Citrullinated and homocitrullinated low- density lipoprotein in rheumatoid arthritis.

Objective: Antibodies to citrullinated and homocitrullinated (also known as carbamylated) proteins, specific for rheumatoid arthritis (RA), are associated with cardiovascular disease (CVD). Immune complexes containing these proteins have been identified in the atherosclerotic plaque of CVD patients. In mice, homocitrullinated low-density lipoprotein (HomoCitLDL) promotes foam cell formation, which is critical in the pathogenesis of atherosclerosis. We aimed to investigate the atherogenic potential of HomoCitLDL and citrullinated low-density lipoprotein (CitLDL) in RA.Method: Human LDL was homocitrullinated in potassium cyanate and citrullinated by rabbit skeletal muscle peptidyl arginine deiminase-2. The modifications were confirmed by mass spectrometry. Primary human monoctyes from healthy subjects (N = 8) were differentiated to macrophages using macrophage colony-stimulating factor and incubated with modified LDL. Foam cells were visualized using Oil Red O staining. Serum from RA patients (N = 101) and controls (N = 32) was tested for immunoglobulin G antibodies to modified LDL using enzyme-linked immunosorbent assay.Results: HomoCitLDL and CitLDL strongly induced foam cell production (> 90%) versus unmodified LDL (11%) (p < 0.0001). The characteristics of the RA subjects were: 73% females, median age 60 [interquartile range (IQR) 17] years and disease duration 7.5 (IQR 13) years; 11% had a prior major cardiovascular event, 66% were ever smokers, 32% had hypertension, 33% dyslipidaemia, and 14% diabetes. Antibodies to HomoCitLDL were detected in 18% of RA patients; they were significantly associated with dyslipidaemia [odds ratio (OR) 3.86; 95% confidence interval (CI) 1.22, 12.17] and antibodies to other homocitrullinated antigens (OR 10.61; 95% CI 1.31, 86.11).Conclusions: HomoCitLDL and CitLDL have atherogenic properties in vitro. Antibody responses to HomoCitLDL, but not CitLDL, were detected in RA patients.

Prevalence and Characteristics of Metabolic Syndrome Differ in Men and Women with Early Rheumatoid Arthritis.

Objective: Metabolic syndrome (MetS) prevalence in early rheumatoid arthritis (ERA) is conflicting. The impact of sex, including menopause, has not been described. We estimated the prevalence and factors associated with MetS in men and women with ERA. Methods: A cross-sectional study of the Canadian Early Arthritis Cohort (CATCH) was performed. Participants with baseline data to estimate key MetS components were included. Sex-stratified logistic regression identified baseline variables associated with MetS. Results: The sample included 1543 participants; 71% were female and the mean age was 54 (SD 15) years. MetS prevalence was higher in men 188 (42%) than women 288 (26%, P < 0.0001) and increased with age. Frequent MetS components in men were hypertension (62%), impaired glucose tolerance (IGT, 40%), obesity (36%), and low high-density lipoprotein cholesterol (36%). Postmenopausal women had greater frequency of hypertension (65%), IGT (32%), and high triglycerides (21%) compared with premenopausal women (P < 0.001). In multivariate analysis, MetS was negatively associated with seropositivity and pulmonary disease in men. Increasing age was associated with MetS in women. In postmenopausal women, corticosteroid use was associated with MetS. Psychiatric comorbidity was associated with MetS in premenopausal women. MetS status was not explained by disease activity or core RA measures. Conclusion: The characteristics and associations of MetS differed in men and women with ERA. Sex differences, including postmenopausal status, should be considered in comorbidity screening. With this knowledge, the interplay of MetS, sex, and RA therapeutic response on cardiovascular outcomes should be investigated.

An electromechanical left ventricular wedge model to study the effects of deformation on repolarization during heart failure.

Heart failure is a major and costly problem in public health, which, in certain cases, may lead to death. The failing heart undergo a series of electrical and structural changes that provide the underlying basis for disturbances like arrhythmias. Computer models of coupled electrical and mechanical activities of the heart can be used to advance our understanding of the complex feedback mechanisms involved. In this context, there is a lack of studies that consider heart failure remodeling using strongly coupled electromechanics. We present a strongly coupled electromechanical model to study the effects of deformation on a human left ventricle wedge considering normal and hypertrophic heart failure conditions. We demonstrate through a series of simulations that when a strongly coupled electromechanical model is used, deformation results in the thickening of the ventricular wall that in turn increases transmural dispersion of repolarization. These effects were analyzed in both normal and failing heart conditions. We also present transmural electrograms obtained from these simulations. Our results suggest that the waveform of electrograms, particularly the T-wave, is influenced by cardiac contraction on both normal and pathological conditions.

Development of nalidixic acid amphotericin B vancomycin (NAV) medium for the isolation of Campylobacter ureolyticus from the stools of patients presenting with acute gastroenteritis.

Recently, Campylobacter ureolyticus has been detected for the first time in the faeces of patients with acute gastroenteritis using polymerase chain reaction (PCR) techniques. Cultural isolation of C. ureolyticusis is not possible using the established selective methods for the isolation of thermophilic Campylobacter spp. from faeces. The aim of the current study is to develop a new selective medium capable of isolating C. ureolyticus from faecal samples. The newly-developed medium consists of Anaerobe Basal Agar with 10 g/L additional agar, 2 g/L sodium formate and 3 g/L sodium fumarate dibasic, to which 10 mg/L nalidixic acid, 10 mg/L amphotericin B and 20 mg/L vancomycin (NAV) are added as selective agents. Validation studies have shown that this experimental selective medium completely inhibits growth of Candida spp. and of Enterococcus spp. and permits reduced growth of selected coliforms and Proteus spp. Growth of Campylobacter ureolyticus on NAV medium is optimal in anaerobic and enriched hydrogen atmospheres. Additionally, an overnight enrichment step using Bolton broth to which 2 g/L sodium formate, 3 g/L sodium fumarate dibasic and the NAV supplement are added, in place of the commercial Bolton broth supplement, allows improved recovery of C. ureolyticus from patients' faeces.

Efficacy of biologic agents in improving the Health Assessment Questionnaire (HAQ) score in established and early rheumatoid arthritis: a meta-analysis with indirect comparisons.

OBJECTIVES: The Health Assessment Questionnaire (HAQ) is a validated physical function measure. It is predictive for disability and mortality. The objective of this study was to determine the comparative efficacy of biologic agents in improving HAQ in patients with established RA who failed DMARDs or anti- TNF agents and in early RA (ERA). METHODS: We performed random effects meta-analyses of published randomised, placebo-controlled trials. Outcome was the mean difference in change in HAQ for biologic agents compared to controls (ΔHAQB-ΔHAQC). Indirect comparisons of the different biologic drugs were conducted using the Q-test based on analysis of variance. Meta-regression was performed using the method of moments. RESULTS: Twenty-eight trials were included: 19 with DMARD-failures; 4 with anti-TNF-failures and 5 ERA. The following biologics were represented: abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab and tocilizumab. Efficacy of biologics at reducing HAQ was significantly different based on prior treatment (p=0.001). In RA patients with DMARD failures, ΔHAQB-ΔHAQC was -0.22; 95%CI: -0.24, -0.20 (I2=55%). Infliximab, abatacept and tocilizumab had lower ΔHAQB-ΔHAQC compared to other biologics (p<0.02). In anti-TNF-failures, ΔHAQB-ΔHAQC was -0.36; 95%CI: -0.42, -0.30 (I2=0%). In ERA, methotrexate-naïve trials, ΔHAQB-ΔHAQC was -0.19; 95% CI: -0.26, -0.13 (I2=0%). There were no significant differences in the efficacy of different biologics for anti-TNF failures and ERA. CONCLUSIONS: Biologic agents were efficacious at lowering HAQ in RA. Differences between agents in RA with DMARD failures were less than the minimally clinically important difference for HAQ; therefore, the clinical significance of these differences is unclear.

Standardization of laparoscopic left hemicolectomy: a single-center experience of 484 cases.

AIM: Laparoscopic surgery has become recognized as an established technique for colon diseases and many different surgical techniques have been described. The aim of our study is to show the results of a single institution where a standardized operative and perioperative procedure for laparoscopic left hemicolectomy (LLH) has been used. METHODS: Between January 2005 and April 2011, 484 patients underwent LLH for colon diseases. Data collected included age, indication for surgery, ASA class, body mass index, operating time, intra and post-operative complications, conversion rate, length of hospital stay, tumor stage, number of lymph nodes harvested, mortality, and a 30-day readmission rate. RESULTS: We found 299 cancer, 29 large dysplastic polyps and 156 complicated diverticular diseases. Average operation time was 120 minutes. The average hospital stay was 5.7 days. In the cancer group, the average number of lymph nodes harvested was 12.7. The intraoperative and early postoperative complications were 3.3% and 10.7 % respectively. The conversion rate was 3.7%. The 30-day readmission rate was 3%. The 30-day mortality rate was 0.4%. CONCLUSION. The standardization of the LLH technique might reduce the technical difficulties and complications. Its potential benefits include the standardization of surgical instrument sets, the definition of benchmarks for conversion before making any inappropriate investment in time and equipment, low rates of complications and readmission rate.

Standardization of laparoscopic left hemicolectomy: a single-center experience of 484 cases.

Aim: Laparoscopic surgery has become recognized as an established technique for colon diseases and many different surgical techniques have been described. The aim of our study is to show the results of a single institution where a standardized operative and perioperative procedure for laparoscopic left hemicolectomy (LLH) has been used. Methods: Between January 2005 and April 2011, 484 patients underwent LLH for colon diseases. Data collected included age, indication for surgery, ASA class, body mass index, operating time, intra and post-operative complications, conversion rate, length of hospital stay, tumor stage, number of lymph nodes harvested, mortality, and a 30-day readmission rate. Results: We found 299 cancer, 29 large dysplastic polyps and 156 complicated diverticular diseases. Average operation time was 120 minutes. The average hospital stay was 5.7 days. In the cancer group, the average number of lymph nodes harvested was 12.7. The intraoperative and early postoperative complications were 3.3% and 10.7 % respectively. The conversion rate was 3.7%. The 30-day readmission rate was 3%. The 30-day mortality rate was 0.4%. Conclusion: The standardization of the LLH technique might reduce the technical difficulties and complications. Its potential benefits include the standardization of surgical instrument sets, the definition of benchmarks for conversion before making any inappropriate investment in time and equipment, low rates of complications and readmission rate.

Effects of deformation on transmural dispersion of repolarization using in silico models of human left ventricular wedge.

Mechanical deformation affects the electrical activity of the heart through multiple feedback loops. The purpose of this work is to study the effect of deformation on transmural dispersion of repolarization and on surface electrograms using an in silico human ventricular wedge. To achieve this purpose, we developed a strongly coupled electromechanical cell model by coupling a human left ventricle electrophysiology model and an active contraction model reparameterized for human cells. This model was then embedded in tissue simulations on the basis of bidomain equations and nonlinear solid mechanics. The coupled model was used to evaluate effects of mechanical deformation on important features of repolarization and electrograms. Our results indicate an increase in the T-wave amplitude of the surface electrograms in simulations that account for the effects of cardiac deformation. This increased T-wave amplitude can be explained by changes to the coupling between neighboring myocytes, also known as electrotonic effect. The thickening of the ventricular wall during repolarization contributes to the decoupling of cells in the transmural direction, enhancing action potential heterogeneity and increasing both transmural repolarization dispersion and T-wave amplitude of surface electrograms. The simulations suggest that a considerable percentage of the T-wave amplitude (15%) may be related to cardiac deformation.

Mortalidad post infarto del miocardio en Chile: comparación de los registros de angioplastía primaria versus trombolisis / Mortality in myocardial Infarction in Chile: a comparison from the angioplasty and thrombolysis registries

Antecedentes: Desde el año 2005, se ha implementado en nuestro país un conjunto de políticas públicas para permitir un acceso universal al tratamiento trombolítico a los pacientes con infarto agudo del miocardio (IAM). Para evaluar sus resultados es importante establecer los estándares locales de las distintas opciones de reperfusión. Objetivos: 1) Comparar la mortalidad precoz y alejada de los pacientes con IAM sometidos a angioplastía primaria (angioplastía) versus los sometidos a trombolisis, en Chile. 2) Establecer los factores de riesgo de mortalidad en estos pacientes. Métodos: Utilizando los registros nacionales de angioplastía (RENAC) y de IAM (GEMI), seleccionamos a todos los pacientes con IAM tratados con angioplastía o trombolisis, durante los años 2003 y 2004. Entre ellos, comparamos mediante prueba de t de Student o chi-cuadrado, según correspondiera, sus características basales y su mortalidad hospitalaria, a 30 días, ya 12 y 24 meses. Además se hizo análisis de regresión logística multivariado para identificar los factores que independientemente se asociaron a mayor riesgo de mortalidad. Resultados: En el estudio se incluyeron 857 pacientes con IAM que recibieron trombolisis y 700 tratados con angioplastía. No hubo diferencias entre los grupos en cuanto a edad, sexo, incidencia de diabetes mellitus, hipertensión arterial, hiperlipidemia ni antecedentes de IAM previo. La mortalidad fue significativamente menor en los pacientes tratados con angioplastía (HR crudo: 0,65; 95 por ciento IC: 0,49-0,86, p=0,03). La diferencia fue evidente tanto para la mortalidad precoz como para la alejada. Así, alcanzó un 10,6 vs 6,3 por ciento (p <0,01), durante la hospitalización inicial, un 11,2 vs 8,1 por ciento a los 30 días (p <0,01), un 15,3vs 10,6 por ciento (p<0,01) a los 12 meses, y un 21,1 vs 11,7 por ciento a los 24 meses (p<0,001), para trombolisis y angioplastía respectivamente. Otros factores que independientemente se asociaron...

Background: From 2005, thrombolysis has been made available as a public health policy to treat acute myocardial infarction (AMI) in Chile. A comparison with results obtained locally with primary PTCA is relevant Aim: to compare early and late mortality in AMI between thrombolysis and PTCA treatments and to determine risk factors associated to mortality Methods: Data from national registries of PTCA (RENAC) and trombolysis (GEMI) of patients treated from 2003 through 2004 were analyzed. Early (<30day) and late (12 and 24 months) mortality was compared between groups. Logistic regression analysis was used to identify independent risk factors for mortality. Results: 857 patients received thrombolysis and 700 were treated by PTCA. Age, sex, prevalence of diabetes, hypertension, dyslipidemia and prior AMI were similar in both groups. PTCA was associated to lower mortality rates compared to thrombolysis (crude HR 0.65, 95 percent C. I. 0.49-0.86, p= 0.03). Early, 12month and 24month mortality rates for thrombolysis and PTCA treated patients were 10.6 vs. 6.3 percent, , 15.3 vs. 10.6 percent and 21.1 vs. 11.7 percent, respectively (p<0.01). Increased age, female gender and presence of diabetes were independently associated to mortality, overall. Conclusion: Primary PTCA was associated to lower early and late mortality rates compared to thrombolysis in Chilean registry data.

Objective assessment of gastroesophageal reflux after extended Heller myotomy and total fundoplication for achalasia with the use of 24-hour combined multichannel intraluminal impedance and pH monitoring (MII-pH).

This study aims to evaluate by the use of 24-hour combined multichannel intraluminal impedance and pH monitoring (MII-pH) the efficacy of the Nissen fundoplication in controlling both acid and nonacid gastroesophageal reflux (GER) in patients that underwent Heller myotomy for achalasia. It has been demonstrated that fundoplication prevents the pathologic acid GER after Heller myotomy, but no objective data exists on the efficacy of this antireflux surgery in controlling all types of reflux events. The study population consisted of 20 patients that underwent laparoscopic Heller myotomy and Nissen fundoplication for achalasia. All patients were investigated with manometry and MII-pH. MII-pH showed no evidence of postoperative pathologic GER. The overall number of GER episodes was normal in both the upright and recumbent position. This reduction was obtained because of the postoperative control of both the acid and nonacid reflux episodes. The Nissen fundoplication adequately controls both acid and nonacid GER after extended Heller myotomy. Further controls with MII-pH are warranted to check at a longer follow-up for the efficacy of this antireflux procedure in achalasic patients.

Receptor-interacting protein 2 is a marker for resolution of peritoneal dialysis-associated peritonitis.

There are no predictive factors for peritoneal dialysis-associated peritonitis; however, its resolution correlates with a cell-mediated Th1 immune response. We tested the hypothesis that induction of receptor-interacting protein 2 (RIP2), an assumed kinase linked with Th1 responses, is a useful marker in this clinical setting. Basal RIP2 expression was measured in human immune cells and during dialysis-associated peritonitis. RIP2 increased with bacterial toxin cell activation and the temporal profile for this differed depending on immune cell involvement in the innate or adaptive phases of the response. Importantly, RIP2 expression increased in peritoneal immune cells during dialysis-associated peritonitis and this upregulation correlated with clinical outcome. An early induction in peritoneal CD14(+) cells correlated with rapid resolution, whereas minimal induction correlated with protracted infection and with catheter loss in 36% of patients. These latter patients had higher levels of MCP-1 consistent with a delayed transition from innate to adaptive immunity. Our study shows that upregulation of RIP2 is a useful marker to monitor dialysis-associated peritonitis and in predicting the clinical outcome of these infections.

Levocetirizine in the treatment of chronic idiopathic urticaria: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Chronic urticaria is a common skin condition. It is frequently a disabling disease because of the persistence of clinical symptoms, the unpredictable course and its negative influence on the quality of life. OBJECTIVES: To determine whether levocetirizine is efficacious in the treatment of chronic idiopathic urticaria. METHODS: A randomized, double-blind, placebo-controlled study was conducted in 106 patients with a diagnosis of chronic idiopathic urticaria. A 1-week single blind placebo run-in period (baseline) was followed by a 6-week double blind active treatment period. The patients were randomized to receive one of the following treatments once daily: (a) oral levocetirizine 5 mg, or (b) oral placebo. The study ended after another 1-week single blind placebo washout period. RESULTS: The evaluable population consisted of 100 patients. Levocetirizine administered once daily is effective and well tolerated in the treatment of the symptoms of chronic idiopathic urticaria and in improving the patient's quality of life. Levocetirizine was superior to placebo in reducing the mean total symptoms score as well as individual symptoms, the number of daily episodes and the number of weals, the overall severity of symptoms and the quality of life. The significant beneficial effects of levocetirizine lasted only during the active trial, while at follow-up there was a significant worsening of all the variables evaluated in this study, after the end of the active trial (week 7). CONCLUSIONS: A global assessment indicates that levocetirizine 5 mg once daily is an effective agent in patients with chronic idiopathic urticaria, as its action provides a rapid and satisfactory control of the symptoms and measures of subjective disease, although this is limited to the duration of treatment.

Identification of specific molecular structures of human immunodeficiency virus type 1 Tat relevant for its biological effects on vascular endothelial cells.

Human immunodeficiency virus type 1 (HIV-1) Tat transactivates viral genes and is released by infected cells, acting as a soluble mediator. In endothelial cells (EC), it activates a proangiogenic program by activating vascular endothelial growth factor receptor type 2 (VEGFR-2) and integrins. A structure-activity relationship study was performed by functional analysis of Tat substitution and deletion variants to define the Tat determinants necessary for EC activation. Variants were made (i) in the basic and (ii) in the cysteine-rich domains and (iii) in the C-terminal region containing the RGD sequence required for integrin recognition. Our results led to the following conclusions. (i) Besides a high-affinity binding site corresponding to VEGFR-2, EC express low-affinity binding sites. (ii) The basic and the cysteine-rich variants bind only to the low-affinity binding sites and do not promote tyrosine phosphorylation of VEGFR-2. Furthermore, they have a reduced ability to activate EC in vitro, and they lack angiogenic activity. (iii) Mutants with mutations in the C-terminal region are partially defective for in vitro biological activities and in vivo angiogenesis, but they activate VEGFR-2 as Tat wild type. In conclusion, regions encoded by the first exon of tat are necessary and sufficient for activation of VEGFR-2. However, the C-terminal region, most probably through RGD-mediated integrin engagement, is indispensable for full activation of an in vitro and in vivo angiogenic program.

Human immunodeficiency virus-1 (HIV-1)-Tat protein promotes migration of acquired immunodeficiency syndrome-related lymphoma cells and enhances their adhesion to endothelial cells.

Human immunodeficiency virus-1 (HIV-1)-Tat, the transactivating gene product of HIV-1, has been shown to interact with different cell types, inducing gene expression, altering their growth and migratory behavior. In this study we examined whether Tat might affect functions of acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphoma (NHL), relevant to the in vivo dissemination. Our results show that Tat significantly augmented the motility of the two AIDS-related Burkitt's lymphoma cell lines (AS283 and PA682PB) and AIDS-primary effusion lymphoma cell line (HBL-6-AIDS-PEL). Mutations in RGD or basic domain of Tat (KGE-MBP and LxI-MBP, respectively) sharply reduced migration compared with wild type, suggesting that both domains are required for migration. In contrast, a Tat protein mutation outside the active domains (NH(2)-TAT-GST) did not reduce lymphoma cell migration. The treatment of lymphoma cells with Tat did not influence their adhesion to matrix proteins or to human vascular endothelial cells, but endothelial cells treated with Tat became more adhesive to lymphoma cells. Flow cytometric analysis showed that treatment of endothelial cells with Tat induced the cell surface expression of the adhesion molecules vascular cell adhesion molecule-1 (VCAM-1) and E-selectin and increased the expression of intercellular adhesion molecule-1 (ICAM-1). Only antibodies against VCAM-1 on endothelial cells or against the VLA-4 integrin expressed on AS283 cells inhibited the increment of adhesion, indicating the relevance of this pathway in the adhesion of lymphoma cells to vascular endothelium. In our work, we show for the first time that Tat can enhance the migration of lymphoma cells and their adhesion to endothelial cells, two processes that may contribute to the malignant behavior of NHL in patients with AIDS.

Larva migrans visceral: forma mista de apresentaçäo em adulto: aspectos clínicos e laboratoriais / Visceral larva migrans: a mixed form of presentation in adult patient: clinical and laboratorial features

We relate a case of an 18-year-old man, resident of Xapuri (state of Acre, Brazil), with a history of repeated episodes of meningoencephalitis (three in one year), each one was examined by a local doctor. In our service (Emílio Ribas Institute of Infectology) we observed a patient with polyjoint aches, radiological and bronchoscopic pulmonary alterations (without clinical features), meningeal and brain stem manifestations--with normal brain computed tomography and cerebrospinal fluid. Blood eosinophils and serological Toxocara canis test (ELISA) were greatly increased. With the hypothesis of Toxocariasis (visceral larva migrans) we administered thiabendazole that brought complete clinical and laboratory remission. Inspite of a new episode of headache with meningeal manifestation approximately one month later (treated with dexamethasone resulting in a full remission after three days) we have not found other manifestations in approximately three and a half years of ambulatory care.