Treatment of acute nonlymphocytic leukemia: use of anthracycline- cytosine arabinoside induction therapy and comparison of two maintenance regimens

Patients with acute nonlymphocytic leukemia were given remission induction therapy consisting of cytosine arabinoside and an anthracycline. Those patients who experienced complete remission received two courses of consolidation therapy and were randomized to receive maintenance therapy consisting of either daily chemotherapy with reinforcements every 3 mo or reinforcement therapy only every 6 wk. The overall complete remission rate was 66%, with 80% complete remission for previously untreated patients less than 60 yr of age who did not have a prior history of malignancy. Remission durations were the same for patients treated with both maintenance regimens. The major determinant for successful remission induction therapy was patient age, with older patients frequently succumbing to intercurrent infection. Documented leukemic cell resistance to the therapy employed was only rarely encountered. Once remission was achieved, age was no longer a determinant of patient survival, since duration of remission was independent of age. Remission durations were directly related to leukemic cell retention of cytosine arabinoside triphosphate. Hence therapy for acute nonlymphocytic leukemia can be divided into two separate areas: remission induction and remission maintenance.     

Cytosol intermediates in the transport of iron

Three 59Fe-labeled nonheme components of the cytosol were identified when rabbit reticuloyctes were incubated with 59Fe-labeled plasma under conditions in which the iron supply was not limiting. Two of these components were identified as ferritin and transferrin. The latter was characterized by gel filtration as having apparent molecular weight higher than transferrin, indicating that the transferrin may be complexed to another moiety. The third component, referred to as iron- binding protein-I (IBP-I), is as yet uncharacterized. When the reticulocytes were incubated with unlabeled plasma after pulse-labeling with 59Fe-labeled plasma, 59Fe radioactivity in these cytosol components decreased; after 15 min of chase, the 59Fe in ferritin, transferrin, and IBP-I fell to 64.6%, 26.5%, and 65.8% of the initial values, respectively. A good correlation existed between the decrease of 59Fe in these three nonheme compartments and the associated increase in 59Fe-heme. The data presented suggest that cytosol ferritin, transferrin, and IBP-I are intermediates in the transport of 59Fe from the plasma membrane to the mitochondria.     

Serum potassium values in relation to the use of diuretics in patients with unstable angina pectoris

Transient hypokalaemia may occur in acutely ill patients andis associated with an increased incidence of life-threateningarrhythmias. Therefore, we performed a retrospective analysisof the serum potassium values of 538 patients with unstableangina included in the Holland Interuniversity Nifedipine/metoprololTrial in relation to the use of diuretics. On admission, 113of these patients used diuretics. Potassium sparing diureticshad been used in 65 Patients (group A) and non-potassium sparingdiuretics in 48 patients (group B). From the 425 patients noton diuretics a random sample of 56 (group C) was drawn. Bloodsamples were taken routinely on admission to the coronary careunit. The serum potassium values found for groups A, B and Cwere 3.77±0.55, 3.44±0.69 and 4.14±0.48,respectively, and the prevalence of hypokalaemia (<3.6 mmol)40, 65 and 14% respectively. Rate ratio [95% confidence interval(C1)] for hypokalaemia when compared to groups C was 2.6 (1.2–5.6)group A and 4.9 (2.4–10.1) for group B. The prevalenceof hypokalaemia was higher for women than for men (rate ratio,95% C1: 1.4, 0.9–2.2). Patients already on beta-blockertherapy showed a 10% lower prevalence of hypokalaemia (rateratio, 95% C1: 0.7, 0.5–1.1). These data were compared with serum potassium values of 104patients with stable angina, who reported to the outpatientclinic. These patients were also divided into three groups accordingto the use of diuretics. Only in 15% of the patients using non-potassiumsparing diuretics was hypokalaemia observed. These findings indicate that patients with unstable angina havelow serum potassium levels and a high prevalence of hypokalaemiaon admission to the coronary care unit. Potassium levels areinfluenced positively by pre-existing beta-blockade and stronglynegatively by diuretics, especially non-potassium sparing diuretics.The effect of beta-blockers suggest a transient catecholaminedependent mechanism.     

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.     

Jejunal Biopsies in Protein-calorie Malnutrition and Intestinal Parasitic Infestation in Brazil

Jejunal biopsies were performed in 71 subjects, who were classified into three groups as follows: Forty-one patients, on a poor diet, without clinical signs of malnutrition, with and without parasitic infestation; nineteen patients with severe protein-calorie malnutrition, with and without parasitic infestation; control group, ten medical students and one of the authors on a normal diet and without parasitic infestation.
The dissecting microscope appearance showed mild alteration of the intestinal villi of Group A patients with parasitic infestation and severe alteration on Group B patients, especially those with parasitism.
On histological examination, only the total mucosal thickness showed statistically significant differences between the Group B (severe protein malnutrition) and the other groups.     

Presence of circulating macromolecular IgA in patients with hematuria due to primary IgA nephropathy

The relation between renal histologic features and the presence of circulating immune complexes was studied in 50 patients with hematuria. Primary IgA nephropathy was found in 25 patients, and various other forms of glomerulopathy were seen in the remaining 25 patients. Circulating immune complexes were detected with the 125I-C1q-binding assay, the conglutinin-binding assay, and the anti-IgA inhibition binding assay, the latter detecting specifically IgA-containing immune complex-like material. The 125I-C1q-binding assay gave negative findings for all patients except one. With the conglutinin-binding assay, immune complexes were found in a similar frequency for patients with and without IgA nephropathy. However, the anti-IgA inhibition binding assay gave positive results only in patients with primary IgA nephropathy (68 percent) and in none of the other patients. Sucrose density ultracentrifugation, as well as experiments in which the anti-IgA inhibition binding assay was performed with and without pretreatment of serum with polyethylene glycol, showed the presumed IgA immune complexes to have intermediate sedimentation coefficients (11 to 21S). The presence and level of this macromolecular IgA in the circulation correlated significantly (p less than 0.001) with the presence of hematuria in patients who had this clinical manifestation intermittently. Furthermore, a significant correlation (r = 0.69, p less than 0.0001) was found between the degree of hematuria and the degree of positive findings of the anti-IgA inhibition binding assay. This study shows that in patients presenting with hematuria, a positive finding on the anti-IgA inhibition binding assay is restricted to patients with primary IgA nephropathy and therefore could be of diagnostic value.     

Direct and indirect measurement of urinary kallikrein excretion in patients with essential hypertension and normotensives: relation to age and plasma renin and aldosterone levels

The relevance of age and activity of the renin-angiotensin-aldosterone system to the excretion of urinary kallikrein (Ukal) was studied in twenty-five patients with essential hypertension and forty normotensive controls. The age range for both study groups was 20-60 years. Ukal was measured by radioimmunoassay and by an amidolytic assay. Results of both assays correlated closely (r = 0.93, n = 65, P less than 0.001). For all hypertensives Ukal excretion was not significantly different from that of controls. However, older hypertensives (greater than 40 years, n = 13) had a significantly lower Ukal excretion than normotensives of the same age (n = 20) (radioimmunoassay 67.2 (SEM 7.2) v. 105.1 (SEM 8.4) micrograms (24 h)-1; and amidolytic method 0.84 (SEM 0.10) v. 1.13 (SEM 0.08) U (24 h)-1). No correlation was found between Ukal excretion and plasma renin or aldosterone. In fact, the aldosterone level was highest in older hypertensives. In conclusion, the lower Ukal excretion in hypertensives over 40 is likely to be secondary to the long-standing high blood pressure. Under basal conditions, Ukal excretion seems little influenced by the activity of the renin-angiotensin-aldosterone system.     

Invalidation of antiglobulin tests by a high thermal amplitude cryoglobulin

A multiply transfused patient was referred for evaluation of a transfusion reaction. The direct and indirect antiglobulin tests (DAT, IAT) for alloantibody were negative. However, IgG-coated control cells failed to agglutinate in the negative reactions, casting doubt on their validity. At 4 degrees C, the patient's serum exhibited a large cryoprecipitate (2.9 mg/mL), made up predominantly of an IgG kappa paraprotein and having trace amounts of IgM and C3. Clear serum separated at 37 degrees C became cloudy within 10 minutes at room temperature (RT); within 4 hours, approximately 60 percent of the total precipitable cryoprotein had precipitated. Red cells (RBCs) incubated in fresh serum that had cooled to RT or RBCs obtained from RT or refrigerated samples contained cryoprecipitate that sedimented with the RBCs during washing with RT saline. On resuspension, enough IgG cryoglobulin redissolved to neutralize completely the commercial anti-IgG reagents. If the patient's samples were maintained at 37 degrees C, cryoprecipitate did not form, and RBCs washed four times at 37 degrees C gave valid DAT and IAT reactions. The removal of all cryoprecipitate from the patient's serum by centrifugation after overnight incubation at 4 degrees C also made possible valid antibody screening and compatibility tests.     

A dichotomy between the expression of IgD on B cells and its requirement for triggering such cells with two T-independent antigens

The majority of adult B lymphocytes in the mouse bear two immunoglobulin isotypes, IgM and IgD (μ(+)δ(+) cells) (1). A small population of IgM-bearing cells lacks, or expresses very low levels of IgD (μ- predominant [μp] cells) (1). These cells are believed to constitute a less mature subset of B cells analogous to neonatal B cells (2). Based on the time during ontogeny when responses to T-independent (TI) and T-dependent (TD) antigens appear (3, 4) and the ability to block in vitro responses with anti- μ or anti-δ (5, 6, D. Mosier, personal communication), it has been suggested that the precursors of two TI-1 responses, trinitrophenyl (TNP)- Brucella (TNP-BA) and TNP-lipopolysaccharide (TNP-LPS) are μp cells (5, 6), whereas the precursor for a TD response, TNP-sheep erythrocytes (TNP-SRBC), bears both IgM and IgD (6). However, the possibility cannot be excluded that IgD is present on some or all of the TI precursors, but that it is not obligatory for triggering. In the present experiments we have examined the phenotypes of TI and TD precursors by treating cells with C’ and either anti-μ or anti-δ before stimulation with antigen. Our results suggest that the majority of B cells that respond to TNP-BA, TNP-LPS, and TNP-SRBC bear IgD, even though in the case of the two TI antigens, IgD is not required for triggering.     

In vitro and in vivo persistence of reticulocytes from donor red cells

BACKGROUND: Reticulocytes are important in the phenotyping of transfused patients. Reticulocytes can persist in blood units for the shelf life of the unit. STUDY DESIGN AND METHODS: Temperature dependence of reticulocyte persistence was examined in vitro at 4, 24, and 37 degrees C by using thiazole orange staining and flow cytometric analysis. Two-color flow cytometric analysis was used to evaluate the persistence of donor reticulocytes in transfused patients. RESULTS: Flow cytometric analysis using thiazole orange demonstrated that persistence of reticulocytes in units of stored CPDA-1 blood was temperature-dependent. Reticulocytes disappeared over 13 and 6 days at 24 degrees C and 37 degrees C, respectively, but at 4 degrees C the reticulocyte count changed little over 35 days. Two-color flow cytometric analysis of reticulocyte antigens was used to follow donor reticulocytes in 14 transfusion events in nine different patients. Donor reticulocytes persisted through 24 hours in 75 percent of the patients and were detectable at 48 hours in three patients. CONCLUSION: This study demonstrates that reticulocytes persist during refrigerated storage; they are detectable in the circulation of most recipients for the first 24 hours after transfusion and in the circulation of a few recipients after 48 hours. These findings may have relevance for separation techniques based on reticulocyte density in samples drawn shortly after transfusion and for evaluation of reticulocyte counts in patients with hematologic abnormalities.