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Prior genome-wide association studies for oral clefts have focused on clinic-based samples with unclear generalizability. Prior samples were also small for investigating effects by cleft type and exclusively studied isolated clefts (those occurring without other birth defects). We estimated the effects of 17 top loci on cleft types in both isolated and nonisolated cases in the largest consortium to date of European-descent population-based studies. Our analytic approach focused on a mother-child dyad case-control design, but it also allowed analyzing mother-only or child-only genotypes to maximize power. Our total sample included 1,875 cases with isolated clefts, 459 cases with nonisolated clefts, and 3,749 controls. After correcting for multiple testing, we observed significant associations between fetal single-nucleotide polymorphisms (SNPs) at IRF6, PAX7, 8q21.3, 8q24, KIAA1598-VAX1, and MAFB and isolated cleft lip only (CLO) and cleft lip and palate (CLP). Significant associations were observed between isolated CLO and fetal SNPs near TPM1 and NOG1 and between CLP and fetal SNPs at ABCA4-ARHGAP29, THADA, FOXE1, and SPRY2. Overall, effects were similar for isolated CLO and CLP, except for ABCA4-ARHGAP29. A protective effect was observed for the fetal NOG1 SNP on cleft palate only, opposite in direction to the effect on CLO. For most fetal SNPs, a dose-response allelic effect was observed. No evidence of parent-of-origin or maternal genome effects was observed. Overall, effect direction and magnitude were similar between isolated and nonisolated clefts, suggesting that several loci are modifiers of cleft risk in both isolated and nonisolated forms. Our results provide reliable estimates of the effects of top loci on risks of oral clefts in a population of European descent. [ABSTRACT FROM AUTHOR]

Objective: We prospectively examined associations between intakes of antioxidants (vitamins C, vitamin E, and carotene) and cognitive function and decline among elderly men and women of the Cache County Study on Memory and Aging in Utah. Participants and Design: In 1995, 3831 residents 65 years of age or older completed a baseline survey that included a food frequency questionnaire and cognitive assessment, Cognitive function was assessed using an adapted version of the Modified Mini-Mental State examination (3MS) at baseline and at three subsequent follow-up interviews spanning approximately 7 years. Multivariable-mixed models were used to estimate antioxidant nutrient effects on average 3MS score over time. Results: Increasing quartiles of vitamin C intake alone and combined with vitamin E were associated with higher baseline average 3MS scores (p-trend = 0.013 and 0.02 respectively); this association appeared stronger for food sources compared to supplement or food and supplement sources combined. Study participants with lower levels of intake of vitamin C, vitamin E and carotene had a greater acceleration of the rate of 3MS decline over time compared to those with higher levels of intake. Conclusion: High antioxidant intake from food and supplement sources of vitamin C, vitamin E, and carotene may delay cognitive decline in the elderly. [ABSTRACT FROM AUTHOR]

Background: Sudden and unexplained death in sleep (SUDS) is a leading cause of death of young men in several Asian populations, but the history and epidemiology of SUDS are not well known.Methods: Autopsy records were reviewed in Manila in a study of the classification of SUDS. Death certificates filed in Manila during 1948-1982 were then reviewed in a study of SUDS incidence. A nested case-control study of death certificates examined birthplace as an indicator of SUDS risk.Results: The classification of SUDS cases in Manila during 1948-1982 (N = 722) evolved from the folk term, bangungut ('to rise and moan during sleep'), to various descriptions of post-mortem artefacts. The characteristics of victims in each of the groups were similar: 96% male, mean age 33 years, and modal time of death 3:00 a.m. The deaths were seasonal, peaking in December-January. SUDS victims were more likely than deceased controls to have been born outside of the Manila region (relative odds = 2.11; 95% CI: 1.59-2.78). The SUDS rate for men aged 25-44 years increased from 10.8 to 26.3 per 100000 person-years from 1948 to 1982.Conclusion: The death certificate classification of SUDS in Manila has changed considerably, obscuring an increase in incidence. SUDS appears to be a regional phenomenon in Southeast Asia and environmental causes are likely because the deaths are seasonal, increased over the timespan studied, and are more common among migrants to Manila than among those born there. [ABSTRACT FROM AUTHOR]

Tatsanavivat P (Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand), Chiravatkul A, Klungboonkrong V. Chaisiri S, Jarerntanyaruk L, Munger R G and Saowakontha S. Sudden and unexplained deaths in sleep (Iaitai) of young men in rural northeastern Thailand. 1992; 21: 904–910. Sudden and unexplained death in sleep (SUDS) is a significant cause of death of young adults in several Asian populations, but its distribution and incidence are not well known. We conducted a survey by mail of SUDS (known as ‘Iaitai’ in the local dialect) that occurred in adults during 1988–1989 in 3867 villages in northeastern Thailand with a total population of 5.42 million. Headmen of 2651 villages (68.6%) returned the questionnaire and sudden deaths of adults 20–49 years old were reported in 396 of these villages. The validity of reports was assessed by interviewing next of kin and witnesses in a sample of 92 villages reporting sudden deaths; 60 of 127 reports of SUDS from these villages were verified (47.2%). Officials and villagers in seven villages that did not respond to the questionnaire were also interviewed and no cases of sudden death were found. The verified SUDS victims were all men wth a mean age of 35.9 years (SD 7.8). A family history of SUDS was reported in 40.3% of index cases and 18.3% had brothers who had died similarly; no such deaths were reported among sisters. The estimated annual rate of death from SUDS among men 20–49 years was 25.9 per 100000 person years (95% confidence interval (CI) : 21.0–30.7). The sudden deaths were seasonal with 38% occurring during March-May and 10% during September-October ( = 9.45, = 0.02). Sudden death in sleep is a leading cause of death of young men in rural northeastern Thailand and the characteristics of Thai victims are similar to those of other Asian victims of this unexplained syndrome. [ABSTRACT FROM PUBLISHER]

The birth prevalence of orofacial clefts, one of the most common congenital anomalies, is approximately one in 700 live births, but varies with geography, ethnicity, and socio-economic status. There is a variation in infant mortality and access to care both between and within countries, so some clefts remain unrepaired into adulthood. Quality of care also varies, and even among repaired clefts there is residual deformity and morbidity that significantly affects some children. The two major issues in attempts to address these inequalities are (a) etiology/possibilities for prevention and (b) management and quality of care. For prevention, collaborative research efforts are required in developing countries, in line with the WHO approach to implement the recommendations of the 2008 Millennium Development Goals (www.un.org/millenniumgoals). This includes the "common risk factor" approach, which analyzes biological and social determinants of health alongside other chronic health problems such as diabetes and obesity, as outlined in the Marmot Health inequalities review (2008) (www.ucl.ac.uk/gheg/marmotreview). Simultaneously, orofacial cleft research should involve clinical researchers to identify inequalities in access to treatment and identify the best interventions for minimizing mortality and residual deformity. The future research agenda also requires engagement with implementation science to get research findings into practice.

Background: Before its recognition, infantile beriberi was the leading cause of infant death in camps for displaced persons of the Karen ethnic minority on Thailand's western border., Objective: This study aimed to document thiamine status in the peripartum period to examine the current supplementation program and the correlation between the clinical manifestations of thiamine deficiency and a biochemical measure of thiamine status., Design: Women were enrolled prospectively at 30 wk of gestation and were followed up weekly until delivery and at 3 mo postpartum. Thiamine supplementation during pregnancy was based on patient symptoms., Results: At 3 mo postpartum, thiamine deficiency reflected by an erythrocyte transketolase activity (ETKA) > or = 1.20% was found in 57.7% (15/26) of mothers, 26.9% (7/26) of whom had severe deficiency (ETKA > 1.25%). No significant associations between ETKA and putative maternal symptoms or use of thiamine supplements were found., Conclusions: Biochemical postpartum thiamine deficiency is still common in Karen refugee women. This situation may be improved by educating lactating women to reduce their consumption of thiaminase-containing foods and by implementing an effective thiamine supplementation program.

Previous studies suggest that the relationship between genes and nonsyndromic cleft lip +/- cleft palate (CLP) or cleft palate only (CP) may be modified by the environment. Using data from a population-based case-control study, we examined allelic variants for three genes, i.e., transforming growth factor alpha (TGFA), transforming growth factor beta 3 (TGFB3), and Msh (Drosophila) homeobox homolog 1 (MSX1), and their interactions with two exposures during pregnancy (maternal cigarette smoking and alcohol consumption) as risk factors for CLP and CP. For each cleft phenotype, risk estimates associated with most allelic variants tended to be near unity. Risk estimates for maternal smoking (> or = 10 cigarettes/day) were significantly elevated for CP and were most elevated among infants with allelic variants at the TGFB3 or MSX1 sites. By comparison, risk estimates for maternal alcohol consumption (> or = 4 drinks/month) were significantly elevated for CLP and were most elevated among infants with allelic variants at the MSX1 site. Our results suggest that development of CLP and CP may be influenced independently by maternal exposures but more significantly by interaction of such exposures and specific allelic variants.

Background: The role of dietary protein intake in osteoporosis remains controversial. Protein is an important structural component of bone and protein supplementation improves the medical outcome of hip fracture patients, but it is unknown whether protein intake can reduce the incidence risk of hip fracture., Objective: The relation between intake of protein and other nutrients and subsequent incidence of hip fracture was evaluated., Design: Nutrient intake was assessed with a food-frequency questionnaire in a cohort of Iowa women aged 55-69 y at baseline in 1986. Incident hip fractures were ascertained through follow-up questionnaires mailed to participants in 1987 and 1989 and verified by physician reports., Results: Forty-four cases of incident hip fractures were included in the analyses of 104338 person-years (the number of subjects studied times the number of years of follow-up) of follow-up data. The risk of hip fracture was not related to intake of calcium or vitamin D, but was negatively associated with total protein intake. Animal rather than vegetable sources of protein appeared to account for this association. In a multivariate model with inclusion of age, body size, parity, smoking, alcohol intake, estrogen use, and physical activity, the relative risks of hip fracture decreased across increasing quartiles of intake of animal protein as follows: 1.00 (reference), 0.59 (95% CI: 0.26, 1.34), 0.63 (0.28, 1.42), and 0.31 (0.10, 0.93); P for trend = 0.037., Conclusion: Intake of dietary protein, especially from animal sources, may be associated with a reduced incidence of hip fractures in postmenopausal women.

The use of a comprehensive follow-up strategy to limit non-participation bias was evaluated in a population-based case-control study of orofacial clefts. Birth parents were requested to provide exposure data, and index children and parents were asked to provide blood specimens. Follow-up included telephone or postal reminders every two weeks for up to three months. Consent to participate was received from 281 (76.6%) case mothers and 246 (72.4%) case fathers. The corresponding totals for controls were 279 (54.7%) and 245 (49.8%). Evaluation of participation rates by intensity of follow-up showed that 23% of case and 18% of control families consented without reminders (first stage); 81% of cases and 83% of controls agreed following one or two reminders (second stage); and the remainder of participants consented following three or more reminders (final stage). Cumulative distributions of sociodemographic characteristics differed little between second and final stage participants. Odds ratios for maternal multivitamin use were similar between second and final stage participants, whereas those for maternal and paternal smoking tended to decline. Although follow-up measures were necessary to enroll most families, use of more than two reminders did not appear to increase the representativeness of the sample; however, termination of recruitment after only two reminders would have led to different conclusions. Future studies require data collection protocols that encourage participation from all population subgroups, and one alternative is presented.

Maternal alcohol use during pregnancy is a known cause of birth defects associated with the fetal alcohol syndrome, but its role in more common, isolated, craniofacial birth defects is not well understood. A population-based, case-control study of orofacial clefts was conducted in Iowa using births during 1987-1991. Cases were identified by the Iowa Birth Defects Registry and classified as having a cleft lip with or without cleft palate (CLP) or cleft palate only (CP) and whether the cleft was isolated or occurred with other birth defects. Controls were selected from normal Iowa births. Maternal alcohol use during pregnancy was classified according to self-reported drinks consumed per month. Results are based on 302 controls and the following numbers in each case group: 118 isolated CLP, 56 isolated CP, 51 CLP with multiple defects, and 62 CP with multiple defects. Compared to women who did not drink alcohol during pregnancy, the relative odds of isolated CLP rose with increasing level of maternal drinking as follows: 1-3 drinks per months, 1.5; 4-10 drinks per month, 3.1; more than 10 drinks per month, 4.7 (chi-square test for trend, P = 0.003). Adjustment for maternal smoking, vitamin use, education, and household income did not substantially alter these results. No significant association was found between alcohol use and isolated cleft palate or clefts in children with multiple birth defects. Alcohol use during pregnancy may be a cause of isolated cleft lip with or without cleft palate.

Genetic analysis and tissue-specific expression studies support a role for transforming growth-factor alpha (TGFA) in craniofacial development. Previous studies have confirmed an association of alleles for TGFA with nonsyndromic cleft lip with or without cleft palate (CL/P) in humans. We carried out a retrospective association study to determine whether specific allelic variants of the TGFA gene are also associated with cleft palate only (CPO). The PCR products from 12 overlapping sets of primers to the TGFA cDNA were examined by using single-strand conformational polymorphism analysis. Four DNA polymorphic sites for TGFA were identified in the 3' untranslated region of the TGFA gene. These variants, as well as previously identified RFLPs for TGFA, were characterized in case and control populations for CPO by using chi 2 analysis. A significant association between alleles of TGFA and CPO was identified which further supports a role for this gene as one of the genetic determinants of craniofacial development. Sequence analysis of the variants disclosed a cluster of three variable sites within 30 bp of each other in the 3' untranslated region previously associated with an antisense transcript. These studies extend the role for TGFA in craniofacial morphogenesis and support an interrelated mechanism underlying nonsyndromic forms of CL/P.

Objective: To test the hypothesis that history of blood transfusion is associated with an increased incidence of cancer in older women., Design: Prospective cohort study., Setting: General community in the state of Iowa., Participants: Random sample of 37,337 cancer-free Iowa women ages 55 to 69 years., Measurements: Transfusion history was assessed with a mailed questionnaire completed in January 1986. Cancer incidence in 5 years was ascertained by a population-based cancer registry., Results: Women who had ever received a blood transfusion were at an increased risk for non-Hodgkin lymphoma (relative risk (RR) = 2.20; 95% CI, 1.35 to 3.58) and kidney cancer (RR = 2.53; CI, 1.34 to 4.78). The relative risks for these cancers were greater with decreasing time from first transfusion. No increased risk occurred for cancers of the breast, lung, uterine corpus, ovary, pancreas, colon, rectum, skin (melanoma), or for all cancers considered together., Conclusion: These findings suggest that previous blood transfusion may be a risk factor for non-Hodgkin lymphoma and kidney cancer but is not associated with the most common neoplasms.

Background: Although the results of animal studies and cross-cultural comparisons generally support a role for dietary fat in the etiology of breast cancer, results of analytic epidemiology studies are equivocal., Purpose: The association between dietary fat and subsequent breast cancer was examined in a cohort of 34,388 postmenopausal women from Iowa., Methods: Dietary habits were assessed by a food-frequency questionnaire mailed in January 1986. Through December 31, 1989, 459 incident cases of breast cancer occurred in this cohort. Proportional hazards regression was used to examine the dietary fat-breast cancer association while adjusting for potential confounders. The effects on this association of four analytic approaches to adjustment for energy intake were also considered., Results: After adjustment for known determinants of breast cancer, a modest positive association of total fat intake with risk of breast cancer was seen. Polyunsaturated fat intake was also positively associated with breast cancer (relative risk from lowest to highest intake, 1.0, 1.25, 1.31, and 1.49; P for trend = .052). Different approaches to adjustment for energy intake, however, provided different impressions of the dietary fat-breast cancer association. One method, involving categorization of crude fat intake and inclusion of total energy intake in regression analysis, gave relative risk estimates from low to high fat intake of 1.0, 1.17, 1.25, and 1.38 (P for trend = .18). Another method, based on categorization of fat intake residuals in which the variation in fat due to total energy intake was removed, gave corresponding estimates of 1.0, 1.24, 1.30, and 1.16 (P for trend = .29). The former suggests increasing breast cancer risk with increasing fat intake; the latter suggests no association., Conclusions: These results are consistent with other cohort studies that have shown a weak association or no association between dietary fat and breast cancer. They are also consistent with studies suggesting that fat intake is a determinant of breast cancer, particularly after accounting for inaccuracies in dietary assessment. The effects of different energy-adjustment methods may account in part for the varying interpretations of four previous cohort studies of dietary fat and breast cancer., Implications: Further work is needed to clarify not only the nature of the dietary fat-breast cancer association, but also the impact of different analytic methods used in the investigation of diet-disease associations.

Sudden death in sleep occurs in substantial numbers among young men in South-East Asia. The frequencies of electrocardiographic abnormalities were measured in groups with varying risks of such sudden death. The mean heart-rate-corrected QT interval (QTc) was significantly (p less than 0.05) greater among 123 Laotian refugees in Thailand at high risk (405 [95% confidence interval 397-413] ms) than in 77 Laotian refugees in the United States at lower risk (364 [359-369] ms) and 199 non-Asian US residents at negligible risk (358 [354-362] ms). Among refugees in Thailand, prolonged QTc interval was associated with poor thiamine status and a history of seizure-like episodes in sleep. Thiamine deficiency may be a cause of prolonged QT interval and sudden death in this region.

To examine the relationship of fish intake with serum fatty acids cross-culturally, we surveyed a total of 136 men aged 34 to 55 years in four different populations: rural Japanese (RJ), urban Japanese (UJ), Japanese Americans (JA), and Caucasian Americans (CA). Mean levels of estimated total fish intake per day were 124.9 g in RJ, 70.8 g in UJ, 45.7 g in JA, and 32.3 g in CA. The percentage of total serum fatty acids contributed by omega-3 polyunsaturated fatty acids in these populations was 11.8% in RJ, 9.0% in UJ, 3.4% in JA and 2.5% in CA. Means of omega-3 fatty acids and intake of fish were correlated at the population level; this relationship was strongest when intake of dark-meat fish was considered (n = 4, r = 0.979, p = 0.02). Within each population, except for UJ, individual omega-3 fatty acid levels and dark-meat fish intake were significantly associated (p less than 0.05). A 20 g increase in dark-meat fish consumption was associated with an estimated relative increase in omega-3 fatty acid content of serum by 0.76% in RJ, 0.75% in UJ, 0.64% in JA, and 0.22% in CA. The association between fish intake and serum omega-3 fatty acids at the individual level was not explained by other coronary risk factors. Mortality from coronary heart disease is much lower in Japan than in the US. Population differences in fish intake and serum omega-3 fatty acid levels may contribute to the population difference in the risk of coronary heart disease.

To study the possible role of plastic embedding in the surgical pathologic diagnosis of Pneumocystis carinii pneumonia, bronchial biopsy specimens from five patients with AIDS were examined using 0.9 micron thick methacrylate sections stained with silver methenamine borate and counterstained with toluidine blue. This technique was found to be superior to paraffin embedding in the demonstration of the fine structural details of both Pneumocystis and the surrounding lung tissue. This method permitted the simultaneous demonstration of both the cyst wall and intracystic sporozoites of Pneumocystis in biopsy tissue, which had been previously possible only by using electron microscopy. This technique assists in the differentiation of Pneumocystis from other opportunistic agents, and may be useful in estimating the relative numbers of cyst and sporozoite forms of the organism. We recommend that bronchoscopic and open lung biopsies from AIDS patients suspected of having Pneumocystis pneumonia be submitted for plastic embedding and high-resolution light microscopy.