bluuebunny/crossref_metadata_2025 huggingface dataset:
Bloodstream Infections Due to
Trichosporon
spp.: Species Distribution,
Trichosporon asahii
Genotypes Determined on the Basis of Ribosomal DNA Intergenic Spacer 1 Sequencing, and Antifungal Susceptibility Testing
Authors: Chagas-Neto Thomas C. , Chaves Guilherme M. , Melo Analy S. A. , Colombo Arnaldo L.
Published: February 2009

The reevaluation of the genus
Trichosporon
has led to the replacement of the old taxon
Trichosporon beigelii
by six new species. Sequencing of the ribosomal DNA (rDNA) intergenic spacer 1 (IGS1) is currently mandatory for accurate
Trichosporon
identification, but it is not usually performed in routine laboratories. Here we describe
Trichosporon
species distribution and prevalence of
Trichosporon asahii
genotypes based on rDNA IGS1 sequencing as well as antifungal susceptibility profiles of 22 isolates recovered from blood cultures. The clinical isolates were identified as follows: 15
T. asahii
isolates, five
Trichosporon asteroides
isolates, one
Trichosporon coremiiforme
isolate, and one
Trichosporon dermatis
isolate. We found a great diversity of different species causing trichosporonemia, including a high frequency of isolation of
T. asteroides
from blood cultures that is lower than that of
T. asahii
only. Regarding
T. asahii
genotyping, we found that the majority of our isolates belonged to genotype 1 (86.7%). We report the first
T. asahii
isolate belonging to genotype 4 in South America. Almost 50% of all
T. asahii
isolates exhibited amphotericin B MICs of ≥2 μg/ml. Caspofungin MICs obtained for all the
Trichosporon
sp. isolates tested were consistently high (MICs ≥ 2 μg/ml). Most isolates (87%) had high MICs for 5-flucytosine, but all of them were susceptible to triazoles, markedly to voriconazole (all MICs ≤ 0.06 μg/ml).
Neuraminidase Stalk Length and Additional Glycosylation of the Hemagglutinin Influence the Virulence of Influenza H5N1 Viruses for Mice
Authors: Matsuoka Yumiko , Swayne David E. , Thomas Colleen , Rameix-Welti Marie-Anne , Naffakh Nadia , Warnes Christine , Altholtz Melanie , Donis Ruben , Subbarao Kanta
Published: February 2009

Following circulation of avian influenza H5 and H7 viruses in poultry, the hemagglutinin (HA) can acquire additional glycosylation sites, and the neuraminidase (NA) stalk becomes shorter. We investigated whether these features play a role in the pathogenesis of infection in mammalian hosts. From 1996 to 2007, H5N1 viruses with a short NA stalk have become widespread in several avian species. Compared to viruses with a long-stalk NA, viruses with a short-stalk NA showed a decreased capacity to elute from red blood cells and an increased virulence in mice, but not in chickens. The presence of additional HA glycosylation sites had less of an effect on virulence than did NA stalk length. The short-stalk NA of H5N1 viruses circulating in Asia may contribute to virulence in humans.
Preclinical Studies of Human Immunodeficiency Virus/AIDS Vaccines: Inverse Correlation between Avidity of Anti-Env Antibodies and Peak Postchallenge Viremia
Authors: Zhao Jun , Lai Lilin , Amara Rama Rao , Montefiori David C. , Villinger Francois , Chennareddi Lakshmi , Wyatt Linda S. , Moss Bernard , Robinson Harriet L.
Published: February 2009

A major challenge for human immunodeficiency virus (HIV)/AIDS vaccines is the elicitation of anti-Env antibodies (Ab) capable of neutralizing the diversity of isolates in the pandemic. Here, we show that high-avidity, but nonneutralizing, Abs can have an inverse correlation with peak postchallenge viremia for a heterologous challenge. Vaccine studies were conducted in rhesus macaques using DNA priming followed by modified vaccinia Ankara boosting with HIV type 1 (HIV-1) immunogens that express virus-like particles displaying CCR5-tropic clade B (strain ADA) or clade C (IN98012) Envs. Rhesus granulocyte-macrophage colony-stimulating factor was used as an adjuvant for enhancing the avidity of anti-Env Ab responses. Challenge was with simian/human immunodeficiency virus (SHIV)-162P3, a CCR5-tropic clade B chimera of SIV and HIV-1. Within the groups receiving the clade B vaccine, a strong inverse correlation was found between the avidity of anti-Env Abs and peak postchallenge viremia. This correlation required the use of native but not gp120 or gp140 forms of Env for avidity assays. The high-avidity Ab elicited by the ADA Env had excellent breadth for the Envs of incident clade B but not clade C isolates, whereas the high-avidity Ab elicited by the IN98012 Env had excellent breadth for incident clade C but not clade B isolates. High-avidity Ab elicited by a SHIV vaccine with a dual-tropic clade B Env (89.6) had limited breadth for incident isolates. Our results suggest that certain Envs can elicit nonneutralizing but high-avidity Ab with broad potential for blunting incident infections of the same clade.
Optimizing Viral Protein Yield of Influenza Virus Strain A/Vietnam/1203/2004 by Modification of the Neuraminidase Gene
Authors: Adamo Joan E. , Liu Teresa , Schmeisser Falko , Ye Zhiping
Published: February 2009

The preparation of high-yield prepandemic influenza virus H5N1 strains has presented a challenge to both researchers and vaccine manufacturers. The reasons for the relatively low yield of the H5N1 strains are not fully understood, but it might be partially dependent on the interactions between the hemagglutinin (HA) or neuraminidase (NA) surface glycoprotein and other influenza virus proteins. In this study, we have constructed chimeras between the A/Puerto Rico/8/34 (PR8) NA gene and the A/Vietnam/1203/2004 (VN1203) NA gene that have resulted in an increase in the virus yield of the reassortant viruses without a significant loss of NA activity. By combining the amino terminus of NA from the PR8 strain with the carboxy terminus of NA from VN1203, the surface epitopes unique to the H5N1 VN1203 NA glycoprotein are maintained. This reassortant virus had a higher titer and total protein yield in eggs, grew to a higher titer, produced large plaques on MDCK cells, and retained NA activity. This work describes a novel recombinant technique designed to increase the yields of vaccine candidates for the production of pandemic influenza virus vaccines. The relationship between the infectivity and protein yield of the reassortants also is discussed.
Diagnosis and treatment in inflammatory neuropathies
Authors: Lunn M P T , Willison H J
Published: February 2009

The inflammatory neuropathies are a large diverse group of immune-mediated neuropathies that are amenable to treatment and may be reversible. Their accurate diagnosis is essential for informing the patient of the likely course and prognosis of the disease, informing the treating physician of the appropriate therapy and informing the scientific community of the results of well-targeted, designed and performed clinical trials. With the advent of biological therapies able to manipulate the immune response more specifically, an understanding of the pathogenesis of these conditions is increasingly important. This review presents a broad overview of the pathogenesis, diagnosis and therapy of inflammatory neuropathies, concentrating on the most commonly encountered conditions.
TNF-induced activation of pulmonary microvessel endothelial cells: a role for GSK3β
Authors: Johnson Arnold
Published: February 2009

The hypothesis tested was PKCα mediates the phosphorylation of glycogen synthetase kinase 3β (GSK3β) and that the GSK3β inhibition modulates the response to tumor necrosis factor-α (TNF) in rat pulmonary microvessel endothelial cells (PMEC). PMEC were treated with TNF for 4.0 h (100 ng/ml) or vehicle. First, to assess the role of PKCα in the phosphorylation of GSK3β (i.e., an indicator of GSK3β inhibition), PMEC were pretreated with 1) nonsense-RNA-PKCα, 2) siRNA-PKCα, and 3) the PKC inhibitor Gö6983. In the nonsense RNA-PKCα+TNF and TNF groups, there was increased phosphorylated GSK3β-Ser9 that did not occur in the Gö6983+TNF group. In the TNF groups, there was a significant correlation between PKCα protein and phosphorylated GSK3β-Ser9 that did not occur in the groups without TNF. Second, to assess the role of GSK3β in β-catenin activity, PMEC were pretreated with 1) wild-type (w) GSK3β plasmid to enhance GSK3β activity, 2) kinase dead (kd)-GSK3β plasmid, and 3) the GSK3β inhibitor SB-216763. In the TNF group, there was increased unphosphorylated β-catenin-Ser37/33 compared with the control group. In the GSK3β-inhibited groups (i.e., SB-216763 and kdGSK3β) ± TNF, the unphosphorylated β-catenin-Ser37/33 was similar to the TNF group. In the GSK3β-enhanced group ± TNF, the unphosphorylated β-catenin-Ser37/33 was similar to the control. Finally, PMEC were also treated with TOPflash, a β-catenin-dependent promoter luciferase reporter, or the mutant construct FOPflash, 2 days before treatment with TNF. In the TNF group, there was an increased TOPflash/FOPflash activity ratio compared with the control group. In the GSK3β-inhibited groups (i.e., SB-216763 and kdGSK3β) ± TNF, the TOPflash/FOPflash activity ratio was similar to the TNF group. In the GSK3β-enhanced group ± TNF, the TOPflash/FOPflash activity ratio was similar to the control. The data indicate that TNF induces endothelial activation that is modulated by a PKCα-dependent inhibition of GSK3β.
Chemotherapy agent cisplatin induces 48-h Fos expression in the brain of a vomiting species, the house musk shrew (Suncus murinus)
Authors: De Jonghe Bart C. , Horn Charles C.
Published: February 2009

Cancer chemotherapy drugs, such as cisplatin, potently produce nausea and vomiting. Acute effects of these treatments are partly controlled by antiemetic drugs, but the delayed effects (>24 h), especially nausea, are more difficult to treat. It is unknown what brain pathways produce this delayed sickness. Our prior data show that brain Fos expression is increased for at least 48 h after cisplatin treatment in the rat, a nonvomiting species. Here, we extend these observations by using house musk shrews ( Suncus murinus), a species with an emetic response. Compared with saline injection, cisplatin treatment (30 mg/kg ip) induced Fos expression in hindbrain areas known to play a role in the generation of emesis, the dorsal motor nucleus (DMN), the area postrema, and the nucleus of the solitary tract (NTS), for up to 48 h. Cisplatin also stimulated Fos expression in the parabrachial nucleus (PBN) of the midbrain and the central nucleus of the amygdala (CeA) for at least 48 h after treatment. When animals were pretreated with the antiemetic palonosetron, a long-term serotonin type 3 (5-HT3) receptor antagonist, cisplatin-induced Fos expression was significantly attenuated in the NTS, DMN, and CeA at 6 h but not at 48 h. These results indicate that cisplatin activates a neural system that includes the dorsal vagal complex and forebrain in the musk shrew, which is partially suppressed by a 5-HT3receptor antagonist. Our findings suggest the existence of an extensive neural system that could be targeted to reduce nausea, vomiting, and malaise in cancer patients receiving chemotherapy.
Direct action of aldosterone on bicarbonate reabsorption in in vivo cortical proximal tubule
Authors: Pergher Patricia Silva , Leite-Dellova Deise , de Mello-Aires Margarida
Published: February 2009

The direct action of aldosterone (10−12M) on net bicarbonate reabsorption ( JHCO3−) was evaluated by stationary microperfusion of an in vivo middle proximal tubule (S2) of rat kidney, using H ion-sensitive microelectrodes. Aldosterone in luminally perfused tubules caused a significant increase in JHCO3−from a mean control value of 2.84 ± 0.08 [49/19 ( n° of measurements/ n° of tubules)] to 4.20 ± 0.15 nmol·cm−2·s−1(58/10). Aldosterone perfused into peritubular capillaries also increased JHCO3−, compared with basal levels during intact capillary perfusion with blood. In addition, in isolated perfused tubules aldosterone causes a transient increase of cytosolic free calcium ([Ca2+]i), monitored fluorometrically. In the presence of ethanol (in similar concentration used to prepare the hormonal solution), spironolactone (10−6M, a mineralocorticoid receptor antagonist), actinomycin D (10−6M, an inhibitor of gene transcription), or cycloheximide (40 mM, an inhibitor of protein synthesis), the JHCO3−and the [Ca2+]iwere not different from the control value; these drugs also did not prevent the stimulatory effect of aldosterone on JHCO3−and on [Ca2+]i. However, in the presence of RU 486 alone [10−6M, a classic glucocorticoid receptor (GR) antagonist], a significant decrease on JHCO3−and on [Ca2+]iwas observed; this antagonist also inhibited the stimulatory effect of aldosterone on JHCO3−and on [Ca2+]i. These studies indicate that luminal or peritubular aldosterone (10−12M) has a direct nongenomic stimulatory effect on JHCO3−and on [Ca2+]iin proximal tubule and that probably GR participates in this process. The data also indicate that endogenous aldosterone stimulates JHCO3−in middle proximal tubule.
GABARAP deficiency modulates expression of NaPi-IIa in renal brush-border membranes
Authors: Reining Sonja C. , Gisler Serge M. , Fuster Daniel , Moe Orson W. , O'Sullivan Gregory A. , Betz Heinrich , Biber Jürg , Murer Heini , Hernando Nati
Published: February 2009

Renal reabsorption of inorganic phosphate (Pi) is mainly mediated by the Na+-dependent Pi-cotransporter NaPi-IIa that is expressed in the brush-border membrane (BBM) of renal proximal tubules. Regulation and apical expression of NaPi-IIa are known to depend on a network of interacting proteins. Most of the interacting partners identified so far associate with the COOH-terminal PDZ-binding motif (TRL) of NaPi-IIa. In this study GABAAreceptor-associated protein (GABARAP) was identified as a novel interacting partner of NaPi-IIa applying a membrane yeast-two-hybrid system (MYTH 2.0) to screen a mouse kidney library with the TRL-truncated cotransporter as bait. GABARAP mRNA and protein are present in renal tubules, and the interaction of NaPi-IIa and GABARAP was confirmed by using glutathione S-transferase pulldowns from BBM and coimmunoprecipitations from transfected HEK293 cells. Amino acids 36–68 of GABARAP were identified as the determinant for the described interaction. The in vivo effects of this interaction were studied in a murine model. GABARAP−/−mice have reduced urinary excretion of Pi, higher Na+-dependent32Piuptake in BBM vesicles, and increased expression of NaPi-IIa in renal BBM compared with GABARAP+/+mice. The expression of Na+/H+exchanger regulatory factor (NHERF)1, an important scaffold for the apical expression of NaPi-IIa, is also increased in GABARAP−/−mice. The absence of GABARAP does not interfere with the regulation of the cotransporter by either parathyroid hormone or acute changes of dietary Picontent.
Instructed Delay Discharge in Primary and Secondary Somatosensory Cortex Within the Context of a Selective Attention Task
Authors: Meftah El-Mehdi , Bourgeon Stéphanie , Chapman C. Elaine
Published: February 2009

The neuronal mechanisms that contribute to tactile perception were studied using single-unit recordings from the cutaneous hand representation of primate primary (S1) and secondary (S2) somatosensory cortex. This study followed up on our recent observation that S1 and S2 neurons developed a sustained change in discharge during the instruction period of a directed-attention task. We determined the extent to which the symbolic light cues, which signaled the modality (tactile, visual) to attend and discriminate, elicited changes in discharge rate during the instructed delay (ID) period of the attention task and the functional importance of this discharge. ID responses, consisting of a sustained increase or decrease in discharge during the 2-s instruction period, were present in about 40% of the neurons in S1 and S2. ID responses in both cortical regions were very similar in most respects (frequency, sign, latency, amplitude), suggesting a common source. A major difference, however, was related to attentional modulation during the ID period: attentional influences were almost entirely restricted to S2 and these effects were always superimposed on the ID response (additive effect). These findings suggest that the underlying mechanisms for ID discharge and attention are independent. ID discharge significantly modified the initial response to the standard stimuli (competing texture and visual stimuli), usually enhancing responsiveness. We also showed that tactile detection in humans is enhanced during the ID period. Together, the results suggest that ID discharge represents a priming mechanism that prepares cortical areas to receive and process sensory inputs.
Repetition Priming Influences Distinct Brain Systems: Evidence From Task-Evoked Data and Resting-State Correlations
Authors: Wig Gagan S. , Buckner Randy L. , Schacter Daniel L.
Published: February 2009

Behavioral dissociations suggest that a single experience can separately influence multiple processing components. Here we used a repetition priming functional magnetic resonance imaging paradigm that directly contrasted the effects of stimulus and decision changes to identify the underlying brain systems. Direct repetition of stimulus features caused marked reductions in posterior regions of the inferior temporal lobe that were insensitive to whether the decision was held constant or changed between study and test. By contrast, prefrontal cortex showed repetition effects that were sensitive to the exact stimulus-to-decision mapping. Analysis of resting-state functional connectivity revealed that the dissociated repetition effects are embedded within distinct brain systems. Regions that were sensitive to changes in the stimulus correlated with perceptual cortices, whereas the decision changes attenuated activity in regions correlated with middle-temporal regions and a frontoparietal control system. These results thus explain the long-known dissociation between perceptual and conceptual components of priming by revealing how a single experience can separately influence distinct, concurrently active brain systems.
Hand-Foot Skin Reaction Increases with Cumulative Sorafenib Dose and with Combination Anti-Vascular Endothelial Growth Factor Therapy
Authors: Azad Nilofer S. , Aragon-Ching Jeanny B. , Dahut William L. , Gutierrez Martin , Figg William D. , Jain Lokesh , Steinberg Seth M. , Turner Maria L. , Kohn Elise C. , Kong Heidi H.
Published: February 2009

Purpose: Sorafenib, a vascular endothelial growth factor (VEGF) receptor-2 and RAF kinase inhibitor, commonly causes skin toxicity. We retrospectively analyzed dermatologic toxicity in patients receiving combined antiangiogenic therapy involving sorafenib and bevacizumab.

Experimental Design: Castration-resistant prostate cancer and metastatic non-small cell lung cancer patients were accrued to phase II studies, receiving sorafenib 400 mg twice daily. A phase I study explored sorafenib 200 to 400 mg twice daily with bevacizumab 5 to 10 mg/kg every 2 weeks in patients with advanced solid tumors. The probability of development of maximum grade of dermatologic toxicity as a function of the cumulative dose of sorafenib was determined. Additional analyses compared extent of toxicity, pharmacokinetics, and patient risk factors.

Results: Ninety-six patients were enrolled: 54 received sorafenib and 42 received bevacizumab/sorafenib. Hand-foot skin reaction (HFSR) was observed in 50 of 96 (52%) patients. Grade 2 to 3 HFSR developed in 16 of 54 (30%) sorafenib patients and 24 of 42 (57%) bevacizumab/sorafenib patients (P = 0.012) and was associated with cumulative sorafenib exposure (P = 0.0008). Twenty-four of 42 phase I patients randomized to start with bevacizumab had increased risk of grade 2 to 3 HFSR than those starting with sorafenib (P = 0.013) after adjusting for association between HFSR risk and hypertension (P = 0.01), which was the only toxicity associated with HFSR. There was no association between HFSR and baseline history of neuropathy, prior taxane/platinum treatment, or systemic sorafenib levels.

Conclusions: Sorafenib-related HFSR is associated with increasing cumulative sorafenib dose. HFSR is increased in patients treated with bevacizumab/sorafenib combination anti-VEGF therapy, and this finding is not explained by pharmacokinetic interaction between the two agents. Our results suggest that the pathophysiology of HFSR may be related to VEGF inhibition.
Molecular Mechanisms of Tamoxifen Therapy for Cholangiocarcinoma: Role of Calmodulin
Authors: Pawar Pritish , Ma Liping , Byon Chang Hyun , Liu Hui , Ahn Eun-Young , Jhala Nirag , Arnoletti Juan P. , McDonald Jay M. , Chen Yabing
Published: February 2009

Purpose: Cholangiocarcinoma is a fatal tumor with limited therapeutic options. We have reported that calmodulin antagonists tamoxifen and trifluoperazine induced apoptosis in cholangiocarcinoma cells. Here, we determined the effects of tamoxifen on tumorigenesis and the molecular mechanisms of tamoxifen-induced apoptosis.

Experimental Design: Nude mice xenograft model of cholangiocarcinoma was used and tamoxifen was given i.p. and intratumorally. Cholangiocarcinoma cells were used to characterize molecular mechanisms of tamoxifen-induced apoptosis in vitro.

Results: I.p. or intratumoral injection of tamoxifen decreased cholangiocarcinoma tumorigenesis by 40% to 80% in nude mice. In cells isolated from tumor xenografts, tamoxifen inhibited phosphorylation of AKT (pAKT) and cellular FLICE like inhibitory protein (c-FLIP). Immunohistochemical analysis further showed that pAKT was identified in all nontreated tumors but was absent in tamoxifen-treated tumors. In vitro, tamoxifen activated caspase-8 and caspase-10, and their respective inhibitors partially blocked tamoxifen-induced apoptosis. Overexpression of c-FLIP inhibited tamoxifen-induced apoptosis and enhanced tumorigenesis of cholangiocarcinoma cells in nude mice, whereas deletion of the calmodulin-binding domain on c-FLIP restored the sensitivity to tamoxifen and inhibited tumorigenesis. With two additional cholangiocarcinoma cell lines, we confirmed that the expression of FLIP is an important factor in mediating spontaneous and tamoxifen-induced apoptosis.

Conclusions: Thus, tamoxifen inhibits cholangiocarcinoma tumorigenesis in nude mice. Tamoxifen-induced apoptosis is partially dependent on caspases, inhibition of pAKT, and FLIP expression. Further, calmodulin-FLIP binding seems to be important in FLIP-mediated resistance to tamoxifen. Therefore, the present studies support the concept that tamoxifen may be used as a therapy for cholangiocarcinoma and possibly other malignancies in which the calmodulin targets AKT and c-FLIP play important roles in the tumor pathogenesis.
Antitumor Activity of an Oncolytic Adenoviral-CD40 Ligand (CD154) Transgene Construct in Human Breast Cancer Cells
Authors: Gomes Erica M. , Rodrigues Margret S. , Phadke Anagha P. , Butcher Lindsay D. , Starling Cherry , Chen Salina , Chang Dongkun , Hernandez-Alcoceba Ruben , Newman Joseph T. , Stone Marvin J. , Tong Alex W.
Published: February 2009

Purpose: CD40 ligand (CD40L, CD154) plays a central role in immunoregulation and also directly modulates epithelial cell growth and differentiation. We previously showed that the CD40 receptor is commonly expressed in primary breast cancer tissues. In this proof-of-principle study, we examined the breast cancer growth–regulatory activities of an oncolytic adenoviral construct carrying the CD40L transgene (AdEHCD40L).

Experimental Design: In vitro and in vivo evaluations were carried out on AdEHCD40L to validate selective viral replication and CD40L transgene activity in hypoxia inducing factor-1α and estrogen receptor–expressing human breast cancer cells.

Results: AdEHCD40L inhibited the in vitro growth of CD40+ human breast cancer lines (T-47D, MDA-MB-231, and BT-20) by up to 80% at a low multiplicity of infection of 1. Incorporation of the CD40L transgene reduced the effective dose needed to achieve 50% growth inhibition (ED50) by ∼10-fold. In contrast, viral and transgene expression of AdEHCD40L, as well its cytotoxicity, was markedly attenuated in nonmalignant cells. Intratumoral injections with AdEHCD40L reduced preexisting MDA-MB-231 xenograft growth in severe combined immunodeficient mice by >99% and was significantly more effective (P < 0.003) than parental virus AdEH (69%) or the recombinant CD40L protein (49%). This enhanced antitumor activity correlated with cell cycle blockade and increased apoptosis in AdEHCD40L-infected tumor cells.

Conclusions: These novel findings, together with the previously known immune-activating features of CD40L, support the potential applicability of AdEHCD40L for experimental treatment of human breast cancer.
Role of ADAMs in Cancer Formation and Progression
Authors: Duffy Michael J. , McKiernan Eadaoin , O'Donovan Norma , McGowan Patricia M.
Published: February 2009

The ADAMs (a disintegrin and metalloproteinase) comprise a family of multidomain transmembrane and secreted proteins. One of their best-established roles is the release of biologically important ligands, such as tumor necrosis factor–α, epidermal growth factor, transforming growth factor–α, and amphiregulin. Because these ligands have been implicated in the formation and progression of tumors, it might be expected that the specific ADAMs involved in their release would also be involved in malignancy. Consistent with this hypothesis, emerging data from model systems suggest that ADAMs, such as ADAM-9, ADAM-12, ADAM-15, and ADAM-17, are causally involved in tumor formation/progression. In human cancer, specific ADAMs are up-regulated, with levels generally correlating with parameters of tumor progression and poor outcome. In preclinical models, selective ADAM inhibitors against ADAM-10 and ADAM-17 have been shown to synergize with existing therapies in decreasing tumor growth. The ADAMs are thus a new family of potential targets for the treatment of cancer, especially malignancies that are dependent on human epidermal growth factor receptor ligands or tumor necrosis factor–α.
Angiopoietin-2 Levels Are Associated with Disease Progression in Metastatic Malignant Melanoma
Authors: Helfrich Iris , Edler Lutz , Sucker Antje , Thomas Markus , Christian Sven , Schadendorf Dirk , Augustin Hellmut G.
Published: February 2009

Purpose: The blood vessel-destabilizing Tie2 ligand angiopoietin-2 (Ang-2) acts in concert with the vascular endothelial growth factor/vascular endothelial growth factor receptor system to control vessel assembly during tumor progression. We hypothesized that circulating soluble Ang-2 (sAng-2) may be involved in melanoma progression.

Experimental Design: Serum samples (n = 98) from melanoma patients (American Joint Committee on Cancer stages I-IV), biopsies of corresponding patients, and human melanoma cell lines were analyzed for expression of Ang-2 and S100β. Multiple sera of a subcohort of 33 patients were tested during progression from stage III to IV. Small interfering RNA-based loss-of-function experiments were done to assess effects of Ang-2 on melanoma cells.

Results: Circulating levels of sAng-2 correlate with tumor progression in melanoma patients (P < 0.0001) and patient survival (P = 0.007). Analysis of serum samples during the transition from stage III to IV identified an increase of sAng-2 up to 400%. Comparative analyses revealed a 56% superiority of sAng-2 as predictive marker over the established marker S100β. Immunohistochemistry and reverse transcription-PCR confirmed the prominent expression of Ang-2 by tumor-associated endothelial cells but identified Ang-2 also as a secreted product of melanoma cells themselves. Corresponding cellular experiments revealed that human melanoma-isolated tumor cells were Tie2 positive and that Ang-2 acted as an autocrine regulator of melanoma cell migration and invasion.

Conclusions: The experiments establish sAng-2 as a biomarker of melanoma progression and metastasis correlating with tumor load and overall survival. The identification of an autocrine angiopoietin/Tie loop controlling melanoma migration and invasion warrants further functional experiments and validate the angiopoietin/Tie system as a promising therapeutic target for human melanomas.
The Combined Therapeutic Effects of Bortezomib and Fenretinide on Neuroblastoma Cells Involve Endoplasmic Reticulum Stress Response
Authors: Pagnan Gabriella , Di Paolo Daniela , Carosio Roberta , Pastorino Fabio , Marimpietri Danilo , Brignole Chiara , Pezzolo Annalisa , Loi Monica , Galietta Luis J.V. , Piccardi Federica , Cilli Michele , Nico Beatrice , Ribatti Domenico , Pistoia Vito , Ponzoni Mirco
Published: February 2009

Purpose: The proteasome inhibitor bortezomib inhibited cell growth and angiogenesis in neuroblastoma. Bortezomib has been shown to induce synergistic activity when combined with other antineoplastic agents. Here we have investigated the antitumor activity of bortezomib in combination with fenretinide, a synthetic retinoid, against neuroblastoma cells.

Experimental Design: Different neuroblastoma cell lines were tested for sensitivity to bortezomib and fenretinide, given alone or in different dose-dependent and time-dependent combination schedules. Cell proliferation, cell viability, and apoptosis were evaluated by measuring 3H-thymidine incorporation, trypan blue staining, DNA fragmentation, and western blot analysis. Angiogenesis was assessed by the chick embryo chorioallantoic membrane assay. An orthotopic neuroblastoma mouse model was used to examine in vivo sensitivity.

Results: Each compound alone was able to induce a dose-dependent inhibition of cell proliferation, with a significant enhanced antiproliferative effect for the drugs used in combination. This inhibition was characterized by marked G2-M and G1 cell cycle arrest with nearly complete depletion of S phase. Bortezomib and fenretinide in association triggered an increased apoptosis through activation of specific genes of the endoplasmic reticulum stress compared with either drug tested alone. Tumor-bearing mice treated with bortezomib plus fenretinide lived statistically significantly longer than mice treated with each drug alone. Histologic evaluation and chorioallantoic membrane analysis of primary tumors showed that the combined therapeutic activity of bortezomib and fenretinide rested upon antitumor and antiangiogenic mechanisms.

Conclusions: These findings provide the rationale for the development of a new therapeutic strategy for neuroblastoma based on this pharmacologic combination.
Turmeric and Green Tea: A Recipe for the Treatment of B-Chronic Lymphocytic Leukemia
Authors: Angelo Laura S. , Kurzrock Razelle
Published: February 2009

Two naturally occurring compounds, curcumin, the active ingredient in the spice turmeric, and the green tea extract epigallocatechin-3-gallate, have marked effects on the apoptotic machinery in chronic lymphocytic leukemia. These results provide a preclinical foundation for future clinical use of these compounds in this disease.
Inferior and Lateral Electrocardiographic Repolarization Abnormalities in Brugada Syndrome
Authors: Sarkozy Andrea , Chierchia Gian-Battista , Paparella Gaetano , Boussy Tim , De Asmundis Carlo , Roos Marcus , Henkens Stefan , Kaufman Leonard , Buyl Ronald , Brugada Ramon , Brugada Josep , Brugada Pedro
Published: February 2009

Background—

Repolarization abnormalities in the inferior-lateral leads in Brugada syndrome (BS) have not been systematically investigated.

Methods and Results—

280 patients (age, 41�18 years; 168 males) with BS were screened for inferior-lateral repolarization abnormalities. The repolarization abnormalities were classified either as early repolarization pattern or coved ≥2-mm Brugada pattern and as spontaneous or class I antiarrhythmic drug (AAD) induced. Thirty-two patients (11%) had inferior-lateral spontaneous early repolarization pattern. These patients were less likely to be asymptomatic at first presentation (13 of 32 versus 156 of 248 patients,
P
=0.02), and spontaneous type I ECG was more frequent among them (38% versus 21%,
P
=0.05). The spontaneous early repolarization pattern occurred more frequently among patients with BS than in 283 family members not having BS (11% versus 6%,
P
=0.03). Class I AAD administration provoked inferior-lateral coved Brugada pattern in 13 patients with BS. These patients had longer baseline PR intervals (206�48 versus 172�31 ms,
P
<0.001) and class I AAD–induced QRS interval prolongation (108 to 178 versus 102 ms to 131 ms,
P
<0.001). In 3 patients, the class I AAD–provoked coved Brugada pattern was only present in the inferior leads.

Conclusions—

Inferior-lateral early repolarization pattern occurs spontaneously relatively frequently in BS. These patients have a more severe phenotype. Class I AAD administration provokes inferior-lateral coved Brugada pattern in 4.6% of patients. We report for the first time 3 patients in whom the class I AAD–provoked coved Brugada pattern was only observed in the inferior leads.
Atrial Fibrillation Ablation Strategies for Paroxysmal Patients
Authors: Di Biase Luigi , Elayi Claude S. , Fahmy Tamer S. , Martin David O. , Ching Chi Keong , Barrett Conor , Bai Rong , Patel Dimpi , Khaykin Yaariv , Hongo Richard , Hao Steven , Beheiry Salwa , Pelargonio Gemma , Russo Antonio Dello , Casella Michela , Santarelli Pietro , Potenza Domenico , Fanelli Raffaele , Massaro Raimondo , Wang Paul , Al-Ahmad Amin , Arruda Mauricio , Themistoclakis Sakis , Bonso Aldo , Rossillo Antonio , Raviele Antonio , Schweikert Robert A. , Burkhardt David J. , Natale Andrea
Published: February 2009

Background—

Whether different ablation strategies affect paroxysmal atrial fibrillation (AF) long-term freedom from AF/atrial tachyarrhythmia is unclear. We sought to compare the effect of 3 different ablation approaches on the long-term success in patients with paroxysmal AF.

Methods and Results—

One hundred three consecutive patients with paroxysmal AF scheduled for ablation and presenting in the electrophysiology laboratory in AF were selected for this study. Patients were randomized to pulmonary vein antrum isolation (PVAI; n=35) versus biatrial ablation of the complex fractionated atrial electrograms (CFAEs; n=34) versus PVAI followed by CFAEs (n=34). Patients were given event recorders and followed up at 3, 6, 9, 12, and 15 months postablation. There was no statistical significant difference between the groups in term of sex, age, AF duration, left atrial size, and ejection fraction. At 1 year follow-up, freedom from AF/atrial tachyarrhythmia was documented in 89% of patients in the PVAI group, 91% in the PVAI plus CFAEs group, and 23% in the CFAEs group (
P
<0.001) after a single procedure and with antiarrhythmic drugs.

Conclusion—

No difference in terms of success rate was seen between PVAI alone and PVAI associated with defragmentation. CFAEs ablation alone had the smallest impact on AF recurrences at 1-year follow-up. These results suggest that antral isolation is sufficient to treat most patients with paroxysmal AF.
Acute Effects of Right Ventricular Apical Pacing on Left Ventricular Synchrony and Mechanics
Authors: Delgado Victoria , Tops Laurens F. , Trines Serge A. , Zeppenfeld Katja , Ajmone Marsan Nina , Bertini Matteo , Holman Eduard R. , Schalij Martin J. , Bax Jeroen J.
Published: February 2009

Background—

Chronic right ventricular (RV) apical pacing has a detrimental effect on left ventricular (LV) function. However, the acute effects of RV apical pacing on LV mechanics remain unclear. The purpose of the study was to assess the acute impact of RV apical pacing on global LV function, evaluating LV contraction synchrony and LV shortening and twist, using 2D speckle-tracking strain imaging.

Methods and Results—

A group of 25 patients with structural normal hearts referred for electrophysiological study were studied. Two-dimensional echocardiography was performed at baseline and during RV apical pacing at the time of the electrophysiological study. Changes in LV synchrony and mechanics (longitudinal shortening and twist) were assessed using speckle-tracking strain imaging. In addition, 25 controls matched by age, sex, and LV function were studied during sinus rhythm. The group of patients (44�12 years, 10 men) and the group of controls (48�3 years, 8 men) showed comparable LV synchrony, LV longitudinal shortening, and LV twist at baseline. However, during RV apical pacing, a more dyssynchronous LV contraction was observed in the patients (from 21 ms [Q
1
:10, Q
3
:53] to 91 ms [Q
1
:40, Q
3
:204],
P
<0.001) together with an impairment in LV longitudinal shortening (from −18.3�3.5% to −11.8�3.6%,
P
<0.001) and in LV twist (from 12.4�3.7� to 9.7�2.6�,
P
=0.001).

Conclusions—

During RV apical pacing, an acute induction of LV dyssynchrony is observed. In addition, LV longitudinal shortening and LV twist are acutely impaired.
Esophageal Capsule Endoscopy After Radiofrequency Catheter Ablation for Atrial Fibrillation
Authors: Di Biase Luigi , Saenz Luis Carlos , Burkhardt David J. , Vacca Miguel , Elayi Claude S. , Barrett Conor D. , Horton Rodney , Bai Rong , Siu Alan , Fahmy Tamer S. , Patel Dimpi , Armaganijan Luciana , Wu Chia Tung , Kai Sonne , Ching Ching Keong , Phillips Karen , Schweikert Robert A. , Cummings Jennifer E. , Arruda Mauricio , Saliba Walid I. , Dodig Milan , Natale Andrea
Published: February 2009

Background—

Left atrioesophageal fistula is a rare but devastating complication that may occur after catheter ablation of atrial fibrillation. We used capsule endoscopy to assess esophageal injury after catheter ablation for atrial fibrillation in a population randomized to undergo general anesthesia or conscious sedation.

Methods and Results—

Fifty patients undergoing atrial fibrillation ablation for paroxysmal symptomatic atrial fibrillation refractory to antiarrhythmic drugs were enrolled and randomized, including those undergoing the procedure under general anesthesia (25 patients, group 1) and those receiving conscious sedation with fentanyl or midazolam (25 patients, group 2). All patients underwent esophageal temperature monitoring during the procedure. The day after ablation, all patients had capsule endoscopy to assess the presence of endoluminal tissue damage of the esophagus. We observed esophageal tissue damage in 12 (48%) patients of group 1 and 1 esophageal tissue damage in a single patient (4%) of group 2 (
P
<0.001). The maximal esophageal temperature was significantly higher in patients undergoing general anesthesia (group 1) versus patients undergoing conscious sedation (group 2) (40.6�1�C versus 39.6�0.8�C;
P
< 0.003). The time to peak temperature was 9�7 seconds in group 1 and 21�9 seconds in group 2, and this difference was statistically significant (
P
<0.001). No complication occurred during or after the administration of the pill cam or during the procedures. All esophageal lesions normalized at the 2-month repeat endoscopic examination.

Conclusion—

The use of general anesthesia increases the risk of esophageal damage detected by capsule endoscopy.
Fragments of a Global Past: Ceramics Manufacture in Song-Yuan-Ming Jingdezhen
Authors: Gerritsen Anne
Published: February 2009

This essay explores textual genres related to the production of ceramics in Jingdezhen, including maps, literati collections, the literature of connoisseurship, local gazetteers, and merchant manuals. An analysis of these genres brings the Chinese textual record of ceramics into sharper focus and reveals what has remained unwritten. Whereas European writings on Chinese ceramics from the seventeenth and eighteenth centuries dwell on modes of manufacture in a global context, Chinese writers generally ignore matters of technology and commerce beyond the confines of the Chinese realm. These omissions emerge in part from the peculiarities of the genres within which these writings have been transmitted. Cet essai examine les différents genres de textes qui ont trait à la production de la céramique dans Jingdezhen. Parmi ces textes, il se trouve des cartes géographiques, des collections d'écrits de 'literati', des monographies locales et des manuels de commerce. L'analyse de ces genres permet d'approfondir notre compréhension de la tradition écrite au sujet de la céramique, tout en révélant en même temps, ce qui reste implicite en ces textes. Les auteurs chinois ne s'attardent pas aux questions de technologie, ni au commerce au-delà des confins de l'Empire chinois. Le présent essai suggère que ces omissions s'expliquent par les conventions des genres auxquels ces écrits appartiennent.
Regulating Corporate Social and Human Rights Responsibilities at the UN Plane: Institutionalising New Forms of Law and Law-making Approaches?
Authors: Buhmann Karin
Published: February 2009

Globalisation's unprecedented growth and transborder activities of business coupled with increasing awareness of the impact of business on societies and human rights has resulted in demands for the international society to regulate corporate social and human rights responsibilities. This not only challenges traditional notions of duty bearers under international law, but also calls for novel approaches for the United Nations (UN) to implement central parts of the Charter's human rights aims and to address corporate behaviour in a state-centred international law-making order that lacks the willingness of States to regulate business. This article explores recent UN responses and argues that in the absence of States acting through ordinary international law-making, the UN as an intergovernmental organisation draws on participatory modes of law-making and new forms of law in order to normatively influence businesses' impact on human rights. The pattern of using these forms suggests an institutionalisation of reflexive regulation as a regulatory process drawing on public-private regulation, and of an emerging UN based 'Global Administrative Law' in order to meet regulatory challenges in living up to the human rights aims embodied in the UN Charter under the conditions posed by globalisation of the economy and emergence of strong transnational non-state actors. The analysis is based on the UN Global Compact, the draft Norms on the Responsibilities of Transnational Corporations and Other Business Enterprises with regard to Human Rights and the process of the Special Representative of the Secretary General on the issue of human rights and transnational corporations and business (SRSG).
'Territorial Non-Application' of the European Convention on Human Rights
Authors: Larsen Kjetil Mujezinović
Published: February 2009

This article examines the issue of when a State can be considered not to exercise jurisdiction under Article 1 of the European Convention on Human Rights in parts of its own territory. The starting point is that the notion of jurisdiction in the Convention is primarily territorial, and that a State is presumed to exercise jurisdiction throughout the entire territory. The presumption can be rebutted in exceptional circumstances. The author argues that this can happen only if the State is prevented from exercising authority and control in parts of the territory, and that the lack of authority and control must be caused by the influence of another State. Even if the State is considered to be in this position, the State retains a "reduced jurisdiction", and is under a positive obligation to take measures to protect the human rights of the population. The article examines the issue with particular reference to the Assanidze and Ilaşcu cases from the European Court of Human Rights, and illustrates the issue by reviewing briefly the current situation in four regions in the Caucasus.
Group Rights and Conflicts in Africa: A Critical Reflection on Ife-Modakeke, Nigeria
Authors: Akanji Olajide
Published: February 2009

The issue of group rights is indubitably an issue that concerns both minority and majority groups. Notwithstanding, minorities are quicker to claim the rights than the dominant groups. But the fact that group rights are a set of rights, though distinguishable from individual rights, within the general framework of fundamental human rights, shows that both minority and majority groups can exercise and enjoy them. The thrust of this article, however, is to fill the lacuna in extant literature on the need to appraise the role and place of group rights in the generation, transformation and sustenance of conflicts in Nigeria. The paper uses the age-long, protracted Ife-Modakeke conflict as a case study. Nigeria, being a plural society, the paper infers, is indeed susceptible to conflicts that border on issues of the collective rights of ethnic, sub-ethnic and religious groups. The article, nonetheless, argues that it is the non-recognition and respect of the rights of groups, both minority and majority, through the non-provision of adequate and appropriate measures by successive governments, contrary to international standards to which the country is a signatory, that often heightened tension and fractured inter-group relations in the country.
Supervisory Review and the Finality of Judgments under Russian Law
Authors: Pomeranz William
Published: February 2009

In this article, the author examines the institution of civil and criminal supervisory review (nadzor) and its compliance with such internationally recognized legal norms as res judicata and the right to a fair trial. Nadzor generally serves as extraordinary appeal of civil and criminal judgments that already have entered into legal force. The author first examines the historical roots of supervisory review during the Soviet period. He then analyzes how the supervisory review process has been transformed by the 2002 Civil Procedure Code and the 2001 Criminal Procedure Code. The author also reviews the role played by the Council of Europe, the European Court of Human Rights and the Russian Constitutional Court in influencing the changes to the supervisory review process. Although this process has become fairer and more transparent, the author shows that nadzor remains controversial, most notably due to the lack of finality associated with the process. The article concludes by discussing the prospects for nadzor and how this process has influenced Russia's transition to a rule of law state.
The Male Involvement Programme and Men's Sexual and Reproductive Health in Northern Namibia
Authors: Mufune Pempelani
Published: February 2009

Sexual and reproductive health (SRH) issues affect both males and females and relate to gender inequalities and HIV/AIDS. In the past, the focus of SRH has not been on men but on women, who get pregnant and nurture the young. This is despite evidence showing that males exercise decision-making power in different social-cultural spheres including the transmission of sexually transmitted diseases (STDs). This article describes research on the impact of the Male Involvement programme in Namibia. The objectives of the programme were to train groups of males (nurses, clergy, police, soldiers and sportsmen) in SRH knowledge and communication skills. The research investigated the extent to which male participants gained SRH knowledge from the programme and the extent to which the knowledge gained affected their views on cultural conceptions of masculinity and femininity that influence their orientation towards SRH. The research utilized focus group interviews with participating males exposed to the programme. The findings showed that male participants increased their knowledge of human sexuality and sexual health. There were, however, differences in the extent of knowledge gained among the different male groups. The implications of these findings for gender relations were noted. Many of the males consequently appreciated the tensions existing in their own relationships with spouses as partly due to lack of appreciation of the other. They now saw that wives were not simply appendages of their husbands and that women are not quite as inferior as their culture had taught them to believe. They appreciated the reality of `emotional abuse' (a concept de-emphasized in their culture). They could perceive the benefits that accrued to them personally as males from greater female empowerment and from changing their attitudes towards them. This study raises the possibility that masculine behaviours driven by culture can be changed through education.