while aspartate was downregulated. CONCLUSION: Our study has characterized several serum metabolites and proteins that could be potential candidate biomarkers in vitiligo, and provides a comprehensive insight into the role of immune system and aspartate metabolism in vitiligo.

Platelet Depletion Impairs Host Defense to Pulmonary Infection with Pseudomonas aeruginosa in Mice.

Platelets have been implicated in pulmonary inflammatory cell recruitment after exposure to allergic and nonallergic stimuli, but little is known about the role of platelets in response to pulmonary infection with Pseudomonas aeruginosa. In this study, we have investigated the impact of the experimental depletion of circulating platelets on a range of inflammatory and bacterial parameters, and their subsequent impact on mortality in a murine model of pulmonary infection with P. aeruginosa. P. aeruginosa infection in mice induced a mild, but significant, state of peripheral thrombocytopenia in addition to pulmonary platelet accumulation. Increased platelet activation was detected in infected mice through increased levels of the platelet-derived mediators, platelet factor-4 and ß-thromboglobulin, in BAL fluid and blood plasma. In mice depleted of circulating platelets, pulmonary neutrophil recruitment was significantly reduced 24 hours after infection, whereas the incidence of systemic dissemination of bacteria was significantly increased compared with non-platelet-depleted control mice. Furthermore, mortality rates were increased in bacterial-infected mice depleted of circulating platelets. This work demonstrates a role for platelets in the host response toward a gram-negative bacterial respiratory infection.

rLj-RGD3, a novel recombinant toxin protein from Lampetra japonica, prevents coronary thrombosis-induced acute myocardial infarction by inhibiting platelet functions in rats.

Recombinant Lampetra japonica RGD-peptide (rLj-RGD3), a soluble protein containing three RGD sequences, was acquired from the oral salivary glands of Lampetra japonica using recombinant DNA technology. The aim of this study was to investigate the protective effects of rLj-RGD3 against acute myocardial infarction (AMI) induced by coronary artery thrombosis, as well as the underlying mechanisms. A rat model of AMI caused by ferric chloride-induced thrombosis on the surface of the left anterior descending (LAD) coronary artery was successfully established. Rats were given various doses of rLj-RGD3 (12 µg/kg, 24 µg/kg and 48 µg/kg) via sublingual intravenous delivery 10 min before AMI. ST segment elevation was recorded by electrocardiogram (ECG) until the end of the model. Left ventricular Evans blue content and histopathological changes were examined. Blood samples were collected to determine 5-hydroxytryptamine (5-HT), ß-thromboglobulin (ß-TG), platelet factor 4 (PF4) and cAMP levels. The effects of rLj-RGD3 on platelet aggregation, adhesion and intracellular calcium concentrations were also measured. rLj-RGD3 significantly reduced ST segment elevation, prevented thrombus formation in the coronary artery and decreased Evans blue content in the left ventricular myocardium. Meanwhile, rLj-RGD3 exerted an inhibitory effect on adenosine diphosphate (ADP)-induced platelet aggregation and blocked platelet adhesion to collagen. Treatment with rLj-RGD3 prevented 5-HT, ß-TG and PF4 release and significantly elevated intracellular cAMP levels in a dose-dependent manner but decreased the level of cytosolic-free Ca2+, an aggregation-inducing molecule. These results show that rLj-RGD3 can effectively reduce coronary thrombosis in AMI rats by strongly inhibiting platelet function, indicating that the recombinant RGD toxin protein rLj-RGD3 may serve as a potent clinical therapeutic agent for AMI.

Platelet sequestration with a new-generation autotransfusion device.

BACKGROUND: Autologous platelet-rich plasma (PRP) can be used either to prevent platelets (PLTs) from lesions during extracorporeal circulation or for wound therapy, when processed into PLT gel. The aim of this study was to evaluate the PLT sequestration abilities of a new-generation autotransfusion device. STUDY DESIGN AND METHODS: In this experimental study the discontinuous, new-generation autotransfusion device XTRA was evaluated using fresh donor blood. The blood was processed in four different size bowls (X55, X125, X175, X225 [bowls' size in mL]) using the device's built-in "PLT sequestration program." PLT functionality was tested using aggregometry; for PLT activation, ß-thromboglobulin (ß-TG) and soluble P-selectin levels were determined. Cell damage was assessed by a morphology score and hypotonic shock response. Additionally, PLTs were tested after 6 hours to identify storage lesions. RESULTS: Platelet recovery in the PRP ranged from 39% to 64% and averaged 6.2-fold PLT enrichment as defined by the increase in PLT concentration. The preparation caused minimal cell damage and a decrease in cell function by only 10%, but a slight activation was observed amounting to 9% of the maximal ß-TG release. The efficiency of the preparation, represented by the PLT recovery rate, increased in a linear fashion with the increasing bowl sizes being tested. After 6 hours of storage the prepared PLTs showed an additional 9% loss in function, but only 4% decrease in viability. CONCLUSION: The autotransfusion device XTRA was capable of high-quality perioperative PRP preparation, and the bowl size was found to have an influence on the efficiency of the preparation.

Genetics of periodontitis: Discovery, biology, and clinical impact.

This review provides an update on genome-wide association studies in periodontitis. Studies in populations with European ancestry have dominated the landscape of periodontitis genetics studies but, increasingly, studies in Asian populations are being reported. The review also summarizes evidence for suggested associated genetic variations. The loci associated with genome-wide association studies consist of noncoding variations, many of which are predicted to modulate levels of gene expression. In this article, the biological functions of the genes that are nearest to the associations and their implications for disease etiology are also examined. A major challenge in the genetics of periodontitis is identification of the causal variant(s) underlying associations with periodontitis, elucidation of the molecular mechanisms that are potentially affected by the associated variants, and understanding how they contribute to disease phenotypes and traits. This will allow emerging medical initiatives to make clinical use of genetic discoveries. Large collaborative studies, across research centers and across subspecialties and disciplines, will be required to realize the promise of genetic discovery in periodontitis.

Expression level of CXCL7 in peripheral blood cells is a potential biomarker for the diagnosis of renal cell carcinoma.

There are no blood biomarkers for the diagnosis of renal cell carcinoma (RCC) in routine clinical use. We focused on the gene expression profile of peripheral blood cells obtained from RCC patients to discover novel biomarkers for RCC diagnosis. Using microarray analysis and quantitative verification, CXCL7 was shown to be significantly upregulated in the peripheral blood cells of RCC patients. Importantly, aberrant CXCL7 expression was confirmed even in peripheral blood cells obtained from early stage (pT1a) RCC patients, and the expression level of CXCL7 in peripheral blood cells was a potential independent biomarker for the diagnosis of RCC by receiver operating characteristic curve analysis (sensitivity, 70.0%; specificity, 64.0%; area under the curve = 0.722; multiple logistic regression analysis: odds ratio, 1.07; 95% confidence interval, 1.03-1.11; P = 0.0004). Moreover, CXCL7 expression in peripheral blood cells significantly decreased after resection of the primary tumor. CXCL7 is more highly expressed in PBMCs than in neutrophils from both healthy controls and RCC patients. Interestingly, CXCL7 expression in PBMCs from healthy volunteers was significantly elevated following coculture with RCC cells compared to those cocultured with normal cells as a control. These results suggest that aberrant CXCL7 expression in peripheral blood cells is induced by RCC cells and may serve as a novel biomarker in the diagnosis of RCC.

CXCL7 is a predictive marker of sunitinib efficacy in clear cell renal cell carcinomas.

BACKGROUND: Sunitinib is one of the first-line standard treatments for metastatic clear cell renal cell carcinoma (ccRCC) with a median time to progression shorter than 1 year. The objective is to discover predictive markers of response to adapt the treatment at diagnosis. METHODS: Prospective phase 2 multi-centre trials were conducted in ccRCC patients initiating sunitinib (54 patients) or bevacizumab (45 patients) in the first-line metastatic setting (SUVEGIL and TORAVA trials). The plasmatic level of CXCL7 at baseline was correlated with progression-free survival (PFS). RESULTS: The cut-off value of CXCL7 for PFS was 250 ng ml-1. Patients with CXCL7 plasmatic levels above the cut-off at baseline (250 ng ml-1) had a significantly longer PFS (hazard ratio 0.323 (95% confidence interval 0.147-0.707), P=0.001). These results were confirmed in a retrospective validation cohort. The levels of CXCL7 did not influence PFS of the bevacizumab-treated patients. CONCLUSIONS: CXCL7 may be considered as a predictive marker of sunitinib efficacy for ccRCC patients.

Higher platelet reactivity and platelet-monocyte complex formation in Gram-positive sepsis compared to Gram-negative sepsis.

Platelets may play a role in the high risk for vascular complications in Gram-positive sepsis. We compared the platelet reactivity of 15 patients with Gram-positive sepsis, 17 with Gram-negative sepsis and 20 healthy controls using a whole blood flow cytometry-based assay. Patients with Gram-positive sepsis had the highest median fluorescence intensity (MFI) of the platelet membrane expression of P-selectin upon stimulation with high dose adenosine diphosphate (ADP; P = 0.002 vs. Gram-negative and P = 0.005 vs. control groups) and cross-linked collagen-related peptide (CRP-XL; P = 0.02 vs. Gram-negative and P = 0.0001 vs. control groups). The Gram-positive group also demonstrated significantly higher ADP-induced fibrinogen binding (P = 0.001), as wll as platelet-monocyte complex formation (P = 0.02), compared to the Gram-negative group and had the highest plasma levels of platelet factor 4, ß-thromboglobulin and soluble P-selectin. In contrast, thrombin-antithrombin complex and C-reactive protein levels were comparable in both patient groups. In conclusion, common Gram-positive pathogens induce platelet hyperreactivity, which may contribute to a higher risk for vascular complications.

ß-Thromboglobulin may not reflect platelet activation during haemodialysis with the HeprAN membrane.

BACKGROUND: When blood passes through the extracorporeal circuit during haemodialysis (HD) undesirable effects including platelet degranulation and coagulation activation take place. ß-thromboglobulin (ß-TG) is a sensitive marker of platelet activation. The aim of this study was to investigate platelet degranulation and coagulation activation during HD with the heparin-coated dialysis membrane HeprAN. METHODS: Four HD sessions were evaluated in each of 12 chronic HD patients. None of the patients used oral warfarin, other anticoagulants or antiplatelet drugs. In the first session the HeprAN membrane or a conventional polyflux membrane was used in a randomized manner and thereafter alternately in a cross-over design, and 50% of the conventional dalteparin dose was given at start of HD. Prothrombin fragment 1 + 2 (PF1 + 2), ß-TG and anti-factor Xa activity were measured repeatedly. RESULTS: No dialysis sessions were terminated early due to clotting of the extracorporeal system. Activation of intravascular coagulation as assessed by change in PF1 + 2 during 4 hours of HD was the same with the two membranes. ß-TG concentration decreased significantly during 4 hours of HD with the HeprAN membrane but remained stable with the polyflux membrane. CONCLUSION: There were no differences in clotting scores or coagulation activation with the two membranes. The decrease in ß-TG during HD with the HeprAN membrane suggests ß-TG to be an inferior marker of platelet degranulation when using a heparin-coated dialysis membrane. A possible mechanism for the decline in ß-TG concentration may be adherence of this heparin-binding protein to the heparin-coated dialysis membrane.

PPBP and DEFA1/DEFA3 genes in hyperlipidaemia as feasible synergistic inflammatory biomarkers for coronary heart disease.

BACKGROUND: Coronary heart disease (CHD) is an important complication of atherosclerosis. Biomarkers, which associate with CHD development, are potential to predict CHD risk. To determine whether genes showing altered expression in hyperlipidaemia (H) and coronary heart disease (CHD) patients compared with controls could be CHD risk biomarkers. METHODS: Control, H, and CHD groups represented atherosclerosis to CHD development. Gene profiling was investigated in peripheral blood mononuclear cells using DNA microarrays. Eight selected genes expressed only in H and CHD groups were validated by real-time quantitative reverse transcription PCR and plasma protein determination. RESULTS: α-defensin (DEFA1/DEFA3), pro-platelet basic protein (PPBP), and beta and alpha2 hemoglobin mRNA expression was significantly increased in H and CHD groups compared with controls, but only plasma PPBP and α-defensin proteins were correspondingly increased. CONCLUSION: PPBP and DEFA1/DEFA3 could be potential CHD biomarkers in Thai hyperlipidaemia patients.