Risk factors and clinical profile of thrombotic thrombocytopenic purpura in systemic lupus erythematosus patients. Is this a distinctive clinical entity in the thrombotic microangiopathy spectrum?: A case control study

Introduction

The association of thrombotic thrombocytopenic purpura (TTP) with systemic lupus erythematosus (SLE) is rare. It is associated with high morbidity and mortality. Information about risk factors and clinical outcomes is scant.

Material and Methods

A retrospective case-control study was performed in a referral center in Mexico City between 1994 and 2013. Patients were diagnosed with TTP if they fulfilled the following criteria: microangiopathic haemolytic anaemia, thrombocytopenia, high LDH levels, normal fibrinogen and negative Coombs’ test. Patients with SLE were diagnosed with ≥ 4 ACR criteria. We included three study groups: group A included patients with SLE-associated TTP (TTP/SLE; cases n = 22, TTP events n = 24); patients with non-autoimmune TTP (NA-TTP; cases n = 19, TTP events n = 22) were included in group B and patients with SLE without TTP (n = 48) in group C.

Results

After multivariate analysis, lymphopenia < 1000/mm3 [OR 19.84, p = 0.037], high SLEDAI score three months prior to hospitalisation [OR 1.54, p = 0.028], Hg < 7 g/dL [OR 6.81, p = 0.026], low levels of indirect bilirubin [OR 0.51, p = 0.007], and less severe thrombocytopenia [OR 0.98, p = 0.009] were associated with TTP in SLE patients. Patients with TTP/SLE received increased cumulative steroid dose vs. NA-TTP (p = 0.006) and a higher number of immunosuppressive drugs (p = 0.015). Patients with TTP/SLE had higher survival than NA-TTP (p = 0.033); however, patients hospitalised for TTP/SLE had a higher risk of death than lupus patients hospitalised for other causes

Conclusions

Lymphopenia is an independent risk factor for TTP/SLE. It is likely that patients with TTP/SLE present with less evident clinical features, so the level of suspicion must be higher to avoid delay in treatment.     

Effects of short-course zidovudine on the selection of nevirapine-resistant HIV-1 in women taking single-dose nevirapine

Single-dose nevirapine (sdNVP) given to prevent mother-to-child-transmission of HIV-1 selects NVP-resistance. Short-course zidovudine (ZDV) was hypothesized to lower rates of NVP-resistance. HIV-1 infected pregnant women administered sdNVP with or without short-course ZDV were assessed for HIV-1 mutations (K103N, Y181C, G190A, and V106M) prior to delivery and postpartum. Postpartum NVP-resistance was lower among 31 taking ZDV+sdNVP compared to 33 taking only sdNVP (35.5% vs. 72.7%; χ2 P = .003). NVP mutants decayed to <2% in 24/35 (68.6%) at a median 6 months postpartum, with no differences based on ZDV use (logrank P = .99). Short-course ZDV was associated with reduced NVP-resistance mutations among women taking sdNVP.     

Benznidazole-resistance in Trypanosoma cruzi is a readily acquired trait that can arise independently in a single population

Benznidazole is the frontline drug used against Trypanosoma cruzi, the causative agent of Chagas disease. However, treatment failures are often reported. Here, we demonstrate that independently acquired mutations in the gene encoding a mitochondrial nitroreductase (TcNTR) can give rise to distinct drug-resistant clones within a single population. Following selection of benznidazole-resistant parasites, all clones examined had lost one of the chromosomes containing the TcNTR gene. Sequence analysis of the remaining TcNTR allele revealed 3 distinct mutant genes in different resistant clones. Expression studies showed that these mutant proteins were unable to activate benznidazole. This correlated with loss of flavin mononucleotide binding. The drug-resistant phenotype could be reversed by transfection with wild-type TcNTR. These results identify TcNTR as a central player in acquired resistance to benznidazole. They also demonstrate that T. cruzi has a propensity to undergo genetic changes that can lead to drug resistance, a finding that has implications for future therapeutic strategies.     

Comparison of High Ribavirin Induction Versus Standard Ribavirin Dosing, Plus Peginterferon-α for the Treatment of Chronic Hepatitis C in HIV-Infected Patients: The PERICO Trial

Background.?Ribavirin (RBV) exposure seems to be critical to maximize treatment response in human immunodeficiency virus (HIV)-positive patients with chronic hepatitis C virus (HCV) infection. Methods.?HIV/HCV-coinfected individuals naive to interferon were prospectively randomized to receive peginterferon-α-2a (180?μg/d) plus either RBV standard dosing (1000 or 1200?mg/d if <75 or ≥75?kg, respectively) or RBV induction (2000?mg/d) along with subcutaneous erythropoietin β (450?IU/kg/wk), both during the first 4 weeks, followed by standard RBV dosing until completion of therapy. Early stopping rules at weeks 12 and 24 were applied in patients with suboptimal virological response. Results.?A total of 357 patients received ≥1 dose of the study medication. No differences in main baseline characteristics were found when comparing treatment arms. Sustained virological response (SVR) was attained by 160 (45%) patients, with no significant differences between RBV induction and standard treatment arms (SVR in 72 of 169 patients [43%] vs 88 of 188 [47%], respectively). At week 4, undetectable HCV RNA (29% vs 25%) and mean RBV trough concentration (2.48 vs 2.14?μg/mL) were comparable in both arms, whereas mean hemoglobin decay was less pronounced in the RBV induction plus erythropoietin arm than in the RBV standard dosing arm (-1.7 vs -2.3?mg/dL; P?相似文献   

The removal from plasma of chylomicrons and remnants is reduced in heterozygous familial hypercholesterolemia subjects with identified LDL receptor mutations: study with artificial emulsions

Chylomicron remnants bind to both their specific receptors (LRP) and to the LDL receptor (LDLR) in the liver. There is controversy whether disturbances of chylomicron metabolism occur in subjects with familial hypercholesterolemia (FH). The aim of this study was to evaluate whether there are defects on the removal from plasma of chylomicrons and their remnants in heterozygous FH patients with determined LDLR mutations. We studied 20 heterozygous FH patients (43.2±12 years old, 60% males) and 50 normolipidemic subjects matched for age and gender. FH subjects were not in use of LDL-lowering drugs for at least 6 weeks. The removal from plasma of chylomicrons and their remnants was measured by isotopic decay after venous injection of a chylomicron-like emulsion radiolabeled with (14)C-cholesteryl ester ((14)C-CE) and (3)H-triolein ((3)H-TO). These track respectively removal from plasma of chylomicrons and remnants and lipolysis. There was a significant reduction in the fractional catabolic rates (FCR in h(-1)) of (14)C-CE in FH in comparison with normolipidemics: 0.048 (1.46.10(-7); 0.57) vs. 0.71(0.049; 1.62), [median (25th-75th percentile)], p=0.003. No differences were found in FCR of (3)H-TO between FH and controls, respectively 1.62 (1.02; 2.331) and 1.914 (1.34; 2.878), p=0.405. In conclusion heterozygous FH subjects had a significant decrease on the removal from plasma of chylomicrons and their remnants compared with normolipidemics.