bluuebunny/crossref_metadata_2025 huggingface dataset:
Gallotannin-rich Caesalpinia spinosa fraction decreases the primary tumor and factors associated with poor prognosis in a murine breast cancer model
Authors: Urueña Claudia , Mancipe Juan , Hernandez John , Castañeda Diana , Pombo Luis , Gomez Alejandra , Asea Alexzander , Fiorentino Susana
Published: April 2013

Background

Several treatment alternatives are available for primary breast cancer, although those for metastatic disease or inflammation associated with tumor progression are ineffective. Therefore, there is a great need for new therapeutic alternatives capable of generating an immune response against residual tumor cells, thus contributing to eradication of micrometastases and cancer stem cells. The use of complex natural products is an excellent therapeutic alternative widely used by Chinese, Hindu, Egyptian, and ancestral Latin-American Indian populations.

Methods

The present study evaluated cytotoxic, antitumor, and tumor progression activities of a gallotannin-rich fraction derived from Caesalpinia spinosa (P2Et). The parameters evaluated in vitro were mitochondrial membrane depolarization, phosphatidylserine externalization, caspase 3 activation, DNA fragmentation, and clonogenic activity. The parameters evaluated in vivo were tumor growth, leukocyte number, metastatic cell number, and cytokine production by flow cytometry.

Results

The in vitro results showed that the P2Et fraction induced apoptosis with mitochondrial membrane potential loss, phosphatidylserine externalization, caspase 3 activation, DNA fragmentation, and decreased clonogenic capacity of 4T1 cells. In vivo, the P2Et fraction induced primary tumor reduction in terms of diameter and weight in BALB/c mice transplanted with 4T1 cells and decreased numbers of metastatic cells, mainly in the spleen. Furthermore, decreases in the number of peripheral blood leukocytes (leukemoid reaction) and interleukin 6 (IL-6) serum levels were found, which are events associated with a poor prognosis. The P2Et fraction exerts its activity on the primary tumor, reduces cell migration to distant organs, and decreases IL-6 serum levels, implying tumor microenvironment mechanisms.

Conclusions

Overall, the P2Et fraction lessens risk factors associated with tumor progression and diminishes primary tumor size, showing good potential for use as an adjuvant in breast cancer ER(+) treatment.
Nutritional status of indigenous children: findings from the First National Survey of Indigenous People’s Health and Nutrition in Brazil
Authors: Horta Bernardo L , Santos Ricardo Ventura , Welch James R , Cardoso Andrey M , dos Santos Janaína Vieira , Assis Ana Marlúcia Oliveira , Lira Pedro CI , Coimbra Jr Carlos EA
Published: April 2013

Introduction

The prevalence of undernutrition, which is closely associated with socioeconomic and sanitation conditions, is often higher among indigenous than non-indigenous children in many countries. In Brazil, in spite of overall reductions in the prevalence of undernutrition in recent decades, the nutritional situation of indigenous children remains worrying. The First National Survey of Indigenous People’s Health and Nutrition in Brazil, conducted in 2008–2009, was the first study to evaluate a nationwide representative sample of indigenous peoples. This paper presents findings from this study on the nutritional status of indigenous children < 5 years of age in Brazil.

Methods

A multi-stage sampling was employed to obtain a representative sample of the indigenous population residing in villages in four Brazilian regions (North, Northeast, Central-West, and Southeast/South). Initially, a stratified probabilistic sampling was carried out for indigenous villages located in these regions. Households in sampled villages were selected by census or systematic sampling depending on the village population. The survey evaluated the health and nutritional status of children < 5 years, in addition to interviewing mothers or caretakers.

Results

Height and weight measurements were taken of 6,050 and 6,075 children, respectively. Prevalence rates of stunting, underweight, and wasting were 25.7%, 5.9%, and 1.3%, respectively. Even after controlling for confounding, the prevalence rates of underweight and stunting were higher among children in the North region, in low socioeconomic status households, in households with poorer sanitary conditions, with anemic mothers, with low birthweight, and who were hospitalized during the prior 6 months. A protective effect of breastfeeding for underweight was observed for children under 12 months.

Conclusions

The elevated rate of stunting observed in indigenous children approximates that of non-indigenous Brazilians four decades ago, before major health reforms greatly reduced its occurrence nationwide. Prevalence rates of undernutrition were associated with socioeconomic variables including income, household goods, schooling, and access to sanitation services, among other variables. Providing important baseline data for future comparison, these findings further suggest the relevance of social, economic, and environmental factors at different scales (local, regional, and national) for the nutritional status of indigenous peoples.
Analysis of RNA base modification and structural rearrangement by single-molecule real-time detection of reverse transcription
Authors: Vilfan Igor D , Tsai Yu-Chih , Clark Tyson A , Wegener Jeffrey , Dai Qing , Yi Chengqi , Pan Tao , Turner Stephen W , Korlach Jonas
Published: April 2013

Background

Zero-mode waveguides (ZMWs) are photonic nanostructures that create highly confined optical observation volumes, thereby allowing single-molecule-resolved biophysical studies at relatively high concentrations of fluorescent molecules. This principle has been successfully applied in single-molecule, real-time (SMRT®) DNA sequencing for the detection of DNA sequences and DNA base modifications. In contrast, RNA sequencing methods cannot provide sequence and RNA base modifications concurrently as they rely on complementary DNA (cDNA) synthesis by reverse transcription followed by sequencing of cDNA. Thus, information on RNA modifications is lost during the process of cDNA synthesis.

Results

Here we describe an application of SMRT technology to follow the activity of reverse transcriptase enzymes synthesizing cDNA on thousands of single RNA templates simultaneously in real time with single nucleotide turnover resolution using arrays of ZMWs. This method thereby obtains information from the RNA template directly. The analysis of the kinetics of the reverse transcriptase can be used to identify RNA base modifications, shown by example for N6-methyladenine (m6A) in oligonucleotides and in a specific mRNA extracted from total cellular mRNA. Furthermore, the real-time reverse transcriptase dynamics informs about RNA secondary structure and its rearrangements, as demonstrated on a ribosomal RNA and an mRNA template.

Conclusions

Our results highlight the feasibility of studying RNA modifications and RNA structural rearrangements in ZMWs in real time. In addition, they suggest that technology can be developed for direct RNA sequencing provided that the reverse transcriptase is optimized to resolve homonucleotide stretches in RNA.
Novel monosaccharide fermentation products in Caldicellulosiruptor saccharolyticus identified using NMR spectroscopy
Authors: Isern Nancy G , Xue Junfeng , Rao Jaya V , Cort John R , Ahring Birgitte K
Published: April 2013

Background

Caldicellulosiruptor saccharolyticus is a thermophilic, Gram-positive, non-spore forming, strictly anaerobic bacterium of interest in potential industrial applications, including the production of biofuels such as hydrogen or ethanol from lignocellulosic biomass through fermentation. High-resolution, solution-state nuclear magnetic resonance (NMR) spectroscopy is a useful method for the identification and quantification of metabolites that result from growth on different substrates. NMR allows facile resolution of isomeric (identical mass) constituents and does not destroy the sample.

Results

Profiles of metabolites produced by the thermophilic cellulose-degrading bacterium Caldicellulosiruptor saccharolyticus DSM 8903 strain following growth on different monosaccharides (D-glucose, D-mannose, L-arabinose, D-arabinose, D-xylose, L-fucose, and D-fucose) as carbon sources revealed several unexpected fermentation products, suggesting novel metabolic capacities and unexplored metabolic pathways in this organism. Both 1H and 13C nuclear magnetic resonance (NMR) spectroscopy were used to determine intracellular and extracellular metabolite profiles. One dimensional 1H NMR spectral analysis was performed by curve fitting against spectral libraries provided in the Chenomx software; 2-D homonuclear and heteronuclear NMR experiments were conducted to further reduce uncertainties due to unassigned, overlapping, or poorly-resolved peaks. In addition to expected metabolites such as acetate, lactate, glycerol, and ethanol, several novel fermentation products were identified: ethylene glycol (from growth on D-arabinose), acetoin and 2,3-butanediol (from growth on D-glucose, L-arabinose, and D-xylose), and hydroxyacetone (from growth on D-mannose, L-arabinose, and D-xylose). Production of ethylene glycol from D-arabinose was particularly notable, with around 10% of the substrate carbon converted into this uncommon fermentation product.

Conclusions

The present research shows that C. saccharolyticus, already of substantial interest due to its capability for biological ethanol and hydrogen production, has further metabolic potential for production of higher molecular weight compounds, such as acetoin and 2,3-butanediol, as well as hydroxyacetone and the uncommon fermentation product ethylene glycol. In addition, application of nuclear magnetic resonance (NMR) spectroscopy facilitates identification of novel metabolites, which is instrumental for production of desirable bioproducts from biomass through microbial fermentation.
Cotrimoxazole plasma levels, dialyzer clearance and total removal by extended dialysis in a patient with acute kidney injury: risk of under-dosing using current dosing recommendations
Authors: Clajus Christian , Kühn-Velten W Nikolaus , Schmidt Julius J , Lorenzen Johan M , Pietsch Daniel , Beutel Gernot , Kielstein Jan T
Published: April 2013

Background

Dosing of antibiotics in critically ill patients is challenging. It becomes even more difficult if renal or hepatic impairment ensue. Modern means of renal replacement therapy are capable of removing antibiotics to a higher rate than decades ago, leaving clinicians with a high degree of uncertainty concerning the dose of antibiotics in this patient population. Cotrimoxazole, a combination of trimethoprim (TMP) and sulfamethoxazole (SMX) is frequently used in the treatment of several infections including Pneumocystis jirovecii pneumonia (PCP).

Case presentation

Here we describe a patient with acute kidney injury in which we investigated the TMP and SMX levels during the course of an ICU stay. Cotrimoxazole was administered every six hours i.v. in a dose of TMP/SMX 15/75 mg/kg/day. Extended dialysis was performed with a high-flux dialyzer. Blood samples, as well as pre- and postdialyzer samples and aliquots of the collected spent dialysate were collected.

Observed peak concentrations (Cmax) were 7.51 mg/l for TMP and 80.80 mg/l for SMX. Decline of blood levels during extended dialysis (TMP 64%; SMX 84%) was mainly due to removal by the dialysis procedure, illustrated by the high dialyzer clearances (median of 4 extended dialysis sessions: TMP 94.0 / SMX 51.0 ml/min), as well as by the absolute amount of both substances in the collected spent dialysate (median of 6 extended dialysis sessions: TMP 556 mg / SMX 130 mg). Within the limitation of a case report our data from 4 consecutive extended dialysis sessions suggest that this procedure substantially removes both TMP and SMX.

Conclusions

Dose reduction, which is usually advocated in patients with acute kidney injury under renal replacement therapy, might lead to significant under-dosing. Pharmacokinetic studies for TMP/SMX dosing in this patient population are necessary to allow adequate dosing.
Non-invasive analytical techniques applied to characterize the components of ancient golden medallions
Authors: Perez-Rodriguez Jose L , Robador María D , Haro María C Jimenez de , Blanes Jose M Martinez , Garofano Isabel , Odriozola Carlos , Duran Adrian
Published: April 2013

Background

The first stable material used to create a gilded surface was gold. False gold was also found in the form of copper-zinc powders or silver covered with resin. There are various ways to make gold leaf adhere to a large surface area. The identification of the materials and processes to make the gilding and the use of non- invasive techniques for gilding study is still an open problem. The gilding of the medallions from the Mudejar palace of Sevilla Alcazar was investigated, and their components were characterised using non-invasive (in situ and laboratory) techniques such as X-ray fluorescence, μ-Raman, infrared spectroscopy, X-ray diffraction and scanning electron microscopy coupled with energy dispersive X-rays. Cross-sections of golden support were also performed and studied by SEM-EDX.

Results

The leaf adhered to the surface was primarily a gold alloy. However, copper, silver and zinc were also found. A layer of lead chromate with some lead sulphate was between the alloy and the support. This yellow pigment (lead chromate) and the layers of bole and white lead were characterised in cross-sections prepared from samples taken from the medallions in which the golden layer was missing. The support was composed of gypsum. Another golden layer applied in oldest time period was also found.

Conclusion

The non-invasive techniques provided useful information about the characterisation of the components of the golden medallions. However, complete characterisation of the medallions required the use of other techniques such as mass spectrometry and scanning electron microscopy- energy dispersive X-ray. This is the first time that lead chromate has been detected in gildings. The external gilding was applied at the beginning of the 19th century using mordant oil (linseed oil).
Fine particulate matter in indoor cultural heritage: a literature review
Authors: Grau-Bové Josep , Strlič Matija
Published: April 2013

Fine particulate matter is, on account of its aerodynamic properties and typical composition (especially diesel particulate matter and carbonaceous particles) the particulate pollutant potentially most harmful to cultural heritage, representing an aesthetic issue and an agent of chemical degradation simultaneously. This paper reviews the current knowledge of the life-cycle of fine particulates, focussing on diesel particulate matter from emission to deposition, including its aesthetic and chemical consequences, and draws attention to some imbalances in the current state of research. The currently available measurements are biased towards coarse dust, and information on the consequences of particle deposition is largely restricted to the outdoor environment. More evidence on the chemical effects of the most common types of fine particulate matter in typical indoor materials is needed to enable risk assessment for indoor collections.
Bone marrow non-mesenchymal mononuclear cells induce functional differentiation of neuroblastoma cells
Authors: Phruksaniyom Chareerut , Dharmasaroja Permphan , Issaragrisil Surapol
Published: April 2013

Less is known about the non-mesenchymal mononuclear cell fraction of human bone marrow on functional adaptation of neuroblastoma cells. Using immunocytochemistry, we showed that bone-marrow mononuclear cell (BMMC)-conditioned medium can induce tyrosine hydroxylase expression in neuroblastoma cells, which is similar to the effect of retinoic acid. Using quantitative RT-PCR, we showed that NGF, CNTF, and BDNF mRNAs were detected in unfractionated BMMC populations from all human donors at different expression levels. Our results suggest that cells of the non-mesenchymal mononuclear cell fraction can induce functional adaptation of neuroblastoma cells, probably via their secreted trophic factors.
Experiences of discrimination among people Using mental health services in England 2008-2011
Authors: Corker Elizabeth , Hamilton Sarah , Henderson Claire , Weeks Craig , Pinfold Vanessa , Rose Diana , Williams Paul , Flach Clare , Gill Valdeep , Lewis-Holmes Elanor , Thornicroft Graham
Published: April 2013

Background

Research suggests that levels of discrimination against people using mental health services are high; however, reports of these people's experiences are rare.

Aims

To determine whether the Time to Change (TTC) programme target of 5% reduction in discrimination has been achieved.

Method

Separate samples of people using mental health services were interviewed annually from 2008 to 2011 using the Discrimination and Stigma Scale to record instances of discrimination.

Results

Ninety-one per cent of participants reported one or more experiences of discrimination in 2008 compared with 88% in 2011 (z=-1.9, P=0.05). The median negative discrimination score was 40% in 2008 and 28% in 2011 (Kruskal-Wallis χ2=83.4, P < 0.001).

Conclusions

The proportion of participants experiencing no discrimination increased significantly over the course of TTC but by less than the initial target The overall median discrimination score fell by 11.5%. Data from 2010 and 2011 suggest that these gains may be hard to maintain during economic austerity.
Newspaper coverage of mental illness in England 2008-2011
Authors: Thornicroft Amalia , Goulden Robert , Shefer Guy , Rhydderch Danielle , Rose Diana , Williams Paul , Thornicroft Graham , Henderson Claire
Published: April 2013

Background

Better newspaper coverage of mental health-related issues is a target for the Time to Change (TTC) anti-stigma programme in England, whose population impact may be influenced by how far concurrent media coverage perpetuates stigma and discrimination.

Aims

To compare English newspaper coverage of mental health-related topics each year of the TTC social marketing campaign (2009-2011) with baseline coverage in 2008.

Method

Content analysis was performed on articles in 27 local and national newspapers on two randomly chosen days each month.

Results

There was a significant increase in the proportion of anti-stigmatising articles between 2008 and 2011. There was no concomitant proportional decrease in stigmatising articles, and the contribution of mixed or neutral elements decreased.

Conclusions

These findings provide promising results on improvements in press reporting of mental illness during the TTC programme in 2009-2011, and a basis for guidance to newspaper journalists and editors on reporting mental illness.
Mental health problems in the workplace: Changes in employers' knowledge, attitudes and practices in England 2006-2010
Authors: Henderson Claire , Williams Paul , Little Kirsty , Thornicroft Graham
Published: April 2013

Background

In 2006 the Shaw Trust charity found high levels of ignorance and poor preparedness to deal with mental health problems among 480 senior employers in the UK. The UK government, non-governmental organisations and Time to Change (TTC) have since provided relevant assistance to employers.

Aims

To examine whether there have been improvements in mental health-related knowledge, attitudes and workplace practices among British senior employers between 2006 and 2010.

Method

A telephone survey was conducted of senior British employers (n = 480 in 2006 and n = 500 in 2009 and 2010).

Results

An increased awareness of common mental health problems was detected. Employers continued to believe that job candidates should disclose a mental health problem, but became less likely to view colleagues' attitudes as a barrier to employing someone with such a problem. Formal policies on mental health and the use of workplace accommodations became increasingly common.

Conclusions

These results are consistent with those of the TTC national public attitudes and the Viewpoint survey of service users between 2008 and 2010, which showed improved public attitudes to mental illness and a reduction in experiences of discrimination in employment.
Public knowledge, attitudes and behaviour regarding people with mental illness in England 2009-2012
Authors: Evans-Lacko Sara , Henderson Claire , Thornicroft Graham
Published: April 2013

Background

Public stigma against people with mental health problems is damaging to individuals with mental illness and is associated with substantial societal burden.

Aims

To investigate whether public knowledge, attitudes and behaviour in relation to people with mental health problems have improved among the English population since the inception of the Time To Change programme in 2009.

Method

We analysed longitudinal trends in public knowledge, attitudes and behaviour between 2009 and 2012 among a nationally representative sample of English adults.

Results

There were improvements in intended behaviour (0.07 standard deviation units, 95% CI 0.01-0.14) and a nonsignificant trend for improvement in attitudes (P=0.08) among the English population. There was, however, no significant improvement in knowledge or reported behaviour.

Conclusions

The findings provide support for effectiveness of the national Time to Change programme against stigma and discrimination in improving attitudes and intended behaviour, but not knowledge, among the public in England.
Anti-stigma training for medical students: The Education Not Discrimination project
Authors: Friedrich Bettina , Evans-Lacko Sara , London Jillian , Rhydderch Danielle , Henderson Claire , Thornicroft Graham
Published: April 2013

Background

Education Not Discrimination (END) is the component of the Time to Change programme intended to reduce mental health stigma among professionals and professional trainees.

Aims

To investigate the impact of the END anti-stigma programme on medical students immediately and after 6 months with regard to knowledge, attitudes, behaviour and empathy.

Method

A total of 1452 medical students participated in the study (intervention group n = 1066, control group n = 386).

Participants completed questionnaires at baseline, and at immediate and 6-month follow-up. Groups were compared for changes in stigma outcomes.

Results

All measures improved in both groups, particularly among students with less knowledge and more stigmatising attitudes and intended behaviour at baseline. At immediate follow-up the intervention group demonstrated significantly greater improvements in stigma-related knowledge and reductions in stigma-related attitudes and intended behaviour, relative to the control group. At 6 months' follow-up, however, only one attitude item remained significantly better.

Conclusions

Although the intervention produced short-term advantage there was little evidence for its persistent effect, suggesting a need for greater integration of ongoing measures to reduce stigma into the medical curriculum.
Anti-stigma campaigns: Time to change
Authors: smith Michael
Published: April 2013

This evaluation of the Time to Change anti-stigma campaign in England represents a milestone in international stigma research. While showing some positive outcomes, the overall picture is mixed and falls short of the wholesale shift in attitudes that is needed. A new approach is proposed for the coming decades.
The drosophila Arf GEF steppke controls MAPK activation in EGFR signaling
Authors: Hahn Ines , Fuß Bernhard , Peters Annika , Werner Tamara , Sieberg Andrea , Gosejacob Dominic , Hoch Michael
Published: April 2013

Guanine nucleotide exchange factors (GEFs) of the cytohesin protein family are regulators of GDP/GTP exchange for members of the ADP ribosylation factor (Arf) of small GTPases. They have been identified as modulators of various receptor tyrosine kinase signaling pathways including the insulin, the vascular epidermal growth factor (VEGF) and the epidermal growth factor (EGF) pathways. These pathways control many cellular functions including cell proliferation and differentiation, and their misregulation is often associated with cancerogenesis. In vivo studies on cytohesins using genetic loss of function alleles are lacking, however, since knock out mouse models are not available yet. We have recently identified mutants for the single cytohesin Steppke (Step) in Drosophila and we could demonstrate an essential role of Step in the insulin signaling cascade. Here we provide in vivo evidence for a role of the Step in EGFR signaling during wing and eye development. By analyzing step mutants, transgenic RNAi and overexpression lines for tissue specific as well as clonal analysis we found that Step acts downstream of the EGFR and is required for the activation of mitogen-activated kinase (MAPK) and the induction of EGFR target genes. We further demonstrate that step transcription is induced by EGFR signaling whereas it is negatively regulated by insulin signaling. Furthermore genetic studies and biochemical analysis show that Step interacts with the Connector Enhancer of KSR (CNK). We propose that Step may be part of a larger signaling scaffold coordinating receptor tyrosine kinase-dependent MAPK activation.
Cancer surgery induces inflammation, immunosuppression and neo-angiogenesis, but is it influenced by analgesics?
Authors: Forget Patrice , Simonet Olivier , De Kock Marc
Published: April 2013

Surgery remains a main part of the treatment of most solid tumors. Paradoxically, rapid disease progression may be a consequence of surgery in patients presenting with a dysregulated inflammatory response, and increased angiogenesis consequent to a suppressed antitumoral immune response. Physicians taking care of cancer patients should be aware of the important findings that indicate that analgesic techniques could play a role in these phenomena.
The effects of behavioral control over stress on GABAergic spontaneous inhibitory postsynaptic currents in prefrontal cortical pyramidal neurons
Authors: Varela Juan A , Wang Jungang , Cooper Donald C
Published: April 2013

Traumatic events may lead to anxiety, depression and post-traumatic stress disorder (PTSD). However, the majority of individuals exposed to trauma do not develop these disorders. The stressor controllability paradigm has been widely used as a model for understanding the neurobiology underlying factors that confer vulnerability and resilience to the outcome of traumatic events. In this paradigm rats receive a series of tail shocks: one group of rats have control over the termination of the shock by means of turning a wheel (escapable shock, ES), while the other “yoked” group of rats receive physically identical shocks but have no control over shock termination (inescapable shock, IS). In subsequent behavioral tests that model components of anxiety and depression, IS rats without control show increased signs of behavioral depression, while ES rats that have control over the shock behave as naïve home caged (HC) rats. We have previously reported that individual deep layer pyramidal neurons from the ventral medial prefrontal cortex (vmPFC) exhibit changes in their intrinsic excitability following ES. To examine if there is a corresponding reduction in synaptic inhibition, we tested IS, ES and HC deep layer pyramidal neurons under identical conditions. Collecting such electrophysiological data from pyramidal neurons after exposure to stress is a technical challenge, yet very useful for conductance-based neural simulations and computational modeling.  Here we present a data set of spontaneous inhibitory postsynaptic currents (sIPSCs) gathered from whole-cell patch-clamp recordings of individual prefrontal cortical deep layer neurons from adult rats (60-70 days old) after exposure to ES, IS or HC. In order to analyze the data, we provide our script used for the detection of synaptic events written for the scientific/engineering program Igor Pro that allows users to define their own event detection parameters.
The Evolution of Compact Binary Star Systems
Authors: Postnov Konstantin A. , Yungelson Lev R.
Published: April 2013

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars — compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.
Modified Newtonian Dynamics (MOND): Observational Phenomenology and Relativistic Extensions
Authors: Famaey Benoît , McGaugh Stacy S.
Published: April 2013

A wealth of astronomical data indicate the presence of mass discrepancies in the Universe. The motions observed in a variety of classes of extragalactic systems exceed what can be explained by the mass visible in stars and gas. Either (i) there is a vast amount of unseen mass in some novel form — dark matter — or (ii) the data indicate a breakdown of our understanding of dynamics on the relevant scales, or (iii) both. Here, we first review a few outstanding challenges for the dark matter interpretation of mass discrepancies in galaxies, purely based on observations and independently of any alternative theoretical framework. We then show that many of these puzzling observations are predicted by one single relation — Milgrom’s law — involving an acceleration constant a0 (or a characteristic surface density Σ† = a0/G) on the order of the square-root of the cosmological constant in natural units. This relation can at present most easily be interpreted as the effect of a single universal force law resulting from a modification of Newtonian dynamics (MOND) on galactic scales. We exhaustively review the current observational successes and problems of this alternative paradigm at all astrophysical scales, and summarize the various theoretical attempts (TeVeS, GEA, BIMOND, and others) made to effectively embed this modification of Newtonian dynamics within a relativistic theory of gravity.
Dynamical Boson Stars
Authors: Liebling Steven L. , Palenzuela Carlos
Published: April 2013

The idea of stable, localized bundles of energy has strong appeal as a model for particles. In the 1950s, John Wheeler envisioned such bundles as smooth configurations of electromagnetic energy that he called geons, but none were found. Instead, particle-like solutions were found in the late 1960s with the addition of a scalar field, and these were given the name boson stars. Since then, boson stars find use in a wide variety of models as sources of dark matter, as black hole mimickers, in simple models of binary systems, and as a tool in finding black holes in higher dimensions with only a single Killing vector. We discuss important varieties of boson stars, their dynamic properties, and some of their uses, concentrating on recent efforts.
Continuum and Discrete Initial-Boundary Value Problems and Einstein’s Field Equations
Authors: Sarbach Olivier , Tiglio Manuel
Published: April 2013

Many evolution problems in physics are described by partial differential equations on an infinite domain; therefore, one is interested in the solutions to such problems for a given initial dataset. A prominent example is the binary black-hole problem within Einstein’s theory of gravitation, in which one computes the gravitational radiation emitted from the inspiral of the two black holes, merger and ringdown. Powerful mathematical tools can be used to establish qualitative statements about the solutions, such as their existence, uniqueness, continuous dependence on the initial data, or their asymptotic behavior over large time scales. However, one is often interested in computing the solution itself, and unless the partial differential equation is very simple, or the initial data possesses a high degree of symmetry, this computation requires approximation by numerical discretization. When solving such discrete problems on a machine, one is faced with a finite limit to computational resources, which leads to the replacement of the infinite continuum domain with a finite computer grid. This, in turn, leads to a discrete initial-boundary value problem. The hope is to recover, with high accuracy, the exact solution in the limit where the grid spacing converges to zero with the boundary being pushed to infinity.

The goal of this article is to review some of the theory necessary to understand the continuum and discrete initial boundary-value problems arising from hyperbolic partial differential equations and to discuss its applications to numerical relativity; in particular, we present well-posed initial and initial-boundary value formulations of Einstein’s equations, and we discuss multi-domain high-order finite difference and spectral methods to solve them.
Efficacy of preparation solutions and cleansing techniques on contamination of the skin in foot and ankle surgery
Authors: Yammine K. , Harvey A.
Published: April 2013

We report a systematic review and meta-analysis of published randomised and quasi-randomised trials evaluating the efficacy of pre-operative skin antisepsis and cleansing techniques in reducing foot and ankle skin flora. The post-preparation culture number (Post-PCN) was the primary outcome. The data were evaluated using a modified version of the Cochrane Collaboration’s tool. We identified eight trials (560 participants, 716 feet) that met the inclusion criteria. There was a significant difference in the proportions of Post-PCN between hallux nailfold (HNF) and toe web spaces (TWS) sites: 0.47 vs 0.22, respectively (95% confidence interval (CI) 0.182937 to 0.304097; p < 0.0001).

Meta-analyses showed that alcoholic chlorhexidine had better efficacy than alcoholic povidone-iodine (PI) at HNF sites (risk difference 0.19 (95% CI 0.08 to 0.30); p = 0.0005); a two-step intervention using PI scrub and paint (S& P) followed by alcohol showed significantly better efficacy over PI (S& P) alone at TWS sites (risk difference 0.13 (95% CI 0.02 to 0.24); p = 0.0169); and a two-step intervention using chlorhexidine scrub followed by alcohol showed significantly better efficacy over PI (S& P) alone at the combined (HNF with TWS) sites (risk difference 0.27 (95% CI 0.13 to 0.40); p < 0.0001). No significant difference was found between cleansing techniques.

Cite this article: Bone Joint J 2013;95-B:498–503.
Risk of Pneumonia in Elderly Nursing Home Residents Using Typical Versus Atypical Antipsychotics
Authors: Aparasu Rajender R , Chatterjee Satabdi , Chen Hua
Published: April 2013

BACKGROUND

Antipsychotic medications are extensively used in nursing homes for management of behavioral and psychiatric disorders in the elderly. Prior research suggests that pneumonia is one of the common causes of anti psychotic-related mortality in this population. None of the studies compared typical and atypical antipsychotics with respect to pneumonia.

OBJECTIVE

To examine the risk of pneumonia with use of typical versus atypical antipsychotics in dual eligible elderly nursing home residents.

METHODS

The study involved a retrospective cohort design matched on propensity score using Medicare and Medicaid Analytical eXtract data from 4 US states. The study population included all elderly dual eligible (Medicaid and Medicare) nursing home residents (aged ≥65 years) who initiated antipsychotics any time between July 1, 2001, and December 31, 2003. The risk of pneumonia during the 6-month follow-up period was modeled using a Cox proportional model and extended Cox hazard model stratified on matched pairs based on propensity score, using atypical agents as the reference category.

RESULTS

Analysis of Medicaid-Medicare data revealed that there were 49,904 new antipsychotic (46,293 atypical and 3611 typical) users in the unmatched cohort and 7218 (3609 atypical and 3609 typical) users in the matched cohort. The unadjusted rate of pneumonia was 8.17% (4.61 events per person year) for atypical users and 5.21% (5.21 events per person year) for typical users. The results of Cox regression (average hazard ratio [HR] 1.24; 95% CI 0.94–1.64) and extended regression (<50 days: HR 1.17, 95% CI 0.83–1.66; and 50–180 days: HR 1.36, 95% CI 0.87–2.14) suggest that there was no significant difference in the risk of pneumonia among typical and atypical users.

CONCLUSIONS

The study found no differential risk of pneumonia between typical versus atypical antipsychotic use in dual eligible nursing home residents. Given the differential risk of mortality with typical and atypical antipsychotic use in nursing homes, more research is needed to evaluate other contributory factors of mortality with respect to these 2 antipsychotic classes.
Effect of the UGT1A1*28 Allele on Unconjugated Hyperbilirubinemia in HIV-Positive Patients Receiving Atazanavir: A Systematic Review
Authors: Culley Celia L , Kiang Tony KL , Gilchrist Samuel E , Ensom Mary HH
Published: April 2013

OBJECTIVE

To systematically examine the literature assessing the effect of uridine 5′-diphospho-glucuronosyltransferase (UGT) 1A1*28 genetic polymorphisms on atazanavir-associated hyperbilirubinemia.

DATA SOURCES

MEDLINE (1948–November 2012), EMBASE (1980–November 2012), International Pharmaceutical Abstracts (1970–November 2012), Google, and Google Scholar were searched using combinations of the following terms: glucuronosyltransferase, glucuronosyltransferase 1A1, atazanavir, atazanavir plus ritonavir, or polymorph$. The reference lists of all identified articles were manually searched.

STUDY SELECTION AND DATA EXTRACTION

Studies were included if at least 1 group of patients received atazanavir therapy and assessed the effect of UGT1A1*28 variants on bilirubin concentrations or atazanavir discontinuation rates. The quality of each study was ranked according to the US Preventive Services Task Force 1996 classification system. Information extracted included study design, baseline characteristics, treatment regimens, UGT1A1*28 genotype frequencies, bilirubin concentrations, incidence of hyperbilirubinemia, and atazanavir discontinuation rates.

DATA SYNTHESIS

Our search produced 12 studies, of which 9 were included (6 full manuscripts [level II-2], 2 abstracts, and 1 letter to the editor [level III]). Reported UGT1A1*28 homozygote genotype frequencies (0.8–23.8%) were in general agreement with the literature for the diverse ethnic population captured in the 9 studies. An association between the incidence of hyperbilirubinemia and UGT1A1*28 genotype (homozygotes > heterozygotes > wild-type) was demonstrated in all studies that reported such data (6 of 9 studies). However, the calculated positive predictive value for homozygosity and hyperbilirubinemia from pooled data was low (40.3%). Only 2 studies (levels II-2 and III) reported rates of atazanavir discontinuation due to hyperbilirubinemia and showed some positive correlation with presence of the UGT1A1*28 allele.

CONCLUSIONS

Based on the available evidence, homozygosity of the UGT1A1*28 allele does not strongly predict the incidence of severe hyperbilirubinemia. Thus, until large, prospective trials demonstrate otherwise, UGT1A1*28 testing does not appear to provide additional information to aid clinical decision-making when initiating atazanavir treatment in HIV-infected patients.
Novel Targets in the Treatment of Advanced Melanoma: New First-Line Treatment Options
Authors: Culos Kathryn A , Cuellar Sandra
Published: April 2013

OBJECTIVE

To discuss the clinical efficacy and safety of ipilimumab, vemurafenib, and investigational agents for the treatment of unresectable stage III and stage IV melanoma and define current strategies of first-line treatment selection.

DATA SOURCES

Literature was accessed through MEDLINE and International Pharmaceutical Abstracts (1970–November 2012) using the terms melanoma, metastatic melanoma, ipilimumab, vemurafenib, dabrafenib, and trametinib. In addition, reference citations from publications identified were reviewed.

STUDY SELECTION AND DATA EXTRACTION

All articles published in English identified from the data sources were evaluated. Studies and abstracts including more than 10 adult patients were included in the review.

DATA SYNTHESIS

Treatment options for unresectable stage III and IV melanoma are poor and have remained largely unchanged for the past 40 years. Two randomized Phase 3 clinical trials have demonstrated a significant survival benefit with the use of ipilimumab compared to a melanoma vaccine (10.1 vs 6.4 months; p = 0.003) and compared to dacarbazine (11.2 months, 95% CI 9.4–13.6 vs 9.1 months, 95% CI 7.8–10.5). Additionally, long-term follow-up has revealed cases of durable responses of greater than 3 years. Response rates of 50% and greater have been described in vemurafenib-treated patients (1 Phase 1, 1 Phase 2, and 1 Phase 3 randomized trial), although duration of response has not been fully determined. Both new agents possess unique toxicity profiles including immune-related adverse events with ipilimumab and secondary cutaneous cancers reported with vemurafenib use.

CONCLUSIONS

Treatment strategies have changed for patients with advanced melanoma with the use of ipilimumab and vemurafenib as first-line agents. Increased clinical experience and further published data with these and investigational agents will guide the development of treatment algorithms outlining optimal drug selection and sequencing as well as improve management of their novel adverse events.
Itch and Analgesia Resulting from Intrathecal Application of Morphine: Contrasting Effects on Different Populations of Trigeminothalamic Tract Neurons
Authors: Moser Hannah R. , Giesler Glenn J.
Published: April 2013

Intrathecal application of morphine is among the most powerful methods used to treat severe chronic pain. However, this approach commonly produces itch sufficiently severe that patients are forced to choose between relief of pain or itch. The neuronal populations responsible for processing and transmitting information underlying itch caused by intrathecal application of morphine have not been identified and characterized. We describe two populations of antidromically identified trigeminothalamic tract (VTT) neurons in anesthetized rats that are differentially affected by morphine and explain several aspects of opioid-induced itch and analgesia. We found that intrathecal application of morphine increased ongoing activity of itch-responsive VTT neurons. In addition, intrathecal application of morphine increased responses to pruritogens injected into the skin and greatly heightened responses to innocuous mechanical stimuli. In contrast, the ongoing activity and responses to noxious pinches in nociceptive VTT neurons were frequently inhibited by the same dose of morphine. These results reveal that i.t. application of morphine affects specific subpopulations of VTT neurons in ways that may produce itch, hyperknesis, alloknesis, and analgesia.
Maladaptive Bias for Extrahippocampal Navigation Strategies in Aging Humans
Authors: Wiener Jan M. , de Condappa Olivier , Harris Mathew A. , Wolbers Thomas
Published: April 2013

Efficient spatial navigation requires not only accurate spatial knowledge but also the selection of appropriate strategies. Using a novel paradigm that allowed us to distinguish between beacon, associative cue, and place strategies, we investigated the effects of cognitive aging on the selection and adoption of navigation strategies in humans. Participants were required to rejoin a previously learned route encountered from an unfamiliar direction. Successful performance required the use of an allocentric place strategy, which was increasingly observed in young participants over six experimental sessions. In contrast, older participants, who were able to recall the route when approaching intersections from the same direction as during encoding, failed to use the correct place strategy when approaching intersections from novel directions. Instead, they continuously used a beacon strategy and showed no evidence of changing their behavior across the six sessions. Given that this bias was already apparent in the first experimental session, the inability to adopt the correct place strategy is not related to an inability to switch from a firmly established response strategy to an allocentric place strategy. Rather, and in line with previous research, age-related deficits in allocentric processing result in shifts in preferred navigation strategies and an overall bias for response strategies. The specific preference for a beacon strategy is discussed in the context of a possible dissociation between beacon-based and associative-cue-based response learning in the striatum, with the latter being more sensitive to age-related changes.
Neural Cell Adhesion Molecule-Mediated Fyn Activation Promotes GABAergic Synapse Maturation in Postnatal Mouse Cortex
Authors: Chattopadhyaya Bidisha , Baho Elie , Huang Z. Josh , Schachner Melitta , Di Cristo Graziella
Published: April 2013

GABAergic basket interneurons form perisomatic synapses, which are essential for regulating neural networks, and their alterations are linked to various cognitive dysfunction. Maturation of basket synapses in postnatal cortex is activity dependent. In particular, activity-dependent downregulation of polysialiac acid carried by the neural cell adhesion molecule (NCAM) regulates the timing of their maturation. Whether and how NCAM per se affects GABAergic synapse development is unknown. Using single-cell genetics to knock out NCAM in individual basket interneurons in mouse cortical slice cultures, at specific developmental time periods, we found that NCAM loss during perisomatic synapse formation impairs the process of basket cell axonal branching and bouton formation. However, loss of NCAM once the synapses are already formed did not show any effect. We further show that NCAM120 and NCAM140, but not the NCAM180 isoform, rescue the phenotype. Finally, we demonstrate that a dominant-negative form of Fyn kinase mimics, whereas a constitutively active form of Fyn kinase rescues, the effects of NCAM knockdown. Altogether, our data suggest that NCAM120/NCAM140-mediated Fyn activation promotes GABAergic synapse maturation in postnatal cortex.