Cost Sharing under Uncertainty: An Algorithmic Approach to Cooperative Interval-Valued Games

Recently, Branzei, Dimitrov, and Tijs (2003) introduced cooperative interval-valued games. Among other insights, the notion of an interval core has been coined and proposed as a solution concept for interval-valued games. In this paper we will present a general mathematical programming algorithm which can be applied to find an element in the interval core. As an example, we discuss lot sizing with uncertain demand to provide an application for interval-valued games and to demonstrate how interval core elements can be computed. Also, we reveal that pitfalls exist if interval core elements are computed in a straightforward manner by considering the interval borders separately.

The bovine dilated cardiomyopathy locus maps to a 1.0-Mb interval on chromosome 18

Cardiomyopathies are myocardial diseases that lead to cardiac dysfunction, heart failure, arrhythmia, and sudden death. In human medicine, cardiomyopathies frequently warrant heart transplantation in children and adults. Bovine dilated cardiomyopathy (BDCMP) is a heart muscle disorder that has been observed during the last 30 years in cattle of Holstein-Friesian origin. In Switzerland BDCMP affects Swiss Fleckvieh and Red Holstein breeds. BDCMP is characterized by a cardiac enlargement with ventricular remodeling and chamber dilatation. The common symptoms in affected animals are subacute subcutaneous edema, congestion of the jugular veins, and tachycardia with gallop rhythm. A cardiomegaly with dilatation and hypertrophy of all heart chambers, myocardial degeneration, and fibrosis are typical postmortem findings. It was shown that all BDCMP cases reported worldwide traced back to a red factor-carrying Holstein-Friesian bull, ABC Reflection Sovereign. An autosomal recessive mode of inheritance was proposed for BDCMP. Recently, the disease locus was mapped to a 6.7-Mb interval MSBDCMP06-BMS2785 on bovine Chr 18 (BTA18). In the present study the BDCMP locus was fine mapped by using a combined strategy of homozygosity mapping and association study. A BAC contig of 2.9 Mb encompassing the crucial interval was constructed to establish the correct marker order on BTA18. We show that the disease locus is located in a gene-rich interval of 1.0 Mb and is flanked by the microsatellite markers DIK3006 and MSBDCMP51.

Electrocardiographic PR interval and adverse outcomes in older adults: the Health, Aging, and Body Composition study

BACKGROUND The electrocardiographic PR interval increases with aging, differs by race, and is associated with atrial fibrillation (AF), pacemaker implantation, and all-cause mortality. We sought to determine the associations between PR interval and heart failure, AF, and mortality in a biracial cohort of older adults. METHODS AND RESULTS The Health, Aging, and Body Composition (Health ABC) Study is a prospective, biracial cohort. We used multivariable Cox proportional hazards models to examine PR interval (hazard ratios expressed per SD increase) and 10-year risks of heart failure, AF, and all-cause mortality. Multivariable models included demographic, anthropometric, and clinical variables in addition to established cardiovascular risk factors. We examined 2722 Health ABC participants (aged 74±3 years, 51.9% women, and 41% black). We did not identify significant effect modification by race for the outcomes studied. After multivariable adjustment, every SD increase (29 ms) in PR interval was associated with a 13% greater 10-year risk of heart failure (95% confidence interval, 1.02-1.25) and a 13% increased risk of incident AF (95% confidence interval, 1.04-1.23). PR interval >200 ms was associated with a 46% increased risk of incident heart failure (95% confidence interval, 1.11-1.93). PR interval was not associated with increased all-cause mortality. CONCLUSIONS We identified significant relationships of PR interval to heart failure and AF in older adults. Our findings extend prior investigations by examining PR interval and associations with adverse outcomes in a biracial cohort of older men and women.

Characterization of 2 genetic variants of Na(v) 1.5-arginine 689 found in patients with cardiac arrhythmias

Hundreds of genetic variants in SCN5A, the gene coding for the pore-forming subunit of the cardiac sodium channel, Na(v) 1.5, have been described in patients with cardiac channelopathies as well as in individuals from control cohorts. The aim of this study was to characterize the biophysical properties of 2 naturally occurring Na(v) 1.5 variants, p.R689H and p.R689C, found in patients with cardiac arrhythmias and in control individuals. In addition, this study was motivated by the finding of the variant p.R689H in a family with sudden cardiac death (SCD) in children. When expressed in HEK293 cells, most of the sodium current (I(Na)) biophysical properties of both variants were indistinguishable from the wild-type (WT) channels. In both cases, however, an ∼2-fold increase of the tetrodotoxin-sensitive late I(Na) was observed. Action potential simulations and reconstruction of pseudo-ECGs demonstrated that such a subtle increase in the late I(Na) may prolong the QT interval in a nonlinear fashion. In conclusion, despite the fact that the causality link between p.R689H and the phenotype of the studied family cannot be demonstrated, this study supports the notion that subtle alterations of Na(v) 1.5 variants may increase the risk for cardiac arrhythmias.

Effects of beta-alanine supplementation and interval training on physiological determinants of severe exercise performance.

INTRODUCTION We aimed to manipulate physiological determinants of severe exercise performance. We hypothesized that (1) beta-alanine supplementation would increase intramuscular carnosine and buffering capacity and dampen acidosis during severe cycling, (2) that high-intensity interval training (HIT) would enhance aerobic energy contribution during severe cycling, and (3) that HIT preceded by beta-alanine supplementation would have greater benefits. METHODS Sixteen active men performed incremental cycling tests and 90-s severe (110 % peak power) cycling tests at three time points: before and after oral supplementation with either beta-alanine or placebo, and after an 11-days HIT block (9 sessions, 4 × 4 min), which followed supplementation. Carnosine was assessed via MR spectroscopy. Energy contribution during 90-s severe cycling was estimated from the O2 deficit. Biopsies from m. vastus lateralis were taken before and after the test. RESULTS Beta-alanine increased leg muscle carnosine (32 ± 13 %, d = 3.1). Buffering capacity and incremental cycling were unaffected, but during 90-s severe cycling, beta-alanine increased aerobic energy contribution (1.4 ± 1.3 %, d = 0.5), concurrent with reduced O2 deficit (-5.0 ± 5.0 %, d = 0.6) and muscle lactate accumulation (-23 ± 30 %, d = 0.9), while having no effect on pH. Beta-alanine also enhanced motivation and perceived state during the HIT block. There were no between-group differences in adaptations to the training block, namely increased buffering capacity (+7.9 ± 11.9 %, p = 0.04, d = 0.6, n = 14) and glycogen storage (+30 ± 47 %, p = 0.04, d = 0.5, n = 16). CONCLUSIONS Beta-alanine did not affect buffering considerably, but has beneficial effects on severe exercise metabolism as well as psychological parameters during intense training phases.

Recognition memory across the lifespan: the impact of word frequency and study-test interval on estimates of familiarity and recollection

The goal of this study was to investigate recognition memory performance across the lifespan and to determine how estimates of recollection and familiarity contribute to performance. In each of three experiments, participants from five groups from 14 up to 85 years of age (children, young adults, middle-aged adults, young-old adults, and old-old adults) were presented with high- and low-frequency words in a study phase and were tested immediately afterwards and/or after a one day retention interval. The results showed that word frequency and retention interval affected recognition memory performance as well as estimates of recollection and familiarity. Across the lifespan, the trajectory of recognition memory followed an inverse u-shape function that was neither affected by word frequency nor by retention interval. The trajectory of estimates of recollection also followed an inverse u-shape function, and was especially pronounced for low-frequency words. In contrast, estimates of familiarity did not differ across the lifespan. The results indicate that age differences in recognition memory are mainly due to differences in processes related to recollection while the contribution of familiarity-based processes seems to be age-invariant.

Interaction between effects of genes coding for dopamine and glutamate transmission on striatal and parahippocampal function

The genes for the dopamine transporter (DAT) and the D-Amino acid oxidase activator (DAOA or G72) have been independently implicated in the risk for schizophrenia and in bipolar disorder and/or their related intermediate phenotypes. DAT and G72 respectively modulate central dopamine and glutamate transmission, the two systems most robustly implicated in these disorders. Contemporary studies have demonstrated that elevated dopamine function is associated with glutamatergic dysfunction in psychotic disorders. Using functional magnetic resonance imaging we examined whether there was an interaction between the effects of genes that influence dopamine and glutamate transmission (DAT and G72) on regional brain activation during verbal fluency, which is known to be abnormal in psychosis, in 80 healthy volunteers. Significant interactions between the effects of G72 and DAT polymorphisms on activation were evident in the striatum, parahippocampal gyrus, and supramarginal/angular gyri bilaterally, the right insula, in the right pre-/postcentral and the left posterior cingulate/retrosplenial gyri (P < 0.05, FDR-corrected across the whole brain). This provides evidence that interactions between the dopamine and the glutamate system, thought to be altered in psychosis, have an impact in executive processing which can be modulated by common genetic variation.

A NEW TUMOR SUPPRESSOR GENE CANDIDATE REGULATED BY THE NON-CODING RNA PCA3 IN HUMAN PROSTATE CANCER

Prostate cancer is the second leading cause of cancer-related death and the most common non-skin cancer in men in the USA. Considerable advancements in the practice of medicine have allowed a significant improvement in the diagnosis and treatment of this disease and, in recent years, both incidence and mortality rates have been slightly declining. However, it is still estimated that 1 man in 6 will be diagnosed with prostate cancer during his lifetime, and 1 man in 35 will die of the disease. In order to identify novel strategies and effective therapeutic approaches in the fight against prostate cancer, it is imperative to improve our understanding of its complex biology since many aspects of prostate cancer initiation and progression still remain elusive. The study of tumor biomarkers, due to their specific altered expression in tumor versus normal tissue, is a valid tool for elucidating key aspects of cancer biology, and may provide important insights into the molecular mechanisms underlining the tumorigenesis process of prostate cancer. PCA3, is considered the most specific prostate cancer biomarker, however its biological role, until now, remained unknown. PCA3 is a long non-coding RNA (ncRNA) expressed from chromosome 9q21 and its study led us to the discovery of a novel human gene, PC-TSGC, transcribed from the opposite strand and in an antisense orientation to PCA3. With the work presented in this thesis, we demonstrate that PCA3 exerts a negative regulatory role over PC-TSGC, and we propose PC-TSGC to be a new tumor suppressor gene that contrasts the transformation of prostate cells by inhibiting Rho-GTPases signaling pathways. Our findings provide a biological role for PCA3 in prostate cancer and suggest a new mechanism of tumor suppressor gene inactivation mediated by non-coding RNA. Also, the characterization of PCA3 and PC-TSGC led us to propose a new molecular pathway involving both genes in the transformation process of the prostate, thus providing a new piece of the jigsaw puzzle representing the complex biology of prostate cancer.

Multiple independent genetic factors at NOS1AP modulate the QT interval in a multi-ethnic population.

Extremes of electrocardiographic QT interval are associated with increased risk for sudden cardiac death (SCD); thus, identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous studies have revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We sought to characterize the effects of NOS1AP genetic variants on QT interval in the multi-ethnic population-based Dallas Heart Study (DHS, n = 3,072). The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in White (P = 0.005) and Black (P = 3.6 x 10(-5)) participants, with the same direction of effect in Hispanics (P = 0.17), and further showed a significant SNP x sex-interaction (P = 0.03). A second SNP, rs16856785, uncorrelated with rs16847548, was also associated with QT interval in Blacks (P = 0.01), with qualitatively similar results in Whites and Hispanics. In a previously genotyped cohort of 14,107 White individuals drawn from the combined Atherosclerotic Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) cohorts, we validated both the second locus at rs16856785 (P = 7.63 x 10(-8)), as well as the sex-interaction with rs16847548 (P = 8.68 x 10(-6)). These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends, though not statistically significant at P<0.05, in Hispanics. In addition, we identify a strong sex-interaction and the presence of a second independent site within NOS1AP associated with the QT interval. These results highlight the consistent and complex role of NOS1AP genetic variants in modulating QT interval.

Explanations for unsuccessful weight loss among bariatric surgery candidates.

BACKGROUND: Our objective was to analyze subjective explanations for unsuccessful weight loss among bariatric surgery candidates. METHODS: This was a retrospective analysis of 909 bariatric surgery candidates (78.2% female, average body mass index [BMI] 47.3) at a university center from 2001 to April 2007 who answered an open-ended question about why they were unable to lose weight. We generated a coding scheme for answers to the question and established inter-rater reliability of the coding process. Associations with demographic parameters and initial BMI were tested. RESULTS: The most common categories of answers were nonspecific explanations related to diet (25.3%), physical activity (21.0%), or motivation (19.7%), followed by diet-related motivation (12.7%) and medical conditions or medications affecting physical activity (12.7%). Categories related to time, financial cost, social support, physical environment, and knowledge occurred in less than 4% each. Men were more likely than women to cite a medical condition or medication affecting physical activity (19.2% vs 10.8%, P = 0.002, odds ratio [OR] = 1.96, 95% confidence interval [CI] = 1.28-2.99) but less likely to cite diet-related motivation (7.1% vs 14.2%, P = 0.008, OR = 0.46, 95% CI = 0.26-0.82). CONCLUSIONS: Our findings suggest that addressing diet, physical activity, and motivation in a comprehensive approach would meet the stated needs of obese patients. Raising patient awareness of under-recognized barriers to weight loss, such as the physical environment and lack of social support, should also be considered. Lastly, anticipating gender-specific attributions may facilitate tailoring of interventions.

The long non-coding RNA NEAT1 is increased in IUGR placentas, leading to potential new hypotheses of IUGR origin/development.

INTRODUCTION Intrauterine Growth Restriction (IUGR) is a multifactorial disease defined by an inability of the fetus to reach its growth potential. IUGR not only increases the risk of neonatal mortality/morbidity, but also the risk of metabolic syndrome during adulthood. Certain placental proteins have been shown to be implicated in IUGR development, such as proteins from the GH/IGF axis and angiogenesis/apoptosis processes. METHODS Twelve patients with term IUGR pregnancy (birth weight < 10th percentile) and 12 CTRLs were included. mRNA was extracted from the fetal part of the placenta and submitted to a subtraction method (Clontech PCR-Select cDNA Subtraction). RESULTS One candidate gene identified was the long non-coding RNA NEAT1 (nuclear paraspeckle assembly transcript 1). NEAT1 is the core component of a subnuclear structure called paraspeckle. This structure is responsible for the retention of hyperedited mRNAs in the nucleus. Overall, NEAT1 mRNA expression was 4.14 (±1.16)-fold increased in IUGR vs. CTRL placentas (P = 0.009). NEAT1 was exclusively localized in the nuclei of the villous trophoblasts and was expressed in more nuclei and with greater intensity in IUGR placentas than in CTRLs. PSPC1, one of the three main proteins of the paraspeckle, co-localized with NEAT1 in the villous trophoblasts. The expression of NEAT1_2 mRNA, the long isoform of NEAT1, was only modestly increased in IUGR vs. CTRL placentas. DISCUSSION/CONCLUSION The increase in NEAT1 and its co-localization with PSPC1 suggests an increase in paraspeckles in IUGR villous trophoblasts. This could lead to an increased retention of important mRNAs in villous trophoblasts nuclei. Given that the villous trophoblasts are crucial for the barrier function of the placenta, this could in part explain placental dysfunction in idiopathic IUGR fetuses.

LINKAGE RELATIONSHIPS AMONG PROTEIN-CODING LOCI IN FISHES OF THE GENUS XIPHOPHORUS

Inbred strains of three species of fishes of the genus Xiphophorus (platyfish and swordtails) were crossed to produce intra- and interspecific F(,1) hybrids, which were then backcrossed to one or both parental stocks. Backcross hybrids were used for the analysis of segregation and linkage of 33 protein-coding loci (whose products were visualized by starch gel electrophoresis) and a sex-linked pigment pattern gene. Segregation was Mendelian for all loci with the exception of one instance of segregation distortion. Six linkage groups of enzyme-coding loci were established: LG I, ADA --6%-- G(,6)PD --24%-- 6PGD; LG II, Est-2 --27%-- Est-3 --0%-- Est-5 --23%-- LDH-1 --16%-- MPI; LG III, AcPh --38%-- G(,3)PD-1 (GUK-2 --14%-- G(,3)PD-1 is also in LG III, but the position of GUK-2 with respect to AcPh has not yet been determined); LG IV, GPI-1 --41%-- IDH-1; LG V, Est-1 --38%-- MDH-2; and LG VI, P1P --7%-- UMPK-1 (P1P is a plasma protein, very probably transferrin).^ Sex-specific recombination appeared absent in LG II and LG IV locus pairs; significantly higher male recombination was demonstrated in LG I but significantly higher female recombination was detected in LG V. Only one significant population-specific difference in recombination was detected, in the G(,6)PD - 6PGD region of LG I; the notable absence of such effects implies close correspondence of the genomes of the species used in the study. Two cases of possible evolutionary conservation of linkage groups in fishes and mammals were described, involving the G(,6)PD - 6PGD linkage in LG I and the cluster of esterase loci in LG II. One clear case of divergence was observed, that of the linkage of ADA in LG I. It was estimated that a minimum of (TURN)50% of the Xiphophorus genome was marked by the loci studied. Therefore, the prior probability that a new locus will assort independently from the markers already established is estimated to be less than 0.5. A maximum of 21 of the 24 pairs of chromosomes could be marked with at least one locus.^ Only the two LG V loci showed a significant association with a postulated gene controlling the severity of a genetically controlled melanoma caused by abnormal proliferation of macromelanophore pigment pattern cells. The independence of melanotic severity from all other informative markers implies that one or at most a few major genes are involved in control of melanotic severity in this system. ^