bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of dsRNA on Mesangial Cell Synthesis of Plasminogen Activator Inhibitor Type 1 and Tissue Plasminogen Activator
Authors: Wörnle Markus , Roeder Maximilian , Sauter Matthias , Merkle Monika , Ribeiro Andrea
Published: July 2009

Background/Aims: Viral infections are a major problem worldwide and many of them are complicated by virally induced glomerulonephritides. Progression of kidney disease to renal failure is mainly attributed to the development of renal fibrosis characterized by the accumulation of extracellular matrix components in the mesangial cell compartment and the glomerular basement membrane. Plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (t-PA) are major regulators of plasmin generation and play an important role in generation and degradation of glomerular extracellular matrix components. Viral receptors expressed by mesangial cells (MC) are known to be key mediators in immune-mediated glomerulonephritis. We investigated the effect of stimulation of the viral receptors toll-like receptor 3 (TLR3) and retinoic acid-inducible gene I (RIG-I) on the expression of PAI-1 and t-PA. Methods: Expression of PAI-1 and t-PA in immortalized human MC stimulated with polyriboinosinic:polyribocytidylic acid [poly(I:C)] RNA and cytokines were analyzed by real-time RT-PCR and ELISA. Results: Incubation of MC with poly(I:C) RNA to activate the viral receptors TLR3 and RIG-I upregulates the expression of PAI-1 and t-PA. Knockdown of viral receptors with specific siRNA abolishes the induction of PAI-1 and t-PA. Conclusion: For the first time a link between the activation of viral receptors on MC and potentially causative agents in the development of glomerulosclerosis and tubulointerstitial fibrosis is shown. The progression of inflammatory processes to glomerulosclerosis can be postulated to be directly enhanced by viral infection.
How Can Second-Line Therapy for Metastatic Renal Cell Carcinoma Help to Define an Overall Management Strategy?
Authors: Melichar Bohuslav
Published: July 2009

For many years, therapy for metastatic renal cell carcinoma (mRCC) was limited to a single line of cytokine therapy with either interferon or interleukin-2. Relatively recently, the novel targeted agents bevacizumab, sorafenib, sunitinib and temsirolimus have each demonstrated activity in patients with mRCC that is refractory to cytokine therapy. Based on phase III trial data of patients who have received no prior therapy for mRCC, targeted agents have now rapidly replaced cytokines or, in the case of bevacizumab, are used in combination with interferon as first-line therapy for mRCC. Thus, second-line therapy for mRCC needs to be re-evaluated. Available data indicate that patients whose disease is refractory to a targeted agent may obtain, in some cases, benefit from a different agent, inhibiting either the same or a different pathway. With the availability of relatively few drugs for the treatment of mRCC, it is important to consider how to ensure that patients are obtaining maximum benefit through optimal use of the agents available. The definition of whether second-line therapy is active and tolerable and which therapy should be used in this setting in individual patients, particularly taking into account prior therapy, will therefore be important in defining the general therapeutic strategy in patients with mRCC.
Macrophage Sphingomyelin Synthase 2 Deficiency Decreases Atherosclerosis in Mice
Authors: Liu Jing , Huan Chongmin , Chakraborty Mahua , Zhang Hongqi , Lu Da , Kuo Ming-Shang , Cao Guoqing , Jiang Xian-Cheng
Published: July 2009

Rationale:

Sphingomyelin synthase (SMS)2 contributes to de novo sphingomyelin (SM) biosynthesis and plasma membrane SM levels. SMS2 deficiency in macrophages diminishes nuclear factor κB and mitogen-activated protein kinase activation induced by inflammatory stimuli.

Objective:

The effects of SMS2 deficiency on the development of atherosclerosis are investigated.

Methods and Results:

We measured cholesterol efflux from macrophages of wild-type (WT) and SMS2 knockout (KO) mice. We transplanted SMS2 KO mouse bone marrow into low-density lipoprotein (LDL) receptor (LDLr) knockout mice (SMS2
−/−
→LDLr
−/−
), creating a mouse model of SMS2 deficiency in the macrophages. We found that SMS2 deficiency caused significant induction of cholesterol efflux in vitro and in vivo. Moreover, we found that SMS2 KO mice had less interleukin-6 and tumor necrosis factor α in the circulation before and after endotoxin stimulation, compared with controls. More importantly, after 3 months on a western-type diet, SMS2
−/−
→LDLr
−/−
mice showed decreased atherosclerotic lesions in the aortic arch, root (57%,
P
<0.001), and the entire aorta (42%,
P
<0.01), compared with WT→LDLr
−/−
mice. Analysis of plaque morphology revealed that SMS2
−/−
→LDLr
−/−
mice had significantly less necrotic core area (71%,
P
<0.001), less macrophage content (37%,
P
<0.01), and more collagen content (35%,
P
<0.05) in atherosclerotic lesions. We also found that SMS2
−/−
→LDLr
−/−
mice had significantly lower free cholesterol and cholesteryl ester levels in the brachiocephalic artery than WT→LDLr
−/−
mice (33 and 52%,
P
<0.01 and
P
<0.001, respectively).

Conclusions:

SMS2 deficiency in the macrophages reduces atherosclerosis in mice. Macrophage SMS2 is thus a potential therapeutic target for treatment of this disease.
The Cost of Pediatric Stroke Acute Care in the United States
Authors: Perkins Elizabeth , Stephens Julie , Xiang Huiyun , Lo Warren
Published: July 2009

Background and Purpose—

The cost of pediatric stroke care has received little attention, but the available data suggest it is expensive. To determine the cost of acute stroke, we analyzed a US national database.

Method—

We used the Kids’ Inpatient Database (KID2003) to determine the hospital-based costs of acute stroke in children ages 3 months to 20 years. Discharges were selected if the first diagnostic position contained an International Classification of Diseases, 9th Revision code pertaining to ischemic or hemorrhagic stroke. We examined the relationship between cost and stroke type by adjusting for variables that predict the cost of adult stroke.

Results—

There were 2224 pediatric cases, after statistical weighting, discharged with a diagnosis of hemorrhagic or ischemic stroke in KID2003. The estimated cost of acute pediatric stroke in the United States was $42 million in 2003. For the entire cohort, the mean cost of acute hospital care was $20 927 per discharge. The mean cost for ischemic stroke was $15 003, for intracerebral hemorrhage $24 117, and for subarachnoid hemorrhage $31 653. Stroke diagnosis, length of stay, hospital ownership, rural/urban teaching status, US geographical region, and discharge disposition were significantly associated with cost. Cost remained significantly associated with stroke diagnosis after adjusting for other predictors in the final multivariable regression model.

Conclusions—

Pediatric stroke is expensive, and the lifetime cost of care is likely greater for a child than an adult. The cost to the family and the larger society underscore the importance of pediatric stroke treatment and prevention.
Wholesale Late Merger: Beyond the A/Ā Distinction
Authors: Takahashi Shoichi , Hulsey Sarah
Published: July 2009

In this article, we develop a substantially expanded theory of late merger. Adopting related insights by Fox (2002), we argue that late merger is permitted whenever an output representation can be interpreted in the semantic component. A consequence of our approach is that late merger is available not only for the well-known case of adjuncts, but also for restrictors of determiners (wholesale late merger). We demonstrate that this theory can explain the different reconstruction possibilities of A-movement and Ā-movement, as well as various otherwise puzzling facts about movement and ellipsis, while still maintaining the copy theory of movement.
The International Court of Justice – New Practice Directions
Authors: Rosenne Shabtai
Published: July 2009

New Practice Directions III, VI and XIII, deal with the written pleadings and the oral pleadings and the relations between the two. This Note examines these new Practice Directions in light of relevant provisions of the Statute and the Rules of Court and suggests that the Court exercise its powers to give the parties suggestions regarding the content of the written pleadings in regular interlocutory stages. This is to meet the Court's desire to maintain succinctness of the written pleadings without prejudice to their adequacy.
Micromechanics of Oxidation in Composites with Impermeable Fibers
Authors: Varghese Julian , Whitcomb John
Published: July 2009

This article describes an approach to determine effective oxidation material properties for a unidirectional laminate or tow. The effective properties will ultimately be used to model the oxidation behavior of textile composites. It is necessary to use homogenized properties for the tow because it is impractical to discretely model all the fibers in a composite. The basic oxidation model is taken from existing work in the literature, which was used to simulate the oxidation behavior of neat PMR-15 resin. The governing equations and the finite element formulation for the model are described as well as approaches for determining the various effective properties. Three configurations were analyzed to test the accuracy of the effective oxidation properties. The configurations were discretely modeled to provide a reference solution. Different idealizations were tested in order to determine the accuracy of the effective properties. The configurations included fully homogenized idealizations as well as mixed idealizations which have a combination of both homogenized and discretely modeled regions. The concentration of oxygen in the model as well as the oxidation state of the materials in the composite are compared to the reference model. The effective oxidation properties performed reasonably well for the three configurations in terms of predicting the oxidation layer growth.
Microstructural Analysis of Composite Tubes through Digital Microscopy
Authors: De Oliveira J.G.Á. , Paciornik S. , D'Almeida J.R.M.
Published: July 2009

A semi-automatic method for the analysis of fiber-reinforced composites manufactured by filament winding is proposed. SEM images were assembled in a mosaic to reveal the microstructure of a complete cross-section of a composite pipe. An image processing and analysis procedure was developed to reduce image noise, discriminate individual fibers, and detect different layers composed of fibers with similar winding angle. Fiber size and shape was measured, allowing the determination of the average winding angle for each layer.
Effects of Nanoclay as a Reinforcement Filler on the Physical and Mechanical Properties of Wood-based Composite
Authors: Ashori Alireza , Nourbakhsh Amir
Published: July 2009

In this study, the effects of nanoclay (layered silicate) loading (0, 2, 4, 6, 8 wt%) as reinforcement filler and press temperature (165 and 175 °C) on the properties of laboratory made medium density fiberboard (MDF) boards were investigated. Physical (thickness swelling) and mechanical properties of the boards were determined according to the procedure of European Norm standards. The results showed considerable improvement in mechanical properties, specifically in bending strength and internal bond strength of the boards as nanoclay was loaded from 2 to 6 wt% to the boards’ furnishes. The boards with 6 wt% nanoclay content showed the optimized mechanical properties. There was a clear trend that both thickness swelling (after 2 and 24 h water soaking) decreased with addition of nanoclay and press temperature. The increasing press temperature had strong positive effect on all physicomechanical properties of the boards. Thus, the data showed that nanoclay can enhance mechanical strength and water stability properties of MDF boards.
Mechanical Properties and Morphology of Nanoclay Filled Different TPU/PP Blend Nanocomposites: Structure - Property Relations
Authors: Kannan M. , Bhagawan S.S. , Joseph K. , Thomas S.
Published: July 2009

Thermoplastic polyurethanes (TPU) (based on ether and ester polyols) were blended with nonpolar polypropylene (PP). Nanoclay was used to reduce the surface energy of the TPU hard segments and make them more compatible with the nonpolar PP. More compatible blends were obtained by using MA-g-PP as the compatibilizer. Blends were produced by melt mixing using a twin screw extruder. Compared to the ether-TPU-based blend nanocomposites, the ester-TPU blends show better compatibility as confirmed by DMA, Tensile strength, XRD, SEM, and AFM analysis.
Preventing State Crimes Against Democracy
Authors: deHaven‐Smith Lance , Witt Matthew T.
Published: July 2009

This article analyzes U.S. vulnerabilities to state crimes against democracy (SCADs). SCADs are actions or inactions by government insiders intended to manipulate democratic processes and undermine popular sovereignty. Watergate and Iran–Contra are well‐known examples of SCADs involving top officials. SCADs in high office are difficult to detect and successfully prosecute because they are usually complex and compartmentalized; investigations are often compromised by conflicts of interests; and powerful norms discourage speculation about corruption in high office. However, liberal democracies can reduce their vulnerability to state political criminality by identifying vulnerabilities proactively and instituting policies for SCAD detection and prevention.
The capabilities approach and critical social policy: Lessons from the majority world?
Authors: Carpenter Mick
Published: July 2009

The capabilities approach (CA) most closely associated with the thinner and thicker versions of Sen and Nussbaum has the potential to provide a paradigm shift for critical social policy, encompassing but also transcending some of the limitations associated with the Marshallian social citizenship approach. The article argues, however, that it cannot simply be imported from the majority world, rather there is a need to bear in mind the critical literature that developed around it. This is generally discussed and then critically applied to case studies of CA in the developed capitalist world, particularly the Equalities Review conducted for the Equality and Human Rights Commission.
Capacity and its Fallacies: International State Building as State Transformation
Authors: Hameiri Shahar
Published: July 2009

Considerable effort in recent years has gone into rebuilding fragile states. However, the debates over the effectiveness of such state-building exercises have tended to neglect that capacity building and the associated good governance programmes which comprise contemporary state building are essentially about transforming the state — meaning the ways in which political power is produced and reproduced. State capacity is now often presented as the missing link required for generating positive development outcomes and security. However, rather than being an objective and technical measure, capacity building constitutes a political and ideological mechanism for operationalising projects of state transnationalisation. The need to question prevailing notions of state capacity has become apparent in light of the failure of many state-building programmes. Such programmes have proven difficult to implement, and implementation has rarely achieved the expected development turnarounds or alleviation of violent conflict in those countries. In this article it is argued that, to identify the potential trajectories of such interventions, we must understand the role state building currently plays in domestic politics, and in particular, the ways in which processes of state transformation affect the development of different and often conflicting power bases within the state. This argument is examined using examples from the Australian-led Regional Assistance Mission to Solomon Islands.
Culture and International Relations: The Culture of International Relations
Authors: Lebow Richard Ned
Published: July 2009

In a response to my critics I further elaborate some of the concepts central to A Cultural Theory of International Relations. I explain why it is a cultural theory, as distinct from a theory of culture; the different levels of reason conceptualised by the Greeks and their utility in moving our thinking beyond the exclusive focus on instrumental rationality of modern social science; and Aristotle's concept of anger and its implications for the behaviour of the weak and the powerful. I justify my case selection and its Western bias, but defend the universality of my theory and its non-hegemonic application to the study of other cultures.
Age, Race, and Gender Differences in Depressive Symptoms: A Lifespan Developmental Investigation
Authors: Bracken Bruce A. , Reintjes Cristina
Published: July 2009

This study considered depressive symptoms among a normative sample of 1,900 children, adolescents, and adults (950 males and 950 females) divided across four age-levels to investigate the developmental progression of depressive symptoms by age, race/ethnicity, and gender. The national normative sample of the Clinical Assessment of Depression (CAD) was used in this study, which provided a large, reliably assessed, representative sample for group comparisons. CAD age, gender, race/ethnicity analyses revealed that depressive symptoms appear to be experienced at fairly uniform levels across the age-span, by both genders, and among Whites, Blacks, and Hispanics. Specific differences within age, race, and gender groups and interactions are discussed.
Selective reduction of JAK2V617F-dependent cell growth by siRNA/shRNA and its reversal by cytokines
Authors: Jedidi Abire , Marty Caroline , Oligo Charleen , Jeanson-Leh Laurence , Ribeil Jean-Antoine , Casadevall Nicole , Galy Anne , Vainchenker William , Villeval Jean-Luc
Published: July 2009

The JAKV617F mutation is responsible for the majority of breakpoint cluster region (BCR)/Abelson (ABL)–negative myeloproliferative disorders. Ongoing clinical trials of Janus kinase 2 (JAK2) inhibitors in myeloproliferative disorder patients use small molecules targeting both wild-type and mutated JAK2. To selectively target malignant cells, we developed JAK2V617F-specific small interfering RNAs or short hairpin RNAs. Expression of these RNAs in cell lines or CD34+ cells from patients reduced JAK2V617F-driven autonomous cell proliferation. Mechanisms of inhibition involved selective JAK2V617F protein down-regulation, and consequently, decrease in signal transducer and activator of transcription 5 phosphorylation, cell-cycle progression, and cell survival. However, the addition of high concentrations of cytokines to cell lines or erythropoietin to patient cells greatly reduced growth inhibition. Similarly, the efficacy of a JAK2 small molecule inhibitor on cell line and patient cell proliferation dose dependently decreased with the addition of cytokines. Our results demonstrate that it is possible to specifically target JAK2V617F by RNA interference (RNAi) strategies. In addition, cytokines partially reverse the inhibition induced by both RNAi and small molecule approaches. This strongly suggests that patient cytokine levels in current JAK2 inhibitor clinical trials modulate the outcome of these therapies.
Lack of specific γ-retroviral vector long terminal repeat promoter silencing in patients receiving genetically engineered lymphocytes and activation upon lymphocyte restimulation
Authors: Burns William R. , Zheng Zhili , Rosenberg Steven A. , Morgan Richard A.
Published: July 2009

Retroviral transduction of tumor antigen-specific T-cell receptor (TCR) genes into lymphocytes redirects T cells to lyse tumors. Furthermore, adoptive transfer of these lymphocytes has mediated objective responses in patients with metastatic cancer. From 2004 to 2006, more than 40 patients were treated with autologous gene-modified lymphocytes expressing a melanoma antigen-specific TCR at the National Cancer Institute. Eighteen such patients were analyzed for persistence and gene expression in vivo. In addition, the impact of epigenetic silencing and of lymphocyte restimulation was studied. Although gene-modified lymphocytes persisted in vivo, the shutdown of TCR transgene expression was observed. Bisulfite sequencing analysis and ex vivo DNA methyltransferase inhibition demonstrated that the decrease in gene expression did not result from DNA methylation. Surprisingly, down-regulation of vector-driven transgene transcriptional activity was not vector specific but mimicked that of endogenous genes. The decrease in TCR transgene expression, however, was reversed upon lymphocyte stimulation. These data demonstrate a lack of γ-retroviral promoter-specific gene silencing in adoptively transferred human lymphocytes and support that transgene expression is largely affected by global cellular mechanisms. The use of immunomodulatory adjuvants, eg, vaccination or cytokine therapy, for in vivo T-cell activation may help overcome this metabolic quiescence and thus augment cellular immunotherapy-based cancer therapy.
Chelation of intracellular iron with the antifungal agent ciclopirox olamine induces cell death in leukemia and myeloma cells
Authors: Eberhard Yanina , McDermott Sean P. , Wang Xiaoming , Gronda Marcela , Venugopal Amudha , Wood Tabitha E. , Hurren Rose , Datti Alessandro , Batey Robert A. , Wrana Jeffrey , Antholine William E. , Dick John E. , Schimmer Aaron D.
Published: July 2009

Off-patent drugs with previously unrecognized anticancer activity could be rapidly repurposed for this new indication. To identify such compounds, we conducted 2 independent cell-based chemical screens and identified the antimicrobial ciclopirox olamine (CPX) in both screens. CPX decreased cell growth and viability of malignant leukemia, myeloma, and solid tumor cell lines as well as primary AML patient samples at low-micromolar concentrations that appear pharmacologically achievable. Furthermore, oral CPX decreased tumor weight and volume in 3 mouse models of leukemia by up to 65% compared with control without evidence of weight loss or gross organ toxicity. In addition, oral CPX prevented the engraftment of primary AML cells in nonobese diabetic/severe combined immunodeficiency mouse models, thereby establishing its ability to target leukemia stem cells. Mechanistically, CPX bound intracellular iron, and this intracellular iron chelation was functionally important for its cytotoxicity. By electron paramagnetic resonance, CPX inhibited the iron-dependent enzyme ribonucleotide reductase at concentrations associated with cell death. Thus, in summary, CPX has previously unrecognized anticancer activity at concentrations that are pharmacologically achievable. Therefore, CPX could be rapidly repurposed for the treatment of malignancies, including leukemia and myeloma.
Glucose-6-phosphate dehydrogenase (G6PD) mutations and haemoglobinuria syndrome in the Vietnamese population
Authors: Hue Nguyen Thi , Charlieu Jean Paul , Chau Tran Thi Hong , Day Nick , Farrar Jeremy J , Hien Tran Tinh , Dunstan Sarah J
Published: July 2009

Background

In Vietnam the blackwater fever syndrome (BWF) has been associated with malaria infection, quinine ingestion and G6PD deficiency. The G6PD variants within the Vietnamese Kinh contributing to the disease risk in this population, and more generally to haemoglobinuria, are currently unknown.

Method

Eighty-two haemoglobinuria patients and 524 healthy controls were screened for G6PD deficiency using either the methylene blue reduction test, the G-6-PDH kit or the micro-methaemoglobin reduction test. The G6PD gene variants were screened using SSCP combined with DNA sequencing in 82 patients with haemoglobinuria, and in 59 healthy controls found to be G6PD deficient.

Results

This study confirmed that G6PD deficiency is strongly associated with haemoglobinuria (OR = 15, 95% CI [7.7 to 28.9], P < 0.0001). Six G6PD variants were identified in the Vietnamese population, of which two are novel (Vietnam1 [Glu3Lys] and Vietnam2 [Phe66Cys]). G6PD Viangchan [Val291Met], common throughout south-east Asia, accounted for 77% of the variants detected and was significantly associated with haemoglobinuria within G6PD-deficient ethnic Kinh Vietnamese (OR = 5.8 95% CI [114-55.4], P = 0.022).

Conclusion

The primary frequency of several G6PD mutations, including novel mutations, in the Vietnamese Kinh population are reported and the contribution of G6PD mutations to the development of haemoglobinuria are investigated.
A functional difficulty and functional pain instrument for hip and knee osteoarthritis
Authors: Jette Alan M , McDonough Christine M , Ni Pengsheng , Haley Stephen M , Hambleton Ronald K , Olarsch Sippy , Hunter David J , Kim Young-jo , Felson David T
Published: July 2009

Introduction

The objectives of this study were to develop a functional outcome instrument for hip and knee osteoarthritis research (OA-FUNCTION-CAT) using item response theory (IRT) and computer adaptive test (CAT) methods and to assess its psychometric performance compared to the current standard in the field.

Methods

We conducted an extensive literature review, focus groups, and cognitive testing to guide the construction of an item bank consisting of 125 functional activities commonly affected by hip and knee osteoarthritis. We recruited a convenience sample of 328 adults with confirmed hip and/or knee osteoarthritis. Subjects reported their degree of functional difficulty and functional pain in performing each activity in the item bank and completed the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Confirmatory factor analyses were conducted to assess scale uni-dimensionality, and IRT methods were used to calibrate the items and examine the fit of the data. We assessed the performance of OA-FUNCTION-CATs of different lengths relative to the full item bank and WOMAC using CAT simulation analyses.

Results

Confirmatory factor analyses revealed distinct functional difficulty and functional pain domains. Descriptive statistics for scores from 5-, 10-, and 15-item CATs were similar to those for the full item bank. The 10-item OA-FUNCTION-CAT scales demonstrated a high degree of accuracy compared with the item bank (r = 0.96 and 0.89, respectively). Compared to the WOMAC, both scales covered a broader score range and demonstrated a higher degree of precision at the ceiling and reliability across the range of scores.

Conclusions

The OA-FUNCTION-CAT provided superior reliability throughout the score range and improved breadth and precision at the ceiling compared with the WOMAC. Further research is needed to assess whether these improvements carry over into superior ability to measure change.
Comparison of cardiac, hepatic, and renal effects of arginine vasopressin and noradrenaline during porcine fecal peritonitis: a randomized controlled trial
Authors: Simon Florian , Giudici Ricardo , Scheuerle Angelika , Gröger Michael , Asfar Pierre , Vogt Josef A , Wachter Ulrich , Ploner Franz , Georgieff Michael , Möller Peter , Laporte Régent , Radermacher Peter , Calzia Enrico , Hauser Balázs
Published: July 2009

Introduction

Infusing arginine vasopressin (AVP) in vasodilatory shock usually decreases cardiac output and thus systemic oxygen transport. It is still a matter of debate whether this vasoconstriction impedes visceral organ blood flow and thereby causes organ dysfunction and injury. Therefore, we tested the hypothesis whether low-dose AVP is safe with respect to liver, kidney, and heart function and organ injury during resuscitated septic shock.

Methods

After intraperitoneal inoculation of autologous feces, 24 anesthetized, mechanically ventilated, and instrumented pigs were randomly assigned to noradrenaline alone (increments of 0.05 μg/kg/min until maximal heart rate of 160 beats/min; n = 12) or AVP (1 to 5 ng/kg/min; supplemented by noradrenaline if the maximal AVP dosage failed to maintain mean blood pressure; n = 12) to treat sepsis-associated hypotension. Parameters of systemic and regional hemodynamics (ultrasound flow probes on the portal vein and hepatic artery), oxygen transport, metabolism (endogenous glucose production and whole body glucose oxidation derived from blood glucose isotope and expiratory 13CO2/12CO2 enrichment during 1,2,3,4,5,6-13C6-glucose infusion), visceral organ function (blood transaminase activities, bilirubin and creatinine concentrations, creatinine clearance, fractional Na+ excretion), nitric oxide (exhaled NO and blood nitrate + nitrite levels) and cytokine production (interleukin-6 and tumor necrosis factor-α blood levels), and myocardial function (left ventricular dp/dtmax and dp/dtmin) and injury (troponin I blood levels) were measured before and 12, 18, and 24 hours after peritonitis induction. Immediate post mortem liver and kidney biopsies were analysed for histomorphology (hematoxylin eosin staining) and apoptosis (TUNEL staining).

Results

AVP decreased heart rate and cardiac output without otherwise affecting heart function and significantly decreased troponin I blood levels. AVP increased the rate of direct, aerobic glucose oxidation and reduced hyperlactatemia, which coincided with less severe kidney dysfunction and liver injury, attenuated systemic inflammation, and decreased kidney tubular apoptosis.

Conclusions

During well-resuscitated septic shock low-dose AVP appears to be safe with respect to myocardial function and heart injury and reduces kidney and liver damage. It remains to be elucidated whether this is due to the treatment per se and/or to the decreased exogenous catecholamine requirements.
Hyperactivated B cells in human inflammatory bowel disease
Authors: Noronha Ansu Mammen , Liang YanMei , Hetzel Jeremy T , Hasturk Hatice , Kantarci Alpdogan , Stucchi Arthur , Zhang Yue , Nikolajczyk Barbara S , Farraye Francis A , Ganley-Leal Lisa M
Published: July 2009

B cells from Crohn’s disease and ulcerative colitis patients have the potential to influence inflammation through elevated expression of Toll-like receptor 2 and IL-8.

IBD is characterized by a chronic, dysregulated immune response to intestinal bacteria. Past work has focused on the role of T cells and myeloid cells in mediating chronic gastrointestinal and systemic inflammation. Here, we show that circulating and tissue B cells from CD patients demonstrate elevated basal levels of activation. CD patient B cells express surface TLR2, spontaneously secrete high levels of IL-8, and contain increased ex vivo levels of phosphorylated signaling proteins. CD clinical activity correlates directly with B cell expression of IL-8 and TLR2, suggesting a positive relationship between these B cell inflammatory mediators and disease pathogenesis. In contrast, B cells from UC patients express TLR2 but generally do not demonstrate spontaneous IL-8 secretion; however, significant IL-8 production is inducible via TLR2 stimulation. Furthermore, UC clinical activity correlates inversely with levels of circulating TLR2+ B cells, which is opposite to the association observed in CD. In conclusion, TLR2+ B cells are associated with clinical measures of disease activity and differentially associated with CD- and UC-specific patterns of inflammatory mediators, suggesting a formerly unappreciated role of B cells in the pathogenesis of IBD
Comparison between Hippocampus-Synthesized and Circulation-Derived Sex Steroids in the Hippocampus
Authors: Hojo Yasushi , Higo Shimpei , Ishii Hirotaka , Ooishi Yuuki , Mukai Hideo , Murakami Gen , Kominami Toshihiro , Kimoto Tetsuya , Honma Seijiro , Poirier Donald , Kawato Suguru
Published: July 2009

Estradiol (E2) and other sex steroids play essential roles in the modulation of synaptic plasticity and neuroprotection in the hippocampus. To clarify the mechanisms for these events, it is important to determine the respective role of circulating vs. locally produced sex steroids in the male hippocampus. Liquid chromatography-tandem mass spectrometry in combination with novel derivatization was employed to determine the concentration of sex steroids in adult male rat hippocampus. The hippocampal levels of 17β-E2, testosterone (T), and dihydrotestosterone (DHT) were 8.4, 16.9, and 6.6 nm, respectively, and these levels were significantly higher than circulating levels. The hippocampal estrone (E1) level was, in contrast, very low around 0.015 nm. After castration to deplete circulating high level T, hippocampal levels of T and DHT decreased considerably to 18 and 3%, respectively, whereas E2 level only slightly decreased to 83%. The strong reduction in hippocampal DHT resulting from castration implies that circulating T may be a main origin of DHT. In combination with results obtained from metabolism analysis of [3H]steroids, we suggest that male hippocampal E2 synthesis pathway may be androstenedione → T → E2 or dehydroepiandrosterone → androstenediol → T → E2 but not androstenedione → E1 → E2.
Differential effects of BMP signaling on parvalbumin and somatostatin interneuron differentiation
Authors: Mukhopadhyay Abhishek , McGuire Tammy , Peng Chian-Yu , Kessler John A.
Published: July 2009

Several different populations of interneurons in the murine cortex,including somatostatin (SST)- or parvalbumin (PV)-expressing cells, are born in the ventral ganglionic eminences during mid-gestation and then migrate tangentially to the cortex. SST is expressed by some interneuron progenitors in the cerebral cortex and in migrating populations in the ventrolateral cortex at birth. However, PV (also known as PVALB) is not expressed by interneurons until the second postnatal week after reaching the cortex,suggesting that molecular cues in the cerebral cortex might be involved in the differentiation process. BMP4 is expressed at high levels in the somatosensory cortex at the time when the PV+ interneurons differentiate. Treatment of cortical cultures containing interneuron precursors is sufficient to generate PV+ interneurons prematurely and inhibit SST differentiation. Furthermore, overexpression of BMP4 in vivo increases the number of interneurons expressing PV, with a reduction in the number of SST+ interneurons. PV+ interneurons in the cortex express BMP type I receptors and a subpopulation displays activated BMP signaling, assessed by downstream molecules including phosphorylated SMAD1/5/8. Conditional mutation of BMP type I receptors in interneuron precursors significantly reduces the number of cortical PV+interneurons in the adult brain. Thus, BMP4 signaling through type I receptors regulates the differentiation of two major medial ganglionic eminence-derived interneuron populations and defines their relative numbers in the cortex.
Fascin is required for blood cell migration during Drosophilaembryogenesis
Authors: Zanet Jennifer , Stramer Brian , Millard Thomas , Martin Paul , Payre François , Plaza Serge
Published: July 2009

Fascin is well characterized in vitro as an actin-bundling protein and its increased expression is correlated with the invasiveness of various cancers. However, the actual roles and regulation of Fascin in vivo remain elusive. Here we show that Fascin is required for the invasive-like migration of blood cells in Drosophila embryos. Fascin expression is highly regulated during embryonic development and, within the blood lineage, is specific to the motile subpopulation of cells, which comprises macrophage-like plasmatocytes. We show that Fascin is required for plasmatocyte migration, both as these cells undergo developmental dispersal and during an inflammatory response to epithelial wounding. Live analyses further demonstrate that Fascin localizes to, and is essential for the assembly of, dynamic actin-rich microspikes within plasmatocyte lamellae that polarize towards the direction of migration. We show that a regulatory serine of Fascin identified from in vitro studies is not required for in vivo cell motility, but is crucial for the formation of actin bundles within epithelial bristles. Together, these results offer a first glimpse into the mechanisms regulating Fascin function during normal development, which might be relevant for understanding the impact of Fascin in cancers.
Cx30.2enhancer analysis identifies Gata4 as a novel regulator of atrioventricular delay
Authors: Munshi Nikhil V. , McAnally John , Bezprozvannaya Svetlana , Berry Jeff M. , Richardson James A. , Hill Joseph A. , Olson Eric N.
Published: July 2009

The cardiac conduction system comprises a specialized tract of electrically coupled cardiomyocytes responsible for impulse propagation through the heart. Abnormalities in cardiac conduction are responsible for numerous forms of cardiac arrhythmias, but relatively little is known about the gene regulatory mechanisms that control the formation of the conduction system. We demonstrate that a distal enhancer for the connexin 30.2 (Cx30.2, also known as Gjd3) gene, which encodes a gap junction protein required for normal atrioventricular (AV) delay in mice, is necessary and sufficient to direct expression to the developing AV conduction system (AVCS). Moreover, we show that this enhancer requires Tbx5 and Gata4 for proper expression in the conduction system, and Gata4+/- mice have short PR intervals indicative of accelerated AV conduction. Thus, our results implicate Gata4 in conduction system function and provide a clearer understanding of the transcriptional pathways that impact normal AV delay.
Adaptable design: Concepts, methods, and applications
Authors: Gu P , Xue D , Nee A Y C
Published: July 2009

Increasing competition in the global marketplace demands products with better functionality, higher quality, lower cost, shorter delivery lead time, and increased environmental friendliness. Although advanced manufacturing technologies can partially address these challenges, advanced design technologies are considered critical, since most design and manufacturing properties of a product are influenced by the design decisions made in the early design stages. This paper provides a comprehensive review on a new design paradigm — adaptable design — that aims at developing adaptable products to satisfy the various requirements of customers. The topics discussed in this review include the fundamental concepts, objectives, methodologies, and applications. The paper also presents the differences between adaptable design and other design methods, such as modular design, platform design, and product customization. The focus is on mechanical product design; however, potential applications of adaptable design in other disciplines are also briefly mentioned.
Functional solving process model toward product innovation design based on a functional solving model with multiple elements and evolutions
Authors: Li W , Li Y , Wang J , Xiong Y
Published: July 2009

According to the evolution of functional solving models, this paper first compares the characteristics and the consistency of the thinking process of three different functional solving models, including the extended function—environment—behaviour—structure (FEBS/e) model, the extended behaviour-driven function—environment-structure (B-FES/e) model, and the extended function—behaviour—implementation—environment (FBIE/e) model. Then, a new functional solving model with multiple elements and evolutions (FSMEE) is proposed. In this model, the reasoning process of product functional design is classified into 12 basic mapping relations by virtue of the regulation analysis of the design process. The evolutionary logic of basic mapping relations is then developed according to the optimal degree. In addition, the computer representation of the hierarchy design process is established by means of the topology relation matrices and adjacency relation matrices. Finally, an example of an emergency cut-off valve is presented to demonstrate the model's feasibility.
Identification of invariant factors that determine labour output on the production line
Authors: Milanovic D D , Klarin M , Misita M , Lj Milanovic D , Zunjic A
Published: July 2009

The efficiency of the production line system has been investigated by gaining a complex insight into a large number of variables affecting its functioning. The basic hypothesis of this paper concerns the existence of invariant factors that determine labour output on the production line. Applying factor analysis to constructed databases, the factors are extracted that confirm the basic hypothesis of this paper. In this research, multivariant analysis has been applied: cluster analysis to display the validity of ramification of the primary sample to small subgroups and factor analysis has been applied to the primary sample and the subgroups. The results of the application of the software package SPSS (Statistical Package for the Social Science) show that there are stable invariant factors that determine labour output on the production line. Invariant factors that determine labour output on the production line include: motivation of workers for production line work; elimination of adverse effects of work on the production line; rhythm of work; and psychophysical fatigue. The identified invariant factors provide a deeper insight into labour output as well as enabling the planning of activities that can improve production line work and make it more efficient.
Parameter optimization of a hydraulic engine mount based on a genetic neural network
Authors: Li Q , Zhao J-C , Zhao B , Zhu X-S
Published: July 2009

Hydraulic engine mounts (HEMs) are important vehicle components to isolate the vehicle structure from engine vibration. A parameter optimization methodology for an HEM based on a genetic neural network (NN) model is proposed in this study. Samples of HEMs with different structures and rubber materials are manufactured and their dynamic characteristics are tested on an MTS 831 elastomer test system. Then the test results are used as samples to train the NN model which defines the non-linear global mapping relationship between the HEM's structural parameters and its dynamic characteristics. The fitness values of the population in the genetic algorithm are calculated by the trained NN model, and the optimal solution was acquired with the mutation of population. Finally, experiments are made to validate the reliability of the optimal solution. The proposed optimization method can specify the structures and materials of HEMs to meet the design requirements automatically.
Real-time estimation of aquaplaning with an optical tyre sensor
Authors: Tuononen A J , Matilainen M J
Published: July 2009

Future active safety systems will require more accurate information about the state of a vehicle and the operating conditions of an individual tyre. Aquaplaning is a dangerous situation in which the contact between the tyre and the road is partially or completely lost. In this paper, the movements of the inner liner of the tyre during aquaplaning are measured optically and exploited to estimate aquaplaning. The results from proving-ground tests are shown and compared with those of the conventional approach of estimating aquaplaning from wheel speeds. The proposed method performs reliably in real time and can detect several different levels of aquaplaning. The results support the future development of production-capable tyre sensors. An optical tyre sensor also provides a research tool for attaining an in-depth understanding of the aquaplaning phenomenon.
Technique of simultaneous synchronized evaluation of the tribological components of an engine under realistic conditions
Authors: Mufti R A , Priest M
Published: July 2009

One of the main drivers in developing advanced engines and formulating new lubricants is fuel economy. The direct relationship of frictional loss to fuel economy in an internal combustion engine has resulted in an increased interest in understanding engine performance at the component level.

With the advances in data acquisition systems and sensor technology, extensive study of the main engine components, i.e. valve train, piston assembly, and engine bearings, have been possible, resulting in the development of a versatile engine friction measurement system. Total engine and component friction measurements were carried out on a single-cylinder Ricardo Hydra gasoline engine under fired conditions. For such measurements, the engine is fitted with more than 50 different sensors and to sample/log data from such a large number of transducers, an advanced high-speed synchronized data acquisition system was designed. This paper explains the experimental techniques used to measure simultaneously total and component friction under fired conditions. This system can be used as a powerful tool for screening lubricants, validating complex mathematical models at system level, and studying the effect of different additives and materials on the performance of each engine component under realistic engine operating conditions.
Performance optimization of hypersonic inlets with pulse periodic energy addition
Authors: Chang Juntao , Bao Wen , Fan Yi , Yu Daren
Published: July 2009

To optimize the law of pulse periodic energy addition and to obtain maximum performance improvement of hypersonic inlets, the performance analysis of hypersonic inlets with pulse periodic energy addition is investigated. First, the unsteady numerical simulation of hypersonic inlets with different pulse periodic energy additions was performed, and then the effect of the duty cycle and pulse frequency of the energy addition on the performance parameters of hypersonic inlets was discussed. The simulation result shows that the averaged performance parameters of hypersonic inlets are improved by increasing the duty cycle or the pulse frequency for the same averaged energy addition rate. These can provide some beneficial references for optimization of the law of pulse periodic energy addition to obtain maximum performance improvement of hypersonic inlets.
A variable stability projectile using an internal moving mass
Authors: Rogers J , Costello M
Published: July 2009

Weapon designers have known for some time that projectiles with low static margin have proven to be more susceptible to launch perturbations than comparable projectiles with high static stability, and that low static margin allows greater control authority. The work reported here examines a mechanism for active static margin control in flight through mass centre modification, demonstrating that such a system has significant impact on required manoeuvre control force to achieve a given control authority. A system is developed wherein a mass translates aft during flight inside a cavity aligned with the projectile centre-line, thereby altering the mass centre. This in turn decreases the projectile's static margin after launch and allows greater control authority later in flight, while at the same time decreasing initial throw-off errors. A seven-degree-of-freedom flight dynamic model is used to predict the performance of the system. Results show that by decreasing static margin after launch the projectile is less susceptible to launch perturbations and has increased control authority through the remainder of flight, leading to a smart projectile that outperforms rigid projectiles that are highly stable or highly manoeuvrable. This smart weapon feature is particularly attractive when the maximum control force and moment are small, and therefore is developed specifically for controllable munitions rather than missiles, which often exhibit ample control authority.