C-reactive protein (CRP) as a marker of of hemodialysis biocompatibility]

Haemodialysis leads to monocytes activation and secretion of cytokines, which stimulates hepatic production of CRP. To assess the biocompatibility of haemodialysis the CRP serum levels were measured. CRP serum levels during haemodialysis with the use of cuprophane membranes increased from 4743.3 +/- 3251.6 ng/ml to 5231.8 +/- 3458.4 ng/ml just after haemodialysis and 5865.4 +/- 3684.8 ng/ml 22 hours after haemodialysis (p < 0.001). During haemodialysis using polysulfone membranes CRP from the initial value of 4819.4 +/- 4328.2 ng/ml decreased to 3316.9 +/- 3882.7 ng/ml just after haemodialysis (p < 0.01) and increased to 5086.9 +/- 4193.0 ng/ml 22 hours after haemodialysis (p < 0.05). Re-counted CRP values, according to changes in total blood protein, increased significantly (p < 0.02) 22 hours after haemodialysis with the use of cuprophane membranes. During haemodialysis using polysulfone membranes above mentioned levels were significantly decreased just after haemodialysis (p < 0.001). The cuprophane membranes surface area and reutilization of dialyzers did not affect the changes of CRP serum levels. No correlation was observed between CRP level changes and dialysis neutropenia and complement activation. Our results indicate, that CRP serum level measurement may be feasible to assess the biocompatibility of dialysis membranes.     

Pathogenesis of acute coronary syndromes

Coronary artery diseases may categorized into asymptomatic disease, angina pectoris, myocardial infarction, chronic heart failure, and sudden coronary death. Unstable angina, acute myocardial infarction, and sudden cardiac death are known as the acute coronary syndromes. Coronary atheroma is unstable in the patients with acute coronary syndromes. Stable plaques will be unstable when dynamic alterations occur. The alterations are plaque rupture, plaque hemorrhage, coronary thrombosis and vasospasm. They act each other. We analysed the histopathology of coronary arteries who died of acute myocardial infarction in 85 cases. It showed that the risk factors of plaque rupture are clusters of form cells, eccentric plaque with soft lipid rich core, and thinning of fibrous cap in atheroma. Most of these cases ruptured at edge of the atheroma.     

Lipoprotein(a) as a risk predictor for cardiac mortality in patients with acute coronary syndromes

AIMS: Raised lipoprotein(a) concentrations are considered to be a risk factor for atherothrombotic diseases. We examined whether baseline concentrations were a risk factor for an adverse outcome in patients admitted with acute coronary syndromes. METHODS AND RESULTS: Five hundred and nineteen patients admitted with suspected acute coronary syndromes were studied and followed prospectively for a median of 3 years. The prognostic significance of a baseline lipoprotein(a) concentration of > or = 30 mg x dl(-1) or lower for subsequent cardiac death was assessed in patients with myocardial infarction (266) and unstable angina (197) and compared with other variables in regression models. In patients with myocardial infarction, a baseline lipoprotein(a) concentration of > or =30 mg x dl(-1) was associated with a 62% increase in subsequent cardiac death compared to the lower concentration group (29.8% vs 18.6%, Log rank P=0.04). In a multivariate regression model a baseline lipoprotein(a) concentration of > or = 30 mg x dl(-1) retained its significance as an independent predictor of cardiac death (P=0.037). In patients with unstable angina, baseline concentrations of > or = 7.9 mg x dl(-1) were found to be significant predictors of cardiac death in univariate (P=0.021) and multivariate (P=0.035) regression models. CONCLUSION: Baseline lipoprotein(a) concentrations in patients admitted with acute coronary syndromes are associated with an increased risk of cardiac death. For patients with myocardial infarction a concentration of > or = 30 mg x dl(-1) appears appropriate as a risk discriminator; for patients admitted with unstable angina, however, much lower concentrations of lipoprotein(a) appear to be prognostically important.     

C-reactive protein as a predictor of cardiac rupture after acute myocardial infarction

Although cardiac rupture is the second most common cause of death after ventricular failure in acute myocardial infarction, no diagnosis has ever been made before an episode of clinical compromise, and no significant predictive factors have been described. This study was designed to determine whether high serum C-reactive protein (CRP) levels could predict the incidence of subacute cardiac rupture after acute myocardial infarction. Nine consecutive patients with cardiac rupture were compared retrospectively with 28 consecutive control patients without rupture after acute myocardial infarction. In the rupture group, peak serum CRP levels increased rapidly and markedly after infarction, reaching more than 20 mg/dl on day 2, and persisted at high levels compared with those in the control group. However, the time course and levels of serum creatine phosphokinase were not significantly different between the two groups. High serum CRP levels ( > 20 mg/dl) had a high diagnostic sensitivity (89%) and specificity (96%) for cardiac rupture. Patients with persistently high serum CRP levels, particularly above 20 mg/dl, might have high probability of occurrence of sub-acute cardiac rupture after acute myocardial infarction.     

Advances in antiplatelet therapy for acute coronary syndromes

In the third of this series of clinical updates on recent advances in medication, RICHARD GRAY summarises the established benefits, safety and clinical side effects of the antidepressant mirtazapene.     

Unstable atherosclerotic plaque and acute coronary syndromes

Acute coronary syndromes (unstable angina pectoris, acute myocardial infarction, sudden cardiac death) participate significantly in cardiovascular and general morbidities and mortalities. Their common pathogenetic mechanism resides in the disturbance of the integrity of atherosclerotic plaque by a fissure, rupture, or ulceration and the origin of unstable atherosclerotic plaque by the formation of thrombi, which together with vasoconstriction, causes a varying degree of the dynamic obstruction of the coronary artery. Thrombogenesis takes place in coincidence with the factors of vascular wall, rheologic, thrombotic (proaggregatory and procoagulatory), and antithrombotic (antiaggregatory and anticoagulatory-fibrinolytic) factors. The formation of unstable atherosclerotic plaque is a critical point of the dissociation of both stable and unstable myocardial ischaemiae. The prevention and therapy of atherosclerosis must be complex, namely antiatherogenic, however most of all endothelium-protective, or cellulo-protective, antilipidogenic and antithrombogenic. They cannot be alternative; one therapy will not substitute another. Regarding the importance of even residual thrombosis and thrombin, new antithrombotic substances are being intensively investigated.     

Myocardial perfusion imagings in acute coronary syndromes

Stress myocardial perfusion imaging(MPI) is one of the most important clinical tools for the evaluation of chronic coronary artery disease. In acute coronary syndromes (ACS), resting MPI was applied in several emergency hospitals in Japan for the purpose of differential diagnosis, estimation of area at risk or myocardial stunning. It was also reported that the severity and the poor prognostic outcome could be predicted using myocardial fatty acid imaging in patients with ACS. However, benefits and clinical utilities of MPI in ACS remains still under clinical investigation with cost-effective aspect.     

Procoagulant and proinflammatory activity in acute coronary syndromes

Free-living elderly people aged > or = 65 y were recruited to assess riboflavin and vitamin B-6 intakes and status and the effect of riboflavin supplementation on biochemical indicators of these 2 vitamins. The status of riboflavin (erythrocyte glutathione reductase activation coefficient; EGRAC) and vitamin B-6 (plasma pyridoxal-5'-phosphate; PLP) were determined in a total sample of 92 subjects, from whom dietary intake data were obtained by using the diet history method (n = 83). Although dietary intakes of both vitamins were considered to be adequate according to current reference values, abnormal EGRAC and plasma PLP values were identified in 49% and 38% of subjects, respectively, with 21% having suboptimal status for both nutrients. A subgroup of subjects from the initial sample (n = 45) was assigned in a double-blind manner to receive either 1.6 or 25 mg riboflavin or placebo daily for 12 wk. In those subjects with a baseline EGRAC or plasma PLP value falling outside the currently accepted threshold value for adequacy, low-dose riboflavin supplementation improved status of the limiting nutrient significantly (P<0.0001 and P = 0.020 for EGRAC and plasma PLP responses, respectively). We conclude that a high proportion of healthy elderly people may have suboptimal status for these nutrients despite apparently adequate dietary intakes. Furthermore, we showed that riboflavin supplementation at physiologic doses corrects biochemical abnormalities of not only EGRAC, but also plasma PLP, confirming the biochemical interdependency of these vitamins and suggesting that riboflavin is the limiting nutrient.     

Endothelin and big endothelin in coronary heart disease and acute coronary syndromes

Endothelin (ET), the most potent endogenous vasoconstrictor with mitogenic potency, is generated from its precursor big-endothelin (BET) in a proteolytic process and discussed as a pathogenetic factor in coronary artery disease and in the acute coronary syndromes. Several studies documented elevated plasma endothelin concentrations in acute myocardial infarction, but conflicting results were reported in patients with stable and unstable angina. Only few studies determined big endothelin, although it half-life and plasma concentrations are higher in comparison to endothelin. ET and BET levels (Radioimmunoassay, Biomedica GmbH, Vienna) were determined in patients with stable angina (SAP, n = 20), unstable angina (IAP, n = 12), acute myocardial infarction (AMI, n = 12) and healthy subjects (NP, n = 11). The concentrations of ET and BET (median (minimum-maximum) in fmol/ml) of the patients with stable angina (SAP: ET 0.7 (0.3-1.1); BET 1.7 (0.7-2.9)), unstable angina (IAP: ET 1.0(0.5-1.7); BET 2.5 (1.3-4.1)) and acute myocardial infarction (AMI: ET 1.2 (0.6-2.3); BET 3.6 (3.2-5.3)) showed a significant difference compared to controls (NP: ET 0.5 (0.4-0.7); BET 1.4 (1.1-1.7)) (SAP vs. NP: ET p < 0.01; BET p < 0.05; IAP and AMI vs. NP: ET and BET p < 0.001). Also, the concentrations of the peptides differed significantly dependent on the clinical severity of coronary artery disease (AMI vs. SAP: ET and BET p < 0.001; AMI vs. IAP: BET p < 0.05; IAP vs. SAP: ET p < 0.05; BET p < 0.01). Twelve of 15 patients with big endothelin concentrations over 3 fmol/ml suffered acute myocardial infarction. Seven of 12 patients with AMI showed elevated ET and BET concentrations before the increase of creatinecinase. There was no correlation between number of risk factors per patient, cholesterin and subfractions, severity of CAD classified in one-two-three-vessel disease or coronary score according to modified criteria of the American Heart Association (AHA). We conclude that in patients with coronary artery disease endothelin and big endothelin levels are elevated and related to the clinical and not to the morphological severity of coronary artery disease. Big endothelin is the more sensitive parameter in comparison to endothelin and indicates a severe course of myocardial ischemia in patients with unstable angina. The development of assays with the possibility of a quick determination of the peptides may be valuable for risk stratification of acute coronary events.     

Advances in the medical management of acute coronary syndromes

Many advances in the treatment of acute coronary syndromes have been realized over recent years. In ST elevation myocardial infarction, new aggressive thrombolytic regimens improve early reperfusion and improve survival. The current focus is on bolus thrombolysis, glycoprotein IIb/IIIa inhibition, and low-molecular-weight heparin as adjuncts. In unstable angina and non-ST elevation myocardial infarction, two major advances are IIb/IIIa inhibition and low-molecular-weight heparin, each of which significantly improves the outcome of patients and which have just been approved for use by the Food and Drug Administration. Following acute coronary syndromes, cholesterol lowering with statin drugs has a major effect, even in the large group of patients with average cholesterol levels. Use of clopidogrel, a more potent antiplatelet agent than aspirin, appears to decrease recurrent ischemic events, which has highlighted the potential benefits of oral IIb/IIIa inhibitors, which are much more potent antiplatelet agents. An additional focus has been on ensuring that patients actually receive the currently available medications. With a great number of new medical treatments, the outcome of patients with acute coronary syndromes has improved and will continue to improve as we enter the next millennium.     

Mast cell infiltration in acute coronary syndromes: implications for plaque rupture

The time-course of uterine growth, cell proliferation, and microvascular development was evaluated during the first 72 h after implanting estradiol-17beta (E2) into ovariectomized (OVX) ewes. Uterine fresh weight increased 2.3-fold by 24 h and increased further (3.3-fold) by 48 h. The majority (approximately 75%) of this growth response was associated with tissue growth rather than a change in the tissue dry weight:fresh weight ratio. Both uterine cell number (DNA content) and cell size (RNA:DNA ratio) increased from 0 to 24 h (1.8-fold and 1.7-fold, respectively). Cell proliferation also increased dramatically between 8 h and 24 h after E2 implantation. Endometrial microvascular volume density (percentage of tissue volume occupied by microvessels) increased approximately 1.8-fold by 24 h and then remained constant or declined slightly through 72 h. The total endometrial microvascular volume, however, increased approximately 5-fold from 0 to 24 h and increased further by 72 h. Thus, treatment of OVX ewes with E2 caused a dramatic increase in uterine fresh and dry weights by 24 h, due primarily to hyperplasia and hypertrophy, with only a relatively small change in tissue dry weight:fresh weight ratio. This dramatic uterine growth was associated with a profound increase in endometrial microvascular volume.     

C-reactive protein serum level is a valuable and simple prognostic marker in non Hodgkin's lymphoma

Interleukin-6 plays a central role in normal B-cell maturation and in proliferation of some B-cell malignancies including multiple myeloma and some non Hodgkin's lymphomas (NHL). Furthermore, this cytokine also plays a major role in acute phase response by mediating synthesis of acute phase proteins such as C-reactive protein (CRP). In order to evaluate the exact role of CRP serum level as a simple prognostic factor, we analyzed CRP and IL-6 serum levels in 39 patients with NHL. Eleven patients had low grade NHL, 15 intermediate grade NHL, and 13 high grade NHL. Thirty percent of the patients presented detectable IL-6 serum levels (mean+/-SD: 33.6+/-95.2 U/ml, range: 0 to 500). Increased serum CRP levels were found in 42% of the patients with a mean of 29.2+/-41.97 mg/l] (range: 0 to 129). Thirty seven patients were studied for both markers. Three groups of patients were determined. One with low IL-6 and CRP serum levels (N=21), a second with high level of both markers (N=10), and the third with high serum CRP levels alone (N = 5). Only one patient had high level of serum IL-6 with no detectable CRP. The correlation of serum IL-6 and CRP levels with patient survival was investigated. Median survival in the group with low IL-6 level was not reached. 67% of patients of this group were still alive at 32 months from diagnosis. The group of patients with detectable IL-6 had a median of survival of 12 months (p<0.025). The survival of patients with a CRP<10 mg/l was not reached. 75% of patients survive at 32 months from diagnosis, whereas the group with higher CRP level reached a median survival at 8.5 months (p<0.009). As expected, on univariate analysis, there is a significant relationship between CRP and IL-6 levels (p<0.00017), and CRP levels and B symptoms (p<0.001). Furthermore there is a significant relationship between CRP and LDH levels (p<0.042).These results indicated that CRP may be considered as a valuable and easy prognostic biomarker of NHL.     

C-reactive protein as an outcome predictor for maintenance hemodialysis patients

We produced the monoclonal antibody RT10F7, characterized its antigenic specificity and expression in the adult and developing retina, in cultured retinal cells and in other parts of the central nervous system. In metabolically-labelled retinal cultures RT10F7 immunoprecipitated a protein of approximately 36,000 mol. wt. In the adult, RT10F7 stained endfeet of Müller cells in the ganglion cell layer, four horizontal bands in the inner plexiform layer, and radial fibres in the outer plexiform layer which terminated at the outer limiting membrane. In the inner nuclear layer, most somata were underlined by Müller processes that wrapped around them, but some cell bodies were immunoreactive for RT10F7 in the cytoplasm. During development, postnatal day 21 was the first age at which the adult pattern of immunoreactivity was present, although a fourth band in the inner plexiform layer was less clear than for the adult. By 14 and eight days after birth, the pattern of RT10F7 immunoreactivity approximated that of the adult; however, only three bands and one band were present, respectively, in the inner plexiform layer. At earlier ages, postnatal days 4, 1 and embryonic ages 19 and 15, the monoclonal antibody stained Müller cell endfeet and radial fibres, from the inner plexiform layer through the neuroblastic layer to the outer limiting membrane. At these ages, the immunoreactivity was more prominent at the level of Müller cell endfeet. The monoclonal antibody stained glia in preparations of dissociated retinal cells maintained in culture but not astrocytes or oligodendrocytes from optic nerve cultures. In brain sections, tanycytes exhibited RT10F7 immunoreactivity. The monoclonal antibody RT10F7 recognized a specific cell type in the retina, the Müller cell. In the adult and developing retina, RT10F7 recognized an antigen that is present primarily in Müller cell processes. This feature allowed us to follow the maturation of the Müller cell and correlate it with developmental events in the retina. RT10F7 is a specific marker for Müller cells in vivo and in vitro and may be useful for studies of function of Müller cells after ablation or after injuries that are known to activate Müller cells.     

Abciximab-induced thrombopenia during treatment of acute coronary syndromes by angioplasty

ReoPro (abciximab) is the Fab fragment of a chimeric monoclonal antibody directed against platelet glycoprotein IIb-IIIa. Its efficacy to prevent ischaemic complications after PTCA has been demonstrated in 3 studies: EPIC, EPILOG, UPTAKE. One hundred and sixty five cases of thrombocytopenia (< 100,000/microliter) were reported in a series of 5461 patients randomized in these 3 studies (i.e. 3.0%), including 46 (2.03%) with placebo and 119 (3.73% with abciximab. Among the 2270 patients randomized to receive placebo, 11 (0.48%) cases of severe thrombocytopenia (< 50,000/microliter) were observed versus 34 (1.07%) with abciximab. Major acute thrombocytopenia (< 20,000/microliter and < 24 hours) occurred in 0.60% (20 patients) of cases with abciximab. Their mechanism remains unknown. A therapeutic challenge did not modify either their incidence, or their severity. The development of thrombocytopenia did not worsen the patient's prognosis and course was always favourable. Twenty five cases of thrombocytopenia (0.60%), including 3 cases of acute major thrombocytopenia (0.08%) were spontaneously reported in France among the first 4000 patients treated with abciximab post-marketing. All patients treated with abciximab must be monitored by platelet count, 2 to 4 hours after the bolus administration, then 12 and 24 hours later. These platelet counts should be performed on 3 tubes (EDTA, citrate, heparin) in order to eliminate pseudothrombocytopenia and a differential diagnosis. In the case of true thrombocytopenia (< 10,000/l), treatment should be suspended and the platelet count should be repeated daily until return to normal. In the case of thrombocytopenia less than 60,000/microliter, heparin and aspirin should also be systematically discontinued and, below 50,000/microliter, platelet transfusion is justified.     

Increased neopterin in patients with chronic and acute coronary syndromes

The effect of aprotinin on Schistosoma mansoni miracidial penetration process, by its direct topical application on Biomphalaria alexandrina snails, was studied The snails were exposed to S. mansoni miracidial suspension which was mixed with aprotinin at concentrations ranging from 0.02 to 20 Kallikrein inactivator units (KIU)/ml of applied solution. Results showed that aprotinin had marked inhibitory effect on miracidial penetration of the snails. The concentration that resulted in 50% inhibition of the miracidial penetration into B. alexandrina snails (LD50) was 2.4 KIU/ml while (LD96) was 20 KIU/ml of the applied solution. Thus, aprotinin may be one of the important methods in the control of schistosomiasis.