Factors associated with the presence of circulating active tissue factor and activated factor XI in stable angina patients

Circulating active tissue factor (TF) and activated factor XI (FXIa) have been detected in subgroups of acute coronary syndromes (ACSs) and stable angina patients. We sought to evaluate the determinants of active TF and FXIa in stable angina patients. We studied 124 consecutive stable angina patients. Recent ACS, atrial fibrillation, and anticoagulant therapy were the exclusion criteria. Plasma active TF and FXIa were determined by measuring the response to inhibitory antibodies. T helper 1 lymphocyte (Th1) and Th2 responses were assessed in plasma by interleukin (IL)-4, IL-6, IL-8, IL-10, IL-18, interferon-γ, and tumor necrosis factor-α, oxidative stress by 8-isoprostaglandin F(2α) (8-iso-PGF(2α)), and coagulation by prothrombin fragments F1+2 (F1+2) and free TF pathway inhibitor (f-TFPI). TF and FXIa activity were detected in 25 (20.2%) and 49 (39.5%) stable angina patients, respectively. Both factors were found in 23 (18.5%) patients. Patients with detectable TF or FXIa had higher F1+2, 8-iso-PGF(2α), IL-6, but not other cytokines, and lower f-TFPI (all P < 0.001) compared with the remainder. There were no intergroup differences with regard to cardiovascular risk factors or medication. Multivariate analysis showed that F1+2 and f-TFPI were the only independent predictors of the TF presence, whereas 8-iso-PGF(2α) and F1+2 predicted the presence of FXIa in stable angina patients. In stable angina patients, circulating active TF and FXIa are associated with enhanced thrombin formation, with a minor effect of inflammatory mediators. Moreover, FXIa is also related to oxidative stress, indicating additional links between coagulation and free radical generation in stable angina.     

IP3 receptor orchestrates maladaptive vascular responses in heart failure

Patients with heart failure (HF) have augmented vascular tone, which increases cardiac workload, impairing ventricular output and promoting further myocardial dysfunction. The molecular mechanisms underlying the maladaptive vascular responses observed in HF are not fully understood. Vascular smooth muscle cells (VSMCs) control vasoconstriction via a Ca²⁺-dependent process, in which the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) on the sarcoplasmic reticulum (SR) plays a major role. To dissect the mechanistic contribution of intracellular Ca²⁺ release to the increased vascular tone observed in HF, we analyzed the remodeling of IP3R1 in aortic tissues from patients with HF and from controls. VSMC IP3R1 channels from patients with HF and HF mice were hyperphosphorylated by both serine and tyrosine kinases. VSMCs isolated from IP3R1^VSMC–/– mice exhibited blunted Ca²⁺ responses to angiotensin II (ATII) and norepinephrine compared with control VSMCs. IP3R1^VSMC–/– mice displayed significantly reduced responses to ATII, both in vivo and ex vivo. HF IP3R^1VSMC–/– mice developed significantly less afterload compared with HF IP3R1^fl/fl mice and exhibited significantly attenuated progression toward decompensated HF and reduced interstitial fibrosis. Ca²⁺-dependent phosphorylation of the MLC by MLCK activated VSMC contraction. MLC phosphorylation was markedly increased in VSMCs from patients with HF and HF mice but reduced in VSMCs from HF IP3R1^VSMC–/– mice and HF WT mice treated with ML-7. Taken together, our data indicate that VSMC IP3R1 is a major effector of increased vascular tone, which contributes to increased cardiac afterload and decompensation in HF.     

Factor XIa and tissue factor activity in patients with coronary artery disease

It has been established that inflammation and enhanced pro-coagulant activity are associated with the pathogenesis of atherosclerotic vascular disease. We evaluated and compared the contributions of the factor (F)XIa and tissue factor (TF) activity in plasma of patients with coronary artery disease (CAD). Citrate plasma was obtained prior to therapy from 53 patients with stable angina (29 with a history of previous myocardial infarction; CAD-MI) and 30 with acute coronary syndrome (ACS) within 12 hours from pain onset. Four ACS patients treated with heparin were excluded. FXIa and TF activity were determined in clotting assays based upon the prolongation of clotting time by inhibitory monoclonal antibodies. Twenty-five of 26ACS patients (96%) and 22 of 29 CAD-MI patients (76%) had quantifiable FXIa (50 +/- 33 and 42 +/- 45pM, respectively). Ten of 26 (38%) ACS patients and only three of 53 (6%) stable CAD patients showed TF activity (<0.4pM). No FXIa or TF activity was observed in age-matched healthy controls (n = 12). For both CAD-MI and ACS patients, there were correlations (p < 0.05) between FXIa and interleukin-6 (R(2) = 0.59 and 0.39, respectively) and between FXIa and TAT (R(2) = 0.64 and 0.63, respectively). In conclusion, the majority of ACS and CAD-MI patients have circulating FXIa that correlates with markers of coagulation and inflammation.     

Polymyositis associated with infliximab treatment for rheumatoid arthritis

SIR, Treatment of rheumatoid arthritis (RA) with the chimericanti-tumour necrosis factor (TNF-) monoclonal antibody infliximabhas been proven efficacious and well tolerated [1, 2]. However,there are concerns about the safety of such treatment, withreports about induction of autoimmune phenomena [anti-double-strandedDNA (dsDNA) antibodies] and, rarely, development of systemiclupus erythematosus [3–5]. We describe a patient withRA who developed polymyositis following treatment with infliximab. A 52-yr-old woman presented in January 2001 with     

Metachromatic leukodystrophy in adult patient initially diagnosed as multiple sclerosis

The article presents a case of metachromatic leucodystrophy (MLD) of the adult onset type, in which atypical initial course could suggest multiple sclerosis. MLD is an inherited, metabolic, degenerative disease of the nervous system. It is caused by a deficiency of a lysosomal enzyme--arylsulphatase A, with the storage of cerebroside sulphate and demyelination affecting mainly the central and peripheral nervous system. In the reported case of a female aged 21 the clinical onset of the disease was at the age 20. The first neurological symptoms included a mild spastic paraparesis, ataxia of lower limbs, and imbalance. The neurological deterioration has been progressing since the onset. There was no family history of neurological or metabolic diseases, but the patient's parents were near relatives (first cousins). T-2 weighted MRI showed high intensity areas in the white matter, mainly periventricular. The clinical symptoms could suggest multiple sclerosis (of the primary progressive type). The patient was admitted to our Dept. in Oct. 2000, i.e. about a year since the onset. Her increasing spastic triparesis, cerebellar ataxia, neuropathy in lower limbs and cognitive deterioration were confirmed. Re-analysis of the patient's clinical picture and family history, her MRI scans and repeated neurophysiological examinations which demonstrated a damage of the central and peripheral nervous system, suggested metachromatic leucodystrophy. Therefore, it was decided to assay arylsulphatase A activity. The result confirmed the diagnosis of the late onset MLD. Additionally, molecular genetic examination was performed of a DNA sample obtained from the patient.     

Effect of deletion of SOS-induced polymerases, pol II, IV, and V, on spontaneous mutagenesis in Escherichia coli mutD5

The E. coli dnaQ gene encodes the epsilon subunit of DNA polymerase III (pol III) responsible for the proofreading activity of this polymerase. The mutD5 mutant of dnaQ chronically expresses the SOS response and exhibits a mutator phenotype. In this study we have constructed a set of E. coli AB1157 mutD5 derivatives deleted in genes encoding SOS-induced DNA polymerases, pol II, pol IV, and pol V, and estimated the frequency and specificity of spontaneous argE3-->Arg(+) reversion in exponentially growing and stationary-phase cells of these strains. We found that pol II exerts a profound effect on the specificity of spontaneous mutation in exponentially growing cells. Analysis of growth-dependent Arg(+) revertants in mutD5 polB(+) strains revealed that Arg(+) revertants were due to tRNA suppressor formation, whereas those in mutD5 DeltapolB strains arose by back mutation at the argE3 ochre site. In stationary-phase bacteria, Arg(+)revertants arose mainly by back mutation, regardless of whether they were proficient or deficient in pol II. Our results also indicate that in a mutD5 background, the absence of pol II led to increased frequency of Arg(+) growth-dependent revertants, whereas the lack of pol V caused its dramatic decrease, especially in mutD5 DeltaumuDC and mutD5 DeltaumuDC DeltapolB strains. In contrast, the rate of stationary-phase Arg(+)revertants increased in the absence of pol IV in the mutD5 DeltadinB strain. We postulate that the proofreading activity of pol II excises DNA lesions in exponentially growing cells, whereas pol V and pol IV are more active in stationary-phase cultures.     

Aspirin sensitivity and IgE antibodies to Staphylococcus aureus enterotoxins in nasal polyposis: studies on the relationship

BACKGROUND: Nasal polyposis is a multifactorial disease characterized by a chronic eosinophilic inflammation of the sinus mucosa, often associated with asthma and aspirin sensitivity. We have recently shown that the presence of IgE antibodies to Staphylococcus aureus enterotoxins (SAEs) was related to the severity of eosinophilic inflammation in nasal polyp tissue. In this study, we therefore aimed to determine, whether aspirin sensitivity was related to an immune response to SAEs, and how both criteria would be related to eosinophilic inflammation. METHODS: 40 subjects with nasal polyposis (NP) were classified as aspirin-sensitive (n=13, ASNP) or aspirin-tolerant (n=27, ATNP) based on a bronchial aspirin challenge test. Homogenates prepared from nasal polyp tissue and inferior nasal turbinates from healthy subjects (n=12) were analyzed for concentrations of IL-5 by enzyme immunoassay and for ECP, total and IgE to a mix of SAEs (A, C, TSST-1) using the ImmunoCAP system. RESULTS: Concentrations of IL-5, ECP, total IgE, and IgE to an SAE mix were significantly increased in ASNP compared with ATNP patients and controls. In addition, a subgroup analysis showed an increase in eosinophilic markers in ATNP-SAE(+) compared to ATNP-SAE(-). This relationship, however, was not found in ATNP-SAE(+) and ATNP-SAE(-) subjects, indicating that SAE immune response is overlapped or not relevant in this condition. CONCLUSIONS: Aspirin sensitivity was associated with increased concentrations of eosinophil-related mediators, as well as IgE antibodies to SAEs in nasal polyp tissue. However, a direct impact of S. aureus could not be established. It seems that aspirin sensitivity and immune reactions to SAEs are independently related to eosinophilic inflammation.