2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mutagenesis in cultured Big Blue rat mammary epithelial and fibroblast cells

Epithelial cells are the primary site of carcinogenesis in most tissues, including the mammary gland. As an alternative to the study of mutation induction in whole tissues in vivo, we have established Big Blue transgenic rat cell lines from the mammary epithelium (BBR/ME) and the mammary stroma (BBR/MFib), to permit a comparison of their mutagenic responses to carcinogens. We previously demonstrated their responsiveness to the alkylating agent N-ethyl-N-nitrosourea (ENU) (McDiarmid H et al. [2001]: Mutat Res 497:39-47). Here, we examined the responses of cultured epithelial and stromal cells to the protein pyrolysis product and mammary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Rat hepatic S9 was used as a source of bioactivation enzymes. Mutant induction (cII locus) and clonogenic survival were measured as a function of PhIP concentration. PhIP mutagenicity was observed in the fibroblast cells, but the greater toxicity of PhIP to the epithelial cells prevented a definitive evaluation of mutagenicity. Since PhIP may be detoxified by conjugation with glutathione, we measured glutathione levels and glutathione-S-transferase expression and activities in both cell lines. The epithelial cells had higher glutathione-S-transferase enzyme activity and protein expression than did the fibroblast cell line. Because the epithelial cells were more sensitive to toxicity, glutathione conjugation evidently plays only a minor role in PhIP toxicity and mutagenicity in our cell lines.     

Musculoskeletal response to exercise is greatest in women with low initial values

INTRODUCTION: The "initial values" principle of exercise training states those with the lowest initial values of a physiologic system have the greatest capacity for improvement in response to training. We sought to determine whether initial values predicted the musculoskeletal response to training in premenopausal women (N = 31) who participated in a 1-yr program of resistance and jump training designed to improve physical indices of fracture risk. Significant improvements in trochanteric bone mineral density (BMD), hip abductor strength, power, and postural stability occurred in response to training. METHODS: To determine the predictive power of initial values, we performed separate stepwise regression analyses for each variable including the following dependent variables: age, initial value, highest weight lifted during training, and total number of exercise sessions attended. RESULTS: In each case, the initial value was the most significant predictor of percent change in response to training. Initial values explained 15-29% of the variance in the magnitude of the training response. For each unit lower BMD of the greater trochanter (0.01 g.cm-2), the training response was 12% greater. For each unit decrease in initial strength (1 N.m), power (1 W), and stability (1 SI unit), the training response was 1.0%, 0.2%, and 8.0% greater, respectively. When categorized by quartile of initial values, women in the lowest quartile had two- to fivefold greater improvements in musculoskeletal measures than those in the upper quartile. CONCLUSION: Women who began training with the lowest initial values had the greatest improvements in hip BMD, hip abductor strength, leg power, and postural stability. These results support the training principle of initial values and suggest that this training program may be most successful in premenopausal women with lower values of musculoskeletal indices of fracture risk.     

Food for trans-Atlantic rowers: a menu planning model and case study

Every 4 years, rowers from around the world compete in a 50- to 60-day trans-Atlantic rowing challenge. These ultra-distance rowers require a diet that provides adequate calories, protein, vitamins, minerals, and fluids so they can perform well day after day, minimize fatigue, and stay healthy. Yet, the rowers are confronted with menu planning challenges. The food needs to be lightweight, compact, sturdy, non-spoiling in tropical temperatures, calorie dense, easy to prepare, quick to cook, and good tasting. Financial concerns commonly add another menu planning challenge. The purpose of this case study is to summarize the rowers' food experiences and to provide guidance for sports nutrition professionals who work with ultra-endurance athletes embarking on a physical challenge with similar food requirements. The article provides food and nutrition recommendations as well as practical considerations for ultra-distance athletes. We describe an 8,000 calorie per day menu planning model that uses food exchanges based on familiar, tasty, and reasonably priced supermarket foods that provide the required nutrients and help contain financial costs.     

Down-regulation of hepatic nicotine metabolism and a CYP2A6-like enzyme in African green monkeys after long-term nicotine administration

Nicotine metabolism is decreased in smokers compared with nonsmokers, but the mechanism(s) responsible for the slower metabolism are unknown. Nicotine is inactivated to cotinine by CYP2A6 in human liver [nicotine C-oxidation (NCO)]. CYP2B6 also metabolizes nicotine to cotinine but with lower affinity than CYP2A6. To evaluate the effects of long-term nicotine treatment on hepatic levels of CYP2A6 and CYP2B6, and nicotine metabolism, an African green monkey (AGM) model was developed. As in humans, approximately 80 to 90% of in vitro hepatic NCO is mediated by a CYP2A6-like protein (CYP2A6agm) in this species, as determined by inhibition studies. Male AGM (n = 6 per group) were treated for 3 weeks with nicotine (s.c., 0.3 mg/kg, b.i.d.), phenobarbital (oral, 20 mg/kg, as a positive control for P450 induction), and/or saline (s.c., b.i.d.). Immunoblotting demonstrated a 59% decrease (p < 0.05) in hepatic CYP2A6agm protein in nicotine-treated animals. A CYP2B6-like protein (CYP2B6agm) was modestly and insignificantly decreased (14%, p = 0.11). In vitro NCO was decreased by 41% in the nicotine-treated group (p < 0.05), mediated by a decrease in CYP2A6agm, as demonstrated using inhibitory antibodies. CYP2A6agm mRNA (33%, P < or = 0.05) and CYP2B6agm (35%, p < 0.01) mRNA were also significantly decreased in the nicotine-treated group. Phenobarbital-treated animals demonstrated an increase in CYP2B6agm (650%, p < 0.001), but not CYP2A6agm (20%, p = 0.49). NCO was increased in the phenobarbital-treated group (55%, p < 0.05) by an increase in CYP2B6agm-mediated NCO. Consistent with the slower nicotine metabolism observed in smokers, nicotine may decrease its own metabolism in primates by decreasing the expression of the primary nicotine-metabolizing enzyme CYP2A6.     

Pretreatment predictors of time to cancer specific death after prostate specific antigen failure

PURPOSE: Whether pretreatment factors that predict for time to prostate specific antigen (PSA) failure also predict for time to prostate cancer specific death after PSA failure for patients with competing causes of mortality treated during the PSA era was the subject of this study. MATERIALS AND METHODS: Of 415 men with a median age of 73 years who underwent external beam radiation therapy between 1988 and 2001 for clinically localized prostate cancer 160 (39%) experienced PSA failure and 96 (23%) died. In 46 men (48%) the cause of death was prostate cancer. Cox regression multivariable analyses (multivariable analysis) were performed to evaluate the ability of the pretreatment PSA and centrally reviewed biopsy Gleason score to predict time to prostate cancer specific death after PSA failure. RESULTS: When analyzed as categorical variables using multivariable analysis, biopsy Gleason score 4 + 3 (p = 0.02), 8 to 10 (p = 0.02) disease and a pretreatment PSA greater than 20 ng./ml. (p = 0.03) were significant predictors of time to prostate cancer specific death after PSA failure. Estimates of prostate cancer specific death 5 years after PSA failure were 24%, 40% and 59% (p = 0.01) for patients with a biopsy Gleason score < or = 6, 3 + 4, 4 + 3 or higher and 22%, 40% and 60% (p = 0.04) for patients with a pretreatment PSA of 10 or less, greater than 10 and 20 or less, or greater than 20 ng./ml., respectively. CONCLUSIONS: Patients at high risk for PSA failure after radiation therapy based on pretreatment PSA greater than 20 ng./ml. or biopsy Gleason score 4 + 3 or greater are also at high risk for death from prostate cancer after PSA failure despite competing causes of mortality.     

Lower risk of urinary tract infection with low‐dose trimethoprim/sulfamethoxazole compared to dapsone prophylaxis in older renal transplant patients on a rapid steroid‐withdrawal immunosuppression regimen

Giullian JA, Cavanaugh K, Schaefer H. Lower risk of urinary tract infection with low‐dose trimethoprim/sulfamethoxazole compared to dapsone prophylaxis in older renal transplant patients on a rapid steroid‐withdrawal immunosuppression regimen.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01129.x
© 2009 John Wiley & Sons A/S. Abstract: Background: Urinary tract infections (UTI) are common in renal transplant recipients. Trimethoprim/sulfamethoxazole (TMP/SMZ) in moderate to high daily doses prevents Pneumocystis jiroveci (PCP) and reduces the risk of UTI in renal transplant patients. Low‐dose TMP/SMZ also reduces the risk of PCP, although its ability to reduce the risk of UTI is uncertain. Design: Retrospective review of 158 patients who received a renal transplant without corticosteroids for maintenance immunosuppression. Results: Forty percent of patients initially prescribed TMP/SMZ ultimately stopped this medication early because of an adverse reaction. Urinary infection occurred in 16% without a significant difference in the risk of UTI between those treated with dapsone vs. those treated with TMP/SMZ (HR [95%CI]: 1.7 [0.75, 3.9], p = 0.2). In the subset of patients who were older than age 47 yr (mean age for this cohort, SD ± 6.2 yr), those treated with dapsone originally or who switched from TMP/SMZ to dapsone had a greater risk of UTI compared to patients who remained on TMP/SMZ (HR [95%CI]: 4.3 [1.2, 15.5], p = 0.024). Conclusions: For renal transplant recipients over the age of 47 yr, treated without long‐term glucocorticoids, our retrospective data suggest that low‐dose TMP/SMZ is associated with a lower risk of UTI compared to dapsone prophylaxis.     

Dietary Sodium in Chronic Kidney Disease: A Comprehensive Approach

Despite existing guidelines, dietary sodium intake among people worldwide often exceeds recommended limits. Research evidence is growing in both animal and human studies showing indirect and direct adverse consequences of high dietary sodium on the kidney. In patients with kidney disease, dietary sodium may have important effects on proteinuria, efficacy of antiproteinuric pharmacologic therapy, hypertension control, maintaining an optimal volume status, and immunosuppressant therapy. Dietary sodium intake is an important consideration in patients with all stages of chronic kidney disease, including those receiving dialysis therapy or those who have received a kidney transplant. We review in detail the dietary sodium recommendations suggested by various organizations for patients with kidney disease. Potential barriers to successfully translating current sodium intake guidelines into practice include poor knowledge about the sodium content of food among both patients and providers, complex labeling information, patient preferences related to taste, and limited support for modifications in public policy. Finally, we offer existing and potential solutions that may assist providers in educating and empowering patients to effectively manage their dietary sodium intake.     

From good ideas to actions: A model-driven community collaborative to prevent childhood obesity

ObjectiveActivate Omaha Kids, a community collaborative, was designed, implemented, and evaluated with the aim of preventing childhood obesity in the Omaha community. Activate Omaha Kids brought together key stakeholders and community leaders to create a community coalition. The coalition's aim was to oversee a long-term sustainable approach to preventing obesity. Following a planning phase, a business plan was developed that prioritized best practices to be implemented in Omaha.MethodsThe business plan was developed using the Ecological Model, Health Policy Model, and Robert Wood Johnson Foundation Active Living by Design 5P model. The three models helped the community identify target populations and activities that then created a single model for sustainable change.ResultsTwenty-four initiatives were identified, over one million dollars in funding was secured, and evaluation strategies were identified.ConclusionBy using the models from the initial steps through evaluation, a clear facilitation of the process was possible, and the result was a comprehensive, feasible plan. The use of the models to design a strategic plan was pivotal in building a sustainable coalition to achieve measurable improvements in the health of children and prove replicable over time.