bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunosuppression induced by expression of a viral RNase enhances susceptibility of Plutella xylostella to microbial pesticides
Authors: Park Bokri , Kim Yonggyun
Published: July 2011

Abstract  Polydnaviruses are a group of insect DNA viruses and are characterized in their segmented genome that is located in the chromosome(s) of host wasps. A polydnavirus, Cotesia plutellae bracovirus (CpBV), encodes a viral ribonuclease (RNase) T2 in a specific segment #3 (CpBV‐S3). This study tested its effect on gene expression associated with host immune responses in the diamondback moth, Plutella xylostella. Micro‐injection of CpBV‐S3 into nonparasitized larvae induced expression of its two encoded genes, CpBV‐ORF301 (=CpBV‐RNase T2) and CpBV‐ORF302. In response to a bacterial challenge, four antimicrobial peptide genes (hemolin, gloverin, cecropin and lysozyme) and six phenoloxidase (PO)–associated genes (proPO‐activating proteinase, PO, serine proteinase homolog and serpins 1–3) were up‐regulated in their expressions. However, the transient expression of CpBV‐S3 suppressed the expressions of cecropin, PO and serpin 1. Double‐stranded RNA specific to the viral RNase T2 could specifically knockdown the viral gene expression and restored the three gene expressions suppressed in the larvae injected with CpBV‐S3. The inhibitory activity of the viral RNase T2 on the target genes was further proven by the suppression of PO activation in response to bacterial challenge in the larvae injected with CpBV‐S3. This immunosuppression by the expression of the viral RNase T2 resulted in significant increase of pathogen susceptibility of P. xylostella against Bacillus thuringiensis or baculovirus infection.
Activation of 5-hydroxytryptamine-1A receptors suppresses cardiovascular responses evoked from the paraventricular nucleus
Authors: Horiuchi Jouji , Atik Alp , Iigaya Kamon , McDowall Lachlan M. , Killinger Suzanne , Dampney Roger A. L.
Published: July 2011

Activation of central 5-hydroxytryptamine-1A (5-HT1A) receptors powerfully inhibits stress-evoked cardiovascular responses mediated by the dorsomedial hypothalamus (DMH), as well as responses evoked by direct activation of neurons within the DMH. The hypothalamic paraventricular nucleus (PVN) also has a crucial role in cardiovascular regulation and is believed to regulate heart rate and renal sympathetic activity via pathways that are independent of the DMH. In this study, we determined whether cardiovascular responses evoked from the PVN are also modulated by activation of central 5-HT1A receptors. In anesthetized rats, the increases in heart rate and renal sympathetic nerve activity evoked by bicuculline injection into the PVN were greatly reduced (by 54% and 61%, respectively) by intravenous administration of (±)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), an agonist of 5-HT1A receptors, but were then completely restored by subsequent administration of WAY-100635, a selective antagonist of 5-HT1A receptors. Microinjection of 8-OH-DPAT directly into the PVN did not significantly affect the responses to bicuculline injection into the PVN, nor did systemic administration of WAY-100635 alone. In control experiments, a large renal sympathoexcitatory response was evoked from both the PVN and DMH but not from the intermediate region in between; thus the evoked responses from the PVN were not due to activation of neurons in the DMH. The results indicate that activation of central 5-HT1A receptors located outside the PVN powerfully inhibits the tachycardia and renal sympathoexcitation evoked by stimulation of neurons in the PVN.
Sarcomatoid Carcinoma of the Prostate: Ductal Adenocarcinoma and Stromal Sarcoma-Like Appearance: A Rare Association
Authors: Parada David , Peña Karla B. , Riu Francesc
Published: July 2011

Sarcomatoid carcinoma (SC) of prostate gland is a rare biphasic tumour. In about half of cases, initial diagnosis is acinar adenocarcinoma, followed by nonsurgical therapy, with a subsequent diagnosis of SC. The survival rate is lower. We report a case of an 59-years-old man with unusual histopathologic finding of prostate sarcomatoid carcinoma, showing characteristics of ductal prostatic adenocarcinoma and prostatic stromal sarcoma-like appearance. Ductal adenocarcinoma was characterized by tall columnar cells with abundant amphophilic to eosinophil cytoplasm. Pleomorphic sarcoma was characterized to have overall glandular growth pattern, simulating a malignant phyllodes tumour. Estrogen and progesterone receptors showed nuclear immunostaining in mesenchymal multinucleated giant cells. In conclusion, SC of the prostate is an exceedingly rare tumour. Retrospective analyses render prostate SC as one of the most aggressive prostate malignancies. The prognosis is dismal regardless of other histologic or clinical findings.
Antitumor Activity of Metal-Chelating Compound Dp44mT Is Mediated by Formation of a Redox-Active Copper Complex That Accumulates in Lysosomes
Authors: Lovejoy David B. , Jansson Patric J. , Brunk Ulf T. , Wong Jacky , Ponka Prem , Richardson Des R.
Published: July 2011

The metal-chelating compound Dp44mT is a di-2-pyridylketone thiosemicarbazone (DpT) which displays potent and selective antitumor activity. This compound is receiving translational attention, but its mechanism is poorly understood. Here, we report that Dp44mT targets lysosome integrity through copper binding. Studies using the lysosomotropic fluorochrome acridine orange established that the copper–Dp44mT complex (Cu[Dp44mT]) disrupted lysosomes. This targeting was confirmed with pepstatin A–BODIPY FL, which showed redistribution of cathepsin D to the cytosol with ensuing cleavage of the proapoptotic BH3 protein Bid. Redox activity of Cu[Dp44mT] caused cellular depletion of glutathione, and lysosomal damage was prevented by cotreatment with the glutathione precursor N-acetylcysteine. Copper binding was essential for the potent antitumor activity of Dp44mT, as coincubation with nontoxic copper chelators markedly attenuated its cytotoxicity. Taken together, our studies show how the lysosomal apoptotic pathway can be selectively activated in cancer cells by sequestration of redox-active copper. Our findings define a novel generalized strategy to selectively target lysosome function for chemotherapeutic intervention against cancer. Cancer Res; 71(17); 5871–80. ©2011 AACR.
Specific PET Imaging of xC− Transporter Activity Using a 18F-Labeled Glutamate Derivative Reveals a Dominant Pathway in Tumor Metabolism
Authors: Koglin Norman , Mueller Andre , Berndt Mathias , Schmitt-Willich Heribert , Toschi Luisella , Stephens Andrew W. , Gekeler Volker , Friebe Matthias , Dinkelborg Ludger M.
Published: July 2011

Purpose: 18F-labeled small molecules targeting adaptations of tumor metabolism possess the potential for early tumor detection with high sensitivity and specificity by positron emission tomography (PET) imaging. Compounds tracing deranged pathways other than glycolysis may have advantages in situations where 2-[18F]fluoro-2-deoxy-d-glucose (FDG) has limitations. The aim of this study was the generation of a metabolically stable 18F-labeled glutamate analogue for PET imaging of tumors.

Experimental Design: Derivatives of l-glutamate were investigated in cell competition assays to characterize the responsible transporter. An automated radiosynthesis was established for the most promising candidate. The resulting 18F-labeled PET tracer was characterized in a panel of in vitro and in vivo tumor models. Tumor specificity was investigated in the turpentine oil-induced inflammation model in rats.

Results: A fluoropropyl substituted glutamate derivative showed strong inhibition in cell uptake assays. The radiosynthesis was established for (4S)-4-(3-[18F]fluoropropyl)-l-glutamate (BAY 94-9392). Tracer uptake studies and analysis of knockdown cells showed specific transport of BAY 94-9392 via the cystine/glutamate exchanger designated as system xC−. No metabolites were observed in mouse blood and tumor cells. PET imaging with excellent tumor visualization and high tumor to background ratios was achieved in preclinical tumor models. In addition, BAY 94-9392 did not accumulate in inflammatory lesions in contrast to FDG.

Conclusions: BAY 94-9392 is a new tumor-specific PET tracer which could be useful to examine system xC− activity in vivo as a possible hallmark of tumor oxidative stress. Both preclinical and clinical studies are in progress for further characterization. Clin Cancer Res; 17(18); 6000–11. ©2011 AACR.
Prognosis and Outcome of the Tympanic Membrane Flap at Traumatic Tympanic Membrane Perforation Edge
Authors: Lou Zheng-Cai , Hu Yun-Xing , Tang Yong-Mei
Published: July 2011

This study aimed to retrospectively evaluate the prognosis and outcome of tympanic membrane perforations with a particular focus on the fate of the perforation edge flaps.Chart records of 329 patients with a single ear traumatic tympanic membrane perforation were retrieved and analyzed. Of these patients, 70 were left to heal spontaneously, 93 received gelatin sponge patching treatment and 114 were subjected to otoendoscopic eardrum repair before gelatin sponge patching. The complete perforation closure rate at 3 months was 94.29% (66/70), 98.92% (92/93) and 98.24% (112/114) in the 3 groups, respectively, with no statistically significant difference (p = 0.608). The mean closure time was 28.2 ± 3.6 days in the spontaneous healing group, which was significantly longer than that in the sponge patching group (11.1 ± 2.1 days, p = 0.0017) and in the eardrum repair + sponge patching group (12.5 ± 1.9 days, p = 0.0032), while there was no significant difference between the 2 gelatin sponge patching groups (p = 1.86). The hearing ability improved in the 3 groups (6.4 ± 0.83, 7.2 ± 1.65 and 9.6 ± 2.37 dB, respectively), with no statistically significant difference (p >0.05). In the gelatin sponge patching group, new tympanic membrane tissue of the eardrum flap edge proliferated, and the contour of the eardrum flap was not obvious. In the eardrum flap repair group, the eardrum flap retracted to the perforation edge. In conclusion, the eardrum flap of the perforation edge does not have any obvious effect on the perforation closure so that it is unnecessary to conduct an intervention procedure on the flap in the clinical treatment.
Decreased α-Synuclein Serum Levels in Patients with Lewy Body Dementia Compared to Alzheimer’s Disease Patients and Control Subjects
Authors: Laske Christoph , Fallgatter Andreas J. , Stransky Elke , Hagen Katja , Berg Daniela , Maetzler Walter
Published: July 2011

Background/Aims: Detection and differentiation of neurodegenerative dementias, such as dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD), with blood-based biomarkers would facilitate diagnosis and treatment. Methods: By use of a commercially available ELISA kit, we measured α-synuclein levels in the serum of 40 DLB patients and controls, and of 80 AD patients. Results: We found significantly reduced α-synuclein serum levels in DLB compared to both AD (p = 0.006) and control subjects (p = 0.001), reaching an area under the curve of >0.70. Conclusion: Although these results do not justify a definition of serum α-synuclein as a potential single biomarker, results may contribute to a multimarker strategy in DLB diagnosis.
Intramural Activation During Early Human Ventricular Fibrillation
Authors: Nair Krishnakumar , Umapathy Karthikeyan , Farid Talha , Masse Stephane , Mueller Erin , Sivanandan Radhika V. , Poku Kwaku , Rao Vivek , Nair Vidhya , Butany Jagdish , Ideker Raymond E. , Nanthakumar Kumaraswamy
Published: July 2011

Background—

We investigated patterns of intramural activation in early human ventricular fibrillation (VF) and hypothesized that intramural reentry colocalizes to sites with increased intramural fibrosis.

Methods and Results—

Thirteen human Langendorff hearts were used for this study. Twenty-five plunge needles (4 unipoles/needle) were used to map 100 intramural sites. For the global mapping component, 11 20-s episodes of early VF were studied in 6 hearts. Simultaneous activation of all 4 electrodes was the most common pattern observed in 48.7% of needles, followed by an endocardial-to-epicardial activation pattern (9.8% of needles) and epicardial-to-endocardial activation pattern (5.5% of needles); 19.3% of needles had nonuniform multidirectional patterns. In 2 orthogonal planes, 1 parallel and 1 perpendicular to the epicardium and endocardium, reentry was detected in 14.3% of beats at any 1 level, and 5.8% of these were transmural. Simultaneous mapping of the epicardium and endocardium in 5 hearts detected concurrently rotating rotors with similar chirality and cycle length, suggesting the presence of transmural scroll waves (n=6), which was confirmed by high-resolution fixed-space mapping in 2 of those hearts plus 1 additional heart. Transmural optical mapping in 1 additional heart confirmed simultaneous epicardial and endocardial activation. Histopathology revealed greater fibrosis at sites of reentry compared to areas without (53.3±11.9% versus 27.5±2.4%,
P
=0.02).

Conclusions—

Intramural activation patterns suggest that early human VF does not organize as multiple reentrant wavefronts but is best explained by transmural scroll wave activation. Intramural reentry localizes to regions of greater intramural fibrosis.
Relation of Peripheral Collagen Markers to Death and Hospitalization in Patients With Heart Failure and Preserved Ejection Fraction
Authors: Krum Henry , Elsik Maros , Schneider Hans G. , Ptaszynska Agata , Black Marion , Carson Peter E. , Komajda Michel , Massie Barry M. , McKelvie Robert S. , McMurray John J. , Zile Michael R. , Anand Inder S.
Published: July 2011

Background—

Heart failure with preserved ejection fraction (HFPEF) is a common and increasing public health problem. Myocardial fibrosis is a key pathological feature of HFPEF. Peripheral collagen markers may reflect this excess fibrosis; however, the relation of these markers to prognosis in patients with HFPEF has not as yet been determined.

Methods and Results—

This substudy of the Irbesartan in Heart Failure With Preserved Systolic Function (I-PRESERVE) trial measured plasma levels of procollagen type I amino-terminal peptide, procollagen type III amino-terminal peptide, and osteopontin in 334 patients with HFPEF. Measurements were performed at baseline and 6 months after randomization to placebo or irbesartan 300 mg/day. The relation of baseline collagen markers to the I-PRESERVE primary end point (all-cause death and hospitalization for prespecified cardiovascular causes) was evaluated by single and multivariable analysis. Similar evaluations were performed for all-cause death alone as well as heart failure events (death or hospitalization because of heart failure). Increased plasma levels of collagen markers at baseline were associated with increased frequency of the study primary end point for all collagen markers. For each 10-μg/L increase in procollagen type I amino-terminal peptide, the hazard ratio (HR) for the primary end point was 1.09 (95% CI, 1.052 to 1.13;
P
<0.0001); for each 10-μg/L increase in procollagen type III amino-terminal peptide procollagen type I amino-terminal peptide, the HR was 2.47 (95% CI, 0.97 to 6.33;
P
=0.059); and for each 10-nmol/L increase in osteopontin, the HR was 1.084 (95% CI, 1.026 to 1.15;
P
=0.004). No variable remained significant as an independent predictor when introduced into a multivariable model. Both treatment groups tended to reduce collagen markers, with the reduction significantly greater for placebo versus irbesartan for procollagen type III amino-terminal peptide only (
P
=0.0185).

Conclusions—

Increased peripheral collagen turnover markers were not independently associated with increased mortality and cardiovascular hospitalization in an HFPEF population on multivariable analysis but were associated on single-variable analysis. These findings provide some support to the hypothesis that pathological fibrosis in the heart, and possibly the peripheral vasculature, may be contributory to adverse clinical outcomes in patients with HFPEF.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00095238.
Supercells in Environments with Atypical Hodographs
Authors: Blanchard David O.
Published: July 2011

An unusual severe weather event with supercell thunderstorms developed across portions of northern Arizona in the midst of the warm-season North American monsoon—a regime characteristically dominated by a subtropical upper-level high over the southwestern United States. The approach of a midlatitude, cold-core, upper-level low brought an environment of enhanced shear and increased instability supportive of supercells. This atypical system is described and how a correct interpretation of the winds and hodograph would allow a forecaster to maintain situational awareness is discussed.
Exercising Social Responsibility in Downsizing: Enrolling and Mobilizing Actors at a Swedish High-Tech Company
Authors: Bergström Ola , Diedrich Andreas
Published: July 2011

This paper critically examines the claim made by previous research that companies exercise corporate social responsibility (CSR) by responding to stakeholder interests. It is based on a field study of the events following the announcement of collective redundancies at a Swedish high-tech company. Although more than 10,000 workers were dismissed, the company was accepted as being socially responsible. The study reveals that this outcome was the result of a process whereby corporate representatives managed to enrol and mobilize a network of actors into being faithful to, and defending, their definition of social responsibility. This indicates that a company can assume an active role in the construction of the same network of actors that it is asked to respond to and impose upon other actors its own definition of what it means to be socially responsible. As a result, the translation of CSR within the network of actors may reinforce the powerful position of the company, rather than curb it.
The Emergence of an Influential Practice: Food for Thought
Authors: Gomez Marie-Léandre , Bouty Isabelle
Published: July 2011

How do influential practices initially emerge? Bourdieu’s work offers an approach to answering this question and connecting local micro and field-level macro phenomena. We empirically build on this framework to analyse how the practice of using vegetables as gastronomic ingredients emerged in the field of haute cuisine at three-star chef Alain Passard’s Arpège restaurant. Based on multilevel and longitudinal data, we describe the practice and account for its emergence based on Passard’s habitus and his position in the field of haute cuisine. Our research contributes to the practice-based literature by highlighting the complicity between the agent and the field, and it contributes to institutional theory-based studies by accounting for the genesis of a new influential practice initiated by an individual insider.
Sodium-phosphorylated chitosan/zinc oxide complexes and evaluation of their cytocompatibility: An approach for periodontal dressing
Authors: Srakaew Veeranuch , Ruangsri Praphansri , Suthin Kanyarat , Thunyakitpisal Pasutha , Tachaboonyakiat Wanpen
Published: July 2011

The aim of this study was to evaluate the possibility of metal complex formation between sodium-phosphorylated chitosan (PCTS) and ZnO. The polymer–metal complex formation was investigated in terms of thermal degradation. The structure deduction of the PCTS/ZnO complex was investigated by means of Fourier transform infrared spectroscopy and X-ray diffraction (XRD). The PCTS/ZnO complexes were formed by the sharing of lone pairs of electrons from the N atoms in the amine groups and O atoms in the phosphate and hydroxyl groups of PCTS to the protonated hydroxyl species on the ZnO surface. Because complex formation occurred at the surface of ZnO particles, it did not change the ZnO crystalline structure. Cytotoxicity, evaluated by a direct contact test with primary human gingival fibroblast cells, revealed that PCTS was biocompatible and reduced the cytotoxicity of ZnO by complexation, making PCTS/ZnO complexes potentially biocompatible. Within the limits of these data, it appears that PCTS could be used as a reaction rate-modifying agent in periodontal dressings.
Becoming a Vampire Without Being Bitten
Authors: Gabriel Shira , Young Ariana F.
Published: July 2011

We propose the narrative collective-assimilation hypothesis—that experiencing a narrative leads one to psychologically become a part of the collective described within the narrative. In a test of this hypothesis, participants read passages from either a book about wizards (from the Harry Potter series) or a book about vampires (from the Twilight series). Both implicit and explicit measures revealed that participants who read about wizards psychologically became wizards, whereas those who read about vampires psychologically became vampires. The results also suggested that narrative collective assimilation is psychologically meaningful and relates to the basic human need for connection. Specifically, the tendency to fulfill belongingness needs through group affiliation moderated the extent to which narrative collective assimilation occurred, and narrative collective assimilation led to increases in life satisfaction and positive mood, two primary outcomes of belonging. The implications for the importance of narratives, the need to belong to groups, and social surrogacy are discussed.
HLA mismatch direction in cord blood transplantation: impact on outcome and implications for cord blood unit selection
Authors: Stevens Cladd E. , Carrier Carmelita , Carpenter Carol , Sung Dorothy , Scaradavou Andromachi
Published: July 2011

Donor-recipient human leukocyte antigen mismatch level affects the outcome of unrelated cord blood (CB) transplantation. To identify possible “permissive” mismatches, we examined the relationship between direction of human leukocyte antigen mismatch (“vector”) and transplantation outcomes in 1202 recipients of single CB units from the New York Blood Center National Cord Blood Program treated in United States Centers from 1993-2006. Altogether, 98 donor/patient pairs had only unidirectional mismatches: 58 in the graft-versus-host (GVH) direction only (GVH-O) and 40 in the host-versus-graft or rejection direction only (R-O). Engraftment was faster in patients with GVH-O mismatches compared with those with 1 bidirectional mismatch (hazard ratio [HR] = 1.6, P = .003). In addition, patients with hematologic malignancies given GVH-O grafts had lower transplantation-related mortality (HR = 0.5, P = .062), overall mortality (HR = 0.5, P = .019), and treatment failure (HR = 0.5, P = .016), resulting in outcomes similar to those of matched CB grafts. In contrast, R-O mismatches had slower engraftment, higher graft failure, and higher relapse rates (HR = 2.4, P = .010). Based on our findings, CB search algorithms should be modified to identify unidirectional mismatches. We recommend that transplant centers give priority to GVH-O-mismatched units over other mismatches and avoid selecting R-O mismatches, if possible.
Characterization of four conventional dendritic cell subsets in human skin-draining lymph nodes in relation to T-cell activation
Authors: van de Ven Rieneke , van den Hout Mari F. C. M. , Lindenberg Jelle J. , Sluijter Berbel J. R. , van Leeuwen Paul A. M. , Lougheed Sinéad M. , Meijer Sybren , van den Tol M. Petrousjka , Scheper Rik J. , de Gruijl Tanja D.
Published: July 2011

To increase (tumor) vaccine efficacy, there is an urgent need for phenotypic and functional characterization of human dendritic cell (DC) subsets residing in lymphoid tissues. In this study we identified and functionally tested 4 human conventional DC (cDC) subsets within skin-draining sentinel lymph nodes (SLNs) from early-stage melanoma patients. These SLNs were all tumor negative and were removed on average 44 days after excision of the primary melanoma. As such, they were considered representative of steady-state conditions. On comparison with skin-migrated cDC, 2 CD1a+ subsets were identified as most likely skin-derived CD11cint Langerhans cells (LC) with intracellular langerin and E-cadherin expression or as CD11chi dermal DCs with variable expression of langerin. Two other CD1a− LN-residing cDC subsets were characterized as CD14−BDCA3hiCD103− and CD14+BDCA3loCD103+, respectively. Whereas the CD1a+ skin-derived subsets displayed greater levels of phenotypic maturation, they were associated with lower levels of inflammatory cytokine release and were inferior in terms of allogeneic T-cell priming and IFNγ induction. Thus, despite their higher maturation state, skin-derived cDCs (and LCs in particular) proved inferior T-cell activators compared with the CD1a− cDC subsets residing in melanoma-draining LNs. These observations should be considered in the design of DC-targeting immunotherapies.
CD3 limits the efficacy of TCR gene therapy in vivo
Authors: Ahmadi Maryam , King Judith W. , Xue Shao-An , Voisine Cécile , Holler Angelika , Wright Graham P. , Waxman Jonathan , Morris Emma , Stauss Hans J.
Published: July 2011

The function of T-cell receptor (TCR) gene modified T cells is dependent on efficient surface expression of the introduced TCR α/β heterodimer. We tested whether endogenous CD3 chains are rate-limiting for TCR expression and antigen-specific T-cell function. We show that co-transfer of CD3 and TCR genes into primary murine T cells enhanced TCR expression and antigen-specific T-cell function in vitro. Peptide titration experiments showed that T cells expressing introduced CD3 and TCR genes recognized lower concentration of antigen than T cells expressing TCR only. In vivo imaging revealed that TCR+CD3 gene modified T cells infiltrated tumors faster and in larger numbers, which resulted in more rapid tumor elimination compared with T cells modified by TCR only. After tumor clearance, TCR+CD3 engineered T cells persisted in larger numbers than TCR-only T cells and mounted a more effective memory response when rechallenged with antigen. The data demonstrate that provision of additional CD3 molecules is an effective strategy to enhance the avidity, anti-tumor activity and functional memory formation of TCR gene modified T cells in vivo.
Fitness for radical treatment of lung cancer patients
Authors: Charloux A.
Published: July 2011

Educational aims

To discuss the strengths and weaknesses of lung function tests, exercise tests and split-function studies used to assess fitness before lung resection

To outline the importance of the perioperative management of lung cancer patients

To understand the lack of clear recommendations and the need for further studies to assess fitness before chemoradiotherapy

Surgical pulmonary resection and chemoradiotherapy both induce significant mortality and morbidity in lung cancer patients. Many studies have intended to identify the patients at increased risk of treatment-induced complications. In this review, we will describe the various tests proposed to assess fitness before radical treatment of lung cancer. We will also consider the strategies aimed at using the less invasive and most powerful investigations, summarised as functional algorithms in scientific societies' guidelines. The main recent studies, published after the guidelines were available, will also be reviewed.
SIV antigen immunization induces transient antigen-specific T cell responses and selectively activates viral replication in draining lymph nodes in retroviral suppressed rhesus macaques
Authors: Hu Haitao , Gama Lucio , Aye Pyone P , Clements Janice E , Barry Peter A , Lackner Andrew A , Weissman Drew
Published: July 2011

Background

HIV infection causes a qualitative and quantitative loss of CD4+ T cell immunity. The institution of anti-retroviral therapy (ART) restores CD4+ T cell responses to many pathogens, but HIV-specific responses remain deficient. Similarly, therapeutic immunization with HIV antigens of chronically infected, ART treated subjects results in poor induction of HIV-specific CD4 responses. In this study, we used a macaque model of ART treatment during chronic infection to study the virologic consequences of SIV antigen stimulation in lymph nodes early after immunization. Rhesus CMV (RhCMV) seropositive, Mamu A*01 positive rhesus macaques were chronically infected with SIVmac251 and treated with ART. The immune and viral responses to SIV gag and RhCMV pp65 antigen immunization in draining lymph nodes and peripheral blood were analyzed. Animals were immunized on contralateral sides with SIV gag and RhCMV pp65 encoding plasmids, which allowed lymph nodes draining each antigen to be obtained at the same time from the same animal for direct comparison.

Results

We observed that both SIV and RhCMV immunizations stimulated transient antigen-specific T cell responses in draining lymph nodes. The RhCMV-specific responses were potent and sustained (50 days post-immunization) in the periphery, while the SIV-specific responses were transient and extinguished quickly. The SIV antigen stimulation selectively induced transient SIV replication in draining lymph nodes.

Conclusions

The data are consistent with a model whereby viral replication in response to SIV antigen stimulation limits the generation of SIV antigen-specific responses and suggests a potential mechanism for the early loss and poor HIV-specific CD4+ T cell response observed in HIV-infected individuals.
Viral shedding in children infected by pandemic A/H1N1/2009 influenza virus
Authors: Esposito Susanna , Daleno Cristina , Baldanti Fausto , Scala Alessia , Campanini Giulia , Taroni Francesca , Fossali Emilio , Pelucchi Claudio , Principi Nicola
Published: July 2011

Background

The aim of this study was to investigate viral shedding in otherwise healthy children with pandemic A/H1N1/2009 influenza in order to define how long children with pandemic A/H1N1/2009 influenza shed the virus, and also plan adequate measures to control the spread of the disease within households.

Findings

In 74 otherwise healthy children with pandemic A/H1N1/2009 influenza, nasopharyngeal swabs were taken for virus detection upon hospital admission and every two days until negative. The nasopharyngeal swabs of all of the children were positive for pandemic A/H1N1/2009 influenza virus in the first three days after the onset of infection, and only 21.6% and 13.5% remained positive after respectively 11 and 15 days. No child was positive after more than 15 days. Viral load also decreased over time, and was not associated with patient age or the risk of pneumonia. Those who shed the virus for ≥ 9 days were not at any increased risk of suffering from more severe disease in comparison with those who shed the virus for a shorter time, but their households experienced a significantly higher number of influenza-like illness during the two weeks after the onset of the initial disease (72.3% vs 41.4%; p < 0.05).

Conclusions

Regardless of their age, healthy children can shed pandemic A/H1N1/2009 influenza virus for up to two weeks after illness onset, and the households of the children who shed the virus for ≥ 9 days suffered a higher number of influenza-like illness in the two weeks following the onset of the first disease. This could suggest that when a completely unknown influenza virus is circulating, isolation period of infected children has to be longer than the 7 days recommended for the infections due to seasonal influenza viruses.
A Wnt1 regulated Frizzled-1/β-Cateninsignaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: Therapeutical relevance for neuron survival and neuroprotection
Authors: L'Episcopo Francesca , Serapide Maria F , Tirolo Cataldo , Testa Nunzio , Caniglia Salvatore , Morale Maria C , Pluchino Stefano , Marchetti Bianca
Published: July 2011

Background

Dopamine-synthesizing (dopaminergic, DA) neurons in the ventral midbrain (VM) constitute a pivotal neuronal population controlling motor behaviors, cognitive and affective brain functions, which generation critically relies on the activation of Wingless-type MMTV integration site (Wnt)/β-catenin pathway in their progenitors. In Parkinson's disease, DA cell bodies within the substantia nigra pars compacta (SNpc) progressively degenerate, with causes and mechanisms poorly understood. Emerging evidence suggests that Wnt signaling via Frizzled (Fzd) receptors may play a role in different degenerative states, but little is known about Wnt signaling in the adult midbrain. Using in vitro and in vivo model systems of DA degeneration, along with functional studies in both intact and SN lesioned mice, we herein highlight an intrinsic Wnt1/Fzd-1/β-catenin tone critically contributing to the survival and protection of adult midbrain DA neurons.

Results

In vitro experiments identifie Fzd-1 receptor expression at a mRNA and protein levels in dopamine transporter (DAT) expressing neurons, and demonstrate the ability of exogenous Wnt1 to exert robust neuroprotective effects against Caspase-3 activation, the loss of tyrosine hydroxylase-positive (TH+) neurons and [3H] dopamine uptake induced by different DA-specific insults, including serum and growth factor deprivation, 6-hydroxydopamine and MPTP/MPP+. Co-culture of DA neurons with midbrain astrocytes phenocopies Wnt1 neuroprotective effects, whereas RNA interference-mediated knockdown of Wnt1 in midbrain astrocytes markedly reduces astrocyte-induced TH+ neuroprotection. Likewise, silencing β-catenin mRNA or knocking down Fzd-1 receptor expression in mesencephalic neurons counteract astrocyte-induced TH+ neuroprotection. In vivo experiments document Fzd-1 co-localization with TH+ neurons within the intact SNpc and blockade of Fzd/β-catenin signaling by unilateral infusion of a Fzd/β-catenin antagonist within the SN induces reactive astrocytosis and acutely inhibits TH+ neuron survival in ipsilateral SNpc, an effect efficiently prevented by pharmacological activation of β-catenin signaling within the SNpc.

Conclusion

These results defining a novel Wnt1/Fzd-1/β-catenin astrocyte-DA autoprotective loop provide a new mechanistic inside into the regulation of pro-survival processes, with potentially relevant consequences for drug design or drug action in Parkinson's disease.
iAB-RBC-283: A proteomically derived knowledge-base of erythrocyte metabolism that can be used to simulate its physiological and patho-physiological states
Authors: Bordbar Aarash , Jamshidi Neema , Palsson Bernhard O
Published: July 2011

Background

The development of high-throughput technologies capable of whole cell measurements of genes, proteins, and metabolites has led to the emergence of systems biology. Integrated analysis of the resulting omic data sets has proved to be hard to achieve. Metabolic network reconstructions enable complex relationships amongst molecular components to be represented formally in a biologically relevant manner while respecting physical constraints. In silico models derived from such reconstructions can then be queried or interrogated through mathematical simulations. Proteomic profiling studies of the mature human erythrocyte have shown more proteins present related to metabolic function than previously thought; however the significance and the causal consequences of these findings have not been explored.

Results

Erythrocyte proteomic data was used to reconstruct the most expansive description of erythrocyte metabolism to date, following extensive manual curation, assessment of the literature, and functional testing. The reconstruction contains 281 enzymes representing functions from glycolysis to cofactor and amino acid metabolism. Such a comprehensive view of erythrocyte metabolism implicates the erythrocyte as a potential biomarker for different diseases as well as a 'cell-based' drug-screening tool. The analysis shows that 94 erythrocyte enzymes are implicated in morbid single nucleotide polymorphisms, representing 142 pathologies. In addition, over 230 FDA-approved and experimental pharmaceuticals have enzymatic targets in the erythrocyte.

Conclusion

The advancement of proteomic technologies and increased generation of high-throughput proteomic data have created the need for a means to analyze these data in a coherent manner. Network reconstructions provide a systematic means to integrate and analyze proteomic data in a biologically meaning manner. Analysis of the red cell proteome has revealed an unexpected level of complexity in the functional capabilities of human erythrocyte metabolism.
Near Infrared Analysis of Fossil Bone from the Western Cape of South Africa
Authors: Thomas Daniel B. , McGoverin Cushla M. , Chinsamy Anusuya , Manley Marena
Published: July 2011

The burial environment of a fossil bone may be poorly suited to long-term preservation of important chemical constituents. Studies of fossil bone chemistry consequently benefit from knowledge of burial environmental change (burial history). Several techniques have been developed to describe alteration of fossil bone, including measurements of crystallinity using infrared spectroscopy. The utility of near infrared (NIR) spectroscopy was investigated for describing the burial history of fossil bone. Spectra from large sample areas (bulk NIR) identified secondary calcite and clay within fossil bone, and were useful for distinguishing fossils from different localities. Spectra from small sample areas (hyperspectral NIR) were used to map constituents within fossil bones. Calcite and clay pervaded the internal cavities of fossil horn cores, indicating saturation with groundwater. The identification and distribution of secondary minerals is relevant for studies of taphonomic process, hence NIR is a useful supplement to existing techniques for assessing the burial history of fossil bone.
Analytical error and interference in immunoassay: minimizing risk
Authors: Sturgeon Catharine M , Viljoen Adie
Published: July 2011

Although generally robust, immunoassays remain vulnerable to occasional analytical errors that may have serious implications for patient care. Sporadic errors that occur as a result of properties of the specimen are particularly difficult to detect. They may be due to the presence of cross-reacting substances, antianalyte antibodies or antireagent antibodies, all of which may lead to erroneously high or low results. Low results may be observed for tumour markers due to high-dose hooking in the presence of very high analyte concentrations. Erroneous results can occur unexpectedly with any specimen and there is no practical means of identifying specimens likely to cause problems in immunoassays. The possibility of interference should always be considered when results do not appear to be in accord with the clinical picture. Errors can occur in even the best-managed laboratories and their early investigation is always desirable. If there is any doubt whatsoever about a result, clinical staff should be encouraged to contact the laboratory. Investigations for possible interference that can be undertaken in most laboratories include testing for linearity on dilution, recovery experiments, treatment with heterophilic blocking tubes and confirmation using a different method. It may be desirable to consult specialist laboratories if more complex studies are necessary. Informing clinical and laboratory staff of the ever-present possibility of unexpected interference, ensuring brief clinical details are available to laboratory staff, and above all facilitating excellent communication between laboratory and clinical staff are key to minimizing the risk of clinical mismanagement due to unsuspected interference.
Intensity of Anticoagulation with Warfarin and Risk of Adverse Events in Patients Presenting to the Emergency Department
Authors: Anthony Crystal J , Karim Saleema , Ackroyd-Stolarz Stacy , Fry Amy , Murphy Nancy G , Christie Russell , Zed Peter J
Published: July 2011

Background:

The ability of patients receiving warfarin to maintain an international normalized ratio (INR) within the desired therapeutic range is important for both efficacy and risk of adverse events. It is unclear whether the desired INR is maintained in patients receiving warfarin who present to the emergency department (ED) and whether they have a higher rate of adverse events.

Objective:

To evaluate the intensity of anticoagulation with warfarin and the risk of bleeding and thromboembolic complications in patients in the ED.

Methods:

A prospective observational study was performed using a convenience sample of patients receiving warfarin and presenting to the ED over an 18-week period. Data were collected using a standardized form that included chief complaint, history of present illness, past medical history, medication history, and allergy status. Information from the physical examination, laboratory results, and other diagnostic tests obtained as part of routine assessment in the ED, was used as necessary. The primary outcome was the proportion of patients whose INR was within, above, or below the desired therapeutic range. Bleeding complications and thromboembolic events were recorded in an attempt to determine the relationship between the intensity of anticoagulation and adverse outcomes.

Results:

Two hundred one patients were included, with a mean (SD) age of 74.0 (13.2) years; 53.7% were female. Primary indications for warfarin were atrial fibrillation (75.6%) and venous thromboembolic disease (14.9%). A therapeutic INR was observed in 88 patients (43.8%; 95% CI 37.1 to 50.7), while 45 patients (22.4%; 95% CI 17.2 to 26.7) and 68 patients (33.8%; 95% CI 27.6 to 40.6) had subtherapeutic and supratherapeutic INRs, respectively. Overall, there were 28 (18 major and 10 minor) bleeding complications (13.9%; 95% CI 9.8 to 19.4) and 4 thromboembolic events (2.0%; 95% CI 0.6 to 5.2). Among patients with a bleeding complication, 14 (50.0%) had a supratherapeutic INR, while 2 patients who experienced a thromboembolic event (50.0%) had a subtherapeutic INR.

Conclusions:

The majority of patients receiving warfarin on presentation to the ED had INRs outside the desired therapeutic range. By establishing the impact of warfarin-related adverse events in this population, focused interventions can be established in this setting to address factors that can be targeted to reduce these events.
Spinosad for Treatment of Head Lice Infestation
Authors: Cole Sabrina W , Lundquist Lisa M
Published: July 2011

Objective:

To review the pharmacology, pharmacokinetics, clinical trials, and safety profile of spinosad 0.9% topical lotion, a recently approved pediculicide for treatment of head lice infestation.

Data Sources:

English-language articles indexed in MEDLINE (1948-May 2011), Toxline, Google Scholar, International Pharmaceutical Abstracts (1970-May 2011), and Cumulative Index to Nursing and Allied Health Literature (1981-May 2011) were identified, using the search terms spinosad, head lice, and pediculosis capitis.

Study Selection and Data Extraction:

Available English-language articles were reviewed.

Data Synthesis:

In the studies that were reviewed, the percentage of patients who were lice free 14 days after the last treatment was significantly higher in the spinosad groups compared to the permethrin groups (84.6% vs 44.9% and 86.7% vs 42.9%, respectively; p < 0.001 for both studies). Additionally, the proportion of all primary and nonprimary participants determined to be lice free following only 1 treatment with the study medication was higher among patients in the spinosad groups compared with those in the permethrin groups. Application-site erythema was observed in patients in both treatment groups; however, it was more common in patients in the permethrin groups compared with those receiving spinosad (6.8% vs 3.1%, respectively; p = 0.007). No serious adverse effects were reported by patients receiving spinosad. Adherence was higher in the spinosad groups compared with the permethrin groups, although adherence overall was high in both studies. These data suggest that spinosad is a safe and effective treatment for the eradication of head lice, and the ease of administration and improved adherence with spinosad could offer an advantage over currently available treatment options.

Conclusions:

Because of its established efficacy, favorable safety profile, and ease of application, spinosad can be considered a convenient and effective treatment for head lice in patients aged 4 years and older.
A Novel Function for the PAR Complex in Subcellular Morphogenesis of Tracheal Terminal Cells in Drosophila melanogaster
Authors: Jones Tiffani A , Metzstein Mark M
Published: July 2011

The processes that generate cellular morphology are not well understood. To investigate this problem, we use Drosophila melanogaster tracheal terminal cells, which undergo two distinct morphogenetic processes: subcellular branching morphogenesis and subcellular apical lumen formation. Here we show these processes are regulated by components of the PAR-polarity complex. This complex, composed of the proteins Par-6, Bazooka (Par-3), aPKC, and Cdc42, is best known for roles in asymmetric cell division and apical/basal polarity. We find Par-6, Bazooka, and aPKC, as well as known interactions between them, are required for subcellular branch initiation, but not for branch outgrowth. By analysis of single and double mutants, and isolation of two novel alleles of Par-6, one of which specifically truncates the Par-6 PDZ domain, we conclude that dynamic interactions between apical PAR-complex members control the branching pattern of terminal cells. These data suggest that canonical apical PAR-complex activity is required for subcellular branching morphogenesis. In addition, we find the PAR proteins are downstream of the FGF pathway that controls terminal cell branching. In contrast, we find that while Par-6 and aPKC are both required for subcellular lumen formation, neither Bazooka nor a direct interaction between Par-6 and aPKC is needed for this process. Thus a novel, noncanonical role for the polarity proteins Par-6 and aPKC is used in formation of this subcellular apical compartment. Our results demonstrate that proteins from the PAR complex can be deployed independently within a single cell to control two different morphogenetic processes.
Identification of Mutations that Delay Somatic or Reproductive Aging ofCaenorhabditis elegans
Authors: Hughes Stacie E , Huang Cheng , Kornfeld Kerry
Published: July 2011

Aging is an important feature of animal biology characterized by progressive, degenerative changes in somatic and reproductive tissues. The rate of age-related degeneration is genetically controlled, since genes that influence lifespan have been identified. However, little is known about genes that affect reproductive aging or aging of specific somatic tissues. To identify genes that are important for controlling these degenerative changes, we used chemical mutagenesis to perform forward genetic screens in Caenorhabditis elegans. By conducting a screen focused on somatic aging, we identified mutant hermaphrodites that displayed extended periods of pharyngeal pumping, body movement, or survival. One of these mutations is a novel allele of the age-1 gene. age-1 encodes a phosphatidylinositol-3-kinase (PI3K) that functions in the insulin/insulin-like growth factor-1 (IGF-1) signaling pathway. age-1(am88) creates a missense change in the conserved PIK domain and causes dramatic extensions of the pharyngeal pumping and body movement spans, as well as a twofold extension of the lifespan. By conducting screens focused on reproductive aging in mated hermaphrodites, we identified mutants that displayed increased progeny production late in life. To characterize these mutations, we developed quantitative measurements of age-related morphological changes in the gonad. The am117 mutation delayed age-related declines in progeny production and morphological changes in the gonad. These studies provide new insights into the genetic regulation of age-related degenerative changes in somatic and reproductive tissues.