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154. Diabetes Mellitus.

Author

Runge, Marschall S., Patterson, Cam, and Lowe, William L.

Abstract

Diabetes mellitus is characterized by fasting and postprandial hyperglycemia. Type 1 diabetes occurs secondary to autoimmune destruction of the insulin-secreting pancreatic β-cells, whereas type 2 diabetes results from a deficiency of insulin action secondary to a combination of insulin resistance and relative β-cell dysfunction. Familial clustering of type 1 and 2 diabetes has suggested a genetic contribution to the etiology of the diseases, but monozygotic twin and other studies have indicated that environmental factors also contribute to their etiology. Although relatively rare monogenic forms of diabetes have been described, type 1 and 2 diabetes are, in general, complex, polygenic diseases. [ABSTRACT FROM AUTHOR]

Published
2006
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155. Transcription Factor-Directed Differentiation of Stem Cells Along an Endocrine Lineage.

Author

Conn, P. Michael, Lester, Linda B., and Lowe, William L.

Abstract

Loss of endocrine gland function from a variety of causes (e.g., autoimmune destruction, infection, injury) is commonly encountered in clinical endocrinology. Although hormone replacement is generally adequate to replace the basic function of the gland and maintain viability, it typically cannot reproduce the intricate regulation of hormone secretion. Thus, despite the availability of hormone replacement, those who require it are often at risk for the development of long-term problems (e.g., microvascular complications or severe hypoglycemia in diabetes, complications of long-term overreplacement of hydrocortisone or inadequate hydrocortisone replacement during times of stress). Thus cell replacement therapy capable of restoring endocrine function similar to that of the native gland would represent a major therapeutic advance. To that end, the differentiation of stem cells to generate new endocrine cells offers great potential. [ABSTRACT FROM AUTHOR]

Published
2005
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156. Growth Factors.

Author

Melmed, Shlomo, Conn, P. Michael, LeRoith, Derek, and Lowe, William L.

Abstract

In this chapter, we discuss various aspects of classic growth factors and their relevance to endocrinology. Although "growth factors" have traditionally been considered to be represented by the family of peptide growth factors, this definition is too restricted given that nonpeptide hormones, e.g., steroid hormones such as estrogen, also stimulate cell growth. Similarly, growth factors have traditionally been considered as tissue factors, functioning locally as autocrine or paracrine factors, as compared to hormones that function in a classic endocrine fashion. We focus here on insulin-like growth factors (IGFs), which represent a paradigm that has both endocrine and autocrine/paracrine modalities. We then discuss other members of classic growth factor families, allowing the reader to compare and contrast them to the IGFs. We also briefly address the numerous cell-surface receptors and the cross talk between receptors. Because we cannot describe here all aspects of the growth factors, their receptors, and interacting proteins, we refer the reader to various other excellent reviews in the Selected Reading section. [ABSTRACT FROM AUTHOR]

Published
2005
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157. Compost Resampling Results at Umatilla Depot Activity, Hermiston, Oregon

Author

WESTON (ROY F) INC WEST CHESTER PA, Hammell, John O., Lowe, WIlliam L., WESTON (ROY F) INC WEST CHESTER PA, Hammell, John O., and Lowe, WIlliam L.

Abstract

Previous Field demonstrations conducted by the U.S. Army Environmental Center (USAEC)have shown that composting can he an effective bioremediation technology for explosives - contaminated soils. Finished compost exhibits extensive reductions in extractable explosives as well as in toxicity compared to the siting materials. USAEC has now conducted testing to evaluate potential long-term changes in compost characteristics, such as my result following redisposal of finished compost. Finished compost form a previous field demonstration was analyzed for extractable explosives, leachable explosives and TNT intermediates (wing USEPA's Multiple Extraction Procedure), and extractable nitratelnitrite. Low levels of extractable explosives were observed in resampled compost consistent with samples from the end of the compost operation. Extractable explosives in the Multiple Extraction Procedure generally declined with successive extractions. As would he expected for organic compost material, detectable nitrate/nitrite concentrations were present in all samples.

Published
1995

160. Decontamination Methods for Explosives-Contaminated Lagoon Rock

Author

WESTON (ROY F) INC WEST CHESTER PA, Salacka, Frye, Russell W., Martino, Joseph F., Lowe, William L., WESTON (ROY F) INC WEST CHESTER PA, Salacka, Frye, Russell W., Martino, Joseph F., and Lowe, William L.

Abstract

The U.S. Army Environmental Center has conducted a field demonstration of composting explosives-contaminated soils from Explosives Washout Lagoons at Umatilla Depot Activity (UMDA) in Hermiston, Oregon. The lagoons are lined with gravel and rocks which may have to be separated from soils prior to composting. Consequently, USAEC conducted this study to evaluate methods for decontaminating lagoon gravel and rocks. This testing was conducted in two phases. In the first test phase, aqueous washing using spray/screen and tumbler methods was evaluated. In the second phase, the potential enhancement achievable by the use of chemical washing solutions (aqueous solutions of surfactants or other reagents) was evaluated. The results of Phase I testing showed that aqueous washing alone could remove the majority of explosives contamination from lagoon gravel and rock. Hot washwater (140 degrees F) may be more effective than lower temperature washwater (70 degrees F) in removing explosives from the rock. The site specific cleanup criteria for UMDA (30 mg/kg TNT and 30 mg/kg RDX) were not achieved by water washing alone. However, testing in Phase II showed that a variety of chemical reagents, including biodegradable surfactants, could be used following initial water washing to achieve the lower required explosives levels on the rock and gravel. Initial explosives levels were lower in Phase 2 than in Phase 1. In addition to these rock and gravel washing tests, a preliminary desk top evaluation of Hot Gas Decontamination for contaminated rock and gravel was conducted. This evaluation indicated that several existing equipment configurations may be adaptable to this use. Further testing of candidate equipment may be useful in confirming performance and developing design and operating criteria.

Published
1994

161. Summary Report for Evaluation of Compost Sample Drying Methods

Author

WESTON (ROY F) INC WEST CHESTER PA, Frye, Russell W., Martino, Joseph F., Lowe, William L., WESTON (ROY F) INC WEST CHESTER PA, Frye, Russell W., Martino, Joseph F., and Lowe, William L.

Abstract

The U.S. Army Environmental Center (USAEC), formerly the U.S. Army Toxic and Hazardous Materials Agency, has evaluated composting methods for treatment of explosive-contaminated soils and sediments at Army installations. Previous work in Support of these efforts developed a compost sample preparation scheme, consisting of air drying followed by milling, to reduce analytical variability in the heterogeneous compost matrix. While this procedure successfully reduced variability, USAEC determined that the time required for air drying results in undesirable delays in analytical results turnaround. The time required to air dry compost samples was typically 3 to 5 days. As a result of this determination, this study on alternative drying methods was conducted. Three drying methods were examined in this test: (1) air drying as used in previous work, (2) oven drying at 60 deg C, and (3) convection oven drying at 60 deg C. The maximum drying temperature of 60 deg C was based upon the low melting points of the target explosives. Drying methods were compared in terms of time required to achieve specified dryness levels and potential effects on residual explosives levels. The results of this testing indicate that convection oven drying at 60 deg C results in rapid and satisfactory drying of compost samples. Required dryness levels (greater than 95% solids) were achieved in approximately 12 hours with this drying method. These tests demonstrate that conventional, commercially available convection ovens can be used for compost sample preparation during field operations.

Published
1994

166. Arsenic Contaminated Groundwater Treatment Pilot Study at the Sharpe Army Depot (SHAD) Lathrop, California. Task Order 9

Author

WESTON (ROY F) INC WEST CHESTER PA, Lowe, William L., Wujcik, Walter J., Marks, Peter J., WESTON (ROY F) INC WEST CHESTER PA, Lowe, William L., Wujcik, Walter J., and Marks, Peter J.

Abstract

Groundwater treatment for the removal of contaminants may be needed at a number of U.S. Army installations, including Army depots. Treatability of potentially applicable technologies may be needed to facilitate design and operation of treatment systems. The study described here is a treatability test for the removal of arsenic from groundwater. The goal of the study was to evaluate the effectiveness of ion exchange (IE), granular activated carbon (GAC) , and activated alumina (AA) for the removal of arsenic from groundwater. Laboratory IE, GAC, and AA isotherms were conducted to select the two best performing carbon and resin types and the operating pH for the carbon and alumina media for further testing. Pilot scale continuous flow column tests were conducted at Sharpe Army Depot in Lathrop, California, using the two carbons (Calgon Filtrasorb 400 and Hydrodarco 3000) and the two resins (Amberlite IRA 402 and Ionac A-641) selected during the isotherm studies. Alcoa F-1 AA was also used during the pilot scale continuous flow column tests. The carbon and AA were tested at an adjusted pH of 4.0 and the resin was tested at natural pH. A pilot scale, conventional packed column air stripper was used to remove volatile organics (primarily trichloroethene) from the ground water prior to treatment by the pilot scale columns. The data from the laboratory and pilot study were analyzed and a report was prepared to present the results and conclusions.

Published
1990

167. Task Order 7. Use of Activated Carbon for Treatment of Explosives-Contaminated Groundwater at the Milan Army Ammunition Plant (MAAP).

Author

WESTON (ROY F) INC WEST CHESTER PA, Dennis, Ronald M., Wujcik, Walter J., Lowe, William L., Marks, Peter J., WESTON (ROY F) INC WEST CHESTER PA, Dennis, Ronald M., Wujcik, Walter J., Lowe, William L., and Marks, Peter J.

Abstract

The primary objective of this task was to determine the feasibility of using GAC to treat ground water contaminated by explosives at the Milan Army Ammunition Plant (MAAP) in Milan, Tennessee. Laboratory GAC isotherm studies were conducted and two carbons, Atochem, Inc. GAC 830 and Calgon Filtrasorb 300, were selected for further testing in continuous flow GAC columns. Three pilot scale continuous flow GAC column tests were performed at MAAP using the two carbons selected from the laboratory GAC isotherm studies. The results from the laboratory and pilot studies are presented in this report. They show that concurrent removal of explosives such as TNT, RDX, HMX, Tetryl, and nitrobenzenes from ground water using continuous flow granular activated carbon is feasible.

Published
1990

170. Short chain fatty acids and their receptors: new metabolic targets.

Author

Layden, Brian T., Angueira, Anthony R., Brodsky, Michael, Durai, Vivek, and Lowe, William L.

Abstract

Fatty acids are carboxylic acids with aliphatic tails of different lengths, where short chain fatty acids (SCFAs) typically refer to carboxylic acids with aliphatic tails less than 6 carbons. In humans, SCFAs are derived in large part from fermentation of carbohydrates and proteins in the colon. By this process, the host is able to salvage energy from foods that cannot be processed normally in the upper parts of the gastrointestinal tract. In humans, SCFAs are a minor nutrient source, especially for people on Western diets. Intriguingly, recent studies, as highlighted here, have described multiple beneficial roles of SCFAs in the regulation of metabolism. Further interest in SCFAs has emerged due to the association of gut flora composition with obesity and other metabolic states. The recent identification of receptors specifically activated by SCFAs has further increased interest in this area. These receptors, free fatty acid receptor-2 and -3 (FFAR2 and FFAR3), are expressed not only in the gut epithelium where SCFAs are produced, but also at multiple other sites considered to be metabolically important, such as adipose tissue and pancreatic islets. Because of these relatively recent findings, studies examining the role of these receptors, FFAR2 and FFAR3, and their ligands, SCFAs, in metabolism are emerging. This review provides a critical analysis of SCFAs, their recently identified receptors, and their connection to metabolism. [ABSTRACT FROM AUTHOR]

Published
2013
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174. Use of diverse electronic medical record systems to identify genetic risk for type 2 diabetes within a genome-wide association study.

Author

Kho, Abel N., Hayes, M. Geoffrey, Rasmussen-Torvik, Laura, Pacheco, Jennifer A., Thompson, William K., Armstrong, Loren L., Denny, Joshua C., Peissig, Peggy L., Miller, Aaron W., Wei, Wei-Qi, Bielinski, Suzette J., Chute, Christopher G., Leibson, Cynthia L., Jarvik, Gail P., Crosslin, David R., Carlson, Christopher S., Newton, Katherine M., Wolf, Wendy A., Chisholm, Rex L., and Lowe, William L.

Abstract

Objective Genome-wide association studies (GWAS) require high specificity and large numbers of subjects to identify genotype-phenotype correlations accurately. The aim of this study was to identify type 2 diabetes (T2D) cases and controls for a GWAS, using data captured through routine clinical care across five institutions using different electronic medical record (EMR) systems. Materials and Methods An algorithm was developed to identify T2D cases and controls based on a combination of diagnoses, medications, and laboratory results. The performance of the algorithm was validated at three of the five participating institutions compared against clinician review. A GWAS was subsequently performed using cases and controls identified by the algorithm, with samples pooled across all five institutions. Results The algorithm achieved 98% and 100% positive predictive values for the identification of diabetic cases and controls, respectively, as compared against clinician review. By standardizing and applying the algorithm across institutions, 3353 cases and 3352 controls were identified. Subsequent GWAS using data from five institutions replicated the TCF7L2 gene variant (rs7903146) previously associated with T2D. Discussion By applying stringent criteria to EMR data collected through routine clinical care, cases and controls for a GWAS were identified that subsequently replicated a known genetic variant. The use of standard terminologies to define data elements enabled pooling of subjects and data across five different institutions to achieve the robust numbers required for GWAS. Conclusions An algorithm using commonly available data from five different EMR can accurately identify T2D cases and controls for genetic study across multiple institutions. [ABSTRACT FROM AUTHOR]

Published
2012
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177. Cord blood ceramides facilitate early risk identification into childhood metabolic health.

Author

Zheng, Jia, Lam, Sin Man, Jiang, Binhua, Mao, Lili, Liu, Jieying, Zhang, Qian, Yu, Miao, Lim, Wei Ling Florence, Tam, Claudia H T, Lowe, William L, Tam, Wing Hung, Gao, Ying, Zhang, Junqing, Ma, Ronald C W, Xiao, Xinhua, and Shui, Guanghou

Subjects
*LOW birth weight, *HDL cholesterol, *LDL cholesterol, *SOMATOMEDIN C, *PREGNANCY proteins, *SELENOPROTEINS, *LOW density lipoproteins, *TUBULINS
Abstract

The article in the National Science Review explores the relationship between cord blood ceramides and childhood metabolic health. The study analyzes sphingolipidome in umbilical cord blood to identify functional sphingolipids associated with birth weight. The research suggests that cord blood ceramides, particularly those with medium to very long fatty acyl chains, are linked to unhealthy birth weights. Additionally, the study demonstrates the predictive potential of cord blood ceramides for childhood metabolic health, highlighting the importance of monitoring and potentially adjusting intrauterine fetal growth to optimize long-term metabolic outcomes. [Extracted from the article]

Published
2024
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178. Elevated Blood Pressure in Pregnancy and Long-Term Cardiometabolic Health Outcomes.

Author

Field, Christine, Grobman, William A., Jiqiang Wu, Kuang, Alan, Scholtens, Denise M., Lowe, William L., Shah, Nilay S., Khan, Sadiya S., and Venkatesh, Kartik K.

Subjects
*PREGNANT women, *TYPE 2 diabetes, *HDL cholesterol, *GLUCOSE tolerance tests, *LDL cholesterol
Abstract

OBJECTIVE: To examine the association between elevated blood pressure (BP) in the early third trimester and cardiometabolic health 10-14 years after delivery. METHODS: This is a secondary analysis from the prospective HAPO FUS (Hyperglycemia and Adverse Pregnancy Outcome Follow-Up Study). Blood pressure in the early third trimester was categorized per American College of Cardiology/American Heart Association thresholds for: normal BP below 120/80 mm Hg (reference), elevated BP 120-129/below 80 mm Hg, stage 1 hypertension 130-139/80-89 mm Hg, and stage 2 hypertension 140/90 mm Hg or higher. Cardiometabolic outcomes assessed 10-14 years after the index pregnancy were type 2 diabetes mellitus and measures of dyslipidemia, including low-density lipoprotein (LDL) cholesterol 130 mg/dL or higher, total cholesterol 200 mg/dL or higher, high-density lipoprotein (HDL) cholesterol 40 mg/dL or lower, and triglycerides 200 mg/dL or higher. Adjusted analysis was performed with the following covariates: study field center, follow-up duration, age, body mass index (BMI), height, family history of hypertension and diabetes, smoking and alcohol use, parity, and oral glucose tolerance test glucose z score. RESULTS: Among 4,692 pregnant individuals at a median gestational age of 27.9 weeks (interquartile range 26.6-28.9 weeks), 8.5% (n5399) had elevated BP, 14.9% (n5701) had stage 1 hypertension, and 6.4% (n5302) had stage 2 hypertension. At a median follow-up of 11.6 years, among individuals with elevated BP, there was a higher frequency of diabetes (elevated BP: adjusted relative risk [aRR] 1.88, 95% CI, 1.06-3.35; stage 1 hypertension: aRR 2.58, 95% CI, 1.62-4.10; stage 2 hypertension: aRR 2.83, 95% CI, 1.65-4.95) compared with those with normal BP. Among individuals with elevated BP, there was a higher frequency of elevated LDL cholesterol (elevated BP: aRR 1.27, 95% CI, 1.03-1.57; stage 1 hypertension: aRR 1.22, 95% CI, 1.02-1.45, and stage 2 hypertension: aRR 1.38, 95% CI, 1.10-1.74), elevated total cholesterol (elevated BP: aRR 1.27, 95% CI, 1.07-1.52; stage 1 hypertension: aRR 1.16, 95% CI, 1.00-1.35; stage 2 hypertension: aRR 1.41 95% CI, 1.16-1.71), and elevated triglycerides (elevated BP: aRR 2.24, 95% CI, 1.42-3.53; stage 1 hypertension: aRR 2.15, 95% CI, 1.46-3.17; stage 2 hypertension: aRR 3.24, 95% CI, 2.05-5.11) but not of low HDL cholesterol. CONCLUSION: The frequency of adverse cardiometabolic outcomes at 10-14 years after delivery was progressively higher among pregnant individuals with BP greater than 120/80 in the early third trimester. [ABSTRACT FROM AUTHOR]

Published
2024
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179. A novel common variant in DCST2 is associated with length in early life and height in adulthood

Author

van der Valk, Ralf J.P., Kreiner-Møller, Eskil, Kooijman, Marjolein N., Guxens, Mònica, Stergiakouli, Evangelia, Sääf, Annika, Bradfield, Jonathan P., Geller, Frank, Hayes, M. Geoffrey, Cousminer, Diana L., Körner, Antje, Thiering, Elisabeth, Curtin, John A., Myhre, Ronny, Huikari, Ville, Joro, Raimo, Kerkhof, Marjan, Warrington, Nicole M., Pitkänen, Niina, Ntalla, Ioanna, Horikoshi, Momoko, Veijola, Riitta, Freathy, Rachel M., Teo, Yik-Ying, Barton, Sheila J., Evans, David M., Kemp, John P., St Pourcain, Beate, Ring, Susan M., Davey Smith, George, Bergström, Anna, Kull, Inger, Hakonarson, Hakon, Mentch, Frank D., Bisgaard, Hans, Chawes, Bo, Stokholm, Jakob, Waage, Johannes, Eriksen, Patrick, Sevelsted, Astrid, Melbye, Mads, van Duijn, Cornelia M., Medina-Gomez, Carolina, Hofman, Albert, de Jongste, Johan C., Taal, H. Rob, Uitterlinden, André G., Armstrong, Loren L., Eriksson, Johan, Palotie, Aarno, Bustamante, Mariona, Estivill, Xavier, Gonzalez, Juan R., Llop, Sabrina, Kiess, Wieland, Mahajan, Anubha, Flexeder, Claudia, Tiesler, Carla M.T., Murray, Clare S., Simpson, Angela, Magnus, Per, Sengpiel, Verena, Hartikainen, Anna-Liisa, Keinanen-Kiukaanniemi, Sirkka, Lewin, Alexandra, Da Silva Couto Alves, Alexessander, Blakemore, Alexandra I., Buxton, Jessica L., Kaakinen, Marika, Rodriguez, Alina, Sebert, Sylvain, Vaarasmaki, Marja, Lakka, Timo, Lindi, Virpi, Gehring, Ulrike, Postma, Dirkje S., Ang, Wei, Newnham, John P., Lyytikäinen, Leo-Pekka, Pahkala, Katja, Raitakari, Olli T., Panoutsopoulou, Kalliope, Zeggini, Eleftheria, Boomsma, Dorret I., Groen-Blokhuis, Maria, Ilonen, Jorma, Franke, Lude, Hirschhorn, Joel N., Pers, Tune H., Liang, Liming, Huang, Jinyan, Hocher, Berthold, Knip, Mikael, Saw, Seang-Mei, Holloway, John W., Melén, Erik, Grant, Struan F.A., Feenstra, Bjarke, Lowe, William L., Widén, Elisabeth, Sergeyev, Elena, Grallert, Harald, Custovic, Adnan, Jacobsson, Bo, Jarvelin, Marjo-Riitta, Atalay, Mustafa, Koppelman, Gerard H., Pennell, Craig E., Niinikoski, Harri, Dedoussis, George V., Mccarthy, Mark I., Frayling, Timothy M., Sunyer, Jordi, Timpson, Nicholas J., Rivadeneira, Fernando, Bønnelykke, Klaus, and Jaddoe, Vincent W.V.

Abstract

Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10−6) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10−8, explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10−4) and adult height (N = 127 513; P = 1.45 × 10−5). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.

Published
2014
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180. Accumulation of cadmium in insulin-producing β cells

Author

El Muayed, Malek, Raja, Meera R., Zhang, Xiaomin, MacRenaris, Keith W., Bhatt, Surabhi, Chen, Xiaojuan, Urbanek, Margrit, O’Halloran, Thomas V., and Lowe, William L.

Abstract

Evidence suggests that chronic low level cadmium exposure impairs the function of insulin-producing β cells and may be associated with type-2 diabetes mellitus. Herein, we describe the cadmium content in primary human islets and define the uptake kinetics and effects of environmentally relevant cadmium concentrations in cultured β cells. The average cadmium content in islets from 10 non-diabetic human subjects was 29 ± 7 nmol/g protein (range 7 to 72 nmol/g protein). Exposure of the β-cell line MIN6 to CdCl2concentrations between 0.1 and 1.0 µmol/L resulted in a dose- and time-dependent uptake of cadmium over 72 h. This uptake resulted in an induction of metallthionein expression, likely enhancing cellular cadmium accumulation. Furthermore, cadmium accumulation resulted in an inhibition of glucose stimulated insulin secretion in MIN6 cells and primary mouse islets. Our results indicate that this impairment in β-cell function is not due to an increase in cell death or due to an increase in oxidative stress. We conclude that mouse β cells accumulate cadmium in a dose- and time-dependent manner over a prolonged time course at environmentally relevant concentrations. This uptake leads to a functional impairment of β-cell function without significant alterations in cell viability, expression of genes important for β-cell function or increase in oxidative stress.

Published
2012
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182. Rapamycin Inhibits Growth Factor-Induced Cell Cycle Regulation in Pancreatic ß Cells

Author

Aronovitz, Amy, Josefson, Jami, Fisher, Amanda, Newman, Marsha, Hughes, Elizabeth, Chen, Fei, Moons, David S., Kiyokawa, Hiroaki, and Lowe, William L.

Abstract

A progressive decline in islet function is a major obstacle to the success of islet transplantation. The cause of this decline in islet function is unclear, but immunosuppressive agents may contribute. Insulin-like growth factor-I (IGF-I) and betacellulin are important for islet cell survival and/or proliferation. In the present study, we performed studies in INS-1 cells and murine islets to define the effect of IGF-I and betacellulin on progression of islet cells through the cell cycle and the impact of immunosuppressive agents. Treatment of INS-1 cells for 24 hours with 20 ng/mL betacellulin or 50 ng/mL IGF-I increased cells in S phase by ~2-fold. Treatment of INS-1 cells with IGF-I or betacellulin also increased cyclin D1 expression and nuclear exclusion of the cyclin-dependent kinase inhibitors p21Cip1and p27Kip1. In INS-1 cells and islets, betacellulin- and IGF-I increased Akt, extracellular signal-related kinase, and p70S6 kinasephosphorylation. Rapamycin, an immunosuppressant which inhibits mammalian target of rapamycin, inhibited the increase in p70S6 kinasephosphorylation stimulated by betacellulin- and IGF-I in INS-1 cells. Rapamycin also inhibited betacellulin- and IGF-I-induced entry of cells into S phase and 5'-Bromo-2'-deoxyuridine incorporation as well as the effect of betacellulin and IGF-I on cyclin D1 expression and nuclear exclusion of p21Cip1and p27Kip1. Together, these data suggest that the effect of betacellulin and IGF-I on islet cell growth and proliferation is mediated, in part, via signaling through mammalian target of rapamycin. As rapamycin is used to treat islet transplant recipients, these results suggest that rapamycin could have deleterious effects on islet proliferation and function over time.

Published
2008
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184. Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics

Author

Beaumont, Robin N, Warrington, Nicole M, Cavadino, Alana, Tyrrell, Jessica, Nodzenski, Michael, Horikoshi, Momoko, Geller, Frank, Myhre, Ronny, Richmond, Rebecca C, Paternoster, Lavinia, Bradfield, Jonathan P, Kreiner-Møller, Eskil, Huikari, Ville, Metrustry, Sarah, Lunetta, Kathryn L, Painter, Jodie N, Hottenga, Jouke-Jan, Allard, Catherine, Barton, Sheila J, Espinosa, Ana, Marsh, Julie A, Potter, Catherine, Zhang, Ge, Ang, Wei, Berry, Diane J, Bouchard, Luigi, Das, Shikta, Hakonarson, Hakon, Heikkinen, Jani, Helgeland, Øyvind, Hocher, Berthold, Hofman, Albert, Inskip, Hazel M, Jones, Samuel E, Kogevinas, Manolis, Lind, Penelope A, Marullo, Letizia, Medland, Sarah E, Murray, Anna, Murray, Jeffrey C, Njølstad, Pål R, Nohr, Ellen A, Reichetzeder, Christoph, Ring, Susan M, Ruth, Katherine S, Santa-Marina, Loreto, Scholtens, Denise M, Sebert, Sylvain, Sengpiel, Verena, Tuke, Marcus A, Vaudel, Marc, Weedon, Michael N, Willemsen, Gonneke, Wood, Andrew R, Yaghootkar, Hanieh, Muglia, Louis J, Bartels, Meike, Relton, Caroline L, Pennell, Craig E, Chatzi, Leda, Estivill, Xavier, Holloway, John W, Boomsma, Dorret I, Montgomery, Grant W, Murabito, Joanne M, Spector, Tim D, Power, Christine, Järvelin, Marjo-Ritta, Bisgaard, Hans, Grant, Struan F A, Sørensen, Thorkild I A, Jaddoe, Vincent W, Jacobsson, Bo, Melbye, Mads, McCarthy, Mark I, Hattersley, Andrew T, Hayes, M Geoffrey, Frayling, Timothy M, Hivert, Marie-France, Felix, Janine F, Hyppönen, Elina, Lowe, William L, Evans, David M, Lawlor, Debbie A, Feenstra, Bjarke, and Freathy, Rachel M

Subjects
Genotype, genotype, Gestational Age, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, duration of gestation, Germinal Center Kinases, single nucleotide polymorphism, Birth Weight, Cytochrome P-450 CYP3A, Humans, genetics, Alleles, Adaptor Proteins, Signal Transducing, genome-wide association study, Kv1.3 Potassium Channel, offspring, Receptor, Melatonin, MT2, Association Studies Articles, HMGA2 Protein, Intracellular Signaling Peptides and Proteins, birth weight, Genetic Variation, Proteins, Actins, DNA-Binding Proteins, fetus, mothers, alleles, biobanks, Trans-Activators, Female, Transcription Factor 7-Like 2 Protein, Genome-Wide Association Study
Abstract

Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother–child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P

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185. Genome-Wide Polygenic Risk Score Predicts Incident Type 2 Diabetes in Women With History of Gestational Diabetes.

Author

Choi, Jaewon, Lee, Hyunsuk, Kuang, Alan, Huerta-Chagoya, Alicia, Scholtens, Denise M., Choi, Daeho, Han, Minseok, Lowe, William L., Manning, Alisa K., Jang, Hak Chul, Park, Kyong Soo, and Kwak, Soo Heon

Subjects
*GENETIC risk score, *GESTATIONAL diabetes, *RECEIVER operating characteristic curves, *TYPE 2 diabetes, *SYSTOLIC blood pressure
Abstract

OBJECTIVE: Women with a history of gestational diabetes mellitus (GDM) are at increased risk of developing type 2 diabetes (T2D). It remains unclear whether genetic information improves prediction of incident T2D in these women. RESEARCH DESIGN AND METHODS: Using five independent cohorts representing four different ancestries (n = 1,895), we investigated whether a genome-wide T2D polygenic risk score (PRS) is associated with increased risk of incident T2D. We also calculated the area under the receiver operating characteristics curve (AUROC) and continuous net reclassification improvement (NRI) following the incorporation of T2D PRS into clinical risk models to assess the diagnostic utility. RESULTS: Among 1,895 women with previous history of GDM, 363 (19.2%) developed T2D in a range of 2 to 30 years. T2D PRS was higher in those who developed T2D (−0.08 vs. 0.31, P = 2.3 × 10−11) and was associated with an increased risk of incident T2D (odds ratio 1.52 per 1-SD increase, 95% CI 1.05–2.21, P = 0.03). In a model that includes age, family history of diabetes, systolic blood pressure, and BMI, the incorporation of PRS led to an increase in AUROC for T2D from 0.71 to 0.74 and an intermediate improvement of NRI (0.32, 95% CI 0.15–0.49, P = 3.0 × 10−4). Although there was variation, a similar trend was observed across study cohorts. CONCLUSIONS: In cohorts of GDM women with diverse ancestry, T2D PRS was significantly associated with future development of T2D. A significant but small improvement was observed in AUROC when T2D PRS was integrated into clinical risk models to predict incident T2D. [ABSTRACT FROM AUTHOR]

Published
2024
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186. Installation Restoration Program Environmental Technology Development. Task Order 3. Use of Activated Carbon for Treatment of Explosives-Contaminated Ground Water at the Badger Army Ammunition Plant (BAAP)

Author

WESTON (ROY F) INC WEST CHESTER PA, Wujcik, Walter J., Lowe, William L., Marks, Peter J., WESTON (ROY F) INC WEST CHESTER PA, Wujcik, Walter J., Lowe, William L., and Marks, Peter J.

Abstract

The United States Army operates explosives manufacturing plants to produce various forms of explosives used in military ordnance. Manufacturing activities at such plants result in the production of organic wastewaters that contain both explosive residues and other organic chemicals. Several treatment technologies have been developed to treat these wastewaters for final discharge. Past waste handling practices at explosives manufacturing plants commonly included the use of the unlined lagoons or pits for containing process wastewaters. As a result of these past practices, some explosives residues may leach through the soil and contaminated groundwater. Therefore, the treatment of contaminated groundwater may be required.

Published
1989

187. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Author

Warrington, Nicole M, Beaumont, Robin N, Horikoshi, Momoko, Day, Felix R, Helgeland, Øyvind, Laurin, Charles, Bacelis, Jonas, Peng, Shouneng, Hao, Ke, Feenstra, Bjarke, Wood, Andrew R, Mahajan, Anubha, Tyrrell, Jessica, Robertson, Neil R, Rayner, N William, Qiao, Zhen, Moen, Gunn-Helen, Vaudel, Marc, Marsit, Carmen J, Chen, Jia, Nodzenski, Michael, Schnurr, Theresia M, Zafarmand, Mohammad H, Bradfield, Jonathan P, Grarup, Niels, Kooijman, Marjolein N, Li-Gao, Ruifang, Geller, Frank, Ahluwalia, Tarunveer S, Paternoster, Lavinia, Rueedi, Rico, Huikari, Ville, Hottenga, Jouke-Jan, Lyytikäinen, Leo-Pekka, Cavadino, Alana, Metrustry, Sarah, Cousminer, Diana L, Wu, Ying, Thiering, Elisabeth, Wang, Carol A, Have, Christian T, Vilor-Tejedor, Natalia, Joshi, Peter K, Painter, Jodie N, Ntalla, Ioanna, Myhre, Ronny, Pitkänen, Niina, Van Leeuwen, Elisabeth M, Joro, Raimo, Lagou, Vasiliki, Richmond, Rebecca C, Espinosa, Ana, Barton, Sheila J, Inskip, Hazel M, Holloway, John W, Santa-Marina, Loreto, Estivill, Xavier, Ang, Wei, Marsh, Julie A, Reichetzeder, Christoph, Marullo, Letizia, Hocher, Berthold, Lunetta, Kathryn L, Murabito, Joanne M, Relton, Caroline L, Kogevinas, Manolis, Chatzi, Leda, Allard, Catherine, Bouchard, Luigi, Hivert, Marie-France, Zhang, Ge, Muglia, Louis J, Heikkinen, Jani, EGG Consortium, Morgen, Camilla S, Van Kampen, Antoine HC, Van Schaik, Barbera DC, Mentch, Frank D, Langenberg, Claudia, Luan, Jian'an, Scott, Robert A, Zhao, Jing Hua, Hemani, Gibran, Ring, Susan M, Bennett, Amanda J, Gaulton, Kyle J, Fernandez-Tajes, Juan, Van Zuydam, Natalie R, Medina-Gomez, Carolina, De Haan, Hugoline G, Rosendaal, Frits R, Kutalik, Zoltán, Marques-Vidal, Pedro, Das, Shikta, Willemsen, Gonneke, Mbarek, Hamdi, Müller-Nurasyid, Martina, Standl, Marie, Appel, Emil VR, Fonvig, Cilius E, Trier, Caecilie, Van Beijsterveldt, Catharina EM, Murcia, Mario, Bustamante, Mariona, Bonas-Guarch, Sílvia, Hougaard, David M, Mercader, Josep M, Linneberg, Allan, Schraut, Katharina E, Lind, Penelope A, Medland, Sarah E, Shields, Beverley M, Knight, Bridget A, Chai, Jin-Fang, Panoutsopoulou, Kalliope, Bartels, Meike, Sánchez, Friman, Stokholm, Jakob, Torrents, David, Vinding, Rebecca K, Willems, Sara M, Atalay, Mustafa, Chawes, Bo L, Kovacs, Peter, Prokopenko, Inga, Tuke, Marcus A, Yaghootkar, Hanieh, Ruth, Katherine S, Jones, Samuel E, Loh, Po-Ru, Murray, Anna, Weedon, Michael N, Tönjes, Anke, Stumvoll, Michael, Michaelsen, Kim F, Eloranta, Aino-Maija, Lakka, Timo A, Van Duijn, Cornelia M, Kiess, Wieland, Körner, Antje, Niinikoski, Harri, Pahkala, Katja, Raitakari, Olli T, Jacobsson, Bo, Zeggini, Eleftheria, Dedoussis, George V, Teo, Yik-Ying, Saw, Seang-Mei, Montgomery, Grant W, Campbell, Harry, Wilson, James F, Vrijkotte, Tanja GM, Vrijheid, Martine, De Geus, Eco JCN, Hayes, M Geoffrey, Kadarmideen, Haja N, Holm, Jens-Christian, Beilin, Lawrence J, Pennell, Craig E, Heinrich, Joachim, Adair, Linda S, Borja, Judith B, Mohlke, Karen L, Eriksson, Johan G, Widén, Elisabeth E, Hattersley, Andrew T, Spector, Tim D, Kähönen, Mika, Viikari, Jorma S, Lehtimäki, Terho, Boomsma, Dorret I, Sebert, Sylvain, Vollenweider, Peter, Sørensen, Thorkild IA, Bisgaard, Hans, Bønnelykke, Klaus, Murray, Jeffrey C, Melbye, Mads, Nohr, Ellen A, Mook-Kanamori, Dennis O, Rivadeneira, Fernando, Hofman, Albert, Felix, Janine F, Jaddoe, Vincent WV, Hansen, Torben, Pisinger, Charlotta, Vaag, Allan A, Pedersen, Oluf, Uitterlinden, André G, Järvelin, Marjo-Riitta, Power, Christine, Hyppönen, Elina, Scholtens, Denise M, Lowe, William L, Davey Smith, George, Timpson, Nicholas J, Morris, Andrew P, Wareham, Nicholas J, Hakonarson, Hakon, Grant, Struan FA, Frayling, Timothy M, Lawlor, Debbie A, Njølstad, Pål R, Johansson, Stefan, Ong, Ken K, McCarthy, Mark I, Perry, John RB, Evans, David M, and Freathy, Rachel M

Subjects
Adult, Male, Heart Diseases, Models, Genetic, Infant, Newborn, Blood Pressure, Polymorphism, Single Nucleotide, Body Height, 3. Good health, Fetal Development, Diabetes Mellitus, Type 2, Metabolic Diseases, Pregnancy, Risk Factors, Birth Weight, Humans, Female, Genetic Predisposition to Disease, Maternal Inheritance, Maternal-Fetal Exchange, Genome-Wide Association Study
Abstract

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.

188. Genome-wide association study of offspring birth weight in 86,577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics

Author

Beaumont, Robin N., Warrington, Nicole M., Cavadino, Alana, Tyrrell, Jessica, Nodzenski, Michael, Horikoshi, Momoko, Geller, Frank, Myhre, Ronny, Richmond, Rebecca C., Paternoster, Lavinia, Bradfield, Jonathan P., Kreiner-Moller, Eskil, Huikari, Ville, Metrustry, Sarah, Lunetta, Kathryn L., Painter, Jodie N., Hottenga, Jouke-Jan, Allard, Catherine, Barton, Sheila J., Espinosa Cardiel, Ana, Marsh, Julie A., Potter, Catherine, Zhang, Ge, Ang, Wei, Berry, Diane J., Bouchard, Luigi, Das, Shikta, Early Growth Genetics (EGG) Consortium, Hakonarson, Hakon, Heikkinen, Jani, Helgeland, Øyvind, Hocher, Berthold, Hofman, Albert, Inskip, Hazel M., Jones, Samuel E., Kogevinas, Manolis, Lind, Penelope A., Marullo, Letizia, Medland, Sarah E., Murray, Anna, Murray, Jeffrey C., Njolstad, Pal R., Nohr, Ellen Aagard, Reichetzeder, Christoph, Ring, Susan M., Ruth, Katherine S., Santa Marina, Loreto, Scholtens, Denise M., Sebert, Sylvain, Sengpiel, Verena, Tuke, Marcus A., Vaudel, Marc, Weedon, Michael N., Willemsen, Gonneke, Wood, Andrew R., Yaghootkar, Hanieh, Muglia, Louis J., Bartels, Meike, Relton, Caroline L., Pennell, Craig E., Chatzi, Leda, Estivill, Xavier, 1955, Holloway, John W., Boomsma, Dorret I., Montgomery, Grant W., Murabito, Joanne M., Spector, Tim D., Power, Christine, Järvelin, Marjo-Ritta, Bisgaard, Hans, Grant, Struan F., Sorensen, Thorkild I. A., Jaddoe, Vincent W., Jacobsson, Bo, Melbye, Mads, McCarthy, Mark I., Hattersley, Andrew T., Hayes, M. Geoffrey, Frayling, Timothy M., Hivert, Marie-France, Felix, Janine F., Hyppönen, Elina, Lowe, William L., Evans, David M., Lawlor, Debbie A., Feenstra, Bjarke, and Freathy, Rachel M.

Subjects
Newborn infants, Polimorfisme genètic, Infants nadons, Genetic polymorphisms
Abstract

Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother–child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P

189. Genome-wide associations for birth weight and correlations with adult disease

Author

Standl, Marie, Grarup, Niels, Mercader, Josep M., Nodzenski, Michael, Warrington, Nicole M., Felix, Janine F., Tuke, Marcus A., Hofman, Albert, Mohlke, Karen L., Strachan, David P., Kadarmideen, Haja N., Bonàs-Guarch, Sílvia, Scholtens, Denise M., Panoutsopoulou, Kalliope, Kovacs, Peter, Li-Gao, Ruifang, Langenberg, Claudia, Bønnelykke, Klaus, Morris, Andrew P., Reynolds, Rebecca M., Sørensen, Thorkild I. A., Day, Felix R., Freathy, Rachel M., Schraut, Katharina E., Feenstra, Bjarke, Bisgaard, Hans, Torrents, David, Carstensen, Lisbeth, De Haan, Hugoline G., Newnham, John P., Ruth, Katherine S., Ring, Susan M., Sánchez, Friman, Pisinger, Charlotta, Bustamante, Mariona, Robertson, Neil R., Rahmioglu, Nilufer, Kutalik, Zoltán, Rueedi, Rico, Boomsma, Dorret I., Horikoshi, Momoko, Rosendaal, Frits R., Van Beijsterveldt, Catharina E. M., Campbell, Harry, Mentch, Frank D., Kreiner, Eskil, Stumvoll, Michael, Fonvig, Cilius E., Willems, Sara M., Willemsen, Gonneke, Prokopenko, Inga, Beaumont, Robin N., Wu, Ying, Geller, Frank, Smith, George Davey, Bennett, Amanda J., Pitkänen, Niina, Dedoussis, George V., Vilor-Tejedor, Natalia, Lindi, Virpi, Jones, Samuel E., Trier, Caecilie, Tam, Claudia H. T., Vrijheid, Martine, Pedersen, Oluf, Tyrrell, Jessica, Widén, Elisabeth, Wareham, Nicholas J., Boh, Eileen Tai Hui, Uitterlinden, André G., De Geus, Eco J. C. N., Mahajan, Anubha, Kiess, Wieland, Vaag, Allan A., Wang, Carol A., Ganesh, Santhi K., Eriksson, Johan G., Van Leeuwen, Elisabeth M., Ong, Ken K., Timpson, Nicholas J., Luan, Jian'An, Murcia, Mario, Hottenga, Jouke-Jan, Van Rooij, Frank J. A., Thiering, Elisabeth, Mook-Kanamori, Dennis O., Davies, Eleanor, Van Zuydam, Natalie R., Ntalla, Ioanna, Vollenweider, Peter, Zhao, Jing Hua, Sebert, Sylvain, Hakonarson, Hakon, Walker, Brian R., Appel, Emil V. R., Joshi, Peter K., Tönjes, Anke, Adair, Linda S., Lakka, Timo A., Have, Christian T., Körner, Antje, Nyholt, Dale R., McMahon, George, Jaddoe, Vincent W. V., Tam, Wing Hung, Tiesler, Carla M. T., Teo, Yik-Ying, Atalay, Mustafa, Raitakari, Olli T., Niinikoski, Harri, Paternoster, Lavinia, Melbye, Mads, Rivadeneira, Fernando, Kähönen, Mika, Bradfield, Jonathan P., Beilin, Lawrence J., Hyppönen, Elina, Loh, Po-Ru, Wood, Andrew R., Ma, Ronald C. W., Scott, Robert A., Viikari, Jorma S., Medina-Gomez, Carolina, Pahkala, Katja, Hansen, Torben, Wilson, James F., Zeggini, Eleftheria, Kooijman, Marjolein N., Joro, Raimo, Cousminer, Diana L., Borja, Judith B., Frayling, Timothy M., Järvelin, Marjo-Riitta, Perry, John R. B., Holm, Jens-Christian, Lagou, Vasiliki, MacKenzie, Scott M., Fernandez-Tajes, Juan, Evans, David M., Pennell, Craig E., McCarthy, Mark I., Waage, Johannes, Heinrich, Joachim, Ahluwalia, Tarunveer S., Grant, Struan F. A., Hemani, Gibran, Lawlor, Debbie A., Lehtimäki, Terho, Van Duijn, Cornelia M., Gaulton, Kyle J., Zondervan, Krina T., Lyytikaïnen, Leo-Pekka, Hollegaard, Mads V., Wang, Xu, Lowe, William L., Yaghootkar, Hanieh, Diver, Louise A., Hattersley, Andrew T., Groves, Christopher J., Hougaard, David M., Power, Christine, Marques-Vidal, Pedro, and Saw, Seang-Mei

Subjects
3. Good health
Abstract

Birth weight (BW) is influenced by both foetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease1. These lifecourse associations have often been attributed to the impact of an adverse early life environment. We performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where foetal genotype was associated with BW (P

191. Insulin-Like Growth Factor-II in Nonislet Cell Tumors Associated with Hypoglycemia: Increased Levels of Messenger Ribonucleic Acid*

Author

LOWE, WILLIAM L., primary, ROBERTS, CHARLES T., additional, LEROITH, DEREK, additional, ROJESKI, MARIA T., additional, MERIMEE, THOMAS J., additional, TENG FUI, SERGE, additional, KEEN, HARRY, additional, ARNOLD, DAGMAR, additional, MERSEY, JAMES, additional, GLUZMAN, SHELDON, additional, SPRATT, DANIEL, additional, EASTMAN, RICHARD C., additional, and ROTH, JESSE, additional

Published
1989
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