bluuebunny/crossref_metadata_2025 huggingface dataset:
Snakebite enquiries to the UK National Poisons Information Service: 2004–2010
Authors: Coulson James Michael , Cooper Gillian , Krishna Channarayapatna , Thompson John Paul
Published: December 2012

Objective

To describe trends regarding snakebite enquiries to the UK National Poisons Information Service (NPIS) from 2004 to 2010.

Methods

The NPIS telephone enquiry database, the UK Poisons Information Database, was interrogated for enquiries to the four NPIS units from 2004 to 2010. Search terms used were ‘snake’ and ‘snakebite’. Information from the national dataset was available from Cardiff and Edinburgh units from 2004 onwards, Birmingham from June 2005 and Newcastle from September 2006.

Results

Five hundred and ten cases were identified, of which 69% were male and 31% female. Average age of cases was 32 years (±1 95% CI). The snake was identified as follows: British Adder in 52% of cases, an exotic species in 26%, unknown in 18% and another UK snake in 4%. 82% of cases occurred between the months of April and September. Cases peaked during August (19%). Forty-two per cent of enquiries involved features of envenoming. Eighty-five cases were assessed as requiring antivenom. Eighty-four cases received treatment with antivenom. No adverse reactions to the antivenom were reported and resolution of clinical features was reported in all treated cases. Advice to use an antidote was followed in 98.8% of cases.

Conclusions

Snakebites account for one to two NPIS cases per week. Adder bites account for over half of cases. A quarter of cases were due to non-UK snakes kept in captivity within the UK. Envenoming was said to have occurred in just under half of all cases. Advice given by the NPIS appears to closely reflect national practice guidelines.
Prolonged moderate-intensity exercise oxygen uptake response following heavy-intensity priming exercise with short- and longer-term recovery
Authors: Spencer Matthew D. , Keir Daniel A. , Nederveen Joshua P. , Murias Juan M. , Kowalchuk John M. , Paterson Donald H.
Published: December 2012

This study examines the effects of recovery duration following heavy-intensity “priming” exercise (Hvy) on pulmonary oxygen (O2) uptake (V̇O2p) during subsequent prolonged moderate-intensity exercise (Mod). Nine participants (6 men and 3 women) (27 ± 7 years) each completed 3 repetitions of 2 continuous Mod 1-Hvy-Mod 2 leg-cycling protocols in which Mod 2 lasted 30 min, but was preceded by a recovery duration of either 6 (R6) or 20 (R20) min at 20 W following Hvy; in each case, Mod 1 and Hvy lasted 6 min and were preceded by 6 min at 20 W. V̇O2p, heart rate (HR), and near-infrared spectroscopy (NIRS)–derived muscle deoxygenation ([HHb]) responses were modeled as a monoexponential; additionally, 60-s averages were computed every 6 min in Mod 1 and Mod 2. V̇O2p was elevated (p < 0.05) throughout Mod 2 compared with Mod 1 in both R6 and R20 (by −82 mL·min−1 or ∼5.0%); this occurred despite a complete recovery of baseline V̇O2p (V̇O2pBsln) following R20. HR and minute ventilation (V̇E), but not [HHb], were also elevated throughout Mod 2. The phase II time constant for V̇O2p (τV̇O2p) was reduced in Mod 2 (22 s (Mod 1), 19 s (Mod 2); p < 0.05), as was the “overshoot” in the normalized [HHb]/O2 uptake ratio (p < 0.05). This study shows that V̇O2p was elevated during Mod following Hvy, regardless of recovery duration; however, a determining role for V̇O2pBsln is precluded. Furthermore, neither V̇O2p, HR, nor V̇E showed any evidence of a readjustment back to no-Hvy conditions during prolonged Mod (p > 0.05). Lastly, regardless of recovery duration, τV̇O2p was reduced to a similar extent with Hvy, likely resulting from an improved matching of local muscle O2 delivery to O2 utilization.
Ecological relationships of wild rice, Zizania spp. 11. Electron microscopy study of iron plaques on the roots of northern wild rice (Zizania palustris)
Authors: Jorgenson Kimberly D. , Lee Peter F. , Kanavillil Nandakumar
Published: December 2012

The deposition, composition, and structure of iron plaques formed on the roots of northern wild rice (Zizania palustris L.) from five wetlands across Ontario, Canada, were examined through a scanning electron microscope and energy-dispersive X-ray analyzer. Iron was oxidized within the rhizosphere resulting in the precipitation of ferric hydroxide onto root surfaces, visible as an orange-brown plaque. The northern wild rice samples analyzed were found to form substantial iron root plaques in a variety of surface water and sediment chemistries. Iron plaques ranged structurally from thin to crust plaques (<1 μm to 14 μm thick) and were composed mainly of Fe, O, Al, and K. Iron plaque was found within and on root epidermal cells, occasionally filling epidermal cells and penetrating into the root cortex. Rounded grooves were observed in the plaque surface of two samples and were reasoned to have been caused by iron-reducing bacteria. Observations on the anatomy of northern wild rice roots are presented along with a model of iron plaque development.
Kinetics of gene expression in bacteria — From models to measurements, and back again
Authors: Ribeiro Andre S.
Published: December 2012

Dennis Salahub has contributed to several scientific areas. Likely, one of the lesser known contributions is the one on the study of the kinetics of gene expression in prokaryotes, which resulted in a delayed stochastic model of transcription and translation dynamics in bacteria. The model has become the basis for modeling stochastic genetic circuits and has provided a framework for interpreting recent measurements of transcripts production dynamics in live cells, one event at a time. Here, we review the contributions by Salahub and colleagues to the modeling strategies of gene expression as a multi-delayed stochastic process. Next, we describe recent findings, which build upon this work and provide experimental validation of the models. Finally, we discuss potential future developments in this field of research.
Comprehensive analysis of the transcription of starch synthesis genes and the transcription factor RSR1 in wheat (Triticum aestivum) endosperm
Authors: Kang Guo-Zhang , Xu Wei , Liu Guo-Qin , Peng Xiao-Qi , Guo Tian-Cai
Published: December 2012

The cDNA sequences of 26 starch synthesis genes were identified in common wheat (Triticum aestivum L.), and their transcript levels were measured using quantitative real-time RT–PCR to assess the function of individual genes and the regulatory mechanism in wheat endosperm. The expression patterns of 26 genes in wheat endosperm were classified into three groups. The genes in group 1 were richly expressed in the early stage of grain development and may be involved in the construction of fundamental cell machinery, synthesis of glucan primers, and initiation of starch granules. The genes in group 2 were highly expressed during the middle and late stages of grain development, and their expression profiles were similar to the accumulation rate of endosperm starch; these genes are presumed to play a crucial role in starch production. The genes in group 3 were scantily expressed throughout the grain development period and might be associated with transitory starch synthesis. Transcripts of the negative transcription factor TaRSR1 were high at the early and late stages of grain development but low during the middle stage. The expression pattern of TaRSR1 was almost opposite to those of the group 2 starch synthesis genes, indicating that TaRSR1 might negatively regulate the expression of many endosperm starch synthesis genes during grain development.
Nutrition and Athletic Performance
Authors: Baracos Vickie E.
Published: December 2012

This supplement is based on presentations made at the “First International Congress on Nutrition and Athletic Performance” held at the Shaw Conference Centre, Edmonton, Alberta, Canada, August 8-11, 2001. This conference was stimulated by an increasing awareness of the potential benefits and risks of diet modification and supplementation for elite athletic performance. This supplement summarizes recentfindings and commentary on new research directions in nutrition and athletic performance by 22 invited plenary speakers from around the world.
Exercise Immunology: Nutritional Countermeasures
Authors: Nieman David C.
Published: December 2012

In contrast to moderate physical activity, prolonged and intensive exertion causes numerous changes in immunity that reflect physiologic stress and suppression, and an increased risk of upper respiratory tract infection. Enzymes in immune cells require the presence of micronutrients, leading to attempts by investigators to alter changes in immunity following heavy exertion through use of nutritional supplements, primarily zinc, dietary fat, vitamin C and other antioxidants, glutamine, and carbohydrate. Except for carbohydrate supplementation, none of these nutrients has emerged as an effective countermeasure to exerciseinduced immunosuppression. Data from several studies of endurance athletes suggest that carbohydrate compared to placebo ingestion is associated with an attenuated cortisol, growth hormone, and epinephrine response to heavy exertion, fewer perturbations in blood immune cell counts, lower granulocyte and monocyte phagocytosis and oxidative burst activity, and a diminished pro- and anti-inflammatory cytokine response. Overall, the hormonal and immune responses to carbohydrate compared to placebo ingestion during intensive exercise suggest that physiologic stress and inflammation are diminished, although clinical significance awaits further research.
Changes in Physiological and Stroke Parameters During a Maximal 400-m Free Swimming Test in Elite Swimmers
Authors: Laffite Laurent Paul , Vilas-Boas Juan Paulo , Demarle Alexandre , Silva José , Fernandes Ricardo , Louise Billat Véronique
Published: December 2012

The aim of this study was to analyse the variations of the metabolic and technical parameters during a maximal 400-m freestyle event. Seven trained male swimmers swam a maximal 400-m freestyle as if in competition (255.8 ± 6.9 s). Intermediate time and stroke rate (SR) were recorded at each length (25 m). To estimate the changes in metabolic parameters during the 400-m event, they swam a 300-, 200-, and 100-m test set from each length of the 400-m event results, resting 90 min between each test. The exact speed at each length was given with a visual light pacer. Oxygen uptake ([Formula: see text]) and blood lactate concentration ([Lac]) were measured before and immediately after each test. [Formula: see text] and [Lac] were stable during the 100-, 200-, and 300-m test but significantly higher (p < 0.05) during 400-m test. The estimated contribution of anaerobic metabolism (EsCANA) during the first 100-m and the 400-m represented 45% and 20% of total energy output, respectively. Speed decreased significantly (p < 0.05) after the first 100-m and remained stable until the end. SR decreased significantly after the first 100-m, then increased until the end, while stroke length (SL) decreased linearly throughout the 400-m. During the first or the last 100-m, ESCANA was not correlated with the changes in V, SR, or SL between the second and the first 100-m, and between the fourth and the third 100-m, respectively. To conclude, this study showed that the swimmers were not able to maintain stable SL during the 400-m event. Thus, to sustain stable velocity and to compensate for the decrease in SL, swimmers increased SR throughout the last 300-m.
FLAVOR MIXINGS AND TEXTURES OF THE FERMION MASS MATRICES
Authors: GUPTA MANMOHAN , AHUJA GULSHEEN
Published: December 2012

A comprehensive review of several aspects of fermion mixing phenomenon and texture specific mass matrices have been presented. Regarding fermion mixings, implications of unitarity and certain new developments for the CKM paradigm have been discussed. In the leptonic sector, the question of possibility of CP violation has been discussed in detail from the unitarity triangle perspective. In the case of texture specific mass matrices, the issues of viability of Fritzsch-like as well as non-Fritzsch-like mass matrices have been detailed for both the quark and leptonic sectors. The relationship of textures, naturalness and weak basis rotations has also been looked into. The issue of the compatibility of texture specific mass matrices with the SO(10)-based GUT mass matrices has also been discussed.
GIANT REDUCTION OF CHARGE CARRIER MOBILITY IN STRAINED GRAPHENE
Authors: SHAH RAHEEL , MOHIUDDIN TARIQ M. G. , SINGH RAM N.
Published: December 2012

Impact of induced strain on charge carrier mobility is investigated for a monolayer graphene sheet. The unsymmetrical hopping parameters between nearest neighbor atoms which emanate from induced strain are included in the density of states description. Mobility is then computed within the Born approximation by including three scattering mechanisms; charged impurity, surface roughness and lattice phonons interaction. Unlike its strained silicon counterpart, simulations reveal a significant drop in mobility for graphene with increasing strain. Additionally, mobility anisotropy is observed along the zigzag and armchair orientations. The prime reason for the drop in mobility can be attributed to the change in Fermi velocity due to strain induced distortions in the graphene honeycomb lattice.
Extracellular guanosine regulates extracellular adenosine levels
Authors: Jackson Edwin K. , Cheng Dongmei , Jackson Travis C. , Verrier Jonathan D. , Gillespie Delbert G.
Published: December 2012

The aim of this investigation was to test the hypothesis that extracellular guanosine regulates extracellular adenosine levels. Rat preglomerular vascular smooth muscle cells were incubated with adenosine, guanosine, or both. Guanosine (30 μmol/l) per se had little effect on extracellular adenosine levels. Extracellular adenosine levels 1 h after addition of adenosine (3 μmol/l) were 0.125 ± 0.020 μmol/l, indicating rapid disposition of extracellular adenosine. Extracellular adenosine levels 1 h after addition of adenosine (3 μmol/l) plus guanosine (30 μmol/l) were 1.173 ± 0.061 μmol/l, indicating slow disposition of extracellular adenosine. Cell injury increased extracellular levels of endogenous adenosine and guanosine, and the effects of cell injury on endogenous extracellular adenosine were modulated by altering the levels of endogenous extracellular guanosine with exogenous purine nucleoside phosphorylase (converts guanosine to guanine) or 8-aminoguanosine (inhibits purine nucleoside phosphorylase). Extracellular guanosine also slowed the disposition of extracellular adenosine in rat preglomerular vascular endothelial cells, mesangial cells, cardiac fibroblasts, and kidney epithelial cells and in human aortic and coronary artery vascular smooth muscle cells and coronary artery endothelial cells. The effects of guanosine on adenosine levels were not mimicked or attenuated by 5-iodotubericidin (adenosine kinase inhibitor), erythro-9-(2-hydroxy-3-nonyl)-adenine (adenosine deaminase inhibitor), 5-aminoimidazole-4-carboxamide (guanine deaminase inhibitor), aristeromycin ( S-adenosylhomocysteine hydrolase inhibitor), low sodium (inhibits concentrative nucleoside transporters), S-(4-nitrobenzyl)−6-thioinosine [inhibits equilibrative nucleoside transporter (ENT) type 1], zidovudine (inhibits ENT type 2), or acadesine (known modulator of adenosine levels). Guanosine also increases extracellular inosine, uridine, thymidine, and cytidine, yet decreases extracellular uric acid. In conclusion, extracellular guanosine regulates extracellular adenosine levels.
PAR-2-mediated control of barrier function and motility differs between early and late phases of postinfectious gut dysfunction in the rat
Authors: Fernández-Blanco Juan A. , Hollenberg Morley D. , Martínez Vicente , Vergara Patri
Published: December 2012

Proteinase-activated receptor-2 (PAR-2) and mast cell (MC) mediators contribute to inflammatory and functional gastrointestinal disorders. We aimed to characterize jejunal PAR-2-mediated responses and the potential MC involvement in the early and late phases of a rat model of postinfectious gut dysfunction. Jejunal tissues of control and Trichinella spiralis-infected (14 and 30 days postinfection) rats, treated or not with the MC stabilizer, ketotifen, were used. Histopathology and immunostaining were used to characterize inflammation, PAR-2 expression, and mucosal and connective tissue MCs. Epithelial barrier function (hydroelectrolytic transport and permeability) and motility were assessed in vitro in basal conditions and after PAR-2 activation. Intestinal inflammation on day 14 postinfection (early phase) was significantly resolved by day 30 (late phase) although MC counts and epithelial permeability remained increased. PAR-2-mediated ion transport (Ussing chambers, in vitro) and epithelial surface PAR-2 expression were reduced in the early phase, with a trend toward normalization during the late phase. In control conditions, PAR-2 activation (organ bath) induced biphasic motor responses (relaxation followed by excitation). At 14 days postinfection, spontaneous contractility and PAR-2-mediated relaxations were enhanced; motor responses were normalized on day 30. Postinfectious changes in PAR-2 functions were not affected by ketotifen treatment. We concluded that, in the rat model of Trichinella spiralis infection, alterations of intestinal PAR-2 function and expression depend on the inflammatory phase considered. A lack of a ketotifen effect suggests no interplay between MCs and PAR-2-mediated motility and ion transport alterations. These observations question the role of MC mediators in PAR-2-modulating postinfectious gut dysfunction.
Effect of contrasted levels of habitual physical activity on metabolic flexibility
Authors: Bergouignan Audrey , Antoun Edwina , Momken Iman , Schoeller Dale A. , Gauquelin-Koch Guillemette , Simon Chantal , Blanc Stéphane
Published: December 2012

The factors regulating the body's ability to switch from fat to carbohydrate oxidation in response to fuel availability changes, or metabolic flexibility (MF), are currently intensively investigated in the context of metabolic diseases. Although numerous metabolic diseases are associated with sedentary behaviors and metabolic inflexibility, the effect of habitual physical activity level (PAL) on MF regulation is surprisingly poorly known. We investigated how PAL affects MF in cross-sectional and interventional studies. MF was assessed in 44 subjects: normal-weight and overweight sedentary men submitted to 2 mo of exercise at current recommendations, normal-weight active men submitted to 1 mo of reduced PAL and normal-weight women submitted to 1 mo of bed rest, with or without exercise. MF was evaluated, before and after interventions, following two standard meals as the relationship between individual mathematical variances in insulin and nonprotein respiratory quotient (NPRQ) daily kinetics. Daily NPRQ and insulin variances differed according to habitual PAL ( P = 0.002 and P = 0.009, respectively); active subjects had higher variances in NPRQ for lower variances in insulin than sedentary subjects, indicating a better MF. Detraining increased insulin variance ( P = 0.009) and decreased NPRQ variance ( P = 0.003), while training tended to have opposite effects. Insulin and NPRQ variances were negatively related along the PAL continuum ( R2 = 0.70, P < 0.001). Variance in NPRQ was also positively related to PAL ( R2 = 0.52, P < 0.001). By assessing MF with mathematical surrogates in conditions of daily pattern in meal's intake, we showed that habitual PAL is associated with MF status, and that MF is modulated by changes in PAL.
FGF-2 Disrupts Mitotic Stability in Prostate Cancer through the Intracellular Trafficking Protein CEP57
Authors: Cuevas Rolando , Korzeniewski Nina , Tolstov Yanis , Hohenfellner Markus , Duensing Stefan
Published: December 2012

Malignant tumors with deregulated FGF-2 expression such as prostate cancer are also frequently aneuploid. Aneuploidy can be caused by cell division errors due to extra centrosomes and mitotic spindle poles. However, a link between FGF-2 overexpression and chromosome missegregation has so far been elusive. Here, we show that FGF-2 rapidly uncouples centrosome duplication from the cell division cycle in prostate cancer cells through CEP57, an intracellular FGF-2–binding and trafficking factor. CEP57 was initially identified as a regulator of centriole overduplication in an RNA interference screen. We subsequently found that CEP57 rapidly stimulates centriole overduplication and mitotic defects when overexpressed and is required not only for FGF-2–induced centriole overduplication but also for normal centriole duplication. We provide evidence that CEP57 functions by modulating tubulin acetylation, thereby promoting daughter centriole stability. CEP57 was found to be overexpressed on the mRNA and protein level in a subset of prostate cancers, of which the vast majority also showed FGF-2 upregulation. Taken together, our results show an unexpected link between altered microenvironmental signaling cues such as FGF-2 overexpression and mitotic instability and provide a rationale for the therapeutic targeting of the FGF-2/FGFR1/CEP57 axis in prostate cancer. Cancer Res; 73(4); 1400–10. ©2012 AACR.
CCR2 Deficiency Prevents Neuronal Dysfunction and Cognitive Impairments Induced by Cranial Irradiation
Authors: Belarbi Karim , Jopson Timothy , Arellano Carla , Fike John R. , Rosi Susanna
Published: December 2012

Cranial irradiation can lead to long-lasting cognitive impairments in patients receiving radiotherapy for the treatment of malignant brain tumors. Recent studies have suggested inflammation as a major contributor to these deficits; we determined if the chemokine (C–C motif) receptor 2 (CCR2) was a mediator of cognitive impairments induced by irradiation. Two-month-old male Ccr2 knockout (−/−) and wild-type mice received 10 Gy cranial irradiation or sham-treatment. One month after irradiation, bromodeoxyuridine was injected intraperitoneally for seven consecutive days to label newly generated cells. At two months postirradiation, cognitive function was assessed by novel object recognition and Morris water maze. Our results show that CCR2 deficiency prevented hippocampus-dependent spatial learning and memory impairments induced by cranial irradiation. Hippocampal gene expression analysis showed that irradiation induced CCR2 ligands such as CCL8 and CCR2 deficiency reduced this induction. Irradiation reduced the number of adult-born neurons in both wild-type and Ccr2−/− mice, but the distribution pattern of the adult-born neurons through the granule cell layer was only altered in wild-type mice. Importantly, CCR2 deficiency normalized the fraction of pyramidal neurons expressing the plasticity-related immediate early gene Arc. These data offer new insight into the mechanism(s) of radiation-injury and suggest that CCR2 is a critical mediator of hippocampal neuronal dysfunction and hippocampal cognitive impairments after irradiation. Targeting CCR2 signaling could conceivably provide an effective approach to reduce or prevent the incidence and severity of this serious side effect of ionizing irradiation. Cancer Res; 73(3); 1201–10. ©2012 AACR.
Triptolide Inhibits MDM2 and Induces Apoptosis in Acute Lymphoblastic Leukemia Cells through a p53-Independent Pathway
Authors: Huang Mei , Zhang Hailong , Liu Tao , Tian Dan , Gu Lubing , Zhou Muxiang
Published: December 2012

Triptolide, a natural product derived from the Chinese plant Tripterygium wilfordii, is reported to exhibit antitumor effects in a broad range of cancers. The antitumor activity of triptolide is associated with its biologic activities, as it inhibits various proproliferative or antiapoptotic factors that are dominantly expressed in given types of cancer cells. Herein, we show that triptolide induced apoptosis in a subgroup of acute lymphoblastic leukemia (ALL) cells overexpressing the MDM2 oncoprotein by inhibiting MDM2 expression. More specifically, we found that triptolide inhibited MDM2 at the transcriptional level by suppressing its mRNA synthesis. This MDM2 inhibition led in turn to increased levels of p53 protein; however, p53 functionality was not activated due to the fact that triptolide-treated cells lacked induction of p21 and PUMA as well as in G1 cell-cycle arrest. Triptolide-mediated downregulation of MDM2 increased inhibition of X-linked inhibitor of apoptosis protein (XIAP), its translational target, in a manner distinct from reactions to cellular stress and DNA-damaging agent ionizing radiation that induce XIAP due to p53-activated MDM2. These results suggest that increased inhibition of XIAP due to downregulation of MDM2 may play a critical role in triptolide-induced apoptosis in MDM2-overexpressing cancers. Mol Cancer Ther; 12(2); 184–94. ©2012 AACR.
Retreatment with Peginterferon α-2a + Ribavirin in Patients Who Failed Previous Peginterferon α-2b + Ribavirin Combination Therapy
Authors: Ueda Taisuke , Tsuchiya Kaoru , Hashimoto Satoru , Inoue Taisuke , Enomoto Nobuyuki , Inao Mie , Tanaka Atsushi , Kaito Masahiko , Imazeki Fumio , Nishiguchi Shuhei , Mochida Satoshi , Yokosuka Osamu , Yatsuhashi Hiroshi , Izumi Namiki , Kudo Masatoshi ,   for the RETRY Study Group
Published: December 2012

Background/Aims: Peginterferon (PEG-IFN) + ribavirin (RBV) combination therapy is the current standard of care for chronic hepatitis C. However, more than half of the patients cannot achieve sustained viral response (SVR). In Japan, the clinical benefit of retreatment with PEG-IFN + RBV combination retreatment is still unknown. Methods: We collected clinical data in 106 chronic hepatitis C patients who failed to achieve SVR with PEG-IFNα-2b + RBV combination therapy and were retreated with PEG-IFNα-2a + RBV. This retrospective study examined the efficacy of retreatment with PEG-IFNα-2a + RBV by evaluating the time to eradication of hepatitis C virus RNA, early virological response (EVR), and SVR. We compared the results of the previous therapy and retreatment in terms of efficacy and analyzed the factors influencing SVR. Results: The SVR rates in the non-responders and relapsers were 11 and 53%, respectively. EVR and prolonged treatment duration were associated with SVR. We also found that a prior response to PEG-IFN + RBV therapy was more important than the Interleukin-28B genotype for predicting the response to retreatment. Conclusions: Retreatment with PEG-IFNα-2a + RBV should be considered for relapsers and partial responders. Our results suggest that prolonged administration is also favorable for EVR cases to attain a higher SVR.
Effect of Response to Interferon-α Therapy on the Occurrence of Hepatocellular Carcinoma in Patients with Chronic Hepatitis B
Authors: Lee Danbi , Chung Young-Hwa , Lee Sae Hwan , Kim Sung Eun , Lee Yoon-Seon , Kim Kang Mo , Lim Young Suk , Lee Han Chu , Lee Yung Sang , Yu Eunsil
Published: December 2012

Objectives: The aim of this study was to examine whether interferon-α (IFN-α) therapy may reduce the occurrence of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) and to determine its effect based on responsiveness to IFN-α therapy. Methods: A total of 641 biopsy-proven CHB patients were treated with IFN-α2b. They were followed by biochemistry and/or imaging studies at 3- to 6-month intervals for a median period of 113 months (range 6–222). Results: HCC was detected in 22 patients and 5- and 10-year cumulative occurrence rates were 0.4 and 3.2%, respectively. In univariate analysis, age (p < 0.001), serum AFP levels (p < 0.001), and serum HBV-DNA levels (p = 0.002) at baseline were associated with HCC development. HCC occurred less frequently in biochemical responders at the end of treatment than in non-responders (p = 0.001). However, virologic response was not associated with HCC development. Multivariate analysis showed that poor biochemical response (p = 0.007) as well as older age (p = 0.018) and a higher serum AFP level (p < 0.001) remained independent predisposing factors of HCC development in CHB patients treated with IFN-α. Conclusion: The results suggest that the biochemical but not virologic response to IFN-α therapy reduces independently the occurrence of HCC in patients with CHB.
Clinical Implications of Arrest-Defective Protein 1 Expression in Hepatocellular Carcinoma: A Novel Predictor of Microvascular Invasion
Authors: Shim Ju Hyun , Chung Young-Hwa , Kim Jeong A. , Lee Danbi , Kim Kang Mo , Lim Young-Suk , Lee Han Chu , Lee Yung Sang , Yu Eunsil , Lee Young Joo
Published: December 2012

Objective: The associations between arrest-defective protein 1 (ARD1) gene expression and the clinicopathological characteristics and clinical outcomes of 94 patients undergoing hepatectomy for hepatocellular carcinoma (HCC) were investigated. Methods: ARD1 mRNA levels in HCC and corresponding non-cancerous tissues were quantified by real-time PCR. The gene expression of the tumor relative to that in the non-tumor tissues was calculated using the 2–ΔΔCT method. The subjects were classified into high expression (2–ΔΔCT > 1, n = 38) and low expression (2–ΔΔCT ≤ 1, n = 56) groups. Results: The HCCs did not differ from matched liver tissues in terms of ARD1 mRNA levels. The high expression group had more often microvascular invasion than the low expression group (32 vs. 14%; p = 0.045). The two groups did not differ significantly in terms of other patient or tumor variables. The median follow-up period was 92.1 months. The 5-year recurrence-free and overall survival rates were 34 and 76% for the high expression group, respectively, which were similar to the rates of the low expression group (46 vs. 73%, p = 0.98 and p = 0.52, respectively). Conclusions: Intratumoral ARD1 mRNA overexpression was involved in the microvascular invasion process in patients with HCC, although it did not associate strongly with postresectional outcomes.
Real-Life Clinical Practice with Sorafenib in Advanced Hepatocellular Carcinoma: A Single-Center Experience
Authors: Kudo Masatoshi , Ueshima Kazuomi , Arizumi Tadaaki
Published: December 2012

To evaluate the efficacy of sorafenib monotherapy, we enrolled 188 patients with hepatocellular carcinoma (HCC) who had undergone sorafenib monotherapy during a 3-year period from May 2009 to June 2012. Median overall survival was 15.6 months, and the 1- and 2-year survival rate was 54.4 and 32.2%, respectively, showing a relatively favorable treatment outcome. In addition, outcome was more favorable in earlier TNM stages. HCC patients with stage IVB had a better outcome than those with stage IVA, indicating the involvement of vascular invasion had poor prognosis. Outcome was more favorable in patients with Child-Pugh class A than in those with Child-Pugh class B. Patients in the long-term treatment group, who received sorafenib for ≥90 days, also showed a favorable outcome compared with those in the short-term treatment group, in which the administration period was <90 days. Multivariate analysis revealed treatment duration as a significant prognostic factor. Furthermore, patients who received post-sorafenib treatment had a better outcome than those who did not.
Developmental Changes in Voltage-Gated Calcium Channel α2δ-Subunit Expression in the Canine Dorsal Root Ganglion
Authors: Rosati Marco , Goedde Thomas , Steffen Frank , Gandini Gualtiero , De Risio Luisa , Reese Sven , Matiasek Kaspar
Published: December 2012

The voltage-gated calcium channel subunit α2δ plays a fundamental role in propagation of excitatory signals associated with release of glutamate and neuropeptides substance P (SP) and calcitonin gene-related protein (CGRP). It can be selectively inhibited by gabapentinoids. Hence, investigation of the α2δ subunit may predict the efficacy of gabapentinoid therapy in neuropathic pain. Since sensory processing underlies significant age-related changes, this study was conducted in order to elucidate the role of the α2δ subunit in the sensory transmission during canine development. Dorsal root ganglia (DRG) were harvested from four spinal segments of 16 puppies and 10 adult dogs without a history of neurological signs, pain, spinal disease or orthopedic disorders. α2δ-Subunit expression and coexpression with SP and CGRP was evaluated immunohistochemically regarding the number of immunopositive ganglion cells, staining intensity and subcellular distribution. All tested ganglia were immunopositive for α2δ. Cell counts and expression levels were significantly lower in pups than in adult dogs (p < 0.05). In the cervical segments of both groups, the number and percentage of immunopositive neurons was significantly higher than in lumbar DRG (p < 0.05). Multilabeling studies in all tested animals confirmed the coexpression of α2δ and pain peptides SP and CGRP. This anatomical study for the first time documents the involvement of α2δ subunits in sensory signal processing in dogs. The proportion of positive neurons and the intracellular expression levels show a net increase from early postnatal life to adulthood. A significant portion of α2δ-positive cells in the dogs exhibited C- and Aδ-phenotypes compatible with nociceptive neurons. The coexpression of α2δ, SP and CGRP imply that these neurons are involved with peptidergic nociception. The cervicolumbar gradient of α2δ expression in adults reflects functional differences in between forelimbs and hind limbs. These data will facilitate translational studies on neuropathic pain states in this species such as common canine nerve entrapment syndromes.
Leukemia Inhibitory Factor Is Essential for Subventricular Zone Neural Stem Cell and Progenitor Homeostasis as Revealed by a Novel Flow Cytometric Analysis
Authors: Buono Krista D. , Vadlamuri Daimler , Gan Qiong , Levison Steven W.
Published: December 2012

Stem cells rely on extracellular signals produced by the niche, which dictate their ability to self-renew, expand and differentiate. It is essential to have sensitive and reproducible methods of either quantifying or isolating these stem cells and progenitors to understand their intrinsic properties and how extrinsic signals regulate their development. However, stem cells are difficult to distinguish from multipotential progenitors, which may look and act like them. Here we define a 4-color flow cytometry panel using CD133, LeX, CD140a, NG2 to define a neural stem cell (NSC) as well as 4 classes of multipotential progenitors and 3 classes of bipotential progenitors, several of which have not been described previously. We performed gain and loss of function studies for leukemia inhibitory factor (LIF) and showed a depletion of NSCs, a subset of multipotential neural precursors and immature oligodendrocytes in LIF null mice. Gain of function studies showed that LIF increased the abundance of these precursors. Our studies also show that these NPs have differential requirements for LIF and ciliary neurotrophic factor (CNTF) and for epidermal growth factor (EGF), fibroblast growth factor (FGF-2) and platelet-derived growth factor (PDGF) for their propagation in vitro. Surprisingly, the related cytokine, CNTF, was less potent than LIF in increasing the NSCs and more potent than LIF in increasing the PDGF responsive multipotential precursors. Finally, we show that LIF increases the expression of the core transcription factors: Klf4, Fbx15, Nanog, Sox2 and c-Myc. Altogether our FACS (fluorescence-activated cell sorter) analyses reveal that the neonatal subventricular zone is far more heterogeneous than previously suspected and our studies provide new insights into the signals and mechanisms that regulate their self-renewal and proliferation.
Wnt Signaling Regulates Intermediate Precursor Production in the Postnatal Dentate Gyrus by Regulating Cxcr4 Expression
Authors: Choe Youngshik , Pleasure Samuel J.
Published: December 2012

Previous studies have examined the role of diverse signaling pathways in dentate neurogenesis, but how these signaling pathways are integrated remains unknown. Using mice that allow genetic manipulation of type 1 radial progenitors in the dentate, we show that forced induction of Wnt signaling leads to expansion of the intermediate progenitor cell (IPC) pool while selective activation of Sonic hedgehog (Shh) signaling drives neurogenesis without significant expansion of IPCs. Thus, both Wnt and Shh signaling are proneurogenic, but they act in distinct manners when their signaling is forced in subgranular zone radial progenitors. We examined potential targets of the Wnt pathway in these cells and found that Cxcr4 is a direct target of Lef1 in dentate gyrus progenitors and that loss of Cxcr4 in postnatal neurogenesis decreases the production of IPCs. This suggests that Wnt activation of dentate gyrus progenitors induces Cxcl12 signaling by regulating receptor expression. This study provides evidence that distinct morphogenic pathways have notably different roles in regulating ongoing dentate neurogenesis.
Psychometric Properties of the German Version of the Borderline Personality Disorder Severity Index - Version IV
Authors: Kröger Christoph , Vonau Melanie , Kliem Sören , Roepke Stefan , Kosfelder Joachim , Arntz Arnoud
Published: December 2012

Background: Although the Borderline Personality Disorder Severity Index - Version IV (BPDSI-IV) has already been used in several studies, psychometric properties are only known from two developing studies. Sampling and Methods: To examine item characteristics, reliability, and validity indicators, a large sample including subjects with borderline personality disorder (n = 163), a mixed psychiatric group (n = 58), and a healthy control group (n = 43) were interviewed with the German version of the Structured Clinical Interview for DSM-IV Personality Disorders (SCID-II) as well as the BPDSI-IV. Results: The indices for interrater reliability as well as internal consistency of the BPDSI-IV were excellent to good. The total score and the subscales of the BPDSI-IV discriminated between diagnostic subgroups. As expected, its subscales were associated with the scores in the SCID-II and applied self-rating measures. Conclusions: In a subsequent version, subscales might have to be adapted to the proposed traits of the borderline type in DSM-V.
Dipyridamole decreases inflammatory metalloproteinase-9 expression and release by human monocytes
Authors: Carluccio Maria Annunziata , Pellegrino Mariangela , Calabriso Nadia , Storelli Carlo , Martines Giuseppe , Massaro Marika , Scoditti Egeria , De Caterina Raffaele
Published: December 2012

Matrix metalloproteinase (MMP)-9 plays an important role in stroke by accelerating matrix degradation, disrupting the blood-brain barrier and increasing infarct size. Dipyridamole is an antiplatelet agent with recognised benefits in ischaemic stroke prevention. In addition to its antiplatelet properties, recent studies have reported that dipyridamole also features anti-inflammatory and anti-oxidant properties. We therefore investigated whether dipyridamole can ameliorate the proinflammatory profile of human monocytes, a source of MMP-9 in stroke, in terms of regulation of MMP-9 activity and expression, and explored underlying mechanisms. Human peripheral blood mononuclear cells (PBMC) and U937 cells were treated with increasing concentrations of dipyridamole (up to 10 µg/ml) for 60 minutes before stimulation with tumour necrosis factor (TNF)-α or phorbol myristate acetate (PMA). Exposure of PBMC and U937 to dipyridamole reduced TNF-α- and PMA-induced MMP-9 activity and protein release as well as MMP-9 mRNA, without significantly affecting the release of TIMP-1. This inhibitory effect was independent of dipyridamole-induced cyclic adeno-sine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) increase. Correspondingly, dipyridamole also significantly inhibited TNF-α-induced nuclear factor (NF)-κB activation and nuclear translocation of the p65 NF-κB subunit through a mechanism involving the inhibition of IkBα degradation and p38 MAPK activation. In conclusion, dipyridamole, at therapeutically achievable concentrations, reduces the expression and release of MMP-9 through a mechanism involving p38 MAPK and NF-κB inhibition. These results indicate that dipyridamole exerts anti-inflammatory properties in human monocytes that may favourably contribute to its actions in the secondary prevention of stroke, independent of its antiplatelet properties.
Integrin-substrate interactions underlying shear-induced inhibition of the inflammatory response of endothelial cells
Authors: Luu Thin , Egginton Stuart , Rainger Ed , Glen Katie , Nash Gerard
Published: December 2012

Conditioning of endothelial cells by shear stress suppresses their response to inflammatory cytokines. We questioned whether signalling through different integrin-matrix interactions, previously associated with the pathogenic effects of disturbed flow, supported the anti-inflammatory action of steady shear. Primary human endothelial cells were cultured on different substrates and exposed to shear stress (2.0Pa) for varying periods before stimulation with tumour necrosis factor-α (TNF). Shear-conditioning inhibited cytokine-induced recruitment of flowing neutrophils. However, the effect was similar for culture on collagen, laminin or fibronectin, even when seeding was reduced to 2hours, and shear to 3hours before TNF treatment (to minimise deposition of endothelial matrix). Nevertheless, in short- or longer- term cultures, reduction in expression of β1-integrin (but not β3-integrin) using siRNA essentially ablated the effect of shear-conditioning on neutrophil recruitment. Studies of focal adhesion kinase (FAK) phosphorylation, siRNA against FAK and a FAK-inhibitor (PF573228) indicated that FAK activity was an essential component downstream of β1-integrin. In addition, MAP-kinase p38 was phosphorylated downstream of FAK and also required for functional modification. Mechanotransduction through β1-integrins, FAK and p38 is required for anti-inflammatory effects of steady shear stress. Separation of the pathways which underlie pathological versus protective responses of different patterns of flow is required to enable therapeutic modification or mimicry, respectively.
Endothelial Acyl-CoA Synthetase 1 Is Not Required for Inflammatory and Apoptotic Effects of a Saturated Fatty Acid-Rich Environment
Authors: Li Xin , Gonzalez Oscar , Shen Xia , Barnhart Shelley , Kramer Farah , Kanter Jenny E. , Vivekanandan-Giri Anuradha , Tsuchiya Kyoichiro , Handa Priya , Pennathur Subramaniam , Kim Francis , Coleman Rosalind A. , Schaffer Jean E. , Bornfeldt Karin E.
Published: December 2012

Objective—

Saturated fatty acids, such as palmitic and stearic acid, cause detrimental effects in endothelial cells and have been suggested to contribute to macrophage accumulation in adipose tissue and the vascular wall, in states of obesity and insulin resistance. Long-chain fatty acids are believed to require conversion into acyl-CoA derivatives to exert most of their detrimental effects, a reaction catalyzed by acyl-CoA synthetases (ACSLs). The objective of this study was to investigate the role of ACSL1, an ACSL isoform previously shown to mediate inflammatory effects in myeloid cells, in regulating endothelial cell responses to a saturated fatty acid-rich environment in vitro and in vivo.

Methods and Results—

Saturated fatty acids caused increased inflammatory activation, endoplasmic reticulum stress, and apoptosis in mouse microvascular endothelial cells. Forced ACSL1 overexpression exacerbated the effects of saturated fatty acids on apoptosis and endoplasmic reticulum stress. However, endothelial ACSL1 deficiency did not protect against the effects of saturated fatty acids in vitro, nor did it protect insulin-resistant mice fed a saturated fatty acid-rich diet from macrophage adipose tissue accumulation or increased aortic adhesion molecule expression.

Conclusion—

Endothelial ACSL1 is not required for inflammatory and apoptotic effects of a saturated fatty acid-rich environment.
Human Apolipoprotein A-II Protects Against Diet-Induced Atherosclerosis in Transgenic Rabbits
Authors: Wang Yao , Niimi Manabu , Nishijima Kazutoshi , Waqar Ahmed Bilal , Yu Ying , Koike Tomonari , Kitajima Shuji , Liu Enqi , Inoue Tomohiro , Kohashi Masayuki , Keyamura Yuka , Yoshikawa Tomohiro , Zhang Jifeng , Ma Loretta , Zha Xiaohui , Watanabe Teruo , Asada Yujiro , Chen Y. Eugene , Fan Jianglin
Published: December 2012

Objective—

Apolipoprotein (apo) A-II is the second major apo of high-density lipoproteins, yet its pathophysiological roles in the development of atherosclerosis remain unknown. We aimed to examine whether apo A-II plays any role in atherogenesis and, if so, to elucidate the mechanism involved.

Methods and Results—

We compared the susceptibility of human apo A-II transgenic (Tg) rabbits to cholesterol diet-induced atherosclerosis with non-Tg littermate rabbits. Tg rabbits developed significantly less aortic and coronary atherosclerosis than their non-Tg littermates, while total plasma cholesterol levels were similar. Atherosclerotic lesions of Tg rabbits were characterized by reduced macrophages and smooth muscle cells, and apo A-II immunoreactive proteins were frequently detected in the lesions. Tg rabbits exhibited low levels of plasma C-reactive protein and blood leukocytes compared with non-Tg rabbits, and high-density lipoproteins of Tg rabbit plasma exerted stronger cholesterol efflux activity and inhibitory effects on the inflammatory cytokine expression by macrophages in vitro than high-density lipoproteins isolated from non-Tg rabbits. In addition, β-very-low-density lipoproteins of Tg rabbits were less sensitive to copper-induced oxidation than β-very-low-density lipoproteins of non-Tg rabbits.

Conclusion—

These results suggest that enrichment of apo A-II in high-density lipoprotein particles has atheroprotective effects and apo A-II may become a target for the treatment of atherosclerosis.
Reduced Mural Cell Coverage and Impaired Vessel Integrity After Angiogenic Stimulation in the
Alk1
-deficient Brain
Authors: Chen Wanqiu , Guo Yi , Walker Espen J. , Shen Fanxia , Jun Kristine , Oh S. Paul , Degos Vincent , Lawton Michael T. , Tihan Tarik , Davalos Dimitrios , Akassoglou Katerina , Nelson Jeffrey , Pile-Spellman John , Su Hua , Young William L.
Published: December 2012

Objective—

Vessels in brain arteriovenous malformations are prone to rupture. The underlying pathogenesis is not clear. Hereditary hemorrhagic telangiectasia type 2 patients with activin receptor-like kinase 1 (
Alk1
) mutation have a higher incidence of brain arteriovenous malformation than the general population. We tested the hypothesis that vascular endothelial growth factor impairs vascular integrity in the
Alk1
-deficient brain through reduction of mural cell coverage.

Methods and Results—

Adult
Alk1
1f/2f
mice (loxP sites flanking exons 4–6) and wild-type mice were injected with 2×10
7
PFU adenovious-cre recombinase and 2×10
9
genome copies of adeno-associated virus-vascular endothelial growth factor to induce focal homozygous
Alk1
deletion (in
Alk1
1f/2f
mice) and angiogenesis. Brain vessels were analyzed 8 weeks later. Compared with wild-type mice, the
Alk1
-deficient brain had more fibrin (99±30×10
3
pixels/mm
2
versus 40±13×10
3
;
P
=0.001), iron deposition (508±506 pixels/mm
2
versus 6±49;
P
=0.04), and Iba1
+
microglia/macrophage infiltration (888±420 Iba1
+
cells/mm
2
versus 240±104 Iba1
+
;
P
=0.001) after vascular endothelial growth factor stimulation. In the angiogenic foci, the
Alk1
-deficient brain had more α-smooth muscle actin negative vessels (52±9% versus 12±7%,
P
<0.001), fewer vascular-associated pericytes (503±179/mm
2
versus 931±115,
P
<0.001), and reduced platelet-derived growth factor receptor-β expression.

Conclusion—

Reduction of mural cell coverage in response to vascular endothelial growth factor stimulation is a potential mechanism for the impairment of vessel wall integrity in hereditary hemorrhagic telangiectasia type 2-associated brain arteriovenous malformation.