Consecutive oral administration of Bifidobacterium longum MM-2 improves the defense system against influenza virus infection by enhancing natural killer cell activity in a murine model.
Bifidobacterium, one of the major components of intestinal microflora, shows anti-influenza virus (IFV) potential as a probiotic, partly through enhancement of innate immunity by modulation of the intestinal immune system. Bifidobacterium longum MM-2 (MM-2), a very safe bacterium in humans, was isolated from healthy humans and its protective effect against IFV infection in a murine model shown. In mice that were intranasally inoculated with IFV, oral administration of MM-2 for 17 consecutive days improved clinical symptoms, reduced mortality, suppressed inflammation in the lower respiratory tract, and decreased virus titers, cell death, and pro-inflammatory cytokines such as IL-6 and TNF-α in bronchoalveolar lavage fluid. The anti-IFV mechanism of MM-2 involves innate immunity through significant increases in NK cell activities in the lungs and spleen and a significant increase in pulmonary gene expression of NK cell activators such as IFN-γ, IL-2, IL-12 and IL-18. Even in non-infected mice, MM-2 administration also induced significant enhancement of both IFN-γ production by Peyer's patch cells (PPs) and splenetic NK cell activity. Oral administration of MM-2 for 17 days activates systemic immunoreactivity in PPs, which contributes to innate immunity, including NK cell activation, resulting in an anti-IFV effect. MM-2 as a probiotic may function as a prophylactic agent in the management of an IFV epidemic.


Endothelium and growth factors in vascular remodeling of hypertension.
The pioneering work of Furchgott, Moncada, and Vane has clearly established that the endothelium plays a critical role in the regulation of vascular tone. The endothelium produces several potent vasoactive substances, including vasodilators such as endothelium-derived relaxing factor and prostacyclin as well as vasoconstrictors such as angiotensin II and endothelin. These vasoactive substances not only have short-term effects on vascular tone but also appear to induce long-term effects on vascular structure. This process of vascular remodeling involves cell growth or regression and extracellular matrix expansion or contraction. As the interface between the bloodstream and the vessel wall, the endothelium plays a pivotal role in sensing and transducing the stimulus that induces vascular remodeling as well as producing the mediators that alter cell growth and the composition of the extracellular matrix. The endothelium maintains homeostasis within the vasculature by a balance between vasodilators and vasoconstrictors or growth inhibitors and growth promoters. Endothelial cell dysfunction may alter the delicate balance of mediators necessary to maintain homeostasis. Indeed, endothelial cell dysfunction is a common pathogenetic defect in animal models of hypertension as well as in hypertensive humans. Further understanding of the cellular and molecular mechanisms of vascular remodeling induced by endothelial cell-derived mediators may have important implications in the pathogenesis and treatment of hypertension.


Insights into prion strains and neurotoxicity.
Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases that are caused by prions and affect humans and many animal species. It is now widely accepted that the infectious agent that causes TSEs is PrP(Sc), an aggregated moiety of the host-derived membrane glycolipoprotein PrP(C). Although PrP(C) is encoded by the host genome, prions themselves encipher many phenotypic TSE variants, known as prion strains. Prion strains are TSE isolates that, after inoculation into distinct hosts, cause disease with consistent characteristics, such as incubation period, distinct patterns of PrP(Sc) distribution and spongiosis and relative severity of the spongiform changes in the brain. The existence of such strains poses a fascinating challenge to prion research.


Infertility care among OEF/OIF/OND women Veterans in the Department of Veterans Affairs.
An increasing number of young women Veterans seek reproductive health care through the VA, yet little is known regarding the provision of infertility care for this population. The VA provides a range of infertility services for Veterans including artificial insemination, but does not provide in vitro fertilization. This study will be the first to characterize infertility care among OEF/OIF/OND women Veterans using VA care. We analyzed data from the OEF/OIF/OND roster file from the Defense Manpower Data Center (DMDC)-Contingency Tracking System Deployment file of military discharges from October 1, 2001-December 30, 2010, which includes 68,442 women Veterans between the ages of 18 and 45 who utilized VA health care after separating from military service. We examined the receipt of infertility diagnoses and care using ICD-9 and CPT codes. Less than 2% (n=1323) of OEF/OIF/OND women Veterans received an infertility diagnosis during the study period. Compared with women VA users without infertility diagnosis, those with infertility diagnosis were younger, obese, black, or Hispanic, have a service-connected disability rating, a positive screen for military sexual trauma, and a mental health diagnosis. Overall, 22% of women with an infertility diagnosis received an infertility assessment or treatment. Thirty-nine percent of women Veterans receiving infertility assessment or treatment received this care from non-VA providers. Overall, a small proportion of OEF/OIF/OND women Veterans received infertility diagnoses from the VA during the study period, and an even smaller proportion received infertility treatment. Nearly 40% of those who received infertility treatments received these treatments from non-VA providers, indicating that the VA may need to examine the training and resources needed to provide this care within the VA. Understanding women's use of VA infertility services is an important component of understanding VA's commitment to comprehensive medical care for women Veterans.


Telomerase and breast cancer: from diagnosis to therapy.
Telomeres are believed to be responsible for chromosomal stability during cellular proliferation. They are created by telomerase, an enzyme present in many human neoplasms. Telomerase is considered to be important in breast cancer since reactivation of the enzyme ensures cell stability allowing malignant cells to divide indefinitely. This article aims to discuss the role of telomerase in breast cancer and explore the future of telomerase research. We have reported on the literature to date in order to present this current review. Telomerase is found in significant levels in breast neoplasms and is reliably detected in fine needle aspirations aiding the diagnosis of breast cancer. There is also a correlation between telomerase and disease prognosis, and there is current work assessing if telomerase can be of benefit in monitoring the efficacy of systemic treatment. The role of telomerase in breast cancer is still being investigated however by understanding the action it has on chromosomal stability, and its detection in tumour cells, there are possibilities to enhance the methods employed to detect and treat breast cancer.


Isochromosome 17q is a negative prognostic factor in poor-risk childhood medulloblastoma patients.
Medulloblastomas are the most common primary malignant childhood intracranial neoplasms. Patients are currently sorted into three risk groups based on clinical criteria: standard, poor, and infant (<18 months old). We hypothesized that genetic copy number aberrations (CNA) predict prognosis and would provide improved criteria for predicting outcome. DNA from 35 medulloblastoma patients from four Children's Cancer Group trials was analyzed by comparative genomic hybridization to determine CNAs. The genetic alterations were evaluated using statistical and cluster analyses. The most frequent CNAs were gains on 17q, 7, 1q, and 7q and losses on 17p, 10q, X, 16q, and 11q. Amplification at 5p15.1-p15.3 was also detected. Isochromosome 17q (i(17)(q10)) was associated with poor overall survival (P = 0.03) and event-free survival (P = 0.04) independent of poor risk group classification. Age <3 tended to be associated with <3 CNAs (P = 0.06). Unsupervised cluster analysis sorted the study patients into four subgroups based on CNAs. Supervised analysis using the program Significance Analysis of Microarrays (SAM) quantitatively validated those CNAs identified by unsupervised clustering that significantly distinguished among the four subgroups. Medulloblastomas are genetically heterogeneous and can be categorized into separate genetic subgroups by their CNAs using unsupervised cluster analysis and SAM. i(17)(q10) was a significant independent negative prognostic factor. Infant medulloblastomas may be a distinct genetic subset from those of older patients.


Lack of heritability of circulating leptin concentration in humans after adjustment for body size and adiposity using a physiological approach.
To construct a simple physiological model of leptin kinetics, based on measures of body size and composition, which is suitable for investigating the influence of genetic and other influences on circulating leptin levels in humans. Consideration of the kinetics of the secretion and clearance of leptin led to a predicted linear relationship between ln(leptin), ln(fat mass), and a function of non-fat body compartments. Results obtained from this model were compared with those from two published empirical models based on adjustment for fat mass alone or for body mass index. Overnight fasted leptin levels, body composition data (dual-energy X-ray absorptiometry) and questionnaire responses were obtained from 527 twin pairs (127 monozygotic, 400 dizygotic; 37 male (age 18-68 y, BMI 18-32 kg/m2), 489 female (age 18-71, BMI 17-44) drawn from the St Thomas' UK Adult Twin Registry. In a partial correlation analysis ln(fat mass) and ln(height) (r=0.80, P<0.0001) and r=-0.22, P<0.0001 respectively) were independent predictors of ln(leptin) in females but ln(lean mass) was not (r=-0.01). A regression model incorporating ln(fat mass), ln(height) and a second order polynomial in age provided an adequate fit of the ln(leptin) data in females (r2=71%). ln(Leptin) values adjusted for body size and composition using the model were not significantly heritable (P=0.11), were significantly related to gender (r2=2.3%) and to ln(insulin) (r2=5.7%), but not to menopausal status (r2=0.7%), hormone replacement therapy (r2=0.4%), past or current smoking (r2=1.1%), or percentage trunk fat (r2=0.5%). Both empirical models found significant heritability (h2=36-42%), overestimated the effect of gender in the data (r2=14-16%), and produced significant relationships between adjusted ln(leptin) and percentage trunk fat (r2=4-12%). We conclude that our physiologically based model provides an adequate description of the relationship between leptin and body composition and provides a more reliable framework than current empirical approaches for the investigation of other influences on circulating leptin levels. Heritable variations in the control of leptin secretion are unlikely to contribute significantly to variations in leptin levels at the population level.


[Posioning by caustic substances].
There are discordant guides and protocols when it comes to treating a patient who has ingested a caustic substance. Different ideas or tendencies speak in favour of dilution, neutralization, provoking vomiting, carrying out stomach washes, etc., depending on the milieu where the problem arises: at home, at the health centre, emergency service or hospital. The same occurs with the type of diluent or neutralizing agent to be used, how and when to start the treatment pattern with corticoids and/or antibiotics and antisecretory, if indeed this is necessary. We have carried out an exhaustive bibliographical study, an experimental work and a study of the different diagnosis and treatment guides and protocols used in different Spanish hospitals. At the experimental level it was found that there are histopathological markers that advise against the use of diluent substances following the ingestion of caustic alkali. Except in the cases of ingestion of solid caustic substances -crystalline or granulated- categorical contraindications are given against dilution. Corticoids are not efficient when a caustic acid is ingested; their use is more than questionable following the ingestion of caustic alkali. Diagnosis and quality of treatment are based on endoscopy. There is no single criterion that defines which moment (the time following ingestion) is the most convenient for carrying this out, although the period between the first 6-12 hours is the most suitable. We present an independent protocol of diagnosis and treatment -in the form of algorithms- that must be followed after the ingestion of caustic acids or caustic alkali.


Cystic fibrosis typing with DNA probes: experience of a screening laboratory.
A sample of 125 individuals from 37 British cystic fibrosis (CF) families with at least one living affected child were typed with probes for restriction fragment length polymorphisms (RFLPs) known to be linked to the CF gene. These probes were MetD, MetH, pJ3.11 and 7C22. Using this combination of probes, 30 out of the 37 families were sufficiently informative to enable prenatal diagnosis of the disease. Linkage analysis has also proved to be useful in excluding CF in two cases where diagnosis of the disease was equivocal in the sibling of an affected child.


Cannabinoids: new promising agents in the treatment of neurological diseases.
Nowadays, Cannabis sativa is considered the most extensively used narcotic. Nevertheless, this fame obscures its traditional employ in native medicine of South Africa, South America, Turkey, Egypt and in many regions of Asia as a therapeutic drug. In fact, the use of compounds containing Cannabis and their introduction in clinical practice is still controversial and strongly limited by unavoidable psychotropic effects. So, overcoming these adverse effects represents the main open question on the utilization of cannabinoids as new drugs for treatment of several pathologies. To date, therapeutic use of cannabinoid extracts is prescribed in patients with glaucoma, in the control of chemotherapy-related vomiting and nausea, for appetite stimulation in patients with anorexia-cachexia syndrome by HIV, and for the treatment of multiple sclerosis symptoms. Recently, researcher efforts are aimed to employ the therapeutic potentials of Cannabis sativa in the modulation of cannabinoid receptor activity within the central nervous system, particularly for the treatment of neurodegenerative diseases, as well as psychiatric and non-psychiatric disorders. This review evaluates the most recent available data on cannabinoids utilization in experimental and clinical studies, and highlights their beneficial effects in the prevention of the main neurological diseases and for the clinical treatment of symptoms with them correlated.


Mapping protein binding sites on the biomolecular corona of nanoparticles.
Nanoparticles in a biological milieu are known to form a sufficiently long-lived and well-organized 'corona' of biomolecules to confer a biological identity to the particle. Because this nanoparticle-biomolecule complex interacts with cells and biological barriers, potentially engaging with different biological pathways, it is important to clarify the presentation of functional biomolecular motifs at its interface. Here, we demonstrate that by using antibody-labelled gold nanoparticles, differential centrifugal sedimentation and various imaging techniques it is possible to identify the spatial location of proteins, their functional motifs and their binding sites. We show that for transferrin-coated polystyrene nanoparticles only a minority of adsorbed proteins exhibit functional motifs and the spatial organization appears random, which is consistent, overall, with a stochastic and irreversible adsorption process. Our methods are applicable to a wide array of nanoparticles and can offer a microscopic molecular description of the biological identity of nanoparticles.


Finding the silver lining without the golden eggs.
Despite the failure of Congress to enact comprehensive health care reform legislation, including the hard-won proposals on behalf of academic medicine, there is much reason for hope for the future. Academic medicine won major victories in having its proposals for a broad-based all-payer system of explicit supports for its various missions included in major reform bills. If the members of the academic medicine community can strengthen further the unity they achieved during the long debate, they will be well positioned to succeed if another opportunity arises in time to rescue academic medicine from a buyer's market that is indifferent to their needs. But prudence dictates that they not depend on being rescued and instead consider the faltering of legislative reform as a wake-up call, summoning them to focus on difficult issues within their own control as they engage the rapidly changing health-care marketplace. Academic medicine has grown phenomenally over the past few decades because its missions have been strongly supported by the public. Continued growth is unlikely, given society's numerous unmet needs and limited resources. Therefore, academic medicine not only must face squarely the challenge of restructuring its work to be more efficient and more productive, but must use the many opportunities that lie ahead to sustain and strengthen its public support by embracing public accountability and rededicating its efforts to meet public expectations.(ABSTRACT TRUNCATED AT 250 WORDS)


Lipid dependant disorder-to-order conformational transitions in apolipoprotein CI derived peptides.
In contrast to the notion established for many years that protein function depends on rigid 3D structures, nowadays there is important evidence suggesting that non-structured segments of proteins play important roles in protein function. Therefore, disorder-to-order dynamic conformational transitions have been proposed as an attractive mechanism involved in protein-protein recognition. Our laboratory using Langmuir monolayers of apolipoproteins has previously shown that upon lateral compression at the air/water and phospholipid/water interfaces, there is an important movement of the C-terminal segment of apolipoprotein CI towards the air, considered the hydrophobic region of the monolayer and the acyl-chain region of the interface when phospholipids are used. Here, in an attempt to define secondary structure changes that might occur within this C-terminal segment of apoCI while moving from the monolayer interface back and forth its hydrophobic region, employing three peptides derived from apoCI we studied by circular dichroism and dynamic light scattering their conformational properties when associated to a series of amphipathic lipids and lipid-like molecules. Our results show that a series of lysophospholipids present the ability to modulate the formation of an alpha helix at the C-terminal peptide of apoCI through a disorder-to-order transition while forming small lipid/peptide aggregates below 10nm in diameter.


Integrative analysis of genomic aberrations associated with prostate cancer progression.
Integrative analysis of genomic aberrations in the context of trancriptomic alterations will lead to a more comprehensive perspective on prostate cancer progression. Genome-wide copy number changes were monitored using array comparative genomic hybridization of laser-capture microdissected prostate cancer samples spanning stages of prostate cancer progression, including precursor lesions, clinically localized disease, and metastatic disease. A total of 62 specific cell populations from 38 patients were profiled. Minimal common regions (MCR) of alterations were defined for each sample type, and metastatic samples displayed the most number of alterations. Clinically localized prostate cancer samples with high Gleason grade resembled metastatic samples with respect to the size of altered regions and number of affected genes. A total of 9 out of 13 MCRs in the putative precursor lesion, high-grade prostatic intraepithelial neoplasia (PIN), showed an overlap with prostate cancer cases (amplifications in 3q29, 5q31.3-q32, 6q27, and 8q24.3 and deletions in 6q22.31, 16p12.2, 17q21.2, and 17q21.31), whereas postatrophic hyperplasia (PAH) did not exhibit this overlap. Interestingly, prostate cancers that do not overexpress ETS family members (i.e., gene fusion-negative prostate cancers) harbor differential aberrations in 1q23, 6q16, 6q21, 10q23, and 10q24. Integrative analysis with matched mRNA profiles identified genetic alterations in several proposed candidate genes implicated in prostate cancer progression.


Trends in attention-deficit hyperactivity disorder medication use: a retrospective observational study using population-based databases.
The use of medications to treat attention deficit hyperactivity disorder (ADHD) has increased, but the prevalence of ADHD medication use across different world regions is not known. Our objective was to determine regional and national prevalences of ADHD medication use in children and adults, with a specific focus on time trends in ADHD medication prevalence. We did a retrospective, observational study using population-based databases from 13 countries and one Special Administrative Region (SAR): four in Asia and Australia, two in North America, five in northern Europe, and three in western Europe. We used a common protocol approach to define study populations and parameters similarly across countries and the SAR. Study populations consisted of all individuals aged 3 years or older between Jan 1, 2001, and Dec 31, 2015 (dependent on data availability). We estimated annual prevalence of ADHD medication use with 95% CI during the study period, by country and region and stratified by age and sex. We reported annual absolute and relative percentage changes to describe time trends. 154·5 million individuals were included in the study. ADHD medication use prevalence in 2010 (in children aged 3-18 years) varied between 0·27% and 6·69% in the countries and SAR assessed (0·95% in Asia and Australia, 4·48% in North America, 1·95% in northern Europe, and 0·70% in western Europe). The prevalence of ADHD medication use among children increased over time in all countries and regions, and the absolute increase per year ranged from 0·02% to 0·26%. Among adults aged 19 years or older, the prevalence of any ADHD medication use in 2010 varied between 0·003% and 1·48% (0·05% in Asia and Australia, 1·42% in North America, 0·47% in northern Europe, and 0·03% in western Europe). The absolute increase in ADHD medication use prevalence per year ranged from 0·0006% to 0·12%. Methylphenidate was the most commonly used ADHD medication in most countries. Using a common protocol and data from 13 countries and one SAR, these results show increases over time but large variations in ADHD medication use in multiple regions. The recommendations of evidence-based guidelines need to be followed consistently in clinical practice. Further research is warranted to describe the safety and effectiveness of ADHD medication in the short and long term, and to inform evidence-based guidelines, particularly in adults. None.


B7RP-1 is not required for the generation of Th2 responses in a model of allergic airway inflammation but is essential for the induction of inhalation tolerance.
The recently described ICOS-B7RP-1 costimulatory pathway has been implicated in the generation of effector Th2 responses and, hence, has become an attractive therapeutic target for allergic diseases. In the present study, we used B7RP-1-deficient mice to investigate the role of B7RP-1 in the generation and maintenance of Th2 responses in a model of mucosal allergic airway inflammation. We found that exposure of B7RP-1 knockout mice to aerosolized OVA in the context of GM-CSF leads to airway eosinophilic inflammation. This response was long lasting because rechallenge of mice with the same Ag recapitulated airway eosinophilia. Moreover, significant expression of T1/ST2 on T cells and production of Th2-affiliated cytokines (IL-5, IL-4, and IL-13) and Igs (IgE and IgG1) conclusively demonstrate the generation of a Th2 response in the absence of B7RP-1. In addition, expression of two major Th2-associated costimulatory molecules-CD28 and ICOS-indicates T cell activation in the absence of B7RP-1 signaling. Finally, B7RP-1 knockout mice are resistant to the induction of inhalation tolerance as indicated by the sustained eosinophilia in the lung and IL-5 production. In summary, our results demonstrate that in a model of mucosal allergic sensitization, the ICOS-B7RP-1 pathway is redundant for the generation of Th2 responses but essential for the induction of inhalation tolerance.


Distinct roles of GABA(A) and GABA(B) receptors in balancing and terminating persistent cortical activity.
Cortical networks spontaneously fluctuate between persistently active Up states and quiescent Down states. The Up states are maintained by recurrent excitation within local circuits, and can be turned on and off by synaptic input. GABAergic inhibition is believed to be important for stabilizing such persistent activity by balancing the excitation, and could have an additional role in terminating the Up state. Here, we report that GABA(A) and GABA(B) receptor-mediated inhibition have distinct and complementary roles in balancing and terminating persistent activity. In a model of Up-Down states expressed in slices of rat entorhinal cortex, the GABA(A) receptor antagonist, gabazine (50-500 nM), concentration-dependently decreased Up state duration, eventually leading to epileptiform bursts. In contrast, the GABA(B) receptor antagonist, CGP55845 (50 nM to 1 microM), increased the duration of persistent network activity, and prevented stimulus-induced Down state transitions. These results suggest that while GABA(A) receptor-mediated inhibition is necessary for balancing persistent activity, activation of GABA(B) receptors contributes to terminating Up states.


Multicultural voices: Attitudes of older adults in the United States about elder mistreatment.
Despite international growth in policies to increase the identification and response to elder abuse and neglect, there remain considerable barriers to treating the problem. Some of these barriers may be attributed to how older adults from different racial/ethnic backgrounds define, experience, and seek to remedy elder mistreatment. Using focus group discussions based on case vignettes, this paper examines how older adults from different racial and ethnic backgrounds in the United States perceive elder mistreatment. Five focus groups were conducted with African Americans, English-speaking Latinos, Spanish-speaking Latinos, non-Latino Whites and African American caregivers for older adults. While similar definitions and meanings of elder abuse were expressed across the different racial/ethnic groups, Latino participants introduced additional themes of machismo, respect, love, and early intervention to stop abuse, suggesting that perceptions/beliefs about elder mistreatment are determined by culture and degree of acculturation in addition to race/ethnicity. Most differences in attitudes occurred within groups, demonstrating that perceptions vary by individual as well as by culture. In identifying scenarios that constitute elder mistreatment, some participants felt that certain cases of abuse are actually the persistence of intimate partner violence into old age. Participants also indicated that victims may prefer to tolerate mistreatment in exchange for other perceived benefits (e.g., companionship, security); and out of fear that they could be placed in an institution if mistreatment is reported. Findings suggest the need for person-centred intervention and prevention models that integrate the cultural background, care needs, and individual preferences of older adults.


Is Nitric Oxide (NO) the Last Word in Radiosensitization? A Review.
As a short-lived radical that diffuses across membranes, rather than interacting with membrane-bound receptors, nitric oxide (NO) represents a significant departure from synthetically derived radiosensitizers. An endogenous compound, NO may equal or surpass its molecular cousin, oxygen, as a hypoxic radiosensitizer, through pleiotropic phenotypic effects on tumor perfusion, cell signaling, mitochondrial respiration, the fixation of radiation-induced damage, and the radioprotection of normal tissue. However, unlike oxygen, in the context of radiosensitization, the clinical role and utility of NO are poorly understood, with often contradictory and controversial reported effects: whether NO functions as a radiosensitizer may ultimately be contextual to the tumor microenvironment. This may make NO manipulation an ideal candidate for a personalized radiosensitization approach tailored to specific patient and tumor types/microenvironmental characteristics. Effective delivery of NO both systemically and directly to the tumor may be critical to the success of this approach. Compounds that release NO or NO precursors have the potential to drive innovation and result in a new fertile branch of the radiosensitizer tree.


A mouse model of gyrate atrophy of the choroid and retina. Early retinal pigment epithelium damage and progressive retinal degeneration.
Gyrate atrophy (GA) of the choroid and retina is a blinding chorioretinal degeneration caused by deficiency of ornithine delta-aminotransferase (OAT). The phenotype of GA is characterized by progressive concentric reduction of the visual fields and ornithine accumulation. To understand better the pathogenesis of GA and to develop a model to test therapeutic strategies, we produced an OAT-deficient mouse by gene targeting. Like human GA patients, adult OAT-deficient mice exhibit chronic hyperornithinemia to levels 10-15-fold above normal and massive ornithinuria. Slowly progressive retinal degeneration is reflected by a gradual decline in electroretinogram amplitudes over the first 12 mo of life. At 2 mo, the retinal pigment epithelium is histologically normal, but electron microscopy reveals sporadic degeneration of scattered pigment epithelial cells. By 6 mo there are more diffuse abnormalities of the pigment epithelium with accumulation of large phagosomes and crystalloid inclusions. Although morphologically normal at 2 mo, the photo-receptor outer segments become highly disorganized and shortened to 60% of control length by 10 mo. Additionally, there is cumulative loss of the photoreceptor cells, which reaches 33% by 10 mo and is most pronounced in the central region of the retina. Our results indicate that retinal pigment epithelial cells are the initial site of insult in GA and that the OAT-deficient mouse is an excellent animal model of GA in human patients.


Cellular membrane-anchored fluorescent probe with aggregation-induced emission characteristics for selective detection of Cu2+ ions.
The exploration of advanced fluorescent probes that can detect divalent copper (Cu2+) in aqueous environments and even in live organisms is particularly valuable for understanding the occurrence and development of Cu2+-related diseases. In this work, we report the design and synthesis of an aggregation-induced emission luminogen (AIEgen)-based probe (TPE-Py-EEGTIGYG) by integrating an AIEgen, TPE-Py, with a peptide, EEGTIGYG, which can selectively detect Cu2+ in both aqueous solution and live cells. Peptide EEGTIGYG has dual functionality in the probe design, namely improving water solubility and providing specific cell membrane-binding ability. TPE-Py-EEGTIGYG can self-assemble into nanoaggregates at high concentration in aqueous solution (e.g., 25 μM), which possess large fluorescence output due to the restriction of intramolecular rotation of the phenyl rings on TPE-Py. The fluorescence of the TPE-Py-EEGTIGYG nanoaggregates can be significantly quenched by Cu2+ but not by other metal ions, achieving the selective detection of Cu2+ in aqueous media. Furthermore, TPE-Py-EEGTIGYG can exist as a molecular species and is very weakly fluorescent in dilute aqueous solution (e.g., 5 μM), but can however largely switch on its fluorescence upon specifically anchoring onto the cell membrane. The emissive probes on the cell membrane can be used for the detection of Cu2+ ions that move in and out of cells with a fluorescence "turn-off" mode.


EXPERIMENTAL RICKETS IN RATS : I. A DIET PRODUCING RICKETS IN WHITE RATS, AND ITS PREVENTION BY THE ADDITION OF AN INORGANIC SALT.
1. A simple diet is presented which regularly induced rickets in young rats. 2. The substitution of 0.4 per cent secondary potassium phosphate for a small part of calcium lactate in this diet completely inhibited the development of rickets. 3. Quantitative determinations of calcium in the bodies of parallel rats showed a marked increase of calcium content in the rats receiving the added phosphate over those which developed rickets. 4. While it is thus shown by x-rays and by histological examinations and by quantitative chemical analysis that added potassium phosphate increased the assimilation and normal deposition of calcium, it may be the quantitative relationship between the inorganic ions rather than actual deficiency of any one of them which was here the determining factor in the cause or prevention of rickets. Our experiments and conclusions do not exclude the possibility of other causes of rickets than those here discussed.


Studies on the post-ictal rise in seizure threshold.
Seizure thresholds were determined by timed infusion of a convulsant drug. Following an electroconvulsive shock (ECS) rats exhibited a raised seizure threshold to infusion of the GABA antagonist drugs, pentylenetetrazol, bicuculline and isopropyl-bicyclophosphate, but not to the glycine antagonist strychnine or the 5-HT agonist, quipazine. The increase in threshold was seen following a bicuculline-induced seizure and 30 min following the last of a course of ECS given once daily for 10 days. The rise in seizure threshold still occurred when animals were pretreated with alpha-methyl-p-tyrosine (200 mg . kg-1), p-chlorophenylalanine (200 mg . kg-2), naloxone (1 mg . kg-1) or indomethacin (20 mg . kg-1). Diazepam (2 mg . kg-1), flurazepam (10 mg . kg-1) and sodium valproate (400 mg . kg-1) elevated basal seizure threshold and a further rise followed the ECS. Phenytoin (40 mg . kg-1) and carbamazepine (40 mg . kg-1) had no effect on basal seizure threshold or the ECS-induce rise. (¿Propranolol (20 mg . kg-1) did not affect basal seizure threshold but prevented the ECS-induced increase. The rise in seizure threshold following a convulsion may be an important adaptive mechanism which could be related to the reported increase in specific benzodiazepine binding following a seizure.


Controlling cyclization pathways in palladium(ii)-catalyzed intramolecular alkene hydro-functionalization via substrate directivity.
We report a series of palladium(ii)-catalyzed, intramolecular alkene hydrofunctionalization reactions with carbon, nitrogen, and oxygen nucleophiles to form five- and six-membered carbo- and heterocycles. In these reactions, the presence of a proximal bidentate directing group controls the cyclization pathway, dictating the ring size that is generated, even in cases that are disfavored based on Baldwin's rules and in cases where there is an inherent preference for an alternative pathway. DFT studies shed light on the origins of pathway selectivity in these processes.


A case of lipomatous pseudohypertrophy of the pancreas diagnosed by typical imaging.
Lipomatous pseudohypertrophy of the pancreas is an extremely rare disease, and is characterized by the replacement of pancreatic acinar cells with adipose tissue, although the pancreatic duct and islets are preserved. We report the case of a 64-year-old female who was undergoing treatment for Hashimoto's disease at a nearby clinic. For the previous two years, she had experienced an unpleasant feeling in the upper abdominal area after eating oily foods. For the previous six months, she had also suffered from lower-back pain, and presented at our hospital. Abdominal computed tomography and magnetic resonance imaging revealed marked fat replacement over the entire pancreas. Endoscopic retrograde cholangiopancreatography revealed no anatomical abnormality or narrowing of the main pancreatic duct; the main pancreatic duct was normal up to the pancreatic tail and the branches of the pancreatic duct did not show any abnormalities. While the serum levels of the pancreatic enzymes were considerably low, according to the data of the pancreatic exocrine function test (N-benzoyl-tyrosyl-p-aminobenzoic acid test), endocrine function was maintained. On the basis of the abovementioned findings, we diagnosed lipomatous pseudohypertrophy of the pancreas. Lipomatous pseudohypertrophy of the pancreas is a very rare disease characterized by the disappearance of pancreatic exocrine tissue due to adipose tissue replacement, although the pancreatic duct and islets remain intact. Even though it has been suggested that the diagnosis of lipomatous pseudohypertrophy of the pancreas should be based on histological findings, this case indicated the possibility that lipomatous pseudohypertrophy of the pancreas may be diagnosed solely by typical imaging findings and serological data.


A chip-based assay for botulinum neurotoxin A activity in pharmaceutical preparations.
The production of botulinum neurotoxin A (BoNT/A) for therapeutic and cosmetic applications requires precise determination of batch potency, and the enzymatic activity of BoNT/A light chain is a crucial index that can be measured in vitro. We previously established a SNAP-25 chip-based assay using surface plasmon resonance (SPR) that is more sensitive than the standard mouse bioassay for the quantification of BoNT/A activity. We have now adapted this procedure for pharmaceutical preparations. The optimized SPR assay allowed multiple measurements on a single chip, including the kinetics of substrate cleavage. The activity of five different batches of a pharmaceutical BoNT/A preparation was determined in a blind study by SPR and found to be in agreement with data from the in vivo mouse lethality assay. Biosensor detection of specific proteolytic products has the potential to accurately monitor the activity of pharmaceutical BoNT/A preparations, and a single chip can be used to assay more than 100 samples.


Overcoming motor "forgetting" through reinforcement of learned actions.
The human motor system rapidly adapts to systematic perturbations but the adapted behavior seems to be forgotten equally rapidly. The reason for this forgetting is unclear, as is how to overcome it to promote long-term learning. Here we show that adapted behavior can be stabilized by a period of binary feedback about success and failure in the absence of vector error feedback. We examined the time course of decay after adaptation to a visuomotor rotation through a visual error-clamp condition--trials in which subjects received false visual feedback showing perfect directional performance, regardless of the movements they actually made. Exposure to this error-clamp following initial visuomotor adaptation led to a rapid reversion to baseline behavior. In contrast, exposure to binary feedback after initial adaptation turned the adapted state into a new baseline, to which subjects reverted after transient exposure to another visuomotor rotation. When both binary feedback and vector error were present, some subjects exhibited rapid decay to the original baseline, while others persisted in the new baseline. We propose that learning can be decomposed into two components--a fast-learning, fast-forgetting adaptation process that is sensitive to vector errors and insensitive to task success, and a second process driven by success that learns more slowly but is less susceptible to forgetting. These two learning systems may be recruited to different degrees across individuals. Understanding this competitive balance and exploiting the long-term retention properties of learning through reinforcement is likely to be essential for successful neuro-rehabilitation.


A systematic review of teamwork training interventions in medical student and resident education.
Teamwork is important for improving care across transitions between providers and for increasing patient safety. This review's objective was to assess the characteristics and efficacy of published curricula designed to teach teamwork to medical students and house staff. The authors searched MEDLINE, Education Resources Information Center, Excerpta Medica Database, PsychInfo, Cumulative Index of Nursing and Allied Health Literature, and Scopus for original data articles published in English between January 1980 and July 2006 that reported descriptions of teamwork training and evaluation results. Two reviewers independently abstracted information about curricular content (using Baker's framework of teamwork competencies), educational methods, evaluation design, outcomes measured, and results. Thirteen studies met inclusion criteria. All curricula employed active learning methods; the majority (77%) included multidisciplinary training. Ten curricula (77%) used an uncontrolled pre/post design and 3 (23%) used controlled pre/post designs. Only 3 curricula (23%) reported outcomes beyond end of program, and only 1 (8%) >6 weeks after program completion. One program evaluated a clinical outcome (patient satisfaction), which was unchanged after the intervention. The median effect size was 0.40 (interquartile range (IQR) 0.29, 0.61) for knowledge, 0.38 (IQR 0.32, 0.41) for attitudes, 0.41 (IQR 0.35, 0.49) for skills and behavior. The relationship between the number of teamwork principles taught and effect size achieved a Spearman's correlation of .74 (p = .01) for overall effect size and .64 (p = .03) for median skills/behaviors effect size. Reported curricula employ some sound educational principles and appear to be modestly effective in the short term. Curricula may be more effective when they address more teamwork principles.


Hospital racial composition and the treatment of localized prostate cancer.
Racial differences in the treatment of men with localized prostate cancer remain poorly understood. This study examines whether hospital racial composition is associated with the type of treatment black and white men receive. The authors performed a retrospective cohort study of men in Surveillance, Epidemiology, and End Results-Medicare diagnosed with localized prostate cancer from 1995 to 2005 linked to hospital and census data. A total of 134,291 men were assigned to the hospital where they received care. Generalized estimating equations were used to determine whether hospital racial composition was associated with the receipt of definitive therapy and type of treatment. Black men were less likely to receive radiation and/or prostatectomy compared with white men (55.5% vs 63.7%, P < .001) and, among those who received definitive therapy, were less likely to undergo prostatectomy (27.5% vs 31.9%, P < .001). The percentage of black men who received their care at hospitals with a high proportion of black patients was 48.0%, compared with only 5.2% of white patients who received care in this subset of hospitals. Men were significantly less likely to receive definitive treatment (odds ratio, 0.81; 95% confidence interval, 0.74-0.90) in hospitals with a high proportion of black patients compared with men seen at hospitals with fewer black patients. The association between hospital racial composition and treatment did not significantly differ by patient race. Hospital racial composition is consistently associated with the care that men receive for localized prostate cancer. Better understanding of the factors that determine where men receive care is an important component in reducing variation in treatment.


Synthetic biology and the ethics of knowledge.
Synthetic biologists aim to generate biological organisms according to rational design principles. Their work may have many beneficial applications, but it also raises potentially serious ethical concerns. In this article, we consider what attention the discipline demands from bioethicists. We argue that the most important issue for ethicists to examine is the risk that knowledge from synthetic biology will be misused, for example, in biological terrorism or warfare. To adequately address this concern, bioethics will need to broaden its scope, contemplating not just the means by which scientific knowledge is produced, but also what kinds of knowledge should be sought and disseminated.


Osteoprogenitor cells from bone marrow and cortical bone: understanding how the environment affects their fate.
Bone is a dynamic organ where skeletal progenitors and hematopoietic cells share and compete for space. Presumptive mesenchymal stem cells (MSC) have been identified and harvested from the bone marrow (BM-MSC) and cortical bone fragments (CBF-MSC). In this study, we demonstrate that despite the cells sharing a common ancestor, the differences in the structural properties of the resident tissues affect cell behavior and prime them to react differently to stimuli. Similarly to the bone marrow, the cortical portion of the bone contains a unique subset of cells that stains positively for the common MSC-associated markers. These cells display different multipotent differentiation capability, clonogenic expansion, and immunosuppressive potential. In particular, when compared with BM-MSC, CBF-MSC are bigger in size, show a lower proliferation rate at early passages, have a greater commitment toward the osteogenic lineage, constitutively produce nitric oxide as a mediator for bone remodeling, and more readily respond to proinflammatory cytokines. Our data suggest that the effect of the tissue's microenvironment makes the CBF-MSC a superior candidate in the development of new strategies for bone repair.


Basketball injuries in children.
Basketball is a popular, worldwide sport played outdoors and indoors year-round. Patterns of injury are related to abrupt changes in the athlete's direction, jumping, contact between athletes, the hard playing surface and paucity of protective equipment. Intensity of play and training in the quest of scholarships and professional careers is believed to contribute to an increasing occurrence of injury. Radiologists' appreciation of the breadth of injury and its relation to imaging and clinical findings should enhance the care of these children. Some of the patterns of injury are well known to radiologists but vary due to age- and size-related changes; the growing skeleton is affected by differing susceptibilities from biomechanical stresses at different sizes. Beyond screening radiographs, the accuracy of MRI and CT has improved diagnosis and treatment plans in this realm. Investigations to detect symptoms and signs in an attempt to prevent the tragedy of sudden cardiac death in basketball players may lead to MRI and CTA studies that compel radiologists to evaluate cardiac function along with myocardial and coronary artery anatomy. Worthy of mention also is the female athlete triad of disordered eating, amenorrhea, and osteoporosis that is observed in some young women participating in this and other sports.


Differentiating phosphate-dependent and phosphate-independent systemic phosphate-starvation response networks in Arabidopsis thaliana through the application of phosphite.
Phosphite is a less oxidized form of phosphorus than phosphate. Phosphite is considered to be taken up by the plant through phosphate transporters. It can mimic phosphate to some extent, but it is not metabolized into organophosphates. Phosphite could therefore interfere with phosphorus signalling networks. Typical physiological and transcriptional responses to low phosphate availability were investigated and the short-term kinetics of their reversion by phosphite, compared with phosphate, were determined in both roots and shoots of Arabidopsis thaliana. Phosphite treatment resulted in a strong growth arrest. It mimicked phosphate in causing a reduction in leaf anthocyanins and in the expression of a subset of the phosphate-starvation-responsive genes. However, the kinetics of the response were slower than for phosphate, which may be due to discrimination against phosphite by phosphate transporters PHT1;8 and PHT1;9 causing delayed shoot accumulation of phosphite. Transcripts encoding PHT1;7, lipid-remodelling enzymes such as SQD2, and phosphocholine-producing NMT3 were highly responsive to phosphite, suggesting their regulation by a direct phosphate-sensing network. Genes encoding components associated with the 'PHO regulon' in plants, such as At4, IPS1, and PHO1;H1, generally responded more slowly to phosphite than to phosphate, except for SPX1 in roots and MIR399d in shoots. Two uncharacterized phosphate-responsive E3 ligase genes, PUB35 and C3HC4, were also highly phosphite responsive. These results show that phosphite is a valuable tool to identify network components directly responsive to phosphate.


Estimation of conventional C-Hπ (arene), unconventional C-Hπ (chelate) and C-Hπ (thiocyanate) interactions in hetero-nuclear nickel(ii)-cadmium(ii) complexes with a compartmental Schiff base.
Three new heteronuclear nickel(ii)/cadmium(ii) complexes, [(SCN)(Cl)Cd(L)Ni(DMF)2] (1), [(SCN)(CH3CO2)Cd(L)Ni(CH3OH)2] (2) and [(SCN)(Cl)Cd(L)Ni(NH2CH2CH2CH2NH2)]n (3) {where H2L = N,N'-bis(3-ethoxy-salicylidene)propane-1,3-diamine is a N2O4 compartmental Schiff base}, have been synthesized and characterized. The structures of the complexes have been confirmed by single crystal X-ray diffraction studies. In each complex, nickel(ii) is placed in the inner N2O2 environment and cadmium(ii) is placed in the outer O4 compartment of the compartmental Schiff base. Furthermore, the importance of unconventional C-Hπ (chelate) interactions in the solid state of both complexes and C-Hπ (thiocyanate) interaction in complex 2 has been described by means of DFT and MEP calculations and characterized using NCI plots. All complexes show photoluminescence at room temperature upon irradiation by ultraviolet light. The lifetimes of excited states are in the range of 2-6 ns.


Hexacyanometallates for sodium-ion batteries: insights into higher redox potentials using d electronic spin configurations.
A fundamental understanding of anomalous redox mechanisms in hexacyanometallate compounds, compared with conventional NaMO2 systems (M: transition metals), is presented based on first-principles calculations and experimental validations. From theoretical calculations, we identified low-spin and high-spin states of Fe ions coordinated by the cyanide group (-CN) with the same oxidation state (Fe2+) in Na2Fe2(CN)6. Considering the site dependency of d electronic spin configurations based on the crystal field theory (CFT) of transition metals (TMs), we calculated the thermodynamic mixing energy using Na2Fe2(CN)6 and Na2Mn2(CN)6 for obtaining a thermodynamically stable phase of Na2FeMn(CN)6. The phase stabilities of Na2Fe2-xMnx(CN)6 among many atomic configurations and lattice parameters originating from octahedral structures (i.e., Fe(CN)6 and Mn(NC)6) are highly dependent on the electronic structures of TMs with spin states. From partial density of states (PDOS) and spatial electron distributions, it was observed that Fe2+ in the low-spin state (t) and Mn2+ in the high-spin states (t and e) in the stable phase lead to higher redox potentials (∼3.55 V vs. Na/Na+) with the removal of Na+ as compared to that of Na2Fe2(CN)6. In addition, lattice parameters from x = 0 to x = 1 in Na2Fe2-xMnx(CN)6 are increased due to the larger ionic radius of Mn2+ in the high-spin states. On the other hand, Fe2+ in the high-spin states (t and e) and Mn2+ in the low-spin state (t) in the most unstable phase of Na2FeMn(CN)6 would have lower redox potentials. Based on the fundamental correlation between redox potentials and CFT with spin configurations of TMs, we suggest a material design concept for intercalation compounds with higher energy densities for rechargeable battery systems.


Relatedness of Streptococcus suis isolates of various serotypes and clinical backgrounds as evaluated by macrorestriction analysis and expression of potential virulence traits.
We evaluated the genetic diversity of Streptococcus suis isolates of different serotypes by macrorestriction analysis and elucidated possible relationships between the genetic background, expression of potential virulence traits, and source of isolation. Virulence traits included expression of serotype-specific polysaccharides, muramidase-released protein (MRP), extracellular protein factor (EF), hemolysin activity, and adherence to epithelial cells. Macrorestriction analysis of streptococcal DNA digested with restriction enzymes SmaI and ApaI allowed differentiation of single isolates that could be assigned to four major clusters, named A1, A2, B1, and B2. Comparison of the genotypic and phenotypic features of the isolates with their source of isolation showed that (i) the S. suis population examined, which originated mainly from German pigs, exhibited a genetic diversity and phenotypic patterns comparable to those found for isolates from other European countries; (ii) certain phenotypic features, such as the presence of capsular antigens of serotypes 2, 1, and 9, expression of MRP and EF, and hemolysin activity (and in particular, combinations of these features), were strongly associated with the clinical background of meningitis and septicemia; and (iii) isolates from pigs with meningitis and septicemia showed a significantly higher degree of genetic homogeneity compared to that for isolates from pigs with pneumonia and healthy pigs. Since the former isolates are considered highly virulent, this supports the theory of a clonal relationship among highly virulent strains.


Thrombospondin stimulates motility of human neutrophils.
Polymorphonuclear leukocytes (PMNs) migrate to sites of inflammation or injury in response to chemoattractants released at those sites. The presence of extracellular matrix (ECM) proteins at these sites may influence PMN accumulation at blood vessel walls and enhance their ability to move through tissue. Thrombospondin (TSP), a 450-kD ECM protein whose major proteolytic fragments are a COOH-terminal 140-kD fragment and an NH2-terminal heparin-binding domain (HBD), is secreted by platelets, endothelial cells, and smooth muscle cells. TSP binds specifically to PMN surface receptors and has been shown, in other cell types, to promote directed movement. TSP in solution at low concentrations (30-50 nM) "primed" PMNs for f-Met-Leu-Phe (fMLP)-mediated chemotaxis, increasing the response two- to fourfold. A monoclonal antibody against the HBD of TSP totally abolished this priming effect suggesting that the priming activity resides in the HBD of TSP. Purified HBD retains the priming activity of TSP thereby corroborating the antibody data. TSP alone, in solution at high concentrations (0.5-3.0 microM), stimulated chemotaxis of PMNs and required both the HBD and the 140-kD fragment of TSP. In contrast to TSP in solution, TSP bound to nitrocellulose filters in the range of 20-70 pmol stimulated random locomotion of PMNs. The number of PMNs migrating in response to bound TSP was approximately two orders of magnitude greater than the number of cells that exhibited chemotaxis in response to soluble TSP or fMLP. Monoclonal antibody C6.7, which recognizes an epitope near the carboxyl terminus of TSP, blocked migration stimulated by bound TSP, suggesting that the activity resides in this domain. Using proteolytic fragments, we demonstrated that bound 140-kD fragment, but not HBD, promoted migration of PMNs. Therefore, TSP released at injury sites, alone or in synergy with chemotactic peptides like fMLP, could play a role in directing PMN movement.


Expression of the pupal determinant broad during metamorphic and neotenic development of the strepsipteran Xenos vesparum Rossi.
Derived members of the endoparasitic order Strepsiptera have acquired an extreme form of sexual dimorphism whereby males undergo metamorphosis and exist as free-living adults while females remain larviform, reaching sexual maturity within their hosts. Expression of the transcription factor, broad (br) has been shown to be required for pupal development in insects in which both sexes progress through metamorphosis. A surge of br expression appears in the last larval instar, as the epidermis begins pupal development. Here we ask if br is also up-regulated in the last larval instar of male Xenos vesparum Rossi (Stylopidae), and whether such expression is lost in neotenic larviform females. We clone three isoforms of br from X. vesparum (Xv'br), and show that they share greatest similarity to the Z1, Z3 and Z4 isoforms of other insect species. By monitoring Xv'br expression throughout development, we detect elevated levels of total br expression and the Xv'Z1, Xv'Z3, and Xv'Z4 isoforms in the last larval instar of males, but not females. By focusing on Xv'br expression in individual samples, we show that the levels of Xv'BTB and Xv'Z3 in the last larval instar of males are bimodal, with some males expressing 3X greater levels of Xv'br than fourth instar femlaes. Taken together, these data suggest that neoteny (and endoparasitism) in females of Strepsiptera Stylopidia could be linked to the suppression of pupal determination. Our work identifies a difference in metamorphic gene expression that is associated with neoteny, and thus provides insights into the relationship between metamorphic and neotenic development.


The consequences of introducing stochasticity in nutrient utilisation models: the case of phosphorus utilisation by pigs.
Simulation models of nutrient utilisation ignore that variation in pig system components can influence the predicted mean and variance of the performance of a group of pigs. The objective of this study was to develop a methodology to investigate how variation in feed composition would (a) affect the outputs of a nutrient utilisation model and (b) interact with variation that arises from the traits of individual pigs. We used a P intake and utilisation model to address these characteristics. Introduction of stochasticity gave rise to a number of methodological challenges--for example, how to generate variation in both feed composition and pigs and account for correlations between ingredients when modelling variation associated with feed mixing efficiency. Introducing variation in feed composition and pig phenotype resulted in moderate decreases in mean digested, retained and excreted P predicted for a population of pigs and an increase in their associated CV. A lower percentage of pigs in the population were predicted to meet their requirements during the feeding period considered, by comparison with the no-variation scenario. Variation in feed ingredient composition contributed more to performance variation than variation due to mixing efficiency. When variations in both feed composition and pig traits were considered, it was the former rather than the latter that had the dominant influence on variability in pig performance. The developed framework emphasises the consequences of random variability on the predictions of nutrient utilisation models. Such consequences will have a significant impact on decisions about management strategies such as feeding that are subject to variation.


Unitary Subharmonic Response and Floquet Majorana Modes.
Detection and manipulation of excitations with non-Abelian statistics, such as Majorana fermions, are essential for creating topological quantum computers. To this end, we show the connection between the existence of such localized particles and the phenomenon of unitary subharmonic response (SR) in periodically driven systems. In particular, starting from highly nonequilibrium initial states, the unpaired Majorana modes exhibit spin oscillations with twice the driving period, are localized, and can have exponentially long lifetimes in clean systems. While the lifetime of SR is limited in translationally invariant systems, we show that disorder can be engineered to stabilize the subharmonic response of Majorana modes. A viable observation of this phenomenon can be achieved using modern multiqubit hardware, such as superconducting circuits and cold atomic systems.


Simple model for image-plane polychromatic speckle contrast.
A simple geometrical model was developed for calculation of the contrast of a polychromatic image-plane speckle pattern from a source of light with high spatial coherence. It is based on counting the number of independent speckle patterns that contribute to a given point in the image plane. This results in a simple equation for the contrast as a function of imaging geometry; relative orientation of the projection direction, observation direction, and specimen normal; bandwidth of the light source; and surface roughness. Its validity was established by comparison with an exact solution: rms errors in the calculated contrast were only 0.033 over a wide range of parameter values likely to be encountered in practice.


The Limitations of Being a Copycat: Learning Golf Putting Through Auditory and Visual Guidance.
The goal of this study was to investigate whether sensory cues carrying the kinematic template of expert performance (produced by mapping movement to a sound or visual cue) displayed prior to and during movement execution can enhance motor learning of a new skill (golf putting) in a group of novices. We conducted a motor learning study on a sample of 30 participants who were divided into three groups: a control, an auditory guide and visual guide group. The learning phase comprised of two sessions per week over a period of 4 weeks, giving rise to eight sessions. In each session participants made 20 shots to three different putting distances. All participants had their measurements taken at separate sessions without any guidance: baseline, transfer (different distances) and retention 2 weeks later. Results revealed a subtle improvement in goal attainment and a decrease in kinematic variability in the sensory groups (auditory and visual) compared to the control group. The comparable changes in performance between the visual and auditory guide groups, particularly during training, supports the idea that temporal patterns relevant to motor control can be perceived similarly through either visual or auditory modalities. This opens up the use of auditory displays to inform motor learning in tasks or situations where visual attention is otherwise constrained or unsuitable. Further research into the most useful template actions to display to learners may thus still support effective auditory guidance in motor learning.


Physiological concentrations of insulin induce cellular desensitization to the mitogenic effects of insulin-like growth factor I.
Insulin and insulin-like growth factor I (IGF-I) are structurally related peptides capable of stimulating a variety of metabolic and mitogenic processes. In this study, we investigated the interaction between these peptides and their receptor-mediated pathways in an untransformed cell line. Cultured bovine fibroblasts specifically bound IGF-I and insulin, and each peptide could stimulate DNA synthesis and cell replication through its own receptor. Preincubation of bovine fibroblasts with concentrations of insulin that did not bind to the IGF-I receptor resulted in complete but reversible cellular desensitization to IGF-I-stimulated mitogenesis. Preincubation with as little as 0.1 nM insulin was sufficient to inhibit subsequent IGF-I action. Various insulin analogs produced desensitization in direct relation to the affinity of the insulin for the insulin receptor. Desensitization required > 4 h of cell exposure to insulin and was blocked in the presence of cycloheximide. Neither serum-stimulated mitogenesis nor IGF-I-stimulated glucose uptake were affected by insulin pretreatment. 125I-labeled IGF-I affinity cross-linking experiments indicated that preincubation with insulin did not affect labeling of the 130,000-M(r) alpha-subunit of the IGF-I receptor, but was associated with the loss of IGF-I- and insulin-inhibitive bands at M(r) = 100,000, 85,000, 58,000, and 34,000. These studies suggest that insulin, via interaction with insulin receptors on bovine fibroblasts, regulates IGF-I action at a step distal to IGF-I receptor binding and are consistent with desensitization occurring at an intracellular step in the mitogenic pathway shared by insulin and IGF-I.


Speckle noise reduction in optical coherence tomography of paint layers.
We present and characterize a sequential angular compounding method for reducing speckle contrast in optical coherence tomography images of paint layers. The results are compared with postprocessing methods, and we show that the compounding technique can improve the speckle contrast ratio in B-scans by better than a factor of 2 in exchange for a negligible loss of resolution. As a result, image aesthetics are improved, thin layers become more distinct, and edge-detection algorithms work more efficiently. The effect of varying the angular scan size and number of averages is investigated, and it is found that a degree of statistical correlation between speckle patterns exists, even for relatively large changes in angle of incidence. Angular compounding is also performed on three-dimensional data sets and compared with a method whereby en face slices are averaged over depth.


A survey of neurointerventionalists on thrombectomy practices for emergent large vessel occlusions.
The effect of the five positive randomized controlled trials on thrombectomy practices and procedural volume has yet to be defined. Further, few studies have attempted to define modern thrombectomy practices in terms of selection criteria and devices used. A 21 question survey of Society of Neurointerventional Surgery (SNIS) physicians was administered using the SurveyMonkey website, addressing current practices as well as changes from before January 1, 2015 to the months after this date. A total of 78 responses were obtained (approximately 10% of SNIS membership). Prior to January 2015, two-thirds of respondents reported performing 1-5 thrombectomies per month (67%), with 31% performing more than 5 per month. Following January 2015, 62% of respondents reported performing more than 5 thrombectomies per month; 45% of respondents reported a higher number of thrombectomies after trial publication. 73% and 80% of respondents indicated that inpatient consultations and hospital to hospital transfers for thrombectomy have increased, respectively. A plurality of respondents reported using A Direct Aspiration First Pass Technique (40%) as the first strategy for revascularization. Most commonly, neurointerventionalists reported using conscious sedation (56%) for anesthesia. 74% of respondents indicated being successful with their primary technique in at least 70% of cases. This survey of predominantly academic SNIS physicians indicates that inpatient consultations, hospital to hospital transfers, and thrombectomy procedural volumes have increased modestly since the publication of the five major stroke trials this year. In addition, many respondents indicated an increase in aggressiveness in pursuing thrombectomy based on selection criteria.


Immunogenicity and effect of a virosomal influenza vaccine on viral replication and T-cell activation in HIV-infected children receiving highly active antiretroviral therapy.
In order to evaluate the immunogenicity and the effect of a virosomal influenza vaccine on viral replication and T-cell activation in HIV-infected children receiving highly active antiretroviral therapy (HAART), 29 children infected with HIV-1 vertically (19 primed with a previous influenza vaccination and 10 who were not been immunized against influenza) were immunized with an intramuscular virosome-adjuvanted influenza vaccine. According to the European Agency for Evaluation of Medical Products (EMEA) criteria, the immunogenicity of the vaccine was adequate against all three influenza strains (A H1N1, A H3N2, and B) in the primed children, and against A H1N1 and A H3N2 in the unprimed children. After in vitro stimulation with vaccine antigens, the IFN-gamma levels in the peripheral blood mononuclear cells cultures increased significantly from a baseline level of 103.0 +/- 229.8 pg/ml to a 30-day level of 390.7 +/- 606.3 pg/ml (P < 0.05), with concentrations significantly higher (P < 0.05) in the primed children than in the unprimed children. No increase in plasma HIV-1 RNA or HIV-1 proviral DNA was observed in either subgroup, and the immunophenotype analyses demonstrated that the CD4+ cell counts and percentages, the CD4/CD8 ratio and activated lymphocytes remained stable in either group from baseline to 1 month after each vaccine dose. This study showed that the virosomal influenza vaccine does seem to be immunogenic in the majority of HIV-infected children receiving HAART and does not induce viral replication or T-cell activation. Given the possible influenza-related complications in children infected with HIV, these results support the use of this influenza vaccine in such patients.


Biological effects of the olive polyphenol, hydroxytyrosol: An extra view from genome-wide transcriptome analysis.
Epidemiological and clinical studies have established the health benefits of the Mediterranean diet, an important component of which are olives and olive oil derived from the olive tree (Olea Europea). It is now well-established that not only the major fatty acid constituents, but also the minor phenolic components, in olives and olive oil have important health benefits. Emerging research over the past decade has highlighted the beneficial effects of a range of phenolic compounds from olives and olive oil, particularly for cardiovascular diseases, metabolic syndrome and inflammatory conditions. Mechanisms of action include potent antioxidant and anti-inflammatory effects. Further, accumulating evidence indicates the potential of the polyphenols and potent antioxidants, hydroxytyrosol and oleuropein in oncology. Numerous studies, both in vitro and in vivo, have demonstrated the anticancer effects of hydroxytyrosol which include chemopreventive and cell-specific cytotoxic and apoptotic effects. Indeed, the precise molecular mechanisms accounting for the antioxidant, anti-inflammatory and anticancer properties are now becoming clear and this is, at least in part, due to high through-put gene transcription profiling. Initially, we constructed phylogenetic trees to visualize the evolutionary relationship of members of the Oleaceae family and secondly, between plants producing hydroxytyrosol to make inferences of potential similarities or differences in their medicinal properties and to identify novel plant candidates for the treatment and prevention of disease. Furthermore, given the recent interest in hydroxytyrosol as a potential anticancer agent and chemopreventative we utilized transcriptome analysis in the erythroleukemic cell line K562, to investigate the effects of hydroxytyrosol on three gene pathways: the complement system, The Warburg effect and chromatin remodeling to ascertain relevant gene candidates in the prevention of cancer.


Binocular rivalry: spreading dominance through complex images.
When different images are presented to the two eyes, each can intermittently disappear, leaving the other to dominate perception. This is called binocular rivalry. When using radial gratings, focal contrast increments can trigger a traveling wave of perceptual dominance change, originating at the locus of the contrast increment and circling the stimulus. This has been linked to a sweep of activity through V1 that can be traced via fMRI. The dominance of more complex images, like human faces, has been linked to higher level processing structures characterized by more holistic object centered properties. We therefore decided to assess how dominance would spread through more complex images. Using Kanisza squares and human faces we found that dominance tended to spread gradually away from the locus of the contrast increment, often along real or illusory contours. We also found that perceptual dominance was slow to spread between facial regions encoded by different monocular channels. These data are consistent with low-level monocular mechanisms, like those found in V1, playing a determinant role in the spread of perceptual dominance through complex images during binocular rivalry.


Analysis of the Genome and Mobilome of a Dissimilatory Arsenate Reducing Aeromonas sp. O23A Reveals Multiple Mechanisms for Heavy Metal Resistance and Metabolism.
Aeromonas spp. are among the most ubiquitous microorganisms, as they have been isolated from different environmental niches including waters, soil, as well as wounds and digestive tracts of poikilothermic animals and humans. Although much attention has been paid to the pathogenicity of Aeromonads, the role of these bacteria in environmentally important processes, such as transformation of heavy metals, remains to be discovered. Therefore, the aim of this study was a detailed genomic characterization of Aeromonas sp. O23A, the first representative of this genus capable of dissimilatory arsenate reduction. The strain was isolated from microbial mats from the Zloty Stok mine (SW Poland), an environment strongly contaminated with arsenic. Previous physiological studies indicated that O23A may be involved in both mobilization and immobilization of this metalloid in the environment. To discover the molecular basis of the mechanisms behind the observed abilities, the genome of O23A (∼5.0 Mbp) was sequenced and annotated, and genes for arsenic respiration, heavy metal resistance (hmr) and other phenotypic traits, including siderophore production, were identified. The functionality of the indicated gene modules was assessed in a series of minimal inhibitory concentration analyses for various metals and metalloids, as well as mineral dissolution experiments. Interestingly, comparative analyses revealed that O23A is related to a fish pathogen Aeromonas salmonicida subsp. salmonicida A449 which, however, does not carry genes for arsenic respiration. This indicates that the dissimilatory arsenate reduction ability may have been lost during genome reduction in pathogenic strains, or acquired through horizontal gene transfer. Therefore, particular emphasis was placed upon the mobilome of O23A, consisting of four plasmids, a phage, and numerous transposable elements, which may play a role in the dissemination of hmr and arsenic metabolism genes in the environment. The obtained results indicate that Aeromonas sp. O23A is well-adapted to the extreme environmental conditions occurring in the Zloty Stok mine. The analysis of genome encoded traits allowed for a better understanding of the mechanisms of adaptation of the strain, also with respect to its presumable role in colonization and remediation of arsenic-contaminated waters, which may never have been discovered based on physiological analyses alone.


Biovolatilisation: a poorly studied pathway of the arsenic biogeochemical cycle.
It has been known for over a hundred years that microorganisms can produce volatile arsenic (As) species, termed "arsines". However, this topic has received relatively little attention compared to As behaviour in soils and biotransformation through the trophic level in the marine and terrestrial environment. We believe this is due to long-standing misconceptions regarding volatile As stability and transport as well as an absence, until recently, of appropriate sampling methods. First and foremost, an attempt is made to unify arsines' designations, notations and formulas, taking into account all the different terms used in the literature. Then, the stability of As volatile species is discussed and new analytical developments are explored. Further, the special cases of diffuse low-level emissions (e.g. soil and sediment biovolatilisation), and point sources with high-level emissions (geothermal environments, landfills, and natural gas) are comprehensively reviewed. In each case, future possible areas of research and unknown mechanisms are identified and their importance towards the global As biogeochemical cycle is explored. This review gathers new information regarding mechanisms, stability, transport and sampling of the very elusive arsines and shows that more research should be conducted on this important process.


Activity of medial mesopontine units during cataplexy and sleep-waking states in the narcoleptic dog.
Narcolepsy has been hypothesized to be a disease of rapid eye movement (REM) sleep. According to this hypothesis, cataplexy is a result of the triggering during waking of the mechanism that normally serves to suppress muscle tone in REM sleep. REM sleep control mechanisms have been localized to the pons. Narcoleptic dogs have increased numbers of cholinergic receptors in the medial pons. These findings suggest that neurons mediating the triggering of cataplexy might be located in medial pontine regions. In the present study, this hypothesis has been investigated by recording the discharge of units in the medial mesopontine region of the narcoleptic dog. Unit activity was examined in the nucleus reticularis pontis oralis, caudalis, and central gray, with each cell being recorded during both cataplexy and sleep states. Maximal discharge rates were observed, in all of these regions, during active waking states (mean rate, 45.3/sec) and REM sleep (16.0/sec), with minimal discharge rates in non-REM sleep (8.3/sec). Unit discharge was reduced in cataplexy relative to precataplexy periods. Cataplexy discharge rates were 8.3/sec, 52% of the mean REM sleep rate. Cataplexy discharge rates were also significantly lower than those at REM sleep onset. Cataplexy discharge rates were comparable to rates in quiet waking and non-REM sleep. While medial mesopontine neurons discharge at high rates in REM sleep, they have little or no activity in cataplexy. We interpret the lack of activation of medial mesopontine units in cataplexy as indicating that the characteristic phasic motor activation of REM sleep does not occur in this state.(ABSTRACT TRUNCATED AT 250 WORDS)


Leucine-Rich α-2-Glycoprotein-1 (LRG-1) Expression in Retinoblastoma.
Retinoblastomas' growth rate is dependent on their ability to induce neovascularization. Leucine-rich α-2-glycoprotein-1 (LRG-1) was recently reported to be upregulated in human retinal disease with neovascular pathology. The purpose of the study was to determine LRG-1 expression in human retinoblastoma and to correlate it with clinical and histopathologic parameters and to assess how its expression correlates with vascular endothelial growth factor (VEGF) expression. LRG-1 expression was immunohistochemically evaluated in 34 retinoblastoma sections. Immunofluorescence for LRG-1/VEGF-A, LRG-1/TGF-β1/CD31, and LRG-1/Ki67 was performed. Quantitative RT-PCR analysis for the expression of LRG-1 was also done. LRG-1 was found to be extensively and robustly expressed in retinoblastoma tumors (88%) irrespective of the degree of invasiveness, differentiation, iris neovascularization, and anterior segment involvement. LRG-1 immunoreactivity was predominantly observed in the central tumor vasculature and in the surrounding rim of ischemia. The higher frequency of LRG-1 expression in the presence of optic nerve infiltration, vitreous seeding, and necrosis was not statistically significant. Colocalization was observed between LRG-1 and VEGF-A staining, and no difference in their counts was detected. Quantitative RT-PCR analysis showed that LRG-1 gene expression was significantly upregulated (4.8-fold increase, P = 0.01). LRG-1 was highly expressed in human retinoblastoma sections, thus providing new insights into the molecular mechanism of retinoblastoma pathogenesis, and suggests a possible new therapeutic target. LRG-1 is a novel oncogene-associated protein shown to be vital to the progression of human cancers. Inhibiting tumor vasculature is progressively evolving as a target in anticancer therapy.


Coping with the economic consequences of ill health in Indonesia.
We assess the economic risk of ill health for households in Indonesia and the role of informal coping strategies. Using household panel data from the Indonesian socio-economic household survey (Susenas) for 2003 and 2004, and applying fixed effects Poisson models, we find evidence of economic risk from illness through medical expenses. For the poor and the informal sector, ill health events impact negatively on income from wage labour, whereas for the non-poor and formal sector, it is income from self-employed business activities which is negatively affected. However, only for the rural population and the poor does this lead to a decrease in consumption, whereas the non-poor seem to be able to protect current household spending. Borrowing and drawing on family network and buffers, such as savings and assets, seem to be key informal coping strategies for the poor, which may have negative long-term effects. While these results suggest scope for public intervention, the economic risk from income loss for the rural poor is beyond public health care financing reforms. Rather, formal sector employment seems to be a key instrument for financial protection from illness, by also reducing income risk.


Transcutaneous oxygen tension during exercise in patients with claudication.
Transcutaneous oxygen tension (TcPO2) was monitored during maximal exercise in 10 patients with stable moderate to severe claudication. The TcPO2 fell by 16% at the onset of claudication and 32% at the maximum walking distance. On resting this decrease reached a maximum of 66% roughly four minutes after exercise. This was followed by a steady recovery. The percentage changes were reproducible in each patient and were appreciably different from the TcPO2 exercise profiles of normal healthy volunteers. TcPO2 monitoring during exercise is a simple, reproducible, cheap, and useful technique for assessing claudication and compares favourably with other techniques used to quantify this condition.


Pilot clinical study of Adacolumn cytapheresis in patients with systemic lupus erythematosus.
The aim of this study is to investigate the clinical effects of cytapheresis using the Adacolumn system (selective removal of circulating monocytes and granulocytes by means of an extracorporeal type column) in patients with active systemic lupus erythematosus (SLE). An open uncontrolled multicenter pilot study was conducted in 18 SLE patients who were showing a SLEDAI score of 8 or more under conventional medication. Patients with lupus nephritis (>class 1, WHO classification) were excluded. Extracorporeal cytapheresis with the Adacolumn system was administered once a week for five consecutive weeks. The efficacy of the treatment was evaluated using the SLEDAI for 10 weeks after the first cytapheresis session. The median SLEDAI decreased from 16 at baseline to six at week 11 (10 weeks after the first apheresis) (p<0.001). Significant improvements in musculoskeletal and dermal systems were observed. Arthritis and alopecia were present in 14 and nine patients at baseline and this number decreased to five and one patients, respectively by week 11. Three mild and one moderate adverse events out of the 42 reported events were judged 'probably related' to the treatment; no serious adverse events were reported. Selective removal of monocytes and granulocytes from the blood in an extracorporeal circulation system was associated with clinical improvement in this small series of patients with SLE. Since this approach seems not to have the disadvantages of pharmacological immunosuppression, further controlled studies of Adacolumn cytapheresis are warranted in SLE.


Online handwritten shape recognition using segmental hidden Markov models.
We investigate a new approach for online handwritten shape recognition. Interesting features of this approach include learning without manual tuning, learning from very few training samples, incremental learning of characters, and adaptation to the user-specific needs. The proposed system can deal with two-dimensional graphical shapes such as Latin and Asian characters, command gestures, symbols, small drawings, and geometric shapes. It can be used as a building block for a series of recognition tasks with many applications.


Tomato fruit carotenoid biosynthesis is adjusted to actual ripening progression by a light-dependent mechanism.
Carotenoids are isoprenoid compounds that are essential for plants to protect the photosynthetic apparatus against excess light. They also function as health-promoting natural pigments that provide colors to ripe fruit, promoting seed dispersal by animals. Work in Arabidopsis thaliana unveiled that transcription factors of the phytochrome-interacting factor (PIF) family regulate carotenoid gene expression in response to environmental signals (i.e. light and temperature), including those created when sunlight reflects from or passes though nearby vegetation or canopy (referred to as shade). Here we show that PIFs use a virtually identical mechanism to modulate carotenoid biosynthesis during fruit ripening in tomato (Solanum lycopersicum). However, instead of integrating environmental information, PIF-mediated signaling pathways appear to fulfill a completely new function in the fruit. As tomatoes ripen, they turn from green to red due to chlorophyll breakdown and carotenoid accumulation. When sunlight passes through the flesh of green fruit, a self-shading effect within the tissue maintains high levels of PIFs that directly repress the master gene of the fruit carotenoid pathway, preventing undue production of carotenoids. This effect is attenuated as chlorophyll degrades, causing degradation of PIF proteins and boosting carotenoid biosynthesis as ripening progresses. Thus, shade signaling components may have been co-opted in tomato fruit to provide information on the actual stage of ripening (based on the pigment profile of the fruit at each moment) and thus finely coordinate fruit color change. We show how this mechanism may be manipulated to obtain carotenoid-enriched fruits.


Number of antenatal visits and women's opinion.
The national recommendation in Sweden regarding number of antenatal care visits was reduced in 1996. The aim of this study was to explore the factors associated with number of visits made and with women's own opinions about these visits. Another aim was to study associations between the number of visits and satisfaction with antenatal care overall. All Swedish-speaking women who came for their first visit to the midwife in 593 participating clinics during 3 weeks evenly spread over 1 year in 1999-2000 were invited to participate in the study. Information was collected by postal questionnaires after the booking visit and 2 months after childbirth. Cases of preterm delivery and intrauterine death were excluded. After excluding miscarriages, non-Swedish-speaking women, and women booked at non-participating clinics, about 69% of all women booked in antenatal care were recruited. Of these, 2421 (83%) completed the two questionnaires. About 25% followed the standard visiting schedule for a normal pregnancy, 57% made more visits, and 17% fewer visits. The number of visits made was associated with parity, medical diagnosis, depressive symptoms, level of education, and women's preferences in early pregnancy. Women's own opinion that they made too few visits was associated with a preference for more visits in early pregnancy and actually receiving fewer visits than the standard schedule. The view that they made too many visits was associated with a previous negative birth experience, a wish for fewer visits, having a medical diagnosis, many children, and major worries. The vast majority of women (87.6%) were satisfied with antenatal care overall but less with emotional (76.9%) than with medical (82.3%) aspects. No association was found between number of visits made and satisfaction, but women's own opinion that they had too few visits was associated with dissatisfaction with medical as well as emotional aspects of care and the opinion that they made too many visits with the emotional aspects of care. Two-thirds of the women did not follow the standard visiting schedule, the majority of women made more visits. The number of antenatal visits seemed to be fairly well adapted to women's individual needs and, to some extent, to their own wishes. Very few women were dissatisfied with the number of visits made as well as the antenatal care overall.


Care-giving as a Canadian-Vietnamese tradition: 'it's like eating, you just do it'.
The objective of this study was to examine how Vietnamese family caregivers (FCGs) perceive, manage and experience end-of-life care-giving for seriously ill family members. Using an instrumental case study design, this longitudinal qualitative research employed the use of cultural brokers/language interpreters to help ensure that the research was conducted in a culturally-appropriate manner. Participants (n = 18) discussed their experiences of care-giving within the context of a traditional cultural framework, which was found to influence their motivations and approaches to care-giving, as well as their propensities towards the use of various supports and services. The study was carried out in southern Ontario, Canada, and participants were providing home-based care-giving in the community. Data were collected throughout 2010 and 2011. The ways in which care-giving was perceived and expressed are reflected in three themes: (i) Natural: identity and care work; (ii) Intentional: whole-person care; and (iii) Intensive: standards, struggle and the context of care. This research confirms the need for culturally-appropriate services and supports while illustrating that Vietnamese FCGs not only value, but are also likely to use healthcare and social services if they are language-accessible, built on trust and demonstrate respect for their values as individuals, regardless of culture.


Action of food preservatives on 14-days dental biofilm formation, biofilm vitality and biofilm-derived enamel demineralisation in situ.
The aims of this double-blind, controlled, crossover study were to assess the influence of food preservatives on in situ dental biofilm growth and vitality, and to evaluate their influence on the ability of dental biofilm to demineralize underlying enamel over a period of 14 days. Twenty volunteers wore appliances with six specimens each of bovine enamel to build up intra-oral biofilms. During four test cycles of 14 days, the subjects had to place the appliance in one of the assigned controls or active solutions twice a day for a minute: negative control 0.9 % saline, 0.1 % benzoate (BA), 0.1 % sorbate (SA) and 0.2 % chlorhexidine (CHX positive control). After 14 days, the biofilms on two of the slabs were stained to visualize vital and dead bacteria to assess biofilm thickness (BT) and bacterial vitality (BV). Further, slabs were taken to determine mineral loss (ML), by quantitative light-induced laser fluorescence (QLF) and transversal microradiography (TMR), moreover the lesion depths (LD). Nineteen subjects completed all test cycles. Use of SA, BA and CHX resulted in a significantly reduced BV compared to NaCl (p < 0.001). Only CHX exerted a statistically significant retardation in BT as compared to saline. Differences between SA and BA were not significant (p > 0.05) for both parameters. TMR analysis revealed the highest LD values in the NaCl group (43.6 ± 44.2 μm) and the lowest with CHX (11.7 ± 39.4 μm), while SA (22.9 ± 45.2 μm) and BA (21.4 ± 38.5 μm) lay in between. Similarly for ML, the highest mean values of 128.1 ± 207.3 vol% μm were assessed for NaCl, the lowest for CHX (-16.8 ± 284.2 vol% μm), while SA and BA led to values of 83.2 ± 150.9 and 98.4 ± 191.2 vol% μm, respectively. With QLF for both controls, NaCl (-33.8 ± 101.3 mm(2) %) and CHX (-16.9 ± 69.9 mm(2) %), negative values were recorded reflecting a diminution of fluorescence, while positive values were found with SA (33.9 ± 158.2 mm(2) %) and BA (24.8 ± 118.0 mm(2) %) depicting a fluorescence gain. These differences were non-significant (p > 0.05). The biofilm model permited the assessment of undisturbed oral biofilm formation influenced by antibacterial components under clinical conditions for a period of 14 days. An effect of BA and SA on the demineralization of enamel could be demonstrated by TMR and QLF, but these new findings have to be seen as a trend. As part of our daily diet, these preservatives exert an impact on the metabolism of the dental biofilm, and therefore may even influence demineralization processes of the underlying dental enamel in situ.


Physical activity, sedentary time, and risk of colorectal cancer: the Singapore Chinese Health Study.
Singapore has experienced a marked increase in colorectal cancer incidence over the past 40 years. Evidence from prospective studies in Western Europe and the USA suggests that low physical activity and high amounts of sedentary time are associated with increased colorectal cancer risk. The aim of this study is to evaluate these relationships in an Asian population. The Singapore Chinese Health Study enrolled 63 257 adults between 1993 and 1998. At enrollment, participants reported past year physical activity and time spent sitting. Incident colorectal cancers (n=1994) were identified through 31 December 2014. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for potential confounders. Any strenuous-vigorous or moderate physical activity was reported by 13.7 and 22.1% of the cohort, respectively. Strenuous-vigorous physical activity was associated with statistically significant reduced colorectal cancer risk (HR=0.85; 95% CI: 0.74-0.99 for ≥0.5 h/week vs. none), but moderate was not. In analysis stratified by time spent watching television, an inverse relationship between moderate physical activity and colorectal cancer risk (HR=0.86; 95% CI: 0.72-1.01 for ≥0.5 h/week vs. none) was observed for those who reported at least 3 h/day sitting watching television (Pinteraction=0.042). Participation in strenuous-vigorous physical activity, such as jogging, swimming, or heavy manual labor, was associated with reduced colorectal cancer risk among Singapore Chinese. Further research on physical activity and sedentary behaviors, independently and in combination, and colorectal cancer risk in Asian populations is needed.


Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial.
Benzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups. In this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (<18 years, 18-65 years, and >65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075. Between Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged <18 years), 186 adults (18-65 years), and 51 older adults (>65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group. Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus. National Institute of Neurological Disorders and Stroke, National Institutes of Health.