Influence of p-chloroamphetamine and methysergide on the escape deficits provoked by inescapable shock.
The effects of serotonergic manipulations on the escape interference engendered by exposure to inescapable shock were assessed. Consistent with the view that the behavioral interference was related to reductions of serotonin (5-HT), treatment with the 5-HT receptor blocker methysergide mimicked the effects of inescapable shock in that it increased escape latencies. Conversely, acute treatment with a moderate dose of the 5-HT releasing agent p-chloroamphetamine (PCA) effectively antagonized the escape interference ordinarily provoked by inescapable shock. The effects of PCA were behaviorally distinguishable from the previously observed effects of catecholamine stimulants. Whereas catecholamine stimulants applied prior to either inescapable shock or escape testing eliminated the interference, PCA antagonized the behavioral disruption only if it was administered before testing. It is suggested that catecholamine alterations may be fundamental in the provocation of the interference, whereas 5-HT variations may contribute to the expression of the behavioral disturbance.


A comprehensive modelling framework to forecast the demand for all hospital services.
Because of increasing demand, hospitals in England are currently under intense pressure resulting in shortages of beds, nurses, clinicians, and equipment. To be able to effectively cope with this demand, the management needs to accurately find out how many patients are expected to use their services in the future. This applies not just to one service but for all hospital services. A forecasting modelling framework is developed for all hospital's acute services, including all specialties within outpatient and inpatient settings and the accident and emergency (A&E) department. The objective is to support the management to better deal with demand and plan ahead effectively. Having established a theoretical framework, we used the national episodes statistics dataset to systematically capture demand for all specialties. Three popular forecasting methodologies, namely, autoregressive integrated moving average (ARIMA), exponential smoothing, and multiple linear regression were used. A fourth technique known as the seasonal and trend decomposition using loess function (STLF) was applied for the first time within the context of health-care forecasting. According to goodness of fit and forecast accuracy measures, 64 best forecasting models and periods (daily, weekly, or monthly forecasts) were selected out of 760 developed models; ie, demand was forecasted for 38 outpatient specialties (first referrals and follow-ups), 25 inpatient specialties (elective and non-elective admissions), and for A&E. This study has confirmed that the best demand estimates arise from different forecasting methods and forecasting periods (ie, one size does not fit all). Despite the fact that the STLF method was applied for the first time, it outperformed traditional time series forecasting methods (ie, ARIMA and exponential smoothing) for a number of specialties. Knowing the peaks and troughs of demand for an entire hospital will enable the management to (a) effectively plan ahead; (b) ensure necessary resources are in place (eg, beds and staff); (c) better manage budgets, ensuring enough cash is available; and (d) reduce risk.


Cardiac risk scores in high-risk Hispanics and the predictive value of BNP.
The purpose of this study was to calculate cardiac risk scores in Hispanic subjects and to determine the predictive value of adding B-type natriuretic peptide in identifying those with asymptomatic left ventricular dysfunction as a measure of cardiovascular disease. Hispanics have higher rates of cardiovascular risk factors leading to coronary heart disease, asymptomatic left ventricular dysfunction and cardiovascular events. Assessing cardiac risk in these groups is important to identify those at high risk for future cardiovascular events. The use of biomarkers such as B-type natriuretic peptide may increase the accuracy of risk prediction. This study used a descriptive, cross-sectional study design to determine the utility of the standard risk assessment tools (Adult Treatment Panel III and the Framingham Risk Scores risk calculator) and the B-type natriuretic peptide biomarker to estimate coronary heart disease risk in low-income, Hispanic participants. A sample of 71 patients (age 52 SD 11, 69% female) with multiple cardiovascular risk factors seen at an ambulatory clinic at a county facility was enrolled in the study. Sociodemographic and medical history information were obtained. Two widely used risk calculators (Adult Treatment Panel III and Framingham Risk Scores) were used to estimate 10-year coronary heart disease risk in each subject. Baseline B-type natriuretic peptide measurement and echocardiography were performed with each subject to evaluate presence of asymptomatic left ventricular dysfunction. Receiver operating curve analyses were performed to compare predictability, sensitivity and specificity of the traditional risk scores against the B-type natriuretic peptide level to detect asymptomatic left ventricular dysfunction. Overall mean risk scores were 5% (SD 5%) (Adult Treatment Panel III) and 10% (SD 7%) (Framingham Risk Scores). Mean B-type natriuretic peptide levels were 108·5 (SD 191·5) pg/ml. Echocardiogram results revealed a high proportion of subjects with asymptomatic left ventricular dysfunction (74·6%). The receiver operating curves showed an area under the curve of 0·67 for B-type natriuretic peptide (p < 0·05), 0·64 (p = NS) for Adult Treatment Panel III and 0·56 (p = NS) for Framingham Risk Scores, evidence that B-type natriuretic peptide does significantly better than Adult Treatment Panel or Framingham Risk Scores in predicting asymptomatic left ventricular dysfunction. The inclusion of B-type natriuretic peptide with traditional risk scores may be helpful in predicting risk and asymptomatic left ventricular dysfunction in high-risk Hispanics. Cardiac risk scores can assist clinicians in identifying patients at high risk for developing coronary heart disease.


Neural Representation of Concurrent Vowels in Macaque Primary Auditory Cortex.
Successful speech perception in real-world environments requires that the auditory system segregate competing voices that overlap in frequency and time into separate streams. Vowels are major constituents of speech and are comprised of frequencies (harmonics) that are integer multiples of a common fundamental frequency (F0). The pitch and identity of a vowel are determined by its F0 and spectral envelope (formant structure), respectively. When two spectrally overlapping vowels differing in F0 are presented concurrently, they can be readily perceived as two separate "auditory objects" with pitches at their respective F0s. A difference in pitch between two simultaneous vowels provides a powerful cue for their segregation, which in turn, facilitates their individual identification. The neural mechanisms underlying the segregation of concurrent vowels based on pitch differences are poorly understood. Here, we examine neural population responses in macaque primary auditory cortex (A1) to single and double concurrent vowels (/a/ and /i/) that differ in F0 such that they are heard as two separate auditory objects with distinct pitches. We find that neural population responses in A1 can resolve, via a rate-place code, lower harmonics of both single and double concurrent vowels. Furthermore, we show that the formant structures, and hence the identities, of single vowels can be reliably recovered from the neural representation of double concurrent vowels. We conclude that A1 contains sufficient spectral information to enable concurrent vowel segregation and identification by downstream cortical areas.


Comprehensive Nutritional and Dietary Intervention for Autism Spectrum Disorder-A Randomized, Controlled 12-Month Trial.
This study involved a randomized, controlled, single-blind 12-month treatment study of a comprehensive nutritional and dietary intervention. Participants were 67 children and adults with autism spectrum disorder (ASD) ages 3-58 years from Arizona and 50 non-sibling neurotypical controls of similar age and gender. Treatment began with a special vitamin/mineral supplement, and additional treatments were added sequentially, including essential fatty acids, Epsom salt baths, carnitine, digestive enzymes, and a healthy gluten-free, casein-free, soy-free (HGCSF) diet. There was a significant improvement in nonverbal intellectual ability in the treatment group compared to the non-treatment group (+6.7 ± 11 IQ points vs. -0.6 ± 11 IQ points, p = 0.009) based on a blinded clinical assessment. Based on semi-blinded assessment, the treatment group, compared to the non-treatment group, had significantly greater improvement in autism symptoms and developmental age. The treatment group had significantly greater increases in EPA, DHA, carnitine, and vitamins A, B2, B5, B6, B12, folic acid, and Coenzyme Q10. The positive results of this study suggest that a comprehensive nutritional and dietary intervention is effective at improving nutritional status, non-verbal IQ, autism symptoms, and other symptoms in most individuals with ASD. Parents reported that the vitamin/mineral supplements, essential fatty acids, and HGCSF diet were the most beneficial.


White matter integrity in brain networks relevant to anxiety and depression: evidence from the human connectome project dataset.
Anxiety and depression are associated with altered communication within global brain networks and between these networks and the amygdala. Functional connectivity studies demonstrate an effect of anxiety and depression on four critical brain networks involved in top-down attentional control (fronto-parietal network; FPN), salience detection and error monitoring (cingulo-opercular network; CON), bottom-up stimulus-driven attention (ventral attention network; VAN), and default mode (default mode network; DMN). However, structural evidence on the white matter (WM) connections within these networks and between these networks and the amygdala is lacking. The current study in a large healthy sample (n = 483) observed that higher trait anxiety-depression predicted lower WM integrity in the connections between amygdala and specific regions of the FPN, CON, VAN, and DMN. We discuss the possible consequences of these anatomical alterations for cognitive-affective functioning and underscore the need for further theory-driven research on individual differences in anxiety and depression on brain structure.


The Sharing of Research Data in the Cell & Tissue Engineering Area: Is It a Common Practice?
The availability of research data sets is an important milestone because it can enhance the dynamics of research. This study aims to analyze the PubMed Central repository to determine the availability and type of raw data sets in Cell & Tissue Engineering journals indexed in Journal Citation Reports. The number and types of files were registered. The main finding of this study is that, beyond the mandatory deposit of data in specific repositories that some journals require, the exchange of data as supplementary material in the Cell & Tissue Engineering journals is not a common practice since researchers are still reticent to do so.


Efficient Genome Editing in Caenorhabditis elegans with a Toolkit of Dual-Marker Selection Cassettes.
Use of the CRISPR/Cas9 RNA-guided endonuclease complex has recently enabled the generation of double-strand breaks virtually anywhere in the C. elegans genome. Here, we present an improved strategy that makes all steps in the genome editing process more efficient. We have created a toolkit of template-mediated repair cassettes that contain an antibiotic resistance gene to select for worms carrying the repair template and a fluorescent visual marker that facilitates identification of bona fide recombinant animals. Homozygous animals can be identified as early as 4-5 days post-injection, and minimal genotyping by PCR is required. We demonstrate that our toolkit of dual-marker vectors can generate targeted disruptions, deletions, and endogenous tagging with fluorescent proteins and epitopes. This strategy should be useful for a wide variety of additional applications and will provide researchers with increased flexibility when designing genome editing experiments.


Intrapartum treatment of preeclamptic hypertension by ketanserin.
Ketanserin was administered intravenously as either 20 or 10 mg boluses to 16 patients with severe preeclampsia in labor. The fetal heart rate was monitored with a scalp electrode and the uterine contractions were evaluated with a fluid-filled catheter connected to a physiologic pressure transducer. A 10-minute recording before every administration of ketanserin was compared to the same period immediately afterward. Ketanserin lowered the systolic and diastolic blood pressure significantly (p less than 0.005, paired Student's t test). Maternal heart rate was unchanged but the mean fetal heart rate increased by 4.6 bpm. Long-term beat-to-beat variability and acceleration patterns were not affected. On four occasions an improvement in variable decelerations of the fetal heart, due to a reduction in uterine activity, was seen. Changes in the amplitude of contractions were not statistically significant. The frequency of contractions, however, was significantly reduced from 3.6 to 2.4 per 10 minutes (p less than 0.005). No serious adverse effects occurred.


Nitrogen dynamics in Turbic Cryosols from Siberia and Greenland.
Turbic Cryosols (permafrost soils characterized by cryoturbation, i.e., by mixing of soil layers due to freezing and thawing) are widespread across the Arctic, and contain large amounts of poorly decomposed organic material buried in the subsoil. This cryoturbated organic matter exhibits retarded decomposition compared to organic material in the topsoil. Since soil organic matter (SOM) decomposition is known to be tightly linked to N availability, we investigated N transformation rates in different soil horizons of three tundra sites in north-eastern Siberia and Greenland. We measured gross rates of protein depolymerization, N mineralization (ammonification) and nitrification, as well as microbial uptake of amino acids and NH4+ using an array of 15N pool dilution approaches. We found that all sites and horizons were characterized by low N availability, as indicated by low N mineralization compared to protein depolymerization rates (with gross N mineralization accounting on average for 14% of gross protein depolymerization). The proportion of organic N mineralized was significantly higher at the Greenland than at the Siberian sites, suggesting differences in N limitation. The proportion of organic N mineralized, however, did not differ significantly between soil horizons, pointing to a similar N demand of the microbial community of each horizon. In contrast, absolute N transformation rates were significantly lower in cryoturbated than in organic horizons, with cryoturbated horizons reaching not more than 32% of the transformation rates in organic horizons. Our results thus indicate a deceleration of the entire N cycle in cryoturbated soil horizons, especially strongly reduced rates of protein depolymerization (16% of organic horizons) which is considered the rate-limiting step in soil N cycling.


Activation of germline-specific genes is required for limb regeneration in the Mexican axolotl.
The capacity for tissue and organ regeneration in humans is dwarfed by comparison to that of salamanders. Emerging evidence suggests that mechanisms learned from the early phase of salamander limb regeneration-wound healing, cellular dedifferentiation and blastemal formation-will reveal therapeutic approaches for tissue regeneration in humans. Here we describe a unique transcriptional fingerprint of regenerating limb tissue in the Mexican axolotl (Ambystoma mexicanum) that is indicative of cellular reprogramming of differentiated cells to a germline-like state. Two genes that are required for self-renewal of germ cells in mice and flies, Piwi-like 1 (PL1) and Piwi-like 2 (PL2), are expressed in limb blastemal cells, the basal layer keratinocytes and the thickened apical epithelial cap in the wound epidermis in the regenerating limb. Depletion of PL1 and PL2 by morpholino oligonucleotides decreased cell proliferation and increased cell death in the blastema leading to a significant retardation of regeneration. Examination of key molecules that are known to be required for limb development or regeneration further revealed that FGF8 is transcriptionally downregulated in the presence of the morpholino oligos, indicating PL1 and PL2 might participate in FGF signaling during limb regeneration. Given the requirement for FGF signaling in limb development and regeneration, the results suggest that PL1 and PL2 function to establish a unique germline-like state that is associated with successful regeneration.


Child abuse and neglect in a rapidly developing country: Parents' perspectives.
To identify parental awareness and knowledge regarding child abuse and neglect in the State of Qatar. A cross-sectional study using a questionnaire was conducted at Hamad Medical Corporation, the only tertiary pediatric hospital in the State of Qatar at the time of the study. Parents of children of all ages were offered a questionnaire that included demographic details, parental knowledge, and awareness of child abuse and neglect. 300 questionnaires were completed (response rate = 95%). More than 70% of parents were older than 30 years of age, 60% of them were females, and 66% were college graduates. The majority of the participants stated their familiarity about child abuse, and 6% witnessed morbidity or mortality due to child abuse in the society. Despite the identified laws, only 50% of the parents were aware of laws restricting child abuse. In regards to children with special needs, only 16% of the participants agreed that disabled children are at a higher risk of abuse compared to healthy children, while 33% were neutral and 52% disagreed. In addition, one-fifth of the respondents stated that hitting is discipline, while 63% disagreed. Almost one-third of the respondents agreed that hitting hands and buttock or hitting with soft objects is acceptable form of discipline. Unexpectedly, one-quarter of participants stated that it is okay to hit a child as long as no damage incurs. As for verbal abuse, around one-third of parents stated that yelling is not a form of child abuse, and that yelling does not affect growth and development. Comparing both corporal and verbal abuse, approximately 70% of parents stated that yelling is less harmful than hitting. In terms of child neglect, around half of the respondents agreed with the statement "Leaving a child (<5 years) unattended at home is a form of neglect," while 42% were neutral. Finally, approximately 50% of the participants believed that it is okay to depend on nannies in assisting their children in eating and using the bathroom. Parents residing in the State of Qatar believe that they have a good knowledge regarding child abuse and neglect. However, this study shows many deficiencies in parental knowledge of child abuse and neglect. Parents' attitudes and perceptions are considered indispensable targets for community health intervention.


Identifying white-matter fiber bundles in DTI data using an automated proximity-based fiber-clustering method.
We present a method for clustering diffusion tensor imaging (DTI) integral curves into anatomically plausible bundles. An expert rater evaluated the anatomical accuracy of the bundles. We also evaluated the method by applying an experimental cross-subject labeling method to the clustering results. We first employ a sampling and culling strategy for generating DTI integral curves and then constrain the curves so that they terminate in gray matter. We then employ a clustering method based on a proximity measure calculated between every pair of curves. We interactively selected a proximity threshold to achieve visually optimal clustering in models from four DTI datasets. An expert rater then assigned a confidence rating about bundle presence and accuracy for each of 12 target fiber bundles of varying calibers and type in each dataset. We then created a fiber bundle template to cluster and label the fiber bundles automatically in new datasets. According to expert evaluation, the automated proximity-based clustering and labeling algorithm consistently yields anatomically plausible fiber bundles on large and coherent clusters. This work has the potential to provide an automatic and robust way to find and study neural fiber bundles within DTI.


The surface barrier phenomenon at the loading of metal-organic frameworks.
Loading with guest molecules is a crucial step for most applications of porous materials. For metal-organic frameworks, which are one of the most intensely investigated classes of porous materials, the experimentally determined rate of mass transfer into the material may vary by several orders of magnitude for different samples of the same material. This phenomenon is commonly attributed to the presence of so-called surface barriers, which appear to be omnipresent but poorly understood. Here we quantitatively study this phenomenon with a quartz crystal microbalance, using well-defined, highly crystalline, epitaxially grown thin films of metal-organic frameworks as a model system. Our results clearly demonstrate that surface barriers are not an intrinsic feature of metal-organic frameworks, as pristine films do not exhibit these limitations. However, by destroying the structure at the outer surface, for instance by exposure to air or water vapour, surface barriers are created and the molecular uptake rate is reduced.


Four Individually Identified Paired Dopamine Neurons Signal Reward in Larval Drosophila.
Dopaminergic neurons serve multiple functions, including reinforcement processing during associative learning [1-12]. It is thus warranted to understand which dopaminergic neurons mediate which function. We study larval Drosophila, in which only approximately 120 of a total of 10,000 neurons are dopaminergic, as judged by the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine biosynthesis [5, 13]. Dopaminergic neurons mediating reinforcement in insect olfactory learning target the mushroom bodies, a higher-order "cortical" brain region [1-5, 11, 12, 14, 15]. We discover four previously undescribed paired neurons, the primary protocerebral anterior medial (pPAM) neurons. These neurons are TH positive and subdivide the medial lobe of the mushroom body into four distinct subunits. These pPAM neurons are acutely necessary for odor-sugar reward learning and require intact TH function in this process. However, they are dispensable for aversive learning and innate behavior toward the odors and sugars employed. Optogenetical activation of pPAM neurons is sufficient as a reward. Thus, the pPAM neurons convey a likely dopaminergic reward signal. In contrast, DL1 cluster neurons convey a corresponding punishment signal [5], suggesting a cellular division of labor to convey dopaminergic reward and punishment signals. On the level of individually identified neurons, this uncovers an organizational principle shared with adult Drosophila and mammals [1-4, 7, 9, 10] (but see [6]). The numerical simplicity and connectomic tractability of the larval nervous system [16-19] now offers a prospect for studying circuit principles of dopamine function at unprecedented resolution.


Prostaglandin E2--mediated relaxation of the ductus arteriosus: effects of gestational age on g protein-coupled receptor expression, signaling, and vasomotor control.
In the preterm newborn, a patent ductus arteriosus is in large part a result of the increased sensitivity of the immature ductus to prostaglandin E2 (PGE2). PGE2 acts through 3 G protein-coupled receptors (EP2, EP3, and EP4) that activate both adenyl cyclase and K(ATP) channels. We explored these pathways to identify the mechanisms responsible for the increased sensitivity of the immature ductus to PGE2. We measured EP receptor content (mRNA and protein), receptor binding, cAMP production, and isometric tension in rings of ductus taken from immature (65% gestation) and mature (95% gestation) sheep and baboon fetuses. Ductus relaxation and cAMP generation were augmented in response to selective EP receptor agonists in the immature ductus. 8-Br-cAMP, a stable cAMP analogue, produced greater relaxation in the immature ductus. In the presence of a selective protein kinase A inhibitor, Rp-8-CPT cAMPS, the developmental differences in sensitivity to PGE2 could no longer be demonstrated. EP2, EP3, and EP4 receptor densities were higher in immature ductus, despite similar receptor mRNA and protein contents at the 2 gestational ages. In contrast, forskolin and NaF, direct activators of adenyl cyclase and Gs, respectively, elicited comparable increases in cAMP in both age groups. KATP channel inhibition also had similar effects on PGE2-induced relaxation in both age groups. Two mechanisms explain the increased sensitivity of the immature ductus to PGE2: (1) increased cAMP production because of increased binding of PGE2 to the individual EP receptors and (2) increased potency of cAMP on protein kinase A-regulated pathways.


Development and Characterization of Cinnamon Leaf Oil Nanocream for Topical Application.
Cinnamon leaf oil contains a high percentage of eugenol and has antimicrobial, antioxidant and antiinflammatory properties. However, the undiluted oil can cause irritation to the skin. Therefore, the aims of this study were to develop and evaluate cinnamon leaf oil nanocream using palm oil. Nanocream base was prepared using different ratios of oil, surfactants and water. The surfactant used were mixture of Tween 80:Carbitol or Tween 80:Span 65 at different hydrophile-lipophile balance values. The pseudoternary phase diagrams were constructed to identify the nanocream base areas and the results showed that the nanocream bases using Span 65 as co-surfactant produced bigger cream area. Fifteen formulations using mixtures of Tween 80:Span 65 were further evaluated for accelerated stability test, droplet size, zeta potential, rheological properties and apparent viscosity. The nanocream base which had an average droplet size of 219 nm and had plastic flow with thixotropic behavior was selected for incorporation of 2% cinnamon leaf oil. The nanocream containing cinnamon leaf oil had the average size of 286 nm and good rheological characteristics. The in vitro release study demonstrated that eugenol as the main constituent of cinnamon leaf oil was released for about 81% in 10 h. The short-term stability study conducted for 6 months showed that the cinnamon leaf oil nanocream was stable at a temperature of 25° and thus, cinnamon leaf oil nanocream is a promising natural based preparation to be used for topical application.


Methods: Using Three-Dimensional Culture (Spheroids) as an In Vitro Model of Tumour Hypoxia.
Regions of hypoxia in tumours can be modelled in vitro in 2D cell cultures with a hypoxic chamber or incubator in which oxygen levels can be regulated. Although this system is useful in many respects, it disregards the additional physiological gradients of the hypoxic microenvironment, which result in reduced nutrients and more acidic pH. Another approach to hypoxia modelling is to use three-dimensional spheroid cultures. In spheroids, the physiological gradients of the hypoxic tumour microenvironment can be inexpensively modelled and explored. In addition, spheroids offer the advantage of more representative modelling of tumour therapy responses compared with 2D culture. Here, we review the use of spheroids in hypoxia tumour biology research and highlight the different methodologies for spheroid formation and how to obtain uniformity. We explore the challenge of spheroid analyses and how to determine the effect on the hypoxic versus normoxic components of spheroids. We discuss the use of high-throughput analyses in hypoxia screening of spheroids. Furthermore, we examine the use of mathematical modelling of spheroids to understand more fully the hypoxic tumour microenvironment.


Risk factors for and molecular characteristics of methicillin-resistant Staphylococcus aureus nasal colonization among healthy children in southern Taiwan, 2005-2010.
Nasal colonization of Staphylococcus aureus is a well-defined risk factor for subsequent infection. This study investigated the prevalence of methicillin-resistant S. aureus (MRSA) in southern Taiwan and aimed to identify the host factors for S. aureus colonization and the virulence factor of Panton-Valentine Leukocidin (PVL) genes. In a hospital-based study in Kaohsiung from Oct. 2005 to Dec. 2010, we performed nasal swab in the healthy children aged 2-60 months. We examined the relationship between the demographic characteristics and S. aureus nasal colonization. MRSA isolates were further analyzed for antimicrobial susceptibility and molecular characteristics. Among 3020 healthy children, 840 (27.8%) children had S. aureus nasal colonization. Of 840 isolates, 246 (29.3%) isolates were MRSA. MRSA colonization was significantly associated with age 2-6 months, day care attendance, and influenza vaccination. Breastfeeding was a protective factor against MRSA colonization. Most MRSA isolates were susceptible to trimethoprim-sulfamethoxazole and doxycycline. Ninety-four percent of MRSA isolates carried either type IV staphylococcal cassette chromosome mec (SCCmec) or SCCmec VT and 87% belonged to the local community strains, namely clonal complex 59/SCCmec IV or VT. MRSA isolates with PVL-negative was associated with children with passive smoking. Between 2005 and 2010, 27.8% and 8.14% of healthy children in southern Taiwan had nasal carriage of S. aureus and MRSA, respectively. Most MRSA isolates were local community strains. Several demographic factors associated with nasal MRSA colonization were identified.


A large chronic pericardial effusion in an ultramarathon runner with anti-CCP positive rheumatoid arthritis.
Pericardial effusions arise as an extra-articular manifestation of rheumatoid arthritis (RA). Pericardial effusions are often asymptomatic, particularly in the early phase, but patients are at risk of cardiac tamponade as the effusion progresses. We discuss the case of a 40-year-old male ultramarathon runner with RA who presented with mild pleuritic chest pain and exertional dyspnoea after a recent long-haul flight. Despite a relative tachycardia, his observations were otherwise unremarkable. His blood tests revealed a C-reactive protein (CRP) of 86 mg/L and an anti-cyclic citrullinated peptide (anti-CCP) titre of 360 units/mL. He was initially diagnosed with a pulmonary embolism; however, a large pericardial effusion was found incidentally on CT pulmonary angiogram with over 1500 mL subsequently drained. The patient's symptoms resolved and CRP normalised 2 weeks later. This unique case illustrates that physically fit patients may physiologically compensate for large pericardial effusions and that arthritic symptoms do not correlate with the severity of extra-articular features in RA.


Magnetic impurities on the surface of a topological insulator.
The surface states of a topological insulator are described by an emergent relativistic massless Dirac equation in 2 + 1 dimensions. In contrast with graphene, there is an odd number of Dirac points, and the electron spin is directly coupled to the momentum. We show that a magnetic impurity opens up a local gap and suppresses the local density of states. Furthermore, the Dirac electronic states mediate an RKKY interaction among the magnetic impurities which is always ferromagnetic, whenever the chemical potential lies near the Dirac point. Through this exchange mechanism, magnetic atoms uniformly deposited on the surface of a topological insulator could naturally form a ferromagnetically ordered film. These effects can be directly measured in STM experiments. We also study the case of quenched disorder through a renormalization group analysis.


CNS-directed therapy for childhood acute lymphoblastic leukemia: Childhood ALL Collaborative Group overview of 43 randomized trials.
A collaborative meta-analysis was performed to clarify the relative effects on relapse and survival of different types of therapies directed at the CNS in childhood acute lymphoblastic leukemia. Data were sought for each individual patient in all trials started in or before 1993 that included unconfounded randomized comparisons of such treatments. Log-rank survival analyses were performed for each trial, and overall results for groups of trials addressing similar questions were obtained from the totals of the observed minus expected number of events and their variances. Radiotherapy and long-term intrathecal therapy gave similar outcomes, with no significant difference in event-free survival despite random assignment of treatment to 2,848 patients, 1,001 of whom suffered relapse or death. Intravenous methotrexate reduced non-CNS rather than CNS relapses, and hence, the addition of intravenous methotrexate to a treatment regimen including radiotherapy or long-term intrathecal therapy improved event-free survival, with a 17% reduction in the event rate (95% confidence interval, 6% to 27%; P =.003). The event-free survival at 10 years in these trials was 61.9% without intravenous methotrexate and 68.1% with intravenous methotrexate. There was no significant difference in survival (14% death rate reduction; P =.09). There were insufficient randomly assigned patients to adequately address other questions, such as effect of different doses. No evidence was found of differences, between trials or between subgroups of different types of patients, in the relative effects of treatment. Radiotherapy can be replaced by long-term intrathecal therapy. Intravenous methotrexate gives some additional benefit by reducing non-CNS relapses.


Distinguishing High-Performing Health Systems Using a Composite of Publicly Reported Measures of Ambulatory Care.
Payers and policymakers are rewarding high-performing health care providers on the basis of summaries of overall quality performance, and the methods they use for measuring performance are increasingly important. To develop and evaluate a measure that ranks health care systems by ambulatory care quality. Systems were ranked using a composite model that summarizes individual measures of quality, accounts for their correlation, and does not require health care systems to report every measure. The composite measure's suitability was evaluated by examining whether it captured the quality indicated by component measures (validity), whether differences in rank between health care systems were larger than statistical noise (reliability), and whether year-to-year changes in rank were small (stability). California and Minnesota, 2014 to 2016. 55 health care systems. Publicly reported measures of ambulatory care quality. The composite measure was valid in that it was broadly representative of the component measures and was not dominated by any single measure. The measure was reliable because the ranks for 93% of California systems and 80% of Minnesota systems were unlikely to be more than 2 places lower or higher. The measure was stable because fewer than half of systems changed ranks by more than 2 ranks from year to year. The analysis is limited to available measures of ambulatory care quality and includes only 2 states. This composite measure uses publicly reported data to produce valid, reliable, and stable ranks of ambulatory care quality for health care systems in Minnesota and California, and this approach could be used in other applications. Agency for Healthcare Research and Quality.


The Association Between Clusterin and APOE Polymorphisms and Late-Onset Alzheimer Disease in a Turkish Cohort.
Previous studies have demonstrated that clusterin (CLU), which is also known as apolipoprotein J, is involved in the pathogenesis of Alzheimer disease (AD). In this study, we investigated the association between rs2279590, rs11136000, and rs9331888 single-nucleotide polymorphisms (SNPs) in CLU and apolipoprotein E (APOE) genotypes in a cohort of Turkish patients with late-onset AD (LOAD). There were 183 patients with LOAD and 154 healthy controls included in the study. The CLU and APOE polymorphisms were genotyped using the LightSNiP assay. The "GG" genotype of rs9331888 was significantly more frequent in patients with LOAD. The "CC" genotype of the SNP was significantly more frequent in controls. The rs9331888 "GG" genotype in patients and the "CC" genotype in controls were significantly higher in non-∊4 allele carriers of APOE The haplotype analysis showed the CLU "GCG" haplotype was a risk haplotype. Our findings indicate the rs9331888 SNP of CLU is associated with LOAD independent of APOE.


6-Gingerol inhibits hair cycle via induction of MMP2 and MMP9 expression.
6-Gingerol is the major active constituent of ginger. In the current study, we aimed to investigate the mechanisms underlying the effects of 6-Gingerol on hair growth. Mice were randomly divided into five groups; after hair depilation (day 0), mice were treated with saline, or different concentrations of 6-Gingerol for 11 days. The histomorphological characteristics of the growing hair follicles were examined after hematoxylin and eosin staining. The results indicated that 6-Gingerol significantly suppressed hair growth compared with that in the control group. And choose the concentration of 6-Gingerol at 1 mg/mL to treated with mice. Moreover, 6-Gingerol (1 mg/mL) significantly reduced hair re-growth ratio, hair follicle number, and hair follicle length, which were associated with increased expression of MMP2 and MMP9. Furthermore, the growth factors, such as EGF, KGF, VEGF, IGF-1 and TGF-β participate in the hair follicle cycle regulation and regulate hair growth. We then measured the concentrations of them using ELISA assays, and the results showed that 6-Gingerol decreased EGF, KGF, VEGF, and IGF-1 concentrations, and increased TGF-β concentration. Thus, this study showed that 6-Gingerol might act as a hair growth suppressive drug via induction of MMP2 and MMP9 expression, which could interfere with the hair cycle.


Promoting research in clinical practice: strategies for implementing research initiatives.
Promoting the use and conduct of research in clinical practice is an essential component in ensuring best practices and promoting positive outcomes for patients. Yet, it is often difficult for nurses in clinical practice to devote time to research activities because the daily demands of practice often take precedence. This article reviews key strategies for implementing research in clinical practice. Examples of ongoing initiatives being conducted at a variety of clinical settings are highlighted to showcase strategies for implementing clinically focused research projects.


[Therapy for elderly family members and couples: concerning the viability of relationships in later life, the role reversal and 'finishing' amicably].
Research shows that in most countries the number of elderly persons is increasing and that close relationships in late life are playing a more important role. Therefore, it is surprising that there have been so few publications about family therapy for the elderly. To formulate some guidelines for psychotherapy for family members in their later years and to make suggestions regarding further research. We summarise the existing literature and focus on important themes about working with the elderly, supplementing major issues with our own clinical experience. Family therapy with the elderly differs from therapy for younger adults in some respects; for instance, the emphasis in the case of the elderly is more on strengthening the viability of a long/standing relationship. The reversal of roles that often accompanies the ageing process and leads to increasing dependency is another factor that affects the elderly more than the younger adults. If the last stage of life is to finish calmly and amicably, therapists need to tackle any tensions or injustices that patients have experienced in the course of their relationships. Psychotherapy for the elderly needs to provide clients with constant opportunities for reflection and should initiate discussions about partners' experiences of tensions and injustices in their earlier relationship. However, the increasing number of elderly persons means that more empirical research needs to be done into systematic psychotherapy.


PropAngio study protocol: a neoadjuvant trial on the efficacy of propranolol monotherapy in cutaneous angiosarcoma-a proof of principle study.
Angiosarcoma is a rare and aggressive malignancy with a high metastatic potential and recurrence rate. Despite optimal treatment with surgery, with or without radiation, the prognosis remains poor and, therefore, new treatment strategies are warranted. Recently, propranolol has effectively been repurposed for the treatment of infantile haemangioma. Propranolol is a β3-sparing antagonist of the β-adrenergic receptor. In infantile haemangioma, the β1, β2 and β3 receptors are highly expressed. Angiosarcoma has several similarities with haemangioma, including its high β-adrenergic receptor expression and the supposedly important role of vascular endothelial growth factor in malignant growth. As a result, propranolol has been administered small scale in individual angiosarcoma cases with promising results. The precise effect of propranolol, however, is not yet established. The goal of this neoadjuvant window of opportunity study is to prospectively evaluate the activity of propranolol monotherapy in patients with cutaneous angiosarcoma. The neoadjuvant setting provides a good opportunity to rapidly evaluate both the clinical response and histological response, without a significant delay in standard anticancer treatment. Fourteen patients with primary, recurrent or metastatic cutaneous angiosarcoma will be included. Propranolol will be administered orally in an escalating dose during 3-6 weeks, before the initiation of standard treatment. The primary endpoint is clinical response according to Response Evaluation Criteria in Solid Tumours, as measured on consecutive coloured photographs or CT/MRI. The histological response will be determined as secondary endpoint, comparing the difference in proliferation index before and after propranolol by measuring the change in immunohistochemistry staining of Ki-67. The study will be considered positive when at least three patients have a response to propranolol. Ethical approval was obtained from the Medical Ethical Committee of the Netherlands Cancer Institute. Independent of the outcome, results of this study will be shared and submitted for publication in an international peer-reviewed journal. NL8118; registry through the Netherlands Trial Register.


Positive direct immunofluorescence and autoantibody profiles in psoriasis patients.
Psoriasis and systemic lupus erythematosus are common, but their coexistence is thought to be infrequent. Each of these diseases has a broad clinical spectrum, so that diagnosis may not be straightforward. This study aimed to investigate the following immunological parameters in psoriasis patients: (i) direct immunofluorescence (DIF); (ii) antinuclear antibody; (iii) anti-double-stranded DNA (dsDNA); (iv) anti-Ro; and (v) anti-nuclear ribonucleoprotein (nRNP). Of 300 cases, comprising 189 men (62.9%) and 111 women (37.1%), 17 (5.7%; 10 men, seven women) were positive for at least one immunological parameter. Nine of 300 (3%; seven male, two female) biopsy specimens from sun-exposed psoriatic lesions demonstrated bright continuous bands of granular IF along the dermoepidermal junction with immunoreactant immunoglobulin (Ig)G, IgM, C3 and fibrinogen. The intensity of IF at the dermoepidermal junction was graded 3+ and 2+. Three cases demonstrated IgM, two had IgG, two fibrinogen and six cases showed C3. Three cases demonstrated more than one immunoreactant. One case demonstrated C3 at the vessels. No specimen demonstrated IgA deposition. Three hundred sera were obtained from patients with psoriasis, of which five demonstrated elevated antinuclear antibody (ANA) titer; dilution titer varied from 1:80-640. Three had a homogeneous pattern and two had a speckled pattern. None had a peripheral pattern. Five (1.7%) of 300 demonstrated anti-Ro, two had negative ANA, and three were positive ANA, two of which were speckled and the other homogenous. Anti-dsDNA, anti-Sm and anti-nRNP were not detected. Ten patients had positive DIF but negative ANA, while five had positive ANA; all had negative DIF results. Thus, the incidence of psoriasis and lupus erythematosus coexistence is low and a baseline immunological screening test for psoriasis might not prove worthwhile.


[Abnormal electroencephalogram features extraction of autistic children based on wavelet transform combined with empirical modal decomposition].
Early detection and timely intervention are very essential for autism. This paper used the wavelet transform and empirical mode decomposition (EMD) to extract the features of electroencephalogram (EEG), to compare the feature differences of EEG between the autistic children and healthy children. The experimental subjects included 25 healthy children (aged 5-10 years old) and 25 children with autism (20 boys and 5 girls aged 5-10 years old) respectively. The alpha, beta, theta and delta rhythm wave spectra of the C3, C4, F3, F4, F7, F8, FP1, FP2, O1, O2, P3, P4, T3, T4, T5 and T6 channels were extracted and decomposed by EMD decomposition to obtain the intrinsic modal functions. Finally the support vector machine (SVM) classifier was used to implement assessment of autism and normal classification. The results showed that the accuracy could reach 87% and which was nearly 20% higher than that of the model combining the wavelet transform and sample entropy in the paper. Moreover, the accuracy of delta (1-4 Hz) rhythm wave was the highest among the four kinds of rhythms. And the classification accuracy of the forehead F7 channel, left FP1 channel and T6 channel in the temporal region were all up to 90%, which expressed the characteristics of EEG signals in autistic children better.


Photo-tautomerization of acetaldehyde to vinyl alcohol: a potential route to tropospheric acids.
Current atmospheric models underestimate the production of organic acids in the troposphere. We report a detailed kinetic model of the photochemistry of acetaldehyde (ethanal) under tropospheric conditions. The rate constants are benchmarked to collision-free experiments, where extensive photo-isomerization is observed upon irradiation with actinic ultraviolet radiation (310 to 330 nanometers). The model quantitatively reproduces the experiments and shows unequivocally that keto-enol photo-tautomerization, forming vinyl alcohol (ethenol), is the crucial first step. When collisions at atmospheric pressure are included, the model quantitatively reproduces previously reported quantum yields for photodissociation at all pressures and wavelengths. The model also predicts that 21 ± 4% of the initially excited acetaldehyde forms stable vinyl alcohol, a known precursor to organic acid formation, which may help to account for the production of organic acids in the troposphere.


Leadership: current theories, research, and future directions.
This review examines recent theoretical and empirical developments in the leadership literature, beginning with topics that are currently receiving attention in terms of research, theory, and practice. We begin by examining authentic leadership and its development, followed by work that takes a cognitive science approach. We then examine new-genre leadership theories, complexity leadership, and leadership that is shared, collective, or distributed. We examine the role of relationships through our review of leader member exchange and the emerging work on followership. Finally, we examine work that has been done on substitutes for leadership, servant leadership, spirituality and leadership, cross-cultural leadership, and e-leadership. This structure has the benefit of creating a future focus as well as providing an interesting way to examine the development of the field. Each section ends with an identification of issues to be addressed in the future, in addition to the overall integration of the literature we provide at the end of the article.


Tissue penetration and activity of camptothecins in solid tumor xenografts.
The ability of a panel of camptothecin derivatives to access the tumor compartment was evaluated to determine the mechanisms by which the architecture of solid tumors may act to limit their activity. Microregional localization and activity of members of the camptothecin class of topoisomerase I targeting agents, including topotecan, irinotecan, and irinophore C, a lipid-based nanoparticulate formulation of irinotecan, were evaluated over time in HCT116 and HT29 colorectal tumor xenografts. Using native drug fluorescence, their distributions in tissue cryosections were related to the underlying tumor vasculature, tumor cell proliferation, and apoptosis. Topotecan exhibited a relatively uniform tumor distribution; in tissue 100 μm away from vessels, it reached 94% ± 5% of levels seen around blood vessels, whereas irinotecan and irinophore C were found to reach only 41% ± 10% and 5% ± 2%, respectively. Surprisingly, all three agents were able to initially inhibit proliferation uniformly throughout the tumors, and it was their rate of washout (topotecan > irinotecan > irinophore C) that correlated with activity. To explain this discrepancy, we looked at SN38, the active metabolite of irinotecan, and found it to penetrate tissue similarly to topotecan. Hence, the poor access to the tumor compartment of irinotecan and irinophore C could be offset by their systemic conversion to SN38. It was concluded that all three agents were effective at reaching tumor cells, and that despite the poor access to the extravascular compartment of irinophore C, its extended plasma exposure and systemic conversion to the diffusible metabolite SN38 enabled it to effectively target solid tumors.


Factors related to the composition and diversity of wound microbiota investigated using culture-independent molecular methods: a scoping review.
All open wounds are often colonized by commensal microbes as a loss of skin can provide a ready portal of entry for microorganisms. Although the wound microbiota is known to be associated with wound infection and with delayed healing, the factors related to the formations of wound microbiota contributing to such poor clinical outcomes are not clear and have not led to effective infection prevention interventions. This review aimed to scope the factors related to the composition and diversity of wound microbiota that have been investigated using culture-independent molecular methods. Original articles on wound microbiota published from January 1986 to February 2020 were included in this review. Thirty-one articles met the inclusion criteria and were grouped according to wound types: chronic, acute, and animal model wounds. The factors identified were categorized according to patient characteristics, wound characteristics, treatment, and sampling. Although some studies reported the effect size of the factors, the values were small. No studies elucidated the mechanism of wound microbiota formation. The results of this scoping review highlight that the factors associated with the diversity of wound microbiota are poorly understood and that further studies are needed.


Immunomagnetic separation and PCR detection show Shigellae to be common faecal agents in children from urban marginal communities of Costa Rica.
Culture and immunomagnetic separation-polymerase chain reaction assays (IMS-PCR) were used to isolate and identify Shigella flexneri, S. dysenteriae type I and S. sonnei in faeces from 250 children up to 5 years and from their mothers (n = 143) selected at random from a large urban marginal community of Costa Rica. Children hospitalized because of severe diarrhoea (n = 110) were also studied. Only S. flexneri, mainly serotype 2a, and S. sonnei were found by culture. All specimens in which Shigella was cultured were also positive by the corresponding IMS-PCR. S. flexneri was isolated by culture from 1 (0.7%) mother and 4 (1.6%) community children. S. sonnei was found in 2 (0.8%) children. An additional 12 S. flexneri and four S. sonnei in the community children were found by IMS-PCR. In total, Shigella was cultured from 0.7% of mothers and 2.4% of children. By the IMS-PCR 2% of mothers and 8% of children were positive. S. flexneri was isolated by culture from 14 (12.7%) hospitalized children and S. sonnei from 1 (0.9%). An additional 11 S. flexneri and three S. sonnei were found by IMS-PCR. In total, Shigella was cultured from 13.6% of hospitalized children. By the IMS-PCR 26% of them were Shigella positive. Thus IMS-PCR was more than twice as effective in diagnosing shigellae as culture. Twelve (60%) Shigella positive community children were above 3-years-old and 25% of them were under one year. Seven (35%) of the Shigella positive children had dysenteric and 9 (45%) normal stools. Half of the Shigella infected community children had been weaned before the 3 months of age. By the age of 5 months, 90% of them were already weaned. Seventeen (59%) of the hospitalized Shigella positive children were under 1 year of age. The stools were watery or semiliquid in 13 (45%) and dysenteric in 12 (41%) of them. We conclude that shigellosis is common in Costa Rica and represents an important cause of severe infant diarrhoea requiring hospitalization.


A new antiproliferative and antioxidant peptide isolated from Arca subcrenata.
A new antitumor and antioxidant peptide (H3) was isolated from Arca subcrenata Lischke using ion exchange and hydrophobic column chromatography. The purity of H3 was over 99.3% in reversed phase-high performance liquid chromatography (RP-HPLC) and the molecular weight was determined to be 20,491.0 Da by electrospray-ionization mass spectrometry (ESI-MS/MS). The isoelectric point of H3 was measured to be 6.65 by isoelectric focusing-polyacrylamide gel electrophoresis. Partial amino acid sequence of this peptide was determined as ISMEDVEESRKNGMHSIDVNH DGKHRAYWADNTYLM-KCMDLPYDVLDTGGKDRSSDKNTDLVDLFELDMVPDRK NNECMNMIMDVIDTN-TAARPYYCSLDVNHDGAGLSMEDVEEDK via MALDI-TOF/ TOF-MS and de novo sequencing. The in vitro antitumor activity of H3 was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The result indicated that H3 exhibited significant antiproliferative activity against HeLa, HepG2 and HT-29 cell lines with IC₅₀ values of 10.8, 10.1 and 10.5 μg/mL. The scavenging percentage of H3 at 8 mg/mL to 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl radicals were 56.8% and 47.5%, respectively.


Glucose-sensitive nanofiber scaffolds with an improved sensing design for physiological conditions.
Continuous physiological monitoring of electrolytes and small molecules such as glucose, creatinine, and urea is currently unavailable but achieving such a capability would be a major milestone for personalized medicine. Optode-based nanosensors are an appealing analytical platform for designing in vivo monitoring systems. In addition to the necessary analytical performance, such nanosensors must also be biocompatible and remain immobile at the implantation site. Blood glucose in particular remains a difficult but high-value analyte to monitor continuously. Previously, we developed glucose-sensitive nanosensors that measure glucose by a competitive binding mechanism between glucose and a fluorescent dye to 4-carboxy-3-fluorophenyl boronic acid. To improve the sensitivity and residency time of our reported sensors, we present here a series of new derivatives of 4-carboxy-3-fluorophenyl boronic acid that we screened in a macrosensor format before translating into a nanofiber format with electrospinning. The lead candidate was then implanted subdermally and its residency time was compared to spherical nanosensor analogues. The nanofiber scaffolds were markedly more stable at the implantation site whereas spherical nanosensors diffused away within three hours. Based on the enhanced sensitivity of the new boronic acids and the residency time of nanofibers, this sensor configuration is an important step towards continuous monitoring of glucose and other analytes.


Herb-drug interactions and mechanistic and clinical considerations.
Herbal medicines are often used in combination with conventional drugs, and this may give rise to the potential of harmful herb-drug interactions. This paper updates our knowledge on clinical herb-drug interactions with an emphasis of the mechanistic and clinical consideration. In silico, in vitro, animal and human studies are often used to predict and/or identify drug interactions with herbal remedies. To date, a number of clinically important herb-drug interactions have been reported, but many of them are from case reports and limited clinical observations. Common herbal medicines that interact with drugs include St John's wort (Hypericum perforatum), ginkgo (Ginkgo biloba), ginger (Zingiber officinale), ginseng (Panax ginseng), and garlic (Allium sativum). For example, St John's wort significantly reduced the area under the plasma concentration-time curve (AUC) and blood concentrations of cyclosporine, midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline. The common drugs that interact with herbal medicines include warfarin, midazolam, digoxin, amitriptyline, indinavir, cyclosporine, tacrolimus and irinotecan. Herbal medicines may interact with drugs at the intestine, liver, kidneys, and targets of action. Importantly, many of these drugs have very narrow therapeutic indices. Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (P-gp). The underlying mechanisms for most reported herb-drug interactions are not fully understood, and pharmacokinetic and/or pharmacodynamic mechanisms are implicated in many of these interactions. In particular, enzyme induction and inhibition may play an important role in the occurrence of some herbdrug interactions. Because herb-drug interactions can significantly affect circulating levels of drug and, hence, alter the clinical outcome, the identification of herb-drug interactions has important implications.


Microtopographic refuges shape consumer-producer dynamics by mediating consumer functional diversity.
Consumer-producer dynamics are critical for ecosystem functioning. In marine environments, primary production is often subject to strong consumer control, and on coral reefs, the grazing pressure exerted by herbivorous fishes has been identified as a major determinant of benthic community structure. Using experimental surfaces, we demonstrate that on coral reefs, microtopographic refuges decrease the overall grazing pressure by more than one order of magnitude. Furthermore, by functionally characterizing consumer communities, we show that refuges also restrict grazer communities to only one functional group, algal croppers, which selectively remove the apical parts of algae. In contrast, detritivorous fishes, which intensively graze flat and exposed microhabitats and can remove both particulate matter and entire stands of algal filaments, are almost entirely excluded. This preclusion of an entire ecosystem process (the removal of particulates) results in two distinct coexisting benthic regimes: communities within refuges are diverse and characterized by numerous algal types and juvenile scleractinian corals, while communities outside refuges support only low-diversity assemblages dominated by simple, unbranched filamentous turf algal mats. Although limited to the scale of a few centimeters, microtopographic refuges can, therefore, mediate the biotic control of community development by affecting both overall grazing rates and the functional diversity of consumer communities. We suggest that the coexistence of two distinct benthic regimes at a small spatial scale may be an important factor for ecosystem functioning and highlight the need to consider the ecological complexity of consumer-producer dynamics when assessing the status of coral reef ecosystems.


Long-lasting alterations of hippocampal GABAergic neurotransmission in adult rats following perinatal Δ9-THC exposure.
The long-lasting effects of gestational cannabinoids exposure on the adult brain of the offspring are still controversial. It has already been shown that pre- or perinatal cannabinoids exposure induces learning and memory disruption in rat adult offspring, associated with permanent alterations of cortical glutamatergic neurotransmission and cognitive deficits. In the present study, the risk of long-term consequences induced by perinatal exposure to cannabinoids on rat hippocampal GABAergic system of the offspring, has been explored. To this purpose, pregnant rats were treated daily with Delta9-tetrahydrocannabinol (Δ9-THC; 5mg/kg) or its vehicle. Perinatal exposure to Δ9-THC induced a significant reduction (p<0.05) in basal and K+-evoked [3H]-GABA outflow of 90-day-old rat hippocampal slices. These effects were associated with a reduction of hippocampal [3H]-GABA uptake compared to vehicle exposed group. Perinatal exposure to Δ9-THC induced a significant reduction of CB1 receptor binding (Bmax) in the hippocampus of 90-day-old rats. However, a pharmacological challenge with either Δ9-THC (0.1μM) or WIN55,212-2 (2μM), similarly reduced K+-evoked [3H]-GABA outflow in both experimental groups. These reductions were significantly blocked by adding the selective CB1 receptor antagonist SR141716A. These findings suggest that maternal exposure to cannabinoids induces long-term alterations of hippocampal GABAergic system. Interestingly, previous behavioral studies demonstrated that, under the same experimental conditions as in the present study, perinatal cannabinoids exposure induced cognitive impairments in adult rats, thus resembling some effects observed in humans. Although it is difficult and sometimes misleading to extrapolate findings obtained from animal models to humans, the possibility that an alteration of hippocampus aminoacidergic transmission might underlie, at least in part, some of the cognitive deficits affecting the offspring of marijuana users, is supported.


The force-driven conformations of heparin studied with single molecule force microscopy.
Using single molecule force spectroscopy we examine the response of heparin chains to mechanical stretching. We find that at forces below 200 pN heparin behaves as a simple entropic spring. At approximately 200 pN heparin displays a large enthalpic elasticity, which is evident as a pronounced plateau in the force-extension relationship. We determine that this enthalpic elasticity is produced by sugar rings of heparin flipping to more energetic and more extended conformations. We estimate that in vivo, the forces which stretch heparin are comparable to the forces that trigger conformational transitions in our single molecule atomic force microscopy measurements. We hypothesize that these conformational transitions have biological significance in that they provide a mechanism to finely regulate the affinity of various ligands toward heparin, for example, in secretory granules undergoing exocytosis and during the mechanical interactions between cells and the extracellular matrix.


Cellular immune response to cryptic epitopes during therapeutic gene transfer.
The immune response has been implicated as a critical factor in determining the success or failure of clinical gene therapy trials. Generally, such a response is elicited by the desired transgene product or, in some cases, the delivery system. In the current study, we report the previously uncharacterized finding that a therapeutic cassette currently being used for human investigation displays alternative reading frames (ARFs) that generate unwanted protein products to induce a cytotoxic T lymphocyte (CTL) response. In particular, we tested the hypothesis that antigenic epitopes derived from an ARF in coagulation factor IX (F9) cDNA can induce CTL reactivity, subsequently killing F9-expressing hepatocytes. One peptide (p18) of 3 candidates from an ARF of the F9 transgene induced CD8(+) T cell reactivity in mice expressing the human MHC class I molecule B0702. Subsequently, upon systemic administration of adeno-associated virus (AAV) serotype 2 vectors packaged with the F9 transgene (AAV2/F9), a robust CD8(+) CTL response was elicited against peptide p18. Of particular importance is that the ARF epitope-specific CTLs eliminated AAV2/F9-transduced hepatocytes but not AAV2/F9 codon-optimized (AAV2/F9-opt)-transduced liver cells in which p18 epitope was deleted. These results demonstrate a previously undiscovered mechanism by which CTL responses can be elicited by cryptic epitopes generated from a therapeutic transgene and have significant implications for all gene therapy modalities. Such unforeseen epitope generation warrants careful analysis of transgene sequences for ARFs to reduce the potential for adverse events arising from immune responses during clinical gene therapy protocols.


Orthosiphon stamineus Extracts Inhibits Proliferation and Induces Apoptosis in Uterine Fibroid Cells
Objectives: The effects of water and 50% ethanolic-water extracts of Orthosiphon stamineus Benth (OS) on cell proliferation and apoptotic activity against uterine leiomyosarcoma (SK-UT-1) cells were investigated. Methods: Anti-proliferation effect was evaluated through cell cycle analysis whereas apoptotic activity was determined via screening and quantifying using fluorescence microscopy and flow cytometric analysis, respectively. The effect of extracts on molecular mechanism was studied using real-time reverse transcription polymerase chain reaction and Western blotting. Results: Cell cycle flow cytometric analysis showed the induction of cell cycle arrests were behaves in a p53-independent manner. The examination using fluorescence microscopy and Annexin V flow cytometry revealed the presence of morphological features of apoptotic bodies. Downregulation of anti-apoptotic gene (Bcl-2) supports the apoptotic activity of OS extracts although poorly induce PARP-1 cleavage in Western blot analysis. The extracts also inhibit the SK-UT-1 growth by suppressing VEGF-A, TGF-β1 and PCNA genes, which involved in angiogenesis and cell proliferation. Conclusion: This study demonstrates that O. stamineus extracts are able to inhibit proliferation and induced apoptosis of uterine fibroid cells and is worth further investigation.


Thermoelectric behavior of segregated-network polymer nanocomposites.
Segregated-network carbon nanotube (CNT)-polymer composites were prepared, and their thermoelectric properties were measured as a function of CNT concentration at room temperature. This study shows that electrical conductivity can be dramatically increased by creating a network of CNTs in the composite, while the thermal conductivity and thermopower remain relatively insensitive to the filler concentration. This behavior results from thermally disconnected, but electrically connected, junctions in the nanotube network, which makes it feasible to tune the properties in favor of a higher thermoelectric figure of merit. With a CNT concentration of 20 wt %, these composites exhibit an electrical conductivity of 4800 S/m, thermal conductivity of 0.34 W/m x K and a thermoelectric figure of merit (ZT) greater than 0.006 at room temperature. This study suggests that polymeric thermoelectrics are possible and provides the basis for further development of lightweight, low-cost, and nontoxic polymer composites for thermoelectric applications in the future.


Fit to Perform: A Profile of Higher Education Music Students' Physical Fitness.
The physical demands of music making are well acknowledged, but understanding of musicians' physical and fitness profiles is nonetheless limited, especially those of advanced music students who are training to enter music's competitive professional landscape. To gain insight into how physical fitness is associated with music making, this study investigated music students' fitness levels on several standardized indicators. Four hundred and eighty three students took part in a fitness screening protocol that included measurements of lung function, flexibility (hypermobility, shoulder range of motion, sit and reach), strength and endurance (hand grip, plank, press-up), and sub-maximal cardiovascular fitness (3-min step test), as well as self-reported physical activity (IPAQ-SF). Participants scored within age-appropriate ranges on lung function, shoulder range of motion, grip strength, and cardiovascular fitness. Their results for the plank, press-up, and sit and reach were poor by comparison. Reported difficulty (22%) and pain (17%) in internal rotation of the right shoulder were also found. Differences between instrument groups and levels of study were observed on some measures. In particular, brass players showed greater lung function and grip strength compared with other groups, and postgraduate students on the whole were able to maintain the plank for longer but also demonstrated higher hypermobility and lower lung function and cardiovascular fitness than undergraduate students. Seventy-nine percent of participants exceeded the minimum recommended weekly amount of physical activity, but this was mostly based on walking activities. Singers were the most physically active group, and keyboard players, composers, and conductors were the least active. IPAQ-SF scores correlated positively with lung function, sit and reach, press-up and cardiovascular fitness suggesting that, in the absence of time and resources to carry out comprehensive physical assessments, this one measure alone can provide useful insight into musicians' fitness. The findings show moderate levels of general health-related fitness, and we discuss whether moderate fitness is enough for people undertaking physically and mentally demanding music making. We argue that musicians could benefit from strengthening their supportive musculature and enhancing their awareness of strength imbalances.


Pentachlorophenol and hydroxylated polychlorinated biphenyl metabolites in umbilical cord plasma of neonates from coastal populations in Québec.
Concentrations of polychlorinated biphenyls (PCBs), hydroxylated metabolites of PCBs (HO-PCBs) and octachlorostyrene (4-HO-HpCS), and pentachlorophenol (PCP) were determined in umbilical cord plasma samples from three different regions of Québec. The regions studied included two coastal areas where exposure to PCBs is high because of marine-food-based diets--Nunavik (Inuit people) and the Lower North Shore of the Gulf of St. Lawrence (subsistence fishermen)--and a southern Québec urban center where PCB exposure is at background levels (Québec City). The main chlorinated phenolic compound in all regions was PCP. Concentrations of PCP were not significantly different among regions (geometric mean concentration 1,670 pg/g, range 628-7,680 pg/g wet weight in plasma). The ratio of PCP to polychlorinated biphenyl congener number 153 (CB153) concentration ranged from 0.72 to 42.3. Sum HO-PCB (sigma HO-PCBs) concentrations were different among regions, with geometric mean concentrations of 553 (range 238-1,750), 286 (103-788), and 234 (147-464) pg/g wet weight plasma for the Lower North Shore, Nunavik, and the southern Québec groups, respectively. Lower North Shore samples also had the highest geometric mean concentration of sum PCBs (sum of 49 congeners; sigma PCBs), 2,710 (525-7,720) pg/g wet weight plasma. sigma PCB concentrations for Nunavik samples and southern samples were 1,510 (309-6,230) and 843 (290-1,650) pg/g wet weight plasma. Concentrations (log transformed) of sigma HO-PCBs and sigma PCBs were significantly correlated (r = 0.62, p < 0.001), as were concentrations of all major individual HO-PCB congeners and individual PCB congeners. In Nunavik and Lower North Shore samples, free thyroxine (T4) concentrations (log transformed) were negatively correlated with the sum of quantitated chlorinated phenolic compounds (sum PCP and sigma HO-PCBs; r = -0.47, p = 0.01, n = 20) and were not correlated with any PCB congeners or sigma PCBs. This suggests that PCP and HO-PCBs are possibly altering thyroid hormone status in newborns, which could lead to neurodevelopmental effects in infants. Further studies are needed to examine the effects of chlorinated phenolic compounds on thyroid hormone status in newborns.


Zeb2 regulates the balance between retinal interneurons and Müller glia by inhibition of BMP-Smad signaling.
The interplay between signaling molecules and transcription factors during retinal development is key to controlling the correct number of retinal cell types. Zeb2 (Sip1) is a zinc-finger multidomain transcription factor that plays multiple roles in central and peripheral nervous system development. Haploinsufficiency of ZEB2 causes Mowat-Wilson syndrome, a congenital disease characterized by intellectual disability, epilepsy and Hirschsprung disease. In the developing retina, Zeb2 is required for generation of horizontal cells and the correct number of interneurons; however, its potential function in controlling gliogenic versus neurogenic decisions remains unresolved. Here we present cellular and molecular evidence of the inhibition of Müller glia cell fate by Zeb2 in late stages of retinogenesis. Unbiased transcriptomic profiling of control and Zeb2-deficient early-postnatal retina revealed that Zeb2 functions in inhibiting Id1/2/4 and Hes1 gene expression. These neural progenitor factors normally inhibit neural differentiation and promote Müller glia cell fate. Chromatin immunoprecipitation (ChIP) supported direct regulation of Id1 by Zeb2 in the postnatal retina. Reporter assays and ChIP analyses in differentiating neural progenitors provided further evidence that Zeb2 inhibits Id1 through inhibition of Smad-mediated activation of Id1 transcription. Together, the results suggest that Zeb2 promotes the timely differentiation of retinal interneurons at least in part by repressing BMP-Smad/Notch target genes that inhibit neurogenesis. These findings show that Zeb2 integrates extrinsic cues to regulate the balance between neuronal and glial cell types in the developing murine retina.


Diets with high-fat cheese, high-fat meat, or carbohydrate on cardiovascular risk markers in overweight postmenopausal women: a randomized crossover trial.
Heart associations recommend limited intake of saturated fat. However, effects of saturated fat on low-density lipoprotein (LDL)-cholesterol concentrations and cardiovascular disease risk might depend on nutrients and specific saturated fatty acids (SFAs) in food. We explored the effects of cheese and meat as sources of SFAs or isocaloric replacement with carbohydrates on blood lipids, lipoproteins, and fecal excretion of fat and bile acids. The study was a randomized, crossover, open-label intervention in 14 overweight postmenopausal women. Three full-diet periods of 2-wk duration were provided separated by 2-wk washout periods. The isocaloric diets were as follows: 1) a high-cheese (96-120-g) intervention [i.e., intervention containing cheese (CHEESE)], 2) a macronutrient-matched nondairy, high-meat control [i.e., nondairy control with a high content of high-fat processed and unprocessed meat in amounts matching the saturated fat content from cheese in the intervention containing cheese (MEAT)], and 3) a nondairy, low-fat, high-carbohydrate control (i.e., nondairy low-fat control in which the energy from cheese fat and protein was isocalorically replaced by carbohydrates and lean meat (CARB). The CHEESE diet caused a 5% higher high-density lipoprotein (HDL)-cholesterol concentration (P = 0.012), an 8% higher apo A-I concentration (P < 0.001), and a 5% lower apoB:apo A-I ratio (P = 0.008) than did the CARB diet. Also, the MEAT diet caused an 8% higher HDL-cholesterol concentration (P < 0.001) and a 4% higher apo A-I concentration (P = 0.033) than did the CARB diet. Total cholesterol, LDL cholesterol, apoB, and triacylglycerol were similar with the 3 diets. Fecal fat excretion was 1.8 and 0.9 g higher with the CHEESE diet than with CARB and MEAT diets (P < 0.001 and P = 0.004, respectively) and 0.9 g higher with the MEAT diet than with the CARB diet (P = 0.005). CHEESE and MEAT diets caused higher fecal bile acid excretion than did the CARB diet (P < 0.05 and P = 0.006, respectively). The dominant type of bile acids excreted differed between CHEESE and MEAT diets. Diets with cheese and meat as primary sources of SFAs cause higher HDL cholesterol and apo A-I and, therefore, appear to be less atherogenic than is a low-fat, high-carbohydrate diet. Also, our findings confirm that cheese increases fecal fat excretion. This trial was registered at clinicaltrials.gov as NCT01739153.


Associations between Antiretrovirals and Cognitive Function in Women with HIV.
Cognitive complications persist in antiretroviral therapy(ART)-treated people with HIV. However, the pattern and severity of domain-specific cognitive performance is variable and may be exacerbated by ART-mediated neurotoxicity. 929 women with HIV(WWH) from the Women's Interagency HIV Study who were classified into subgroups based on sociodemographic and longitudinal behavioral and clinical data using semi-parametric latent class trajectory modelling. Five subgroups were comprised of: 1) well-controlled HIV with vascular comorbidities(n = 116); 2) profound HIV legacy effects(CD4 nadir <250 cells/μL; n = 275); 3) primarily <45 year olds with hepatitis C(n = 165); 4) primarily 35-55 year olds(n = 244), and 5) poorly-controlled HIV/substance use(n = 129). Within each subgroup, we fitted a constrained continuation ratio model via penalized maximum likelihood to examine adjusted associations between recent ART agents and cognition. Most drugs were not associated with cognition. However, among the few drugs, non-nucleoside reverse transcriptase inhibitor (NNRTIs) and protease inhibitors(PIs) were most commonly associated with cognition, followed by nucleoside reverse transcriptase inhibitors(NRTIs) and integrase inhibitors(IIs). Directionality of ART-cognition associations varied by subgroup. Better psychomotor speed and fluency were associated with ART for women with well-controlled HIV with vascular comorbidities. This pattern contrasts women with profound HIV legacy effects for whom poorer executive function and fluency were associated with ART. Motor function was associated with ART for younger WWH and primarily 35-55 year olds. Memory was associated with ART only for women with poorly-controlled HIV/substance abuse. Findings demonstrate interindividual variability in ART-cognition associations among WWH and highlight the importance of considering sociodemographic, clinical, and behavioral factors as an underlying contributors to cognition. Are antiretroviral agents a risk factor for cognitive complications in women with HIV? We examind associations between ART-agents and cognitive function among similar subgroups of women with HIV from the Women's Interagency HIV study. The patterns of associations depended on sociodemographic, clinical, and behavioral characteristics of women.


Stress-dependent amplification of active forces in nonlinear elastic media.
The production of mechanical stresses in living organisms largely relies on localized, force-generating active units embedded in filamentous matrices. Numerical simulations of discrete fiber networks with fixed boundaries have shown that buckling in the matrix dramatically amplifies the resulting active stresses. Here we extend this result to a continuum elastic medium prone to buckling subjected to an arbitrary external stress, and derive analytical expressions for the active, nonlinear constitutive relations characterizing the full active medium. Inserting these relations into popular "active gel" descriptions of living tissues and the cytoskeleton will enable investigations into nonlinear regimes previously inaccessible due to the phenomenological nature of these theories.


An evaluation of the District Health Information System in rural South Africa.
Since reliable health information is essential for the planning and management of health services, we investigated the functioning of the District Health Information System (DHIS) in 10 rural clinics. Semi-structured key informant interviews were conducted with clinic managers, supervisors and district information staff. Data collected over a 12-month period for each clinic were assessed for missing data, data out of minimum and maximum ranges, and validation rule violations. Our investigation was part of a larger study on improving information systems for primary care in rural KwaZulu-Natal. We assessed data quality, the utilisation for facility management, perceptions of work burden, and usefulness of the system to clinic staff. A high perceived work burden associated with data collection and collation was found. Some data collation tools were not used as intended. There was good understanding of the data collection and collation process but little analysis, interpretation or utilisation of data. Feedback to clinics occurred rarely. In the 10 clinics, 2.5% of data values were missing, and 25% of data were outside expected ranges without an explanation provided. The culture of information use essential to an information system having an impact at the local level is weak in these clinics or at the sub-district level. Further training and support is required for the DHIS to function as intended.


Aptamer-based polyvalent ligands for regulated cell attachment on the hydrogel surface.
Natural biomolecules are often used to functionalize materials to achieve desired cell-material interactions. However, their applications can be limited owing to denaturation during the material functionalization process. Therefore, efforts have been made to develop synthetic ligands with polyvalence as alternatives to natural affinity biomolecules for the synthesis of functional materials and the control of cell-material interactions. This work was aimed at investigating the capability of a hydrogel functionalized with a novel polyvalent aptamer in inducing cell attachment in dynamic flow and releasing the attached cells in physiological conditions through a hybridization reaction. The results show that the polyvalent aptamer could induce cell attachment on the hydrogel in dynamic flow. Moreover, cell attachment on the hydrogel surface was significantly influenced by the value of shear stress. The cell density on the hydrogel was increased from 40 cells/mm(2) to nearly 700 cells/mm(2) when the shear stress was decreased from 0.05 to 0.005 Pa. After the attachment onto the hydrogel surface, approximately 95% of the cells could be triggered to detach within 20 min by using an oligonucleotide complementary sequence that displaced polyvalent aptamer strands from the hydrogel surface. While it was found that the cell activity was reduced, the live/dead staining results show that ≥98% of the detached cells were viable. Therefore, this work has suggested that the polyvalent aptamer is a promising synthetic ligand for the functionalization of materials for regulated cell attachment.


Targeted silver nanoparticles for ratiometric cell phenotyping.
Affinity targeting is used to deliver nanoparticles to cells and tissues. For efficient targeting, it is critical to consider the expression and accessibility of the relevant receptors in the target cells. Here, we describe isotopically barcoded silver nanoparticles (AgNPs) as a tool for auditing affinity ligand receptors in cells. Tumor penetrating peptide RPARPAR (receptor: NRP-1) and tumor homing peptide GKRK (receptor: p32) were used as affinity ligands on the AgNPs. The binding and uptake of the peptide-functionalized AgNPs by cultured PPC-1 prostate cancer and M21 melanoma cells was dependent on the cell surface expression of the cognate peptide receptors. Barcoded peptide-functionalized AgNPs were synthesized from silver and palladium isotopes. The cells were incubated with a cocktail of the barcoded nanoparticles [RPARPAR (R), GKRK (K), and control], and cellular binding and internalization of each type of nanoparticle was assessed by inductively coupled plasma mass spectrometry. The results of isotopic analysis were in agreement with data obtained using optical methods. Using ratiometric measurements, we were able to classify the PPC-1 cell line as mainly NRP-1-positive, with 75 ± 5% R-AgNP uptake, and the M21 cell line as only p32-positive, with 89 ± 9% K-AgNP uptake. The isotopically barcoded multiplexed AgNPs are useful as an in vitro ratiometric phenotyping tool and have potential uses in functional evaluation of the expression of accessible homing peptide receptors in vivo.


Externalizing Behaviors Exacerbate the Link between Discrimination and Adolescent Health Risk Behaviors.
Discrimination based on race/ethnicity, sexual minority status, and gender is associated with higher rates of drinking, drug use and risky sexual behavior during adolescence. The current study explored variation in the link between these three types of discrimination and health risk behaviors by focusing on how this association differed according to externalizing problem behavior status. Participants in the Study of Early Child Care and Youth Development were asked about discrimination and their drinking, drug use and risky sexual behavior (age 15; 50% female, 82% White, n = 939). The association between discrimination and health risk behaviors varied according to both externalizing problem status and the type of discrimination, suggesting that individual-level characteristics (i.e., externalizing behaviors) shape variation in the consequences of discrimination for adolescent health outcomes. Ultimately, these findings point to the need for future research to better understand which adolescents are the most vulnerable to the consequences of discrimination, and when these vulnerabilities are most likely to occur.


Complement peptide C3a stimulates neural plasticity after experimental brain ischaemia.
Ischaemic stroke induces endogenous repair processes that include proliferation and differentiation of neural stem cells and extensive rewiring of the remaining neural connections, yet about 50% of stroke survivors live with severe long-term disability. There is an unmet need for drug therapies to improve recovery by promoting brain plasticity in the subacute to chronic phase after ischaemic stroke. We previously showed that complement-derived peptide C3a regulates neural progenitor cell migration and differentiation in vitro and that C3a receptor signalling stimulates neurogenesis in unchallenged adult mice. To determine the role of C3a-C3a receptor signalling in ischaemia-induced neural plasticity, we subjected C3a receptor-deficient mice, GFAP-C3a transgenic mice expressing biologically active C3a in the central nervous system, and their respective wild-type controls to photothrombotic stroke. We found that C3a overexpression increased, whereas C3a receptor deficiency decreased post-stroke expression of GAP43 (P < 0.01), a marker of axonal sprouting and plasticity, in the peri-infarct cortex. To verify the translational potential of these findings, we used a pharmacological approach. Daily intranasal treatment of wild-type mice with C3a beginning 7 days after stroke induction robustly increased synaptic density (P < 0.01) and expression of GAP43 in peri-infarct cortex (P < 0.05). Importantly, the C3a treatment led to faster and more complete recovery of forepaw motor function (P < 0.05). We conclude that C3a-C3a receptor signalling stimulates post-ischaemic neural plasticity and intranasal treatment with C3a receptor agonists is an attractive approach to improve functional recovery after ischaemic brain injury.


OpenFDA: an innovative platform providing access to a wealth of FDA's publicly available data.
The objective of openFDA is to facilitate access and use of big important Food and Drug Administration public datasets by developers, researchers, and the public through harmonization of data across disparate FDA datasets provided via application programming interfaces (APIs). Using cutting-edge technologies deployed on FDA's new public cloud computing infrastructure, openFDA provides open data for easier, faster (over 300 requests per second per process), and better access to FDA datasets; open source code and documentation shared on GitHub for open community contributions of examples, apps and ideas; and infrastructure that can be adopted for other public health big data challenges. Since its launch on June 2, 2014, openFDA has developed four APIs for drug and device adverse events, recall information for all FDA-regulated products, and drug labeling. There have been more than 20 million API calls (more than half from outside the United States), 6000 registered users, 20,000 connected Internet Protocol addresses, and dozens of new software (mobile or web) apps developed. A case study demonstrates a use of openFDA data to understand an apparent association of a drug with an adverse event. With easier and faster access to these datasets, consumers worldwide can learn more about FDA-regulated products.


Efficacy of Mycophenolate Mofetil as a Remission Maintaining Agent in Idiopathic Childhood Nephrotic Syndrome.
Of all cases of idiopathic steroid-sensitive nephrotic syndrome (NS) in children, 40%-75% cases need long-term continuous steroids and/or other immunosuppressants to maintain remission, the effects of which on growth and renal function remain an issue of concern. The study aimed at exploring the safety and efficacy of mycophenolate mofetil (MMF) as a remission-maintaining agent in children with a diagnosis of frequent relapsing or steroid-dependent NS (FRNS/SDNS) requiring continuous medication for at least 1 year. Thirty-two children thus included received MMF (1000-1200 mg/m2/day) for 7 months along with tapering doses of oral prednisolone if it was being given from before with an attempt at tapering at 0.25 mg/kg/month ultimately stopping it altogether. Individuals were followed up for at least 5 more months after stopping MMF. Out of 32 children, 26 had SDNS and 6 had FRNS with male:female ratio being 2.2:1. The mean standard deviation (± SD) age of onset of disease was 2.72 ± 1.3 years and that entry to the study was 7.17 ± 2.2 years. Significant fall in number of relapses was observed following the introduction of MMF (110 in pre-MMF12 month period vs. 52 in post-MMF 12 months [p = 0.002]). The mean relapse rate/year/patient also decreased from 3.43 ± 1.26 to 1.62 ± 1.14 after entry in the study. Significant reduction of the cumulative dose of steroid regarding mean ± SD of mg/kg/year was also found following the introduction of MMF (190.9 ± 47.81 vs. 119.09 ± 60.09 [p = 0.001]). MMF is an efficacious agent in maintaining remission and reducing steroid requirement in children with FRNS and SDNS.


Reorganization of microtubules in endosperm cells and cell fragments of the higher plant Haemanthus in vivo.
The reorganization of the microtubular meshwork was studied in intact Haemanthus endosperm cells and cell fragments (cytoplasts). This higher plant tissue is devoid of a known microtubule organizating organelle. Observations on living cells were correlated with microtubule arrangements visualized with the immunogold method. In small fragments, reorganization did not proceed. In medium and large sized fragments, microtubular converging centers formed first. Then these converging centers reorganized into either closed bushy microtubular spiral or chromosome-free cytoplasmic spindles/phragmoplasts. Therefore, the final shape of organized microtubular structures, including spindle shaped, was determined by the initial size of the cell fragments and could be achieved without chromosomes or centrioles. Converging centers elongate due to the formation of additional structures resembling microtubular fir trees. These structures were observed at the pole of the microtubular converging center in anucleate fragments, accessory phragmoplasts in nucleated cells, and in the polar region of the mitotic spindle during anaphase. Therefore, during anaphase pronounced assembly of new microtubules occurs at the polar region of acentriolar spindles. Moreover, statistical analysis demonstrated that during the first two-thirds of anaphase, when chromosomes move with an approximately constant speed, kinetochore fibers shorten, while the length of the kinetochore fiber complex remains constant due to the simultaneous elongation of their integral parts (microtubular fir trees). The half-spindle shortens only during the last one-third of anaphase. These data contradict the presently prevailing view that chromosome-to-pole movements in acentriolar spindles of higher plants are concurrent with the shortening of the half-spindle, the self-reorganizing property of higher plant microtubules (tubulin) in vivo. It may be specific for cells without centrosomes and may be superimposed also on other microtubule-related processes.


Cometary science. Dust measurements in the coma of comet 67P/Churyumov-Gerasimenko inbound to the Sun.
Critical measurements for understanding accretion and the dust/gas ratio in the solar nebula, where planets were forming 4.5 billion years ago, are being obtained by the GIADA (Grain Impact Analyser and Dust Accumulator) experiment on the European Space Agency's Rosetta spacecraft orbiting comet 67P/Churyumov-Gerasimenko. Between 3.6 and 3.4 astronomical units inbound, GIADA and OSIRIS (Optical, Spectroscopic, and Infrared Remote Imaging System) detected 35 outflowing grains of mass 10(-10) to 10(-7) kilograms, and 48 grains of mass 10(-5) to 10(-2) kilograms, respectively. Combined with gas data from the MIRO (Microwave Instrument for the Rosetta Orbiter) and ROSINA (Rosetta Orbiter Spectrometer for Ion and Neutral Analysis) instruments, we find a dust/gas mass ratio of 4 ± 2 averaged over the sunlit nucleus surface. A cloud of larger grains also encircles the nucleus in bound orbits from the previous perihelion. The largest orbiting clumps are meter-sized, confirming the dust/gas ratio of 3 inferred at perihelion from models of dust comae and trails.


An algorithm applied to national surveillance data for the early detection of major dengue outbreaks in Cambodia.
Dengue is a national priority disease in Cambodia. The Cambodian National Dengue Surveillance System is based on passive surveillance of dengue-like inpatients reported by public hospitals and on a sentinel, pediatric hospital-based active surveillance system. This system works well to assess trends but the sensitivity of the early warning and time-lag to usefully inform hospitals can be improved. During The ECOnomic development, ECOsystem MOdifications, and emerging infectious diseases Risk Evaluation (ECOMORE) project's knowledge translation platforms, Cambodian hospital staff requested an early warning tool to prepare for major outbreaks. Our objective was therefore to find adapted tools to improve the early warning system and preparedness. Dengue data was provided by the National Dengue Control Program (NDCP) and are routinely obtained through passive surveillance. The data were analyzed at the provincial level for eight Cambodian provinces during 2008-2015. The R surveillance package was used for the analysis. We evaluated the effectiveness of Bayesian algorithms to detect outbreaks using count data series, comparing the current count to an expected distribution obtained from observations of past years. The analyses bore on 78,759 patients with dengue-like syndromes. The algorithm maximizing sensitivity and specificity for the detection of major dengue outbreaks was selected in each province. The overall sensitivity and specificity were 73% and 97%, respectively, for the detection of significant outbreaks during 2008-2015. Depending on the province, sensitivity and specificity ranged from 50% to 100% and 75% to 100%, respectively. The final algorithm meets clinicians' and decisionmakers' needs, is cost-free and is easy to implement at the provincial level.


Marathon running increases ERK1/2 and p38 MAP kinase signalling to downstream targets in human skeletal muscle.
1. We tested the hypothesis that long-distance running activates parallel mitogen-activated protein kinase (MAPK) cascades that involve extracellular signal regulated kinase 1 and 2 (ERK1/2) and p38 MAPK and their downstream substrates. 2. Eleven men completed a 42.2 km marathon (mean race time 4 h 1 min; range 2 h 56 min to 4 h 33 min). Vastus lateralis muscle biopsies were obtained before and after the race. Glycogen content was measured spectrophotometrically. ERK1/2 and p38 MAPK phosphorylation was determined by immunoblot analysis using phosphospecific antibodies. Activation of the downstream targets of ERK1/2 and p38 MAPK, MAPK-activated protein kinase-1 (MAPKAP-K1; also called p90 ribosomal S6 kinase, p90rsk), MAPK-activated protein kinase-2 (MAPKAP-K2), mitogen- and stress-activated kinase 1 (MSK1) and mitogen- and stress-activated kinase 2 (MSK2) was determined using immune complex assays. 3. Muscle glycogen content was reduced by 40 +/- 6 % after the marathon. ERK1/2 phosphorylation increased 7.8-fold and p38 MAPK phosphorylation increased 4.4-fold post-exercise. Prolonged running did not alter ERK1/2 and p38 MAPK protein expression. The activity of p90rsk, a downstream target of ERK1/2, increased 2.8-fold after the marathon. The activity of MAPKAPK-K2, a downstream target of p38 MAPK, increased 3.1-fold post-exercise. MSK1 and MSK2 are downstream of both ERK1/2 and p38 MAPK. MSK1 activity increased 2.4-fold post-exercise. MSK2 activity was low, relative to MSK1, with little activation post-exercise. 4. In conclusion, prolonged distance running activates MAPK signalling cascades in skeletal muscle, including increased activity of downstream targets: p90rsk, MAPKAP-K2 and MSK. Activation of these downstream targets provides a potential mechanism by which exercise induces gene transcription in skeletal muscle.