New active substances authorized in the United Kingdom between 1972 and 1994

Aims Dihydropyrimidine dehydrogenase (DPD) catalyses the reduction of pyrimidines, including the anticancer agent 5-fluorouracil (5FU). Impaired 5FU degradation, through low DPD activity, has led to severe, life-threatening or fatal toxicity after administration of 5FU. Complete DPD deficiency is associated with the inherited metabolic disease thymine uraciluria. Several mutations in the gene encoding DPD have recently been identified, but the phenotype-genotype concordance of these alterations in the general population has not been reported.
Methods Mononuclear cells were isolated from whole blood and DPD activity was determined after ex vivo incubation with ¹⁴C-5FU followed by h.p.l.c. analysis of 5FU metabolites. Analysis of mutations in the DPD gene at an exon splice site, codons 534, 543, and 732, and a deletion at base 1897 (ΔC1897) were performed in 30 subjects with the lowest and 30 subjects with the highest enzyme activity using PCR-RFLP.
Results DPD activity was measured in 226 Caucasian subjects and was highly variable (range 19.1–401.4  pmol  min⁻¹  mg⁻¹ protein). Mutations were frequently observed at codons 543 (allele frequency 28%), 732 (allele frequency 5.8%), and 534 (allele frequency 0.8%), but were not associated with low DPD activity. There were no splice site or ΔC1897 mutations found in this population.
Conclusions The five mutations analysed in this study are insufficient for identification of patients at risk for 5FU toxicity or thymine uraciluria. Both the splice site mutation and ΔC1897 are relatively rare in the general Caucasian population. Therefore, identification of further molecular alterations is required to facilitate the use of DPD analysis in genetic diagnosis and cancer therapeutics.     

Anxiety and Optimism Associated with Gestational Age at Birth and Fetal Growth

Psychosocial factors such as anxiety or optimism may be related to the risk of adverse pregnancy outcomes, but the evidence is conflicting. We investigated the relation between maternal anxiety, optimism, gestational age and infant birth weight in a cohort of 667 nulliparous women from the Prenatal Exposures and Preeclampsia Prevention study, Pittsburgh PA. Women completed the Spielberger Trait Anxiety Inventory and the Life Orientation Test at 18 weeks gestation. Linear and logistic regression models assessed the relation of anxiety and optimism to gestational age, birth weight centile, preterm delivery (<37 weeks) or small for gestational age (<10th percentile) births. After adjustment for age, race, preeclampsia, and smoking, higher anxiety was associated with decreasing gestational age (−1.6 days per SD increase in anxiety score, P = 0.06). This relationship was modified by maternal race (P < 0.01 for interaction). Among African American women, each SD increase in anxiety was associated with gestations that were, on average, 3.7 days shorter (P = 0.03). African American women with anxiety in the highest quartile had gestations that were 8.2 days shorter, and they had increased risk for preterm birth after excluding cases of preeclampsia (OR 1.69, 95% CI 1.08, 2.64). There was no association between anxiety and gestational age among White women. There was also no relation between anxiety, optimism and birth weight centile. Trait anxiety was associated with a reduction in gestational age and increased risk for preterm birth among African American women. Interventions that reduce anxiety among African American pregnant women may improve pregnancy outcomes.     

Vitamin K Treatment Reduces Undercarboxylated Osteocalcin but Does Not Alter Bone Turnover,Density, or Geometry in Healthy Postmenopausal North American Women

Low vitamin K status is associated with low BMD and increased fracture risk. Additionally, a specific menaquinone, menatetrenone (MK4), may reduce fracture risk. However, whether vitamin K plays a role in the skeletal health of North American women remains unclear. Moreover, various K vitamers (e.g., phylloquinone and MK4) may have differing skeletal effects. The objective of this study was to evaluate the impact of phylloquinone or MK4 treatment on markers of skeletal turnover and BMD in nonosteoporotic, postmenopausal, North American women. In this double‐blind, placebo‐controlled study, 381 postmenopausal women received phylloquinone (1 mg daily), MK4 (45 mg daily), or placebo for 12 mo. All participants received daily calcium and vitamin D₃ supplementation. Serum bone‐specific alkaline phosphatase (BSALP) and n‐telopeptide of type 1 collagen (NTX) were measured at baseline and 1, 3, 6, and 12 mo. Lumbar spine and proximal femur BMD and proximal femur geometry were measured by DXA at baseline and 6 and 12 mo. At baseline, the three treatment groups did not differ in demographics or study endpoints. Compliance with calcium, phylloquinone, and MK4 treatment was 93%, 93%, and 87%, respectively. Phylloquinone and MK4 treatment reduced serum undercarboxylated osteocalcin but did not alter BSALP or NTX. No effect of phylloquinone or MK4 on lumbar spine or proximal femur BMD or proximal femur geometric parameters was observed. This study does not support a role for vitamin K supplementation in osteoporosis prevention among healthy, postmenopausal, North American women receiving calcium and vitamin D supplementation.     

Girls' calcium intake is associated with bone mineral content during middle childhood

We examined longitudinally the association between calcium intake and total body bone mineral content (TBBMC) in 151 non-Hispanic white girls. Intakes of dairy, energy, and calcium were assessed using three 24-h dietary recalls in girls at ages 5, 7, 9, and 11 y. We assessed their total-body bone mineral content with dual-energy X-ray absorptiometry at ages 9 and 11 y. Dairy foods comprised the major contributor (70%) to calcium intake over the 6-y period; 28% of calcium came from other foods, and 2% from supplements. By age 9 and 11 y, the majority of girls did not meet calcium recommendations. Higher calcium intake at ages 7 and 9 y was associated with higher TBBMC at age 11 y. Calcium intake at age 9 y was also positively associated with TBBMC gained from age 9 to 11 y. Calcium intake at age 11 y was not correlated with TBBMC at the same age. Relations between calcium intake and TBBMC did not differ for total calcium and for calcium from dairy sources, likely reflecting the fact that dairy products were the major source of calcium in this sample. Results from the present study provide new longitudinal evidence that calcium intake, especially calcium from dairy foods, can have a favorable effect on girls' TBBMC during middle childhood.     

Base excision repair deficiency caused by polymerase beta haploinsufficiency: accelerated DNA damage and increased mutational response to carcinogens

The base excision repair pathway (BER) is believed to maintain genomic integrity by repairing DNA damage arising spontaneously or induced by oxidizing and alkylating agents. To establish the role of DNA polymerase beta (beta-pol) in BER and beta-pol-dependent BER in maintaining genomic stability, we have measured the impact of a gene-targeted disruption in the beta-pol gene on DNA repair capacity and on in vivo sensitivity to carcinogens. We have extensively phenotyped the DNA beta-pol heterozygous (beta-pol(+/-)) mouse as expressing approximately 50% less beta-pol mRNA and protein and as exhibiting an equivalent reduction in the specific activity of beta-pol. We measured BER activity by in vitro G:U mismatch and (8-OH)G:C repair and find that there is a significant reduction in the ability of extracts from beta-pol(+/-) mice to repair these types of DNA damage. In vivo, the beta-pol(+/-) mice sustain higher levels of DNA single-strand breaks as well as increased chromosomal aberrations as compared with beta-pol(+/+) littermates. Additionally, we show that reduction in beta-pol expression and BER activity results in increased mutagenicity of dimethyl sulfate as evidenced by a 2-fold increase in LacI mutation frequency. Importantly, the beta-pol(+/-) mice do not exhibit increased sensitivity to DNA damage induced by N-nitroso-N-ethylurea, ionizing radiation, or UV radiation, which induce damage processed by alternative repair pathways, demonstrating that this model is specifically a BER-deficient model.     

Position of the American Dietetic Association: food and nutrition misinformation

It is the position of the American Dietetic Association that food and nutrition misinformation can have harmful effects on the health and economic status of consumers. It is the role of nationally credentialed dietetics professionals to advocate for and promote sound, science-based nutrition information to the public, function as primary nutrition educators to health professionals, and actively counter and correct food and nutrition misinformation. The federal government has recognized the strong link between nutrition and health in recent years. Consumers are taking greater responsibility for self-care and are hungry for food and nutrition information, creating opportunities for nutrition misinformation, health fraud, and quackery to flourish. The media are consumers' leading source of nutrition information, but news reports rarely provide enough context for consumers to interpret the advice given. Promoters turn preliminary findings into sales pitches with baseless claims, often for the sole purpose of economic gain. Effective nutrition communication is consumer focused and presented with sufficient context to allow consumers to weigh the information and determine whether it applies to his or her unique needs. Nationally credentialed dietetics professionals are best prepared to communicate sound advice and scientific advances about nutrition. These dietetics professionals have a responsibility to take an active role in providing accurate, easily understood food and nutrition information, interpreting emerging research for media and consumers and encouraging consumers to look for credentialed dietetics professionals as nutrition experts.