bluuebunny/crossref_metadata_2025 huggingface dataset:
Atrial Natriuretic Peptide Promotes Pancreatic Islet β-Cell Growth and Akt/Foxo1a/Cyclin D2 Signaling
Authors: You Hui , Laychock Suzanne G.
Published: October 2009

The adult differentiated insulin-secreting pancreatic islet β-cell experiences slow growth. This study shows that atrial natriuretic peptide (ANP) stimulates cell proliferation and [3H]thymidine incorporation in INS-1E glucose-sensitive rat β-cell line cells and isolated rat islet DNA. In addition, cGMP, the second messenger of natriuretic peptide receptors (NPR) A and B, stimulated islet DNA biosynthesis. The NPR-A receptor was expressed in INS-1E cells and islets. ANP-stimulated INS-1E cell DNA biosynthesis was blocked by preincubation with LY294002 (50 μm), an inhibitor of phosphatidylinositol 3′-kinase (PI3K). An indicator of cell cycle progression, cyclin D2 mRNA was increased by 2- to 3-fold in ANP- or 8-Br-cGMP-treated INS-1E cells and islets, and these responses were inhibited by LY294002. ANP and 8-Br-cGMP stimulated the phosphorylation of Akt and Foxo1a in INS-1E cells and islets, and LY294002 inhibited these responses. In contrast, ANP reduced the levels of phospho-ERK in INS-1E cells. Pancreas duodenum homeobox-1 (PDX-1) is essential for pancreas development, insulin production, and glucose homeostasis, and ANP increased PDX-1 mRNA levels by 2- to 3-fold in INS-1E cells and islets. The levels of glucokinase mRNA in islets and INS-1E cells were also increased in response to ANP. The evidence suggests that pancreatic β-cell NPR-A stimulation results in activation of a growth-promoting signaling pathway that includes PI3K/Akt/Foxo1a/cyclin D2. These data support the conclusion that the activation of Akt by ANP or 8-Br-cGMP promotes cyclin D2, PDX-1, and glucokinase transcription by phosphorylating and restricting Foxo1a activity.
Expression of Guanylyl Cyclase (GC)-A and GC-B during Brain Development: Evidence for a Role of GC-B in Perinatal Neurogenesis
Authors: Müller Dieter , Hida Balanes , Guidone Gabriela , Speth Robert C. , Michurina Tatyana V. , Enikolopov Grigori , Middendorff Ralf
Published: October 2009

Atrial (ANP) and C-type (CNP) natriuretic peptide generate physiological effects via selective activation of two closely related membrane receptors with guanylyl cyclase (GC) activity, known as GC-A and GC-B. As yet, however, the discrete roles for ANP/GC-A vs. CNP/GC-B signaling in many mammalian tissues are still poorly understood. We here used receptor affinity labeling and GC assays to characterize comparatively GC-A/GC-B expression and functional activity during rat brain development. The study revealed that GC-B predominates in the developing and GC-A in the adult brain, with regional differences each between cerebral cortex, cerebellum, and brain stem. Whereas GC-A levels nearly continuously increase between embryonal d 18 and adult, GC-B expression in brain is highest and widely distributed around postnatal d 1. The striking perinatal GC-B peak coincides with elevated expression of nestin, a marker protein for neural stem/progenitor cells. Immunohistochemical investigations revealed a cell body-restricted subcellular localization of GC-B and perinatal abundance of GC-B-expressing cells in regions high in nestin-expressing cells. However, and supported by examination of nestin-GFP transgenic mice, GC-B and nestin are not coexpressed in the same cells. Rather, GC-B+ cells are distinguished by expression of NeuN, an early marker of differentiating neurons. These findings suggest that GC-B+ cells represent neuronal fate-specific progeny of nestin+ progenitors and raise the attention to specific and pronounced activities of CNP/GC-B signaling during perinatal brain maturation. The absence of this activity may cause the neurological disorders observed in GC-B-deficient mice.
Brain-Endocrine Interactions: A Microvascular Route in the Mediobasal Hypothalamus
Authors: Ciofi Philippe , Garret Maurice , Lapirot Olivier , Lafon Pierrette , Loyens Anne , Prévot Vincent , Levine Jon E.
Published: October 2009

Blood-borne hormones acting in the mediobasal hypothalamus, like those controlling food intake, require relatively direct access to target chemosensory neurons of the arcuate nucleus (ARC). An anatomical substrate for this is a permeable microvasculature with fenestrated endothelial cells in the ARC, a system that has awaited comprehensive documentation. Here, the immunofluorescent detection of endothelial fenestral diaphragms in the rat ARC allowed us to quantitate permeable microvessels throughout its rostrocaudal extent. We have determined that permeable microvessels are part of the subependymal plexus irrigating exclusively the ventromedial (vm) ARC from the subadjacent neuroendocrine median eminence. Unexpectedly, permeable microvessels were concentrated proximal to the pituitary stalk. This marked topography strongly supports the functional importance of retrograde blood flow from the pituitary to the vmARC, therefore making a functional relationship between peripheral long-loop, pituitary short-loop, and neuroendocrine ultra-short loop feedback, altogether converging for integration in the vmARC (formerly known as the hypophysiotrophic area), thereby so pivotal as a multicompetent brain endocrinostat.
Forkhead Box O1/Pancreatic and Duodenal Homeobox 1 Intracellular Translocation Is Regulated by c-Jun N-Terminal Kinase and Involved in Prostaglandin E2-Induced Pancreatic β-Cell Dysfunction
Authors: Meng Zhuoxian , Lv Jinghuan , Luo Ying , Lin Yan , Zhu Yunxia , Nie Jia , Yang Tao , Sun Yujie , Han Xiao
Published: October 2009

Prostaglandin E2 (PGE2) is a well-known mediator of β-cell dysfunction in both type 1 and type 2 diabetes. We recently reported that down-regulation of the Akt pathway activity is implicated in PGE2-induced pancreatic β-cell dysfunction. The aim of this study was to further dissect the signaling pathway of this process in pancreatic β-cell line HIT-T15 cells and primary mouse islets. We found that PGE2 time-dependently increased the c-Jun N-terminal kinase (JNK) pathway activity. JNK inhibition by the JNK-specific inhibitor SP600125 reversed PGE2-inhibited glucose-stimulated insulin secretion (GSIS). PGE2 induced dephosphorylation of Akt and FOXO1, leading to nuclear localization and transactivation of FOXO1. Activation of FOXO1 induced nuclear exclusion but had no obvious effect on the whole-cell protein level of pancreatic and duodenal homeobox 1 (PDX1). However, these effects were all attenuated by JNK inhibition. Furthermore, adenovirus-mediated overexpression of dominant-negative (DN)-FOXO1 abolished whereas constitutively active (CA)-FOXO1 mimicked the effects of PGE2 on GSIS in isolated mouse islets. In addition, we demonstrated that DN-JNK1 but not DN-JNK2 or CA-Akt abolished the PGE2-induced AP-1 luciferase reporter activity, whereas DN-JNK1 and CA-Akt but not DN-JNK2 reversed the effect of PGE2 on FOXO1 transcriptional activity, and overexpression of DN-JNK1 rescued PGE2-impaired GSIS in mouse islets. Our results revealed that activation of the JNK is involved in PGE2-induced β-cell dysfunction. PGE2-mediated JNK1 activation, through dephosphorylation of Akt and FOXO1, leads to nuclear accumulation of FOXO1 and nucleocytoplasmic shuttling of PDX1, finally resulting in defective GSIS in pancreatic β-cells.
Skeletal Muscle Lipogenic Protein Expression Is Not Different between Lean and Obese Individuals: A Potential Factor in Ceramide Accumulation
Authors: Thrush A. Brianne , Brindley David N. , Chabowski Adrian , Heigenhauser George J. , Dyck David J.
Published: October 2009

Context: Skeletal muscle lipid content is increased in obesity. Recent evidence suggests that fatty acid (FA) storage as triacylglycerol (TAG) represents a metabolically safe pool compared to the more bioactive diacylglycerol (DAG) and ceramide.

Objective/Design: The purpose of this study was to compare the expression of lipogenic proteins and ceramide and DAG content in skeletal muscle of lean and obese humans. We hypothesized that lipogenic protein expression would be increased in obese to facilitate the storage of excess FA as TAG.

Participants: Eighteen lean (BMI ≤26 kg/m2) and 15 obese (BMI >29 kg/m2) women participated in this study.

Results: There was no difference in the expression of any lipogenic (stearoyl-CoA desaturase-1, stearoyl retinol binding protein-1c, mitochondrial glycerol-3-phosphate acyltransferase, diacylglycerol acyltransferase-1) or sphingolipid proteins measured between lean and obese humans. Total ceramide was increased in muscle from obese humans (lean vs. obese, 529.4 ± 54.8 vs. 672.4 ± 57.4 nmol/g; P < 0.05), but there was no difference in total DAG content (lean vs. obese, 2244.1 ± 278.2 vs. 1941.4 ± 165.0 nmol/g). Content of protein phosphatase 2A, a ceramide target, was increased in muscle of obese humans (P < 0.05).

Conclusions: We propose that in muscle of obese humans there is an insufficient lipogenic response to the lipid oversupply, allowing more FA to be stored as reactive lipid species, particularly ceramide, potentially contributing to subsequent metabolic complications.
The Stability of Metabolic Syndrome in Children and Adolescents
Authors: Gustafson Jennifer K. , Yanoff Lisa B. , Easter Benjamin D. , Brady Sheila M. , Keil Margaret F. , Roberts Mary D. , Sebring Nancy G. , Han Joan C. , Yanovski Susan Z. , Hubbard Van S. , Yanovski Jack A.
Published: October 2009

Context: Some studies suggest the presence of metabolic syndrome before adulthood may identify those at high risk for later cardiovascular morbidity, but there are few data examining the reliability of pediatric metabolic syndrome.

Objective: To examine the short- and long-term stability of pediatric metabolic syndrome.

Design: Metabolic syndrome was defined as having at least three of the following: waist circumference, blood pressure, and fasting serum triglycerides in the 90th or higher percentile for age/sex; high-density lipoprotein-cholesterol 10th or lower percentile for age/sex; and fasting serum glucose of at least 100 mg/dl. Short-term metabolic syndrome stability (repeated measurements within 60 d) was assessed in obese youth ages 6–17 yr. Long-term metabolic syndrome stability (repeated measurements more than 1.5 yr apart) was studied in 146 obese and nonobese children age 6–12 yr at baseline.

Patients and Setting: Convenience samples of obese and nonobese youth ages 6–17 yr participating in research studies were collected at a clinical research hospital.

Results: Short-term metabolic syndrome stability (repeat measurements performed 19.7 ± 13.1 d apart) was assessed in 220 children. The diagnosis of metabolic syndrome was unstable in 31.6% of cases. At their short-term follow-up visit, incidence of metabolic syndrome among participants who did not have metabolic syndrome at baseline was 24%. In the long term (repeat measurements performed 5.6 ± 1.9 yr apart), the diagnosis of metabolic syndrome was unstable in 45.5% of cases.

Conclusions: Cutoff-point-based definitions for pediatric metabolic syndrome have substantial instability in the short and long term. The value of making a cutoff-point-based diagnosis of metabolic syndrome during childhood or adolescence remains in question.
Six New Mutations of the Thyroglobulin Gene Discovered in Taiwanese Children Presenting with Thyroid Dyshormonogenesis
Authors: Niu Dau-Ming , Hsu Ju-Hui , Chong Kah-Wai , Huang Cheng-Hung , Lu Yung-Hsiu , Kao Chuan-Hong , Yu Hsiao-Chi , Lo Ming-Yu , Jap Tjin-Shing
Published: October 2009

Background: Thyroglobulin (TG) defect is a rare cause of congenital hypothyroidism. Although only 44 mutations of the human TG gene have been identified, we have suspected a TG defect in 38% of Taiwan Chinese children/adolescents presenting with moderate or severe thyroidal dyshormonogenesis.

Study Objective: The aim of the study is to report the discovery of new TG gene mutations and associated clinical manifestations of the defective TG protein.

Patients and Results: In seven patients from six families, we detected six new TG gene mutations, including c.1348delT, p.R432X (c.1351C>T), g.IVS3 + 2T>G, c.1712delT, p.Q1765X (c.5350C>T), and c.6047delA. The c.1348delT and p.R432X mutations were the most common, detected in 33 and 25%, respectively, of alleles studied. Haplotype analysis suggested that the c.1348delT and g.IVS3 + 2T>G mutations are due to founder effects, whereas p.R432X is probably due to independently recurrent de novo mutations. mRNA transcript of the g.IVS3 + 2T>G mutant, detected in whole blood by reverse transcription-nested PCR, showed skipping of exon 3 (98-bp deletion) and a frameshift, with a terminal signal after 17 altered amino acid residues.

Conclusions: TG defects have an important role in severe thyroidal dyshormonogenesis (pretreatment, or after a 3-wk T4 withdrawal, plasma T4 ≦ 30 nmol/liter) in Taiwanese. Its genetic characteristics are markedly different from those described in other populations presenting with mutations of the TG gene.
Expression of Progesterone Receptor A form and Its Role in the Interaction of Progesterone with Cortisol on Cyclooxygenase-2 Expression in Amnionic Fibroblasts
Authors: Guo C. M. , Zhu X. O. , Ni X. T. , Yang Z. , Myatt L. , Sun K.
Published: October 2009

Context: Human amnion fibroblasts produce abundant prostaglandins toward the end of gestation, which is believed to be one of the major events leading to parturition. Glucocorticoids have been shown to up-regulate cyclooxygenase-2 (COX-2) expression, the crucial enzyme catalyzing prostaglandin synthesis, in human amnion fibroblasts. Although a major propregnancy hormone, the effect of progesterone and the associated progesterone receptor subtypes in the regulation of both basal and glucocorticoid-induced COX-2 expression in human amnion fibroblasts have not been resolved.

Methods and Results: Cultured human amnion fibroblasts prepared from the fetal membranes at term pregnancy without labor mainly expressed the progesterone receptor A form (PRA). Inhibition of endogenous progesterone production with trilostane or knockdown of PRA expression with small interfering RNA significantly enhanced the glucocorticoid receptor (GR)-mediated COX-2 induction by cortisol, whereas overexpression of PRA attenuated the induction by cortisol. Co-immunoprecipitation assay revealed PRA in the GR protein complex. Although exogenous progesterone did not alter COX-2 expression under basal conditions, it attenuated cortisol-induced COX-2 expression at concentrations about 10- to 50-fold higher, which might be achieved by competition with cortisol for GR.

Conclusions: We demonstrated in this study that endogenous progesterone might counteract the induction of prostaglandin synthesis by cortisol via PRA transdominant repression of GR function, whereas high levels of progesterone might further inhibit the induction by cortisol via competitive binding to GR in human amnion fibroblasts. These inhibitory actions of progesterone and PRA on glucocorticoids and GR may partly explain the inconsistent effects of glucocorticoids on parturition in humans.
Human Adipose Tissue Macrophages: M1 and M2 Cell Surface Markers in Subcutaneous and Omental Depots and after Weight Loss
Authors: Aron-Wisnewsky Judith , Tordjman Joan , Poitou Christine , Darakhshan Froogh , Hugol Danielle , Basdevant Arnaud , Aissat Abdelhalim , Guerre-Millo Michèle , Clément Karine
Published: October 2009

Context: Macrophages accumulate in adipose tissue and possibly participate in metabolic complications in obesity. Macrophage number varies with adipose tissue site and weight loss, but whether this is accompanied by phenotypic changes is unknown.

Objective: The objective of the study was to characterize the activation state of adipose tissue macrophages in human obesity.

Design/Setting: We performed a single-center prospective study.

Participants/Interventions: Paired biopsies of sc and omental adipose tissue were obtained during gastric surgery in 16 premenopausal obese women (aged 41.1 ± 8.6 yr; body mass index 43.8 ± 3.4 kg/m2). Subcutaneous adipose tissue biopsies were obtained 3 months later in obese subjects and in 10 nonobese women (aged 43.3 ± 3.5 yr; body mass index 22.5 ± 0.75 kg/m2). The number of macrophages stained with CD40, CD206, and CD163 surface markers was determined by immunochemistry.

Main Outcomes: The number of CD40+ macrophages significantly increased with obesity and in omental vs. sc adipose tissue in obese women. No significant changes in CD163+ and CD206+ macrophage counts was found with obesity and fat pad anatomical location. Three months after gastric surgery, the ratio of CD40+ to CD206+ macrophages was 2-fold lower than before surgery in the sc adipose tissue of obese subjects (P < 0.001) due to a concomitant decrease of CD40+ and increase of CD206+ macrophages counts.

Conclusion: We suggest that the activation state of adipose tissue macrophages is weighted toward M1 over M2 status in obese subjects and switch to a less proinflammatory profile 3 months after gastric bypass.

Immunohistochemistry analyses suggest that gastric surgery switches the activation state of adipose tissue macrophages towards a M2-oriented, less pro-inflammatory phenotype in morbidly obese subjects.
Influence of Preterm Birth and Birth Size on Gonadal Function in Young Men
Authors: Kerkhof Gerthe F. , Leunissen Ralph W. J. , Willemsen Ruben H. , de Jong Frank H. , Stijnen Theo , Hokken-Koelega Anita C. S.
Published: October 2009

Background/Objectives: Preterm birth has been associated with reduced reproduction rates and being born small for gestational age (SGA) with reduced gonadal function. We hypothesized that alterations concerning gonadal function in young men are not due to preterm birth or being born SGA, but are due to other (environmental) factors.

Methods: In 207 young men of the PROGRAM/PREMS cohort study, aged 18–24 yr, the influence of preterm birth, birth length, and birth weight on serum levels of anti-Mullerian hormone, inhibin B, testosterone, SHBG, non-SHBG-bound testosterone, LH, and FSH was analyzed with multiple regression modeling. In addition, markers of male gonadal function were analyzed in four subgroups: men born SGA with either short stature or catch-up growth, or men born appropriate for gestational age with idiopathic short stature or with normal stature (control).

Results: Preterm birth and SGA did not affect gonadal function. After adjustment for age, birth size, adult height, fat mass, and socioeconomic status (SES), preterm birth even showed a positive relation with inhibin B. Higher SES was associated with higher inhibin B levels. Higher fat mass was associated with decreased testosterone and SHBG levels and maternal smoking with increased LH and non-SHBG-bound testosterone levels. After adjustment for confounders, there were no significant differences in gonadal function between the subgroups.

Conclusion: Preterm birth and SGA did not affect gonadal function in young men. Factors that affected gonadal function were: lower SES, a higher fat mass, and maternal smoking during pregnancy.

Preterm birth and small birth size for gestational age do not affect male gonadal function in early adulthood.
Activating Autoantibodies against the Calcium-Sensing Receptor Detected in Two Patients with Autoimmune Polyendocrine Syndrome Type 1
Authors: Kemp E. Helen , Gavalas Nikos G. , Krohn Kai J. E. , Brown Edward M. , Watson Philip F. , Weetman Anthony P.
Published: October 2009

Context: Autoimmune polyendocrine syndrome type 1 (APS1) is an autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. Hypoparathyroidism occurs in 80% of patients with APS1 and has been suggested to result from an autoimmune reaction against the calcium-sensing receptor (CaSR) in parathyroid cells. Anti-CaSR binding antibodies have previously been detected in patients with APS1.

Objective: The aim of this study was to determine whether anti-CaSR antibodies present in APS1 patients could modulate the response of the CaSR to stimulation by Ca2+.

Results: The results indicated that two of the 14 APS1 patients included in the study had anti-CaSR antibodies that stimulated the receptor. These antibodies were detected by their ability to increase both Ca2+-dependent extracellular signal-regulated kinase phosphorylation and inositol phosphate accumulation in human embryonic kidney 293 cells expressing the CaSR.

Conclusion: An important implication of the present results is that although the majority of APS1 patients do not have CaSR-stimulating antibodies, there may be a small but substantial minority of patients in whom the hypoparathyroid state is the result of functional suppression of the parathyroid glands rather than their irreversible destruction.
High Prevalence of Metabolic Syndrome in First-Degree Male Relatives of Women with Polycystic Ovary Syndrome Is Related to High Rates of Obesity
Authors: Coviello Andrea D. , Sam Susan , Legro Richard S. , Dunaif Andrea
Published: October 2009

Context: Women with polycystic ovary syndrome (PCOS) have twice the risk for metabolic syndrome (MetS) compared to women from the general population. Mothers and sisters of affected women also have an increased prevalence of MetS.

Objective: The aim of the study was to determine the prevalence of MetS in fathers and brothers of women with PCOS compared to men from the general population.

Design and Setting: We conducted a cross-sectional observational study at academic medical centers.

Participants: A total of 211 fathers and 58 brothers of women with PCOS were studied and compared to 1153 and 582 Third National Health and Nutrition Survey (NHANES III) men of similar age and race/ethnicity, respectively.

Main Outcome Measure: We measured MetS prevalence.

Results: The prevalence of MetS was increased in fathers (42 vs. 32%; P = 0.006) and brothers (22 vs. 9%; P = 0.001) compared to NHANES III men. Fathers and brothers had higher body mass index (BMI) than NHANES III men (P < 0.0001). MetS rates were similar in fathers and brothers compared to NHANES III groups after adjusting for BMI. Total testosterone was inversely related to MetS in both fathers and brothers, but this relationship was also accounted for by the higher BMI in male relatives.

Conclusion: Male relatives of women with PCOS had increased prevalence rates of MetS and obesity compared to the general U.S. male population from NHANES III. In contrast to women with PCOS and their female relatives, the higher prevalence of MetS in male relatives was accounted for by elevated BMI. These findings suggest that the high rates of MetS in male relatives of women with PCOS are related to higher rates of obesity than the general population.

The high prevalence of metabolic syndrome in first degree male relatives of women affected by PCOS compared to similar men in the NHANES III population is attributable to higher rates of obesity than the general population.
Development of a method to measure plasma and whole blood choline by liquid chromatography tandem mass spectrometry
Authors: Griffith C A , Owen L J , Body R , McDowell G , Keevil B G
Published: October 2009

Background

Current gold standard markers for myocardial damage are troponins I and T, which are both sensitive and specific for the detection of myocardial infarction, but require up to 6 h to become reliably elevated in serum. Investigation into markers with potential to identify patients with early ischaemic changes is therefore intense. Choline is reported to be prognostic in patients presenting with acute coronary syndromes via its release from ischaemic cell membranes.

Methods

Liquid chromatography tandem mass spectrometry was used to develop a method to quantitate choline in plasma and blood. The method involves addition of a deuterated internal standard to an aliquot of plasma or blood followed by organic solvent addition, which precipitates the proteins in the sample. Preparation was carried out directly into a 96-deep-well plate. Chromatography of choline used a strong cation exchange column and separation used a Waters Atlantis dC18 analytical column positioned directly before the mass spectrometer source, allowing on-line preanalytical clean up of the sample.

Results

The lower limit of quantitation was 0.38 μmol/L, linearity was observed up to 754 μmol/L, with a working concentration range of 0.38–224 μmol/L, inter- and intra-assay coefficients of variation were <6% and <4%, respectively. Samples were stable throughout five freeze–thaw cycles and recovery was between 94% and 114%.

Conclusions

The assay was successfully validated in accordance with FDA guidelines and is suitable for quantitation of choline in research and clinical settings.
Development of a high-resolution melting method for mutation detection in familial hypercholesterolaemia patients
Authors: Whittall R A , Scartezini M , Li KaWah , Hubbart C , Reiner Z , Abraha A , Neil H A W , Dedoussis G , Humphries S E
Published: October 2009

Aims

Current screening methods, such as single strand conformational polymorphism (SSCP) and denaturing high performance liquid chromatography (dHPLC) that are used for detecting mutations in familial hypercholesterolaemia (FH) subjects are time consuming, costly and only 80–90% sensitive. Here we have tested high-resolution melt (HRM) analysis for mutation detection using the Rotor-Gene6000 realtime rotary analyser.

Methods and subjects

Polymerase chain reaction and melt conditions (HRM) for 23 fragments of the LDL-receptor gene, a region of exon 26 in the APOB gene (including p.R3527Q) and exon 7 of the PCSK9 gene (including p.D374Y) were optimized. Two double stranded DNA saturating dyes, LC-Green and Syto9, were compared for sensitivity. Eighty-two samples with known mutations were used as positive controls. Twenty-eight Greek FH heterozygous patients and two homozygous patients from the UK and Croatia were screened.

Results

HRM was able to identify all the positive control mutations tested, with similar results with either dye. Eight different variations were found in 17 of the 28 Greek FH patients for an overall detection rate of 61%: c.41delT (1), p.W165X (1), p.C173R (3), p.S286R (2), p.V429M (4), p.G549D (4), p.V613I (1), and a previously unreported mutation p.F694V (1) which is predicted to be FH-causing by functional algorithms. Mutations were found in both the homozygous patients; p.Q92X (Croatia) and p.Y489C (UK); both patients were homozygous for their respective mutations.

Conclusions

HRM is a sensitive, robust technique that could significantly reduce the time and cost of screening for mutations in a clinical setting.
Critical difference calculations revised: inclusion of variation in standard deviation with analyte concentration
Authors: Jones Graham Ross Dallas
Published: October 2009

Background

The critical difference (CD), the smallest difference between sequential laboratory results which is associated with a true change in the patient, is commonly calculated by assuming the same standard deviation (SD) for the initial and subsequent measurements. The calculation of the CD is re-examined without making this assumption.

Methods

A formula for CD is developed, which specifies that even with the assumption of constant coefficient of variations (CV) at the two measurement concentrations used in the calculation, there will be different SDs due to different concentrations.

Results

The effect of removing the assumption of constant SD is to increase the CD for rises in analyte concentration and to decrease the CD for falls in concentration. These effects are caused by increased SD for the second measurement compared with the first when the second measurement is higher, and the reverse when the second is lower.

Conclusions

Replacing the usual assumption of similar total result SD for both measurements included in the CD calculation with a calculation of the SD at both analyte concentrations leads to an increase in the magnitude of the CD for rises in analyte concentration and a decrease for falls in analyte concentration. This change is proposed for all forms of CD calculations.
Lone Inventors as Sources of Breakthroughs: Myth or Reality?
Authors: Singh Jasjit , Fleming Lee
Published: October 2009

Are lone inventors more or less likely to invent breakthroughs? Recent research has attempted to resolve this question by considering the variance of creative outcome distributions. It has implicitly assumed a symmetric thickening or thinning of both tails, i.e., that a greater probability of breakthroughs comes at the cost of a greater probability of failures. In contrast, we propose that collaboration can have opposite effects at the two extremes: it reduces the probability of very poor outcomes—because of more rigorous selection processes—while simultaneously increasing the probability of extremely successful outcomes—because of greater recombinant opportunity in creative search. Analysis of over half a million patented inventions supports these arguments: Individuals working alone, especially those without affiliation to organizations, are less likely to achieve breakthroughs and more likely to invent particularly poor outcomes. Quantile regressions demonstrate that the effect is more than an upward mean shift. We find partial mediation of the effect of collaboration on extreme outcomes by the diversity of technical experience of team members and by the size of team members' external collaboration networks. Supporting our meta-argument for the importance of examining each tail of the distribution separately, experience diversity helps trim poor outcomes significantly more than it helps create breakthroughs, relative to the effect of external networks.
Competition Under Generalized Attraction Models: Applications to Quality Competition Under Yield Uncertainty
Authors: Federgruen Awi , Yang Nan
Published: October 2009

We characterize the equilibrium behavior in a broad class of competition models in which the competing firms' market shares are given by an attraction model, and the aggregate sales in the industry depend on the aggregate attraction value according to a general function. Each firm's revenues and costs are proportional with its expected sales volume, with a cost rate that depends on the firm's chosen attraction value according to an arbitrary increasing function. Whereas most existing competition papers with attraction models can be viewed as special cases of this general model, we apply our general results to a new set of quality competition models. Here an industry has N suppliers of a given product, who compete for the business of one or more buyers. Each of the suppliers encounters an uncertain yield factor, with a given general yield distribution. The buyers face uncertain demands over the course of a given sales season. The suppliers compete by selecting key characteristics of their yield distributions, either their means, their standard deviations, or both. These choices have implications for their per-unit cost rates.
The “I Designed It Myself” Effect in Mass Customization
Authors: Franke Nikolaus , Schreier Martin , Kaiser Ulrike
Published: October 2009

Many companies offer websites that enable customers to design their own individual products, which the manufacturer can then produce to order. To date, the economic value of products self-designed using mass customization (MC) toolkits has been attributed to the two factors of preference fit achieved (which should be as high as possible) and design effort (which should be as low as possible). On the basis of literature on behavioral decision making, we suggest a third factor, namely the awareness of being the creator of the product design. In the course of five different studies, we provide experimental evidence that this “I designed it myself” effect creates economic value for the customer. Regardless of the two other factors, self-designed products generate a significantly higher willingness to pay. This effect is mediated by feelings of accomplishment and moderated by the outcome of the process as well as the individual's perceived contribution to the self-design process. These findings have important implications for MC companies: It is not enough merely to design MC toolkits in such a way that preference fit is maximized and design effort is minimized. To capture the full value of MC, toolkits should also elicit “I designed it myself” feelings.
Another Hidden Cost of Incentives: The Detrimental Effect on Norm Enforcement
Authors: Fuster Andreas , Meier Stephan
Published: October 2009

Monetary incentives, such as subsidies or bonuses, are often considered as a way to foster contributions to public goods in society and firms. This paper investigates experimentally the effect of private contribution incentives in the presence of a norm enforcement mechanism. Norm enforcement through peer punishment has been shown to be effective in raising contributions by itself. We test whether and how (centrally provided) private incentives interact with (decentralized) punishment, both of which affect subjects' monetary payoffs. The results of our experiment show that private incentives for contributors can reduce the effectiveness of the norm enforcement mechanism: Free riders are punished less harshly in the treatment with incentives, and as a consequence, average contributions to the public good are no higher than without incentives. This finding ties to and extends previous research on settings in which monetary incentives may fail to have the desired effect.
Multiattribute Utility Satisfying a Preference for Combining Good with Bad
Authors: Tsetlin Ilia , Winkler Robert L.
Published: October 2009

An important challenge in multiattribute decision analysis is the choice of an appropriate functional form for the utility function. We show that if a decision maker prefers more of any attribute to less and prefers to combine good lotteries with bad, as opposed to combining good with good and bad with bad, her utility function should be a weighted average (a mixture) of multiattribute exponential utilities (“mixex utility”). In the single-attribute case, mixex utility satisfies properties typically thought to be desirable and encompasses most utility functions commonly used in decision analysis. In the multiattribute case, mixex utility implies aversion to any multivariate risk. Risk aversion with respect to any attribute decreases as that attribute increases. Under certain restrictions, such risk aversion also decreases as any other attribute increases, and a multivariate one-switch property is satisfied. One of the strengths of mixex utility is its ability to represent cases where utility independence does not hold, but mixex utility can be consistent with mutual utility independence and take on a multilinear form. An example illustrates the fitting of mixex utility to preference assessments.
Total-Cost Procurement Auctions: Impact of Suppliers' Cost Adjustments on Auction Format Choice
Authors: Kostamis Dimitris , Beil Damian R. , Duenyas Izak
Published: October 2009

We consider sealed- and open-bid total-cost procurement auctions where two attributes are used for contract award decisions: price, which is bid by the supplier, and a fixed cost adjustment, which is included by the buyer to capture nonprice factors such as logistics costs. Suppliers know only their own true production cost and their own cost adjustment, and the buyer does not know the suppliers' true production costs but does know all suppliers' cost adjustments, which she herself sets in order to make an informed total-cost decision. The buyer, who seeks to minimize her total (price and cost adjustment) procurement cost, can choose to run a first-price sealed-bid auction, where suppliers' bids are affected by their beliefs about each other's total costs, or a descending open-bid auction, where only the actual realizations of suppliers' total costs drive the auction outcome. We characterize the buyer's choice between the two formats as a threshold decision over suppliers' cost adjustments and analyze the effect of supplier beliefs on her decision. We also study the impact of additional suppliers on the buyer's decision, the effect of correlation between suppliers' production costs and their cost adjustments, and additive as well as multiplicative total-cost functions. The results suggest that procurement managers can use their evaluations of suppliers' cost adjustments to make better auction format decisions.
Ambiguity Aversion and the Preference for Established Brands
Authors: Muthukrishnan A. V. , Wathieu Luc , Xu Alison Jing
Published: October 2009

We propose that ambiguity aversion, as introduced in the literature on decision making under uncertainty, drives a preference for established brands in multiattribute choices among branded alternatives. Established brands are those for which belief in quality is held with greater confidence, even if specific attributes might be inferior to those of competing, less-established brands. In five experiments, we examine the role of ambiguity aversion in the preference for dominated, established brands. We first show a correlation between ambiguity aversion (revealed through choices among monetary lotteries) and the preference for established brands. We then show that the preference for established brands is enhanced when ambiguity aversion is made more salient in unrelated preceding lottery choices. Thus, ambiguity aversion carries across choices. In addition, ambiguity aversion and the preference for established brands are both enhanced when subjects anticipate that others will evaluate their lottery choices. Finally, ambiguous information about brand attributes tends to increase the preference for established brands.
The Entropy Solutions for the Lighthill-Whitham-Richards Traffic Flow Model with a Discontinuous Flow-Density Relationship
Authors: Lu Yadong , Wong S. C. , Zhang Mengping , Shu Chi-Wang
Published: October 2009

In this paper we explicitly construct the entropy solutions for the Lighthill-Whitham-Richards (LWR) traffic flow model with a flow-density relationship which is piecewise quadratic, concave, but not continuous at the junction points where two quadratic polynomials meet, and with piecewise linear initial condition and piecewise constant boundary conditions. The existence and uniqueness of entropy solutions for such conservation laws with discontinuous fluxes are not known mathematically. We have used the approach of explicitly constructing the entropy solutions to a sequence of approximate problems in which the flow-density relationship is continuous but tends to the discontinuous flux when a small parameter in this sequence tends to zero. The limit of the entropy solutions for this sequence is explicitly constructed and is considered to be the entropy solution associated with the discontinuous flux. We apply this entropy solution construction procedure to solve four representative traffic flow cases, compare them with numerical solutions obtained by a high order weighted essentially nonoscillatory (WENO) scheme, and discuss the results from traffic flow perspectives.
Models for Evaluating and Planning City Logistics Systems
Authors: Crainic Teodor Gabriel , Ricciardi Nicoletta , Storchi Giovanni
Published: October 2009

City logistics aims to reduce the nuisances associated to freight transportation in urban areas while supporting their economic and social development. The fundamental idea is to view individual stakeholders and decisions as components of an integrated logistics system. This implies the coordination of shippers, carriers, and movements as well as the consolidation of loads of several customers and carriers into the same environment-friendly vehicles. City logistics explicitly aims to optimize such advanced urban transportation systems. We focus on a challenging city logistics planning issue, the integrated short-term scheduling of operations and management of resources, for the general case involving a two-tiered distribution structure. We investigate the main issues related to the problem, introduce a new problem class, propose both a general model and formulations for the main system components, and identify promising solution avenues.
Eliciting Coordination with Rebates
Authors: Maillé Patrick , Stier-Moses Nicolás E.
Published: October 2009

This article considers a mechanism based on rebates that aims at reducing congestion in urban networks. The framework helps select rebate levels so that enough commuters switch to modes that are under used. Indeed, getting a relative small number of drivers to switch to public transportation can significantly improve congestion. This mechanism is modeled by a Stackelberg game in which the transportation authority offers rebates, and participants factor them into the costs of each mode. A new Wardrop equilibrium arises when participants selfishly select one of the modes of transportation with the lowest updated costs. Rebate levels are chosen taking into account not only the potential reduction of the participants' cost, but also the cost of providing those rebates. Part of the budget for rebates may come from the savings that arise from the more efficient use of capacity. We characterize the Stackelberg equilibria of the game, and describe a polynomial-time algorithm to compute the optimal rebates for each mode. In addition, we provide tight results on the worst-case inefficiency of the resulting Wardrop equilibrium, measured by the so-called price of anarchy. Specifically, we describe the tradeoff between the sensitivity of the owner towards rebate costs and the worst-case inefficiency of the system.
Ground Delay Program Planning Under Uncertainty Based on the Ration-by-Distance Principle
Authors: Ball Michael O. , Hoffman Robert , Mukherjee Avijit
Published: October 2009

This paper presents ration-by-distance (RBD), a new allocation method to be used in planning ground delay programs (GDPs) for traffic flow management. It is shown that RBD minimizes total expected delay, under certain assumptions related to the manner in which GDPs are dynamically controlled. On the other hand, RBD taken to the extreme has poor characteristics with respect to the equity of the allocation it produces. To address this issue, we propose a constrained version of RBD as a practical alternative to allocation procedures used in operations today. It is shown that this algorithm has superior overall performance in terms of efficiency and equity relative to existing procedures.
Force field for the atomistic simulation of the properties of hydrazine, organic hydrazine derivatives, and energetic hydrazinium ionic liquids
Authors: Gutowski Keith E. , Gurkan Burcu , Maginn Edward J.
Published: October 2009

A force field (FF) is reported for hydrazine (N2H4) and organic hydrazine derivatives, including monomethylhydrazine, 1,1-dimethylhydrazine, monoethylhydrazine, and 2-hydroxyethylhydrazine. The FF successfully reproduces a range of equilibrium properties, including vapor–liquid coexistence densities, vapor pressures, enthalpies of vaporization, and critical properties. Several dynamic properties, including self-diffusion coefficients and rotational time constants, are reported and found to be qualitatively consistent with experimental viscosities. Using this as a basis, a FF is also developed for the protonated forms of these species, i.e., hydrazinium-based cations. Properties of 1:1 energetic salts formed by pairing these cations with the nitrate anion are computed and compared with a limited amount of experimental data. The simulations indicate that the ionic liquid (IL) 2-hydroxyethylhydrazinum nitrate (2-HEHN) has significantly slower dynamics than the other hydrazinium ILs.
Tobacco as a Substance of Abuse
Authors: Sims Tammy H. ,   the Committee on Substance Abuse
Published: October 2009

Tobacco use is the leading preventable cause of morbidity and death in the United States. Because 80% to 90% of adult smokers began during adolescence, and two thirds became regular, daily smokers before they reached 19 years of age, tobacco use may be viewed as a pediatric disease. Every year in the United States, approximately 1.4 million children younger than 18 years start smoking, and many of them will die prematurely from a smoking-related disease. Moreover, there is recent evidence that adolescents report symptoms of tobacco dependence early in the smoking process, even before becoming daily smokers. The prevalence of tobacco use is higher among teenagers and young adults than among older adult populations. The critical role of pediatricians in helping to reduce tobacco use and addiction and secondhand tobacco-smoke exposure in the pediatric population includes education and prevention, screening and detection, and treatment and referral.
Alsóvégtag-amputált érbetegek új protetizációs lehetősége: kezdeti tapasztalataink az osszeointegrációs technikávalr
Authors: Ferencz Sándor , Mangold Viktória , Dérczy Katalin , Takács Ildikó , Balatonyi Borbála , Horváth Szabolcs , Jávor Szaniszló , Brånemark Rickard , Horváth Örs Péter , Rőth Erzsébet , Wéber György
Published: October 2009

Absztrakt

Bevezetés/célkitűzés:Az alsóvégtag-amputált betegek nagy része a művégtagját nehezen tudja használni. A panaszok legtöbbször a művégtag tokjával hozhatók összefüggésbe, ezért javulást a tokot nem igénylő osszeointegrációs technika bevezetésétől várhatunk. Célunk a módszer hazai bevezetése, illetve az indikációs terület érbetegekre való kiterjesztésének vizsgálata volt.Anyag és módszerek:A technika két műtéti és egy rehabilitációs fázisból áll. Az első műtét során titániumcsavar kerül beültetésre a combcsont velőüregébe, majd ehhez rögzül a második műtét után egy, a csonk bőrén is keresztülhaladó, a protézist a combcsonthoz közvetlenül rögzítő fémtoldalék. Ezután a beteg a rehabilitációs fázis során csonterősítő gyakorlatokat végez, és járni tanul új művégtagjával.Eredmények:2005-ben két combamputált nőbeteg operációjával kezdtük a módszer első magyarországi alkalmazását, majd a második műtét 2006 januárjában történt (ekkor két férfibetegnél csavarbeültető műtétet is végeztünk). A titániumcsavar valamennyi betegnél maradéktalanul beépült a csont velőüregébe, első betegeink rehabilitációja is sikeresen végződött, a betegek az új végtagjukat könnyebben használják. Egyik férfibetegünk nyolc hónappal az első műtét után szívinfarktus következtében meghalt.Következtetések:Tapasztalataink alapján osszeointegrációs technikával protetizált betegeink művégtagjukat könnyebben használják. Tapasztalataink szerint az érbetegség önmagában nem képezi az osszeointegrációs technika ellenjavallatát, de a szigorú kritériumok meghatározásához további klinikai vizsgálat indokolt.
Pancreas- és periampullaris tumorok kezelése az elmúlt 10 évben klinikánkonr
Authors: Kelemen Dezső , Papp Róbert , Baracs József , Káposztás Zsolt , Al-Farhat Yousuf , Horváth Örs Péter
Published: October 2009

Absztrakt

A szerzők 10 év során operált és kezelt 363 pancreas- vagy periampullaris tumoros beteg kórtörténetét elemzik. 175 esetben a folyamat operábilis, míg 188 esetben inoperábilis volt. Ismertetik a preoperatív adatokat (kor, nem, daganat kiindulási helye, főbb klinikai tünetek), valamint a választott műtéti típusokat. A leggyakoribb kuratív beavatkozás a pancreatoduodenectomia volt, míg palliatiónál főleg kettős bypass történt. Részletezik a posztoperatív szövődményeket, különös tekintettel a pancreasfistulára, mely összefüggött az alkalmazott anastomosistechnikával. A reoperációs és korai posztoperatív mortalitási ráta az operábilis esetekben 5,7%, illetve 4,5% volt, míg palliatiókor 1,6%, illetve 6,9%. A radikális műtét után onkológiai konzíliumra került sor, a kezelés eredményeit is taglalják a szerzők. Összefoglalva megállapítják, hogy törekedni kell a kuratív műtétre és a posztoperatív onkológiai kezelésre, mert csak így van esély a hoszszú távú túlélésre.