Immunological Detection and Quantitation of DNA Adducts Formed by 4-Aminoazobenzene Species in vivo

Antibodies to 3-methoxy-4-aminoazobenzene (3-MeO-AAB) and 2-methoxy-4-aminoazobenzene (2-MeO-AAB) DNA adducts were raised in rabbits against in vitro-adducted DNA samples. The enzyme-linked immunosorbent assay (ELISA) was used to determine the sensitivity and specificity of these antibodies. They proved highly specific for the modified DNA used as the immunogen, but cross-reacted with each other. Moreover, they showed cross reactivity with DNA modified by 4-( o -tolylazo)- o -toluidine, but not by other carcinogens, such as 4-aminobiphenyl or 4-nitroquinoline 1-oxide. The 50% inhibition level of antibody binding in the competitive ELISA was at 10–20 fmol of modified base per assay (equivalent to 1–2 adducts per 10⁶ bases). Immunohistochemical staining indicated that these antibodies bind specifically to nuclear components of the liver in rats given either 3-MeO-AAB or 2-MeO-AAB at the dose of 50 mg/kg body weight.     

Preferential inhibitions of hepatic P450IA2 expression and induction by lead nitrate in the rat

Male F344 rats were treated with lead nitrate and changes inthe expression and induction of P450IA subfamily enzymes anda placental form of glutathione-S-transferase (GST-P) in theliver were assessed by means of a bacterial mutation test, immunoblottingwith a monoclonal antibody reactive to P450IA1/IA2 and anti-GST-Psera and Northern blotting with P450IA2 cDNA as a probe. Treatmentof rats with lead nitrate (20, 50 or 100 µmol/kg bodywt) decreased P450IA2 mRNA and protein in the liver in the dose-dependentfashion and also decreased the microsomal activity for P450IA2-dependentmutagenization of aromatic amines. Pretreatment of rats withlead nitrate suppressed the inductions of both P450IA2 mRNAand protein by an inducer of P450IA subfamily enzymes in theliver. In addition, amount of the induced P450IA2 was decreasedalong with increase in that of the induced GST-P.     

Clinical results of staged repair with complete unifocalization for pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries.

OBJECTIVE: Our treatment strategy for pulmonary atresia with ventricular septal defect (VSD) and major aortopulmonary collateral arteries is a staged repair that comprises the first complete unifocalization (UF) with 'unification' of intrapulmonary arteries and then the definitive repair. The purpose of this study is to evaluate the outcome of our staged repair strategy with complete UF and to determine the results of our current management strategy. METHODS: From 1982 to 2004, 113 consecutive patients were treated with staged repair at our institute. We evaluated the risk of definitive repair failure or death in the 3 years after definitive repair using logistic regression. Furthermore, we compared the early group (patients who underwent UF before December 1995) and the late group (patients who underwent UF after January 1996). RESULTS: The mean follow-up interval was 8.8 years (0.8 months to 23.3 years), and Kaplan-Meier-estimated overall survival rates after first UF were 80.9, 73.8, and 69.9% at 5, 10, and 15 years, respectively. Survival in patients with an absent central pulmonary artery (PA) was significantly lower than in those with a central PA (p<0.05), and the factor that was significantly associated with definitive repair failure or death in the 3 years after definitive repair was central PA morphology (p<0.05). Higher mean PA pressure after UF was detected in patients with hypoplastic central PA, compared with those without hypoplastic PA (30.9 mmHg vs 23.3 mmHg, p<0.05). In the late group, age (in years) at first UF (3.9 vs 8.4, p<0.01), second UF (4.3 vs 9.2, p<0.01), and definitive repair (5.8 vs 9.1, p<0.01) was significantly younger than in early group, and the survival rate after first UF in the late group was 96.2 and 91.3% at 3 and 7 years, respectively. Systolic right ventricular pressure and the pressure ratio between the right and the left ventricles after definitive repair in the late group were significantly lower than in the early group (53.6 mmHg vs 75.0 mmHg, p<0.01; 61.7% vs 75.9%, p<0.05). CONCLUSIONS: Hypoplastic central PA was a significant risk factor in this disease. The overall survival was improved by our current management strategy. Improved RV pressure after definitive repair appears to affect the long-term outcome.     

Ganglioglial Differentiation in Medulloblastoma

A case of cerebellar medulloblastoma with clusters of mature ganglion cells and glial cells is described. The patient, a 15 -year -old girl, underwent three operations followed each time by radiation and chemotherapy during the four-year clinical course. Histologically, the ganglion cells were clearly identifiable by their abundant eosino-philic cytoplasm, round nuclei with prominent nucleoli, tigroid granules, and argyrophilic fibrils and axons. Im-munohistochemically, the cells were NSE- and NF positive, and ultrastructurally they contained abundant tubules and filaments, neurosecretory granules and well developed rough endoplasmic reticulum. There were many cells transitional in appearance between primitive cells and mature ganglion cells. The tumor also had many mature yet atypical astrocytes and oligodendrocytes. The exact mechanism of the extensive neuronal and glial maturation of medulloblastoma cells is unclear, but the repetitive surgical interventions, radiation and chemotherapy might have had certain cytostatic effects on rapidly dividing medulloblastoma cells, giving them a chance to mature into postmitotic cells with potential for neuronal and glial differentiation. Acta Pathol Jpn 40: 50–56, 1990.     

A case with breast cancer under the nipple who underwent breast conserving treatment

Although breast conserving treatment (BCT) has become the standard therapy for early breast cancer, breast removal is still recommended for patients with a tumor beneath the nipple or with Paget’s disease. We have employed transposition of a latissimus dorsi myocutaneous (LD-MC) flap after wide local excision of a tumor with the nipple-areola complex. A new nipple-areola complex was reconstructed on the LD-MC flap after breast irradiation. Utilizing reconstructive techniques, BCT will likely become the treatment of choice for more patients with early breast cancer.     

The role of hormonal therapy in breast cancer

This review reassesses the role of hormonal therapy in breast cancer specifically the sequential or concurrent use of endocrine therapy and the combined use of chemotherapy with endocrine therapy. In advanced disease the sequential use of hormone therapies is generally recommended rather than the combined use of various hormonal agents, though combination hormonal therapy offers advantages in certain subsets of patients. The efficacy of combined chemo-endocrine therapy is questionable. Chemotherapy with estrogenic recruitment is an attractive but still experimental concept. However, in an adjuvant setting there is evidence that combined chemo-endocrine therapy causes a significant increase in disease-free and/or overall survival, particularly in postmenopausal patients with estrogen receptor (Expositive tumors. While hormonal treatment strategies have clearly benefitted from randomized studies, data regarding optimal endocrine therapy are still insufficient.     

Decrease in serum thyroxine level by phenobarbital in rats is not necessarily dependent on increase in hepatic UDP-glucuronosyltransferase.

We have previously reported that there is a poor correlation between increase in the levels of UDP-glucuronosyltransferases, UGT1A1 and UGT1A6, and decrease in the levels of serum total thyroxine (T4) and free T4 in phenobarbital (PB)-treated rats, although the PB-induced decrease in rats is generally thought to occur through induction of the UDP-glucuronosyltransferase (T4-UDP-GT: UGT1A1 and UGT1A6). In the present study, to clarify a relationship between the decrease in serum T4 level and the increase in the T4-UDP-GT activity by PB in rats, we examined the relationship using Gunn rats, a mutant strain of Wistar rats deficient in UGT1A isoforms. Levels of serum total T4, free T4, and total triiodothyronine (T3) were markedly decreased not only in Wistar rats but also in Gunn rats 1 day after the final administration of PB (80 mg/kg i.p., once daily for 4 days), and no significant difference in magnitude of the decrease between Wistar and Gunn rats was observed. On the other hand, the level and activity of T4-UDP-GT were significantly increased by treatment with PB in Wistar rats but not in Gunn rats. Furthermore, significant decrease in the activity of hepatic type I iodothyronine deiodinase, which mediates the deiodination of T4 and T3, by PB treatment was observed in both Wistar and Gunn rats. In addition, no significant change in the level of serum thyroid-stimulating hormone, the activity of hepatic sulfotransferase, and the binding of [125I]T4 to serum transthyretin and albumin by PB treatment was observed in either Wistar or Gunn rats. In conclusion, the present results demonstrate that the decrease in serum total T4 level by PB in Gunn rats is not dependent on the increase in hepatic T4-UDP-GT activity and suggest that even in Wistar rats, the PB-induced decrease in serum T4 level does not occur only through increase in hepatic T4-UDP-GT.