Apoptosis and T cell hyporesponsiveness in pulmonary tuberculosis

Mycobacterium tuberculosis (MTB)-induced T cell responses are depressed in peripheral blood mononuclear cells of persons with newly diagnosed pulmonary tuberculosis (TB), and levels of interferon (IFN)-gamma remain low even after completion of antituberculous therapy. Loss of MTB-reactive T cells through apoptotic mechanisms could account for this prolonged T cell hyporesponsiveness. T cell apoptosis was studied in TB patients and healthy control subjects. Both spontaneous and MTB-induced apoptosis (in CD4 and non-CD4 T cells) from TB patients was increased when compared with healthy control subjects, whereas coculture with control antigen (candida) had no effect on T cell apoptosis in either group of study subjects. An inverse correlation existed between increased MTB-induced T cell apoptosis and IFN-gamma and interleukin (IL)-2 immunoreactivities. Successful antituberculous chemotherapy resulted in a 50% reduction in both spontaneous and MTB-induced apoptosis, which coincided with 3- and 8-fold increases in levels of MTB-stimulated IL-2 and IFN-gamma, respectively. These data indicate that apoptotic pathways are operant during active MTB infection and may contribute to deletion of MTB-reactive T cells and the immunopathogenesis of this disease.     

A selective cyclooxygenase 2 inhibitor suppresses the growth of H-ras-transformed rat intestinal epithelial cells

BACKGROUND & AIMS: Constitutive expression of cyclooxygenase 2 (COX-2) has been found in 85% of colorectal cancers. Ras mutations are found in 50% of colorectal adenocarcinomas. The aim of this study was to determine the role of COX-2 in ras-induced transformation in rat intestinal epithelial (RIE) cells. METHODS: Cell growth was determined by cell counts. The expression of COX-2 was examined by Northern and Western analyses. For tumorigenicity assays, cells were inoculated into dorsal subcutaneous tissue of athymic nude mice. DNA-fragmentation assays were performed to detect apoptosis. RESULTS: The expression of COX-2 was increased in RIE-Ras cells at both messenger RNA (9-fold) and protein (12-fold) levels. Prostaglandin I2 levels were elevated 2.15-fold in RIE-Ras cells. Serum deprivation further increased COX-2 expression 3.8-fold in RIE-Ras cells. Treatment with a selective COX-2 antagonist (SC58125) inhibited the growth of RIE-Ras cells through inhibition of cell proliferation and by induction of apoptosis. SC-58125 treatment reduced the colony formation in Matrigel by 83.0%. Intraperitoneal administration of SC-58125 suppressed RIE-Ras tumor growth in nude mice by 60.3% in 4 weeks. SC-58125 treatment also induced apoptosis in RIE-Ras cells as indicated by increased DNA fragmentation. CONCLUSIONS: Overexpression of COX-2 may contribute to tumorigenicity of ras-transformed intestinal epithelial cells. Selective inhibition of COX-2 activity inhibits growth of ras-transformed intestinal epithelial cells and induces apoptosis. (Gastroenterology 1997 Dec;113(6):1883-91)     

Carrier testing and prenatal diagnosis of haemophilia — utilisation and psychological consequences

Summary. Attitudes towards prenatal diagnosis, and abortion vary widely between different countries, religions, cultures and over time. Carrier testing and prenatal diagnosis (PD) of haemophilia have become an integrated part of the comprehensive care for haemophilia in Sweden as well as in many other countries. Almost all carriers are interested in carrier testing if they are aware of the possibility. With the development of PD by chorionic villus sampling in the first trimester, the method became acceptable for many carriers, and it has in Sweden actually had an effect on the incidence of haemophilia in the 1990s. The use of PD is more common among women who perceive haemophilia as a very serious disease and who have a positive attitude towards legal abortion. The main reason for carriers not to use PD was that they do not find haemophilia to be a sufficiently serious disorder to justify an abortion. Women and their spouses are under a great deal of psychological pressure in association with the PD procedure, and the psychological consequences of having to terminate a pregnancy are long-lasting. At follow-up, about 6 years after PD and abortion, these women, however, do not have more signs of psychological distress than women without PD experience. Nevertheless, they must be offered qualified assistance both before and after PD as well as adequate follow-up after an abortion to help them cope with the emotional strain they are under.     

Relationship Between Literacy, Knowledge, Self-Care Behaviors, and Heart Failure-Related Quality of Life Among Patients With Heart Failure

BACKGROUND

We sought to examine the relationship between literacy and heart failure-related quality of life (HFQOL), and to explore whether literacy-related differences in knowledge, self-efficacy and/or self-care behavior explained the relationship.

METHODS

We recruited patients with symptomatic heart failure (HF) from four academic medical centers. Patients completed the short version of the Test of Functional Health Literacy in Adults (TOFHLA) and questions on HF-related knowledge, HF-related self-efficacy, and self-care behaviors. We assessed HFQOL with the Heart Failure Symptom Scale (HFSS) (range 0?C100), with higher scores denoting better quality of life. We used bivariate (t-tests and chi-square) and multivariate linear regression analyses to estimate the associations between literacy and HF knowledge, self-efficacy, self-care behaviors, and HFQOL, controlling for demographic characteristics. Structural equation modeling was conducted to assess whether general HF knowledge, salt knowledge, self-care behaviors, and self-efficacy mediated the relationship between literacy and HFQOL.

RESULTS

We enrolled 605 patients with mean age of 60.7 years; 52% were male; 38% were African-American and 16% Latino; 26% had less than a high school education; and 67% had annual incomes under $25,000. Overall, 37% had low literacy (marginal or inadequate on TOFHLA). Patients with adequate literacy had higher general HF knowledge than those with low literacy (mean 6.6 vs. 5.5, adjusted difference 0.63, p?p?p?p?CONCLUSION Low literacy was associated with worse HFQOL and lower HF-related knowledge, self-efficacy, and self-care behaviors, but differences in knowledge, self-efficacy and self-care did not explain the relationship between low literacy and worse HFQOL.     

Comparison of the subacute toxicity and efficacy of 3-hydroxypyridin-4- one iron chelators in overloaded and nonoverloaded mice

Five orally effective iron chelators of the 3-hydroxypyridin-4-one series have been administered intraperitoneally to iron-overloaded and nonoverloaded male mice at a dose of 200 mg/kg/24 h for a total of 60 days to investigate the effect on iron loading and toxicity. There was a significant reduction in hepatic iron at the end of the study in the iron-overloaded mice with all compounds studied using chemical iron quantitation (P less than .001) and with Perls' stain (P less than .01). Liver iron removal with the hydroxypyridinones ranged from 37% with CP20 to 63% with CP51, compared with 46% removal for desferrioxamine (DFO). There was no significant reduction in splenic or cardiac iron with any chelator. There were no deaths in iron-overloaded animals receiving any of the hydroxypyridin-4-ones, but significantly more deaths in the nonoverloaded groups as a whole (P less than .03). No weight loss was observed with any chelator. Significant reductions in hemoglobin and white cell count were observed with CP20(L1). No histologic abnormalities of kidney, spleen, bone marrow, or stifle joints were observed. Intracytoplasmic inclusion bodies were observed in the centrilobular hepatocytes of animals administered each of the hydroxypyridin-4-ones, while the DFO-treated and control groups showed no such changes.     

Acute leukemia associated with the t(4;11) chromosome rearrangement: ultrastructural and immunologic characteristics

The acute leukemia associated with the t(4;11) chromosome rearrangement is characterized by relatively consistent clinical features: occurrence primarily in young individuals, hyperleukocytosis, and poor response to therapy. This study describes the morphological, ultrastructural, and immunologic characteristics of the leukemic cells from ten patients with this type of leukemia. The morphological features of the leukemic blasts vary from lymphoid-appearing to monocytic. Ultrastructurally and cytochemically, some of the lymphoid-appearing blasts possess features of myeloid origin. The immunologic phenotype is characteristically E- SIg- CALLA- BA-1- BA-2+ HLA-DR+ and TdT+. These findings suggest that the t(4;11)-associated acute leukemia represents a proliferation of an early myeloid progenitor cell.     

Additive effect of erythropoietin and heme on murine hematopoietic recovery after azidothymidine treatment [see comments]

The ability of combination treatment with erythropoietin (Epo) and heme to rescue hematopoietic activity in mice from the suppressive effect of azidothymidine (AZT) was determined. Exposure of mice to AZT for 5 weeks produced marked anemia, thrombocytopenia, neutropenia, and weight loss, whereas mice that received Epo and heme for 3 subsequent weeks showed significant alleviation of AZT cytotoxicity. Treatment with Epo (10 U for 5 times/week) stimulated hematopoietic recovery in the AZT- treated animals and reduced the severe anemia and thrombocytopenia by 3 weeks. Administration of a lower Epo dose (1 U Epo) resulted in only a modest retardation of AZT-induced anemia, although, when combined with heme, there was a great improvement in recovery of erythropoiesis. The combination of heme with Epo (10 U) produced the optimum response, resulting in almost normal recovery of bone marrow cellularity as well as recovery of burst-forming units-erythroid (BFU-E) and splenic hematopoietic progenitor content (colony-forming unit-spleen [CFU-S]) by the end of 3 weeks of post-AZT treatment. Treatment with heme alone markedly enhanced the recovery of BFU-E and CFU-S, as well as body weight post-AZT; however, this recovery was not to the extent seen in combination with Epo (10 U). Long-term bone marrow cultures (LTBMCs) established from mice exposed to AZT for 8 weeks showed a marked reduction in cellularity and this was completely alleviated when mice received heme and Epo (10 U) for 3 weeks after 5 weeks of AZT administration. The additive effect of heme and Epo was seen in BFU-E production, as well as in CFU-S production, in LTBMCs. Thus, heme exerts a significant protective effect on hematopoietic progenitors in vivo and may be of potential clinical use in combination with Epo to promote effective erythropoiesis in the setting of AZT therapy.