Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. We report a genome-wide screen of 96 cases and 50 controls for polymorphisms associated with AMD. Among 116,204 single-nucleotide polymorphisms genotyped, an intronic and common variant in the complement factor H gene (CFH) is strongly associated with AMD (nominal P value <10(-7)). In individuals homozygous for the risk allele, the likelihood of AMD is increased by a factor of 7.4 (95% confidence interval 2.9 to 19). Resequencing revealed a polymorphism in linkage disequilibrium with the risk allele representing a tyrosine-histidine change at amino acid 402. This polymorphism is in a region of CFH that binds heparin and C-reactive protein. The CFH gene is located on chromosome 1 in a region repeatedly linked to AMD in family-based studies.

This article summarizes the new 2011 report on dietary requirements for calcium and vitamin D from the Institute of Medicine (IOM). An IOM Committee charged with determining the population needs for these nutrients in North America conducted a comprehensive review of the evidence for both skeletal and extraskeletal outcomes. The Committee concluded that available scientific evidence supports a key role of calcium and vitamin D in skeletal health, consistent with a cause-and-effect relationship and providing a sound basis for determination of intake requirements. For extraskeletal outcomes, including cancer, cardiovascular disease, diabetes, and autoimmune disorders, the evidence was inconsistent, inconclusive as to causality, and insufficient to inform nutritional requirements. Randomized clinical trial evidence for extraskeletal outcomes was limited and generally uninformative. Based on bone health, Recommended Dietary Allowances (RDAs; covering requirements of ≥97.5% of the population) for calcium range from 700 to 1300 mg/d for life-stage groups at least 1 yr of age. For vitamin D, RDAs of 600 IU/d for ages 1–70 yr and 800 IU/d for ages 71 yr and older, corresponding to a serum 25-hydroxyvitamin D level of at least 20 ng/ml (50 nmol/liter), meet the requirements of at least 97.5% of the population. RDAs for vitamin D were derived based on conditions of minimal sun exposure due to wide variability in vitamin D synthesis from ultraviolet light and the risks of skin cancer. Higher values were not consistently associated with greater benefit, and for some outcomes U-shaped associations were observed, with risks at both low and high levels. The Committee concluded that the prevalence of vitamin D inadequacy in North America has been overestimated. Urgent research and clinical priorities were identified, including reassessment of laboratory ranges for 25-hydroxyvitamin D, to avoid problems of both undertreatment and overtreatment.

It is well-recognized that young women with untreated premature ovarian failure (POF) are at increased risk of osteoporosis and bone fracture. Large, randomized trials have demonstrated that hormone replacement therapy with estrogen/progesterone in postmenopausal women can dramatically improve bone mineral density (BMD) and reduce fracture risk; however, there are little data on the effect of hormone replacement in young women with POF. At present, young women with POF are given either combined hormone replacement treatment or physiologic SSR (pSSR) consisting of combined transdermal estradiol and vaginal progesterone replacement regimens.This open-label, randomized controlled crossover pilot trial was designed to determine whether a regimen of pSSR could improve skeletal health among young women with POF caused by a variety of reasons. A total of 34 patients were randomized to receive a 4-week cycle of either pSSR (transdermal estradiol 100 g daily for week 1 and 150 g for weeks 2-4, with progesterone 200 mg twice daily for weeks 3-4) or standard hormone replacement therapy (sHRT) (oral ethinyl estradiol 30 g and norethisterone 1.5 mg daily for weeks 1-3, followed by 7 "pill-free" days for 12 months). Dual-energy x-ray absorptiometry was used to measure BMD at baseline and after each 12-month treatment period. During the study period, blood samples were collected for hormonal measurements and for markers of bone formation (bone alkaline phosphatase and procollagen type I aminoterminal propeptide) and bone resorption (CrossLaps [cross-linked C-terminal telopeptide of type I collagen]) before and after each washout period, and at 3, 6, and 12 months. Of the 34 women, 18 (mean age 27; range, 19-39 years) completed the study. LH (luteinizing hormone) and FSH (follicle-stimulating hormone) were decreased to a similar extent by both pSSR and sHRT. Treatment with pSSR increased the mean baseline lumbar spine BMD z-score by ϩ0.17 (95% confidence interval: ϩ0.07 to ϩ0.27; P ϭ 0.003), whereas there was no significant increase in response to sHRT (ϩ0.07, with a 95% confidence interval: Ϫ0.03 to ϩ0.18; P ϭ 0.2). During pSSR, the increment in lumbar spine BMD z-score was positively associated with estradiol (r ϭ ϩ0.49; P ϭ 0.04) and inversely associated with FSH (r ϭ Ϫ0.65; P ϭ 0.004). Both bone alkaline phosphatase and procollagen type I amino-terminal propeptide were increased significantly by pSSR ( ANOVA P Ͻ 0.001). In contrast, both of these bone formation markers were decreased by sHRT (P Ͻ 0.01). The bone resorption marker, CrossLaps, was suppressed by both regimens (P Ͻ 0.001). GYNECOLOGYVolume 66, Number 6 OBSTETRICAL AND GYNECOLOGICAL SURVEY

A proinflammatory cytokine genetic profile increases the risk of noncardia gastric adenocarcinoma but not other upper gastrointestinal cancers, possibly by inducing a hypochlorhydric and atrophic response to gastric H. pylori infection.

In this population, a few known risk factors account for a majority of esophageal and gastric cancers. These results suggest that the incidence of these cancers may be decreased by reducing the prevalence of smoking, gastroesophageal reflux, and being overweight and by increasing the consumption of fruits and vegetables.

A growing body of literature exists regarding the effects of beta-carotene and other carotenoids on chronic diseases in humans. This article reviews and critically evaluates this literature and identifies areas for further research. This review is restricted to studies in humans, with a major emphasis on the most recent literature in the area of carotenoids and selected cancers. Effects of carotenoids on cardiovascular diseases, photosensitivity diseases, cataracts, and age-related macular degeneration are also discussed briefly. Numerous observational studies have found that people who ingest more carotenoids in their diets have a reduced risk of several chronic diseases. However, intervention trials of supplemental beta-carotene indicate that supplements are of little or no value in preventing cardiovascular disease and the major cancers occurring in well-nourished populations, and may actually increase, rather than reduce, lung cancer incidence in smokers. As a consequence of these findings, some of the ongoing trials of beta-carotene and disease prevention have been terminated or have dropped beta-carotene from their interventions. Researchers should now seek explanations for the apparently discordant findings of observational studies vs. intervention trials. The most pressing research issues include studies of interactions of carotenoids with themselves and with other phytochemicals and mechanistic studies of the actions of beta-carotene in lung carcinogenesis and cardiovascular disease. Paradoxically, the finding that lung carcinogenesis and cardiovascular disease can be enhanced by supplemental beta-carotene may ultimately lead to a clearer understanding of the role of diet in the etiology and prevention of these diseases. The conclusion that major public health benefits could be achieved by increasing consumption of carotenoid-rich fruits and vegetables still appears to stand; however, the pharmacological use of supplemental beta-carotene for the prevention of cardiovascular disease and lung cancer, particularly in smokers, can no longer be recommended.

Because of the long lag time before risk of these tumors is reduced among ex-smokers, smoking may affect early stage carcinogenesis. The increase in smoking prevalence during the first two thirds of this century may be reflected in the rising incidence of these tumors in the past few decades among older individuals. The recent decrease in smoking may not yet have had an impact.

Background: Incidence rates have risen rapidly for esophageal adenocarcinoma and moderately for gastric cardia adenocarcinoma, while rates have remained stable for esophageal squamous cell carcinoma and have declined steadily for noncardia gastric adenocarcinoma. We examined anthropometric risk factors in a population-based casecontrol study of esophageal and gastric cancers in Connecticut, New Jersey, and western Washington. Methods: Healthy control subjects (n = 695) and case patients with esophageal squamous cell carcinoma or noncardia gastric adenocarcinoma (n = 589) were frequency-matched to case patients with adenocarcinomas of esophagus or gastric cardia (n = 554) by 5-year age groups, sex, and race (New Jersey only). Classification of cases by tumor site of origin and histology was determined by review of pathology materials and hospital records. Data were collected using in-person structured interviews. Associations with obesity, measured by body mass index (BMI), were estimated by odds ratios (ORs). All ORs were adjusted for geographic location, age, sex, race, cigarette smoking, and proxy response status. Results: The ORs for esophageal adenocarcinoma rose with increasing adult BMI. The magnitude of association with BMI was greater among the younger age groups and among nonsmokers. The ORs for gastric cardia adenocarcinoma rose moderately with increasing BMI. Adult BMI was not associated with risk