Current therapeutic approaches to equine protozoal myeloencephalitis

Equine protozoal myeloencephalitis is the most important infectious neurologic disease of horses in the Western Hemisphere. Equine protozoal myeloencephalitis can interfere with a horse\u27s ability to race, work, and perform; untreated, EPM can be lethal. Antemortem diagnosis of EPM is challenging, requiring careful evaluation of the animal\u27s history, clinical signs, and laboratory data, with rigorous exclusion of other causes. Therapeutic approaches to EPM are evolving. First-generation therapeutic approaches for EPM were based on the classic anti–Toxoplasma gondii pyrimethamine–sulfonamide combinations; treatment is prolonged and can be associated with a considerable relapse rate, which may be associated with the difficulty in maintaining effective CNS concentrations of pyrimethamine. Second-generation therapeutic approaches are based on diclazuril and related triazine agentsa; in 2001, toltrazuril sulfoneb (ponazuril) became the first FDA-approved treatment for EPM. Triazine agents may have prolonged plasma half-lives, and their therapeutic efficacy would likely be enhanced by application of loading-dose schedules. A pyrimethamine-sulfonamide combination formulationc received FDA approval in 2004 for the treatment of EPM. Additionally, a diclazuril-based topical feed dressing formulationd received FDA approval in 2011. The ideal therapeutic agents for use against EPM would be effective when administered orally, with high efficacy against Sarcocystis neurona and minimal toxicity for horses. This article reviews the current information available for EPM, including the clinical pharmacology and efficacy of FDA-approved and nonapproved investigational medications for the treatment or prophylaxis of EPM. Equine protozoal myeloencephalitis is caused by 2 apicomplexan protozoal parasites: S neurona and, much less commonly, Neospora hughesi. Location of the causative organism in the CNS is random, so clinical signs of EPM are highly variable. Any combination of neurologic signs is possible, although spinal cord involvement is most common. Onset may be gradual or acute, with the usual pattern being mild clinical signs that progress with time. Furthermore, the intracellular localization of the causative organisms in the CNS creates difficulties for chemotherapeutic approaches and may also interfere with host-based immunologic defenses. Antemortem diagnosis of EPM is particularly challenging, requiring careful evaluation of the animal\u27s history, clinical signs, and laboratory data, with rigorous exclusion of other causes. Definitive diagnosis of EPM is dependent on necropsy detection of typical CNS lesions of the disease or presence of the appropriate causative organisms. Although careful clinical examination remains the most important antemortem diagnostic technique for EPM, laboratory methods have been developed to assist clinical diagnosis. As such, for horses with clinical signs consistent with EPM, it is optimal to perform immunoblotting, an indirect florescent antibody test, or ELISA analyses on blood and CSF samples prior to diagnosis and initiation of treatment. Preventative approaches to EPM are not well defined. Prevention of EPM with daily pyrantel tartratee administration at the current labeled dose has not been effective in immunocompetent horses1 or in interferon-γ knockout mice,2 even though the compound is active against S neurona in vitro.3 An EPM vaccine based on homogenates of S neurona merozoites with conditional licensure has been marketed for prevention of EPM, but this vaccine was removed from the market due to lack of efficacy data in prospective studies

Basal body stability and ciliogenesis requires the conserved component Poc1

Centrioles are the foundation for centrosome and cilia formation. The biogenesis of centrioles is initiated by an assembly mechanism that first synthesizes the ninefold symmetrical cartwheel and subsequently leads to a stable cylindrical microtubule scaffold that is capable of withstanding microtubule-based forces generated by centrosomes and cilia. We report that the conserved WD40 repeat domain–containing cartwheel protein Poc1 is required for the structural maintenance of centrioles in Tetrahymena thermophila. Furthermore, human Poc1B is required for primary ciliogenesis, and in zebrafish, DrPoc1B knockdown causes ciliary defects and morphological phenotypes consistent with human ciliopathies. T. thermophila Poc1 exhibits a protein incorporation profile commonly associated with structural centriole components in which the majority of Poc1 is stably incorporated during new centriole assembly. A second dynamic population assembles throughout the cell cycle. Our experiments identify novel roles for Poc1 in centriole stability and ciliogenesis

Breast milk and in utero transmission of HIV-1 select for envelope variants with unique molecular signatures

Additional file 5: Figure S5. Representative CD4 infectivity curves using Affinofile cells for IUT (top) and BMT (bottom) maternal–infant pairs. Affinofile cells were induced to generate a 100-fold range of CD4 surface density (ABS/cell) and infected with 2000 IU pseudotyped virus. Percent infection was measured as the percent luciferase relative to infected and maximally induced Affinofile cells. Data shown are representative curves among 3–4 experimental replicates

Nucleation and Growth of the Superconducting Phase in the Presence of a Current

We study the localized stationary solutions of the one-dimensional time-dependent Ginzburg-Landau equations in the presence of a current. These threshold perturbations separate undercritical perturbations which return to the normal phase from overcritical perturbations which lead to the superconducting phase. Careful numerical work in the small-current limit shows that the amplitude of these solutions is exponentially small in the current; we provide an approximate analysis which captures this behavior. As the current is increased toward the stall current J*, the width of these solutions diverges resulting in widely separated normal-superconducting interfaces. We map out numerically the dependence of J* on u (a parameter characterizing the material) and use asymptotic analysis to derive the behaviors for large u (J* ~ u^-1/4) and small u (J -> J_c, the critical deparing current), which agree with the numerical work in these regimes. For currents other than J* the interface moves, and in this case we study the interface velocity as a function of u and J. We find that the velocities are bounded both as J -> 0 and as J -> J_c, contrary to previous claims.Comment: 13 pages, 10 figures, Revte

Women, men and coronary heart disease: a review of the qualitative literature

Aim. This paper presents a review of the qualitative literature which examines the experiences of patients with coronary heart disease. The paper also assesses whether the experiences of both female and male patients are reflected in the literature and summarizes key themes. Background. Understanding patients' experiences of their illness is important for coronary heart disease prevention and education. Qualitative methods are particularly suited to eliciting patients' detailed understandings and perceptions of illness. As much previous research has been 'gender neutral', this review pays particular attention to gender. Methods. Published papers from 60 qualitative studies were identified for the review through searches in MEDLINE, EMBASE, CINAHL, PREMEDLINE, PsychINFO, Social Sciences Citation Index and Web of Science using keywords related to coronary heart disease. Findings. Early qualitative studies of patients with coronary heart disease were conducted almost exclusively with men, and tended to generalize from 'male' experience to 'human' experience. By the late 1990s this pattern had changed, with the majority of studies including women and many being conducted with solely female samples. However, many studies that include both male and female coronary heart disease patients still do not have a specific gender focus. Key themes in the literature include interpreting symptoms and seeking help, belief about coronary 'candidates' and relationships with health professionals. The influence of social roles is important: many female patients have difficulties reconciling family responsibilities and medical advice, while male patients worry about being absent from work. Conclusions. There is a need for studies that compare the experiences of men and women. There is also an urgent need for work that takes masculinity and gender roles into account when exploring the experiences of men with coronary heart disease

Performance of the LHCb vertex locator

The Vertex Locator (VELO) is a silicon microstrip detector that surrounds the proton-proton interaction region in the LHCb experiment. The performance of the detector during the first years of its physics operation is reviewed. The system is operated in vacuum, uses a bi-phase CO2 cooling system, and the sensors are moved to 7 mm from the LHC beam for physics data taking. The performance and stability of these characteristic features of the detector are described, and details of the material budget are given. The calibration of the timing and the data processing algorithms that are implemented in FPGAs are described. The system performance is fully characterised. The sensors have a signal to noise ratio of approximately 20 and a best hit resolution of 4 μm is achieved at the optimal track angle. The typical detector occupancy for minimum bias events in standard operating conditions in 2011 is around 0.5%, and the detector has less than 1% of faulty strips. The proximity of the detector to the beam means that the inner regions of the n+-on-n sensors have undergone space-charge sign inversion due to radiation damage. The VELO performance parameters that drive the experiment's physics sensitivity are also given. The track finding efficiency of the VELO is typically above 98% and the modules have been aligned to a precision of 1 μm for translations in the plane transverse to the beam. A primary vertex resolution of 13 μm in the transverse plane and 71 μm along the beam axis is achieved for vertices with 25 tracks. An impact parameter resolution of less than 35 μm is achieved for particles with transverse momentum greater than 1 GeV/c

Precision luminosity measurements at LHCb

Measuring cross-sections at the LHC requires the luminosity to be determined accurately at each centre-of-mass energy √s. In this paper results are reported from the luminosity calibrations carried out at the LHC interaction point 8 with the LHCb detector for √s = 2.76, 7 and 8 TeV (proton-proton collisions) and for √sNN = 5 TeV (proton-lead collisions). Both the "van der Meer scan" and "beam-gas imaging" luminosity calibration methods were employed. It is observed that the beam density profile cannot always be described by a function that is factorizable in the two transverse coordinates. The introduction of a two-dimensional description of the beams improves significantly the consistency of the results. For proton-proton interactions at √s = 8 TeV a relative precision of the luminosity calibration of 1.47% is obtained using van der Meer scans and 1.43% using beam-gas imaging, resulting in a combined precision of 1.12%. Applying the calibration to the full data set determines the luminosity with a precision of 1.16%. This represents the most precise luminosity measurement achieved so far at a bunched-beam hadron collider