bluuebunny/crossref_metadata_2025 huggingface dataset:
Radiolarians and Diatoms from the mid-Cretaceous Successions of the Sergipe Basin, Northeastern Brazil: palaeoceanographic Assessment
Authors: Koutsoukos Eduardo A. M. , Hart Malcolm B.
Published: July 2010

Abstract. Radiolarians and diatoms are documented for the first time from the mid-Cretaceous succession of the Sergipe Basin, a passive marginal basin in northeastern Brazil. Prevailing palaeoceanographic conditions are inferred for the episodes of siliceous radiolarian and diatom biomineralization/preservation. Radiolarian faunas are first recorded in the middle to upper Albian, from scattered occurrences, and subsequently throughout most of the Cenomanian-Turonian succession. Spumellarian forms are dominant in all the sections. Nassellarian forms seem to have thrived in relatively deep-water environments, in middle neritic to upper bathyal pelagic biotopes, and have been recovered from upper Albian and uppermost Cenomanian to middle Turonian sediments. Diatom frustules are only recorded from upper Cenomanian and lower Turonian deposits. These seem to have been more abundant in shallower neritic environments. The onset of the radiolarian assemblages in middle-late Albian times (with waning low-oxygen pelagic conditions) is thought to be a response to better developed oceanic circulation patterns and to a water mass saturated in dissolved silica, perhaps generated by deep-sea volcanic processes in the formation of early oceanic crust and the mid-oceanic ridge in the northern South Atlantic. On the other hand, the record of radiolarian and diatom tests throughout the Cenomanian-Turonian succession is commonly associated with dysaerobic to quasi-anaerobic bottom conditions. This is not only in keeping with high epipelagic primary productivity in well-oxygenated surface waters and that the sea water apparently contained a high level of dissolved silica, but also suggests that the bottom and interstitial waters were enriched in carbon dioxide, had a low pH and slightly negative redox-potential (Eh). The overall conditions would have favoured the biomineralization and post-mortem preservation of siliceous organisms increasing, therefore, the radiolaria+diatom/foraminifera ratio in the sediments, which supports the conclusions of several previous authors.
Plio/Pleistocene Candonidae (Freshwater Ostracoda) from boreholes in The Nanning Area, Guangxi Province, Southern China
Authors: Deying Su , Neale John W.
Published: July 2010

Abstract. Six cored boreholes in Guangxi Province, southern China yielded a fauna of Cypridacea as well as diverse Limnocytheridae which will be the subject of a separate publication. This paper deals only with the Cypridacea. Four species of Candona were present of which three are new, one previously described species of Candoniella (a controversial genus which is probably a synonym of Candona) and one new species of Pontoniella.
Notes on the benthic foraminiferal genus Heteromorphina R.W. Jones, and Heteromorphina amplivestibulata sp. nov
Authors: Clark Fred E.
Published: July 2010

Abstract. Oolina heteromorpha Parr, 1950, the type species of the genus Heteromorphina R.W. Jones, 1984 is demonstrated to be a junior synonym of Lagena collaris Cushman, 1913. In addition, two of the three species transferred by Jones to this genus are shown to belong to other genera. From the Miocene of DSDP Site 357 (Leg 39), located on the Rio Grande Rise, a new species, Heteromorphina amplivestibulata, is described and illustrated. It is characterized by an extremely large chamberlet in comparison to the principal chamber, which has a slightly produced caudal structure with a hollow central canal.
Some Middle Jurassic dinocysts from the Brent Group of the northern North Sea
Authors: Bailey David A. , Partington Mark
Published: July 2010

Abstract. Selected dinocyst taxa from the Brent Group equivalent (Bathonian-Aalenian) of the northern North Sea are described. The diagnosis of Dissiliodinium (Drugg 1978) is emended. Two new species: Dissiliodinium willei and Durotrigia aspera are introduced. In addition, several new taxa are informally described and illustrated.
The Foraminiferid Osangularia schloenbachi (Reuss, 1863); the erection of a neotype
Authors: Crittenden Stephen , Price Roger J.
Published: July 2010

Abstract. The benthonic foraminiferid Osangularia schloenbachi (Reuss, 1863) is an established index taxon for Albian to Aptian age sediments worldwide. It is a very useful marker species commonly encountered in cuttings sampled from offshore boreholes on the north-west European continental shelf. However, despite its biostratigraphical utility there is no known holotype for this species. This short article rectifies this taxonomic point of order by erecting a neotype for the species.
Mafic alkaline metasomatism in the lithosphere underneath East Serbia: evidence from the study of xenoliths and the host alkali basalts
Authors: Cvetković V. , Downes H. , Höck V. , Prelević D. , Lazarov M.
Published: July 2010

Effects of mafic alkaline metasomatism have been investigated by a combined study of the East Serbian mantle xenoliths and their host alkaline rocks. Fertile xenoliths and tiny mineral assemblages found in depleted xenoliths have been investigated. Fertile lithologies are represented by clinopyroxene (cpx)-rich lherzolite and spinel (sp)-rich olivine websterite containing Ti–Al-rich Cr-augite, Fe-rich olivine, Fe–Al-rich orthopyroxene and Al-rich spinel. Depleted xenoliths, which are the predominant lithology in the suite of East Serbian xenoliths, are harzburgite, cpx-poor lherzolite and rare Mg-rich dunite. They contain small-scale assemblages occurring as pocket-like, symplectitic or irregular, deformation-assisted accumulations of metasomatic phases, generally composed of Ti–Al- and incompatible element-rich Cr-diopside, Cr–Fe–Ti-rich spinel, altered glass, olivine, apatite, ilmenite, carbonate, feldspar, and a high-TiO
2
(
c
. 11 wt%) phlogopite. The fertile xenoliths are too rich in Al, Ca and Fe to simply represent undepleted mantle. By contrast, their composition can be reproduced by the addition of 5–20 wt% of a basanitic melt to refractory mantle. However, textural relationships found in tiny mineral assemblages inside depleted xenoliths imply the following reaction: opx+sp1 (primary mantle Cr-spinel) ±phlogopite+Si-poor alkaline melt=Ti–Al-cpx+sp2 (metasomatic Ti-rich spinel)±ol±other minor phases. Inversion modelling, performed on the least contaminated and most isotopically uniform host basanites (
87
Sr/
86
Sr=
c
. 0.7031;
143
Nd/
144
Nd=
c
. 0.5129), implies a source that was enriched in highly and moderately incompatible elements (
c
. 35–40× chondrite for U–Th–Nb–Ta, 2× chondrite for heavy rare earth elements (HREE), made up of clinopyroxene, carbonate (
c
. 5%), and traces of ilmenite (
c
. 1%) and apatite (
c
. 0.05%). A schematic model involves: first, percolation of CO
2
- and H
2
O-rich fluids and precipitation of metasomatic hydrous minerals; and, second, the subsequent breakdown of these hydrous minerals due to the further uplift of hot asthenospheric mantle. This model links intraplate alkaline magmatism to lithospheric mantle sources enriched by sublithospheric melts at some time in the past.
Mantle metasomatism by melts of HIMU piclogite components: new insights from Fe-lherzolite xenoliths (Calatrava Volcanic District, central Spain)
Authors: Bianchini Gianluca , Beccaluva Luigi , Bonadiman Costanza , Nowell Geoff M. , Pearson D. Graham , Siena Franca , Wilson Marjorie
Published: July 2010

Mantle xenoliths from the Calatrava Volcanic District (CLV), central Spain, are characterized by a wide compositional range that includes lherzolites (prevalent), as well as minor amounts of wehrlite, olivine (ol)-websterite and rare dunites. They generally have a bulk-rock Mg# of less than 89, lower than any primordial mantle estimates. Intra-suite variations in modal proportions are inconsistent with those predicted by melting models irrespective of the starting composition; mineral and bulk-rock variation diagrams show inconsistencies between the CLV compositions (anomalously enriched in Fe–Ti) and those predicted from the partial melting of primordial mantle material. Processes other than pure melt extraction are confirmed by the whole-rock REE (rare earth element) budget, typically characterized by LREE enrichments, with La
N
/Yb
N
(up to 6.7), probably related to pervasive metasomatism. CLV mantle clinopyroxenes (cpx) generally display fractionated REE patterns with upwards-convex shapes, characterized by low HREE (Tm–Lu) concentrations (typically <6× chondrite) and enrichments in middle–light REE (MREE–LREE) (Nd
N
/Yb
N
up to 7, La
N
/Yb
N
up to 5). These ‘enriched’ cpx compositions either result from re-equilibration of primary mantle cpx with an incoming melt, or represent cpx crystallization directly from the metasomatic agent. The latter was plausibly generated at greater depths in the presence of residual garnet (from peridotite or eclogite starting materials). Separated cpx have homogeneous
87
Sr/
86
Sr compositions between 0.7031 and 0.7032;
143
Nd/
144
Nd ranges from 0.51288 to 0.51295 (εNd 4.74–6.07) and
176
Hf/
177
Hf is in the range 0.28302–0.28265 (εHf −3.6 to 9.0). Unlike mantle xenoliths and alpine-type peridotites from other Iberian occurrences, which range in composition from the depleted mantle (DM) to the enriched mantle (EM), the CLV mantle cpx approach the composition of the HIMU mantle end member, the genesis of which is generally interpreted as the result of long-term recycling of oceanic basalts/gabbros (or their eclogitic equivalent) via ancient subduction. A model is proposed for the mantle evolution under central Iberia, where sublithospheric convective instabilities – possibly triggered by the neighbouring subduction along the Betic collisional belt – could have remobilized deep domains from the mantle ‘transition zone’ (410–660 km), which may include relicts of older subducted slabs. Within these remobilized domains, characterized by the coexistence of peridotite and eclogite and referred to as a ‘piclogite’ association, the eclogites melt preferentially generating Fe–Ti rich melts characterized by a HIMU isotopic signature that infiltrates and metasomatizes the shallower lithospheric mantle.
Geochemical and Sr–Nd isotopic characteristics and pressure–temperature estimates of mantle xenoliths from the French Massif Central: evidence for melting and multiple metasomatism by silicate-rich carbonatite and asthenospheric melts
Authors: Yoshikawa M. , Kawamoto T. , Shibata T. , Yamamoto J.
Published: July 2010

Ultramafic xenoliths from Mont Briançon, Ray Pic and Puy Beaunit in the French Massif Central show variable mineral compositions that indicate a residual origin after various degrees of partial melting of a fertile peridotite. Furthermore, trace element and Sr–Nd isotopic variations of clinopyroxenes indicate mixing processes between depleted mantle and enriched components such as asthenospheric melt and silicate carbonatite melt. Pyroxene geothermometer and CO
2
geobarometer estimates are 860–1060 °C at 0.92–1.10 GPa for Mont Briançon, 930–980 °C at 0.89–1.04 GPa for Ray Pic and 840–940 °C at 0.59–0.71 GPa for Puy Beaunit. From south to north, the xenoliths show the following trends: (1) deeper to shallower origin; (2) more depleted mineral compositions, suggesting higher degrees of partial melting; and (3) more enriched isotopes and trace elements, indicating a mixing process with a silicate-rich carbonatite melt characterized by high H
2
O and K
2
O, possibly during Variscan subduction.
PGC-1α is required for AICAR-induced expression of GLUT4 and mitochondrial proteins in mouse skeletal muscle
Authors: Leick Lotte , Fentz Joachim , Biensø Rasmus S. , Knudsen Jakob G. , Jeppesen Jacob , Kiens Bente , Wojtaszewski Jørgen F. P. , Pilegaard Henriette
Published: July 2010

We tested the hypothesis that repeated activation of AMP-activated protein kinase (AMPK) induces mitochondrial and glucose membrane transporter mRNA/protein expression via a peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)-dependent mechanism. Whole body PGC-1α-knockout (KO) and littermate wild-type (WT) mice were given either single or repeated subcutaneous injections of the AMPK activator AICAR or saline. Skeletal muscles were removed either 1 or 4 h after the single AICAR treatment or 24 h after the last injection following repeated AICAR treatment. Repeated AICAR treatment increased GLUT4, cytochrome (cyt) c oxidase I, and (cyt) c protein expression ∼10–40% relative to saline in white muscles of WT but not of PGC-1α-KO mice, whereas fatty acid translocase/CD36 (FAT/CD36) protein expression was unaffected by AICAR treatment in both genotypes. GLUT4, cyt c, and FAT/CD36 mRNA content increased 30–60% 4 h after a single AICAR injection relative to saline in WT, and FAT/CD36 mRNA content decreased in PGC-1α-KO mice. One hour after a single AICAR treatment, phosphorylation of AMPK and the downstream target acetyl-coenzyme A carboxylase increased in all muscles investigated independent of genotype, indicating normal AICAR-induced AMPK signaling in the absence of PGC-1α. The hexokinase II (HKII) mRNA and protein response was similar in muscles of WT and PGC-1α-KO mice after single and repeated AICAR treatments, respectively, confirming that HKII is regulated independently of PGC-1α in response to AICAR. In conclusion, here we provide genetic evidence for a role of PGC-1α in AMPK-mediated regulation of mitochondrial and glucose membrane transport protein expression in skeletal muscle.
Potentiation of Short-Latency Cortical Responses by High-Frequency Repetitive Transcranial Magnetic Stimulation
Authors: Veniero Domenica , Maioli Claudio , Miniussi Carlo
Published: July 2010

It is generally accepted that low- and high-frequency repetitive transcranial magnetic stimulation (rTMS) induces changes in cortical excitability, but there is only indirect evidence of its effects despite a large number of studies employing different stimulation parameters. Typically the cortical modulations are inferred through indirect measurements, such as recording the change in electromyographic responses. Recently it has become possible to directly evaluate rTMS-induced changes at the cortical level using electronencephalography (EEG). The present study investigates the modulation induced by high-frequency rTMS via EEG by evaluating changes in the latency and amplitude of TMS-evoked responses. In this study, rTMS was applied to the left primary motor cortex (MI) in 16 participants while an EEG was simultaneously acquired from 29 scalp electrodes. The rTMS consisted of 40 trains at 20 Hz with 10 stimuli each (a total of 400 stimuli) that were delivered at the individual resting motor threshold. The on-line modulation induced by the high-frequency TMS was characterized by a sequence of EEG responses. Two of the rTMS-induced responses, P5 and N8, were specifically modulated according to the protocol. Their latency decreased from the first to the last TMS stimuli, while the amplitude values increased. These results provide the first direct, on-line evaluation of the effects of high-frequency TMS on EEG activity. In addition, the results provide a direct demonstration of cortical potentiation induced by rTMS in humans.
Attentional Modulation of Affective Versus Sensory Processing: Functional Connectivity and a Top-Down Biased Activation Theory of Selective Attention
Authors: Grabenhorst Fabian , Rolls Edmund T.
Published: July 2010

Top-down selective attention to the affective properties of taste stimuli increases activation to the taste stimuli in the orbitofrontal cortex (OFC) and pregenual cingulate cortex (PGC), and selective attention to the intensity of the stimuli increases the activation in the insular taste cortex, but the origin of the top-down attentional biases is not known. Using psychophysiological interaction connectivity analyses, we showed that in the anterior lateral prefrontal cortex (LPFC) at Y = 53 mm the correlation with activity in OFC and PGC seed regions was greater when attention was to pleasantness compared with when attention was to intensity. Conversely, we showed that in a more posterior region of the LPFC at Y = 34 the correlation with activity in the anterior insula seed region was greater when attention was to intensity compared with when attention was to pleasantness. We also showed that correlations between areas in these separate processing streams were dependent on selective attention to affective value versus physical intensity of the stimulus. We then propose a biased activation theory of selective attention to account for the findings and contrast this with a biased competition theory of selective attention.
Facilitatory Mechanisms Shape Selectivity for the Rate and Direction of FM Sweeps in the Inferior Colliculus of the Pallid Bat
Authors: Williams Anthony J. , Fuzessery Zoltan M.
Published: July 2010

The inferior colliculus (IC) of the pallid bat has a large percentage of neurons that respond selectively to the rate and direction of the bat's echolocation pulse, a downward FM sweep. Three underlying mechanisms have been previously described. Here we describe a fourth mechanism, facilitation, that shapes selectivity for both sweep rate and direction. The neurons studied are termed FM specialists, because they do not respond to tones. Most were selective for the downward sweep direction, and this preference was expressed even when presented with narrowband, 1 kHz sweeps that crossed only a fraction of their excitatory receptive fields. This selectivity was also expressed in response to two tones delayed in time, termed two-tone facilitation (TTF). Direction-selective neurons showed a greatly facilitated response when a higher-frequency tone preceded a lower-frequency tone, simulating conditions in a downward sweep. The degree of temporal asymmetry in facilitation accurately predicted direction selectivity. When the spectral difference between the two tones was increased, the best delay also increased and could be used to predict a neuron's preferred sweep rate. To determine whether TTF alone created rate and direction selectivity, low- and high-frequency inhibitory sidebands, which can also shape selectivity, were eliminated from sweeps. In most cases, selectivity persisted. These results support the idea of spectral delay lines that produce an overlap and summation of excitatory inputs only when a dynamic stimulus traverses a receptive field in one direction at a specific velocity.
Increased Range of Motion and Function in an Individual with Breast Cancer and Necrotizing Fasciitis—Manual Therapy and Pulsed Short-Wave Diathermy Treatment
Authors: Johnson Wayne , Draper David O.
Published: July 2010

Necrotizing fasciitis is a severe soft tissue infection of the subcutaneous tissue and fascia affecting those predisposed to immune system compromise. It is a life threatening condition; mortality can be reduced by rapid diagnosis, adequate early surgical debridement and antibiotic ointment. In this case report we present the use of manual therapy (MT) techniques, joint and soft tissue mobilization, following a regimen of pulsed short wave diathermy (PSWD) in the treatment of a woman 3 years post necrotizing fasciitis developed during chemotherapy treatment for breast cancer. During her course of chemotherapy, she developed necrotizing fasciitis which was treated with extensive surgical debridement (8 linear feet of incisions) followed by debridement to both hips and the pelvis area. When we started working with her, we put her on a course of PSWD/MT. After six weeks of following this regimen, she gained of external rotation in both her left and right hips, of left hip flexion and of right hip flexion. The patient gained of right hip extension, yet there was no improvement in left hip extension. The treatments led to a dramatic reduction in pain and scarring from previous surgeries. The patient also returned to running.
A Road Map for the Global Elimination of Congenital Syphilis
Authors: Kamb Mary L. , Newman Lori M. , Riley Patricia L. , Mark Jennifer , Hawkes Sarah J. , Malik Tasneem , Broutet Nathalie
Published: July 2010

Congenital syphilis is the oldest recognized congenital infection, and continues to account for extensive global perinatal morbidity and mortality today. Serious adverse pregnancy outcomes caused by maternal syphilis infection are prevented with screening early in pregnancy and prompt treatment of women testing positive. Intramuscular penicillin, an inexpensive antibiotic on the essential medicine list of nations all over the world, effectively cures infection and prevents congenital syphilis. In fact, at a cost of $11–15 per disability adjusted life year (DALY) averted, maternal syphilis screening and treatment is among the most cost‐effective public health interventions in existence. Yet implementation of this basic public health intervention is sporadic in countries with highest congenital syphilis burden. We discuss the global burden of this devastating disease, current progress and ongoing challenges for its elimination in countries with highest prevalence, and next steps in ensuring a world free of preventable perinatal deaths caused by syphilis.
Interacting Urns Processes for Clustering of Large-Scale Networks of Tiny Artifacts
Authors: Leone Pierre , Schiller Elad M.
Published: July 2010

We analyze a distributed variation on the Pólya urn process in which a network of tiny artifacts manages the individual urns. Neighboring urns interact by repeatedly adding the same colored ball based on previous random choices. We discover that the process rapidly converges to a definitive random ratio between the colors in every urn. Moreover, the rate of convergence of the process at a given node depends on the global topology of the network. In particular, the same ratio appears for the case of complete communication graphs. Surprisingly, this effortless random process supports useful applications, such as clustering and computation of pseudo-geometric coordinate. We present numerical studies that validate our theoretical predictions.
High Levels of Nucleolar Expression of Nucleolin Are Associated with Better Prognosis in Patients with Stage II Pancreatic Ductal Adenocarcinoma
Authors: Peng Lan , Liang John , Wang Hua , Song Xianzhou , Rashid Asif , Gomez Henry F. , Corley Lynda J. , Abbruzzese James L. , Fleming Jason B. , Evans Douglas B. , Wang Huamin
Published: July 2010

Purpose: Nucleolin is a major nucleolar protein that has been shown to be overexpressed in rapidly dividing cells and plays an essential role in cell proliferation and survival. However, the expression and significance of nucleolin in pancreatic ductal adenocarcinoma (PDA) have not been studied.

Experimental Design: We used a tissue microarray consisting of 1.0-mm cores of tumor and paired nonneoplastic pancreatic tissue from 69 pancreaticoduodenectomy specimens with stage II PDA. Nucleolin expression was evaluated by immunohistochemistry and scored quantitatively by image analysis. Nucleolin expression was classified as nucleolin-high or nucleolin-low using the median nucleolin labeling index of 3.5% as cutoff. Staining results were correlated with clinicopathologic features and survival.

Results: Both PDAs and PDA cell lines showed nucleolar staining for nucleolin. Nucleolin expression was higher in PDAs and PDA cell lines than in nonneoplastic ductal epithelial cells. Among the 69 stage II PDAs, 34 (49%) were nucleolin-high. The median overall survival was 65.2 ± 16.3 months for patients who had nucleolin-high PDAs compared with 19.5 ± 3.3 months for patients whose tumors were nucleolin-low (P = 0.03, log-rank method). No significant correlation between nucleolin expression and other clinicopathologic parameters was found. In multivariate analysis, nucleolin expression was a prognostic factor for overall survival in patients with stage II PDA independent of patient's age, gender, tumor size, differentiation, and lymph node status.

Conclusions: Nucleolin was overexpressed in PDAs and PDA cell lines. A high level of nucleolar expression of nucleolin was an independent prognostic marker for better survival for patients with stage II PDAs. Clin Cancer Res; 16(14); 3734–42. ©2010 AACR.
Inhibition of Src Impairs the Growth of Met-Addicted Gastric Tumors
Authors: Bertotti Andrea , Bracco Cecilia , Girolami Flavia , Torti Davide , Gastaldi Stefania , Galimi Francesco , Medico Enzo , Elvin Paul , Comoglio Paolo M. , Trusolino Livio
Published: July 2010

Purpose: We examined whether inhibition of Src tyrosine kinase, a downstream effector of the MET oncogene, can hinder the malignant properties of gastric tumors dependent on Met for growth and survival.

Experimental Design: Sensitivity to Src inhibition was determined in vitro by measuring clonogenic survival (anchorage-independent growth) and in vivo by establishing xenograft models. Four “Met-addicted” gastric carcinoma cell lines (GTL16, MKN45, HS746T, and SNU5) and three Met-independent gastric carcinoma cell lines (KATO III, AGS, and NCI-N87) were treated with the Src inhibitor saracatinib (AZD0530). In GTL16 and KATO III, Src neutralization was also achieved by dasatinib and RNA interference. The biochemical and transcriptional consequences of Src inhibition were explored using anti-phosphoprotein antibodies and oligonucleotide microarrays.

Results: Inhibition of Src in Met-addicted gastric carcinoma cell lines (a) decreased the phosphorylation/activation levels of signaling intermediates involved in cell proliferation and protection from apoptosis and down-modulated the expression of several cell cycle regulators; (b) reduced anchorage-independent growth; (c) enhanced impairment of cell viability produced by Met inhibition; and (d) delayed tumorigenesis in xenotransplantation models. Immunohistochemical analysis of tumor xenograft tissues following systemic treatment with saracatinib showed a reduction of tumor cell proliferation index, increased apoptosis, and diminished phospho-focal adhesion kinase and phospho-paxillin staining. Tumor stroma parameters such as angiogenesis or inflammatory infiltration were unaffected. In clonogenic survival assays, gastric carcinoma cells without addiction to Met were less sensitive than Met-addicted cells to Src inhibition.

Conclusions: Src is as a key downstream transducer of Met-driven tumor growth. Targeting Src might provide therapeutic benefit in Met-addicted tumors. Clin Cancer Res; 16(15); 3933–43. ©2010 AACR.
Preclinical Colorectal Cancer Chemopreventive Efficacy and p53-Modulating Activity of 3′,4′,5′-Trimethoxyflavonol, a Quercetin Analogue
Authors: Howells Lynne M. , Britton Robert G. , Mazzoletti Marco , Greaves Peter , Broggini Massimo , Brown Karen , Steward William P. , Gescher Andreas J. , Sale Stewart
Published: July 2010

Some naturally occurring flavonols, exemplified by quercetin, seem to possess experimental cancer chemopreventive efficacy. Modulation of p53 is a mechanism thought to contribute to their activity. The hypothesis was tested that a synthetic flavonol, 3′,4′,5′-trimethoxyflavonol (TMFol), can interfere with tumor development and p53 expression in two models of colorectal carcinogenesis, ApcMin mice and human-derived HCT116 adenocarcinoma–bearing nude mice. Mice received TMFol with their diet (0.2%) from weaning to week 16 in the case of ApcMin or from either day 7 before (“TMFol early”) or day 7 after (“TMFol late”) tumor inoculation in HCT116 mice. The ability of TMFol to affect tumor proliferation or apoptosis, as reflected by staining for Ki-67 or cleaved caspase-3, respectively, was studied in HCT116 tumors. TMFol tumor levels were measured by high-performance liquid chromatography. Consumption of TMFol reduced small intestinal adenoma burden in ApcMin mice by 47%, compared with control mice (P < 0.002). The TMFol early regimen approximately halved HCT116 tumor size (P < 0.05), decreased tumor proliferation, and increased apoptosis, whereas the TMFol late regimen had no significant effect when compared with controls. In tumor tissues from mice, in which TMFol reduced tumor development, p53 expression was increased 3-fold in ApcMin and 1.5-fold in HCT116 tumor–bearing mice (P = 0.02). TMFol increased p53 also in cells derived from these tumors. TMFol was detected in HCT116 tumors, but levels did not correlate with tumor burden. TMFol was not mutagenic in the Ames test. The results suggest that chemical modification of the flavonol structure may generate safe and efficacious cancer chemopreventive agents. Cancer Prev Res; 3(8); 929–39. ©2010 AACR.
Cryptotanshinone Inhibits Cancer Cell Proliferation by Suppressing Mammalian Target of Rapamycin–Mediated Cyclin D1 Expression and Rb Phosphorylation
Authors: Chen Wenxing , Luo Yan , Liu Lei , Zhou Hongyu , Xu Baoshan , Han Xiuzhen , Shen Tao , Liu Zhijun , Lu Yin , Huang Shile
Published: July 2010

Cryptotanshinone (CPT), a natural compound isolated from the plant Salvia miltiorrhiza Bunge, is a potential anticancer agent. However, little is known about its anticancer mechanism. Here, we show that CPT inhibited cancer cell proliferation by arresting cells in G1-G0 phase of the cell cycle. This is associated with the inhibition of cyclin D1 expression and retinoblastoma (Rb) protein phosphorylation. Furthermore, we found that CPT inhibited the signaling pathway of the mammalian target of rapamycin (mTOR), a central regulator of cell proliferation. This is evidenced by the findings that CPT inhibited type I insulin-like growth factor I– or 10% fetal bovine serum–stimulated phosphorylation of mTOR, p70 S6 kinase 1, and eukaryotic initiation factor 4E binding protein 1 in a concentration- and time-dependent manner. Expression of constitutively active mTOR conferred resistance to CPT inhibition of cyclin D1 expression and Rb phosphorylation, as well as cell growth. The results suggest that CPT is a novel antiproliferative agent. Cancer Prev Res; 3(8); 1015–25. ©2010 AACR.
Hook Effect: A Pitfall Leading to Misdiagnosis of Hypoaldosteronism in an Infant with Pseudohypoaldosteronism
Authors: Akın Leyla , Kurtoglu Selim , Kendirci Mustafa , Akın Mustafa Ali , Hartmann Michaela F. , Wudy Stefan A.
Published: July 2010

We report herein the case of a premature infant who presented with failure to thrive, hyponatremia, hyperkalemia and metabolic acidosis. Initial serum hormone profiling suggested isolated hypoaldosteronism (aldosterone: 0.01 pg/ml, normal range: 50–900 pg/ml). A gas chromatography-mass spectrometry spot urinary steroid profile showed grossly elevated levels of 18-hydroxy-tetrahydro-11-dehydrocorticosterone (18-hydroxy-THA: 5,893 µg/l; normal upper limit 36 µg/l) and tetrahydroaldosterone (TH-Aldo: 5,749 µg/l; normal upper limit 36 µg/l) which are aldosterone precursor metabolite and aldosterone metabolite, respectively. Thus, aldosterone synthase deficiency was excluded and pseudohypoaldosteronism (PHA) was suggested. A repeated test after dilution of the serum revealed a very high level of aldosterone (6,490 pg/ml), confirming the diagnosis of PHA in this case.
Estrogen Prevents Senescence through Induction of WRN, Werner Syndrome Protein
Authors: Lee Su-Jin , Lee Sun-Hye , Ha Nam-Chul , Park Bum-Joon
Published: July 2010

Werner syndrome is a well-known human progeria. It has been revealed that loss of human WRN is a causal factor of this disease. Since pathological features of Werner syndrome resemble those of menopausal women and become apparent during puberty, we examined the effect of estrogen on WRN gene expression. Here, we reveal that WRN is induced by estrogen but not testosterone. Treatment with estrogen can induce WRN expression at the transcription and translation level in a human breast cell line. Forced expression of the estrogen receptor can restore the responsiveness of WRN to estrogen in a non-responsive cell line. Treatment with estrogen can block DNA damage-induced senescence. Moreover, WRN is suppressed by ATR that is activated by DNA damage, whereas WRN can be induced by ATR elimination. Our results suggest that WRN is essential for prevention of senescence. In addition, our results imply that the reduction of WRN in menopause could be an important factor for menopausal syndrome.
Influence of Socioeconomic Status and Body Mass Index on Bone Age
Authors: Chaumoitre K. , Lamtali S. , Baali A. , Saliba-Serre B. , Lahmam A. , Aboussad A. , Boëtsch G. , Panuel M.
Published: July 2010

Background/Aims: To evaluate the relationship of socioeconomic status (SES) and body mass index (BMI) with skeletal maturation in children from Marrakech (Morocco). Methods: SES, BMI z-score and bone age (BA) were measured in a cohort of 623 children (280 boys and 343 girls, chronological age (CA) ranged from 6.6 to 18.8 years, mean 14.1 years). BA estimation was performed with the Greulich and Pyle atlas. Two social groups (privileged and unfavorable SES) were defined. A multiple linear regression analysis was performed to assess the relationship between BA-CA and age-and sex-specific BMI z-score. Results: Global maturation delay was seen in the sample (BA-CA –0.56; SD 1.29). There was a significant relationship between skeletal maturation (BA-CA) and child BMI z-score among both genders. Bone age was more advanced in children with a greater BMI z-score. Privileged SES was positively associated with children’s BA-CA for girls but there was no association for boys. In the boys’ sample, there was no evidence that BA-CA variations with BMI z-score depended on socioeconomic status (p = 0.664). Whatever the gender of the child, a greater BMI z-score increases the maturation. Conclusion: The multiple linear regression analysis is an interesting approach to understand the links between skeletal maturation, BMI and SES. In Moroccan children, excess weight is associated with privileged SES.
Difficulties in Diagnosis and Treatment of 5α-Reductase Type 2 Deficiency in a Newborn with 46,XY DSD
Authors: Walter Kerstin N. , Kienzle Frederike B. , Frankenschmidt Alexander , Hiort Olaf , Wudy Stefan A. , van der Werf-Grohmann Natascha , Superti-Furga Andrea , Schwab Karl Otfried
Published: July 2010

Background/Aims: Steroid 5α-reductase deficiency (MIM*607306) caused by mutations in the SRD5A2 gene is characterized by a predominantly female phenotype at birth and significant virilization at puberty. The undermasculinization at birth results from low dihydrotestosterone (DHT) levels during fetal development as the type 2 isoenzyme activity is reduced. In puberty, when the type 1 isoenzyme activity increases, significant virilization occurs. Most 46,XY individuals with 5α-reductase 2 deficiency develop a male gender identity. Case Report and Results: We present a case with a predominantly female phenotype and ambiguous external genitalia but a normal 46,XY karyotype. Plasma steroid analysis after β-hCG stimulation at 8 days of age revealed a steroid profile estimated as normal with a testosterone (T)/DHT ratio of 9.5 initially misleading to the exclusion of 5α-reductase deficiency. However, mutation analysis of the SRD5A2 gene revealed a homozygote point mutation (Leu55Gln) confirming the diagnosis of 5α-reductase deficiency. A male phenotype was successfully achieved by hormone treatment with T and DHT after diagnosing 5α-reductase deficiency and a masculinization operation. As a side effect skeletal age accelerated temporarily. Conclusion: In individuals with predominantly female phenotype and suspected 5α-reductase deficiency, a T/DHT ratio during the neonatal period >8.5 might point to 5α-reductase deficiency. After confirmation of the diagnosis by molecular analysis of the SRD5A2 gene, a satisfactory change to a male phenotype can be achieved by hormone treatment preceding surgery.
Impaired Growth Hormone Receptor Signaling during Non-Catch-Up Growth in Rats Born Small for Gestational Age
Authors: Huang Yuefang , Du Minlian , Zhuang Siqi , Shen Zhenyu , Li Yijuan
Published: July 2010

Background/Aims: Non-catch-up growth (NCG) in children born small for gestational age (SGA) is associated with growth hormone (GH) resistance, although the mechanisms of this association are unknown. Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling is involved in GH signal transduction. This study examined the role of JAK/STAT signaling in GH resistance of SGA rats. Methods: NCG-SGA was induced by uterine artery ligation in pregnant rats. NCG-SGA rats were treated with GH for 7 days and rats appropriate for gestational age (AGA) served as controls. Phosphorylation of JAK2/STAT5 and expression of GH receptor, suppressor of cytokine signaling 2 (SOCS-2) and cytokine-inducible SH2-containing protein (CIS) in the liver were determined by Western blotting. The expression of insulin-like growth factor 1 (IGF-1) mRNA was examined by the reverse transcription-polymerase chain reaction. Results: GH treatment significantly increased body weight and length growth rate in AGA but not in NCG-SGA rats. The increase in serum IGF-1 level and expression of IGF-1 mRNA in response to GH treatment in NCG-SGA rats was significantly less than in AGA rats. GH-induced increase in phosphorylation of JAK2/STAT5 in response to acute GH stimulation was significantly lower in NCG-SGA rats compared to AGA controls. SOCS-2 and CIS expressions significantly increased in NCG-SGA rats following GH treatment. Conclusion: GH resistance in NCG-SGA rats is associated with impaired JAK/STAT signaling and upregulated SOCS-2 and CIS expression.
Preeclampsia and Adiponectin in Cord Blood
Authors: Ogland Bjorn , Romundstad Pål R. , Vefring Hege , Forman Michele R. , Nilsen Stein Tore , Vatten Lars J.
Published: July 2010

Aims: To compare cord blood concentrations of total adiponectin in the offspring of pregnancies with and without preeclampsia. Methods: Using a Luminex analyzer, cord blood adiponectin was measured in 182 singleton pregnancies with preeclampsia and compared to adiponectin measured in 511 singleton pregnancies without preeclampsia. Results: Adiponectin levels in cord blood increased with increasing gestational age, but overall, crude levels were similar in pregnancies with and without preeclampsia. However, in pregnancies with early delivery (weeks 32–36), and in pregnancies with delivery after spontaneous contractions, adiponectin levels were higher in the preeclampsia group. Conclusion: In preterm pregnancies and in pregnancies with spontaneous contractions, adiponectin levels in cord blood were higher in the preeclampsia group than in pregnancies without preeclampsia, maybe reflecting the need to optimize energy in preeclampsia.
Prolonged Physical Training Decreases mRNA Levels of Glucocorticoid Receptor and Inflammatory Genes
Authors: Sousa e Silva Tatiane , Longui Carlos Alberto , Rocha Mylene Neves , Faria Claudia Dutra Costantin , Melo Murilo Rezende , Faria Thelma Gomes , de Souza Julio Antonio , Rizzo Luiz Vicente
Published: July 2010

Background/Aims: Prolonged physical exercise induces adaptive alterations in the hypothalamic-pituitary axis, increasing cortisol metabolism, and reducing cortisol synthesis and glucocorticoid sensitivity. The mechanisms responsible for this relative glucocorticoid resistance remain unknown but may involve expression of genes encoding glucocorticoid receptor (GR) and/or inflammatory molecules of nuclear factor kappa B1 (NFkB1) signaling pathway and cytokines. This study aimed to determine the impact of prolonged physical training on the expression of genes involved in glucocorticoid action and inflammatory response. Methods: Normal sedentary male cadets of the Brazilian Air Force Academy were submitted to 6 weeks of standardized physical training. Eighteen of 29 initially selected cadets were able to fully complete the training program. Fasting glucose, insulin and cortisol levels, cytokine concentration and the expression of genes encoding GR, NFkB1, inhibitor of NFkB1 and IkB kinase A were determined before and after the training period. Results: Prolonged physical exercise reduced the basal cortisol levels and the percent cortisol reduction after dexamethasone. These findings were associated with a significant reduction in the mRNA levels of GR (6.3%), NFkB1 (63%), inhibitor of NFkB1 (25%) and IkB kinase A (46%) with concomitant reduction in cytokine concentrations (ELISA). Conclusions: Prolonged physical training decreases the glucocorticoid sensitivity and the mRNA levels of the GR gene combined with decreased mRNA of genes related to the NFkB pathway.
Growth Hormone Treatment Does Not Affect Incidences of Middle Ear Disease or Hearing Loss in Infants and Toddlers with Turner Syndrome
Authors: Davenport Marsha L. , Roush Jackson , Liu Chunhua , Zagar Anthony J. , Eugster Erica , Travers Sharon , Fechner Patricia Y. , Quigley Charmian A.
Published: July 2010

Context: No randomized, controlled, prospective study has evaluated the effect of growth hormone (GH) on the rates of middle ear (ME) disease and hearing loss in girls with Turner syndrome (TS). Design: A 2-year, prospective, randomized, controlled, open-label, multicenter, clinical trial (‘Toddler Turner Study’; August 1999 to August 2003) was carried out. Setting: The study was conducted at 11 US pediatric endocrine centers. Subjects: Eighty-eight girls with TS, aged 9 months to 4 years, were enrolled. Intervention: The interventions comprised recombinant GH (50 µg/kg/day, n = 45) or no treatment (n = 43) for 2 years. Main Outcome Measures: The outcome measures included occurrence rates of ear-related problems, otitis media (OM) and associated antibiotic treatments, tympanometric assessment of ME function and hearing assessment by audiology. Results: At baseline, 57% of the girls (mean age = 1.98 ± 1.00 years) had a history of recurrent OM, 33% had undergone tympanostomy tube (t-tube) insertion and 27% had abnormal hearing. There was no significant difference between the treatment groups for annual incidence of OM episodes (untreated control: 1.9 ± 1.4; GH-treated: 1.5 ± 1.6, p = 0.17). A quarter of the subjects underwent ear surgeries (mainly t-tube insertions) during the study. Recurrent or persistent abnormality of ME function on tympanometry was present in 28–45% of the girls without t-tubes at the 6 postbaseline visits. Hearing deficits were found in 19–32% of the girls at the annual postbaseline visits. Most of these were conductive deficits, however, 2 girls had findings consistent with sensorineural hearing loss, which was evident before 3 years of age. Conclusions: Ear and hearing problems are common in infants and toddlers with TS and are not significantly influenced by GH treatment. Girls with TS need early, regular and thorough ME monitoring by their primary care provider and/or otolaryngologist, and at least annual hearing evaluations by a pediatric audiologist.
Preproenkephalin Expression in Peripheral Blood Mononuclear Cells of Acutely Underweight and Recovered Patients with Anorexia Nervosa
Authors: Weiss Deike , Infante-Duarte Carmen , Salbach-Andrae Harriet , Burghardt Roland , Hamann Isabell , Pfeiffer Ernst , Lehmkuhl Ulrike , Ehrlich Stefan
Published: July 2010

Background: The prohormone preproenkephalin (ppE) and its derived peptides are involved in leukocyte functioning as well as in the regulation of hunger and satiety. Various abnormalities of the immune and endocrine systems have been described in states of malnutrition such as anorexia nervosa (AN). We hypothesized that ppE expression in AN patients may vary depending on the state of the disorder and the extent of malnutrition. Methods: Expression of ppE mRNA was analysed in peripheral blood mononuclear cells of 29 underweight and 29 weight-recovered patients with AN and compared to that in 29 healthy control women. The extent of malnutrition was characterized by BMI and plasma leptin. Psychological distress and eating disorder specific-psychopathology was determined with the Symptom Checklist-90-Revised and the Eating Disorders Inventory-2. Results: ppE gene expression was similar in all 3 groups and was not related to nutritional status or eating disorder symptoms. However, a significant negative correlation was found between ppE expression and obsessive-compulsive, depressive and anxious symptoms. In addition, ppE expression was higher in smokers compared to non-smokers. Conclusion:Although malnutrition and hypoleptinaemia as seen in patients with AN were not related to peripheral ppE expression, we demonstrated reduced ppE expression in patients with elevated psychological distress. Similar associations have been shown in animal models of stress. It remains speculative if psychological symptoms and/or stress may augment immune abnormalities in AN patients via a pathway that is independent of nutritional status and involves ppE.
Relative Hyperhomocysteinemia in Patients with Panic Disorder: A Case-Control Study
Authors: Meier Christian , Harbrecht Ursula , Liedtke Reinhard , Oldenburg Johannes , Conrad Rupert , Imbierowicz Katrin , Klingmüller Dietrich , Geiser Franziska
Published: July 2010

Background: The aim of this work was to examine a possible association between a clinically relevant panic disorder and plasma total homocysteine concentration. Methods: 23 patients with panic disorder with or without agoraphobia confirmed by a standardized clinical interview (Structural Clinical Interview for DSM-IV-German version) and 23 healthy controls matched for gender and age completed questionnaires (SCL-K9, STAI, ADS, STAXI) and had blood drawn after a 15 min rest. Plasma total homocysteine concentrations were measured by competitive enzyme immunoassay. Interfering variables such as age, gender, smoking status, comorbid depression and medication were controlled for. Results: Patients with panic disorder had higher plasma homocysteine concentrations in comparison to the control group (mean value 11.00 vs. 9.14 µmol/l, p = 0.04 with age, gender, smoking status, comorbid depression and antidepressant medication being controlled for). Furthermore, homocysteine plasma concentration was positively correlated with Global Severity of Symptoms (SCL-K9, rPearson = 0.41, p < 0.01). Conclusion: The findings of this study suggest a link between elevated plasma homocysteine levels and panic disorder. This raises a new hypothesis of another pathway to an increased risk of cardiovascular events in anxious individuals.
Estrogen Receptors and Endothelium
Authors: Arnal Jean-François , Fontaine Coralie , Billon-Galés Audrey , Favre Julie , Laurell Henrik , Lenfant Françoise , Gourdy Pierre
Published: July 2010

Estrogens, and in particular 17β-estradiol (E2), play a pivotal role in sexual development and reproduction and are also implicated in a large number of physiological processes, including the cardiovascular system. Both acetylcholine-induced and flow-dependent vasodilation are preserved or potentiated by estrogen treatment in both animal models and humans. Indeed, E2 increases the endothelial production of nitric oxide and prostacyclin and prevents early atheroma through endothelial-mediated mechanisms. Furthermore, whereas it prevents endothelial activation, E2 potentiates the ability of several subpopulations of the circulating or resident immune cells to produce proinflammatory cytokines. The balance between these 2 actions could determine the final effect in a given pathophysiological process. E2 also promotes endothelial healing, as well as angiogenesis. Estrogen actions are essentially mediated by 2 molecular targets: estrogen receptor-α (ERα) and ERβ. The analysis of mouse models targeted for ERα or ERβ demonstrated a prominent role of ERα in vascular biology. ERα directly modulates transcription of target genes through 2 activation functions (AFs), AF-1 and AF-2. Interestingly, an AF-1-deficient ERα isoform can be physiologically expressed in the endothelium and appears sufficient to mediate most of the vasculoprotective actions of E2. In contrast, AF-1 is necessary for the E2 actions in reproductive targets. Thus, it appears conceivable to uncouple the vasculoprotective and sexual actions with appropriate selective ER modulators.