Measurement of the Charge-Averaged Elastic Lepton-Proton Scattering Cross Section by the OLYMPUS Experiment.

We report the first measurement of the average of the electron-proton and positron-proton elastic scattering cross sections. This lepton charge-averaged cross section is insensitive to the leading effects of hard two-photon exchange, giving more robust access to the proton's electromagnetic form factors. The cross section was extracted from data taken by the OLYMPUS experiment at DESY, in which alternating stored electron and positron beams were scattered from a windowless gaseous hydrogen target. Elastic scattering events were identified from the coincident detection of the scattered lepton and recoil proton in a large-acceptance toroidal spectrometer. The luminosity was determined from the rates of Møller, Bhabha, and elastic scattering in forward electromagnetic calorimeters. The data provide some selectivity between existing form factor global fits and will provide valuable constraints to future fits.

The impact of social complexity on the visual exploration of others' actions in preschoolers with autism spectrum disorder.

BACKGROUND: Typical development of socio-communicative skills relies on keen observation of others. It thus follows that decreased social attention negatively impacts the subsequent development of socio-communicative abilities in children with autism spectrum disorders (ASD). In addition, studies indicate that social attention is modulated by context and that greater social difficulties are observed in more socially demanding situations. Our study aims to investigate the effect of social complexity on visual exploration of others' actions in preschoolers. METHODS: To investigate the impact of social complexity, we used an eye-tracking paradigm with 26 typically developing preschoolers (TD, age = 3.60 ± 1.55) and 37 preschoolers with ASD (age = 3.55 ± 1.21). Participants were shown videos of two children engaging in socially simple play (parallel) versus socially complex play (interactive). We subsequently quantified the time spent and fixation duration on faces, objects, bodies, as well as the background and the number of spontaneous gaze shifts between socially relevant areas of interest. RESULTS: In the ASD group, we observed decreased time spent on faces. Social complexity (interactive play) elicited changes in visual exploration patterns in both groups. From the parallel to the interactive condition, we observed a shift towards socially relevant parts of the scene, a decrease in fixation duration, as well as an increase in spontaneous gaze shifts between faces and objects though there were fewer in the ASD group. LIMITATIONS: Our results need to be interpreted cautiously due to relatively small sample sizes and may be relevant to male preschoolers, given our male-only sample and reported phenotypic differences between males and females. CONCLUSION: Our results suggest that similar to TD children, though to a lesser extent, visual exploration patterns in ASD are modulated by context. Children with ASD that were less sensitive to context modulation showed decreased socio-communicative skills or higher levels of symptoms. Our findings support using naturalistic designs to capture socio-communicative deficits in ASD.

Study of Two-Photon Exchange via the Beam Transverse Single Spin Asymmetry in Electron-Proton Elastic Scattering at Forward Angles over a Wide Energy Range.

We report on a new measurement of the beam transverse single spin asymmetry in electron-proton elastic scattering, A_{⊥}^{ep}, at five beam energies from 315.1 to 1508.4 MeV and at a scattering angle of 30°<θ<40°. The covered Q^{2} values are 0.032, 0.057, 0.082, 0.218, 0.613 (GeV/c)^{2}. The measurement clearly indicates significant inelastic contributions to the two-photon-exchange (TPE) amplitude in the low-Q^{2} kinematic region. No theoretical calculation is able to reproduce our result. Comparison with a calculation based on unitarity, which only takes into account elastic and πN inelastic intermediate states, suggests that there are other inelastic intermediate states such as ππN, KΛ, and ηN. Covering a wide energy range, our new high-precision data provide a benchmark to study those intermediate states.

Circulating breast-derived DNA allows universal detection and monitoring of localized breast cancer.

BACKGROUND: Tumor-derived circulating cell-free DNA (cfDNA) is present in the plasma of individuals with cancer. Assays aimed at detecting common cancer mutations in cfDNA are being developed for the detection of several cancer types. In breast cancer, however, such assays have failed to detect the disease at a sensitivity relevant for clinical use, in part due to the absence of multiple common mutations that can be co-detected in plasma. Unlike individual mutations that exist only in a subset of tumors, unique DNA methylation patterns are universally present in cells of a common type and therefore may be ideal biomarkers. Here we describe the detection and quantification of breast-derived cfDNA using a breast-specific DNA methylation signature. PATIENTS AND METHODS: We collected plasma from patients with localized breast cancer before and throughout treatment with neoadjuvant chemotherapy and surgery (N = 235 samples). RESULTS: Pretreatment breast cfDNA was detected in patients with localized disease with a sensitivity of 80% at 97% specificity. High breast cfDNA levels were associated with aggressive molecular tumor profiles and metabolic activity of the disease. During neoadjuvant chemotherapy, breast cfDNA levels decreased dramatically. Importantly, the presence of breast cfDNA towards the end of the chemotherapy regimen reflected the existence of residual disease. CONCLUSION: We propose that breast-specific cfDNA is a universal and powerful marker for the detection and monitoring of breast cancer.

The potential of δ2Hn-alkanes and δ18Osugar for paleoclimate reconstruction - A regional calibration study for South Africa.

The hydrogen isotopic composition of leaf wax-derived n-alkanes (δ2Hn-alkanes) is a widely applied proxy for (paleo)climatic changes. It has been suggested that the coupling with the oxygen isotopic composition of hemicellulose-derived sugars (δ18Osugar) - an approach dubbed 'paleohygrometer' - might allow more robust and quantitative (paleo)hydrological reconstructions. However, the paleohygrometer remains to be evaluated and tested regionally. In this study, topsoil samples from South Africa, covering extensive environmental gradients, are analysed. δ2Hn-alkanes correlates significantly with the isotopic composition of precipitation (δ2Hp), whereas no significant correlation exists between δ18Osugar and δ18Op. The apparent fractionation (εapp) is the difference between δ2Hn-alkanes and δ2Hp (εapp 2H) and δ18Osugar and δ18Op (εapp 18O), respectively, and integrates i) isotopic enrichment due to soil water evaporation, ii) leaf (and xylem) water transpiration and iii) biosynthetic fractionation. We find no correlation of εapp 18O nor for εapp 2H with temperature, and no correlation of εapp 2H with potential evapotranspiration and an aridity index. By contrast, εapp 18O correlates significantly with both potential evapotranspiration and the aridity index. This highlights the strong effect of evapotranspirative enrichment on δ18Osugar. In study areas without plant predominance using Crassulacean Acid Metabolism (CAM), coupling δ18Osugar and δ2Hn-alkanes enables to reconstruct δ2Hp and δ18Op with an offset of Δδ2H = 6 ± 27‰ and Δδ18O = 0.8 ± 3.7‰, respectively, as well as relative humidity (RH) with an offset of ΔRH = 6 ± 17%. The paleohygrometer does, however, not work well for our study areas where CAM plants prevail (reconstructed δ18Op, δ2Hp and RH are off by 3.1‰, 27.2‰ and 31.7%). This probably reflects plant-specific (phenological) adaptations and/or post-photosynthetic exchange reactions related to CAM metabolism. Overall, our findings corroborate that δ2Hn-alkanes and δ18Osugar are valuable proxies, and the paleohygrometer is a promising approach for paleoclimate reconstructions in southern Africa.

Does differential visual exploration contribute to visual memory impairments in 22q11.2 microdeletion syndrome?

BACKGROUND: Chromosome 22q11.2 microdeletion syndrome (22q11.2DS) is a genetic syndrome characterised by a unique cognitive profile. Individuals with the syndrome present several non-verbal deficits, including visual memory impairments and atypical exploration of visual information. In this study, we seek to understand how visual attention may contribute to memory difficulties in 22q11.2DS by tracking eye movements during the encoding phase of a visual short-term memory task. METHOD: Eye movements were recorded during a computerised version of the multiple-choice Benton Visual Retention Test, which consisted of exploring and then recognising complex visual stimuli. Seventy-four participants affected by 22q11.2DS were compared with 70 typically developing participants. RESULTS: Participants with 22q11.2DS performed less well than healthy controls on the task and spent more time and fixations on the principal (larger central) figures and less time and fixations on the smaller peripheral figures within the stimuli. CONCLUSIONS: This study is the first to investigate visual attention in 22q11.2DS during a memory task. The results delineate impaired processes during encoding that affect visual memory performance. The findings may be especially useful for informing interventions intended to boost visual learning in patients with 22q11.2DS.

Understanding others: a pilot investigation of cognitive and affective facets of social cognition in patients with 22q11.2 deletion syndrome (22q11DS).

BACKGROUND: Although significant impairments in the affective and cognitive facets of social cognition have been highlighted in patients with 22q11.2 deletion syndrome (22q11DS) in previous studies, these domains have never been investigated simultaneously within the same group of participants. Furthermore, despite theoretical evidence, associations between these two processes and schizotypal symptoms or social difficulties in this population have been scarcely examined. METHODS: Twenty-nine participants with 22q11DS and 27 typically developing controls (N = 5 siblings; N = 22 unrelated controls) aged between 11 and 21 years participated in the study. Both groups were matched for age and gender distribution. Two computerized social cognition tasks evaluating perspective and emotion recognition abilities were administered to all participants. The levels of schizotypal trait expression and social functioning were further investigated in both groups, based on a validated self-report questionnaire (Schizotypal Personality Questionnaire) and parental interview (Vineland Adaptive Behavior Scales). RESULTS: Participants with 22q11DS exhibited lower perspective-taking and emotion recognition capacities than typically developing controls. The two socio-cognitive dimensions investigated here were further correlated in healthy controls. The efficiency of perspective-taking processes (response time) was marginally related to the degree of schizotypal trait expression in patients with 22q11DS. CONCLUSIONS: This study first provides support for significant deficits in two core facets of social cognition in 22q11DS. The associations observed between the experimental tasks and measures of social functioning or schizotypal symptoms in 22q11DS open promising research avenue, which should be more deeply investigated in future studies.

New Measurements of the Beam Normal Spin Asymmetries at Large Backward Angles with Hydrogen and Deuterium Targets.

New measurements of the beam normal single spin asymmetry in the electron elastic and quasielastic scattering on the proton and deuteron, respectively, at large backward angles and at ⟨Q^{2}⟩=0.22 (GeV/c)^{2} and ⟨Q^{2}⟩=0.35 ( GeV/c)^{2} are reported. The experimentally observed asymmetries are compared with the theoretical calculation of Pasquini and Vanderhaeghen [Phys. Rev. C 70, 045206 (2004).PRVCAN0556-281310.1103/PhysRevC.70.045206]. The agreement of the measurements with the theoretical calculations shows a dominance of the inelastic intermediate excited states of the nucleon, πN and the Δ resonance. The measurements explore a new, important parameter region of the exchanged virtual photon virtualities.

Hard Two-Photon Contribution to Elastic Lepton-Proton Scattering Determined by the OLYMPUS Experiment.

The OLYMPUS Collaboration reports on a precision measurement of the positron-proton to electron-proton elastic cross section ratio, R_{2γ}, a direct measure of the contribution of hard two-photon exchange to the elastic cross section. In the OLYMPUS measurement, 2.01 GeV electron and positron beams were directed through a hydrogen gas target internal to the DORIS storage ring at DESY. A toroidal magnetic spectrometer instrumented with drift chambers and time-of-flight scintillators detected elastically scattered leptons in coincidence with recoiling protons over a scattering angle range of ≈20° to 80°. The relative luminosity between the two beam species was monitored using tracking telescopes of interleaved gas electron multiplier and multiwire proportional chamber detectors at 12°, as well as symmetric Møller or Bhabha calorimeters at 1.29°. A total integrated luminosity of 4.5 fb^{-1} was collected. In the extraction of R_{2γ}, radiative effects were taken into account using a Monte Carlo generator to simulate the convolutions of internal bremsstrahlung with experiment-specific conditions such as detector acceptance and reconstruction efficiency. The resulting values of R_{2γ}, presented here for a wide range of virtual photon polarization 0.456<ε<0.978, are smaller than some hadronic two-photon exchange calculations predict, but are in reasonable agreement with a subtracted dispersion model and a phenomenological fit to the form factor data.

Effects of ageing and senescence on pancreatic ß-cell function.

Ageing is generally associated with deterioration of organ function and regenerative potential. In the case of pancreatic ß-cells, an age-related decline in proliferative potential is well documented, and was proposed to contribute to the increased prevalence of type 2 diabetes in the elderly. The effects of ageing on ß-cell function, namely glucose-stimulated insulin secretion (GSIS), have not been studied as extensively. Recent work revealed that, surprisingly, ß-cells of mature mice and humans secrete more insulin than young ß-cells in response to high glucose concentrations, potentially serving to counteract age-related peripheral insulin resistance. This functional change appears to be orchestrated by p16(Ink4A) -driven cellular senescence and downstream remodelling of chromatin structure and DNA methylation, enhancing the expression of genes controlling ß-cell function. We propose that activation of the cellular senescence program drives life-long functional maturation of ß-cells, due to ß-cell hypertrophy, enhanced glucose uptake and more efficient mitochondrial metabolism, in parallel to locking these cells in a non-replicative state. We speculate that the beneficial aspects of this process can be harnessed to enhance GSIS. Other age-related mechanisms, which are currently poorly understood, act to increase basal insulin secretion levels also in low glucose conditions. This leads to an overall reduction in the amplitude of insulin secretion between low and high glucose at old age, which may contribute to a deterioration in metabolic control.

Visual processing of emotional dynamic faces in 22q11.2 deletion syndrome.

INTRODUCTION: The 22q11.2 deletion syndrome (22q11DS) is a neurogenetic syndrome. Individuals affected by this syndrome present poor social functioning and a high risk for the development of psychiatric disorders. Accurate emotion recognition and visual exploration of faces represent important skills for appropriate development of social cognition in individuals with 22q11DS. For these reasons, there is elevated interest in establishing relevant ways to test the mechanisms associated with emotion recognition in patients with 22q11DS. METHODS: This study investigated emotional recognition and visual exploration of emotional faces in persons with 22q11DS, with a dynamic emotion task using an eye-tracking device. To our knowledge, no previous studies have used emotional dynamic stimuli with 22q11DS, despite improved ecological validity of dynamic stimuli compared with static images. Furthermore, these stimuli provide the opportunity to collect reaction times, as indicators of the emotional intensity necessary for identifying each emotion. RESULTS: In our task, we observed comparable accuracy in emotion recognition in the 22q11DS and healthy control groups. However, individuals with 22q11DS were slower to recognise the emotions. They also spent less time looking at the nose during happy and fearful faces. CONCLUSIONS: These results suggest that individuals with 22q11DS may need either more time or more pronounced emotional cues to correctly label facial expressions.

Efficacy of subthreshold micropulse laser in the treatment of diabetic macular edema is influenced by pre-treatment central foveal thickness.

PURPOSE: To determine if the severity of diabetic macular edema influences the effectiveness of subthreshold micropulse (STMP) laser treatment. METHODS: A total of 63 eyes of 58 patients with diabetic macular edema were divided into two groups based on their initial central foveal thickness (CFT). Group 1 had CFT ≤400 µm, group 2 had CFT >400 µm. The change from baseline in CFT and visual acuity were compared at 3, 6 and 12 months follow-up. Patients were considered for retreatment with micropulse laser at 3 months if macular edema had not improved. Patients were considered for rescue anti-VEGF injections if there was clinically significant macular edema at 6 months follow-up. Number of laser retreatments, injections, and any adverse effects from STMP laser were recorded. RESULTS: Group 1 (n=33) experienced an average of 55 µm reduction in CFT and 0.2 log MAR gain in visual acuity at 12 months (P<0.001). No patient required rescue anti-VEGF injections. Group 2 (n=30) experienced no significant change in CFT or visual acuity by 6 months despite retreatment with STMP in 19 eyes. From 6 to 12 months follow-up, all the patients in group 2 received rescue Bevacizumab injections that resulted in 307 µm reduction in CFT and 0.3 log MAR improvement in visual acuity (P<0.001). No adverse effects from STMP laser were recorded. CONCLUSION: Severity of edema can influence the effects of STMP laser. STMP monotherapy is safe and effective in treating edema of mild to moderate severity.

Gadolinium induced recurrent acute pancreatitis.

Acute pancreatitis is a sudden swelling and inflammation of the pancreas. The two most common causes are alcohol use and biliary stones. Drug-induced acute pancreatitis are rare (1.4-2%). In this present study, we present a case of recurrent acute pancreatitis induced by a specific magnetic-resonance-imaging (MRI) contrast agent called gadobenate dimeglumine.

Glucose metabolism: key endogenous regulator of ß-cell replication and survival.

Recent studies in mice have shown that pancreatic ß-cells have a significant potential for regeneration, suggesting that regenerative therapy for diabetes is feasible. Genetic lineage tracing studies indicate that ß-cell regeneration is based on the replication of fully differentiated, insulin-positive ß-cells. Thus, a major challenge for this field is to identify and enhance the molecular pathways that control ß-cell replication and mass. We review evidence, from human genetics and mouse models, that glucose is a major signal for ß-cell replication. The mitogenic effect of blood glucose is transmitted via glucose metabolism within ß-cells, and through a signalling cascade that resembles the pathway for glucose-stimulated insulin secretion. We introduce the concept that the individual ß-cell workload, defined as the amount of insulin that an individual ß-cell must secrete to maintain euglycaemia, is the primary determinant of replication, survival and mass. We also propose that a cell-autonomous pathway, similar to that regulating replication, appears to be responsible for at least some of the toxic effects of glucose on ß-cells. Understanding and uncoupling the mitogenic and toxic effects of glucose metabolism on ß-cells may allow for the development of effective regenerative therapies for diabetes.

[Time processing in the velo-cardio-facial syndrome (22q11) and its link with the caudate nucleus]. / Noyau caudé et traitement temporel dans le syndrome vélocardiofacial (22q11).

INTRODUCTION: Velocardiofacial syndrome (VCFS) is a neurogenetic disorder caused by a microdeletion on chromosome 22q11. Among other cognitive impairments and learning difficulties, affected individuals show difficulties in estimating time intervals (Debbané et al., 2005). Interestingly, neuroimaging studies have found an increased volume of the basal ganglia of people with VCFS (Eliez et al., 2002; Kates et al., 2004; Campbell et al., 2006). Given that the caudate nucleus represents a central component of the cerebral network underlying temporal perception skills, the present report proposes to examine potential relationships between cerebral alteration to the caudate nucleus and time estimation in individuals with VCFS. METHODS: A group of 30 patients with VCFS and 38 age-matched healthy individuals participated in time perception and time reproduction tasks. In the time perception task, individuals listened to two sequential stimuli and had to choose the longer of both stimuli by pressing a button. In the time reproduction task, subjects listened to a succession of sounds and once this succession had stopped they had to reproduce the same rhythm with their dominant index. Cerebral MRI images were also obtained for each participant. A manual tracing procedure was performed to measure the basal ganglia volume. RESULTS: Participants with VCFS demonstrated significantly poorer performances during the time perception and time reproduction tasks in comparison to the control participants. Further, increased volume of the caudate nucleus was found in individuals with VCFS. Correlational analyses revealed a significant relationship between the caudate nucleus's volume and the performances obtained in the time perception task for control participants. This correlation was not found for individuals with VCFS. CONCLUSION: The present results suggest that cerebral alterations to the caudate nucleus in VCFS may alter the temporal perception function it sustains.

Age- and puberty-dependent association between IQ score in early childhood and depressive symptoms in adolescence.

BACKGROUND: Lower cognitive functioning in early childhood has been proposed as a risk factor for depression in later life but its association with depressive symptoms during adolescence has rarely been investigated. Our study examines the relationship between total intelligence quotient (IQ) score at age 8 years, and depressive symptoms at 11, 13, 14 and 17 years. METHOD: Study participants were 5250 children and adolescents from the Avon Longitudinal Study of Parents and their Children (ALSPAC), UK, for whom longitudinal data on depressive symptoms were available. IQ was assessed with the Wechsler Intelligence Scale for Children III, and self-reported depressive symptoms were measured with the Short Mood and Feelings Questionnaire (SMFQ). RESULTS: Multi-level analysis on continuous SMFQ scores showed that IQ at age 8 years was inversely associated with depressive symptoms at age 11 years, but the association changed direction by age 13 and 14 years (age-IQ interaction, p<0.0001; age squared-IQ interaction, p<0.0001) when a higher IQ score was associated with a higher risk of depressive symptoms. This change in IQ effect was also found in relation to pubertal stage (pubertal stage-IQ interaction, 0.00049

Perinatal folate-related exposures and risk of psychotic symptoms in the ALSPAC birth cohort.

BACKGROUND: It is unclear to what extent non-clinical psychotic experiences during childhood and adolescence share underlying aetiological mechanisms with schizophrenia. One candidate mechanism for schizophrenia involves the epigenetic status of the developing fetus, which depends on the internal folate-status of mother and child. Our study examines the relationships between multiple determinants of perinatal folate-status and development of psychotic experiences in adolescence. METHODS: Study participants were up to 5344 mother-child pairs from the Avon Longitudinal Study of Parents and their Children, UK, with information on maternal and/or child MTHFR C677T genotype, maternal folate intake (supplementation at 18/32- weeks gestation; dietary intake at 32- weeks gestation) and psychosis-like symptoms (PLIKS) for children assessed at age 12. RESULTS: Nominal evidence was observed that maternal folate supplementation at 18 weeks increased the odds of PLIKS in children (odds ratio(OR)=1.34; 95%-CI:[1.00;1.76]) and, consistent with this, that children of MTHFR C667T TT homozygous mothers had decreased odds of PLIKS (OR=0.72; 95%CI:[0.50;1.02]; recessive model) with strongest effects in boys (OR=0.44, 95%-CI:[0.22;0.79]; sex-specific p=0.029). None of the reported effects remained significant when corrected for multiple testing. CONCLUSIONS: Overall, this study found no support that maternal/child MTHFR C677T genotype and maternal folate intake during pregnancy contribute to common aetiological pathways that are shared between schizophrenia and non-clinical psychotic symptoms in adolescents, assuming that decreased folate-status increases schizophrenia risk.

Measurement of strange quark contributions to the vector form factors of the proton at Q2 = 0.22 (GeV / c)2.

A new measurement of the parity violating asymmetry in elastic electron scattering on hydrogen at backward angles and at a four momentum transfer of Q;{2} = 0.22 (Ge V / c);{2} is reported here. The measured asymmetry is A_{LR} = (-17.23 +/- 0.82_{stat} +/- 0.89_{syst}) x 10;{-6}. The standard model prediction assuming no strangeness is A_{0} = (-15.87 +/- 1.22) x 10;{-6}. In combination with previous results from measurements at forward angles, it is possible to disentangle for the first time the strange form factors at this momentum transfer, G_{E};{s} = 0.050 +/- 0.038 +/- 0.019 and G_{M};{s} = -0.14 +/- 0.11 +/- 0.11.

Generation of a dendritic cell-based vaccine in chronic lymphocytic leukaemia using CliniMACS platform for large-scale production.

We previously demonstrated that dendritic cells (DC) that have endocytosed apoptotic bodies of autologous leukemic cells (Apo-DC) can boost antileukemic T-cell responses. In this study, we report a description of the production procedure and product specification of the Apo-DC vaccine preparations for clinical use. Enriched populations of CD14+ monocytic precursors and CD19+ leukaemic cells were obtained using CliniMACS technology from a single leukapheresis product. Apoptotic bodies were obtained by irradiating (5 Gy) CD19+ selected B cells. DC were generated ex vivo by culturing monocytes with granulocyte macrophage colony-stimulating factor and interleukin-4. Following coculture with apoptotic bodies, DCs were matured with tumour necrosis factor-alpha. The mean percentage of CD14+ cells in the peripheral blood as well as in the leukapheresis product of the patients (n = 10) was approximately 2% (range, 0.8-3.3). Immunomagnetic selection using the CD14 reagent yielded a CD14+ population that was 91 +/- 2.2% (mean +/- SEM) pure. Immunomagnetic selection of CD19 expressing cells yielded a population that was 100 +/- 0.03% pure. Cell viability immediately after selection was 97% and 98% after 7 days of culture. The Apo-DC cellular vaccine product showed a mature phenotype, with a high rate of endocytosis (84%) of apoptotic leukemic B-cells. In conclusion, despite significant variability in the circulating monocyte frequency of the chronic lymphocytic leukaemia patients, our method permitted the production of a DC vaccine with high reproducibility and conforming with recommended quality standards.

Impact of polymorphisms in WFS1 on prediabetic phenotypes in a population-based sample of middle-aged people with normal and abnormal glucose regulation.

AIM/HYPOTHESIS: Recently, variants in WFS1 have been shown to be associated with type 2 diabetes. We aimed to examine metabolic risk phenotypes of WFS1 variants in glucose-tolerant people and in individuals with abnormal glucose regulation. METHODS: The type 2 diabetes-associated WFS1 variant rs734312 (His611Arg) was studied in the population-based Inter99 cohort involving 4,568 glucose-tolerant individuals and 1,471 individuals with treatment-naive abnormal glucose regulation, and in an additional 3,733 treated type 2 diabetes patients. RESULTS: The WFS1 rs734312 showed a borderline significant association with type 2 diabetes with directions and relative risks consistent with previous reports. In individuals with abnormal glucose regulation, the diabetogenic risk A allele of rs734312 was associated in an allele-dependent manner with a decrease in insulinogenic index (p = 0.025) and decreased 30-min serum insulin levels (p = 0.047) after an oral glucose load. In glucose-tolerant individuals the same allele was associated with increased fasting serum insulin concentration (p = 0.019) and homeostasis model assessment of insulin resistance (HOMA-IR; p = 0.026). To study the complex interaction of WFS1 rs734312 on insulin release and insulin resistance we introduced Hotelling's T (2) test. Assuming bivariate normal distribution, we constructed standard error ellipses of the insulinogenic index and HOMA-IR when stratified according to glucose tolerance status around the means of each WFS1 rs734312 genotype level. The interaction term between individuals with normal glucose tolerance and abnormal glucose regulation on the insulinogenic index and HOMA-IR was significantly associated with the traits (p = 0.0017). CONCLUSIONS/INTERPRETATION: Type 2 diabetes-associated risk alleles of WFS1 are associated with estimates of a decreased pancreatic beta cell function among middle-aged individuals with abnormal glucose regulation.