Objectives To assess the prevalence of the main causes of morbi-mortality in the antiphospholipid syndrome (APS) during a 10-year-follow-up period and to compare the frequency of early manifestations ...with those that appeared later. Methods In 1999, we started an observational study of 1000 APS patients from 13 European countries. All had medical histories documented when entered into the study and were followed prospectively during the ensuing 10 years. Results 53.1% of the patients had primary APS, 36.2% had APS associated with systemic lupus erythematosus and 10.7% APS associated with other diseases. Thrombotic events appeared in 166 (16.6%) patients during the first 5-year period and in 115 (14.4%) during the second 5-year period. The most common events were strokes, transient ischaemic attacks, deep vein thromboses and pulmonary embolism. 127 (15.5%) women became pregnant (188 pregnancies) and 72.9% of pregnancies succeeded in having one or more live births. The most common obstetric complication was early pregnancy loss (16.5% of the pregnancies). Intrauterine growth restriction (26.3% of the total live births) and prematurity (48.2%) were the most frequent fetal morbidities. 93 (9.3%) patients died and the most frequent causes of death were severe thrombosis (36.5%) and infections (26.9%). Nine (0.9%) cases of catastrophic APS occurred and 5 (55.6%) of them died. The survival probability at 10 years was 90.7%. Conclusions Patients with APS still develop significant morbidity and mortality despite current treatment. It is imperative to increase the efforts in determining optimal prognostic markers and therapeutic measures to prevent these complications.
Objectives:To identify the main causes of morbidity and mortality in patients with antiphospholipid syndrome (APS) during a 5-year period and to determine clinical and immunological parameters with ...prognostic significance.Methods:The clinical and immunological features of a cohort of 1000 patients with APS from 13 European countries who had been followed up from 1999 to 2004 were analysed.Results:200 (20%) patients developed APS-related manifestations during the 5-year study period. Recurrent thrombotic events appeared in 166 (16.6%) patients and the most common were strokes (2.4% of the total cohort), transient ischaemic attacks (2.3%), deep vein thromboses (2.1%) and pulmonary embolism (2.1%). When the thrombotic events occurred, 90 patients were receiving oral anticoagulants and 49 were using aspirin. 31/420 (7.4%) patients receiving oral anticoagulants presented with haemorrhage. 3/121 (2.5%) women with only obstetric APS manifestations at the start of the study developed a new thrombotic event. A total of 77 women (9.4% of the female patients) had one or more pregnancies and 63 (81.8% of pregnant patients) had one or more live births. The most common fetal complications were early pregnancy loss (17.1% of pregnancies) and premature birth (35% of live births). 53 (5.3% of the total cohort) patients died. The most common causes of death were bacterial infection (21% of deaths), myocardial infarction (19%) and stroke (13%). No clinical or immunological predictor of thrombotic events, pregnancy morbidity or mortality was detected.Conclusion:Patients with APS still develop significant morbidity and mortality despite current treatment (oral anticoagulants or antiaggregants, or both).
In yeast, the import of tRNA
Lys
with CUU anticodon (tRK1) relies on a complex mechanism where interaction with enolase 2 (Eno2p) dictates a deep conformational change of the tRNA. This event is ...believed to mask the tRNA from the cytosolic translational machinery to re-direct it towards the mitochondria. Once near the mitochondrial outer membrane, the precursor of the mitochondrial lysyl-tRNA synthetase (preMsk1p) takes over enolase to carry the tRNA within the mitochondrial matrix, where it is supposed to participate in translation following correct refolding. Biochemical data presented in this report focus on the role of enolase. They show that despite the inability of Eno2p alone to form a complex with tRK1, mitochondrial import can be recapitulated
in vitro
using fractions of yeast extracts sharing either recombinant or endogenous yeast Eno2p as one of the main components. Taken together, our data suggest the existence of a protein complex containing Eno2p that is involved in RNA mitochondrial import.
Mitochondria are obligate organelles of most eukaryotic cells that perform many different functions important for cellular homeostasis. The main role of mitochondria is supplying cells with energy in ...a form of ATP, which is synthesized in a chain of oxidative phosphorylation reactions on the organelle inner membrane. It is commonly believed now that mitochondria have the endosymbiotic origin. In the course of evolution, they have lost most of their genetic material as a result of genome reduction and gene transfer to the nucleus. The majority of mitochondrial proteins are synthesized in the cytosol and then imported to the mitochondria. However, almost all known mitochondria still contain genomes that are maintained and expressed. The processes of protein biosynthesis in the mitochondria — mitochondrial translation — substantially differs from the analogous processes in bacteria and the cytosol of eukaryotic cells. Mitochondrial translation is characterized by a high degree of specialization and specific regulatory mechanisms. In this review, we analyze available information on the common principles of mitochondrial translation with emphasis on the molecular mechanisms of translation initiation in the mitochondria of yeast and mammalian cells.
Mitochondria are essential organelles of eukaryotic cell that provide its respiratory function by means of the electron transfer chain. Expression of mitochondrial genes is organized in a ...bacterial-like manner; however multiple evolutionary differences are observed between the two systems, including translation initiation machinery. This review is dedicated to the mitochondrial translation initiation factor 3 (IF3mt), which plays a key role in the protein synthesis in mitochondria. Involvement of IF3mt in human health and disease is discussed.
Mitochondria are energy producing organelles of the eukaryotic cell, involved in the synthesis of key metabolites, calcium homeostasis and apoptosis. Protein biosynthesis in these organelles is a ...relic of its endosymbiotic origin. While mitochondrial translational factors have homologues among prokaryotes, they possess a number of unique traits. Remarkably as many as four mammalian mitochondrial proteins possess a clear similarity with translation termination factors. The review focuses on the ICT1, which combines several functions. It is a non-canonical termination factor for protein biosynthesis, a rescue factor for stalled mitochondrial ribosomes, a structural protein and a regulator of proliferation, cell cycle, and apoptosis. Such a diversity of roles demonstrates the high functionality of mitochondrial translation associated proteins and their relationship with numerous processes occurring in a living cell.
The optical constant dispersions of ion-beam-synthesized Mg2Si phase in Si matrix are obtained from the transmittance and reflectance spectra. Two types of samples are studied - one of them with ...Mg2Si phase embedded in n-type (100)Si and the other with Mg2Si phase embedded in p-type (100)Si. The formation of the phase is proved by Raman scattering and infrared transmittance measurements. From the interpretation of the optical constant dispersions, the energies of the transitions nearby the material band edge are determined. As a result the band diagram of the heterojunction Mg2Si/Si is obtained. The results about the Mg2Si band gap value are compared with the theoretically predicted and experimentally determined ones. The value of the conduction band offsets of Mg2Si and Si is not reported by now.
BackgroundRheumatoid arthritis (RA) is an autoimmune rheumatic disease with unknown etiology. It is believed that the disease pathogenesis results from the interaction between environmental factors ...and genetic and epigenetic factors which leads to immune dysregulation. The autoimmune process responsible for the disease onset and progression raises the interest for investigating immune and genetic factors in the serum and synovial fluid of RA patients. This could show individual characteristics of the pathogenic process and possible correlation with the clinical phenotype and treatment respond.ObjectivesThe objectives of our study were to analyze the serum and synovial fluid (SF) cytokine levels in RA patients and to compare them with known genetic risk factor for RA and clinical and immunological data in regard to their use as biomarkers for disease activity and treatment decisions.Methods42 RA patients according to the 1987 ACR criteria were included in the study. Serum and SF samples were used for measuring the levels of IL-1α, TNF-α, IL-6, sIL-6R by ELISA kit (Immunotech, FRA) and IFN-γ by ELISA kit (Genzyme, USA). The blood samples were used for detecting the HLA-DR4 phenotype. The results were analyzed in regard to the clinical picture including radiological stage, the laboratory data for disease activity, immunological markers and possible targeted treatment.ResultsSF samples showed higher levels of IL-6 and lower levels of sIL-6R compared to serum levels. Serum and SF TNF-α levels correlated with serum and SF sIL-6R levels. Patients with high disease activity score showed higher serum TNF-α, IL-6 and higher SF sIL-6R level than patients with low disease activity according to RA Disease Activity Score 28 (DAS28). Serum TNF-α levels were higher in patients with active disease as defined by DAS28 score, in IgM rheumatoid factor positive patients and in patients with higher scores for disease progression based on the results from the ultrasound and radiologic examination. IL-1α and IFN-γ were detected in serum and SF samples of few patients with no significant correlations to any clinical setting or disease activity. There was no association between HLA-DR4 positivity and serum and SF levels of the pro-inflammatory cytokines (IL-1α, TNF-α, IL-6, sIL-6R) in this subset of RA patients.ConclusionsLevels of pro-inflammatory cytokines in the serum and SF of RA patients correlate with disease activity and progression. In the era of biological drugs such studies will eventually show if cytokine levels could be used in the clinical practice in the process of making treatment decisions with personalizing the biological therapy.ReferencesMoura RA, Cascão R, Perpétuo et al. Cytokine profile in serum and synovial fluid of patients with established rheumatoid arthritis, Ann. Rheum. Dis, 2010; 69: A51Takeuchi T, Miyasaka N, Tatsuki Y et al. Baseline tumour necrosis factor alpha levels predict the necessity for dose escalation of infliximab therapy with rheumatoid arthritis, Ann. Rheum. Dis., 2011; 70(7): 1208-1215.Wang J, Platt A, Upmanyu R et al. IL-6 pathway-driven investigation of response to IL-6 receptor inhibition in rheumatoid arthritis, BMJ Open, 2013; 3: e003199.Disclosure of InterestNone declared
This concise review summarizes the role of reduced ANXA5 expression through carriage of the M2/ANXA5 haplotype as a predisposing factor for various thrombophilia related obstetric complications. A ...revised ANXA5 ‘protective shield’ model is emphasized, where decreased coverage resulting of M2 carriage at placental villi could lead directly to the observed pathology and on the other hand through exposing of antiphospholipid antigenic determinants, to the development of antiphospholipid antibodies (aPL). The aPL then can further disrupt the ANXA5 protective shield. Available and prospective evidence for this revised model is discussed. Conclusions are made about the diagnostic implications of M2 carriage and possible therapeutic strategies with anticoagulants, proven successful in obstetric antiphospholipid syndrome (APS) treatment.
Mitochondrial genomes of many eukaryotic organisms do not code for the full tRNA set necessary for organellar translation. Missing tRNA species are imported from the cytosol. In particular, one out ...of two cytosolic lysine tRNAs of the yeast
Saccharomyces cerevisiae
is partially internalized by mitochondria. The key protein factor of this process is the precursor of mitochondrial lysyl-tRNA synthetase, preMsk1p. In this work, we show that recombinant preMsk1p purified from
E. coli
in native conditions, when used in an
in vitro
tRNA import system, demonstrates some properties different from those shown by the renatured protein purified from
E. coli
in the denatured state. We also discuss the possible mechanistic reasons for this phenomenon.
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