Pregnancy failure in patients with obstetric antiphospholipid syndrome with conventional treatment: the influence of a triple positive antibody profile.

Conventional treatment of obstetric antiphospholipid syndrome fails in approximately 20-30% of pregnant women without any clearly identified risk factor. It is important to identify risk factors that are associated with these treatment failures. This study aimed to assess the impact of risk factors on pregnancy outcomes in women with obstetric antiphospholipid syndrome treated with conventional treatment. We carefully retrospectively selected 106 pregnancies in women with obstetric antiphospholipid syndrome treated with heparin + aspirin. Pregnancy outcomes were evaluated according to the following associated risk factors: triple positivity profile, double positivity profile, single positivity profile, history of thrombosis, autoimmune disease, more than four pregnancy losses, and high titers of anticardiolipin antibodies and/or anti-ßeta-2-glycoprotein-I (aß2GPI) antibodies. To establish the association between pregnancy outcomes and risk factors, a single binary logistic regressions analysis was performed. Risk factors associated with pregnancy loss with conventional treatment were: the presence of triple positivity (OR = 5.0, CI = 1.4-16.9, p = 0.01), high titers of aß2GPI (OR = 4.4, CI = 1.2-16.1, p = 0.023) and a history of more than four pregnancy losses (OR = 3.5, CI = 1.2-10.0, p = 0.018). The presence of triple positivity was an independent risk factor associated with gestational complications (OR = 4.1, CI = 1.2-13.9, p = 0.02). Our findings reinforce the idea that triple positivity is a categorical risk factor for poor response to conventional treatment.

Association between severe disease course and nephritis with Q222R polymorphism in DNAse I gene among lupus patients: An Argentine multicenter study.

UNLABELLED: Objetives: Systemic lupus erythematosus is a multifactorial autoimmune disease and the glomerulonephritis is one of the most severe complications, which leads to severe persistent proteinuria, chronic renal failure, and end-stage renal disease. This multicenter study investigated the genetic associations of a non-synonymous single-nucleotide polymorphism in DNase I with the risk of lupus and its influence on development of nephropathy in an Argentinean population. METHODS: Using the Polymerase chain reaction restriction fragment length polymorphism method, the Q222R (+2373A→G; Gln244Arg) DNase I polymorphism was studied in 156 systemic lupus erythematosus patients and 170 healthy controls. RESULTS: Although no significant association between Q222R polymorphism and the risk of systemic lupus erythematosus was found, the presence of the A allele was associated with an increased risk for the development of nephropathy (p=0.019, Odd Ratio=2.196, 95 % confidence interval [1.135-4.247]) and a worse disease course [moderate disease course: p=0.006, Odd Ratio=3.250, 95% confidence interval (1.401-7.539); severe disease course: p=0.040, Odd Ratio=2.339, 95% confidence interval (1.040-5.260)]. CONCLUSIONS: A better understanding of the genetic basis of systemic lupus erythematosus will help in the development of new and more effectives strategies for the treatment of the disease in the future.

Paternal factor V Leiden and recurrent pregnancy loss: a new concept behind fetal genetics?

BACKGROUND: In up to 50% of couples affected by recurrent pregnancy loss, no identifiable cause is established. Fetal and maternal factors may be equally important in the establishment and maintenance of the placental/maternal arteriovenous anastomoses. Therefore,the inheritance of thrombophilia-related genes may be an important factor in the pathophysiology of recurrent pregnancy loss. Most of the research on recurrent pregnancy loss and thrombophilia has focused on maternal factors, but little is known about the paternal contribution. OBJECTIVES: On that basis, we studied the association between inherited paternal thrombophilias and recurrent pregnancy loss in a narrowly selective group of 42 Argentine males from couples that presented without any known risk factors for recurrent pregnancy loss. PATIENTS AND METHODS: The genotypic distributions of factor (F) V Leiden and prothrombin G20210A among cases were compared with those from a reference group composed of 200 Argentine men. RESULTS: We found a significant difference in the distribution of FV Leiden between both groups (16.7% vs. 3.0%), but no difference was found in the distribution of prothrombin G20210A (2.4% vs.2.0%). Those couples with paternal FV Leiden carriage would be six times more likely to experience recurrent pregnancy loss despite no other apparent cause (OR = 6.47; 95% CI, 2.06­20.39). CONCLUSION: We found evidence of an association between the paternal carriage of FV Leiden and the predisposition to recurrent pregnancy loss, thereby supporting the hypothesis that genetic contributions from both parents are essential factors in the development of this obstetric disorder.

Nuevos enfoques en farmacogenómica de la tuberculosis / New approaches in tuberculosis pharmacogenomics

INTRODUCCIÓN La isoniacida (INH) es un fármaco de primera línea contra la tuberculosis (TB) y está considerada como la principal responsable de inducir hepatotoxicidad por fármacos anti-TB (HIFA). Ciertas mutaciones en las enzimas que metabolizan INH (NAT-2 y CYP2E1) pueden estar directamente asociadas con susceptibilidad a HIFA. OBJETIVOS Analizar el nivel de concordancia entre el tagSNP (rs1495741) de NAT-2 y el fenotipo de acetilador lento (AL) en la predicción de HIFA. Investigar por primera vez si la región del número variable de repeticiones en tándem (VNTR) del promotor del gen CYP2E1 está asociado con HIFA. MÉTODOS Se estudió a 304 pacientes con TB tratados con INH. Se analizaron las variables clínicas y demográficas tomadas en fichas de datos. La genotipificación del tagSNP de NAT2 y el VNTR de CYP2E1 se determinaron por PCR-RFLP. Los 7 SNP de NAT-2, por secuenciación del gen completo. El análisis de concordancia se realizó mediante el coeficiente de Kendall (w) y el grado, de acuerdo con el coeficiente Kappa de Cohen (k). Se obtuvieron las curvas ROC para medir especificidad y sensibilidad del método. Se realizó una regresión logística binaria para buscar variables asociadas al desarrollo de HIFA. Un p<0,05 fue considerado como estadísticamente significativo. RESULTADOS Se encontró una destacable concordancia w=0,947 (p<0,0001), entre el tagSNP y el perfil acetilador predicho. El tagSNP arrojó una sensibilidad del 95% y una especificidad del 99% en predecir el fenotipo AL por NAT-2. El estudio mostró por primera vez que el genotipo A2/A4 del VNTR de CYP2E1 (OR=3,086; IC=1,163-8,190, p=0,024) es una variable involucrada en la predicción de HIFA. DISCUSIÓN Dado el aumento en los casos de TB, se sugiere realizar un frecuente monitoreo clínico y bioquímico de la función hepática para hallar precozmente HIFA en los pacientes acetiladores lentos y con presencia de la variante alélica A4 del VNTR de CYP2E1. Esto evitaría la prolongación del tratamiento y ahorraría costos al sistema de salud.

Rotura de quiste dermoide intracraneal tras ablación de vía accesoria por arritmia cardiaca / Intracranial dermoid cyst rupture after accessory pathway ablation for cardiac arrhythmia

Los quistes dermoides son lesiones benignas e infrecuentes de origen embrionario, que suponen menos del 1% de los tumores intracraneales. En raras ocasiones pueden romperse, diseminando su contenido graso al espacio subaracnoideo o a los ventrículos laterales. La rotura de un quiste dermoide se puede producir de forma espontánea o estar relacionada con la existencia de un traumatismo craneal cerrado previo. La presentación clínica es variable. Describimos el caso de una paciente sin antecedentes neurológicos de interés, que sufre una rotura de quiste dermoide tras ablación de vía accesoria por arritmia cardiaca y exponemos su posible mecanismo etiopatogénico (AU)

Dermoid cysts are rare benign tumors of embryonic origin; they account for less than 1% of all intracranial tumors. Rarely, they may rupture and spread their fatty content into the subarachnoid space or lateral ventricles. Dermoid cyst rupture may occur spontaneously or be associated with previous closed head trauma. The clinical presentation can vary. We report a case of ruptured intracranial dermoid cyst after accessory pathway ablation for cardiac arrhythmia in a 54-year-old woman with no relevant neurologic history, and we discuss hypotheses about its etiopathogenic mechanism (AU)

[Intracranial dermoid cyst rupture after accessory pathway ablation for cardiac arrhythmia]. / Rotura de quiste dermoide intracraneal tras ablación de vía accesoria por arritmia cardiaca.

Dermoid cysts are rare benign tumors of embryonic origin; they account for less than 1% of all intracranial tumors. Rarely, they may rupture and spread their fatty content into the subarachnoid space or lateral ventricles. Dermoid cyst rupture may occur spontaneously or be associated with previous closed head trauma. The clinical presentation can vary. We report a case of ruptured intracranial dermoid cyst after accessory pathway ablation for cardiac arrhythmia in a 54-year-old woman with no relevant neurologic history, and we discuss hypotheses about its etiopathogenic mechanism.

Relationship between hepatitis C virus (HCV) and insulin resistance, endothelial perturbation, and platelet activation in HIV-HCV-coinfected patients under highly active antiretroviral treatment.

Insulin resistance is associated with highly active antiretroviral therapy in HIV-infected patients, and the risk of developing insulin resistance is increased in hepatitis C virus (HCV)-infected patients. The aim of the present study was to determine whether hepatitis C virus infection constitutes an additional risk factor for insulin resistance or other prothrombotic conditions in HIV-HCV coinfected patients under highly active antiretroviral therapy. One hundred eighteen HIV-infected patients were studied: 50 who had no history of anti-HIV treatment and 68 who were receiving therapy with highly active antiretroviral treatment. The treatment-naive group consisted of 35 HCV-negative subjects and 15 HCV-positive ones. Within the treated group, 50 patients were HCV negative and 18 were HCV positive. For each patient, the lipid profile was determined and the following values measured: glucose, soluble P-selectin (as a marker of platelet activation), soluble thrombomodulin, von Willebrand factor and soluble vascular cell adhesion molecule-1 (as endothelial markers), and insulin resistance. No significant difference (p>0.05) for any variable was found among subjects with or without HCV coinfection in the treatment-naïve group. Among patients under highly active antiretroviral therapy, however, those with HCV coinfection showed higher values (p<0.05) for insulin resistance (homeostasis model assessment value: 2.65 vs. 1.79), glucose (93 vs. 86 mg/dl), endothelial markers (von Willebrand factor, 204 vs. 123%; soluble vascular cell adhesion molecule-1, 650 vs. 482 ng/ml), and platelet activation marker (soluble P-selectin, 78 vs. 51 ng/ml) in parallel with lower CD4+ cells counts (289 vs. 402 cells/mm3) and higher HIV-1 viral loads (305 vs. 50 copies/ml) compared to patients without HCV coinfection. Glucose, soluble P-selectin, and von Willebrand factor were independently related to HCV infection. The presence of HCV coinfection during HIV treatment was closely related to higher values of insulin resistance, to activated platelets, and to endothelial perturbation in parallel with lower CD4+ cell counts and higher HIV-1 viral loads compared to patients without HCV coinfection. On the basis of these results, it may be preferable to treat HCV infection prior to initiating treatment for HIV infection in HIV-HCV-coinfected patients.

Circulating levels of tissue factor and proinflammatory cytokines in patients with primary antiphospholipid syndrome or leprosy related antiphospholipid antibodies.

The antiphospholipid syndrome (APS) is characterized by the presence of antiphospholipid antibodies (aPL) in patients with thromboembolic complications. In APS, most aPL are autoantibodies to beta2-glycoprotein I and prothrombin, which play a major role in the APS pathogenesis. Nevertheless, antibodies with the same antigen specificity are also found in aPL patients with leprosy, in whom thromboembolic complications are uncommon. The in vivo upregulation of the tissue factor (TF) pathway and the imbalance of cytokines have been proposed as potential mechanisms of thrombosis in the APS. We measured the circulating levels of TF, interleukin 6 (IL-6), IL-6 receptor (sIL-6R), tumor necrosis factor (TNF-alpha) and interferon gamma (IFN-gamma) in 83 patients with autoimmune aPL (42 with and 41 without clinical features of definite primary APS), 48 leprosy patients (33 with aPL) and 48 normal controls. There was a trend (P = 0.06) to higher median sTF in patients with autoimmune aPL (139 pg/mL) compared with leprosy patients (103.5 pg/mL) and controls (123 pg/mL). In addition, the frequency of raised sTF levels (> 187 pg/mL) was significantly higher in the group with autoimmune aPL [22.9% (APS 21.4%, non-APS 24.4%)] but not in leprosy (10.4%) compared with controls (4.2%). Elevated levels of IL-6 and TNF-alpha and a trend to lower IFN-gamma were found in patients with definite APS. Leprosy patients with aPL, however, had increased TNF-alpha and IFN-gamma but normal IL-6 levels. Levels of sIL-6R did not differ between controls and either patients with autoimmune aPL or leprosy. The different cytokine profiles as well as differences in circulating levels of TF might contribute to the high thrombotic risk found in patients with autoimmune aPL but not in leprosy related aPL patients.

Catastrophic antiphospholipid syndrome and Kikuchi-Fujimoto disease: the first case reported.

The case of a man with diagnosis of Kikuchi-Fujimoto disease (KFD) and catastrophic antiphospholipid syndrome (CAPS) is reported. He presented prolonged fever, lymphadenopathies, arthralgia, weight loss, hepatosplenomegaly and positive IgM for cytomegalovirus. While he was empirically treated with tuberculostatic drugs, he suddenly developed systemic inflammatory response syndrome, multiple organ failure and distal necrosis. On suspicion of severe sepsis, antibiotics, corticoids and recombinant human activated protein C (XIGRIS) were administrated. Exhaustive laboratory searching was negative. Histopathologic examinations of lymph node first disclosed malignant lymphoma but later KFD was confirmed. One month later, laboratory tests showed the presence of antiphospholipid antibodies (aPL). The patient was discharged after two months of hospitalization. This case exhibits a KFD complicated by definite CAPS. Cytomegalovirus could be involved in the development of both CAPS and KFD. Because of the severity of the case, we believe that XIGRIS noticeable improved the altered coagulation profile associated with CAPS.

Markers of platelet, endothelial cell and blood coagulation activation in leprosy patients with antiphospholipid antibodies.

OBJECTIVE: To evaluate plasma levels of markers of platelet, endothelial cell and blood coagulation activation in leprosy patients with or without antiphospholipid antibodies (aPL) and to compare them to those found in patients with antiphospholipid syndrome (APS). METHODS: 42 patients with leprosy (35 lepromatous and 7 borderline): 29 aPL(+) and 13 aPL(-), as well as 26 healthy subjects as normal controls (NC) and 79 control aPL patients without leprosy (59 with and 20 without APS) were included in the study. Plasma soluble P and E selectin (sPsel and sEsel), and VCAM-1 (sVCAM-1), prothrombin F1 + 2 fragment (F1 + 2), thrombin-antithrombin complexes (TAT) and D dimer (DD) were measured by ELISA. The protein C pathway was assessed by the ProC global test. RESULTS: Leprosy patients with aPL presented increased median levels of sPsel [ng/ml (82.0 vs 36.0, p < 0.001)] and sVCAM-1 [ng/ml (495 vs 335, p < 0.001)] compared to NC, as observed in control aPL patients without leprosy. Levels of sPsel in aPL(+) patients with leprosy were significantly higher than in aPL(-) ones (52.5 ng/ml), p = 0.005. However, plasma markers of thrombin generation were increased in control aPL patients without leprosy but not in those with leprosy. ProcC global test was abnormal in 24.1% of leprosy patients with aPL compared to 4.4% of NC (p < 0.024), and to 57.2% of control patients with aPL without leprosy (p = 0.005). CONCLUSIONS: We demonstrated that although patients with leprosy present a high prevalence of aPL, and platelet and endothelial cell activation in vivo to the same extent than patients with APS, they do not show a procoagulant state.

Markers of platelet, endothelial cell and blood coagulation activation in leprosy patients with antiphospholipid antibodies

OBJECTIVE: To evaluate plasma levels of markers of platelet, endothelial cell and blood coagulation activation in leprosy patients with or without antiphospholipid antibodies (aPL) and to compare them to those found in patients with antiphospholipid syndrome (APS). METHODS: 42 patients with leprosy (35 lepromatous and 7 borderline): 29 aPL(+) and 13 aPL(-), as well as 26 healthy subjects as normal controls (NC) and 79 control aPL patients without leprosy (59 with and 20 without APS) were included in the study. Plasma soluble P and E selectin (sPsel and sEsel), and VCAM-1 (sVCAM-1), prothrombin F1 + 2 fragment (F1 + 2), thrombin-antithrombin complexes (TAT) and D dimer (DD) were measured by ELISA. The protein C pathway was assessed by the ProC global test. RESULTS: Leprosy patients with aPL presented increased median levels of sPsel [ng/ml (82.0 vs 36.0, p smaller 0.001)] and sVCAM-1 [ng/ml (495 vs 335, p smaller 0.001)] compared to NC, as observed in control aPL patients without leprosy. Levels of sPsel in aPL(+) patients with leprosy were significantly higher than in aPL(-) ones (52.5 ng/ml), p = 0.005. However, plasma markers of thrombin generation were increased in control aPL patients without leprosy but not in those with leprosy. ProcC global test was abnormal in 24.1 per cent of leprosy patients with aPL compared to 4.4 per cent of NC (p smaller 0.024), and to 57.2 per cent of control patients with aPL without leprosy (p = 0.005). CONCLUSIONS: We demonstrated that although patients with leprosy present a high prevalence of aPL, and platelet and endothelial cell activation in vivo to the same extent than patients with APS, they do not show a procoagulant state.

Activated protein C resistance in patients with arterial ischemic stroke.

BACKGROUND: Activated C protein resistance (APC-R) has recently been reported to be a common cause of thrombophilia; it may be acquired or caused by a genetic defect (factor V Leiden mutation). It is clear that there is an association between APC-R and venous thrombosis. It has been suggested that there is a possible relationship of APC-R with arterial ischemic stroke (IS), but case-control studies have not given enough clues for considering APC-R as a main risk factor. OBJECTIVES: To assess the incidence of APC-R in patients with IS of several ethiologies in Buenos Aires. PATIENTS AND METHODS: Seventy-two patients with IS were assessed for signs or symptoms of previous clinical thrombophilia and the presence of vascular risk factors (RF). They were searched for APC-R (COATEST, APC resistance-V, with a predilution of the samples) test. Determinations were carried out between 1 to 4 months after the ischemic episode. The plasma of 50 healthy control subjects (blood donors) was used as controls. RESULTS: None of the patients had signs of previous thrombophilia; 57 (79.2%) had RF for IS, and 3 (4.2%) had APC-R (all of them with RF). One subject in the control group (2%) showed a low APC response (1/50). The occurrence of APC-R among patients with stroke was not significantly higher when compared with the occurrence of APC-R among the control subjects. CONCLUSIONS: In the present series, the incidence of factor V Leiden related APC-R in the group with IS was similar to the healthy population. Other risk factors were associated in patients showing APC-R.

Clinical characteristics of nonneoplastic cavernomatous transformation of the portal vein at a Gastroenterology Service in Spain.

OBJECTIVE: To identify predisposing factors, clinical characteristics and effective treatment in patients with nonneoplastic cavernomatous transformation of the portal vein in our gastroenterology service. METHODS: We retrospectively reviewed the clinical records of 2,201 patients diagnosed as having portal hypertension (2,165 with cirrhosis and 36 with noncirrhotic portal vein hypertension) during the period from 1977 to 1998. The diagnosis of cavernomatous transformation was confirmed with angiographic or Doppler echographic studies, or both. RESULTS: Thirteen patients (6 males, 7 females, age range 8 to 69 years) with cavernomatous transformation were found. Predisposing factors were omphalitis (1), echinococcal cyst (1), major abdominal surgery (3), liver cirrhosis (3), Sjögren syndrome (1), and no apparent cause (4). Eleven of the 13 patients had upper digestive tract bleeding from varices, 9 had splenomegaly, and 2 had cirrhotic decompensation. Splenectomy was done in 3 patients on admission, and in 5 patient shunts were used (splenorenal in 4, mesenteroatrial in 1) because of repeated bleeding. CONCLUSIONS: Of the patients with noncirrhotic portal hypertension, 27.7% had nontumoral cavernomatous transformation of the portal vein. Previous abdominal surgery was the most frequent predisposing factor; the 2 cases of echinococcal liver disease and Sjögren disease were exceptional. Age younger than 30 years, bleeding esophageal varices and splenomegaly were the most frequent clinical features. Portosystemic shunt was the only effective treatment alternative in these patients.

High prevalence of antiphospholipid antibodies in leprosy: evaluation of antigen reactivity.

Antiphospholipid antibodies (aPL) have been reported not only in autoimmune disorders but also in various infectious diseases. Accumulating evidence indicates that beta2 glycoprotein I (beta2GPI) and prothrombin are the main proteins to which autoimmune aPL bind. The aim of this study was to evaluate the prevalence of different aPL in patients with leprosy. We included 51 outpatients (42 lepromatous and 9 borderline leprosy) without any clinical feature of the antiphospholipid syndrome (APS). 35 had lupus anticoagulant and 31 had anticardiolipin antibodies (aCL). Anti-beta2GPI antibodies were highly positive in 29/51 and anti- prothrombin antibodies (anti-II) were detected in 23/51. Almost all aCL and anti-beta2GPI were of IgM isotype, while IgG isotype was more frequent among anti-II. No statistical difference was found when aPL were evaluated in patients grouped according to their bacteriological status. Furthermore, patients under treatment (n=33) had a similar frequency of positive aPL compared to patients in vigilance (n=14). Assessing the specificity of antibody binding to CL and beta2GPI in ELISA by means of inhibition studies with cardiolipin-beta2GPI liposomes, leprosy and APS sera showed a similar behaviour. Comparable results were also found in both groups of patients when inhibition experiments with lysate of Mycobacterium leprae were carried out. In summary, leprosy-related aPL resemble those found in patients with APS but the immunoglobulin isotype is different, with IgM much more prevalent in leprosy patients.