bluuebunny/crossref_metadata_2025 huggingface dataset:
Diel vertical distribution of early marine phase juvenile pink salmon (Oncorhynchus gorbuscha) and behaviour when exposed to salmon louse (Lepeophtheirus salmonis)
Authors: Tang S. , Lewis A.G. , Sackville M. , Nendick L. , DiBacco C. , Brauner C.J. , Farrell A.P.
Published: September 2011

We observed diel vertical migration patterns in juvenile pink salmon ( Oncorhynchus gorbuscha (Walbaum, 1792)) and tested the hypothesis that fish behaviour is altered by exposure to sea lice copepodids. Experiments involved replicated field deployments of a large (9 m) plankton column, which provided a vertical distribution enclosure under natural light and salinity conditions. Diel vertical distributions of juvenile pink salmon were observed during the first 3 weeks of seawater acclimation in both the presence and the absence of the ectoparasitic salmon louse ( Lepeophtheirus salmonis (Krøyer, 1838)). Immediately upon entering seawater, juvenile pink salmon preferred the top 1 m of the water column, but they moved significantly deeper down the vertical water column as seawater acclimation time increased. A significant diel migration pattern was observed, which involved a preference for the surface at night-time, compared with daytime. When fish in the column were exposed to L. salmonis copepodids for 3 h, 43%–62% of fish became infected, fish expanded their vertical distribution range, and significant changes in vertical distribution patterns were observed.
Microsatellite population structure of Newfoundland black bears (Ursus americanus hamiltoni)
Authors: Marshall H. Dawn , Yaskowiak Edward S. , Dyke Casidhe , Perry Elizabeth A.
Published: September 2011

We investigated population structure of black bears ( Ursus americanus hamiltoni Cameron, 1957) from insular Newfoundland using the microsatellite profiles of 12 loci from three broadly distributed areas (Northern, Baie Verte, and Bonavista peninsulas). Our goals were to revisit earlier findings of low heterozygosity in Newfoundland and increase knowledge of intraspecific variability in black bears, and make inferences about postglacial colonization and contemporary movements of island black bears. Ninety-three individuals (42 males) were identified among 543 hair samples: 21 from Bonavista, 25 from Northern Peninsula, and 47 from Baie Verte. Genetic diversity is relatively low (HE = 0.42) and decreases from northwest to southeast. Small but significant subpopulation differentiation revealed by F statistics is greatest between Northern and Baie Verte peninsulas; it is lower and comparable in the remaining pairwise comparisons. We hypothesize that postglacial colonization proceeded from the Northern Peninsula southeastward. Bears migrated from the Northern Peninsula to Baie Verte at some more distant time in the past, then diverged by genetic drift. More recently, migration occurred from these two populations to Bonavista, characterized by positive FISindicative of admixture. Tests of biased dispersal and posterior probability of correct assignment to locality reveal contemporary movements of both males and females with historical dispersal attributable to males.
Spatial and behavioral changes by red foxes (Vulpes vulpes) in response to artificial territory intrusion
Authors: Arnold J. , Soulsbury C.D. , Harris S.
Published: September 2011

Urine marking is thought to play a pivotal role in territory demarcation by red foxes ( Vulpes vulpes (L., 1758)), but little is known about how individuals respond to alien scent marks, and whether there are sex-related differences in territorial defense. We radio-tracked dominant male and female urban foxes before and after synthetic fox urine was applied to approximately a third of their territories and compared spatial and behavioral reactions both before and after scent application and with foxes on territories where no urine was applied. Home-range boundaries of male foxes shifted towards the scent-marked area, but this change did not affect the total territory size. Larger males shifted their home ranges to a greater degree than small males. Scent application did not affect total activity, but males spent more time in the scent-marked area. Behaviors such as distance moved per night and speed of movement did not differ before and after application, but foxes searched a greater percentage of their home range each night following scent marking. Females showed no significant spatial or behavioral response to the synthetic scent marks. Overall, responses of foxes to synthetic scent marks were male-biased and related to changes in space use rather than movement behaviors.
SUPER TENSOR MODELS, SUPER FUZZY SPACES AND SUPER n-ARY TRANSFORMATIONS
Authors: SASAKURA NAOKI
Published: September 2011

By extending the algebraic description of the bosonic rank-three tensor models, a general framework for super rank-three tensor models and correspondence to super fuzzy spaces is proposed. The corresponding super fuzzy spaces must satisfy a certain cyclicity condition on the algebras of functions on them. Due to the cyclicity condition, the symmetry of the super rank-three tensor models are represented by super n-ary transformations. The Leibnitz rules and the fundamental identities for the super n-ary transformations are discussed from the perspective of the symmetry of the algebra of a fuzzy space. It is shown that the super n-ary transformations of finite orders which conserve the algebra of a fuzzy space form a finite closed n-ary super Lie algebra. Super rank-three tensor models would be of physical interest as background independent models for dynamical generation of supersymmetric fuzzy spaces, in which quantum corrections are under control.
MAXIMUM ELECTRICAL CONDUCTANCE OF A METALLIC PARABOLIC QUANTUM DOT VERSUS DOT-LEAD COUPLING
Authors: GRADO-CAFFARO M. A. , GRADO-CAFFARO M.
Published: September 2011

Starting from assuming that the electrical zero-bias conductance in a metallic quantum dot may be represented well by the Breit–Wigner model (which, on the other hand, is certainly appropriate for one-atom metallic wires), the strength of the coupling between a metallic parabolic quantum dot and the involved leads is determined for maximum conductance through the dot. In fact, this maximal conductance is calculated and issues related to off-resonant conduction states are discussed.
POLY(3, 4-ETHYLENEDIOXYTHIOPHENE): POLY(STYRENESULFONATE)/SINGLE-WALL CARBON NANOTUBE COMPOSITE FILM FOR THE HOLE TRANSPORT LAYER IN POLYMER SOLAR CELLS
Authors: KISHI NAOKI , KATO SHINYA , SAITO TAKESHI , HAYASHI JUNKI , ITO DAIKI , HAYASHI YASUHIKO , SOGA TETSUO , JIMBO TAKASHI
Published: September 2011

The composite thin film of poly(3, 4-ethylenedioxythiophene):poly(styrenesulfonate)/single-wall carbon nanotubes (PEDOT:PSS/SWCNTs) for a hole transport layer in polymer solar cells have been explored. PEDOT:PSS/SWCNT composite film exhibited higher electrical conductivity than the control PEDOT:PSS film, suggesting the increase in carrier transport passes through SWCNTs in the hole transport layer. We also demonstrated the improvement of a fill factor and short circuit current density in the polymer solar cells with the hole transport layer of PEDOT:PSS/SWCNT as compared with PEDOT:PSS.
Estrogen deficiency worsens steatohepatitis in mice fed high-fat and high-cholesterol diet
Authors: Kamada Yoshihiro , Kiso Shinichi , Yoshida Yuichi , Chatani Norihiro , Kizu Takashi , Hamano Mina , Tsubakio Mayumi , Takemura Takayo , Ezaki Hisao , Hayashi Norio , Takehara Tetsuo
Published: September 2011

Recent studies indicate an accelerated progression of nonalcoholic steatohepatitis (NASH) in postmenopausal women. Hypercholesterolemia, an important risk factor for NASH progression, is often observed after menopause. This study examined the effects of estrogen on NASH in ovariectomized (OVX) mice fed a high-fat and high-cholesterol (HFHC) diet. To investigate the effects of estrogen deficiency, OVX mice and sham-operated (SO) mice were fed normal chow or HFHC diet for 6 wk. Next, to investigate the effects of exogenous estrogen replenishment, OVX mice fed with HFHC diet were treated with implanted hormone release pellets (containing 17β-estradiol or placebo vehicle) for 6 wk. OVX mice on the HFHC diet showed enhanced liver injury with increased liver macrophage infiltration and elevated serum cholesterol levels compared with SO-HFHC mice. Hepatocyte monocyte chemoattractant protein-1 (MCP1) protein expression in OVX-HFHC mice was also enhanced compared with SO-HFHC mice. In addition, hepatic inflammatory gene expressions, including monocytes chemokine (C-C motif) receptor 2 (CCR2), were significantly elevated in OVX-HFHC mice. Estrogen treatment improved serum cholesterol levels, liver injury, macrophage infiltration, and inflammatory gene expressions in OVX-HFHC mice. Moreover, the elevated expression of liver CCR2 and MCP1 were decreased by estrogen treatment in OVX-HFHC mice, whereas low-density lipoprotein dose dependently enhanced CCR2 expression in THP1 monocytes. Our study demonstrated that estrogen deficiency accelerated NASH progression in OVX mice fed HFHC diet and that this effect was improved by estrogen therapy. Hypercholesterolemia in postmenopausal women would be a potential risk factor for NASH progression.
Ascorbic acid or l-arginine improves cutaneous microvascular function in chronic kidney disease
Authors: DuPont Jennifer J. , Farquhar William B. , Townsend Raymond R. , Edwards David G.
Published: September 2011

We sought to determine whether oxidative stress or a relative deficit of l-arginine plays a role in reducing cutaneous vasodilation in response to local heating in chronic kidney disease (CKD). Eight patients with stage 3–4 CKD and eight age- and sex-matched healthy control (HC) subjects were instrumented with four microdialysis (MD) fibers for the local delivery of 1) Ringers solution (R), 2) 20 mM ascorbic acid (AA), 3) 10 mM l-arginine (l-Arg), and 4) 10 mM NG-nitro-l-arginine methyl ester (l-NAME). Red blood cell (RBC) flux was measured via laser Doppler flowmetry. A standardized nonpainful local heating protocol (42°C) was used. Cutaneous vascular conductance (CVC) was calculated as RBC flux/MAP and all data were expressed as a percentage of the maximum CVC at each site (28 mM sodium nitroprusside, Tloc = 43°C). The plateau %CVCmax was attenuated in CKD (CKD: 76 ± 4 vs. HC: 91 ± 2%CVCmax; P < 0.05) and the NO contribution to the plateau was lower in CKD (CKD: 39 ± 7, HC: 54 ± 5; P < 0.05). The plateau %CVCmax in the CKD group was significantly greater at the AA and l-Arg sites compared with R (AA: 89 ± 2; l-Arg: 90 ± 1; R: 76 ± 4; P < 0.05) and did not differ from HC. Initial peak %CVCmax was also significantly attenuated at the R and l-Arg sites in CKD ( P < 0.05) but did not differ at the AA site. These results suggest that cutaneous microvascular function is impaired in stage 3–4 CKD and that oxidative stress and a deficit of l-arginine play a role in this impairment.
In ovo administration of rhIGF-1 to duck eggs affects the expression of myogenic transcription factors and muscle mass during late embryo development
Authors: Liu H. H. , Wang J. W. , Chen X. , Zhang R. P. , Yu H. Y. , Jin H. B. , Li L. , Han C. C.
Published: September 2011

In ovo administration of IGF-1 to poultry eggs has effective roles on post hatching muscle development. However, the secondary muscle development stages at the late embryo development stage are important for muscle fiber formation and differentiation. To investigate the roles of in ovo administration of IGF-1 on duck secondary muscle development, we injected rhIGF-1 into duck eggs in hatching at day 12. After administration on days 18, 21, 24, and 27 in hatching (E18d, E21d, E24d, and E27d, respectively), muscle samples were isolated, and the muscle tissue weight, muscle fiber parameters, and myoblast proliferation rate in leg and breast muscle were analyzed. Additionally, the expression levels of the transcription factors MyoG and MRF4 were detected using qPCR. Results show that embryo body weight and muscle fiber parameters, including muscle fiber diameter (MFD) and the number of myofibers per unit area, are upregulated in IGF-1-treated groups. Moreover, the transcription factors MyoG and MRF4 are expressed at higher levels in the experimental groups compared with the control groups. These results suggest that in ovo administration of IGF-1 to poultry eggs can mediate the expression of MyoG and MRF4, induce myoblast proliferation, and finally influence muscle development during the secondary muscle development stages.
Determinants of time trial performance and maximal incremental exercise in highly trained endurance athletes
Authors: Jacobs R. A. , Rasmussen P. , Siebenmann C. , Díaz V. , Gassmann M. , Pesta D. , Gnaiger E. , Nordsborg N. B. , Robach P. , Lundby C.
Published: September 2011

Human endurance performance can be predicted from maximal oxygen consumption (V̇o2max), lactate threshold, and exercise efficiency. These physiological parameters, however, are not wholly exclusive from one another, and their interplay is complex. Accordingly, we sought to identify more specific measurements explaining the range of performance among athletes. Out of 150 separate variables we identified 10 principal factors responsible for hematological, cardiovascular, respiratory, musculoskeletal, and neurological variation in 16 highly trained cyclists. These principal factors were then correlated with a 26-km time trial and test of maximal incremental power output. Average power output during the 26-km time trial was attributed to, in order of importance, oxidative phosphorylation capacity of the vastus lateralis muscle ( P = 0.0005), steady-state submaximal blood lactate concentrations ( P = 0.0017), and maximal leg oxygenation (sO2LEG) ( P = 0.0295), accounting for 78% of the variation in time trial performance. Variability in maximal power output, on the other hand, was attributed to total body hemoglobin mass (Hbmass; P = 0.0038), V̇o2max( P = 0.0213), and sO2LEG( P = 0.0463). In conclusion, 1) skeletal muscle oxidative capacity is the primary predictor of time trial performance in highly trained cyclists; 2) the strongest predictor for maximal incremental power output is Hbmass; and 3) overall exercise performance (time trial performance + maximal incremental power output) correlates most strongly to measures regarding the capability for oxygen transport, high V̇o2maxand Hbmass, in addition to measures of oxygen utilization, maximal oxidative phosphorylation, and electron transport system capacities in the skeletal muscle.
Local control of skeletal muscle blood flow during exercise: influence of available oxygen
Authors: Casey Darren P. , Joyner Michael J.
Published: September 2011

Reductions in oxygen availability (O2) by either reduced arterial O2 content or reduced perfusion pressure can have profound influences on the circulation, including vasodilation in skeletal muscle vascular beds. The purpose of this review is to put into context the present evidence regarding mechanisms responsible for the local control of blood flow during acute systemic hypoxia and/or local hypoperfusion in contracting muscle. The combination of submaximal exercise and hypoxia produces a “compensatory” vasodilation and augmented blood flow in contracting muscles relative to the same level of exercise under normoxic conditions. A similar compensatory vasodilation is observed in response to local reductions in oxygen availability (i.e., hypoperfusion) during normoxic exercise. Available evidence suggests that nitric oxide (NO) contributes to the compensatory dilator response under each of these conditions, whereas adenosine appears to only play a role during hypoperfusion. During systemic hypoxia the NO-mediated component of the compensatory vasodilation is regulated through a β-adrenergic receptor mechanism at low-intensity exercise, while an additional (not yet identified) source of NO is likely to be engaged as exercise intensity increases during hypoxia. Potential candidates for stimulating and/or interacting with NO at higher exercise intensities include prostaglandins and/or ATP. Conversely, prostaglandins do not appear to play a role in the compensatory vasodilation during exercise with hypoperfusion. Taken together, the data for both hypoxia and hypoperfusion suggest NO is important in the compensatory vasodilation seen when oxygen availability is limited. This is important from a basic biological perspective and also has pathophysiological implications for diseases associated with either hypoxia or hypoperfusion.
A6 Peptide Activates CD44 Adhesive Activity, Induces FAK and MEK Phosphorylation, and Inhibits the Migration and Metastasis of CD44-Expressing Cells
Authors: Piotrowicz Randolph S. , Damaj Bassam B. , Hachicha Mohamed , Incardona Francesca , Howell Stephen B. , Finlayson Malcolm
Published: September 2011

The A6 peptide (acetyl-KPSSPPEE-amino) has antitumor activity in the absence of significant adverse events in murine tumor models and clinical trials. A6 shares sequence homology with CD44, an adhesion receptor involved in metastasis that is also a marker of cancer stem cells and drug-resistant phenotypes. We investigated the mechanism of action of A6 by examining its effects on CD44 activity, cell migration, and metastasis. A6 inhibited the migration of a subset of ovarian and breast cancer cell lines, exhibiting IC50 values of 5 to 110 nmol/L. The ability of A6 to inhibit migration in vitro correlated with CD44 expression. Immunopreciptation studies showed that CD44 binds A6 and that biotin-tagged A6 can be cross-linked to CD44. The binding of A6 altered the structure of CD44 such that it was no longer recognized by a monoclonal antibody to a specific epitope. Importantly, A6 potentiated the CD44-dependent adhesion of cancer cells to hyaluronic acid and activated CD44-mediated signaling, as evidenced by focal adhesion kinase and MAP/ERK kinase phosphorylation. In vivo, A6 (100 mg/kg delivered s.c. twice daily) reduced the number of lung foci generated by the i.v. injection of B16-F10 melanoma cells by 50% (P = 0.029 in an unpaired t test). We conclude that A6 potently blocks the migration of CD44-positive cells in vitro through an interaction with CD44 that alters its structure and activates CD44 to enhance ligand binding and downstream signaling. The concurrent ability of A6 to agonize the CD44 receptor suggests that CD44 activation may represent a novel strategy for inhibiting metastatic disease. Mol Cancer Ther; 10(11); 2072–82. ©2011 AACR.
Changes in Breast Density and Circulating Estrogens in Postmenopausal Women Receiving Adjuvant Anastrozole
Authors: Prowell Tatiana M. , Blackford Amanda L. , Byrne Celia , Khouri Nagi F. , Dowsett Mitchell , Folkerd Elizabeth , Tarpinian Karineh S. , Powers Pendleton P. , Wright Laurie A. , Donehower Michele G. , Jeter Stacie C. , Armstrong Deborah K. , Emens Leisha A. , Fetting John H. , Wolff Antonio C. , Garrett-Mayer Elizabeth , Skaar Todd C. , Davidson Nancy E. , Stearns Vered
Published: September 2011

Factors associated with an increased risk of breast cancer include prior breast cancer, high circulating estrogens, and increased breast density. Adjuvant aromatase inhibitors are associated with a reduction in incidence of contralateral breast cancer. We conducted a prospective, single-arm, single-institution study to determine whether use of anastrozole is associated with changes in contralateral breast density and circulating estrogens. Eligible patients included postmenopausal women with hormone receptor-positive early-stage breast cancer who had completed local therapy, had an intact contralateral breast, and were recommended an aromatase inhibitor as their only systemic therapy. Participants received anastrozole 1 mg daily for 12 months on study. We assessed contralateral breast density and serum estrogens at baseline, 6, and 12 months. The primary endpoint was change in contralateral percent breast density from baseline to 12 months. Secondary endpoints included change in serum estrone sulfate from baseline to 12 months. Fifty-four patients were accrued. At 12 months, compared with baseline, there was a nonstatistically significant reduction in breast density (mean change: −16%, 95% CI: −30 to 2, P = 0.08) and a significant reduction in estrone sulfate (mean change: −93%, 95% CI: −94 to −91, P < 0.001). Eighteen women achieved 20% or greater relative reduction in contralateral percent density at 12 months compared with baseline; however, no measured patient or disease characteristics distinguished these women from the overall population. Large trials are required to provide additional data on the relationship between aromatase inhibitors and breast density and, more importantly, whether observed changes in breast density correlate with meaningful disease-specific outcomes. Cancer Prev Res; 4(12); 1993–2001. ©2011 AACR.
Inhibition by Resistant Starch of Red Meat–Induced Promutagenic Adducts in Mouse Colon
Authors: Winter Jean , Nyskohus Laura , Young Graeme P. , Hu Ying , Conlon Michael A. , Bird Anthony R. , Topping David L. , Le Leu Richard K.
Published: September 2011

Population studies have shown that high red meat intake may increase colorectal cancer risk. Our aim was to examine the effect of different amounts and sources of dietary protein on induction of the promutagenic adduct O6-methyl-2-deoxyguanosine (O6MeG) in colonocytes, to relate these to markers of large bowel protein fermentation and ascertain whether increasing colonic carbohydrate fermentation modified these effects. Mice (n = 72) were fed 15% or 30% protein as casein or red meat or 30% protein with 10% high amylose maize starch as the source of resistant starch. Genetic damage in distal colonocytes was detected by immunohistochemical staining for O6MeG and apoptosis. Feces were collected for measurement of pH, ammonia, phenols, p-cresol, and short-chain fatty acids (SCFA). O6MeG and fecal p-cresol concentrations were significantly higher with red meat than with casein (P < 0.018), with adducts accumulating in cells at the crypt apex. DNA adducts (P < 0.01) and apoptosis (P < 0.001) were lower and protein fermentation products (fecal ammonia, P < 0.05; phenol, P < 0.0001) higher in mice fed resistant starch. Fecal SCFA levels were also higher in mice fed resistant starch (P < 0.0001). This is the first demonstration that high protein diets increase promutagenic adducts (O6MeG) in the colon and dietary protein type seems to be the critical factor. The delivery of fermentable carbohydrate to the colon (as resistant starch) seems to switch from fermentation of protein to that of carbohydrate and a reduction in adduct formation, supporting previous observations that dietary resistant starch opposes the mutagenic effects of dietary red meat. Cancer Prev Res; 4(11); 1920–8. ©2011 AACR.
Chemoprevention of Colon and Small Intestinal Tumorigenesis in APCMin/+ Mice by Licofelone, a Novel Dual 5-LOX/COX Inhibitor: Potential Implications for Human Colon Cancer Prevention
Authors: Mohammed Altaf , Janakiram Naveena B. , Li Qian , Choi Chang-In , Zhang Yuting , Steele Vernon E. , Rao Chinthalapally V.
Published: September 2011

Preclinical and clinical studies suggest that 5-lipoxygenase (5-LOX), such as COX-2, is a potential target for colon cancer inhibition and, in part, contributes to cardiovascular side effects associated with COX-2 inhibitors. Experiments were designed to assess the chemopreventive effects of a novel dual 5-LOX/COX inhibitor, licofelone {[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid}, in APCMin/+ mouse intestinal tumorigenesis. Six-week-old male and female APCMin/+ mice (n = 10 per group) were fed with control American Institute of Nutrition-76A diet or diets containing 150 or 300 ppm licofelone for 14 weeks (∼100 days), and intestinal tumors were evaluated for tumor multiplicity and size. Licofelone significantly inhibited total intestinal tumor multiplicity and size in a dose-dependent manner (P < 0.0001; mean tumors for 0, 150, and 300 ppm: 48.8, 17, and 8, respectively, in male mice; and 34.3, 8.8, and 5.5, respectively, in female mice). Licofelone at high dose showed more than 83% (P < 0.0001) tumor inhibition in both genders of mice. One hundred and fifty and 300 ppm licofelone resulted in 86% to 97% inhibition of polyps having size greater than 2 mm. One hundred and fifty and 300 ppm licofelone caused more than 72% and 100% inhibition of colonic tumors, respectively. Importantly, in mice fed with licofelone, tumors showed significantly reduced proliferating cell nuclear antigen expression (70%, P < 0.0001), increased terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling–positive cells (75%, P < 0.0001), and there was dose-dependent suppression of serum triglycerides (71%–83%, P < 0.0001), decreased inflammatory cytokines; and decreased COX and 5-LOX activities (57%–64%, P < 0.0001). Also, compared with 300 ppm celecoxib, 300 ppm licofelone provided better efficacy in suppressing tumor growth. These observations show that a novel dual 5-LOX/COX inhibitor dramatically suppresses small intestinal and colonic tumor formation in APCMin/+ mice. Cancer Prev Res; 4(12); 2015–26. ©2011 AACR.
Nonsteroidal Anti-inflammatory Drugs and Glioma in the NIH-AARP Diet and Health Study Cohort
Authors: Daugherty Sarah E. , Moore Steven C. , Pfeiffer Ruth M. , Inskip Peter D. , Park Yikyung , Hollenbeck Albert , Rajaraman Preetha
Published: September 2011

Several case–control studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce risk for glioblastoma, an aggressive form of brain cancer. Prospective investigations have not observed such an association, but these studies lacked adequate brain cancer case numbers and did not stratify by histologic subtype. We prospectively investigated the association between NSAID use and risk of all glioma as well as the risk of glioblastoma subtype in the National Institutes of Health (NIH)-AARP Diet and Health Study. The frequency of aspirin and nonaspirin NSAID use 1 year prior to baseline was ascertained using a self-administered questionnaire. Hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox regression models with age as the underlying time metric, adjusted for sex, race, and history of heart disease. The analysis included 302,767 individuals, with 341 incident glioma cases (264 glioblastoma). No association was observed between regular use (>2 times/wk) of aspirin and risk of glioma (HR = 1.16; 95% CI, 0.87–1.56) or glioblastoma (HR = 1.17; 95% CI, 0.83–1.64) as compared with no use. Null associations were also observed for nonaspirin NSAID use (HR for glioma = 0.90; 95% CI, 0.65–1.25 and HR for glioblastoma = 0.83; 95% CI, 0.56–1.20) as compared with no use. Our findings from this large prospective study do not support an inverse association between NSAIDs and risk of all glioma or glioblastoma. Cancer Prev Res; 4(12); 2027–34. ©2011 AACR.
Stable Precursor Fragments of Vasoactive Peptides in Umbilical Cord Blood of Term and Preterm Infants
Authors: Koch L. , Dabek M.T. , Frommhold D. , Poeschl J.
Published: September 2011

Background:Though various neurohormonal systems are concurrently activated during birth, their biological effectors are not always easy to measure due to their short half-life in vivo, instability in biological samples, or very low concentrations. Methods: Using a recently discovered chemiluminescence assay, we measured the stable precursor fragments mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1) and C-terminal pro-vasopressin (CT-proAVP or copeptin) immediately after birth in umbilical venous cord blood from 119 infants with a gestational age of 23–42 weeks and evaluated their possible functions. Results:Cord blood levels of MR-proANP, MR- proADM, CT-proET-1, and CT-proAVP were considerably higher compared with normal adult levels. The CT-proAVP concentrations were 10-fold higher in term, and 70-fold higher in extremely preterm infants. MR-proANP showed 4-fold higher levels in term infants and 20-fold higher levels in extremely preterm infants. Levels of MR-proADM and CT-proET-1 were 2- to 3-fold higher in preterm and term infants. All four parameters showed significantly decreased values with increasing gestational age and a significant correlation between CT-proET-1 and MR-proADM. Conclusion:Our results indicate that vasoactive and natriuretic mediators play a functionally relevant role in circulatory transition from fetal to neonatal life.
The Psychiatric Presentation of Fragile X: Evolution of the Diagnosis and Treatment of the Psychiatric Comorbidities of Fragile X Syndrome
Authors: Tranfaglia Michael R.
Published: September 2011

Fragile X syndrome (FXS) is the leading inherited cause of mental retardation and autism spectrum disorders worldwide. It presents with a distinct behavioral phenotype which overlaps significantly with that of autism. Unlike autism and most common psychiatric disorders, the neurobiology of fragile X is relatively well understood. Lack of the fragile X mental retardation protein causes dysregulation of synaptically driven protein synthesis, which in turn causes global disruption of synaptic plasticity. Thus, FXS can be considered a disorder of synaptic plasticity, and a developmental disorder in the purest sense: mutation of the FMR1 (fragile X mental retardation 1) gene results in abnormal synaptic development in response to experience. Accumulation of this abnormal synaptic development, over time, leads to a characteristic and surprisingly consistent behavioral phenotype of attention deficit, hyperactivity, impulsivity, multiple anxiety symptoms, repetitive/perseverative/stereotypic behaviors, unstable affect, aggression, and self-injurious behavior. Many features of the behavioral and psychiatric phenotype of FXS follow a developmental course, waxing and waning over the life span. In most cases, symptoms present as a mixed clinical picture, not fitting established diagnostic categories. There have been many clinical trials in fragile X subjects, but no placebo-controlled trials of adequate size or methodology utilizing the most commonly prescribed psychiatric medications. However, large and well-designed trials of investigational agents which target the underlying pathology of FXS have recently been completed or are under way. While the literature offers little guidance to the clinician treating patients with FXS today, potentially disease-modifying treatments may be available in the near future.
Metabolic Impact of Growth Hormone Treatment in Short Children Born Small for Gestational Age
Authors: Lebl Jan , Lebenthal Yael , Kolouskova Stanislava , Steensberg Adam , Jøns Kirsten , Kappelgaard Anne-Marie , Ibáñez Lourdes , Phillip Moshe
Published: September 2011

Background: Growth hormone (GH) treatment in short children born small for gestational age (SGA) may result in metabolic changes with potential long-term effects. Methods: 149 short SGA children (mean birth weight 2.0 ± 0.6 kg, age 5.5 ± 1.5 years, height standard deviation score (SDS) –3.1 ± 0.6) were randomised to: low-dose GH therapy (0.033 mg/kg/day) for 2 years; high-dose GH therapy (0.100 mg/kg/day) for 1 year, or mid-dose GH therapy (0.067 mg/kg/day) for 1 year. Leptin, ghrelin, insulin-like growth factor-I (IGF-I), IGF binding protein-1 (IGFBP-1), lipids, fasting blood glucose and fasting insulin were assessed at baseline, 12 and 24 months. Results: After 1 year of active treatment, GH significantly reduced serum ghrelin and increased IGF-I SDS and insulin levels. Regression analysis showed an inverse correlation between ghrelin and IGF-I SDS (p < 0.001). Leptin and IGFBP-1 also declined (both p < 0.05). Changes in insulin levels reversed upon discontinuation. Improvements in lipid profile were nonsignificant and fasting blood glucose levels remained within the normal range. Conclusion: In short SGA children, ghrelin and leptin reductions associated with GH treatment may occur through a negative feedback loop of the GH–IGF-I axis. Consequently, via ghrelin and leptin suppression, GH treatment may modify food intake and body composition and potentially improve long-term metabolic outcomes.
KRAS Mutation in Metastatic Pancreatic Ductal Adenocarcinoma: Results of a Multicenter Phase II Study Evaluating Efficacy of Cetuximab plus Gemcitabine/Oxaliplatin (GEMOXCET) in First-Line Therapy
Authors: Kullmann F. , Hartmann A. , Stöhr R. , Messmann H. , Dollinger M.M. , Trojan J. , Fuchs M. , Hollerbach S. , Harder J. , Troppmann M. , Kutscheidt A. , Endlicher E.
Published: September 2011

Background: Genetic alterations within the epidermal growth factor receptor (EGFR) pathway, including KRAS mutations, have been demonstrated to be associated with response to EGFR inhibitors like cetuximab in colorectal cancers. Mutations in the KRAS gene have been found in 70–90% of pancreatic cancers. Unfortunately, the addition of cetuximab to chemotherapy did not increase response or survival in patients with advanced pancreatic cancer in phase II and phase III studies. The aim of this study was to evaluate the relationship between KRAS mutations and response or survival in patients with metastatic pancreatic cancer treated with cetuximab plus chemotherapy. Methods: Within a multicenter phase II trial, 64 patients with metastatic pancreatic cancer were treated with cetuximab in combination with gemcitabine and oxaliplatin until disease progression. Analyses of the EGFR pathway, including KRAS mutations, could be performed in 25 patients. Analyses were carried out following microdissection of the tumor. Results: Fourteen (56%) of the 25 patients examined harbored a point mutation in codon 12 of the KRAS gene. No differences between the groups were noted in median progression-free survival (104 days in KRAS wild-type patients vs. 118 days in patients with KRAS mutations). Overall survival was longer in wild-type patients compared to patients with KRAS mutations (263 vs. 162 days), but the difference did not reach statistical significance. A further analysis of our clinical phase II trial showed that the presence of a rash was significantly correlated with overall survival. Conclusions: KRAS mutation in codon 12 may be associated with reduced survival compared to KRAS wild type. The role of KRAS mutations for cetuximab therapy in pancreatic cancer warrants further investigation in larger trials to exclude an epiphenomenon. Furthermore, the development of a rash is indicative of clinical benefit.
A New Endotoxin Adsorber in Septic Shock: Observational Case Series
Authors: Ala-Kokko T.I. , Laurila J. , Koskenkari J.
Published: September 2011

Aims: Effects of a new endotoxin adsorber on the length of noradrenaline (NA) treatment, LPS (lipopolysaccharide) levels and SOFA (sequential organ failure assessment) scores in septic shock were evaluated. Methods: Two-hour hemoperfusion with LPS adsorber was initiated in patients with septic shock and endotoxemia. Controls were matched for age, focus and severity of illness. Results: Adsorption treatment (n = 9) exhibited a significant decrease in EAA (endotoxin activity assay) activity (0.55 [0.44–0.68] vs. 0.25 [0.13–0.41], p = 0.019) and NA infusion rate (0.217 µg/kg/min [0.119–0.0508] vs. 0 µg/kg/min [0–0.09], p = 0.026) from pretreatment to 24 h post-treatment. The median decrease in SOFA scores from pretreatment to 24 h was 3.0 points (1.5–4.5), p = 0.002. Duration of NA infusion was significantly shorter compared to controls (39 h [31–48] vs. 54 h [43–151], p = 0.03). Conclusions: LPS adsorber treatment was associated with a decrease in NA dose, decrease in SOFA scores and LPS concentrations.
Reduction in Serum High Mobility Group Box-1 Level by Polymyxin B-Immobilized Fiber Column in Patients with Idiopathic Pulmonary Fibrosis with Acute Exacerbation
Authors: Abe Shinji , Hayashi Hiroki , Seo Yoshitsugu , Matsuda Kuniko , Kamio Koichiro , Saito Yoshinobu , Usuki Jiro , Azuma Arata , Kudo Shoji , Gemma Akihiko
Published: September 2011

Background/Aim: Recent reports suggest that polymyxin B (PMX)-immobilized fiber may have beneficial effects in idiopathic pulmonary fibrosis (IPF) with acute exacerbation (AE). High mobility group box-1 (HMGB-1) is an important pro-inflammatory mediator that contributes to acute lung inflammation. This study was aimed to investigate whether PMX treatment affects serum HMGB-1 levels and oxygenation in IPF patients with AE. Materials and Methods: Twenty IPF patients with AE were treated by PMX. PMX treatment was carried out once daily for 2 successive days. Serum HMGB-1 levels were measured before and after PMX treatment. We also monitored arterial oxygen tension (PaO2)/inspiratory oxygen fraction (FiO2) (P/F) ratio. PMX fiber columns were analyzed to examine whether HMGB-1 was absorbed by PMX. Results: PMX treatment significantly improved both the serum HMGB-1 level and P/F ratio. HMGB-1 was detected in washing medium from the PMX column. Conclusion: PMX treatment may reduce serum HMGB-1 and improve oxygenation in patients with IPF with AE.
Incretin Receptors in Non-Neoplastic and Neoplastic Thyroid C Cells in Rodents and Humans: Relevance for Incretin-Based Diabetes Therapy
Authors: Waser Beatrice , Beetschen Karin , Pellegata Natalia S. , Reubi Jean Claude
Published: September 2011

While incretins are of great interest for the therapy of diabetes 2, the focus has recently been brought to the thyroid, since rodents treated with glucagon-like peptide-1 (GLP-1) analogs were found to occasionally develop medullary thyroid carcinomas. Incretin receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) were therefore measured in various rodent and human thyroid conditions. In vitroGLP-1 and GIP receptor autoradiography were performed in normal thyroids, C-cell hyperplasia and medullary thyroid carcinomas in rodents. Receptor incidence and density were assessed and compared with the receptor expression in human thyroids, medullary thyroid carcinomas, and TT cells. GLP-1 receptors are expressed in C cells of normal rat and mice thyroids. Their density is markedly increased in rat C-cell hyperplasia and medullary thyroid carcinomas, where their incidence amounts to 100%. GIP receptors are neither detected in normal rodent thyroids nor in C-cell hyperplasia, but are present in all rat medullary thyroid carcinomas. No GLP-1 or GIP receptors are detected in normal human thyroids. Whereas only 27% of all human medullary thyroid carcinomas express GLP-1 receptors, up to 89% express GIP receptors in a high density. TT cells lack GLP-1 receptors but express GIP receptors. GLP-1 receptors are frequently expressed in non-neoplastic and neoplastic C cells in rodents while they are rarely detected in human C-cell neoplasia, suggesting species differences. Conversely, GIP receptors appear to be massively overexpressed in neoplastic C cells in both species. The presence of incretin receptors in thyroid C cell lesions suggests that this organ should be monitored before and during incretin-based therapy of diabetes.
Benzodiazepine Use in Breast Cancer Survivors: Findings from a Consecutive Series of 1,000 Patients
Authors: Vaidya Rakhee , Sood Richa , Karlin Nina , Jatoi Aminah
Published: September 2011

Objective: This study reports the percentage of breast cancer survivors receiving ongoing benzodiazepines and the circumstances surrounding their usage. Methods: The medical records of 1,000 consecutive breast cancer survivors who were no longer receiving adjuvant chemotherapy were reviewed. Results: Among those patients, 7.9% (95% confidence interval 6.2–9.6; higher than the 3% rate in the general population) were receiving benzodiazepines. Lorazepam was most commonly prescribed. Sixty-eight patients were cancer free at their last visit, and 51 had not been taking benzodiazepines prior to their cancer diagnosis. Anxiety was the single most frequent reason for initiating and continuing benzodiazepines. Conclusion: Anxiety appears to be a common explanation for relatively high rates of benzodiazepine use in breast cancer survivors. This finding merits further study.
On the Promise of Pharmacotherapies Targeted at Cognitive and Neurodegenerative Components of Down Syndrome
Authors: Costa Alberto C.S.
Published: September 2011

Down syndrome (DS) is the phenotypic consequence of trisomy 21 and is the most common genetically defined cause of intellectual disability. The most complete, widely available, and well-studied animal model of DS is the Ts65Dn mouse. Recent preclinical successes in rescuing learning and memory deficits in Ts65Dn mice are legitimate causes for optimism that pharmacotherapies for cognitive deficits in DS might be within reach. This article provides a snapshot of potential pharmacotherapies for DS, with emphasis on our recent results showing that the N-methyl-D-aspartate receptor antagonist memantine can reverse learning and memory deficits in Ts65Dn mice. Because memantine has already been approved for the therapy of Alzheimer’s dementia, we have been able to very rapidly translate these results into human research and are currently conducting a 16-week, randomized, double-blind, placebo-controlled evaluation of the efficacy, tolerability and safety of memantine hydrochloride on enhancing the cognitive abilities of young adults with DS. The design and current status of this clinical trial will be discussed, which will be followed by some speculation on the potential impact of this and future clinical trials in the field of DS.
Antimicrobial Peptides – Promising Alternatives to Conventional Antibiotics
Authors: Baltzer Sylvia A. , Brown Melissa H.
Published: September 2011

Antimicrobial peptides (APs) have been described as evolutionary ancient weapons. Produced by a wide variety of organisms as part of a non-specific immune response, these peptides are involved in the direct destruction of various microorganisms. Several APs have been shown to have broad activity spectra against microorganisms such as Gram-positive and Gram-negative bacteria, enveloped viruses, fungi and parasites. Given that resistance to a number of antibiotics has developed in a wide range of microbes, the potential of APs as novel therapeutic agents is being evaluated. However, optimisation of APs designed for therapy will need to focus on such factors as their susceptibility to proteolytic degradation and reduction of toxicity to mammalian cells. Strict guidelines pertaining to their use should also be established to prevent or hinder future development of bacterial resistance to such peptides.
Epidemiology of Interdialytic Ambulatory Hypertension and the Role of Volume Excess
Authors: Agarwal Rajiv
Published: September 2011

Background: The epidemiology of hypertension among hemodialysis (HD) patients is difficult to describe accurately because of difficulties in the assessment of blood pressure (BP). Methods: Using 44-hour interdialytic ambulatory BP measurements, we describe the epidemiology of hypertension in a cohort of 369 patients. To seek correlates of hypertension control, antihypertensive agents were withdrawn among patients with controlled hypertension and ambulatory BP monitoring was repeated. Results: Hypertension (defined as an average ambulatory systolic BP ≧135 mm Hg or diastolic BP ≧85 mm Hg, or the use of antihypertensive medications) was prevalent in 82% of the patients and independently associated with epoetin use, lower body mass index and fewer years on dialysis. Although 89% of the patients were being treated, hypertension was controlled adequately in only 38%. Poor control was independently associated with greater antihypertensive drug use. Inferior vena cava (IVC) diameter in expiration was associated with increased risk of poorly controlled hypertension both in cross-sectional analysis and after withdrawal of antihypertensive drugs. Conclusions: Interdialytic hypertension is highly prevalent and difficult to control among HD patients. End-expiration IVC diameter is associated with poor control of hypertension in cross-sectional analyses as well as after washout of antihypertensive drugs. Among HD patients, an attractive target for improving hypertension control appears to be the reduction of extracellular fluid volume.
Dysregulated Selectin Expression and Monocyte Recruitment During Ischemia-Related Vascular Remodeling in Diabetes Mellitus
Authors: Carr Chad L. , Qi Yue , Davidson Brian , Chadderdon Scott , Jayaweera Ananda R. , Belcik J. Todd , Benner Cameron , Xie Aris , Lindner Jonathan R.
Published: September 2011

Objective—

Diabetes mellitus (DM) is associated with impaired ischemia-related vascular remodeling and also dysregulation of the inflammatory response. We sought to determine whether impaired selectin-mediated monocyte recruitment in ischemic tissues contributes to blunted ischemia-mediated angiogenesis in DM.

Methods and Results—

Contrast-enhanced ultrasound perfusion imaging and molecular imaging of endothelial P-selectin expression in the proximal hindlimb were performed at 1, 3, and 21 days after arterial ligation in wild-type and db/db mice. Ligation reduced muscle blood flow to ≈0.05 mL/minute per gram in both strains. Significant recovery of flow occurred only in wild-type mice (60%–65% of baseline flow). On molecular imaging, baseline P-selectin signal was 4-fold higher in db/db compared with wild-type mice (
P
<0.01) but increased minimally at day 1 after ischemia, whereas signal increased approximately 10-fold in wild-type mice (
P
<0.01). Immunohistology of the hindlimb skeletal muscle demonstrated severely reduced monocyte recruitment in db/db mice compared with wild-type mice. Local treatment with monocyte chemotactic protein-1 corrected the deficits in postischemic P-selectin expression and monocyte recruitment in db/db mice and led to greater recovery in blood flow.

Conclusion—

In DM, there is dysregulation of the selectin response to limb ischemia, which leads to impaired monocyte recruitment, which may be mechanistically related to reduced vascular remodeling in limb ischemia.
MicroRNA-758 Regulates Cholesterol Efflux Through Posttranscriptional Repression of ATP-Binding Cassette Transporter A1
Authors: Ramirez Cristina M. , Dávalos Alberto , Goedeke Leigh , Salerno Alessandro G. , Warrier Nikhil , Cirera-Salinas Daniel , Suárez Yajaira , Fernández-Hernando Carlos
Published: September 2011

Objective—

The ATP-binding cassette transporter A1 (ABCA1) is a major regulator of macrophage cholesterol efflux and protects cells from excess intracellular cholesterol accumulation; however, the mechanism involved in posttranscriptional regulation of ABCA1 is poorly understood. We previously showed that microRNA-33 (miR-33) is 1 regulator. Here, we investigated the potential contribution of other microRNAs (miRNAs) to posttranscriptional regulation of ABCA1 and macrophage cholesterol efflux.

Methods and Results—

We performed a bioinformatic analysis for identifying miRNA target prediction sites in ABCA1 gene and an unbiased genome-wide screen to identify miRNAs modulated by cholesterol excess in mouse peritoneal macrophages. Quantitative real-time reverse transcription–polymerase chain reaction confirmed that miR-758 is repressed in cholesterol-loaded macrophages. Under physiological conditions, high dietary fat excess in mice repressed miR-758 both in peritoneal macrophages and, to a lesser extent, in the liver. In mouse and human cells in vitro, miR-758 repressed the expression of ABCA1, and conversely, the inhibition of this miRNA by using anti-miR-758 increased ABCA1 expression. In mouse cells, miR-758 reduced cellular cholesterol efflux to apolipoprotein A1 (apoA1), and anti-miR-758 increased it. miR-758 directly targets the 3′-untranslated region of
Abca1
as assessed by 3′-untranslated region luciferase reporter assays. Interestingly, miR-758 is highly expressed in the brain, where it also targets several genes involved in neurological functions, including
Slc38a1, Ntm, Epha7
, and
Mytl1
.

Conclusion—

We identified miR-758 as a novel miRNA that posttranscriptionally controls ABCA1 levels in different cells and regulates macrophage cellular cholesterol efflux to apoA1, opening new avenues to increase apoA1 and raise high-density lipoprotein levels.