Auxin-induced developmental patterns in Brassica juncea embryos.
To investigate the mechanism of auxin action during pattern formation in dicot embryos, we tested the effects of the natural auxin indole-3-acetic acid (IAA), the auxin transport inhibitor N-(1-naphthyl)thalamic acid (NPA) and the antiauxin p-chlorophenoxyisobutyric acid (PCIB). In vitro treatments of isolated zygotic Brassica juncea embryos with these substances led to a wide range of morphogenetic alterations. Treatment of globular embryos with exogenous auxin (10-40 microM) either completely inhibited morphogenesis, resulting in ball-shaped embryos, or caused the development of egg- and cucumber-shaped embryos, which only consisted of a shortened hypocotyl without any apical structures. Axis duplication was observed sometimes after inhibition of auxin transport in globular embryos, and led to the development of twin embryos. During the transition from globular to heart stage, changes in auxin distribution or activity frequently caused the development of either split-collar or collar-cotyledons. Antiauxin inhibited cotyledon growth, leading to embryos with single or no cotyledons, or inhibited the development of the hypocotyl and the radicle. Inhibition of auxin transport in transition embryos sometimes led to axis broadening, which resulted in the development of two radicles. The described changes in embryo shapes represent arrests in different auxin-regulated developmental steps and phenocopy some Arabidopsis morphogenetic mutants.


Mediastinal Solitary Fibrous Tumor Diagnosed by Endobronchial Ultrasound-Directed Biopsy.
BACKGROUND Solitary fibrous tumors of the middle mediastinal space are uncommon and often not discovered until symptoms secondary to compression of adjacent structures occur. Diagnosis requires surgical biopsy and histological tissue analysis. We describe the ECHO appearance of the solitary fibrous tumor and successful non-invasive EBUS diagnosis. This method of diagnosis allowed for surgical planning for resection and allowed us to exclude non-surgical diseases, such as small cell carcinoma. CASE REPORT A 32-year-old man presented to his primary care physician with worsening intermittent chronic chest pain with recent progressive dysphagia, cough, and dyspnea. Physical examination and routine laboratory work-up were unrevealing. Chest radiograph and computed tomography (CT) of the chest revealed a middle mediastinal mass. Flexible bronchoscopy confirmed extrinsic compression of right and left bronchial trees. Endobronchial ultrasound (EBUS) was used to biopsy the mass and the diagnosis of solitary fibrous tumor was confirmed. The patient underwent successful tumor resection and was discharged home after an uneventful postoperative period. CONCLUSIONS Endobronchial ultrasound-directed tissue biopsy is an appropriate modality for suspected solitary fibrous tumors of the mediastinum. To our knowledge, this is only the second reported case of SFT diagnosed by EBUS-TBNA. Our case uniquely demonstrates the advantages of pre-surgical diagnosis of mediastinal masses with EBUS-TBNA when the diagnosis SFT is suggested on CT and US imaging.


A pilot metagenomic study reveals that community derived mobile phones are reservoirs of viable pathogenic microbes.
There is increasing attention focussed on the risks associated with mobile phones possibly serving as 'Trojan Horse' fomites for microbial transmission in healthcare settings. However, little is reported on the presence of microbes on community derived mobile phones which in 2021, numbered in the billions in circulation with majority being used on a daily basis. Identify viable microbial organisms swabbed from smartphones on a university campus. Entire surfaces of 5 mobile phones were swabbed and examined for their microbial content using pre-agar-based growths followed by downstream DNA metagenomic next-generation sequencing analysis. All phones were contaminated with viable microbes. 173 bacteria, 8 fungi, 8 protists, 53 bacteriophages, 317 virulence factor genes and 41 distinct antibiotic resistant genes were identified. While this research represents a pilot study, the snapshot metagenomic analysis of samples collected from the surface of mobile phones has revealed the presence of a large population of viable microbes and an array of antimicrobial resistant factors. With billions of phones in circulation, these devices might be responsible for the rise of community acquired infections. These pilot results highlight the importance of public health authorities considering mobile phones as 'Trojan Horse' devices for microbial transmission and ensure appropriate decontamination campaigns are implemented.


Economic Analysis of Exclusionary EGFR Test Versus Up-Front NGS for Lung Adenocarcinoma in High EGFR Mutation Prevalence Areas.
This study sought to determine whether exclusionary EGFR mutation testing followed by next-generation sequencing (NGS) is a cost-efficient and timely strategy in areas with high prevalence rates of EGFR mutation. We developed a decision tree model to compare exclusionary EGFR testing followed by NGS and up-front NGS. Patients entered the model upon diagnosis of metastatic lung adenocarcinoma. Gene alterations with FDA-approved targeted therapies included EGFR, ALK, ROS1, BRAF, RET, MET, NTRK, and KRAS. Model outcomes were testing-related costs; time-to-test results; monetary loss, taking both costs and time into consideration; and percentage of patients who could be treated by FDA-approved therapies. Stacked 1-way and 3-way sensitivity analyses were performed. Exclusionary EGFR testing incurred testing-related costs of US $1,387 per patient, a savings of US $1,091 compared with the costs of up-front NGS. The time-to-test results for exclusionary EGFR testing and up-front NGS were 13.0 and 13.6 days, respectively. Exclusionary EGFR testing resulted in a savings of US $1,116 in terms of net monetary loss, without a reduction of patients identified with FDA-approved therapies. The EGFR mutation rate and NGS cost had the greatest impact on minimizing monetary loss. Given that the tissue-based NGS turnaround time was shortened to 7 days, up-front NGS testing would become the best strategy if its price could be reduced to US $568 in Taiwan. In areas with high prevalence rates of EGFR mutation, exclusionary EGFR testing followed by NGS, rather than up-front NGS, is currently a cost-efficient strategy for metastatic lung adenocarcinoma.


A detailed analysis of the recombination landscape of the button mushroom Agaricus bisporus var. bisporus.
The button mushroom (Agaricus bisporus) is one of the world's most cultivated mushroom species, but in spite of its economic importance generation of new cultivars by outbreeding is exceptional. Previous genetic analyses of the white bisporus variety, including all cultivars and most wild isolates revealed that crossing over frequencies are low, which might explain the lack of introducing novel traits into existing cultivars. By generating two high quality whole genome sequence assemblies (one de novo and the other by improving the existing reference genome) of the first commercial white hybrid Horst U1, a detailed study of the crossover (CO) landscape was initiated. Using a set of 626 SNPs in a haploid offspring of 139 single spore isolates and whole genome sequencing on a limited number of homo- and heterokaryotic single spore isolates, we precisely mapped all COs showing that they are almost exclusively restricted to regions of about 100kb at the chromosome ends. Most basidia of A. bisporus var. bisporus produce two spores and pair preferentially via non-sister nuclei. Combined with the COs restricted to the chromosome ends, these spores retain most of the heterozygosity of the parent thus explaining how present-day white cultivars are genetically so close to the first hybrid marketed in 1980. To our knowledge this is the first example of an organism which displays such specific CO landscape.


Major depressive disorder, mental health care, and the use of guidelines in the Middle East.
A large gap exists between the number of people needing treatment and the number of people receiving treatment for depression in the Middle East. Barriers to mental health care in the region have included the lack of education for primary health care providers about mental illnesses, the scarcity of trained mental health care specialists, the lack of resources in developing countries, and the stigmatization of mental illness in Middle Eastern cultures. Guidelines for the treatment of depression have not been developed in most countries of the region. Guidelines have been published for both general practitioners and for psychiatrists in Turkey, and they are similar to guidelines published in the West. These guidelines are assessed using the AGREE instrument. Although guidelines recommend antidepressants as a first-line treatment for depression, many physicians in Middle Eastern countries prescribe benzodiazepines. One reason for this treatment gap may be that patients with depression often seek treatment from primary care providers and report somatic symptoms. Primary care providers may not be as knowledgeable about the diagnosis of depression or its treatment as psychiatrists and may not have access to certain classes of medications. More education for both physicians and patients in the Middle East is needed to decrease the stigma associated with depression.


Profile of the average organ non-donor: can it be used predictively?
To describe the profile of the average organ non-donor, compare it to that of the average donor, and identify characteristics that predict the likelihood that a given individual will be a non-donor. The charts of 397 consenting potential organ donors of LifeLink of Puerto Rico from 2009 through 2011 were reviewed. Data regarding gender, age, BMI, the presence of diabetes, hypertension and/or kidney injury, death from cerebrovascular accident, and smoking were collected. Of the 397 charts reviewed, 283 were from donors, 96 were from non-donors, and 18 were excluded from the analysis. When compared to donors, non-donors were found more frequently to be 60 years old or older, diabetic, hypertensive, or obese; to have suffered from kidney injury, to have smoked and to have died of a cerebrovascular accident. On multivariate analysis, age, diabetes, kidney injury and smoking remained significant. However, after adjusting for age, only smoking and death from cerebrovascular accident remained statistically associated to non-donor status. Although being over 60 years old, having smoked and dying from a cerebrovascular accident were characteristics found significantly more frequently in non-donors, these characteristics were also present in some donors. Therefore, a careful evaluation of each potential donor is still mandatory to avoid the loss of transplantable organs.


A mixture model for sucking patterns of breast-fed infants.
Previous studies of sucking patterns have mainly been on bottle-fed babies and have assumed that the babies' sucks occur within bursts separated by gaps of predetermined minimum length which is fixed over the feed. This study considers babies that are breast-fed, a more complex and natural process than bottle-feeding, and develops a more sophisticated model for the pattern of bursts and gaps which allows the parameters of the process to vary over the feed. We consider data from four breast feeds of each of 32 babies. We develop a two-component mixture model based on an underlying Markov chain model for the switching between bursts and gaps. We use the model to provide summary statistics for each feed and give estimates of the normal range of each of the model's parameters.


Results of salvage surgery for metastatic sarcomas.
Between January 1970 and December 1988, 105 consecutive patients underwent complete resection for lung metastases from sarcoma, 33 of them in the years from 1970 to 1983 and 72 between 1984 and 1988. In the latter period, new criteria consisting of early bilateral surgical staging and lung resection through median sternotomy were adopted for the management of lung metastases, in all patients with purely intrathoracic relapse. There was no operative mortality, follow-up was updated in August 1989, and actuarial survivals were calculated by the logrank method at 36 months from the time of first lung resection. During the second period, the overall actuarial survival at three years improved significantly (24% vs. 50%, P less than 0.02), notwithstanding the higher incidence of patients with unfavourable prognostic factors. The three-year survival was also significantly better in the subset of patients with a disease-free interval less than or equal to 12 mos. and/or multiple pathological lesions (9% vs. 45%, P less than 0.05). Contralateral occult metastases were resected in 10 of 29 subjects who underwent sternotomy for monolateral clinical lesions. Of 26 patients with further intrapulmonary recurrence, 16 (62%) were amenable to re-operation and eventual surgical rescue. These data suggest that median sternotomy and early management of occult contralateral disease may contribute to an improvement in the long-term survival of patients with metastatic sarcomas. On the other hand, it is possible that the effectiveness of salvage surgery is related to the higher activity and wider application of adjuvant and salvage chemotherapy.


Epithelial-mesenchymal interactions are linked to neovascularization.
Lung morphogenesis is dependent on interactions between mesenchymal and epithelial cells. We have previously demonstrated that inhibition of neovascularization by endothelial monocyte-activating polypeptide (EMAP) II also attenuates fetal lung morphogenesis in vivo, and hypothesized that epithelial-mesenchymal interactions are regulated by vascular signals. To address this postulate, we evaluated the formation of epithelial cysts in vitro and assessed this complex interaction through: (i) identification of vascular formation in vitro; (ii) assessment of the effect of selective vascular inhibition on cell viability, proliferation, and cellular interactions as measured by epithelial cyst formation; and (iii) examination of whether there is an interdependent relationship between epithelial and mesenchymal cells and a vascular mediator's protein expression. Vascular networks in vitro formed in direct relationship to the presence of epithelial cysts. Disruption of the vasculature by delivery of a selective antiangiogenic protein EMAP II was associated with disruption of epithelial cyst formation. Lastly, control of the vascular formation regulatory protein EMAP II is a direct result of epithelial-mesenchymal cell interactions. These findings suggest that vascular formation modulates and is modulated by the normal cellular communication and interactions that direct lung morphology.


Aging and spinal cord injury: medical, functional, and psychosocial changes.
Fifty years ago, people who had a spinal cord injury had very limited life expectancies. Today, these individuals can expect to live into their 60s, 70s, and beyond. Advances in rehabilitation, technology, surgery, and medicines have been chiefly responsible for this change. Recent research in both Europe and the United States now indicates that as these people age, they often develop medical and functional problems that are not as common in their nondisabled peers until much later in life. The importance of these "premature" age-related problems has led the National Institute on Disability and Rehabilitation Research to fund the Rehabilitation Research and Training Center (RRTC) on Aging With a Spinal Cord Injury at Rancho Los Amigos National Rehabilitation Center in Downey, California. This article summarizes some of the important findings from this RRTC and from other sources.


From cineradiography to biorobots: an approach for designing robots to emulate and study animal locomotion.
Robots are increasingly used as scientific tools to investigate animal locomotion. However, designing a robot that properly emulates the kinematic and dynamic properties of an animal is difficult because of the complexity of musculoskeletal systems and the limitations of current robotics technology. Here, we propose a design process that combines high-speed cineradiography, optimization, dynamic scaling, three-dimensional printing, high-end servomotors and a tailored dry-suit to construct Pleurobot: a salamander-like robot that closely mimics its biological counterpart, Pleurodeles waltl Our previous robots helped us test and confirm hypotheses on the interaction between the locomotor neuronal networks of the limbs and the spine to generate basic swimming and walking gaits. With Pleurobot, we demonstrate a design process that will enable studies of richer motor skills in salamanders. In particular, we are interested in how these richer motor skills can be obtained by extending our spinal cord models with the addition of more descending pathways and more detailed limb central pattern generator networks. Pleurobot is a dynamically scaled amphibious salamander robot with a large number of actuated degrees of freedom (DOFs: 27 in total). Because of our design process, the robot can capture most of the animal's DOFs and range of motion, especially at the limbs. We demonstrate the robot's abilities by imposing raw kinematic data, extracted from X-ray videos, to the robot's joints for basic locomotor behaviours in water and on land. The robot closely matches the behaviour of the animal in terms of relative forward speeds and lateral displacements. Ground reaction forces during walking also resemble those of the animal. Based on our results, we anticipate that future studies on richer motor skills in salamanders will highly benefit from Pleurobot's design.


HPLC glycosaminoglycan analysis in patients with Graves' disease.
1. Orbital accumulation of hydrophilic, interstitial glycosaminoglycans (GAGs) and subsequent expansion of retrobulbar tissue lead to the clinical manifestation of exophthalmos in patients with Graves' eye disease. 2. A highly specific method to determine the concentration and biochemical composition of different GAGs was developed in order to obtain a sensitive test system for the activity of the disease. By means of this method, GAG excretion in 24 h urine collections of 56 patients and 21 controls was analysed by precipitation with cetylpyridinium chloride and potassium acetate in ethanol, followed by sequential enzymic hydrolysis with chondroitin AC lyase, chondroitin ABC lyase and hyaluronate lyase, with HPLC analysis of the resulting alpha, beta-unsaturated disaccharides by anion-exchange chromatography. 3. Concentrations of GAG, chondroitin sulphate A (CA), dermatan sulphate (DS) and hyaluronic acid (HA) were determined in patients and controls, with high recovery rates [72.2 +/- 5.3%, mean +/- SEM; detection limit, 4.2 micrograms/l (0.01 mumol/l)], revealing marked differences in urinary concentrations of total GAG and HA, as well as an elevation of CA in patients compared with controls. 4. Method sensitivity was 0.86 for patients with active Graves' eye disease, and 0.87 for patients with untreated ophthalmopathy, whereas specificity was 1.0 for patients with inactive disease. Patients with increased GAG concentration responded well to steroids and/or orbital irradiation (before therapy: GAG, 111.49 +/- 40.32; CA, 59.58 +/- 21.34; DS, 25.05 +/- 8.12; HA, 26.88 +/- 11.63 mg/24 h; during therapy: GAG, 54.22 +/- 10.94; CA, 20.52 +/- 4.58; DS, 17.65 +/- 3.46; HA, 16.05 +/- 3.69 mg/24 h), whereas GAG excretion increased markedly 2-3 months after stopping prednisone therapy in patients with still active eye disease (GAG, 109.9 +/- 10.51; CA, 63.8 +/- 7.34; DS, 24.1 +/- 5.07; HA, 22.0 +/- 6.28 mg/24 h). 5. This sensitive method determines the nature of renally excreted GAGs, reflecting the aberrant synthesis pattern of fibroblasts in patients with Graves' disease.


Information-theoretic method for the inversion of the lidar equation.
A new solution is presented for the reconstruction of profiles of aerosol volume extinction coefficients from the noisy backscattered returns of a monostatic single-wavelength lidar system. This inverse problem is solved by utilizing an information-theoretic method based on the principle of minimum cross-entropy (MCE), which represents an objective and rational approach for the effective incorporation, into the inversion procedure, of both prior information in the form of an initial estimate of the extinction coefficient and additional information in the form of the observed lidar data. A simple and robust numerical procedure, based on the ellipsoid algorithm, is developed to compute the MCE reconstruction of the extinction function. A number of numerical examples, based on noisy synthetic lidar data, are employed to demonstrate and evaluate the utility and efficacy of the inversion method.


Localization versus Delocalization in Chiral Single Component Conductors of Gold Bis(dithiolene) Complexes.
The first examples of chiral single component conductors are reported. Both (S,S) and (R,R) enantiomers of 5,6-dimethyl-5,6-dihydro-1,4-dithiin-2,3-dithiolate (dm-dddt) ligand have been used to prepare anionic metal bis(dithiolene) complexes formulated as ([(n-Bu)4N][M(dm-dddt)2] (M = Au, Ni), which are isostructural according to single crystal X-ray analysis. Single crystal transport measurements indicate semiconducting behavior for the anionic radical Ni complexes, with low room temperature conductivity values and high activation energies. Electrocrystallization experiments provided neutral [M(dm-dddt)2] (M = Au, Ni) complexes. The neutral radical gold compounds show intermolecular S···S interactions in the solid state giving rise to layers interconnected through weak C-H···S hydrogen bonds. The most peculiar structural feature concerns a dissymmetry between the two dithiolene moieties, while the nickel counterpart is symmetric. Single crystal resistivity measurements show thermally activated behavior for the open-shell gold complexes, with room temperature conductivity values of 0.02-0.04 S·cm(-1) and activation energies strongly influenced by hydrostatic pressure. A thorough theoretical study on nickel anion radical and gold neutral radical bis(dithiolene) complexes applied to the chiral complexes [M(dm-dddt)2] (M = Au, Ni(-)) and to a series of previously reported compounds addressed the issue of symmetry versus asymmetry from an electronic coupling perspective between the two dithiolene ligands. It results that neutral gold complexes with dithiolene ligands without extended delocalization are Class II mixed-valent compounds in the Robin and Day classification, presenting an inherent tendency toward asymmetric structures, which can be however modulated by the intermolecular organization in the solid state.


Performance of rapid diagnostic tests for imported malaria in clinical practice: results of a national multicenter study.
We compared the performance of four rapid diagnostic tests (RDTs) for imported malaria, and particularly Plasmodium falciparum infection, using thick and thin blood smears as the gold standard. All the tests are designed to detect at least one protein specific to P. falciparum (Plasmodium histidine-rich protein 2 (PfHRP2) or Plasmodium LDH (PfLDH)) and one pan-Plasmodium protein (aldolase or Plasmodium LDH (pLDH)). 1,311 consecutive patients presenting to 9 French hospitals with suspected malaria were included in this prospective study between April 2006 and September 2008. Blood smears revealed malaria parasites in 374 cases (29%). For the diagnosis of P. falciparum infection, the three tests detecting PfHRP2 showed high and similar sensitivity (96%), positive predictive value (PPV) (90%) and negative predictive value (NPV) (98%). The PfLDH test showed lower sensitivity (83%) and NPV (80%), despite good PPV (98%). For the diagnosis of non-falciparum species, the PPV and NPV of tests targeting pLDH or aldolase were 94-99% and 52-64%, respectively. PfHRP2-based RDTs are thus an acceptable alternative to routine microscopy for diagnosing P. falciparum malaria. However, as malaria may be misdiagnosed with RDTs, all negative results must be confirmed by the reference diagnostic method when clinical, biological or other factors are highly suggestive of malaria.


K-ras is critical for modulating multiple c-kit-mediated cellular functions in wild-type and Nf1+/- mast cells.
p21(ras) (Ras) proteins and GTPase-activating proteins (GAPs) tightly modulate extracellular growth factor signals and control multiple cellular functions. The specific function of each Ras isoform (H, N, and K) in regulating distinct effector pathways, and the role of each GAP in negatively modulating the activity of each Ras isoform in myeloid cells and, particularly, mast cells is incompletely understood. In this study, we use murine models of K-ras- and Nf1-deficient mice to examine the role of K-ras in modulating mast cell functions and to identify the role of neurofibromin as a GAP for K-ras in this lineage. We find that K-ras is required for c-kit-mediated mast cell proliferation, survival, migration, and degranulation in vitro and in vivo. Furthermore, the hyperactivation of these cellular functions in Nf1(+/-) mast cells is decreased in a K-ras gene dose-dependent fashion in cells containing mutations in both loci. These findings identify K-ras as a key effector in multiple mast cell functions and identify neurofibromin as a GAP for K-ras in mast cells.


How do emergency departments and emergency leaders catalyze positive change through quality improvement collaborations?
Quality Improvement and Patient Safety (QIPS) plays an important role in addressing shortcomings in optimal healthcare delivery. However, there is little published guidance available for emergency department (ED) teams with respect to developing their own QIPS programs. We sought to create recommendations for established and aspiring ED leaders to use as a pathway to better patient care through programmatic QIPS activities, starting internally and working towards interdepartmental collaboration. An expert panel comprised of ten ED clinicians with QIPS and leadership expertise was established. A scoping review was conducted to identify published literature on establishing QIPS programs and frameworks in healthcare. Stakeholder consultations were conducted among Canadian healthcare leaders, and recommendations were drafted by the expert panel based on all the accumulated information. These were reviewed and refined at the 2018 CAEP Academic Symposium in Calgary using in-person and technologically-supported feedback. Recommendations include: creating a sense of urgency for improvement; engaging relevant stakeholders and leaders; creating a formal local QIPS Committee; securing funding and resources; obtaining local data to guide the work; supporting QIPS training for team members; encouraging interprofessional, cross-departmental, and patient collaborations; using an established QIPS framework to guide the work; developing reward mechanisms and incentive structures; and considering to start small by focusing on a project rather than a program. A list of 10 recommendations is presented as guiding principles for the establishment and sustainable deployment of QIPS activities in EDs throughout Canada and abroad. ED leaders are encouraged to implement our recommendations in an effort to improve patient care.


Analytic webs support the synthesis of ecological data sets.
A wide variety of data sets produced by individual investigators are now synthesized to address ecological questions that span a range of spatial and temporal scales. It is important to facilitate such syntheses so that "consumers" of data sets can be confident that both input data sets and synthetic products are reliable. Necessary documentation to ensure the reliability and validation of data sets includes both familiar descriptive metadata and formal documentation of the scientific processes used (i.e., process metadata) to produce usable data sets from collections of raw data. Such documentation is complex and difficult to construct, so it is important to help "producers" create reliable data sets and to facilitate their creation of required metadata. We describe a formal representation, an "analytic web," that aids both producers and consumers of data sets by providing complete and precise definitions of scientific processes used to process raw and derived data sets. The formalisms used to define analytic webs are adaptations of those used in software engineering, and they provide a novel and effective support system for both the synthesis and the validation of ecological data sets. We illustrate the utility of an analytic web as an aid to producing synthetic data sets through a worked example: the synthesis of long-term measurements of whole-ecosystem carbon exchange. Analytic webs are also useful validation aids for consumers because they support the concurrent construction of a complete, Internet-accessible audit trail of the analytic processes used in the synthesis of the data sets. Finally we describe our early efforts to evaluate these ideas through the use of a prototype software tool, SciWalker. We indicate how this tool has been used to create analytic webs tailored to specific data-set synthesis and validation activities, and suggest extensions to it that will support additional forms of validation. The process metadata created by SciWalker is readily adapted for inclusion in Ecological Metadata Language (EML) files.


Stroking or Buzzing? A Comparison of Somatosensory Touch Stimuli Using 7 Tesla fMRI.
Studying body representations in the brain helps us to understand how we humans relate to our own bodies. The in vivo mapping of the somatosensory cortex, where these representations are found, is greatly facilitated by the high spatial resolution and high sensitivity to brain activation available at ultra-high field. In this study, the use of different stimulus types for somatotopic mapping of the digits at ultra-high field, specifically manual stroking and mechanical stimulation, was compared in terms of sensitivity and specificity of the brain responses. Larger positive responses in digit regions of interest were found for manual stroking than for mechanical stimulation, both in terms of average and maximum t-value and in terms of number of voxels with significant responses to the tactile stimulation. Responses to manual stroking were higher throughout the entire post-central sulcus, but the difference was especially large on its posterior wall, i.e. in Brodmann area 2. During mechanical stimulation, cross-digit responses were more negative than during manual stroking, possibly caused by a faster habituation to the stimulus. These differences indicate that manual stroking is a highly suitable stimulus for fast somatotopic mapping procedures, especially if Brodmann area 2 is of interest.


Tuberculosis exposure in HIV-exposed infants in a high-prevalence setting.
Exposure to TB was quantified by screening human immunodeficiency virus (HIV) exposed infants aged 3-4 months for an isoniazid prophylaxis study where tuberculosis (TB) exposure excluded enrolment. Seventy-seven (10.1%, 95%CI 8.0-12.4) of 766 infants had contact with a TB source case. Nurses and lay counsellors identified 52 infants during pre-screening and doctors identified 25 during formal screening. High exposure may contribute to high rates of TB in HIV-exposed infants. Programs to prevent mother-to-child transmission of HIV offer an important opportunity to screen for TB. In-depth assessment is required for evaluating TB exposure.


Mismatched dNTP incorporation by DNA polymerase beta does not proceed via globally different conformational pathways.
Understanding how DNA polymerases control fidelity requires elucidation of the mechanisms of matched and mismatched dNTP incorporations. Little is known about the latter because mismatched complexes do not crystallize readily. In this report, we employed small-angle X-ray scattering (SAXS) and structural modeling to probe the conformations of different intermediate states of mammalian DNA polymerase beta (Pol beta) in its wild-type and an error-prone variant, I260Q. Our structural results indicate that the mismatched ternary complex lies in-between the open and the closed forms, but more closely resembles the open form for WT and the closed form for I260Q. On the basis of molecular modeling, this over-stabilization of mismatched ternary complex of I260Q is likely caused by formation of a hydrogen bonding network between the side chains of Gln(260), Tyr(296), Glu(295) and Arg(258), freeing up Asp(192) to coordinate MgdNTP. These results argue against recent reports suggesting that mismatched dNTP incorporations follow a conformational path distinctly different from that of matched dNTP incorporation, or that its conformational closing is a major contributor to fidelity.


Provision of oncology services in remote rural areas: a Scottish perspective.
There is a paucity of research into rural health care services. In particular little is known about the provision of specialist cancer services for patients who live in remote rural areas of the UK. This study set out to investigate current models of medical and clinical oncology care in Scotland. A national survey with key health professionals was conducted to identify rural oncology schemes currently in operation. Detailed quantitative data about the schemes together with qualitative data on how health professionals view current models of care were collected by a computer-assisted telephone survey. Schemes that currently provide outpatient and chemotherapy oncology services for remote rural patients fell into three categories: central clinics (5); shared care outreach clinics with chemotherapy provision (11); and shared care outreach clinics without chemotherapy provision (7). All radiotherapy was conducted at central clinics (5). Widely varying practices in delivery of cancer care were found across the country. The main issues for professionals about current models of care involved expertise, travelling and accessibility (for patients), communication and expansion of the rural service. Nation-wide consistency in cancer care has still to be achieved. Travelling for treatment was seen to take its toll on all patients but particularly for the very remote, elderly and poor. Most professionals believe that an expansion of rural services would be of benefit to these patients. It is clear, however, that the proper infrastructure needs to be in place in terms of local expertise, ensured quality of care, and good communication links with cancer centres before this could happen.


Nepal Health Insurance Bill: Possible Challenges and Way Forwards.
Nepal has one of the highest proportions of out of pocket expenditures on health and one quarter of the people is living below poverty line. In recent time, there is some increase of the health budget but country still relies on development partners. The endorsement of the national health insurance bill has enabled government to establish the national health insurance scheme through development of adequate policies, strategies and mechanisms for implementation at national and federal level. The scheme has many challenges to address on governance and leadership, financing, information, health services, workforce, and essential medicines and technologies. Therefore, it is imperative to establish a robust mechanism like a "tree", which has strong roots of building blocks of health systems, which produces fruits that ensure improved responsiveness, efficiency and equity and financial protection. It is necessary to learn and apply from the experiences of other countries while implementing the national health insurance scheme. Keywords: bill; health; insurance; Nepal.


Extracts and Flavonoids of Passiflora Species as Promising Anti-inflammatory and Antioxidant Substances.
There is increasing interest in evaluating anti-inflammatory activities of plant substances such as extracts and flavonoid rich fractions. A promising source of new medicinal drugs may be species from the Passifloraceae family. The most interesting group of principal chemical substances in Passiflora species are polyphenolic compounds, including flavonoids (quercetin, rutin, apigenin, luteolin, chrysin, and C-glycosylflavones i.e., vitexin, isovitexin, orientin, isoorientin), due to their antioxidant activity demonstrated in various studies. However, each extract from Passiflora spp. as multi-component mixtures should be estimated for chemical composition (in the standardization process) and its activity using in vitro and in vivo tests. The current standard for drug discovery and development from plants indicates that only collective assessment allows estimating plant substances by definition of the origin of raw materials and their quality, methods of extractions, and metabolite profiles. Increasingly, due to complex phytochemical procedures to obtain extracts, individual flavonoid compounds are also tested for anti-inflammatory action. However, it should be emphasized that various sources of potential new drugs from plant origin are not mutually exclusive, but are complementary. A review of bibliographic data includes the following information about Passiflora species, such as distribution, classification, phytochemical compounds, the anti-inflammatory activity of the extracts, the anti-inflammatory activity of flavonoids, and antioxidant potential. The review concluded that extracts and flavonoids (mainly quercetin, apigenin, and vitexin) from Passiflora spp. can be a valuable source of anti-inflammatory and anti-oxidative medications for the prevention and treatment of many diseases, which occur with complex inflammatory processes.


A low dose alcohol drug discrimination in social drinkers: relationship with subjective effects.
Although well characterised in animals, relatively little is known about alcohol discriminative stimulus effects in humans. The study was carried out to investigate the correspondence of subjective effects and the discriminative response during the acquisition of a low dose alcohol discrimination in humans. Healthy volunteers completed an Alcohol Use Questionnaire and were then trained to discriminate a dose of 0.2 g/kg alcohol from placebo using a money reinforced technique. Subjects sampled drinks during training, but also completed rating scales measuring Taste, Like/Dislike and Subjective Effects for each drink. Thirty-two subjects learned the discrimination (discriminators; Ds). In these subjects, differences between placebo scores and alcohol scores for Lightheadedness, Relaxed, Arousal and Fatigue were greater following acquisition of the discrimination, compared with differences at the start of training. Differences in other measures remained consistent. Twenty-six of the volunteers failed to learn the discrimination (non-discriminators; NDs). These subjects reported drinking approximately twice as much alcohol during the preceding 6 months, as the Ds (4.35+/-0.53 g/kg per week versus 2.08+/-0.19 g/kg per week, respectively, P<0.001). There were no alcohol specific differences in ratings for Lightheadedness, Relaxed, Arousal or Fatigue between the Ds and the NDs. However, Dislike scores did differentiate between the Ds and the NDs in that the NDs had reduced ratings for the alcohol drink only compared with the Ds (P<0.02). These results support the suggestion from animal studies, that the alcohol stimulus is a compound, and characterise the subjective effects which contribute to a low dose cue in humans. In addition, the data suggest that previous drinking experience may selectively alter aversive responses to alcohol and that this, in addition to differences in general arousal levels, may have affected subjects' ability to learn the discrimination.


Adult stem cell plasticity: will engineered tissues be rejected?
The dogma that adult tissue-specific stem cells remain committed to supporting only their own tissue has been challenged; a new hypothesis, that adult stem cells demonstrate plasticity in their repertoires, is being tested. This is important because it seems possible that haematopoietic stem cells, for example, could be exploited to generate and perhaps deliver cell-based therapies deep within existing nonhaematopoietic organs. Much of the evidence for plasticity derives from histological studies of tissues from patients or animals that have received grafts of cells or whole organs, from a donor bearing (or lacking) a definitive marker. Detection in the recipient of appropriately differentiated cells bearing the donor marker is indicative of a switch in phenotype of a stem cell or a member of a transit amplifying population or of a differentiated cell. In this review, we discuss evidence for these changes occurring but do not consider the molecular basis of cell commitment. In general, the extent of engraftment is low but may be increased if tissues are damaged. In model systems of liver regeneration, the repeated application of a selection pressure increases levels of engraftment considerably; how this occurs is unclear. Cell fusion plays a part in regeneration and remodelling of the liver, skeletal muscle and even regions of the brain. Genetic disease may be amenable to some forms of cell therapy, yet immune rejection will present challenges. Graft-vs.-host disease will continue to present problems, although this may be avoided if the cells were derived from the recipient or they were tolerized. Despite great expectations for cellular therapies, there are indications that attempts to replace missing proteins could be confounded simply by the development of specific immunity that rejects the new phenotype.


Scatter and crosstalk corrections for (99m)Tc/(123)I dual-radionuclide imaging using a CZT SPECT system with pinhole collimators.
The energy spectrum for a cadmium zinc telluride (CZT) detector has a low energy tail due to incomplete charge collection and intercrystal scattering. Due to these solid-state detector effects, scatter would be overestimated if the conventional triple-energy window (TEW) method is used for scatter and crosstalk corrections in CZT-based imaging systems. The objective of this work is to develop a scatter and crosstalk correction method for (99m)Tc/(123)I dual-radionuclide imaging for a CZT-based dedicated cardiac SPECT system with pinhole collimators (GE Discovery NM 530c/570c). A tailing model was developed to account for the low energy tail effects of the CZT detector. The parameters of the model were obtained using (99m)Tc and (123)I point source measurements. A scatter model was defined to characterize the relationship between down-scatter and self-scatter projections. The parameters for this model were obtained from Monte Carlo simulation using SIMIND. The tailing and scatter models were further incorporated into a projection count model, and the primary and self-scatter projections of each radionuclide were determined with a maximum likelihood expectation maximization (MLEM) iterative estimation approach. The extracted scatter and crosstalk projections were then incorporated into MLEM image reconstruction as an additive term in forward projection to obtain scatter- and crosstalk-corrected images. The proposed method was validated using Monte Carlo simulation, line source experiment, anthropomorphic torso phantom studies, and patient studies. The performance of the proposed method was also compared to that obtained with the conventional TEW method. Monte Carlo simulations and line source experiment demonstrated that the TEW method overestimated scatter while their proposed method provided more accurate scatter estimation by considering the low energy tail effect. In the phantom study, improved defect contrasts were observed with both correction methods compared to no correction, especially for the images of (99m)Tc in dual-radionuclide imaging where there is heavy contamination from (123)I. In this case, the nontransmural defect contrast was improved from 0.39 to 0.47 with the TEW method and to 0.51 with their proposed method and the transmural defect contrast was improved from 0.62 to 0.74 with the TEW method and to 0.73 with their proposed method. In the patient study, the proposed method provided higher myocardium-to-blood pool contrast than that of the TEW method. Similar to the phantom experiment, the improvement was the most substantial for the images of (99m)Tc in dual-radionuclide imaging. In this case, the myocardium-to-blood pool ratio was improved from 7.0 to 38.3 with the TEW method and to 63.6 with their proposed method. Compared to the TEW method, the proposed method also provided higher count levels in the reconstructed images in both phantom and patient studies, indicating reduced overestimation of scatter. Using the proposed method, consistent reconstruction results were obtained for both single-radionuclide data with scatter correction and dual-radionuclide data with scatter and crosstalk corrections, in both phantom and human studies. The authors demonstrate that the TEW method leads to overestimation in scatter and crosstalk for the CZT-based imaging system while the proposed scatter and crosstalk correction method can provide more accurate self-scatter and down-scatter estimations for quantitative single-radionuclide and dual-radionuclide imaging.


Conversion of tyrosine phenol-lyase to dicarboxylic amino acid beta-lyase, an enzyme not found in nature.
Tyrosine phenol-lyase (TPL), which catalyzes the beta-elimination reaction of L-tyrosine, and aspartate aminotransferase (AspAT), which catalyzes the reversible transfer of an amino group from dicarboxylic amino acids to oxo acids, both belong to the alpha-family of vitamin B6-dependent enzymes. To switch the substrate specificity of TPL from L-tyrosine to dicarboxylic amino acids, two amino acid residues of AspAT, thought to be important for the recognition of dicarboxylic substrates, were grafted into the active site of TPL. Homology modeling and molecular dynamics identified Val-283 in TPL to match Arg-292 in AspAT, which binds the distal carboxylate group of substrates and is conserved among all known AspATs. Arg-100 in TPL was found to correspond to Thr-109 in AspAT, which interacts with the phosphate group of the coenzyme. The double mutation R100T/V283R of TPL increased the beta-elimination activity toward dicarboxylic amino acids at least 10(4)-fold. Dicarboxylic amino acids (L-aspartate, L-glutamate, and L-2-aminoadipate) were degraded to pyruvate, ammonia, and the respective monocarboxylic acids, e.g. formate in the case of L-aspartate. The activity toward L-aspartate (kcat = 0.21 s-1) was two times higher than that toward L-tyrosine. beta-Elimination and transamination as a minor side reaction (kcat = 0.001 s-1) were the only reactions observed. Thus, TPL R100T/V283R accepts dicarboxylic amino acids as substrates without significant change in its reaction specificity. Dicarboxylic amino acid beta-lyase is an enzyme not found in nature.


Long-term integrated telerehabilitation of COPD Patients: a multicentre randomised controlled trial (iTrain).
Pulmonary rehabilitation (PR) is an effective intervention for the management of people with chronic obstructive pulmonary disease (COPD). However, available resources are often limited, and many patients bear with poor availability of programmes. Sustaining PR benefits and regular exercise over the long term is difficult without any exercise maintenance strategy. In contrast to traditional centre-based PR programmes, telerehabilitation may promote more effective integration of exercise routines into daily life over the longer term and broaden its applicability and availability. A few studies showed promising results for telerehabilitation, but mostly with short-term interventions. The aim of this study is to compare long-term telerehabilitation with unsupervised exercise training at home and with standard care. An international multicentre randomised controlled trial conducted across sites in three countries will recruit 120 patients with COPD. Participants will be randomly assigned to telerehabilitation, treadmill and control, and followed up for 2 years. The telerehabilitation intervention consists of individualised exercise training at home on a treadmill, telemonitoring by a physiotherapist via videoconferencing using a tablet computer, and self-management via a customised website. Patients in the treadmill arm are provided with a treadmill only to perform unsupervised exercise training at home. Patients in the control arm are offered standard care. The primary outcome is the combined number of hospitalisations and emergency department presentations. Secondary outcomes include changes in health status, quality of life, anxiety and depression, self-efficacy, subjective impression of change, physical performance, level of physical activity, and personal experiences in telerehabilitation. This trial will provide evidence on whether long-term telerehabilitation represents a cost-effective strategy for the follow-up of patients with COPD. The delivery of telerehabilitation services will also broaden the availability of PR and maintenance strategies, especially to those living in remote areas and with no access to centre-based exercise programmes. ClinicalTrials.gov: NCT02258646 .


An analysis from the Quality Outcomes Database, Part 1. Disability, quality of life, and pain outcomes following lumbar spine surgery: predicting likely individual patient outcomes for shared decision-making.
OBJECTIVE Quality and outcomes registry platforms lie at the center of many emerging evidence-driven reform models. Specifically, clinical registry data are progressively informing health care decision-making. In this analysis, the authors used data from a national prospective outcomes registry (the Quality Outcomes Database) to develop a predictive model for 12-month postoperative pain, disability, and quality of life (QOL) in patients undergoing elective lumbar spine surgery. METHODS Included in this analysis were 7618 patients who had completed 12 months of follow-up. The authors prospectively assessed baseline and 12-month patient-reported outcomes (PROs) via telephone interviews. The PROs assessed were those ascertained using the Oswestry Disability Index (ODI), EQ-5D, and numeric rating scale (NRS) for back pain (BP) and leg pain (LP). Variables analyzed for the predictive model included age, gender, body mass index, race, education level, history of prior surgery, smoking status, comorbid conditions, American Society of Anesthesiologists (ASA) score, symptom duration, indication for surgery, number of levels surgically treated, history of fusion surgery, surgical approach, receipt of workers' compensation, liability insurance, insurance status, and ambulatory ability. To create a predictive model, each 12-month PRO was treated as an ordinal dependent variable and a separate proportional-odds ordinal logistic regression model was fitted for each PRO. RESULTS There was a significant improvement in all PROs (p < 0.0001) at 12 months following lumbar spine surgery. The most important predictors of overall disability, QOL, and pain outcomes following lumbar spine surgery were employment status, baseline NRS-BP scores, psychological distress, baseline ODI scores, level of education, workers' compensation status, symptom duration, race, baseline NRS-LP scores, ASA score, age, predominant symptom, smoking status, and insurance status. The prediction discrimination of the 4 separate novel predictive models was good, with a c-index of 0.69 for ODI, 0.69 for EQ-5D, 0.67 for NRS-BP, and 0.64 for NRS-LP (i.e., good concordance between predicted outcomes and observed outcomes). CONCLUSIONS This study found that preoperative patient-specific factors derived from a prospective national outcomes registry significantly influence PRO measures of treatment effectiveness at 12 months after lumbar surgery. Novel predictive models constructed with these data hold the potential to improve surgical effectiveness and the overall value of spine surgery by optimizing patient selection and identifying important modifiable factors before a surgery even takes place. Furthermore, these models can advance patient-focused care when used as shared decision-making tools during preoperative patient counseling.


Flexibility of interdomain contacts revealed by topological isomers of bivalent consolidated ligands to the dual Src homology domain SH(32) of abelson.
Src homology (SH)2 and SH3 domains are found in a variety of proteins involved in the control of cellular signaling and architecture. The possible interrelationships between domains are not easily investigated, even though several cases of multiple domain-containing constructs have been studied structurally. As a complement to direct structural methods, we have developed consolidated ligands and tested their binding to the Abl SH(32) complex. Consolidated ligands combine in the same molecule peptide sequences recognized by SH2 and SH3 domains, i.e., Pro-Val-pTyr-Glu-Asn-Val and Pro-Pro-Ala-Tyr-Pro-Pro-Pro-Pro-Val-Pro, respectively; these are joined by oligoglycyl linkers. Four types of ligands were chemically synthesized, representing all the possible relative orientations of ligands. Their affinities were found to vary with binding portion topologies and linker lengths. Two of these types were shown to bind to both SH2 and SH3 dual domains with high affinities and specificities, showing increases of one order of magnitude, as compared to the most strongly bound monovalent equivalent. These results suggest that the relative orientation of SH2 and SH3 in Abl SH(32) is not fixed, and this synthetic approach may be generally useful for determining the structures of ligated complexes and for developing reagents with high affinities and specificities.


Potential conversion of adult clavicle-derived chondrocytes into neural lineage cells in vitro.
Neural stem cells (NSC) can be isolated from a variety of adult tissues and become a valuable cell source for the repair of peripheral and central nervous diseases. However, their origin and identity remain controversial because of possible de-differentiation/trans-differentiation or contaminations by hematopoietic stem cells (HSCs) or mesenchymal stem cells (MSCs). We hypothesize that the commonly used NSC culture medium can induce committed cartilage chondrocytes to de-differentiate and/or trans-differentiate into neural cell lineages. Using a biological isolation and purification method with explants culture, we here show that adult rat clavicle cartilage chondrocytes migrate out from tissue blocks, form sphere-like structures, possess the capability of self-renewal, express nestin and p75NTR, markers for neural crest progenitors, and differentiate into neurons, glia, and smooth muscle cells. Comparing with adult cartilage, the spherical-forming neural crest cell-like cells downregulate the chondrocytic marker genes, including collagen II, collagen X, and sox9, as well as neural-lineage repressors/silencers REST and coREST, but upregulate a set of well-defined genes related to neural crest cells and pro-neural potential. Nerve growth factor (NGF) and glial growth factor (GGF) increase glial and neuronal differentiation, respectively. These results suggest that chondrocytes derived from adult clavicle cartilage can become neural crest stem-like cells and acquire neuronal phenotypes in vitro. The possible de-differentiation/trans-differentiation mechanisms underlying the conversion were discussed.


Investigating Possible Trans/Intergenerational Associations With Obesity in Young Adults Using an Exposome Approach.
Animal experiments demonstrate ways in which an exposure in one generation can be reflected in a variety of outcomes in later generations. In parallel human observational studies have shown associations between grandparental and parental exposures to cigarette smoking and/or nutrition and growth and survival of the grandchild. These studies have controlled for just a few confounders selected ad hoc. Here we use an exposome approach (using all available measures of exposure) to determine trans/inter-generational factors that may be important in studying environmental factors associated with fat mass in young human adults. The study takes advantage of the rich data available in the Avon Longitudinal Study of Parents and Children (ALSPAC). We test associations with features of grandparents (G0) and the childhood of the parents (G1) of 24-year olds (G2). We hypothesized that intergenerational associations would be revealed, particularly with exposure to cigarette smoke, and that these would vary with the sexes of all three generations. The study exposome analyzed 172 exposures to the maternal line and 182 to the paternal line. A series of stepwise regression analyses reduced the initial 40 unadjusted factors (P < 0.05) to eight independent features on the maternal line, and of 26 on the paternal line to five. We found strong associations between the father starting to smoke cigarettes regularly before age 11 and increased fat mass in his adult children (unadjusted = +7.82 [95% CI +2.75, +12.90] Kg; adjusted = +11.22 [+5.23, +17.22] Kg); this association was stronger in male offspring. In addition, when the paternal grandmother had smoked in pregnancy her adult granddaughters, but not grandsons had elevated mean fat mass (interaction with sex after adjustment, P = 0.001). The exposome technique identified other factors that were independently associated with fat mass in young adults. These may be useful in identifying appropriate confounders in other more proximal analyses, but also may identify features that may be on epigenetic pathways leading to increased fat mass in subsequent generations. We acknowledge that the results need to be replicated in other cohorts and encourage further linkage of outcomes with previous generational exposures, particularly along the paternal line.


Emotional Intelligence in Physical Activity, Sports and Judo: A Global Approach.
Emotional intelligence (EI) has been studied in relation to health and physical activity (PA) or in a sport-specific approach. EI is related to sports performance; however, combat sports seem to show characteristics of their own that involve better control of emotions than other sports. This study aimed to analyse whether there are differences in EI dimensions between those who do not achieve World Health Organization (WHO) PA recommendations, those who meet WHO PA recommendations, those who meet WHO PA recommendations practising sports, and judokas of different levels. A descriptive and cross-sectional study was conducted. The sample comprised 2938 undergraduate students from Madrid and 487 active Spanish judokas. PA was measured by the Global Physical Activity Questionnaire (GPAQ). EI was assessed by the Trait Meta-Mood Scale (TMMS-24). Three different one-way ANOVA and ANCOVA (controlling for gender and age) were conducted to compare the effect of type of group studied on the EI dimensions. Significant differences in EI dimensions were found between those who do not meet PA recommendations, those who meet PA recommendations, those who meet PA recommendations practising sports, and judo athletes of different levels. However, when controlling for gender and age, these differences remained specifically in emotional attention and in emotional repair. Judo athletes and high-performance judo athletes showed better EI than the rest of the studied groups.


Education as important predictor for successful employment in adults with congenital heart disease worldwide.
Conflicting results have been reported regarding employment status and work ability in adults with congenital heart disease (CHD). Since this is an important determinant for quality of life, we assessed this in a large international adult CHD cohort. Data from 4028 adults with CHD (53% women) from 15 different countries were collected by a uniform survey in the cross-sectional APPROACH International Study. Predictors for employment and work limitations were studied using general linear mixed models. Median age was 32 years (IQR 25-42) and 94% of patients had at least a high school degree. Overall employment rate was 69%, but varied substantially among countries. Higher education (OR 1.99-3.69) and having a partner (OR 1.72) were associated with more employment; female sex (OR 0.66, worse NYHA functional class (OR 0.67-0.13), and a history of congestive heart failure (OR 0.74) were associated with less employment. Limitations at work were reported in 34% and were associated with female sex (OR 1.36), increasing age (OR 1.03 per year), more severe CHD (OR 1.31-2.10), and a history of congestive heart failure (OR 1.57) or mental disorders (OR 2.26). Only a university degree was associated with fewer limitations at work (OR 0.62). There are genuine differences in the impact of CHD on employment status in different countries. Although the majority of adult CHD patients are employed, limitations at work are common. Education appears to be the main predictor for successful employment and should therefore be encouraged in patients with CHD.


Interface-engineered templates for molecular spin memory devices.
The use of molecular spin state as a quantum of information for storage, sensing and computing has generated considerable interest in the context of next-generation data storage and communication devices, opening avenues for developing multifunctional molecular spintronics. Such ideas have been researched extensively, using single-molecule magnets and molecules with a metal ion or nitrogen vacancy as localized spin-carrying centres for storage and for realizing logic operations. However, the electronic coupling between the spin centres of these molecules is rather weak, which makes construction of quantum memory registers a challenging task. In this regard, delocalized carbon-based radical species with unpaired spin, such as phenalenyl, have shown promise. These phenalenyl moieties, which can be regarded as graphene fragments, are formed by the fusion of three benzene rings and belong to the class of open-shell systems. The spin structure of these molecules responds to external stimuli (such as light, and electric and magnetic fields), which provides novel schemes for performing spin memory and logic operations. Here we construct a molecular device using such molecules as templates to engineer interfacial spin transfer resulting from hybridization and magnetic exchange interaction with the surface of a ferromagnet; the device shows an unexpected interfacial magnetoresistance of more than 20 per cent near room temperature. Moreover, we successfully demonstrate the formation of a nanoscale magnetic molecule with a well-defined magnetic hysteresis on ferromagnetic surfaces. Owing to strong magnetic coupling with the ferromagnet, such independent switching of an adsorbed magnetic molecule has been unsuccessful with single-molecule magnets. Our findings suggest the use of chemically amenable phenalenyl-based molecules as a viable and scalable platform for building molecular-scale quantum spin memory and processors for technological development.


Using hidden Markov models to analyze gene expression time course data.
Cellular processes cause changes over time. Observing and measuring those changes over time allows insights into the how and why of regulation. The experimental platform for doing the appropriate large-scale experiments to obtain time-courses of expression levels is provided by microarray technology. However, the proper way of analyzing the resulting time course data is still very much an issue under investigation. The inherent time dependencies in the data suggest that clustering techniques which reflect those dependencies yield improved performance. We propose to use Hidden Markov Models (HMMs) to account for the horizontal dependencies along the time axis in time course data and to cope with the prevalent errors and missing values. The HMMs are used within a model-based clustering framework. We are given a number of clusters, each represented by one Hidden Markov Model from a finite collection encompassing typical qualitative behavior. Then, our method finds in an iterative procedure cluster models and an assignment of data points to these models that maximizes the joint likelihood of clustering and models. Partially supervised learning--adding groups of labeled data to the initial collection of clusters--is supported. A graphical user interface allows querying an expression profile dataset for time course similar to a prototype graphically defined as a sequence of levels and durations. We also propose a heuristic approach to automate determination of the number of clusters. We evaluate the method on published yeast cell cycle and fibroblasts serum response datasets, and compare them, with favorable results, to the autoregressive curves method.


Reference set of Mycobacterium tuberculosis clinical strains: A tool for research and product development.
The Mycobacterium tuberculosis complex (MTBC) causes tuberculosis (TB) in humans and various other mammals. The human-adapted members of the MTBC comprise seven phylogenetic lineages that differ in their geographical distribution. There is growing evidence that this phylogeographic diversity modulates the outcome of TB infection and disease. For decades, TB research and development has focused on the two canonical MTBC laboratory strains H37Rv and Erdman, both of which belong to Lineage 4. Relying on only a few laboratory-adapted strains can be misleading as study results might not be directly transferrable to clinical settings where patients are infected with a diverse array of strains, including drug-resistant variants. Here, we argue for the need to expand TB research and development by incorporating the phylogenetic diversity of the MTBC. To facilitate such work, we have assembled a group of 20 genetically well-characterized clinical strains representing the seven known human-adapted MTBC lineages. With the "MTBC clinical strains reference set" we aim to provide a standardized resource for the TB community. We hope it will enable more direct comparisons between studies that explore the physiology of MTBC beyond the laboratory strains used thus far. We anticipate that detailed phenotypic analyses of this reference strain set will increase our understanding of TB biology and assist in the development of new control tools that are broadly effective.


Silkworm HP1a transcriptionally enhances highly expressed euchromatic genes via association with their transcription start sites.
Heterochromatin protein 1 (HP1) is an evolutionarily conserved protein across different eukaryotic species and is crucial for heterochromatin establishment and maintenance. The silkworm, Bombyx mori, encodes two HP1 proteins, BmHP1a and BmHP1b. In order to investigate the role of BmHP1a in transcriptional regulation, we performed genome-wide analyses of the transcriptome, transcription start sites (TSSs), chromatin modification states and BmHP1a-binding sites of the silkworm ovary-derived BmN4 cell line. We identified a number of BmHP1a-binding loci throughout the silkworm genome and found that these loci included TSSs and frequently co-occurred with neighboring euchromatic histone modifications. In addition, we observed that genes with BmHP1a-associated TSSs were relatively highly expressed in BmN4 cells. RNA interference-mediated BmHP1a depletion resulted in the transcriptional repression of highly expressed genes with BmHP1a-associated TSSs, whereas genes not coupled with BmHP1a-binding regions were less affected by the treatment. These results demonstrate that BmHP1a binds near TSSs of highly expressed euchromatic genes and positively regulates their expression. Our study revealed a novel mode of transcriptional regulation mediated by HP1 proteins.


New-onset depression following stable, slow, and rapid rate of prescription opioid dose escalation.
Recent studies suggest that longer durations of opioid use, independent of maximum morphine equivalent dose (MED) achieved, is associated with increased risk of new-onset depression (NOD). Conversely, other studies, not accounting for duration, found that higher MED increased probability of depressive symptoms. To determine whether rate of MED increase is associated with NOD, a retrospective cohort analysis of Veterans Health Administration data (2000-2012) was conducted. Eligible patients were new, chronic (>90 days) opioid users, aged 18 to 80, and without depression diagnoses for 2 years before start of follow-up (n = 7051). Mixed regression models of MED across follow-up defined 4 rate of dose change categories: stable, decrease, slow increase, and rapid increase. Cox proportional hazard models assessed the relationship of rate of dose change and NOD, controlling for pain, duration of use, maximum MED, and other confounders using inverse probability of treatment-weighted propensity scores. Incidence rate for NOD was 14.1/1000PY (person-years) in stable rate, 13.0/1000PY in decreasing, 19.3/1000PY in slow increasing, and 27.5/1000PY in rapid increasing dose. Compared with stable rate, risk of NOD increased incrementally for slow (hazard ratio = 1.22; 95% confidence interval: 1.05-1.42) and rapid (hazard ratio = 1.58; 95% confidence interval: 1.30-1.93) rate of dose increase. Faster rates of MED escalation contribute to NOD, independent of maximum dose, pain, and total opioid duration. Dose escalation may be a proxy for loss of control or undetected abuse known to be associated with depression. Clinicians should avoid rapid dose increase when possible and discuss risk of depression with patients if dose increase is warranted for pain.


TAVR update: Contemporary data from the UK TAVI and US TVT registries.
The introduction of transcatheter aortic valve replacement (TAVR in US - TAVI in Europe) has resulted in a paradigm shift in the treatment of patients with severe aortic stenosis. Although three randomized trials and multiple single-center and multicenter registry studies have been published, the profile and longer-term outcome of patients undergoing transcatheter aortic valve replacement (TAVR) in patients with severe aortic stenosis have been limited. The recently published reports from the United Kingdom (UK)(1) and United States (US)(2) TAVR registries add tremendously to the currently available literature. These studies provide an excellent model to clinicians that would aid in the proper patient selection and help in guiding discussions with patients who are undergoing TAVR. The present review discusses the recently published UK and US TAVR registry data.


End-of-life concerns and care preferences: congruence among terminally ill elders and their family caregivers.
This study examined the end-of-life challenges, concerns, and care preferences of terminally ill elders and their family caregivers, with a focus on areas of congruence and incongruence. Ten elders and 10 family caregivers participated in separate, semi-structured, face-to-face interviews. Data analysis included team coding and thematic analysis, guided by an a priori set of categories based on the study questions. Shared challenges and concerns included experiencing decline, managing pain and discomfort, and living with uncertainty. There was also congruence regarding end-of-life care preferences, specifically the importance of quality care, treatment with dignity and respect, and avoiding unnecessary life-sustaining treatment. Areas of incongruence included the elders' difficulties in accepting dependence, their fears of becoming a burden, and desire to be prepared for death. Family caregivers were most concerned with providing adequate care to meet the elders' physical and spiritual care needs. Open family communication was associated with greater congruence. The authors discuss implications of these findings for research and intervention.


Calcium isotope constraints on the end-Permian mass extinction.
The end-Permian mass extinction horizon is marked by an abrupt shift in style of carbonate sedimentation and a negative excursion in the carbon isotope (delta(13)C) composition of carbonate minerals. Several extinction scenarios consistent with these observations have been put forward. Secular variation in the calcium isotope (delta(44/40)Ca) composition of marine sediments provides a tool for distinguishing among these possibilities and thereby constraining the causes of mass extinction. Here we report delta(44/40)Ca across the Permian-Triassic boundary from marine limestone in south China. The delta(44/40)Ca exhibits a transient negative excursion of approximately 0.3 per thousand over a few hundred thousand years or less, which we interpret to reflect a change in the global delta(44/40)Ca composition of seawater. CO(2)-driven ocean acidification best explains the coincidence of the delta(44/40)Ca excursion with negative excursions in the delta(13)C of carbonates and organic matter and the preferential extinction of heavily calcified marine animals. Calcium isotope constraints on carbon cycle calculations suggest that the average delta(13)C of CO(2) released was heavier than -28 per thousand and more likely near -15 per thousand; these values indicate a source containing substantial amounts of mantle- or carbonate-derived carbon. Collectively, the results point toward Siberian Trap volcanism as the trigger of mass extinction.


Nanostructures of designed geometry and functionality enable regulation of cellular signaling processes.
Extracellular matrices (ECM) triggered cellular signaling processes often begin with the clustering of the cellular receptors such as integrin and FcεRI. The sizes of these initial protein complexes or clusters are tens to 100 nm in dimension; therefore, engineered nanostructures could provide effective mimics of ECM for investigation and control of the initial and downstream specific signaling processes. This current topic discusses recent advances in nanotechnology in the context of design and production of matching chemical functionality and geometry for control of specific cellular signaling processes. Two investigations are reported to demonstrate this concept: (a) how the presentation of antigen at the nanometer scale would influence the aggregation of FcεRI, which would impact the formation of activation complexes, leading to the rearrangement of actin in cytoskeleton and degranulation or activation of mast cells; (b) how the engineered nanostructure could guide the initial integrin clustering, which would impact the formation of focal adhesion and downstream cell signaling cascades, leading to polarization, migration, and morphological changes. Complementary to engineered ECMs using synthetic ligands or peptides, or topographic control at the micrometer scale, nanostructures of designed geometry and chemical functionality provide new and effective biochemical cues for regulation of cellular signaling processes and downstream behaviors.


Combined Iron Deficiency and Low Aerobic Fitness Doubly Burden Academic Performance among Women Attending University.
Academic success is a key determinant of future prospects for students. Cognitive functioning has been related to nutritional and physical factors. Here, we focus on iron status and aerobic fitness in young-adult female students given the high rate of iron deficiency and declines in fitness reported in this population. We sought to explore the combined effects of iron status and fitness on academic success and to determine whether these associations are mediated by cognitive performance. Women (n = 105) aged 18-35 y were recruited for this cross-sectional study. Data were obtained for iron biomarkers, peak oxygen uptake (VO2peak), grade point average (GPA), performance on computerized attention and memory tasks, and motivation and parental occupation. We compared the GPA of groups 1) with low compared with normal iron status, 2) among different fitness levels, and 3) by using a combined iron status and fitness designation. Mediation analysis was applied to determine whether iron status and VO2peak influence GPA through attentional and mnemonic function. After controlling for age, parental occupation, and motivation, GPA was higher in women with normal compared with low ferritin (3.66 ± 0.06 compared with 3.39 ± 0.06; P = 0.01). In analyses of combined effects of iron status and fitness, GPA was higher in women with normal ferritin and higher fitness (3.70 ± 0.08) than in those with 1) low ferritin and lower fitness (3.36 ± 0.08; P = 0.02) and 2) low ferritin and higher fitness (3.44 ± 0.09; P = 0.04). Path analysis revealed that working memory mediated the association between VO2peak and GPA. Low iron stores and low aerobic fitness may prevent female college students from achieving their full academic potential. Investigators should explore whether integrated lifestyle interventions targeting nutritional status and fitness can benefit cognitive function, academic success, and postgraduate prospects.


Spiritual peace predicts 5-year mortality in congestive heart failure patients.
Spirituality is favorably related to depression, quality of life, hospitalizations, and other important outcomes in congestive heart failure (CHF) patients but has not been examined as a predictor of mortality risk in this population. Given the well-known difficulties in managing CHF, we hypothesized that spirituality would be associated with lower mortality risk, controlling for baseline demographics, functional status, health behaviors, and religiousness. Participants were 191 CHF patients (64% male; M age = 68.6 years, SD = 10.1) who completed a baseline survey and were then followed for 5 years. Nearly 1/3 of the sample (32%) died during the study period. Controlling for demographics and health status, smoking more than doubled the risk of mortality, whereas alcohol consumption was associated with slightly lower risk of mortality. Importantly, adherence to healthy lifestyle recommendations was associated with halved mortality risk. Although both religion and spirituality were associated with better health behaviors at baseline in bivariate analyses, a proportional hazard model showed that only spirituality was significantly associated with reduced mortality risk (by 20%), controlling for demographics, health status, and health behaviors. Experiencing spiritual peace, along with adherence to a healthy lifestyle, were better predictors of mortality risk in this sample of CHF patients than were physical health indicators such as functional status and comorbidity. Future research might profitably examine the efficacy of attending to spiritual issues along with standard lifestyle interventions.


A randomized controlled trial of the Korean version of the PEERS(®) parent-assisted social skills training program for teens with ASD.
Impaired social functioning is a hallmark feature of autism spectrum disorder (ASD), often requiring treatment throughout the life span. PEERS(®) (Program for the Education and Enrichment of Relational Skills) is a parent-assisted social skills training for teens with ASD. Although PEERS(®) has an established evidence base in improving the social skills of adolescents and young adults with ASD in North America, the efficacy of this treatment has yet to be established in cross-cultural validation trials. The objective of this study is to examine the feasibility and treatment efficacy of a Korean version of PEERS(®) for enhancing social skills through a randomized controlled trial (RCT).The English version of the PEERS(®) Treatment Manual (Laugeson & Frankel, 2010) was translated into Korean and reviewed by 21 child mental health professionals. Items identified as culturally sensitive were surveyed by 447 middle school students, and material was modified accordingly. Participants included 47 teens between 12 and 18 years of age with a diagnosis of ASD and a verbal intelligence quotient (IQ) ≥ 65. Eligible teens were randomly assigned to a treatment group (TG) or delayed treatment control group (CG). Primary outcome measures included questionnaires and direct observations quantifying social ability and problems directly related to ASD. Secondary outcome measures included scales for depressive symptoms, anxiety, and other behavioral problems. Rating scales for parental depressive symptoms and anxiety were examined to detect changes in parental psychosocial functioning throughout the PEERS(®) treatment. Independent samples t-tests revealed no significant differences at baseline across the TG and CG conditions with regard to age (14.04 ± 1.64 and 13.54 ± 1.50 years), IQ (99.39 ± 18.09 & 100.67 ± 16.97), parental education, socioeconomic status, or ASD symptoms (p < 0.05), respectively. Results for treatment outcome suggest that the TG showed significant improvement in communication and social interaction domain scores on the Autism Diagnostic Observation Schedule, interpersonal relationship and play/leisure time on the subdomain scores of the Korean version of the Vineland Adaptive Behavior Scale (p's < 0.01), social skills knowledge total scores on the Test of Adolescent Social Skills Knowledge-Revised (p < 0.01), and decreased depressive symptoms on the Child Depression Inventory following treatment (p < 0.05). Analyses of parental outcome reveal a significant decrease in maternal state anxiety in the TG after controlling for potential confounding variables (p < 0.05). Despite cultural and linguistic differences, the PEERS(®) social skills intervention appears to be efficacious for teens with ASD in Korea with modest cultural adjustment. In an RCT, participants receiving the PEERS(®) treatment showed significant improvement in social skills knowledge, interpersonal skills, and play/leisure skills, as well as a decrease in depressive symptoms and ASD symptoms. This study represents one of only a few cross-cultural validation trials of an established evidence-based treatment for adolescents with ASD.


Characterization of opioid agonist efficacy in a C6 glioma cell line expressing the mu opioid receptor.
In C6 glioma cells stably expressing a homogeneous population of the cloned rat mu opioid receptor, the binding affinities of opioid agonists and subsequent activation of G protein were examined. Opioid receptor number in membranes of these cells was high (10-30 pmol/mg protein [3H]diprenorphine binding sites). Opioids were found to bind to the receptor with high affinity [Tyr-D-Ala-Gly-(Me)Phe-Gly-ol (DAMGO) 0.23 nM; sufentanil 0.034 nM; morphine 0.16 nM]. Activation of G protein by opioid agonists was examined by measuring the stimulation of guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTP gamma S) binding. Sufentanil increased [35S]GTP gamma S binding by 326% with an EC50 value of 2.39 nM. Agonist stimulation of [35S]GTP gamma S binding was stereoselective, naltrexone-reversible, and pertussis toxin-sensitive. The "intrinsic activity" of opioids at the mu receptor was reflected by the magnitude of agonist-mediated activation of G protein. The rank order of the stimulation of [35S]GTP gamma S binding was etonitazene = sufentanil = DAMGO = PLO17 = fentanyl > morphine > profadol > meperidine > butorphanol = nalbuphine = pentazocine > cyclazocine = nalorphine > levallorphan > naltrexone. High affinity binding of ligands to the mu opioid receptor was reduced by the addition of sodium and guanosine diphosphate at concentrations used in the [35S]GTP gamma S binding assay. Ligand affinity was reduced in a manner correlating with "intrinsic activity". DAMGO, 1229-fold, nalbuphine 35-fold, naltrexone, 3-fold. The results presented show that the stable expression of the rat mu opioid receptor in C6 cells provides an effective tool to examine opioid receptor signal transduction mechanisms and evaluate the activity of novel opioids at the mu receptor.


Why patient participation groups stop functioning: general practitioners' viewpoint.
Out of the 87 patient participation groups that were known to the National Association for Patient Participation as having been established by the end of 1983, 17 (25%) are not functioning. The general practitioners concerned with these non-functioning groups were interviewed to identify problems that they had had in keeping the group going and to seek possible explanations for the problems. Fourteen of the groups had stopped functioning in part owing to lack of interest by patients. Groups become non-functioning often in the first year of starting up, and this may be because of the nature of the practice population that they seek to represent.


Are hospital services for self-harm getting better? An observational study examining management, service provision and temporal trends in England.
To describe the characteristics and management of individuals attending hospital with self-harm and assess changes in management and service quality since an earlier study in 2001, a period in which national guidance has been available. Observational study. A stratified random sample of 32 hospitals in England, UK. 6442 individuals presenting with 7689 episodes of self-harm during a 3-month audit period between 2010 and 2011. Self-harm episodes, key aspects of individual management relating to psychosocial assessment and follow-up, and a 21-item measure of service quality. Overall, 56% (3583/6442) of individuals were women and 51% (3274/6442) were aged under 35 years. Hospitals varied markedly in their management. The proportion of episodes that received a psychosocial assessment by a mental health professional ranged from 22% to 88% (median 58%, IQR 48-70%); the proportion of episodes resulting in admission to general hospitals varied from 22% to 85% (median 54%, IQR 41-63%); a referral for specialist mental health follow-up was made in 11-64% of episodes (median 28%, IQR 22-38%); a referral to non-statutory services was made in 4-62% of episodes (median 15%, IQR 8-23%); 0-21% of episodes resulted in psychiatric admission (median 7%, QR 4-12%). The specialist assessment rate varied by method of harm; the median rate for self-cutting was 45% (IQR 28-63%) vs 58% (IQR 48-73%) for self-poisoning. Compared with the 2001 study, there was little difference in the proportion of episodes receiving specialist assessment; there was a significant increase in general hospital admission but a decrease in referrals for specialist mental health follow-up. However, scores on the service quality scale had increased from a median of 11.5-14.5 (a 26% increase). Services for the hospital management of self-harm remain variable despite national guidelines and policy initiatives. We found no evidence for increasing levels of assessment over time but markers of service quality may have improved. This paper forms part of the study 'Variations in self-harm service delivery: an observational study examining outcomes and temporal trends'. The National Institute for Health Research Clinical Research Network (NIHR CRN) Portfolio database registration number: HOMASH 2 (7333). The NIHR Coordinated System for gaining NHS Permission (CSP) registration number: 23226.


Effects of silicone hydrogel contact lens wear on ocular surface sensitivity to tactile, pneumatic mechanical, and chemical stimulation.
To determine the effects of silicone hydrogel lens wear and lens-solution interactions on ocular surface sensitivity. Forty-eight adapted lens wearers completed the study, which comprised two phases. Phase 1 included habitual lens wear, no lens wear (7 ± 3 days), and balafilcon A lenses (PV; PureVision; Bausch & Lomb, Rochester, NY) with a hydrogen peroxide-based regimen for 2 weeks; phase 2 included wear of PV with the use of a multipurpose solution containing either polyhexamethylene-biguanide (PHMB) or Polyquad/Aldox (Alcon Laboratories, Fort Worth, TX) preservative, each for 1 week, with a 2-week washout period between solutions. Tactile and pneumatic (mechanical and chemical) stimuli were delivered, and thresholds were determined by Cochet-Bonnet (Luneau Ophthalmologie, Chartres, France) and Belmonte (Cooperative Research Centre for Eye Research and Technology, Sydney, NSW, Australia) pneumatic esthesiometers, respectively. Corneal and conjunctival thresholds and staining scores were assessed at baseline, after 2 and 8 hours of lens wear on day 1 and at the end of each wearing cycle (2 hours). In phase 1, compared to the no-lens baseline, corneal tactile thresholds increased at the 1-day, 8-hour and the 2-week visits (P < 0.05), whereas conjunctival mechanical thresholds decreased at the 1-day, 2-hour and the 2-week visits (P < 0.05). In phase 2, the chemical thresholds were lower with PHMB-preserved solution compared with the Polyquad/Aldox system at the 1-day, 2-hour and the 1-week visits (P < 0.05). Staining scores correlated inversely with conjunctival chemical thresholds (all P < 0.05). Ocular surface sensitivity changed in adapted lens wearers, when lenses were refit after a no-lens interval and during lens wear with different care regimens. The corneal staining that was observed with certain lens-solution combinations was accompanied by sensory alteration of the ocular surface-that is, higher levels of staining correlated with increased conjunctival chemical sensitivity. (ClinicalTrials.gov number, NCT00455455.).


Preoperative thrombolysis and venoplasty affords no benefit in patency following first rib resection and scalenectomy for subacute and chronic subclavian vein thrombosis.
Axillosubclavian vein thrombosis, also known as Paget-Schroetter syndrome, is a rare presentation of thoracic outlet syndrome (TOS) representing approximately 5% of all cases. Conventional management consists of routine anticoagulation, operative decompression via first rib resection and scalenectomy (FRRS), and, recently, thrombolysis. The purpose of our study was to retrospectively review our experience with this condition and compare the effectiveness of preoperative endovascular intervention with thrombolysis and venoplasty to anticoagulation alone in those undergoing FRRS to preserve subclavian vein patency. A retrospective review was conducted for all venous TOS patients from July 2003 to May 2009 from a prospectively maintained database. Preoperative clinic notes were reviewed to allow stratification into two groups. One group consisted of patients undergoing preoperative endovascular intervention with thrombolysis and venoplasty, while the other group consisted of patients managed medically with anticoagulation alone prior to FRSS. Operative notes, postoperative venograms, and postoperative duplex imaging results were reviewed for presence of recanalization, chronic nonocclusive thrombus, or continued occlusion. One hundred three patients had 110 FRRS for subclavian vein thrombosis (53 men, 50 women), seven of which had contralateral FRRS for thrombosis. The cohort averaged 31 years of age (range, 16-54 years) with an overall, mean follow-up time of 16 months (range, 1-52 months). Of the 110 veins evaluated, 45 underwent endovascular intervention (thombolysis, with or without venoplasty) prior to FRRS, and at 1 year, 41 (91%) were patent with improvement of symptoms. In the 65 veins on anticoagulation alone, 59 (91%) ultimately were patent, with symptomatic improvement in all. Overall, 91% (100/110) of subclavian veins were patent in patients completing follow-up, were asymptomatic, and back to their previous active lifestyle. Preoperative endovascular intervention offered no benefit over simple anticoagulation prior to FRRS, since the use of thrombolysis prior to FRRS, regardless of need for postoperative venoplasty, had little impact on overall rates of patency. The optimal treatment algorithm may merely be routine anticoagulation for all effort thrombosis patients prior to FRRS followed by venography with venoplasty if needed. The role of thrombolysis for Paget-Schroetter syndrome should be further investigated in randomized trials.


Analysis of stationary droplets in a generic Turing reaction-diffusion system.
Solitonlike structures called "droplets" are found to exist within a paradigm reaction-diffusion model that can be used to describe patterning in a number of biological systems, for example, on the skin of various fish species. They have also been found in many other systems that can be modeled with a complex Ginzburg-Landau system. These droplets can be analyzed in the biological paradigm model because the system has two nonzero stable steady states that are symmetric; however, the asymmetric case is more challenging. We first review the properties of the paradigm system and then extend a recently developed perturbation technique [D. Gomila, J. Opt. B: Quantum Semiclassical Opt. 6, S265 (2004)] to investigate the weakly asymmetric case. We compare the results of our mathematical analysis with numerical simulations and show good agreement in the region where the assumptions hold.


Reconstitution of immune cell interactions in free-standing membranes.
The spatiotemporal regulation of signalling proteins at the contacts formed between immune cells and their targets determines how and when immune responses begin and end. Therapeutic control of immune responses therefore relies on thorough elucidation of the molecular processes occurring at these interfaces. However, the detailed investigation of each component's contribution to the formation and regulation of the contact is hampered by the complexities of cell composition and architecture. Moreover, the transient nature of these interactions creates additional challenges, especially in the use of advanced imaging technology. One approach that circumvents these problems is to establish in vitro systems that faithfully mimic immune cell interactions, but allow complexity to be 'dialled-in' as needed. Here, we present an in vitro system that makes use of synthetic vesicles that mimic important aspects of immune cell surfaces. Using this system, we began to explore the spatial distribution of signalling molecules (receptors, kinases and phosphatases) and how this changes during the initiation of signalling. The GUV/cell system presented here is expected to be widely applicable.


Ancestry informative markers clarify the regional admixture variation in the Costa Rican population.
The genetic structure of Costa Rica's population is complex, both by region and by individual, due to the admixture process that started during the 15th century and historical events thereafter. Previous studies have been done mostly on Amerindian populations and the Central Valley inhabitants using various microsatellites and mitochondrial DNA markers. Here, we study for the first time a random sample from all regions of the country with ancestry informative markers (AIMs) to address the individual and regional admixture proportions. A sample of 160 male individuals was screened for 78 AIMs customized in a GoldenGate platform from Illumina. We observed that this small set of AIMs has the same power of hundreds of microsatellites and thousands of single-nucleotide polymorphisms to evaluate admixture, with the benefit of reducing genotyping costs. This type of investigation is necessary to explore new genetic markers useful for forensic and genetic investigation. Our data showed a mean admixture proportion of 49.2% European (EUR), 37.8% Native American (NAM), and 12.9% African (AFR), with a disproportionate admixture composition by region. In addition, when Chinese (CHB) was included as a fourth component, the proportions changed to 45.6% EUR, 33.5% NAM, 11.7% AFR, and 9.2% CHB. The admixture trend is consistent among all regions (EUR > NAM > AFR), and individual admixture estimates vary broadly in each region. Though we did not find stratification in Costa Rica's population, gene admixture should be evaluated in future genetic studies of Costa Rica, especially for the Caribbean region, as it contains the largest proportion of African ancestry (30.9%).


Influence of Different Inertial Loads on Basic Training Variables During the Flywheel Squat Exercise.
To analyze the effects of different inertial loads on power production and power maintenance, as well as the number of sessions required for proper familiarization during the flywheel quarter-squat. Twenty-four high-level handball players attended 4 testing sessions consisting of 4 sets of 10 repetitions using 4 different inertial loads (0.025, 0.050, 0.075, and 0.100 kg·m2). In addition, a 5th set of 15 repetitions was performed. Both concentric and eccentric peak power and the eccentric:concentric ratio were recorded. The results showed the need to perform 3 sessions for a proper familiarization (ie, outcomes stabilization). The inertial load of 0.025 kg·m2 led to greater concentric peak power compared with the other inertial loads (from likely to most likely greater values). Both 0.025 and 0.050 kg·m2 inertial loads entailed greater eccentric peak power compared with 0.075 and 0.100 kg·m2 (most likely greater). Conversely, the 0.025-kg·m2 inertial load showed a lower eccentric:concentric ratio, presenting negative effects (most likely lower values) compared with the inertial loads of 0.050, 0.075, and 0.100 kg·m2. Participants were able to perform 5-12 repetitions per set without significant peak power output decrements. This study highlights the importance of performing at least 3 sessions to obtain a stable measure during flywheel squat exercise. Lower inertial loads (0.025 kg·m2) are the better option for eliciting high concentric peak power output values. In contrast, medium to high inertial loads are more appropriate to achieve greater eccentric overload values.