Correlation between electrocardiographic subtypes of anterior myocardial infarction and regional abnormalities of wall motion

BACKGROUND: Examination of the electrocardiogram is the most widely used means for diagnosis and early stratification of risk of acute myocardial infarction (AMI). The classical classification of the subtypes of anterior AMI is based on results of studies comparing the electrocardiograms recorded at various stages, mostly in the subacute or chronic stage of AMI, with autopsy findings. Reports regarding the correlation between electrocardiographic findings in the acute phase and regional abnormality of wall motion (AWM) detected by echocardiographic evaluation are sparse. OBJECTIVE: To investigate the relationship between the electrocardiographic and two-dimensional echocardiographic findings regarding patients with their first anterior AMI. DESIGN AND METHODS: We studied 58 patients, 44 men and 14 women of mean age 61.5 +/- 14.6 years, with their first anterior AMI who had undergone two-dimensional echocardiographic evaluation within 48 h of admission. Deviation of ST-segment trace from baseline was measured manually 0.06 s after the J point for all leads on the admission electrocardiogram. ST-segment elevation in the various leads was correlated to the incidence of regional AWM detected by echocardiography. RESULTS: ST-segment elevations > or = 0.1 mV in V1 leads were found for 21 (36.2%) patients. Basal anterior, basal anteroseptal, and basal septal AWM were seen more often for patients with than they were for patients without ST-segment elevation in V1 (57 versus 16%, P=0.003; 43 versus 13.5%, P=0.03; 43 versus 11%, P=0.01 respectively). In contrast to ST-segment elevation in lead V1, the only statistically significant difference in prevalence in the presence of regional AWM between patients with (n = 48) and without (n = 10) ST-segment elevation > or = 0.2 mV in lead V2 was in the inferoapical region (87.5 versus 40%; P=0.003). ST-segment elevation > or = 0.1 mV in leads aVL and V5 was found for 11 (19%) and 23 (40%) patients, respectively. There was no correlation between either lateral or apical regional AWM and the presence of ST-segment elevation in the anterolateral leads except for mid-lateral AWM, which was more often detected for patients with than it was for patients without ST-segment elevation in aVL leads (36.3 versus 6.4%, P=0.026). CONCLUSIONS: ST-segment elevation in lead V1 during the acute phase of anterior AMI is associated with a high incidence of regional AWM in the basal anterior, anteroseptal, and anterior regions, whereas ST-segment elevation in lead V2 is more often associated with AWM in the inferoapical region. ST-segment elevation in aVL leads is related to mid-lateral regional AWM.     

Effect of transfusional iron intake on response to chelation therapy in beta-thalassemia major

The success of chelation therapy in controlling iron overload in patients with thalassemia major is highly variable and may partly depend on the rate of transfusional iron loading. Using data from the 1-year phase III study of deferasirox, including volumes of transfused red blood cells and changes in liver iron concentration (LIC) in 541 patients, the effect of iron loading on achieving neutral or negative iron balance was assessed in patients receiving different doses of deferasirox and the comparator deferoxamine. After dose adjustment, reductions in LIC after 1 year of deferasirox or deferoxamine therapy correlated with transfusional iron intake. At a deferasirox dose of 20 mg/kg per day, neutral or negative iron balance was achieved in 46% and 75% of patients with the highest and lowest transfusional iron intake, respectively; 30 mg/kg per day produced successful control of iron stores in 96% of patients with a low rate of transfusional iron intake. Splenectomized patients had lower transfusional iron intake and greater reductions in iron stores than patients with intact spleens. Transfusional iron intake should be monitored on an ongoing basis in thalassemia major patients, and the rate of transfusional iron loading should be considered when choosing the appropriate dose of an iron-chelating agent. This study is registered at http://clinicaltrials.gov as NCT00061750.     

Allogeneic marrow transplantation for refractory anemia: a comparison of two preparative regimens and analysis of prognostic factors

From 1990 to 1993 we performed a prospective study of busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) in 30 patients with refractory anemia (RA) undergoing related (n = 17) or unrelated (n = 13) donor marrow transplantation. Nineteen patients survive disease free (63% 3- year actuarial disease-free survival [DFS]) and no patient relapsed. These results were compared to those of 38 historical controls with RA treated with cyclophosphamide and total body irradiation, of whom 22 are disease-free survivors and 1 relapsed. After correcting for significant variables between the two treatment groups, we found no statistically significant difference in outcome based on preparative regimen. Combining data from these 68 patients plus 2 additional patients with RA treated before 1993 with busulfan and cyclophosphamide, we identified four variables independently associated with improved survival: younger age, shorter disease duration, lower neutrophil count pretransplant, and lower hematocrit pretransplant. We also found that 15 patients 40 to 55 years of age had a 46% 3-year actuarial DFS and 26 patients receiving unrelated or mismatched related donor marrow had a 50% 3-year actuarial DFS. We conclude that there does not appear to be any significant difference in outcome based on preparative regimen in this patient population. In addition, allogeneic bone marrow transplantation may be a reasonable approach to therapy of RA early after diagnosis. However, whether early intervention with transplantation prolongs survival over that expected without transplantation cannot be ascertained with certainty from available data.     

Characterization of human erythroid burst-promoting activity derived from bone marrow conditioned media

Bone marrow conditioned media (BMCM) increases burst number and the incorporation of 59Fe into heme by bursts when peripheral blood or bone marrow cells are cultured at limiting serum concentrations. Burst- promoting activity (BPA) has now been purified approximately 300-fold from this source by ion-exchange chromatography on DEAE-Sephadex and absorption chromatography on hydroxyapatite agarose gel. Marrow BPA increased burst number and hemoglobin (Hb) synthesis in a dose- dependent manner. A larger increase in Hb synthesis than in burst number was consistently observed, which was probably a consequence of the increase in the number of cells per burst that occurs in the presence of BPA. The role of BPA in culture could be distinguished from erythropoietin (Ep), since no bursts grew in the absence of Ep, whether or not BPA was present, and since it had no effect on the growth of erythroid colonies scored at day 5 of culture. Our purified fraction did not support the growth of CFU-C in culture. Activity was stable at temperatures of 70 degrees C or lower for 10 min; exposure to 80 degrees C resulted in approximately 50% loss of activity. BPA was completely inactivated by treatment at 100 degrees C for 10 min. Thus, human bone marrow cells produce a heat-sensitive factor that specifically promotes the growth of early erythroid progenitors in culture.     

Rapid and specific diagnosis of HIV-1 and HIV-2 infections: an evaluation of testing strategies

To identify cost-effective testing strategies for HIV-1 and HIV-2 infections, we evaluated different combinations of tests on serum specimens from 1134 consecutive patients attending tuberculosis treatment centers in Abidjan, C?te d'lvoire. Virus-specific whole-virus enzyme-linked immunosorbent assay (WVE), Western blot (WB) and synthetic peptide enzyme-linked immunosorbent assay (SPE) were used in sequential fashion to determine the true prevalence of infection; 27% were reactive to HIV-1, 5% to HIV-2, and 10% to both viruses. Of 239 specimens positive on WB for both HIV-1 and HIV-2, SPE diagnosed 38% as HIV-1-reactive and 16% as HIV-2-reactive, while 46% remained reactive to both viruses. Using WVE or one of two rapid (5-10 min) mixed (HIV-1 and HIV-2) antigen tests (RMATs) as a screening test, followed by SPE as a supplemental test, gave results with sensitivity of 97.3-99.2%, specificity of 99.5-99.7%, and positive predictive value for diagnosing HIV infection of 99.4-99.6%, with important savings in time and reagent costs. SPE allows more specific distinction between HIV-1 and HIV-2 infections than WB, and could replace it as a supplemental test in many settings. WB may be required for specimens reactive on screening tests but negative on SPE, until sensitivity of the SPE is further evaluated. A mixed antigen screening test followed by SPE seems to be an efficient testing strategy for diagnosing HIV-1 and HIV-2 infections.     

Concentration and molecular forms of active and inactive renin in human fetal kidney, amniotic fluid and adrenal gland: evidence for renin-angiotensin system hyperactivity in 2nd trimester of pregnancy

In a study of 38 fetuses total kidney renin was significantly correlated with gestational age (r = 0.63). Although whole fetal kidney renin specific activity was found to decrease with gestational age (r = -0.65), the mean value of the specific activity was about 20 times greater than in normal adult cortex and double that in tissue from patients with renal artery stenosis, suggesting renin-angiotensin system hyperactivity. In approximately 40% of fetal kidneys examined, evidence for an inactive (trypsin-activatable) renin precursor was found. The molecular weight of this form was indistinguishable from active renin (45 000 daltons) by Sephadex chromatography. Amniotic fluid from nine cases (100%) contained angiotensin (ANG) 1, angiotensin converting enzyme (ACE), renin substrate, active and inactive renin (both 45 000 daltons). Five of the 38 (13%) fetal adrenal glands contained renin, but no evidence for trypsin-activatable forms. Aldosterone was present in low concentration in the earliest adrenals examined, and a positive correlation existed between total tissue aldosterone and gestational age (r = 0.73). These findings suggest that the fetal renin-angiotensin system has an important role to play in the maintenance of extracellular fluid volume and blood pressure in the developing fetus.     

Donor leukocyte infusions in acute lymphocytic leukemia

Donor leukocyte infusion (DLI) has well-documented activity in CML but the role of DLI in other diseases is less well defined. To evaluate the strategy in acute lymphocytic leukemia (ALL) we evaluated 44 ALL patients from 27 centers who were treated with DLI. Patients with persistent or recurrent disease received DLI from the original marrow donor (30 matched related, four mismatched family, and 10 matched unrelated). Chemotherapy was given before DLI to 28 patients. Of 15 patients who received no pre-DLI chemotherapy, two achieved complete remissions, lasting 1112 and 764+ days. In four patients who received DLI as consolidation of remission induced by chemotherapy or immunosuppression-withdrawal, duration of remission post DLI was 65, 99, 195 and 672+ days. Of 25 patients who received DLI in the nadir after chemotherapy, 13 survived > or =30 days post DLI but did not achieve remission, seven died within less than 30 days post DLI, and five entered remissions that lasted 42, 68, 83, 90, 193 days. Seven patients who did not respond to the initial DLI received a second DLI; none of these patients attained durable remission. Eighteen of 37 evaluable patients developed acute GVHD and five of 20 evaluable patients developed chronic GVHD. Overall actuarial survival is 13% at 3 years. In conclusion, DLI has limited benefit in ALL. New approaches are needed in this group of patients.     

Intensive graft-versus-host disease prophylaxis is required after unrelated-donor nonmyeloablative stem cell transplantation

Nonmyeloablative stem cell transplantation (NST) harnesses the graft-versus-tumor effect while minimizing regimen-related toxicity, and can result in donor chimerism and remission. Acute graft-versus-host disease (GVHD) and infections are major complications after sibling NST. Toxicity of unrelated-donor (UD) NST and the most appropriate GVHD prophylaxis in this setting remain poorly defined. We describe 25 patients who received UD-NST conditioned with fludarabine and cyclophosphamide. The first six patients received cyclosporine (Cs) and mycophenolate mofetil (MMF) (n=5) or methotrexate (MTX) (n=1) as GVHD prophylaxis (group 1) and all developed grade III-IV acute GVHD. The next 19 patients received the same conditioning regimen with the addition of alemtuzumab, and all received Cs/MTX post-transplant. Engraftment and donor chimerism were achieved in all but one evaluable patient. In all, 15 patients died: five of six deaths in group 1 were attributable to acute GVHD, while deaths in group 2 were due to infection or progressive disease (P=0.05). The combination of Cs/MMF is inadequate GVHD prophylaxis for UD-NST. The use of Cs, MTX, and alemtuzumab eliminated severe acute GVHD; its impact on response merits further study.     

Sickle cell disorders and chronic intravascular haemolysis are associated with low plasma heparin cofactor II

Thrombotic events are known to be increased in patients with sickle cell syndromes and a variety of abnormalities of coagulation or endothelial function have been described, although the relevance of these findings either to the pathogenesis of vaso-occlusive phenomena or the risk of thrombosis are unclear. Heparin cofactor II (HCII) and antithrombin III are circulating inhibitors of thrombin and low plasma levels have been associated with an increased risk of thrombosis in otherwise healthy individuals. We describe for the first time abnormally low plasma levels of HCII in patients with sickle cell syndromes. 45 adult patients with sickle cell syndromes (31 SS, 10 SC, 4 SβThal) were compared with 61 age matched control patients for HCII in plasma. There was a highly significant reduction in HCII in SS patients irrespective of crisis or transfusion state 0.68 ± 0.15 U/ml (mean ± SD) compared with controls 1.00 ± 0.19 U/ml ( P < 0.001). HCII antigen was also significantly reduced (0.53 ± 0.19 U/ml) compared with controls (1.02 ± 0.23 U/ml, P < 0.0001). By contrast there was no reduction in antithrombin III in this group. HCII (0.63 ± 0.13 U/ml, P < 0.001) and HCII antigen (0.54 ± 0.08 U/ml, P < 0.001) are also significantly reduced in SC patients HCII levels increased towards control values during sickle cell crises, in patients taking the contraceptive pill, or with regular blood transfusion; however, plasma HCII concentrations were not increased acutely by exchange transfusion. HCII was also decreased in thalassaemia intermedia and pyruvate kinase deficiency, suggesting that intravascular haemolysis may be the cause of reduced HCII levels.     

Prognostic significance of mild mitral regurgitation by color Doppler echocardiography in acute myocardial infarction

Mitral regurgitation (MR) complicating acute myocardial infarction (AMI) is associated with increased mortality. The prognostic significance of only mild MR detected by echocardiography in patients with AMI is unknown. This study assessed the long-term risk associated with mild MR detected by color Doppler echocardiography within the first 48 hours of admission in 417 consecutive patients with AMI. No MR was detected in 271 patients (65%), mild MR was seen in 121 patients (29%), and moderate or severe MR was noted in 25 patients (6%). One-year mortality rates were 4.8%, 12.4%, and 24%, respectively (p<0.001). Multivariate analysis revealed that mild MR was independently associated with increased 1-year mortality (p<0.05) after adjustment for age, gender, previous myocardial infarction, diabetes mellitus, systemic hypertension, Killip grade > or =2 on admission, and left ventricular ejection fraction < or =40%. The hazard ratio for 1-year mortality was 2.31 (95% confidence interval 1.03 to 5.20) for mild MR and 2.85 (95% confidence interval 0.95 to 8.51) for moderate or severe MR. Thus, mild MR detected by color Doppler echocardiography within the first 2 days of admission in patients with AMI is a significant independent risk predictor for 1-year all-cause mortality.