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Aims of this study This descriptive ethnobiological research is the first documentation of the materials utilized in the pharmacopeia of a novel group of herbalists, Rasta bush doctors, found in the botanically diverse Western Cape of South Africa. This article suggests that medicinal plants used by bush doctors unite the disparate ethnomedicines found in South Africa. Materials and methods Ethnospecies name and parts used were recorded during detailed inventories of 39 bush doctors. Collection of voucher specimens for botanical identification occurred in 15 locations. Herbal remedies were classified into use categories and were compared to historical ethnobotanical literature to ascertain previous cultural affiliations. Results There were 205 ethnospecies found in the Rastafari ethnobiology, 181 were used medicinally. Ethnospecies belong to 71 plant families and 71% belonged to six plant families: Rutaceae (13), Asteraceae (13), Apiaceae (9), Lamiaceae (8), Fabaceae (8), and Euphorbiaceae (7). The majority of remedies (49%) were foliage. Medicinal plants treated over 30 ailments including: gastrointestinal symptoms (11%), urogential complaints (11%), skin ailments (9%), and cardiovascular diseases (8%). Bush doctors appropriated remedies traditionally important to Zulu, KhoiSan, European and Xhosa healing traditions. Novel plants and plant utilization were noted for 22 plant species. Conclusions Use of previously undocumented plant materials as medicinals denote distinct local knowledge including novel Rastafarian utilization of herbs for spiritual and ritual purposes. The range of the largely herbaceous pharmacopeia is narrow compared to the region's highly biodiverse materials and historical records of medicinal use. Bush doctors’ experimentation with known herbal remedies illustrates a striking level of cross-cultural adaptation. This syncretic pharmacopeia reflects the cultural diversity of Southern Africa, drawing upon recent invasive species, European influence and traditional herbs used by the KhoiSan, Zulu and Xhosa peoples.

OBJECTIVE Increased oxidative stress and immune dysfunction are implicated in preeclampsia (PE) and may contribute to the two- to fourfold increase in PE prevalence among women with type 1 diabetes. Prospective measures of fat-soluble vitamins in diabetic pregnancy are therefore of interest. RESEARCH DESIGN AND METHODS Maternal serum carotenoids (α- and β-carotene, lycopene, and lutein) and vitamins A, D, and E (α- and γ-tocopherols) were measured at first (12.2 ± 1.9 weeks [mean ± SD], visit 1), second (21.6 ± 1.5 weeks, visit 2), and third (31.5 ± 1.7 weeks, visit 3) trimesters of pregnancy in 23 women with type 1 diabetes who subsequently developed PE (DM PE+) and 24 women with type 1 diabetes, matched for age, diabetes duration, HbA1c, and parity, who did not develop PE (DM PE−). Data were analyzed without and with adjustment for baseline differences in BMI, HDL cholesterol, and prandial status. RESULTS In unadjusted analysis, in DM PE+ versus DM PE−, α-carotene and β-carotene were 45 and 53% lower, respectively, at visit 3 (P < 0.05), before PE onset. In adjusted analyses, the difference in β-carotene at visit 3 remained significant. Most participants were vitamin D deficient ( CONCLUSIONS In pregnant women with type 1 diabetes, low serum α- and β-carotene were associated with subsequent development of PE, and vitamin D deficiency may also be implicated.

Apartheid isolated South Africa economically and politically from the global arena and its citizens culturally from one another. Post-apartheid policymakers have sought to address prior inequalities in education, health care and employment, concerns central to biodiversity conservation initiatives. This article examines the role of school gardening programs on the distribution and transmission of local phytomedicinal knowledge. Urban Cape Town, an area of high biocultural diversity, presents a unique environment in which to observe cultural distinctions in medicinal plant utilization, the impact of school gardening, and the recent cultural amalgamation in local knowledge transmission. Local healers chose 16 common medicinal plants, which were used to examine fifth and seventh graders’ knowledge of local remedies. Results indicate that knowledge of different plants was concentrated in specific ethnic groups and amongst recent migrants. It is proposed that ethnic separation during the apartheid era insulated cultures on socioeconomic and geo-environmental strata, thereby preserving local knowledge.

Objective Green tea ( Camellia sinensis ) has shown to exert cardioprotective benefits in observational studies. The objective of this clinical trial was to assess the effects of green tea on features of metabolic syndrome and inflammation in obese subjects. Methods We conducted a randomized controlled trial in obese subjects with metabolic syndrome. Thirty-five subjects [(mean ± SE) age 42.5 ± 1.7 y, body mass index 36.1 ± 1.3 kg/m 2 ] completed the 8-wk study and were randomly assigned to receive green tea (4 cups/d), green tea extract (2 capsules and 4 cups water/d), or no treatment (4 cups water/d). Both the beverage and extract groups had similar dosing of epigallocatechin-3-gallate, the active green tea polyphenol. Fasting blood samples were collected at screening, 4 and 8 wk of the study. Results Green tea beverage or extract supplementation did not significantly alter features of metabolic syndrome or biomarkers of inflammation including adiponectin, C-reactive protein, interleukin-6, interleukin-1β, soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1, leptin, or leptin:adiponectin ratio. However, both green tea beverage and extracts significantly reduced plasma serum amyloid alpha versus no treatment ( P Conclusion This study suggests that the daily consumption of green tea beverage or extracts for 8 wk was well tolerated but did not affect the features of metabolic syndrome. However, green tea significantly reduced plasma serum amyloid alpha, an independent cardiovascular disease risk factor, in obese subjects with metabolic syndrome.

The current study reports the single and combined toxicities of Pb, Zn, and Cu to Acidithiobacillus caldus strain BC13. The observed half-maximal inhibitory concentrations (IC50), ± 95% confidence intervals, for Pb, Zn, and Cu were 0.9 ± 0.1 mM, 39 ± 0.5 mM, and 120 ± 8 mM, respectively. The observed minimum inhibitory concentrations (MIC) for Pb, Zn, and Cu were 7.5 mM, 75 mM, and 250 mM, respectively. When metals were presented in binary mixtures, the toxicities were less than additive. For example, when 50% of the Pb MIC and 50% of the Cu MIC were presented together, the specific growth rate was inhibited by only 59 ± 3%, rather than 100%. In addition, the presence of ferrous iron in the growth media decreased Pb and Zn toxicity to A. caldus strain BC13. The importance of inoculum history was evaluated by pre-adapting cultures through subsequent transfers in the presence of Pb, Zn, and Cu at their respective IC50s. After pre-adaptation, cultures had specific growth rates 39 ± 11, 32 ± 7, and 28 ± 12% higher in the presence of Pb, Zn, and Cu IC50s, respectively, compared with cultures that had not been pre-adapted. In addition, when cells exposed to the MICs of Pb, Zn, and Cu were harvested, washed, and re-inoculated into fresh, metal-free medium, they grew, showing that the cells remained viable with little residual toxicity. Finally, metal chlorides showed more toxicity than metal sulfates, and studies using sodium chloride or a mixture of metal sulfates and sodium chloride suggested that this was attributable to an additive combination of the metal and chloride toxicities.

Among all fruits, berries have shown substantial cardio-protective benefits due to their high polyphenol content. However, investigation of their efficacy in improving features of metabolic syndrome and related cardiovascular risk factors in obesity is limited. We examined the effects of blueberry supplementation on features of metabolic syndrome, lipid peroxidation, and inflammation in obese men and women. Forty-eight participants with metabolic syndrome [4 males and 44 females; BMI: 37.8 ± 2.3 kg/m2; age: 50.0 ± 3.0 y (mean ± SE)] consumed freeze-dried blueberry beverage (50 g freeze-dried blueberries, #126 350 g fresh blueberries) or equivalent amounts of fluids (controls, 960 mL water) daily for 8 wk in a randomized controlled trial. Anthropometric and blood pressure measurements, assessment of dietary intakes, and fasting blood draws were conducted at screening and at wk 4 and 8 of the study. The decreases in systolic and diastolic blood pressures were greater in the blueberry-supplemented group (− 6 and − 4%, respectively) than in controls (− 1.5 and − 1.2%) (P lt 0.05), whereas the serum glucose concentration and lipid profiles were not affected. The decreases in plasma oxidized LDL and serum malondialdehyde and hydroxynonenal concentrations were greater in the blueberry group (− 28 and − 17%, respectively) than in the control group (− 9 and − 9%) (P lt 0.01). Our study shows blueberries may improve selected features of metabolic syndrome and related cardiovascular risk factors at dietary achievable doses.

Introduction Patients with heart failure face enormous challenges with disease burden. Socioeconomic and lifestyle patterns and disease insights have been sparsely reported in the past. The current study aims to go in-depth into understanding these characteristics in patients with heart failure. Methods 110 patients with heart failure with reduced ejection fraction (HFrEF) were enrolled in the study. During clinic/hospital visit, patients filled out a questionnaire survey identifying various socioeconomic and lifestyle characteristics. Data were expressed as %. Gender comparisons were made using Pearson chi-squared tests. Results Of the 110 patients. 56% were male. Mean age was 63± 14 yrs. 49% of patients were >65 yrs. Major self-reported co-morbidities were heart attack (35%), erectile dysfunction (55%), rhythm issues (60%), diabetes (44%) and arthritis (49%). Depression was common at 44%. 70% of the subjects had Medicare and 9% were uninsured. 81% had NYHA class 2 or more symptoms. Vision (79%) and hearing issues (33%) were common and 8% had trouble with combined vision, hearing and reading. 22% had trouble reading pill bottles. 39% of patients lived alone. Only 42% of the patients knew the names of their HF medications and 84% set their own pill schedules. 35% of patients reported forgetfulness as the main reason for missing pills. A summary of author reported significant characteristics are listed in the table with gender-based differences. While no key gender-based differences exist, females fared better in being able to recollect the names of their HF medications. Conclusion The current analysis highlights the significant limitations HFrEF. patients face on a day to day basis. While certain variables are non-modifiable; patients, caregivers and healthcare systems need to continue to evolve and adapt to these limitations/barriers to make a meaningful improvement in the morbidity and mortality associated with HFrEF.

Objectives The aim of this study was to compare the procedural and clinical outcomes of femoral arterial access with ultrasound (US) guidance with standard fluoroscopic guidance. Background Real-time US guidance reduces time to access, number of attempts, and complications in central venous access but has not been adequately assessed in femoral artery cannulation. Methods Patients (n = 1,004) undergoing retrograde femoral arterial access were randomized 1:1 to either fluoroscopic or US guidance. The primary end point was successful common femoral artery (CFA) cannulation by femoral angiography. Secondary end points included time to sheath insertion, number of forward needle advancements, first pass success, accidental venipunctures, and vascular access complications at 30 days. Results Compared with fluoroscopic guidance, US guidance produced no difference in CFA cannulation rates (86.4% vs. 83.3%, p = 0.17), except in the subgroup of patients with CFA bifurcations occurring over the femoral head (82.6% vs. 69.8%, p Conclusions In this multicenter randomized controlled trial, routine real-time US guidance improved CFA cannulation only in patients with high CFA bifurcations but reduced the number of attempts, time to access, risk of venipunctures, and vascular complications in femoral arterial access. (Femoral Arterial Access With Ultrasound Trial [FAUST]; NCT00667381 )

The ability of Acidithiobacillus caldus to grow aerobically using pyruvate, acetate, citrate, 2-ketoglutarate, succinate, and malate as either an electron donor and carbon source (heterotrophic growth), or as a carbon source when potassium tetrathionate was added as an electron donor (mixotrophic growth), was tested in chemostat cultures. Under both heterotrophic and mixotrophic conditions, organic acids were added to a sub-lethal concentration (50 μM). Under mixotrophic conditions, potassium tetrathionate was added to an excess concentration (10 mM). No cell growth was observed under heterotrophic conditions; however, effluent cell concentrations increased over threefold when pyruvate was coupled with potassium tetrathionate. Under these conditions, the effluent pyruvate concentration was reduced to below the detection limit (2 μM), and oxygen consumption increased by approximately 100%. Although pyruvate provided a carbon source in these experiments, ambient carbon dioxide was also available to the cells. To test whether At. caldus could grow mixotrophically using pyruvate as a sole carbon source and potassium tetrathionate as an electron donor, cells were batch cultured in a medium free of dissolved inorganic carbon, and with no carbon dioxide in the headspace. These experiments showed that At. caldus was able to convert between 65 ± 8 and 82 ± 15% of the pyruvate carbon to cellular biomass, depending on the initial pyruvate concentrations. This work is the first to identify a defined organic-carbon source, other than glucose, that At. caldus can assimilate. This has important implications, as mixotrophic and heterotrophic activity has been shown to increase mineral leaching in acidic systems.

We have examined the association of 14 tagging single nucleotide polymorphisms (tagSNPs) in peroxisome proliferator activated receptor-gamma transcripts 1 and 2 (PPARG1 and 2) and 5 tagSNPs in adiponectin (ADIPOQ) genes for their effect on type 2 diabetes mellitus (T2D) risk in Asian Indian Sikhs. A total of 554 T2D cases and 527 normoglycemic controls were examined for association with T2D and other subphenotypes of T2D. With the exception of a strong association of PPARG2/Pro12Ala with T2D (odds ratio, 0.13; 95% confidence interval, 0.03-0.56; P = .0007), no other tagSNP in the PPARG locus revealed any significant association with T2D in this population. Similarly, none of the tagSNPs in the ADIPOQ gene was associated with T2D susceptibility in single-site analysis. However, haplotype analysis provided strong evidence of association of these loci with T2D. Three-site haplotype analysis in the PPARG locus using the 2 marginally associated SNPs (P/rs11715073 and P/rs3892175) in combination with Pro12 Ala (P/rs1801282) revealed a strong association of 1 "risk" (CGC) (P = .003, permutation P = .015) and 1 "protective" (CAC) (P = .001, permutation P = .005) haplotype associated with T2D. However, the major effect still appears to be driven by Pro12Ala, as the association of these haplotypes did not remain significant when analyzed conditional upon Pro12Ala (P = .262). In addition, 2-site haplotype analysis in the ADIPOQ locus using only 2 marginally associated SNPs (AD/rs182052 and AD/rs7649121) revealed a significant protective association of the GA haplotype with T2D (P = .009, permutation P = .026). Multiple linear regression analysis also revealed significant association of an ADIPOQ variant (AD/rs12495941) with total body weight (P = .010), waist (P = .024), and hip (P = .021), although these associations were not significant after adjusting for multiple testing. Our new findings strongly suggest that the genetic variation in PPARG and ADIPOQ loci could contribute to the risk for the development of T2D in Indian Sikhs. Identification of causal SNPs in these important biological and positional candidate genes would help determine the true physiologic significance of these loci in T2D and obesity.

Objective: To compare the effectiveness of accessing the common femoral artery (CFA) using fluoroscopic guidance (FG) versus traditional anatomic landmark guidance (TALG) during cardiac catheterization and to determine the effect of the two modalities on the appropriateness for use of vascular closure devices (VCDs). Background: Previous studies have shown a consistent relationship between the head of the femur and the CFA, yet there is no prospective data validating the superiority of fluoroscopy-assisted CFA access. Methods: A total of 972 patients were randomized to either FG or TALG access. The primary endpoint of the study was the angiographic suitability of the puncture site for VCD use. Secondary endpoints included arteriotomy location, time and number of attempts needed to obtain access, and the incidence of vascular complications. Results: Of these, 474 patients were randomized into the FG arm and 498 patients into the TALG arm. A total of 79.5% of patients in the fluoroscopy arm and 80.7% in the traditional arm (P = 0.7) were deemed angiographically suitable for VCD based on the arteriotomy. The fluoroscopy group had significantly less arteriotomies below the inferior border of the head of the femur (P = 0.03). Total time for sheath insertion (105.7 ± 130.7 vs. 106.5 ± 152.6 sec) and number of arterial punctures (1.1 ± 0.4 vs. 1.1 ± 0.5) did not differ among the FG and TALG, respectively. The rates of vascular complications were not different. Conclusion: The angiographic suitability for VCD was not different between FG and TALG groups. Fluoroscopy decreased the number of low arteriotomies. The time to sheath insertion, number of arterial punctures needed to obtain access, and the incidence of complications were also similar. © 2009 Wiley-Liss, Inc.

National reports outlining disparities in oral health care in the United States have focused attention on ways to encourage health care providers to become more involved in the public health arena. Utilization of service-learning in professional health education programs is one method being explored. The purpose of this study was to conduct a retrospective review of a service-learning rotation within a dental hygiene public health course. The study utilized data sources generated by students as part of a course evaluation. These sources included student journals (qualitative/quantitative) and Likert-scaled (quantitative) and open-ended (qualitative) student satisfaction survey items. Mixed methodology data analysis techniques were used to analyze and triangulate data in order to form conclusions related to the effectiveness of service-learning as a teaching strategy in dental hygiene. This investigation suggests that service-learning is an effective learning strategy for increasing student awareness of underserved populations, cultural diversity, and ethical patient care. The study also suggests that service-learning helped students to determine their level of interest in public health as a career choice by giving them a real-world experience in public health patient care.

A recent meta-analysis on three genome-wide association (GWA) scans identified six loci (NOTCH2, THADA, ADAMTS9, JAZF1, CDC123/CAMKID and TSPAN8/LGRS) highly associated with type II diabetes (T2D) in Caucasians. This investigation seeks to confirm this association with diabetes and related metabolic traits in Khatri Sikh diabetics of North India. We genotyped highly significant variants from each locus in a case-control cohort consisting of 680 T2D cases and 637 normoglycemic (NG) controls. Only CDC123/CAMKID (rs12779790) replicated earlier evidence of association with T2D under a dominant model (odds ratio (OR): 1.27; 95% confidence interval (CI): 1.02-1.57; P=0.031) during initial testing. However, we could not confirm this association using multiple testing corrections. In a multiple linear-regression analysis, the same variant in the CDC123/CAMKID revealed a marked decrease in fasting insulin levels among 'G' (risk) allele carriers independently in NG controls (P=0.030) and in T2D cases (P=0.009), as well as in the combined sample (P=0.003) after adjusting for covariates. Evidence of impaired beta-cell function was also observed among 'G' (risk) allele carriers in T2D cases (P=0.008) and in a combined cohort (P=0.026). Our data could not confirm the role of the remaining variants with risk either for T2D or quantitative phenotypes measuring insulin secretion or insulin resistance. These findings suggest that CDC123/CAMKID could be a major risk factor for the development of T2D in Sikhs by affecting beta-cell function. To our knowledge, this is the first study reporting the role of recently emerging loci in this high-risk population from the South Asian subcontinent.

Elevated anti-angiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1), a soluble form of vascular endothelial growth factor receptor, and endoglin, a co-receptor for TGFbeta1, confer high risk of pre-eclampsia in healthy pregnant women. In this multicentre prospective study, we determined levels of these and related factors in pregnant women with type 1 diabetes, a condition associated with a fourfold increase in pre-eclampsia.Maternal serum sFlt1, endoglin, placental growth factor (PlGF) and pigment epithelial derived factor were measured in 151 type 1 diabetic and 24 healthy non-diabetic women at each trimester and at term.Approximately 22% of the diabetic women developed pre-eclampsia, primarily after their third trimester visit. In women with pre-eclampsia (diabetic pre-eclampsia, n = 26) vs those without hypertensive complications (diabetic normotensive, n = 95), significant changes in angiogenic factors were observed, predominantly in the early third trimester and prior to clinical manifestation of pre-eclampsia. Serum sFlt1 levels were increased approximately twofold in type 1 diabetic pre-eclampsia vs type 1 diabetic normotensive women at the third trimester visit (p0.05) and the normal rise of PlGF during pregnancy was blunted (p0.05). Among type 1 diabetic women, third trimester sFlt1 and PlGF were inversely related (r(2) = 42%, p0.0001). Endoglin levels were increased significantly in the diabetic group as a whole vs the non-diabetic group (p0.0001).Higher sFlt1 levels, a blunted PlGF rise and an elevated sFlt1/PlGF ratio are predictive of pre-eclampsia in pregnant women with type 1 diabetes. Elevated endoglin levels in women with type 1 diabetes may confer a predisposition to pre-eclampsia and may contribute to the high incidence of pre-eclampsia in this patient group.

The Snoring, Tiredness, Observed apnea, high blood Pressure (STOP)-Body mass index (BMI), Age, Neck circumference, and Gender (BANG) questionnaire is a well validated screening tool for diagnosis of Obstructive sleep apnea (OSA) by an in- lab sleep study. However, performance of STOP-BANG as a screening tool for diagnosis of OSA in patients undergoing portable monitoring (PM) sleep study has not been well validated. We conducted a retrospective chart review of patients older than 18 years who had unattended portable monitoring sleep study done at a VA medical center between June 2012 and October 2014. STOP-BANG questionnaire and Epworth sleepiness scale (ESS) were routinely done prior to study. Sensitivity, specificity, and positive predictive value (PPV) various STOP-BANG score thresholds were calculated for diagnosis of OSA defined by Apnea Hypopnea Index (AHI) ≥5. Out of 502 unattended portable monitoring sleep studies, there were 465 males and 37 females. STOP-BANG thresholds of ≥2 and 3 have high sensitivity of 99.8 and 98.9 %, respectively, but very low specificity. Higher score thresholds of ≥7 and 8 have high specificity of 95 and 98.3 %, and PPV of 98.1 and 98.5 %, respectively, but very low sensitivity. A threshold of ≥7 in patients with BMI ≥30 was 100 % specific. The false negative rate for unattended portable monitoring sleep study compared to in-lab study was 80 %. STOP-BANG score thresholds of ≥7 and 8 are highly specific and have high PPV and therefore can potentially reduce need of diagnostic sleep studies in selected patients. Score thresholds of ≤2 or 3 are highly sensitive for AHI ≥5 by unattended portable monitoring sleep study but have high false negative rates. Therefore, in-lab sleep study should be performed to rule out OSA.

This observational study: (a) compared serum creatinine (estimated glomerular filtration rate (EGFR)) to renal isotopeObservational study.VA Medical Center affiliated with Oklahoma University.Veterans with SCI and regularly followed in SCI clinic. Demographic and clinical data, as well as, EGFR, GFR, blood urea nitrogen (BUN) and serum creatinine levels, and presence of UTI, renal and urinary bladder lesions on renal nuclear scan, renal ultrasound, and cystoscopy studies were recorded.None.Urological lesions, UTI, and Mortality.For 161 patients with SCI and NGB the mean ± SD for EGFR was 104 ± 36 and 84 ± 32 for GFR. EGFR and GFR were positively correlated (r = 0.34, P = 0.015). GFR was significantly (P 0.05) more sensitive and specific in determining renal functional state. Neither measures were significant indicator for UTI, renal or urological lesions; GFR was a significant predictor of risk of death (1.2 times increase in risk per 10 unit drop in GFR) even after adjusting for age (P = 0.040).While GFR and EGFR are comparable measures of glomerular filtration, GFR was a more informative measure of renal functional state and risk of mortality than EGFR. Neither method predicted the presence of UTI related renal or urological lesions.

We investigate the effect of selection in a meta-genetic algo- rithm designed to optimize mutation rate control, based on the fitness of sequences relative to a defined optimum, in asexual evolution. Multiple innovations in the algorithm are required to achieve the evolution of optimal mutation rate control un- der selection. Before implementing selection, results from this improved algorithm clarify the optimal relationship of mutation rate to distance from the optimum as being a dou- ble sigmoid for binary sequences. Furthermore, the results clarify how such control functions depend on alphabet size, sequence length and the time horizon over which evolution is assessed. Incorporating selection leads to a distinctive shape of optimal mutation rate control function. This function has a mutation rate less that a third of 1/length at a Hamming dis- tance of one from the optimum and beyond. This surprising result for a simple, universally monotonic single-peaked fit- ness landscape highlights the need for further research using models such as this. Future work will therefore explore how this control function may vary, for instance with population size and alternative selection mechanisms common in Artifi- cial Life models.

BACKGROUND: Offspring of women with diabetes mellitus (DM) during pregnancy have a risk of developing metabolic disease in adulthood greater than that conferred by genetics alone. The mechanisms responsible are unknown, but likely involve fetal exposure to the in utero milieu, including glucose and circulating adipokines. The purpose of this study was to assess the impact of maternal DM on fetal adipokines and anthropometry in infants of Hispanic and Native American women.METHODS: We conducted a prospective study of offspring of mothers with normoglycemia (Con-O; n = 79) or type 2 or gestational DM (DM-O; n = 45) pregnancies. Infant anthropometrics were measured at birth and 1-month of age. Cord leptin, high-molecular-weight adiponectin (HMWA), pigment epithelium-derived factor (PEDF) and C-peptide were measured by ELISA. Differences between groups were assessed using the Generalized Linear Model framework. Correlations were calculated as standardized regression coefficients and adjusted for significant covariates.RESULTS: DM-O were heavier at birth than Con-O (3.7 ± 0.6 vs. 3.4 ± 0.4 kg, p = 0.024), but sum of skinfolds (SSF) were not different. At 1-month, there was no difference in weight, SSF or % body fat or postnatal growth between groups. Leptin was higher in DM-O (20.1 ± 14.9 vs. 9.5 ± 9.9 ng/ml in Con-O, p CONCLUSIONS: Maternal DM results in fetal hyperleptinemia independent of adiposity. HMWA appears to influence postnatal growth. Thus, in utero exposure to DM imparts hormonal differences on infants even without aberrant growth.

Preeclampsia (PE) affects approximately 5% of all pregnancies, but is increased several-fold in women with pre-gestational type 1 diabetes mellitus (T1DM). Increased oxidative stress and altered maternal plasma trace elements that modulate the antioxidant system have been implicated in PE. In non-diabetic women, increased plasma copper and iron and decreased manganese, selenium, and zinc have been associated with PE in cross-sectional studies. In a longitudinal study, we hypothesized that plasma levels of trace elements differ between T1DM women with vs. without subsequent PE. Samples were collected during the first (gestation 12.2 ± 1.9 weeks, [mean ± SD]), second (21.6 ± 1.5 weeks), and third (31.5 ± 1.7 weeks) trimesters of pregnancy, all before the onset of PE. We compared 23 T1DM women who subsequently developed PE with 24 T1DM women who remained normotensive; and we included 19 non-diabetic (non-DM) normotensive pregnant women as reference controls. Trace elements were measured using inductively coupled plasma mass spectroscopy. In T1DM women with subsequent PE vs normotensive, only plasma zinc was significantly higher at the first trimester, while copper:zinc and copper:high-density lipoprotein cholesterol ratios were higher throughout gestation (all P < .05). These findings persisted after adjustment for covariates. Higher copper:zinc ratios may contribute to oxidative stress in T1DM women who develop PE. Ratios of pro- to anti-oxidant factors may predict risk for PE in diabetic pregnancies more effectively than individual trace element levels.

An observational study based on retrospective review of the medical charts and death records of 163 individuals with traumatic spinal cord injuries (SCI). To determine whether HMG coA Reductase Inhibitor (‘statin’) use in a cohort of patients with traumatic SCI reduced overall and cause-specific mortality. An outpatient clinic designated for veterans with SCI at the Oklahoma City Veterans Administration Hospital. Review and analysis of the medical records of 163 veterans with traumatic SCI cared for between the years 2000 and 2014. Data collected included statin use, duration of statin use and intensity of statin therapy, as well as cause-specific mortality. Seventy five participants had taken statins for an average of 5.7±3.7 years, and had greater cardiovascular risk burdens than those who had not taken statins (n=88). Statin use was associated with a reduced risk of death. The mortality rate for those patients on statins was 33.8–49.9 per 1000 person-years, depending on assumptions made regarding residual effects of statin use. Under most assumptions this was significantly lower than the mortality rate seen in those not on statins (47.4–66.8 deaths per 1000 person-years). Within the statin group, neither duration nor average intensity of statin therapy affected mortality. Statin use among a cohort of veterans with traumatic SCI reduced all-cause mortality. This retrospective study ought to spur further investigations into the potential benefits of statin use among people with chronic SCI, and begin a discussion as to whether individuals with injuries should routinely be offered statin therapy.

A review of gender role (GR) differentiation from early childhood through adulthood was conducted on males and females in general, as well as on females affected by congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency or complete androgen insensitivity syndrome (CAIS). Additionally, retrospective and current, self-rated GR assessments were evaluated from women with CAH (n = 9) or CAIS (n = 12), and unaffected women and men ranging in age from 16 to 59 years. Overall, GR differentiation occurs in early childhood and persists through adulthood. With advanced age, this differentiation may evolve into androgyny or even become undifferentiated for the general population. While more studies of GR exist for girls and women with CAH compared to those affected by CAIS, some developmental patterns can be observed from the limited data that exist. First, girls and women with CAIS report a female GR that persists through adulthood. Second, girls and women with CAH are more likely to report less feminine/ more masculine play in childhood followed by interests in male-typical leisure activities and career choices in adulthood. However, our data indicate that women with CAH report more feminine/ less masculine patterns of GR with age. Self-reported GR for women with CAH was indistinguishable from that of women with CAIS at the time of study participation in adulthood. With the availability of effective medications for treating hormone deficiencies associated with CAH, affected women are expected to live a full lifespan. Thus, our understanding of psychosexual development into older age is warranted.

Differential DNA methylation has been suggested to contribute to differential activity of alleles C and T and thereby to genetic associations between the C/T(102) polymorphism in the 5-HT2A receptor gene (5HT2AR) and psychiatric disorders. We surveyed methylation in two CpG sites, which are specific to allele C. The majority of allele C-specific CpG sites were methylated in human temporal cortex and peripheral leukocytes and levels of methylation varied between individuals. Levels of methylation in the promoter correlated significantly with the expression of 5HT2AR. Methylation of allele C-specific CpG sites in the first exon correlated significantly with the expression of DNA methylase 1 (DNMT1) but not S-adenosylhomocysteine hydrolase (AHCY). These findings support the hypothesis that allele-specific DNA methylation is involved in regulation of 5HT2AR expression, influencing expression differences between alleles C and T.

Objective: To determine the extent of misreporting of energy intake (EI) and its anthropometric, demographic, and psychosocial correlates in a bi-racial cohort of young women. Research Methods and Procedures: This was a cross-sectional study of 60 black and 60 white young women, 18 to 21 years old, enrolled in a longitudinal study. Total energy expenditure was assessed using doubly labeled water. Self-reported EI was obtained from 3-day food records. BMI was computed from height and weight. Fat mass was assessed by DXA. Multivariate analyses examined racial differences on the extent of misreporting and its effect on other potential correlates of misreporting. Race-specific step-wise linear regression analysis was performed to examine the effect of BMI, parental education, and drive for thinness on misreporting of EI. Results: More white women tended to under-report EI than black women (22% vs. 13%, p = 0.07). In black women, under-reporting was significantly (p = 0.01) associated with drive for thinness score but was only marginally (p = 0.1) associated with BMI. Each point increase in drive for thinness score was associated with under-reporting by 40 kcal/d. In white women, under-reporting was significantly (p = 0.03) associated with higher parental education by 440 kcal/d and also only marginally (p = 0.09) with BMI. Discussion: This tendency for under-reporting of EI limits the use of self-reported EI in studying energy balance in free-living subjects. Most black and almost all white women in their late teens significantly under-reported their EI, whereas under-reporting was not as evident among lean young black women.

Common, but weakly penetrant, functional polymorphisms probably account for most of the genetic risk for breast cancer in the general population. Current polygenic risk models assume that component genes act independently. To test for potential gene-gene interactions, single nucleotide polymorphisms in ten genes with known or predicted roles in breast carcinogenesis were examined in a case-control study of 631 Caucasian women diagnosed with breast cancer under the age of 53 years and 1,504 controls under the age of 53 years. Association of breast cancer risk with individual genes and with two- and three-gene combinations was analyzed. Sixty-nine oligogenotypes from 37 distinct two- and three-gene combinations met stringent criteria for significance. Significant odds ratios (ORs) covered a 12-fold range: 0.5-5.9. Of the observed ORs, 17% differed significantly from the ORs predicted by a model of independent gene action, suggesting epistasis, i.e., that these genes interact to affect breast cancer risk in a manner not predictable from single gene effects. Exploration of the biological basis for these oligogenic interactions might reveal etiologic or therapeutic insights into breast cancer and other cancers.

In yeast Saccharomyces cerevisiae the G protein betagamma subunits (Ste4/Ste18) have long been known to transmit the signal required for mating. Here we demonstrate that GTPase-deficient mutants of Galpha (Gpa1) directly activate the mating response pathway. We also show that signaling by activated Gpa1 requires direct coupling to an RNA binding protein Scp160. These findings suggest an additional role for Gpa1 and reveal Scp160 as a component of the mating response pathway in yeast.

Alcohol abuse is a common human disorder with high rate of comorbidity with other psychiatric disorders. To identify candidate mechanisms for alcohol abuse, the expression of 12,626 genes was measured in postmortem temporal cortex from 11 subjects with a history of alcohol abuse or dependence, with or without other psychiatric diagnoses and compared pairwise with the expression in 11 nonalcoholic subjects matched for the other psychiatric diagnoses and demographics. Genes were defined to have altered expression in alcohol abuse if: 1) the gene showed decreased expression in at least 10 of 11 subjects with alcohol abuse, or showed increased expression in at least 10 of 11 subjects with this diagnosis compared to matched non-abusers (P 0.007, 2 test); or 2) the difference in the mean abuser/ non-abuser ratio for the gene from value of 1.0 was significant at P 0.05 (one sample t-test). In subjects with a history of alcohol abuse or dependence, 163 genes were changed significantly. The most abundant and consistent changes were in gene families encoding mitochondrial proteins, the ubiquitin system, and signal transduction. These alterations indicate disturbances in energy metabolism and multiple signaling mechanisms in the temporal cortex of subjects with a history of alcohol abuse or dependence. We hypothesize that these mechanisms may be related to alcohol abuse traits or longterm effects of alcohol. © 2003 Wiley-Liss, Inc.

Background and Objectives Apolipoprotein E ( APOE ) gene polymorphisms have been examined extensively in multiple global populations particularly due to their crucial role in lipid metabolism and cardiovascular disease. However, the overall contribution of APOE polymorphisms in type 2 diabetes (T2D) and coronary artery disease (CAD) in South Asians is still under-investigated. The objectives of this investigation were: 1) to evaluate the distribution of APOE polymorphisms in a large diabetic case–control sample from South Asia, 2) to examine the impact of APOE polymorphisms on quantitative risk factors of T2D and CAD, and 3) to explore the contribution of APOE genotypes in the response to anti-diabetic therapy. Subjects and Methods A total of 3564 individuals (1956 T2D cases and 1608 controls) used in this study were part of the Asian Indian Diabetic Heart Study/Sikh Diabetes Study (AIDHS/SDS). We assessed the association of APOE polymorphisms with T2D, CAD and cardiometabolic traits using logistic and linear regression analysis. Results and Conclusions No significant differences in the distribution of APOE genotypes were observed between T2D and CAD cases and controls. The APOE4 genotype carriers had moderately higher diastolic blood pressure (BP) (p=0.022), and lower HDL-cholesterol (p=0.026) compared to E4 non-carriers. Overall, the APOE genotype was not a significant predictor of cardiometabolic disease in this population. Further stratification of data from diabetic patients by APOE genotypes and anti-hyperglycemic agents revealed a significant (~23%) decrease in 2-hour glucose (p=0.004) and ~7% decrease in systolic BP (p APOE4 carriers compared to non-carriers on metformin and sulphonylurea (SU) combination therapy, and no such differences were seen in patients on other agents. Our preliminary findings point to the need for evaluating population-specific genetic variation and its interactions with therapeutic effects.

Objective To test the hypothesis that lower sex hormone–binding globulin (SHBG) concentrations are associated with heterozygosity for the G972R variant of the IRS-1 gene among adolescent girls with a history of precocious pubarche (PP) and hyperinsulinemic ovarian hyperandrogenism. Design Association study. Setting Academic research environment. Patient(s) Adolescent girls with a history of PP and healthy adolescent female control subjects. Intervention(s) Determine body mass index; measure serum androgen, insulin-like growth factor (IGF)–binding protein 1, lipids, IGF-1, and SHBG concentrations; perform glucose tolerance tests; and assay for G972R variant of the IRS-1 gene. Main outcome measure(s) Serum androgen, IGFBP-1, and SHBG concentrations; IRS-1 genotypes. Result(s) Twenty-five of 54 (45%) girls with a history of PP developed hyperinsulinemic ovarian hyperandrogenism at adolescence. Frequency of heterozygosity for G972 was 31% among girls with a history of PP, 40% among girls with hyperinsulinemic ovarian hyperandrogenism, and 19% among healthy control subjects. Sex hormone–binding globulin concentrations were lower among girls heterozygous for G972R variant. Predictors of progression from PP to hyperinsulinemic ovarian hyperandrogenism included chronological age, insulin, low-density lipoprotein cholesterol, and IGFBP-1 concentrations. Conclusion(s) The low mean SHBG concentration found among G972R carriers suggests that this variant may be a minor locus associated with development of hyperinsulinemic insulin resistance and ovarian androgen excess in girls with a history of PP.

Objective: To ascertain the extent of phenotypic heterogeneity for premature pubarche and polycystic ovary syndrome between and within families. Design: Association study. Setting: Academic research environment. Patient(s): Three families in which the propositus had presented with either premature pubic hair or adolescent hyperandrogenism. Intervention(s): Detailed medical histories, hormone determinations, and genotype analyses. Main Outcome Measure(s): Clinical phenotype. Genotypes for CYP21, HSD3B2 , G972R variant of IRS-1 , N363S variant of GRL , W64R variant of ADRB3 , CAG repeat in exon 1 of AR , Msp AI polymorphism in CYP17 , and R264C variant of CYP19 . Result(s): Significant phenotypic and genetic heterogeneity was observed both within and between families. In one family, CYP21 and IRS-1 variants were observed to co-segregate with symptoms of androgen excess and obesity. No genetic markers were consistently noted to associate with clinical features of hyperandrogenism in the other two families. Conclusion(s): The difficulties in classifying female family members as clearly affected or unaffected and lack of definitive male phenotype complicate the use of linkage analysis to identify the polycystic ovary syndrome genes. Each family is best considered on an individual basis to identify genetic markers that segregate with the clinical features of androgen excess.

Hemolytic anemia is aforme frusteof systemic lupus erythematosus (SLE), being observed months or even years before the onset of other clinical manifestations in some patients. We hypothesized that hemolytic anemia in those SLE-affected patients would identify a group of SLE pedigrees that share a high degree of genetic homogeneity. From 160 multiplex SLE pedigrees, we sought evidence for linkage in 35 (16 African-American, 17 European-American, and 2 Hispanic) who had at least one SLE-affected patient with hemolytic anemia. Significant linkage was present at 11q14 in the 16 African-American pedigrees, yielding a maximum two-point logarithm of odds (LOD) score of 4.5 at D11S2002. The segregation pattern of SLE in these African-American pedigrees suggested a dominant mode of inheritance and, when maximized across penetrance and disease allele frequencies, produced a multipoint LOD of 4.7. Multipoint analysis yielded a multipoint heterogeneity LOD score of 3.6 (α = 0.63), again with maximum LOD at D11S2002. Finally, markers typed 7 centimorgans to either side of D11S2002 achieved LOD scores of 3 or better by using the maximized model, supporting linkage to 11q14. Clearly, pedigree ascertainment based on select clinical manifestations is an important tool, capable of revealing otherwise cryptic genetic linkages in complex genetic diseases. Thus, we show strong evidence for an SLE susceptibility gene,SLEH1, near D11S2002 in African-American pedigrees multiplex for SLE that have at least one SLE-affected patient with hemolytic anemia.

Within the chronic medical illness literature, associations exist between caring for an affected child and parent mental health. The few studies examining both mothers and fathers provide mixed results. The purpose of this study is to examine associations between caregiver anxiety, depression, and parenting variables in caregivers of youth with SB as these relate to marital status, age, education, household income, work status, and child's severity of SB.The aim of this study is to examine associations between anxiety, depression, and parenting variables in caregivers of youth with spina bifida and how they relate to demographic and disease variables. Exploratory analyses examined the relationship between participation in support activities and depressive and anxious symptomatology and parenting characteristics.Eighty-four primary caregivers (49 mothers) of 51 youth with spina bifida completed measures of depressive and anxious symptomology, parenting stress, parent overprotection, and perceived child vulnerability.There were differences between mothers and fathers on several parenting characteristics; however, these were related more to marital status and employment than to gender of the caretaker per se. In the 33 married/remarried couples for whom both spouses participated, stress for the mothers was correlated with stress for the fathers. This correlation was strongest in the 12 married couples in which the mother works. Higher perceived vulnerability scores were reported in parents of SB patients in the younger age group, especially preschoolers (0-4 years). Parents of children with shunts reported more anxiety, depression and perceived child vulnerability. Both male and female caregivers of younger children reported significantly higher protectiveness scores. Involvement in recreational activities with other families affected by SB was associated with more positive parenting characteristics for mothers.Stress and protectiveness were found to be positively correlated (r0.6); depression, anxiety, and perceived vulnerability were not (0.3r-0.3). Overall, mothers reported more stress and anxiety than fathers. Higher perceived vulnerability scores were reported in parents of SB patients in the younger age group, especially preschoolers (0-4 years). Parents of children with shunts reported more anxiety, depression and perceived child vulnerability. Both male and female caregivers of younger children reported significantly higher protectiveness scores compared to caregivers of older children. Involvement in recreational activities with other families affected by SB was associated with more positive parenting characteristics for mothers. There were differences between mothers and fathers on several parenting characteristics; however, these were related more to marital status and employment than to gender of the caretaker per se. Limitations to the current study qualify our results and conclusions. Associations do not prove causation. Our measure of parent protection had a lower Cronbach's alpha score for male caregivers (0.68) than female caregivers (0.83), consistent with an examination of the factor structure of the PPS that found the measure to have a poor factor structure and limited reliability in samples with a chronic medical condition.Anxiety, depression, and parenting characteristics were differentially impacted by variables such as caregiver and child age, shunt status, and employment status/income for parents of youth with SB. Interventions to improve parenting skills and mental health of these caregivers can be designed to target specific needs of parents. Groups such as the Greater Oklahoma Disabled Sports Association (GODSA) offer real-world support to improve the lives of caregivers of SB children, and should be studied further to optimize outcomes for children.

OBJECTIVES: Direct DNA testing is now available for hereditary pancreatitis (HP). This study aimed to identify the factors that motivated individuals to participate in research and to determine how research participants used their genetic test results. METHODS: A survey was mailed to 247 participants (110 male, 137 female) who were ≥18 yr of age and living in the US. Data analysis was primarily a description of frequency distribution of the responses. RESULTS: Ninety-one of 247 participants (37%) completed the survey. Of the 55 female and 36 male respondents, 60% were 31–55 yr old, and a total of 54% tested positive for HP. The most common reason for participating in research was “to help a relative/family member” (61%), and genetic testing was pursued because of “the disturbance of seeing affected relatives” (48%) and “the desire to help future generations” (33%). Perceived risk of developing HP in the future was the least important motivating factor in seeking genetic testing. Sixty-two percent of respondents had received their genetic test results. All but one chose to share their results with at least one person: most often with family members (96%) and physicians (62%), and least often with insurance companies (4%). The most common influential factor in withholding information was “the fear of insurance discrimination” (23%). CONCLUSIONS: The major motivations to participate in the HP genetic research study were to obtain genetic testing and to help current family members and future generations. The major concern was insurance discrimination. Participants clearly appreciate the availability of genetic testing for HP. These results suggest that a mechanism to disclose results to research participants should be considered, and effective ways to protect at-risk individuals from insurance discrimination must remain a genetics health care priority.

BACKGROUND—Hereditary pancreatitis (HP) is a rare autosomal dominant disorder with variable expression and an overall lifetime penetrance of 80%. We hypothesised that (1) monozygotic twins within similar environments would develop the typical signs of HP at a similar age, and (2) if penetrance were due to modifier genes or environment, all twin pairs would be concordant for expression of HP. AIM—Identify monozygotic twins with HP and determine the penetrance, concordance, and age of onset of symptoms. METHODS—Twins from HP kindreds were identified from the Midwest Multicenter Pancreatic Study group database, referrals, and literature searches. Each twin set was assessed for phenotypic expression, concordance, and difference in age of phenotypic onset of pancreatitis. The difference in onset of symptoms for symptomatic affected non-twin sibling pairs as well as non-twin pairs that were mutation, sex, and age matched were calculated as two comparison groups. RESULTS—Seven of 11 monozygotic pairs identified were suitable for evaluation and four were concordant for pancreatitis. Forty eight affected sibling pairs and 33 pairs of mutation, sex, and age matched (cationic trypsinogen R122H (30 pairs) and N29I (three pairs)) subjects were identified for comparison groups. The median (quartiles Q1, Q3) difference in the age of phenotypic onset in the concordant twins was 1 (0, 2.4) years, 2 (1, 6) for the affected siblings, and 7 (2, 15) years in the comparison control group. Three of the seven sets of twins (43%) were discordant for phenotypic expression of pancreatitis. The overall penetrance in the seven pairs of monozygotic twins was 78.6%. CONCLUSIONS—Genetic and/or environmental factors contribute to expression and age of onset of HP. Nuclear genes or general environmental factors alone cannot explain the 80% penetrance. Determining the mechanism of non-penetrance may help in developing a strategy to prevent the phenotypic expression of pancreatitis in individuals with an underlying genetic predisposition. Keywords: hereditary pancreatitis; genetic; twins; penetrance; trypsinogen

Objective: To identify genetic markers associated with premature pubarche in children and hyperandrogenism in adolescent girls. Design: Association study. Setting: Academic research environment. Patient(s): Forty children with premature pubarche (PP), 29 adolescent girls with hyperandrogenism (HA), and 15 healthy control women. Intervention(s): None. Main Outcome Measure(s): Genetic variations at five loci selected because of known associations with hyperandrogenism, insulin resistance, hyperinsulinemia, or obesity. Result(s): Heterozygosity for CYP21 mutations was identified in 14 of 40 (35%) PP, 8 of 29 (28%) HA, and 1 of 30 (3%) controls. Heterozygosity for HSD3B2 variants was identified in 3 of 40 (7.5%) PP, 5 of 29 (17%) HA, and 0/15 controls. Among the PP, 11 of 80 (14%), 5 of 80 (6%), and 7 of 80 (9%) alleles showed the IRS-1 , GRL , and ADRB3 variants, respectively. Among the HA, 5 of 58 (8.6%), 3 of 58 (5%), and 6 of 58 (10%) alleles showed the IRS-1 , GRL , and ADRB3 variants, respectively. Among the control participants, variant allele frequency was 1 of 30 (3.3%) for IRS-1 , 2 of 30 (6.6%) for GRL , and 2 of 30 (6.6%) for ADRB3 . Conclusion(s): Our findings suggest that the development of PP and HA can be associated with the occurrence of multiple sequence variants at five susceptibility loci, especially steroidogenic enzyme genes. This approach offers a novel paradigm to investigate and identify the genetic factors relevant to polycystic ovary syndrome.

The lipoprotein lipase (LPL) enzyme plays a major role in lipid metabolism, primarily by regulating the catabolism of triglyceride (TG)-rich lipoprotein particles. The gene for LPL is an important candidate for affecting the risk of atherlosclerosis in the general population. Previously, we have shown that the HindIII polymorphism in intron 8 of the LPL gene is associated with plasma TG and HDL-cholesterol variation in Hispanics and non-Hispanic whites (NHWs). However, this polymorphism is located in an intron and hence may be in linkage disequilibrium with a functional mutation in the coding region or intron-exon junctions of the LPL gene. The aim of this study was to initially screen the LPL coding region and the intron-exon junctions by single-strand conformation polymorphism (SSCP) analysis for mutation detection in a group of 86 individuals expressing the phenotype of high TG/low HDL, followed by association studies in a population-based sample of 1,014 Hispanics and NHWs. Four sequence variations were identified by SSCP and DNA sequencing in the coding region of the gene, including two missense mutations (D9N in exon 2 and N291S in exon 6), one samesense mutation (V108V in exon 3), and one nonsense mutation (S447X in exon 9). Multiple regression analyses, including these four mutations and the HindIII polymorphic site, indicate that the association of the HindIII site with plasma TG (P=0.001 in NHWs and P=0.002 in Hispanics) and HDL-cholesterol (P=0.007 in NHWs and P=0.127 in Hispanics) is independent of all other LPL variable sites examined. These observations reinforce the concept that the intronic 8 HindIII site is functional by itself and provide a strong rationale for future comprehensive functional studies to delineate its biological significance.

Human apolipoprotein C-IV (apoC-IV, protein; APOC4, gene) is a new member of the APO E/C1/C2 gene cluster. In transgenic mice, human apoC-IV is predominantly associated with very low-density lipoprotein (VLDL) and thus may play an important role in lipid metabolism. To our knowledge, the extent and nature of APOC4 genetic variation and its role in lipid metabolism are unknown. In this study we have assessed the presence of genetic variation in all three exons of APOC4 and their flanking intronic sequence by SSCP and DNA sequencing. A total of five point mutations were observed, including two in the non-coding part of exon 1 (A609G and G620A), two in exon 2 (codons 36 and 52) and one in exon 3 (codon 96). The three mutations in exons 2 and 3 predict amino acid substitutions, Leu36Pro, Gly52Asp, and Leu96Arg. The frequencies of the variant alleles were: 0.010 for 609G, 0.039 for 620A, 0.502 for Pro36, 0.003 for Asp52 and 0.357 for Arg96. Significant pairwise linkage disequilibrium was observed between five of the ten APOC4 pairs, including nt. 620/codon 36, nt. 620/codon 96, codon 36/codon 52, codon 36/codon 96 and codon 52/codon 96. A general linear model analysis reveled a significant association of the Leu36Pro and the Leu96Arg polymorphisms with triglyceride levels in women. This is consistent with the proposed role of apoC-IV in triglyceride metabolism. The characterization of APOC4 genetic variation may lead to the identification of a specific role of apoC-IV in lipid metabolism or in other physiologic pathways.

Families are being increasingly recognized as carrying an inherited susceptibility for pancreatic cancer, apparently unrelated to any currently recognized syndrome. The authors provide a review of the current evidence for familial susceptibility to pancreatic cancer. A formal segregation analysis of the pattern of inheritance of pancreatic cancer in 70 families from the National Registry for Familial Pancreatic Cancer is described. This analysis suggests a single major gene with an autosomal dominant mode of inheritance controlling susceptibility for pancreatic cancer in these families.

Factor XIII (F XIII), a plasma transglutaminase, is essential for normal hemostasis and fibrinolysis. Plasma F XIII consists of two catalytic A (F XIIIA) and two non-catalytic B (F XIIIB) subunits. Activated F XIII is involved in the formation of fibrin gel by covalently crosslinking fibrin monomers. As the characteristics of the fibrin gel structure have been shown to be associated with the risk of coronary heart disease (CHD), F XIII activity may play a seminal role in its etiology. In this investigation, we determined plasma F XIII activity in two racial groups, including Asian Indians (n = 258) and Chinese (n = 385). Adjusted plasma F XIII activity was significantly higher in Indian men (142 vs. 110%; P

In an earlier investigation, we did not detect a major genetic component to lung cancer in families of nonsmoking lung cancer probands. However, heterogeneity with respect to familial aggregation, based on probands' age at diagnosis, was evident. We reanalyzed our previously collected data of 257 families, stratified by age at diagnosis of the probands, using complex segregation analysis. We specifically tested the effects of a Mendelian diallelic gene, history of tobacco use, and history of selected chronic lung diseases in families with a proband diagnosed at the age of 60 years or older and in families with a younger proband (i.e. , under 60 years of age). Cases were identified from the Metropolitan Detroit Cancer Surveillance System. Information on lung cancer occurrence, smoking history, and chronic respiratory diseases in first-degree relatives was obtained for 210 older probands and for 47 younger probands. In older probands' families, no evidence of a major genetic effect was detected. A history of emphysema and tobacco-smoke exposure were found to be significant risk factors. In younger probands' families, a Mendelian codominant model with significant modifying effects of smoking and chronic bronchitis best explained the observed data. Our results suggest the presence of a high-risk gene contributing to early-onset lung cancer in a population where the probands are nonsmokers.

Elevated levels of lipoprotein(a) [Lp(a)] are associated with increased risk for coronary heart disease (CHD). However, racial differences in both Lp(a) levels and their associated CHD risk are observed, with African Americans having, on average, higher Lp(a) levels than US whites but not the expected increase in CHD risk. We determined Lp(a) levels and their correlates in a large cohort (n = 2379) of black and white girls, ages 9 to 10 years, at the baseline visit of a longitudinal study of obesity development, the National Heart, Lung, and Blood Institute Growth and Health Study. Lp(a) levels were available for 1269 girls. The median Lp(a) level in black girls was over 3-fold higher than that in white girls. Associations were examined between Lp(a) levels and low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, apolipoprotein B, triglycerides, adiposity, pubertal maturation stage, body fat patterning (triceps/truncal skinfold ratio), and dietary fat (Keys’ score). In black girls multiple regression analysis identified LDL-C ( P P = .08) as predictors of Lp(a) levels. In white girls only LDL-C ( P = .02) was associated with Lp(a). In conclusion, the level of Lp(a) was significantly higher in black girls. Our study also revealed a racial difference in correlates of Lp(a), such as LDL-C and adiposity. Whether this racial difference is due to an underlying biologic difference or is merely a reflection of a greater statistical power to detect a relationship with the level, which was 2.5-fold higher in black girls than in white girls, needs further investigation. (J Pediatr 1999;135:169-76)

Serum PEDF levels (mean (S.D.)) were increased in 96 Type 2 diabetic vs. 54 non-diabetic subjects; 5.3 (2.8) vs. 3.2 (2.0)mug/ml, p

For complex disorders where the actions of several interacting loci must be taken into account, current methods of joint linkage analysis are problematic. We have undertaken an exploration of simultaneous search statistics originally proposed by Dupuis et al. [1995]. Additionally, we have extended these methods slightly and propose here a simple simultaneous search statistic based upon the single-point allele sharing statistic calculated from GENEHUNTER (GH). The use of conditional search techniques is also explored.

Genetic studies carried out mainly in European and European-derived populations have shown that common polymorphisms in genes coding for apolipoproteins are significant determinants of serum lipoprotein-lipid levels variation. However, except for a few sporadic studies, the distribution of apolipoprotein polymorphisms and their association with serum lipoprotein-lipid levels have not been evaluated systematically in African or African-derived populations. In this investigation we have studied five apolipoprotein polymorphisms, including APOA1/MspI-75 bp, APOA1/MspI+83 bp, APOC3/PvuII, APOE, and APOH in 786 Africans (493 men, 293 women) from Nigeria. The sample is comprised of Nigerian civil servants consisting of 462 junior staff (less affluent) and 324 senior staff (more affluent) where staff status is a correlate of their socioeconomic status. We first examined genetic associations in the total sample stratified by gender to determine the role of apolipoprotein polymorphisms in affecting serum lipid profile in the general population, and then by staff status to evaluate possible gene-environment interactions. In the total sample, the APOC3/PvuII polymorphism showed significant effect on HDL-cholesterol (P = 0.029) and HDL3-cholesterol (P = 0.009) in women, and the APOE polymorphism was significantly associated with total cholesterol (P = 0.031) and LDL-cholesterol (P = 0.0006) in women. Multiple regression analyses showed that the APOC3/PvuII polymorphism accounts for about 2 and 3% of the variation in HDL-cholesterol and HDL3-cholesterol, respectively, in women; while the APOE polymorphism accounted for about 5 and 6% of the variation in total- and LDL-cholesterol, respectively, in women. Whereas the association of the APOE polymorphism was independent of the staff status, the significant affect of the APOC3/PvuII polymorphism on HDL- and HDL3-cholesterol was confined to senior staff women where it explained about 7% of their variation. We also observed an interaction between staff and the APOH polymorphism in affecting cholesterol levels. The APOH polymorphism showed significant association with total cholesterol (P = 0.010) and LDL-cholesterol (P = 0.016) in senior staff women and explained about 7 and 5% of their phenotypic variations, respectively. These data indicate that gene-environment interaction may play an important role in affecting serum lipid profile in African populations.

Summary Genetic epidemiological studies have shown that genetic factors are important in the pathogenesis of the idiopathic inflammatory bowel diseases (IBD), Crohn disease (CD), and ulcerative colitis (UC). A genome screen in the United Kingdom found linkage of IBD to a 41-cM region of chromosome 12, surrounding D12S83. We aimed to replicate this linkage and to narrow the region of interest. Nonparametric linkage analyses at microsatellites surrounding D12S83 were performed in 122 North American Caucasian families containing 208 genotyped IBD-affected relative pairs. Transmission/disequilibrium tests (TDTs) were also performed. We confirmed that IBD is linked to chromosome 12 (peak GENEHUNTER-PLUS LOD* score 2.76 [ P = .00016] between D12S1724 and D12S90). The evidence for linkage is contributed by both the group of CD-affected relative pairs (peak GENEHUNTER-PLUS LOD* score 1.79 [ P = .0021] between D12S1724 and D12S90) and the group of UC-affected relative pairs (peak GENEHUNTER-PLUS LOD* score 1.82 [ P = .0019] at D12S335). The TDT is positive at the D12S83 locus (global χ 2 = 16.41, 6 df, P = .012). In conclusion, we have independently confirmed linkage of IBD to the chromosome 12 region that we investigated. A positive TDT at D12S83 suggests that we have greatly narrowed the chromosome 12 region that contains an IBD locus.

A common polymorphism at codon 192 in the human paraoxonase (PON) 1 gene has been shown to be associated with increased risk for coronary heart disease (CHD) in Caucasian populations. However, these findings have not been reported consistently in all Caucasian and non-Caucasian populations, suggesting that this is not a functional mutation but may mark a functional mutation present in either PON1 or a nearby gene. Recently, two other PON-like genes, designated "PON2" and "PON3," have been identified, and they are linked with the known PON1 gene on chromosome 7. Identification of additional polymorphisms in the PON-gene cluster may help to locate the functional polymorphism. In this report, we describe the existence of a common polymorphism at codon 311 (Cys-->Ser; PON2*S) in the PON2 gene, as well as its association with CHD alone and in combination with the PON1 codon 192 polymorphism in Asian Indians. The frequency of the PON2*S allele was significantly higher in cases than in controls (.71 vs. .61; P=.016). The age- and sex-adjusted odds ratio (OR) was 2.5 (95% confidence interval &sqbl0;95% CI&sqbr0;=1.8-3.1; P=.0090) for the PON2*S allele carriers. Further stratification of the PON2*S association, on the basis of the presence or absence of the PON1*B allele, showed that the CHD risk associated with the PON2*S allele was confined to PON1*B-allele carriers. Likewise, the PON1*B-allele risk was present only among PON2*S carriers. Age- and sex-adjusted ORs for the PON2*S and PON1*B were 3.6 (95% CI=2.6-4.6; P=.011) and 2.9 (95% CI=2.4-3.5; P=.0002) among the PON1*B and PON2*S carriers, respectively. Our data indicate that both polymorphisms synergistically contribute to the CHD risk in this sample and that this genetic risk is independent of the conventional plasma lipid profile.

Background Patients with postural tachycardia syndrome ( POTS ) have exaggerated orthostatic tachycardia often following a viral illness, suggesting autoimmunity may play a pathophysiological role in POTS . We tested the hypothesis that they harbor functional autoantibodies to adrenergic receptors ( AR ). Methods and Results Fourteen POTS patients (7 each from 2 institutions) and 10 healthy subjects were examined for α1AR autoantibody‐mediated contractility using a perfused rat cremaster arteriole assay. A receptor‐transfected cell‐based assay was used to detect the presence of β1AR and β2AR autoantibodies. Data were normalized and expressed as a percentage of baseline. The sera of all 14 POTS patients demonstrated significant arteriolar contractile activity (69±3% compared to 91±1% of baseline for healthy controls, P P cAMP response curves to the left, consistent with enhanced β1AR and β2AR agonist activity. Autoantibody‐positive POTS sera demonstrated specific binding to β1AR, β2AR, and α1AR in transfected cells. Conclusions POTS patients have elevated α1 AR autoantibodies exerting a partial peripheral antagonist effect resulting in a compensatory sympathoneural activation of α1 AR for vasoconstriction and concurrent β AR ‐mediated tachycardia. Coexisting β1 AR and β2 AR agonistic autoantibodies facilitate this tachycardia. These findings may explain the increased standing plasma norepinephrine and excessive tachycardia observed in many POTS patients.