bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic analysis of group composition and relatedness in white‐headed langurs
Authors: LIU Zhijin , HUANG Chengming , ZHOU Qihai , Li Youbang , WANG Yuefeng , LI Ming , TAKENAKA Osamu , TAKENAKA Akiko
Published: May 2013

We collected fecal samples of white‐headed langurs from 3 of the 4 remaining habitat fragments (Fa, Fb and CZ) located in southwestern Guangxi, China in Nov 2005, and used 5 microsatellite loci and the SRY gene to assess the relatedness between 46 langurs within and between groups. We observed 2 forms of group structure: one‐male/multi‐female groups (OMGs) and all‐male groups (AMGs). One AMG in Fa was composed of 2 generations, included a father, 2 sons and 1 unrelated male, and all OMGs in all 3 habitats included 1 resident male, several adult females and offspring. Of the 21 identified father‐offspring cases, the resident male fathered 20 (95%) and the non‐resident male sired 1 (5%), suggesting that adult males had overwhelming priority of access to females as the resident male in an OMG, while the non‐resident male may also have the opportunity to adopt surreptitious mating strategies.
Long‐term results of a randomized, double‐blind, and placebo‐controlled phase III trial: Endostar (rh‐endostatin) versus placebo in combination with vinorelbine and cisplatin in advanced non‐small cell lung cancer
Authors: Sun Yan , Wang Jin Wan , Liu Yong Yu , Yu Qi Tao , Zhang Yi Ping , Li Kai , Xu Li Yan , Luo Su Xia , Qin Feng Zhan , Chen Zheng Tang , Liu Wen Chao , Zhou Qing Hua , Chen Qiang , Nan Ke Jun , Liu Xiao Qing , Liu Wei , Liang Hou Jie , Lu Hui Shan , Wang Xiu Wen , Wang Jie Jun , Song Shu Ping , Tu Yuan Rong , Zhou Jing Min , Li Wei Lian , Yao Chen ,   Endostar Phase III NSCLC Study Group
Published: May 2013

Background: 

Phase II‐III trials in patients with untreated and previously treated locally advanced or non‐small cell lung cancer (NSCLC) suggested that Endostar was able to enhance the effect of platinum‐based chemotherapy (NP regimen) with tolerable adverse effects.

Methods

Four hundred and eighty six patients were randomized into two arms: study arm A: NP plus Endostar (n = 322; vinorelbine, cisplatin, Endostar), and study arm B: NP plus placebo (n = 164; vinorelbine, cisplatin, 0.9% sodium chloride). Patients were treated every third week for two to six cycles.

Results: 

Overall response rates were 35.4% in arm A and 19.5% in arm B (P = 0.0003). The median time to progression was 6.3 months for arm A and 3.6 months for B, respectively (P < 0.001). The clinical benefit rates were 73.3% in arm A and 64.0% in arm B (P = 0.035). Grade 3/4 neutropenia, anemia, and nausea/vomiting were 28.5%, 3.4%, and 8.0%, respectively, in Arm A compared with 28.2%, 3.0%, and 6.6%, respectively, in Arm B (P > 0.05). There were two treatment related deaths in arm A and one in arm B (P > 0.05). The median overall survival was longer in arm A than in arm B (P < 0.0001).

Conclusion: 

Long‐term follow‐up revealed that the addition of Endostar to an NP regimen can result in a significant clinical and survival benefit in advanced NSCLC patients, compared with NP alone.
Simple recessive mutation in ENAM is associated with amelogenesis imperfecta in Italian Greyhounds
Authors: Gandolfi Barbara , Liu Hongwei , Griffioen Layle , Pedersen Niels C.
Published: May 2013

We report a familial enamel hypoplasia in Italian Greyhounds resembling non‐syndromic autosomal recessive amelogenesis imperfecta (AI) of humans. The condition uniformly affects deciduous and permanent teeth and is manifested by enamel roughening/thinning and brownish mottling. Affected teeth are often small and pointed with increased gaps. However, basic tooth structure is usually maintained throughout life, and fractures and dental cavities are not a serious problem as in humans. No tissues or organs other than teeth were affected by this mutation, and there was no relationship between enamel hypoplasia and either autoimmunity or periodontal disease, which also are prevalent in the breed. The enamel hypoplasia was associated with a 5‐bp deletion in exon 10 of the enamelin (ENAM) gene. The prevalence of the enamel defect in Italian Greyhounds was 14%, and 30% of dogs with normal teeth were carriers. Genome analyses suggest that the trait is under inadvertent positive selection. Based on the deletion detected in the ENAM gene, a genetic test was developed for identifying mutation carriers, which would enable breeders to manage the trait.
Gene‐Specific Effect of Beta‐Adrenergic Blockade on Corrected QT Interval in the Long QT Syndrome
Authors: Extramiana Fabrice , Maison‐Blanche Pierre , Denjoy Isabelle , De Jode Patrick , Messali Anne , Labbé Jean‐Philippe , Leenhardt Antoine
Published: May 2013

Background

In the long QT syndrome (LQTS) the effects of beta‐blocker treatment on prevention of cardiac events differs according to the genotype. We aimed to assess the effect of beta‐blocker treatment on QT/QTc duration in Type 1 LQTS (LQT1) and Type 2 LQTS (LQT2) patients.

Methods

24‐hour digital Holter ECG were recorded before and after beta‐blocking therapy initiation in LQT1 (n = 30) and LQT2 patients (n = 16). QT duration was measured on consecutive 1‐minute averaged QRS‐T complexes leading to up to 1440 edited QT‐RR pairs for each recording. We computed subject‐ and treatment‐specific log/log QT/RR relationships which were used to correct the QT intervals. The QT duration was also evaluated at predefined heart rates and after correction using Bazett and Fridericia coefficients.

Results

At baseline, individual QT/RR coefficients were higher in LQT2 than in LQT1 patients (0.53 ± 0.10 vs. 0.40 ± 0.11, P < 0.001) and QT1000 was longer in LQT2 than in LQT1 patients (521 ± 38 vs. 481 ± 39 ms, P < 0.01). Beta‐blockers significantly prolonged the mean RR interval (from 827 ± 161 to 939 ± 197 ms, P < 0.0001). The individual QT/RR coefficients were not significantly modified by beta‐blockers. Beta‐blocker treatment was associated with a prolongation of the QT1000 interval (from 481 ± 39 to 498 ± 43 ms, P < 0.01) in LQT1 patients but with a shortening in LQT2 patients (from 521 ± 38 to 503 ± 32 ms, P < 0.01).

Conclusions

The effect of beta‐adrenergic blockade on QTc duration is different in LQT1 and LQT2 patients. Our data suggest that, in LQT1 patients, the well‐known positive effect of beta‐blockade might be associated with a prolongation of QTc duration. The mechanisms of beta‐blockade protection may be different in LQT1 and in LQT2 patients.
Oral Contraceptive Use and the ECG: Evidence of an Adverse QT Effect on Corrected QT Interval
Authors: Sedlak Tara , Shufelt Chrisandra , Iribarren Carlos , Lyon Liisa L. , Bairey Merz C. Noel
Published: May 2013

Background

A prolonged corrected QT (QTc) interval is a marker for an increased risk of sudden cardiac death. We evaluated the relationship between oral contraceptive (OC) use, type of OC, and QTc interval.

Methods

We identified 410,782 ECGs performed at Northern California Kaiser Permanente on female patients between 15 and 53 years from January, 1995 to June, 2008. QT was corrected for heart rate using log‐linear regression. OC generation (first, second and third) was classified by increasing progestin androgenic potency, while the fourth generation was classified as antiandrogenic.

Results

Among 410,782 women, 8.4% were on OC. In multivariate analysis after correction for comorbidities, there was an independent shortening effect of OCs overall (slope = −0.5 ms; SE = 0.12, P < 0.0002). Users of first and second generation progestins had a significantly shorter QTc than nonusers (P < 0.0001), while users of fourth generation had a significantly longer QTc than nonusers (slope = 3.6 ms, SE = 0.35, P < 0.0001).

Conclusion

Overall, OC use has a shortening effect on the QTc. Shorter QTc is seen with first and second generation OC while fourth generation OC use has a lengthening effect on the QTc. Careful examination of adverse event rates in fourth generation OC users is needed.
T‐Wave Alternans and ST Depression Assessment Identifies Low Risk Individuals with Ischemic Cardiomyopathy in the Absence of Left Ventricular Hypertrophy
Authors: Friedman Daniel J. , Bender Seth R. , Markowitz Steven M. , Lerman Bruce B. , Okin Peter M.
Published: May 2013

Background

Although ECG left ventricular hypertrophy (LVH) by Cornell product (CP) predicts increased mortality in patients with ischemic cardiomyopathy (ICM), those without CP LVH remain at relatively high risk. We examined whether T‐wave alternans (TWA) testing and ST depression can improve risk stratification in these patients.

Methods and Results

This study examined 317 patients with ICM, nonsustained ventricular tachycardia, and a resting ECG in sinus rhythm, who presented for electrophysiology and TWA testing, and potential implantable cardioverter defibrillator (ICD) implantation. LVH was defined by CP :[(RaVL + SV3) +6 mm in women] × QRS duration > 2440 mm * msec. ST depression was examined as a categorical variable using an established threshold of depression of ≥50 μV in V5 or V6. In Cox multivariate models, abnormal TWA testing and ST depression were independent predictors of mortality in patients without CP LVH (HR 2.52, CI 1.09–5.80, P = 0.030 and HR 2.87, CI 1.41–5.81, P = 0.004, respectively). Individuals with no LVH by CP, normal TWA, and no significant ST depression, comprised 23% of the study population and had a 5.6% 3‐year mortality, compared to an overall 20% mortality.

Conclusions

TWA and ST depression testing are strong predictors of mortality among ICM patients without CP LVH, with normal testing conversely predicting low 3‐year mortality. Thus, risk assessment with TWA testing and a resting ECG can identify ICM patients at low risk who may be less likely to benefit from ICD implantation.
Positive Brugada Challenge Test in V1R–V3R as a Predictor of Malignant Prognosis in Brugada Patients
Authors: Hashemi Arash , Shahrzad Shahab , Shahrzad Sorayya , Saber Siamak , Taban Samira , Aslani Amir , Emkanjoo Zahra
Published: May 2013

Background

The Brugada syndrome is a heterogeneous genetic disease that predisposes to life‐threatening ventricular tachyarrhythmias and sudden cardiac death (SCD). The only proven way to prolong the survival of patients with Brugada syndrome is to implant an implantable cardioverter‐defibrillator (ICD). This should be implanted for high‐risk patients only.

Method

The patients with type 2 or 3 Brugada ECG pattern were selected for the study. We evaluated 126 patients with Brugada type ECG patterns. Nineteen patients had positive response. Those who had positive result in right side located leads had poorer prognosis.

Conclusion

Positive flecainide challenge test in right side located pericordial leads can be used as a predictor of poor prognosis in Brugada patients. This can be evaluated in another research for its role in the implantation of ICD. Also, the oral flecainide is not sensitive enough to rule out the presence of Brugada syndrome and it should not be trusted as a screening test for suspected cases.
Successful Use of Wearable Cardioverter Defibrillator in a Patient with Dextrocardia and Persistent Left Superior Vena Cava
Authors: Wan Chingping , Oren Jess W. , Szymkiewicz Steven J.
Published: May 2013

Congenital disorders, such as dextrocardia and persistent left superior vena cava, are rare. However, their presence is often associated with other cardiac anomalies, and may lead to lethal ventricular tachyarrhythmias, which result in sudden cardiac death. Treating patients with these disorders can present a challenge to clinicians, as it may cause technical difficulties during interventional procedures, and more often, altered defibrillation techniques in a setting of prehospital sudden cardiac arrest. This report describes the first case of successful defibrillation therapy delivered by the wearable cardioverter defibrillator to a patient with dextrocardia and persistent left superior vena cava during a ventricular tachycardia arrest.
Effects of Angiotensin II Type 1 Receptor Antagonist and Temperature on Prolonged Cardioplegic Arrest in Neonatal Rat Myocytes
Authors: Lucchese Gianluca , Cambi Giulia Elisa , De Rita Fabrizio , Franzoi Mauro , Faggian Giuseppe , Mazzucco Alessandro , Modesti Pietro Amedeo , Luciani Giovanni Battista
Published: May 2013

Cardioplegic arrest is a model of ischemia/reperfusion injury and results in the death of irreplaceable cardiac myocytes by a programmed cell death or apoptosis. Signal transducers and activators of transcription (STAT) signaling pathways play an important role in the modulation of apoptosis after ischemia and reperfusion. Angiotensin II type 1 (AT1) receptor antagonist added to cardioplegia could represent an additional modality for enhancing myocardial protection during cardioplegic arrest. To test that hypothesis, we studied the effect of AT1 receptor antagonism and cardioplegia temperature perfusion on STATs modulation during cardioplegic arrest in neonatal rat hearts. Isolated, nonworking hearts (n = 4 per group) from neonatal rats were perfused aerobically in the Langendorff mode according to the following scheme: Dulbecco's Modified Eagle's Medium solution (Group 1); cold (4°C) modified St. Thomas' Hospital no. 2 (MSTH2) cardioplegic solution (Group 2); cold (4°C) MSTH2 cardioplegic solution plus AT1 antagonist (Valsartan) (Group 3); and warm (34°C) MSTH2 cardioplegic solution (Group 4). Thus, myocytes were isolated by enzymatic digestion, and STAT1, STAT2, STAT3, and STAT5 were investigated in Western blot studies. Times to arrest after cardioplegia were 6–10 s for all groups with the exception of Group 1 (spontaneous arrest after 12–16 s). Total cardioplegia delivery volume was about 300 mL in 15 min. Perfusion with cold MSTH2 supplemented with AT1 receptor antagonist (Group 3) induced a significant reduction in STAT1, STAT2, and STAT5 tyrosine phosphorylation versus other groups (P < 0.05). The decreased activation of STAT1, STAT2, and STAT5 observed in Group 3 was accompanied by reduction of interleukin‐1β (P < 0.05). On the other hand, STAT3 activation was significantly reduced in Groups 1 and 4 (P < 0.05). Only perfusion with AT1 receptor antagonist supplemented with cold MSTH2 significantly decreases the inflammatory response of the neonatal rat cardiomyocytes without affecting antiapoptotic influence provided by activation of STAT3. Therefore, AT1 receptor antagonist could play a pivotal role in cytoprotective effect and cardiac recovery in neonates and infants.
A new method for determining gastric acid output using a wireless pH‐sensing capsule
Authors: Weinstein D. H. , deRijke S. , Chow C. C. , Foruraghi L. , Zhao X. , Wright E. C. , Whatley M. , Maass‐Moreno R. , Chen C. C. , Wank S. A.
Published: May 2013

Background

Gastro‐oesophageal reflux disease (GERD) and gastric acid hypersecretion respond well to suppression of gastric acid secretion. However, clinical management and research in diseases of acid secretion have been hindered by the lack of a non‐invasive, accurate and reproducible tool to measure gastric acid output (GAO). Thus, symptoms or, in refractory cases, invasive testing may guide acid suppression therapy.

Aim

To present and validate a novel, non‐invasive method of GAO analysis in healthy subjects using a wireless pH sensor, SmartPill (SP) (SmartPill Corporation, Buffalo, NY, USA).

Methods

Twenty healthy subjects underwent conventional GAO studies with a nasogastric tube. Variables impacting liquid meal‐stimulated GAO analysis were assessed by modelling and in vitro verification. Buffering capacity of Ensure Plus was empirically determined. SP GAO was calculated using the rate of acidification of the Ensure Plus meal. Gastric emptying scintigraphy and GAO studies with radiolabelled Ensure Plus and SP assessed emptying time, acidification rate and mixing. Twelve subjects had a second SP GAO study to assess reproducibility.

Results

Meal‐stimulated SP GAO analysis was dependent on acid secretion rate and meal‐buffering capacity, but not on gastric emptying time. On repeated studies, SP GAO strongly correlated with conventional basal acid output (BAO) (r = 0.51, P = 0.02), maximal acid output (MAO) (r = 0.72, P = 0.0004) and peak acid output (PAO) (r = 0.60, P = 0.006). The SP sampled the stomach well during meal acidification.

Conclusions

SP GAO analysis is a non‐invasive, accurate and reproducible method for the quantitative measurement of GAO in healthy subjects. SP GAO analysis could facilitate research and clinical management of GERD and other disorders of gastric acid secretion.
Naloxone increases maturation rate and ratio of inner cell mass to total cells in blastocysts in pigs
Authors: Dang‐Nguyen Thanh Quang , Viet Linh Nguyen , Minoia Rosa , Kaneda Masahiro , Somfai Tamas , Haraguchi Seiki , Akagi Satoshi , Kikuchi Kazuhiro , Nakai Michiko , Tajima Atsushi , Nagai Takashi
Published: May 2013

The purposes of the present study were to examine the effect of naloxone, a mu‐opioid receptor (MOR) antagonist, on porcine oocyte maturation and embryo development. MOR gene was expressed in germinal vesicle (GV) and metaphase II (M‐II) porcine oocytes, one‐, four‐cell stage embryos and blastocysts. In blastocysts, MOR gene was mainly expressed in inner cell mass (ICM) cells. Supplementation of 10−8 mol/L naloxone in in vitro maturation (IVM) medium increased the maturation rate (P < 0.05). However, 10−4 mol/L naloxone reduced the maturation rate (P < 0.05) compared with the control. The presence of naloxone during IVM had no effects on fertilization status and subsequent embryonic development after in vitro culture (IVC). The addition of 10−3 mol/L dibutyryl cyclic adenosine monophosphate (dbcAMP), and 10−8 mol/L naloxone together into IVM medium increased nuclear maturation (P < 0.05) compared with the addition of either dbcAMP or naloxone alone. Supplementation with naloxone in IVC medium did not improve embryonic development. However, at the concentrations of 10−6 mol/L and 10−8 mol/L, naloxone increased the ratio of ICM to total cells in blastocysts (P < 0.05). In conclusion, at low concentration, naloxone increases maturation rate and the ratio of ICM to total cells in blastocysts. Naloxone and cAMP have a synergistic effect on oocyte maturation.
Effect of bromochloromethane and fumarate on phylogenetic diversity of the formyltetrahydrofolate synthetase gene in bovine rumen
Authors: Mitsumori Makoto , Matsui Hiroki , Tajima Kiyoshi , Shinkai Takumi , Takenaka Akio , Denman Stuart E. , McSweeney Christopher S.
Published: May 2013

Effect of the methane inhibitor, bromochloromethane (BCM) and dietary substrate, fumarate, on microbial community structure of acetogen bacteria in the bovine rumen was investigated through analysis of the formyltetrahydrofolate synthetase gene (fhs). The fhs sequences obtained from BCM‐untreated, BCM‐treated, fumarate‐untreated and fumarate‐treated bovine rumen were categorized into homoacetogens and nonhomoacetogenic bacteria by homoacetogen similarity scores. Phylogenetic tree analysis indicated that most of the fhs sequences categorized into homoacetogens were divided into nine clusters, which were in close agreement with a result shown in a self‐organizing map. The diversity of the fhs sequences from the BCM‐treated rumen was significantly different from those from BCM‐non‐treated rumen. Principal component analysis also showed that addition of BCM to the rumen altered the population structure of acetogenic bacteria significantly but the effect of fumarate was comparatively minor. These results indicate that BCM affects diversity of actogens in the bovine rumen, and changes in acetogenic community structure in response to methane inhibitors may be caused by different mechanisms.
Distribution of radioactive cesium in edible parts of cattle
Authors: Okada Keiji , Sato Itaru , Deguchi Yoshitaka , Morita Shigeru , Yasue Takeshi , Yayota Masato , Takeda Ken‐ichi , Sato Shusuke
Published: May 2013

After the disastrous incident of the Fukushima Daiichi Nuclear Power Station, various agricultural, livestock and fishery products have been inspected for radioactive contamination with cesium in Japan. In this study, radioactive cesium was measured in various edible parts of cattle to verify the current inspection method for cattle, in which the neck tissues are generally used as samples. Radioactive cesium concentration in the short plate, diaphragm, liver, lung, omasum, abomasum and small intestine were lower and sirloin, tenderloin, top round meat and tongue were higher than that in the neck. There was no significant difference between the other organs (heart, kidney, lumen and reticulum) and the neck. Ninety‐five percent upper tolerance limits of the relative concentration to the neck were 1.88 for sirloin, 1.74 for tenderloin, 1.87 for top round and 1.45 for tongue. These results suggest that a safety factor of 2 is recommended for the radioactivity inspection of cattle to prevent a marketing of meat with higher cesium than the legal limit. Re‐inspection should be conducted using another part of muscle, for example, top round, when suspicious levels of 50–100 Bq/kg are detected in the neck.
Controlling the Type I error rate by using the nonparametric bootstrap when comparing means
Authors: Parra‐Frutos Isabel
Published: May 2013

Of the several tests for comparing population means, the best known are the ANOVA, Welch, Brown–Forsythe, and James tests. Each performs appropriately only in certain conditions, and none performs well in every setting. Researchers, therefore, have to select the appropriate procedure and run the risk of making a bad selection and, consequently, of erroneous conclusions. It would be desirable to have a test that performs well in any situation and so obviate preliminary analysis of data. We assess and compare several tests for equality of means in a simulation study, including non‐parametric bootstrap techniques, finding that the bootstrap ANOVA and bootstrap Brown–Forsythe tests exhibit a similar and exceptionally good behaviour.
Chronology, stratigraphy and palaeoenvironmental interpretation of a Late Pleistocene to mid‐Holocene cave accumulation on Kangaroo Island, South Australia
Authors: McDowell Matthew C. , Bestland Erick A. , Bertuch Fiona , Ayliffe Linda K. , Hellstrom John C. , Jacobsen Geraldine E. , Prideaux Gavin J.
Published: May 2013

Chronological, sedimentological and geochemical analyses of a clastic infill from Kelly Hill Cave (5K1), Kangaroo Island, document a palaeoenvironmental record that spans from the Late Pleistocene to the middle Holocene. We AMS radiocarbon‐dated bone collagen and U–Th‐dated speleothem to determine that fossiliferous sediments were deposited between >20 ka and 7 ka ago. Most of the 15 sedimentary layers are dominated by sand‐ and silt‐sized quartz that is physically and geochemically comparable with surface soils in the Kelly Hill area. Late Pleistocene and Last Glacial Maximum strata are represented primarily by homogeneous, poorly sorted quartz‐rich sediments that contain little organic matter, but include a thin layer composed largely of silt‐sized clay pellets that resemble sediments deflated from playa lakes. Microstructures observed in petrographic slides indicate that, with the exception of one layer, all sediments experienced little reworking once deposited in the cave. Some layers display pedogenic microstructures such as redeposited clays and opaline silica infilling that indicate postdepositional modification; that is, cave‐floor soil development. Overlying Holocene‐aged sediments also consist mainly of quartz but have much greater organic matter content. Some of these sediments have been strongly influenced by re‐precipitated organic matter that appears to have been transported into the cave via vadose drip water. The presence of dissolved organic matter in soil/vadose waters suggests a high vegetation density and acidic soils, which are congruent with the more equitable climatic conditions characteristic of the Holocene. The sediments described here provide a valuable palaeoenvironmental record that will facilitate future interpretation of associated vertebrate fossils.
Late Quaternary glaciation in the Nun‐Kun massif, northwestern India
Authors: Lee Su Young , Seong Yeong Bae , Owen Lewis A. , Murari Madhav K. , Lim Hyoun Soo , Yoon Ho Il , Yoo Kyu‐Cheul
Published: May 2013

The late Quaternary glacial history of the Nun‐Kun massif, located on the boundary between the Greater Himalaya and the Zanskar range in northwestern India, was reconstructed. On the basis of morphostratigraphy and 10Be dating of glacial landforms (moraines and glacial trimlines), five glacial stages were recognized and defined, namely: (i) the Achambur glacial stage dated to Marine Oxygen Isotope Stage 3 to 4 (38.7–62.7 ka); (ii) the Tongul glacial stage dated to the early part of the Lateglacial (16.7–17.4 ka); (iii) the Amantick glacial stage dated to the later part of the Lateglacial (14.3 ka, 11.7–12.4 ka); (iv) the Lomp glacial stage dated to the Little Ice Age; and (v) the Tanak glacial stage, which has the youngest moraines, probably dating to the last few decades or so. Present and former equilibrium‐line altitudes (ELAs) were calculated using the standard area accumulation ratio method. The average present‐day ELA of ∼4790 m above sea level in the Greater Himalaya is lower than those in the Ladakh and Zanskar ranges, namely 5380 and ∼5900 m a.s.l., respectively. The ELA in the Zanskar range is higher than in the Ladakh range, possibly due to the higher peaks in the Ladakh range that are able to more effectively capture and store snow and ice. ELA depressions decrease towards the Ladakh range (i.e. inner Plateau). Peat beds interbedded with aeolian deposits that cap the terminal moraine of Tarangoz Glacier suggest millennial‐time‐scale climate change throughout the Holocene, with soil formation times at c. 1.5, c. 3.4 and c. 5.2 ka, probably coinciding with Holocene abrupt climate change events. Given the style and timing of glaciation in the study area, it is likely that climate in the Nun‐Kun region is linked to Northern Hemisphere climate oscillations with teleconnections via the mid‐latitude westerlies.
Vitamin D analogue TX 527 down‐regulates the NF‐κB pathway and controls the proliferation of endothelial cells transformed by Kaposi sarcoma herpesvirus
Authors: González‐Pardo V , Verstuyf A , Boland R , Russo de Boland A
Published: May 2013

Background and Purpose

The Kaposi sarcoma (KS)‐associated herpesvirus GPCR (vGPCR) is a key molecule in the pathogenesis of KS, where it increases NF‐κB gene expression and activates the NF‐κB pathway. We investigated whether the less calcemic vitamin D analogue TX 527 inhibited the proliferation of endothelial cells transformed by vGPCR by modulation of the NF‐κB pathway.

Experimental Approach

Endothelial cells transformed by vGPCR (SVEC‐vGPCR) were treated with TX 527. Proliferation was measured by 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium, inner salt (MTS) and cell cycle by flow cytometry. mRNA and protein levels were measured by real‐time quantitative reverse transcriptase‐PCR (qRT‐PCR) and immunoblot analysis respectively.

Key Results

TX 527, similar to bortezomib (0.5 nM), a proteasome inhibitor that inhibits the activation of NF‐κB, reduced proliferation and induced G0/G1 cell cycle arrest in SVEC‐vGPCR. TX 527 like 1α,25(OH)2D3, biological active form of vitamin D, decreased the activity of NF‐κB comparable with the effect of bortezomib. Time‐response studies showed that TX 527 significantly decreased NF‐κB and increased IκBα mRNA and protein levels. The increase of IκBα was accompanied by a reduction in p65/NF‐κB translocation to the nucleus. These responses were abolished when vitamin D receptor (VDR) expression was suppressed by stable transfection of shRNA against VDR. In parallel with NF‐κB inhibition, there was a down‐regulation of inflammatory genes such as IL‐6, CCL2/MCP and CCL20/MIP3α.

Conclusions and Implications

These results suggest that the anti‐proliferative effects of the vitamin D analogue TX 527 in SVEC‐vGPCR occur by modulation of the NF‐κB pathway and are VDR dependent.
Activation of adenosine A2A receptor reduces osteoclast formation via PKA‐ and ERK1/2‐mediated suppression of NFκB nuclear translocation
Authors: Mediero Aránzazu , Perez‐Aso Miguel , Cronstein Bruce N
Published: May 2013

Background and Purpose

We previously reported that adenosine, acting at adenosine A2A receptors (A2AR), inhibits osteoclast (OC) differentiation in vitro (A2AR activation OC formation reduces by half) and in vivo. For a better understanding how adenosine A2AR stimulation regulates OC differentiation, we dissected the signalling pathways involved in A2AR signalling.

Experimental Approach

OC differentiation was studied as TRAP+ multinucleated cells following M‐CSF/RANKL stimulation of either primary murine bone marrow cells or the murine macrophage line, RAW264.7, in presence/absence of the A2AR agonist CGS21680, the A2AR antagonist ZM241385, PKA activators (8‐Cl‐cAMP 100 nM, 6‐Bnz‐cAMP) and the PKA inhibitor (PKI). cAMP was quantitated by EIA and PKA activity assays were carried out. Signalling events were studied in PKA knockdown (lentiviral shRNA for PKA) RAW264.7 cells (scrambled shRNA as control). OC marker expression was studied by RT‐PCR.

Key Results

A2AR stimulation increased cAMP and PKA activity which and were reversed by addition of ZM241385. The direct PKA stimuli 8‐Cl‐cAMP and 6‐Bnz‐cAMP inhibited OC maturation whereas PKI increased OC differentiation. A2AR stimulation inhibited p50/p105 NFκB nuclear translocation in control but not in PKA KO cells. A2AR stimulation activated ERK1/2 by a PKA‐dependent mechanism, an effect reversed by ZM241385, but not p38 and JNK activation. A2AR stimulation inhibited OC expression of differentiation markers by a PKA‐mechanism.

Conclusions and Implications

A2AR activation inhibits OC differentiation and regulates bone turnover via PKA‐dependent inhibition of NFκB nuclear translocation, suggesting a mechanism by which adenosine could target bone destruction in inflammatory diseases like Rheumatoid Arthritis.
Molecular modelling, synthesis, cytotoxicity and anti‐tumour mechanisms of 2‐aryl‐6‐substituted quinazolinones as dual‐targeted anti‐cancer agents
Authors: Hour M J , Lee K H , Chen T L , Lee K T , Zhao Yu , Lee H Z
Published: May 2013

Background and Purpose

Our previous study demonstrated that 6‐(pyrrolidin‐1‐yl)‐2‐(3‐methoxyphenyl)quinazolin‐4‐one (HMJ38) was a potent anti‐tubulin agent. Here, HMJ38 was used as a lead compound to develop more potent anti‐cancer agents and to examine the anti‐cancer mechanisms.

Experimental Approach

Using computer‐aided drug design, 2‐aryl‐6‐substituted quinazolinones (MJ compounds) were designed and synthesized by introducing substituents at C‐2 and C‐6 positions of HMJ38. The cytotoxicity of MJ compounds towards human cancer cells was examined by Trypan blue exclusion assay. Microtubule distribution was visualized using TubulinTrackerTM Green reagent. Protein expression of cell cycle regulators and JNK was assessed by Western blot analysis.

Key Results

Compounds MJ65–70 exhibited strong anti‐proliferative effects towards melanoma M21, lung squamous carcinoma CH27, lung non‐small carcinoma H460, hepatoma Hep3B and oral cancer HSC‐3 cells, with one compund MJ66 (6‐(pyrrolidin‐1‐yl)‐2‐(naphthalen‐1‐yl)quinazolin‐4‐one) highly active against M21 cells (IC50 about 0.033 μM). Treatment of CH27 or HSC‐3 cells with MJ65–70 resulted in significant mitotic arrest accompanied by increasing multiple asters of microtubules. JNK protein expression was involved in the MJ65–70‐induced CH27 and M21 cell death. Consistent with the cell cycle arrest at G2/M phase, marked increases in cyclin B1 and Bcl‐2 phosphorylation were also observed, after treatment with MJ65–70.

Conclusions and Implication

MJ65–70 are dual‐targeted, tubulin‐ and JNK‐binding, anti‐cancer agents and induce cancer cell death through up‐regulation of JNK and interfering in the dynamics of tubulin. Our work provides a new strategy and mechanism for developing dual‐targeted anti‐cancer drugs, contributing to clinical anti‐cancer drug discovery and application.
Functional and morphological characterization of glutamate transporters in the rat locus coeruleus
Authors: Medrano M C , Gerrikagoitia I , Martínez‐Millán L , Mendiguren A , Pineda J
Published: May 2013

Background and Purpose

Excitatory amino acid transporters (EAATs) in the CNS contribute to the clearance of glutamate released during neurotransmission. The aim of this study was to explore the role of EAATs in the regulation of locus coeruleus (LC) neurons by glutamate.

Experimental Approach

We measured the effect of different EAAT subtype inhibitors/enhancers on glutamate‐ and KCl‐induced activation of LC neurons in rat slices. EAAT2–3 expression in the LC was also characterized by immunohistochemistry.

Key Results

The EAAT2–5 inhibitor DL‐threo‐β‐benzyloxaspartic acid (100 μM), but not the EAAT2, 4, 5 inhibitor L‐trans‐pyrrolidine‐2,4‐dicarboxylic acid (100 μM) or the EAAT2 inhibitor dihydrokainic acid (DHK; 100 μM), enhanced the glutamate‐ and KCl‐induced activation of the firing rate of LC neurons. These effects were blocked by ionotropic, but not metabotrobic, glutamate receptor antagonists. DHK (100 μM) was the only EAAT inhibitor that increased the spontaneous firing rate of LC cells, an effect that was due to inhibition of EAAT2 and subsequent AMPA receptor activation. Chronic treatment with ceftriaxone (200 mg·kg−1 i.p., once daily, 7 days), an EAAT2 expression enhancer, increased the actions of glutamate and DHK, suggesting a functional impact of EAAT2 up‐regulation on the glutamatergic system. Immuhistochemical data revealed the presence of EAAT2 and EAAT3 surrounding noradrenergic neurons and EAAT2 on glial cells in the LC.

Conclusions and Implications

These results remark the importance of EAAT2 and EAAT3 in the regulation of rat LC by glutamate. Neuronal EAAT3 would be responsible for terminating the action of synaptically released glutamate, whereas glial EAAT2 would regulate tonic glutamate concentrations in this nucleus.
Calcium channel blockers and dementia
Authors: Nimmrich V , Eckert A
Published: May 2013

Degenerative dementia is mainly caused by Alzheimer's disease and/or cerebrovascular abnormalities. Disturbance of the intracellular calcium homeostasis is central to the pathophysiology of neurodegeneration. In Alzheimer's disease, enhanced calcium load may be brought about by extracellular accumulation of amyloid‐β. Recent studies suggest that soluble forms facilitate influx through calcium‐conducting ion channels in the plasma membrane, leading to excitotoxic neurodegeneration. Calcium channel blockade attenuates amyloid‐β‐induced neuronal decline in vitro and is neuroprotective in animal models. Vascular dementia, on the other hand, is caused by cerebral hypoperfusion and may benefit from calcium channel blockade due to relaxation of the cerebral vasculature. Several calcium channel blockers have been tested in clinical trials of dementia and the outcome is heterogeneous. Nimodipine as well as nilvadipine prevent cognitive decline in some trials, whereas other calcium channel blockers failed. In trials with a positive outcome, BP reduction did not seem to play a role in preventing dementia, indicating a direct protecting effect on neurons. An optimization of calcium channel blockers for the treatment of dementia may involve an increase of selectivity for presynaptic calcium channels and an improvement of the affinity to the inactivated state. Novel low molecular weight compounds suitable for proof‐of‐concept studies are now available.
Learning From Their Own Actions: The Unique Effect of Producing Actions on Infants' Action Understanding
Authors: Gerson Sarah A. , Woodward Amanda L.
Published: May 2013

Prior research suggests that infants' action production affects their action understanding, but little is known about the aspects of motor experience that render these effects. In Study 1, the relative contributions of self‐produced (n = 30) and observational (n = 30) action experience on 3‐month‐old infants' action understanding was assessed using a visual habituation paradigm. In Study 2, generalization of training to a new context was examined (n = 30). Results revealed a unique effect of active over observational experience. Furthermore, findings suggest that benefits of trained actions do not generalize broadly, at least following brief training.
Auction Design, Incentives, and Buying Back Maryland and Virginia Crab Licenses
Authors: DePiper Geret S. , Higgins Nathaniel , Lipton Douglas W. , Stocking Andrew
Published: May 2013

Fisheries managers use buybacks to reduce fleet capacity, conserve fish stocks, and accomplish other goals. In 2009, Maryland and Virginia conducted auctions to buy back commercial fishing licenses. The auctions in both States had similar timing, objectives, and target populations. The divergent designs of the auctions, however, provide a case study with which to investigate effective buyback practices. We compare and contrast the market designs used by Maryland and Virginia, and describe how those differing designs influenced the respective outcomes.
RIGHT ON TARGET: EXPLORING THE FACTORS LEADING TO INFLATION TARGETING ADOPTION
Authors: SAMARINA ANNA , DE HAAN JAKOB
Published: May 2013

This paper examines which economic, fiscal, external, financial, and institutional characteristics of countries affect the likelihood that they adopt inflation targeting (IT) as their monetary policy strategy. We estimate a panel binary response model for 60 countries and two subsamples consisting of Organization for Economic Cooperation and Development (OECD) and non‐OECD countries over the period 1985–2008. The findings suggest that past macroeconomic performance of a country, its fiscal discipline, exchange rate arrangements, as well as the structure and development of its financial system have a significant impact on the likelihood to adopt IT. However, the factors leading to IT adoption differ significantly between OECD and non‐OECD countries. (JEL E42, E52)
Conservation management and sustainable harvest quotas are sensitive to choice of climate modelling approach for two marine gastropods
Authors: Fordham D. A. , Brook B. W. , Caley M. J. , Bradshaw C. J. A. , Mellin C.
Published: May 2013

Aim

To establish the robustness of two alternative methods for predicting the future ranges and abundances for two wild‐harvested abalone species (Haliotis rubra Donovan 1808 and H. laevigata Leach 1814): single atmosphere–ocean general circulation model (GCM) or ensemble‐averaged GCM forecasts.

Location

South Australia.

Methods

We assessed the ability of 20 GCMs to simulate observed seasonal sea surface temperature (SST) between 1980–1999, globally, and regionally for the Indian and Pacific Oceans south of the Equator. We used model rankings to characterize a set of representative climate futures, using three different‐sized GCM ensembles and two individual GCMs (the Parallel Climate Model and the Community Climate System Model, version 3.0). Ecological niche models were then coupled to physiological information to compare forecast changes in area of occupancy, population size and harvest area based on forecasts using the various GCM selection methods, as well as different greenhouse gas emission scenarios and climate sensitivities.

Results

We show that: (1) the skill with which climate models reproduce recent SST records varies considerably amongst GCMs, with multimodel ensemble averages showing closer agreement to observations than single models; (2) choice of GCM, and the decision on whether or not to use ensemble‐averaged climate forecasts, can strongly influence spatiotemporal predictions of range, abundance and fishing potential; and (3) comparable hindcasting skill does not necessarily guarantee that GCM forecasts and ecological and evolutionary responses to these forecast changes, will be similar amongst closely ranked models.

Conclusion

By averaging across an ensemble of seven highly ranked skilful GCMs, inherent uncertainties stemming from GCM differences are incorporated into forecasts of change in species range, abundance and sustainable fishing area. Our results highlight the need to make informed and explicit decisions on GCM choice, model sensitivity and emission scenarios when exploring conservation options for marine species and the sustainability of future harvests using ecological niche models.
Molecular identification of a phytoplasma associated with Sophora Root yellows
Authors: Chen X. F. , Liang Y. C. , Chen N. , Su W. M. , Xiao H. , Wang X. , Zhu X. P.
Published: May 2013

A phytoplasma infecting Sophora Root (Sophora alopecuroides) was detected and identified in Alar, Xinjiang Uygur Autonomous Region of China. Typical phytoplasma bodies were observed in sieve tubes of the diseased plants by transmission electron microscopy. A partial 16S rRNA gene and ribosomal protein (rp) genes containing rpl22 (rplV) and rps3 (rpsC) were amplified by direct and nested PCR. Based on the sequence similarity of the 16S rRNA and rp genes with accompanying phylogenetic analyses, the phytoplasma associated with Sophora Root yellows belongs to the 16SrI group (aster yellows group). Virtual RFLP analysis of these 16S rRNA and rp gene sequences showed distinct differences from those of reference phytoplasma strains representing previously described subgroups of the 16SrI group. Moreover, the similarity coefficient (0.92) of the RFLP profile of this phytoplasma was less than the threshold similarity coefficient (0.97) required for subgroup classification. Thus, the phytoplasma isolate of Sophora Root plants, designated as ‘SoRY’, represents a new subgroup. Furthermore, this is the first report of phytoplasma disease associated with Sophora Root plants.
The Fragility of Consensus: Public Reason, Diversity and Stability
Authors: Thrasher John , Vallier Kevin
Published: May 2013

John Rawls's transition from A Theory of Justice to Political Liberalism was driven by his rejection of Theory's account of stability. The key to his later account of stability is the idea of public reason. We see Rawls's account of stability as an attempt to solve a mutual assurance problem. We maintain that Rawls's solution fails because his primary assurance mechanism, in the form of public reason, is fragile. His conception of public reason relies on a condition of consensus that we argue is unrealistic in modern, pluralistic democracies. After rejecting Rawls's conception of public reason, we offer an ‘indirect alternative’ that we believe is much more robust. We cite experimental evidence to back up this claim.
Prevention of sudden unexpected death in epilepsy: A realistic goal?
Authors: Ryvlin Philippe , Nashef Lina , Tomson Torbjörn
Published: May 2013

Sudden unexpected death in epilepsy (SUDEP) represents one of the most severe consequences of drug‐resistant epilepsy, for which no evidence‐based prevention is available. Development of effective prevention will depend on the following: (1) better understanding of the pathophysiology of SUDEP to define the most appropriate targets of intervention, and (2) identification of risk factors for SUDEP that would allow for the design of feasible clinical trials to test targeted interventions in high‐risk populations. The most important known risk factor is the occurrence and frequency of generalized tonic–clonic seizure (GTCS), a seizure type that triggers the majority of witnessed SUDEP. Therefore, one likely way to prevent SUDEP is to minimize the risk of GTCS with optimal medical management and patient education. However, whether one might prevent SUDEP in patients with refractory epilepsy by using more frequent review of antiepileptic treatment and earlier referral for presurgical evaluation, remains to be seen. Another hypothetical strategy to prevent SUDEP is to reduce the risk of GTCS‐induced postictal respiratory distress. This might be achieved by using lattice pillow, providing nocturnal supervision, reinforcing interictal serotoninergic tone, and lowering opiate‐ or adenosine‐induced postictal brainstem depression. Promising interventions can be tested first on surrogate markers, such as postictal hypoxia in epilepsy monitoring units (EMUs), before SUDEP trials can be implemented. EMU safety should also be improved to avoid SUDEP occurrence in that setting. Finally, the development of ambulatory SUDEP prevention devices should be encouraged but raises a number of unsolved issues.
Animal and human data: Where are our concepts for drug‐resistant epilepsy going?
Authors: Potschka Heidrun
Published: May 2013

Drug‐resistant epilepsy remains a challenge in the therapeutic management of patients with epilepsy. Identification of factors contributing to drug resistance might render a basis for the development of novel therapeutic approaches, for the reorganization of screening programs in drug development, and for the design of personalized treatment concepts. Therefore, experimental and clinical studies need to link efforts and collaborate in order to elucidate drug‐resistance mechanisms, to define the relative clinical relevance of selected mechanisms, and to develop and validate novel therapeutic concepts in overcoming resistance.
EEG abnormalities as a biomarker for cognitive comorbidities in pharmacoresistant epilepsy
Authors: Holmes Gregory L.
Published: May 2013

Cognitive impairment is a common and often devastating comorbidity of pharmacoresistent epilepsy. The cognitive comorbidity can be both chronic, primarily due to the underlying etiology of the epilepsy, and dynamic or evolving because of recurrent seizures or interictal spikes. There is now considerable evidence that interictal spikes can contribute to cognitive impairment. Interictal spikes in both rodents and humans result in transient impairment of memory retrieval, whereas in immature animals, interictal spikes can result in long‐term adverse effects on brain development. Interictal spikes therefore contribute to the cognitive impairment in the pharmacoresistant epilepsies. Effective treatment of pharmacoresistant epilepsy needs to target not only the overt seizures but interictal electroencephalography (EEG) abnormalities as well.
Multimodal neuroimaging: Potential biomarkers for response to antiepileptic drugs?
Authors: Coan Ana C. , Cendes Fernando
Published: May 2013

Neuroimaging techniques in epilepsy are used widely for definition of the epileptogenic lesion and surgical decision. However, its applications extend to the knowledge of epileptic mechanisms and include the identification of prognostic features that can help our decisions on the appropriate type of treatment on an individual basis. Structural neuroimaging may be able to identify patients more likely to respond to antiepileptic drug (AED) treatment and also patients who are better candidates for earlier surgical treatment. In the past decades, quantitative analyses have also improved our knowledge about epileptogenic lesions and networks as well as the following prognoses: seizure control, cognitive outcome, and comorbidities. New advanced neuroimaging techniques such as functional magnetic resonance imaging (MRI) and the development biotracers that could be associated with inflammation and specific genetic patterns will add further knowledge to the development of epilepsy treatments.