Thiamine status in humans and content of phosphorylated thiamine derivatives in biopsies and cultured cells.
Thiamine (vitamin B1) is an essential molecule for all life forms because thiamine diphosphate (ThDP) is an indispensable cofactor for oxidative energy metabolism. The less abundant thiamine monophosphate (ThMP), thiamine triphosphate (ThTP) and adenosine thiamine triphosphate (AThTP), present in many organisms, may have still unidentified physiological functions. Diseases linked to thiamine deficiency (polyneuritis, Wernicke-Korsakoff syndrome) remain frequent among alcohol abusers and other risk populations. This is the first comprehensive study on the distribution of thiamine derivatives in human biopsies, body fluids and cell lines. Thiamine derivatives were determined by HPLC. In human tissues, the total thiamine content is lower than in other animal species. ThDP is the major thiamine compound and tissue levels decrease at high age. In semen, ThDP content correlates with the concentration of spermatozoa but not with their motility. The proportion of ThTP is higher in humans than in rodents, probably because of a lower 25-kDa ThTPase activity. The expression and activity of this enzyme seems to correlate with the degree of cell differentiation. ThTP was present in nearly all brain and muscle samples and in ∼60% of other tissue samples, in particular fetal tissue and cultured cells. A low ([ThTP]+[ThMP])/([Thiamine]+[ThMP]) ratio was found in cardiovascular tissues of patients with cardiac insufficiency. AThTP was detected only sporadically in adult tissues but was found more consistently in fetal tissues and cell lines. The high sensitivity of humans to thiamine deficiency is probably linked to low circulating thiamine concentrations and low ThDP tissue contents. ThTP levels are relatively high in many human tissues, as a result of low expression of the 25-kDa ThTPase. Another novel finding is the presence of ThTP and AThTP in poorly differentiated fast-growing cells, suggesting a hitherto unsuspected link between these compounds and cell division or differentiation.


Managing NAFLD in Type 2 Diabetes: The Effect of Lifestyle Interventions, a Narrative Review.
The prevalence of non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) is increasing. As a strong association between these two diseases exist, it is unsurprising that the number of patients with coexisting NAFLD and T2D is also increasing. These patients display a deleterious metabolic profile (e.g. hypertriglyceridemia), and increased mortality rates relative to those with only NAFLD or T2D in isolation; therefore, effective treatment strategies are required. Here we review the available intervention studies that have investigated the effects of changes in lifestyle (diet and exercise/physical activity) on NAFLD in patients with both NAFLD and T2D. On the basis of the available evidence, it appears that the addition of any kind of exercise (i.e. resistance, aerobic, or high-intensity intermittent exercise) is beneficial for patients with both NAFLD and T2D. These effects appear to occur independently of changes in body weight. Hypocaloric diets leading to weight loss are also effective in improving metabolic parameters in patients with both NAFLD and T2D, with data indicating that ~ 7-10% weight loss is required in order to observe beneficial effects. It is unclear if multidisciplinary interventions incorporating changes in both diet and physical activity levels are a more effective treatment strategy in this population than diet or exercise interventions in isolation. In conclusion, it is clear that lifestyle interventions are an effective treatment strategy in patients with both NAFLD and T2D, although further research is required to optimise these interventions and determine their scalability.


The influence of early-life allocation to antlers on male performance during adulthood: Evidence from contrasted populations of a large herbivore.
To secure mating opportunities, males often develop and maintain conspicuous traits that are involved in intrasexual and/or intersexual competition. While current models of sexual selection rely on the assumption that producing such traits is costly, quantifying the cost of allocating to secondary sexual traits remains challenging. According to the principle of allocation, high energy allocation to growth or sexual traits in males should lead to reduced energy allocation to the maintenance of cellular and physiological functions, potentially causing them to age faster, with impaired survival. We evaluated the short-term and delayed consequences of energy allocation to antlers early in life in two contrasted populations of roe deer, Capreolus capreolus. Although most males mate successfully for the first time in their fourth year, antlers are grown annually from the first year of life onwards. We tested the prediction that a high level of allocation to antler growth during the first two years of life should lead to lower body mass, antler size and survival during the early and late prime stages, as well as to reduced longevity overall. Growing and carrying long antlers during the first years of life was not associated with any detectable cost in the late prime stage. The positive association between antler growth in early life and adult body mass instead supports that fawn antler acts as an honest signal of phenotypic quality in roe deer. For a given body mass, yearling males growing longer antlers displayed impaired performance during their late prime. We also found a trend for a short-term survival cost of allocation to relative antler length during the second year of life. Yearling males that grow long antlers relative to their mass might display a fast life-history tactic. We argue that differential allocation to secondary sexual traits generates a diversity of individual trajectories that should impact population dynamics.


Astrocytic swelling, phospholipase A2, glutathione and glutamate: interactions in methylmercury-induced neurotoxicity.
Methylmercury (MeHg) is a significant environmental contaminant that will continue to pose great risk to human health. Considerable attention in the scientific and health policy fora is focused on the question of whether MeHg intake from a diet high in fish is associated with aberrant CNS function. A number of recent studies (McKeown-Eyssen et al., 1983; Kjellstrom et al., 1989; Grandjean et al., 1997) suggest that fetal exposure at levels attained by mothers eating fish regularly during pregnancy are associated with neurological deficits in their offspring. Astrocytes play a key role in MeHg-induced excitotoxicity as evidence by the following points: 1) MeHg preferentially accumulates in astrocytes; 2) MeHg potently and specifically inhibits glutamate uptake in astrocytes; 3) Neuronal dysfunction is secondary to disturbances in astrocytes; 4) Co-application of non-toxic concentrations of MeHg and glutamate leads to the typical appearance of neuronal lesions associated with excitotoxic stimulation, and 5) MeHg induces swelling of astrocytes. These observations are fully consistent with MeHg-induced dysregulation of excitatory amino acid homeostasis, and indicate that a glutamate-mediated excitotoxic mechanism is involved. The manuscript will outline a number of critical target sites for MeHg-induced neurotoxicity. It will address the interrelationship between the activation of cytosolic phospholipase A2 (cPLA2) and the ensuing hydrolysis and release of arachidonic acid (AA) as potential mediators for glutamate release upon exposure to MeHg, and determine the relationship between cytosolic cPLA2 activation, regulatory volume decrease (RVD), and glutamate release. In addition, the effect of MeHg on glutathione (GSH) homeostasis will be discussed, with particular emphasis on its effects on cystine and cysteine uptake, precursors of GSH synthesis.


The effect of phencyclidine on the turnover rate of acetylcholine in various regions of rat brain.
Although the mechanism of action of phencyclidine is poorly understood, an interaction of phencyclidine with central cholinergic systems has been proposed. To test this hypothesis directly, we investigated the effects of this compound on the turnover rate of acetylcholine (TRACh) in various areas of the rat brain. In doses of 14.3 to 114.4 mumol/kg (i.p.), phencyclidine increased the TRACh in the frontal cortex, parietal cortex and diencephalon when rats were sacrificed 30 min after drug treatment. In contrast, these doses of phencyclidine had no effect on the TRACh in the hippocampus or striatum. The increases in cortical and diencephalic TRACh were temporally correlated with the behavioral activity elicited by phencyclidine. A 7 day chronic treatment regimen (28.6 mumol/kd/day) provided no further evidence for tolerance development to the effects of phencyclidine on the TRACh in the frontal cortex or diencephalon. These results demonstrate that phencyclidine differentially affects cholinergic dynamics in various areas of the rat brain. The neurochemical profile of phencyclidine reported herein is similar to those previously described for central stimulants such as d-amphetamine, nomifensine and cocaine.


The dawn of open access to phylogenetic data.
The scientific enterprise depends critically on the preservation of and open access to published data. This basic tenet applies acutely to phylogenies (estimates of evolutionary relationships among species). Increasingly, phylogenies are estimated from increasingly large, genome-scale datasets using increasingly complex statistical methods that require increasing levels of expertise and computational investment. Moreover, the resulting phylogenetic data provide an explicit historical perspective that critically informs research in a vast and growing number of scientific disciplines. One such use is the study of changes in rates of lineage diversification (speciation--extinction) through time. As part of a meta-analysis in this area, we sought to collect phylogenetic data (comprising nucleotide sequence alignment and tree files) from 217 studies published in 46 journals over a 13-year period. We document our attempts to procure those data (from online archives and by direct request to corresponding authors), and report results of analyses (using Bayesian logistic regression) to assess the impact of various factors on the success of our efforts. Overall, complete phylogenetic data for [Formula: see text] of these studies are effectively lost to science. Our study indicates that phylogenetic data are more likely to be deposited in online archives and/or shared upon request when: (1) the publishing journal has a strong data-sharing policy; (2) the publishing journal has a higher impact factor, and; (3) the data are requested from faculty rather than students. Importantly, our survey spans recent policy initiatives and infrastructural changes; our analyses indicate that the positive impact of these community initiatives has been both dramatic and immediate. Although the results of our study indicate that the situation is dire, our findings also reveal tremendous recent progress in the sharing and preservation of phylogenetic data.


Assessment of Unilateral Spatial Neglect Using a Free Mobile Application for Italian Clinicians.
Background: Unilateral Spatial Neglect (USN) is traditionally assessed with paper-and-pencil tests or computer-based tests. Thanks to the wide-spreading of mobile devices, and the extensive capabilities that they have in dealing complex elements, it is possible to provide clinicians with tools for cognitive assessment. Contemporary 3D engine is, in general generally, able to deploy complex 3D environments for iOS, Android and Windows mobile, i.e., most of the mobile phone and tablet operative systems. Results: This brand-new scenario and pressing requests from professionals, pushed us to build an application for the assessment of USN. Our first attempt was to replicate the classic cognitive tests, traditionally used at this purpose. Ecological assessment is difficult in real scenarios so we implemented virtual environments to assess patients' abilities in realistic situations. At the moment, the application is available only for iPad and iPhone for free, from the Apple Store, under the name of "Neglect App." The App contains traditional tests (e.g., barrage with and without distractors) and ecological tests (e.g., to distribute the tea in a table to close people). Scoring of each test is available to the clinicians through a database with the executed ecological tasks, that are stored locally. Conclusion: In conclusion, Neglect App is an advanced mobile platform for the assessment of Neglect.


Decoding of cytoplasmic Ca(2+) oscillations through the spatial signature drives gene expression.
Cytoplasmic Ca(2+) oscillations are a universal signaling mode that activates numerous cellular responses [1, 2]. Oscillations are considered the physiological mechanism of Ca(2+) signaling because they occur at low levels of stimulus intensity [3]. Ca(2+) oscillations are proposed to convey information in their amplitude and frequency, leading to activation of specific downstream targets [4-6]. Here, we report that the spatial Ca(2+) gradient within the oscillation is key. Ca(2+) oscillations in mast cells evoked over a range of agonist concentrations in the presence of external Ca(2+) were indistinguishable from those in the absence of Ca(2+) when plasmalemmal Ca(2+) extrusion was suppressed. Nevertheless, only oscillations with accompanying Ca(2+) entry through store-operated CRAC channels triggered gene expression. Increased cytoplasmic Ca(2+) buffering prevented oscillations but not gene activation. Local Ca(2+) influx and not global Ca(2+) oscillations therefore drives gene expression at physiological levels of stimulation. Rather than serving to maintain Ca(2+) oscillations by replenishing stores, we suggest that the role of oscillations might be to activate CRAC channels, thereby ensuring the generation of spatially restricted physiological Ca(2+) signals driving gene activation. Furthermore, we show that the spatial profile of a Ca(2+) oscillation provides a novel mechanism whereby a pleiotropic messenger specifically activates gene expression.


Revision of the species of the Merodon nanus group (Diptera: Syrphidae) including three new species.
The nanus group of the genus Merodon Meigen (Diptera, Syrphidae) is revised, yielding an illustrated key, a discussion of taxonomic characters and morphological diagnosis for the five species of this group. Three new cryptic species are described, Merodon kopensis Vujić et Hayat sp. n., M. neonanus Vujić et Taylor sp. n. and M. rasicus Vujić et Radenković sp. n. New diagnostic characters are given for M. nanus Sack and M. telmateia Hurkmans. In addition, environmental profiles for each investigated species have been defined and compared, and maps of distribution and richness created. Niche dissimilarity was found for each species. Eastern Anatolia and the southern Aegean region of Turkey are reported as the most species rich regions for the nanus group.


Nuclear proteins in the heart of the cardiomyopathic Syrian hamster. Phosphorylation of phenol-soluble nonhistone proteins.
We examined incorporation of 32P into phenol-soluble nonhistone nuclear acidic proteins (NHNP) obtained from myolytic, hypertrophic, and failing phases of hamster cardiomyopathy. NHNP from these dystrophic hamster hearts were phosphorylated much less than their controls, despite a 9-fold increase in uptake of 32P into their nuclei. After fractionation of NHNP by isoelectrofocusing polyacrylamide gel electrophoresis, two major fractions focusing from pH 6.0 to 6.2 and 6.6 to 6.8 were highly phosphorylated in both the control and dystrophic hearts. The latter fraction was much more phosphorylated in the control. Two fractions of NHNP focusing at pH 4.9 and 5.1 were more highly phosphorylated in the dystrophic hearts than in the controls. Autoradiographs obtained from the two-dimensional polyacrylamide slab gel electrophoresis showed that two proteins (pH 4.9 and 5.1; mol wt 25,000 and 60,000, respectively) were highly phosphorylated in the dystrophic heart. There was no detectable phosphorylation of these proteins in the controls. These changes in the phosphorylation of cardiac NHNP may be important in determining the alteration of gene expression in hamster cardiomyopathy.


A scoping review of evaluation frameworks and their applicability to real-world physical activity and dietary change programme evaluation.
Physical activity and dietary change programmes play a central role in addressing public health priorities. Programme evaluation contributes to the evidence-base about these programmes; and helps justify and inform policy, programme and funding decisions. A range of evaluation frameworks have been published, but there is uncertainty about their usability and applicability to different programmes and evaluation objectives, and the extent to which they are appropriate for practitioner-led or researcher-led evaluation. This review appraises the frameworks that may be applicable to evaluation of physical activity and/or dietary change programmes, and develops a typology of the frameworks to help guide decision making by practitioners, commissioners and evaluators. A scoping review approach was used. This included a systematic search and consultation with evaluation experts to identify evaluation frameworks and to develop a set of evaluation components to appraise them. Data related to each framework's general characteristics and components were extracted. This was used to construct a typology of the frameworks based on their intended programme type, evaluation objective and format. Each framework was then mapped against the evaluation components to generate an overview of the guidance included within each framework. The review identified 71 frameworks. These were described variously in terms of purpose, content, or applicability to different programme contexts. The mapping of frameworks highlighted areas of overlap and strengths and limitations in the available guidance. Gaps within the frameworks which may warrant further development included guidance on participatory approaches, non-health and unanticipated outcomes, wider contextual and implementation factors, and sustainability. Our typology and mapping signpost to frameworks where guidance on specific components can be found, where there is overlap, and where there are gaps in the guidance. Practitioners and evaluators can use these to identify, agree upon and apply appropriate frameworks. Researchers can use them to identify evaluation components where there is already guidance available and where further development may be useful. This should help focus research efforts where it is most needed and promote the uptake and use of evaluation frameworks in practice to improve the quality of evaluation and reporting.


Mutation screening in Borjeson-Forssman-Lehmann syndrome: identification of a novel de novo PHF6 mutation in a female patient.
Börjeson-Forssman-Lehmann syndrome (BFLS; MIM 301900) is an infrequently described X linked disorder caused by mutations in PHF6, a novel zinc finger gene of unknown function. To present the results of mutation screening in individuals referred for PHF6 testing and discuss the value of prior X-inactivation testing in the mothers of these individuals. 25 unrelated individuals were screened (24 male, one female). Five PHF6 mutations were detected, two of which (c.940A-->G and c.27_28insA) were novel. One of these new mutations, c.27_28insA, was identified in a female BFLS patient. This was shown to be a de novo mutation arising on the paternal chromosome. This is the first report of a clinically diagnosed BFLS female with a confirmed PHF6 mutation. In addition, the X-inactivation status of the mothers of 19 males with suggested clinical diagnosis of BFLS was determined. Skewed (> or =70%) X-inactivation was present in five mothers, three of whom had sons in whom a PHF6 mutation was detected. The mutation positive female also showed skewing. The results indicate that the success of PHF6 screening in males suspected of having BFLS is markedly increased if there is a positive family history and/or skewed X-inactivation is found in the mother.


Boysenberry Polyphenols Suppressed Elevation of Plasma Triglyceride Levels in Rats.
Boysenberry, a hybrid Rubus berry, is mainly cultivated in New Zealand. We previously reported that consumption of boysenberry juice (BBJ) exhibited anti-obesity effects in high-fat feeding rats. In this study, we focused on the suppressive effect of BBJ and its fraction on triglyceride absorption from the gastrointestinal tract. BBJ effectively inhibited pancreatic lipase activity in vitro, and was separated into four fractions (Fr1, Fr2, Fr3 and Fr4) by HP-20 column chromatography. Among all the fractions, Fr3, the ellagic acid-rich fraction, showed the most potent inhibition against pancreatic lipase in vitro with Fr2, the anthocyanin-rich fraction, second. Authentic ellagic acid equivalent in Fr3 showed poor activity against pancreatic lipase. Then, each fraction was orally administered with corn oil to rats fitted with a jugular catheter to examine the effects of each fraction on plasma triglyceride levels. Both Fr2 and Fr3 effectively suppressed the plasma triglyceride level elevation at a dose of 1,000 mg/kg body weight. These findings demonstrated that BBJ contains chemical components which inhibit triglyceride absorption from the gastrointestinal tract.


Bone structure and perfusion quantification of bone marrow edema pattern in the wrist of patients with rheumatoid arthritis: a multimodality study.
To quantify bone structure and perfusion parameters in regions of bone marrow edema pattern (BMEP), non-edematous bone marrow (NBM), and pannus tissue areas in the wrists of patients with rheumatoid arthritis (RA) using 3-Tesla (3T) magnetic resonance imaging (MRI), and high resolution peripheral quantitative computed tomography (HR-pQCT). Sixteen subjects fulfilling American College of Rheumatology classification were imaged using a HR-pQCT system and a 3T MRI scanner with an 8-channel wrist coil. Coronal T2-weighted and dynamic contrast-enhanced (DCE-MRI) images were acquired. BMEP and pannus tissue areas were segmented semiautomatically in T2-weighted images. NBM areas were placed at a similar distance from the joint space as BMEP regions. MR and HR-pQCT images were registered, and bone variables were calculated within the BMEP and NBM regions. Perfusion parameters in BMEP, pannus tissue, and NBM regions were calculated based on the signal-time curve obtained from DCE-MRI. Eighteen BMEP areas were segmented, 15 of them presented proximal to pannus-filled erosions. Significant increases in bone density and trabecular thickness and number were observed in all BMEP regions compared to NMB (p < 0.05). Significantly elevated perfusion measures were observed in both BMEP and pannus tissue regions compared to NBM (p < 0.05). BMEP regions showed significantly increased bone density and structures as well as perfusion measures, suggesting bone remodeling and active inflammation. Combining MRI and HR-pQCT provides a powerful multimodality approach for understanding BMEP and erosions, and for potentially identifying novel imaging markers for disease progression in RA.


Hydrodynamic interactions in active colloidal crystal microrheology.
In dense colloids it is commonly assumed that hydrodynamic interactions do not play a role. However, a found theoretical quantification is often missing. We present computer simulations that are motivated by experiments where a large colloidal particle is dragged through a colloidal crystal. To qualify the influence of long-ranged hydrodynamics, we model the setup by conventional Langevin dynamics simulations and by an improved scheme with limited hydrodynamic interactions. This scheme significantly improves our results and allows to show that hydrodynamics strongly impacts the development of defects, the crystal regeneration, as well as the jamming behavior.


The efficacy of aloe vera gel in the treatment of oral lichen planus: a randomized controlled trial.
Oral lichen planus (OLP) is a chronic inflammatory disease that can be painful especially in the atrophic and erosive forms. Several therapies have been tried, with varying results. There is one case report in which aloe vera (AV) was used successfully in the treatment of lichen planus. To compare the efficacy of AV and placebo in the topical management of OLP. A randomized, double-blind, placebo-controlled trial was designed. Fifty-four patients were randomized into two groups to receive AV gel or placebo for 8 weeks. Fifty-four consecutive patients (34 women and 20 men) participated in the study. We found erosive and ulcerative lesions in 83% and 17%, respectively. The most common site of OLP was the lower lip. Twenty-two of 27 patients treated with AV (81%) had a good response after 8 weeks of treatment, while one of 27 placebo-treated patients (4%) had a similar response (P<0.001). Furthermore, two patients treated with AV (7%) had a complete clinical remission. Burning pain completely disappeared in nine patients treated with AV (33%) and in one treated with placebo (4%) (P=0.005). Symptomatology improved by at least 50% (good response) in 17 patients treated with AV (63%) and in two treated with placebo (7%) (P<0.001). No serious side-effects were found in both groups. AV gel is statistically significantly more effective than placebo in inducing clinical and symptomatological improvement of OLP. Therefore, AV gel can be considered a safe alternative treatment for patients with OLP.


Rationale, design, and methodology of the Evaluation of Perceptions, Knowledge, and Compliance with the Guidelines in Real Life Practice: A Survey on the Under-treatment of Hypercholesterolemia.
A wide gap exists between dyslipidemia guidelines and their implementation in the real world, which is primarily attributed to physician and patient compliance. The aim of this study is to determine physician and patient adherence to dyslipidemia guidelines and various influential factors. The Evaluation of Perceptions, Knowledge, and Compliance with the Guidelines in Real Life Practice: A Survey on the Under-treatment of Hypercholesterolemia (EPHESUS) trial (ClinicalTrials.gov number NCT02608645) will be an observational, multicenter, non-interventional study. The study targets enrollment of 2000 patients from 50 locations across Turkey. All of the data will be collected in a single visit and current clinical practice will be evaluated. A cross-sectional survey of public perception and knowledge of cholesterol treatment among Turkish adults will be performed. All consecutive patients admitted to cardiology clinics who are in the secondary prevention group (coronary heart disease, peripheral artery disease, atherosclerotic cerebrovascular disease) and who are in the high-risk primary prevention group (type 2 diabetes mellitus with no prior known coronary heart disease; patients who had markedly elevated single risk factors, in particular, cholesterol >8 mmol/L [>310 mg/dL], blood pressure ≥180/110 mmHg, a calculated Systematic Coronary Risk Evaluation [SCORE] ≥5%, or <10% 10-year risk of fatal cardiovascular disease) will be included. Demographic, lifestyle, medical, and therapeutic data will be collected with a survey designed for the study. The EPHESUS registry will be the largest study conducted in Turkey evaluating the adherence to dyslipidemia guidelines both in secondary and high-risk primary prevention patients.


Allogeneic Hemopoietic Stem Cell Transplants in Patients with Acute Myeloid Leukemia (AML) Prepared with Busulfan and Fludarabine (BUFLU) or Thiotepa, Busulfan, and Fludarabine (TBF): A Retrospective Study.
This is a multicenter retrospective comparison of 2 myeloablative conditioning regimens in 454 patients with acute myeloid leukemia (AML) in remission: busulfan (4 days) and fludarabine (BUFLU) versus thiotepa, busulfan, and fludarabine (TBF). Eligible for this study were patients allografted between January 2008 and December 2018 in 10 transplant centers, with AML in first or second remission: 201 patients received BUFLU, whereas 253 received TBF. The 2 groups (BUFLU and TBF) were comparable for age (P = .13) and adverse AML risk factors (P = .3). The TBF group had more second remissions and more haploidentical grafts. The donor type included HLA-identical siblings, unrelated donors, and family haploidentical donors. The 5-year cumulative incidence of nonrelapse mortality (NRM) was 19% for BUFLU and 22% for TBF (P = .8), and the 5-year cumulative incidence of relapse was 30% and 15%, respectively (P = .0004). The 5-year actuarial survival was 51% for BUFLU and 68% for TBF (P = .002). In a multivariate Cox analysis, after correcting for confounding factors, the use of TBF reduced the risk of relapse compared with BUFLU (P = .03) and the risk of death (P = .03). In a matched pair analysis of 108 BUFLU patients matched with 108 TBF patients, with the exclusion of haploidentical grafts, TBF reduced the risk of relapse (P = .006) and there was a trend for improved survival (P = .07). Superior survival of patients receiving TBF as compared with BUFLU is due to a reduced risk of relapse, with comparable NRM. The survival advantage is independent of donor type and AML risk factors.


Combining slanted-frame classifiers for improved HMM-based Arabic handwriting recognition.
The problem addressed in this study is the offline recognition of handwritten Arabic city names. The names are assumed to belong to a fixed lexicon of about 1,000 entries. A state-of-the-art classical right-left hidden Markov model (HMM)-based recognizer (reference system) using the sliding window approach is developed. The feature set includes both baseline-independent and baseline-dependent features. The analysis of the errors made by the recognizer shows that the inclination, overlap, and shifted positions of diacritical marks are major sources of errors. In this paper, we propose coping with these problems. Our approach relies on the combination of three homogeneous HMM-based classifiers. All classifiers have the same topology as the reference system and differ only in the orientation of the sliding window. We compare three combination schemes of these classifiers at the decision level. Our reported results on the benchmark IFN/ENIT database of Arabic Tunisian city names give a recognition rate higher than 90 percent accuracy and demonstrate the superiority of the neural network-based combination. Our results also show that the combination of classifiers performs better than a single classifier dealing with slant-corrected images and that the approach is robust for a wide range of orientation angles.


Karyotype plasticity in crickets: numerical, morphological, and nucleolar organizer region distribution pattern of Anurogryllus sp.
Within the Orthopteran species, those of the suborder Ensifera have been rarely studied from the cytogenetic point of view, mainly due to the difficulties for taxonomic identification of its species. The Gryllidae is the second largest family of this suborder and possesses some genera, such as Anurogryllus, that occur only on the American continents. The aim of this work was to determine the karyotype characteristics, the meiotic chromosome behaviour, and the nucleolar organizer region (NOR) pattern of Anurogryllus sp (Orthoptera: Gryllidae). In the analyzed sample, high levels of numerical, morphological, and NORs polymorphisms were detected. Within five distinct karyotypes that were found, the basic karyotype of Anurogryllus sp. showed 2n(male symbol) = 22 + X0 with acrocentric autosomes and a metacentric X sex chromosome; furthermore, a conspicuous secondary constriction related to the NOR was present along the entire short arm on pair 5. The other four types of karyotypes arose from centric fusions between elements of pairs 1/3, 2/6, 4/7 and a NOR partial translocation from pair 5 onto the long arm terminal region of one element of the fused pair 2/6. Such intraspecific variability and the consequences of high levels of polymorphism are discussed, leading to conjectures about the mechanisms that led to these chromosome rearrangements.


Serum concentrations of pegylated interferon alpha-2b in patients with resected stage III melanoma receiving adjuvant pegylated interferon alpha-2b in a randomized phase III trial (EORTC 18991).
The EORTC 18991 trial assessed the effect of long-term adjuvant pegylated interferon (Peg-IFN) alpha-2b administered weekly in patients with lymph node-positive melanoma. Serum concentrations were analyzed to determine exposure to Peg-IFN alpha-2b. After surgery, patients were randomized to receive Peg-IFN alpha-2b or to observation only. The treatment group received 6 microg/kg/week Peg-IFN alpha-2b subcutaneously for 8 weeks, followed by a maintenance dose of 3 microg/kg/week for up to 5 years. Blood samples were collected between months 3 and 60. A total of 208 Peg-IFN alpha-2b concentrations from 48 patients were available. Serum trough concentrations increased in a dose-related manner. Mean dose-normalized serum concentrations and intersubject variability over the 5-year study period in patients with melanoma were similar to those observed in patients with chronic hepatitis. Data suggest that the exposure to Peg-IFN alpha-2b was sustained during long-term adjuvant treatment with Peg-IFN alpha-2b in patients with melanoma, consistent with the EORTC 18991 trial's conclusion of a significant, sustained, and relapse-free survival benefit.


The role of nurse practitioners in hospital settings: implications for interprofessional practice.
Expansion of the nurse practitioner (NP) role worldwide indicates a need to understand how the role functions in interprofessional healthcare teams. Through the adoption of a mixed methods approach that gathered on-site tracking and observation, self-recorded logs of consultations and focus group interviews of team members and NPs, we describe the extent of role activity and the nature of interprofessional practices of 46 NPs and their team members in nine hospital sites across the province of Ontario, Canada. Findings outline the nature of the NP role activities, which largely focused on providing clinical care, with the support of their team, to a range of patients across the study settings. We discuss how 'embedding' the NP in this way appears to contribute to utilization of expertise of all professions as well as enabling team members to promote evidence-based practices. We argue that the use of NPs augments interprofessional role utilization through their desire to consult with a range of professionals and the capacity to perform holistic care for patients that is not limited to traditional nursing boundaries.


Patterns in Reduction or Cessation of Drinking in Australia (2001-2013) and Motivation for Change.
This paper examines: (a) change over time (2001-2013) in recently reducing or ceasing drinking in the Australian population and (b) the reasons given for reducing or ceasing drinking in the most recent survey (2013); stratified by sex and age group. Rates of reducing and ceasing drinking increased between 2001 and 2013 in Australia. Young people were more likely to modify drinking due to lifestyle and enjoyment reasons; older groups were more likely to report health reasons. These trends contribute to the broader context of declining alcohol consumption in Australia. Data are from five waves of the National Drug Strategy Household Survey (N = 119,397). Logistic regression models with interaction terms were used to identify a shift in sex or age over time in predicting reduction or cessation of drinking and to predict motivations for reducing or ceasing drinking by sex and age. Reports of recently reducing the quantity or frequency of drinking increased from 2001 to 2007 and remained stable between 2007 and 2013. There was a steady increase in the number of Australians reporting recently ceasing drinking from 2001 to 2013, with a significant effect for age (younger groups more likely than older groups to cease drinking in the past two waves). Reasons for reducing or ceasing drinking varied by age, with older people more likely to report health reasons and younger people more likely to report lifestyle reasons or enjoyment. Increases over time in reports of reduction or cessation of drinking due to health, lifestyle, social and enjoyment reasons suggest that the social position of alcohol in Australia may be shifting, particularly among young people.


Bi-directional gene set enrichment and canonical correlation analysis identify key diet-sensitive pathways and biomarkers of metabolic syndrome.
Currently, a number of bioinformatics methods are available to generate appropriate lists of genes from a microarray experiment. While these lists represent an accurate primary analysis of the data, fewer options exist to contextualise those lists. The development and validation of such methods is crucial to the wider application of microarray technology in the clinical setting. Two key challenges in clinical bioinformatics involve appropriate statistical modelling of dynamic transcriptomic changes, and extraction of clinically relevant meaning from very large datasets. Here, we apply an approach to gene set enrichment analysis that allows for detection of bi-directional enrichment within a gene set. Furthermore, we apply canonical correlation analysis and Fisher's exact test, using plasma marker data with known clinical relevance to aid identification of the most important gene and pathway changes in our transcriptomic dataset. After a 28-day dietary intervention with high-CLA beef, a range of plasma markers indicated a marked improvement in the metabolic health of genetically obese mice. Tissue transcriptomic profiles indicated that the effects were most dramatic in liver (1270 genes significantly changed; p < 0.05), followed by muscle (601 genes) and adipose (16 genes). Results from modified GSEA showed that the high-CLA beef diet affected diverse biological processes across the three tissues, and that the majority of pathway changes reached significance only with the bi-directional test. Combining the liver tissue microarray results with plasma marker data revealed 110 CLA-sensitive genes showing strong canonical correlation with one or more plasma markers of metabolic health, and 9 significantly overrepresented pathways among this set; each of these pathways was also significantly changed by the high-CLA diet. Closer inspection of two of these pathways--selenoamino acid metabolism and steroid biosynthesis--illustrated clear diet-sensitive changes in constituent genes, as well as strong correlations between gene expression and plasma markers of metabolic syndrome independent of the dietary effect. Bi-directional gene set enrichment analysis more accurately reflects dynamic regulatory behaviour in biochemical pathways, and as such highlighted biologically relevant changes that were not detected using a traditional approach. In such cases where transcriptomic response to treatment is exceptionally large, canonical correlation analysis in conjunction with Fisher's exact test highlights the subset of pathways showing strongest correlation with the clinical markers of interest. In this case, we have identified selenoamino acid metabolism and steroid biosynthesis as key pathways mediating the observed relationship between metabolic health and high-CLA beef. These results indicate that this type of analysis has the potential to generate novel transcriptome-based biomarkers of disease.


DDB1 maintains genome integrity through regulation of Cdt1.
DDB1, a component of a Cul4A ubiquitin ligase complex, promotes nucleotide excision repair (NER) and regulates DNA replication. We have investigated the role of human DDB1 in maintaining genome stability. DDB1-depleted cells accumulate DNA double-strand breaks in widely dispersed regions throughout the genome and have activated ATM and ATR cell cycle checkpoints. Depletion of Cul4A yields similar phenotypes, indicating that an E3 ligase function of DDB1 is important for genome maintenance. In contrast, depletion of DDB2, XPA, or XPC does not cause activation of DNA damage checkpoints, indicating that defects in NER are not involved. One substrate of DDB1-Cul4A that is crucial for preventing genome instability is Cdt1. DDB1-depleted cells exhibit increased levels of Cdt1 protein and rereplication, despite containing other Cdt1 regulatory mechanisms. The rereplication, accumulation of DNA damage, and activation of checkpoint responses in DDB1-depleted cells require entry into S phase and are partially, but not completely, suppressed by codepletion of Cdt1. Therefore, DDB1 prevents DNA lesions from accumulating in replicating human cells, in part by regulating Cdt1 degradation.


Venous thrombosis in unusual sites: A practical review for the hematologist.
Thrombosis of unusual venous sites encompasses a large part of consultative hematology and is encountered routinely by practicing hematologists. Contrary to the more commonly encountered lower extremity venous thrombosis and common cardiovascular disorders, the various thromboses outlined in this review have unique presentations, pathophysiology, workup, and treatments that all hematologists should be aware of. This review attempts to outline the most up to date literature on cerebral, retinal, upper extremity, hepatic, portal, splenic, mesenteric, and renal vein thrombosis, focusing on the incidence, pathophysiology, provoking factors, and current recommended treatments for each type of unusual thrombosis to provide a useful and practical review for the hematologist.


Perioperative hyperoxia: perhaps a malady in disguise.
Oxygen is an element, which is used liberally during several medical procedures. The use of oxygen during perioperative care is a controversial issue. Anesthesiologists use oxygen to prevent hypoxemia during surgical procedures, but the effects of its liberal use can be harmful. Another argument for using high oxygen concentrations is to prevent surgical site infections by increasing oxygen levels at the incision site. Although inconclusive, literature concerning the use of high oxygen concentrations during anesthesia show that this approach may cause hemodynamic changes, altered microcirculation and increased oxidative stress. In intensive care it has been shown that high oxygen concentrations may be associated with increased mortality in certain patient populations such as post cardiac arrest patients. In this paper, a review of literature had been undertaken to warn anesthesiologists about the potential harmful effects of high oxygen concentrations.


[Structural characterization of a glucan isolated from Gastrodia elata].
To study a glucan (GB II) isolated from Gastrodia elata. The glucan was obtained with water extraction, alcohol precipitate, DEAE-Sepharose Fast Flow column and Sepharose CL-6B column chromatography; sugar composition analysis, IR and NMR were used to determine the structural feature. The molecular weight of the glucan was 4 300 dalton estimated by HPGPC; it contained 27 glucose residues, which mainly composed of alpha-D-(1-->4)-glucose with little glucuronic acid and branch O-6 points. The glucan was a new glucan for the first report from Gastrodia elata.


The Effect of Inkjet Printing over Polymeric Films as Potential Buccal Biologics Delivery Systems.
The buccal mucosa appears as a promissory route for biologic drug administration, and pharmaceutical films are flexible dosage forms that can be used in the buccal mucosa as drug delivery systems for either a local or systemic effect. Recently, thin films have been used as printing substrates to manufacture these dosage forms by inkjet printing. As such, it is necessary to investigate the effects of printing biologics on films as substrates in terms of their physical and mucoadhesive properties. Here, we explored solvent casting as a conventional method with two biocompatible polymers, hydroxypropyl methylcellulose, and chitosan, and we used electrospinning process as an electrospun film fabrication of polycaprolactone fibers due to its potential to elicit mucoadhesion. Lysozyme was used as biologic drug model and was formulated as a solution for printing by thermal inkjet printing. Films were characterized before and after printing by mechanical and mucoadhesive properties, surface, and ultrastructure morphology through scanning electron microscopy and solid state properties by thermal analysis. Although minor differences were detected in micrographs and thermograms in all polymeric films tested, neither mechanical nor mucoadhesive properties were affected by these differences. Thus, biologic drug printing on films was successful without affecting their mechanical or mucoadhesive properties. These results open way to explore biologics loading on buccal films by inkjet printing, and future efforts will include further in vitro and in vivo evaluations.


The natural history of multiple sclerosis.
Studies which have attempted to define the outcome of multiple sclerosis (MS) have methodologic difficulties arising from patient referral biases and the length of follow-up required, which make prospective studies of an inception cohort unrealistic. Means to improve the validity of retrospective natural history studies are suggested. Results of existing series are summarized and compared. Survival is only rarely shortened by MS, but disability to the point of requiring aids for ambulation occurs in 30-70% of patients by 15 years from onset of symptoms. Disagreement as to the percentage of patients who are ultimately bedridden by MS likely arises in large part due to differences in patient ascertainment and follow-up. The need to develop early clinical markers for the patient at high risk for rapid development of major disability is stressed.


Identifying dementia outcomes in UK Biobank: a validation study of primary care, hospital admissions and mortality data.
Prospective, population-based studies that recruit participants in mid-life are valuable resources for dementia research. Follow-up in these studies is often through linkage to routinely-collected healthcare datasets. We investigated the accuracy of these datasets for dementia case ascertainment in a validation study using data from UK Biobank-an open access, population-based study of > 500,000 adults aged 40-69 years at recruitment in 2006-2010. From 17,198 UK Biobank participants recruited in Edinburgh, we identified those with ≥ 1 dementia code in their linked primary care, hospital admissions or mortality data and compared their coded diagnoses to clinical expert adjudication of their full-text medical record. We calculated the positive predictive value (PPV, the proportion of cases identified that were true positives) for all-cause dementia, Alzheimer's disease and vascular dementia for each dataset alone and in combination, and explored algorithmic code combinations to improve PPV. Among 120 participants, PPVs for all-cause dementia were 86.8%, 87.3% and 80.0% for primary care, hospital admissions and mortality data respectively and 82.5% across all datasets. We identified three algorithms that balanced a high PPV with reasonable case ascertainment. For Alzheimer's disease, PPVs were 74.1% for primary care, 68.2% for hospital admissions, 50.0% for mortality data and 71.4% in combination. PPV for vascular dementia was 43.8% across all sources. UK routinely-collected healthcare data can be used to identify all-cause dementia in prospective studies. PPVs for Alzheimer's disease and vascular dementia are lower. Further research is required to explore the geographic generalisability of these findings.


Randomized phase 3 trial of ombitasvir/paritaprevir/ritonavir for hepatitis C virus genotype 1b-infected Japanese patients with or without cirrhosis.
GIFT-I is a phase 3 trial evaluating the efficacy and safety of a 12-week regimen of coformulated ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) for treatment of Japanese hepatitis C virus genotype 1b-infected patients. It consists of a double-blind, placebo-controlled substudy of patients without cirrhosis and an open-label substudy of patients with compensated cirrhosis. Patients without cirrhosis were randomized 2:1 to once-daily OBV/PTV/r (25 mg/150 mg/100 mg; group A) or placebo (group B). Patients with cirrhosis received open-label OBV/PTV/r (group C). The primary efficacy endpoint was the rate of sustained virological response 12 weeks posttreatment in interferon-eligible, treatment-naive patients without cirrhosis and hepatitis C virus RNA ≥100,000 IU/mL in group A. A total of 321 patients without cirrhosis were randomized and dosed with double-blind study drug (106 received double-blind placebo and later received open-label OBV/PTV/r), and 42 patients with cirrhosis were enrolled and dosed with open-label OBV/PTV/r. In the primary efficacy population, the rate of sustained virological response 12 weeks posttreatment was 94.6% (106/112, 95% confidence interval 90.5-98.8). Sustained virological response 12 weeks posttreatment rates were 94.9% (204/215) in group A, 98.1% (104/106) in group B (open-label), and 90.5% (38/42) in group C. Overall, virological failure occurred in 3.0% (11/363) of patients who received OBV/PTV/r. The rate of discontinuation due to adverse events was 0%-2.4% in the three patient groups receiving OBV/PTV/r. The most frequent adverse event in patients in any group was nasopharyngitis. In this broad hepatitis C virus genotype 1b-infected Japanese patient population with or without cirrhosis, treatment with OBV/PTV/r for 12 weeks was highly effective and demonstrated a favorable safety profile.


Evolution of viviparous reproduction in Paleozoic and Mesozoic reptiles.
Although viviparity (live-bearing reproduction) is widely distributed among lizards and snakes, it is entirely absent from other extant Reptilia and many extinct forms. However, paleontological evidence reveals that viviparity was present in at least nine nominal groups of pre-Cenozoic reptiles, representing a minimum of six separate evolutionary origins of this reproductive mode. Two viviparous clades (sauropterygians and ichthyopterygians) lasted more than 155 million years, a figure that rivals the duration of mammalian viviparity. Circumstantial evidence indicates that extinct viviparous reptiles had internal fertilization, amniotic fetal membranes, and placentas that sustained developing embryos via provision of respiratory gases, water, calcium, and possibly organic nutrients. Production of offspring via viviparity facilitated the invasion of marine habitats in at least five reptilian lineages. Thus, this pattern of embryonic development and reproduction was central to the ecology and evolution of these ancient animals, much as it is to numerous extant species of vertebrates.


Pneumococcal carriage in households in Karonga District, Malawi, before and after introduction of 13-valent pneumococcal conjugate vaccination.
Thirteen-valent pneumococcal conjugate vaccine (PCV13) was introduced in Malawi in November 2011 and is offered to infants at 6, 10 and 14 weeks of age as part of routine immunisation. PCV13 is expected to reduce vaccine type (VT) nasopharyngeal carriage, leading to reduced transmission and herd protection. We compared pneumococcal carriage in rural Karonga District, Malawi, pre-vaccine in 2009-2011 and post-vaccine in 2014 using a combination of cross-sectional and longitudinal analyses. Nasopharyngeal swabs were collected from a cohort of mother-infant pairs and household members <16 years. Pneumococci from 2009 to 2011 were serogrouped using latex agglutination and serotyped by Quellung reaction. In 2014, latex agglutination was used for both steps. Carriage prevalence ratios using prevalence data from before and after vaccine introduction were calculated by log-binomial regression, adjusted for age, seasonality and household composition. Participating infants in 2014 received PCV13 as part of routine immunisation. VT carriage prior to PCV-13 introduction was 11.4%, 45.1%, 28.2%, 21.2% and 6.6% for 6-week old infants, 18-week old infants, children 1-4 years, children 5-15 years and mothers, respectively. After vaccine introduction, VT carriage decreased among vaccinated 18-week old infants (adjusted prevalence ratio 0.24 (95%CI 0.08-0.75)), vaccinated children 1-4 years (0.54 (0.33-0.88)), unvaccinated children 5-15 years (0.37 (0.17-0.78)) and mothers (0.34 (0.15-0.79)). No decrease in VT carriage was observed for 6-week old infants too young to be vaccinated (1.07 (0.38-3.02)) and PCV-13 ineligible children 1-4 years (0.84 (0.53-1.33)). Non-VT carriage increased only among vaccinated children 1-4 years (1.58 (1.21-2.06)). There is evidence of reduced VT pneumococcal carriage three years after vaccine introduction in this rural Malawian population with good vaccine coverage using a 3 + 0 schedule. However carriage was sustained among 6-week-old infants and PCV13 ineligible 1-4 year olds, and there was some indication of serotype replacement in vaccinated 1-4 year olds.


The neutralization breadth of HIV-1 develops incrementally over four years and is associated with CD4+ T cell decline and high viral load during acute infection.
An understanding of how broadly neutralizing activity develops in HIV-1-infected individuals is needed to guide vaccine design and immunization strategies. Here we used a large panel of 44 HIV-1 envelope variants (subtypes A, B, and C) to evaluate the presence of broadly neutralizing antibodies in serum samples obtained 3 years after seroconversion from 40 women enrolled in the CAPRISA 002 acute infection cohort. Seven of 40 participants had serum antibodies that neutralized more than 40% of viruses tested and were considered to have neutralization breadth. Among the samples with breadth, CAP257 serum neutralized 82% (36/44 variants) of the panel, while CAP256 serum neutralized 77% (33/43 variants) of the panel. Analysis of longitudinal samples showed that breadth developed gradually starting from year 2, with the number of viruses neutralized as well as the antibody titer increasing over time. Interestingly, neutralization breadth peaked at 4 years postinfection, with no increase thereafter. The extent of cross-neutralizing activity correlated with CD4(+) T cell decline, viral load, and CD4(+) T cell count at 6 months postinfection but not at later time points, suggesting that early events set the stage for the development of breadth. However, in a multivariate analysis, CD4 decline was the major driver of this association, as viral load was not an independent predictor of breadth. Mapping of the epitopes targeted by cross-neutralizing antibodies revealed that in one individual these antibodies recognized the membrane-proximal external region (MPER), while in two other individuals, cross-neutralizing activity was adsorbed by monomeric gp120 and targeted epitopes that involved the N-linked glycan at position 332 in the C3 region. Serum antibodies from the other four participants targeted quaternary epitopes, at least 2 of which were PG9/16-like and depended on the N160 and/or L165 residue in the V2 region. These data indicate that fewer than 20% of HIV-1 subtype C-infected individuals develop antibodies with cross-neutralizing activity after 3 years of infection and that these antibodies target different regions of the HIV-1 envelope, including as yet uncharacterized epitopes.


Blindness due to leptomeningeal carcinomatosis as an initial manifestation of recurrent acute lymphoblastic leukemia.
Leptomeningeal carcinomatosis (LC) is an uncommon presentation of acute lymphoblastic leukemia (ALL), and it is a devastating and life-threatening complication. The disease affects all levels of the central nervous system, and most patients present with different multifocal neurological symptoms. This case was a 34-year-old male who had acute bilateral blindness secondary to recurrent ALL with meningeal infiltration. Diagnosis of LC is made based on the clinical symptoms and the test results including cranial and spinal magnetic resonance imaging and cerebrospinal fluid (CSF) survey. The differential diagnosis of meningeal enhancement and early treatment are also important for prognosis. This case had a good visual recovery after treatment.


Wideband and low dispersion slow-light waveguide based on a photonic crystal with crescent-shaped air holes.
We present a procedure to generate slow light with a large group index, wideband, and low dispersion in our suggested photonic crystal waveguide. By modulation of the declinations in the first two rows of air holes, the group index, the bandwidth, and the dispersion can be tuned effectively. Utilizing the two-dimensional plane wave expansion method (PWE) and the finite-difference time-domain method (FDTD), we demonstrate slow light with the group indices of 23, 35, and 45, respectively, while restricting the group-index variation within a 10% range. We accordingly attain an available bandwidth of 40.7, 23.7, and 5.1 nm, respectively. Meanwhile, the normalized delay-bandwidth product stays around 0.45, with minimal dispersion less than 0.2 (ps2/m) for all the cases.


Towards an alternative for the acute fish LC(50) test in chemical assessment: the fish embryo toxicity test goes multi-species -- an update.
After its standardisation at the national level in Germany (DIN 38415-6, 2001, 2001), the 48 h sewage testing assay with zebrafish (Danio rerio) embryos has been submitted for standardisation to ISO. As an alternative to the conventional acute (96 h) fish test, a modified fish embryo test will be submitted to the OECD for chemical testing in late 2005. For this, a protocol originally designed for zebrafish was adapted to fit also the requirements of other OECD species, namely medaka (Oryzias latipes) and fathead minnow (Pimephales promelas). Results document that the transfer of the protocol is possible with only minor modifications. Data obtained from embryo tests with the three species are comparable. Statistical analysis of existing zebrafish embryo toxicity data resulted in the conclusions (1) that there is a reliable correlation between the fish embryo test and the acute fish test, (2) that the confidence belt of the regression line was relatively small, but that the prediction range was relatively wide. The regression thus seems appropriate to describe the relationship between acute fish and embryo LC(50) with good confidence, but is less appropriate as a prediction model. Investigations into oxygen requirements of zebrafish embryos reveal that they adapt to a broad range of oxygen levels and survive at concentrations of 2 mg/l without malformations. Zebrafish embryos can thus be exposed in very small toxicant volumes (100 microl), which is of particular interest for the testing of metabolites. Dechorionation studies with 48 h old zebrafish embryos indicate that the barrier function of the chorion increases with the lipophilicity of the test compound. Finally, examples are given as to how additional endpoints can be incorporated into the fish embryo test protocol to extend its scope, e.g. to sediment toxicity assessment or genotoxicity and mutagenicity testing.


Research priorities for harnessing plant microbiomes in sustainable agriculture.
Feeding a growing world population amidst climate change requires optimizing the reliability, resource use, and environmental impacts of food production. One way to assist in achieving these goals is to integrate beneficial plant microbiomes-i.e., those enhancing plant growth, nutrient use efficiency, abiotic stress tolerance, and disease resistance-into agricultural production. This integration will require a large-scale effort among academic researchers, industry researchers, and farmers to understand and manage plant-microbiome interactions in the context of modern agricultural systems. Here, we identify priorities for research in this area: (1) develop model host-microbiome systems for crop plants and non-crop plants with associated microbial culture collections and reference genomes, (2) define core microbiomes and metagenomes in these model systems, (3) elucidate the rules of synthetic, functionally programmable microbiome assembly, (4) determine functional mechanisms of plant-microbiome interactions, and (5) characterize and refine plant genotype-by-environment-by-microbiome-by-management interactions. Meeting these goals should accelerate our ability to design and implement effective agricultural microbiome manipulations and management strategies, which, in turn, will pay dividends for both the consumers and producers of the world food supply.


Highly intense upconversion luminescence in Yb/Er:NaGdF4@NaYF4 core-shell nanocrystals with complete shell enclosure of the core.
The purpose of the present work is to demonstrate that the hexagonal Yb/Er:NaGdF4 core size has a great impact on the completeness of the NaYF4 shell covering the core. With the increase of core size, the morphology of core-shell nanocrystals evolves from nanosphere to hexagonal nanoprism and finally to hexagonal nanoplate and, impressively, compared to that on the lateral faces of cores, the shell thickness on the top/bottom faces of cores becomes thinner. The shell growth mechanism is proposed to be the separate nucleation of the shell precursors followed by their ripening-mediated deposition on the cores. Based on this mechanism, controlling the thickness and completeness of the shell on the core can be easily realized by adopting appropriate size cores, which results in the intensification of upconversion luminescence of core-shell nanocrystals 10 000 times as high as that of the core-only ones. Generally, these new findings should be beneficial for designing and fabricating complex core-shell architecture and the understanding of structure-related properties of core-shell nanocrystals.


Cimetidine for prevention and treatment of gastroduodenal mucosal lesions in patients in an intensive care unit.
The efficacy of cimetidine in the prevention and treatment of stress-induced gastroduodenal lesions was evaluated in a randomized, double-blind, placebo-controlled study in which serial endoscopy was used to examine patients without clinical evidence of bleeding who were admitted to a medical intensive care unit. Endoscopy showed that 14 of 21 patients treated with cimetidine, compared with 5 of 18 patients treated with placebo, had normal or improved gastroduodenal mucosa (p less than 0.05). Endoscopic signs of bleeding cleared or did not develop in 20 patients treated with cimetidine and in 11 patients treated with placebo (p less than 0.01). Significantly fewer blood transfusions were given to patients with endoscopic signs of bleeding in the cimetidine-treated group (0.5 +/- 0.3 [SE] units) than in placebo-treated patients (4.5 +/- 1.5 units; p less than 0.05). The mortality rate was not statistically different between treatment groups. By preventing established gastroduodenal stress lesions from progressing in severity, cimetidine diminished both bleeding and the need for transfusions.


Quaternary ammonium biocides: efficacy in application.
Quaternary ammonium compounds (QACs) are among the most commonly used disinfectants. There has been concern that their widespread use will lead to the development of resistant organisms, and it has been suggested that limits should be place on their use. While increases in tolerance to QACs have been observed, there is no clear evidence to support the development of resistance to QACs. Since efflux pumps are believe to account for at least some of the increased tolerance found in bacteria, there has been concern that this will enhance the resistance of bacteria to certain antibiotics. QACs are membrane-active agents interacting with the cytoplasmic membrane of bacteria and lipids of viruses. The wide variety of chemical structures possible has seen an evolution in their effectiveness and expansion of applications over the last century, including non-lipid-containing viruses (i.e., noroviruses). Selection of formulations and methods of application have been shown to affect the efficacy of QACs. While numerous laboratory studies on the efficacy of QACs are available, relatively few studies have been conducted to assess their efficacy in practice. Better standardized tests for assessing and defining the differences between increases in tolerance versus resistance are needed. The ecological dynamics of microbial communities where QACs are a main line of defense against exposure to pathogens need to be better understood in terms of sublethal doses and antibiotic resistance.


Characteristics of an overdose prevention, response, and naloxone distribution program in Pittsburgh and Allegheny County, Pennsylvania.
Prevention Point Pittsburgh (PPP) is a public health advocacy organization that operates Allegheny County's only needle exchange program. In 2002, PPP implemented an Overdose Prevention Program (OPP) in response to an increase in heroin-related and opioid-related overdose fatalities in the region. In 2005, the OPP augmented overdose prevention and response trainings to include naloxone training and prescription. The objective of our study is to describe the experiences of 426 individuals who participated in the OPP between July 1, 2005, and December 31, 2008. Of these, 89 individuals reported administering naloxone in response to an overdose in a total of 249 separate overdose episodes. Of these 249 overdose episodes in which naloxone was administered, participants reported 96% were reversed. The data support findings from a growing body of research on similar programs in other cities. Community-based OPPs that equip drug users with skills to identify and respond to an overdose and prescribe naloxone can help users and their peers prevent and reverse potentially fatal overdoses without significant adverse consequences.


Bovine Colostrum and Its Potential for Human Health and Nutrition.
Colostrum is the first milk produced post-partum by mammals and is compositionally distinct from mature milk. Bovine colostrum has a long history of consumption by humans, and there have been a number of studies investigating its potential for applications in human nutrition and health. Extensive characterization of the constituent fractions has identified a wealth of potentially bioactive molecules, their potential for shaping neonatal development, and the potential for their application beyond the neonatal period. Proteins, fats, glycans, minerals, and vitamins are abundant in colostrum, and advances in dairy processing technologies have enabled the advancement of bovine colostrum from relative limitations of a fresh and unprocessed food to a variety of potential applications. In these forms, clinical studies have examined bovine colostrum as having the substantial potential to improve human health. This review discusses the macro-and micronutrient composition of colostrum as well as describing well-characterized bioactives found in bovine colostrum and their potential for human health. Current gaps in knowledge are also identified and future directions are considered in order to elevate the potential for bovine colostrum as a component of a healthy diet for a variety of relevant human populations.


The role of sports physiotherapy at the London 2012 Olympic Games.
There is a lack of information on the utilisation of physiotherapy services at the Olympic Games. To better understand the athlete and non-athlete requirements of the physiotherapy services at the Olympic Village Polyclinic during the London 2012 Olympic Games. From 16 July to 14 August 2012, physiotherapy encounters for athletes and non-athletes (National Olympic Committee (NOC) team officials, coaches, team managers, workforce, Olympic family, technical officials and press) were recorded on the ATOS electronic medical records system at the polyclinic in the main Athletes' Village in Stratford. Of the 1778 encounters, 1219 (69%) were administered to athletes and 559 (31%) to non-athletes. The anatomical areas most frequently recorded at the first visits for athletes were knee (15.4%), lumbar spine/lower back (15.2%) and upper leg (12.6%) and that for non-athletes were lumbar spine/lower back (19.8%), knee (15.8%) and neck/cervical spine. Muscle (33.3%) and joint injuries (24.8%) were the most common diagnoses in athletes and non-athletes (24.4% and 30.1%). The five most frequently used treatment modalities were therapeutic soft tissue techniques (23.3%), mobilisation techniques (21.8%), taping (8.9%), cryotherapy (6.9%) and exercise prescription (6.4%). The most common cause of athletes' injuries was overuse (43.6%). This study of the London 2012 Olympic Games workload highlights the physiotherapy needs of athletes as well as non-athletes and identifies the high numbers of pre-existing and overuse injuries in this setting, providing an insight into the reasons why the athletes seek physiotherapy support during the Olympic Games.


Interrelationships among shrub encroachment, land management, and litter decomposition in a semidesert grassland.
Encroachment of woody plants into grasslands, and subsequent brush management, are among the most prominent changes to occur in arid and semiarid systems over the past century. Despite the resulting widespread changes in landcover, substantial uncertainty about the biogeochemical impacts of woody proliferation and brush management exists. We explored the role of shrub encroachment and brush management on leaf litter decomposition in a semidesert grassland where velvet mesquite (Prosopis velutina) abundance has increased over the past 100 years. This change in physiognomy may affect decomposition directly, through altered litter quality or quantity, and indirectly through altered canopy structure. To assess the direct and indirect impacts of shrubs on decomposition, we quantified changes in mass, nitrogen, and carbon in litterbags deployed under mesquite canopies and in intercanopy zones. Litterbags contained foliage from mesquite and Lehmann lovegrass (Eragrostis lehmanniana), a widespread, nonnative grass in southern Arizona. To explore short- and long-term influences of brush management on the initial stages of decomposition, litterbags were deployed at sites where mesquite canopies were removed three weeks, 45 years, or 70 years prior to study initiation. Mesquite litter decomposed more rapidly than lovegrass, but negative indirect influences of mesquite canopies counteracted positive direct effects. Decomposition was positively correlated with soil infiltration into litterbags, which varied with microsite placement, and was lowest under canopies. Low under-canopy decomposition was ostensibly due to decreased soil movement associated with high under-canopy herbaceous biomass. Decomposition rates where canopies were removed three weeks prior to study initiation were comparable to those beneath intact canopies, suggesting that decomposition was driven by mesquite legacy effects on herbaceous cover-soil movement linkages. Decomposition rates where shrubs were removed 45 and 70 years prior to study initiation were comparable to intercanopy rates, suggesting that legacy effects persist less than 45 years. Accurate decomposition modeling has proved challenging in arid and semiarid systems but is critical to understanding biogeochemical responses to woody encroachment and brush management. Predicting brush-management effects on decomposition will require information on shrub-grass interactions and herbaceous biomass influences on soil movement at decadal timescales. Inclusion of microsite factors controlling soil accumulation on litter would improve the predictive capability of decomposition models.


Integrating medication therapy management in the primary care medical home: A review of randomized controlled trials.
Randomized controlled trials (RCTs) that evaluated the effect of medication therapy management (MTM) on patient outcomes in the primary care medical home were reviewed to determine how these services may be integrated into the primary care medical home. A literature search was conducted to identify RCTS published between 1989 and 2009 that evaluated the impact of MTM services on patient outcomes. To qualify as MTM services, the interventions had to include both a review of medication therapy and patient interactions, including educating patients about drug therapy, identifying potential barriers to medication adherence, and helping patients manage their diseases. The internal validity of the studies was evaluated using previously published criteria. The description, specification, and appropriateness of study objectives, study population, intervention, randomization, blinding, outcome measures, statistical analysis, and conclusions were evaluated. A total of 1795 publications were identified, but only 8 met the inclusion criteria. These studies targeted patients with specific medical conditions or patients with multiple medications without specifying a medical condition. The interventions varied in intensity (i.e., frequency and length of patient contact), ranging from a single patient contact in a community pharmacy setting to multiple visits with an ambulatory care pharmacist practicing in a collaborative care model. Two of the 8 studies obtained expected results. These studies targeted patients with unrealized therapeutic goals, and the interventions involved collaboration between pharmacists and physicians and extensive patient follow-up. Of 1795 publications identified, 8 were RCTs meeting selection criteria for evaluation of the effect of MTM services on patient outcomes. Two service elements that benefit patient care were identified: (1) selecting patients with specific therapeutic problems and (2) implementing MTM services that involve timely communication with primary care providers to discuss therapeutic problems, along with routine patient follow-up to support medication adherence to changes in therapy.


Effects of short-term in-season plyometric training in adolescent female basketball players.
In this study, we tested the hypothesis that, during the regular in-seasonal basketball training, an additional 7-week plyometric training program improves lower extremity strength, balance, agility, and jump performance in adolescent female basketball players. Eighteen female basketball players less than 17 years of age were randomly assigned into an experimental group (plyometric training) and a control group. Both groups underwent the same basketball training program. Pre- and post-training test periods included quadriceps and hamstring strength, balance, jump performance, and agility measurements. Illinois agility test time (p = 0.000) and quadriceps strength (p = 0.035) increased uniformly in the two groups. Significant group by test period interaction was found for countermovement jump (p = 0.007), and countermovement height reduced significantly in the plyometric training group (p = 0.012), while it remained unchanged in controls. No significant change was found for T agility test, balance, hamstring strength or H:Q ratio. This study shows that the training program used in-season did not improve the measured variables, except for knee extensor strength. It is possible that regular basketball trainings and games combined with high-volume plyometric training did not show positive functional effects because of the fatigue caused by incomplete recovery between sessions.


The link between intravenous multiple pump flow errors and infusion system mechanical compliance.
IV drug delivery in intensive care often takes the form of simultaneous multiple infusions from separate infusion devices via either shared or individual fluid pathways. Because of the potency of the drugs administered and the acuity of the patients, accurate drug delivery is required. Instances of unexpected and unacceptable accuracy degradation have been reported when the equilibrium of the infusion system is disturbed. We describe a mathematical model of a simple infusion system used to investigate and verify results reported from a simple experimental multiple pump fault scenario. The results suggest that flow degradation is attributable to small changes in infusion system extracorporeal volume, referred to as "compliance." The model may, by expansion, be used to determine the nature of fluid flow within other multiple pump systems, be applied to the design of future IV systems, and explain the need for small-volume infusion systems with small mechanical compliance.


The Interaction Between Like-Charged Nanoparticles Mediated by Rod-Like Ions.
We present a brief review of recent studies of the interaction between charged nanoparticles immersed in a solution of oppositely charged rod-like counterions. To analyze these systems, we extend and employ an approximate field theory for point charges that has been shown to be accurate from the weak to the intermediate through to the strong coupling regimes. The resulting theory compares well with simulation data. We find that in the weak coupling limit, the interactions between the plates in the rod system are only repulsive. In the intermediate coupling regime, the multivalent rod-like counterions can mediate attractive interactions between the nanoparticles through two mechanisms. Charge correlations between different counterion rods lead to attractions between the plates, as in the case for the point charge counterions. For sufficiently long rods, however, bridging contributes to the attractive interaction, where the correlation of the charges within the rods is important. In the strong coupling limit, the inter-ionic charge correlations dominate the attractive interactions at short separations between the charged nanoparticles.


Exciton-Plasmon Coupling Enhancement via Metal Oxidation.
In this paper, we report on the effect of metal oxidation on strong coupling interactions between silver nanostructures and a J-aggregated cyanine dye. We show that metal oxidation can sensibly affect the plexcitonic system, inducing a change in the coupling strength. In particular, we demonstrate that the presence of oxide prevents the appearance of Rabi splitting in the extinction spectra for thick spacers. In contrast, below a threshold percentage, the oxide layer results in an higher coupling strength between the plasmon and the Frenkel exciton. Contrary to common belief, a thin oxide layer seems thus to act, under certain conditions, as a coupling mediator between an emitter and a localized surface plasmon excited in a metallic nanostructure. This suggests that metal oxidation can be exploited as a means to enhance light-matter interactions in strong coupling applications.


Stereodivergent, Diels-Alder-initiated organocascades employing α,β-unsaturated acylammonium salts: scope, mechanism, and application.
Chiral α,β-unsaturated acylammonium salts are novel dienophiles enabling enantioselective Diels-Alder-lactonization (DAL) organocascades leading to cis- and trans-fused, bicyclic γ- and δ-lactones from readily prepared dienes, commodity acid chlorides, and a chiral isothiourea organocatalyst under mild conditions. We describe extensions of stereodivergent DAL organocascades to other racemic dienes bearing pendant secondary and tertiary alcohols, and application to a formal synthesis of (+)-dihydrocompactin is described. A combined experimental and computational investigation of unsaturated acylammonium salt formation and the entire DAL organocascade pathway provide a rationalization of the effect of Brønsted base additives and enabled a controllable, diastereodivergent DAL process leading to a full complement of possible stereoisomeric products. Evaluation of free energy and enthalpy barriers in conjunction with experimentally observed temperature effects revealed that the DAL is a rare case of an entropy-controlled diastereoselective process. NMR analysis of diene alcohol-Brønsted base interactions and computational studies provide a plausible explanation of observed stabilization of exo transition-state structures through hydrogen-bonding effects.


Evidence of a biological effect of light therapy on the retina of patients with seasonal affective disorder.
Retinal sensitivity anomalies have been reported in patients affected by seasonal affective disorder (SAD). We used the electroretinogram (ERG) to assess seasonal change in retinal function in patients with SAD and healthy participants, as well as in patients following 4 weeks of light therapy. ERG assessments were obtained in 22 SAD patients (2 men, 20 women, mean age 31 +/- 9 years) in the fall/winter season before and after 2 and 4 weeks of light therapy and in summertime. Matched healthy participants (2 men, 14 women; mean age 29 +/- 8 years) were evaluated once in the fall/winter and once in summer. The 29-item Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorder version was administered. Standard ERG parameters were derived from the photopic and scotopic luminance response functions. Salivary melatonin concentration during ERG was assessed in both groups but during fall/winter assessments only. A significantly lower cone ERG maximal amplitude and lower rod sensitivity was found in SAD patients before light therapy compared with healthy participants. Following 4 weeks of light therapy, a normalization of cone and rod ERG function occurred. ERG parameters in the summer and melatonin concentrations in fall/winter were not significantly different between groups. Depressed patients with SAD demonstrate ERG changes in the winter compared with healthy comparison subjects with lower rod retinal sensitivity and lower cone maximal amplitude. These changes normalized following 4 weeks of light therapy and during the summer, suggesting that ERG changes are state markers for SAD.


Deglycosylation of alpha 1-proteinase inhibitor is impaired in the faeces of patients with active inflammatory bowel disease (Crohn's disease).
1. alpha 1-Proteinase inhibitor (alpha 1-antitrypsin) was excreted in the faeces of patients with inflammatory bowel disease in different molecular forms: Mr-51,000 and Mr-45,000 forms were widely found in the stools of patients with active disease, whereas a Mr-38,000 species was frequently recovered from healthy subjects and patients with quiescent disease (Mizon, Becuwe, Balduyck et al. Clin. Chem. 1988; 34, 2268-70). 2. N-Terminal sequencing of the Mr-38,000 form of alpha 1-proteinase inhibitor, after SDS/PAGE and electrotransfer on polyvinyl difluoride membranes, showed that it differed from plasma alpha 1-proteinase inhibitor by the loss of 17 N-terminal amino acids. 3. Carbohydrate analysis of the isolated Mr-38,000 form revealed a total lack of neutral sugars. 4. In contrast, the Mr-51,000 form of alpha 1-proteinase inhibitor is glycosylated and thus could be differentiated by virtue of its reactivity with concanavalin A. The analysis of 25 faecal extracts from patients with Crohn's disease allowed us to confirm that the presence of the glycosylated form of alpha 1-proteinase inhibitor was closely related to the degree of inflammation. 5. From these data, it may be hypothesized that the hydrolytic activity of some glycosidases is greatly reduced in active Crohn's disease.


A diacylglycerol-activated Ca2+ channel in PC12 cells (an adrenal chromaffin cell line) correlates with expression of the TRP-6 (transient receptor potential) protein.
The structures, and mechanisms of activation, of plasma membrane intracellular-messenger-activated, non-selective cation channels in animal cells are not well understood. The PC12 adrenal chromaffin cell line is a well-characterized example of a nerve cell. In PC12 cells, 1-oleolyl-2-acetyl-sn-glycerol (OAG), a membrane-permeant analogue of diacylglycerol, initiated the inflow of Ca(2+), Mn(2+) and Sr(2+). Acetylcholine and thapsigargin initiated the inflow of Ca(2+) and Mn(2+), but not of Sr(2+). The activation of bivalent cation inflow by OAG: (i) was mimicked by another membrane-permeant diacylglycerol analogue, 1,2-dioctanoyl-sn-glycerol, but not by the membrane-impermeant analogue 1-stearoyl-2-arachidonyl-sn-glycerol; (ii) was not blocked by staurosporin or chelerythrine, inhibitors of protein kinase C; (iii) was enhanced by RHC80267 and R50922, inhibitors of diacylglycerol lipase and diacylglycerol kinase respectively; and (iv) was inhibited by extracellular Ca(2+). When OAG was added after acetylcholine, the effect of OAG on Ca(2+) inflow was over-and-above that induced by acetylcholine. 2-Aminoethyl diphenylborate (2-APB) inhibited Ca(2+) inflow initiated by either acetylcholine or thapsigargin, but not that initiated by OAG. Flufenamic acid inhibited OAG-initiated, but not acetylcholine-initiated, Ca(2+) and Mn(2+) inflow. OAG-initiated Ca(2+) inflow was less sensitive to inhibition by SK&F96365 than acetylcholine-initiated Ca(2+) inflow. In polyadenylated RNA prepared from PC12 cells, mRNA encoding TRP (transient receptor potential) proteins 1-6 was detected by reverse transcriptase (RT)-PCR, and in lysates of PC12 cells the endogenous TRP-6 protein was detected by Western blot analysis. It is concluded that PC12 cells express a diacylglycerol-activated, non-selective cation channel. Expression of this channel function correlates with expression of the TRP-3 and TRP-6 proteins, which have been shown previously to be activated by diacylglycerol when expressed heterologously in animal cells [Hofmann, Obukhov, Schaefer, Harteneck, Gudermann, and Schultz (1999) Nature (London) 397, 259-263].


The gender composition of the medical profession in Mexico: implications for employment patterns and physician labor supply.
The gender composition of the medical profession is changing rapidly in many parts of the world, including Mexico. We analyze cross-sectional and longitudinal data on sex differences in physician employment from household employment surveys. The results suggest that Mexico is a particularly interesting example of the feminization of physician employment. Female enrollment in medical school increased from 11% in 1970 to about 50% in 1998. The increased participation of women in medicine seems to be accompanied by differences in employment patterns that could generate significant reductions in the total supply of physician hours of service. Women physicians are unemployed at a much higher rate than men and hence account for half of underused physician human capital. The results suggest that improved educational opportunities do not translate automatically into equal employment opportunities.


A model-based approach for making ecological inference from distance sampling data.
We consider a fully model-based approach for the analysis of distance sampling data. Distance sampling has been widely used to estimate abundance (or density) of animals or plants in a spatially explicit study area. There is, however, no readily available method of making statistical inference on the relationships between abundance and environmental covariates. Spatial Poisson process likelihoods can be used to simultaneously estimate detection and intensity parameters by modeling distance sampling data as a thinned spatial point process. A model-based spatial approach to distance sampling data has three main benefits: it allows complex and opportunistic transect designs to be employed, it allows estimation of abundance in small subregions, and it provides a framework to assess the effects of habitat or experimental manipulation on density. We demonstrate the model-based methodology with a small simulation study and analysis of the Dubbo weed data set. In addition, a simple ad hoc method for handling overdispersion is also proposed. The simulation study showed that the model-based approach compared favorably to conventional distance sampling methods for abundance estimation. In addition, the overdispersion correction performed adequately when the number of transects was high. Analysis of the Dubbo data set indicated a transect effect on abundance via Akaike's information criterion model selection. Further goodness-of-fit analysis, however, indicated some potential confounding of intensity with the detection function.


Current status of indwelling urinary catheter utilization and catheter-associated urinary tract infection throughout hospital wards in Korea: A multicenter prospective observational study.
To evaluate the frequency and appropriateness of indwelling urinary catheters (IUC) use and the incidence of catheter-associated urinary tract infections (CA-UTI), and explore the risk factors for CA-UTI in hospitals as a whole, we conducted a study. This study was divided into two parts; a point-prevalence study on Dec 12th 2012 and a prospective cohort study from Dec 13th 2012 to Jan 9th 2013 were performed in six hospitals in Korea. All hospitalized patients with newly-placed IUCs were enrolled and monitored weekly for 28 days after IUC placement. In the point-prevalence study, the IUCs were present in median 14.9/100 hospitalized patients (1Q 14, 3Q 16) across the six hospitals. In the prospective cohort study, the median IUC-days per patient was 5 (1Q 3, 3Q 10) and the median CA-UTI prevalence per 1,000 catheter days was 1.9 (1Q 0.7, 3Q 3.8) with significant inter-hospital variation. The proportion of patients with inappropriate IUC maintenance increased with number of IUC-days (8.5% on day 7, 9.4% on day 14, 16.3% on day 21, and 23.1% on day 28). Urinary output monitoring (23/36, 63.9%) was the most common indication for inappropriate use after 1 week of ICU placement. In multivariate analysis, IUC-days was significantly associated with the development of CA-UTI (odds ratio 1.122, 95% confidence interval 1.074-1.173, P< 0.001). IUC-days and CA-UTI rates vary between hospitals. IUC-days is a risk factor for CA-UTI, and is correlated with inappropriate use.


pH- and GSH-Sensitive Hyaluronic Acid-MP Conjugate Micelles for Intracellular Delivery of Doxorubicin to Colon Cancer Cells and Cancer Stem Cells.
A dual-sensitive polymeric drug conjugate (HA-SS-MP) was synthesized by conjugating hydrophobic 6-mercaptopurine (MP) to thiolated hyaluronic acid (HA) as the carrier and ligand to deliver doxorubicin (Dox) to parental colon cancer and colon cancer stem cells. Because of the amphiphilic nature of HA-SS-MP, it was self-assembled in the aqueous media, and Dox was physically encapsulated in the core of the micelles. The particle size and the zeta potential of the micelle were analyzed by dynamic light scattering (DLS), and the morphology of the micelle was investigated using transmission electron microscopy (TEM). Drug release study results revealed more drug release at pH 5.0 in the presence of GSH than that at the physiological pH value. The cytotoxicity of free Dox was slightly greater than that of Dox-loaded HA-SS-MP micelles. In vitro cytotoxicity of HA-SS-MP and Dox-loaded HA-SS-MP micelles was greater for cancer stem cells (HCT116-CSCs) than for parental HCT116 colon cancer cells and L929 normal fibroblast cells. The MTT and flow cytometry results confirmed that free HA competitively inhibited Dox-loaded HA-SS-MP uptake. Similarly, flow cytometry results revealed anti-CD44 antibody competitively inhibited cellular uptake of Rhodamine B isothiocyanate conjugated micelles, which confirms that the synthesized micelle is uptaken via CD44 receptor. Cell cycle analysis revealed that free drugs and Dox-loaded HA-SS-MP arrested parental HCT116 colon cancer cells at the S phase, while cell arrest was observed at the G0G1 phase in HCT116-CSCs. In addition, ex vivo biodistribution study showed that Dox-loaded HA-SS-MP micelles were accumulated more in the tumor region than in any other organ. Furthermore, the in vivo results revealed that Dox-loaded HA-SS-MP micelles exhibited more therapeutic efficacy than the free drugs in inhibiting tumor growth in BALB/C nude mice. Overall, the results suggested that the synthesized micelles could be promising as a stimuli carrier and ligand for delivering Dox to colon cancer cells and also to eradicate colon cancer stem cells.


Analysis of the petrous portion of the internal carotid artery: landmarks for an endoscopic endonasal approach.
While there are many benefits to the endoscopic endonasal approach to the infratemporal fossa, involvement of the petrous portion of the internal carotid artery (ICA) poses a unique challenge. The endoscopic endonasal approach requires establishing the relationship of the petrous ICA to anatomical landmarks to guide the surgeon. This study evaluates the relationship of petrous ICA to specific anatomic landmarks, both radiographically and through cadaveric dissections. Cadaveric and radiographic study. An endoscopic endonasal approach was used to access the petrous carotid and infratemporal fossa. Dissections exposed the petrous portion of the carotid artery and identified the foramen rotundum, ovale, and spinosum. Both anatomical and radiographic representations of these landmarks were then evaluated and compared relative to the petrous carotid. The endoscopic endonasal approach to the infratemporal fossa with exposure of the petrous ICA afforded complete visualization of the entire segment of this portion of the ICA with limited anatomical obstruction. The foramen rotundum, ovale, and spinosum were successfully identified and dissected with preservation of their neuro/vascular contents. Computed tomography analysis calculated a mean distance to the petrous ICA of 16.34 mm from the foramen rotundum, 4.88 mm from the ovale, and 5.11 mm from the spinosum in males. For females, the values were 16.40 mm from the rotundum and 4.36 mm each from the ovale and spinosum. An endonasal endoscopic approach to the infratemporal fossa with exposure of the petrous ICA is feasible. The anatomical landmarks can serve as both radiographic and surgical landmarks in this approach.


Sucrose-mediated translational control.
Environmental factors greatly impact plant gene expression and concentrations of cellular metabolites such as sugars and amino acids. The changed metabolite concentrations affect the expression of many genes both transcriptionally and post-transcriptionally. Sucrose acts as a signalling molecule in the control of translation of the S1 class basic leucine zipper transcription factor (bZIP) genes. In these genes the main bZIP open reading frames (ORFs) are preceded by upstream open reading frames (uORFs). The presence of uORFs generally inhibits translation of the following ORF but can also be instrumental in specific translational control. bZIP11, a member of the S1 class bZIP genes, harbours four uORFs of which uORF2 is required for translational control in response to sucrose concentrations. This uORF encodes the Sucrose Control peptide (SC-peptide), which is evolutionarily conserved among all S1 class bZIP genes in different plant species. Arabidopsis thaliana bZIP11 and related bZIP genes seem to be important regulators of metabolism. These proteins are targets of the Snf1-related protein kinase 1 (SnRK1) KIN10 and KIN11, which are responsive to energy deprivation as well as to various stresses. In response to energy deprivation, ribosomal biogenesis is repressed to preserve cellular function and maintenance. Other key regulators of ribosomal biogenesis such as the protein kinase Target of Rapamycin (TOR) are tightly regulated in response to stress. Plants use translational control of gene expression to optimize growth and development in response to stress as well as to energy deprivation. This Botanical Briefing discusses the role of sucrose signalling in the translational control of bZIP11 and the regulation of ribosomal biogenesis in response to metabolic changes and stress conditions.


Oral metamizol (1 g and 2 g) versus ibuprofen and placebo in the treatment of lower third molar surgery pain: randomised double-blind multi-centre study. Cooperative Study Group.
To assess the efficacy of metamizol 1 g and 2 g in the relief of pain after surgical extraction of the lower third molar, and to compare the therapeutic effect with that of ibuprofen 600 mg or placebo. A total of 253 patients aged between 18 years and 60 years who had undergone extraction of the lower third molar (types II-IV) under local anaesthesia, up to a maximum of 108 mg of mepivacaine, were randomly assigned to a single oral dose of a new galenic form (drinkable vials) of metamizol 1 g (n = 75), metamizol 2 g (n = 72), ibuprofen 600 mg (n = 74) or placebo (n = 32). Pain intensity was evaluated by a 100-mm visual analogue scale. To enter the study, a pain level of 50 mm or more was required. The duration of the trial was 1 h. Assessments were carried out at 15, 30 and 60 min after treatment. The analgesic efficacy of metamizol 2 g was significantly better than ibuprofen and placebo with regard to all evaluated parameters. The values of the pain intensity difference at 15 min, the percentage of patients with a decrease of 50% or more on the visual analogue scale at 60 min and the sum of pain intensity differences at 60 min showed metamizol 2 g to be significantly more effective than metamizol 1 g. In general, metamizol 1 g was as effective as ibuprofen 600 mg. The analgesic efficacy of placebo was significantly lower than that of all active treatments. A lower number of patients treated with metamizol 1 g (n = 1) or metamizol 2 g (n = 1) needed rescue medication than those given ibuprofen (n = 7) or placebo (n = 5). No serious adverse effects developed and none of the patients had to leave the study for this reason. The model of the lower third molar, for which the analgesic outcome referred to the first hour after drug administration, demonstrated that the analgesic efficacy of oral metamizol 2 g was significantly higher than that of ibuprofen 600 mg or placebo. Metamizol 1 g and ibuprofen 600 mg showed a similar therapeutic effect. All regimens were as well tolerated as placebo.