Haplotype and genotype effects of the F7 gene on circulating factor VII,coagulation activation markers and incident coronary heart disease in UK men

Background: Evidence for the associations of single nucleotide polymorphisms (SNPs) in the F7 gene and factor (F)VII levels and with risk of coronary heart disease (CHD) is inconsistent. We examined whether F7 tagging SNPs (tSNPs) and haplotypes were associated with FVII levels, coagulation activation markers (CAMs) and CHD risk in two cohorts of UK men. Methods: Genotypes for eight SNPs and baseline levels of FVIIc, FVIIag and CAMs (including FVIIa) were determined in 2773 healthy men from the Second Northwick Park Heart Study (NPHS‐II). A second cohort, Whitehall II study (WH‐II, n = 4055), was used for replication analysis of FVIIc levels and CHD risk. Results: In NPHS‐II the minor alleles of three SNPs (rs555212, rs762635 and rs510317; haplotype H2) were associated with higher levels of FVIIag, FVIIc and FVIIa, whereas the minor allele for two SNPs (I/D323 and rs6046; haplotype H5) was associated with lower levels. Adjusted for classic risk factors, H2 carriers had a CHD hazard ratio of 1.34 [95% confidence interval (CI): 1.12–1.59; independent of FVIIc], whereas H5 carriers had a CHD risk of 1.29 (95% CI: 1.01–1.56; not independent of FVIIc) and significantly lower CAMs. Effects of haplotypes on FVIIc levels were replicated in WH‐II, as was the association of H5 with higher CHD risk [pooled‐estimate odds ratio (OR) 1.16 (1.00–1.36), P = 0.05], but surprisingly, H2 exhibited a reduced risk for CHD. Conclusion: tSNPs in the F7 gene strongly influence FVII levels. The haplotype associated with low FVIIc level, with particularly reduced functional activity, was consistently associated with increased risk for CHD, whereas the haplotype associated with high FVIIc level was not.     

Subchronic and Reproduction Studies with Dibutyl Phenyl Phosphate in Sprague-Dawley Rats

Dibutyl phenyl phosphate (DBPP) was administered to male andfemale. Sprague-Dawley rats in their diets in separate subchronic(91-day) and two-generation reproduction studies. Dose levelsof DBPP were 5, 50, and 250 mg/kg/day in both studies. In thereproduction study, cross-fostering was performed between somehigh-exposure and control litter offspring and dams followinga second mating of F₀ animals. Compared to control animals,body weights were consistently lower in high-exposure adultanimals in both studies; this observation was less consistentin mid-exposure adult rats. High-exposure rats in the subchronicstudy had decreased erythrocyte counts and hematocrit and hemoglobinlevels. They also had increased absolute and/or relative liverweights with concomitant decreased hepatocytic vacuolation andincreased fatty accumulation. In the reproduction study, matingand fertility indices were comparable among the parental animalsin both generations, but survivability among high-exposure pupsreared by control dams appeared to be decreased. Urinary bladderhistopathologic changes, consisting of mononuclear cell infiltrationand transitional epithelial hyperplasia, were noted in mid-and high-exposure rats from both studies. The no observableadverse effect level in both of these studies was 5 mg/kg/ day.     

The role of community pharmacists and medicines counter assistants in health promotion: reflections from a folic acid campaign

Context — In the UK in 1996, the National Pharmaceutical Association collaborated with the Health Education Authority to pilot a resource pack that would enable community pharmacists and their medicines counter assistants to contribute to the promotion of the use of folic acid in planned pregnancy. Objective — To determine the views of pharmacists and medicines counter assistants about the use of the resource pack. Method — Depth interviews were carried out to elicit views, underlying feelings, experiences and attitudes towards staging and managing the project. The data were analysed using the constant comparison as outlined in grounded theory. Themes were identified and quotes from interviewees used to illustrate the themes. Setting — 14 pharmacists and 14 medicines counter assistants in a West London health authority. Key findings — Most pharmacists and medicines counter assistants reported feeling more comfortable when advising regular customers rather than unknown customers. Leaflets, posters and displays were thought to be better ways to target passing trade. The majority of the minority ethnic pharmacists and medicines counter assistants considered that they had an important role in communicating information about folic acid to customers from minority ethnic groups, provided they both spoke the same language. Conclusions — Most pharmacists will only raise sensitive issues, such as the importance of taking folic acid to prevent neural tube defects, with customers with whom they already have a relationship. Stimulating inquiries from passing trade by targeting with leaflets, displays and other health education resources offers an additional benefit. Pharmacies are an important setting for disseminating health messages to people from minority ethnic groups in their own languages.     

Evaluation of Teratogenic Potential of N-Formylpiperidine in Rats

Evaluation of Teratogenic Potential of N-Formylpiperidine inRats. NAIR, R. S., ALVAREZ, L., AND JOHANNSEN, F. R. (1992).Fundam. Appl. Toxicol. 18, 96–101. The teratogenic potential of a versatile solvent, N-formylpiperidine(NFP), was evaluated in the rat. Three groups of 25 mated femaleSprague-Dawley rats were given 110, 220, or 440 mg/kg/day NFPin distilled water by gavage on Days 6 through 20 of gestation.A control group of 25 animals received distilled water on acomparable regimen. Maternal animals were observed daily forsigns of toxicity; body weights and food consumption were measuredat regular intervals throughout the study. All animals wereeuthanized on Gestation Day 21 and the fetuses examined forcleft palate and external abnormalities. One-half of the fetusesin each litter were examined for visceral anomalies while theremaining fetuses were examined for skeletal malformations afterappropriate staining. One female in the high dosage group diedon Gestation Day 12. Clinical signs of toxicity, observed in6 females in the high dosage group, included tremors, convulsivemovements, and an apparent weakness of the legs. Maternal toxicity,in terms of significantly decreased body weight and food consumption,was observed in the mid and high dosage groups. Food consumptionwas also significantly depressed for the first 4 days of dosingin the low dosage group. There was a significant increase innumber of resorptions in the high dosage group when comparedto controls. No effects were observed on other reproductiveparameters. Mean fetal body weight was significantly lower inthe high dosage group when compared to controls. While the incidenceof fetal malformations on a litter basis was higher in the highdosage group, this change was not statistically significant.The incidence of ossification variations was also higher inthe high dosage group. Thus, a dosage of 440 mg/kg NFP producedmaternal toxicity, embryolethality, fetal growth retardation,and an increased number of malformations. Maternal body weightswere depressed at 220 mg/kg but no embryo- or fetotoxicity wasobserved at or below 220 mg/kg NFP. The number and type of fetalmalformations in the 110 and 220 mg/kg dosage groups were alsocomparable to controls. In conclusion, NFP produced fetal effectsonly at 440 mg/kg, a dosage which resulted in marked toxicityto the dams.     

Subchronic Inhalation and Oral Toxicity of Hydrogenated Terphenyls in Rats

The subchronic toxicity of a commercial blend of partially hydrogenatedterphenyl was evaluated in rats by inhalation and oral routesof exposure. Animals were exposed to target concentrations of0, 10, 100, or 500 mg/m³ for 6 hr/day, 5 days/week or were offereddiets daily with concentrations of 0, 50, 200, or 2000 ppm.Each study lasted approximately 14 weeks. The study designsincluded observations for clinical signs, body weights, ophthalmicexams, hematology and clinical chemistry, major organ weights,and gross and histopathology. No treatment-related effects werenoted in the ophthalmic exams. Body weights were slightly depressedin high-dose males from the inhalation study and high-dose femalesin the dietary study. Liver and liver/body weights were increasedin high-dose animals of both sexes and high-and mid-dose malesin the dietary and inhalation studies, respectively. In thehigh-dose females of the dietary study, kidney and kidney/bodyweights were increased with increased adrenal and adrenal/bodyweights were also observed. No compound-related gross lesionsnor pathological correlates to the organ weight changes wereobserved in either study. The no-adverse effect levels wereconsidered to be 100 mg/m³ and 200 ppm (15.9 mg/kg) for theinhalation and dietary studies, respectively. These data indicatethat a wide margin of safety exists for hydrogenated terphenylworkplace exposure.