Wendy Y. Craig

Cigarette smoking and serum lipid and lipoprotein concentrations: an analysis of published data.

To examine the association between cigarette smoking in adults and serum lipid and lipoprotein concentrations the results of 54 published studies were analysed. Overall, smokers had significantly higher serum concentrations of cholesterol (3.0%), triglycerides (9.1%), very low density lipoprotein cholesterol (10.4%), and low density lipoprotein cholesterol (1.7%) and lower serum concentrations of high density lipoprotein cholesterol (-5.7%) and apolipoprotein AI (-4.2%) compared with nonsmokers. Among non-smokers and light, moderate, and heavy smokers a significant dose response effect was present for cholesterol (0, 1.8, 4.3, and 4.5% respectively), triglycerides (0, 10.7, 11.5, and 18.0%), very low density lipoprotein cholesterol (0, 7.2, 44.4, and 39.0%), low density lipoprotein cholesterol (0, -1.1, 1.4, and 11.0%), high density lipoprotein cholesterol (0, -4.6, -6.3, and -8.9%), and apolipoprotein AI (0, -3.7 and -5.7% in non-smokers and light and heavy smokers). These dose response effects may provide new evidence for a causal relation between exposure to cigarette smoke and changes in serum lipid and lipoprotein concentrations whether as a direct result of physiological changes or of dietary changes induced by smoking. Adequate prospective data to estimate the excess risk of coronary artery disease existed only for cholesterol concentration. When that information was combined with data from the present study, and given that smokers as a group face an average overall excess risk of coronary artery disease of 70%, it was estimated that the observed increased serum cholesterol concentration in smokers may account for at least 9% of that excess risk. Furthermore, the dose response effect of smoking on serum cholesterol concentration suggests a gradient of increased absolute risk of coronary artery disease between light and heavy smokers.

Reference distributions for the negative acute-phase serum proteins, albumin, transferrin and transthyretin: A practical, simple and clinically relevant approach in a large cohort

Inflammation is associated with diverse clinical conditions accompanied by characteristic changes in serum levels of the acute‐phase proteins that can be used to stage the inflammatory process and evaluate the impact of treatment. Some acute‐phase proteins increase during inflammation, while others, such as albumin, transferrin, and transthyretin, decrease. The current study reports reference ranges for serum levels of albumin, transferrin, and transthyretin based on a cohort of over 124,000 Caucasian individuals from northern New England, tested in our laboratory between 1986 and 1998. Measurements were standardized against CRM 470 (RPPHS) and analyzed using a previously validated statistical approach. Individuals with laboratory evidence of inflammation (C‐reactive protein of 10 mg/L or higher) were excluded. The levels of all three analytes varied by age, generally rising until the second or third decade of life and then decreasing thereafter. Albumin and transthyretin levels were higher during midlife among males as compared to females; the maximum being at 25 years for albumin (5%) and 35 years for transthyretin (16%). In contrast, above the age of 10 years, transferrin levels were increasingly higher among females (7% at 20 years). When values were expressed as multiples of the age‐ and gender‐specific median levels, the resulting distributions fitted a log‐Gaussian distribution. When patient data are normalized in this manner, the distribution parameters can be used to assign a corresponding centile to an individuals measurement simplifying interpretation. The ultimate interpretation of an individuals measurement relies upon the clinical setting. J. Clin. Lab. Anal. 13:273–279, 1999.

Maternal obesity and markers of inflammation in pregnancy.

OBJECTIVES To evaluate whether obesity is associated with changes in pro-inflammatory and immunomodulatory cytokines in pregnancy. METHODS We performed a cross-sectional study using maternal serum from the early second trimester to examine biomarkers associated with inflammation in relation to maternal body mass index (n=80 total). RESULTS Leptin and high sensitivity C-reactive protein were significantly different between groups and increased with increasing body mass index. MCP-1 was significantly increased in the morbidly obese mothers. Interleukin-2 exhibited a U-shaped relationship with body mass index; transforming growth factor-beta1 demonstrated a nonsignificant negative trend with body mass index; and the levels of hepatocyte growth factor and tumor necrosis factor-alpha did not differ appreciably between groups. CONCLUSIONS Maternal obesity in pregnancy is associated with changes in cytokines, protein hormones and acute phase proteins in the second trimester, with an increase in MCP-1 in the morbid obesity category, and an increase in Leptin and hsCRP with increasing BMI category.

Cross-national Study of Fighting and Weapon Carrying as Determinants of Adolescent Injury

Objectives. We sought to (1) compare estimates of the prevalence of fighting and weapon carrying among adolescent boys and girls in North American and European countries and (2) assess in adolescents from a subgroup of these countries comparative rates of weapon carrying and characteristics of fighting and injury outcomes, with a determination of the association between these indicators of violence and the occurrence of medically treated injury. Design and Setting. Cross-sectional self-report surveys using 120 questions were obtained from nationally representative samples of 161082 students in 35 countries. In addition, optional factors were assessed within individual countries: characteristics of fighting (9 countries); characteristics of weapon carrying (7 countries); and medically treated injury (8 countries). Participants. Participants included all consenting students in sampled classrooms (average age: 11–15 years). Measures. The primary measures assessed included involvement in physical fights and the types of people involved; frequency and types of weapon carrying; and frequency and types of medically treated injury. Results. Involvement in fighting varied across countries, ranging from 37% to 69% of the boys and 13% to 32% of the girls. Adolescents most often reported fighting with friends or relatives. Among adolescents reporting fights, fighting with total strangers varied from 16% to 53% of the boys and 5% to 16% of the girls. Involvement in weapon carrying ranged from 10% to 21% of the boys and 2% to 5% of the girls. Among youth reporting weapon carrying, those carrying handguns or other firearms ranged from 7% to 22% of the boys and 3% to 11% of the girls. In nearly all reporting countries, both physical fighting and weapon carrying were significantly associated with elevated risks for medically treated, multiple, and hospitalized injury events. Conclusions. Fighting and weapon carrying are 2 common indicators of physical violence that are experienced by young people. Associations of fighting and weapon carrying with injury-related health outcomes are remarkably similar across countries. Violence is an important issue affecting the health of adolescents internationally.

Genetic Variation in Lectin-Like Oxidized Low-Density Lipoprotein Receptor 1 (LOX1) Gene and the Risk of Coronary Artery Disease

Background—We examined the association of 3 polymorphisms in the lectin-like oxidized LDL receptor-1 (LOX1 or OLR1) gene with coronary artery disease in the Women’s Ischemia Syndrome Evaluation (WISE) study population. Methods and Results—The WISE sample comprised 589 white and 122 black women who underwent angiography for suspected ischemia. The sample was divided into 3 groups: <20% stenosis (38.7%), 20% to 49% stenosis (24.9%), and ≥50% stenosis (35.3%). The three LOX1 polymorphisms (intron 4/G→A, intron 5/T→G, and 3′ UTR/T→C) were in linkage disequilibrium and thus behaved as a single polymorphism. The frequency of the 3′UTR/T allele was significantly higher in whites than blacks (49% versus 19%; P <0.0001). Among white women, the frequency of the 3′UTR/T allele carriers (TC+TT genotypes) increased gradually from 67.9% to 75.0% and 79.2% in the <20%, 20% to 49%, and ≥50% stenosis groups, respectively (&khgr;2 trend=6.23; P =0.013). Logistic regression analyses indicated that APOE (odds ratio, 1.90; P =0.007) and LOX1 (odds ratio, 1.67; P =0.025) genotypes were independently associated with the risk of disease and that there was no interaction between the two genes. The 3′UTR/T allele carriers also had significantly higher IgG anti-oxLDL levels than individuals carrying the CC genotype (0.94±0.20 versus 0.86±0.16; P =0.032). Furthermore, our electrophoretic mobility shift assay data show that the 3′UTR polymorphic sequence affects the binding of a putative transcription factor in an allele-specific manner. Conclusions—Our data suggest that common genetic variation in the LOX1 gene may be associated with the risk of coronary artery disease in white women.

Regulation of rat biliary cholesterol secretion by agents that alter intrahepatic cholesterol metabolism. Evidence for a distinct biliary precursor pool.

Propensity for cholesterol gallstone formation is determined in part by biliary cholesterol content relative to bile salts and phospholipid. We examined the hypothesis that the rate of biliary cholesterol secretion can be controlled by availability of an hepatic metabolically active free cholesterol pool whose size is determined in part by rates of sterol synthesis, as reflected by activity of the primary rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase and of sterol esterification, as reflected by the activity of the enzyme acyl coenzyme A/cholesterol acyltransferase (ACAT). Rats were prepared with biliary, venous, and duodenal catheters. The enterohepatic circulation of biliary lipids was maintained constant by infusion of a bile salt, lecithin, cholesterol replacement solution. Administration of 25-hydroxycholesterol decreased HMG CoA reductase activity, increased ACAT activity, and decreased biliary cholesterol output 26% by 1 h. By 2 h, ACAT activity and biliary cholesterol secretion were at control levels. Administration of mevinolin, a competitive inhibitor of HMG CoA reductase, had no effect on ACAT activity and decreased biliary cholesterol secretion 16%. Administration of progesterone, an inhibitor of ACAT, had no effect on HMG CoA reductase and increased biliary cholesterol output 32% at 1 h. By 2 h, all parameters were near control levels. None of these agents had any significant effect on biliary bile salt or phospholipid secretion. Thus, acutely altering rates of esterification and/or synthesis can have profound effects on biliary cholesterol secretion independent of the other biliary lipids. These experiments suggest the existence of a metabolically active pool of free cholesterol that serves as a precursor pool for biliary cholesterol secretion. Furthermore, the size of this precursor pool is determined in part both by rates of cholesterol synthesis and esterification and is a key determinant of biliary cholesterol secretion.

Mid-Gestational Maternal Free Thyroxine Concentration and Offspring Neurocognitive Development at Age Two Years

CONTEXT Lower neurocognitive development scores at age 2 yr have been reported in association with euthyroid hypothyroxinemia during early pregnancy. OBJECTIVE The objective of this study was to further explore this association with euthyroid hypothyroxinemia during early pregnancy. DESIGN This was an observational, nested case-control study. SETTING The study was conducted at physician offices and prenatal clinics throughout Maine. STUDY SUBJECTS Between May 2004 and March 2006, TSH was measured in 5734 women in conjunction with second-trimester Down syndrome screening. After completion of pregnancy, free T(4) was measured in stored second-trimester sera from euthyroid women (TSH 0.1-3.5 mIU/ml; n = 5560). Women with free T(4) at the third centile or less (n = 99) were matched with women whose free T(4) was at the 10th to the 90th centile (n = 99). INTERVENTIONS There were no interventions. MAIN OUTCOME MEASURE Bayley Scales of Infant Development (BSID III) were administered to the 198 offspring at age 2 yr. Scores for cognitive, language, and motor development were compared between matched pairs of offspring from the two groups before and after correcting for relevant variables. RESULTS Unadjusted BSID-III scores (cognitive, language, and motor) were lower by about 3% at age 2 yr among offspring of 98 hypothyroxinemic women (cases), reaching borderline significance for cognitive and motor scores. After adjustment for gestational age, the childs age at testing, maternal weight, and education, all differences diminished and became nonsignificant. Scores less than 85 were more frequent among case children but did not reach statistical significance (P = 0.14). CONCLUSIONS Isolated hypothyroxinemia during the second trimester is not associated with significantly lower BSID-III scores at age 2 yr, compared with scores for offspring of matched euthyroxinemic women.

Reference distributions for immunoglobulins A, G, and M: A practical, simple, and clinically relevant approach in a large cohort

Serum immunoglobulins are measured millions of times each year, yet clinical interpretations remain hampered by inadequate age‐ and gender‐specific reference limits. In order to provide more reliable and comprehensive reference distributions for IgA, IgG, and IgM measurements, we analyzed automated immunoassay values from 115,017 serum samples from northern New England patients (99% Caucasian) who were tested in our laboratory between 1986 and 1995. Measurements were standardized to reference material, CRM 470 (RPPHS). A simple, practical, and clinically relevant approach was used to determine reference distributions for the immunoglobulins over a wide range of ages for males and females. Levels of IgA and IgM varied considerably by age, and by gender for IgM. For each of the analytes, the observed 5th and 95th centiles were symmetric about the median and approximately constant over the entire age range. When immunoglobulin reference values are expressed as multiples of the age‐ and gender‐specific regressed medians, the resulting distributions fit a log‐Gaussian distribution well. This finding enables interpretation of serum immunoglobulin measurements using a common unit (multiples of the median) that is independent of age or gender. Insights gained from this study can help improve and simplify the interpretation of immunoglobulin measurements. J. Clin. Lab. Anal. 12:363–370, 1998.

Assigning risk for Smith-Lemli-Opitz syndrome as part of 2nd trimester screening for Down's syndrome.

Objectives: To design a reliable model in the context of prenatal screening for assigning the risk in an individual pregnancy of Smith-Lemli-Opitz syndrome (SLOS) and assess its performance. Setting: A 2nd trimester screening programme for Downs syndrome that measures unconjugated estriol (uE3) along with other serum markers. Methods: Development of individual risk estimates with a trivariate model incorporating measurements of maternal serum uE3, α-fetoprotein (AFP), and human chorionic gonadotropin (hCG) in both SLOS and unaffected pregnancies. Results: Population parameters were computed for the three analytes, as were pairwise correlation coefficients and truncation limits, based on an unbiased collection of 29 affected pregnancies. Published parameters were used for unaffected pregnancies. With a cut off level of risk of 1:50, 62% of SLOS pregnancies can be detected by initially identifying 0.34% of unaffected pregnancies as screen positive. About 1 in 90 screen positive pregnancies will be affected. Conclusions: It is possible to screen for SLOS as an add on to existing 2nd trimester maternal serum screening, if uE3 is already being measured. A large, prospective trial is necessary to determine whether diagnostic testing can be performed in maternal urine or serum rather than amniotic fluid.

Oxidation-Related Analytes and Lipid and Lipoprotein Concentrations in Healthy Subjects

The relations between oxidation-related analytes and lipoprotein risk factors for coronary heart disease are poorly understood. To address this issue, ceruloplasmin, copper, iron, ferritin, cotinine, lipid peroxides, cholesterol, triglyceride, apoB, apoA-I, and lipoprotein(a) levels were measured in sera from apparently healthy subjects (51 men and 115 women). Pairwise comparisons revealed strong positive associations (P < .001) of copper and ceruloplasmin with lipid peroxides, total cholesterol, triglycerides and apoB, of transferrin with apoA-I and cholesterol, and of ferritin with triglycerides. Serum levels of oxidation-related analytes did not differ between smokers and nonsmokers. In multivariate analysis, serum copper was the major independent determinant of serum lipid peroxide level, accounting for 15% of the variability in concentration (ferritin accounted for 1.6%). Copper and ceruloplasmin accounted for 20.5% of the variation in triglyceride levels; triglycerides and apoB accounted for 12% of the variability in ferritin levels; apoB and apoA-I accounted for 9% of the variability in transferrin levels. The data suggest that serum copper contributes to lipid peroxidation in vivo. There are significant associations between lipoprotein and transition metal-related analytes, and further work is needed to elucidate the physiological basis for these relations.