Studies on antibody to intrinsic factor.

Sera from a group of 79 patients with pernicious anemia were studied for the presence of antibody to intrinsic factor. Two general types of antibody activity were found, and it was possible to distinguish three groups of pernicious anemia sera on the basis of their content of these types. Type I antibody blocks the binding of radioactive vitamin B(12) to intrinsic factor when added to intrinsic factor before the B(12); it is not detected on intrinsic factor when added after B(12). This antibody blocks intrinsic factor-mediated B(12) absorption in vivo when mixed in the sequence intrinsic factor + antibody I + B(12), but not when mixed in the sequence intrinsic factor + B(12) + antibody I. Type II antibody reacts with intrinsic factor when B(12) is attached. This antibody prevents the absorption of B(12) from intrinsic factor in pernicious anemia patients when mixed in the sequence intrinsic factor + B(12) + antibody II, and is thereby distinguished from antibody I.

Iron homeostasis in plasmacytoma-bearing mice.

Plasmacytomas in mice have been shown to contain significant quantities of nonheme iron, half of which is in the form of ferritin. The livers of animals with plasmacytomas have a decreased iron content, and plasma iron is reduced. The animals develop an anemia that is partially corrected by parenteral iron. However, when plasmacytoma-bearing mice are given excessive amounts of parenteral iron, the surplus is stored in the liver of animals rather than in the tumor itself. These findings suggest that plasmacytomas sequester iron and deprive other organs of it to satisfy their own need. However, the tumors do not function as a storage site for iron above their own need.

Splenic sequestration with sickle cell-C disease.

During an episode of pneumonia and multiple pulmonary thromboembolic events, an adult male patient with sickle cell-C hemoglobinopathy developed a severe anemia associated with rapidly increasing splenic size and diminished splenic uptake of technetium Tc 99m sulfur colloid, indicating diminished splenic function due to hypersequestration, a rare and noteworthy phenomenon in adult patients with sickle cell-C disease.

Effectiveness of triglycyl vasopressin in persistent hematuria associated with sickle cell hemoglobin.

Two cases of persistent hematuria associated with the presence of sickle cell hemoglobin were treated intravenously with triglycyl vasopressin, a drug not previously used for this condition. One patient, a 16-year-old boy, had hemoglobin AS. Both patients had a history of severe hematuria persisting over several months, resistant to the usual forms of therapy, and requiring numerous transfusions. In each patient, the condition responded to intravenous triglycyl vasopression therapy, with cessation of hematuria. Experimental studies in dogs indicate that triglycyl vasopressin reduces renal blood flow substantially. Further trial of triglycyl vasopressin in severe hematuria associated with the presence of sickle cell hemoglobin appears to be indicated.

Effect of plasma proteins and temperature on echogenicity of blood.

An explanation is proposed for the echogenicity to ultrasound scanning at 5 mHz and above of unclotted blood under conditions of stasis. In vitro experiments using blood from normal subjects and from patients with myeloma revealed that: 1) lysis of red cells prevented echogenicity, 2) echogenicity increased with increasing hematocrit, fibrinogen and other macromolecules, and temperature, and 3) blood from myeloma patients showed increased echogenicity and rouleau formation, a form of aggregation seen on peripheral smears. From these experiments it was concluded that red cell aggregation is a major cause of echogenicity of unclotted blood, requiring both intact red cells and conditions which are known to enhance red cell aggregation, such as the presence of macromolecules and increased temperature.

Inferior vena cava thrombosis. Unusual presentation of testicular tumor.

We report an unusual case of testicular tumor presenting as thrombosis of the inferior vena cava. However, in contrast to a previous report, thrombosis in this patient was not caused by compression of the vena cava by neoplasm metastases. In our patient, we postulate that tumor invaded the vena cava and that thrombosis was exacerbated by a hypercoagulable state induced by the tumor.

Suppressive effect of endotoxin on erythropietin-responsive cells in mice.

Infection may be associated with failure of erythropoiesis, and endotoxin has been shown to cause a decrease in the number of erythroid cells in the marrow of mice. We have investigated the effect of endotoxin on erythropoiesis in BDF1 mice by studying its effect on the incorporation of intravenously administered 59Fe into peripheral red cells. In normal mice the injection of endotoxin 2 and 3 days prior to the administration of 59Fe results in suppression of its incorporation into red cells. In exhypoxic polycythemic mice, endotoxin suppresses the response to erythropoietin injection when the endotoxin is given prior to or at the same time as the erythropoietin. This effect is much less marked when endotoxin is given after erythropoietin. We conclude that endotoxin either 1) impairs the function of erythropoietin-responsive cells, 2) competively decreases erythroid progenitors by stimulating granulocytes, or 3) inactivates erythropoietin.

The utilization of senescent red cell and hemolysate iron for erythropoiesis.

We report experiments to determine the availability for new hemoglobin production of radioiron from nonviable red cells at various times after deposition in the reticulo-endothelial system and to determine the relative availability of radioiron derived from hemolysates versus that derived from nonviable red cells. When heated nonviable red cells labeled with 59Fe are injected into polycythemic mice the iron is deposited in the reticulo-endothelial system, and less than 1% of it is reutilized for hemoglobin synthesis. If the polycythemic mice are given nonviable red cells 48 hours after exposure to hypoxia, when hemoglobin synthesis is maximal, 25% of the iron is reutilized. When the cells are given 36 hr after exposure to hypoxia, iron reutilization declines to 16%, and when exposure to hypoxia is further delayed, reutilization of the iron falls to a plateau level of 11%. Radioiron from hemolysates, primarily deposited in parenchymal cells of the liver, is less available for new hemoglobin synthesis than is radioiron from nonviable red cells, which is primarily deposited in Kupffer cells of the liver. When transferrin-bound iron is given to polycythemic mice, this iron is also deposited in parenchymal cells of the liver and is also less available for new hemoglobin synthesis. Thus, in relation to an erythropoietic stimulus, the site and time of deposition of iron influence its accessibility for erythropoiesis.

Platelet activation during pain crisis in sickle cell anemia patients.

Platelet activation at sites of enmeshed sickled red cells in the microcirculation may contribute to platelet plug formation and microinfarction in sickle cell anemia. To test this hypothesis platelets from 116 sickle cell anemia patients free of crisis, 32 patients with crisis, 16 convalescents within 1 week of crisis, and 180 normal controls were studied. Platelets store 90% of their ADP in dense secretory granules. During activation ADP is secreted and permanently lost from the cell. This leads to a decrease in cellular ADP concentration and a sharp rise in the ATP/ADP ratio. ATP and ADP were ethanol-extracted from platelet-rich plasma, measured in the luciferase-luciferin assay and expressed in nmoles per 10(8) cells. No adenine nucleotide differences were found in platelets from patients free of crisis compared with normal controls. The ADP concentration of platelets from patients in crisis was significantly lowered, indicating that in vivo platelet secretion of ADP had occurred. Total and released ADP was decreased from 2.69 to 1.66, and from 1.90 to 1.21 respectively, and the total ATP/ADP ratio was increased from 1.85 to 2.84 (P less than 0.001). ADP stores in platelets from convalescents were significantly different from sickle controls (P less than 0.001) but were less abnormal than ADP stores in platelets from crisis patients (P less than 0.01), indicating recovery. Total and released ADP was decreased to 1.97 and 1.31 respectively, and the ATP/ADP ratio was increased to 2.38. Platelets from patients in crisis were able to release their remaining granular ADP in response to thrombin as effectively as normal platelets. Thus significant platelet activation with ADP release occurs during acute sickle pain crisis. This might contribute to platelet plug formation and microvascular obstruction.

The spectrum of vitamin B12 deficiency.

Low serum vitamin B12 levels are not uncommon in the elderly. Patients with vitamin B12 deficiency manifest a spectrum of clinical findings. Pernicious anemia and malabsorption syndrome are the usual causes of vitamin B12 deficiency. Pernicious anemia is confirmed by the presence of intrinsic factor blocking antibody or abnormal results on the Schilling test. Patients with neuropsychiatric symptoms of vitamin B12 deficiency may have a normal Schilling test and no evidence of macrocytic anemia. In such patients, vitamin B12 deficiency is confirmed by determining serum levels of homocysteine and methylmalonic acid.

Do not resuscitate decisions: discussions with patients.

The problem of psychological pain caused by discussions of do not resuscitate status with patients is addressed. Case histories of patients with such distress are given. We propose that not all patients should be informed of their do not resuscitate status, that the information about such status be given incrementally, and that the giving of further information be guided by the patient's reaction to earlier information. While some affirm the duty of the physician always to inform the patient about his or her do not resuscitate status, we affirm the duty of the physician to determine whether the patient wishes to enter into this discussion.

Retinal vein thrombosis in a patient with pernicious anemia and anticardiolipin antibodies.

A 45-year-old man with pernicious anemia presented with sudden loss of vision due to central retinal vein thrombosis, and was found to have anticardiolipin antibodies and a clotting disorder consistent with the presence of a lupus anticoagulant. He was treated with low dose aspirin and has remained free of recurrent thrombosis over a period of one year. The association between lupus anticoagulant and pernicious anemia is rare, having been reported in only one prior case.

Prolonged and concurrent lactic acidosis and hypoglycemia in a patient with monocytic leukemia.

Lactic acidosis or hypoglycemia occasionally occurs in patients with neoplastic diseases. We have described a patient with monocytic leukemia who had both, apparently as a result of marked leukemic infiltration of the liver. These metabolic anomalies were greatly ameliorated by chemotherapy. Thus, in leukemia and other malignant disorders in which significant liver infiltration is present, these metabolic derangements should be looked for, as their presence may call for a prompt and intensive treatment.

Electronic communication in ethics committees: experience and challenges.

Experience with electronic communication in ethics committees at two hospitals is reviewed and discussed. A listserver of ethics committee members transmitted a synopsis of the ethics consultation shortly after the consultation was initiated. Committee comments were sometimes incorporated into the recommendations. This input proved to be most useful in unusual cases where additional, diverse inputs were informative. Efforts to ensure confidentiality are vital to this approach. They include not naming the patient in the e-mail, requiring a password for access to the listserver, and possibly encryption. How this electronic communication process alters group interactions in ethics committees is a fruitful area for future investigation.

Blastic transformation in a case of essential thrombocythemia.

After five years of stable disease, a 58-year-old man with essential thrombocythemia had an acute terminal illness, characterized by severe pancytopenia, micromegakaryoblasts in the peripheral blood, and bone marrow replacement by extensive fibrosis, blasts, and numerous atypical megakaryocytes. The patient died of bronchopneumonia. Autopsy showed extramedullary hemopoiesis in the liver, spleen, and lymph nodes. These features are characteristic of both acute megakaryoblastic leukemia and acute myelofibrosis, and implicate involvement of the megakaryocytes in the pathogenesis of acute myelofibrosis.

Report of two cases of acute myelogenous leukemia immunized with autologous leukemia-derived hybrid cells.

Reports that immunizations with leukemia-derived hybrid cells prolonged the survival of leukemic mice led us to attempt an analogous approach in two adult patients with acute myeloid leukemia (AML). Hybrid cells were prepared from the pretreatment marrows of the newly-diagnosed patients with D98OR cells, in the first case, and with KR12 cells, in the second case. (D98OR and KR12 cells are human cell-lines.) Hybrids formed with KR12 cells expressed HLA antigens of both parental sources and some of the clonal isolates expressed myeloid-associated determinants. The immunizations were performed during the first complete clinical remission; the patients were demonstrably immunocompetent. Positive delayed type hypersensitivity responses to both (X-irradiated) hybrid cells and to (X-irradiated) autologous pretreatment marrow were observed following the immunizations. Mixed lymphocyte reactions toward autologous marrow were positive in one of the patients. In both, relapse occurred approximately two months after the first immunization and eight months after first diagnosis. The first patient remained in complete remission for two and one-half years following reinduction chemotherapy; reinduction chemotherapy was unsuccessful in the second patient.