bluuebunny/crossref_metadata_2025 huggingface dataset:
Neonatal stress affects the aging trajectory of female rats on the endocrine, temperature, and ventilatory responses to hypoxia
Authors: Fournier Sébastien , Gulemetova Roumiana , Baldy Cécile , Joseph Vincent , Kinkead Richard
Published: February 2015

Human and animal studies on sleep-disordered breathing and respiratory regulation show that the effects of sex hormones are heterogeneous. Because neonatal stress results in sex-specific disruption of the respiratory control in adult rats, we postulate that it might affect respiratory control modulation induced by ovarian steroids in female rats. The hypoxic ventilatory response (HVR) of adult female rats exposed to neonatal maternal separation (NMS) is ∼30% smaller than controls (24), but consequences of NMS on respiratory control in aging female rats are unknown. To address this issue, whole body plethysmography was used to evaluate the impact of NMS on the HVR (12% O2, 20 min) of middle-aged (MA; ∼57 wk old) female rats. Pups subjected to NMS were placed in an incubator 3 h/day for 10 consecutive days (P3 to P12). Controls were undisturbed. To determine whether the effects were related to sexual hormone decline or aging per se, experiments were repeated on bilaterally ovariectomized (OVX) young (∼12 wk old) adult female rats. OVX and MA both reduced the HVR significantly in control rats but had little effect on the HVR of NMS females. OVX (but not aging) reduced the anapyrexic response in both control and NMS animals. These results show that hormonal decline decreases the HVR of control animals, while leaving that of NMS female animals unaffected. This suggests that neonatal stress alters the interaction between sex hormone regulation and the development of body temperature, hormonal, and ventilatory responses to hypoxia.
Statistical context shapes stimulus-specific adaptation in human auditory cortex
Authors: Herrmann Björn , Henry Molly J. , Fromboluti Elisa Kim , McAuley J. Devin , Obleser Jonas
Published: February 2015

Stimulus-specific adaptation is the phenomenon whereby neural response magnitude decreases with repeated stimulation. Inconsistencies between recent nonhuman animal recordings and computational modeling suggest dynamic influences on stimulus-specific adaptation. The present human electroencephalography (EEG) study investigates the potential role of statistical context in dynamically modulating stimulus-specific adaptation by examining the auditory cortex-generated N1 and P2 components. As in previous studies of stimulus-specific adaptation, listeners were presented with oddball sequences in which the presentation of a repeated tone was infrequently interrupted by rare spectral changes taking on three different magnitudes. Critically, the statistical context varied with respect to the probability of small versus large spectral changes within oddball sequences (half of the time a small change was most probable; in the other half a large change was most probable). We observed larger N1 and P2 amplitudes (i.e., release from adaptation) for all spectral changes in the small-change compared with the large-change statistical context. The increase in response magnitude also held for responses to tones presented with high probability, indicating that statistical adaptation can overrule stimulus probability per se in its influence on neural responses. Computational modeling showed that the degree of coadaptation in auditory cortex changed depending on the statistical context, which in turn affected stimulus-specific adaptation. Thus the present data demonstrate that stimulus-specific adaptation in human auditory cortex critically depends on statistical context. Finally, the present results challenge the implicit assumption of stationarity of neural response magnitudes that governs the practice of isolating established deviant-detection responses such as the mismatch negativity.
Pallidal stimulation suppresses pathological dysrhythmia in the parkinsonian motor cortex
Authors: McCairn Kevin W. , Turner Robert S.
Published: February 2015

Although there is general consensus that deep brain stimulation (DBS) yields substantial clinical benefit in patients with Parkinson's disease (PD), the therapeutic mechanism of DBS remains a matter of debate. Recent studies demonstrate that DBS targeting the globus pallidus internus (GPi-DBS) suppresses pathological oscillations in firing rate and between-cell spike synchrony in the vicinity of the electrode but has negligible effects on population-level firing rate or the prevalence of burst firing. The present investigation examines the downstream consequences of GPi-DBS at the level of the primary motor cortex (M1). Multielectrode, single cell recordings were conducted in the M1 of two parkinsonian nonhuman primates ( Macaca fasicularis). GPi-DBS that induced significant reductions in muscular rigidity also reduced the prevalence of both beta (12–30 Hz) oscillations in single unit firing rates and of coherent spiking between pairs of M1 neurons. In individual neurons, GPi-DBS-induced increases in mean firing rate were three times more common than decreases; however, averaged across the population of M1 neurons, GPi-DBS induced no net change in mean firing rate. The population-level prevalence of burst firing was also not affected by GPi-DBS. The results are consistent with the hypothesis that suppression of both pathological, beta oscillations and synchronous activity throughout the cortico-basal ganglia network is a major therapeutic mechanism of GPi-DBS.
Experimental and computational evidence for an essential role of NaV1.6 in spike initiation at stretch-sensitive colorectal afferent endings
Authors: Feng Bin , Zhu Yi , La Jun-Ho , Wills Zachary P. , Gebhart G. F.
Published: February 2015

Stretch-sensitive afferents comprise ∼33% of the pelvic nerve innervation of mouse colorectum, which are activated by colorectal distension and encode visceral nociception. Stretch-sensitive colorectal afferent endings respond tonically to stepped or ramped colorectal stretch, whereas dissociated colorectal dorsal root ganglion neurons generally fail to spike repetitively upon stepped current stimulation. The present study investigated this difference in the neural encoding characteristics between the soma and afferent ending using pharmacological approaches in an in vitro mouse colon-nerve preparation and complementary computational simulations. Immunohistological staining and Western blots revealed the presence of voltage-gated sodium channel (NaV) 1.6 and NaV1.7 at sensory neuronal endings in mouse colorectal tissue. Responses of stretch-sensitive colorectal afferent endings were significantly reduced by targeting NaV1.6 using selective antagonists (μ-conotoxin GIIIa and μ-conotoxin PIIIa) or tetrodotoxin. In contrast, neither selective NaV1.8 (A803467) nor NaV1.7 (ProTX-II) antagonists attenuated afferent responses to stretch. Computational simulation of a colorectal afferent ending that incorporated independent Markov models for NaV1.6 and NaV1.7, respectively, recapitulated the experimental findings, suggesting a necessary role for NaV1.6 in encoding tonic spiking by stretch-sensitive afferents. In addition, computational simulation of a dorsal root ganglion soma showed that, by adding a NaV1.6 conductance, a single-spiking neuron was converted into a tonic spiking one. These results suggest a mechanism/channel to explain the difference in neural encoding characteristics between afferent somata and sensory endings, likely caused by differential expression of ion channels (e.g., NaV1.6) at different parts of the neuron.
Dopaminergic modulation of locomotor network activity in the neonatal mouse spinal cord
Authors: Sharples Simon A. , Humphreys Jennifer M. , Jensen A. Marley , Dhoopar Sunny , Delaloye Nicole , Clemens Stefan , Whelan Patrick J.
Published: February 2015

Dopamine is now well established as a modulator of locomotor rhythms in a variety of developing and adult vertebrates. However, in mice, while all five dopamine receptor subtypes are present in the spinal cord, it is unclear which receptor subtypes modulate the rhythm. Dopamine receptors can be grouped into two families—the D1/5 receptor group and the D2/3/4 group, which have excitatory and inhibitory effects, respectively. Our data suggest that dopamine exerts contrasting dose-dependent modulatory effects via the two receptor families. Our data show that administration of dopamine at concentrations >35 μM slowed and increased the regularity of a locomotor rhythm evoked by bath application of 5-hydroxytryptamine (5-HT) and N-methyl-d(l)-aspartic acid (NMA). This effect was independent of the baseline frequency of the rhythm that was manipulated by altering the NMA concentration. We next examined the contribution of the D1- and D2-like receptor families on the rhythm. Our data suggest that the D1-like receptor contributes to enhancement of the stability of the rhythm. Overall, the D2-like family had a pronounced slowing effect on the rhythm; however, quinpirole, the D2-like agonist, also enhanced rhythm stability. These data indicate a receptor-dependent delegation of the modulatory effects of dopamine on the spinal locomotor pattern generator.
Transmitter release is evoked with low probability predominately by calcium flux through single channel openings at the frog neuromuscular junction
Authors: Luo Fujun , Dittrich Markus , Cho Soyoun , Stiles Joel R. , Meriney Stephen D.
Published: February 2015

The quantitative relationship between presynaptic calcium influx and transmitter release critically depends on the spatial coupling of presynaptic calcium channels to synaptic vesicles. When there is a close association between calcium channels and synaptic vesicles, the flux through a single open calcium channel may be sufficient to trigger transmitter release. With increasing spatial distance, however, a larger number of open calcium channels might be required to contribute sufficient calcium ions to trigger vesicle fusion. Here we used a combination of pharmacological calcium channel block, high-resolution calcium imaging, postsynaptic recording, and 3D Monte Carlo reaction-diffusion simulations in the adult frog neuromuscular junction, to show that release of individual synaptic vesicles is predominately triggered by calcium ions entering the nerve terminal through the nearest open calcium channel. Furthermore, calcium ion flux through this channel has a low probability of triggering synaptic vesicle fusion (∼6%), even when multiple channels open in a single active zone. These mechanisms work to control the rare triggering of vesicle fusion in the frog neuromuscular junction from each of the tens of thousands of individual release sites at this large model synapse.
Modulatory effects of activation of metabotropic glutamate receptors on GABAergic circuits in the mouse thalamus
Authors: Liu Tingting , Petrof Iraklis , Sherman S. Murray
Published: February 2015

Metabotropic glutamate receptors (mGluRs) are widely distributed in the central nervous system and modulate the release of neurotransmitters in different ways. We have previously shown that activation of presynaptic group II mGluRs reduces the gain of GABAergic inputs in both primary visual and auditory cortices (V1 and A1). In the present study, we sought to determine whether activation of mGluRs can also affect the inhibitory inputs in thalamus. Using whole cell recordings in a mouse slice preparation, we studied two GABAergic inputs to thalamic relay cells: that of the thalamic reticular nucleus (TRN) to cells of the ventral posteromedial nucleus (VPM) and that of interneurons to cells of the lateral geniculate nucleus (LGN). We found that activation of mGluRs significantly reduced the amplitudes of inhibitory postsynaptic currents (IPSCs) evoked from TRN inputs to VPM cells, and further experiments indicated that this was due to activation of presynaptic group I and group II mGluRs. Similar results were found in the interneuronal inputs to LGN cells. Activation of presynaptic group I (type 1 but not type 5) and group II mGluRs significantly reduced the amplitudes of evoked IPSCs of the axonal inputs to relay cells, and additional experiments were consistent with previous observations that activation of type 5 mGluRs on the dendritic terminals of interneurons enhanced postsynaptic IPSCs. We concluded that group I and II mGluRs may generally reduce the amplitude of evoked GABAergic IPSCs of axonal inputs to thalamic relay cells, operating through presynaptic mechanisms, and this extends our previous findings in cortex.
Cinnabar Induces Renal Inflammation and Fibrogenesis in Rats
Authors: Wang Ying , Wang Dapeng , Wu Jie , Wang Bohan , Wang Liangjun , Gao Xin , Huang Hai , Ma Honglin
Published: February 2015

The purpose of this study was to investigate whether cinnabar causes renal inflammation and fibrosis in rats. Rats were dosed orally with cinnabar (1 g/kg/day) for 8 weeks or 12 weeks. The control rats were treated with solvent (5% carboxymethylcellulose solution) over the same time periods, respectively. Renal mercury (RHg), urinary mercury (UHg), serum creatinine (SCr), urine kidney injury molecule 1 (KIM-1), renal pathology, and renal mediators were examined. At both 8 weeks and 12 weeks, RHg, UHg, and urine KIM-1 were significantly higher in the cinnabar group than in the control group, although SCr was unchanged. Kidney lesions in the cinnabar-treated rats occurred mainly in the tubules and interstitium, including vacuolization, protein casts, infiltration of inflammatory cells, and slight increase in interstitial collagen. In addition, mild mesangial proliferation was observed in glomeruli. Moreover, the expression of inflammatory and fibrogenic mediators was upregulated in the cinnabar group. In conclusion, cinnabar may cause kidney damage due to the accumulation of mercury, and renal inflammation and slight fibrogenesis may occur in rats. In the clinic, the potential risk of renal injury due to the prolonged consumption of cinnabar should be considered even though the agent is relatively nontoxic.
Prognostic Utility of Vitamin D in Acute Coronary Syndrome Patients in Coastal Norway
Authors: Naesgaard Patrycja A. , Pönitz Volker , Aarsetoey Hildegunn , Brügger-Andersen Trygve , Grundt Heidi , Harris William S. , Staines Harry , Nilsen Dennis W. T.
Published: February 2015

Background.An inverse relationship between cardiovascular risk and levels of vitamin D and omega-3 index may exist.Objectives.To evaluate the prognostic utility of serum 25-hydroxyvitamin D [25(OH)D] in 871 patients with suspected acute coronary syndrome (ACS) and to assess the seasonal correlation between 25(OH)D and the omega-3 index in 456 ACS patients from southwestern Norway.Results.In the univariate analysis the hazard ratio (HR) at 2-year follow-up for all-cause mortality in the highest as compared to the lowest quartile of 25(OH)D in the total population was 0.61 (95% confidence interval (CI), 0.37–1.00),P=0.050. At 7-year follow-up, the corresponding HR for all-cause mortality was 0.66 (95% CI, 0.49–0.90),P=0.008, and for females alone 0.51 (95% CI, 0.32–0.83),P=0.006. Quartile survival did not differ in the multivariable analysis, whereas 25(OH)D < 40 nM (<16 ng/mL) was found to be independently related to mortality. Seasonal differences in 25(OH)D, but not for the omega-3 index, were noted, and the two biomarkers were positively correlated, especially during winter-spring; Pearson’s correlation coefficient was 0.358,P<0.001.Conclusion.Vitamin D levels are related to survival, especially in females, and correlate with the omega-3 index.
The Interplay between Cyclic AMP, MAPK, and NF-κB Pathways in Response to Proinflammatory Signals in Microglia
Authors: Ghosh Mousumi , Aguirre Vladimir , Wai Khine , Felfly Hady , Dietrich W. Dalton , Pearse Damien D.
Published: February 2015

Cyclic AMP is an important intracellular regulator of microglial cell homeostasis and its negative perturbation through proinflammatory signaling results in microglial cell activation. Though cytokines, TNF-αand IL-1β, decrease intracellular cyclic AMP, the mechanism by which this occurs is poorly understood. The current study examined which signaling pathways are responsible for decreasing cyclic AMP in microglia following TNF-αstimulation and sought to identify the role cyclic AMP plays in regulating these pathways. In EOC2 microglia, TNF-αproduced a dramatic reduction in cyclic AMP and increased cyclic AMP-dependent PDE activity that could be antagonized by Rolipram, myristoylated-PKI, PD98059, or JSH-23, implicating a role for PDE4, PKA, MEK, and NF-κB in this regulation. Following TNF-αthere were significant increases in iNOS and COX-2 immunoreactivity, phosphorylated ERK1/2 and NF-κB-p65, IκB degradation, and NF-κB p65 nuclear translocation, which were reduced in the presence of high levels of cyclic AMP, indicating that reductions in cyclic AMP during cytokine stimulation are important for removing its inhibitory action on NF-κB activation and subsequent proinflammatory gene expression. Further elucidation of the signaling crosstalk involved in decreasing cyclic AMP in response to inflammatory signals may provide novel therapeutic targets for modulating microglial cell activation during neurological injury and disease.
Novel Mutation in a Patient with Cholesterol Ester Storage Disease
Authors: Lin Patrick , Raikar Sheela , Jimenez Jennifer , Conard Katrina , Furuya Katryn N.
Published: February 2015

Cholesterol ester storage disease (CESD) is a chronic liver disease that typically presents with hepatomegaly. It is characterized by hypercholesterolemia, hypertriglyceridemia, high-density lipoprotein deficiency, and abnormal lipid deposition within multiple organs. It is an autosomal recessive disease that is due to a deficiency in lysosomal acid lipase (LAL) activity, which is coded by the lysosomal acid lipase gene (LIPA). We describe the case of a 5-year-old south Asian female incidentally found to have hepatomegaly, and subsequent workup confirmed the diagnosis of CESD. DNA sequencing confirmed the presence of a novel hepatic mutation. It is a four-nucleotide deletion c.57_60delTGAG in exon 2 of the LIPA gene. This mutation is predicted to result in a premature translation stop downstream of the deletion (p.E20fs) and, therefore, is felt to be a disease-causing mutation.
Effects on Serum Fractalkine by Diet and Omega‐3 Fatty Acid Intervention: Relation to Clinical Outcome
Authors: Laake Kristian , Seljeflot Ingebjørg , Fagerland Morten Wang , Njerve Ida Unhammer , Arnesen Harald , Solheim Svein
Published: February 2015

Introduction. Fractalkine is a chemokine associated with atherosclerosis. Increased serum levels have been reported in unstable coronary artery disease (CAD) and to predict mortality in heart failure. Mediterranean‐like diet and omega‐3 fatty acids (n3‐PUFA) have documented cardioprotective and anti‐inflammatory effects. We have investigated the effect of Mediterranean‐like dietary counseling and n‐3 PUFA on serum fractalkine in an elderly population and its ability to predict cardiovascular disease (CVD). Materials and Methods. 563 men (age 64–75 yrs) at high risk of CAD were randomized into a 2 × 2 factorial designed trial for 3‐year dietary counseling and/or n‐3 PUFA supplementation (2.4 g/d). Circulating levels of fractalkine were measured at baseline and at end of study. Clinical events were recorded after 3 years. Results. Fractalkine levels were significantly reduced in all groups from baseline to 3 years (P < 0.001, all), but without between‐group differences in changes. Fractalkine levels at baseline were not predictive for CVD events (n = 68) or total mortality. Lower fractalkine levels were observed in smokers (P = 0.019). Conclusions. Reduced levels of fractalkine from baseline to 3 years were observed, however, without any influence of Mediterranean‐like diet or n‐3 PUFA supplementation. Fractalkine levels at baseline were not predictive for later CVD events.
The Mechanism of Intragranular Acicular Ferrite Nucleation Induced by Mg-Al-O Inclusions
Authors: Hui Kong , YaHui Zhou , Hao Lin , Yunjin Xia , Jie Li , Qiang Yue , ZhengYu Cai
Published: February 2015

The features of inclusion and microstructure for carbon structural steel containing Mg-Al-O inclusions were studied through the scanning electron microscope (SEM) and Energy Dispersive Spectrometer (EDS). It can be seen that, in Mg-Al-O inclusions, the elements of Mn, Si, and S coexist, and their central mole ratio of Mg/Al varies in a wide range. This value for most inclusions is larger than 0.5, which suggests the formation of solid solution between MgAl2O4and MgO. After etching, the typical microstructure of intragranular acicular ferrites is observed, which is due to the nucleation effect induced by Mg-Al-O inclusions. From the SEM-EDS mapping images, it is found that the element of sulfur accumulates on the periphery of nucleation inclusion. Moreover, line EDS analysis hints that Mn-depletion zone (MDZ) exists in steel matrix, which is adjacent to the complex inclusion. Combined with the theoretical analysis, this phenomenon can be explained by the absorption of Mn due to the magnesium vacancy in MgAl2O4, and this MDZ promotes the nucleation of intragranular acicular ferrite. Through statistical analysis of SEM images for microstructure, the probabilistic nature of inducing nucleation effect is revealed. These results may be helpful to clarify the nature of oxide metallurgy.
Remarkably Few Sputum Cultures from People with Parkinson’s Disease during Hospital In-Patient Admission
Authors: Walker Richard W. , English Joel , Tan Grace , Fisher Annette , Gray William K.
Published: February 2015

Although respiratory tract infections can be a common complication in people with Parkinson’s disease (PD), there is little published data on the nature of such infections in this patient group. We wished to investigate whether sputum samples were being taken from PD patients in order to establish whether an infection was present and if so which bacteria were responsible for the infection. We recorded the number of positive sputum samples taken from admission to North Tyneside General Hospital in North-East England across a ten-year period from June 2001 to June 2011. Of 643 in-patient episodes involving people with PD, positive sputum samples were recorded for only 12 episodes (1.9%) in eight patients. All patients were in early stage disease. In all admissions to the NHS Trust running the hospital, there were 23,069 sputum cultures from 1,056,693 in-patient episodes (2.2%). Our findings may reflect the difficultly of expectorating in many people with PD, particularly in late-stage disease. Since people with PD are especially vulnerable to respiratory tract infections, clinicians need to ensure that, where possible, a sputum sample is obtained from people with PD when clinically indicated.
Helicobacter pylori: Genomic Insight into the Host-Pathogen Interaction
Authors: Haley Kathryn P. , Gaddy Jennifer A.
Published: February 2015

The advent of genomic analyses has revolutionized the study of human health. Infectious disease research in particular has experienced an explosion of bacterial genomic, transcriptomic, and proteomic data complementing the phenotypic methods employed in traditional bacteriology. Together, these techniques have revealed novel virulence determinants in numerous pathogens and have provided information for potential chemotherapeutics. The bacterial pathogen,Helicobacter pylori, has been recognized as a class 1 carcinogen and contributes to chronic inflammation within the gastric niche. Genomic analyses have uncovered remarkable coevolution between the human host andH. pylori. Perturbation of this coevolution results in dysregulation of the host-pathogen interaction, leading to oncogenic effects. This review discusses the relationship ofH. pyloriwith the human host and environment and the contribution of each of these factors to disease progression, with an emphasis on features that have been illuminated by genomic tools.
A DNA Barcode-Based Evaluation of the Southeast Asian Catfish Genus Hemibagrus Bleeker, 1862 (Teleostei: Siluriformes; Bagridae)
Authors: Dodson Julian J. , Lecomte Frédéric
Published: February 2015

Species of the genus Hemibagrus are large river catfishes found throughout South-east Asia. The complexity of the region’s biogeographical history and the lack of well-defined morphological characters render the taxonomy and phylogenetic reconstruction of Hemibagrus problematical. Early molecular studies of the H. nemurus species group revealed extensive genetic subdivisions, the taxonomic status of which remained unclear. A recent, morphologically-based, revision of the genus provides an opportunity to clarify the taxonomic status of these lineages. We employ a DNA barcode derived from the mitochondrial cytochrome b gene to expand our genetic analyses of the genus and to test the congruence of morphologically and genetically based taxonomies. Secondly, we evaluate phylogenetic relationships among taxa. Thirdly, we describe the phylogeography of Hemibagrus in South-east Asia. The species groups and nominal species proposed in the morphology-based revision generally reflect a hierarchy of monophyletic groups based on phenetic and maximum likelihood reconstructions of mtDNA phylogenies. The most notable exception involves the definition of a morphologically cryptic group from North Borneo. H. nemurus from West Java appears to be a regional population of H. capitulum. The phylogeography of the genus has been principally influenced by the formation of North Borneo and the emergence of the Sunda Islands.
ScalaLab and GroovyLab: Comparing Scala and Groovy for Scientific Computing
Authors: Papadimitriou Stergios , Schwark Kirsten , Mavroudi Seferina , Theofilatos Kostas , Likothanasis Spiridon
Published: February 2015

ScalaLab and GroovyLab are both MATLAB-like environments for the Java Virtual Machine. ScalaLab is based on the Scala programming language and GroovyLab is based on the Groovy programming language. They present similar user interfaces and functionality to the user. They also share the same set of Java scientific libraries and of native code libraries. From the programmer's point of view though, they have significant differences. This paper compares some aspects of the two environments and highlights some of the strengths and weaknesses of Scala versus Groovy for scientific computing. The discussion also examines some aspects of the dilemma of using dynamic typing versus static typing for scientific programming. The performance of the Java platform is continuously improved at a fast pace. Today Java can effectively support demanding high-performance computing and scales well on multicore platforms. Thus, both systems can challenge the performance of the traditional C/C++/Fortran scientific code with an easier to use and more productive programming environment.
Solar CPC Pilot Plant Photocatalytic Degradation of Indigo Carmine Dye in Waters and Wastewaters Using Supported-TiO2: Influence of Photodegradation Parameters
Authors: Saggioro Enrico Mendes , Oliveira Anabela Sousa , Pavesi Thelma , Tototzintle Margarita Jiménez , Maldonado Manuel Ignacio , Correia Fábio Verissimo , Moreira Josino Costa
Published: February 2015

The photocatalytic degradation of indigo carmine (IC) dye in the presence of titanium dioxide under different conditions was reported. Several factors which interfere with the photodegradation efficiency as catalyst concentration, pH, initial concentration of dye, presence of inorganic anions, temperature, and the addition of hydrogen peroxide were studied under artificial irradiation with a 125 W mercury vapor lamp. Additionally, the catalyst supported on glass spheres was used for the photocatalytic degradation of the dye present in several types of waters in a CPC solar pilot plant. The photocatalytic products, carboxylic acids, andSO42-andNH4+were followed during IC mineralization. Formate, acetate, and oxalate were detected in real MWWTP secondary effluent. The mineralization efficiency was of 42 and 21% using in suspension and supported TiO2, respectively. In order to evaluate biological effects,Eisenia andreiearthworms were used as a model organism. No significant difference (P>0.05) of weight was observed in the earthworm submitted to different concentrations of IC and its photoproducts. The photocatalytic degradation of IC on TiO2supported on glass spheres suffered strong influence of the water matrix; nevertheless the method has the enormous advantage that it eliminates the need for the final catalyst removal step, reducing therefore the cost of treatment.
Vascular Leakage in Dengue Hemorrhagic Fever Is Associated with Dengue Infected Monocytes, Monocyte Activation/Exhaustion, and Cytokines Production
Authors: Chunhakan Sirichan , Butthep Punnee , Yoksan Sutee , Tangnararatchakit Kanchana , Chuansumrit Ampaiwan
Published: February 2015

The vascular leakage was shown by the increment of hematocrit (Hct), dengue viral infected monocyte, monocyte status, and cytokines production in patients infected with dengue virus. Dengue viral antigens were demonstrated in monocytes (CD14+) from peripheral blood mononuclear cells. The increased levels of Hct, interleukin- (IL-) 10, and tumor necrosis factor-alpha (TNF-α) were detected in dengue fever (DF), dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) patients as compared with other febrile illnesses (OFIs). The highest levels of Hct and IL-10 were detected in DSS patients as compared with other groups (P<0.05) especially on one day before and after defervescence. The unstimulated and lipopolysaccharide- (LPS-) stimulated monocytes from DSS patients showed the significantly decreased of intracellular IL-1βand TNF-α. In addition, the lowest level of mean fluorescence intensity (MFI) of CD11b expression on monocytes surface in DSS patients was also demonstrated. Furthermore, the negative correlations between IL-10 levels and intracellular IL-1βand MFI of CD11b expression in unstimulated and LPS-stimulated monocytes were also detected. Nevertheless, not only were the relationships between the prominent IL-10 and the suppression of intracellular monocyte secretion, namely, IL-1β, TNF-α, demonstrated but also the effect of vascular leakage was observed.
First-in-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR in Patients with Advanced Cancer
Authors: Shapiro Geoffrey I. , Bell-McGuinn Katherine M. , Molina Julian R. , Bendell Johanna , Spicer James , Kwak Eunice L. , Pandya Susan S. , Millham Robert , Borzillo Gary , Pierce Kristen J. , Han Lixin , Houk Brett E. , Gallo Jorge D. , Alsina Maria , Braña Irene , Tabernero Josep
Published: February 2015

Purpose: To evaluate safety (primary endpoint), tolerability, pharmacokinetics, pharmacodynamic profile, and preliminary activity of the intravenous, pan-class I isoform PI3K/mTOR inhibitor PF-05212384 in patients with advanced solid tumors.

Experimental Design: Part 1 of this open-label phase I study was designed to estimate the maximum-tolerated dose (MTD) in patients with nonselected solid tumors, using a modified continual reassessment method to guide dose escalation. Objectives of part 2 were MTD confirmation and assessment of preliminary activity in patients with selected tumor types and PI3K pathway dysregulation.

Results: Seventy-seven of the 78 enrolled patients received treatment. The MTD for PF-05212384, administered intravenously once weekly, was estimated to be 154 mg. The most common treatment-related adverse events (AE) were mucosal inflammation/stomatitis (58.4%), nausea (42.9%), hyperglycemia (26%), decreased appetite (24.7%), fatigue (24.7%), and vomiting (24.7%). The majority of patients treated at the MTD experienced only grade 1 treatment-related AEs. Grade 3 treatment-related AEs occurred in 23.8% of patients at the MTD. No treatment-related grade 4–5 AEs were reported at any dose level. Antitumor activity was noted in this heavily pretreated patient population, with two partial responses (PR) and an unconfirmed PR. Eight patients had long-lasting stable disease (>6 months). Pharmacokinetic analyses showed a biphasic concentration–time profile for PF-05212384 (half-life, 30–37 hours after multiple dosing). PF-05212384 inhibited downstream effectors of the PI3K pathway in paired tumor biopsies.

Conclusions: These findings demonstrate the manageable safety profile and antitumor activity of the PI3K/mTOR inhibitor PF-05212384, supporting further clinical development for patients with advanced solid malignancies. Clin Cancer Res; 21(8); 1888–95. ©2015 AACR.
Suppression of CHK1 by ETS Family Members Promotes DNA Damage Response Bypass and Tumorigenesis
Authors: Lunardi Andrea , Varmeh Shohreh , Chen Ming , Taulli Riccardo , Guarnerio Jlenia , Ala Ugo , Seitzer Nina , Ishikawa Tomoki , Carver Brett S. , Hobbs Robin M. , Quarantotti Valentina , Ng Christopher , Berger Alice H. , Nardella Caterina , Poliseno Laura , Montironi Rodolfo , Castillo-Martin Mireia , Cordon-Cardo Carlos , Signoretti Sabina , Pandolfi Pier Paolo
Published: February 2015

The ETS family of transcription factors has been repeatedly implicated in tumorigenesis. In prostate cancer, ETS family members, such as ERG, ETV1, ETV4, and ETV5, are frequently overexpressed due to chromosomal translocations, but the molecular mechanisms by which they promote prostate tumorigenesis remain largely undefined. Here, we show that ETS family members, such as ERG and ETV1, directly repress the expression of the checkpoint kinase 1 (CHK1), a key DNA damage response cell-cycle regulator essential for the maintenance of genome integrity. Critically, we find that ERG expression correlates with CHK1 downregulation in human patients and demonstrate that Chk1 heterozygosity promotes the progression of high-grade prostatic intraepithelial neoplasia into prostatic invasive carcinoma in Pten+/− mice. Importantly, CHK1 downregulation sensitizes prostate tumor cells to etoposide but not to docetaxel treatment. Thus, we identify CHK1 as a key functional target of the ETS proto-oncogenic family with important therapeutic implications.

Significance: Genetic translocation and aberrant expression of ETS family members is a common event in different types of human tumors. Here, we show that through the transcriptional repression of CHK1, ETS factors may favor DNA damage accumulation and consequent genetic instability in proliferating cells. Importantly, our findings provide a rationale for testing DNA replication inhibitor agents in ETS-positive TP53-proficient tumors. Cancer Discov; 5(5); 550–63. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 453
Liver Disease and Other Comorbidities in Wolcott-Rallison Syndrome: Different Phenotype and Variable Associations in a Large Cohort
Authors: Habeb Abdelhadi M. , Deeb Asma , Johnson Matthew , Abdullah Mohammed , Abdulrasoul Majidah , Al-Awneh Hussain , Al-Maghamsi Mohammed S.F. , Al-Murshedi Fathiya , Al-Saif Ramlah , Al-Sinani Siham , Ramadan Dina , Tfayli Hala , Flanagan Sarah E. , Ellard Sian
Published: February 2015

Background: Wolcott-Rallison syndrome (WRS) is caused by recessive EIF2AK3 mutations and characterized by early-onset diabetes and skeletal dysplasia. Hepatic dysfunction has been reported in 60% of patients. Aims: To describe a cohort of WRS patients and discuss the pattern and management of their liver disease. Methods: Detailed phenotyping and direct sequencing of EIF2AK3 gene were conducted in all patients. Results: Twenty-eight genetically confirmed patients (67% male; mean age 4.6 years) were identified. 17 different EIF2AK3 mutations were detected, of which 2 were novel. The p.S991N mutation was associated with prolonged survival and p.I650T with delayed onset. All patients presented before 25 months with diabetes with variation in the frequency and severity of 10 other features. Liver disease, first manifested as non-autoimmune hepatitis, was the commonest extra-pancreatic feature identified in 85.7% (24/28). 22/24 had at least one episode of acute hepatic failure which was the cause of death in all deceased patients (13/28). One child was treated by liver transplantation and had no liver disease and better diabetes control for the following 6 years. Conclusions: Liver disease in WRS is more frequent than previously described and carries high mortality. The first experience with liver transplantation in WRS is encouraging.
Does Uterine Prolapse Alter Endometrial Cyclooxygenase 2 Expression and Promote the Development of Premalignant Lesions?
Authors: Genc Mine , Sivrikoz Oya Nermin , Sahin Nur , Celik Esin , Turan Guluzar Arzu , Guclu Serkan
Published: February 2015

Objective: The aim of this study was to evaluate the expression of cyclooxygenase 2 (COX-2) and its association with the development of premalignant lesions in gland structures of the endometrium in patients with uterine prolapse, a condition which exposes the uterus to mechanical and infectious stress. Methods: The study included 102 patients who underwent hysterectomy to correct grade 3-4 uterine prolapse and 105 patients who underwent hysterectomy for other causes. Endometrial gland structures underwent immunohistochemical staining and COX-2 expression was graded. Grades 0 and 1 represent low expression; grades 2 and 3 correspond to high levels of COX-2 expression. Results: The prevalence of grade 2-3 COX-2 expression was significantly higher in the endometrial gland structures of patients with prolapse and hyperplasia compared to the remaining patients (p = 0.014). Grade 0-1 COX-2 expression was significantly more common in the endometrial gland structures of patients without uterine prolapse or hyperplasia (p = 0.004). Among the patients without endometrial hyperplasia, COX-2 expression was elevated in the endometrial gland structures of those with uterine prolapse compared to those without prolapse. Conclusion: Elevated COX-2 expression may explain the presence of unexpected premalignant lesions of the endometrium in patients with uterine prolapse.
Trichotillomania in Children
Authors: Chandran Nisha Suyien , Novak Jeroen , Iorizzo Matilde , Grimalt Ramon , Oranje Arnold P.
Published: February 2015

Background: Trichotillomania is an often underdiagnosed condition. Little is known about trichotillomania in childhood. We aimed to analyze the characteristics of children with trichotillomania to increase information on this condition. Methods: A retrospective study of an electronic database was performed in a tertiary children's hospital. Information from patients with trichotillomania was systematically classified under the categories ‘who', ‘what', ‘when', ‘where', ‘why', and ‘how'. Results: A total of 33 patients had a diagnosis of trichotillomania (28 females, 5 males; peak age between 3 and 4 years). Scalp involvement was most common and nail biting was observed in 5 patients. Only 51.5% of patients had parents who noticed their child's hairpulling. Hair on or under the bed was the most common clue suggesting that hairpulling occurred. Triggering factors identified in 16 children included physical appearance, family-related issues, school-related issues, and concurrent illness. The noninvasive hair pull test was negative in all children. There was a high non-follow-up rate, and treatment outcomes varied. Conclusion: A set of 6 specific questions, based on the ‘5Ws and 1H' principle, facilitates the gathering of important information on children with unexplained nonscarring hair loss and helps clinicians be cognizant of possible outcomes of trichotillomania. This will be especially useful to clinicians who are not familiar with this elusive condition.
Coagulation factor XIII: a multifunctional transglutaminase with clinical potential in a range of conditions
Authors: Herwald Heiko , Korte Wolfgang , Allanore Yannick , Denton Christopher P. , Cerinic Marco Matucci , Dickneite Gerhard
Published: February 2015

Coagulation factor XIII (FXIII), a plasma transglutaminase, is best known as the final enzyme in the coagulation cascade, where it is responsible for cross-linking of fibrin. However, a growing body of evidence has demonstrated that FXIII targets a wide range of additional substrates that have important roles in health and disease. These include antifibrinolytic proteins, with cross-linking of α2-antiplasmin to fibrin, and potentially fibrinogen, being the principal mechanism(s) whereby plasmin-mediated clot degradation is minimised. FXIII also acts on endothelial cell VEGFR-2 and α2β3 integrin, which ultimately leads to downregulation of the antiangiogenic protein thrombospondin-1, promoting angiogenesis and neovascularisation. Under infectious disease conditions, FXIII cross-links bacterial surface proteins to fibrinogen, resulting in immobilisation and killing, while during wound healing, FXIII induces cross-linking of the provisional matrix. The latter process has been shown to influence the interaction of leukocytes with the provisional extracellular matrix and promote wound healing. Through these actions, there are good rationales for evaluating the therapeutic potential of FXIII in diseases in which tissue repair is dysregulated or perturbed, including systemic sclerosis (scleroderma), invasive bacterial infections, and tissue repair, for instance healing of venous leg ulcers or myocardial injuries. Adequate levels of FXIII are also required in patients undergoing surgery to prevent or treat perioperative bleeding, and its augmentation in patients with/at risk for perioperative bleeding may also have potential clinical benefit. While there are preclinical and/or clinical data to support the use of FXIII in a range of settings, further clinical evaluation in these underexplored applications is warranted.
Tissue factor and Toll-like receptor (TLR)4 in hyperglycaemia-hyperinsulinaemia
Authors: Singh Anamika , Boden Guenther , Rao A. Koneti
Published: February 2015

Diabetes mellitus (DM) patients have an increased incidence of cardiovascular events. Blood tissue factor-procoagulant activity (TF-PCA), the initiating mechanism for blood coagulation, is elevated in DM. We have shown that hyperglycaemia (HG), hyperinsulinaemia (HI) and combined HG+HI (induced using 24-hour infusion clamps) increases TF-PCA in healthy and type 2 DM (T2DM) subjects, but not in type 1 DM (T1DM) subjects. The mechanisms for this are unknown. DM patients have elevated plasma lipopolysaccharide (LPS), a toll-like receptor (TLR) 4 ligand. We postulated that TLR4 plays a role in modulating TF levels. We studied the effect of HG+HI on TLR4 and TF-PCA in vivo during 24-hour HG+HI infusion clamps in healthy subjects, and T1DM and T2DM subjects, and in vitro in blood. In vivo, in healthy subjects, 24-hour HG + HI infusion increased TLR4 six-fold, which correlated with TF-PCA (r=0.91, p<0.0001). T2DM patients showed smaller increases in both. In T1DM subjects, TLR4 declined (50%, p<0.05) and correlated with TF-PCA (r=0.55; p<0.05). In vitro, HG (200 mg/dl added glucose) and HI (1-100 nM added insulin) increased TF-PCA in healthy subjects (˜2-fold, 2-4 hours). Insulin inhibited by ~30% LPSinduced increase in TF-PCA and high glucose reversed it. TLR4 levels paralleled TF-PCA (r=0.71, p<0.0001); HG and HI increased TLR4 and insulin inhibited LPS-induced TLR4 increase. This is first evidence that even in healthy subjects, HG of short duration increases TLR4 and TFPCA, key players in inflammation and thrombosis. TLR4-TF interplay is strikingly different in non-diabetic, T1DM and T2DM subjects.
Percutaneous Pulmonary Valve Implantation: 5 Years of Follow-Up
Authors: Borik Sharon , Crean Andrew , Horlick Eric , Osten Mark , Lee Kyong-Jin , Chaturvedi Rajiv , Friedberg Mark K. , McCrindle Brian W. , Manlhiot Cedric , Benson Lee
Published: February 2015

Background—

Percutaneous pulmonary valve implantation (PPVI) is a safe, less invasive alternative to surgical valve replacement for the congenital heart disease patient with right ventricular (RV) outflow tract dysfunction. The aim of this study was to determine whether reverse RV remodeling after PPVI was persistent in the longer term and whether timing of PPVI influenced outcomes.

Methods and Results—

Consecutive patients from the pediatric and adult congenital heart disease programs were enrolled. Cardiac MRI, echocardiography, metabolic exercise testing, chest radiography, and hemodynamics before intervention were compared with repeated follow-up measurements to assess changes over time. Fifty-one patients (including 23 patients <16 years old) were followed for a mean 4.5±1.9 (0.9–6.9) years after implantation, 59% of patients having available comparative cardiac MRI data. Freedom from any reintervention was 87% and 68% at 3 and 5 years, and freedom from surgery was 90% at 5 years. For every decade younger at implantation, there was an increase of 3.9%±1.0% in cardiac MRI left ventricular ejection fraction (
P
<0.001) and 2.4±0.9 mL/kg/min in maxVO
2
(
P
=0.005) and a decrease of 0.7±0.2 cm in RV end-diastolic dimension (
P
<0.001) after intervention. Younger patients displayed an additional decline in the RV/left ventricular end-diastolic volume ratio (
P
=0.05) and trended toward improved RV ejection fraction in late follow-up (50%±7% versus 41%±12%,
P
=0.07).

Conclusions—

This is the largest series to show that PPVI at a younger age yields incremental improvements in RV size and maximum oxygen consumption. Early valve implantation is associated with better RV function and should be considered in management planning for this population.
Comparison of Histopathologic Analysis Following Renal Sympathetic Denervation Over Multiple Time Points
Authors: Sakakura Kenichi , Tunev Stefan , Yahagi Kazuyuki , O’Brien Amanda J. , Ladich Elena , Kolodgie Frank D. , Melder Robert J. , Joner Michael , Virmani Renu
Published: February 2015

Background—

The pathology of radiofrequency-derived sympathetic renal denervation has not been studied over time and may provide important understanding of the mechanisms resulting in sustained blood pressure reduction. The purpose of this study was to investigate chronological changes after radiofrequency-renal denervation in the swine model.

Methods and Results—

A total of 49 renal arteries from 28 animals with 4 different time points (7, 30, 60, and 180 days) were examined. Semiquantitative histological assessment of arteries and associated tissue was performed to characterize the chronological progression of the radiofrequency lesions. Arterial medial circumferential injury (%) was greatest at 7 days (38±13%), followed by 30 days (31±6%) and 60 days (31±15%), and least at 180 days (21±12%) (
P
=0.046). Nerve injury score was significantly greater (
P
<0.001) at 7 days (3.9±0.4) compared with 30 days (2.5±0.5), 60 days (2.6±0.5), and 180 days (1.9±0.9). Tyrosine hydroxylase score, which assesses functional nerve damage, was significantly less after 7 (1±1) and 30 days (0.7±0.6) compared with 60 (2.7±0.6) and 180 days (2.7±0.6;
P
=0.01). Focal nerve regeneration at the sites of radiofrequency ablation was observed in 17% of renal arteries at 60 days and 71% of 180 days.

Conclusions—

Nerve injury after radiofrequency ablation was greatest at 7 days, with maximum functional nerve damage sustained ≤30 days. Focal terminal nerve regeneration was observed only at the sites of ablation as early as 60 days and continued to 180 days. Renal artery and peri-arterial soft tissue injury is greatest in the subacute phase, and least in the chronic phase, suggesting gradual recovery of the renal arterial wall and surrounding tissue.
Nonconstituent Coordination in Japanese as Constituent Coordination: An Analysis in Hybrid Type-Logical Categorial Grammar
Authors: Kubota Yusuke
Published: February 2015

Nonconstituent coordination poses a particularly challenging problem for standard kinds of syntactic theories in which the notion of phrase structure (or constituency) is taken to be a primitive in some way or other. Previous approaches within such theories essentially equate nonconstituent coordination with coordination of full-fledged clauses at some level of grammatical representation. I present data from Japanese that pose problems for such approaches and argue for an alternative analysis in which the apparent nonconstituents are in fact surface constituents having full-fledged meanings, couched in a framework called Hybrid Type-Logical Categorial Grammar ( Kubota 2010 , Kubota and Levine 2012 , Kubota 2014 ).