Hip fractures among infertile women

A retrospective cohort study was conducted in a population-based inception cohort of 1,157 Olmsted County, Minnesota, women with infertility (failure to conceive after 1 year despite intercourse without contraception) that was first diagnosed at the Mayo Clinic (Rochester, Minnesota) between 1935 and 1964. In this relatively young cohort, 31 hip fractures were observed during 35,849 person-years of follow-up; 36.5 had been expected (standardized incidence ratio = 0.85, 95% confidence interval 0.58-1.20). Standardized incidence ratios did not differ by type or cause of infertility. The data suggested that women with consistently irregular menses may have a greater risk of hip fracture. This finding should be confirmed by additional studies with longer follow-up periods and with assessment of other fracture outcomes.     

Antibody-directed enzyme prodrug therapy (ADEPT)

A conjugate of the bacterial enzyme carboxypeptidase G2 and the F(ab)(2) fragment of the anti-CEA monoclonal antibody A5B7 was directed in vitro at the human colon tumour cell line LS174T and the human non-small cell lung line COR-L23. Indirect immunofluorescence microscopy was used to show that the conjugate bound to LS174T cells but not to COR-L23. The cytotoxicity generated by addition of a phenol mustard prodrug to each cell line after pre-incubation with conjugate was found to be significantly greater for LS174T cells (IC50=0.24 mu M) than COR-L23 cells (IC50=108 mu M). However, for a 1:1 mixture of these cells an IC50, of 3.4 mu M was obtained. These data show that phenol mustard released by a localised conjugate can exert a bystander effect on neighbouring cells to which the conjugate does not bind.     

The bioactivation of 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB1954)--I. Purification and properties of a nitroreductase enzyme from Escherichia coli--a potential enzyme for antibody-directed enzyme prodrug therapy (ADEPT).

A nitroreductase enzyme has been isolated from Escherichia coli B. This enzyme is an FMN-containing flavoprotein with a molecular mass of 24 kDa and requires either NADH or NADPH as a cofactor. Partial protein sequence analysis showed extensive homology with the "classical nitroreductase" of Salmonella typhimurium and a nitroreductase induced in Enterobacter cloacae. In common with the Salmonella enzyme, the E. coli B enzyme is capable of reducing nitrofurazone. The E. coli nitroreductase is also capable of reducing the anti-tumour agent CB1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide], a property shared with the mammalian enzyme DT diaphorase [NAD(P)H dehydrogenase (quinone)] as isolated from Walker cells. The reduction of CB1954 by the E. coli enzyme results in the generation of cytotoxic species. Both enzymes also share the properties of being able to reduce quinones and are both inhibited by dicoumarol. The nitroreductase is a more active enzyme against CB1954 (kcat = 360 min-1) than Walker DT diaphorase (kcat = 4 min-1) and also has a lower Km for NADH (6 vs 75 microM).     

Dibenzo[a,l]pyrene-induced DNA adduction, tumorigenicity, and Ki-ras oncogene mutations in strain A/J mouse lung

Dibenzo[a,l]pyrene (DB[a,l]P), an environmental polycyclic aromatic hydrocarbon, is the most potent carcinogen ever tested in mouse skin and rat mammary gland. In this study, DB[a,l]P was examined for DNA adduction, tumorigenicity, and induction of Ki-ras oncogene mutations in tumor DNA in strain A/J mouse lung. Groups of mice received a single i.p. injection of 0.3, 1.5, 3.0, or 6.0 mg/kg DB[a,l]P in tricaprylin. Following treatment, DNA adducts were measured at times between 1 and 28 days, while tumors were counted at 250 days and analyzed for the occurrence of point mutations in codons 12 and 61 of the Ki-ras oncogene. DB[a,l]P in strain A/J mouse lung induced six major and four minor DNA adducts. Maximal levels of adduction occurred between 5 and 10 days after injection followed by a gradual decrease. DB[a,l]P-DNA adducts in lung tissue were derived from both anti- and syn-11,12- dihydroxy-13,14-epoxy- 11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DB[a,l]PDE) and both deoxyadenosine (dAdo) and deoxyguanosine (dGuo) residues in DNA as revealed by cochromatography. The major adduct was identified as a product of the reaction of an anti-DB[a,l]PDE with dAdo in DNA. DB[a,l]P induced significant numbers of lung adenomas in a dose- dependent manner, with the highest dose (6.0 mg/kg) yielding 16.1 adenomas/mouse. In tricaprylin-treated control animals, there were 0.67 adenomas/mouse. Based on the administered dose, DB[a,l]P was more active than other environmental carcinogens including benzo[a]pyrene. As a function of time-integrated DNA adduct levels, DB[a,l]P induced lung adenomas with about the same potency as other PAHs, suggesting that the adducts formed by DB[a,l]P are similar in carcinogenic potency to other PAHs in the strain A/J mouse lung model. Analysis of the Ki- ras mutation spectrum in DB[a,l]P-induced lung tumors revealed the predominant mutations to be G-->T transversions in the first base of codon 12, A-->G transitions in the second base of codon 12, and A-->T transversions in the second or third base of codon 61, concordant with the DNA adduct profile.      

Changes in femur neck bone density in US adults between 1988–1994 and 2005–2008: demographic patterns and possible determinants

Summary  

This analysis compares femur neck bone mineral density (FNBMD) and bone determinants in adults between National Health and Nutrition Examination Survey (NHANES) III (1988–1994) and NHANES 2005–2008. FNBMD was higher in NHANES 2005–2008 than in NHANES III, but between-survey differences varied by age, sex, and race/ethnicity. The likelihood that FNBMD has improved appears strongest for older white women.