Chemoprevention of esophageal tumorigenesis by dietary administration of lyophilized black raspberries

Fruit and vegetable consumption has consistently been associated with decreased risk of a number of aerodigestive tract cancers, including esophageal cancer. We have taken a "food-based" chemopreventive approach to evaluate the inhibitory potential of lyophilized black raspberries (LBRs) against N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in the F344 rat, during initiation and postinitiation phases of carcinogenesis. Anti-initiation studies included a 30-week tumorigenicity bioassay, quantification of DNA adducts, and NMBA metabolism study. Feeding 5 and 10% LBRs, for 2 weeks prior to NMBA treatment (0.25 mg/kg, weekly for 15 weeks) and throughout a 30-week bioassay, significantly reduced tumor multiplicity (39 and 49%, respectively). In a short-term bioassay, 5 and 10% LBRs inhibited formation of the promutagenic adduct O(6)-methylguanine (O(6)-meGua) by 73 and 80%, respectively, after a single dose of NMBA at 0.25 mg/kg. Feeding 5% LBRs also significantly inhibited adduct formation (64%) after NMBA administration at 0.50 mg/kg. The postinitiation inhibitory potential of berries was evaluated in a second bioassay with sacrifices at 15, 25, and 35 weeks. Administration of LBRs began after NMBA treatment (0.25 mg/kg, three times per week for 5 weeks). LBRs inhibited tumor progression as evidenced by significant reductions in the formation of preneoplastic esophageal lesions, decreased tumor incidence and multiplicity, and reduced cellular proliferation. At 25 weeks, both 5 and 10% LBRs significantly reduced tumor incidence (54 and 46%, respectively), tumor multiplicity (62 and 43%, respectively), proliferation rates, and preneoplastic lesion development. Yet, at 35 weeks, only 5% LBRs significantly reduced tumor incidence and multiplicity, proliferation indices and preneoplastic lesion formation. In conclusion, dietary administration of LBRs inhibited events associated with both the initiation and promotion/progression stages of carcinogenesis, which is promising considering the limited number of chemopreventives with this potential.     

Delirium in the intensive care unit: are we helping the patient?

The intensive care unit (ICU) represents a dynamic interaction between patient factors and interventional factors. The complexity of this situation can generate an impaired consciousness in the patients. The critical care provider is faced with deducing the etiology and treatment of delirium in the ICU. Many of the therapeutic agents that are used in the ICU may precipitate delirium. Patients may also experience delirium as part of their underlying medical conditions. Withdrawal syndromes, delirium tremens in particular, are known to cause delirium. By a combination of appropriate selection of medications and an awareness of delirium as a side effect, the patient in the ICU may be treated in a manner to minimize the clouding of consciousness. An understanding of the proposed pathophysiology of various types of delirium will allow appropriate clinical measures to be taken.     

Incidence and effects of Ha-ras codon 12 G-->A transition mutations in preneoplastic lesions induced by N-nitrosomethylbenzylamine in the rat esophagus

N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis is an important model for squamous cell carcinoma of the human esophagus. In this model, previous studies have shown that the GGA-->GAA Ha-ras codon 12 mutation is present in the majority of papillomas. No other Ha-ras mutation has been identified. Studies using other models of chemical carcinogenesis suggest that Ha-ras activation has a critical role during tumor initiation. We have used laser-capture microdissection and polymerase chain reaction-restriction fragment length polymorphism analysis to study the role of codon 12 Ha-ras mutation at various stages of tumor development in the rat esophagus. Our results indicate that Ha-ras mutation was present infrequently (4.3%) in premalignant lesions. The incidence of Ha-ras mutation was high in papillomas (57.1%), however, and 50% of papillomas expressed mutant Ha-ras RNA message. Additionally, there was a linear trend correlating increased incidence of Ha-ras mutation with later papilloma stage. These data suggest the role of ras activation later in neoplastic development. To evaluate the potential mechanism of action by which Ha-ras contributes to promotion and progression in this model, we compared mRNA expression of cyclin D1 and p27 in Ha-ras mutant and Ha-ras normal papillomas. We found no differences in mRNA expression of either cyclin D1 or p27 between these two papilloma populations. Our data suggest an important paradigm shift for the role of ras mutations in this model of chemical carcinogenesis, indicating a functional role of Ha-ras activation in promotion/progression and not in the initiation phase of NMBA-induced papillomagenesis.     

A test of the maternal stress theory of human male homosexuality

Both the neurohormonal theory of sexual orientation and previous research on humans and animals suggest that male homosexuality may arise from prenatal stress during the brain's sexual differentiation. Stress-proneness and retrospective reports of stress during pregnancy were obtained from mothers of male and female heterosexuals, bisexuals, and homosexuals. Each mother also rated pregnancy stress for a heterosexual sibling of the subject. For males, neither between-family nor within-family analyses revealed a maternal stress effect for either sexual orientation or childhood gender nonconformity. However, mothers of effeminate children reported more stress-proneness than other mothers. Male homosexuality nevertheless was strongly familial, suggesting a reconsideration of genetic and familial environmental mechanisms.     

Hemicorporectomy: back to front

Hemicorporectomy involves amputation of the pelvis and lower extremities by disarticulation through the lumbar spine with concomitant transection of the aorta, inferior vena cava, and spinal cord, as well as creation of conduits for diversion of the urinary and fecal streams. A review of the literature reveals that the surgical technique has been relatively unchanged since 1960. The standard anterior to posterior approach is associated with significant blood loss and morbidity, likely contributing to lengthy hospital stay. Herein, we describe our back-to-front approach to hemicorporectomy, involving early division of the vertebral structures and spinal cord, pre-empting engorgement of Batson's plexus, thus minimizing blood loss. In addition, this approach greatly improves exposure of the pelvic vessels, allowing for a technically less challenging and safer procedure.     

Optimization of metabolic activation for four mutagens in a bacterial, fungal and two mammalian cell mutagenesis assays

The optimum concentrations of Aroclor-induced rat liver S9 microsomal fraction for the mutagenic activity of the four standard mutagens 2-aminofluorene (2-AF), acriflavine (ACR), benzo[a]pyrene (BP) and cyclophosphamide (CP) were determined in four mutation assays. The four assays were the Ames test using Salmonella typhimurium strain TA100, cycloheximide resistance in the yeast Saccharomyces cerevisiae, the mouse lymphoma TK assay and the human peripheral lymphocyte cytogenetic assay. BP was the only mutagen to be most active at comparable S9 concentrations, of approximately 1%, for all four assays. The optimum S9 concentrations for each of the remaining three mutagens varied substantially between the four assays. ACR was a potent direct-acting mutagen in both mammalian cell assays. The mouse lymphoma TK assay results showed similar optimal values of 1.5% S9 or below for each of the four test agents. The assay with the largest variation of optimal S9 values for the four mutagens was the Ames test in strain TA100, although it also had the widest peaks of activity over the range of S9 concentrations tested. It is likely that the diversity of findings is due to a variety of metabolites affecting the different genetic endpoints that are measured in these assays. Thus from these results it is not possible for bacterial optimization data to be related to other routine in vitro systems. The use of more than one concentration of S9 would contribute useful information.