Radionuclide imaging of bone marrow metastases with a Tc-99m labeled monoclonal antibody to small cell lung carcinoma.
The detection of metastatic disease confined to the bone marrow compartment has in the past been technically limited. We have identified excellent imaging of bone marrow metastases during the evaluation of a Tc-99m labeled monoclonal antibody (NR-LU-10 Fab) (NeoRx Corp., Seattle, WA). This occurred during a study to assess the monoclonal antibody's ability to detect sites of small cell cancer (primary and metastatic). The study by design compares areas seen by the monoclonal antibody scan with those found by standard staging methods in patients with small cell lung cancer. Standard staging included chest x-rays, bone scans, CT studies of the abdomen, and histologic examination of the bone marrow. Fifteen patients have been evaluated, four on two occasions, for a total of 19 monoclonal imaging studies. Metastasis to the marrow compartment was identified by the monoclonal imaging in all patients whose bone marrow biopsies were positive for small cell carcinoma, and it was primarily responsible for the eventual detection of extensive disease (marrow involvement) in one patient. Thus it appears that compartmental bone marrow imaging for metastatic disease is possible with immunoscintigraphy.


Mapping (15)O production rate for proton therapy verification.
This work was a proof-of-principle study for the evaluation of oxygen-15 ((15)O) production as an imaging target through the use of positron emission tomography (PET), to improve verification of proton treatment plans and to study the effects of perfusion. Dynamic PET measurements of irradiation-produced isotopes were made for a phantom and rabbit thigh muscles. The rabbit muscle was irradiated and imaged under both live and dead conditions. A differential equation was fitted to phantom and in vivo data, yielding estimates of (15)O production and clearance rates, which were compared to live versus dead rates for the rabbit and to Monte Carlo predictions. PET clearance rates agreed with decay constants of the dominant radionuclide species in 3 different phantom materials. In 2 oxygen-rich materials, the ratio of (15)O production rates agreed with the expected ratio. In the dead rabbit thighs, the dynamic PET concentration histories were accurately described using (15)O decay constant, whereas the live thigh activity decayed faster. Most importantly, the (15)O production rates agreed within 2% (P>.5) between conditions. We developed a new method for quantitative measurement of (15)O production and clearance rates in the period immediately following proton therapy. Measurements in the phantom and rabbits were well described in terms of (15)O production and clearance rates, plus a correction for other isotopes. These proof-of-principle results support the feasibility of detailed verification of proton therapy treatment delivery. In addition, (15)O clearance rates may be useful in monitoring permeability changes due to therapy.


Patient-reported adverse drug reactions and drug-drug interactions: a cross-sectional study on Malaysian HIV/AIDS patients.
This study aimed to explore the adverse drug reactions (ADRs) reported by patients and to identify drug-drug interactions (DDIs) among human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) patients. This cross-sectional study was conducted at the Medication Therapy Adherence Clinic, Hospital Sungai Buloh, an HIV/AIDS referral centre. The patients were randomly selected and were encouraged to describe ADRs caused specifically by any of the prescribed antiretroviral drugs (ARDs). Sociodemographic characteristics were recorded from the patients' medical records. In addition data on antiretroviral treatment (ART), DDIs and other conventional medication were also documented. A total of 325 randomly selected HIV/AIDS patients with a mean age of 22.94 years participated in the study. The most frequently prescribed ARDs were lamivudine (64.6%), zidovudine (40.6%) and efavirenz (42.5%). Commonly reported ADRs were fatigue (54.8%), allergic reactions (41.5%), weight loss (41.5%), dry mouth (35.1%) and memory loss (35.1%). Female (87.8%), non-complementary and alternative medicine (CAM) users (87.3%) and participants below 50 years old (81.1%) were identified as having a higher prevalence of ADRs compared to males (79.6%), CAM users (78.7%) and participants aged 50 years or more (77.5%). Patient age was found to be significantly associated (p = 0.048) with the ADRs. In addition, a total of 44 cases of DDIs belonging to category D were also found in this study. This study enabled us to identify the most common ADRs and DDIs associated with the use of ART. Safe and effective treatment depends on the healthcare providers' knowledge of the same.


Extrapulmonary sites of Pseudomonas aeruginosa in adults with cystic fibrosis.
Pseudomonas aeruginosa infection is seldom eradicated in patients with cystic fibrosis despite intensive antipseudomonal treatment. Upper airway sites of infection may contribute to perpetuation of lower airways infection. This study was designed to find out which extrapulmonary sites are infected and whether the strains at these sites are identical to those in the lungs. Sputum and upper airway samples from 42 patients were cultured for P aeruginosa and stool samples from 20 patients were also tested. Nineteen isolates from sputum and extrapulmonary sites from four patients were genotyped with the pCM tox probe. P aeruginosa was isolated from the sputum of 36 patients, 34 of whom had infection in the upper airways. Six of the 20 patients tested were positive for P aeruginosa in the stool. The nasopharynx was colonised in 30 patients, the oropharynx in 29, the middle meatus in 13, the external nares in six, and the inferior turbinate in four. Three of four patients tested had the same strain of P aeruginosa (a different one in each individual) in the sputum and the upper airways, and in two of the three the stool isolate was a different strain. Most adults with cystic fibrosis and P aeruginosa pulmonary infection have upper airway reservoirs of the organism and strains from these sites are identical to those in the lungs.


Magnetic resonance imaging as a prognostic disability marker in clinically isolated syndrome: A systematic review.
Magnetic resonance imaging (MRI) is the key prognostic tool in people with a clinically isolated syndrome (CIS). There is increasing interest in treating people following a CIS in the hope that conversion to multiple sclerosis (MS) will be prevented and future disability reduced. So far, the prognostic value of MRI for disability following a CIS has not been evaluated systematically. We systematically searched MEDLINE and EMBASE. Cohort studies were selected if they reported associations of MRI and disability following a CIS, included at least 50 people with a CIS at baseline, had at least 5 years of follow-up and obtained at least one structural MRI measurement (T1 lesions, T2 lesions, T1 contrast-enhancing lesions or brain atrophy). We assessed the studies for quality and rated the completeness of MRI reporting. In total, 13 studies were identified reporting on the following: T2 lesion number and volume, T2 infratentorial lesion number and volume, T1 contrast-enhancing lesions and grey matter fraction. T2 brain lesion number determined soon after the occurrence of a CIS was associated with disability progression after 5-7 years, with an increased risk when 10 or more lesions were present. Infratentorial lesions were also associated with a higher risk of subsequent disability. The number and distribution of MRI-visible lesions soon after a CIS are associated with disability later on, and may offer additional useful information when making treatment decisions in people with early MS. Further work is required to determine whether other measures have a higher predictive potential.


Proton Pump Inhibitor and Histamine-2 Receptor Antagonist Use and Iron Deficiency.
Proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) suppress gastric acid production, which can inhibit iron absorption. However, few data exist regarding whether these medications increase the risk of clinical iron deficiency. A community-based case-control study evaluated the association between acid-suppressing medication use and the subsequent risk of iron deficiency. It contrasted 77,046 patients with new iron deficiency diagnoses (January 1999-December 2013), with 389,314 controls. Medication exposures, outcomes, and potential confounders used electronic databases. We excluded patients with pre-existing risk factors for iron deficiency. Associations were estimated using conditional logistic regression. Among cases, 2343 (3.0%) received a prior ≥2-year supply of PPIs and 1063 (1.4%) received H2RAs (without PPI use). Among controls, 3354 (0.9%) received a prior ≥2-year supply of PPIs and 2247 (0.6%) H2RAs. Both ≥2 years of PPIs (adjusted odds ratio, 2.49; 95% confidence interval, 2.35-2.64) and ≥2 years of H2RAs (odds ratio, 1.58; 95% CI, 1.46-1.71) were associated with an increased subsequent risk for iron deficiency. Among PPI users, the associations were stronger for higher daily doses (>1.5 vs <0.75 PPI pills/d; P value interaction = .004) and decreased after medication discontinuation (P-trend < .001). Some of the strongest associations were among persons taking >1.5 pills per day for at least 10 years (odds ratio, 4.27; 95% CI, 2.53-7.21). No similar strong associations were found for other commonly used prescription medications. Among patients without known risk factors for iron deficiency, gastric acid inhibitor use for ≥2 years was associated with an increased subsequent risk of iron deficiency. The risk increased with increasing potency of acid inhibition and decreased after medication discontinuation.


Multiple solutions to inefficient lesion bypass by T7 DNA polymerase.
We hypothesize that enzymatic switching during translesion synthesis (TLS) to relieve stalled replication forks occurs during transitions from preferential to disfavored use of damaged primer-templates, and that the polymerase or 3'-exonuclease used for each successive nucleotide incorporated is the one whose properties result in the highest efficiency and the highest fidelity of bypass. Testing this hypothesis requires quantitative determination of the relative lesion bypass ability of both TLS polymerases and major replicative polymerases. As a model of the latter, here we measure the efficiency and fidelity of cis-syn TT dimer and abasic site bypass using the structurally well-characterized T7 DNA polymerase. No bypass of either lesion occurred during a single round of synthesis, and the exonuclease activity of wild-type T7 DNA polymerase was critical in preventing TLS. When repetitive cycling of the exonuclease-deficient enzyme was allowed, limited bypass did occur but hundreds to thousands of cycles were required to achieve even a single bypass event. Analysis of TLS fidelity indicated that these rare bypass events involved rearrangements of the template and primer strands, insertions opposite the lesion, and combinations of these events, with the choice among these strongly depending on the sequence context of the lesion. Moreover, the presence of a lesion affected the fidelity of copying adjacent undamaged template bases, even when lesion bypass itself was correct. The results also indicate that a TT dimer presents a different type of block to the polymerase than an abasic site, even though both lesions are extremely potent blocks to processive synthesis. The approaches used here to quantify the efficiency and fidelity of TLS can be applied to other polymerase-lesion combinations, to provide guidance as to which of many possible polymerases is most likely to bypass various lesions in biological contexts.


Cell culture isolation of piscine neuropathy nodavirus from juvenile sea bass, Dicentrarchus labrax.
A virus causing a vacuolating encephalopathy and retinopathy in juvenile sea bass, Dicentrarchus labrax, was isolated from brain tissue in a fish cell line (SSN-1) derived from striped snakehead, Channa striatus. The isometric, non-enveloped, 30 nm diameter virus particles were resistant to pH 2-9 and heating at 56 degrees C for 30 min. Infectious particles had a buoyant density of approximately 1.31 g/cm3 in CsCl. Two structural polypeptides of molecular mass 40 and 42 kDa were identified and the ssRNA consisted of two fragments of molecular mass 1.10 and 0.51 x 10(6) Da. From these characteristics the virus was identified as a nodavirus. Due to the broad range of susceptible fish hosts and the consistent neuropathology of the disease condition, the generic term piscine neuropathy nodavirus (PNN) is proposed for this infectious agent.


The P-glycoprotein multidrug transporter.
Pgp (P-glycoprotein) (ABCB1) is an ATP-powered efflux pump which can transport hundreds of structurally unrelated hydrophobic amphipathic compounds, including therapeutic drugs, peptides and lipid-like compounds. This 170 kDa polypeptide plays a crucial physiological role in protecting tissues from toxic xenobiotics and endogenous metabolites, and also affects the uptake and distribution of many clinically important drugs. It forms a major component of the blood-brain barrier and restricts the uptake of drugs from the intestine. The protein is also expressed in many human cancers, where it probably contributes to resistance to chemotherapy treatment. Many chemical modulators have been identified that block the action of Pgp, and may have clinical applications in improving drug delivery and treating cancer. Pgp substrates are generally lipid-soluble, and partition into the membrane before the transporter expels them into the aqueous phase, much like a 'hydrophobic vacuum cleaner'. The transporter may also act as a 'flippase', moving its substrates from the inner to the outer membrane leaflet. An X-ray crystal structure shows that drugs interact with Pgp within the transmembrane regions by fitting into a large flexible binding pocket, which can accommodate several substrate molecules simultaneously. The nucleotide-binding domains of Pgp appear to hydrolyse ATP in an alternating manner; however, it is still not clear whether transport is driven by ATP hydrolysis or ATP binding. Details of the steps involved in the drug-transport process, and how it is coupled to ATP hydrolysis, remain the object of intensive study.


Determination of minimum enzymatic decolorization time of reactive dye solution by spectroscopic & mathematical approach.
Synthetic dyes are very important for textile dyeing, paper printing, color photography and petroleum products. Traditional methods of dye removal include biodegradation, precipitation, adsorption, chemical degradation, photo degradation, and chemical coagulation. Dye decolorization with enzymatic reaction is an important issue for several research field (chemistry, environment) In this study, minimum decolorization time of Remazol Brilliant Blue R dye with Horseradish peroxidase enzyme was calculated using with mathematical equation depending on experimental data. Dye decolorization was determined by monitoring the absorbance decrease at the specific maximum wavelength for dye. All experiments were carried out with different initial dye concentrations of Remazol Brilliant Blue R at 25 degrees C constant temperature for 30 minutes. The development of the least squares estimators for a nonlinear model brings about complications not encountered in the case of the linear model. Decolorization times for completely removal of dye were calculated according to equation. It was shown that mathematical equation was conformed exponential curve for dye degradation.


NIKEI: a new inexpensive and non-invasive scoring system to exclude advanced fibrosis in patients with NAFLD.
To develop, validate and compare a non-invasive fibrosis scoring system for non-alcoholic fatty liver disease (NAFLD) derived from routinely obtained clinical and biochemical parameters. 267 consecutive patients with biopsy proven fatty liver or non-alcoholic steatohepatitis were randomly assigned to the estimation (2/3) or validation (1/3) group to develop a model for the prediction of advanced fibrosis. Univariate statistics were performed to compare patients with and without advanced fibrosis, and following a multivariate logistic regression analysis a new scoring system was constructed. This non-invasive Koeln-Essen-index (NIKEI) was validated and compared to the FIB-4 index by calculating the area under the receiver operating characteristic curve (AUC). We evaluated a stepwise combination of both scoring systems for the precise prediction of advanced fibrosis. To set in contrast, we additionally tested the diagnostic accuracy of the AST/ALT ratio, BARD score and the NAFLD fibrosis score in our cohort. Age, AST, AST/ALT ratio, and total bilirubin were identified as significant predictors of advanced fibrosis and used to construct the NIKEI with an AUC of 0.968 [0.937; 0.998] compared to 0.929 [0.869; 0.989] for the FIB-4 index. The absence of advanced fibrosis could be confirmed with excellent accuracy (99-100%). The positive predictive value of the FIB-4 index was higher (100% vs. 60%), however, the false negative rate was also high (33%). With a stepwise combination of both indices 82%-84% of biopsies would have been avoidable without a single misclassification. The AUROC for AST/ALT ratio, the NAFLD fibrosis score, and the BARD score were 0.81 (95% CI, 0.72-0.90), 0.96 (95% CI 0.92-0.99), and 0.67 (95% CI 0.55-0.78), respectively. The NIKEI can reliably exclude advanced fibrosis in subjects with NAFLD. In combination with the FIB-4 index misclassification with inadequate clinical management can be avoided while the need for liver biopsies can be reduced.


Hyper-Dependence on NHEJ Enables Synergy Between DNA-PK Inhibitors and Low-Dose Doxorubicin in Leiomyosarcoma.
Leiomyosarcoma (LMS) is an aggressive sarcoma for which standard chemotherapies achieve response rates under 30%. There are no effective targeted therapies against LMS. Most LMS are characterized by chromosomal instability (CIN), resulting in part from TP53 and RB1 co-inactivation and DNA damage repair defects. We sought to identify therapeutic targets that could exacerbate intrinsic CIN and DNA damage in LMS, inducing lethal genotoxicity. We performed clinical targeted sequencing in 287 LMS and genome-wide loss-of-function screens in 3 patient-derived LMS cell lines, to identify LMS-specific dependencies. We validated candidate targets by biochemical and cell-response assays in vitro and in 7 mouse models. Clinical targeted sequencing revealed a high burden of somatic copy number alterations (median fraction of the genome altered=0.62) and demonstrated homologous recombination deficiency signatures in 35% of LMS. Genome-wide shRNA screens demonstrated PRKDC (DNA-PKcs) and RPA2 essentiality, consistent with compensatory non-homologous end joining hyper-dependence. DNA-PK inhibitor combinations with unconventionally low-dose doxorubicin had synergistic activity in LMS in vitro models. Combination therapy with peposertib and low-dose doxorubicin (standard or liposomal formulations) inhibited growth of 5 of 7 LMS mouse models without toxicity. Combinations of DNA-PK inhibitors with unconventionally low, sensitizing, doxorubicin dosing showed synergistic effects in LMS in vitro and in vivo models, without discernable toxicity. These findings underscore the relevance of DNA damage repair alterations in LMS pathogenesis and identify dependence on NHEJ as a clinically actionable vulnerability in LMS.


Infected aortic aneurysms: clinical outcome and risk factor analysis.
Infected aortic aneurysms are difficult to treat, and are associated with significant mortality. Hospital survival is poor in patients with severe aortic infection, Salmonella species infection, Staphylococcus aureus infection, aneurysm rupture, and suprarenal aneurysm location. We reviewed the clinical outcome in 46 patients with primary infected aortic aneurysms and identified clinical variables associated with prognosis. Data were collected by means of retrospective chart review. Univariate and multivariate logistic regression models were used for risk factor analysis. Between August 1995 and March 2003, 48 patients with primary infected aortic aneurysms were treated at our hospitals. Two patients with negative culture results were excluded. Of the remaining 46 patients, 35 patients had aortic aneurysms infected with Salmonella species and 11 patients had aortic aneurysms infected with microorganisms other than Salmonella species. There were 20 suprarenal infections and 26 infrarenal infections. Surgical debridement and in situ graft replacement were performed in 35 patients, with an early mortality rate of 11%. The incidence of late prosthetic graft infection was 10%. The 90-day mortality rate in patients operated on was 0% for elective operation and 36% for nonelective operation (P =.006, Fisher exact test). Independent predictors of aneurysm-related death were advanced age, non-Salmonella infection, and no operation. With timely surgical intervention and prolonged antibiotic treatment, in situ graft replacement provides an excellent outcome in patients with primary infected aortic aneurysms and elective operation. Mortality is still high in patients undergoing urgent operation. Advanced age, non-Salmonella infection, and no operation are major determinants of mortality.


The Aspergillus fumigatus transcriptional regulator AfYap1 represents the major regulator for defense against reactive oxygen intermediates but is dispensable for pathogenicity in an intranasal mouse infection model.
Macrophages and neutrophils kill the airborne fungal pathogen Aspergillus fumigatus. The dependency of this killing process on reactive oxygen intermediates (ROI) has been strongly suggested. Therefore, we investigated the enzymatic ROI detoxifying system by proteome analysis of A. fumigatus challenged by H(2)O(2). Since many of the identified proteins and genes are apparently regulated by a putative Saccharomyces cerevisiae Yap1 homolog, the corresponding gene of A. fumigatus was identified and designated Afyap1. Nuclear localization of a functional AfYap1-eGFP fusion was stress dependent. Deletion of the Afyap1 gene led to drastically increased sensitivity of the deletion mutant against H(2)O(2) and menadione, but not against diamide and NO radicals. Proteome analysis of the DeltaAfyap1 mutant strain challenged with 2 mM H(2)O(2) indicated that 29 proteins are controlled directly or indirectly by AfYap1, including catalase 2. Despite its importance for defense against reactive agents, the Afyap1 deletion mutant did not show attenuated virulence in a murine model of Aspergillus infection. These data challenge the hypothesis that ROI such as superoxide anions and peroxides play a direct role in killing of A. fumigatus in an immunocompromised host. This conclusion was further supported by the finding that killing of A. fumigatus wild-type and DeltaAfyap1 mutant germlings by human neutrophilic granulocytes worked equally well irrespective of whether the ROI scavenger glutathione or an NADPH-oxidase inhibitor was added to the cells.


Choice of Moisturiser for Eczema Treatment (COMET): study protocol for a randomized controlled trial.
Eczema is common in children and in the UK most cases are managed in primary care. The foundation of all treatment is the regular use of leave-on emollients to preserve and restore moisture to the skin. This not only improves comfort but may also reduce the need for rescue treatment for 'flares', such as topical corticosteroids. However, clinicians can prescribe many different types of emollient and there is a paucity of evidence to guide this choice. One reason for this may be the challenges of conducting a clinical trial: are parents or carers of young children willing to be randomly allocated an emollient and followed up for a meaningful amount of time? This is a single-centre feasibility study of a pragmatic, four-arm, single-masked, randomized trial. Children with eczema who are eligible (from 1 month to less than 5 years of age, not known to be sensitive or allergic to any of study emollients or their constituents) are recruited via their general practices. Participants are allocated Aveeno® lotion, Diprobase® cream, Doublebase® gel or Hydromol® ointment via a web-based system, using a simple randomization process in a 1:1:1:1 fashion. Researchers are masked to the study emollient. Participants are assessed at baseline and followed up for 3 months. Data are collected by daily diaries, monthly researcher visits and review of electronic medical records. Because this is a feasibility study, a formal sample size calculation for the estimation of treatment effectiveness has not be made but we aim to recruit 160 participants. Recruitment is on-going. At the end of the study, as well as being able to answer the question, 'Is it is possible to recruit and retain children with eczema from primary care into a four-arm randomized trial of emollients?', we will also have collected important data on the acceptability and effectiveness of four commonly used emollients. Current Controlled Trials ISRCTN21828118 and Clinical Trials Register EudraCT2013-003001-26.


Reflux episodes are similar in healthy African Americans and non-Hispanic whites.
Ambulatory esophageal pH monitoring is the current gold standard diagnostic exam for gastroesphageal reflux disease. Presently, no data are available for normal 24-hour esophageal pH monitoring among any US ethnic group. The aim of the present study was to obtain normal values of 24-hour esophageal pH monitoring in healthy adult African American (AA) volunteers and compare these with values obtained in healthy non-Hispanic white (nHw) volunteers to determine if ethnic variation exists in 24-hour esophageal pH testing. Twenty-four-hour dual esophageal pH monitoring was performed in healthy AA and nHw. Values for total number of reflux episodes, episodes longer than 5 min, total reflux time in minutes, and longest reflux episode in the proximal and distal esophagus were obtained for both ethnic groups. Differences between groups were considered significant if P < 0.05. Eighty subjects volunteered for the study and completed 24-hour pH testing. Forty-one were AAs and 39 were nHws, with males making up 49% of each group. The AAs were older and had higher body mass index than the nHws. No difference was observed between the AA and the nHw subjects for any measured pH parameter in either the proximal or distal esophagus. There is no difference in values obtained during esophageal pH monitoring in healthy African Americans and non-Hispanic whites. This indicates that the currently accepted normal values of ambulatory esophageal pH monitoring are readily applicable to African Americans and can be used without compromising diagnostic accuracy in this ethnic group.


T-cell reactivity to beta-cell membrane antigens associated with beta-cell destruction in IDDM.
Insulin-dependent diabetes mellitus (IDDM) results from a T-cell-mediated destruction of the insulin-producing beta-cells. In this study, we designed a sensitive assay to detect and identify islet cell-reactive T-cells in patients with newly diagnosed IDDM. The relation between T-cell recognition of beta-cell antigens with IDDM and the pathogenesis of the disease (the beta-cell destruction process) was tested in a large group of IDDM patients and compared with T-cell responses in nondiabetic children with other chronic inflammations and in immunologically normal, age-matched control subjects. The results demonstrate that peripheral blood T-cells reacting with a beta-cell membrane preparation enriched for insulin-secretory granule antigen were detectable in the majority of newly diagnosed IDDM patients (27 of 40 [67%]; mean stimulation index [SI] 37.0). Such reactivity was reduced postonset in IDDM patients proportionally to the duration of the disease (11 of 30 [37%]; mean SI 8.7). Nondiabetic age-matched control subjects showed no responses or moderate responses to the granule preparation (4 of 48 [8%]; mean SI 3.4). The magnitude of the T-cell response was significantly greater in newly diagnosed IDDM patients than in IDDM patients tested at least 2 years postonset (P < 0.001). Two children in remission for insulin dependency (so-called honeymoon period) displayed exceptionally high proliferative responses to insulin-secretory granules (mean SI 86.7). These results imply that T-cell recognition of insulin-secretory granule antigens is associated with IDDM and in particular with the immune-mediated process of beta-cell destruction.


From the mouths of social media users: A focus group study exploring the social casino gaming-online gambling link.
Background and aims The potential link between social casino gaming and online gambling has raised considerable concerns among clinicians, researchers and policy makers. Unfortunately, however, there is a paucity of research examining this potential link, especially among young adults. This represents a significant gap given young adults are frequently exposed to and are players of social casino games. Methods To better understand the potential link between social casino games and online gambling, we conducted three focus groups (N = 30) at two large Canadian Universities with college students who were avid social media users (who are regularly exposed to social casino games). Results Many participants spontaneously mentioned that social casino games were a great opportunity to build gambling skills before playing for real money. Importantly, some participants expressed a belief that there is a direct progression from social casino gaming to online gambling. Conversely, others believed the transition to online gambling depended on a person's personality, rather than mere exposure to social casino games. While many young adults in our focus groups felt immune to the effects of social casino games, there was a general consensus that social casino games may facilitate the transition to online gambling among younger teenagers (i.e., 12-14 yr olds), due to the ease of accessibility and early exposure. Discussion The results of the present research point to the need for more study on the effects of social casino gambling as well as a discussion concerning regulation of social casino games in order to minimize their potential risks.


Introduced fire ants can exclude native ants from critical mutualist-provided resources.
Animals frequently experience resource imbalances in nature. For ants, one resource that may be particularly valuable for both introduced and native species is high-carbohydrate honeydew from hemipteran mutualists. We conducted field and laboratory experiments: (1) to test if red imported fire ants (Solenopsis invicta) competed with native ants for access to mutualisms with aphids, and (2) to quantify the effects of aphid honeydew presence or absence on colony growth of native ants. We focused on native dolichoderine ants (Formicidae, Dolichoderinae) because they are abundant ants that have omnivorous diets that frequently include mutualist-provided carbohydrates. At two sites in the southeastern US, native dolichoderine ants were far less frequent, and fire ants more frequent, at carbohydrate baits than would be expected based on their frequency in pitfall traps. A field experiment confirmed that a native ant species, Dorymyrmex bureni, was only found tending aphids when populations of S. invicta were suppressed. In the laboratory, colonies of native dolichoderine ants with access to both honeydew and insect prey had twice as many workers and over twice as much brood compared to colonies fed only ad libitum insect prey. Our results provide the first experimental evidence that introduced ants compete for access to mutualist-provided carbohydrates with native ants and that these carbohydrates represent critical resources for both introduced and native ants. These results challenge traditional paradigms of arthropod and ant nutrition and contribute to growing evidence of the importance of nutrition in mediating ecological interactions.


Persistent homology and many-body atomic structure for medium-range order in the glass.
The characterization of the medium-range (MRO) order in amorphous materials and its relation to the short-range order is discussed. A new topological approach to extract a hierarchical structure of amorphous materials is presented, which is robust against small perturbations and allows us to distinguish it from periodic or random configurations. This method is called the persistence diagram (PD) and introduces scales to many-body atomic structures to facilitate size and shape characterization. We first illustrate the representation of perfect crystalline and random structures in PDs. Then, the MRO in amorphous silica is characterized using the appropriate PD. The PD approach compresses the size of the data set significantly, to much smaller geometrical summaries, and has considerable potential for application to a wide range of materials, including complex molecular liquids, granular materials, and metallic glasses.


Enhanced in vivo fitness of carbapenem-resistant oprD mutants of Pseudomonas aeruginosa revealed through high-throughput sequencing.
An important question regarding the biologic implications of antibiotic-resistant microbes is how resistance impacts the organism's overall fitness and virulence. Currently it is generally thought that antibiotic resistance carries a fitness cost and reduces virulence. For the human pathogen Pseudomonas aeruginosa, treatment with carbapenem antibiotics is a mainstay of therapy that can lead to the emergence of resistance, often through the loss of the carbapenem entry channel OprD. Transposon insertion-site sequencing was used to analyze the fitness of 300,000 mutants of P. aeruginosa strain PA14 in a mouse model for gut colonization and systemic dissemination after induction of neutropenia. Transposon insertions in the oprD gene led not only to carbapenem resistance but also to a dramatic increase in mucosal colonization and dissemination to the spleen. These findings were confirmed in vivo with different oprD mutants of PA14 as well as with related pairs of carbapenem-susceptible and -resistant clinical isolates. Compared with OprD(+) strains, those lacking OprD were more resistant to killing by acidic pH or normal human serum and had increased cytotoxicity against murine macrophages. RNA-sequencing analysis revealed that an oprD mutant showed dramatic changes in the transcription of genes that may contribute to the various phenotypic changes observed. The association between carbapenem resistance and enhanced survival of P. aeruginosa in infected murine hosts suggests that either drug resistance or host colonization can cause the emergence of more pathogenic, drug-resistant P. aeruginosa clones in a single genetic event.


FibroTest is an independent predictor of virologic response in chronic hepatitis C patients retreated with pegylated interferon alfa-2b and ribavirin in the EPIC³ program.
EPIC-3 is a prospective, international study that has demonstrated the efficacy of PEG-IFN alfa-2b plus weight-based ribavirin in patients with chronic hepatitis C and significant fibrosis who previously failed any interferon-alfa/ribavirin therapy. The aim of the present study was to assess FibroTest (FT), a validated non-invasive marker of fibrosis in treatment-naive patients, as a possible alternative to biopsy as the baseline predictor of subsequent early virologic (EVR) and sustained virologic response (SVR) in previously treated patients. Of 2312 patients enrolled, 1459 had an available baseline FT, biopsy, and complete data. Uni- (UV) and multi-variable (MV) analyses were performed using FT and biopsy. Baseline characteristics were similar as in the overall population; METAVIR stage: 28% F2, 29% F3, and 43% F4, previous relapsers 29%, previous PEG-IFN regimen 41%, high baseline viral load (BVL) 64%. 506 patients (35%) had undetectable HCV-RNA at TW12 (TW12neg), with 58% achieving SVR. The accuracy of FT was similar to that in naive patients: AUROC curve for the diagnosis of F4 vs F2=0.80 (p<0.00001). Five baseline factors were associated (p<0.001) with SVR in UV and MV analyses (odds ratio: UV/MV): fibrosis stage estimated using FT (4.5/5.9) or biopsy (1.5/1.6), genotype 2/3 (4.5/5.1), BVL (1.5/1.3), prior relapse (1.6/1.6), previous treatment with non-PEG-IFN (2.6/2.0). These same factors were associated (p ≤ 0.001) with EVR. Among patients TW12neg, two independent factors remained highly predictive of SVR by MV analysis (p ≤ 0.001): genotype 2/3 (odds ratio=2.9), fibrosis estimated with FT (4.3) or by biopsy (1.5). FibroTest at baseline is a possible non-invasive alternative to biopsy for the prediction of EVR at 12 weeks and SVR, in patients with previous failures and advanced fibrosis, retreated with PEG-IFN alfa-2b and ribavirin.


Effect of sesaminol on plasma and tissue alpha-tocopherol and alpha-tocotrienol concentrations in rats fed a vitamin E concentrate rich in tocotrienols.
We have shown that sesame lignans added to rat diet resulted in significantly greater plasma and tissue concentrations of alpha- and gamma-tocopherol concentrations in supplemented rats than in rats without supplementation. In the present studies we examined whether sesaminol, a sesame lignan, enhances tocotrienol concentrations in plasma and tissues of rats fed diets containing a tocotrienol-rich fraction of palm oil (T-mix). In Experiment 1, effects of sesaminol on tocotrienol concentrations in plasma, liver, and kidney were evaluated in rats fed diets containing 20 mg/kg of T-mix (20T) and 50 mg/kg of T-mix (50T) with or without 0.1% sesaminol. Although the T-mix contained 23% alpha-tocopherol, 22% alpha-tocotrienol, and 34% gamma-tocotrienol, alpha-tocopherol constituted most or all of the vitamin E in plasma and tissue (from 97% in kidney to 100% in plasma), with no or very little alpha-tocotrienol and no gamma-tocotrienol at all. Addition of sesaminol to the T-mix resulted in significantly higher plasma, liver, and kidney alpha-tocopherol concentrations compared to values for T-mix alone. Further, T-mix with sesaminol resulted in significantly higher alpha-tocotrienol concentrations in kidney, although the concentration was very low. In Experiment 2, we examined whether sesaminol caused enhanced absorption of alpha-tocopherol and alpha-tocotrienol in a dosage regimen supplying T-mix and sesaminol on alternating days and observed significantly higher levels of alpha-tocopherol and alpha-tocotrienol in rats fed sesaminol, even without simultaneous intake, compared to those in rats without sesaminol. In Experiment 3, alpha-tocopherol was supplied to the stomach with and without sesaminol, and alpha-tocopherol concentrations in the lymph fluid were measured. a-Tocopherol concentrations were not different between groups. These results indicated that sesaminol produced markedly higher alpha-tocopherol concentrations in plasma and tissue and significantly greater alpha-tocotrienol concentrations in kidney and various other tissues, but the concentrations of alpha-tocotrienol were extremely low compared to those of a-tocopherol (Exps. 1 and 2). However, the sesaminol-induced increases of a-tocopherol and a-tocotrienol concentrations in plasma and tissue were not caused by their enhanced absorption since sesaminol did not enhance their absorption.


Nut clusters and crisps: atrocity stories and co-narration in interviews with approved mental health professionals.
The article explores the telling of co-narrated atrocity stories in accomplishing professional identity. Building on previous work, it is argued that group membership is a prerequisite for such stories to be told. Extracts from empirical data from interviews with social work approved mental health professionals are analysed using an ethnomethodological approach. The findings show how atrocity stories can be co-narrated, not only by longstanding colleagues, but also by two unacquainted persons who share the same professional identity. The article concludes that the ethnomethodological concepts of vulgar competency, unique adequacy, indexicality and the documentary method of interpretation are key to understanding the accomplishment of co-narrated atrocity stories.


TRDistiller: a rapid filter for enrichment of sequence datasets with proteins containing tandem repeats.
The dramatic growth of sequencing data evokes an urgent need to improve bioinformatics tools for large-scale proteome analysis. Over the last two decades, the foremost efforts of computer scientists were devoted to proteins with aperiodic sequences having globular 3D structures. However, a large portion of proteins contain periodic sequences representing arrays of repeats that are directly adjacent to each other (so called tandem repeats or TRs). These proteins frequently fold into elongated fibrous structures carrying different fundamental functions. Algorithms specific to the analysis of these regions are urgently required since the conventional approaches developed for globular domains have had limited success when applied to the TR regions. The protein TRs are frequently not perfect, containing a number of mutations, and some of them cannot be easily identified. To detect such "hidden" repeats several algorithms have been developed. However, the most sensitive among them are time-consuming and, therefore, inappropriate for large scale proteome analysis. To speed up the TR detection we developed a rapid filter that is based on the comparison of composition and order of short strings in the adjacent sequence motifs. Tests show that our filter discards up to 22.5% of proteins which are known to be without TRs while keeping almost all (99.2%) TR-containing sequences. Thus, we are able to decrease the size of the initial sequence dataset enriching it with TR-containing proteins which allows a faster subsequent TR detection by other methods. The program is available upon request.


Cotranscriptional recruitment of She2p by RNA pol II elongation factor Spt4-Spt5/DSIF promotes mRNA localization to the yeast bud.
Pre-mRNA processing is coupled with transcription. It is still unclear if the transcription machinery can also directly affect the cytoplasmic fate of a transcript, such as its intracellular localization. In yeast, the RNA-binding protein She2p binds several mRNAs and targets them for localization at the bud. Here we report that She2p is recruited cotranscriptionally to the nascent bud-localized ASH1, IST2, and EAR1 mRNA. She2p interacts in vivo with the elongating forms of RNA polymerase II (pol II) via the transcription elongation factor Spt4-Spt5. Mutations in either SPT4 or SPT5 reduce the cotranscriptional recruitment of She2p on the ASH1 gene, disrupt the proper localization of ASH1 mRNA at the bud tip, and affect Ash1p sorting to the daughter cell nucleus. We propose that She2p is recruited by the RNA pol II machinery prior to its transfer to nascent bud-localized mRNAs. Indeed, She2p is present with RNA pol II on genes coding for localized or nonlocalized transcripts, but is associated with nascent mRNA only on genes coding for bud-localized transcripts. Moreover, a She2p mutant defective in RNA binding still associates with RNA pol II transcribed genes. This study uncovers a novel mechanism for the cotranscriptional assembly of mRNP complexes primed for localization in the cytoplasm.


Insufficient histone-3 lysine-9 deacetylation in human oocytes matured in vitro is associated with aberrant meiosis.
To characterize histone acetylation during meiosis in human oocytes matured in vitro or in vivo. Experimental study. University reproductive medical center. Patients undergoing routine intracytoplasmic sperm injection (ICSI) cycles. Immature and mature oocytes were collected from patients undergoing intracytoplasmic sperm injection. Immunohistochemical assessment of the levels of acetylated lysine-9 of histone-3 (H3K9) and lysine-12 of histone-4 (H4K12) combined with spindle and chromosome configurations in in vitro- and in vivo-matured human oocytes. Transcript levels of histone deacetylases (HDACs) 1 and 2 were measured by single-cell quantitative polymerase chain reaction. Acetylation of H3K9 and H4K12 decreased during human oocyte maturation. Residual H3K9 acetylation was found in 37.7% of oocytes matured in vitro, compared with 11.8% in oocytes matured in vivo. Abnormal metaphase spindle was more frequent in oocytes with residual histone acetylation than without (51.6% vs. 25.4%, respectively). Treatment with the HDAC inhibitor trichostatin A increased the incidence of an abnormal metaphase but had no adverse effect on maturation efficiency. Furthermore, expression of HDAC1 transcripts was significantly lower in oocytes matured in vitro versus in vivo. Reduced HDAC1 expression and insufficient histone deacetylation are associated with metaphase defects in human oocytes matured in vitro.


Attenuation of angiotensin II- and III-induced aldosterone release by prostaglandin synthesis inhibitors.
The effect of two prostaglandin synthesis inhibitors, indomethacin and meclofenamate, on angiotensin II (AII)- and III (AIII)-induced aldosterone release was studied in normal and sodium-depleted conscious rats and in adrenal capsular cell suspensions obtained from normal rats. In normal rats, in vivo AII and AIII were equipotent in causing dose-related increases in serum aldosterone concentrations. Indomethacin decreased the basal serum aldosterone levels by 50% and serum renin levels by 43%. In addition, the steroidogenic effects of AII and AIII were reduced by 45 and 63% with 3 mg/kg of indomethacin and 63 and 73% with 10 mg/kg, respectively. In contrast, meclofenamate failed to alter basal serum levels of aldosterone or AII-stimulated aldosterone release but inhibited serum renin levels by 27% and the aldosterone-stimulating effect of AIII by 99%. Indomethacin (3 mg/kg) and meclofenamate (2 mg/kg) inhibited urinary prostaglandin (PG)E(2) and PGF(2alpha) excretion by 63 and 52% and 37 and 31%, respectively. Both inhibitors significantly decreased the adrenal capsular PGE(2) and PGF(2alpha) content and the conversion of [(14)C]arachidonate to [(14)C]PGE(2) and [(14)C]PGF(2alpha). In sodium-depleted rats, indomethacin produced similar effects reducing the control serum aldosterone levels by 29%, AII-stimulated aldosterone by 47%, and completely suppressing the aldosterone response to AIII without altering serum renin activity. In adrenal cell suspensions, similar results were observed with indomethacin inhibiting basal and AII- and AIII-stimulated aldosterone release by 29, 81, and 93%, respectively. Meclofenamate failed to alter basal and AII-stimulated aldosterone release but inhibited that stimulated by AIII by 86%. The present findings suggest that prostaglandins modulate the effects of the renin-angiotensin system by stimulating the release of renin from the kidney and augmenting the steroidogenic effects of AII and AIII in the adrenal cortex.


Development of an effective method for dendritic cell immunotherapy of mouse melanoma.
Dendritic cell (DC) immunotherapy is a strong candidate for the treatment of incurable cancers especially malignant melanoma. Nevertheless, the proper guideline of DC immunotherapy does not exist. The absence of the guideline is also an obstacle to clinical trials of DC immunotherapy. So we conducted this study in order to develop an effective DC preparation method for immunotherapy in mouse malignant melanoma. Mouse bone marrow-derived DC were stimulated with tumour antigen alone or tumour antigen plus a cocktail (anti-CD40 antibody +TNF-alpha+ IL-1beta) for 8, 24 or 48 h and the characteristics of these DC, such as surface molecules (CD40, CD80, CD86, MHC class II, CCR7), cytokines(IL-12, IFN-gamma, and IL-10), DC-induced T cell proliferation in vitro, and the production of IFN-gamma by those cells, were evaluated. Mice with melanoma were then treated with DC stimulated with tumour antigen alone and tumour antigen plus cocktail for 8 or 48 h. The tumour size and survival rate of these mice were then evaluated. (1) Beneficial clinical effects such as a reduction of tumour size and an increased survival rate were best observed in the group treated with DC stimulated for 8 h with tumour antigen plus cocktail. (2) The single prominent characteristic of DC stimulated for 8 h with tumour antigen plus cocktail was an elevated IL-12 secretion. The cytokine IL-12 was not secreted by other DC. Consequently, proper production of IL-12 was found to be an important requirement for DC used in immunotherapy of mouse melanoma.


Cosmetics use and age at menopause: is there a connection?
Cosmetics contain a vast number of chemicals, most of which are not under the regulatory purview of the Food and Drug Administration. Only a few of these chemicals have been evaluated for potential deleterious health impact: parabens, phthalates, polycyclic aromatic hydrocarbons, and siloxanes. A review of the ingredients in the best-selling and top-rated products of the top beauty brands in the world, as well as a review of highlighted chemicals by nonprofit environmental organizations, reveals 11 chemicals and chemical families of concern: butylated hydroxyanisole/butylated hydroxytoluene, coal tar dyes, diethanolamine, formaldehyde-releasing preservatives, parabens, phthalates, 1,4-dioxane, polycyclic aromatic hydrocarbons, siloxanes, talc/asbestos, and triclosan. Age at menopause can be affected by a variety of mechanisms, including endocrine disruption, failure of DNA repair, oxidative stress, shortened telomere length, and ovarian toxicity. There is a lack of available studies to make a conclusion regarding cosmetics use and age at menopause. What little data there are suggest that future studies are warranted. Women with chronic and consistent use of cosmetics across their lifespan may be a population of concern. More research is required to better elucidate the relationship and time windows of vulnerability and the effects of mixtures and combinations of products on ovarian health.


Functionalisation of lanthanide complexes via microwave-enhanced Cu(I)-catalysed azide-alkyne cycloaddition.
Cu(I)-catalysed azide-alkyne cycloaddition reactions were used to functionalise lanthanide(III)-complexes (Ln; La, Eu and Tb) incorporating alkyne or azide reactive groups. Microwave irradiation significantly accelerated the reactions, enabling full conversion to the triazole products in some cases in 5 min. Alkyl and aryl azides and alkyl and aryl alkynes could all serve as coupling partners. These reaction conditions proved efficient for cyclen-tricarboxylates and previously unreactive cyclen-tris-primary amide chelates. The synthesis of heterobimetallic (Eu/Tb, EuTb17 and Eu/La, EuLa17) and heterotrimetallic (Eu/La/Eu) complexes was achieved in up to 60% isolated yield starting from coumarin 2-appended alkynyl complexes Tb16 or La16 and an azido-Eu complex Eu4, and bis-alkynyl La-complex La5 and Eu4, respectively. EuTb17 displayed dual Eu(III) and Tb(III)-emission upon antenna-centred excitation.


A quantitative ELISA assay for the fragile x mental retardation 1 protein.
Non-coding (CGG-repeat) expansions in the fragile X mental retardation 1 (FMR1) gene result in a spectrum of disorders involving altered neurodevelopment (fragile X syndrome), neurodegeneration (late-onset fragile X-associated tremor/ataxia syndrome), or primary ovarian insufficiency. While reliable and quantitative assays for the number of CGG repeats and FMR1 mRNA levels are now available, there has been no scalable, quantitative assay for the FMR1 protein (FMRP) in non-transformed cells. Using a combination of avian and murine antibodies to FMRP, we developed a sensitive and highly specific sandwich enzyme-linked immunosorbent assay (ELISA) for FMRP in peripheral blood lymphocytes. This ELISA method is capable of quantifying FMRP levels throughout the biologically relevant range of protein concentrations and is specific for the intact FMRP protein. Moreover, the ELISA is well-suited for replicate protein determinations across serial dilutions in non-transformed cells and is readily scalable for large sample numbers. The FMRP ELISA is potentially a powerful tool in expanding our understanding of the relationship between FMRP levels and the various FMR1-associated clinical phenotypes.


Expression pattern of Wnt signaling components in the adult intestine.
In the intestine, the canonical Wnt signaling cascade plays a crucial role in driving the proliferation of epithelial cells. Furthermore, aberrant activation of Wnt signaling is strongly associated with the development of colorectal cancer. Despite this evidence, little is known about the precise identity and localization of Wnts and their downstream effectors in the adult intestine. To address this issue, we examined the expression pattern of all Wnts, Frizzleds (Fzs), low-density lipoprotein receptor-related proteins, Wnt antagonists, and T-cell factors in the murine small intestine and colon and adenomas. Embryonic, postnatal, and adult intestinal samples were subjected to in situ hybridization by using specific RNA probes for the various genes tested. Our analysis showed high expression of several signaling components (including Wnt-3, Wnt-6, Wnt-9b, Frizzled 4, Frizzled 6, Frizzled 7, low-density lipoprotein receptor-related protein 5, and secreted Frizzled-related protein 5) in crypt epithelial cells. We also detected Wnt-2b, Wnt-4, Wnt-5a, Wnt-5b, Frizzled 4, and Frizzled 6 in differentiated epithelial and mesenchymal cells of the small intestine and colon. Finally, several factors (Frizzled 4, T-cell factor 1, lymphoid enhancer factor, Dickkopf 2, Dickkopf 3, and Wnt-interacting factor) displayed differential expression in normal vs neoplastic tissue. Our study predicts a much broader role for Wnt signaling in gut development and homeostasis than was previously anticipated from available genetic studies and identifies novel factors likely involved in promoting canonical and noncanonical Wnt signals in the intestine.


The impact of digital technology on health of populations affected by humanitarian crises: Recent innovations and current gaps.
Digital technology is increasingly used in humanitarian action and promises to improve the health and social well-being of populations affected by both acute and protracted crises. We set out to (1) review the current landscape of digital technologies used by humanitarian actors and affected populations, (2) examine their impact on health and well-being of affected populations, and (3) consider the opportunities for and challenges faced by users of these technologies. Through a systematic search of academic databases and reports, we identified 50 digital technologies used by humanitarian actors, and/or populations affected by crises. We organized them according to the stage of the humanitarian cycle that they were used in, and the health outcomes or determinants of health they affected. Digital technologies were found to facilitate communication, coordination, and collection and analysis of data, enabling timely responses in humanitarian contexts. A lack of evaluation of these technologies, a paternalistic approach to their development, and issues of privacy and equity constituted major challenges. We highlight the need to create a space for dialogue between technology designers and populations affected by humanitarian crises.


Five polymorphisms and breast cancer risk: results from the Breast Cancer Association Consortium.
Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small sample size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97-1.02), minor allele frequency = 27.5%; TNF 1.00 (0.95-1.06), 5.0%; CASP10 1.02 (0.98-1.07), 6.5%; PGR 1.02 (0.99-1.06), 15.3%; and BID 0.98 (0.86-1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent.


Service-oriented science.
New information architectures enable new approaches to publishing and accessing valuable data and programs. So-called service-oriented architectures define standard interfaces and protocols that allow developers to encapsulate information tools as services that clients can access without knowledge of, or control over, their internal workings. Thus, tools formerly accessible only to the specialist can be made available to all; previously manual data-processing and analysis tasks can be automated by having services access services. Such service-oriented approaches to science are already being applied successfully, in some cases at substantial scales, but much more effort is required before these approaches are applied routinely across many disciplines. Grid technologies can accelerate the development and adoption of service-oriented science by enabling a separation of concerns between discipline-specific content and domain-independent software and hardware infrastructure.


Molecular and functional basis of phenotypic convergence in white lizards at White Sands.
There are many striking examples of phenotypic convergence in nature, in some cases associated with changes in the same genes. But even mutations in the same gene may have different biochemical properties and thus different evolutionary consequences. Here we dissect the molecular mechanism of convergent evolution in three lizard species with blanched coloration on the gypsum dunes of White Sands, New Mexico. These White Sands forms have rapidly evolved cryptic coloration in the last few thousand years, presumably to avoid predation. We use cell-based assays to demonstrate that independent mutations in the same gene underlie the convergent blanched phenotypes in two of the three species. Although the same gene contributes to light phenotypes in these White Sands populations, the specific molecular mechanisms leading to reduced melanin production are different. In one case, mutations affect receptor signaling and in the other, the ability of the receptor to integrate into the melanocyte membrane. These functional differences have important ramifications at the organismal level. Derived alleles in the two species show opposite dominance patterns, which in turn affect their visibility to selection and the spatial distribution of alleles across habitats. Our results demonstrate that even when the same gene is responsible for phenotypic convergence, differences in molecular mechanism can have dramatic consequences on trait expression and ultimately the adaptive trajectory.


Cost Effective Chemical Oxidative Synthesis of Soluble and Electroactive Polyaniline Salt and Its Application as Anticorrosive Agent for Steel.
The cost effective synthesis of electroactive polyaniline (PANI) while retaining its desirable properties is one of the most debatable and challenging tasks for researchers in the field. Herein, we report a cost effective inverse emulsion polymerization pathway for the synthesis of soluble and processable PANI salt by using diesel as a novel dispersion medium. Different reaction parameters and their effects on the properties and yield of polyaniline were optimized. The polymer exhibited a highly porous morphology and was found to be stable up to 417 °C. The PANI salt showed good solubility in common solvents, such as chloroform, N-Methyl-2-pyrrolidone (NMP), dimethyl sulphoxide (DMSO) and in a 1:3 mixtures by volume of 2-propanol and toluene. The coating of the synthesized PANI salt on stainless steel has shown good corrosion resistant behavior in marine water by reducing the corrosion rate to 67.9% as compared to uncoated stainless steel.


The association between upper gastrointestinal lesions and high-sensitivity C-reactive protein in coronary artery disease patients.
Although high-sensitivity C-reactive protein (hs-CRP) testing is not specific for coronary atherosclerosis, elevated hs-CRP is recently accepted as an independent predictor of future cardiovascular events. Also, a connection between upper gastrointestinal lesions (UGILs) and coronary artery disease (CAD) has been observed. The authors hypothesized that UGILs increase hs-CRP in CAD patients. One hundred fifty patients with stable CAD were enrolled in the study. Demographic and clinical variables and chronic medication used were gathered from a structured questionnaire. UGIL severity was determined by a modified Lanza score, H. pylori status by histology of the gastric mucosa, and the severity of CAD by a modified Gensini score. Independent correlation between hs-CRP and UGIL was tested by logistic regression analysis. The overall hs-CRP value was higher in patients with UGIL than in those with normal endoscopic results (8.14+/-4.53 mg/l vs. 4.64+/-3.06 mg/l, P<0.0001). hs-CRP level positively correlated with UGIL severity (r=0.434, P<0.0001). Correlation between UGIL and hs-CRP level remained significant after adjustment for coronary risk factors, medication used, CAD severity, and H. pylori status (standardized coefficient beta=1.272, P<0.0001). However, when hs-CRP level was used as a categorical variable, multivariate analysis revealed independent correlation only between UGIL and hs-CRP categories > or =6.1 mg/l. Elevated hs-CRP levels may be predictive of UGIL; thus endoscopy should be considered in CAD patients with elevated hs-CRP even with no dyspeptic symptoms. Because CRP plays an active role in atherothrombosis, UGILs with subsequent elevated CRP levels could increase cardiovascular risk in those patients.


In vivo evaluation of cerebral transplantation of resovist-labeled bone marrow stromal cells in Parkinson's disease rats using magnetic resonance imaging.
The effectiveness of Resovist-labeled bone marrow stem cells (BMSCs) was evaluated in vivo following their cerebral transplantation in a model of Parkinson's disease (PD) in rats using MRI, and the MRI findings were further compared with the behavior and histopathological manifestations of these rats. Forty PD rats were randomly assigned into five groups according to the cell doses injected into the rat brain site: control group (normal saline injection) and groups injected with 1 × 10(5), 1.5 × 10(5), 2 × 10(5), and 2.5 × 10(5) BMSCs. Gradient echo T2-weighted images were obtained immediately after cell transplantation and repeatedly taken 1, 4, 8, and 12 week(s) after cell transplantation. The rotational behavior of the animals was observed before and 1, 4, and 8 week(s) after transplantation. The rats were killed after the last MRI scanning, the brain tissues were analyzed by histopathology techniques, and RNAs were extracted for the expression analysis of selected genes using RT-PCR. One week following cell transplantation, all injected sites showed well-defined hypointense areas on MR images, with the most significant effect observed in rats injected with 2 × 10(5) BMSCs. These MR findings in PD rats lasted up to 12 weeks. The effectiveness of BMSC transplantation revealed by MRI was well confirmed by the behavioral and histopathological observations as well as indirectly supported by gene expression analyses. With the use of SPIO labeling, MRI techniques provided a dynamic evaluation of the spatial and temporal changes following cell transplantation and allowed the association analysis among the imaging, functions, and gene expression analysis in rats. These data also suggest the therapeutic potential of transplanted BMSCs. It is reasonable to speculate that the use of MRI in in vivo evaluation of the effect and fate of transplanted cells in various disease models will be beneficial to developing new strategies of cell-based gene therapy.


Combination of statistical approaches for analysis of 2-DE data gives complementary results.
Five methods for finding significant changes in proteome data have been used to analyze a two-dimensional gel electrophoresis data set. We used both univariate (ANOVA) and multivariate (Partial Least Squares with jackknife, Cross Model Validation, Power-PLS and CovProc) methods. The gels were taken from a time-series experiment exploring the changes in metabolic enzymes in bovine muscle at five time-points after slaughter. The data set consisted of 1377 protein spots, and for each analysis, the data set were preprocessed to fit the requirements of the chosen method. The generated results were one list from each analysis method of proteins found to be significantly changed according to the experimental design. Although the number of selected variables varied between the methods, we found that this was dependent on the specific aim of each method. CovProc and P-PLS focused more on getting the minimum necessary subset of proteins to explain properties of the samples. These methods ended up with less selected proteins. There was also a correlation between level of significance and frequency of selection for the selected proteins.


NTP Toxicology and Carcinogenesis Studies of Boric Acid (CAS No. 10043-35-3) in B6C3F1 Mice (Feed Studies).
Boric acid is a component of cosmetics and pharmaceuticals and is also used in numerous industrial processes. Earlier long-term studies did not demonstrate a carcinogenic effect in Sprague-Dawley rats. Because of potential widespread human exposure, corroborative evidence was sought in a second species. Toxicology and carcinogenesis studies were conducted by feeding technical-grade boric acid (99.7% pure) to groups of male and female B6C3F1 mice for 14 days, 13 weeks, and 2 years. In the 14-day studies (five mice per group), mortality occurred in mice fed 25,000 ppm, 50,000 ppm, or 100,000 ppm boric acid; hyperplasia and/or dysplasia of the forestomach was also seen in these dose groups. No compound-related gross pathologic or histopathologic effects were seen in male or female mice exposed at concentrations up to 12,500 ppm in feed. In the 13-week studies, groups of 10 male and 10 female mice were fed boric acid at concentrations up to 20,000 ppm; 8 male mice and 1 female mouse receiving 20,000 ppm and 1 male receiving 10,000 ppm boric acid died before the end of the studies. Male and female mice receiving 20,000 ppm boric acid weighed 23% and 18% less, respectively, than did the controls at the end of the studies. Testicular atrophy in 8/10 male mice, hyperkeratosis and acanthosis of the stomach in 8/10 male and female mice, and extramedullary hematopoiesis of the spleen in all male and female mice receiving 20,000 ppm boric acid indicated that the testis, stomach, and spleen were potential target organs in the 2-year studies. Based on these results, 2-year toxicology and carcinogenesis studies were conducted by feeding diets containing boric acid at concentrations of 0, 2,500, or 5,000 ppm to groups of 50 male and 50 female mice. Survival of high dose male mice after week 63 and of low dose mice after week 84 was lower than that of the controls (final survival: control, 41; low dose, 30; high dose, 22), which may have reduced the sensitivity of the carcinogenicity study; the numbers of female mice (33; 33; 37) that survived to the end of the studies were considered adequate for toxicologic evaluation. Body weight gain was reduced in each sex after week 30; mean final body weights were 7% and 13% below control values for exposed male mice and 7% and 20% below those of controls for exposed female mice. No chemically related clinical signs were reported. At the top dose, boric acid caused an increased incidence of testicular atrophy (control, 3/49; low dose, 6/50; high dose, 27/47) and interstitial cell hyperplasia (0/49; 0/50; 7/47) inmale mice. The testicular atrophy was characterized by variable loss of spermatogonia, primary and secondary spermatocytes, spermatids, and spermatozoa from the seminiferous tubules. The seminiferous tubules contained primarily Sertoli cells and variable numbers of spermatogonia. In some mice, there were accumulations of interstitial cells, indicating hyperplasia. In low dose male mice, there were increased incidences of hepatocellular carcinomas (5/50; 12/50; 8/49) and hepatocellular adenomas or carcinomas (combined) (14/50; 19/50; 15/49) and an increased incidence of subcutaneous tissue fibromas, sarcomas, fibrosarcomas, or neurofibrosarcomas (combined) (2/50; 10/50; 2/50). No increased incidence of subcutaneous tissue neoplasms was seen in male mice receiving 5,000 ppm. Because the incidence of subcutaneous tissue tumors is variable in historical controls, because there was no corresponding increase in the high dose male mice, and because the incidence of hepatocellular tumors was not significant by the incidental tumor test and was within the historical control range, neither of these tumors was considered to be related to the administration of boric acid. Boric acid was not mutagenic in the Salmonella/microsome assay with Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537. Boric acid was negative in the mouse lymphoma L5178Y/TK+/- assay and did not induce sister-chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells. All assays were preformed with anhamster ovary cells. All assays were preformed with and without metabolic activation. The data, documents, and pathology materials from the 2-year studies of boric acid were audited at the NTP Archives. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Under the conditions of these 2--year feed studies, there was no evidence of carcinogenicity of boric acid at doses of 2,500 or 5,000 ppm for male or female B6C3F1 mice. Testicular atrophy and interstitial cell hyperplasia were observed in high dose male mice. The decrease in survival of dosed male mice may have reduced the sensitivity of this study. Synonyms: orthoboric acid; boracic acid


Ophiostoma arduennense sp. nov. (Ophiostomatales, Ascomycota) from Fagus sylvatica in southern Belgium.
Ophiostoma arduennense sp. nov. is described from several cultures isolated from Fagus sylvatica in southern Belgium. The species is mainly characterized by globose perithecia with small button-like bases ornamented with brown hyphal hairs of variable length and, long cylindrical necks ending in ostiolate hyphae. It is homothallic with small reniform ascospores and no apparent anamorph. It is closely associated with the ambrosia beetles Xyloterus domesticus and X. signatus. Its phylogenetic relationships within Ophiostoma are discussed and the species is compared with other Ophiostoma species associated with European beech or other broad-leaved trees in Europe, especially species of the O. quercus-O. piceae complex. The species is responsible for a dark brown staining of the sapwood and its role in the decline of beech in Southern Belgium is also discussed.


Intrahepatic cholestasis of pregnancy: observational study of the treatment with low-dose ursodeoxycholic acid.
To exam the biochemical, obstetric management and pregnancy outcome in women with intrahepatic cholestasis of pregnancy (ICP) and treatment with ursodeoxycholic acid (UDCA). Pregnancy outcome in patients with ICP (N = 307) was studied and patients treated with UDCA (N = 208) vs. no UDCA were compared. The data of the antenatal visits, deliveries and neonatal outcome of 307 pregnancies with ICP was collected from the hospital computerized delivery room log book. UDCA was used in 208 pregnancies. The diagnosis was made by maternal pruritus and elevation of total fasting bile acid (BA) (>6 μmol/l) and elevation of serum alanine aminotransferases (ALT) (>45 U/l). Maternal and neonatal data was analysed and data of the patients who used UDCA during pregnancy was analysed separately and compared with the data from patients without medication. UDCA was well tolerated. Mothers receiving UDCA had ICP diagnosed five weeks earlier than mothers without medication. At the diagnosis, levels of total BA and ALT were higher in the group using UDCA compared to the group without medication. Most deliveries were induced and perinatal outcome was good. Apgar scores at 5 min were significantly lower in UDCA group (p < 0.05), but fetal umbilical artery pH values were similar in both groups (p > 0.05). There were 30 patients with total BA > 40 μmol/l at diagnosis, 24 with UDCA and 6 without medication and those deliveries were induced soon after diagnosis. The preterm labour was also more common in these patents (p < 0.05). Women with preterm babies had significantly early onset pruritus and ICP was diagnosed earlier. Serum ALT and total BA levels were significantly higher in those pregnancies at diagnosis and also at first control. Preterm labour was associated in severe ICP (total BA > 40 μmol/l), ALT levels were also significantly higher and ICP was diagnosed earlier (p < 0.05). Apgar scores were lower in preterm babies (p < 0.05), but umbilical artery pHvalues were not significantly lower. UDCA was well tolerated by pregnant women. With low-dose UDCA treatment the obstetric outcome was good. We still recommend careful obstetrical follow-up.


Microbiological quality of milk from small processing units in Senegal.
Consumption of milk and dairy products has increased significantly in Senegal in the last decade, and a large part of the local production comes from small processing units spread all over the country. We collected 85 bulk-tank milk samples from 68 smallholder dairy farms throughout the territory. Microbiological quality of milk samples was analyzed according to the official standards. Further, raw milk and pasteurized milk were screened for Mycobacterium bovis, Coxiella burnetii, and anti-Brucella abortus antibodies. Ninety-three percent of pasteurized milk samples, 92% of raw milk samples, and 81% of sour milk samples failed to meet official standards. Pathogens detected in milk were C. burnetii (6/41, 15%), which seems to be endemic in Senegal, coagulase-positive staphylococci (18/70, 26%), and Salmonella Johannesburg in one sample. Further analysis of coagulase-positive staphylococci isolated from samples containing more than 10(4) colony-forming units per gram showed the presence of enterotoxigenic strains in 9 of the 10 samples. These results confirm the poor microbiological quality of milk produced by small units in Senegal, especially and surprisingly of pasteurized milk. This highlights the need to implement good hygiene practices, particularly in the postpasteurization process, and an effective monitoring throughout the production and delivery chain.


Diastolic Blood Pressure is a Risk Factor for Peri-procedural Stroke Following Carotid Endarterectomy in Asymptomatic Patients.
Carotid endarterectomy (CEA) prevents future stroke, but this benefit depends on detection and control of high peri-operative risk factors. In symptomatic patients, diastolic hypertension has been causally related to procedural stroke following CEA. The aim was to identify risk factors causing peri-procedural stroke in asymptomatic patients and to relate these to timing of surgery and mechanism of stroke. In the first Asymptomatic Carotid Surgery Trial (ACST-1), 3,120 patients with severe asymptomatic carotid stenosis were randomly assigned to CEA plus medical therapy or to medical therapy alone. In 1,425 patients having their allocated surgery, baseline patient characteristics were analysed to identify factors associated with peri-procedural (< 30 days) stroke or death. Multivariate analysis was performed on risk factors with a p value < .3 from univariate analysis. Event timing and mechanism of stroke were analysed using chi-square tests. A total of 36 strokes (27 ischaemic, four haemorrhagic, five unknown type) and six other deaths occurred during the peri-procedural period, resulting in a stroke/death rate of 2.9% (42/1,425). Diastolic blood pressure at randomisation was the only significant risk factor in univariate analysis (odds ratio [OR] 1.34 per 10 mmHg, 95% confidence interval [CI] 1.04-1.72; p = .02) and this remained so in multivariate analysis when corrected for sex, age, lipid lowering therapy, and prior infarcts or symptoms (OR 1.34, 95% CI 1.05-1.72; p = .02). In patients with diastolic hypertension (> 90 mmHg) most strokes occurred during the procedure (67% vs. 20%; p = .02). In ACST-1, diastolic blood pressure was the only independent risk factor associated with peri-procedural stroke or death. While the underlying mechanisms of the association between lower diastolic blood pressure and peri-procedural risk remain unclear, good pre-operative control of blood pressure may improve procedural outcome of carotid surgery in asymptomatic patients.


Proteomic response to 5,6-dimethylxanthenone 4-acetic acid (DMXAA, vadimezan) in human non-small cell lung cancer A549 cells determined by the stable-isotope labeling by amino acids in cell culture (SILAC) approach.
5,6-Dimethylxanthenone 4-acetic acid (DMXAA), also known as ASA404 and vadimezan, is a potent tumor blood vessel-disrupting agent and cytokine inducer used alone or in combination with other cytotoxic agents for the treatment of non-small cell lung cancer (NSCLC) and other cancers. However, the latest Phase III clinical trial has shown frustrating outcomes in the treatment of NSCLC, since the therapeutic targets and underlying mechanism for the anticancer effect of DMXAA are not yet fully understood. This study aimed to examine the proteomic response to DMXAA and unveil the global molecular targets and possible mechanisms for the anticancer effect of DMXAA in NSCLC A549 cells using a stable-isotope labeling by amino acids in cell culture (SILAC) approach. The proteomic data showed that treatment with DMXAA modulated the expression of 588 protein molecules in A549 cells, with 281 protein molecules being up regulated and 306 protein molecules being downregulated. Ingenuity pathway analysis (IPA) identified 256 signaling pathways and 184 cellular functional proteins that were regulated by DMXAA in A549 cells. These targeted molecules and signaling pathways were mostly involved in cell proliferation and survival, redox homeostasis, sugar, amino acid and nucleic acid metabolism, cell migration, and invasion and programed cell death. Subsequently, the effects of DMXAA on cell cycle distribution, apoptosis, autophagy, and reactive oxygen species (ROS) generation were experimentally verified. Flow cytometric analysis showed that DMXAA significantly induced G1 phase arrest in A549 cells. Western blotting assays demonstrated that DMXAA induced apoptosis via a mitochondria-dependent pathway and promoted autophagy, as indicated by the increased level of cytosolic cytochrome c, activation of caspase 3, and enhanced expression of beclin 1 and microtubule-associated protein 1A/1B-light chain 3 (LC3-II) in A549 cells. Moreover, DMXAA significantly promoted intracellular ROS generation in A549 cells. Collectively, this SILAC study quantitatively evaluates the proteomic response to treatment with DMXAA that helps to globally identify the potential molecular targets and elucidate the underlying mechanism of DMXAA in the treatment of NSCLC.


Micrometastases: marker of metastatic potential or evidence of residual disease?
Micrometastases within bone marrow have been shown to indicate a poor prognosis in patients with epithelial tumours. However, the degree to which micrometastases represent true residual disease or cell shedding and metastatic potential, is unclear. To explore whether micrometastases represent residual disease, bone marrow taken from carefully staged patients before and after (> 6 months) "curative" resection of a primary gastrointestinal cancer was studied prospectively. Seventy two consecutive patients were studied; the only exclusions were patients with known overt metastatic disease at the time of surgery. Micrometastatic cells were quantified per 10(5) marrow cells by flow cytometry after staining for contaminant cytokeratin-18 positive cells. Micrometastases were detected preoperatively in 22% (16/72) of all patients, comprising 11 (23%) of 48 with colorectal cancer, five (33%) of 15 with gastric adenocarcinoma and none (0%) of nine with oesophageal squamous cancer. Although fewer metastatic cells were detected in postoperative bone marrow, and clearance of marrow deposits was evident in most patients, the persistence of micrometastases in five of 16 patients after resection, without evidence of tumour recurrence, indicates a subset with true residual disease. Detection of micrometastases postoperatively (persistent or newly developed) was significantly associated with development of overt metastases during the subsequent 12-18 months of follow up (nine of 19 patients) when compared with patients testing negative for micrometastases (eight of 53; p < 0.01). Preoperative detection of micrometastases may reflect either transient shedding of cells, metastatic potential or residual disease, but postoperative micrometastases indicate minimal residual disease. Identification of these patients is important because they may benefit from adjuvant therapy.


Time for a paradigm shift: managing smarter by moving from data and information to knowledge and wisdom in healthcare decision-making.
Senior decision-makers in the Canadian healthcare system have to continuously make significant, and complex, policy and program decisions. However, it appears that, often, the evidence they have available is fairly simple descriptive information, collected for operational purposes. Trying to solve complex problems with fairly simple data may lead to suboptimal decisions. This article presents a new knowledge development system (KDS) that should allow senior decision-makers and others to manage smarter and take their decision-making to the next level. A KDS represents the integration of information systems, and research and analysis, into one system. It can generate sophisticated, strategic information around complex issues, which should ultimately lead to wiser decisions. This article describes the KDS, provides an example of a current KDS and concludes by presenting a self-diagnostic tool for decision-makers to allow them to determine whether their organization could benefit from a KDS.


The cortisol response to ACTH in pigs, heritability and influence of corticosteroid-binding globulin.
In the search for biological basis of robustness, this study aimed (i) at the determination of the heritability of the cortisol response to ACTH in juvenile pigs, using restricted maximum likelihood methodology applied to a multiple trait animal model, and (ii) at the study of the relationships between basal and stimulated cortisol levels with corticosteroid-binding globulin (CBG), IGF-I and haptoglobin, all important players in glucose metabolism and production traits. At 6 weeks of age, 298 intact male and female piglets from 30 litters (30 dams and 30 boars) were injected with 250 µg ACTH(1-24) (Synacthen). Blood was taken before ACTH injection to measure basal levels of cortisol, glucose, CBG, IGF-I and haptoglobin, and 60 min later to measure stimulated cortisol levels and glucose. Cortisol increased 2.8-fold after ACTH injection, with a high correlation between basal and stimulated levels (phenotypic correlation, r p=0.539; genetic correlation, r g=0.938). Post-ACTH cortisol levels were highly heritable (h 2=0.684) and could therefore be used for genetic selection of animals with a more reactive hypothalamic-pituitary-adrenocortical axis. CBG binding capacity correlated with cortisol levels measured in basal conditions in males only. No correlation was found between CBG binding capacity and post-ACTH cortisol levels. Basal IGF-I concentration was positively correlated with BW at birth and weaning, and showed a high correlation with CBG binding capacity with a strong sexual dimorphism, the correlation being much higher in males than in females. Basal haptoglobin concentrations were negatively correlated with CBG binding capacity and IGF-I concentrations. Complex relationships were also found between circulating glucose levels and these different variables that have been shown to be related to glucose resistance in humans. These data are therefore valuable for the genetic selection of animals to explore the consequences on production and robustness traits, but also point at pigs as a relevant model to explore the underlying mechanisms of the metabolic syndrome including the contribution of genetic factors.


Consequences of poststroke falls: activity limitation, increased dependence, and the development of fear of falling.
We used qualitative data to explore the perceived consequences of poststroke falls during the first 6 months after discharge from the hospital. We interviewed 132 male stroke survivors 1 and 6 months after discharge to describe stroke recovery trajectories. Interviews of participants who discussed falling after stroke as one of their major concerns were analyzed to explore the consequences of poststroke falls. During the first 6 months after stroke, 42 (32%) participants discussed poststroke falls. The results of the qualitative analysis indicate three important emergent themes related to the consequences of poststroke falls: (1) limiting activity and participation, (2) increasing dependence, and (3) developing a fear of falling. Falls after discharge home were common in this group of stroke survivors. Future research is needed to better understand the impact of fall-related consequences and to explore strategies for fall prevention.


MicroRNAs in the pathophysiology and treatment of status epilepticus.
MicroRNA (miRNA) are an important class of non-coding RNA which function as post-transcriptional regulators of gene expression in cells, repressing and fine-tuning protein output. Prolonged seizures (status epilepticus, SE) can cause damage to brain regions such as the hippocampus and result in cognitive deficits and the pathogenesis of epilepsy. Emerging work in animal models has found that SE produces select changes to miRNAs within the brain. Similar changes in over 20 miRNAs have been found in the hippocampus in two or more studies, suggesting conserved miRNA responses after SE. The miRNA changes that accompany SE are predicted to impact levels of multiple proteins involved in neuronal morphology and function, gliosis, neuroinflammation, and cell death. miRNA expression also displays select changes in the blood after SE, supporting blood genomic profiling as potential molecular biomarkers of seizure-damage or epileptogenesis. Intracerebral delivery of chemically modified antisense oligonucleotides (antagomirs) has been shown to have potent, specific and long-lasting effects on brain levels of miRNAs. Targeting miR-34a, miR-132 and miR-184 has been reported to alter seizure-induced neuronal death, whereas targeting miR-134 was neuroprotective, reduced seizure severity during status epilepticus and reduced the later emergence of recurrent spontaneous seizures. These studies support roles for miRNAs in the pathophysiology of status epilepticus and miRNAs may represent novel therapeutic targets to reduce brain injury and epileptogenesis.


Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities.
Patients with chromosome 5 abnormalities and high-risk myelodysplastic syndromes or acute myeloid leukemia have a poor outcome. We hypothesized that increasing doses of lenalidomide may benefit this group of patients by inhibiting the tumor clone, as assessed by fluorescence in situ hybridization for del(5q31). Twenty-eight patients at diagnosis or with relapsed disease and not eligible for standard therapy (16 with acute myeloid leukemia, 12 with intermediate-risk 2 or high-risk myelodysplastic syndrome) were enrolled in this prospective phase II multicenter trial and treated with lenalidomide up to 30 mg daily for 16 weeks. Three patients had isolated del(5q), six had del(5q) plus one additional aberration, 14 had del(5q) and a complex karyotype, four had monosomy 5, and one had del(5q) identified by fluorescence in situ hybridization only. Major and minor cytogenetic responses, assessed by fluorescence in situ hybridization, were achieved in 5/26 (19%) and 2/26 (8%) patients, respectively, who received one or more dose of lenalidomide, while two patients achieved only a bone marrow response. Nine of all 26 patients (35%) and nine of the ten who completed the 16 weeks of trial responded to treatment. Using the International Working Group criteria for acute myeloid leukemia and myelodysplastic syndrome the overall response rate in treated patients with acute myeloid leukemia was 20% (3/15), while that for patients with myelodysplastic syndrome was 36% (4/11). Seven patients stopped therapy due to progressive disease and nine because of complications, most of which were disease-related. Response rates were similar in patients with isolated del(5q) and in those with additional aberrations. Interestingly, patients with TP53 mutations responded less well than those without mutations (2/13 versus 5/9, respectively; P=0.047). No responses were observed among 11 cases with deleterious TP53 mutations. Our data support a role for higher doses of lenalidomide in poor prognosis patients with myelodysplastic syndrome and acute myeloid leukemia with deletion 5q. (Clinicaltrials.gov identifier NCT00761449).


Decreased Visual Acuity by an Irregular Corneal Posterior Surface After Repeat Descemet Stripping Automated Endothelial Keratoplasty.
To investigate the impact of higher-order aberrations (HOAs) on visual acuity after repeat Descemet stripping automated endothelial keratoplasty (DSAEK) in the same eyes. This retrospective comparative case series includes 23 patients who underwent DSAEK twice in the same eyes (46 DSAEK in total). We evaluated the HOAs of the anterior and posterior corneal surfaces, and total cornea using the Fourier analysis data from anterior segment optical coherence tomography. Eyes were divided into one of the following groups, based on the improvement and decline in the best-corrected visual acuity (BCVA) after repeat DSAEK; group A: 12 eyes with an improvement ≥ 2 lines, group B: 12 eyes with a decline ≤ 2 lines, and group C: 11 eyes with no change or change within 1 line. The HOAs of the posterior surface in group B were significantly greater than those of group A (P=0.028), whereas there were no significant differences in the anterior surface and total corneal HOAs between groups A and B (P=0.12 and 0.08). There were no significant differences in the anterior and posterior surface as well as total cornea HOAs between initial DSAEK and repeat DSAEK in group C (P=0.87, 0.65, and 0.42). The postoperative BCVA had a significant correlation with the HOAs of the anterior and posterior surfaces as well as the total cornea (R=0.40, 0.46, and 0.53; P=0.01, 0.002, and 0.001). Posterior corneal HOAs can have a negative influence on the visual acuity after endothelial keratoplasty.


A mixed method multi-country assessment of barriers to implementing pediatric inpatient care guidelines.
Accelerating progress in reducing child deaths is needed in order to achieve the Sustainable Development Goal child mortality target. This will require a focus on vulnerable children-including young children, those who are undernourished or with acute illnesses requiring hospitalization. Improving adherence to inpatient guidelines may be an important strategy to reduce child mortality, including among the most vulnerable. The aim of our assessment of nine sub-Saharan African and South Asian hospitals was to determine adherence to pediatric inpatient care recommendations, in addition to capacity for and barriers to implementation of guideline-adherent care prior to commencing the Childhood Acute Illness and Nutrition (CHAIN) Cohort study. The CHAIN Cohort study aims to identify modifiable risk factors for poor inpatient and post discharge outcomes above and beyond implementation of guidelines. Hospital infrastructure, staffing, durable equipment, and consumable supplies such as medicines and laboratory reagents, were evaluated through observation and key informant interviews. Inpatient medical records of 2-23 month old children were assessed for adherence to national and international guidelines. The records of children with severe acute malnutrition (SAM) were oversampled to reflect the CHAIN study population. Seven core adherence indicators were examined: oximetry and oxygen therapy, fluids, anemia diagnosis and transfusion, antibiotics, malaria testing and antimalarials, nutritional assessment and management, and HIV testing. All sites had facilities and equipment necessary to implement care consistent with World Health Organization and national guidelines. However, stockouts of essential medicines and laboratory reagents were reported to be common at some sites, even though they were mostly present during the assessment visits. Doctor and nurse to patient ratios varied widely. We reviewed the notes of 261 children with admission diagnoses of sepsis (17), malaria (47), pneumonia (70), diarrhea (106), and SAM (119); 115 had multiple diagnoses. Adherence to oxygen therapy, antimalarial, and malnutrition refeeding guidelines was >75%. Appropriate antimicrobials were prescribed for 75% of antibiotic-indicative conditions. However, 20/23 (87%) diarrhea and 20/27 (74%) malaria cases without a documented indication were prescribed antibiotics. Only 23/122 (19%) with hemoglobin levels meeting anemia criteria had recorded anemia diagnoses. HIV test results were infrequently documented even at hospitals with universal screening policies (66/173, 38%). Informants at all sites attributed inconsistent guideline implementation to inadequate staffing. Assessed hospitals had the infrastructure and equipment to implement guideline-consistent care. While fluids, appropriate antimalarials and antibiotics, and malnutrition refeeding adherence was comparable to published estimates from low- and high-resource settings, there were inconsistencies in implementation of some other recommendations. Stockouts of essential therapeutics and laboratory reagents were a noted barrier, but facility staff perceived inadequate human resources as the primary constraint to consistent guideline implementation.


Finite-difference time-domain analysis of photonic crystal slab cavities with two-level systems.
In this paper, we report the numerical simulation of an atom-cavity interaction within photonic crystal nano-cavities. The numerical model is based on a damping oscillator description of a dipole current and it is implemented with a finite-difference time-domain method. Using the method, we successfully simulate the atom-cavity mode field interactions of a two-level system embedded in a photonic crystal cavity under several coupling strength conditions. We show that enhancement and suppression of optical emission rate from a two-level system are also shown by this model.


World Congress of Epidemiology 2011: themes and highlights.
Modern-day epidemiologists are confronted with huge changes, such as the rise in the global population due to reduced mortality, migration within and across countries, massive shifts in economic standing and lifestyles, and environmental degradation. With over 1000 posters, more than 100 oral presentations, 16 workshops, four lunchtime symposia, many exhibitions and immeasurable discussions, the task of capturing all highlights of the International Epidemiology Association (IEA) World Congress of Epidemiology 2011 is impossible, but this article has provided a sample. Many presenters showed that the challenges facing global health are complex, changing and in demand of measurement, and they demonstrated the central role of epidemiology. The cutting-edge methodologies theme promised the emergence of a more transparent, better balanced, but also more critical approach to dealing with bias. Preceding the United Nations high-level meeting on non-communicable diseases (New York, 19th-20th September 2011), the Congress's chronic diseases stream was especially timely. The neglected conditions theme illustrated inspiring work battling against apathy, inertia and ignorance; perhaps the special challenge of the 'neglected conditions epidemiologist'. Translating epidemiology's insights into effective policies and programmes to prevent diseases or reduce their impact is not easy. Speakers highlighted the common failure of epidemiologists to contribute actively to improving the health of the populations they serve, especially the poor and disadvantaged, but also provided many examples where they had done so. The 'other' theme ensured that important studies were not lost from the programme just because they did not fit easily into the specific themes. The studies focused on identified risk factors throughout the life course. A variety of methods were used to identify factors that altered the rate of birth, disease and death. Ongoing epidemiology is not only broad but is also deep, and ever more so as collaborative pooling of expertise, data, populations and ideas has emerged, accelerated by modern-day communication technologies. Epidemiology, and epidemiologists, seem poised for tomorrow's world.