Genetic deficiencies of glucose-6-phosphate dehydrogenase (G6PD) and NADPH predispose affected erythrocytes to destruction from peroxides. Conversely, genetic deficiencies of catalase do not predispose affected erythrocytes to peroxide-induced destruction. These observations have served to strengthen the assumption that the NADPH/glutathione/glutathione peroxidase pathway is the principal means for disposal of H2O2 in human erythrocytes. Recently, however, mammalian catalase was found to have tightly bound NADPH and to require NADPH for the prevention and reversal of inactivation by its toxic substrate (H2O2). Since both catalase and the glutathione pathway are dependent on NADPH for function, this finding raises the possibility that both mechanisms destroy H2O2 in human erythrocytes. A comparison of normal and acatalasemic erythrocytes in the present study indicated that catalase accounts for more than half of the destruction of H2O2 when H2O2 is generated at a rate comparable to that which leads to hemolysis in G6PD- deficient erythrocytes.

The catalase within normal, intact human erythrocytes was completely inactivated with amino triazole. The rate of 14CO2 evolution, when the cells were subsequently incubated with 14C-labeled glucose, provided a measure of the rate at which NADPH was being oxidized by the glutathione peroxidase/reductase system for the disposal of H2O2. This rate was determined in control cells and in catalase-inactivated cells while the cells were exposed to H2O2, which was generated at various constant and predetermined rates by glucose oxidase. The results indicated that catalase handles approximately half of the generated H2O2. The glutathione peroxidase/reductase mechanism accounted for the other half. These results are in agreement with our earlier findings on erythrocytes of a subject with a genetic deficiency of catalase. However, an unexpected result with the present approach was the finding that the increased dependence on the glutathione peroxidase/reductase mechanism did not occur until greater than 98% of the catalase had been inactivated. The latter observation indicates that catalase and the glutathione peroxidase/reductase system function intracellularly in a manner very different from that previously ascribed to them. An explanation of the findings requires that the two methods of H2O2 disposal function in a coordinated way, such as a sequential action in which the glutathione peroxidase/reductase system is the rate-limiting step.

Serum LDH levels have been found to be significantly increased in non- Hodgkin lymphoma (NHL) patients, both histiocytic and lymphocytic. The duration of survival of NHL negatively correlates with the level of serum lactic dehydrogenase (LDH), and statistical analysis reveals that patients with lower levels of LDH have a longer survival rate than the patients with higher LDH activity, irrespective of their histologic classification. The analysis of the results by the Test for Trend in Prognosis allows us to establish that the correlation of the rate of survival and LDH levels is independent from other clinical parameters.

Serum LDH levels have been found to be significantly increased in non- Hodgkin lymphoma (NHL) patients, both histiocytic and lymphocytic. The duration of survival of NHL negatively correlates with the level of serum lactic dehydrogenase (LDH), and statistical analysis reveals that patients with lower levels of LDH have a longer survival rate than the patients with higher LDH activity, irrespective of their histologic classification. The analysis of the results by the Test for Trend in Prognosis allows us to establish that the correlation of the rate of survival and LDH levels is independent from other clinical parameters.

The endemic occurrence of favism in certain Mediterranean regions provided an investigative opportunity for testing in vivo the validity of claims as to the role of catalase in protecting human erythrocytes against peroxidative injury. Reduced activity of catalase was found in the erythrocytes of six boys who were deficient in erythrocytic glucose- 6-phosphate dehydrogenase (G6PD) and who were studied while suffering hemolysis after ingesting fava beans. Activity of catalase was further reduced when their red blood cells were incubated with aminotriazole. In contrast, minimal reduction of catalase activity was found, both with and without incubation with aminotriazole, in erythrocytes of a G6PD-deficient boy who had ingested fava beans 7 days earlier and in erythrocytes of seven G6PD-deficient men with a past history of favism. These results confirmed earlier studies in vitro indicating that catalase is a major disposer of hydrogen peroxide in human erythrocytes and, like the glutathione peroxidase/reductase pathway, is dependent on the availability of reduced nicotinamide adenine dinucleotide phosphate (NADPH). The effect of divicine on purified catalase and on the catalase of intact G6PD-deficient erythrocytes was similar to the previously demonstrated effect on catalase of a known system for generating hydrogen peroxide. This effect of divicine strengthens earlier arguments that divicine is the toxic peroxidative component of fava beans.

A patient with primary thrombocythemia, who was heterozygous for glucose-6-phosphate dehydrogenase deficiency (GdB/GdMed), was investigated to test for the clonal origin of this myeloproliferative disorder. In order to assess somatic cell mosaicism in various tissues, we have made use of the different rate of utilization of 2-deoxyglucose- 6-phosphate, an analog of glucose-6-phosphate, by normal glucose-6- phosphate dehydrogenase and by the Mediterranean variant: the results demonstrate that essential thrombocythemia is a clonal disease involving the erythrocytic, granulocytic, and megakaryocytic series, without affecting monocytes, T lymphocytes, and non-T lymphocytes.

In order to study the pattern of B cell involvement in acute nonlymphocytic leukemia (ANLL), multiple B lymphoid cell lines were established by Epstein-Barr virus transformation of peripheral blood mononuclear cells from two patients with the disease who were heterozygous for the X chromosome-linked glucose-6-phosphate dehydrogenase (G6PD). In one patient, the progenitor cells involved by the leukemia exhibited multipotent differentiative expression, whereas in the other patient the cells showed differentiative expression restricted to the granulocytic pathway. In the patient whose abnormal clone showed multipotent expression, the ratio of B-A G6PD in B lymphoid cell lines was skewed in the direction of type B (the enzyme characteristic of the leukemia clone) and significantly different from the 1:1 ratio expected. It is, therefore, likely that the neoplastic event occurred in a stem cell common to the lymphoid series as well as to the myeloid series. In contrast, evidence for B cell involvement was not detected in the patient whose ANLL progenitor cells exhibited restricted differentiative expression. These findings underscore the heterogeneity of ANLL. Clinically and morphologically similar malignancies in these two patients originated in progenitors with different patterns of stem cell differentiative expression. This difference may reflect differences in cause and pathogenesis.

The relative incidence of Hodgkin's disease (HD) has been found to have increased approximately seven times in HIV-infected patients. We analyzed the histological distribution of HIV-associated HD with the aim of clarifying purported difference(s) from de novo HD. References on HIV/AIDS-associated HD were retrieved from the most complete databases. Nineteen articles were the subject of our analysis. Seventeen of them reported data on the histological type of HIV/AIDS-associated HD patients; the route of infection and age of the patients were also considered when available. According to the Peto's methodology, histological types were compared with those from two large studies in the United States on de novo HD: 3,245 cases from the Surveillance, Epidemiology, and End Results (SEER) and 1,140 from Stanford University. The analysis of the two groups showed statistically significant differences (p<0.001) in the percentage of all histological types and odds ratios (OR) of the pooled effect of 0.4 (95% CI: 0.3-0.6) for lymphocyte predominance (LP), 0.3 (95% CI: 0.2-0.4) for nodular sclerosis (NS), 3.2 (95% CI: 2.6-3.8) for mixed cellularity (MC), and 6.3 (95% CI: 4.5-8.8) for lymphocyte depletion (LD). Comparison with the Stanford University series yielded similar results. Whilst retrospective and based on a limited number of cases, our data confirm a higher incidence of unfavorable histological subtypes in HIV-infected patients and show a reduction in the observed cases of good prognosis subtypes. Prospective studies, with careful histological observations, are required to better evaluate the characteristics of the LP subtype in the special setting of HIV infection.