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.

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.

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.

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.

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.

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.

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.

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.

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.

Longitudinal analysis of haplotypes and polymorphisms of the APOA5 and APOC3 genes associated with variation in serum triglyceride levels: the Bogalusa Heart Study.

Polymorphisms in the APOC3 and APOA5 genes, from the APOA1/APOC3/APOA4/APOA5 gene cluster on chromosome 11q23, have been associated with interindividual variation in plasma triglycerides. APOA5 polymorphisms implicated include 2 in the promoter region (-1131 T/C and -3 A/G) and 1 in exon 2 (+56 C/G). APOC3 polymorphisms implicated include 1 (SstI) in the 3' untranslated region and 1 (-2854 G/T) in the APOC3-APOA4 intergenic region. We analyzed the associations of haplotypes and multilocus genotypes of these polymorphisms on longitudinal serum triglyceride profiles in 360 African American and 823 white subjects from the Bogalusa Heart Study. Subjects were examined from 2 to 8 times (mean +/- SD, 5.4 +/- 1.3) between 1973 and 1996, at ages ranging from 4 to 38 years, with 1978 observations in African Americans and 4465 in whites. Serum triglycerides were significantly higher among whites across all ages. Allele frequencies differed significantly between African Americans and whites at all but the APOA5 +56 C/G locus. Linkage disequilibrium among the loci was higher in whites and haplotype diversity lower: 6 haplotypes had estimated frequencies of more than 1% in African Americans, 5 in whites. Individually, all polymorphisms except APOC3 -2854 G/T showed significant associations with triglyceride levels in the full sample. However, genotype models including all 5 loci showed significant triglyceride associations for only 3 (APOC3 SstI, APOA5 -1131 T/C, and APOA5 +56 C/G); significant interactions among them indicated their effects were not independent. Neither APOC3 -2854 G/T nor APOA5 -3 A/G had significant effects when the other 3 loci were in the models. The EM algorithm was used to estimate haplotype frequencies and assign haplotype probabilities to individuals, which is conditional on their genotypes; individuals' haplotype probability vectors were then used as predictors in multilevel mixed models of longitudinal triglyceride profiles. Of haplotypes comprising, in order, APOC3 SstI and -2854 G/T and APOA5 -1131 T/C, -3 A/G, and +56 C/G, 3 were significantly associated with higher triglycerides, even after adjusting for multiple tests: GGTAG (P = .002), GTTAG (P < .0001), and CGCGC (P = .0002). Each GGTAG haplotype carried would be expected to raise triglyceride levels (relative to those of GTTAC homozygotes) by approximately 19 mg/dL, each GTTAG haplotype by approximately 15 mg/dL, and each CGCGC haplotype by approximately 7 mg/dL. Haplotypes comprising the 3 loci implicated by genotype analyses (SstI, -1131 T/C, and +56 C/G) were also tested: haplotypes C_C_C and G_T_G significantly raised triglycerides, even after adjustment for multiple comparisons (P < .002 for both), with each copy of C_C_C expected to raise triglycerides by approximately 7 mg/dL and each copy of G_T_G by approximately 15 mg/dL. Overall, our findings support those of others in associating specific polymorphisms and haplotypes in the APOA1/C3/A4/A5 gene cluster with higher serum triglyceride levels. However, the degree to which polymorphisms in the APOC3 and APOA5 genes may be independently associated with triglyceride levels remains to be determined.

Apolipoprotein-E polymorphism and response to pravastatin in men with coronary artery disease (REGRESS).

OBJECTIVE: [corrected] The influence ofApoE polymorphism on the efficacy of statins in lowering plasma lipids and lipoproteins and improving angiographic parameters was assessed. METHODS: ApoE genotypes were studied in a group (n = 815) of well-characterised male coronary artery disease (CAD) patients who participated in the lipid-lowering regression study 'Regression Growth Evaluation Statin Study (REGRESS)'. RESULTS: There was a significant interaction between treatment (placebo/pravastatin) and APOE genotype when lipid levels were considered, APOE2 + carriers exhibited the largest improvement of HDL levels (+0.15 mmol/l) and LDL/HDL ratios (-0.60) compared with APOE3 + (+ 0.06 mmol/l, -0.043, respectively) and APOE4 + carriers (+ 0.07 mmol/l, -0.040). In contrast,APOE2 + allele carriers had the least effect in terms of angiographic parameters, although the difference was not statistically significant. CONCLUSIONS: The effects of statins in subjects with different ApoE genotypes were different with regard to the lipoprotein profile, but not with regard to angiographic parameters.

Familial aggregation of severity of diabetic retinopathy in Mexican Americans from Starr County, Texas.

OBJECTIVE: Diabetic retinopathy is a major cause of blindness. To determine whether retinopathy itself or only its severity aggregates in families, we examined the occurrence and severity of diabetic retinopathy in Mexican-American siblings with type 2 diabetes. RESEARCH DESIGN AND METHODS: Using stereoscopic fundus photography of seven standard fields, we measured retinopathy in 656 type 2 diabetic patients from 282 Mexican-American families from Starr County, Texas. Retinopathy severity was scored using the Early Treatment of Diabetic Retinopathy Study system and classified as no retinopathy, early nonproliferative diabetic retinopathy (NPDR-E), moderate-to-severe nonproliferative diabetic retinopathy (NPDR-S), or proliferative diabetic retinopathy (PDR). RESULTS: Of 249 siblings of randomly selected probands with retinopathy, 169 (67.9%) had retinopathy, compared with 95 of 125 siblings of unaffected probands (76.0%; P = 0.11). Proband retinopathy class was associated (P = 0.03) with sibling retinopathy class, with significant odds ratios (ORs) for NPDR-E versus no retinopathy (OR 0.57 [95% CI 0.35-0.93]) and PDR versus NPDR-E (2.02 [1.13-3.63]); the contrast of NPDR-S versus NPDR-E approached significance (1.78 [0.99-3.20]). With the more severe classes (PDR and NPDR-S) combined in one group and the less severe ones (none and NPDR-E) in another, more severe proband retinopathy was associated with more severe sibling retinopathy (1.72 [1.03-2.88]). CONCLUSIONS: More severe diabetic retinopathy showed evidence of familial aggregation, but the occurrence of diabetic retinopathy per se did not. The factors involved in the onset of diabetic retinopathy may differ from those involved in its progression to more severe forms.

Calcitonin gene-related peptide is a depressor in subtotal nephrectomy hypertension.

We previously demonstrated that the neuronal expression of calcitonin gene-related peptide (CGRP), a potent vasodilator, is increased in deoxycorticosterone-salt-induced hypertension where it acts as a compensatory vasodilator to attenuate the elevated blood pressure. To determine whether CGRP is playing a similar role in subtotal nephrectomy-salt-induced hypertension, hypertension was induced in Sprague-Dawley rats (n=6) by subtotal nephrectomy and 1.0% saline drinking water. Control rats (n=6) were sham operated and given tap water to drink. CGRP(8-37), a CGRP receptor antagonist, was used to assess the hemodynamic role of CGRP in this setting. CGRP mRNA and peptide levels in dorsal root ganglia were also determined. Three weeks after either protocol, all rats had intravenous (for drug administration) and arterial (for continuous mean arterial pressure monitoring) catheters surgically placed and were studied in the conscious, unrestrained state. CGRP(8-37) (3.2 or 6.4 x 10(4) pmol/L in 0.1 mL saline) and vehicle were administered intravenously to all rats. Baseline mean arterial pressure was higher in the subtotal nephrectomized rats compared with the controls (173+/-5 versus 113+/-5 mm Hg, P<.001). Vehicle administration did not change mean arterial pressure in either group, and CGRP(8-37) administration did not alter mean arterial pressure in the normotensive group. In contrast, CGRP(8-37) administration to the subtotal nephrectomized rats rapidly increased the already elevated mean arterial pressure at both the 3.2 x 10(4) pmol/L dose (7.8+/-1.1 mm Hg, P<.05) and the 6.4 x 10(4) pmol/L dose (9.6+/-0.8 mm Hg, P<.01). CGRP mRNA and peptide levels in the dorsal root ganglia were not significantly different between the two groups. These data suggest that in subtotal nephrectomy-salt-induced hypertension, CGRP may play a compensatory depressor role in an attempt to lower the elevated blood pressure.

Calcitonin gene-related peptide is a depressor of deoxycorticosterone-salt hypertension in the rat.

Calcitonin gene-related peptide (CGRP) is a potent vasodilator neuropeptide. We previously demonstrated that neuronal CGRP expression is significantly increased in deoxycorticosterone (DOC)-salt hypertensive rats. To determine the hemodynamic role of CGRP in this setting, we used CGRP8-37, a specific CGRP receptor antagonist. DOC-salt hypertension was induced in Sprague-Dawley rats. To control for DOC pellet implantation, left nephrectomy, and/or saline drinking water, we also studied four normotensive groups. Four week after the initiation of each protocol, all rats had intravenous (for drug administration) and arterial (for continuous mean arterial pressure monitoring) catheters surgically placed and were studied in the conscious, unrestrained state. Baseline mean arterial pressure was higher in the DOC-salt than normotensive rats (175 +/- 5 versus 119 +/- 4 mm Hg, P < .001). Vehicle administration did not alter mean arterial pressure in any group, and CGRP8-37 administration (bolus doses of 3.2 x 10(4) or 6.4 x 10(4) pmol/L) did not change mean arterial pressure in the four normotensive groups. However, CGRP8-37 administration to the DOC-salt rats rapidly and significantly increased mean arterial pressure at both the lower dose (9 +/- 1 mm Hg, P < .001) and higher dose (14 +/- 1 mm Hg, P < .001). In addition, the increase in mean arterial pressure between the two CGRP8-37 doses was also significant (P < .01), indicating a dose-dependent response. We conclude that the increase in neuronal CGRP expression in DOC-salt hypertension plays a compensatory vasodilator role to attenuate the elevated blood pressure. These results provide the first conclusive evidence that CGRP plays a direct role in DOC-salt hypertension.

Calcitonin gene-related peptide is a depressor in NG-nitro-L-arginine methyl ester-induced hypertension during pregnancy.

Inhibition of nitric oxide production with NG-nitro-L-arginine methyl ester (L-NAME) increases blood pressure and fetal mortality in pregnant rats. We previously reported that administration of calcitonin gene-related peptide (CGRP) reduces the blood pressure and fetal death produced by L-NAME. To determine the hemodynamic role of endogenous CGRP in this setting, CGRP8-37, a CGRP receptor antagonist, was used. In addition, CGRP mRNA and peptide levels were determined in dorsal root ganglia. L-NAME or control rats had intravenous (for drug administration) and arterial (for continuous mean blood pressure monitoring) catheters surgically placed and were studied in the conscious unrestrained state. Baseline blood pressure was higher in the L-NAME than the control rats on days 19, 20, and 21 or pregnancy and postpartum day 1. Vehicle administration did not change blood pressure in any group, and CGRP8-37 (100 micrograms) did not change blood pressure in control groups. However, CGRP8-37 administration to the L-NAME rats further increased blood pressure (P < .05) on days 19 (8 +/- 1), 20 (12 +/- 2), and 21 (7 +/- 1) of gestation but was without effect on postpartum day 1. Furthermore, CGRP mRNA or peptide levels in dorsal root ganglia were not different between the L-NAME and control rats at any of the time points studied. These data indicate that in experimental preeclampsia, CGRP is playing a compensatory vasodilator role to attenuate the elevated blood pressure. The mechanism of this effect appears to be an enhanced vascular responsiveness to CGRP that is attenuated after the birth of pups.

The beta(2)-adrenergic receptor Arg16-gly polymorphism and interactions involving beta(2)- and beta(3)-adrenergic receptor polymorphisms are associated with variations in longitudinal serum lipid profiles: the Bogalusa Heart Study.

We examined the effects of combined genotypes of the beta(2)-adrenergic receptor (AR) Arg(16)-Gly and beta(3)-AR Trp(64)-Arg polymorphisms on longitudinal serum total (T-C) and low-density lipoprotein cholesterol (LDL-C) profiles in 1,198 subjects examined multiple times (6,488 observations) from 1973 to 1996 in the Bogalusa Heart Study, at ages from 4.5 to 38 years. Within 5-year age groups, T-C was significantly (P <.05) higher in beta(2)-AR Arg(16)/Arg(16) homozygotes than in Gly(16) carriers among those 4 to 8 (171.4 +/- 30.0 v 161.5 +/- 27.7 mg/dL), 9 to 13 (167.7 +/- 28.6 v 162.4 +/- 27.4 mg/dL), and 14 to 18 (158.8 +/- 29.6 v 154.7 +/- 27.5 mg/dL) years of age, but not in those 19 to 23, 24 to 28, 29 to 33, or 34 to 38 years of age. The beta(3)-AR polymorphism was not associated with variation in either T-C or LDL-C. In multilevel polynomial growth curve models, the combination of the beta(2)-AR Arg(16)/Arg(16) genotype with either the beta(3)-AR Arg(64)/Arg(64) or Trp(64)/Arg(64) genotypes, denoted AA/AX, was associated with variation in longitudinal T-C (P <.01) and LDL-C (P <.01) profiles. The association between combined beta(2)/beta(3)-AR genotype and lipid profiles differed among race/sex groups, being most marked in black females, in whom the AA/AX combination was associated with higher T-C and LDL-C profiles across all ages. In White males, the AA/AX combination was most strongly associated with higher lipids in adults. In black males and white females, lipid profiles differed little between genotype groups. Our findings suggest that the beta(2)-AR Arg(16)-Gly genotype influences T-C and LDL-C levels in an age-specific manner, that it may interact with beta(3)-AR Trp(64)-Arg genotypes to influence longitudinal T-C and LDL-C profiles, and that the effect of combined beta(2)/beta(3)-AR genotypes on T-C and LDL-C profiles may differ among race/sex groups.

The Ser(447)-Stop polymorphism of lipoprotein lipase is associated with variation in longitudinal serum high-density lipoprotein-cholesterol profiles: the Bogalusa Heart Study.

The Ser(447)-Stop polymorphism of lipoprotein lipase (LPL) has been associated with altered high-density lipoprotein-cholesterol (HDL-C) and triglyceride (TG) levels at individual measurements, but nothing is known of its associations with lipid profiles derived from serial measurements. We used multilevel statistical models to study effects of this polymorphism on longitudinal lipid profiles in 1,006 Bogalusa Heart Study subjects examined 4 to 9 times between the ages of 4 and 38 years. Stop(447) allele frequencies in African Americans (0.053 +/- 0.011) and whites (0.091 +/- 0.009) differed significantly (chi(2) = 7.595, 1 df, P =.006; Stop(447) homozygotes and heterozygotes combined). Overall, TG levels were lower and HDL-C levels higher in blacks than in whites of the same age and sex. Longitudinal TG profiles were lower in Stop(447) carriers at all ages. However, longitudinal HDL-C profiles differed among genotype groups with age: the Stop(447) allele was associated with higher HDL-C only in subjects above approximately 10 years of age. Genotype-specific HDL-C profiles also differed significantly among race/sex groups. Thus, we found evidence of LPL genotype effects that vary within individuals with age. Possible mechanisms, which could account for age-related changes in the effects of LPL variants, are discussed.

Alpha 2-adrenergic receptor activation inhibits calcitonin gene-related peptide expression in cultured dorsal root ganglia neurons.

Calcitonin gene-related peptide (CGRP), a potent vasodilator, is produced in dorsal root ganglia (DRG) neurons which extend nerves peripherally to blood vessels and centrally to the spinal cord. We previously reported that neuronal CGRP expression is significantly reduced in the spontaneously hypertensive rat (SHR) which could contribute to the elevated BP. Other studies suggest that the enhanced activity of the sympathetic nervous system in the SHR may mediate, at least in part, this reduction in neuronal CGRP expression via activation of alpha 2-adrenoreceptors (alpha 2-AR) on DRG neurons. To test this hypothesis in vitro we employed primary cultures of adult rat DRG neurons. Neuronal cultures were initially exposed (24 h) to either the alpha 2-AR agonist UK 14,304 (10(-6) M) or vehicle; however, no changes in CGRP mRNA content or immunoreactive CGRP (iCGRP) release were observed. Using the rationale that in vivo DRG neurons receive a continuous supply of target tissue derived nerve growth factor (NGF), which stimulates CGRP synthesis, the cultured neurons were treated (24 h) with either vehicle, NGF (25 ng/ml) alone, or NGF plus UK. NGF treatment increased CGRP mRNA accumulation 5.5 +/- 0.9-fold (p < 0.001) and iCGRP release 2.9 +/- 0.4-fold (p < 0.001) over control levels. The stimulatory effects of NGF were markedly attenuated, but not abolished, by UK (NGF + UK vs. control, CGRP mRNA, 2.9 +/- 0.4-fold, p < 0.05; iCGRP, 1.7 +/- 0.2-fold, p < 0.05). These values were also significant (p < 0.05) when compared to NGF treatment alone. Experiments performed using the alpha 2-antagonist yohimbine confirmed that the effects of UK were mediated by the alpha 2-AR. These results, therefore, demonstrate that alpha 2-AR activation attenuates the stimulatory effects of NGF on CGRP expression in DRG neurons.

Dexamethasone and activators of the protein kinase A and C signal transduction pathways regulate neuronal calcitonin gene-related peptide expression and release.

Primary cultures of adult rat dorsal root ganglia (DRG) neurons were used to determine if activation of either the protein kinase A or C signal transduction pathways or treatment with the synthetic glucocorticoid dexamethasone modulate neuronal calcitonin gene-related peptide (CGRP) synthesis and release. DRG are the sites of neuronal cell bodies known to produce abundant CGRP levels, and to send axons peripherally to blood vessels and centrally to the spinal cord. Using immunocytochemical techniques, we confirmed that synthesis of immunoreactive CGRP (iCGRP) is restricted to a subpopulation of DRG neurons. Subsequently, we determined that treatment (24 h) of the neurons with either dibutyryl cAMP (1 mM) or phorbol 12-myristate 13-acetate (2 microM) increased CGRP mRNA content 2.2 +/- 0.4 (n = 6, p < 0.03) and 3.0 +/- 0.6-fold (n = 6, P < 0.02) respectively, while secreted iCGRP levels were increased 1.8 +/- 0.2 (n = 14, P < 0.005) and 4.5 +/- 1.0 (n = 14, P < 0.001)-fold over control levels. Treatment of the neurons with dexamethasone alone had no effect on CGRP expression; however, this agent was able to significantly attenuate the stimulatory effects of NGF on both CGRP mRNA accumulation and release of iCGRP. Time course studies demonstrated that in the phorbol ester treated neurons CGRP mRNA levels continued to increase at 48 h, while maximal induction with dibutyryl cAMP occurred at approximately 12 h. These results indicate that local and/or circulating factors which act through the protein kinase A and C signal transduction pathways upregulate both CGRP expression and release, while glucocorticoids attenuate the stimulatory effects of NGF.