bluuebunny/crossref_metadata_2025 huggingface dataset:
Transplantation of human neural stem/progenitor cells overexpressing galectin-1 improves functional recovery from focal brain ischemia in the mongolian gerbil
Authors: Yamane Junichi , Ishibashi Satoru , Sakaguchi Masanori , Kuroiwa Toshihiko , Kanemura Yonehiro , Nakamura Masaya , Miyoshi Hiroyuki , Sawamoto Kazunobu , Toyama Yoshiaki , Mizusawa Hidehiro , Okano Hideyuki
Published: September 2011

Transplantation of human neural stem/progenitor cells (hNSPCs) is a promising method to regenerate tissue from damage and recover function in various neurological diseases including brain ischemia. Galectin-1(Gal1) is a lectin that is expressed in damaged brain areas after ischemia. Here, we characterized the detailed Gal1 expression pattern in an animal model of brain ischemia. After brain ischemia, Gal1 was expressed in reactive astrocytes within and around the infarcted region, and its expression diminished over time. Previously, we showed that infusion of human Gal1 protein (hGal1) resulted in functional recovery after brain ischemia but failed to reduce the volume of the ischemic region. This prompted us to examine whether the combination of hNSPCs-transplantation and stable delivery of hGal1 around the ischemic region could reduce the ischemic volume and promote better functional recovery after brain ischemia. In this study, we transplanted hNSPCs that stably overexpressed hGal1 (hGal1-hNSPCs) in a model of unilateral focal brain ischemia using Mongolian gerbils. Indeed, we found that transplantation of hGal1-hNSPCs both reduced the ischemic volume and improved deficits in motor function after brain ischemia to a greater extent than the transplantation of hNSPCs alone. This study provides evidence for a potential application of hGal1 with hNSPCs-transplantation in the treatment of brain ischemia.
The expression and role of protein kinase C (PKC) epsilon in clear cell renal cell carcinoma
Authors: Huang Bin , Cao Kaiyuan , Li Xiubo , Guo Shengjie , Mao Xiaopeng , Wang Zhu , Zhuang Jintao , Pan Jincheng , Mo Chengqiang , Chen Junxing , Qiu Shaopeng
Published: September 2011

Protein kinase C epsilon (PKCε), an oncogene overexpressed in several human cancers, is involved in cell proliferation, migration, invasion, and survival. However, its roles in clear cell renal cell carcinoma (RCC) are unclear. This study aimed to investigate the functions of PKCε in RCC, especially in clear cell RCC, to determine the possibility of using it as a therapeutic target. By immunohistochemistry, we found that the expression of PKCε was up-regulated in RCCs and was associated with tumor Fuhrman grade and T stage in clear cell RCCs. Clone formation, wound healing, and Borden assays showed that down-regulating PKCε by RNA interference resulted in inhibition of the growth, migration, and invasion of clear cell RCC cell line 769P and, more importantly, sensitized cells to chemotherapeutic drugs as indicated by enhanced activity of caspase-3 in PKCε siRNA-transfected cells. These results indicate that the overexpression of PKCε is associated with an aggressive phenotype of clear cell RCC and may be a potential therapeutic target for this disease.
Framing the social in biomedical HIV prevention trials: a 20‐year retrospective
Authors: MacQueen Kathleen M
Published: September 2011

Biomedical research is critical to identifying effective and safe interventions, such as vaccines, microbicides, male circumcision and antiretrovirals, for prevention. Funding for clinical prevention trials is highly competitive and the benchmarks of success ultimately reduce to quickly enrolling a select group of people at risk, keeping them enrolled, and inducing them to be compliant with trial requirements ‐ all at the lowest cost possible. Juxtaposed with this reality is the fact that HIV is situated with poverty, exploitation, assaults on human dignity, and human rights abuses. The result is a complex web of ethical challenges that are socially constructed along lines of wealth and power. While social science research methods are commonly employed to examine such topics, they have played a marginal role in biomedical HIV prevention research. Why? To answer this question, a core set of persistent interlocking social, behavioural and ethical challenges to biomedical HIV prevention research are described. A critique is offered on how the social has been framed relative to the behavioural, ethical and biomedical components. Examples of how this framing has devalued social knowledge are provided, including the conflation of qualitative research with anecdotal reporting, a bias toward brevity and accuracy over external validity, and difficulties in distinguishing between a moral understanding of social norms and achieving a moral outcome when confronted with ethical challenges in research. Lastly, opportunities are identified for enhancing the success of biomedical HIV prevention research through development of a coherent programme of social science research. Recommendations are offered for reframing the social as a valid domain of scientific inquiry in this highly applied and interdisciplinary context.
Critically engaging: integrating the social and the biomedical in international microbicides research
Authors: Montgomery Catherine M , Pool Robert
Published: September 2011

Randomized controlled trials and critical social theory are known not to be happy bedfellows. Such trials are embedded in a positivist view of the world, seeking definitive answers to testable questions; critical social theory questions the methods by which we deem the world knowable and may consider experiments in the biomedical sciences as social artifacts. Yet both of these epistemologically and methodologically divergent fields offer potentially important advances in HIV research. In this paper, we describe collaboration between social and biomedical researchers on a large, publicly funded programme to develop vaginal microbicides for HIV prevention. In terms of critical engagement, having integrated and qualitative social science components in the protocol meant potentially nesting alternative epistemologies at the heart of the randomized controlled trial. The social science research highlighted the fallibility and fragility of trial data by demonstrating inconsistencies in key behavioural measurements. It also foregrounded the disjuncture between biomedical conceptions of microbicides and the meanings and uses of the study gel in the context of users’ everyday lives. These findings were communicated to the clinical and epidemiological members of the team on an ongoing basis via a feedback loop, through which new issues of concern could also be debated and, in theory, data collection adjusted to the changing needs of the programme. Although critical findings were taken on board by the trialists, a hierarchy of evidence nonetheless remained that limited the utility of some social science findings. This was in spite of mutual respect between clinical epidemiologists and social scientists, equal representation in management and coordination bodies, and equity in funding for the different disciplines. We discuss the positive role that social science integrated into an HIV prevention trial can play, but nonetheless highlight tensions that remain where a hierarchy of epistemologies exists alongside competing paradigms and priorities.
Outcome effectiveness of the severe sepsis resuscitation bundle with addition of lactate clearance as a bundle item: a multi-national evaluation
Authors: Nguyen H Bryant , Kuan Win Sen , Batech Michael , Shrikhande Pinak , Mahadevan Malcolm , Li Chih-Huang , Ray Sumit , Dengel Anna ,   the ATLAS (Asia Network to Regulate Sepsis care) Investigators
Published: September 2011

Introduction

Implementation of the Surviving Sepsis Campaign (SSC) guidelines has been associated with improved outcome in patients with severe sepsis. Resolution of lactate elevations or lactate clearance has also been shown to be associated with outcome. The purpose of the present study was to examine the compliance and effectiveness of the SSC resuscitation bundle with the addition of lactate clearance.

Methods

This was a prospective cohort study over 18 months in eight tertiary-care medical centers in Asia, enrolling adult patients meeting criteria for the SSC resuscitation bundle in the emergency department. Compliance and outcome results of a multi-disciplinary program to implement the Primary SSC Bundle with the addition of lactate clearance (Modified SSC Bundle) were examined. The implementation period was divided into quartiles, including baseline, education and four quality improvement phases.

Results

A total of 556 patients were enrolled, with median (25th to 75th percentile) age 63 (50 to 74) years, lactate 4.1 (2.2 to 6.3) mmol/l, central venous pressure 10 (7 to 13) mmHg, mean arterial pressure (MAP) 70 (56 to 86) mmHg, and central venous oxygen saturation 77 (69 to 82)%. Completion of the Primary SSC Bundle over the six quartiles was 13.3, 26.9, 37.5, 45.9, 48.8, and 54.5%, respectively (P <0.01). The Modified SSC Bundle was completed in 10.2, 23.1, 31.7, 40.0, 42.5, and 43.6% patients, respectively (P <0.01). The ratio of the relative risk of death reduction for the Modified SSC Bundle compared with the Primary SSC Bundle was 1.94 (95% confidence interval = 1.45 to 39.1). Logistic regression modeling showed that the bundle items of fluid bolus given, achieve MAP >65 mmHg by 6 hours, and lactate clearance were independently associated with decreased mortality - having odds ratios (95% confidence intervals) 0.47 (0.23 to 0.96), 0.20 (0.07 to 0.55), and 0.32 (0.19 to 0.55), respectively.

Conclusions

The addition of lactate clearance to the SSC resuscitation bundle is associated with improved mortality. In our study patient population with optimized baseline central venous pressure and central venous oxygen saturation, the bundle items of fluid bolus administration, achieving MAP >65 mmHg, and lactate clearance were independent predictors of outcome.
Exome sequencing identifies a novel missense variant in RRM2B associated with autosomal recessive progressive external ophthalmoplegia
Authors: Takata Atsushi , Kato Maiko , Nakamura Masayuki , Yoshikawa Takeo , Kanba Shigenobu , Sano Akira , Kato Tadafumi
Published: September 2011

Background

Whole-exome sequencing using next-generation technologies has been previously demonstrated to be able to detect rare disease-causing variants. Progressive external ophthalmoplegia (PEO) is an inherited mitochondrial disease that follows either autosomal dominant or recessive forms of inheritance (adPEO or arPEO). AdPEO is a genetically heterogeneous disease and several genes, including POLG1 and C10orf2/Twinkle, have been identified as responsible genes. On the other hand, POLG1 was the only established gene causing arPEO with mitochondrial DNA deletions. We previously reported a case of PEO with unidentified genetic etiology. The patient was born of a first-cousin marriage. Therefore, the recessive form of inheritance was suspected.

Results

To identify the disease-causing variant in this patient, we subjected the patient's DNA to whole-exome sequencing and narrowed down the candidate variants using public data and runs of homozygosity analysis. A total of 35 novel, putatively functional variants were detected in the homozygous segments. When we sorted these variants by the conservation score, a novel missense variant in RRM2B, whose heterozygous rare variant had been known to cause adPEO, was ranked at the top. The list of novel, putatively functional variants did not contain any other variant in genes encoding mitochondrial proteins registered in MitoCarta.

Conclusions

Exome sequencing efficiently and effectively identified a novel, homozygous missense variant in RRM2B, which was strongly suggested to be causative for arPEO. The findings in this study indicate arPEO to be a genetically heterogeneous disorder, as is the case for adPEO.
Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice
Authors: Youn Je-In , Collazo Michelle , Shalova Irina N , Biswas Subhra K , Gabrilovich Dmitry I
Published: September 2011

MDSCs are a group of cells with potent immune-suppressive activity. These cells accumulate in many pathologic conditions and play a major role in the regulation of immune responses. The nature of MDSC remains highly debatable. In cancer, most MDSCs are represented by cells with granulocytic phenotype and morphology, G-MDSC. The relationship between G-MDSCs and Neu remains unclear. In this study, we have found that G-MDSCs, from tumor-bearing, and Neu, from tumor-free, mice share a common morphology and phenotype. However, in contrast to Neu, a substantial proportion of G-MDSCs expressed M-CSFR and a CD244 molecule. Neu had significantly higher phagocytic activity, expression of lysosomal proteins, and TNF-α than corresponding G-MDSCs, which had significantly higher activity of arginase, MPO, and ROS. In contrast to G-MDSC, neither rested nor mobilized Neu suppressed T cells. G-MDSC survived 2 days in culture in the presence of GM-CSF and within 24 h, became phenotypic and functionally similar to Neu. Tumor-associated G-MDSC shared most characteristics of splenic G-MDSC, rather then Neu. These data suggest that in cancer, despite morphological and phenotypic similarities, G-MDSCs are functionally distinct from Neu and are comprised of pathologically activated precursors of Neu.
Testicular Somatic Cells, not Gonocytes, Are the Major Source of Functional Activin A during Testis Morphogenesis
Authors: Archambeault Denise R. , Tomaszewski Jessica , Childs Andrew J. , Anderson Richard A. , Yao Humphrey Hung-Chang
Published: September 2011

Proper development of the seminiferous tubules (or testis cords in embryos) is critical for male fertility. Sertoli cells, somatic components of the seminiferous tubules, serve as nurse cells to the male germline, and thus their numbers decide the quantity of sperm output in adulthood. We previously identified activin A, the protein product of the activin βA (Inhba) gene, as a key regulator of murine Sertoli cell proliferation and testis cord expansion during embryogenesis. Although our genetic studies implicated fetal Leydig cells as the primary producers of testicular activin A, gonocytes are another potential source. To investigate the relative contribution of gonocyte-derived activin A to testis morphogenesis, we compared testis development in the Inhba global knockout mouse, which lacks activin A production in all cells (including the gonocytes), and a steroidogenic factor 1 (Sf1)-specific conditional knockout model in which activin A expression in testicular somatic cells is disrupted but gonocyte expression of activin A remains intact. Surprisingly, testis development was comparable in these two models of activin A insufficiency, with similar reductions in Sertoli cell proliferation and minor differences in testis histology. Thus, our findings suggest activin A from male gonocytes is insufficient to promote Sertoli cell proliferation and testis cord expansion in the absence of somatic cell-derived activin A. Evaluation of adult male mice with fetal disruption of activin A revealed reduced testis size, lowered sperm production, altered testicular histology, and elevated plasma FSH levels, defects reminiscent of human cases of androgen-sufficient idiopathic oligozoospermia.
Minireview: Putting Physiology Back into Estrogens' Mechanism of Action
Authors: Koos Robert D.
Published: September 2011

After decades of research, the mechanism by which estrogens stimulate the proliferation of epithelial cells in the endometrium and mammary gland, and in the carcinomas that arise in those tissues, is still not understood. Cells do not proliferate in response to 17β-estradiol (E2) alone, and although it is widely recognized that growth factors play a role in E2's proliferative effect, exactly how they are involved is unclear. It has long been known that the proliferation of endometrial epithelial cells is preceded by dramatic increases in blood flow and microvascular permeability, filling the subepithelial stroma with plasma and the proteins it contains, such as IGF-I, which is known to synergize with E2 in the induction of cell proliferation. The hyperpermeability is caused by vascular endothelial growth factor (VEGF), which is rapidly induced by E2, via the transcription factors hypoxia-inducible factor 1 and estrogen receptor α, in luminal epithelial cells in vivo. As we recently showed, VEGF is also strongly induced in endometrial cancer cells in vitro when excessive degradation of hypoxia-inducible factor 1α, caused by the abnormally high oxygen level to which cultured cells are exposed, is prevented. Putting these facts together, we now propose a new model of E2-induced proliferation in which VEGF-induced vascular hyperpermeability plays an essential role. E2 first induces the expression by endometrial epithelial cells of VEGF, which then acts in a paracrine manner to induce interendothelial cell gaps in subepithelial blood vessels, through which plasma and the proteins therein enter the adjacent stroma. Plasma carries even more E2, which circulates bound to proteins, and IGF-l, which together drive epithelial cells completely through the cell cycle.
Repletion of TNFα or leptin in calorically restricted mice suppresses post-restriction hyperphagia
Authors: Hambly Catherine , Duncan Jacqueline S. , Archer Zoë A. , Moar Kim M. , Mercer Julian G. , Speakman John R.
Published: September 2011

The causes of post-restriction hyperphagia (PRH) represent a target for drug-based therapies to prevent obesity. However, the factors causing PRH are poorly understood. We show that, in mice, the extent of PRH was independent of the time under restriction, but depended on its severity, suggesting that PRH was driven by signals from altered body composition. Signals related to fat mass were important drivers. Circulating levels of leptin and TNFα were significantly depleted following caloric restriction (CR). We experimentally repleted their levels to match those of controls, and found that in both treatment groups the level of PRH was significantly blunted. These data establish a role for TNFα and leptin in the non-pathological regulation of energy homeostasis. Signals from adipose tissue, including but not limited to leptin and TNFα, regulate PRH and might be targets for therapies that support people engaged in CR to reduce obesity.
Characteristics of the anterior lateral line nerve input to the Mauthner cell
Authors: Mirjany Mana , Faber Donald S.
Published: September 2011

The goldfish Mauthner (M-) cells, a bilateral pair of reticulospinal neurons, initiate the auditory evoked escape behavior of teleosts. In an open field the fish reliably turns away from the sound source. This implies that the M-cells are capable of a decision-making process that requires the two cells to receive differential directional inputs. Recent studies have indicated that the lateral line (LL) system is necessary in the initial directionality of the escape. This information is thought to be transmitted to the M-cell by the anterior branch of the lateral line nerve (aLLn), which has a shorter conduction time then the posterior branch. This study is the first attempt to characterize the inputs from the aLLn to the M-cell. M-cell intracellular responses to aLLn stimulation indicate a fast monosynaptic input (0.80±0.03 ms) that has a small amplitude averaging 5.85±0.42 mV. This input is bilateral and has a significantly longer latency and smaller amplitude in the contralateral M-cell. Superimposed on the evoked excitatory postsynaptic potential (EPSP) is a shunting inhibition with a delay of 1 ms, which is characteristic of other sensory inputs to the M-cell. Pharmacological manipulation and 50 Hz stimulation reveal a component of the evoked EPSP that is electrotonic, a property favoring speed of transmission. In addition, this input is localized to the lateral dendrite proximal to the inputs from the inner ear. The short latency of these inputs and their proximity to the posterior eighth nerve afferents indicate a crucial role for the aLLn in influencing the excitability and directionality of the M-cell.
Biomechanics of octopedal locomotion: kinematic and kinetic analysis of the spiderGrammostola mollicoma
Authors: Biancardi Carlo M. , Fabrica C. Gabriel , Polero Patricia , Loss Jefferson Fagundes , Minetti Alberto E.
Published: September 2011

Despite the abundance of octapodal species and their evolutionary importance in originating terrestrial locomotion, the locomotion mechanics of spiders has received little attention so far. In this investigation we use inverse dynamics to study the locomotor performance of Grammostola mollicoma (18 g). Through 3-D kinematic measurements, the trajectory of the eight limbs and cephalothorax or abdomen allowed us to estimate the motion of the body centre of mass (COM) at different speeds. Classic mechanics of locomotion and multivariate analysis of several variables such as stride length and frequency, duty factor, mechanical external work and energy recovery, helped to identify two main gaits, a slow (speed <11 cm s–1) one and a fast one characterised by distinctive 3-D trajectories of COM. The total mechanical work (external + internal) calculated in the present study and metabolic data from the literature allowed us to estimate the locomotion efficiency of this species, which was less than 4%. Gait pattern due to alternating limb support, which generates asymmetrical COM trajectories and a small but consistent energy transfer between potential and kinetic energies of COM, is discussed both in terms of coordination indices and by referring to the octopod as formed by two quadrupeds in series. Analogies and differences of the newly obtained parameters with the allometric data and predictions are also illustrated.
Salt stress alters fluid and ion transport by Malpighian tubules ofDrosophila melanogaster: evidence for phenotypic plasticity
Authors: Naikkhwah Wida , O'Donnell Michael J.
Published: September 2011

Drosophila are tolerant of high levels of dietary salt and can provide a useful model for studies of the physiology of salt stress. The effects of NaCl- and KCl-rich diets on haemolymph ionoregulation and Malpighian tubule (MT) fluid secretion, Na+ and K+ secretion and transepithelial potential were examined in larval and adult Drosophila melanogaster. K+ concentrations in the haemolymph of adults reared on the KCl-rich (0.4 mol l–1) diet did not differ from the values for insects reared on the control diet. In the haemolymph of larvae reared on the K-rich diet, K+ concentrations increased from 23 to 75 mmol l–1 after 6 h, then returned to the control value within 48 h. Na+ concentrations in the haemolymph of adults or larvae reared for 1–7 days on the NaCl-rich (0.4 mol l–1) diet increased by ∼50% relative to values for insects reared on the control diet. Rates of secretion of fluid, Na+ and K+ by MTs isolated from larvae reared on the Na-rich diet for >6 h and bathed in control saline containing 20 mmol l–1 K+ did not differ from the values for tubules of larvae reared on the control diet. Evidence of phenotypic plasticity was seen in the response of MTs isolated from larvae reared on the K-rich diet for >6 h and bathed in saline containing 60 mmol l–1 K+; secretion of fluid and K+ increased by >50% relative to the values for tubules of larvae reared on the control diet. Secretion of fluid, Na+ and K+ increased when tubules were bathed in haemolymph collected from larvae reared on the Na- or K-rich diets. Secretion was further increased by addition of exogenous cAMP but not by addition of thapsigargin to the haemolymph. The results show that haemolymph ionoregulation in larvae reared on salt-rich diets involves both alterations in the basal secretion rates of Na+ and/or K+ as well as stimulatory effects of diuretic factors present in the haemolymph. The results suggest that such factors stimulate tubule fluid and ion secretion through increases in intracellular Ca2+ in response to salt stress.
Extracoelenteric zooplankton feeding is a key mechanism of nutrient acquisition for the scleractinian coral Galaxea fascicularis
Authors: Wijgerde Tim , Diantari Rara , Lewaru Muhammad Wahyudin , Verreth Johan A. J. , Osinga Ronald
Published: September 2011

Internal and external feeding on zooplankton may provide scleractinian corals with important nutrients. However, the latter process has never been properly quantified. To quantify the dynamics of zooplankton capture, digestion and release for a scleractinian coral, we performed detailed video analyses of Galaxea fascicularis feeding on Artemia nauplii. A highly dynamic process of prey capture, digestion and release was observed. A single G. fascicularis polyp (N=3) captured 558±67 and released 383±75 Artemia nauplii over a 6 h interval. On average, 98.6% of prey captured was not ingested. Instead, prey items were clustered into aggregates that were digested externally by mesenterial filaments. In addition, we employed carbon, nitrogen and phosphorus analysis of zooplankton before and after digestion by G. fascicularis colonies (N=6). For total organic carbon, 43.1% (0.298±0.148 μg Artemia–1) was lost after 6 h of digestion. For total organic nitrogen, total organic phosphorus and orthophosphate (PO43–), these values were 51.3% (0.059±0.028 μg Artemia–1), 50.9% (0.009±0.004 μg Artemia–1) and 84.6% (0.0019±0.0008 μg Artemia–1), respectively. For extracoelenteric zooplankton feeding alone, total estimated nutrient inputs for G. fascicularis colonies were 76.5±0.0 μg organic carbon, 15.2±0.0 μg organic nitrogen, 2.3±0.2 μg organic phosphorus and 0.5±0.8 μg inorganic phosphorus per cm2 coral tissue per day. These values exceed calculations based on intracoelenteric feeding by up to two orders of magnitude. Our results demonstrate that extracoelenteric zooplankton feeding is a key mechanism of nutrient acquisition for a scleractinian coral. These results are of importance to coral aquaculture and our understanding of benthic–pelagic coupling on coral reefs.
Visible Light Responsive Electrospun TiO2 Fibers Embedded with WO3 Nanoparticles
Authors: Nakata Kazuya , Liu Baoshun , Goto Yuri , Ochiai Tsuyoshi , Sakai Munetoshi , Sakai Hideki , Murakami Taketoshi , Abe Masahiko , Fujishima Akira
Published: September 2011

TiO2–WO3 composite fibers were prepared by electrospinning. The fibers have an average diameter of 1.0 µm. The XRD pattern of the TiO2–WO3 composite fibers indicates the presence of anatase and rutile phases of TiO2 and an orthorhombic phase of WO3. The photocatalytic degradation of acetaldehyde under visible light was achieved with the TiO2–WO3 composite fibers.
We can't afford my chronic illness! The out-of-pocket burden associated with managing chronic obstructive pulmonary disease in western Sydney, Australia
Authors: Essue Beverley , Kelly Patrick , Roberts Mary , Leeder Stephen , Jan Stephen
Published: September 2011

Objectives

To examine the household economic consequences that are associated with out-of-pocket spending for the care and management of chronic obstructive pulmonary disease (COPD).

Methods

A cross-sectional study. A self-administered questionnaire was posted to all patients enrolled ( n = 656) in the Respiratory Ambulatory Care Service in western Sydney, Australia, between 1 January 2001 and 31 August 2008. Two hundred and eighteen completed questionnaires were received.

Results

One hundred and sixty-nine (78%) respondents experienced economic hardship while managing their illness. Fifty-nine (27%) reported being unable to pay for medical or dental expenses, 38 (18%) were unable to pay for medication, 59 (27%) were unable to pay rent or mortgage and 40 (19%) were unable to pay utility bills. Respondents experiencing economic hardship paid more out-of-pocket overall ([Formula: see text] versus [Formula: see text]; t148 = −2.03, P = 0.04) and for medications and oxygen specifically ([Formula: see text] versus [Formula: see text]; t83 = −3.98, P < 0.0001). Fifty-six (46%) respondents had catastrophic levels of out-of-pocket spending which made them 7.5 times more likely to experience economic hardship (95% confidence interval [CI]: 1.2-46.3).

Conclusions

The costs associated with living with COPD make it difficult for patients and their families to afford necessary living expenses while also paying health care expenses. This is alarming within Australia where a well-funded universal health insurance system is in place. Rising co-payments for medications and private medical consultations, poorly subsidised health support (e.g. home oxygen), non-health logistics (e.g. transport) and eligibility barriers for existing social support are making chronic illness management seriously economically stressful, especially for those with low incomes, including the retired.
Yeast Nrd1, Nab3, and Sen1 transcriptome-wide binding maps suggest multiple roles in post-transcriptional RNA processing
Authors: Jamonnak Nuttara , Creamer Tyler J. , Darby Miranda M. , Schaughency Paul , Wheelan Sarah J. , Corden Jeffry L.
Published: September 2011

RNA polymerase II transcribes both coding and noncoding genes, and termination of these different classes of transcripts is facilitated by different sets of termination factors. Pre-mRNAs are terminated through a process that is coupled to the cleavage/polyadenylation machinery, and noncoding RNAs in the yeast Saccharomyces cerevisiae are terminated through a pathway directed by the RNA-binding proteins Nrd1, Nab3, and the RNA helicase Sen1. We have used an in vivo cross-linking approach to map the binding sites of components of the yeast non-poly(A) termination pathway. We show here that Nrd1, Nab3, and Sen1 bind to a number of noncoding RNAs in an unexpected manner. Sen1 shows a preference for H/ACA over box C/D snoRNAs. Nrd1, which binds to snoRNA terminators, also binds to the upstream region of some snoRNA transcripts and to snoRNAs embedded in introns. We present results showing that several RNAs, including the telomerase RNA TLC1, require Nrd1 for proper processing. Binding of Nrd1 to transcripts from tRNA genes is another unexpected observation. We also observe RNA polymerase II binding to transcripts from RNA polymerase III genes, indicating a possible role for the Nrd1 pathway in surveillance of transcripts synthesized by the wrong polymerase. The binding targets of Nrd1 pathway components change in the absence of glucose, with Nrd1 and Nab3 showing a preference for binding to sites in the mature snoRNA and tRNAs. This suggests a novel role for Nrd1 and Nab3 in destruction of ncRNAs in response to nutrient limitation.
The Role of Apixaban for Venous and Arterial Thromboembolic Disease
Authors: Prom Rathasen , Spinler Sarah A
Published: September 2011

Objective:

To provide a comprehensive review of the pharmacology, pharmacokinetics, pharmacodynamics, clinical trial data, adverse effects, and drug interactions of apixaban.

Data Sources:

An English-language literature search was performed with MEDLINE/PubMed from January 2007 to August 2011 using the search terms apixaban, factor Xa inhibitors. FXa inhibitors, BMS-562247-01, venous thromboembolism. deep vein thrombosis, pulmonary embolism, myocardial infarction, acute coronary syndrome, ACS, atrial fibrillation, atrial arrhythmias, total hip replacement or arthroplasty, total knee replacement or arthroplasty, and orthopedic surgery to identify relevant articles. The references of the retrieved articles, professional society meeting abstracts, and the Web site www.clinicaltrials.gov were reviewed to identify other pertinent articles.

Study Selection And Data Abstraction:

Pertinent original studies involving apixaban's pharmacology, pharmacokinetics, drug interactions, and clinical efficacy and safety data were included.

Data Synthesis:

Results of 2 large Phase 3 trials suggest that apixaban is superior for stroke and systemic embolism prevention compared to both aspirin and warfarin in patients with atrial fibrillation (AF); rates of major bleeding and intracranial hemorrhage were similar to those of aspirin but significantly reduced compared to warfarin. Completed trials in orthopedic surgery found apixaban to be superior to enoxaparin in total hip replacement (THR) surgery but inferior in total knee replacement (TKR) surgery, with similar rates of major Weeding. A Phase 3 trial of apixaban in acute coronary syndrome was stopped early because of excess bleeding. Future Phase 3 trials will help to determine apixaban's role for treatment of deep vein thrombosis and pulmonary embolism. Currently, apixaban is approved only in Europe for prophylaxis of venous thromboembolism in adults who have undergone elective THR or TKR.

Conclusions:

A Phase 3 trial in patients with AF revealed apixaban to be superior to warfarin for stroke and systemic embolism prophylaxis, with lower rates of major bleeding. Further studies will help to confirm the role of apixaban for other indications.
Treatment of IgA Nephropathy: An Update
Authors: Rosselli Jennifer L , Thacker Stacey M , Karpinski Julie P , Petkewicz Katherine A
Published: September 2011

Objective:

To review current literature regarding treatment options for immunoglobulin A nephropathy (IgAN).

Data Sources:

A MEDLINE search was performed using the terms IgA nephropathy, Berger's disease, immunoglobulin A nephropathy, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, fish oil, omega-3 fatty acids, statins. hydroxymethylglutaryl-CoA reductase Inhibitors, immunosuppressive therapy, corticosteroids, mycophenolate mofetil, cyclophosphamide, cyclosporine, azathioprine, leflunomide, antiplatelets, anticoagulants, vitamin E, infliximab, calcitriol, and intravenous immunoglobulins. A date limit was not set; however, focus was on publications from 1999 to June 2011 to review recent literature and therapeutic recommendations.

Study Selection and Data Extraction:

All articles in English, including studies conducted in humans, meta-analyses, review articles, guidelines, statements, and reference citations, were identified and evaluated.

Data Synthesis:

IgAN is the most common primary glomerulonephritis worldwide, leading to end-stage renal disease in 20–30% of patients. Evidence guiding management of IgAN has been sparse and clinical trials have not conclusively demonstrated effective treatments, largely due to suboptimal methodologies. Treatment strategies have included management of blood pressure and lipids, improvement or stabilization of kidney function, and reduction of proteinuria. This review of IgAN provides an update regarding standard and nonconventional treatment options based on recently published literature.

Conclusions:

Supportive therapies, including angiotensin blockade, should be considered as first-line therapy for patients with urine protein >0.5 g/day and/or blood pressure > 140/90 mmHg, Corticosteroids could be considered as add-on or monotherapy for patients with urine protein >1 g/day with preserved renal function. Conclusive data are lacking for general treatment recommendations for the use of other therapies for IgAN.
Hybrid Offerings: How Manufacturing Firms Combine Goods and Services Successfully
Authors: Ulaga Wolfgang , Reinartz Werner J.
Published: September 2011

This article examines key success factors for designing and delivering combinations of goods and services (i.e., hybrid offerings) in business markets. Goods manufacturers, unlike pure service providers, find themselves in a unique position to grow revenues through hybrid offerings but must learn how to leverage unique resources and build distinctive capabilities. Using case studies and depth interviews with senior executives in manufacturing companies, the authors develop a resource–capability framework as a basis for research and practice. Executives identify four critical resources: (1) product usage and process data derived from the firm's installed base of physical goods, (2) product development and manufacturing assets, (3) an experienced product sales force and distribution network, and (4) a field service organization. In leveraging these specific resources, successful firms build five critical capabilities: (1) service-related data processing and interpretation capability, (2) execution risk assessment and mitigation capability, (3) design-to-service capability, (4) hybrid offering sales capability, and (5) hybrid offering deployment capability. These capabilities influence manufacturers’ positional advantage in two directions: differentiation and cost leadership. The authors propose a new typology of industrial services and discuss how resources and capabilities affect success across categories of hybrid offers.
Homeodomain Interacting Protein Kinase 2 Regulates Postnatal Development of Enteric Dopaminergic Neurons and Glia via BMP Signaling
Authors: Chalazonitis Alcmène , Tang Amy A. , Shang Yulei , Pham Tuan D. , Hsieh Ivy , Setlik Wanda , Gershon Michael D. , Huang Eric J.
Published: September 2011

Trophic factor signaling is important for the migration, differentiation, and survival of enteric neurons during development. The mechanisms that regulate the maturation of enteric neurons in postnatal life, however, are poorly understood. Here, we show that transcriptional cofactor HIPK2 (homeodomain interacting protein kinase 2) is required for the maturation of enteric neurons and for regulating gliogenesis during postnatal development. Mice lacking HIPK2 display a spectrum of gastrointestinal (GI) phenotypes, including distention of colon and slowed GI transit time. Although loss of HIPK2 does not affect the enteric neurons in prenatal development, a progressive loss of enteric neurons occurs during postnatal life inHipk2−/−mutant mice that preferentially affects the dopaminergic population of neurons in the caudal region of the intestine. The mechanism by which HIPK2 regulates postnatal enteric neuron development appears to involve the response of enteric neurons to bone morphogenetic proteins (BMPs). Specifically, compared towild typemice, a larger proportion of enteric neurons inHipk2−/−mutants have an abnormally high level of phosphorylated Smad1/5/8. Consistent with the ability of BMP signaling to promote gliogenesis,Hipk2−/−mutants show a significant increase in glia in the enteric nervous system. In addition, numbers of autophagosomes are increased in enteric neurons inHipk2−/−mutants, and synaptic maturation is arrested. These results reveal a new role for HIPK2 as an important transcriptional cofactor that regulates the BMP signaling pathway in the maintenance of enteric neurons and glia, and further suggest that HIPK2 and its associated signaling mechanisms may be therapeutically altered to promote postnatal neuronal maturation.
Protection and Expression of Human Motor Memories
Authors: Pekny Sarah E. , Criscimagna-Hemminger Sarah E. , Shadmehr Reza
Published: September 2011

When we adapt our movements to a perturbation, and then adapt to another perturbation, is the initial memory destroyed, or is it protected? Despite decades of experiments, this question remains unresolved. The confusion, in our view, is due to the fact that in every instance the approach has been to assay contents of motor memory by retesting with the same perturbations. When performance in retesting is the same as naive, this is usually interpreted as the memory being destroyed. However, it is also possible that the initial memory is simply masked by the competing memory. We trained humans in a reaching task in fieldBand then in fieldA(or washout) over an equal number of trials. To assay contents of motor memory, we used a new tool: after completion of training inA, we withheld reinforcement (i.e., reward) for a brief block of trials and then clamped movement errors to zero over a long block of trials. We found that this led to spontaneous recovery ofB. That is, withholding reinforcement for the current motor output resulted in the expression of the competing memory. Therefore, adaptation followed by washout or reverse adaptation produced competing motor memories. The protection from unlearning was unrelated to sudden changes in performance errors that might signal a contextual change, as competing memories formed even when the perturbations were introduced gradually. Rather, reinforcement appears to be a critical signal that affords protection to motor memories, and lack of reinforcement encourages retrieval of a competing memory.
Systematic Representation of Sound Locations in the Primary Auditory Cortex
Authors: Razak Khaleel A.
Published: September 2011

The primary auditory cortex (A1) is involved in sound localization. A consistent observation in A1 is a clustered representation of binaural properties, but how spatial tuning varies within binaural clusters is unknown. Here, this issue was addressed in A1 of the pallid bat, a species that relies on passive hearing (as opposed to echolocation) to localize prey. Evidence is presented for systematic representations of sound azimuth within two binaural clusters in the pallid bat A1: the binaural inhibition (EI) and peaked (P) binaural interaction clusters. The representation is not a “point-to-point” space map as seen in the superior colliculus, but is in the form of a systematic increase in the area of activated cortex as azimuth changes from ipsilateral to contralateral locations. The underlying substrate in the EI cluster is a systematic representation of the medial boundary of azimuth receptive fields. The P cluster is activated mostly for sounds near the midline, providing a spatial acoustic fovea. Activity in the P cluster falls off systematically as the sound is moved to more lateral locations. Sensitivity to interaural intensity differences predicts azimuth tuning in the vast majority of neurons. Azimuth receptive field properties are relatively stable across intensity over a moderate range (20–40 dB above threshold) of intensities. This suggests that the maps will be similar across the intensities tested. These results challenge the current view that no systematic representation of azimuth is present in A1 and show that such representations are present locally within individual binaural clusters.
Single-Channel and Structural Foundations of Neuronal α7 Acetylcholine Receptor Potentiation
Authors: daCosta Corrie J. B. , Free Chris R. , Corradi Jeremías , Bouzat Cecilia , Sine Steven M.
Published: September 2011

Potentiation of neuronal nicotinic acetylcholine receptors by exogenous ligands is a promising strategy for treatment of neurological disorders including Alzheimer's disease and schizophrenia. To gain insight into molecular mechanisms underlying potentiation, we examined ACh-induced single-channel currents through the human neuronal α7 acetylcholine receptor in the presence of the α7-specific potentiator PNU-120596 (PNU). Compared to the unusually brief single-channel opening episodes elicited by agonist alone, channel opening episodes in the presence of agonist and PNU are dramatically prolonged. Dwell time analysis reveals that PNU introduces two novel components into open time histograms, indicating at least two degrees of PNU-induced potentiation. Openings of the longest potentiated class coalesce into clusters whose frequency and duration change over a narrow range of PNU concentration. At PNU concentrations approaching saturation, these clusters last up to several minutes, prolonging the submillisecond α7 opening episodes by several orders of magnitude. Mutations known to reduce PNU potentiation at the whole-cell level still give rise to multisecond-long single-channel clusters. However mutation of five residues lining a cavity within each subunit's transmembrane domain abolishes PNU potentiation, defining minimal structural determinants of PNU potentiation.
Scene-Selective Cortical Regions in Human and Nonhuman Primates
Authors: Nasr Shahin , Liu Ning , Devaney Kathryn J. , Yue Xiaomin , Rajimehr Reza , Ungerleider Leslie G. , Tootell Roger B. H.
Published: September 2011

fMRI studies have revealed three scene-selective regions in human visual cortex [the parahippocampal place area (PPA), transverse occipital sulcus (TOS), and retrosplenial cortex (RSC)], which have been linked to higher-order functions such as navigation, scene perception/recognition, and contextual association. Here, we document corresponding (presumptively homologous) scene-selective regions in the awake macaque monkey, based on direct comparison to human maps, using identical stimuli and largely overlapping fMRI procedures. In humans, our results showed that the three scene-selective regions are centered near—but distinct from—the gyri/sulci for which they were originally named. In addition, all these regions are located within or adjacent to known retinotopic areas. Human RSC and PPA are located adjacent to the peripheral representation of primary and secondary visual cortex, respectively. Human TOS is located immediately anterior/ventral to retinotopic area V3A, within retinotopic regions LO-1, V3B, and/or V7. Mirroring the arrangement of human regions fusiform face area (FFA) and PPA (which are adjacent to each other in cortex), the presumptive monkey homolog of human PPA is located adjacent to the monkey homolog of human FFA, near the posterior superior temporal sulcus. Monkey TOS includes the region predicted from the human maps (macaque V4d), extending into retinotopically defined V3A. A possible monkey homolog of human RSC lies in the medial bank, near peripheral V1. Overall, our findings suggest a homologous neural architecture for scene-selective regions in visual cortex of humans and nonhuman primates, analogous to the face-selective regions demonstrated earlier in these two species.
FXR1P But Not FMRP Regulates the Levels of Mammalian Brain-Specific microRNA-9 and microRNA-124
Authors: Xu Xia-Lian , Zong Ruiting , Li Zhaodong , Biswas Md Helal Uddin , Fang Zhe , Nelson David L. , Gao Fen-Biao
Published: September 2011

Mammalian brain-specific miR-9 and miR-124 have been implicated in several aspects of neuronal development and function. However, it is not known how their expression levels are regulatedin vivo. We found that the levels of miR-9 and miR-124 are regulated by FXR1P but not by the loss of FXR2P or FMRPin vivo, a mouse model of fragile X syndrome. Surprisingly, the levels of miR-9 and miR-124 are elevated infmr1/fxr2double-knock-out mice, in part reflecting posttranscriptional upregulation of FXR1P. Indeed, FXR1P is required for efficient processing of pre-miR-9 and pre-miR-124in vitroand forms a complex with Dicer and pre-miRNAs. These findings reveal differential roles of FMRP family proteins in controlling the expression levels of brain-specific miRNAs.
TheDrosophilaSK Channel (dSK) Contributes to Photoreceptor Performance by Mediating Sensitivity Control at the First Visual Network
Authors: Abou Tayoun Ahmad N. , Li Xiaofeng , Chu Brian , Hardie Roger C. , Juusola Mikko , Dolph Patrick J.
Published: September 2011

The contribution of the SK (small-conductance calcium-activated potassium) channel to neuronal functions in complex circuits underlying sensory processing and behavior is largely unknown in the absence of suitable animal models. Here, we generated aDrosophilaline that lacks the single highly conservedSKgene in its genome (dSK). In R1–R6 photoreceptors,dSKencodes a slow Ca2+-activated K+current similar to its mammalian counterparts. Compared with wild-type,dSK−photoreceptors and interneurons showed accelerated oscillatory responses and adaptation. These enhanced kinetics were accompanied with more depolarizeddSK−photoreceptors axons, assigning a role for dSK in network gain control during light-to-dark transitions. However, compensatory network adaptation, through increasing activity between synaptic neighbors, overcame many detriments of missing dSK current enablingdSK−photoreceptors to maintain normal information transfer rates to naturalistic stimuli. While demonstrating important functional roles for dSK channel in the visual circuitry, these results also clarify how homeostatically balanced network functions can compensate missing or faulty ion channels.