The link between high factor VIII to protein C ratio values and poor liver function after major hepatectomy.

Our goal was to assess the coagulation profile in the immediate postoperative time after major liver surgery and its association with the liver function. Our hypothesis is that a decreased synthesis of the coagulation factor levels reflects an impaired liver synthesis following hepatic resection and will be associated with poor outcomes. This is a prospective, observational study recruiting consecutive patients scheduled for major liver resection in a tertiary hospital. Coagulation profile was assessed by conventional assays, viscoelastic assays and coagulation factor levels preoperatively and, on postoperative days 1, 2 and 6. Factor VIII to protein C (FVIII/PC) ratio has been used as a surrogate marker of hemostatic imbalance. Liver function was measured with conventional and indocyanine green (ICG) clearance tests, which were obtained preoperatively and on postoperative days 1 and 2. Sixty patients were recruited and 51 were included in the study. There is a clear increase in FVIII/PC ratio after surgery, which was significantly associated with low liver function, being more pronounced beyond postoperative day 2 and in patients with poorer liver function ( P  < 0.001). High FVIII/PC ratio values were significantly associated with higher postoperative morbidity, prolonged ICU and hospital stay and less survival ( P  < 0.05). High FVIII/PC ratio on postoperative day 2 was found to be predictor of posthepatectomy liver failure (PHLF; area under the ROC curve = 0.8129). Early postoperative high FVIII/PC ratio values are associated with low liver function, PHLF and poorer outcomes in patients undergoing major hepatic resection.

von Willebrand factor to protein C ratio-related thrombogenicity with systemic inflammation is predictive of graft dysfunction after liver transplantation: Retrospective cohort study.

INTRODUCTION: Early allograft dysfunction (EAD) is known to be a prototype of graft failure and ultimately influences long-term graft failure or death. We hypothesized that pretransplant thrombogenicity evaluated by procoagulant and anticoagulant, von Willebrand factor (vWF), factor Ⅷ (FⅧ), protein C (PC) and their imbalance ratio of vWF-to-PC (vWFPCR) and FVIII-to-PC (FⅧPCR), is associated with EAD and 90-day graft failure after living-related liver transplantation (LDLT) and contributes to further exacerbation of graft dysfunction when coexists with systemic inflammation. MATERIAL AND METHODS: Of 1199 prospectively registered LDLT patients, 698 with measurements of each thrombogenicity parameters were analyzed. Risk factors for EAD development were searched and subsequent best cut-offs was calculated according to the receiver operator characteristic curve analysis. When comparing the outcome, multivariable regression analysis and inverse probability of treatment weighting (IPTW) of the propensity score were performed. RESULTS: The prevalence of EAD was 10.7% (n = 75/698) after LDLT. Of parameters, vWFPCR had highest predictivity potential of EAD with the best cut-off of 8.06. The relationship between vWFPCR≥8.06 showed significant association with EAD development (OR [95%CI], 2.55[1.28-5.09], P = 0.008) and 90-day graft failure (HR [95%CI], 2.24 [1-4.98], P = 0.043) after IPTW-adjustment. Furthermore, risk of EAD increased proportionally with increasing C-reactive protein as a continuous metric of systemic inflammation, and more steeply in those with higher thrombogenicity (i.e., higher vWFPCR). Adding vWFPCR to MELD score improved EAD risk prediction by 21.9%. CONCLUSIONS: Pretransplant thrombogenicity assessed by imbalance of pro- and anticoagulant, was significantly associated with EAD and 90-day graft failure after LDLT and this association was worsened by systemic inflammation.

Carboxypeptidase B-Assisted Charge-Based Fractional Diagonal Chromatography for Deep Screening of C-Terminome.

The determination of protein C-termini is of great significance for protein function annotation and proteolysis research. However, the progress of C-terminomics is still far behind its counterpart, N-terminomics, because of the low reactivity of the carboxyl group. Herein, we developed a negative selection strategy, termed carboxypeptidase B-assisted charge-based fractional diagonal chromatography (CPB-ChaFRADIC), to achieve a global C-terminome analysis. The highly reactive carboxypeptidase B cleavage was utilized to reduce the charge state of non-C-terminal peptides. Together with high-performance charge-based fractional diagonal chromatography, the C-terminal peptides could be isolated. Such a strategy was applied for profiling C-termini from Escherichia coli cell lysates and 441 canonical C-termini and 510 neo-C-termini originating from proteolytic processing were identified. These findings represent 2-fold and 5.8-fold that of identified C-termini via direct analysis, respectively. Using parallel digestion with trypsin and LysC, such a strategy enabled the identification of 604 canonical C-termini and 818 neo-C-termini, representing the largest C-terminome data set of E. coli, and no deficiency in His/Lys/Arg-containing C-terminal peptides was observed. The presented CPB-ChaFRADIC strategy is therefore a highly efficient and unbiased strategy for large-scale C-terminome analysis. Furthermore, using the CPB-ChaFRADIC strategy, we identified 107 cleavage sites and 102 substrates of caspase-3 in Jurkat cells, demonstrating that the CPB-ChaFRADIC strategy shows great promise in promoting proteolysis research. Data are available via ProteomeXchange with identifier PXD018520.

Human acute Chagas disease: changes in factor VII, activated protein C and hepatic enzymes from patients of oral outbreaks in Pará State (Brazilian Amazon)

Oral transmission of Chagas disease has been increasing in Latin American countries. The present study aimed to investigate changes in hepatic function, coagulation factor levels and parasite load in human acute Chagas disease (ACD) secondary to oral Trypanosoma cruzi transmission. Clinical and epidemiological findings of 102 infected individuals attended in the State of Pará from October 2013 to February 2016 were included. The most common symptoms were fever (98%), asthenia (83.3%), face and limb edema (80.4%), headache (74.5%) and myalgia (72.5%). The hepatic enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) of 30 ACD patients were higher compared with controls, and this increase was independent of the treatment with benznidazole. Moreover, ACD individuals had higher plasma levels of activated protein C and lower levels of factor VII of the coagulation cascade. Patients with the highest parasite load had also the most increased transaminase levels. Also, ALT and AST were associated moderately (r = 0.429) and strongly (r = 0.595) with parasite load respectively. In conclusion, the present study raises the possibility that a disturbance in coagulation and hepatic function may be linked to human ACD.

Endothelial Dysfunction Is Associated with Mortality and Severity of Coagulopathy in Patients with Sepsis and Disseminated Intravascular Coagulation.

The role of the endothelium in sepsis-associated disseminated intravascular coagulation (DIC) is multifaceted and may contribute substantially to disease severity and outcome. The purpose of this study was to quantify measures of endothelial function, including markers of activation (endocan, Angiopoietin-2 [Ang-2], and von Willebrand Factor), endogenous anticoagulants (tissue factor pathway inhibitor and protein C), and damage-associated factors (High Mobility Group Box 1 [HMGB-1]) in the plasma of patients with sepsis and DIC, and to determine the relationship of these factors with severity of illness and outcome. Plasma samples were collected from 103 adult patients with sepsis within 48 hours of intensive care unit admission. Biomarker levels were measured using commercially available, standardized methods. Disseminated intravascular coagulation was diagnosed according to the International Society of Thrombosis and Hemostasis scoring algorithm. Twenty-eight-day mortality was used as the primary end point. In this study, endothelial damage and dysfunction were associated with the severity of coagulopathy and mortality in DIC patients. Loss of the endogenous anticoagulant protein C and elevation in the vascular regulator Ang-2 were associated with the development of overt DIC. In addition to Ang-2 and protein C, endocan, a biomarker of endothelial activation, and HMGB-1, a mediator of endothelial damage and activation, were significantly associated with mortality. This underscores the contribution of the endothelium to the pathogenesis of sepsis-associated DIC.

Are there differences in basal thrombophilias and C-reactive protein between women with or without PCOS?

RESEARCH QUESTION: Polycystic ovary syndrome (PCOS) women have increased cardiovascular risks, although it is unclear whether the haemostatic system and coagulation contribute to that increased risk. DESIGN: Women attending the Gynecology Unit of the 'Virgen de la Arrixaca' University Hospital (Murcia, Spain) for routine gynaecological examinations between September 2014 and May 2016 were assessed for PCOS using the Rotterdam criteria (hyperandrogenism [H], oligo/amenorrhoea [O] and polycystic ovarian morphology [POM]) and were classified into four phenotypic. In total, 126 cases were identified and 159 control women were selected. All women underwent physical and gynaecological examinations, and blood tests between the second and fifth day of the menstrual cycle. Differences in hormonal, basal thrombophilia and metabolic parameters, and C-reactive protein (CRP) between PCOS and controls were analysed. RESULTS: After adjusting by BMI and age, PCOS women had higher LH (P < 0.001), testosterone (P < 0.001), free testosterone (P = 0.01) and anti-Müllerian hormone (P < 0.001) and lower FSH (P = 0.03) compared with controls, whereas sex hormone-binding globulin was no different. Cases showed significantly higher protein S, glucose, insulin and insulin resistance (HOMA-IR) compared with controls (P < 0.05). There were no differences in protein C levels, antithrombin III, prothrombin time, homocysteine, D-dimer, factor V Leyden, prothrombin G20210A polymorphism or CRP. The H+O phenotype showed the poorest results for insulin and HOMA-IR (P = 0.04 and 0.05). CONCLUSIONS: The results suggest that there are no differences in the basal thrombophilias between women with and without PCOS. However, PCOS with H+O shows the poorest metabolic profile.

Bariatric surgery in morbidly obese individuals affects plasma levels of protein C and thrombomodulin.

Obesity is associated with a prothrombotic milieu and an increased risk for thrombotic events. Bariatric surgery is the most effective treatment for obesity resulting in dramatic weight loss and reduced inflammation and extrinsic coagulation pathway activation. Blood samples were drawn from 60 patients undergoing Roux-en-Y gastric bypass surgery before and 1 year after the intervention. Protein C (PC), activated PC (APC), soluble thrombomodulin (TM), soluble E-selectin (E-Sel), prothrombin time (PT) and activated partial thromboplastin time (aPTT) were evaluated. Both PC (187.4 ± 64.5% before surgery to 118.1 ± 48% 1 year after surgery, p < 0.001) and APC (138.7 ± 64.4% before surgery to 69.1 ± 65.7% after surgery, p < 0.001) were reduced following surgical intervention. TM showed a similar behavior with a reduction of soluble TM after the procedure from 5.7 ± 2.6 to 3.2 ± 1.4 ng/ml (p < 0.001). Similarly, soluble E-Sel was reduced after surgery from 26.6 ± 12.7 to 5.5 ± 4.1 ng/ml (p < 0.001). In contrast, aPTT was not shortened but slightly increased from 29.1 ± 4.8 s. before surgery to 31 ± 4.4 s. (p = 0.001) after surgery and levels of PT were reduced after surgery to 89.6 ± 15.5% from an initial 97.5 ± 13.5% (p < 0.001). In conclusion, we demonstrate a reduction of PC and APC 1 year after bariatric surgery accompanied by a reduction in soluble TM and soluble E-Sel. The reduction of PC and APC is not paralleled by a reduction but in contrast by a prolongation of aPTT suggesting a compensatory upregulation of PC during obesity. The reduction of TM and E-Sel might hint towards an improved endothelial function in this cohort of patients.

A lung image reconstruction from computed radiography images as a tool to tuberculosis treatment control

Background: Tuberculosis (TB) is an infectious lung disease with high worldwide incidence that severely compromises the quality of life in affected individuals. Clinical tests are currently employed to monitor pulmonary status and treatment progression. The present study aimed to apply a three-dimensional (3D) reconstruction method based on chest radiography to quantify lung-involvement volume of TB acute-phase patients before and after treatment. In addition, these results were compared with indices from conventional clinical exams to show the coincidence level. Methods: A 3D lung reconstruction method using patient chest radiography was applied to quantify lung-involvement volume using retrospective examinations of 50 patients who were diagnosed with pulmonary TB and treated with two different drugs schemes. Twenty-five patients were treated with Scheme I (rifampicin, isoniazid, and pyrazinamide), whereas twenty-five patients were treated with Scheme II (rifampicin, isoniazid, pyrazinamide, and ethambutol). Acute-phase reaction: Serum exams included C-reactive protein levels, erythrocyte sedimentation rate, and albumin levels. Pulmonary function was tested posttreatment. Results: We found strong agreement between lung involvement and serum indices pre- and posttreatment. Comparison of the functional severity degree with lung involvement based on 3D image quantification for both treatment schemes found a high correlation. Conclusions: The present 3D reconstruction method produced a satisfactory agreement with the acute-phase reaction, most notably a higher significance level with the C-reactive protein. We also found a quite reasonable coincidence between the 3D reconstruction method and the degree of functional lung impairment posttreatment. The performance of the quantification method was satisfactory when comparing the two treatment schemes. Thus, the 3D reconstruction quantification method may be useful tools for monitoring TB treatment. The association with serum indices are not only inexpensive and sensitive but also may be incorporated into the assessment of patients during TB treatment.(AU)

Alterações da proteína C reativa e fator reumatoide em cães naturalmente infectados por Leishmania spp / Changes in C-reactive protein and rheumatoid factor in dogs naturally infected by Leishmania spp

A leishmaniose visceral canina é uma zoonose considerada doença tropical de prioridade. A leishmaniose afeta vários sistemas do corpo dos cães, incluindo vísceras e pele. A proteína C reativa (PCR) e o fator reumatoide (FR) são exames realizados na medicina para detecção de inflamação e artrites em seres humanos, no entanto, há poucos trabalhos voltados para cães com leishmaniose que demonstrem as alterações ocorridas na PCR e FR. Este trabalho teve como objetivo demonstrar as alterações de PCR e FR e sua correlação com a hiperproteinemia e hiperalbuminemia, além da compararação com o desvio a esquerda presente no exame hematológico. O trabalho foi realizado no Hospital Veterinário do Centro Universitário da Grande Dourados/MS e Centro de Controle de Zoonoses, no qual foram avaliados 34 cães, de diversar raças e idade e submetidos a colheita de sangue venosa para realização de exames em imuno-látex, bioquímica sérica e hemograma, em cães naturalmente infectados por Leishmania spp. Foram utilizados somente cães positivos ao teste rápido DPP® para leishmaniose, juntamente com resultado positivo no exame parasitológico, depois de diagnosticados foram realizados exames hematológicos e bioquímicos. Quando realizado o teste para quantificação de FR em soro sanguíneo, para os 34 animais estudados, foi observado positividade em apenas 1 animal, enquanto que os cães foram positivos para a PCR em 38,23% dos casos estudados. Em casos de animais com leishmaniose é possível estabelecer níveis inflamatórios precocemente, enquanto que o FR demonstrou não ser um bom marcador para animais soropositivos para a doença.(AU)

Canine visceral leishmaniasis is a zoonosis considered a priority tropical disease. The disease affects various body systems of dogs, including viscera and skin. C-reactive protein (CRP) and rheumatoid factor (RF) are tests performed in medicine for the detection of inflammation and arthritis in humans, however, there are few studies aimed at dogs with leishmaniasis that demonstrate changes in CRP and RF. This work aimed to demonstrate the changes of CRP and RF and its correlation with hyperproteinemia and hyperalbuminemia, in addition to the comparison with the left deviation present in the hematological examination. The work was carried out at the Veterinary Hospital of the University Center of Grande Dourados/MS and Zoonoses Control Center, in which 34 dogs of different breeds and ages were submitted to venous blood collection for immuno-latex exams, Biochemistry and blood count in dogs naturally infected with Leishmania spp. Only dogs to the DPP® rapid test for leishmaniasis were used, together with a positive result in parasitological examination, after hematological and biochemical tests were performed. When the test for the quantification of FR in serum was performed, for the 34 animals studied, positivity was observed in only 1 animal, while the dogs were PCR positive in 38.23% of the cases studied. In cases of animals with leishmaniasis it is possible to establish inflammatory levels early, whereas the FR showed not to be a good marker for animals seropositive for the disease.(AU)

Closed Or Open after Source Control Laparotomy for Severe Complicated Intra-Abdominal Sepsis (the COOL trial): study protocol for a randomized controlled trial.

Background: Severe complicated intra-abdominal sepsis (SCIAS) has an increasing incidence with mortality rates over 80% in some settings. Mortality typically results from disruption of the gastrointestinal tract, progressive and self-perpetuating bio-mediator generation, systemic inflammation, and multiple organ failure. Principles of treatment include early antibiotic administration and operative source control. A further therapeutic option may be open abdomen (OA) management with active negative peritoneal pressure therapy (ANPPT) to remove inflammatory ascites and ameliorate the systemic damage from SCIAS. Although there is now a biologic rationale for such an intervention as well as non-standardized and erratic clinical utilization, this remains a novel therapy with potential side effects and clinical equipoise. Methods: The Closed Or Open after Laparotomy (COOL) study will constitute a prospective randomized controlled trial that will randomly allocate eligible surgical patients intra-operatively to either formal closure of the fascia or use of the OA with application of an ANPTT dressing. Patients will be eligible if they have free uncontained intra-peritoneal contamination and physiologic derangements exemplified by septic shock OR a Predisposition-Infection-Response-Organ Dysfunction Score ≥ 3 or a World-Society-of-Emergency-Surgery-Sepsis-Severity-Score ≥ 8. The primary outcome will be 90-day survival. Secondary outcomes will be logistical, physiologic, safety, bio-mediators, microbiological, quality of life, and health-care costs. Secondary outcomes will include days free of ICU, ventilation, renal replacement therapy, and hospital at 30 days from the index laparotomy. Physiologic secondary outcomes will include changes in intensive care unit illness severity scores after laparotomy. Bio-mediator outcomes for participating centers will involve measurement of interleukin (IL)-6 and IL-10, procalcitonin, activated protein C (APC), high-mobility group box protein-1, complement factors, and mitochondrial DNA. Economic outcomes will comprise standard costing for utilization of health-care resources. Discussion: Although facial closure after SCIAS is considered the current standard of care, many reports are suggesting that OA management may improve outcomes in these patients. This trial will be powered to demonstrate a mortality difference in this highly lethal and morbid condition to ensure critically ill patients are receiving the best care possible and not being harmed by inappropriate therapies based on opinion only. Trial registration: ClinicalTrials.gov, NCT03163095.

Simvastatin reverses multiple myeloma serum-induced prothrombotic phenotype in endothelial cells via ERK 1/2 signalling pathway.

: The introduction of new agents in multiple myeloma therapy has increased the overall response rate and improved clinical outcomes, but the increased risk of thrombotic complications impairs the quality of life of patient and the optimal thromboprophylaxis remains unknown. Increasing evidence has shown that statins can prevent venous thrombosis. Hence, we investigated the effects of simvastatin on multiple myeloma serum-related haemostatic imbalance in endothelial cells in vitro. The effects of simvastatin on procoagulant and anticoagulant protein expression were assessed on mixed multiple myeloma serum-treated human umbilical vein endothelial cells (HUVECs). The activity of these proteins was measured by thrombin generation and protein C activation assay. Then, the effects of extracellular signal-regulated kinase (ERK) 1/2 on endothelial activation were assessed by western blot and inhibition assay. We found that simvastatin inhibited multiple myeloma serum-induced expression of procoagulant protein tissue factor and phosphatidylserine and generation of thrombin on HUVECs. In contrast, simvastatin increased multiple myeloma serum-inhibited expression of anticoagulant protein endothelial protein C receptor and activation of protein C on HUVECs. Moreover, simvastatin reversed the multiple myeloma serum-induced prothrombotic phenotype, at least in part, via the inhibition of ERK 1/2 activation in endothelial cells. This study supports the beneficial effects of simvastatin on multiple myeloma serum-induced endothelial haemostatic imbalance, which suggests that simvastatin may serve as a new and appropriate antithrombotic approach for multiple myeloma patients.

Trastornos asociados y factores de riesgo aterogénicos en escolares y adolescentes obesos / Associated disorders and atherogenic risk factors in obese school children and adolescents

Introducción: la obesidad en la edad pediátrica predispone a la enfermedad aterosclerótica precoz en la adultez, independientemente del peso futuro. Objetivo: caracterizar el patrón antropométrico, morbilidad asociada y factores de riesgo aterogénico en obesos. Métodos: se realizó un estudio descriptivo y prospectivo con 62 pacientes obesos atendidos en la consulta de Endocrinología del Hospital Pediátrico William Soler , entre enero y diciembre de 2016. Fueron analizadas variables demográficas, antropométricas y de riesgo aterogénico por medio de prevalencia (por ciento) y pruebas de hipótesis (significativo: p< 0,05 o coeficiente Eta 1). Resultados: la obesidad fue significativa en escolares y el sexo masculino (p= 0,000). La obesidad abdominal (n= 48/77,4 por ciento) predominó en el sexo femenino (n= 20/90,9 por ciento), y entre los 6 y 10 años (n= 14/63,6 por ciento). La obesidad generalizada tuvo diagnóstico significativamente superior que la obesidad abdominal (p= 0,001) y fue independiente del sexo (Eta= 0,049) y la edad (p= 0,066). La prevalencia de acantosis nigricans (n= 39/62,9 por ciento) fue significativa (p= 0,042). Las alteraciones humorales, clínicas y ecográficas analizadas se manifestaron por encima de 70 por ciento en presencia de obesidad abdominal y la generalizada, ambas asociadas con elevación de proteína C reactiva (p< 0,05), y a su vez, la generalizada con remodelación ventricular izquierda (p= 0,049). Conclusión: la obesidad es distintiva de los escolares y del sexo masculino, pero la de tipo abdominal caracteriza a las niñas; existe una baja prevalencia de factores de riesgo aterogénico en los pacientes estudiados. La adiposidad abdominal y la generalizada implican un incremento de la proteína C reactiva plasmática; se evidencia el remodelado ventricular izquierdo cuando existe obesidad generalizada(AU)

Introduction: obesity in the pediatric age predisposes to early atherosclerotic disease in adulthood, regardless of future weight. Objective: to characterize the anthropometric pattern, associated morbidity and atherogenic risk factors in obese patients. Methods: a descriptive and prospective study was carried out with 62 obese patients attended in the Endocrinology clinic of William Soler Pediatric Hospital, from January to December 2016. Demographic, anthropometric and atherogenic risk variables were analyzed by means of prevalence (percent) and hypothesis testing (significant: p< 0.05 or Eta coefficient 1). Results: obesity was significant in schoolchildren and male sex (p= 0.000). Abdominal obesity (n= 48/77.4 percent) predominated in females (n= 20/90.9 percent), and among 6 and 10 years old (n= 14/63.6 percent). Generalized obesity had a significantly higher diagnosis than abdominal obesity (p = 0.001) and didn´t have relation with sex (Eta= 0.049) and age (p= 0.066). The prevalence of acanthosis nigricans (n= 39 / 62.9 percent) was significant (p= 0.042). The humoral, clinical and ultrasonographic alterations analyzed were above 70 percent in the presence of abdominal and generalized obesity, both associated with elevated C-reactive protein (p< 0.05), and at the same time, the generalized with left ventricular remodeling (p= 0.049). Conclusions: obesity is distinctive among school children and males, but abdominal type characterizes girls. There is a low prevalence of atherogenic risk factors in the patients studied. Abdominal and generalized adiposity imply an increase in plasma C-reactive protein. Left ventricular remodeling is evidenced when there is generalized obesity(AU)

A preliminary estimation of tissue factor pathway inhibitor (TFPI) and protein C in patients with intracranial tumors.

BACKGROUND: In patients with intracranial tumors, hypercoagulability is observed due to brain tissue and tumor cells being the source of tissue factor. OBJECTIVES: The aim of the study was to assess tissue factor (TF), tissue factor pathway inhibitor (TFPI) and protein C in the plasma and tumor tissue homogenate in patients with intracranial tumors. MATERIAL AND METHODS: The study included 77 patients; 24 patients were diagnosed with glioma, 20 patients with meningioma and 33 patients with metastatic tumors; mean age - 54 years. The material for the study was the plasma and tumor tissue homogenate sampled during surgery. The control group consisted of 30 controls; mean age - 51 years. In the plasma of all the participants and in tumor tissue homogenate, the concentrations of TF-Ag, TFPI-Ag and protein C activity, and the concentration of total protein were measured. The results were converted per mg of protein. RESULTS: In patients with intracranial tumors, elevated concentrations of TF-Ag, TFPI-Ag and protein C activity were noted, also after the conversion per mg of protein. A 100-fold higher concentration of TF per 1 mg of protein was found in tumor tissue compared to the patients' plasma. In tumor tissue homogenate, a lower TFPI concentration and a lower protein C activity were recorded. CONCLUSIONS: The study confirmed the essential prothrombotic properties in patients with intracranial tumors, expressed with an elevated TF level, as well as a tremendous amount of TF in tumor tissue homogenate derived from tumors. The elevated concentration of TFPI and protein C activity converted per mg of total protein should be analyzed in terms of their pleiotropic function, along with the participation in hemostasis control. It seems that the reduced protein C activity and low TFPI level are associated with the enormous TF value in tumor tissue homogenates.

Association between protein C levels and mortality in patients with advanced prostate, lung and pancreatic cancer.

INTRODUCTION: Procoagulant factors promote cancer progression and metastasis. Protein C is involved in hemostasis, inflammation and signal transduction, and has a protective effect on the endothelial barrier. In mice, administration of activated protein C reduced experimental metastasis. We assessed the association between protein C and mortality in patients with three types of cancer. METHODS: The study population consisted of patients with advanced prostate, non-small cell lung or pancreatic cancer, who participated in the INPACT trial (NCT00312013). The trial evaluated the addition of nadroparin to chemotherapy in patients with advanced malignancy. Patients were divided into tertiles based on protein C at baseline. The association between protein C levels and mortality was evaluated with Cox proportional hazard models. RESULTS: We analysed 477 patients (protein C tertiles: <97, 97-121 and ≥121%). Mean age was 65±9years; 390 (82%) were male; 191 patients (40%) had prostate cancer, 161 (34%) had lung cancer, and 125 (26%) pancreatic cancer. During a median follow-up of 10.4months, 291 patients (61%) died. Median protein C level was 107% (IQR 92-129). In the lowest tertile, 75 patients per 100 patient-years died, as compared to 60 and 54 in the middle and high tertile, respectively. Lower levels of protein C were associated with increased mortality (in tertiles: HR for trend 1.18, 95%CI 1.02-1.36, adjusted for age, sex and nadroparin use; as a continuous variable: HR 1.004, 95%CI 1.00-1.008, p=0.07). CONCLUSION: Protein C seems inversely associated with mortality in patients with advanced prostate, lung and pancreatic cancer. Further research should validate protein C as a biomarker for mortality, and explore the effects of protein C on progression of cancer.

La resistina se asocia con la proteína C reactiva y marcadores de riesgo cardiovascular en niños obesos / Resistin is associated with C reactive protein and cardiovascular risk markers in obese children / A resistina associa-se à proteína C reativa e aos marcadores de risco cardiovascular em crianças obesas

El objetivo del trabajo fue evaluar los niveles de resistina sérica y su asociación con la proteína C reactiva (PCR-hs), óxido nítrico (NO) y lípidos plasmáticos (LP) en sujetos de edad pediátrica. Participaron 366 niños y adolescentes (10-16 años), agrupados en eutróficos (n=162) y obesos (n=204). Se les estudió peso, talla, circunferencia de la cintura, resistina sérica, glucosa e insulina basal, LP, NO, PCR-hs, malondialdehído y tensión arterial. Se calculó el IMC, el índice cintura-talla (IC/T) y el HOMA-IR. Se utilizaron las pruebas t de Student, ANOVA, U de Mann y Whitney o Kruskal- Wallis para comparar entre grupos y la correlación de Spearman para determinar asociación entre variables. Los obesos masculinos presentaron niveles superiores de resistina (p<0,05). El género femenino presentó valores más altos de resistina en eutróficos (p=0,012) y con IC/T normal (p=0,011). A mayor concentración de resistina los eutróficos presentaron niveles más altos de triacilglicéridos, pero los obesos mostraron niveles más bajos de triacilglicéridos, HDLc y NO, más altos de PCR-hs y mayor IMC. Los resultados sugieren que la resistina podría ser un factor de riesgo para la enfermedad cardiovascular por su asociación positiva con la PCR-hs e inversa con el NO y la HDLc, parámetros involucrados en la inflamación y la disfunción endotelial.

The aim of this study was to evaluate seric levels of resitin and their association with high-sensitivity C Reactive Protein (hs-CRP), nitric oxide (NO) and plasmatic lipids (PL) in a pediatric age population. A total of 366 children and adolescents (between 10-16 years old) participated, and were grouped into eutrophic (n=162) and obese (n=204). Weight, height, waist circumference, resistin, fasting blood glucose and insulin levels, PL, hs-CRP, NO, malondialdehyde and blood pressure were measured. BMI, waist to height ratio (W/HR) and HOMA-IR were calculated. T-student, ANOVA, Mann-Whitney U-value or Kruskal-Wallis were used to compare between groups and Spearman correlation was used to determine association among variables. Male obese subjects showed higher resistin levels (p<0.05). Female subjects showed higher resistin values in the eutrophic group (p=0.012) and in the normal W/HR (p=0.011). At higher levels of resistin, the eutrophic group showed higher levels of triacylglycerides, but the obese group showed lower triacylglycerides, HDLc and NO levels and higher hs-CRP levels and BMI. These results suggest that resistin could be a risk factor for cardiovascular disease because of its positive association with hs-CRP and inverse association with NO and HDLc, parameters involved in inflammation and endothelial dysfunction.

O objetivo da pesquisa foi avaliar os níveis séricos de resistina sérica e sua associação com a proteína C-reativa (PCR-hs), óxido nítrico (NO) e lipídios plasmáticos (LP) em crianças e adolescentes. O estudo envolveu 366 crianças e adolescentes (10-16 anos), agrupados em eutróficos (n=162) e obesos (n=204). Os sujeitos foram estudados em relação ao peso, altura, circunferência da cintura, resistina sérica, glicose e insulina basal, LP, NO, PCR-hs, malondialdeído e pressão arterial. Os IMC, índice cintura-altura (IC/A) e HOMA-IR foram calculados. Foram utilizados os Testes t de Student, ANOVA, U de Mann e Whitney ou Kruskal-Wallis para comparar entre os grupos e a correlação de Spearman para verificar a associação entre variáveis. Os obesos masculinos mostraram níveis mais elevados de resistina (p<0,05). O sexo feminino apresentou valores mais altos de resistina em eutróficos (p=0,012) e com IC/T normal (p=0,011). À maior concentração de resistina, os eutróficos apresentaram maiores níveis de triacilglicerídeos, mas os obesos apresentaram níveis mais baixos de triacilglicerídeos, HDLc e NO, mais altos de PCR-hs e maior IMC. Os resultados sugerem que a resistina poderia ser um fator de risco para a doença cardiovascular devido à sua associação positiva com a PCR-hs e inversa com o NO e a HDLc, parâmetros envolvidos na inflamação e disfunção endotelial.

Activated protein C levels and outcome in patients with cardiogenic shock complicating acute myocardial infarction.

INTRODUCTION: In patients with severe sepsis, low levels of activated protein C are associated with high morbidity and mortality. In an observational study we investigated whether patients with cardiogenic shock have decreased circulatory levels of activated protein C, and if these are associated with increased mortality. METHODS: We measured serum activated protein C and interleukin-6 levels in 43 patients with cardiogenic shock following acute myocardial infarction and in 15 control patients with uncomplicated myocardial infarction at days 0-5 and 7 after the onset of shock/myocardial infarction. RESULTS: Activated protein C levels were significantly lower in patients with cardiogenic shock compared to controls. In cardiogenic shock patients, there was no difference in activated protein C levels at baseline, whereas activated protein C levels significantly declined in 28-day non-survivors at day 2, compared with 28-day survivors. Lower levels of activated protein C were associated with a higher degree of vasopressor need, whereas there was no significant association with multiple organ failure in the first days. Regarding the inflammatory response, a strong inverse correlation was observed between interleukin-6 and activated protein C levels. CONCLUSION: Patients with cardiogenic shock who did not survive up to 28 days showed a decline in activated protein C levels during the course of the disease, which was inversely correlated with interleukin-6. This study underlines sustained inflammatory mechanisms in the development and persistence of cardiogenic shock, highlighting a potential effect of anti-inflammatory interventions early during cardiogenic shock.

Genetic Risk Factors of Venous Thromboembolism in the East Algerian Population.

Many genetic risk factors have been identified for causing venous thromboembolism (VTE). Most of them affect the function of natural anticoagulant pathways, particularly the protein C system, although recent studies suggest a role of components of the hematopoietic pathway in the etiology of venous thrombosis. In this case-control study, we aimed to determine the frequency of prothrombin G20210A and factor V Leiden (FVL) G1691A polymorphisms and protein C, protein S, and antithrombin III deficiencies in the East Algerian population and to investigate whether these genetic factors are associated with VTE. On the other hand, our study tends to evaluate the status of JAK2V617F and calreticulin (CALR) mutations among these cases. The participants consisted of 121 cases with VTE and 146 healthy controls. Polymorphisms of FVL G1691A and prothrombin G20210A were genotyped by polymerase chain reaction (PCR) restriction fragment length polymorphism. JAK2-V617F and calreticulin mutations were analyzed by quantitative PCR and PCR followed by capillary electrophoresis sequencing, respectively. Protein C, protein S, and antithrombin levels were determined and then hereditary deficiencies were identified. Of all cases and controls, none was a carrier of the antithrombin III deficiency, prothrombin gene G20210A, and CALR mutations. Only 1 case reported having a positive JAK2 mutation (mutant allele burden was 15%). The FVL mutation (GA/AA) was found in 14 (11.6%) cases and 2 (1.4%) controls and it was significantly different between both the groups ( P = .001). Deficiencies of protein S and protein C were detected in 17 (18.8%) cases. The univariate analysis resulted in a significant impact of FVL (odds ratio [OR] = 9.4, 95% confidence interval [CI] = 2.1-42.3; P = .003) and of protein S deficiency (OR = 16.9, 95% CI =2.1-132.8, P = .007) on the VTE status. Both factors stayed significant after adjustment for sex and age. The OR of the protein C deficiency was slightly elevated (OR = 6.4, 95% CI = 0.7-55.5), but it did not reach the level of statistical significance ( P = .091), and it was therefore not considered as a risk factor. In conclusion, coagulant factor V gene G1691A mutation and protein S deficiency constitute important genetic risk factors in patients with VTE in Eastern Algeria. The somatic mutation of JAK2 V617F and CALR mutations are less frequent causes of VTE, thus routine testing for these mutations is not recommended.

C-reactive protein serum level in patients with psoriasis before and after treatment with narrow-band ultraviolet B

Abstract: Background: C-reactive protein is an inflammatory biomarker and its level increases in the serum of psoriatic patients. Its level is also associated with Psoriasis Area and Severity Index score. Objective: The aim of this study was to assess the decrement of serum C-reactive protein level with narrow-band ultraviolet B (NB-UVB) therapy. Methods: C-reactive protein serum levels in psoriasis patients were measured before and after treatment with NB-UVB and the data were analyzed in relation to the Psoriasis Area and Severity Index score improvement. Results: Baseline C-reactive protein levels among psoriatic patients were higher than normal. These levels decreased significantly after treatment (P<0.001). At the beginning of the study, patients with higher levels of C-reactive protein also had more extensive and severe skin involvement. The highest decrease in C-reactive protein was observed in patients who responded better to the treatment and achieved a higher Psoriasis Area and Severity Index 75%. There was an association between baseline Psoriasis Area and Severity Index scores and C-reactive protein levels. Conclusion: Patients with moderate to severe plaque-type psoriasis had active systemic inflammation, which was demonstrated by increased levels of C-reactive protein. Furthermore, skin disease severity was correlated with C-reactive protein levels. Phototherapy healed the psoriatic skin lesions and reduced inflammation, while decreasing C-reactive protein levels.

Hemostatic variables, plasma lactate concentration, and inflammatory biomarkers in dogs with gastric dilatation-volvulus.

OBJECTIVE: Prospective characterization of hemostastatic variables, plasma lactate concentration, and inflammatory biomarkers in dogs with gastric dilatation-volvulus (GDV). MATERIAL AND METHODS: Coagulation variables (platelets, prothrombin time [PT], activated partial thromboplastin time [aPTT], fibrinogen, antithrombin [AT], protein C [PC], protein S [PS], D-dimers), plasma lactate concentration and inflammatory biomarkers (C-reactive protein, white blood cell [WBC] count, lymphocyte and neutrophil numbers) were assessed in 20 dogs with GDV presented between 2011 and 2012. Blood was taken preoperatively and at days 1 and 3 postoperatively. The prognostic value of these variables before and after surgery was evaluated as well as the behavior of variables during the study. RESULTS: Overall, 7/20 (35%) dogs did not survive; two dogs (29%) were euthanized during surgery due to severe gastric necrosis and 5 (71%) dogs after surgery due to sepsis and disseminated intravascular coagulopathy. Prior to surgery, median plasma lactate concentration was significantly (p = 0.01) lower in survivors (6.2 mmol/l, range 1.9-9.7 mmol/l) when compared to non-survivors (11.8 mmol/l, range 7.5-16.2 mmol/l). In dogs dying after surgery, significantly higher plasma lactate concentration, coagulation times and D-dimer concentration were present as well as lower fibrinogen concentration and activity of PC and AT compared to survivors. At discharge, activity of AT, PC and PS were markedly below the reference interval in 6/13 (46%), 11/13 (85%), and 8/13 (62%) dogs, respectively. CLINICAL RELEVANCE: Only lactate plasma concentration was of preoperative prognostic value. After surgery, severe abnormalities of coagulation variables, especially the endogenous anticoagulants were present in most of the dogs. The severity of the abnormalities was associated with survival.

Prospective evaluation of protein C and factor VIII in prediction of cancer-associated thrombosis.

Venous thromboembolism (VTE) is a preventable disease, yet it is one of the leading causes of death among patients with cancer. Improving risk stratification mechanisms will allow us to personalize thrombo-prophylaxis strategies. We sought to evaluate Collagen and Thrombin Activated Platelets (COAT-platelets) as well as protein C and factor VIII as biomarkers predictive of cancer-associated thrombosis in a prospective cohort of patients with cancer. Protein C was selected as a candidate based on bioinformatics prediction. Blood samples were collected before chemotherapy. All specimen processing was blinded to clinical data. Surveillance and adjudication of the main outcome of VTE was performed for up to 1 year. We used Cox proportional hazard regression to measure the association of biomarkers and incident events using SAS 9.2 for all statistical analysis. Death was modeled as a competing event. Among 241 patients followed for an average of 10.4 months, 15% died and 13% developed a VTE. COAT-platelets were not predictive of VTE. Low levels of pre-chemotherapy protein C (<118%) (HR 2.5; 95% CI 1.1-5.5) and high baseline factor VIII (>261% I) (HR 3.0; 95% CI 1.1-8.0) were predictive of VTE after adjusting for age, Khorana prediction risk, metastatic disease and D dimer. In addition, low protein C was predictive of overall mortality independent of age, metastatic disease and functional status (HR 2.8; 95% CI 1.3-6.0). Addition of these biomarkers to cancer-VTE risk prediction models may add to risk stratification and patient selection to optimize thrombo-prophylaxis.