Feline glucose-6-phosphate dehydrogenase cellular mosaicism. Application to the study of retrovirus-induced pure red cell aplasia.

Neoplasms result from the uncontrolled proliferation of abnormal or transformed cells. The early stages of this process are difficult to study because of the lack of sensitive and specific markers of clonal evolution in an experimental system. We have developed a cat model using cellular mosaicism for glucose-6-phosphate dehydrogenase (G-6-PD). Our findings confirm that the structural locus for feline G-6-PD is on the X-chromosome and demonstrate that it is randomly inactivated in somatic cells. Heterozygous cats have balanced ratios of G-6-PD enzyme types in peripheral blood cells and hematopoietic progenitors that remain stable over time. In our initial studies, we used the model to analyze the events surrounding marrow failure experimentally induced by selected strains of feline leukemia virus (FeLV). Two G-6-PD heterozygous cats, one F1 male hybrid and one domestic cat were infected with FeLV (C or KT) and developed pure red cell aplasia (PRCA). Colonies arising from the more mature erythroid colony-forming cell were not detected in marrow culture of anemic animals although erythroid bursts persisted, suggesting that the differentiation of early erythroid progenitors (BFU-E) was inhibited in vivo. The ratio of G-6-PD types in hematopoietic progenitors and peripheral blood cells from the heterozygous cats did not change when the animals developed PRCA. Thus, the anemia did not result from the clonal expansion of a transformed myeloid stem cell. With this experimental approach, one may prospectively assess clonal evolution and cellular interactions in other FeLV-induced diseases.

Multiple-dose study of imipenem/cilastatin in patients with end-stage renal disease undergoing long-term hemodialysis.

Multiple doses of imipenem/cilastatin were administered to patients with end-stage renal disease undergoing long-term hemodialysis. Schedules of 250 mg every six hours, 500 mg every six hours, and 500 mg every 12 hours were studied. Five hundred mg every 12 hours was the most efficient schedule that maintained effective trough antibiotic activity. Twelve volunteers including two patients with clinical infections using the dose schedule of 500 mg every 12 hours received imipenem/cilastatin for two to 14 days without any notable clinical side effects. Imipenem peak and trough concentrations averaged 29 +/- 5 micrograms/ml and 10 +/- 3 micrograms/ml, respectively. No accumulation of imipenem occurred during the trial. Cilastatin peak and trough concentrations were 89 +/- 38 micrograms/ml and 70 +/- 27 micrograms/ml, respectively. The plasma concentration of cilastatin increased with each dose until the next hemodialysis session.

The polymerase chain reaction and its applications.

The advent of recombinant DNA technology has brought us many new techniques for the detection of genetic defects. With these methods it has become possible to do prenatal screening of the DNA of fetuses and to detect genetic defects that would lead to congenital disease. The biggest problem facing researchers has been the limited sensitivity of the techniques of molecular biology especially in detecting small changes in the DNA.

Asymptomatic intrathoracic extramedullary hematopoiesis: a report of three cases.

Extramedullary hematopoiesis (EMH) is observed in people suffering from severe anemia of prolonged duration and appears to be a compensatory mechanism for disturbed medullary hematopoiesis. The hemoglobinopathies (such as thalassemia, spherocytosis, and sickle cell disease), neoplastic diseases such as leukemia and lymphoma, and others, including myelofibrosis and osteitis fibrosa cystica, are associated with EMH. These diseases and their resultant anemia have in common the ability to stimulate erythropoietin production, which in turn may stimulate hematopoiesis in organs of mesenchymal origin. The liver and spleen are the most common sites of EMH; however, other sites, including the falx cerebri, thoracic cavity, retroperitoneal area and pelvis have been reported. When present, intrathoracic EMH is most frequently associated with thalassemia. Spinal cord compression and hemothorax have also been reported as complications of intrathoracic EMH.

Plasmapheresis with exchange as primary treatment for thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is an uncommon disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, fever and renal and neurologic dysfunction. As a result of the availability of plasmapheresis, we can report the results of 5 patients treated with plasmapheresis and exchange transfusion who also received intravenous corticosteroids as adjunctive therapy. Our 5 patients had a mean age of 41 years, and presented with a mean platelet count of 39 x 10(9)/L. Four of the 5 patients responded to treatment and were discharged in excellent condition. The 5th patient succumbed to her disease. We concluded that plasmapheresis with exchange transfusion is a rapid and effective therapy for TTP.

Infection with the human T-lymphotropic virus type I. A review for clinicians.

The human T-cell lymphotropic virus type I (HTLV-I) is the first retrovirus identified in humans. It has been responsible for a number of clinical syndromes, most notably adult T-cell leukemia or lymphoma and tropical spastic paraparesis. In the United States, infection with this virus is most frequently found in specific subsets of our population, particularly in those who live in the southeastern states, have southern Japanese ancestry, or share intravenous drug paraphernalia. Understanding the epidemiology and clinical manifestations of this virus is necessary to properly diagnose and care for patients with HTLV-I infection.

Strongyloidiasis associated with human T-cell lymphotropic virus type I infection in a nonendemic area.

Concomitant strongyloidiasis and human T-cell lymphotropic virus type I (HTLV-I) infection has been reported from areas in Japan where both organisms are endemic. We present four cases of concomitant infection with these organisms from an area that is not endemic for Strongyloides stercoralis. Three of the four patients had adult T-cell leukemia, an aggressive neoplasm resulting from HTLV-I infection, while the other was an asymptomatic carrier of HTLV-I. Three of the patients had spent their childhoods in an endemic location for both organisms, suggesting an initial infection at that time. Three patients were symptomatic from their parasitism. We conclude that strongyloidiasis may be found in nonendemic locations in patients with either adult T-cell leukemia or an asymptomatic HTLV-I carrier state. Whether infestation with this parasite contributes to the leukemogenesis of HTLV-I, as postulated by others, cannot at this time be determined.

Human T-lymphotropic virus type I (HTLV-I) and tropical spastic paraparesis or HTLV-I-associated myelopathy in Hawaii.

Tropical spastic paraparesis or human T-lymphotropic virus type I (HTLV-I)-associated myelopathy is a degenerative encephalomyelopathy with pyramidal tract dysfunction affecting the lower extremities. It is associated with HTLV-I infection and found primarily in the Caribbean region and in southwestern Japan. Five cases of tropical spastic paraparesis (or HTLV-I-associated myelopathy) in Hawaii are reported. All five patients were born in Hawaii; four are women. Each of the patients has parents who were from HTLV-I-endemic areas of Japan. Two of these patients had serum antibodies to HTLV-I. Five of six of the spouses and children of the seropositive patients were also seropositive. Viral cultures of lymphocytes from both seropositive patients and two of the three seropositive children were positive for HTLV-I. None of the five patients had a history of antecedent blood transfusion, multiple sexual partners, or intravenous drug use. There is no evidence of adult T-cell leukemia or lymphoma in any of the patients or their families. Given the increasing seroprevalence of HTLV-I in the United States, clinicians need to be alert to new cases of this disorder.

Pure red cell aplasia: response to therapy with anti-thymocyte globulin.

Pure red cell aplasia (PRCA) results from the failure of erythrocyte differentiation and may respond to immunosuppressive therapies. We have treated nine patients with PRCA refractory to steroids and/or cyclophosphamide with anti-thymocyte globulin (ATG). Six patients had normal numbers of erythroid bursts (from erythroid burst-forming units) or erythroid colonies (from erythroid colony-forming units) detectable in vitro, and all responded to therapy with ATG. In vitro studies suggested T-cell inhibition of erythropoiesis in four of these six patients and humorally mediated erythroid suppression in one. In three individuals, virtually no erythroid progenitors were detected in marrow culture. None of these patients responded to ATG. Myelofibrosis, 5q- chromosomal abnormality, or the subsequent development of thrombocytopenia in these individuals suggested that PRCA resulted from an intrinsic stem cell disorder. Our studies demonstrate that ATG is effective therapy for PRCA, and it may be especially useful in children or other patients in whom alkylating agents are not appropriate. We also confirm that erythroid growth in marrow culture predicts those patients who will respond to ATG or other immunosuppressive therapies.

A seroepidemiologic survey of human T-cell lymphotropic virus type I in two Hawaiian hematologic-oncologic practices.

A seroepidemiologic survey for antibodies to the human T-cell lymphotropic virus type I (HTLV-I) was carried out in two Hawaiian hematologic-oncologic practices. Specimens of serum or plasma from 215 donors were assayed using the ELISA technique, followed by the Western blot technique to confirm antibody specificity to HTLV-I. Of 214 seropositive donors, 16 (7.5%) were positive. Of 172 donors of Japanese ancestry, 16 (9.3%) were seropositive; none were white, Chinese, Filipino, or Pacific Islander. One donor contracted the virus through blood transfusions. The results suggest that HTLV-I was introduced to Hawaii with the Japanese immigration.

Human T-cell lymphotropic virus type I (HTLV-I) antibodies in pre-diagnostic serum of patients with familial adult T-cell leukemia/lymphoma (ATL).

In a study of 7498 American men of Japanese ancestry in Hawaii, 26 incident cases of leukemia or non-Hodgkin's lymphoma were identified after a follow-up period of 19 years. Two of the cases, who were brothers, were diagnosed with adult T-cell leukemia/lymphoma (ATL). Both of these brothers had human T-cell lymphotropic virus type I (HTLV-I) antibodies in their stored serum which were obtained 4 and 18 years before diagnosis. None of the 24 patients with other hematologic malignancies or the 26 matched controls were HTLV-I antibody positive. This finding lends further support for a role of HTLV-I in the etiology of adult T-cell leukemia/lymphoma.