Quantitative, Kinetic and Thermodynamic Analysis of Weak B60 Erythrocyte Phenotypes

Abstract. 16 weak B₆₀ erythrocyte samples belonging to six families were studied using three series of quantitative measurements. The results show that the so-called B₆₀, group is heterogeneous and does not correspond to a genetic entity.     

Left ventricular hypertrophy and cardiovascular mortality by race and ethnicity

Background

Left ventricular hypertrophy is a major independent risk factor for cardiovascular mortality. The contribution of left ventricular hypertrophy to racial and ethnic differences in cardiovascular mortality is poorly understood.

Methods

We used data from the Third National Health and Nutrition Examination Survey and from the National Death Index to compare mortality for those with an electrocardiographic (ECG) diagnosis of left ventricular hypertrophy to those without left ventricular hypertrophy separately for whites, African Americans, and Latinos. We used Cox proportional hazards regression to control for other known prognostic factors.

Results

ECG left ventricular hypertrophy was significantly associated with 10-year cardiovascular mortality in all 3 racial/ethnic groups, both unadjusted and adjusted for other known prognostic factors. The hazard ratio for this association was significantly greater for African Americans (2.31; 95% confidence interval [CI], 1.55-3.42) than for whites and Latinos (1.32; 95% CI, 1.14-1.76 and 2.11; 95% CI, 1.35-3.30, respectively), independent of systolic blood pressure.

Conclusions

ECG left ventricular hypertrophy contributes more to the risk of cardiovascular mortality in African Americans than it does in whites. Using regression of ECG left ventricular hypertrophy as a goal of therapy might be a means to reduce racial differences in cardiovascular mortality; prospective validation is required.     

Directly observed treatment for tuberculosis in pharmacies compared with self-administered therapy in Spain.

OBJECTIVES: To compare directly observed treatment (DOT) of tuberculosis through pharmacy offices with self-administered treatment (SAT) in patients at risk for non-adherence. METHODS: Prospective study for DOT (1999-2002) and retrospective study for SAT (1996-1998) in patients at risk for non-adherence (human immunodeficiency virus [HIV] infection, alcoholism, illicit drug use, immigrant or homeless status and/or previous failure to complete). Patients in the DOT programme received medication as out-patients twice a week in pharmacies that supervised adherence and provided socio-sanitary support to patients. RESULTS: There were 101 and 112 patients in the DOT and SAT groups, respectively. Demographic and clinical characteristics were similar in both groups. Differences were observed in risk factors for non-adherence (more immigrants and fewer intravenous drug users in the DOT vs. the SAT groups; P < 0.05). In the DOT group, 76 patients (75.2%) completed treatment and were cured compared to only 30 patients (26.7%) in the SAT group (P < 0.001). Implementation of DOT increased the cost of treatment by 400 Euro per patient compared to SAT. CONCLUSION: In patients at risk for non-adherence, DOT implemented through pharmacy offices was better than SAT; however, completion rates were still low.     

Recombinant human interleukin-3 stimulation of hematopoiesis in humans: loss of responsiveness with differentiation in the neutrophilic myeloid series

Recombinant human (rh) interleukin-3 (IL-3) stimulated the proliferation and differentiation of erythroid, granulocyte, macrophage, eosinophil (Eo), and mixed colonies as well as megakaryocytes from human bone marrow cells. rh IL-3 was a weaker stimulus than rh granulocyte-macrophage colony-stimulating factor (GM- CSF) for day 14 myeloid cell colonies. At day 7 of incubation, rh IL-3 stimulated a few G, M, and Eo clusters but no colonies. This loss of responsiveness of myeloid cells to rh IL-3 was accentuated with further differentiation of the cells. rh IL-3 stimulated very few or no clones after five-day incubation with enriched promyelocytes and myelocytes, whereas rh GM-CSF was an efficient stimulus. Responsiveness to rh IL-3 was completely lost in postmitotic mature neutrophils. Incubation of these cells with rh IL-3 did not result in enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) of tumor cells or superoxide anion production after stimulation with formyl-methyl-leucyl-phenylalanine (FMLP), although they could be stimulated by rh GM-CSF. In addition, preincubation of neutrophils with different concentrations of rh IL-3 failed to increase or decrease their response to rh GM-CSF. In contrast to neutrophils, mature Eos could be stimulated by rh IL-3 to kill antibody-coated tumor cells. These results show that cells of the neutrophilic myeloid series lose their responsiveness to h IL-3 as they differentiate and suggest that although h IL-3 may be an important therapeutic agent to use for hematopoietic regeneration in vivo, the lack of stimulation of mature neutrophil function makes it an unlikely sole candidate as adjunct therapy for treatment of infectious diseases.     

A mutation of the common receptor subunit for interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor, and IL-5 that leads to ligand independence and tumorigenicity

The cytokines interleukin-3, interleukin-5, and granulocyte-macrophage colony-stimulating factor bind with high affinity to a receptor complex that contains a ligand-specific alpha-chain and a common beta-chain, h beta c. We report here the isolation of a mutant form of h beta c, from growth factor-independent cells, that arose spontaneously after infection of a murine factor-dependent hematopoietic cell line (FDC-P1) with a retroviral h beta c expression construct. Analysis of this h beta c mutation shows that a small (37 amino acid) duplication of extracellular sequence that includes two conserved sequence motifs is sufficient to confer ligand-independent growth on these cells and lead to tumourigenicity. Because this is a conserved region in the cytokine receptor superfamily, our results suggest that the large family of cytokine receptors has the capacity to become oncogenically active.     

CD2-mediated IL-12-dependent signals render human gamma delta-T cells resistant to mitogen-induced apoptosis, permitting the large-scale ex vivo expansion of functionally distinct lymphocytes: implications for the development of adoptive immunotherapy strategies

The ability of human gamma delta-T cells to mediate a number of in vitro functions, including innate antitumor and antiviral activity, suggests these cells can be exploited in selected examples of adoptive immunotherapy. To date, however, studies to examine such issues on a clinical scale have not been possible, owing in large measure to the difficulty of obtaining sufficient numbers of viable human gamma delta-T cells given their relative infrequency in readily available tissues. Standard methods used to expand human T cells often use a combination of mitogens, such as anti-T-cell receptor antibody OKT3 and interleukin (IL)-2. These stimuli, though promoting the expansion of alpha beta-T cells, usually do not promote the efficient expansion of gamma delta-T cells. CD2-mediated, IL-12-dependent signals that result in the selective expansion of human gamma delta-T cells from cultures of mitogen-stimulated human peripheral blood mononuclear cells are identified. It is first established that human gamma delta-T cells are exquisitely sensitive to apoptosis induced by T-cell mitogens OKT3 and IL-2. Next it is shown that the CD2-mediated IL-12-dependent signals, which lead to the expansion of gamma delta-T cells, do so by selectively protecting subsets of human gamma delta-T cells from mitogen-induced apoptosis. Finally, it is demonstrated that apoptosis-resistant gamma delta-T cells are capable of mediating significant antitumor cytotoxicity against a panel of human-derived tumor cell lines in vitro. Both the biologic and the practical implications of induced resistance to apoptosis in gamma delta-T cells are considered and discussed because these findings may play a role in the development of new forms of adoptive cellular immunotherapy. (Blood. 2000;96:3827-3837)