bluuebunny/crossref_metadata_2025 huggingface dataset:
Cheatgrass invasion alters the abundance and composition of dark septate fungal communities in sagebrush steppe
Authors: Gehring Catherine A. , Hayer Michaela , Flores-Rentería Lluvia , Krohn Andrew F. , Schwartz Egbert , Dijkstra Paul
Published: January 2016

Invasive, non-native plant species can alter soil microbial communities in ways that contribute to their persistence. While most studies emphasize mycorrhizal fungi, invasive plants also may influence communities of dark septate fungi (DSF), which are common root endophytes that can function like mycorrhizas. We tested the hypothesis that a widespread invasive plant in the western United States, cheatgrass (Bromus tectorum L.), influenced the abundance and community composition of DSF by examining the roots and rhizosphere soils of cheatgrass and two native plant species in cheatgrass-invaded and noninvaded areas of sagebrush steppe. We focused on cheatgrass because it is negatively affected by mycorrhizal fungi and colonized by DSF. We found that DSF root colonization and operational taxonomic unit (OTU) richness were significantly higher in sagebrush (Artemisia tridentata Nutt.) and rice grass (Achnatherum hymenoides (Roem. & Schult.) Barkworth) from invaded areas than noninvaded areas. Cheatgrass roots had similar levels of DSF colonization and OTU richness as native plants. The community composition of DSF varied with invasion in the roots and soils of native species and among the roots of the three plant species in the invaded areas. The substantial changes in DSF we observed following cheatgrass invasion argue for comparative studies of DSF function in native and non-native plant species.
Role of metalliferous mudstones and detrital shales in the localization, genesis, and paleoenvironment of volcanogenic massive sulphide deposits of the Tally Pond volcanic belt, central Newfoundland, Canada
Authors: Lode Stefanie , Piercey Stephen J. , Squires Gerald C.
Published: January 2016

The Cambrian Tally Pond volcanic belt in central Newfoundland contains numerous volcanogenic massive sulphide (VMS) deposits and prospects associated with exhalative metalliferous mudstones. Deposits in the belt are bimodal felsic VMS deposits that are both base metal bearing (e.g., Duck Pond – Boundary), and base metal and precious metal bearing (Lemarchant). At the Lemarchant deposit, metalliferous mudstones are stratigraphically and genetically associated with mineralization. In the remainder of the Tally Pond belt, detrital shales occur predominantly in the northeastern part of the belt (mostly as unrelated mid-Ordovician structural blocks) in the upper sections of the Cambrian volcanic stratigraphy, but locally also are intercalated with metalliferous mudstones. Their relationships to massive sulphides are less obvious, with many spatially, but not necessarily genetically, related to mineralization. Upper Cambrian to Lower Ordovician black shales from Bell Island, which represent pelagic sedimentation not associated with hydrothermal activity and volcanism, are compared with the Tally Pond belt mudstones and shales. Exhalative mudstones, like those at Lemarchant, have elevated Fe/Al and base-metal values, and have shale-normalized negative Ce and positive Eu anomalies, indicative of deposition from high-temperature (>250 °C) hydrothermal fluids within an oxygenated water column. Mudstones and shales sampled from other Tally Pond prospects have more variable signatures, ranging from hydrothermal to nonhydrothermal black shales (no positive Eu anomalies, flat rare earth element patterns, low Fe/Al and base-metal contents), to those that have mixed signatures. Accordingly, mudstones from areas with a Lemarchant-like hydrothermal and vent-proximal character are more attractive exploration targets than mudstones and shales with predominantly detrital signatures.
Rapid gut growth but persistent delay in digestive function in the postnatal period of preterm pigs
Authors: Hansen Carl Frederik , Thymann Thomas , Andersen Anders Daniel , Holst Jens Juul , Hartmann Bolette , Hilsted Linda , Langhorn Louise , Jelsing Jacob , Sangild Per Torp
Published: January 2016

Preterm infants often tolerate full enteral nutrition a few weeks after birth but it is not known how this is related to gut maturation. Using pigs as models, we hypothesized that intestinal structure and digestive function are similar in preterm and term individuals at 3–4 wk after birth and that early enteral nutrition promotes maturation. Preterm or term cesarean-delivered pigs were fed total parenteral nutrition, or partial enteral nutrition [Enteral (Ent), 16–64 ml·kg−1·day−1of bovine colostrum] for 5 days, followed by full enteral milk feeding until day 26. The intestine was collected for histological and biochemical analyses at days 0, 5, and 26 ( n = 8–12 in each of 10 treatment groups). Intestinal weight (relative to body weight) was reduced in preterm pigs at 0–5 days but ENT feeding stimulated the mucosal volume and peptidase activities. Relative to term pigs, mucosal volume remained reduced in preterm pigs until 26 days although plasma glucagon-like peptide 2 (GLP-2) and glucose-dependent insulin-trophic peptide (GIP) levels were increased. Preterm pigs also showed reduced hexose absorptive capacity and brush-border enzyme (sucrase, maltase) activities at 26 days, relative to term pigs. Intestinal structure shows a remarkable growth adaptation in the first week after preterm birth, especially with enteral nutrition, whereas some digestive functions remain immature until at least 3–4 wk. It is important to identify feeding regimens that stimulate intestinal maturation in the postnatal period of preterm infants because some intestinal functions may show long-term developmental delay.
Rapid disruption of intestinal epithelial tight junction and barrier dysfunction by ionizing radiation in mouse colon in vivo: protection byN-acetyl-l-cysteine
Authors: Shukla Pradeep K. , Gangwar Ruchika , Manda Bhargavi , Meena Avtar S. , Yadav Nikki , Szabo Erzsebet , Balogh Andrea , Lee Sue Chin , Tigyi Gabor , Rao RadhaKrishna
Published: January 2016

The goals of this study were to evaluate the effects of ionizing radiation on apical junctions in colonic epithelium and mucosal barrier function in mice in vivo. Adult mice were subjected to total body irradiation (4 Gy) with or without N-acetyl-l-cysteine (NAC) feeding for 5 days before irradiation. At 2–24 h postirradiation, the integrity of colonic epithelial tight junctions (TJ), adherens junctions (AJ), and the actin cytoskeleton was assessed by immunofluorescence microscopy and immunoblot analysis of detergent-insoluble fractions for TJ and AJ proteins. The barrier function was evaluated by measuring vascular-to-luminal flux of fluorescein isothiocyanate (FITC)-inulin in vivo and luminal-to-mucosal flux in vitro. Oxidative stress was evaluated by measuring protein thiol oxidation. Confocal microscopy showed that radiation caused redistribution of occludin, zona occludens-1, claudin-3, E-cadherin, and β-catenin, as well as the actin cytoskeleton as early as 2 h postirradiation, and this effect was sustained for at least 24 h. Feeding NAC before irradiation blocked radiation-induced disruption of TJ, AJ, and the actin cytoskeleton. Radiation increased mucosal permeability to inulin in colon, which was blocked by NAC feeding. The level of reduced-protein thiols in colon was depleted by radiation with a concomitant increase in the level of oxidized-protein thiol. NAC feeding blocked the radiation-induced protein thiol oxidation. These data demonstrate that radiation rapidly disrupts TJ, AJ, and the actin cytoskeleton by an oxidative stress-dependent mechanism that can be prevented by NAC feeding.
Identification of different functional types of spinal afferent neurons innervating the mouse large intestine using a novel CGRPα transgenic reporter mouse
Authors: Hibberd Timothy J. , Kestell Garreth R. , Kyloh Melinda A. , Brookes Simon J. H. , Wattchow David A. , Spencer Nick J.
Published: January 2016

Spinal afferent neurons detect noxious and physiological stimuli in visceral organs. Five functional classes of afferent terminals have been extensively characterized in the colorectum, primarily from axonal recordings. Little is known about the corresponding somata of these classes of afferents, including their morphology, neurochemistry, and electrophysiology. To address this, we made intracellular recordings from somata in L6/S1 dorsal root ganglia and applied intraluminal colonic distensions. A transgenic calcitonin gene-related peptide-α (CGRPα)-mCherry reporter mouse, which enabled rapid identification of soma neurochemistry and morphology following electrophysiological recordings, was developed. Three distinct classes of low-threshold distension-sensitive colorectal afferent neurons were characterized; an additional group was distension-insensitive. Two of three low-threshold classes expressed CGRPα. One class expressing CGRPα discharged phasically, with inflections on the rising phase of their action potentials, at low frequencies, to both physiological (<30 mmHg) and noxious (>30 mmHg) distensions. The second class expressed CGRPα and discharged tonically, with smooth, briefer action potentials and significantly greater distension sensitivity than phasically firing neurons. A third class that lacked CGRPα generated the highest-frequency firing to distension and had smaller somata. Thus, CGRPα expression in colorectal afferents was associated with lower distension sensitivity and firing rates and larger somata, while colorectal afferents that generated the highest firing frequencies to distension had the smallest somata and lacked CGRPα. These data fill significant gaps in our understanding of the different classes of colorectal afferent somata that give rise to distinct functional classes of colorectal afferents. In healthy mice, the majority of sensory neurons that respond to colorectal distension are low-threshold, wide-dynamic-range afferents, encoding both physiological and noxious ranges.
KV7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine
Authors: Goodwill Adam G. , Fu Lijuan , Noblet Jillian N. , Casalini Eli D. , Sassoon Daniel , Berwick Zachary C. , Kassab Ghassan S. , Tune Johnathan D. , Dick Gregory M.
Published: January 2016

Hydrogen peroxide (H2O2) and voltage-dependent K+ (KV) channels play key roles in regulating coronary blood flow in response to metabolic, ischemic, and paracrine stimuli. The KV channels responsible have not been identified, but KV7 channels are possible candidates. Existing data regarding KV7 channel function in the coronary circulation (limited to ex vivo assessments) are mixed. Thus we examined the hypothesis that KV7 channels are present in cells of the coronary vascular wall and regulate vasodilation in swine. We performed a variety of molecular, biochemical, and functional (in vivo and ex vivo) studies. Coronary arteries expressed KCNQ genes (quantitative PCR) and KV7.4 protein (Western blot). Immunostaining demonstrated KV7.4 expression in conduit and resistance vessels, perhaps most prominently in the endothelial and adventitial layers. Flupirtine, a KV7 opener, relaxed coronary artery rings, and this was attenuated by linopirdine, a KV7 blocker. Endothelial denudation inhibited the flupirtine-induced and linopirdine-sensitive relaxation of coronary artery rings. Moreover, linopirdine diminished bradykinin-induced endothelial-dependent relaxation of coronary artery rings. There was no effect of intracoronary flupirtine or linopirdine on coronary blood flow at the resting heart rate in vivo. Linopirdine had no effect on coronary vasodilation in vivo elicited by ischemia, H2O2, or tachycardia. However, bradykinin increased coronary blood flow in vivo, and this was attenuated by linopirdine. These data indicate that KV7 channels are expressed in some coronary cell type(s) and influence endothelial function. Other physiological functions of coronary vascular KV7 channels remain unclear, but they do appear to contribute to endothelium-dependent responses to paracrine stimuli.
Influence of segmented vessel size due to limited imaging resolution on coronary hyperemic flow prediction from arterial crown volume
Authors: van Horssen P. , van Lier M. G. J. T. B. , van den Wijngaard J. P. H. M. , VanBavel E. , Hoefer I. E. , Spaan J. A. E. , Siebes M.
Published: January 2016

Computational predictions of the functional stenosis severity from coronary imaging data use an allometric scaling law to derive hyperemic blood flow (Q) from coronary arterial volume (V), Q = αVβ. Reliable estimates of α and β are essential for meaningful flow estimations. We hypothesize that the relation between Q and V depends on imaging resolution. In five canine hearts, fluorescent microspheres were injected into the left anterior descending coronary artery during maximal hyperemia. The coronary arteries of the excised heart were filled with fluorescent cast material, frozen, and processed with an imaging cryomicrotome to yield a three-dimensional representation of the coronary arterial network. The effect of limited image resolution was simulated by assessing scaling law parameters from the virtual arterial network at 11 truncation levels ranging from 50 to 1,000 μm segment radius. Mapped microsphere locations were used to derive the corresponding relative Q using a reference truncation level of 200 μm. The scaling law factor α did not change with truncation level, despite considerable intersubject variability. In contrast, the scaling law exponent β decreased from 0.79 to 0.55 with increasing truncation radius and was significantly lower for truncation radii above 500 μm vs. 50 μm ( P < 0.05). Hyperemic Q was underestimated for vessel truncation above the reference level. In conclusion, flow-crown volume relations confirmed overall power law behavior; however, this relation depends on the terminal vessel radius that can be visualized. The scaling law exponent β should therefore be adapted to the resolution of the imaging modality.
Nedd4-2 but not Nedd4-1 is critical for protein kinase C-regulated ubiquitination, expression, and transport activity of human organic anion transporter 1
Authors: Xu Da , Wang Haoxun , Zhang Qiang , You Guofeng
Published: January 2016

Human organic anion transporter 1 (hOAT1) expressed at the membrane of the kidney proximal tubule cells mediates the body disposition of a diverse array of clinically important drugs, including anti-HIV therapeutics, antitumor drugs, antibiotics, antihypertensives, and antiinflammatories. Therefore, understanding the regulation of hOAT1 will provide significant insights into kidney function and dysfunction. We previously established that hOAT1 transport activity is inhibited by activation of protein kinase C (PKC) through accelerating hOAT1 internalization from cell surface into intracellular endosomes and subsequent degradation. We further established that PKC-induced hOAT1 ubiquitination is an important step preceding hOAT1 internalization. In the current study, we identified two closely related E3 ubiquitin ligases, neural precursor cell expressed, developmentally downregulated 4-1 and 4-2 (Nedd4-1 and Nedd4-2), as important regulators for hOAT1: overexpression of Nedd4-1 or Nedd4-2 enhanced hOAT1 ubiquitination, reduced the hOAT1 amount at the cell surface, and suppressed hOAT1 transport activity. In further exploring the relationship among PKC, Nedd4-1, and Nedd4-2, we discovered that PKC-dependent changes in hOAT1 ubiquitination, expression, and transport activity were significantly blocked in cells transfected with the ligase-dead mutant of Nedd4-2 (Nedd4-2/C821A) or with Nedd4-2-specific siRNA to knockdown endogenous Nedd4-2 but not in cells transfected with the ligase-dead mutant of Nedd4-1 (Nedd4-1/C867S) or with Nedd4-1-specific siRNA to knockdown endogenous Nedd4-1. In conclusion, this is the first demonstration that both Nedd4-1 and Nedd4-2 are important regulators for hOAT1 ubiquitination, expression, and function. Yet they play distinct roles, as Nedd4-2 but not Nedd4-1 is a critical mediator for PKC-regulated hOAT1 ubiquitination, expression, and transport activity.
Temperature and blood flow distribution in the human leg during passive heat stress
Authors: Chiesa Scott T. , Trangmar Steven J. , González-Alonso José
Published: January 2016

The influence of temperature on the hemodynamic adjustments to direct passive heat stress within the leg's major arterial and venous vessels and compartments remains unclear. Fifteen healthy young males were tested during exposure to either passive whole body heat stress to levels approaching thermal tolerance [core temperature (Tc) + 2°C; study 1; n = 8] or single leg heat stress (Tc + 0°C; study 2; n = 7). Whole body heat stress increased perfusion and decreased oscillatory shear index in relation to the rise in leg temperature (Tleg) in all three major arteries supplying the leg, plateauing in the common and superficial femoral arteries before reaching severe heat stress levels. Isolated leg heat stress increased arterial blood flows and shear patterns to a level similar to that obtained during moderate core hyperthermia (Tc + 1°C). Despite modest increases in great saphenous venous (GSV) blood flow (0.2 l/min), the deep venous system accounted for the majority of returning flow (common femoral vein 0.7 l/min) during intense to severe levels of heat stress. Rapid cooling of a single leg during severe whole body heat stress resulted in an equivalent blood flow reduction in the major artery supplying the thigh deep tissues only, suggesting central temperature-sensitive mechanisms contribute to skin blood flow alone. These findings further our knowledge of leg hemodynamic responses during direct heat stress and provide evidence of potentially beneficial vascular alterations during isolated limb heat stress that are equivalent to those experienced during exposure to moderate levels of whole body hyperthermia.
Selective IT neurons are selective along many dimensions
Authors: Zhivago Kalathupiriyan A. , Arun S. P.
Published: January 2016

Our visual abilities are unsurpassed because of a sophisticated code for objects located in the inferior temporal (IT) cortex. This code has remained a mystery because IT neurons show extremely diverse shape selectivity with no apparent organizing principle. Here, we show that there is an intrinsic component to selectivity in IT neurons. We tested IT neurons on distinct shapes and their parametric variations and asked whether neurons selective along one dimension were also selective along others. Selective neurons responded to fewer shapes and were narrowly tuned to local variations of these shapes, both along arbitrary morph lines and along variations in size, position, or orientation. For a subset of neurons, selective neurons were selective for both shape and texture. Finally, selective neurons were also more invariant in that they preserved their shape preferences across changes in size, position, and orientation. These observations indicate that there is an intrinsic constraint on the sharpness of tuning for the features coded by each IT neuron, making it always sharply tuned or always broadly tuned along all dimensions. We speculate that this may be an organizing principle throughout visual cortex.
The Dual MEK/FLT3 Inhibitor E6201 Exerts Cytotoxic Activity against Acute Myeloid Leukemia Cells Harboring Resistance-Conferring FLT3 Mutations
Authors: Zhang Weiguo , Borthakur Gautam , Gao Chen , Chen Ye , Mu Hong , Ruvolo Vivian R. , Nomoto Kenichi , Zhao Nanding , Konopleva Marina , Andreeff Michael
Published: January 2016

Fms-like tyrosine kinase 3 (FLT3) inhibition has elicited encouraging responses in acute myeloid leukemia (AML) therapy. Unfortunately, unless combined with a bone marrow transplant, disease relapse is frequent. In addition to the acquired point mutations in the FLT3 kinase domain that contribute to FLT3 inhibitor resistance, MEK/ERK signaling is persistently activated in AML cells even when FLT3 phosphorylation is continually suppressed. Thus, concomitant targeting of FLT3 and MAPK may potentially exert synergistic activity to counteract the resistance of AML cells to FLT3-targeted therapy. In this study, we investigated the antileukemia activity of a MEK1 and FLT3 dual inhibitor, E6201, in AML cells resistant to FLT3 inhibition. We found that E6201 exerted profound apoptogenic effects on AML cells harboring resistance-conferring FLT3 mutations. This activity appeared to be p53 dependent, and E6201-induced cytotoxicity was retained under hypoxic culture conditions and during coculture with mesenchymal stem cells that mimic the AML microenvironment. Furthermore, E6201 markedly reduced leukemia burden and improved the survival of mice in a human FLT3–mutated AML model. Collectively, our data provide a preclinical basis for the clinical evaluation of E6201 in AML patients harboring FLT3 mutations, including those who relapse following FLT3-targeted monotherapy. Cancer Res; 76(6); 1528–37. ©2016 AACR.
Small RNAs Recruit Chromatin-Modifying Enzymes MMSET and Tip60 to Reconfigure Damaged DNA upon Double-Strand Break and Facilitate Repair
Authors: Wang Qinhong , Goldstein Michael
Published: January 2016

Recent reports have demonstrated that DNA double-strand break (DSB)–induced small RNAs (diRNA) play an important role in the DNA damage response (DDR). However, the molecular mechanism by which diRNAs regulate the DDR remains unclear. Here, we report that Dicer- and Drosha-dependent diRNAs function as guiding molecules to promote the recruitment of the methyltransferase MMSET (WHSC1) and the acetyltransferase Tip60 (KAT5) to the DSB, where local levels of histone H4 di- and tri-methylation at lysine 20 (H4K20me2, 3) and H4 acetylation at lysine 16 (H4K16Ac) were enhanced. These histone modification events resulted in an open, flexible chromatin configuration, as indicated by the increased release of histones γH2AX, H2AX, and H3 from damaged chromatin. Furthermore, we found that diRNA-associated AGO2 interacted with MMSET and Tip60 and that the diRNA binding and catalytic activities of AGO2 were dispensable for the interaction but required for the recruitment of MMSET and Tip60 to DSBs. Consequently, diRNA-mediated chromatin remodeling promoted DSB repair by enhancing the recruitment of Rad51 and BRCA1 to the DSB site. Taken together, our findings reveal an unexpected direct role for diRNAs in regulating chromatin remodeling to facilitate DSB repair, revealing a new layer of DDR regulation involving specialized RNA molecules. Cancer Res; 76(7); 1904–15. ©2016 AACR.
Angiogenesis- and Hypoxia-Associated Proteins as Early Indicators of the Outcome in Patients with Metastatic Breast Cancer Given First-Line Bevacizumab-Based Therapy
Authors: Lam Siu W. , Nota Nienke M. , Jager Agnes , Bos Monique M.E.M. , van den Bosch Joan , van der Velden Ankie M.T. , Portielje Johanneke E.A. , Honkoop Aafke H. , van Tinteren Harm , Boven Epie
Published: January 2016

Purpose: We examined whether pretreatment levels of angiogenesis- or hypoxia-related proteins and their changes after one cycle of first-line bevacizumab-based therapy were associated with response, PFS, or OS in patients with metastatic breast cancer.

Experimental Design: We included 181 patients enrolled in the phase II ATX trial evaluating first-line paclitaxel and bevacizumab without or with capecitabine (NTR1348). Plasma samples were analyzed for VEGF-A, soluble VEGFR2 (sVEGFR2), angiopoietin 2 (ANG2), soluble TIE2 (sTIE2), IL6, IL8, and carbonic anhydrase 9 (CA9). Baseline serum CA15-3 was documented. HR was adjusted for confounding factors. Where appropriate, an optimal cut-off value defining a high and a low group was determined with Martingale residuals.

Results: At baseline, multiple proteins were significantly associated with PFS (ANG2, IL6, IL8, CA9, CA15-3) and OS (ANG2, sTIE2, IL6, IL8, CA9, CA15-3). After one cycle, VEGF-A, ANG2, sTIE2, and IL8 significantly decreased, while sVEGFR2 and CA9 significantly increased. The relative change in sVEGFR2 (P = 0.01) and IL8 (P = 0.001) was associated with response. Defining optimal cut-off, patients with a high CA9 rise (>2.9%) had better PFS (HR 0.45) and OS (HR 0.54) than those with low/no rise.

Conclusions: Multiple angiogenesis- or hypoxia-related proteins were prognostic for PFS and OS. Molecular agents targeting these proteins might be beneficial in patients with high levels. Changes in IL8 or sVEGFR2 levels at second cycle appear predictive for response. Changes in CA9 levels during bevacizumab-based therapy for prediction of PFS and OS merit further study. Clin Cancer Res; 22(7); 1611–20. ©2016 AACR.
CAR T Cells Targeting Podoplanin Reduce Orthotopic Glioblastomas in Mouse Brains
Authors: Shiina Satoshi , Ohno Masasuke , Ohka Fumiharu , Kuramitsu Shunichiro , Yamamichi Akane , Kato Akira , Motomura Kazuya , Tanahashi Kuniaki , Yamamoto Takashi , Watanabe Reiko , Ito Ichiro , Senga Takeshi , Hamaguchi Michinari , Wakabayashi Toshihiko , Kaneko Mika K. , Kato Yukinari , Chandramohan Vidyalakshmi , Bigner Darell D. , Natsume Atsushi
Published: January 2016

Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults with a 5-year overall survival rate of less than 10%. Podoplanin (PDPN) is a type I transmembrane mucin-like glycoprotein, expressed in the lymphatic endothelium. Several solid tumors overexpress PDPN, including the mesenchymal type of GBM, which has been reported to present the worst prognosis among GBM subtypes. Chimeric antigen receptor (CAR)–transduced T cells can recognize predefined tumor surface antigens independent of MHC restriction, which is often downregulated in gliomas. We constructed a lentiviral vector expressing a third-generation CAR comprising a PDPN-specific antibody (NZ-1–based single-chain variable fragment) with CD28, 4-1BB, and CD3ζ intracellular domains. CAR-transduced peripheral blood monocytes were immunologically evaluated by calcein-mediated cytotoxic assay, ELISA, tumor size, and overall survival. The generated CAR T cells were specific and effective against PDPN-positive GBM cells in vitro. Systemic injection of the CAR T cells into an immunodeficient mouse model inhibited the growth of intracranial glioma xenografts in vivo. CAR T-cell therapy that targets PDPN would be a promising adoptive immunotherapy to treat mesenchymal GBM. Cancer Immunol Res; 4(3); 259–68. ©2016 AACR.
Cohort Differences in Psychosocial Function over 20 Years: Current Older Adults Feel Less Lonely and Less Dependent on External Circumstances
Authors: Hülür Gizem , Drewelies Johanna , Eibich Peter , Düzel Sandra , Demuth Ilja , Ghisletta Paolo , Steinhagen-Thiessen Elisabeth , Wagner Gert G. , Lindenberger Ulman , Gerstorf Denis
Published: January 2016

Background: Lifespan psychological and life course sociological perspectives indicate that individual development is shaped by social and historical circumstances. Increases in fluid cognitive performance over the last century are well documented and researchers have begun examining historical trends in personality and subjective well-being in old age. Relatively less is known about secular changes in other key components of psychosocial function among older adults. Objective: In the present study, we examined cohort differences in key components of psychosocial function, including subjective age, control beliefs, and perceived social integration, as indicated by loneliness and availability of very close others. Methods: We compared data obtained 20 years apart in the Berlin Aging Study (in 1990-1993) and the Berlin Aging Study II (in 2013-2014) and identified case-matched cohort groups based on age, gender, cohort-normed education, and marital or partner status (n = 153 in each cohort, mean age = 75 years). In follow-up analyses, we controlled for having lived in former East versus West Germany, physical diseases, cohort-normed household income, cognitive performance, and the presence of a religious affiliation. Results: Consistently across analyses, we found that, relative to the earlier-born BASE cohort (year of birth: mean = 1916; SD = 3.38 years; range = 1901-1922), participants in the BASE-II sample (year of birth: mean = 1939; SD = 3.22 years; range = 1925-1949) reported lower levels of external control beliefs (d = -1.01) and loneliness (d = -0.63). Cohorts did not differ in subjective age, availability of very close others, and internal control beliefs. Conclusion: Taken together, our findings suggest that some aspects of psychosocial function of older adults have improved across the two recent decades. We discuss the possible role of sociocultural factors that might have led to the observed set of cohort differences.
Patterns of Behaviour, Group Structure and Reproductive Status Predict Levels of Glucocorticoid Metabolites in Zoo-Housed Ring-Tailed Lemurs, Lemur catta
Authors: Smith Tessa E. , McCusker Cara M. , Stevens Jeroen M.G. , Elwood Robert W.
Published: January 2016

In ring-tailed lemurs, Lemur catta, the factors modulating hypothalamic-pituitary-adrenal (HPA) activity differ between wild and semi-free-ranging populations. Here we assess factors modulating HPA activity in ring-tailed lemurs housed in a third environment: the zoo. First we validate an enzyme immunoassay to quantify levels of glucocorticoid (GC) metabolites in the faeces of L. catta. We determine the nature of the female-female dominance hierarchies within each group by computing David's scores and examining these in relation to faecal GC (fGC). Relationships between female age and fGC are assessed to evaluate potential age-related confounds. The associations between fGC, numbers of males in a group and reproductive status are explored. Finally, we investigate the value of 7 behaviours in predicting levels of fGC. The study revealed stable linear dominance hierarchies in females within each group. The number of males in a social group together with reproductive status, but not age, influenced fGC. The 7 behavioural variables accounted for 68% of the variance in fGC. The amounts of time an animal spent locomoting and in the inside enclosure were both negative predictors of fGC. The study highlights the flexibility and adaptability of the HPA system in ring-tailed lemurs.
Cost-Effectiveness of Immunotherapy in the Treatment of Seasonal Allergic Rhinitis: Identifying Product-Specific Parameters of Relevance for Health Care Decision-Makers and Clinicians
Authors: Bachert Claus , Noergaard Andreasen Jakob
Published: January 2016

Pharmacotherapy is widely used to manage allergic rhinitis (AR), but often does not adequately control symptoms. Allergy immunotherapy (AIT) should be considered for patients who are not adequately controlled on symptomatic treatment. AIT is gaining attention because of its potential to improve symptom relief and quality of life, and to provide sustained effect after the end of treatment by modifying the course of disease. However, evidence of efficacy needs to be shown for each individual AIT product, based on state-of-the-art studies. The majority of products cannot truly claim efficacy and disease-modifying potential, as evidence of such an effect from robust randomized double-blind, placebo-controlled long-term trials is lacking. The potential of a specific immunotherapy product should be evaluated against four levels of benefit defined by the European Medicines Agency (EMA) guideline on clinical development of AIT products. These clearly distinguish between efficacy of symptom relief in the first year, efficacy over 2-3 treatment years, sustained efficacy and disease modification treatment ends, and sustained absence of allergic symptoms in posttreatment years. The clinician's choice of a specific AIT product should take the level of evidence and risk/benefit into account, as the patient's quality of life and the product's potential long-term effect are important components of its overall cost-effectiveness. Without evidence of maintained clinical benefit and disease modification after the end of treatment, claims of long-term economic benefit of specific AIT products cannot be justified. This paper discusses the evidence that is essential for critical evaluation of product claims in health economic analysis comparing AIT products.
Prenatal Associated Features in Fetuses Diagnosed with an Aberrant Right Subclavian Artery
Authors: Pico Harmony , Mancini Julien , Lafouge Antoine , Bault Jean-Philippe , Gorincour Guillaume , Quarello Edwin
Published: January 2016

Objective: The objective of this study was to determine the frequency and the nature of associated anomalies, especially malformations and chromosome abnormalities, in a population of fetuses with an aberrant right subclavian artery (ARSA). Materials and Methods: This is a 7-year descriptive study. All patients whose fetus had an ARSA diagnosed by ultrasound performed during the 1st, 2nd, or 3rd trimester of pregnancy were included, regardless of their risk of chromosomal abnormalities. Results: Between May 2007 and April 2014, an ARSA was diagnosed in 120 fetuses. The outcome was found in 108 cases (90%). ARSA was an isolated finding in 54/108 cases (50%). In 20% (22/108) of the fetuses, chromosomal abnormalities were detected. No chromosomal abnormalities were found in fetuses with an isolated ARSA. 82% (18/22) of chromosomal abnormalities were usual, such as trisomies 21 and 18, monosomy X, and 22q11.2 deletion. 21% (23/108) of the fetuses presenting an ARSA were associated with having a congenital heart disease. Conclusion: The presence of an isolated ARSA is a condition rarely associated with a chromosomal abnormality. The decision to perform an invasive karyotyping procedure under such circumstances or not may be made according to the principle of parental autonomy after extensive counselling and mostly a thorough assessment of the fetus.
Software Tools in Endoscopy - Nice to Have or Essential?
Authors: Möschler Oliver
Published: January 2016

Background: Documentation of findings and of the treatment implications resulting from them is one of the central tasks involved in medical work. The introduction of software tools for managing and providing technical support for this task is a logical development. Methods: A literature search was conducted in September 2015 using PubMed and the search terms ‘gastrointestinal endoscopy AND electronic documentation' and ‘software tools AND gastrointestinal endoscopy AND documentation'. Results: The requirements in relation to documentation, patient information and sedation, dealing with histological findings, materials logistics, recording video documents, and hygiene documentation are discussed. Conclusion: Software tools are essential for managing basic documentation requirements. However, for many aspects of the documentation required in a modern endoscopy department, there are various - and sometimes substantial - gaps in the programs currently available. More intensive discussions need to take place regarding existing gaps and requirements, both with the suppliers concerned and among colleagues and specialist societies.
Right Sided Colon Cancer as a Distinct Histopathological Subtype with Reduced Prognosis
Authors: Nitsche Ulrich , Stögbauer Fabian , Späth Christoph , Haller Bernhard , Wilhelm Dirk , Friess Helmut , Bader Franz G.
Published: January 2016

Background/Aims: Recent data suggest that tumors of the right and left colon should be distinguished as they differ in clinical and molecular characteristics. Methods: A total of 1,319 patients who underwent surgical resection for colon cancer (CC) were investigated. Tumors between the ileocecal valve and the hepatic flexure were classified as right CC (RCC), tumors between the splenic flexure and the rectum as left CC (LCC). Results: RCC revealed a higher cause-specific mortality risk (hazard ratio 1.36, 95% CI 1.10-1.68, p = 0.005) and lower 5-year cause-specific (RCC 64.9%, 95% CI 60.4-69.4, LCC 70.7%, 95% CI 67.2-74.2, p = 0.032) and disease-free (RCC 56.0%, 95% CI 51.5-60.5, LCC 59.9%, 95% CI 56.2-63.6, p = 0.025) survival rates. RCCs were more often microsatellite instable (RCC 37.2%, LCC 13.0%, p < 0.001) and more often showed KRAS (RCC 42.5%, LCC 18.9%, p = 0.001) and BRAF mutations (RCC 26.6%, LCC 3.2%, p < 0.001). Conclusion: RCC and LCC differ significantly regarding clinical, histopathological and molecular genetic features and can be considered as distinct entities. The reduced prognosis of RCC may be caused by higher rates of microsatellite instability, KRAS and BRAF mutations.
Quality Assurance in Endoscopy: Which Parameters?
Authors: Denzer Ulrike W.
Published: January 2016

Background: The verbalisation of quality standards and parameters by medical societies are relevant for qualitative improvement but may also be an instrument to demand more resources for health care or be a unique characteristic. Within the health care system 3 different quality levels can be defined: structure, process and result quality. Methods: The current S2k guideline of the German Society for Gastroenterology (quality requirements for gastrointestinal endoscopy) AWMF registry no. 021-022 provides recommendations based on the available evidence for the structure quality (requirements for equipment, human resources) as well as for the process quality (patient preparation, conduct, documentation) and result quality (follow-up of specific endoscopic procedures). Results: Based on these recommendations, measurable quality indicators/parameters for the endoscopy have been selected and formulated. General quality parameters for endoscopic examinations are given as well as quality parameters for specific procedures for the preparation, conduct, and follow-up of specific endoscopic interventions. Conclusion: Only the regular review of processes and courses by means of defined measurement parameters builds up the basis for corrections based on facts. In addition, the implementation of recommended standards may be an instrument in demanding more resources from the health care system and, therefore, should be embedded as routine.
Bioactive Components in Human Milk Along the First Month of Life: Effects of Iodine Supplementation during Pregnancy
Authors: Velasco Inés , Santos Cristina , Limón Juan , Pascual Elena , Zarza Lucía , Marina Elena , Gutierrez-Repiso Carolina , García-Fuentes Eduardo
Published: January 2016

Background/Aims: Human milk is considered the most suitable food for infants. The potential benefits of breastfeeding can be explained by the presence of different growth and neurotrophic factors in human milk. This study was designed to detect some biomarkers in human milk, which could be involved in the infant neurodevelopment and in the regulation of the maturation of neonatal intestine (brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), glial fibrillary acidic protein (GFAP), fibroblast growth factor 21 (FGF21), lysophosphatidic acid (LPA) and autotaxin (ATX)), and compare them on the basis of the consumption of iodine supplements or multivitamins. Methods: A prospective study included 37 healthy breastfeeding mothers, divided into 3 different groups: (1) 10 mothers who did not take supplements, (2) 17 mothers who took potassium iodine (KI) 200 µg/day and (3) 10 mothers who took a multivitamin supplement. Results: The concentrations of BDNF, GDNF, GFAP, FGF21, LPA and ATX in human milk were not significantly different in women who took a multivitamin or KI supplement compared with those who did not take any supplement. Conclusions: The presence of neurotrophic factors in human milk is neither modified by the consumption of supplements nor by their type.
Formas alternativas de visualização de dados na área de História: algumas notas de pesquisa
Authors: Gil Tiago Luís , Barleta Leonardo
Published: January 2016

O objetivo deste artigo é apresentar algumas inquietações teóricas e metodológicas sobre a forma como os historiadores representam o conhecimento histórico, dando especial atenção ao uso de gráficos interativos, mapas dinâmicos e animações. Se o objeto do conhecimento histórico tem diferentes movimentos, distintas intensidades, por que seria o papel impresso o principal (senão único) veículo de divulgação deste conhecimento? Diante de objeto tão escorregadio e de difícil apreensão, os historiadores optaram, desde o século XIX até o presente, por narrar (através da escrita) as dinâmicas sociais, sem preocupação com formas alternativas de representação. Muito recentemente, o fenômeno das mídias digitais e da internet trouxe inspiração para os profissionais do tempo social, permitindo algumas experiências inovadoras. É sobre algumas destas experiências que o texto tratará.
Fronteiras e impérios na Amazônia ibérica
Authors: Bastos Carlos Augusto
Published: January 2016

GÓMEZ GONZÁLEZ, Sebastián. Frontera selvática: Españoles, portugueses y su disputa por el noroccidente amazónico, siglo XVIII. Bogotá: Instituto Colombiano de Antropología e Historia – ICANH, 2014, 399 p.
Cartas e redes de comunicação no Mediterrâneo durante a Antiguidade tardia: o caso da controvérsia pelagiana
Authors: Oliveira Julio Cesar Magalhães
Published: January 2016

O Saque de Roma de 410 inundou o Mediterrâneo de refugiados e fez com que questões que preocupavam a Igreja latina fossem também levadas à atenção dos cristãos do Oriente. Esse é o caso de Pelágio que, ao buscar refúgio em Hipona e depois na Palestina, levaria Agostinho a enfrentá-lo em uma controvérsia que afetaria toda a tradição cristã ocidental: o debate sobre a graça. As cartas trocadas entre Agostinho e seus correspondentes durante a controvérsia pelagiana nos mostram não apenas o papel das redes epistolares no desenrolar desses debates, mas também de que modo os fluxos habituais de pessoas e de notícias no Mediterrâneo podiam ser mobilizados, ainda que nem sempre controlados, pelos atores desse jogo. O objetivo deste texto é investigar os meios, as formas e os atores envolvidos na comunicação entre Roma, o norte da África e a Palestina durante a controvérsia pelagiana.
Mediadores do sagrado: os auxiliares indígenas dos missionários nas reduções jesuíticas da Amazônia ocidental (c. 1638-1767)
Authors: Carvalho Francismar Alex Lopes de
Published: January 2016

Este artigo analisa a participação indígena na difusão da doutrina cristã nas missões jesuíticas instaladas na Amazônia ocidental. Estudiosos têm destacado, nas últimas décadas, o papel de intermediários dos chefes nativos, que atuavam em instituições municipais aos moldes ibéricos, a saber, os cabildos, as confrarias e as milícias. Este texto aborda particularmente a figura dos auxiliares indígenas dos missionários. Ao iniciar uma redução, os jesuítas geralmente treinavam alguns caciques para exercerem a tarefa de catequistas; com o tempo, educavam os filhos dos chefes destacados e algumas crianças escolhidas entre os índios comuns e cativos para formar, através deles, um grupo seleto de “fiscais da doutrina”, sacristãos e músicos. Também estimulavam a constituição de confrarias, em que apenas os índios de comportamento exemplar e provada devoção religiosa podiam participar. Em todos os casos, esses índios atuavam como mediadores entre duas culturas. O presente estudo estabelece uma análise de situações e casos relevantes sucedidos nas missões de Maynas, Mojos e Chiquitos. O argumento central consiste em demonstrar que, ao depender de agentes indígenas para viabilizar a tradução da doutrina cristã aos neófitos, os jesuítas não podiam desterrar completamente certas práticas e representações que asseguravam a legitimidade dos seus mediadores. Assim, era comum que costumes nativos, como festas e danças, se introduzissem em celebrações cristãs. Do mesmo modo, a delegação aos mesmos índios da tarefa de catequizar conduzia a formas híbridas de apropriação da doutrina cristã.

 
Interaction Between ALK1 Signaling and Connexin40 in the Development of Arteriovenous Malformations
Authors: Gkatzis Konstantinos , Thalgott Jérémy , Dos-Santos-Luis Damien , Martin Sabrina , Lamandé Noël , Carette Marie France , Disch Frans , Snijder Repke J. , Westermann Cornelius J. , Mager Johannes J. , Oh S. Paul , Miquerol Lucile , Arthur Helen M. , Mummery Christine L. , Lebrin Franck
Published: January 2016

Objective—

To determine the role of
Gja5
that encodes for the gap junction protein connexin40 in the generation of arteriovenous malformations in the hereditary hemorrhagic telangiectasia type 2 (HHT2) mouse model.

Approach and Results—

We identified
GJA5
as a target gene of the bone morphogenetic protein-9/activin receptor-like kinase 1 signaling pathway in human aortic endothelial cells and importantly found that connexin40 levels were particularly low in a small group of patients with HHT2. We next took advantage of the
Acvrl1

+/−

mutant mice that develop lesions similar to those in patients with HHT2 and generated
Acvrl1

+/−

; Gja5

EGFP/+

mice.
Gja5
haploinsufficiency led to vasodilation of the arteries and rarefaction of the capillary bed in
Acvrl1

+/−

mice. At the molecular level, we found that reduced
Gja5
in
Acvrl1

+/−

mice stimulated the production of reactive oxygen species, an important mediator of vessel remodeling. To normalize the altered hemodynamic forces in
Acvrl1

+/−

; Gja5

EGFP/+

mice, capillaries formed transient arteriovenous shunts that could develop into large malformations when exposed to environmental insults.

Conclusions—

We identified
GJA5
as a potential modifier gene for HHT2. Our findings demonstrate that
Acvrl1
haploinsufficiency combined with the effects of modifier genes that regulate vessel caliber is responsible for the heterogeneity and severity of the disease. The mouse models of HHT have led to the proposal that 3 events—heterozygosity, loss of heterozygosity, and angiogenic stimulation—are necessary for arteriovenous malformation formation. Here, we present a novel 3-step model in which pathological vessel caliber and consequent altered blood flow are necessary events for arteriovenous malformation development.
Evidence That Cingulin Regulates Endothelial Barrier Function In Vitro and In Vivo
Authors: Schossleitner Klaudia , Rauscher Sabine , Gröger Marion , Friedl Heinz Peter , Finsterwalder Richard , Habertheuer Andreas , Sibilia Maria , Brostjan Christine , Födinger Dagmar , Citi Sandra , Petzelbauer Peter
Published: January 2016

Objective—

Cingulin is a cytoplasmic component of tight junctions. Although modulation of cingulin levels in cultured epithelial model systems has no significant effect on barrier function, evidence from cingulin knockout mice suggests that cingulin may be involved in the regulation of the behavior of epithelial or endothelial cells. Here, we investigate the role of cingulin in the barrier function of endothelial cells.

Approach and Results—

We show that cingulin is expressed in human endothelial cells of the skin, brain, and lung in vivo and in vitro. Endothelial cingulin colocalizes and coimmunoprecipitates with the tight junction proteins zonula occludens-1 and guanine nucleotide exchange factor-H1. Cingulin overexpression in human umbilical vein endothelial cell induces tight junction formation, increases transendothelial electric resistance, and strengthens barrier function for low and high molecular weight tracers. In contrast, cultured endothelial cells lacking cingulin are more permeable for low molecular weight tracers. In cingulin knockout mice, neurons of the area postrema and Purkinje cells show an increased uptake of small molecular weight tracers indicating decreased barrier function at these sites.

Conclusions—

We demonstrate that cingulin participates in the modulation of endothelial barrier function both in human cultured cells in vitro and in mouse brains in vivo. Understanding the role of cingulin in maintaining tight barriers in endothelia may allow developing new strategies for the treatment of vascular leak syndromes.