Circulating monocytes in patients with acute coronary syndromes lack sufficient interleukin-10 production after lipopolysaccharide stimulation.

Acute coronary syndromes (ACS) are associated with inflammation resulting from monocyte activation. We sought for differences in the production of pro- and anti-inflammatory cytokines by monocytes from patients with ACS. C-reactive protein (CRP) and neopterin were measured in 22 patients with acute coronary syndromes, 50 patients with stable vascular disease and 22 healthy controls. Production of tumour necrosis factor (TNF)-alpha and interleukin (IL)-10 was determined after, respectively, 6 and 24 h of incubation of full blood with lipopolysaccharide (LPS). Levels of CRP [median, interquartile range (IQR)][1.5 mg/l (0.8-4.5) ACS patient versus 2.1 (0.9-3.6) stable disease versus 0.4 (0.3-1.2) healthy controls] (P < 0.001) and neopterin [7.4 nmol/l (6.0-8.7) ACS patient versus 7.1(6.0-8.9) stable disease versus 6.4 (5.6-7.3) healthy controls] (P = 0.07) were higher in both the patient groups. IL-10 production after LPS stimulation was greatly reduced in patients with acute coronary syndromes (16 175 pg/ml, 7559-28 470 pg/ml) as opposed to patients with stable disease (28 379 pg/ml, 12 601-73 968 pg/ml) and healthy controls (63 830 pg/ml, 22 040-168 000 pg/ml) (P = 0.003). TNF-alpha production was not signi fi cantly different between the groups [7313 pg/ml (4740-12 615) ACS patient versus 11 002 (5913-14 190) stable disease versus 8229 (5225-11 364) healthy controls] (P = 0.24). Circulating monocytes in unstable coronary syndromes produce equal amounts of TNF-alpha but less IL-10 after stimulation with LPS in vitro as compared with healthy controls. We hypothesize that, in acute coronary syndromes, the production proinflammatory cytokines is not counterbalanced by anti-inflammatory cytokines such as IL-10.

The reliability of different formulae to predict creatinine clearance.

OBJECTIVES: Creatinine clearance (CCR) is a commonly used tool to measure glomerular filtration rate (GFR) in clinical practice. This tool requires collection of 24-h urine, which is quite bothersome. Several different formulae have been used to estimate GFR using plasma creatinine and other easy formulae to obtain biometrical data. We examined 10 formulae and compared them with actually measured CCR in a large sample of the general population. DESIGN: Cross-sectional cohort study. SETTING: University hospital outpatient clinic, a population based study. SUBJECTS: A total of 8592 inhabitants of the city of Groningen, 28-75 years of age. The cohort is enriched for microalbuminuria. RESULTS: In general, the formulae did not give an accurate estimation of CCR, particularly not in male and in obese subjects. Six formulae, including the Cockcroft-Gault gave a fairly good estimation of CCR in the overall population and in subgroups of specific gender, body mass index and age. All formulae however, gave an underestimation of the measured CCR in higher ranges of CCR and an overestimation in the lower ranges. Moreover, the age-related decline of CCR is hard to approximate with a formula. CONCLUSIONS: We conclude that formulae to estimate CCR in the general population, although giving a fairly good estimate of mean CCR, do not offer reliable data on CCR in the upper and lower ranges and do not adequately estimate the age-related decline in CCR.

Safety evaluation of routine intracoronary acetylcholine infusion in patients undergoing a first diagnostic coronary angiogram.

BACKGROUND: Recent findings imply prognostic significance of intracoronary acetylcholine infusion for endothelial function testing. We evaluated whether routine use of this test in coronary angiography patients is safe. METHODS: Patients undergoing a first diagnostic coronary angiography were selected to receive intracoronary acetylcholine for endothelial function evaluation. The relation between adverse reactions during infusion and risk factors was analyzed with a logistic regression model. Included in the multiple logistic regression model were the variables with a univariate P value < 0.20. RESULTS: Adverse reactions occurred in 16% (49/299) of the patients. This included two life-threatening events caused by occlusive spasm and flow limitation in the left coronary artery. Other adverse events were chest pain (n = 38), AV block or sinus bradycardia (n = 10), dyspnea (n = 3). Adverse reactions were more likely to occur in patients younger than 60 years of age (relative risk, 5.6 [2.2-14.3]). CONCLUSION: Intracoronary acetylcholine infusion is safe, but may lead to serious adverse reactions. Care should be taken especially in patients younger than 60 years of age. Routine use of acetylcholine infusion can thus only be justified if it has important prognostic significance. This has to be proven further in large prospective studies.

Eptifibatide and abciximab exhibit equivalent antiplatelet efficacy in an experimental model of stenting in both healthy volunteers and patients with coronary artery disease.

Platelet deposition and aggregation are the major determinants of acute thrombosis in coronary stents. We aimed to compare the antiplatelet efficacy of different treatments--glycoprotein (Gp) IIb/IIIa inhibitors and conventional antiaggregants--in an experimental model for stenting. Blood samples were obtained from patients with coronary artery disease (n = 15) and healthy volunteers (n = 8) and incubated either with eptifibatide (2.0 microg/ml), abciximab (3.0 microg/ml), indomethacin (15 microg/ml), or saline. Platelet adenosine diphosphate-induced aggregation in whole blood was assessed for all groups. Blood was also tested in an experimental circulation model containing metallic probes, on which platelet deposition in shear flow conditions was assessed by means of fluorescent-labeled platelet-specific (anti-GpIIIa and Ib) antibodies. Eptifibatide and abciximab, in comparison with indomethacin and no treatment, significantly reduced platelet aggregation (0, 0, 4, and 3 arbitrary units [AU], respectively; p < 0.001), anti-GpIIIa (2.25, 1.83, 11.24, and 13.42 counts per second [cps]/mg, respectively; p < 0.001), and anti-GpIb binding (0.61, 0.61, 1.00, and 1.83 cps/mg, respectively; p < 0.001). Anti-GpIIIa and anti-GpIb binding were significantly correlated (R = 0.36; p < 0.01). Patients showed a higher anti-GpIIIa, but not anti-GpIb binding, than controls (8.43 versus 3.33 cps/mg; p < 0.01), irrespective of treatment. In conclusion, eptifibatide and abciximab show equivalent in vitro antiplatelet efficacy, superior to that of indomethacin. Given the occurrence of GpIIb/IIIa platelet overexpression in the course of coronary artery disease, an extended use of GpIIb/IIIa inhibitors may be proposed to prevent acute thrombosis during routine coronary stenting.

Autologous peripheral blood stem cell transplantation in patients with relapsed lymphoma results in accelerated haematopoietic reconstitution, improved quality of life and cost reduction compared with bone marrow transplantation: the Hovon 22 study.

The present study analysed whether autologous peripheral blood stem cell transplantation (PSCT) improves engraftment, quality of life and cost-effectiveness when compared with autologous bone marrow transplantation (ABMT). Relapsing progressive lymphoma patients (n = 204; non-Hodgkin's lymphoma n = 166; Hodgkin's disease n = 38) were, after induction treatment with the DHAP-VIM (cisplatin, cytarabine, dexamethasone, etoposide, ifosfamide, methotrexate) regimen, randomly (2:1) assigned to the harvest of granulocyte-macrophage colony-stimulating factor-mobilized stem cells after the second DHAP course or autologous bone marrow cells before the second DHAP course. These stem cells were reinfused following high-dose myeloblative chemotherapy. After induction, 118 patients obtained a partial or complete response and were eligible for randomization. In the PSCT arm (n = 76) significantly faster engraftment of neutrophils [> or = 0.1 and > or = 0.5 x 10(9)/l: 10.7 d (7-36, median, range), 15 (9-45) versus 13 (8-25) and 26 (14-80), P < 0.01] and thrombocytes [> or = 20 x 10(9)/l: 13 d (7-51) versus 18 (11-65), P < 0.01] were observed. In addition, significantly fewer transfusions of red blood cells [6 (0-23) versus 8 (2-24), P < 0.01] and platelets [4 (0-60) versus 8 (2-55), P = 0.01] were required in the PSCT arm. These findings were associated with a significant reduction in the median days of intravenous antibiotics in patients with fever [8.5 (0-30) versus 14 (0-34), P = 0.04] and hospital stay [27 (8-51) versus 34 (24-78), P < 0.05]. Quality of life demonstrated a significant difference in favour of the PSCT arm. Total transplantation costs were significantly lower in the PSCT arm [$13,954 ($4913- 29,532) versus $17 668 ($10,170-44,083) P < 0.05], as a result of the reduced hospital stay and lower antibiotic costs. In summary, these results indicate that PSCT is superior to ABMT with regard to engraftment, supportive care, quality of life and cost.

VERDICT: the Verapamil versus Digoxin Cardioversion Trial: A randomized study on the role of calcium lowering for maintenance of sinus rhythm after cardioversion of persistent atrial fibrillation.

INTRODUCTION: Many relapses of atrial fibrillation (AF) occur, especially during the first week(s) after electrical cardioversion (ECV). The aim of the present study was to compare in a randomized design the efficacy of verapamil (intracellular calcium lowering) versus digoxin (calcium increasing) for maintenance of sinus rhythm after ECV. METHODS AND RESULTS: Ninety-seven patients with persistent AF were randomized to verapamil (n = 49) or digoxin (n = 48) for 1 month before and 1 month after ECV. The first month after ECV, patients recorded heart rhythm using daily transtelephonic monitoring. No additional antiarrhythmic drugs were given. Of the 97 patients, 43 patients (20 verapamil) underwent ECV per protocol. Median previous AF duration was 18 and 26 days for verapamil and digoxin, respectively. There were no differences in atrial dimensions and underlying heart disease between the two groups. The success rate of ECV was 75% versus 83% (P = NS). After 1 month, 47% versus 53% (P = NS) had recurrence of AF. Median time to recurrence was 5 days (range 0 to 26) versus 8 days (range 2 to 28) (P = NS), respectively. CONCLUSION: Stand-alone intracellular calcium lowering by verapamil around ECV does not enhance cardioversion outcome.

Multilink stent promotes less platelet and leukocyte adhesion than a traditional stainless steel stent: an in vitro experimental study.

BACKGROUND: Platelet and leukocyte deposition onto metallic struts can be a crucial factor in the outcome of a coronary stenting procedure. By means of an in vitro, closed-loop circulation model, we aimed to assess blood-stent interaction patterns for a new stainless steel stent (MultiLink, Guidant Nederland BV, Nieuwegein, the Netherlands). METHODS: The effect of MultiLink (n=20) on blood cells and blood activation was studied by biochemical assays. Platelet and leukocyte adhesion to MultiLink were studied by immunofluorocytometric assays (anti-GpIIIa [CD 61] and anti-CD11b labeled antibodies, respectively), and by scanning electron microscopy. MultiLink was compared with empty circuits (n=20) and to the Palmaz Schatz stent (n=20). Experiments were performed both in the presence and in the absence of an antiplatelet agent (15 microg/mL of indomethacin). RESULTS: No significant effect on blood cells and blood activation was demonstrated for MultiLink. Antiplatelet treatment significantly reduced platelet adhesion to MultiLink (from 3.78+/-1.28 to 2.23+/-0.57 x 10(6) count per second [cps]/stent) but not to the Palmaz Schatz stent (from 4.11+/-0.31 to 5.02+/-1.29 x 10(6) cps/stent)(P=0.011). Leukocyte adhesion to MultiLink was significantly less than adhesion to the Palmaz Schatz stent (7.95+/-1.59 vs. 9.16+/-1.36 x 10(6) cps/stent, respectively; P=0.016), regardless of the presence of antiplatelet treatment. CONCLUSIONS: When compared with a traditional stainless steel stent, MultiLink seems to have features of improved hemocompatibility, and single antiplatelet treatment is proposed as the treatment of choice to prevent platelet deposition.

Prospective evaluation of early cardiac damage induced by epirubicin-containing adjuvant chemotherapy and locoregional radiotherapy in breast cancer patients.

PURPOSE: To evaluate prospectively the cardiotoxic effects of epirubicin-containing adjuvant chemotherapy in breast cancer patients. PATIENTS AND METHODS: Patients (median age, 46 years; range, 28 to 55 years) were treated with five cycles of fluorouracil, epirubicin (90 mg/m2), and cyclophosphamide (FEC) (group I, n = 21) or with four cycles of FEC followed by high-dose chemotherapy consisting of cyclophosphamide, thiotepa, and carboplatin (group II, n = 19). Locoregional radiotherapy was applied subsequently. Cardiac evaluation was performed before chemotherapy (T0), 1 month after chemotherapy, 1 month after radiotherapy (T2), and 1 year after start of chemotherapy (T3). Left ventricular ejection fraction (LVEF) was determined by radionuclide ventriculography and diastolic function by echocardiography. Autonomic function was assessed by 24-hour ECG registration for heart rate variability (HRV) analysis. Time-corrected QT (QTc) was assessed and N-terminal atrial natriuretic peptide (NT-ANP) and brain natriuretic peptide (BNP) were measured as biochemical markers of cardiac dysfunction. RESULTS: No patient developed overt congestive heart failure (CHF) and the mean LVEF declined from 0.61 at T0 to 0.54 at T3 (P =.001), resulting in an LVEF below 0.50 (range, 0.42 to 0.49) in 17% of the patients, whereas 28% had a decline of more than 0.10. Plasma NT-ANP levels increased gradually from 237 pmol/L at T0 to 347 pmol/L at T3 (P <.01), whereas plasma BNP levels increased from 2.9 pmol/L to 5.1 pmol/L (P =.04). Mean QTc increased from 406 msec at T0 to 423 msec at T3 (P <.01). No persistent alterations were found in diastolic function and HRV. CONCLUSION: Relatively low doses of epirubicin in adjuvant chemotherapy for breast cancer results in mild subclinical myocardial damage demonstrated by a decline in LVEF, an increase in natriuretic peptide levels, and an increase in QTc, which may indicate a long-term risk of CHF.

Drug-prescribing patterns in old age. A study of the impact of hospitalization on drug prescriptions and follow-up survey in patients 75 years and older.

A prospective drug surveillance study was undertaken in 300 elderly patients admitted to a geriatric clinic. Prescribing patterns were determined on admission, at discharge and 3.6 and 18 months after discharge. Patients referred from long-term care institutions were on significantly more drugs than non-institutionalized subjects. A 34% reduction in the number of medicines prescribed at discharge was accompanied by a significant decrease in the mean number of prescriptions per patient, from 4.3 to 2.8, irrespective of whether the patient was institutionalized. Polypharmacy, defined by 5 or more concomitant drugs, declined from 43 to 17%. Dosage schedules were simplified in the majority of patients, as expressed by a significant decrease in the mean number of daily doses to be taken from 6.7 on admission to 4.4 at discharge. Cardiovascular drugs, diuretics and psychotropic drugs accounted for 64% of all drug prescriptions. At discharge, prescription frequencies were reduced for most medication categories, except diuretics and gastrointestinal drugs, which were being taken more often. The prescribing frequency of cardiac glycosides, the single most frequently prescribed drug class, decreased from 60 to 33% of the patients. Three months after discharge, prescribing patterns and frequencies were found to be very similar to the pre-admission situation. Eighteen months after discharge, overall drug use had increased by 15% compared to admission, and polypharmacy was recorded in 54% of patients. It is concluded that a substantial reduction in drug prescriptions was possible in the majority of elderly patients, particularly if they are institutionalized, on admission to a geriatric clinic.(ABSTRACT TRUNCATED AT 250 WORDS)

Thymosin-inducible lymphocytes in the peripheral blood of patients with malignant melanoma.

E rosette-forming (T) lymphocytes and surface immunoglobulin-bearing lymphocytes were estimated in 85 patients with malignant melanoma. The melanoma patient group had lower mean levels of T lymphocytes and higher mean levels of immunoglobulin-bearing (? B) lymphocytes than did normal subjects. The absolute and percentage depressions of T-cell levels in the melanoma patients were stage-related, as was the depression of total lymphocyte and B-lymphocyte levels. The T lymphopenia in the melanoma patients could, in vitro, be partially abolished by fetal calf serum (as used in many E rosetting methods), and could be totally abolished by thymosin fraction 5 (Hoffmann-La Roche) at optimum concentration. In view of the ability of thymosin to restore T cells to normal levels in all of the T-lymphopenic patients, a clinical trial of this hormone in selected melanoma patients of all stages appears to be warranted.

The significance of urinary melanoma antigen excretion and the ability of thymosin to raise the level of depleted lymphocytes in vitro in malignant melanoma.

One hundred and fifty-six patients were screened for the presence of urinary melanoma antigen and serum cytoplasmic antibody. It was found that 44% of symptomless Stage 1 patients tested five to 15 years after operation had detectable antigen (Ag) in their urine; the urines of 67% of Stage 2A (local recurrence) patients were positive for Ag; while in only 38% of those patients graded 2B (lymph-node involvement) were these tests positive. Urines of 83% of patients with generalized metastases (Stage 3) were positive. A sequential study was made of 23 patients seen and treated in 1976. Of this group, 14 reverted from a positive state to a negative one following excision of their tumour, while six were negative on first postoperative testing and subsequently became positive. Three out of the 23 remained persistently negative. T lymphocyte levels were assessed in 71 melanoma patients, and a stage-related fall was noticed. Thymosin (Hoffman LaRoche) on in vitro incubation significantly raised the levels of T lymphocytes.