Considering sex as a biological variable in preclinical research.

In June 2015, the National Institutes of Health (NIH) released a Guide notice (NOT-OD-15-102) that highlighted the expectation of the NIH that the possible role of sex as a biologic variable be factored into research design, analyses, and reporting of vertebrate animal and human studies. Anticipating these guidelines, the NIH Office of Research on Women's Health, in October 2014, convened key stakeholders to discuss methods and techniques for integrating sex as a biologic variable in preclinical research. The workshop focused on practical methods, experimental design, and approaches to statistical analyses in the use of both male and female animals, cells, and tissues in preclinical research. Workshop participants also considered gender as a modifier of biology. This article builds on the workshop and is meant as a guide to preclinical investigators as they consider methods and techniques for inclusion of both sexes in preclinical research and is not intended to prescribe exhaustive/specific approaches for compliance with the new NIH policy.-Miller, L. R., Marks, C., Becker, J. B., Hurn, P. D., Chen, W.-J., Woodruff, T., McCarthy, M. M., Sohrabji, F., Schiebinger, L., Wetherington, C. L., Makris, S., Arnold, A. P., Einstein, G., Miller, V. M., Sandberg, K., Maier, S., Cornelison, T. L., Clayton, J. A. Considering sex as a biological variable in preclinical research.

Considerations of sex and gender differences in preclinical and clinical trials.

Women continue to be underrepresented in clinical trials, particularly in Phases I and II of experimental drug studies in spite of legislative guidelines in the USA, Canada, the European Union, Australia, and Japan requiring the inclusion of women in clinical trials. As such, women remain a vulnerable population subject to the adverse effects of pharmacological therapies. Thus, women experience higher rates of adverse drug reactions than do men and for women of reproductive age or who may be pregnant, therapeutic options may be limited. This chapter provides a brief history of inclusion of sex and gender as variables in clinical trials, summarizes governmental legislation for consideration of sex and gender in clinical trials and provides specific examples of drugs which have been withdrawn from the market because of side effects in women. Additional information related to sex and gender in preclinical testing, trial design, challenges to recruitment of women for clinical trials and statistical methods for analysis of data also is considered.

Vitamin B-6 vitamer levels in plasma and related symptoms in hemodialysis subjects taking low- and high-dose renal multivitamin supplements.

INTRODUCTION: The purpose of this study was to evaluate the B-6 vitamers in plasma and related symptoms in hemodialysis subjects taking high- or low-dose vitamins. METHODS: A total of 24 hemodialysis (HD) subjects were divided into two groups. Twelve subjects received a high-dose vitamin supplement [50 mg pyridoxine hydrochloride (PN-HCl) /tablet] and 12 received a low-dose vitamin supplements containing (10 mg PN-HCl/tablet) for 6+ months. Plasma B-6 vitamers were analyzed using HPLC. Other data were obtained from subjects' medical records. Subjects were assessed for vitamin B-6 related symptoms. Cluster analysis was used to form symptom groups. Student t-tests and analysis of variance were used to determine differences (p < 0.05) in group means. RESULTS: The mean ± SD plasma B-6 vitamer and 4-pyridoxic acid concentrations (nmol/L) were as follows in the 10-mg and 50-mg PN-HCl groups, respectively: pyridoxal- 5'-phosphate (PLP) 10 ± 3 and 16 ± 8 (p = 0.04); pyridoxal (PL) 50 ± 96 and 68 ± 06; pyridoxine (PN) 26 ± 50 and 191 ± 107; and 4-pyridoxic acid (4-PA) 43 ± 64 and 99 ± 361. The cluster group with a significantly higher (p = 0.04) plasma 4-PA concentration of 167 ± 697 nmol/L reported more tingling hands, tachycardia, and diarrhea. CONCLUSION: Plasma PLP levels and symptoms related to B-6 in HD subjects are impacted by dose of PN-HCl.

Serum levels of folate and cobalamin are lower in depressed than in nondepressed hemodialysis subjects.

OBJECTIVE: The purpose of this study was to evaluate if there was a significant difference in serum and RBC folate or serum cobalamin levels in depressed and nondepressed subjects on hemodialysis (HD). DESIGN: A cross-sectional design was used in this study. Each subject's serum folate and cobalamin, and red blood cell (RBC) folate were measured. The Beck Depression Index II (BDI-II) was used to assess for depression. Subjects with scores of 10 or greater were considered depressed. Other laboratory, anthropometric, and demographic data were obtained from the subjects' medical records. To assess for significant differences (P < 0.05) in the laboratory values of the outcome variables between depressed and nondepressed subjects, t tests were performed on the groups' mean values. SETTING: The study was conducted with patients in two dialysis centers in Texas. PATIENTS OR OTHER PARTICIPANTS: Seventy-three individuals undergoing HD for at least six months who met study inclusion criteria were solicited to participate in the study after the study was approved by the respective institutional review board. INTERVENTION: Depression and mental status of each subject were assessed using the BDI-II and the Folstein Mini-Mental State Exam, respectively. MAIN OUTCOME MEASURE: Serum folate, cobalamin, total homocysteine, and RBC folate were measured and mean values were evaluated for significant differences in the depressed and nondepressed groups. RESULTS: Of the subjects in this study, 43.8% had BDI-II scores > 10 indicating depression. The nondepressed subjects had significantly higher mean serum folate (281 +/- 649 vs. 52 +/- 137 ng/mL), serum cobalamin (1162 +/- 1014 vs. 757 +/- 463 pg/mL), and RBC folate (1433 +/- 1757 vs. 810 +/- 654 ng/mL) levels than did depressed subjects. In the nondepressed group, 39% of subjects were taking a supplement containing 35-42 mg folacin and 7 mg cobalamin per week while only 9.1% of depressed subjects were taking a vitamin containing these levels of B vitamins. The group means were not significantly different for age, months on HD, body mass index, erythropoietin/kg body weight, total homocysteine, hemoglobin, albumin, or ferritin. CONCLUSION: As with the general population, lower serum folate, RBC folate, and serum cobalamin levels were found in depressed as compared to nondepressed subjects on HD. Plasma levels of these vitamins may be one of many factors related to depression, but larger studies with stronger designs are needed to confirm the results of this study.