Expression of the ABL-BCR fusion gene in Philadelphia-positive acute lymphoblastic leukemia.

We have previously shown that the chimeric gene ABL-BCR, formed on the derivative chromosome 9q+ as a result of the t(9;22) translocation, is transcriptionally active in 65% of chronic myeloid leukemia patients. We have now used the same technique, reverse transcription/polymerase chain reaction amplification of ABL-BCR transcripts, to study nine patients with Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL); seven expressed the P190 and two the P210 type of BCR-ABL fusion protein. All seven patients with P190 had ABL-BCR transcripts containing a junction between ABL exon Ib and BCR exon 2 (Ib-e2); in two cases, ABL-BCR transcripts with the Ia-e2 junction type were also present. Of the two P210 ALL patients, one had a Ib-b4 ABL-BCR transcript and the other showed no detectable ABL-BCR expression. Although the BCR-ABL gene is probably fundamental in the pathogenesis of the Ph+ leukemias, differential expression of the ABL-BCR gene could contribute to the biologic heterogeneity of the disease.

The ABL-BCR fusion gene is expressed in chronic myeloid leukemia.

Although the BCR-ABL hybrid gene on chromosome 22q-plays a pivotal role in the pathogenesis of chronic myeloid leukemia (CML), little is known of the reciprocal chimeric gene, ABL-BCR, formed on chromosome 9q+. By reverse transcription/polymerase chain reaction amplification (RT/PCR) we have detected ABL-BCR mRNA in cells from 31 of 44 BCR-ABL positive CML patients and 3 of 5 CML cell lines. Of the 34 positive samples, 31 had classical t(9;22) (q34;q11) translocations; in 3 samples there was no Philadelphia (Ph) and/or 9q+ chromosomes. ABL-BCR expression consisted of ABL(Ib)-BCR mRNA in 26 patients and of both ABL(Ib)-BCR and ABL(Ia)-BCR mRNA species in 6 patients. The ABL-BCR transcripts encoded one or, more rarely, both of the two potential junctions, designated ABL-b3 and ABL-b4, which differed in size by 75 bp. In 2 patients, the BCR exon b3 was not present in either the BCR-ABL or the corresponding ABL-BCR transcript, whereas in 5 patients exon b3 was present in both transcripts. Direct sequencing of PCR fragments representing the full-length coding sequence of ABL-BCR cDNAs type Ib-b3, Ia-b3, Ib-b4, and Ia-b4 showed an open reading frame predicted to encode fusion proteins of 370 to 414 amino-acids. If an ABL-BCR gene product is produced in CML cells, it may be relevant as a mechanism for deregulating the GTPase activating protein (GAP) function of BCR.

Toxic interactions of the munitions compounds TNT and RDX in F344 rats.

The potential toxic interactions in F344 rats of the munitions compounds trinitrotoluene (TNT) and hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) were examined following their coadministration in the diet. Groups of 10 rats per sex received TNT at doses of 5 or 125 mg/kg/day, RDX at doses of 30, 100, or 300 mg/kg/day, and combinations thereof for 13 weeks. Thirty rats per sex served as controls. Toxicologic endpoints included clinical observations, body weight, food consumption, hematology, clinical chemistry, organ weights, and tissue morphology. The major toxic effects following dietary administration of TNT to rats included anemia, hypercholesterolemia, and hepatomegaly, splenomegaly, and testicular atrophy with their accompanying histologic lesions. RDX intoxication in rats included hypotriglyceridemia, behavioral changes, and mortality. Most of the toxic effects of these chemicals were partially antagonized following their coadministration.

Formal operational thinking: the role of cognitive-developmental processes in adolescent decision-making about pregnancy and contraception.

The role of formal operational thinking in adolescent decision-making about pregnancy and contraception is explored through an integration of the cognitive-developmental and pregnancy-contraception literatures. The ways in which cognitive-developmental change mechanisms initiate or hinder formal thinking on pregnancy-contraception are considered, and implications for counseling pregnant adolescents are discussed.

PIP: This symposium paper in its review of the literature on cognitive development and pregnancy and contraception suggests that teenagers have difficulty in envisioning alternatives and evaluating alternatives (if, thens). Adolescents engage in confused or inappropriate perspective-taking (for example, seeing intercourse without contraception as an act of love) and egocentrism (having a baby in order to get married and leave home). There is flawed reasoning about chance and probability (it won't happen to me syndrome). The author suggests that helping teenagers discuss and think out pregnancy and contraception by using formal operation reasoning as defined by Piaget may assist in generating more effective decisions. Real life crises make it difficult for teenagers to sort out appropriate options, and some will avoid helpful role models, or over-accommodate and rely perhaps solely on their peers. Tasks involving perspective-taking (role-playing, babysitting) may encourage better thinking about parenthood. Promoting developmental techniques (problem-solving, exploration, assimilation, and accommodation) may provide opportunities to consider the balance between self and other needs and societal concerns. Adaptive decision-making may stimulate teenagers own thinking about sexual issues, since providing information alone has not been effective in altering behavior. Counselors may encourage role models such as teen mothers, those who've aborted pregnancy, and adoption spokesmen, so that the range of options is clear. Counseling does not have to be confined to providing emotional support but can involve cognitive growth.

Subchronic toxicity of trinitrotoluene in Fischer 344 rats.

This study was conducted to evaluate the toxicity of trinitrotoluene (TNT) in Fischer 344 rats when administered in the diet for 13 weeks. Groups of 10 rats per sex received TNT at doses of 1, 5, 25, 125 or 300 mg/kg/day. Thirty rats per sex served as untreated controls. Toxicologic endpoints included clinical signs, body weight, food consumption, hematology, clinical biochemistry, organ weights and gross/histopathology. Toxic effects following 125 mg/kg/day or greater included decreased food intake and body weight gains, elevated serum cholesterol levels, and anemia (reduced hemoglobin, hematocrit and RBC counts). Splenomegaly, hepatomegaly/hepatocytomegaly and testicular atrophy with degeneration of the seminiferous tubular epithelium were also seen at 125 and 300 mg/kg/day. Hemosiderin-laden macrophages, congestion of the splenic red pulp, methemoglobin production indicative of the oxidizing activity of TNT and/or its metabolites, and the lack of bone marrow toxicity suggested hemolysis as the mechanism of anemia.

Toxicity and residue studies in dairy animals with firemaster FF-1 (polybrominated biphenyls).

Two studies (one in Holstein calves and one in Holstein cows) were conducted to determine potential toxicity and residue levels following oral ingestion of polybrominated biphenyls (PBB). The material was FireMaster FF-1. Administration was by gelatin capsules. Doses in calves were 0.1, 1.0, 10, or 100 mg/kg body weight, while doses in cows were equivalent to 0.01, 0.1, 1.0, or 10 ppm in the diet. The calves were sacrificed after 2, 4, 6, or 12 weeks. The cows were fed 158 or 228 days, and were then in a recovery period for 182 or 112 days. In the calf study, signs of toxicity were observed only in animals fed 100 mg/kg-day. Administration of 10 mg/kg-day or less for up to 12 weeks caused no overt signs of toxicity. Histologic studies were conducted upon selected organs and tissues taken at time of sacrifice. The only treatment-induced lesions among animals fed 0.1 mg/kg-day were minimal lesions in the kidney and skin in the one calf fed at this level for 12 weeks. Treatment-induced lesions were present in the kidneys, skin, and/or liver from some animals fed levels of 1.0 mg/kg-day and above. The relative severity of these lesions was related to the level and length of exposure. Treatment-associated changes were observed in the testes of all males in this study. The hypospermatogenesis observed was consistent with the age of the animals due to prepuberal development of the testes. No clinical signs of toxicity or histologic changes attributed to PBB were observed in the cows. Two cows were pregnant at the initiation of the study and give birth to normal, healthy calves during the study. These calves grew normally and appeared healthy when sacrificed at about 6 months of age. Residue levels were quantitated as the hexabromobiphenyl isomer (BP-6) which is the major isomer present in the PBB mixture. Tissue residue levels in calves increased with dose and duration of administration of PBB with highest levels being found in the fat. At 100 mg/kg the levels in fat were about 6000 to 6300 ppm after 6 to 12 weeks. Residue levels of BP-6 in milk and fat of the cows also increased with dose and duration of administration. Maximum levels in milk were about 1/3 the levels in the diet. In general, the levels plateaued after about 4 to 6 weeks and did not go appreciably higher even though administration of the FireMaster FF-1 was continued. Maximum levels in fat were on the order of approximately 4.5 times the levels in the diet, except at the lowest dose level. Residues decreased in milk after administration of PBB was discontinued, but detectable levels were still present 6 months later. Residues were found in the calves born of treated cows indicating passage of the PBBs through the placental barrier and/or ingestion through the milk.