Predicting 5-fluorouracil toxicity: DPD genotype and 5,6-dihydrouracil:uracil ratio

AIM Decreased DPD activity is a major cause of 5-fluorouracil (5-FU) toxicity, but known reduced-function variants in the DPD gene (DPYD) explain only a part of DPD-related 5-FU toxicities. Here, we evaluated the baseline (pretherapeutic) plasma 5,6-dihydrouracil:uracil (UH2:U) ratio as a marker of DPD activity in the context of DPYD genotypes. MATERIALS & METHODS DPYD variants were genotyped and plasma U, UH2 and 5-FU concentrations were determined by liquid chromatography-tandem mass spectrometry in 320 healthy blood donors and 28 cancer patients receiving 5-FU-based chemotherapy. RESULTS Baseline UH2:U ratios were strongly correlated with generally low and highly variable U concentrations. Reduced-function DPYD variants were only weakly associated with lower baseline UH2:U ratios. However, the interindividual variability in the UH2:U ratio was reduced and a stronger correlation between ratios and 5-FU exposure was observed in cancer patients during 5-FU administration. CONCLUSION These results suggest that the baseline UH2:U plasma ratio in most individuals reflects the nonsaturated state of DPD and is not predictive of decreased DPD activity. It may, however, be highly predictive at increased substrate concentrations, as observed during 5-FU administration.

The stable carbon isotopic composition of Daphnia ephippia in small, temperate lakes reflects in-lake methane availability

Daphnia can ingest methane-oxidizing bacteria and incorporate methanogenic carbon into their biomass, leading to low stable carbon isotope ratios (expressed as δ13C values) of their tissue. Therefore, δ13C analysis of Daphnia resting eggs (ephippia) in lake sediment records can potentially be used to reconstruct past in-lake availability of methane (CH4). However, detailed multilake studies demonstrating that δ13C values of recently deposited Daphnia ephippia (δ13Cephippia) are systematically related to in-lake CH4 concentrations (CH4aq) are still missing. We measured δ13Cephippia from surface sediments of 15 small lakes in Europe, and compared these values with late-summer CH4aq. δ13Cephippia ranged from −51.6‰ to −25.9‰, and was strongly correlated with CH4aq in the surface water and above the sediment (r −0.73 and −0.77, respectively), whereas a negative rather than the expected positive correlation was found with δ13C values of carbon dioxide (CO2) (r −0.54), and no correlation was observed with CO2aq. At eight sites, offsets between δ13 CCO2 and δ13Cephippia exceeded offsets between δ13 CCO2 and δ13Calgae reported in literature. δ13Cephippia was positively correlated with δ13C values of sedimentary organic matter (r 0.54), but up to 20.7‰ lower in all except one of the lakes (average −6.1‰). We conclude that incorporation of methanogenic carbon prior to ephippia formation must have been widespread by Daphnia in our study lakes, especially those with high CH4aq. Our results suggest a systematic relationship between δ13Cephippia values and CH4aq in small temperate lakes, and that δ13Cephippia analysis on sediment records may provide insights into past changes in in-lake CH4aq.

Influence of muscle fiber orientation on water and metabolite relaxation times, magnetization transfer, and visibility in human skeletal muscle

PURPOSE To gain a deeper understanding of the influence of skeletal muscle fiber orientation on metabolite visibility, magnetization transfer from water, and water proton relaxation rates in (1) H MR spectra. METHODS Non-water-suppressed MR spectroscopy was performed in tibialis anterior muscle (TA) of 10 healthy adults, with the TA oriented either parallel or at the magic angle to the 3T field. Spectra were acquired with metabolite-cycled PRESS, and water inversion from 50 to 2510 ms before excitation. Water proton T2 relaxation was sampled with STEAM with echo times from 12 to 272 ms. RESULTS Apparent concentrations of total creatine (tCr), taurine, and trimethylammonium compounds were reduced by 29% to 67% when TA was parallel to B0 . Both tCr peak areas were strongly correlated to the methylene peak splitting. Magnetization transfer rates from water to tCr CH3 were not significantly different between orientations. Water T1 s were similar between orientations, but T2 s were statistically significantly shorter by 1 ms in the parallel orientation (P = 0.002). CONCLUSION Muscle metabolite visibilities in MR spectroscopy and water T2 times depend substantially on muscle fiber orientation relative to B0 . In contrast, magnetization transfer rates appear to depend on muscle composition, rather than fiber orientation. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

Loss of tapasin correlates with diminished CD8(+) T-cell immunity and prognosis in colorectal cancer.

BACKGROUND Tapasin is a crucial component of the major histocompatibility (MHC) class I antigen presentation pathway. Defects in this pathway can lead to tumor immune evasion. The aim of this study was to test whether tapasin expression correlates with CD8(+) cytotoxic T lymphocyte (CTL) infiltration of colorectal cancer (CRC) and overall survival. METHODS A next-generation tissue microarray (ngTMA) of 198 CRC patients with full clinicopathological information was included in this study. TMA slides were immunostained for tapasin, MHC I and CD8. Marker expression was analyzed with immune-cell infiltration, patient survival and TNM-staging. RESULTS A reduction of tapasin expression strongly correlated with venous invasion (AUC 0.682, OR 2.7, p = 0.002; 95% CI 1.7-5.0), lymphatic invasion (AUC 0.620, OR 2.0, p = 0.005; 95 % CI 1.3-3.3), distant metastasis (AUC 0.727, OR 2.9, p = 0.004; 95% CI 1.4-5.9) and an infiltrative tumor border configuration (AUC 0.621, OR 2.2, p = 0.017; 95% CI 1.2-4.4). Further, tapasin expression was associated with CD8(+) CTL infiltration (AUC 0.729, OR 5.4, p < 0.001; 95% CI 2.6-11), and favorable overall survival (p = 0.004, HR 0.6, 95% CI 0.42-0.85). CONCLUSIONS Consistent with published functional data showing that tapasin promotes antigen presentation, as well as tumor immune recognition and destruction by CD8(+) CTLs, a reduction in tapasin expression is associated with tumor progression in CRC.

Reduction of cement leakage by sequential PMMA application in a vertebroplasty model

PURPOSE Leakage is the most common complication of percutaneous cement augmentation of the spine. The viscosity of the polymethylmethacrylate (PMMA) cement is strongly correlated with the likelihood of cement leakage. We hypothesized that cement leakage can be reduced by sequential cement injection in a vertebroplasty model. METHODS A standardized vertebral body substitute model, consisting of aluminum oxide foams coated by acrylic cement with a preformed leakage path, simulating a ventral vein, was developed. Three injection techniques of 6 ml PMMA were assessed: injection in one single step (all-in-one), injection of 1 ml at the first and 5 ml at the second step with 1 min latency in-between (two-step), and sequential injection of 0.5 ml with 1-min latency between the sequences (sequential). Standard PMMA vertebroplasty cement was used; each injection type was tested on ten vertebral body substitute models with two possible leakage paths per model. Leakage was assessed by radiographs using a zonal graduation: intraspongious = no leakage and extracortical = leakage. RESULTS The leakage rate was significantly lower in the "sequential" technique (2/20 leakages) followed by "two-step" (15/20) and "all-in-one" (20/20) techniques (p < 0.001). The RR for a cement leakage was 10.0 times higher in the "all-in-one" compared to the "sequential" group (95 % confidence intervals 2.7-37.2; p < 0.001). CONCLUSIONS The sequential cement injection is a simple approach to minimize the risk for leakage. Taking advantage of the temperature gradient between body and room temperature, it is possible to increase the cement viscosity inside the vertebra while keeping it low in the syringe. Using sequential injection of small cement volumes, further leakage paths are blocked before further injection of the low-viscosity cement.

Eosinophilic oesophagitis: relationship of quality of life with clinical, endoscopic and histological activity.

BACKGROUND Knowledge about determinants of quality of life (QoL) in eosinophilic oesophagitis (EoO) patients helps to identify patients at risk of experiencing poor QoL and to tailor therapeutic interventions accordingly. AIM To evaluate the impact of symptom severity, endoscopic and histological activity on EoE-specific QoL in adult EoE patients. METHODS Ninety-eight adult EoE patients were prospectively included (64% male, median age 39 years). Patients completed two validated instruments to assess EoE-specific QoL (EoO-QoL-A) and symptom severity (adult EoE activity index patient-reported outcome) and then underwent esophagogastroduodenoscopy with biopsy sampling. Physicians reported standardised information on EoE-associated endoscopic and histological alterations. The Spearman's rank correlation coefficient was calculated to determine the relationship between QoL and symptom severity. Linear regression and analysis of variance was used to quantify the extent to which variations in severity of EoE symptoms, endoscopic and histological findings explain variations in QoL. RESULTS Quality of life strongly correlated with symptom severity (r = 0.610, P < 0.001). While the variation in severity of symptoms, endoscopic and histological findings alone explained 38%, 35% and 22% of the variability in EoE-related QoL, respectively, these together explained 60% of variation. Symptom severity explained 18-35% of the variation in each of the five QoL subscale scores. CONCLUSIONS Eosinophilic oesophagitis symptom severity and biological disease activity determine QoL in adult patients with eosinophilic oesophagitis. Therefore, reduction in both eosinophilic oesophagitis symptoms as well as biological disease activity is essential for improvement of QoL in adult patients. Clinicaltrials.gov number, NCT00939263.

The utility of preoperative six-minute-walk distance in lung transplantation

RATIONALE The use of 6-minute-walk distance (6MWD) as an indicator of exercise capacity to predict postoperative survival in lung transplantation has not previously been well studied. OBJECTIVES To evaluate the association between 6MWD and postoperative survival following lung transplantation. METHODS Adult, first time, lung-only transplantations per the United Network for Organ Sharing database from May 2005 to December 2011 were analyzed. Kaplan-Meier methods and Cox proportional hazards modeling were used to determine the association between preoperative 6MWD and post-transplant survival after adjusting for potential confounders. A receiver operating characteristic curve was used to determine the 6MWD value that provided maximal separation in 1-year mortality. A subanalysis was performed to assess the association between 6MWD and post-transplant survival by disease category. MEASUREMENTS AND MAIN RESULTS A total of 9,526 patients were included for analysis. The median 6MWD was 787 ft (25th-75th percentiles = 450-1,082 ft). Increasing 6MWD was associated with significantly lower overall hazard of death (P < 0.001). Continuous increase in walk distance through 1,200-1,400 ft conferred an incremental survival advantage. Although 6MWD strongly correlated with survival, the impact of a single dichotomous value to predict outcomes was limited. All disease categories demonstrated significantly longer survival with increasing 6MWD (P ≤ 0.009) except pulmonary vascular disease (P = 0.74); however, the low volume in this category (n = 312; 3.3%) may limit the ability to detect an association. CONCLUSIONS 6MWD is significantly associated with post-transplant survival and is best incorporated into transplant evaluations on a continuous basis given limited ability of a single, dichotomous value to predict outcomes.

Endothelial progenitor cells as a biological marker of peripheral artery disease.

The role of endothelial progenitor cells (EPCs) in peripheral artery disease (PAD) remains unclear. We hypothesized that EPC mobilization and function play a central role in the development of endothelial dysfunction and directly influence the degree of atherosclerotic burden in peripheral artery vessels. The number of circulating EPCs, defined as CD34(+)/KDR(+) cells, were assessed by flow cytometry in 91 subjects classified according to a predefined sample size of 31 non-diabetic PAD patients, 30 diabetic PAD patients, and 30 healthy volunteers. Both PAD groups had undergone endovascular treatment in the past. As a functional parameter, EPC colony-forming units were determined ex vivo. Apart from a broad laboratory analysis, a series of clinical measures using the ankle-brachial index (ABI), flow-mediated dilatation (FMD) and carotid intima-media thickness (cIMT) were investigated. A significant reduction of EPC counts and proliferation indices in both PAD groups compared to healthy subjects were observed. Low EPC number and pathological findings in the clinical assessment were strongly correlated to the group allocation. Multivariate statistical analysis revealed these findings to be independent predictors of disease appearance. Linear regression analysis showed the ABI to be a predictor of circulating EPC number (p=0.02). Moreover, the functionality of EPCs was correlated by linear regression (p=0.017) to cIMT. The influence of diabetes mellitus on EPCs in our study has to be considered marginal in already disease-affected patients. This study demonstrated that EPCs could predict the prevalence and severity of symptomatic PAD, with ABI as the determinant of the state of EPC populations in disease-affected groups.

Normal values for pancreatic stone protein in different age groups.

BACKGROUND Pancreatic stone protein (PSP) has been identified as a promising sepsis marker in adults, children and neonates. However, data on population-based reference values are lacking. This study aimed to establish age-specific reference values for PSP. METHODS PSP was determined using a specific ELISA. PSP serum concentrations were determined in 372 healthy subjects including 217 neonates, 94 infants and children up to 16 years, and 61 adults. The adjacent categories method was used to determine which age categories had significantly different PSP concentrations. RESULTS PSP circulating levels were not gender-dependent and ranged from 1.0 to 99.4 ng/ml with a median of 9.2 ng/ml. PSP increased significantly between the age categories, from a median of 2.6 ng/ml in very preterm newborns, to 6.3 ng/ml in term newborns, to 16.1 ng/ml in older children (p < 0.001). PSP levels were higher on postnatal day three compared to levels measured immediately post delivery (p < 0.001). Paired umbilical artery and umbilical vein samples were strongly correlated (p < 0.001). Simultaneously obtained capillary heel-prick versus venous samples showed a good level of agreement for PSP (Rho 0.89, bias 19 %). CONCLUSIONS This study provides age-specific normal values that may be used to define cut-offs for future trials on PSP. We demonstrate an age-dependent increase of PSP from birth to childhood.

A legacy of human-induced ecosystem changes: spatial processes drive the taxonomic and functional diversities of testate amoebae in Sphagnum peatlands of the Galápagos

Aim Our aims were to compare the composition of testate amoeba (TA) communities from Santa Cruz Island, Galápagos Archipelago, which are likely in existence only as a result of anthropogenic habitat transformation, with similar naturally occurring communities from northern and southern continental peatlands. Additionally, we aimed at assessing the importance of niche-based and dispersal-based processes in determining community composition and taxonomic and functional diversity. Location The humid highlands of the central island of Santa Cruz, Galápagos Archipelago. Methods We survey the alpha, beta and gamma taxonomic and functional diversities of TA, and the changes in functional traits along a gradient of wet to dry habitats. We compare the TA community composition, abundance and frequency recorded in the insular peatlands with that recorded in continental peatlands of Northern and Southern Hemispheres. We use generalized linear models to determine how environmental conditions influence taxonomic and functional diversity as well as the mean values of functional traits within communities. We finally apply variance partitioning to assess the relative importance of niche- and dispersal-based processes in determining community composition. Results TA communities in Santa Cruz Island were different from their Northern Hemisphere and South American counterparts with most genera considered as characteristic for Northern Hemisphere and South American Sphagnum peatlands missing or very rare in the Galápagos. Functional traits were most correlated with elevation and site topography and alpha functional diversity to the type of material sampled and site topography. Community composition was more strongly correlated with spatial variables than with environmental ones. Main conclusions TA communities of the Sphagnum peatlands of Santa Cruz Island and the mechanisms shaping these communities contrast with Northern Hemisphere and South American peatlands. Soil moisture was not a strong predictor of community composition most likely because rainfall and clouds provide sufficient moisture. Dispersal limitation was more important than environmental filtering because of the isolation of the insular peatlands from continental ones and the young ecological history of these ecosystems.

Antifactor Xa Activity for the Management of Anticoagulation during Cardiac Surgery

Background In patients with autoimmune diseases associated with antiphospholipid antibodies, precise management of anticoagulation during extracorporeal circulation (ECC) is complicated. It was the aim of the present study to determine whether antifactor Xa (aXa) activity is useful in guiding heparin therapy during ECC. Methods In 15 patients undergoing cardiac surgery, anticoagulation with unfractionated heparin (UFH) and its reversal with protamine were guided using activated clotting time (ACT) (>400 second during ECC; ≤100 second for UFH reversal). For each ACT, the corresponding aXa activity levels were measured. Results A total of 144 blood samples were obtained. ACT and aXa activity were significantly correlated (r = 0.771, p< 0.0001, Spearman rank-order correlation). Using receiver operating characteristic curve (ROC) analyses, the cutoffvalues for aXa activity were 1.14 IU/mL (area under the ROC curve [AUC]: 0.89; inaccuracy rate: 9.4%) to predict ACT > 400 seconds and 0.55 IU/mL (AUC: 0.85; inaccuracy rate: 13.3%) for ACT ≤ 100 seconds. Conclusion AXa activity is strongly correlated with ACT, and therefore may be feasible for managing anticoagulation with UFH during ECC.

Interstellar neutral helium in the heliosphere from Interstellar Boundary Explorer observations. III. Mach number of the flow, velocity vector, and temperature from the first six years of measurements

We analyzed observations of interstellar neutral helium (ISN He) obtained from the Interstellar Boundary Explorer (IBEX) satellite during its first six years of operation. We used a refined version of the ISN He simulation model, presented in the companion paper by Sokol et al. (2015b), along with a sophisticated data correlation and uncertainty system and parameter fitting method, described in the companion paper by Swaczyna et al. We analyzed the entire data set together and the yearly subsets, and found the temperature and velocity vector of ISN He in front of the heliosphere. As seen in the previous studies, the allowable parameters are highly correlated and form a four-dimensional tube in the parameter space. The inflow longitudes obtained from the yearly data subsets show a spread of similar to 6 degrees, with the other parameters varying accordingly along the parameter tube, and the minimum chi(2) value is larger than expected. We found, however, that the Mach number of the ISN He flow shows very little scatter and is thus very tightly constrained. It is in excellent agreement with the original analysis of ISN He observations from IBEX and recent reanalyses of observations from Ulysses. We identify a possible inaccuracy in the Warm Breeze parameters as the likely cause of the scatter in the ISN He parameters obtained from the yearly subsets, and we suppose that another component may exist in the signal or a process that is not accounted for in the current physical model of ISN He in front of the heliosphere. From our analysis, the inflow velocity vector, temperature, and Mach number of the flow are equal to lambda(ISNHe) = 255 degrees.8 +/- 0 degrees.5, beta(ISNHe) = 5 degrees.16 +/- 0 degrees.10, T-ISNHe = 7440 +/- 260 K, nu(SNHe) = 25.8 +/- 0.4 km s(-1), and M-ISNHe = 5.079 +/- 0.028, with uncertainties strongly correlated along the parameter tube.

Asset Pricing with Heterogeneous Agents, Incomplete Markets and Trading Constraints

The consumption capital asset pricing model is the standard economic model used to capture stock market behavior. However, empirical tests have pointed out to its inability to account quantitatively for the high average rate of return and volatility of stocks over time for plausible parameter values. Recent research has suggested that the consumption of stockholders is more strongly correlated with the performance of the stock market than the consumption of non-stockholders. We model two types of agents, non-stockholders with standard preferences and stock holders with preferences that incorporate elements of the prospect theory developed by Kahneman and Tversky (1979). In addition to consumption, stockholders consider fluctuations in their financial wealth explicitly when making decisions. Data from the Panel Study of Income Dynamics are used to calibrate the labor income processes of the two types of agents. Each agent faces idiosyncratic shocks to his labor income as well as aggregate shocks to the per-share dividend but markets are incomplete and agents cannot hedge consumption risks completely. In addition, consumers face both borrowing and short-sale constraints. Our results show that in equilibrium, agents hold different portfolios. Our model is able to generate a time-varying risk premium of about 5.5% while maintaining a low risk free rate, thus suggesting a plausible explanation for the equity premium puzzle reported by Mehra and Prescott (1985).

The roles of costimulatory molecules in the cooperative effects of combination epinephrine and dexamethasone on type-1/type-2 cytokine production in tetanus-toxoid specific stimulated human peripheral blood mononuclear cells

A growing number of studies show strong associations between stress and altered immune function. In vivo studies of chronic and acute stress have demonstrated that cognitive stressors are strongly correlated with high circulating levels of catecholamines (CT) and corticosteroids (CS) that are associated with changes in type-1/type-2 cytokine expression. Although individual pharmacologic doses of CS and CT can inhibit the expression of T-helper 1 (Th1, type-1 like) and promote the production of T-helper 2 (Th2, type-2 like) cytokines in antigen-specific and mitogen stimulated human leukocyte cultures in vitro, little attention has been focused on the effects of combination physiologic-stress doses of CT and CS that may be more physiologically relevant. In addition, both in-vivo and in-vitro studies suggest that the differential expression of the B7 family of costimulatory molecules CD80 and CD86 may promote the expression of type-1 or type-2 cytokines, respectively. Furthermore, corticosteroids can influence the expression of β2-adrenergic receptors in various human tissues. We therefore investigated the combined effects of physiologic-stress doses of in vitro CT and CS upon the type-1/type-2 cytokine balance and expression of B7 costimulatory molecules of human peripheral blood mononuclear cells (PBMC) as a model to study the immunomodulatory effects of physiologic stress. Results demonstrated a significant decrease in type-1 cytokine expression and a significant increase in type-2 cytokine production in our CS+CT incubated cultures when compared to either CT or CS agents alone. In addition, we demonstrated the differential expression of CD80/CD86 in favor of CD86 at the cellular and population level as determined by flow cytometry in lipopolysaccharide stimulated human Monocytes. Furthermore, we developed flow cytometry based assays to detect total β2AR in human CD4+ T-lymphocytes that demonstrated decreased expression of β2AR in mitogen stimulated CD4+ T-lymphocytes in the presence of physiologic stress levels of CS and CT as single in vitro agents, however, when both CS and CT were combined, significantly higher expression of β2AR was observed. In summary, our in vitro data suggest that both CS and CT work cooperatively to shift immunity towards type-2 responses. ^

Evaluation of therapist and client language in Motivational Interviewing (MI) sessions: A secondary analysis of data from the Southern Methodist Alcohol Research Trial (SMART) study

In the United States, “binge” drinking among college students is an emerging public health concern due to the significant physical and psychological effects on young adults. The focus is on identifying interventions that can help decrease high-risk drinking behavior among this group of drinkers. One such intervention is Motivational interviewing (MI), a client-centered therapy that aims at resolving client ambivalence by developing discrepancy and engaging the client in change talk. Of late, there is a growing interest in determining the active ingredients that influence the alliance between the therapist and the client. This study is a secondary analysis of the data obtained from the Southern Methodist Alcohol Research Trial (SMART) project, a dismantling trial of MI and feedback among heavy drinking college students. The present project examines the relationship between therapist and client language in MI sessions on a sample of “binge” drinking college students. Of the 126 SMART tapes, 30 tapes (‘MI with feedback’ group = 15, ‘MI only’ group = 15) were randomly selected for this study. MISC 2.1, a mutually exclusive and exhaustive coding system, was used to code the audio/videotaped MI sessions. Therapist and client language were analyzed for communication characteristics. Overall, therapists adopted a MI consistent style and clients were found to engage in change talk. Counselor acceptance, empathy, spirit, and complex reflections were all significantly related to client change talk (p-values ranged from 0.001 to 0.047). Additionally, therapist ‘advice without permission’ and MI Inconsistent therapist behaviors were strongly correlated with client sustain talk (p-values ranged from 0.006 to 0.048). Simple linear regression models showed a significant correlation between MI consistent (MICO) therapist language (independent variable) and change talk (dependent variable) and MI inconsistent (MIIN) therapist language (independent variable) and sustain talk (dependent variable). The study has several limitations such as small sample size, self-selection bias, poor inter-rater reliability for the global scales and the lack of a temporal measure of therapist and client language. Future studies might consider a larger sample size to obtain more statistical power. In addition the correlation between therapist language, client language and drinking outcome needs to be explored.^