Increased left ventricular torsion in hypertrophic cardiomyopathy mutation carriers with normal wall thickness

Background

Increased left ventricular (LV) torsion has been observed in patients with manifest familial hypertrophic cardiomyopathy (HCM), and is thought to be caused by subendocardial dysfunction. We hypothesize that increased LV torsion is already present in healthy mutation carriers with normal wall thickness.

Methods

Seventeen carriers with an LV wall thickness <10 mm, and seventeen age and gender matched controls had cardiovascular magnetic resonance (CMR) cine imaging and tissue tagging. LV volumes and mass were calculated from the cine images. LV torsion, torsion rate, endocardial circumferential strain and torsion-to-endocardial-circumferential-shortening (TECS) ratio, which reflects the transmural distribution in contractile function, were determined using tissue tagging.

Results

LV volumes, mass and circumferential strain were comparable between groups, whereas LV ejection fraction, torsion and TECS-ratio were increased in carriers compared to controls (63 ± 3% vs. 60 ± 3%, p = 0.04, 10.1 ± 2.5° vs. 7.7 ± 1.2°, p = 0.001, and 0.52 ± 0.14°/% vs. 0.42 ± 0.10°/%, p = 0.02, respectively).

Conclusions

Carriers with normal wall thickness display increased LV torsion and TECS-ratio with respect to controls, which might be due to subendocardial myocardial dysfunction. As similar abnormalities are observed in patients with manifest HCM, the changes in healthy carriers may be target for clinical intervention to delay or prevent the onset of hypertrophy.     

Eradication of minimal disease in severe combined immunodeficient mice with disseminated Daudi lymphoma using chemotherapy and an immunotoxin cocktail

Severe combined immunodeficient (SCID) mice injected intravenously with a human Burkitt's lymphoma cell line (Daudi) develop disseminated lymphoma (SCID/Daudi), which is fatal in 100% of the mice. Early treatment of these mice with either an immunotoxin (IT) cocktail (consisting of anti-CD19-ricin A chain plus anti-CD22-ricin A chain) or chemotherapy significantly prolonged survival but was not curative. Combination therapy with the IT cocktail and any one of three chemotherapeutic drugs (doxorubicin, cytoxan, or camptothecin) cured the mice. Cure was demonstrated by both histopathologic examination of treated mice and, more importantly, by adoptive transfer of cells from organs of the cured mice to naive SCID mice where 100 tumor cells would have caused disease in the recipients. These results provide a strong rationale for combining IT therapy with conventional chemotherapy in the treatment of B-cell neoplasia.     

The anemia of chronic disorders: studies of marrow regulation and iron metabolism

Marrow regulation and iron metabolism were evaluated in 17 patients with mild or moderate anemia associated with chronic disorders. In addition, whole blood P50 and red cell 2,3-diphosphoglycerate (DPG) levels were measured. The study group consisted of seven patients with non-hematologic malignancies, nine with infection or inflammation, and one with idiopathic hypoproliferative anemia. The mean whole blood P50 and DPG levels were elevated to 28.5 +/- 1.9 mm Hg and 7.03 +/- 0.83 mumole/ml packed RBC, respectively, as compared to normal values of 26.6 +/- 0.6 mm Hg and 4.83 +/- 0.33 mumole/ml packed RBC. Erythropoietin (ESF) excretion was variable (1.1-28.7 IRP U, day), clearly elevated above normal in only three patients and, within the study group, bore no relation to hematocrit. While nine of the 17 subjects had ESF excretion rates within the 95% limits predicted by hematocrit, the remaining eight had lower than expected values. No significant differences in ferrokinetics, ESF excretion, or hematologic profile were found between patients with malignancy and those with inflammation. Marrow transit times correlated inversely with both serum and urine ESF activity (r = -0.57, p less than 0.02; and r = -0.63, p less than 0.01, respectively), indicating that the marrow reticulocyte release response to ESF stimulation was unimpaired. Erythroid iron turnovers were unrelated to serum or urinary ESF activity but were significantly correlated with serum iron levels expressed as microgram/100 ml whole blood (r = 0.56, p less than 0.02). These studies suggest that there is an intraerythrocytic response to the anemia in this group of patients, document that reduced ESF production is not a uniform finding with the anemia of chronic disorders, and provide evidence that the marrow proliferative response to anemia is limited in many patients primarily by the availability of iron.     

Busulfan pharmacokinetics using a single daily high-dose regimen in children with acute leukemia

The pharmacokinetics of busulfan, given as a single daily dose (either 4 mg/kg or 150 mg/m2), was determined in 22 children undergoing bone marrow transplantation for acute leukemia. The single daily dose regimen showed similar pharmacokinetics to previously reported regimens of 4 x 1 mg/kg, except for fourfold higher mean peak plasma levels and negligible trough levels. Daily systemic exposure for single dose regimens based on weight (4 mg/kg) or surface area (150 mg/m2), respectively were very similar to regimens of (4 x 1 mg/kg) or (4 x 37.5 mg/m2). Dose (milligrams per kilogram), peak plasma level, and area under the curve (AUC) were all higher in 12 children treated with 150 mg/m2 busulfan than in 9 children treated with 4 mg/kg. AUC was age dependent for the 4 mg/kg dose but not for the 150 mg/m2 dose. The use of a 150 mg/m2 dose allows escalation of the dose above 4 mg/kg, eliminating the tendency for younger children to receive lower systemic exposure. Little toxicity was observed in this study. Clearance and distribution volume correlated negatively with age, and AUC correlated positively with dose (milligram per kilogram). Administration of busulfan as crushed rather than whole tablets reduced the delay time for appearance of busulfan in plasma but had no effect on absorption or other pharmacokinetic parameters.