Evidence of Antineutrinos from Distant Reactors Using Pure Water at SNO.

The SNO+ Collaboration reports the first evidence of reactor antineutrinos in a Cherenkov detector. The nearest nuclear reactors are located 240 km away in Ontario, Canada. This analysis uses events with energies lower than in any previous analysis with a large water Cherenkov detector. Two analytical methods are used to distinguish reactor antineutrinos from background events in 190 days of data and yield consistent evidence for antineutrinos with a combined significance of 3.5σ.

Nurse and patient characteristics predict communication about complementary and alternative medicine.

BACKGROUND: The aim of this study was to identify nurse factors (eg, knowledge, practices, and clinical habits regarding complementary and alternative medicine [CAM] as well as demographic factors) and patient characteristics (eg, age, sex, and treatment status) associated with nurses' CAM inquiry and referral patterns. METHODS: Baseline data were collected with nurse/patient questionnaires about CAM use and knowledge as part of a multicenter CAM educational clinical trial. Frequencies and nested regression models were used to assess predictors of nurses' inquiries about and referral to CAM therapies. RESULTS: Six hundred ninety-nine patients participated in the study. For patients, female sex (odds ratio [OR], 1.50; P = .019) and cancer recurrence (OR, 1.45; P = .05) were predictive of nurses' inquiries about and referral to CAM therapies. A total of 175 nurses with a mean age of 45 years and a mean experience of 20 years participated; 79% were staff nurses, and 11% were nurse practitioners. Fifty-three percent asked at least 1 of their last 5 patients about CAM use; 42% referred patients to CAM therapy. Nurses who reported being "somewhat comfortable" (OR, 2.70; P = .0001) or "very comfortable" (OR, 3.88; P < .0001) about discussing CAM, self-reported use of massage (OR, 2.20; P < .0001), and had formal CAM education (OR, 4.14; P = .0001) were more likely to ask about CAM use. Nurses who reported being "somewhat comfortable" (OR, 2.54; 95% confidence interval, 1.47-4.41; P = .0008) or "very comfortable" (OR, 7.46; P < .00001) and had formal CAM education (OR, 2.96; P < .0001) were also more likely to refer patients to CAM therapies. CONCLUSIONS: Both patient and nurse characteristics were associated with discussions about CAM. Oncology institutions that prioritize evidence-based medicine should consider introducing CAM education to their nursing staff. Cancer 2016;122:1552-9. © 2016 American Cancer Society.

Cyclooxygenase-2 expression in non-metastatic triple-negative breast cancer patients.

Triple-negative breast cancer (TNBC) is characterised by lack of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER)2/neu gene amplification. TNBC patients typically present at a younger age, with a larger average tumor size, higher grade and higher rates of lymph node positivity compared to patients with ER/PR-positive tumors. Cyclooxygenase (COX)-2 regulates the production of prostaglandins and is overexpressed in a variety of solid tumors. In breast cancer, the overexpression of COX-2 is associated with indicators of poor prognosis, such as lymph node metastasis, poor differentiation and large tumor size. Since both TNBC status and COX-2 overexpression are known poor prognostic markers in primary breast cancer, we hypothesized that the COX-2 protein is overexpressed in the primary tumors of TNBC patients. The purpose of this study was to determine whether there exists an association between TNBC status and COX-2 protein overexpression in primary breast cancer. We prospectively evaluated COX-2 expression levels in primary tumor samples obtained from 125 patients with stage I-III breast cancer treated between February, 2005 and October, 2007. Information on clinicopathological factors was obtained from a prospective database. Baseline tumor characteristics and patient demographics were compared between TNBC and non-TNBC patients using the Chi-square and Fisher's exact tests. In total, 60.8% of the patients were classified as having ER-positive tumors, 51.2% were PR-positive, 14.4% had HER-2/neu amplification and 28.0% were classified as TNBC. COX-2 overexpression was found in 33.0% of the patients. TNBC was associated with COX-2 overexpression (P=0.009), PR expression (P=0.048) and high tumor grade (P=0.001). After adjusting for age, menopausal status, body mass index (BMI), lymph node status and neoadjuvant chemotherapy (NACT), TNBC was an independent predictor of COX-2 overexpression (P=0.01). In conclusion, the association between TNBC and COX-2 overexpression in operable breast cancer supports further investigation into COX-2-targeted therapy for patients with TNBC.

Associations between dietary intake of choline and betaine and lung cancer risk.

Evidence from human and animal research indicates that choline metabolic pathways may be activated during a variety of diseases, including cancer. We report results of a case-control study of 2821 lung cancer cases and 2923 controls that assessed associations of choline and betaine dietary intakes with lung cancer. Using multivariable logistic regression analyses, we report a significant association between higher betaine intake and lower lung cancer risk that varied by smoking status. Specifically, no significant association was observed between betaine intake and lung cancer among never-smokers. However, higher betaine intake was significantly associated with reduced lung cancer risk among smokers, and the protective effect was more evident among current than former smokers: for former and current smokers, the ORs (95% CI) of lung cancer for individuals with highest as compared to lowest quartiles of intake were 0.70(0.55-0.88) and 0.51(0.39-0.66) respectively. Significant linear trend of higher betaine intake and lower lung cancer risk was observed among both former (p(trend) = 0.002) and current (p(trend)<0.0001) smokers. A similar protective effect was also observed with choline intake both in overall analysis as well as among current smokers, with p-values for chi-square tests being 0.001 and 0.004 respectively, but the effect was less evident, as no linear trend was observed. Our results suggest that choline and betaine intake, especially higher betaine intake, may be protective against lung cancer through mitigating the adverse effect of smoking.

Temporal strategy and performance during a fatiguing short-cycle repetitive task.

This study investigated temporal changes in movement strategy and performance during fatiguing short-cycle work. Eighteen participants performed six 7-min work blocks with repetitive reaching movements at 0.5 Hz, each followed by a 5.5-min rest break for a total duration of 1 h. Electromyography (EMG) was collected continuously from the upper trapezius muscle, the temporal movement strategy and timing errors were obtained on a cycle-to-cycle basis, and perceived fatigue was rated before and after each work block. Clear signs of fatigue according to subjective ratings and EMG manifestations developed within each work block, as well as during the entire hour. For most participants, timing errors gradually increased, as did the waiting time at the near target. Changes in temporal movement strategy were negatively correlated with changes in the level and variability of EMG, suggesting that an adaptive temporal strategy offset the development of unstable motor solutions in this fatiguing, short-cycle work. PRACTITIONER SUMMARY: Sustained performance of operators is essential to maintain competitiveness. In this study of repetitive work, participants gradually changed their temporal movement strategy, for possibly alleviating the effects of fatigue. This suggests that in order to effectively counteract fatigue and sustain performance, industrial production should allow extensive spatial and temporal flexibility.

The association of variants in the FTO gene with longitudinal body mass index profiles in non-Hispanic white children and adolescents.

OBJECTIVE: To investigate possible age-related changes in associations between polymorphisms in the fat mass and obesity-associated (FTO) gene and higher body mass index (BMI). DESIGN AND SUBJECTS: Multilevel mixed regression models were used to examine associations between four FTO variants and longitudinal BMI profiles in non-Hispanic white and African American children and adolescents 8-17 years of age from two different longitudinal cohort studies, the Bogalusa Heart Study (BHS) and Project HeartBeat! (PHB). In the BHS, there were 1551 examinations of 478 African Americans and 3210 examinations of 1081 non-Hispanic whites; in PHB, there were 971 examinations of 131 African Americans and 4458 examinations of 505 non-Hispanic whites. RESULTS: In African Americans, no significant FTO associations with BMI were found. In non-Hispanic whites, linkage disequilibrium among all four variants made haplotype analysis superfluous, so we focused on the single-nucleotide polymorphism, rs9939609. In longitudinal multilevel models, the A/A genotype of rs9939609 was associated with higher BMI in non-Hispanic whites in both cohorts at all ages. A significant age-by-genotype interaction found only in the BHS cohort predicted that in those with the A/A genotype, BMI would be ∼0.7 kg m(-2) higher at age 8 and ∼1.6 kg m(-2) higher at age 17 than in those with A/T or T/T genotypes. The design of PHB limited follow-up of any single individual to 4 years, and may have reduced the ability to detect any age-by-genotype interaction in this cohort. CONCLUSIONS: The A/A genotype of rs9939609 in the FTO gene is associated with higher longitudinal BMI profiles in non-Hispanic whites from two different cohorts. The association may change with age, with the A/A genotype being associated with a larger BMI difference in late adolescence than in childhood, though this was observed only in the BHS cohort and requires verification.

A magnetically driven piston pump for ultra-clean applications.

A magnetically driven piston pump for xenon gas recirculation is presented. The pump is designed to satisfy extreme purity and containment requirements, as is appropriate for the recirculation of isotopically enriched xenon through the purification system and large liquid xenon time projection chamber of EXO-200. The pump, using sprung polymer gaskets, is capable of pumping more than 16 standard liters per minute of xenon gas with 750 Torr differential pressure.

Genome-wide association and meta-analysis in populations from Starr County, Texas, and Mexico City identify type 2 diabetes susceptibility loci and enrichment for expression quantitative trait loci in top signals.

AIMS/HYPOTHESIS: We conducted genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) analyses to identify and characterise risk loci for type 2 diabetes in Mexican-Americans from Starr County, TX, USA. METHOD: Using 1.8 million directly interrogated and imputed genotypes in 837 unrelated type 2 diabetes cases and 436 normoglycaemic controls, we conducted Armitage trend tests. To improve power in this population with high disease rates, we also performed ordinal regression including an intermediate class with impaired fasting glucose and/or glucose tolerance. These analyses were followed by meta-analysis with a study of 967 type 2 diabetes cases and 343 normoglycaemic controls from Mexico City, Mexico. RESULT: The top signals (unadjusted p value <1 × 10(-5)) included 49 single nucleotide polymorphisms (SNPs) in eight gene regions (PER3, PARD3B, EPHA4, TOMM7, PTPRD, HNT [also known as RREB1], LOC729993 and IL34) and six intergenic regions. Among these was a missense polymorphism (rs10462020; Gly639Val) in the clock gene PER3, a system recently implicated in diabetes. We also report a second signal (minimum p value 1.52 × 10(-6)) within PTPRD, independent of the previously implicated SNP, in a population of Han Chinese. Top meta-analysis signals included known regions HNF1A and KCNQ1. Annotation of top association signals in both studies revealed a marked excess of trans-acting eQTL in both adipose and muscle tissues. CONCLUSIONS/INTERPRETATION: In the largest study of type 2 diabetes in Mexican populations to date, we identified modest associations of novel and previously reported SNPs. In addition, in our top signals we report significant excess of SNPs that predict transcript levels in muscle and adipose tissues.

Diameter and compliance of the greater saphenous vein - effect of age and nitroglycerine.

OBJECTIVES: The greater saphenous vein (GSV) is commonly used in autologous vein graft surgery. GSV diameter has proven to influence graft patency, and furthermore venous compliance might be of importance. The purpose of the study was to evaluate the effect of age on GSV diameter and compliance, and to evaluate the effect of nitroglycerine (NTG). METHODS: The diameter and compliance of the GSV, with and without NTG, were examined with B-mode ultrasound in 12 elderly (70·3 ± 1·2 year) and 15 young (25·1 ± 0·6 year) men. The GSV diameter at the thigh and calf level was measured at rest, after 6 min of venous stasis (60 mmHg) and after NTG administration. Pressure-area curves during a linear venous pressure decrease were produced. Venous compliance was calculated using the quadratic regression equation (area) = ß(0) + ß(1) (cuff pressure) + ß(2) (cuff pressure)(2) . RESULTS: GVS diameter between the groups showed significant lower diameter in elderly compared to young men (P<0·05). Venous occlusion increased GSV diameter in elderly men (P<0·01) as well as young men (P<0·001). NTG increased GSV diameter in elderly men (P<0·01) with an equal trend in young men. During venous occlusion, after administration of NTG, GSV diameter increased further in both elderly (P<0·01) and young men (P<0·001). GSV compliance was decreased in elderly (ß(1) , 0·037 ± 0019, ß(2,) -0·000064 ± 00017) versus young men (ß(1) , 0·128 ± 0·013, ß(2) , -0·00010 ± 000018) [P<0·001 (ß(1) ), P<0·02 (ß(2) )]. CONCLUSIONS: Baseline GSV diameter as well as GSV compliance is decreased in elderly men compared to the young subjects. As reduced GSV diameter as well as reduced compliance is related to decreased graft patency, these findings might be of importance for the uses of GSV as graft material in cardiovascular bypass surgery. The clinical value has to be clarified in future studies.

A simple radionuclide-driven single-ion source.

We describe a source capable of producing single barium ions through nuclear recoils in radioactive decay. The source is fabricated by electroplating (148)Gd onto a silicon α-particle detector and vapor depositing a layer of BaF(2) over it. (144)Sm recoils from the alpha decay of (148)Gd are used to dislodge Ba(+) ions from the BaF(2) layer and emit them in the surrounding environment. The simultaneous detection of an α particle in the substrate detector allows for tagging of the nuclear decay and of the Ba(+) emission. The source is simple, durable, and can be manipulated and used in different environments. We discuss the fabrication process, which can be easily adapted to emit most other chemical species, and the performance of the source.

Identification of Diabetic Retinopathy Genes through a Genome-Wide Association Study among Mexican-Americans from Starr County, Texas.

To identify genetic loci for severe diabetic retinopathy, 286 Mexican-Americans with type 2 diabetes from Starr County, Texas, completed physical examinations including fundus photography for diabetic retinopathy grading. Individuals with moderate-to-severe non-proliferative and proliferative diabetic retinopathy were defined as cases. Direct genotyping was performed using the Affymetrix GeneChip Human Mapping 100 K Set, and SNPs passing quality control criteria were used to impute markers available in HapMap Phase III Mexican population (MXL) in Los Angeles, California. Two directly genotyped markers were associated with severe diabetic retinopathy at a P-value less than .0001: SNP rs2300782 (P = 6.04 × 10(-5)) mapped to an intron region of CAMK4 (calcium/calmodulin-dependent protein kinase IV) on chromosome 5, and SNP rs10519765 (P = 6.21 × 10(-5)) on chromosomal 15q13 in the FMN1 (formin 1) gene. Using well-imputed markers based on the HapMap III Mexican population, we identified an additional 32 SNPs located in 11 chromosomal regions with nominal association with severe diabetic retinopathy at P-value less than .0001. None of these markers were located in traditional candidate genes for diabetic retinopathy or diabetes itself. However, these signals implicate genes involved in inflammation, oxidative stress and cell adhesion for the development and progression of diabetic retinopathy.

The relationship between birthweight and longitudinal changes of blood pressure is modulated by beta-adrenergic receptor genes: the Bogalusa Heart Study.

This study examines the genetic influence of beta-adrenergic receptor gene polymorphisms (beta(2)-AR Arg16Gly and beta(3)-AR Trp64Arg) on the relationship of birthweight to longitudinal changes of blood pressure (BP) from childhood to adulthood in 224 black and 515 white adults, aged 21-47 years, enrolled in the Bogalusa Heart Study. Blacks showed significantly lower birthweight and frequencies of beta(2)-AR Gly16 and beta(3)-AR Trp64 alleles and higher BP levels and age-related trends than whites. In multivariable regression analyses using race-adjusted BP and birthweight, low birthweight was associated with greater increase in age-related trend of systolic BP (standardized regression coefficient beta = -0.09, P = .002) and diastolic BP (beta = -0.07, P = .037) in the combined sample of blacks and whites, adjusting for the first BP measurement in childhood, sex, age, and gestational age. Adjustment for the current body mass index strengthened the birthweight-BP association. Importantly, the strength of the association, measured as regression coefficients, was modulated by the combination of beta(2)-AR and beta(3)-AR genotypes for systolic (P = .042 for interaction) and diastolic BP age-related trend (P = .039 for interaction), with blacks and whites showing a similar trend in the interaction. These findings indicate that the intrauterine programming of BP regulation later in life depends on beta-AR genotypes.

Day 1 multiple organ dysfunction syndrome is associated with poor functional outcome and mortality in the pediatric intensive care unit.

OBJECTIVE: The epidemiology and outcomes of multiple organ dysfunction syndrome (MODS) are incompletely characterized in the pediatric population due to small sample size and conflicting diagnoses of organ failure. We sought to describe the epidemiology and outcomes of early MODS in a large clinical database of pediatric intensive care unit (PICU) patients based on consensus definitions of organ failure. DESIGN: Retrospective analysis of a contemporaneously collected clinical PICU database. SETTING: Virtual Pediatric Intensive Care Unit Performance System database patient admissions from January 2004 to December 2005 for 35 U.S. children's hospitals. PATIENTS: : We evaluated 63,285 consecutive PICU admissions from January 2004 to December 2005 in the Virtual Pediatric Intensive Care Unit Performance System database. We excluded patients younger than 1 month or older than 18 years of age, and hospitals with >10% missing values for MODS variables. We identified day 1 MODS by International Pediatric Sepsis Consensus Conference criteria with day 1 laboratory and vital sign values. We evaluated functional status using Pediatric Overall Performance Category and Pediatric Cerebral Performance Category scores from PICU admission and discharge. ANALYSIS: Student's t test, chi-square test, Mann-Whitney rank sum, Kruskal-Wallis, and linear and logistic regression. MEASUREMENTS AND MAIN RESULTS: We analyzed 44,693 admissions from 28 hospitals meeting inclusion criteria. Overall PICU mortality was 2.8%. We identified day 1 MODS in 18.6% of admissions. Patients with day 1 MODS had higher mortality (10.0% vs. 1.2%, p < .001), longer PICU length of stay (3.6 vs. 1.3 days, p < .001), and larger change from baseline Pediatric Overall Performance Category and Pediatric Cerebral Performance Category scores at time of PICU discharge (p < .001). Infants had the highest incidence of day 1 MODS (25.2% vs. 16.5%, p < .001) compared with other age groups. CONCLUSIONS: Using the largest clinical dataset to date and consensus definitions for organ failure, we found that children with MODS present on day 1 of intensive care unit admission have worse functional outcomes, higher mortality, and longer PICU length of stay than children who do not have MODS on day 1. Infants are disproportionally affected by MODS.

Assessment of 193 candidate genes for retinopathy in African Americans with type 1 diabetes.

OBJECTIVE: To report in African Americans with type 1 diabetes the association of single-nucleotide polymorphisms in 193 candidate genes with diabetic retinopathy (DR) and/or its progression. METHODS: A custom panel of 1536 single-nucleotide polymorphisms located on 193 candidate genes for DR was genotyped in 437 African Americans with type 1 diabetes who participated in the New Jersey 725 study. Clinical evaluations at baseline and follow-up examinations included structured clinical interview, ocular examination, 7-field stereoscopic fundus photographs, and blood pressure measurements. Severity of DR was determined via masked grading of fundus photographs. Biological evaluations included blood and urine assays. RESULTS: Single-nucleotide polymorphisms in 13 candidate genes for DR involved in glucose metabolism, angiogenesis, inflammation, neurotransmission, hypertension, and retinal development were significantly associated with the prevalence of severe DR. Three of these genes were also significantly associated with progression of DR. Adjusting for sex, duration of diabetes, glycosylated hemoglobin, systemic hypertension, and total cholesterol did not alter the results. CONCLUSIONS: Our data support the role of genetic factors to account for severity and/or progression of DR in African Americans with type 1 diabetes and to identify several prime genes that likely contribute to the risk of DR.

Adverse association between diabetic retinopathy and cardiac structure and function.

BACKGROUND: Recent work has demonstrated a link between retinopathy, a marker of microvascular disease, and the development of heart failure, a finding particularly relevant in individuals with diabetes. Our objective was to assess the relationship between retinopathy and cardiac structure and function in a cohort of individuals with type 2 diabetes mellitus. METHODS: Stereoscopic fundus photography of 7 standard fields was obtained in 531 Mexican American adults with type 2 diabetes mellitus recruited as sibships from Starr County, Texas. Retinopathy was centrally scored and classified as no retinopathy, early nonproliferative diabetic retinopathy, moderate to severe nonproliferative diabetic retinopathy, or proliferative diabetic retinopathy. Echocardiography was used to assess cardiac structure and function. Multilevel mixed models were used to assess associations of clinical and echocardiographic variables with retinopathy while accounting for correlations among siblings. RESULTS: More severe diabetic retinopathy was associated with the presence of hypertension, previous cardiovascular disease, longer duration of diabetes, elevated glycosylated hemoglobin, and greater albuminuria. With worsening severity of diabetic retinopathy, left ventricular (LV) mass and left atrial dimension increased, and LV ejection fraction and LV fractional shortening decreased, independent of potential confounding variables. CONCLUSIONS: More severe diabetic retinopathy was associated with worse cardiac structure and function by echocardiography independent of potential confounding variables. These data suggest a possible microvascular contribution to the development of diabetes-associated cardiac enlargement and dysfunction. Alternatively, common pathways may be leading to both disorders.

Genome-wide linkage and admixture mapping of type 2 diabetes in African American families from the American Diabetes Association GENNID (Genetics of NIDDM) Study Cohort.

OBJECTIVE: We used a single nucleotide polymorphism (SNP) map in a large cohort of 580 African American families to identify regions linked to type 2 diabetes, age of type 2 diabetes diagnosis, and BMI. RESEARCH DESIGN AND METHODS: After removing outliers and problematic samples, we conducted linkage analysis using 5,914 SNPs in 1,344 individuals from 530 families. Linkage analysis was conducted using variance components for type 2 diabetes, age of type 2 diabetes diagnosis, and BMI and nonparametric linkage analyses. Ordered subset analyses were conducted ranking on age of type 2 diabetes diagnosis, BMI, waist circumference, waist-to-hip ratio, and amount of European admixture. Admixture mapping was conducted using 4,486 markers not in linkage disequilibrium. RESULTS: The strongest signal for type 2 diabetes (logarithm of odds [LOD] 4.53) was a broad peak on chromosome 2, with weaker linkage to age of type 2 diabetes diagnosis (LOD 1.82). Type 2 diabetes and age of type 2 diabetes diagnosis were linked to chromosome 13p (3-22 cM; LOD 2.42 and 2.46, respectively). Age of type 2 diabetes diagnosis was linked to 18p (66 cM; LOD 2.96). We replicated previous reports on chromosome 7p (79 cM; LOD 2.93). Ordered subset analysis did not overlap with linkage of unselected families. The best admixture score was on chromosome 12 (90 cM; P = 0.0003). CONCLUSIONS: The linkage regions on chromosomes 7 (27-78 cM) and 18p overlap prior reports, whereas regions on 2p and 13p linkage are novel. Among potential candidate genes implicated are TCF7L1, VAMP5, VAMP8, CDK8, INSIG2, IPF1, PAX8, IL18R1, members of the IL1 and IL1 receptor families, and MAP4K4. These studies provide a complementary approach to genome-wide association scans to identify causative genes for African American diabetes.

Genetic variation and antipsychotic drug effects on serum lipids.

Evaluation of: Smith RC, Segman RH, Golcer Dubner T, Pavlov V, Lerer B: Allelic variation in ApoC3, ApoA5, and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia. Pharmacogenomics J. DOI: 10.1038/sj.tpj.6500474 (2007) (Epub ahead of print) [1] . Some newer antipsychotic drugs may raise serum lipid levels, but it is not known whether specific genetic variants affect an individual's susceptibility to this. In 189 schizophrenia patients treated with either first- or second-generation antipsychotic drugs, Smith and colleagues analyzed drug-by-genotype interaction effects on serum cholesterol and triglyceride levels using five polymorphisms in three genes that affect serum lipids: APOC3, APOA5 and LPL. Three interactions involving the APOA5 -1131 T/C polymorphism remained significant after adjustment for multiple testing; the rarer C allele was associated with higher serum cholesterol levels in patients treated with first-generation antipsychotics, and lower levels in those treated with clozapine or olanzapine. This article emphasizes aspects of their study which illustrate points that may be useful in planning future pharmacogenetic studies.

Relation of PCSK9 mutations to serum low-density lipoprotein cholesterol in childhood and adulthood (from The Bogalusa Heart Study).

Specific mutations in the gene for proprotein convertase, subtilisin-kexin type 9 (PCSK9), that are associated with lower coronary heart disease risk may produce lifelong decreases in low-density lipoprotein (LDL) cholesterol levels, but data on their effects in younger subjects are lacking. We analyzed associations of 1 missense (R46L) and 2 nonsense (Y142X and C679X) PCSK9 mutations with serum LDL cholesterol in 478 African-Americans and 1,086 whites, 4 to 38 years of age, examined 3 to 8 times in the Bogalusa Heart Study. L46 allele frequency in whites was 0.017 +/- 0.003; the combined frequency of X142 or X679 alleles in African-Americans was 0.016 +/- 0.005. In whites, LDL cholesterol was lower in L46 carriers (78.9 +/- 21.8 mg/dl) than in noncarriers (89.7 +/- 24.9 mg/dl, p = 0.027) at their first examination (mean age 9.4 +/- 3.2 years). African-Americans carrying the X142 or X679 allele had lower LDL cholesterol levels than did noncarriers (77.3 +/- 15.1 vs 91.4 +/- 23.9 mg/dl, p = 0.043) at their first examination (mean age 9.0 +/- 3.0 years). Longitudinal LDL cholesterol profiles were significantly lower in whites with the L46 allele and in African-Americans with the X142 or X679 allele. In conclusion, our results show that these PCSK9 variants are associated with significantly lower LDL cholesterol levels starting in childhood.

A genome-wide linkage scan for diabetic retinopathy susceptibility genes in Mexican Americans with type 2 diabetes from Starr County, Texas.

We conducted a genome-wide linkage scan for genes contributing to retinopathy risk using 794 diabetes case subjects from 393 Mexican-American families from Starr County, Texas, having at least two diabetic siblings. The sample included 567 retinopathy case subjects comprising 282 affected sibling pairs. Retinopathy was classified as none, early nonproliferative, moderate-to-severe nonproliferative, or proliferative. Using 360 polymorphic markers (average spacing 9.4 cM), we conducted nonparametric linkage analysis followed by ordered-subset analysis (OSA) ranking families by average age of diabetes diagnosis. For any retinopathy, the highest LOD scores including all families were on chromosomes 3 (2.41 at 117 cM) and 12 (2.47 at 15.5). OSA logarithm of odds (LOD) scores >2 for any retinopathy occurred on chromosomes 12 (4.47 at 13.2 cM), 15 (3.65 at 100.6), and 20 (2.67 at 54.1). Scores >2 for either moderate-to-severe nonproliferative or proliferative retinopathy occurred on chromosomes 5 (2.53 at 11.2 cM), 6 (2.28 at 30.6), and 19 (2.21 at 100.6). Thus, unconditional linkage analysis revealed suggestive evidence of linkage with retinopathy on two chromosomes, whereas OSA revealed strong evidence of linkage on two chromosomes, and suggestive evidence on four. Candidate genes were identified in most implicated regions.