bluuebunny/crossref_metadata_2025 huggingface dataset:
Dielectric Tunability, Dielectric Relaxation, and Impedance Spectroscopic Studies on (Ba0.85Ca0.15)(Ti0.9Zr0.1)O3 Lead‐Free Ceramics
Authors: Tao Jun , Yi Zhiguo , Liu Yin , Zhang Mingxu , Zhai Jiwei
Published: March 2013

Dielectric and impedance spectroscopies were employed to study the electrical behavior of (Ba0.85Ca0.15)(Ti0.9Zr0.1)O3 (abbr. BCTZ) lead‐free ceramic. The dielectric properties versus dc bias electric field experiment revealed high dielectric tunability (> 65%) as well as figure of merit (> 27) at 10 kHz and room temperature. At elevated temperature range, a dielectric loss peak was observed and verified to be correlate of oxygen vacancy relaxation. The impedance spectra studies indicate that the ceramic is a mixed ionic conductor of p‐type nature at the paraelectric phase and, the grain and total conductivity at 600°C reaches 6.0 × 10−5 and 2.0 × 10−5 S/cm, respectively.
New Sintered Li2O–Al2O3–SiO2 Ultra‐Low Expansion Glass‐Ceramic
Authors: Soares Viviane O. , Peitl Oscar , Zanotto Edgar D.
Published: March 2013

We developed a new Li2O–Al2O3–SiO2 (LAS) ultra‐low expansion glass‐ceramic by nonisothermal sintering with concurrent crystallization. The optimum sintering conditions were 30°C/min with a maximum temperature of 1000°C. The best sintered material reached 98% of the theoretical density of the parent glass and has an extremely low linear thermal expansion coefficient (0.02 × 10−6/°C) in the temperature range of 40°C–500°C, which is even lower than that of the commercial glass‐ceramic Ceran® that is produced by the traditional ceramization method. The sintered glass‐ceramic presents a four‐point bending strength of 92 ± 15 MPa, which is similar to that of Ceran® (98 ± 6 MPa), in spite of the 2% porosity. It is white opaque and does not have significant infrared transmission. The maximum use temperature is 600°C. It could thus be used on modern inductively heated cooktops.
Crystallization of Rhenium Salts in a Simulated Low‐Activity Waste Borosilicate Glass
Authors: Riley Brian J. , McCloy John S. , Goel Ashutosh , Liezers Martin , Schweiger Michael J. , Liu Juan , Rodriguez Carmen P. , Kim Dong‐Sang
Published: March 2013

This study presents the characterization of salt phases that formed on simulated low‐activity waste glass melts during a rhenium solubility study. This study with rhenium salts is also applicable to real applications involving radioactive technetium salts. In this synthesis method, oxide glass powder is mixed with the volatile species, vacuum‐sealed in a fused quartz ampoule, and then heated in a furnace. This technique restricts the volatile species to the headspace above the melt but still within the sealed ampoule, thus maximizing the concentration of these species that are in contact with the glass. Above the previously determined solubility of Re7+ in this glass, a molten salt phase segregated to the top of the melt and crystallized into a solid layer. This salt was analyzed with X‐ray diffraction, scanning electron microscopy, energy dispersive spectroscopy, as well as wavelength dispersive spectroscopy and was found to be composed of alkali perrhenates (NaReO4, KReO4) and alkali sulfates. Similar crystalline inclusions were found in the bulk of some glasses as well.
Evaluation of Fracture Resistance and Failure Risks of Posterior Partial Coverage Restorations
Authors: Kois Dean E. , Isvilanonda Vara , Chaiyabutr Yada , Kois John C.
Published: March 2013

Statement of Problem

Interest in posterior partial coverage restorations has increased because these restorations provide a more conservative treatment option than traditional cohesively based restorations; however, material selection has been a controversial topic in the current literature.

Purpose

To evaluate the fracture resistance of posterior partial coverage restorations restored with different materials, examine their stress distribution, and calculate failure risks using three‐dimensional (3D) finite element analysis.

Methods

Sixty extracted third molar teeth received 2‐mm occlusal reduction maintaining cusp steepness of 45 degrees relative to occlusal surface. Teeth were allocated into four groups (N = 15) and restored with different materials: feldspathic ceramic, leucite‐reinforced ceramic, lithium disilicate‐reinforced ceramic (EMX), or indirect resin‐based composite (COM). Restorations were luted with resin cement and submitted to compressive loads (Instron Corp, Norwood, MA, USA). The data were analyzed with one‐way analysis of variance, followed by Tukey's HSD tests. A 3D finite element model of posterior partial coverage restorations was developed and validated. The model was used to approximate the maximum principal stress in each of the materials under a 100‐N static vertical compression at the occlusal surface of the tooth. The risk of restoration failure was quantified and compared among the four different materials.

Results

Group EMX had fracture resistance significantly higher than other testing groups. Group COM presented the most extensive fractures involving tooth and root structures. When compared with the other materials, group EMX exhibited higher stress concentration; however, the failure risk of the restoration was lower.

Conclusions

Fracture resistance and failure risks of posterior partial coverage restorations are significantly influenced by material selection.

Clinical Significance

Many restorative materials have been advocated for partial coverage restorations. It is essential to ensure that restorative materials have sufficient strength to support occlusal forces and, in case of fracture, the remaining tooth structure is not compromised or placed at risk. This study revealed that all‐ceramic materials had high incidences of fractures involving the materials themselves, whereas the predominant failure of resin‐based composite involved the tooth structure in a catastrophic manner.
‘Viewing in slow motion’: patients', families', nurses' and doctors' perspectives on end‐of‐life care in critical care
Authors: Pattison Natalie , Carr Susan M , Turnock Chris , Dolan Shelley
Published: March 2013

Aims and objectives

To explore the meaning of end‐of‐life care for critically ill cancer patients, families, oncologists, palliative care specialists, critical care consultants and nurses.

Background

End‐of‐life care for critically ill patients, of whom nearly 20% will die in critical care, remains somewhat problematic (Truog et al. 2008). End‐of‐life care is an established domain in cancer; however, research has not been conducted previously into dying, critically ill cancer patients' experiences.

Design

Qualitative, phenomenological in‐depth interviews were undertaken.

Methods

Phenomenology was used to explore experiences of 27 participants: surviving patients at high risk of dying, bereaved families, oncologists, palliative and critical care consultants, and nurses. Purposive sampling from a UK critical care unit was carried out. In‐depth interviews were taped analysed using Van Manen's phenomenological analysis framework.

Results

A phenomenological interpretation of dying in cancer critical illness, and the impact on opportunities for end‐of‐life care, is presented. Three main themes included: dual prognostication; the meaning of decision‐making; and care practices at end of life: choreographing a good death. End‐of‐life care was an emotive experience for all participants; core tenets for good end‐of‐life care included comfort, less visible technology, privacy and dignity. These findings are discussed in relation to end‐of‐life care, cancer and critical illness.

Conclusion

The speed of progressing towards dying in critical illness is often unknown and subsequently affects potential for end‐of‐life care. Caring was not unique to nurses and end‐of‐life care in critical care came with considerable emotional cost.

Relevance to clinical practice

There is an opportunity for nurses to use the care of patients dying in critical care to develop specialist knowledge and lead in care, but it requires mastery and reconciliation of both technology and end‐of‐life care. Healthcare professionals can help facilitate acceptance for families and patients, particularly regarding involvement in decisions and ensuring patient advocacy.
Law, Stock Markets, and Innovation
Authors: BROWN JAMES R. , MARTINSSON GUSTAV , PETERSEN BRUCE C.
Published: March 2013

We study a broad sample of firms across 32 countries and find that strong shareholder protections and better access to stock market financing lead to substantially higher long‐run rates of R&D investment, particularly in small firms, but are unimportant for fixed capital investment. Credit market development has a modest impact on fixed investment but no impact on R&D. These findings connect law and stock markets with innovative activities key to economic growth, and show that legal rules and financial developments affecting the availability of external equity financing are particularly important for risky, intangible investments not easily financed with debt.
The Determinants of Attitudes toward Strategic Default on Mortgages
Authors: GUISO LUIGI , SAPIENZA PAOLA , ZINGALES LUIGI
Published: March 2013

We use survey data to measure households’ propensity to default on mortgages even if they can afford to pay them (strategic default) when the value of the mortgage exceeds the value of the house. The willingness to default increases in both the absolute and the relative size of the home‐equity shortfall. Our evidence suggests that this willingness is affected by both pecuniary and non‐pecuniary factors, such as views about fairness and morality. We also find that exposure to other people who strategically defaulted increases the propensity to default strategically because it conveys information about the probability of being sued.
Opening the Black Box: Internal Capital Markets and Managerial Power
Authors: GLASER MARKUS , LOPEZ‐DE‐SILANES FLORENCIO , SAUTNER ZACHARIAS
Published: March 2013

We analyze the internal capital markets of a multinational conglomerate, using a unique panel data set of planned and actual allocations to business units and a survey of unit CEOs. Following cash windfalls, more powerful managers obtain larger allocations and increase investment substantially more than their less connected peers. We identify cash windfalls as a source of misallocation of capital, as more powerful managers overinvest and their units exhibit lower ex post performance and productivity. These findings contribute to our understanding of frictions in resource allocation within firms and point to an important channel through which power may lead to inefficiencies.
Clinical assessment of disease severity in recurrent aphthous stomatitis
Authors: Tappuni Anwar R. , Kovacevic Tatjana , Shirlaw Penelope J. , Challacombe Stephen J.
Published: March 2013

Background

Recurrent aphthous stomatitis (RAS) is one of the most common oral mucosal diseases in many parts of the world. However, there is very limited published clinical evidence for the therapies used in this condition. This could be partly due to the difficulty in evaluating the efficacy of oral ulcer treatment objectively. In this paper, we present a method for assessing and monitoring the severity of oral ulcers before and after treatment.

Methods

Six ulcer characteristics, number, size, duration, ulcer‐free period, site and pain, were used to generate an ulcer severity score (USS). The scores for 223 RAS patients were determined, and 79 were scored again after 3‐month therapy with topical betamethasone.

Results

The scores for the minor RAS group were between 18 and 43 (mean 29.2 ± 5.3). The mean score in the major ulcers group (range: 28–60, mean 39.9 ± 6.1) was significantly greater than in the minor group (P < 0.001). The herpetiform recurrent ulcers score range was wide (range: 18–57, mean 36.6 ± 8.4). The mean severity score decreased significantly after treatment (P < 0.001).

Conclusions

The USS was indicative of the disease activity in recurrent oral ulceration. It helped in assessing the efficacy of therapy, as the change in the numerical score reflected the change in ulcer severity in response to treatment. This tool may well prove to be of value in clinical management, research and in clinical trials.
Anti-inflammatory effect of hexane fraction from Myagropsis myagroides ethanolic extract in lipopolysaccharide-stimulated BV-2 microglial cells
Authors: Kim Sunghee , Kim Jae-Il , Choi Ji-Woong , Kim Michelle , Yoon Na Young , Choi Chang-Geun , Choi Jae-Sue , Kim Hyeung-Rak
Published: March 2013

Objectives

Microglial activation has been implicated in neurological disorders for its inflammatory and neurotrophic effects. We investigated the anti-inflammatory effect of the hexane fraction from Myagropsis myagroides (Mertens ex Turner) Fensholt ethanolic extract and its underlying molecular mechanism in lipopolysaccharide-stimulated microglia.

Methods

Various solvent fractions prepared from the ethanolic extract of M. myagroides were analysed for total phenolic content, 2,2-diphenyl-1-picrylhydrazyl radical-scavenging activity and inhibitory effect on nitric oxide (NO) production in activated BV-2 microglia. We measured prostaglandin E2 (PGE2) and pro-inflammatory cytokine levels by enzyme-linked immunosorbent assay. Expression of inflammatory enzymes was analysed by Western blot. Nuclear translocation and activation of nuclear factor-kappaB (NF-κB) were determined by immunofluorescence and reporter gene assay, respectively.

Key findings

Among the fractions, the hexane fraction (MMH), rich in fatty acid, showed the highest inhibitory activity on NO generation. Pretreatment with MMH decreased mRNA and protein levels of inducible NO synthase and cyclooxygenase-2, resulting in a decrease in NO and PGE2 in LPS-stimulated BV-2 cells. Furthermore, MMH inhibited the production of inducible pro-inflammatory cytokines at their transcriptional level via inactivation of NF-κB. MMH inhibited the activation of extracellular signal-regulated kinase and c-Jun N-terminal kinase.

Conclusions

These results indicate that MMH has a strong anti-inflammatory activity in LPS-stimulated microglia, suggesting that MMH can be used as a therapeutic agent against neuroinflammatory diseases.
Downregulation of β1-adrenergic receptors in rat C6 glioblastoma cells by hyperforin and hyperoside from St John's wort
Authors: Jakobs Daniel , Hage-Hülsmann Anne , Prenner Lars , Kolb Christiane , Weiser Dieter , Häberlein Hanns
Published: March 2013

Objectives

While the use of St John's wort extracts as treatment for mild to moderate depression is well established the mode of action is still under investiation. Individual constituents of St John's wort extract were tested for possible effects on the β1AR density and a subsequent change in downstream signalling in rat C6 glioblastoma cells.

Methods

The effect of compounds from St John's wort extract on the downregulation of β1-adrenergic receptor-GFP fusion proteins (β1AR-green fluorescent protein (GFP)) of transfected rat C6 gliobastoma cells (C6-β1AR-GFP) was investigated by means of confocal laser scanning microscopy (LSM). The influence on the lateral mobility of β1AR-GFP in C6-β1AR-GFP was investigated by fluorescence correlation spectroscopy. The formation of second messenger was determined by c-AMP-assay.

Key findings

Confocal LSM revealed that pretreatment of cells with 1 μm of hyperforin and hyperoside for 6 days, respectively, led to an internalization of β1AR-GFP under non-stimulating conditions. Observation by fluorescence correlation spectroscopy showed two diffusion time constants for control cells, with τdiff1 = 0.78 ± 0.18 ms and τdiff2 = 122.53 ± 69.41 ms, similarly distributed. Pretreatment with 1 μm hyperforin or 1 μm hyperoside for 3 days did not alter the τdiff values but decreased the fraction of τdiff1 whereas the fraction of τdiff2 increased significantly. An elevated level of β1AR-GFP with hindered lateral mobility was in line with β1AR-GFP internalization induced by hyperforin and hyperoside, respectively. A reduced β1-adrenergic responsiveness was assumed for C6 gliobastoma cells after pretreatment for 6 days with 1 μm of both hyperforin and hyperoside, which was confirmed by decreased cAMP formation of about 10% and 5% under non-stimulating conditions. Decrease in cAMP formation by 23% for hyperforin and 15% for hyperoside was more pronounced after stimulation with 10 μm dobutamine for 30 min.

Conclusions

The treatment of C6 gliobastoma cells with hyperforin and hyperoside results in a reduced β1AR density in the plasma membrane and a subsequent reduced downstream signalling.
Advocacy for the “Abandonados”: Harnessing Cultural Beliefs for Latino Families and Their Children With Intellectual Disabilities
Authors: Cohen Shana R.
Published: March 2013

Community services and supports for children with intellectual disabilities (ID) can ameliorate the negative effects of caregiving and enhance child outcomes. For example, in Central and South America, many children with disabilities are institutionalized with inadequate sanitation and medical care. In the United States, certain demographic factors (e.g., poverty, limited access to healthcare, language barriers, and immigrant status) contribute to the underdiagnosis and poor‐quality treatment of Latino families and their children with ID, thus limiting their access to effective community and family supports. This paper utilizes a cultural lens to target advocacy as a mechanism for improving access to local community services and social supports for children with ID. The author examines specific cultural beliefs regarding family support and child development among Latino families, and provides policy recommendations derived from these cultural beliefs that aim to enhance advocacy efforts among Latino caregivers. The author notes that effective advocacy, at the family and at the policy level, can be a useful tool to access crucial community and social supports that enhance child and family outcomes.
Obtaining Medical Records for Women With Intellectual Disabilities in a Community‐Based Health Promotion Intervention
Authors: Swaine Jamie G. , Parish Susan L. , Ghosh Subharati , Luken Karen , Wright Grace A.
Published: March 2013

There is a critical need for objective data about receipt of preventive healthcare screenings that are not subject to self‐response bias. However, no available evidence indicates which methods are effective for obtaining retrospective medical record data for women with intellectual disabilities (ID) receiving care in the community. This article describes a procedure for obtaining retrospective medical record data for 199 women with ID who took part in a community‐based, multisite, randomized controlled trial of a health education intervention. Data were analyzed to determine rates of correct physician identification and physician response rates during the 2006–2009 study periods. To assess accuracy in identifying physicians and response rates over time, McNemar's test of paired proportions for dependent samples was used. Physician identification varied over time with correct identification being highest in more recent years. The majority of practices responded to our requests for medical record data; however, response rates and item completion rates were highest for the most recent data, with rates declining significantly for data from earlier years. Obtaining retrospective medical record data from community‐based medical practices is possible, but difficult. Therefore, researchers should budget resources to accommodate a lengthy process with extensive follow‐up. Researchers interested in older medical data face additional challenges in obtaining complete records.
Residual proteinuria and eGFR predict progression of renal impairment within 2 years in type 2 diabetic patients with nephropathy who are receiving optimal treatment with angiotensin receptor blockers
Authors: Ivory Sara E , Packham David K , Reutens Anne T , Wolfe Rory , Rohde Richard D , Lewis Julia , Atkins Robert C ,   the Collaborative Study Group
Published: March 2013

Aim

Proteinuria and estimated glomerular filtration rate (eGFR) predict progression of renal impairment in type 2 diabetic nephropathy (DN) but are they still predictive when these patients are treated with angiotensin receptor blockers (ARB)? We investigated whether residual (after ≥3 months of ARB treatment) urinary protein/creatinine ratio (rPCR) or urinary albumin/creatinine ratio (rACR) and residual eGFR (reGFR), predict subsequent progression.

Methods

One thousand, two hundred and forty‐five patients with type 2 DN from two international multi‐center studies were analysed. Cross classification of rPCR, rACR with reGFR (rPCR: <1000, 1000–<2000 and ≥2000 mg/g; rACR: <666.7, 666.7–<1333.3 and ≥1333.3 mg/g; reGFR: 15–29, 30–44 and 45–59 mL/min per 1.73 m2). Progression of renal disease exhibited as: end stage renal failure, doubling of serum creatinine, or serum creatinine ≥6 mg/dL.

Results

Increasing rPCR or rACR, and decreasing reGFR were strongly associated with increasing risk of renal disease progression, with no evidence of interaction between rPCR and reGFR, or rACR and reGFR. The estimated 24‐month risk was low (<8%) for patients with rPCR <1000 mg/g regardless of reGFR, for patients with reGFR ≥45 mL/min per 1.73 m2 regardless of rPCR, or with rPCR between 1000–<2000 mg/g and reGFR ≥30 mL/min per 1.73 m2. However, the risk rose steeply (to 39.4%) for reGFR <30 mL/min per 1.73 m2 and rPCR ≥2000 mg/g.

Conclusion

Despite DN patients being treated with ARB, renal disease progression risk over 2 years increases with increasing proteinuria, albuminuria and decreasing eGFR. Recognition of these risk factors’ impact is important in patient management and future clinical trial design.
Drug provocation tests in the diagnosis of hypersensitivity reactions to non‐steroidal anti‐inflammatory drugs in children
Authors: Zambonino Maria A. , Torres Maria J. , Muñoz Candelaria , Requena Gloria , Mayorga Cristobalina , Posadas Teresa , Urda Antonio , Blanca Miguel , Corzo Jose L.
Published: March 2013

Introduction

Hypersensitivity reactions to non‐steroidal anti‐inflammatory drugs (NSAIDs) are the most frequently reported reaction to drugs. They can be induced by pharmacological mechanisms (cyclooxygenase inhibition), with patients classified as cross‐intolerant (CI), or by specific immunological mechanisms, IgE or T cell, with patients classified as selective reactors (SR).

Objective

To analyse a large group of children with a history of NSAID hypersensitivity diagnosed by drug provocation test (DPT).

Methods

A group of 63 children with a history of NSAID hypersensitivity were evaluated by DPT. The children were classified as CI or SR depending on the acetyl salicylic acid (ASA) response in DPT. The atopic status was also assessed by prick tests and total IgE in serum.

Results

Using DPT, 68.2% were confirmed as having hypersensitivity, 58.1% classified as CI and 41.9% as SR. Of the 119 DPT performed, 73 were positive (53.4% to ibuprofen, 37% to ASA, 8.2% to metamizol and 14% to paracetamol); angio‐oedema was present in 86.3% of cases. All CI cases tolerated the administration of paracetamol. A significant number of the CI children were atopic compared with the SR children and non‐allergic controls.

Conclusion

In these children, CI hypersensitivity to NSAIDs was the most frequent type of hypersensitivity reaction. Ibuprofen was the drug most often involved, angio‐oedema the most common entity, and frequently associated with atopy. DPT proved a safe approach for diagnosing these patients.
Microbes, mud and methane: cause and consequence of recurrent Early Jurassic anoxia following the end‐Triassic mass extinction
Authors: van de Schootbrugge Bas , Bachan Aviv , Suan Guillaume , Richoz Sylvain , Payne Jonathan L.
Published: March 2013

The end‐Triassic mass extinction (c. 201.6 Ma) was one of the five largest mass‐extinction events in the history of animal life. It was also associated with a dramatic, long‐lasting change in sedimentation style along the margins of the Tethys Ocean, from generally organic‐matter‐poor sediments during the Triassic to generally organic‐matter‐rich black shales during the Jurassic. New core material from Germany provides biomarker evidence of persistent photic‐zone euxinia during the Hettangian, the onset of which is associated with a series of both negative and positive carbon isotope excursions. Combined inorganic and organic geochemical and micropalaeontological analyses reveal strong similarities between the Hettangian and the better‐known Toarcian anoxic event. These events appear to be the most clearly expressed events within a series of anoxic episodes that also include poorly studied black shale intervals during the Sinemurian and Pliensbachian. Both the Hettangian and Toarcian events are marked by important changes in phytoplankton assemblages from chromophyte‐ to chlorophyte‐dominated assemblages within the European Epicontinental Seaway. Phytoplankton changes occurred in association with the establishment of photic‐zone euxinia, driven by a general increase in salinity stratification and warming of surface waters. For both events, the causes of large negative carbon isotope excursions remain incompletely understood; evidence exists for both variation in the δ13C of atmospheric CO2 and variation in the sources of organic carbon. Regardless of the causes of δ13C variability, long‐term ocean anoxia during the Early Jurassic can be attributed to greenhouse warming and increased nutrient delivery to the oceans triggered by flood basalt volcanism.
Biological and biochemical characterization of HIV‐1 Gag/dgp41 virus‐like particles expressed in Nicotiana benthamiana
Authors: Kessans Sarah A. , Linhart Mark D. , Matoba Nobuyuki , Mor Tsafrir
Published: March 2013

The transmembrane HIV‐1 envelope protein gp41 has been shown to play critical roles in the viral mucosal transmission and infection of CD4+ cells. Gag is a structural protein configuring the enveloped viral particles and has been suggested to constitute a target of the cellular immunity that may control viral load. We hypothesized that HIV enveloped virus‐like particles (VLPs) consisting of Gag and a deconstructed form of gp41 comprising the membrane proximal external, transmembrane and cytoplasmic domains (dgp41) could be expressed in plants. To this end, plant‐optimized HIV‐1 genes were constructed and expressed in Nicotiana benthamiana by stable transformation, or transiently using a Tobamovirus‐based expression system or a combination of both. Our results of biophysical, biochemical and electron microscopy characterization demonstrates that plant cells could support not only the formation of enveloped HIV‐1 Gag VLPs, but also the accumulation of VLPs that incorporated dgp41. These findings provide further impetus for the journey towards a broadly efficacious and inexpensive subunit vaccine against HIV‐1.
Europe without an Endpoint. Period
Authors: Ferrer‐Gallardo Xavier , Van Houtum Henk
Published: March 2013

This contribution focuses on the borderscape of a flat area situated at the southernmost tip of Gibraltar, at the edge of the European Continent, which is illustratively and interestingly named Europa Point. We will argue that, as an evoking geographical belvedere of cultural and continental interrelationships, Europa Point directs attention to the inherent sociospatial ambiguities of EUrope. Embodying a crucial topo within the European sociospatial b/ordering process, this borderscape stimulates to observe Europe's limits through a non‐binary lens. The text aims at providing an unfrozen alternative visualisation of the symbolic and territorial margins of the EU. Echoing De Rougemont's conceptualisation of Europe's existence through its search for the infinite, it depicts Europa Point as a springboard and platform to the perpetual commencement of the European adventure.
Imported malaria: a possible threat to the elimination of malaria from Sri Lanka?
Authors: Galappaththy G. N. L. , Fernando S. D. , Abeyasinghe R. R.
Published: March 2013

Objective

To discuss epidemiological aspects of imported malaria and the potential impact of imported malaria cases reported in Sri Lanka 2008–2011 in terms of a possible resurgence of the disease.

Methods

The national malaria database was used to assess details regarding country where the infection was possibly acquired, species of Plasmodium, number of days lapsed between disembarkation in Sri Lanka and diagnosis, compliance with national treatment guidelines including percentage of patients followed up as per the national guidelines.

Results

After the strengthening of malaria surveillance, during the 4‐year period, 152 imported malaria cases were recorded: an increase of 176% in the number of cases. Most of the imported malaria infections were acquired by Sri Lankan Nationals mainly from South Asia, especially India. Plasmodium vivax accounted for 64% of the infections. Approximately 50% of the cases were diagnosed in the Western Province. The average period from disembarkation in Sri Lanka to malaria diagnosis was 3.6 days. Patients were managed and treated according to the national guidelines. 82% of the patients were followed up for 28 days to ensure parasite clearance.

Conclusions

There is a possible increasing risk of re‐introduction of malaria to the country from imported cases. Enhanced surveillance activities and the increase in international travel have contributed to an increase in recorded case numbers. There is a need to further strengthen surveillance, especially for monitoring and timely addressing of imported malaria, if the country is to prevent the re‐establishment of transmission within. The importance of having an efficient response mechanism to deal with imported malaria is also highlighted.
Expression and functionality of TRPV1 receptor in human MCF‐7 and canine CF.41 cells
Authors: Vercelli C. , Barbero R. , Cuniberti B. , Odore R. , Re G.
Published: March 2013

As canine mammary tumours (CMT) and human breast cancer share clinical and prognostic features, the former have been proposed as a model to study carcinogenesis and improved therapeutic treatment in human breast cancer. In recent years, it has been shown that transient receptor potential vanilloid 1 (TRPV1) is expressed in different neoplastic tissues and its activation has been associated with regulation of cancer growth and progression. The aim of the present research was to demonstrate the presence of TRPV1 in human and canine mammary cancer cells, MCF‐7 and CF.41, respectively, and to study the role of TRPV1 in regulating cell proliferation. The images obtained by Western blot showed a signal at 100 kDa corresponding to the molecular weight of TRPV1 receptor. All tested TRPV1 agonists and antagonists caused a significant decrease (P < 0.05) of cell growth rate in MCF‐7 cells. By contrast, in CF.41 cells capsaicin and capsazepine induced a significant increase (P < 0.05) in cell proliferation, whereas resiniferatoxin (RTX) and 5‐iodo‐resiniferatoxin (5‐I‐RTX) had no influence on CF.41 cell proliferation. Further studies are needed to elucidate the underlying molecular mechanism responsible for the different effects evoked by TRPV1 activation in MCF‐7 and CF.41 cells.
Science Signaling
Podcast: 19 March 2013
Authors: Chen Ching-Shih , VanHook Annalisa M.
Published: March 2013

Vitamin E promotes dephosphorylation of the kinase Akt to suppress the growth of prostate cancer cells.
Synchronizing Photosynthetic Capacity
Authors: Hines Pamela J.
Published: March 2013

In plants, day/night information is communicated from a nuclear-encoded circadian oscillator to the chloroplast.
The Healing Switch
Authors: Ferrarelli Leslie K.
Published: March 2013

Wound healing relies on a posttranscriptional switch to inversely regulate the translation of a microRNA and a protein encoded within a single transcript.
Opposing Hippo
Authors: VanHook Annalisa M.
Published: March 2013

Epidermal growth factor receptor signaling antagonizes Hippo-dependent repression of the transcriptional coactivator Yorkie.
In Vitro
and
In Vivo
Efficacy of β-Lactams against Replicating and Slowly Growing/Nonreplicating Mycobacterium tuberculosis
Authors: Solapure Suresh , Dinesh Neela , Shandil Radha , Ramachandran Vasanthi , Sharma Sreevalli , Bhattacharjee Deepa , Ganguly Samit , Reddy Jitendar , Ahuja Vijaykamal , Panduga Vijender , Parab Manish , Vishwas K. G. , Kumar Naveen , Balganesh Meenakshi , Balasubramanian V.
Published: March 2013

Beta-lactams, in combination with beta-lactamase inhibitors, are reported to have activity against
Mycobacterium tuberculosis
bacteria growing in broth, as well as inside the human macrophage. We tested representative beta-lactams belonging to 3 different classes for activity against replicating
M. tuberculosis
in broth and nonreplicating
M. tuberculosis
under hypoxia, as well as against streptomycin-starved
M. tuberculosis
strain 18b (ss18b) in the presence or absence of clavulanate. Most of the combinations showed bactericidal activity against replicating
M. tuberculosis
, with up to 200-fold improvement in potency in the presence of clavulanate. None of the combinations, including those containing meropenem, imipenem, and faropenem, killed
M. tuberculosis
under hypoxia. However, faropenem- and meropenem-containing combinations killed strain ss18b moderately. We tested the bactericidal activities of meropenem-clavulanate and amoxicillin-clavulanate combinations in the acute and chronic aerosol infection models of tuberculosis in BALB/c mice. Based on pharmacokinetic/pharmacodynamic indexes reported for beta-lactams against other bacterial pathogens, a cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (%
T
MIC
) of 20 to 40% was achieved in mice using a suitable dosing regimen. Both combinations showed marginal reduction in lung CFU compared to the late controls in the acute model, whereas both were inactive in the chronic model.
Potency and Spectrum of Activity of AN3365, a Novel Boron-Containing Protein Synthesis Inhibitor, Tested against Clinical Isolates of Enterobacteriaceae and Nonfermentative Gram-Negative Bacilli
Authors: Mendes Rodrigo E. , Alley M. R. K. , Sader Helio S. , Biedenbach Douglas J. , Jones Ronald N.
Published: March 2013

AN3365 (MIC
50/90
, 0.5/1 μg/ml) was active against
Enterobacteriaceae
, including a subset of
Klebsiella pneumoniae
carbapenemase (KPC)-producing
K. pneumoniae
strains (MIC
50/90
, 1/2 μg/ml). AN3365 inhibited 98.0 and 92.2% of wild-type (MIC
50/90
, 2/8 μg/ml) and carbapenem-resistant (MIC
50/90
, 4/8 μg/ml)
Pseudomonas aeruginosa
strains, respectively, at ≤8 μg/ml. AN3365 also demonstrated activity against wild-type
Acinetobacter baumannii
(MIC
50/90
, 2/8 μg/ml) and
Stenotrophomonas maltophilia
(MIC
50/90
, 2/4 μg/ml), while it was less active against multidrug-resistant
A. baumannii
(MIC
50/90
, 8/16 μg/ml) and
Burkholderia cepacia
(MIC
50/90
, 8/32 μg/ml).
Randomized, Double-Blind, Multicenter Phase 2 Study Comparing the Efficacy and Safety of Oral Solithromycin (CEM-101) to Those of Oral Levofloxacin in the Treatment of Patients with Community-Acquired Bacterial Pneumonia
Authors: Oldach David , Clark Kay , Schranz Jennifer , Das Anita , Craft J Carl , Scott Drusilla , Jamieson Brian D. , Fernandes Prabhavathi
Published: March 2013

Solithromycin, a new macrolide, and the first fluoroketolide in clinical development, with activity against macrolide-resistant bacteria, was tested in 132 patients with moderate to moderately severe community-acquired bacterial pneumonia (CABP) in a multicenter, double-blind, randomized phase 2 study. Patients were enrolled and randomized (1:1) to either 800 mg solithromycin orally (PO) on day 1, followed by 400 mg PO daily on days 2 to 5, or 750 mg levofloxacin PO daily on days 1 to 5. Efficacy outcome rates of clinical success at the test-of-cure visit 4 to 11 days after the last dose of study drug were comparable in the intent-to-treat (ITT) (84.6% for solithromycin versus 86.6% for levofloxacin) and microbiological-intent-to-treat (micro-ITT) (77.8% for solithromycin versus 71.4% for levofloxacin) populations. Early response success rates at day 3, defined as improvement in at least two cardinal symptoms of pneumonia, were also comparable (72.3% for solithromycin versus 71.6% for levofloxacin). More patients treated with levofloxacin than with solithromycin experienced treatment-emergent adverse events (TEAEs) during the study (45.6% versus 29.7%). The majority of TEAEs were mild or moderate gastrointestinal symptoms and included nausea (1.6% for solithromycin; 10.3% for levofloxacin), diarrhea (7.8% for solithromycin; 5.9% for levofloxacin), and vomiting (0% for solithromycin; 4.4% for levofloxacin). Six patients, all of whom received levofloxacin, discontinued the study drug due to an adverse event. Solithromycin demonstrated comparable efficacy and favorable safety relative to levofloxacin. These findings support a phase 3 study of solithromycin for the treatment of CABP. (This study has been registered at ClinicalTrials.gov under registration no. NCT01168713.)
In Vivo
Anti-Herpes Simplex Virus Activity of a Sulfated Derivative of Agaricus brasiliensis Mycelial Polysaccharide
Authors: Cardozo F. T. G. S. , Larsen I. V. , Carballo E. V. , Jose G. , Stern R. A. , Brummel R. C. , Camelini C. M. , Rossi M. J. , Simões C. M. O. , Brandt C. R.
Published: March 2013

Agaricus brasiliensis
(syn.
A. subrufescens
), a basidiomycete fungus native to the Atlantic forest in Brazil, contains cell walls rich in glucomannan polysaccharides. The β-(1→2)-gluco-β-(1→3)-mannan was isolated from
A. brasiliensis
mycelium, chemically modified by sulfation, and named MI-S. MI-S has multiple mechanisms of action, including inhibition of herpes simplex virus (HSV) attachment, entry, and cell-to-cell spread (F. T. G. S. Cardozo, C. M. Camelini, A. Mascarello, M. J. Rossi, R. J. Nunes, C. R. Barardi, M. M. de Mendonça, and C. M. O. Simões, Antiviral Res. 92:108–114, 2011). The antiherpetic efficacy of MI-S was assessed in murine ocular, cutaneous, and genital infection models of HSV. Groups of 10 mice were infected with HSV-1 (strain KOS) or HSV-2 (strain 333). MI-S was given either topically or by oral gavage under various pre- and posttreatment regimens, and the severity of disease and viral titers in ocular and vaginal samples were determined. No toxicity was observed in the uninfected groups treated with MI-S. The topical and oral treatments with MI-S were not effective in reducing ocular disease. Topical application of MI-S on skin lesions was also not effective, but cutaneously infected mice treated orally with MI-S had significantly reduced disease scores (
P
< 0.05) after day 9, suggesting that healing was accelerated. Vaginal administration of MI-S 20 min before viral challenge reduced the mean disease scores on days 5 to 9 (
P
< 0.05), viral titers on day 1 (
P
< 0.05), and mortality (
P
< 0.0001) in comparison to the control groups (untreated and vehicle treated). These results show that MI-S may be useful as an oral agent to reduce the severity of HSV cutaneous and mucosal lesions and, more importantly, as a microbicide to block sexual transmission of HSV-2 genital infections.
Comparison of Oseltamivir and Oseltamivir Carboxylate Concentrations in Venous Plasma, Venous Blood, and Capillary Blood in Healthy Volunteers
Authors: Instiaty Insti , Lindegardh Niklas , Jittmala Podjanee , Hanpithakpong Warunee , Blessborn Daniel , Pukrittayakamee Sasithon , White Nicholas J. , Tarning Joel
Published: March 2013

Oseltamivir and oseltamivir carboxylate concentrations were measured in venous plasma, venous blood, and capillary blood taken simultaneously from 24 healthy volunteers. Median (range) venous-blood-to-plasma ratios were 1.42 (0.920 to 1.97) for oseltamivir and 0.673 (0.564 to 0.814) for oseltamivir carboxylate. Capillary blood/venous plasma ratios were 1.32 (0.737 to 3.16) for oseltamivir and 0.685 (0.502 to 1.34) for oseltamivir carboxylate. Oseltamivir concentrations in venous and capillary blood were similar. Oseltamivir carboxylate showed a time-dependent distribution between venous and capillary blood.
Semen-Derived Enhancer of Viral Infection (SEVI) Binds Bacteria, Enhances Bacterial Phagocytosis by Macrophages, and Can Protect against Vaginal Infection by a Sexually Transmitted Bacterial Pathogen
Authors: Easterhoff David , Ontiveros Fernando , Brooks Lauren R. , Kim Yoel , Ross Brittany , Silva Jharon N. , Olsen Joanna S. , Feng Changyong , Hardy Dwight J. , Dunman Paul M. , Dewhurst Stephen
Published: March 2013

The semen-derived enhancer of viral infection (SEVI) is a positively charged amyloid fibril that is derived from a self-assembling proteolytic cleavage fragment of prostatic acid phosphatase (PAP248-286). SEVI efficiently facilitates HIV-1 infectionin vitro, but its normal physiologic function remains unknown. In light of the fact that other amyloidogenic peptides have been shown to possess direct antibacterial activity, we investigated whether SEVI could inhibit bacterial growth. Neither SEVI fibrils nor the unassembled PAP248-286peptide had significant direct antibacterial activityin vitro. However, SEVI fibrils bound to both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coliandNeisseria gonorrhoeae) bacteria, in a charge-dependent fashion. Furthermore, SEVI fibrils but not the monomeric PAP248-286peptide promoted bacterial aggregation and enhanced the phagocytosis of bacteria by primary human macrophages. SEVI also enhanced binding of bacteria to macrophages and the subsequent release of bacterially induced proinflammatory cytokines (tumor necrosis factor alpha [TNF-α], interleukin-6 [IL-6], and IL-1β). Finally, SEVI fibrils inhibited murine vaginal colonization withNeisseria gonorrhoeae. These findings demonstrate that SEVI has indirect antimicrobial activity and that this activity is dependent on both the cationic charge and the fibrillar nature of SEVI.
Plasmodium coatneyi in Rhesus Macaques Replicates the Multisystemic Dysfunction of Severe Malaria in Humans
Authors: Moreno Alberto , Cabrera-Mora Monica , Garcia AnaPatricia , Orkin Jack , Strobert Elizabeth , Barnwell John W. , Galinski Mary R.
Published: March 2013

Severe malaria, a leading cause of mortality among children and nonimmune adults, is a multisystemic disorder characterized by complex clinical syndromes that are mechanistically poorly understood. The interplay of various parasite and host factors is critical in the pathophysiology of severe malaria. However, knowledge regarding the pathophysiological mechanisms and pathways leading to the multisystemic disorders of severe malaria in humans is limited. Here, we systematically investigate infections withPlasmodium coatneyi, a simian malaria parasite that closely mimics the biological characteristics ofP. falciparum, and develop baseline data and protocols for studying erythrocyte turnover and severe malaria in greater depth. We show that rhesus macaques (Macaca mulatta) experimentally infected withP. coatneyidevelop anemia, coagulopathy, and renal and metabolic dysfunction. The clinical course of acute infections required suppressive antimalaria chemotherapy, fluid support, and whole-blood transfusion, mimicking the standard of care for the management of severe malaria cases in humans. Subsequent infections in the same animals progressed with a mild illness in comparison, suggesting that immunity played a role in reducing the severity of the disease. Our results demonstrate thatP. coatneyiinfection in rhesus macaques can serve as a highly relevant model to investigate the physiological pathways and molecular mechanisms of malaria pathogenesis in naïve and immune individuals. Together with high-throughput postgenomic technologies, such investigations hold promise for the identification of new clinical interventions and adjunctive therapies.
Parasitic Nematode-Induced Modulation of Body Weight and Associated Metabolic Dysfunction in Mouse Models of Obesity
Authors: Yang Zhonghan , Grinchuk Viktoriya , Smith Allen , Qin Bolin , Bohl Jennifer A. , Sun Rex , Notari Luigi , Zhang Zhongyan , Sesaki Hiromi , Urban Joseph F. , Shea-Donohue Terez , Zhao Aiping
Published: March 2013

Obesity is associated with a chronic low-grade inflammation characterized by increased levels of proinflammatory cytokines that are implicated in disrupted metabolic homeostasis. Parasitic nematode infection induces a polarized Th2 cytokine response and has been explored to treat autoimmune diseases. We investigated the effects of nematode infection against obesity and the associated metabolic dysfunction. Infection of RIP2-Opa1KO mice or C57BL/6 mice fed a high-fat diet (HFD) with
Nippostrongylus brasiliensis
decreased weight gain and was associated with improved glucose metabolism. Infection of obese mice fed the HFD reduced body weight and adipose tissue mass, ameliorated hepatic steatosis associated with a decreased expression of key lipogenic enzymes/mediators, and improved glucose metabolism, accompanied by changes in the profile of metabolic hormones. The infection resulted in a phenotypic change in adipose tissue macrophages that was characterized by upregulation of alternative activation markers. Interleukin-13 (IL-13) activation of the STAT6 signaling pathway was required for the infection-induced attenuation of steatosis but not for improved glucose metabolism, whereas weight loss was attributed to both IL-13/STAT6-dependent and -independent mechanisms. Parasitic nematode infection has both preventive and therapeutic effects against the development of obesity and associated features of metabolic dysfunction in mice.
The Fimbrial Protein FlfA from Gallibacterium anatis Is a Virulence Factor and Vaccine Candidate
Authors: Bager Ragnhild J. , Nesta Barbara , Pors Susanne E. , Soriani Marco , Serino Laura , Boyce John D. , Adler Ben , Bojesen Anders M.
Published: March 2013

The Gram-negative bacterium
Gallibacterium anatis
is a major cause of salpingitis and peritonitis in egg-laying chickens, leading to decreased egg production worldwide. Widespread multidrug resistance largely prevents treatment of this organism using traditional antimicrobial agents, while antigenic diversity hampers disease prevention by classical vaccines. Thus, insight into its pathogenesis and knowledge about important virulence factors is urgently required. A key event during the colonization and invasion of mucosal surfaces is adherence, and recently, at least three F17-like fimbrial gene clusters were identified in the genomes of several
G. anatis
strains. The objective of this study was to characterize the putative F17-like fimbrial subunit protein FlfA from
G. anatis
12656-12 and determine its importance for virulence.
In vitro
expression and surface exposure of FlfA was demonstrated by flow cytometry and immunofluorescence microscopy. The predicted function of FlfA as a fimbrial subunit protein was confirmed by immunogold electron microscopy. An
flfA
deletion mutant (Δ
flfA
) was generated in
G. anatis
12656-12, and importantly, this mutant was significantly attenuated in the natural chicken host. Furthermore, protection against
G. anatis
12656-12 could be induced by immunizing chickens with recombinant FlfA. Finally,
in vitro
expression of FlfA homologs was observed in a genetically diverse set of
G. anatis
strains, suggesting the potential of FlfA as a serotype-independent vaccine candidate This is the first study describing a fimbrial subunit protein of
G. anatis
with a clear potential as a vaccine antigen.