Genome Sequencing and Comparative Genomics Analysis Revealed Pathogenic Potential in Penicillium capsulatum as a Novel Fungal Pathogen Belonging to Eurotiales.
Penicillium capsulatum is a rare Penicillium species used in paper manufacturing, but recently it has been reported to cause invasive infection. To research the pathogenicity of the clinical Penicillium strain, we sequenced the genomes and transcriptomes of the clinical and environmental strains of P. capsulatum. Comparative analyses of these two P. capsulatum strains and close related strains belonging to Eurotiales were performed. The assembled genome sizes of P. capsulatum are approximately 34.4 Mbp in length and encode 11,080 predicted genes. The different isolates of P. capsulatum are highly similar, with the exception of several unique genes, INDELs or SNPs in the genes coding for glycosyl hydrolases, amino acid transporters and circumsporozoite protein. A phylogenomic analysis was performed based on the whole genome data of 38 strains belonging to Eurotiales. By comparing the whole genome sequences and the virulence-related genes from 20 important related species, including fungal pathogens and non-human pathogens belonging to Eurotiales, we found meaningful pathogenicity characteristics between P. capsulatum and its closely related species. Our research indicated that P. capsulatum may be a neglected opportunistic pathogen. This study is beneficial for mycologists, geneticists and epidemiologists to achieve a deeper understanding of the genetic basis of the role of P. capsulatum as a newly reported fungal pathogen.


Simple analytical model for low-frequency frequency-modulation noise of monolithic tunable lasers.
We employ simple analytical models to construct the entire frequency-modulation (FM)-noise spectrum of tunable semiconductor lasers. Many contributions to the laser FM noise can be clearly identified from the FM-noise spectrum, such as standard Weiner FM noise incorporating laser relaxation oscillation, excess FM noise due to thermal fluctuations, and carrier-induced refractive index fluctuations from stochastic carrier generation in the passive tuning sections. The contribution of the latter effect is identified by noting a correlation between part of the FM-noise spectrum with the FM-modulation response of the passive sections. We pay particular attention to the case of widely tunable lasers with three independent tuning sections, mainly the sampled-grating distributed Bragg reflector laser, and compare with that of a distributed feedback laser. The theoretical model is confirmed with experimental measurements, with the calculations of the important phase-error variance demonstrating excellent agreement.


Orbital-resolved partial charge transfer from the methoxy groups of substituted pyrenes in complexes with tetracyanoquinodimethane--a NEXAFS study.
It is demonstrated that the near-edge X-ray absorption fine structure (NEXAFS) provides a powerful local probe of functional groups in novel charge transfer (CT) compounds and their electronic properties. Microcrystals of tetra-/hexamethoxypyrene as donors with the strong acceptor tetracyano-p-quinodimethane (TMP/HMP-TCNQ) were grown by vapor diffusion. The oxygen and nitrogen K-edge spectra are spectroscopic fingerprints of the functional groups in the donor and acceptor moieties, respectively. The orbital selectivity of the NEXAFS pre-edge resonances allows us to precisely elucidate the participation of specific orbitals in the charge transfer process. Upon complex formation, the intensities of several resonances change substantially and a new resonance occurs in the oxygen K-edge spectrum. This gives evidence of a corresponding change of hybridization of specific orbitals in the functional groups of the donor (those derived from the frontier orbitals 2e and 6a(1) of the isolated methoxy group) and acceptor (orbitals b(3g), a(u), b(1g), and b(2u), all located at the cyano group) with π*-orbitals of the ring systems. Along with this intensity effect, the resonance positions associated with the oxygen K-edge (donor) and nitrogen K-edge (acceptor) shift to higher and lower photon energies in the complex, respectively. A calculation based on density functional theory qualitatively explains the experimental results. NEXAFS measurements shine light on the action of the functional groups and elucidate charge transfer on a submolecular level.


Age and the means of bypassing stasis influence the intrinsic subtype of immortalized human mammary epithelial cells.
Based on molecular features, breast cancers are grouped into intrinsic subtypes that have different prognoses and therapeutic response profiles. With increasing age, breast cancer incidence increases, with hormone receptor-positive and other luminal-like subtype tumors comprising a majority of cases. It is not known at what stage of tumor progression subtype specification occurs, nor how the process of aging affects the intrinsic subtype. We examined subtype markers in immortalized human mammary epithelial cell lines established following exposure of primary cultured cell strains to a two-step immortalization protocol that targets the two main barriers to immortality: stasis (stress-associated senescence) and replicative senescence. Cell lines derived from epithelial cells obtained from non-tumorous pre- and post-menopausal breast surgery tissues were compared. Additionally, comparisons were made between lines generated using two different genetic interventions to bypass stasis: transduction of either an shRNA that down-regulated p16(INK4A), or overexpressed constitutive active cyclin D1/CDK2. In all cases, the replicative senescence barrier was bypassed by transduction of c-Myc. Cells from all resulting immortal lines exhibited normal karyotypes. Immunofluorescence, flow cytometry, and gene expression analyses of lineage-specific markers were used to categorize the intrinsic subtypes of the immortalized lines. Bypassing stasis with p16 shRNA in young strains generated cell lines that were invariably basal-like, but the lines examined from older strains exhibited some luminal features such as keratin 19 and estrogen receptor expression. Overexpression of cyclin D1/CDK2 resulted in keratin 19 positive, luminal-like cell lines from both young and old strains, and the lines examined from older strains exhibited estrogen receptor expression. Thus age and the method of bypassing stasis independently influence the subtype of immortalized human mammary epithelial cells.


Dark and bright localized surface plasmons in nanocrosses.
A metallic nanocross geometry sustaining broad dipole and sharp higher order localized surface plasmon resonances is investigated. Spectral tunability is achieved by changing the cross arm length and the angle between the arms. The degree of rotational symmetry of the nanocross is varied by adding extra arms, changing the arm angle and shifting the arm intersection point. The particle's symmetry is shown to have a crucial influence on the plasmon coupling to incident radiation. Pronounced dipole, quadrupole, octupole and Fano resonances are observed in individual cross structures. Furthermore, the nanocross geometry proves to be a useful building block for coherently coupled plasmonic dimers and trimers where the reduced symmetry results in hybridized subradiant and superradiant modes and multiple Fano interferences. Finite difference time domain calculations of absorption and scattering cross-sections as well as charge density profiles are used to reveal the nature of the different plasmon modes. Experimental spectra for the discussed geometries support the calculations.


Looking beyond inhibition of VEGF/mTOR: emerging targets for renal cell carcinoma drug development.
The incidence rates of renal cell carcinoma (RCC) have continued to rise with 58,000 new cases in the United States. RCC has notoriously been refractory to traditional chemotherapeutic including radiation and cytokine therapies. The advent of the use of molecularly targeted therapies for RCC has significantly improved the standard of care. Yet, there still remains room for improvement as many of the current therapies are limited by acquired resistance and dosing restrictions due to toxicity. In this review we discuss many potential therapeutic targets that have been suggested for development as advancements are made in discovering the underlying molecular biology of RCC. Among the targets that discussed are additional targets within the well-established VHL/HIF axis, the PI3K/AKT/mTOR pathway, independent targets, and those identified by synthetic lethality screens.


Activation of the complement system by pathogenic fungi.
Fungi have been studied as prototype activators of the complement cascade since the early 1900s. More recently, attention has focused on the role of the complement system in the pathogenesis of fungal infections. The interactions of Cryptococcus neoformans and Candida albicans with the complement system are the most widely characterized; however, all pathogenic fungi examined to date have the ability to initiate the complement cascade. The molecular mechanisms for initiation and regulation of the complement cascade differ from one fungus to another, most likely reflecting differences in the structure of the outer layers of the cell wall. The molecular bases for such differences remain to be identified. Studies of mycoses in experimental animals with induced or congenital deficiencies in the complement system demonstrate that complement is an important innate system for control of fungal infection. Contributions to host resistance include opsonization and generation of inflammatory mediators. Inflammation induced by chemotactic products of the complement system may contribute to the pathogenesis of some fungal infections.


Extending the Use of the SCORS-G Composite Ratings in Assessing Level of Personality Organization.
The Social Cognition and Object Relations Scale-Global Rating Method (SCORS-G; Stein, Hilsenroth, Slavin-Mulford, & Pinsker, 2011 ; Westen, 1995b ) reliably measures the quality of object relations in narrative material. It assesses 8 dimensions (on a continuum from maladaptive to adaptive) that mediate interpersonal functioning. The 8 dimensions can be averaged to create a global or composite score to represent a person's overall object relational functioning. This study aimed to create levels of personality organization using the SCORS-G global score ratings of Thematic Apperception Test (TAT) narratives and to explore the construct validity of these levels using a multimethod approach (i.e., psychopathology, normal personality, and life-event data). Meaningful relationships were found between the SCORS-G level of personality organization and aspects of psychopathology (Personality Assessment Inventory; Morey, 1991 ), regulation and control (NEO Five-Factor Inventory; Costa & McCrae, 1989, 1992b ), and number of psychiatric hospitalizations, suicide attempts, and educational level. Overall, this study demonstrates the potential value of creating levels of personality organization (LPO) using the SCORS-G composite or global ratings as a supplement to the psychological assessment process and further highlights the utility of this measure in the field of personality assessment. Clinical and research-related implications as well as limitations are discussed.


Assessment of the retinal posterior pole in dominant optic atrophy by spectral-domain optical coherence tomography and microperimetry.
To assess posterior pole (PP) retinal structure in patients with genetically confirmed autosomal dominant optic atrophy (ADOA) using new spectral domain optical coherence tomography (SD-OCT) segmentation technology. To analyze retinal PP thickness in relation to retinal sensitivity data from microperimetry (MP) in ADOA patients. This prospective cross-sectional study included 11 patients with ADOA and 11 age-matched healthy subjects. All participants underwent both a "Posterior Pole" and "peripapillary RNFL (pRNFL)" scanning protocol using SD-OCT. Functional mapping of the PP was also performed using MP. A customized program was implemented in order to achieve accurate superimposition of MP sensitivity map onto SD-OCT map. The thickness of the PP different retinal layers and pRNFL was obtained and measured for each eye. Mean retinal sensitivity values and fixation stability were obtained and compared between ADOA patients and healthy subjects. Correlation analysis was performed on a point-to-point basis to evaluate the association between mean thickness and retinal sensitivity of each retinal layer. Total retinal thickness (TRT), Retinal Nerve Fiber Layer (RNFL), Ganglion Cell Layer (GCL), Inner Plexiform Layer (IPL), Inner Nuclear Layer (INL) and Inner Retinal Layers (IRL) at the posterior pole as well as pRNFL were significantly thinner in ADOA patients (P < 0.0001). On the contrary, the Outer Plexiform Layer (OPL) and the Outer Nuclear Layer (ONL) were significantly thicker in the ADOA group (P < 0.001). No significant differences were found in Retinal Pigment Epithelium (RPE) and Outer Retinal Layers (ORL) thickness between ADOA and controls. The average PP retinal sensitivity was significantly reduced in ADOA patients compared with controls (P < 0.001), as measured by microperimeter Nidek MP-1 (MP1). Fixation stability was significantly worse in the ADOA group (P = 0.01). The most severe sensitivity defects in ADOA patients were found at the level of the papillo-macular bundle (PMB). Inner retinal layers showed pathological changes in ADOA patients. In addition, the whole retinal PP (not only the PMB) was significantly altered in ADOA, both in terms of retinal thickness and sensitivity.


Characteristics of smokers and long-term changes in smoking behavior in consecutive patients with myocardial infarction.
The prognosis of patients with estabLished coronary artery improves if smoking is stopped. Still, about half of patients who suffer a myocardial infarction continue smoking after that event. In order to predict to whom additional support should be offered, various baseline characteristics were compared with smoking status at short-term and long-term follow-up. Demographics, medical history, presence of coronary risk factors, psychological determinants, and the clinical course were recorded in a group of 530 unselected consecutive patients who had been admitted with a myocardial infarction and were smoking. Patients who were smoking at admission, and who were alive at 4-year follow-up, were studied to relate smoking status and baseline characteristics. At 3 months, persistent smokers were younger than quitters, had shorter hospital stays, underwent revascularization procedures less often, smoked more cigarettes per day at baseline, and were more socially isolated. After 4 years, patients who stopped smoking had had a more serious myocardial infarction and had a lower displeasure score than those who continued smoking. Also, quitters received more support from their social environment. Although the majority of the patients try to stop smoking after a myocardial infarction, about half smokes after 4 years. In the future, special support should be offered to smokers who suffer myocardial infarction, especially to those whose psychosocial profiles are less favorable.


The tfdK gene product facilitates uptake of 2,4-dichlorophenoxyacetate by Ralstonia eutropha JMP134(pJP4).
Uptake of 2,4-dichlorophenoxyacetate (2,4-D) by Ralstonia eutropha JMP134(pJP4) was studied and shown to be an energy-dependent process. The uptake system was inducible with 2,4-D and followed saturation kinetics in a concentration range of up to 60 microM, implying the involvement of a protein in the transport process. We identified an open reading frame on plasmid pJP4, which was designated tfdK, whose translation product TfdK was highly hydrophobic and showed resemblance to transport proteins of the major facilitator superfamily. An interruption of the tfdK gene on plasmid pJP4 decimated 2,4-D uptake rates, which implies a role for TfdK in uptake. A tfdA mutant, which was blocked in the first step of 2,4-D metabolism, still took up 2,4-D. A mathematical model describing TfdK as an active transporter at low micromolar concentrations fitted the observed uptake data best.


Southampton needle sensation questionnaire: development and validation of a measure to gauge acupuncture needle sensation.
The specific sensations (deqi) generated during acupuncture are thought to be important for a positive clinical outcome, particularly when treating pain. It is important to be able to measure these sensations and discriminate between deqi and pain. A greater understanding of this will greatly aid researchers who wish to conduct mechanistic studies of acupuncture. Previous questionnaire designs failed to consider patient experience and, hence, may have been flawed. The aim of this study was to generate and validate a new sensation questionnaire, that was able to discriminate between pain and deqi, taking into account patient experience and expert opinions. The questionnaire was designed following qualitative interviews with patients, literature review, and consultation with experts. The questionnaire was piloted and then validated. It was successfully completed by 227 patients and analyzed using factor analysis and partial correlation. Patients were recruited via the physical therapy department at Southampton General Hospital and from private practice clinics in and around the Southampton area. The subjects were patients receiving acupuncture for any condition. Two (2) factors were clearly demonstrated: "Aching deqi" (7 items) which suggested deqi with pain and "Tingling deqi" (7 items) suggesting deqi only. One (1) item related solely to pain and 2 further items did not load into any factor. The final questionnaire is presented containing 17 items and is shown to be a valid, rigorous, soundly grounded, and patient-centered measure, capable of accurately recording deqi. We suggest that analysis should include a partial correlation of certain sensations against a pain visual analogue scale to ascertain how painful each sensation was, particularly if the questionnaire is to be used in a context in which pain and deqi need to be separated or their relationship clarified.


Determining life-stage groups and extrapolating nutrient intake values (NIVs).
The derivation of reference values in 11 current dietary reference standards is often based on methods of extrapolation or interpolation, but these are not consistent across reports. Such methods are frequently employed to derive nutrient intake values (NIVs) for infants and children owing to the paucity of relevant research data available. The most common method is to extrapolate values for children down from those of adults, employing a weight or metabolic factor and adjusting for growth. In some instances, values for young children are extrapolated up from infants, values for adults are extrapolated up from children, or values for older adults are extrapolated up from young adults. Extrapolation is employed to estimate not only nutrient requirement or adequate intake but also the upper tolerable levels of intake. Extrapolation methods may also form the basis of estimates of tissue deposition of nutrients during growth in children and for the maternal/fetal dyad in pregnancy with adjustments for metabolic efficiency. Likewise, recommended intakes during lactation are extrapolated from known secretion of the nutrient in milk with adjustments for bioavailability. For future dietary standards, a first priority is to obtain relevant scientific data using current methodology, such as stable isotope tracers, body composition analysis, and appropriate biomarkers, from which NIVs for each age group can be derived. Extrapolation to derive an NIV is only acceptable in the sheer absence of sound scientific data and must be modeled with a consistent approach. For the purpose of harmonization of dietary standards, we recommend the following approaches that should be clearly described in reports: standardization of age groups on a biological basis (growth and pubertal stages) with consideration of relevant developmental milestones throughout childhood; application of internationally accepted standards for growth, body size, body composition, fetal and maternal nutrient accretion in pregnancy, and milk composition; and inclusion of appropriate adjustments (metabolic efficiency, weight change, or physical activity).


Histone deacetylases play distinct roles in telomeric VSG expression site silencing in African trypanosomes.
African trypanosomes evade the host immune response through antigenic variation, which is achieved by periodically expressing different variant surface glycoproteins (VSGs). VSG expression is monoallelic such that only one of approximately 15 telomeric VSG expression sites (ESs) is transcribed at a time. Epigenetic regulation is involved in VSG control but our understanding of the mechanisms involved remains incomplete. Histone deacetylases are potential drug targets for diseases caused by protozoan parasites. Here, using recombinant expression we show that the essential Trypanosoma brucei deacetylases, DAC1 (class I) and DAC3 (class II) display histone deacetylase activity. Both DAC1 and DAC3 are nuclear proteins in the bloodstream stage parasite, while only DAC3 remains concentrated in the nucleus in insect-stage cells. Consistent with developmentally regulated localization, DAC1 antagonizes SIR2rp1-dependent telomeric silencing only in the bloodstream form, indicating a conserved role in the control of silent chromatin domains. In contrast, DAC3 is specifically required for silencing at VSG ES promoters in both bloodstream and insect-stage cells. We conclude that DAC1 and DAC3 play distinct roles in subtelomeric gene silencing and that DAC3 represents the first readily druggable target linked to VSG ES control in the African trypanosome.


Effect of a single inflation of the lungs on oxygenation during total extracorporeal carbon dioxide removal in experimental respiratory distress syndrome.
Respiratory distress syndrome (RDS) was modelled in rabbits using pulmonary lavage to remove surfactant. The stability of the resulting pressure-volume hysteresis of the lungs in vivo was studied with the aid of whole-body plethysmography during apnoeic oxygenation made possible by total extracorporeal carbon dioxide removal. Systemic oxygen delivery was measured as a function of the constant airway pressure during apnoea. In 6 subjects a single brief inflation of the lungs to 3.5 kPa resulted in a doubling of both expired lung volume (volume above functional residual capacity) and arterial oxygen partial pressure at an airway pressure of 0.65 kPa. These rises were well maintained for 40 min following the inflation. In a further 6 subjects with RDS single inflations permitted optimum systemic oxygen transport to occur at the low airway pressure of 0.3 kPa, similar to the optimum airway pressure in 6 healthy control subjects. Where pressure-volume hysteresis is present in RDS it can be exploited during apnoeic oxygenation, and probably during high frequency ventilation, to improve oxygenation by the use of infrequent single inflations of the lungs.


Multifactorial modulation of binding and dissociation kinetics on two-dimensional DNA nanostructures.
We use single-particle fluorescence resonance energy transfer (FRET) to show that organizing oligonucleotide probes into patterned two-dimensional arrays on DNA origami nanopegboards significantly alters the kinetics and thermodynamics of their hybridization with complementary targets in solution. By systematically varying the spacing of probes, we demonstrate that the rate of dissociation of a target is reduced by an order of magnitude in the densest probe arrays. The rate of target binding is reduced less dramatically, but to a greater extent than reported previously for one-dimensional probe arrays. By additionally varying target sequence and buffer composition, we provide evidence for two distinct mechanisms for the markedly slowed dissociation: direct hopping of targets between adjacent sequence-matched probes and nonsequence-specific, salt-bridged, and thus attractive electrostatic interactions with the DNA origami pegboard. This kinetic behavior varies little between individual copies of a given array design and will have significant impact on hybridization measurements and overall performance of DNA nanodevices as well as microarrays.


Cannabidiol treatment in an adolescent with multiple substance abuse, social anxiety and depression.
In this report, we present a case of a 16,9-year-old patient with multiple substance use disorder (cannabis, MDMA, cocaine, ecstacy), severe depression, social phobia and narcissistic personality disorder.We administered Cannabidiol (CBD) capsules in different dosages (starting dosage 100 mg up to 600 mg over 8 weeks) after unsuccessful treatment with antidepressants.CBD was a safe and well tolerated medication for this patient. Upon treatment with CBD and cessation of the antidepressant medication, the patient improved regarding depressive as well as anxiety symptoms including simple phobias and symptoms of paranoia and dissociation. Furthermore, the patient quit abusing illegal drugs including THC without showing withdrawal symptoms. This is the first report of CBD medication in a patient with multiple substance use disorder with a positive outcome.Until today it is not clear if CBD holds promise as a therapeutic option in substance use disorder as RCTs are lacking, but in this single case the substance seems to work in various domains.


TNF-Alpha Promotes Invasion and Metastasis via NF-Kappa B Pathway in Oral Squamous Cell Carcinoma.
BACKGROUND Recent evidence reveals that the inflammatory microenvironment is associated with tumor migration, invasion, and metastasis. Tumor necrosis factor-α (TNF-α) play a vital role in regulation of the inflammatory process in tumor development. Nuclear factor-kappa B (NF-κB) is one of the key transcription factors which regulate processes in tumor promotion. The aim of this study was to explore the role of NF-κB on the invasion and migration of oral squamous cell carcinoma (OSCC). MATERIAL AND METHODS The IKKβ and p65 mRNA and protein levels were determined by quantitative RT-PCR and western blot. Wound scratch healing assays and transwell migration assays were used to evaluate the effect of TNF-α and BAY11-7082 on the migration of the OSCC cell lines (HN4, HN6, and CAL27). RESULTS We observed a significant increase of the expression level of IKKβ and p65 in OSCC cells from the experimental group at 24 h, 48 h, and 72 h after TNF-α stimulation. Invasion and metastasis of OSCC cells was obviously improved after the TNF-α stimulation. Invasion and metastasis ability of OSCC cells was inhibited in the suppression group, and no significant changes were observed in expression level of IKKβ and p65 after the use of BAY11-7082. CONCLUSIONS Our results suggest that TNF-α enhances the invasion and metastasis ability of OSCC cells via the NF-κB signaling pathway.


Dynamic holographic 3-D image projection.
The display of dynamic holographic images is possible by computing the hologram of objects in a three-dimensional scene and then transcribing the two-dimensional digital hologram onto a digital micromirror system illuminated with coherent light. Proof-of-principle instruments that reconstruct real and virtual images are described. The underlying process, its characteristics, limitations and utility are discussed.


Osteoarthritis: Pathophysiology, Prevalence, Risk Factors, and Exercise for Reducing Pain and Disability.
Osteoarthritis (OA) is a disorder involving deterioration of articular cartilage and underlying bone and is associated with symptoms of pain and disability. The incidence of OA in the military increased over the period 2000 to 2012 and was the first or second leading cause of medical separations in this period. Risk factors for OA include older age, black race, genetics, higher body mass index, prior knee injury, and excessive joint loading. Animal studies indicate that moderate exercise can assist in maintaining normal cartilage, and individuals performing moderate levels of exercise show little evidence of OA. There is considerable evidence that among individuals who develop OA, moderate and regular exercise can reduce pain and disability. There is no firm evidence that any particular mode of exercise (e.g., aerobic training, resistance exercise) is more effective than another for reducing OA-related pain and disability, but limited research suggests that exercise should be lifelong and conducted at least three times per week for optimal effects.


Diffuse malignant pleural mesothelioma: Part I. An overview of diagnosis, staging, and treatment options.
Diffuse malignant mesothelioma is an uncommon, aggressive malignancy that occurs most often in the pleura of the lung. This article reviews the risk factors, incidence, signs, symptoms, diagnosis, staging, treatment options, and follow-up care of diffuse malignant pleural mesothelioma (DMPM). Curative approaches for treating DMPM are limited, and survival rates rarely exceed two years. Treatments such as surgery, chemotherapy, and radiotherapy have shown limited benefit in improving survival. Extrapleural pneumonectomy combined with multimodal treatments provides a potentially curative approach, and newer efforts in multimodality therapy are promising. Clinical trials utilizing intrapleural chemo-photodynamic, gene, and immunotherapies currently are under way.


Review: Cav2.3 R-type Voltage-Gated Ca2+ Channels - Functional Implications in Convulsive and Non-convulsive Seizure Activity.
Researchers have gained substantial insight into mechanisms of synaptic transmission, hyperexcitability, excitotoxicity and neurodegeneration within the last decades. Voltage-gated Ca2+ channels are of central relevance in these processes. In particular, they are key elements in the etiopathogenesis of numerous seizure types and epilepsies. Earlier studies predominantly targeted on Cav2.1 P/Q-type and Cav3.2 T-type Ca2+ channels relevant for absence epileptogenesis. Recent findings bring other channels entities more into focus such as the Cav2.3 R-type Ca2+ channel which exhibits an intriguing role in ictogenesis and seizure propagation. Cav2.3 R-type voltage gated Ca2+ channels (VGCC) emerged to be important factors in the pathogenesis of absence epilepsy, human juvenile myoclonic epilepsy (JME), and cellular epileptiform activity, e.g. in CA1 neurons. They also serve as potential target for various antiepileptic drugs, such as lamotrigine and topiramate. This review provides a summary of structure, function and pharmacology of VGCCs and their fundamental role in cellular Ca2+ homeostasis. We elaborate the unique modulatory properties of Cav2.3 R-type Ca2+ channels and point to recent findings in the proictogenic and proneuroapoptotic role of Cav2.3 R-type VGCCs in generalized convulsive tonic-clonic and complex-partial hippocampal seizures and its role in non-convulsive absence like seizure activity. Development of novel Cav2.3 specific modulators can be effective in the pharmacological treatment of epilepsies and other neurological disorders.


Pollen transmission of asparagus virus 2 (AV-2) may facilitate mixed infection by two AV-2 isolates in asparagus plants.
Asparagus virus 2 (AV-2) is a member of the genus Ilarvirus and thought to induce the asparagus decline syndrome. AV-2 is known to be transmitted by seed, and the possibility of pollen transmission was proposed 25 years ago but not verified. In AV-2 sequence analyses, we have unexpectedly found mixed infection by two distinct AV-2 isolates in two asparagus plants. Because mixed infections by two related viruses are normally prevented by cross protection, we suspected that pollen transmission of AV-2 is involved in mixed infection. Immunohistochemical analyses and in situ hybridization using AV-2-infected tobacco plants revealed that AV-2 was localized in the meristem and associated with pollen grains. To experimentally produce a mixed infection via pollen transmission, two Nicotiana benthamiana plants that were infected with each of two AV-2 isolates were crossed. Derived cleaved-amplified polymorphic sequence analysis identified each AV-2 isolate in the progeny seedlings, suggesting that pollen transmission could indeed result in a mixed infection, at least in N. benthamiana.


Protocol to develop sustainable day care for children aged 1-4 years in disadvantaged urban communities in Dhaka, Bangladesh.
Lack of safe, stimulating and health-promoting environments for children under-5 hinders their physical, social and cognitive development, known as early childhood development (ECD). Improving ECD impacts on children, and can improve educational attainment for girls, who often care for younger siblings, and employment prospects for mothers. Developing and evaluating the impacts of ECD programmes within childcare needs to assess a range of social, health, educational and economic impacts, including women's empowerment.Children living in slums are at high risk of poor early development and holistic, sustainable interventions are needed to address ECD in these contexts. This study will be undertaken in Dhaka, Bangladesh, a city where over 8.5 million inhabitants live in slums. In collaboration with government, non-governmental organisations and communities, we are developing and testing a sustainable day-care model for low-income communities in Dhaka. A sequential mixed methods approach is being used in the study, with qualitative work exploring quantitative findings. Two hundred households with children under-5 will be surveyed to determine day-care needs and to assess ECD (parent-reported and direct assessment). The feasibility of four ECD measuring tools Caregiver-Reported Early Development Index, Measuring Early Learning Quality and Outcomes, The Early Human Capability Index and International Development and Early Learning Assessment will be assessed quantitatively and qualitatively. Qualitative methods will help understand demand and perceptions of day care while mothers work. Participatory action research will be used to develop a locally appropriate and potentially sustainable model of day care for under-5 children. A ward in the south of Dhaka has been selected for the study as this typifies communities with slum and non-slum households living next to each other, allowing us to explore potential for better-off household to subsidise day care for poorer households. Findings will be published and inform decision makers at the national, regional and the local actors in order to embed the study into the policy and practice on childcare and ECD. Ethical approvals for this study were obtained from the School of Medicine Research Ethics Committee at the Faculty of Medicine and Health at the University of Leeds (ref: MREC16-106) and the Bangladesh Medical Research Council (ref: BMRCAIREC/20 I 6-20 I 9 I 250).


Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions.
Mast cells are primary effectors in allergic reactions, and may have important roles in disease by secreting histamine and various inflammatory and immunomodulatory substances. Although they are classically activated by immunoglobulin (Ig)E antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. The pathogenic roles of these substances have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, Mrgprb2, the orthologue of the human G-protein-coupled receptor MRGPRX2. Secretagogue-induced histamine release, inflammation and airway contraction are abolished in Mrgprb2-null mutant mice. Furthermore, we show that most classes of US Food and Drug Administration (FDA)-approved peptidergic drugs associated with allergic-type injection-site reactions also activate Mrgprb2 and MRGPRX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that Mrgprb2 and MRGPRX2 are targets of many small-molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice; and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.


Can, and should, behavioural neuroscience influence public policy?
Recent years have seen enormous demand amongst policy makers for new insights from the behavioural sciences, especially neuroscience. This demand is matched by an increasing willingness on behalf of behavioural scientists to translate the policy implications of their work. But can neuroscience really help shape the governance of a nation? Or does this represent growing misuse of neuroscience to attach scientific authority to policy, plus a clutch of neuroscientists trying to overstate their findings for a taste of power?


Evaluation of adherence to current guidelines for treatment of hyperlipidemia in adults in an outpatient setting.
Adherence to the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol guideline at an outpatient clinic was evaluated. This retrospective chart review study was conducted from December 1, 2013, through November 30, 2014, at an urban outpatient clinic. Estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk was calculated based on the pooled cohort equation for all patients. Patients were categorized into one of four statin-benefit groups, in descending order of ASCVD risk. The recommended intensity of a statin and the therapeutic response were determined for each patient. If statin therapy was indicated, patients were assigned to the moderate-intensity, moderate- or high-intensity, or high-intensity group according to guideline recommendations. These guideline-recommended statin intensities were then compared to the patient's prescribed statin to determine guideline concordance. Therapeutic response, expressed as the percent decrease in low-density lipoprotein cholesterol, was determined based on recommended statin intensity. A total of 255 patients were initiated on statin therapy; 193 were included for data analysis. Overall adherence to the guideline was 65.8%, with the highest rate in the group of patients with the lowest risk of ASCVD (97.8%). The group with the lowest rate of adherence to recommendations was patients with clinical ASCVD (46.9%). Only 31.6% of patients had a follow-up lipid panel performed, and even fewer achieved a therapeutic response. A majority of patients were initiated on the appropriate intensity of statin therapy according to the ACC/AHA cholesterol guideline. Of the small number of patients who had follow-up visits, few achieved a therapeutic response based on their prescribed statin therapy.


Co-occurring nonnative woody shrubs have additive and non-additive soil legacies.
To maximize limited conservation funds and prioritize management projects that are likely to succeed, accurate assessment of invasive nonnative species impacts is essential. A common challenge to prioritization is a limited knowledge of the difference between the impacts of a single nonnative species compared to the impacts of nonnative species when they co-occur, and in particular predicting when impacts of co-occurring nonnative species will be non-additive. Understanding non-additivity is important for management decisions because the management of only one co-occurring invader will not necessarily lead to a predictable reduction in the impact or growth of the other nonnative plant. Nonnative plants are frequently associated with changes in soil biotic and abiotic characteristics, which lead to plant-soil interactions that influence the performance of other species grown in those soils. Whether co-occurring nonnative plants alter soil properties additively or non-additively relative to their effects on soils when they grow in monoculture is rarely addressed. We use a greenhouse plant-soil feedback experiment to test for non-additive soil impacts of two common invasive nonnative woody shrubs, Lonicera maackii and Ligustrum sinense, in deciduous forests of the southeastern United States. We measured the performance of each nonnative shrub, a native herbaceous community, and a nonnative woody vine in soils conditioned by each shrub singly or together in polyculture. Soils conditioned by both nonnative shrubs had non-additive impacts on native and nonnative performance. Root mass of the native herbaceous community was 1.5 times lower and the root mass of the nonnative L. sinense was 1.8 times higher in soils conditioned by both L. maackii and L. sinense than expected based upon growth in soils conditioned by either shrub singly. This result indicates that when these two nonnative shrubs co-occur, their influence on soils disproportionally favors persistence of the nonnative L. sinense relative to this native herbaceous community, and could provide an explanation of why native species abundance is frequently depressed in these communities. Additionally, the difference between native and nonnative performance demonstrates that invasive impact studies focusing on the impact only of single species can be insufficient for determining the impact of co-occurring invasive plant species.


Detection of myxoma viruses encoding a defective M135R gene from clinical cases of myxomatosis; possible implications for the role of the M135R protein as a virulence factor.
Myxoma virus is a member of the Poxviridae and causes disease in European rabbits. Laboratory confirmation of the clinical disease, which occurs in the autumn of most years in Denmark, has been achieved previously using antigen ELISA and electron microscopy. An unusually large number of clinically suspected cases of myxomatosis were observed in Denmark during 2007. Myxoma virus DNA was detected, using a new real time PCR assay which targets the M029L gene, in over 70% of the clinical samples submitted for laboratory confirmation. Unexpectedly, further analysis revealed that a high proportion of these viral DNA preparations contained a frame-shift mutation within the M135R gene that has previously been identified as a virulence factor. This frame-shift mutation results in expression of a greatly truncated product. The same frame-shift mutation has also been found recently within an avirulent strain of myxoma virus (6918). However, three other frame-shift mutations found in this strain (in the genes M009L, M036L and M148R) were not shared with the Danish viruses but a single nucleotide deletion in the M138R/M139R intergenic region was a common feature. It appears that expression of the full-length myxoma virus M135R protein is not required for virulence in rabbits. Hence, the frame-shift mutation in the M135R gene in the nonpathogenic 6918 virus strain is not sufficient to explain the attenuation of this myxoma virus but one/some of the other frame-shift mutations alone or in conjunction with one/some of the thirty two amino acid substitutions must also contribute. The real time PCR assay for myxoma virus is a useful diagnostic tool for laboratory confirmation of suspected cases of myxomatosis.


New trends in hepatitis C management.
Approximately 2% of the world population is infected by the hepatitis C virus (HCV). The incidence of new HCV infections is decreasing today, with new contaminations limited to specific risk groups: intravenous drug users and homosexual men. On the other hand, morbidity and mortality due to infections that occurred in the late 1970s and early 1980s are rising quite substantially. Approximately 20% of patients infected by HCV develop cirrhosis in about 20 years and every year 5% of them develop hepatocellular carcinoma (HCC). Current epidemiologic models suggest that the incidence of HCC and of the mortality associated with chronic HCV infection will continue to increase through 2015, a finding consisting with the perception of liver specialists today.


EEG applications for sport and performance.
One approach to understanding processes that underlie skilled performing has been to study electrical brain activity using electroencephalography (EEG). A notorious problem with EEG is that genuine cerebral data is often contaminated by artifacts of non-cerebral origin. Unfortunately, such artifacts tend to be exacerbated when the subject is in motion, meaning that obtaining reliable data during exercise is inherently problematic. These problems may explain the limited number of studies using EEG as a methodological tool in the sports sciences. This paper discusses how empirical studies have generally tackled the problem of movement artifact by adopting alternative paradigms which avoid recording during actual physical exertion. Moreover, the specific challenges that motion presents to obtaining reliable EEG data are discussed along with practical and computational techniques to confront these challenges. Finally, as EEG recording in sports is often underpinned by a desire to optimise performance, a brief review of EEG-biofeedback and peak performance studies is also presented. A knowledge of practical aspects of EEG recording along with the advent of new technology and increasingly sophisticated processing models offer a promising approach to minimising, if perhaps not entirely circumventing, the problem of obtaining reliable EEG data during motion.


The labor curve of the grand multipara: does progress of labor continue to improve with additional childbearing?
Our purpose was to test the hypothesis that progress of labor slows as parity exceeds 4 by comparing labor curves of grand multiparous women (para 5 and over) (GMs) with those of nulliparous and lower-parity multiparous women. Retrospective cohorts of spontaneously laboring, vertex-presenting, term GMs who were admitted to two medical centers during the period from January 1990 through June 1995 were randomly computer-matched to a nulliparous and a lower-parity multiparous control subject, matched for age, hospital, and year of delivery. Cervical examination data were graphed retrospectively from the time of full dilatation. Curves were compared by pairwise likelihood ratio tests, by using a random effects model to adjust for obstetric interventions, with significance set at P <.05. Pregnancies in 1095 GMs, 1174 lower-parity multiparous women, and 908 nulliparous women were studied. GMs exhibit a longer initial phase of labor than either nulliparous women or lower-parity multiparous women, begin to dilate rapidly at a greater dilatation than nulliparous women, and experience acceleration of labor at a rate no faster than lower-parity multiparous women. The average labor curve of GMs resembles that of nulliparous women before dilatation of 4 cm is attained, then transitions to the typical curve of the lower-parity multiparous women until dilatation of 6 cm is attained and thereafter is indistinguishable from that of the lower-parity multiparous women (P <.001). Once parity exceeds 4, progress of labor slows. "Poor progress" beyond dilatation of 4 cm should not be considered abnormal for a GM, because she is likely still in the latent phase until dilatation of 6 cm is attained. Nor should she be expected to progress through her active phase any faster than lower-parity multiparous women.


Variability of cardiovascular and plasma noradrenaline responses to sustained isometric contraction in normal human subjects.
1. Eight healthy adult males underwent three sustained isometric contractions at 30% of maximal voluntary contraction for 3 min, within a 9 day period. 2. The study focuses on the inter-individual and day-to-day intra-individual variability of cardiovascular and plasma noradrenaline responses to sustained isometric contraction. 3. The results of this study indicate that inter-individual variability is generally greater than intra-individual variability. Diastolic blood pressure was the most sensitive as well as the least variable cardiovascular parameter measured. 4. The variability of plasma noradrenaline levels in both the basal and the stimulated state was high. The present study suggests that it is preferable to determine the 'true' noradrenaline peak after the release of handgrip, as this is associated with a lower variability than the plasma noradrenaline peak taken at the time of the release of handgrip.


Immunotherapy of patients with advanced cancer using tumor-infiltrating lymphocytes and recombinant interleukin-2: a pilot study.
Clinical investigations using the adoptive transfer of lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) to treat patients with advanced cancer have yielded encouraging results. We have thus sought ways to enhance the effectiveness of adoptive immunotherapy while minimizing its toxic side effects. Murine experiments have identified tumor-infiltrating lymphocytes (TIL) as killer cells more effective than LAK cells and less dependent on adjunctive systemically administered IL-2 to mediate antitumor effects. Accordingly, we performed a pilot protocol to investigate the feasibility and practicality of administering IL-2-expanded TIL to humans with metastatic cancers. Twelve patients, including six with melanoma, four with renal cell carcinoma, one with breast carcinoma, and one with colon carcinoma, were treated with varying doses and combinations of TIL (8.0 X 10(9) to 2.3 X 10(11) cells per patient), IL-2 (10,000 to 100,000 U/kg three times daily to dose-limiting toxicity), and cyclophosphamide (CPM) (up to 50 mg/kg). Two partial responses (PR) to therapy were observed: pulmonary and mediastinal masses regressed in a patient with melanoma, and a lymph node mass regressed in a patient with renal cell carcinoma. One additional patient with breast cancer experienced a partial regression of disease in lymph nodal and cutaneous sites with complete elimination of malignant cells from a pleural effusion, although cutaneous disease recurred at 4 weeks. The toxicities of therapy were similar to those ascribed to IL-2; no toxic effects were directly attributable to TIL infusions. In five of six melanoma patients, TIL demonstrated lytic activity specific for the autologous tumor target in short-term chromium-release assays, distinct from the nonspecific lytic activity characteristic of LAK cells. This study represents an initial attempt to identify and use lymphocyte subsets with enhanced tumoricidal capacity in the adoptive immunotherapy of human malignancies.


Effects of Yoga in Patients with Chronic Heart Failure: A Meta-Analysis.
The use of yoga as an effective cardiac rehabilitation in patients with chronic heart failure (CHF) remains controversial. We performed a meta-analysis to examine the effects of yoga on exercise capacity and health-related quality of life (HRQOL) in patients with CHF. Methods: We searched MEDLINE, Cochrane Central Register of Controlled Trials, Excerpta Medica database, LILACS, Physiotherapy Evidence Database, The Scientific Electronic Library Online, and Cumulative Index to Nursing and Allied Health (from the earliest date available to December 2013) for randomized controlled trials (RCTs) examining the effects of yoga versus exercise and/or of yoga versus control on exercise capacity (peakVO2) and quality-of-life (HRQOL) in CHF. Two reviewers selected studies independently. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated, and heterogeneity was assessed using the I2 test. Two studies met the selection criteria (total: 30 yoga and 29 control patients). The results suggested that yoga compared with control had a positive impact on peak VO2 and HRQOL. Peak VO2, WMD (3.87 95% CI: 1.95 to 5.80), and global HRQOL standardized mean differences (-12.46 95% CI: -22.49 to -2.43) improved in the yoga group compared to the control group. Yoga enhances peak VO2 and HRQOL in patients with CHF and could be considered for inclusion in cardiac rehabilitation programs. Larger RCTs are required to further investigate the effects of yoga in patients with CHF.


Urokinase-type Plasminogen Activator Promotes Synaptic Recovery in the Ischemic Brain.
Synaptic dysfunction underlies the development of neurological impairment following an acute ischemic stroke. Unfortunately, to this date there is no therapeutic approach to protect and repair the synapse that has suffered an ischemic injury. However, recent research with in vitro models of hypoxia, in vivo models of cerebral ischemia and different neuroradiological techniques has revealed that during the recovery phase from a hypoxic injury neurons release the serine proteinase urokinase-type plasminogen activator (uPA) and astrocytes recruit its receptor (uPAR) to their plasma membrane; and that binding of neuronal uPA to astrocytic uPAR promotes the recovery of the "tripartite synapse" that has suffered an acute ischemic injury. The translational relevance of these findings is underscored by the fact that intravenous treatment with recombinant uPA promotes synaptic recovery and functional improvement following an acute ischemic stroke.


IL-12 prevents mortality in mice infected with Histoplasma capsulatum through induction of IFN-gamma.
Histoplasma capsulatum is a pathogenic fungus found in discrete geographic locations throughout the world. The fungus invades the reticuloendothelial organs such as the spleen and liver of immunocompetent hosts where it is usually controlled. However, in individuals with immune deficiency, histoplasmosis is a severe and potentially fatal disease. Resistance to this infection is due primarily to a cellular immune response mediated by T cells and macrophages. Moreover, IFN-gamma is critical in activating macrophages to kill the organism. Herein we study the regulation of cytokine induction in mice infected with H. capsulatum and the effects of IL-12 in the course of infection. Mice infected with H. capsulatum and treated with neutralizing Abs to IFN-gamma, TNF-alpha, or IL-12 experienced accelerated mortality, indicating that endogenous production of these cytokines plays an important role in response to infection. In contrast, mice treated with IL-12 or a neutralizing Ab to IL-4 at the initiation of infection had substantially diminished mortality. Moreover, mice infected and treated with IL-12 show a two- to threefold increase in the amount of IFN-gamma following in vitro stimulation with specific H. capsulatum Ag compared with the control infected mice. The protective effect of IL-12 could be abrogated if a neutralizing Ab to IFN-gamma was given at the same time, demonstrating that the role of IL-12 in protection was mediated by IFN-gamma. Additionally, infected mice treated with IL-12 had a severalfold decrease in the colony counts of H. capsulatum in spleen cells after 5 days of infection as compared with control animals. Lastly, spleen cells from infected animals treated with IL-12 showed a striking decrease in their proliferative response to mitogen or H. capsulatum Ag. Responses could be restored by adding inhibitors of IFN-gamma or of nitric oxide to the in vitro cultures. The above observations suggest that IL-12 may be useful in immunologic intervention against this opportunistic pathogen.


What happens to your brain on the way to Mars.
As NASA prepares for the first manned spaceflight to Mars, questions have surfaced concerning the potential for increased risks associated with exposure to the spectrum of highly energetic nuclei that comprise galactic cosmic rays. Animal models have revealed an unexpected sensitivity of mature neurons in the brain to charged particles found in space. Astronaut autonomy during long-term space travel is particularly critical as is the need to properly manage planned and unanticipated events, activities that could be compromised by accumulating particle traversals through the brain. Using mice subjected to space-relevant fluences of charged particles, we show significant cortical- and hippocampal-based performance decrements 6 weeks after acute exposure. Animals manifesting cognitive decrements exhibited marked and persistent radiation-induced reductions in dendritic complexity and spine density along medial prefrontal cortical neurons known to mediate neurotransmission specifically interrogated by our behavioral tasks. Significant increases in postsynaptic density protein 95 (PSD-95) revealed major radiation-induced alterations in synaptic integrity. Impaired behavioral performance of individual animals correlated significantly with reduced spine density and trended with increased synaptic puncta, thereby providing quantitative measures of risk for developing cognitive decrements. Our data indicate an unexpected and unique susceptibility of the central nervous system to space radiation exposure, and argue that the underlying radiation sensitivity of delicate neuronal structure may well predispose astronauts to unintended mission-critical performance decrements and/or longer-term neurocognitive sequelae.


Using complexity theory to build interventions that improve health care delivery in primary care.
Previous observational research confirms abundant variation in primary care practice. While variation is sometimes viewed as problematic, its presence may also be highly informative in uncovering ways to enhance health care delivery when it represents unique adaptations to the values and needs of people within the practice and interactions with the local community and health care system. We describe a theoretical perspective for use in developing interventions to improve care that acknowledges the uniqueness of primary care practices and encourages flexibility in the form of intervention implementation, while maintaining fidelity to its essential functions.


Toll-like receptor-mediated tumor necrosis factor and interleukin-10 production differ during systemic inflammation.
Major trauma is associated with a decreased capacity of patients' leukocytes to produce proinflammatory cytokines on in vitro stimulation. We studied leukocytes from 48 patients with trauma and showed that this hyporeactivity was restricted to gram-negative bacteria, Escherichia coli endotoxin, and unmethylated bacterial DNA, whereas Leptospira interrogans endotoxin-induced tumor necrosis factor production was similar to that observed with healthy donors. As well, tumor necrosis factor and interleukin-6 production in response to gram-positive bacteria was not altered. The expression of toll-like receptor (TLR) 2 was not reduced on patients' monocytes as compared with healthy control subjects, whereas that of TLR4 was reduced. However, the hyporeactivity to gram-negative bacteria and E. coli endotoxin cannot be fully explained by the downregulation of TLR4. Indeed, unlike proinflammatory cytokines, after stimulation with these microbial products the release of antiinflammatory cytokines was increased as compared with healthy control subjects. The increased interleukin-10 production was analyzed in terms of intracellular signaling in peripheral blood mononuclear cells from patients with trauma: our results suggest the involvement of p38 mitogen-activated protein kinase, Sp-1 transcription factor, heterotrimeric Gi protein, and phosphatidylinositol-3'-kinase. In conclusion, the immunodysregulation described for patients with trauma is not a generalized phenomenon but depends on the stimulus and the signaling pathway.


Useful Effects of Melatonin in Peripheral Nerve Injury and Development of the Nervous System.
This review summarizes the role of melatonin (MLT) in defense against toxic-free radicals and its novel effects in the development of the nervous system, and the effect of endogenously produced and exogenously administered MLT in reducing the degree of tissue and nerve injuries. MLT was recently reported to be an effective free radical scavenger and antioxidant. Since endogenous MLT levels fall significantly in senility, these findings imply that the loss of this antioxidant could contribute to the incidence or severity of some age-related neurodegenerative diseases. Considering the high efficacy of MLT in overcoming much of the injury not only to the peripheral nerve but also to other organs, clinical trials for this purpose should be seriously considered.


Effects of dry needling on gait and muscle tone in Parkinson's disease: a randomized clinical trial.
Alterations in gait and muscular rigidity are common and disabling in persons with Parkinson's disease (PD). The aim of this study was to determine whether a single dry needling (DN) session can promote changes in gait and muscle tone in the lower extremities as well as in the evolution of the disease in persons with PD. A randomized double-blind clinical trial was designed. Participants were randomly assigned to an intervention group (IG) that received a session of DN over the semitendinosus, medial gastrocnemius, soleus and rectus femoris muscles, or to a control group (CG) that received a session of sham DN in the same muscles. The effects of DN were assessed using the timed up and go test (TUG), 10 meter walk test (10MWT), 6 minute walk test (6MWT) and myotonometry before, immediately after, and 7 days after the intervention. Thirty-three participants were analyzed aged 69.9 ± 7.2 years (mean ± SD; 39% female). There were no significant differences between the IG and CG for any outcomes. Significant differences were observed when comparing the Pre and Follow-up values in the IG for functional mobility of gait in the TUG (p = 0.049), gait speed in the 10MWT (p = 0.041) and muscle tone in the lower extremities by myotonometry (frequency (p = 0.027) and stiffness (p = 0.013)). By comparison, there were no significant within-group differences in the CG. A single session of DN had no measurable benefit compared to a single session of sham DN. Within-group changes in the IG suggested improvements in functional mobility of gait and gait speed, as well as changes in the muscle tone in the lower extremities of PD patients, which could be worthy of further exploration by future research.


Atypical presentation of an advanced obstructive biliary cancer without jaundice.
Female, 60 FINAL DIAGNOSIS: Cholangiocarcinoma Symptoms: Abdominal pain • abdominal discomfort - Clinical Procedure: - Specialty: Oncology. Unusual natural history/clinical course. Cholangiocarcinoma remains to be a challenging case to diagnose and manage as it usually presents in advanced stage and survival rate remains dismal despite the medical breakthroughs. It is usually classified as intrahepatic, perihilar or distal tumor which can lead to bile duct obstruction causing sluggish flow of bile through the biliary tract and promoting increased absorption of bilirubin, bile acids and bile salts into systemic circulation accounting for the occurrence of jaundice, dark-colored urine and generalized pruritus. It usually becomes symptomatic when the tumor has significantly obstructed the biliary drainage causing painless jaundice and deranged liver function with cholestatic pattern. Jaundice occurs in 90% of the cases when the tumor has obstructed the biliary drainage system. A markedly dilated gallbladder as initial presenting feature in the absence of other typical obstructive clinical manifestations of an advanced stage of the cholangiocarcinoma is rare. This case report presents an atypical case of an elderly woman who presented with advanced metastatic ductal cholangiocarcinoma with markedly dilated gallbladder and liver mass without other clinical manifestations and laboratory evidence of cholestatic jaundice. The mere presence of Courvoisier's sign, even in the absence of other signs of biliary obstruction, could be suggestive of advanced neoplastic process along the biliary tract. Laboratory evidence of cholestasis might lag behind the clinical severity of the biliary obstruction in cholangiocarcinoma.


Cognitive assessment of dyslexic students in higher education.
Previous studies have shown that the phonological deficits that characterise dyslexia persist into adulthood. There is a growing number of dyslexic students in higher education for whom sensitive diagnostic tests of their reading and reading related difficulties are required. The main aim of this study was to compare the cognitive skills of dyslexic students with those of their non-dyslexic peers, and to ascertain the impact of cognitive difficulties on their study skills. A second aim was to produce guidelines for the assessment of dyslexia in higher education. The performance of 23 dyslexic students was compared with that of a comparison group of 50 students from the same university who did not report a history of reading difficulty. Participants completed standardised tests of IQ, reading, spelling and arithmetic and tests tapping phonological processing, verbal fluency and speed of processing. Their performance on a set of study-related tasks including proof reading and précis writing was also assessed and they completed the Brown ADD scales. Although dyslexic students did not differ in general cognitive ability from controls, they had deficits in reading and reading related phonological processes. Discriminant function analyses indicated that dyslexia in adulthood can be confirmed with 95% accuracy using only four tests: spelling, nonword reading, digit span and writing speed. The study highlighted the difficulties of dyslexic adults. The persisting difficulties of dyslexic students that affect their study skills need to be recognised by HE institutions so that appropriate support programmes can be put in place.


Hypoxia-induced acute mountain sickness is associated with intracellular cerebral edema: a 3 T magnetic resonance imaging study.
Acute mountain sickness is common among not acclimatized persons ascending to high altitude; the underlying mechanism is unknown, but may be related to cerebral edema. Nine healthy male students were studied before and after 6-h exposure to isobaric hypoxia. Subjects inhaled room air enriched with N(2) to obtain arterial O(2) saturation values of 75 to 80%. Acute mountain sickness was assessed with the environmental symptom questionnaire, and cerebral edema with 3 T magnetic resonance imaging in 18 regions of interest in the cerebral white matter. The main outcome measures were development of intra- and extracellular cerebral white matter edema assessed by visual inspection and quantitative analysis of apparent diffusion coefficients derived from diffusion-weighted imaging, and B0 signal intensities derived from T2-weighted imaging. Seven of nine subjects developed acute mountain sickness. Mean apparent diffusion coefficient increased 2.12% (baseline, 0.80+/-0.09; 6 h hypoxia, 0.81+/-0.09; P=0.034), and mean B0 signal intensity increased 4.56% (baseline, 432.1+/-98.2; 6 h hypoxia, 450.7+/-102.5; P<0.001). Visual inspection of magnetic resonance images failed to reveal cerebral edema. Cerebral acute mountain sickness scores showed a negative correlation with relative changes of apparent diffusion coefficients (r=-0.83, P=0.006); there was no correlation with relative changes of B0 signal intensities. In conclusion, isobaric hypoxia is associated with mild extracellular (vasogenic) cerebral edema irrespective of the presence of acute mountain sickness in most subjects, and severe acute mountain sickness with additional mild intracellular (cytotoxic) cerebral edema.


Evaluation of hypercoagulability with rotational thromboelastometry in children with iron deficiency anemia.
Iron deficiency anemia (IDA) has been demonstrated to be a risk factor for thromboembolic events, although the pathogenesis of the development of thromboembolism in IDA is as yet unclear. The likelihood of children with IDA contracting hypercoagulability was evaluated in this cross-sectional study using rotational thromboelastometry (ROTEM). A total of 57 children with IDA (median age 11 years; 37 female, 20 male) and 48 healthy children (median age 9.9 years; 23 female, 25 male) were enrolled in the study. Whole blood count, serum iron, transferrin saturation, ferritin level, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen levels were ascertained, while ROTEM assays [intrinsic TEM (INTEM) and extrinsic TEM (EXTEM)] were used to measure and analyze coagulation time (CT), clot formation time (CFT), maximum clot firmness (MCF) and rate of maximum lysis (ML60%). This study conforms to ethical standards, has been approved by the appropriate Institutional Review Board. Hemoglobin, serum iron, transferrin saturation and ferritin levels were lower in the IDA group than in the control group (p < 0.001, for all), while the EXTEM and INTEM CT in the two groups were similar (p > 0.05). The EXTEM and INTEM MCF in the IDA group was higher than in the control group, while the INTEM CFT and rate of ML60% were lower than in the control group (p < 0.001, p < 0.001, p < 0.05, p < 0.001, respectively). The ROTEM results suggest that although the platelet count and coagulation tests were within normal ranges in IDA, the tendency to coagulate may have been increased.


Effectiveness of pentavalent rotavirus vaccine against severe disease.
To determine the vaccine effectiveness (VE) of complete and partial vaccination with the pentavalent rotavirus vaccine (RV5) in the prevention of rotavirus acute gastroenteritis (AGE) hospitalizations and emergency department visits during the first 3 rotavirus seasons after vaccine introduction. Active, prospective population-based surveillance for AGE and acute respiratory infection (ARIs) in inpatient and emergency department settings provided subjects for a case-control evaluation of VE in 3 US counties from January 2006 through June 2009. Children with laboratory-confirmed rotavirus AGE (cases) were matched according to date of birth and onset of illness to 2 sets of controls: children with rotavirus-negative AGE and children with ARI. The main outcome measure was VE with complete (3 doses) or partial (1 or 2 doses) RV5 vaccination. Of age-eligible children enrolled, 18% of cases, 54% of AGE controls, and 54% of ARI controls received ≥1 dose of RV5. The VE of RV5 for 1, 2, and 3 doses against all rotavirus genotypes with the use of rotavirus-negative AGE controls was 74% (95% confidence interval [CI]: 37%-90%), 88% (95% CI: 66%-96%), and 87% (95% CI: 71%-94%), respectively, and with the use of ARI controls was 73% (95% CI: 43%-88%), 88% (95% CI: 68%-95%), and 85% (95% CI: 72%-91%), respectively. The overall VE estimates were comparable during the first and second years of life and against AGE caused by different rotavirus strains. RV5 was highly effective in preventing severe rotavirus disease, even after a partial series, with protection persisting throughout the second year of life.


Surface chemistry. Probing the transition state region in catalytic CO oxidation on Ru.
Femtosecond x-ray laser pulses are used to probe the carbon monoxide (CO) oxidation reaction on ruthenium (Ru) initiated by an optical laser pulse. On a time scale of a few hundred femtoseconds, the optical laser pulse excites motions of CO and oxygen (O) on the surface, allowing the reactants to collide, and, with a transient close to a picosecond (ps), new electronic states appear in the O K-edge x-ray absorption spectrum. Density functional theory calculations indicate that these result from changes in the adsorption site and bond formation between CO and O with a distribution of OC-O bond lengths close to the transition state (TS). After 1 ps, 10% of the CO populate the TS region, which is consistent with predictions based on a quantum oscillator model.


Chairs and chiefs of plastic surgery: is it an insider job?
There is no more important decision an academic Plastic Surgery Department or Division can make than naming a chair or chief. Externally recruited leadership brings fresh perspectives and connections. Critics, however, argue that they lack the in-depth knowledge of the institution's culture and history that may be needed to succeed. The ability and skill of an internal candidate is already known and can increase the odds of that person's success in the leadership position. Finally, external recruitment can be a more costly process. Ultimately, the decision is really a litmus test for a Plastic Surgery program. The authors aim to evaluate factors influencing ascent in Plastic Surgery leadership, including training history, internal promotion, and external recruiting. All Plastic Surgery residency programs accredited by the Accreditation Council for Graduate Medical Education were noted (n = 71). Academic departmental chairs or divisional chiefs of these residency programs were identified at the time of study design (October 1, 2011). For each chair or chief, gender, training history, and faculty appointment immediately prior to the current leadership position was recorded. There were 71 academic chairs or chiefs of Plastic Surgery residency programs at the time of data collection. The majority (62%) had done fellowship training following Plastic Surgery residency. Fellowships included hand (43%), craniofacial (29%), microsurgery (18%), and other types (10%). The majority (73%) of leaders were internal hires (P < 0.01), having faculty appointments at their institutions prior to promotion. However, only a fraction (22%) of these internal hires had done Plastic Surgery residency or fellowship training at that institution (P < 0.01). External recruits consisted of 27% of all 71 academic hires (P < 0.01). Many factors influence the decision to recruit leadership from internally or to hire an external candidate. These include the time to fill the position, program culture, candidate experience, and cost. These results support that the insider/outsider hire decision is ultimately one of duality. That dichotomy is achieved with an emphasis on internal promotion, but always with an eye towards the advantages of bringing in external talent as a valuable contribution to increase organizational success.


A single domain of yeast poly(A)-binding protein is necessary and sufficient for RNA binding and cell viability.
The poly(A)-binding protein (PAB) gene of Saccharomyces cerevisiae is essential for cell growth. A 66-amino acid polypeptide containing half of a repeated N-terminal domain can replace the entire protein in vivo. Neither an octapeptide sequence conserved among eucaryotic RNA-binding proteins nor the C-terminal domain of PAB is required for function in vivo. A single N-terminal domain is nearly identical to the entire protein in the number of high-affinity sites for poly(A) binding in vitro (one site with an association constant of approximately 2 X 10(7) M-1) and in the size of the binding site (12 A residues). Multiple N-terminal domains afford a mechanism of PAB transfer between poly(A) strands.


The social ecology of girls' bullying practices: exploratory research in two London schools.
This exploratory study adopts a socio-ecological approach to examine the context of school bullying. It asks: (1) what are students' accounts of bullying practices?; (2) how are these enabled and constrained by the school-environment?; (3) how is gender implicated? Qualitative data were collected from girls in two schools in London via focus groups (one in each school; students aged 12-15) and seven semi-structured interviews (in one school; students aged 16-18); and from school policy documents. Our interpretation of girls' accounts, informed by Giddens' structuration theory, suggests that bullying practices were spatially patterned in the schools and often characterised by the regulation of girls' sexuality and sexual-harassment. Repeated acts of aggression were fluid with regard to the bully and victim role, challenging the dominant view of bullying as characterised by consistent disparities in power between individuals. Schools structured bullying behaviour via policies and practices that ignored these forms of abuse and which focused on and may have been complicit in the making of stable 'bully' and 'victim' roles, thus indirectly contributing to the reproduction of unhealthy relationships between students. In terms of gender, traditional gendered and sexual discourses appear to structure the identities of the schools and girls in our study.


Singles' Reasons for Being Single: Empirical Evidence From an Evolutionary Perspective.
A relatively large number of people in Western societies are single; that is, they are not involved in any romantic relationship. In this study, we have attempted to investigate the reasons for singlehood by asking singles themselves. A final sample of 648 American singles (307 of them women) rated 92 possible reasons for singlehood. These reasons were classified into 18 broad factors and four general domains. Among the most important reasons were poor flirting skills, freedom, fear of getting hurt, having different priorities, and being too picky. Significant sex and age effects were found across different factors and domains. More specifically, men were more likely than women to indicate that they were single in order to be free to flirt around, and because they were not into family making; while women were more likely to indicate that they were single in order to avoid getting hurt, and because they have considered themselves not to be desirable as mates. Younger people were more likely to indicate that they were single because they had poor flirting skills, because they did not see themselves as desirable mates, and because they did not like commitment; whereas older people were more likely to indicate that they were single in order to be free to do what they have wanted. Findings were examined and discussed using evolutionary theories relating to mate selection and evolutionary mismatch.


Quantifying the extent of North American mammal extinction relative to the pre-anthropogenic baseline.
Earth has experienced five major extinction events in the past 450 million years. Many scientists suggest we are now witnessing a sixth, driven by human impacts. However, it has been difficult to quantify the real extent of the current extinction episode, either for a given taxonomic group at the continental scale or for the worldwide biota, largely because comparisons of pre-anthropogenic and anthropogenic biodiversity baselines have been unavailable. Here, we compute those baselines for mammals of temperate North America, using a sampling-standardized rich fossil record to reconstruct species-area relationships for a series of time slices ranging from 30 million to 500 years ago. We show that shortly after humans first arrived in North America, mammalian diversity dropped to become at least 15%-42% too low compared to the "normal" diversity baseline that had existed for millions of years. While the Holocene reduction in North American mammal diversity has long been recognized qualitatively, our results provide a quantitative measure that clarifies how significant the diversity reduction actually was. If mass extinctions are defined as loss of at least 75% of species on a global scale, our data suggest that North American mammals had already progressed one-fifth to more than halfway (depending on biogeographic province) towards that benchmark, even before industrialized society began to affect them. Data currently are not available to make similar quantitative estimates for other continents, but qualitative declines in Holocene mammal diversity are also widely recognized in South America, Eurasia, and Australia. Extending our methodology to mammals in these areas, as well as to other taxa where possible, would provide a reasonable way to assess the magnitude of global extinction, the biodiversity impact of extinctions of currently threatened species, and the efficacy of conservation efforts into the future.


Role of New Hydrophilic Surfaces on Early Success Rate and Implant Stability: 1-Year Post-loading Results of a Multicenter, Split-Mouth, Randomized Controlled Trial.
To compare early implant failure and implant stability of one-stage Hiossen ET III implants with its new hydrophilic (NH) surface, compared with Hiossen ET III implants with the sandblasted and acid-etched (SA) surface at 1-year follow-up. This study was designed as a split-mouth, multicenter randomized controlled trial aimed to compare SA surface implants (SA group) and NH surface, (NH group). Outcomes were implant and prosthetic survival rates, complications, the insertion torque at implant placement, and implant stability quotient (ISQ) values. Twenty-nine patients (mean age 59.9 ± 11.3 years) were treated and followed up to 1 year after loading. No patient dropped out. Fifty-eight implants (29 SA group and 29 NH group) were placed. No implants or prostheses failed and no complications were experienced during follow-up. The mean insertion torque was 40.5 ± 3.23 (38.17-41.83) Ncm in the SA group and 40.48 ± 3.49 (38.02-41.98) Ncm in the NH group (p = 0.981). There was a statistically significant difference at the second week (T2) with higher values in the NH group (p = 0.041). Similar results were found in the maxilla (p = 0.045), but not in the mandible (p = 0.362). A positive correlation was found between initial insertion torque and ISQ with higher value in the NH group (0.73 vs. 0.66). NH implants are a viable alternative to SA surface, as they seem to avoid the ISQ drop during the bone remodeling phase.


Physics-Based Simulations to Predict the Differential Effects of Motor Control and Musculoskeletal Deficits on Gait Dysfunction in Cerebral Palsy: A Retrospective Case Study.
Physics-based simulations of walking have the theoretical potential to support clinical decision-making by predicting the functional outcome of treatments in terms of walking performance. Yet before using such simulations in clinical practice, their ability to identify the main treatment targets in specific patients needs to be demonstrated. In this study, we generated predictive simulations of walking with a medical imaging based neuro-musculoskeletal model of a child with cerebral palsy presenting crouch gait. We explored the influence of altered muscle-tendon properties, reduced neuromuscular control complexity, and spasticity on gait dysfunction in terms of joint kinematics, kinetics, muscle activity, and metabolic cost of transport. We modeled altered muscle-tendon properties by personalizing Hill-type muscle-tendon parameters based on data collected during functional movements, simpler neuromuscular control by reducing the number of independent muscle synergies, and spasticity through delayed muscle activity feedback from muscle force and force rate. Our simulations revealed that, in the presence of aberrant musculoskeletal geometries, altered muscle-tendon properties rather than reduced neuromuscular control complexity and spasticity were the primary cause of the crouch gait pattern observed for this child, which is in agreement with the clinical examination. These results suggest that muscle-tendon properties should be the primary target of interventions aiming to restore an upright gait pattern for this child. This suggestion is in line with the gait analysis following muscle-tendon property and bone deformity corrections. Future work should extend this single case analysis to more patients in order to validate the ability of our physics-based simulations to capture the gait patterns of individual patients pre- and post-treatment. Such validation would open the door for identifying targeted treatment strategies with the aim of designing optimized interventions for neuro-musculoskeletal disorders.


Functional Connectivity Alterations in Epilepsy from Resting-State Functional MRI.
The study of functional brain connectivity alterations induced by neurological disorders and their analysis from resting state functional Magnetic Resonance Imaging (rfMRI) is generally considered to be a challenging task. The main challenge lies in determining and interpreting the large-scale connectivity of brain regions when studying neurological disorders such as epilepsy. We tackle this challenging task by studying the cortical region connectivity using a novel approach for clustering the rfMRI time series signals and by identifying discriminant functional connections using a novel difference statistic measure. The proposed approach is then used in conjunction with the difference statistic to conduct automatic classification experiments for epileptic and healthy subjects using the rfMRI data. Our results show that the proposed difference statistic measure has the potential to extract promising discriminant neuroimaging markers. The extracted neuroimaging markers yield 93.08% classification accuracy on unseen data as compared to 80.20% accuracy on the same dataset by a recent state-of-the-art algorithm. The results demonstrate that for epilepsy the proposed approach confirms known functional connectivity alterations between cortical regions, reveals some new connectivity alterations, suggests potential neuroimaging markers, and predicts epilepsy with high accuracy from rfMRI scans.


In search of the perfect comorbidity measure for use with administrative claims data: does it exist?
Numerous measures of comorbidity have been developed for health services research with administrative claims. We sought to compare the performance of 4 claims-based comorbidity measures. We undertook a retrospective cohort study of 5777 Medicare beneficiaries ages 66 and older with stage III colon cancer reported to the Surveillance, Epidemiology, and End Results Program between January 1, 1992 and December 31, 1996. Comorbidity measures included Elixhauser's set of 30 condition indicators, Klabunde's outpatient and inpatient indices weighted for colorectal cancer patients, Diagnostic Cost Groups, and the Adjusted Clinical Group (ACG) System. Outcomes included receipt of adjuvant chemotherapy and 2 year noncancer mortality. For all measures, greater comorbidity significantly predicted lower receipt of chemotherapy and higher noncancer death. Nested logistic regression modeling suggests that using more claims sources to measure comorbidity generally improves the prediction of chemotherapy receipt and noncancer death, but depends on the measure type and outcome studied. All 4 comorbidity measures significantly improved the fit of baseline regression models for both chemotherapy receipt (baseline c-statistic 0.776; ranging from 0.779 after adding ACGs and Klabunde to 0.789 after Elixhauser) and noncancer death (baseline c-statistic 0.687; ranging from 0.717 after adding ACGs to 0.744 after Elixhauser). Although some comorbidity measures demonstrate minor advantages over others, each is fairly robust in predicting both chemotherapy receipt and noncancer death. Investigators should choose among these measures based on their availability, comfort with the methodology, and outcomes of interest.


Dlg protein is required for junction structure, cell polarity, and proliferation control in Drosophila epithelia.
The Discs large (Dlg) protein of Drosophila is the prototypic member of a growing family of proteins termed membrane-associated guanylate kinase homologs (MAGUKs). The MAGUKs are composed of a series of peptide domains that include one or three DHR/PDZs, an SH3, and a region homologous to guanylate kinase (GUK). We have previously shown that the product of this gene, the Dlg protein, is localized at the septate junctions between epithelial cells, and that mutations in the gene cause neoplastic overgrowth of the imaginal discs. The dlg locus is therefore defined as a tumor suppressor gene. In this paper, we show that the Dlg protein is localized on the cytoplasmic face of the septate junction and is required for the maintenance of this structure. It is also required for proper organization of the cytoskeleton, for the differential localization of membrane proteins, and for apicobasal polarity of epithelial cells. However, these other functions can be uncoupled from Dlg's role as a tumor suppressor since mutations in two domains of the protein, the SH3 and GUK, cause loss of normal cell proliferation control without affecting the other functions of the protein. These results suggest that, besides regulating cellular proliferation, the Dlg protein is a critical component of the septate junctions and is required for maintaining apicobasal polarity in Drosophila epithelium.


Risperidone in the treatment of conduct disorder in preschool children without intellectual disability.
The DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, 4th edition Textrevision) highlights the especially poor outcomes of early-onset conduct disorder (CD). The strong link between the patient's age at treatment and its efficacy points the importance of early intervention. Risperidone is one of the most commonly studied medications used to treat CD in children and adolescents. The aim of this study is to obtain preliminary data about the efficacy and tolerability of risperidone treatment in otherwise typically developing preschool children with conduct disorder and severe behavioral problems. We recruited 12 otherwise normally developing preschoolers (ten boys and two girls) with CD for this study. We could not follow up with 4 children at control visits properly; thus, 8 children (six girls, two boys; mean age: 42.4 months) completed the study. We treated the patients with risperidone in an open-label fashion for 8 weeks, starting with a daily dosage of 0.125 mg/day or 0.25 mg/day depending on the patient's weight (<20 kg children: 0.125 mg/day; >20 kg children: 0.25 mg/day). Dosage titration and increments were performed at 2-week interval clinical assessments. The Turgay DSM-IV Based Disruptive Behavior Disorders Child and Adolescent Rating & Screening Scale (T-DSM-IV-S) as well as the Clinical Global Impression Scale (CGI) assessed treatment efficacy; the Extrapyramidal Symptom Rating Scale (ESRS) and laboratory evaluations assessed treatment safety. The mean daily dosage of risperidone at the end of 8 weeks was 0.78 mg/day (SD: 0.39) with a maximum dosage of 1.50 mg/day. Based on the CGI global improvement item, we classified all patients as "responders" (very much or much improved). Risperidone was associated with a 78% reduction in the CGI Severity score. We also detected significant improvements on all of the subscales of the T-DSM-IV-S. Tolerability was good, and serious adverse effects were not observed. We detected statistically significant prolactin level increments (p < 0.05), but no clinical symptoms associated with prolactinemia. The results of this study suggest that risperidone may be an effective and well-tolerated atypical antipsychotic for the treatment of CD in otherwise normally developing preschool children. The findings of the study should be interpreted as preliminary data considering its small sample size and open-label methodology.


Field Efficacy of Larvivorous Fish and Pyriproxyfen Combined with Community Engagement on Dengue Vectors in Cambodia: A Randomized Controlled Trial.
Evidence on the effectiveness of low-cost, sustainable biological vector control tools for Aedes mosquitoes is limited. Therefore, the purpose of this trial was to estimate the impact of guppy fish in combination with the larvicide pyriproxyfen (PPF) (Sumilarv® 2MR) and communication for behavioral impact (COMBI) activities to reduce entomological indices in Cambodia. In this cluster randomized, controlled superiority trial, 30 clusters comprised of one or more villages each was allocated in a 1:1:1 ratio to receive either 1) all three interventions (guppies, PPF, and COMBI), 2) two interventions (guppies and COMBI), or 3) control (standard vector control). Entomological surveys among 40 randomly selected households per cluster were carried out quarterly. The primary outcome was the population abundance of adult female Aedes mosquitoes trapped using adult resting collections. In the primary analysis, adult female Aedes abundance and mosquito infection rates was aggregated over follow-up time points to give a single rate per cluster. These data were analyzed by negative binomial regression, yielding abundance ratios (ARs). The number of Aedes females was reduced roughly by half compared with the control in both the guppy, PPF, and COMBI arm (AR = 0.54; 95% CI, 0.34-0.85; P = 0.0073); and the guppy and COMBI arm (AR = 0.49; 95% CI, 0.31-0.77; P = 0.0021). The effectiveness demonstrated and extremely low cost of including fish rearing in community-based health structures suggest they should be considered as a vector control tool as long as the benefits outweigh any potential environmental concerns. Sumilarv® 2MR was also highly accepted and preferred over current vector control tools used in Cambodia.


Randomized Trial of Community Treatment With Azithromycin and Ivermectin Mass Drug Administration for Control of Scabies and Impetigo.
Scabies is a public health problem in many countries, with impetigo and its complications important consequences. Ivermectin based mass drug administration (MDA) reduces the prevalence of scabies and, to a lesser extent, impetigo. We studied the impact of co-administering azithromycin on the prevalence of impetigo and antimicrobial resistance. Six communities were randomized to receive either ivermectin-based MDA or ivermectin-based MDA co-administered with azithromycin. We measured scabies and impetigo prevalence at baseline and 12 months. We collected impetigo lesions swabs at baseline, 3 and 12 months to detect antimicrobial resistance. At baseline, scabies and impetigo prevalences were 11.8% and 10.1% in the ivermectin-only arm and 9.2% and 12.1% in the combined treatment arm. At 12 months, the prevalences had fallen to 1.0% and 2.5% in the ivermectin-only arm and 0.7% and 3.3% in the combined treatment arm. The proportion of impetigo lesions containing Staphylococcus aureus detected did not change (80% at baseline vs 86% at 12 months; no significant difference between arms) but the proportion containing pyogenic streptococci fell significantly (63% vs 23%, P < .01). At 3 months, 53% (8/15) of S. aureus isolates were macrolide-resistant in the combined treatment arm, but no resistant strains (0/13) were detected at 12 months. Co-administration of azithromycin with ivermectin led to similar decreases in scabies and impetigo prevalence compared to ivermectin alone. The proportion of impetigo lesions containing pyogenic streptococci declined following MDA. There was a transient increase in the proportion of macrolide-resistant S. aureus strains following azithromycin MDA. clinicaltrials.gov (NCT02775617).


Tandem transcription termination sites in the dnaN gene of Escherichia coli.
The dnaN gene of Escherichia coli encodes the beta-subunit of DNA polymerase III and maps between the dnaA and recF genes. We demonstrated previously that dnaN and recF constitute a transcriptional unit under control of the dnaN promoters. However, the recF gene has its own promoter region located in the middle of the dnaN structural gene. In this report, we use S1 mapping of mRNAs, transcriptional and translational fusions to the galK and lacZ genes, and in vitro mutagenesis to identify and characterize three tandem transcription termination sites responsible for transcriptional polarity in the dnaN-recF operon. These sites are located in the dnaN gene, downstream from the recF promoter region. Cumulatively, they terminate about 80% of the untranslated transcripts started at the recF promoters. As expected, they do not reduce transcription coming from the dnaN promoters unless dnaN translation was prematurely disrupted by the presence of a nonsense codon. The particular arrangement of regulatory elements (promoters and terminators) in the dnaN-recF region provides an exceptional in vivo system to confirm the latent termination site model of transcriptional polarity. In addition, our results contribute to the understanding of the complex regulation of the dnaA, dnaN, and recF genes. We propose that these three genes constitute an operon and that the terminators described in this work could be used to reduce expression of the distal genes of the operon under circumstances in which the dnaN translation happens to be slowed down.


A conceptual framework for training of trainers (ToT) interventions in global health.
Global health partnerships (GHP) between high or low-middle income countries are considered one of the best approaches to health systems strengthening. They typically involve highly skilled healthcare workers who volunteer to deliver capacity strengthening projects overseas, often in the form of peer-to-peer support through training and mentoring. Given GHP's strong focus on education and training, a common assumption is that training of trainers (ToT) is a strong predictor of sustainability because of its potential for up-skilling the workforce rapidly, cheaply and exponentially by developing local educators. Our aim is to test this assumption and identify the strengths and limitations of this approach by analysing qualitative data from a set of GHP funded by the UK Department for International Development through the Tropical Health and Education Trust. Our analysis identifies some of the common features of the ToT model and a number of limitations that can prevent it from being both effective and sustainable. Whilst most GHP strive for the long-term sustainability of the training by focusing on adequate training provision and support of local trainers, the wider issues that can facilitate or prevent the continuation of training are not always considered. We propose a conceptual framework (TRAIN) for ToT interventions to help inform practice and project evaluation. We illustrate the applicability of our framework through five case studies, each chosen to illustrate one aspect of the framework. TRAIN is intended as a starting point for further refinements and discussions about the factors affecting capacity building strategies based on training cascades. Although we envisage its usefulness to GHP as a guidance to design and operationalise ToT, we recognise that in practice it may be difficult to implement it in its entirety. The key message underlying TRAIN is that the sustainability of a cascade depends on a number of factors being present or developing at different operational levels during the course of a project. These are crucial to transform the opportunities that ToT affords to health systems in developing countries into the actual achievement of a training cascade that ultimately upskills the workforce and improves health outcomes in these countries.