Determining EMIC Wave Vector Properties Through Multi-Point Measurements: The Wave Curl Analysis.

Electromagnetic ion cyclotron (EMIC) waves play important roles in particle loss processes in the magnetosphere. Determining the evolution of EMIC waves as they propagate and how this evolution affects wave-particle interactions requires accurate knowledge of the wave vector, k. We present a technique using the curl of the wave magnetic field to determine k observationally, enabled by the unique configuration and instrumentation of the Magnetospheric MultiScale (MMS) spacecraft. The wave curl analysis is demonstrated for synthetic arbitrary electromagnetic waves with varying properties typical of observed EMIC waves. The method is also applied to an EMIC wave interval observed by MMS on October 28, 2015. The derived wave properties and k from the wave curl analysis for the observed EMIC wave are compared with the Waves in Homogenous, Anisotropic, Multi-component Plasma (WHAMP) wave dispersion solution and with results from other single- and multi-spacecraft techniques. We find good agreement between k from the wave curl analysis, k determined from other observational techniques, and k determined from WHAMP. Additionally, the variation of k due to the time and frequency intervals used in the wave curl analysis is explored. This exploration demonstrates that the method is robust when applied to a wave containing at least 3-4 wave periods and over a rather wide frequency range encompassing the peak wave emission. These results provide confidence that we are able to directly determine the wave vector properties using this multi-spacecraft method implementation, enabling systematic studies of EMIC wave k properties with MMS.

Solar Wind Ion Entry Into the Magnetosphere During Northward IMF.

Extended periods of northward interplanetary magnetic field (IMF) lead to the formation of a cold, dense plasma sheet due to the entry of solar wind plasma into the magnetosphere. Identifying the paths that the solar wind takes to enter the magnetosphere, and their relative importance has remained elusive. Any theoretical model of entry must satisfy observational constraints, such as the overall entry rate and the dawn-dusk asymmetry observed in the cold, dense plasma sheet. We model, using a combination of global magnetohydrodynamic and test particle simulations, solar wind ion entry into the magnetosphere during northward IMF and compare entry facilitated by the Kelvin-Helmholtz instability to cusp reconnection. For Kelvin-Helmholtz entry we reproduce transport rates inferred from observation and kinetic modeling and find that intravortex reconnection creates buoyant flux tubes, which provides, through interchange instability, a mechanism of filling the central plasma sheet with cold magnetosheath plasma. For cusp entry we show that an intrinsic dawn-dusk asymmetry is created during entry that is the result of alignment of the westward ion drift with the dawnward electric field typically observed during northward IMF. We show that both entry mechanisms provide comparable mass but affect entering plasma differently. The flank-entering plasma is cold and dawn-dusk symmetric, whereas the cusp-entering plasma is accelerated and preferentially deflected toward dawn. The combined effect of these entry mechanisms results in a plasma sheet population that exhibits dawn-dusk asymmetry in the manner that is seen in nature: a two-component (hot and cold) dusk flank and hotter, broadly peaked dawn population.

EMIC Waves in the Outer Magnetosphere: Observations of an Off-Equator Source Region.

Electromagnetic ion cyclotron (EMIC) waves at large L shells were observed away from the magnetic equator by the Magnetospheric MultiScale (MMS) mission nearly continuously for over four hours on 28 October 2015. During this event, the wave Poynting vector direction systematically changed from parallel to the magnetic field (toward the equator), to bidirectional, to antiparallel (away from the equator). These changes coincide with the shift in the location of the minimum in the magnetic field in the southern hemisphere from poleward to equatorward of MMS. The local plasma conditions measured with the EMIC waves also suggest that the outer magnetospheric region sampled during this event was generally unstable to EMIC wave growth. Together, these observations indicate that the bidirectionally propagating wave packets were not a result of reflection at high latitudes but that MMS passed through an off-equator EMIC wave source region associated with the local minimum in the magnetic field.

Energetic Oxygen and Sulfur Charge States in the Outer Jovian Magnetosphere: Insights From the Cassini Jupiter Flyby.

On 10 January 2001, Cassini briefly entered into the magnetosphere of Jupiter, en route to Saturn. During this excursion into the Jovian magnetosphere, the Cassini Magnetosphere Imaging Instrument/Charge-Energy-Mass Spectrometer detected oxygen and sulfur ions. While Charge-Energy-Mass Spectrometer can distinguish between oxygen and sulfur charge states directly, only 95.9 ± 2.9 keV/e ions were sampled during this interval, allowing for a long time integration of the tenuous outer magnetospheric (~200 RJ) plasma at one energy. For this brief interval for the 95.9 keV/e ions, 96% of oxygen ions were O+, with the other 4% as O2+, while 25% of the energetic sulfur ions were S+, 42% S2+, and 33% S3+. The S2+/O+ flux ratio was observed to be 0.35 (±0.06 Poisson error).

Pluto's Interaction With Energetic Heliospheric Ions.

Pluto energies of a few kiloelectron volts and suprathermal ions with tens of kiloelectron volts and above. We measure this population using the Pluto Energetic Particle Spectrometer Science Investigation (PEPSSI) instrument on board the New Horizons spacecraft that flew by Pluto in 2015. Even though the measured ions have gyroradii larger than the size of Pluto and the cross section of its magnetosphere, we find that the boundary of the magnetosphere is depleting the energetic ion intensities by about an order of magnitude close to Pluto. The intensity is increasing exponentially with distance to Pluto and reaches nominal levels of the interplanetary medium at about 190R P distance. Inside the wake of Pluto, we observe oscillations of the ion intensities with a periodicity of about 0.2 hr. We show that these can be quantitatively explained by the electric field of an ultralow-frequency wave and discuss possible physical drivers for such a field. We find no evidence for the presence of plutogenic ions in the considered energy range.

Wave Phenomena and Beam-Plasma Interactions at the Magnetopause Reconnection Region.

This paper reports on Magnetospheric Multiscale observations of whistler mode chorus and higher-frequency electrostatic waves near and within a reconnection diffusion region on 23 November 2016. The diffusion region is bounded by crescent-shaped electron distributions and associated dissipation just upstream of the X-line and by magnetic field-aligned currents and electric fields leading to dissipation near the electron stagnation point. Measurements were made southward of the X-line as determined by southward directed ion and electron jets. We show that electrostatic wave generation is due to magnetosheath electron beams formed by the electron jets as they interact with a cold background plasma and more energetic population of magnetospheric electrons. On the magnetosphere side of the X-line the electron beams are accompanied by a strong perpendicular electron temperature anisotropy, which is shown to be the source of an observed rising-tone whistler mode chorus event. We show that the apex of the chorus event and the onset of electrostatic waves coincide with the opening of magnetic field lines at the electron stagnation point.

Effects of prior exposure to antibiotics on bacterial adaptation to phages.

Understanding adaptation to complex environments requires information about how exposure to one selection pressure affects adaptation to others. For bacteria, antibiotics and viral parasites (phages) are two of the most common selection pressures and are both relevant for treatment of bacterial infections: increasing antibiotic resistance is generating significant interest in using phages in addition or as an alternative to antibiotics. However, we lack knowledge of how exposure to antibiotics affects bacterial responses to phages. Specifically, it is unclear how the negative effects of antibiotics on bacterial population growth combine with any possible mutagenic effects or physiological responses to influence adaptation to other stressors such as phages, and how this net effect varies with antibiotic concentration. Here, we experimentally addressed the effect of pre-exposure to a wide range of antibiotic concentrations on bacterial responses to phages. Across 10 antibiotics, we found a strong association between their effects on bacterial population size and subsequent population growth in the presence of phages (which in these conditions indicates phage-resistance evolution). We detected some evidence of mutagenesis among populations treated with fluoroquinolones and ß-lactams at sublethal doses, but these effects were small and not consistent across phage treatments. These results show that, although stressors such as antibiotics can boost adaptation to other stressors at low concentrations, these effects are weak compared to the effect of reduced population growth at inhibitory concentrations, which in our experiments strongly reduced the likelihood of subsequent phage-resistance evolution.

The association of PTPN22 rs2476601 with juvenile idiopathic arthritis is specific to females.

A preponderance of females develop autoimmune disease, including juvenile idiopathic arthritis (JIA), yet the reason for this bias remains elusive. Evidence suggests that genetic risk of disease may be influenced by sex. PTPN22 rs2476601 is associated with JIA and numerous other autoimmune diseases, and has been reported to show female-specific association with type 1 diabetes. We performed main effect and sex-stratified association analyses to determine whether a sex-specific association exists in JIA. As expected, rs2476601 was associated with JIA in our discovery (413 cases and 690 controls) and replication (1008 cases and 9284 controls) samples. Discovery sample sex-stratified analyses demonstrated an association specifically in females (odds ratio (OR)=2.35, 95% confidence interval (CI)=1.52-3.63, P=0.00011) but not males (OR=0.91, 95% CI=0.52-1.60, P=0.75). This was similarly observed in the replication sample. There was evidence for genotype-by-sex interaction (Pinteraction=0.009). The association between rs2476601 and JIA appears restricted to females, partly accounting for the predominance of females with this disease.

Chronic topical administration of WIN-55-212-2 maintains a reduction in IOP in a rat glaucoma model without adverse effects.

Glaucoma, one of the leading causes of blindness, is associated with high intraocular pressure (IOP) as a risk factor. The aim of this study was to examine both local and systemic effects of chronic topical administration of the synthetic CB1/CB2 agonist, WIN-55-212-2 and its potential to sustain ocular hypotension. WIN-55-212-2 (0.5%) or Tocrisolve, the vehicle, was administered topically three times daily to rats with surgically created glaucoma for 4 weeks, followed by a 1-week washout period. IOP, blood pressure and heart rate were measured weekly along with confocal microscopy and slit lamp biomicroscopy to detect ocular toxicity. IOP decreased rapidly by up to 47% in the WIN-55-212-2 treated group from 14.1+/-0.7 to 6.6+/-0.2 mmHg. The decrease was maintained during the treatment period. After the washout period, IOP (12.3+/-0.2 mmHg) was not different from baseline. In the contralateral eye, IOP showed a downward trend. Tocrisolve alone had no effect on IOP. No changes in blood pressure, heart rate or indicators of ocular toxicity were noted within either group. Topical application of WIN-55-212-2 significantly deceased IOP for duration of treatment. The decrease was sustained without the development of tolerance. Following cessation of therapy, IOP rapidly returned to baseline. No significant cardiovascular effects or ocular toxicity were noted during chronic topical therapy with either drug or vehicle.

Phenotypic heterogeneity associated with a novel mutation (Gly112Glu) in the Norrie disease protein.

PURPOSE: To determine the molecular pathology and clinical severity of two pedigrees with a history of early retinal detachment and peripheral retinal vascular abnormalities. DESIGN: Longitudinal cohort study. METHODS: A longitudinal clinical study and DNA analysis was performed on 49 family members of two pedigrees. RESULTS: Nine individuals were found to be hemizygous for a mutation at codon 112 (Gly112Glu) of the Norrie disease protein (NDP) in one pedigree. Significant phenotypic heterogeneity was found. The proband presented with a unilateral subtotal retinal detachment at the age of 3 years, and subsequently developed a slowly progressive tractional retinal detachment involving the macula in the contralateral eye at the age of 4 years. One individual had only mild peripheral retinal pigmentary changes with normal vision at the age of 79 years. The remaining seven individuals had varying degrees of peripheral retinal vascular abnormalities and anterior segment findings. Seven affected members of a second pedigree affected by a previously reported mutation, Arg74Cys, also demonstrated wide ocular phenotypic variation. CONCLUSION: A novel mutation (Gly112Glu), which represents the most carboxy located, NDP mutation reported, results in significant phenotypic heterogeneity. These data support the contention that the spectrum of ocular disease severity associated with these NDP mutations is broad. Use of terms that characterize this entity by phenotypic appearance, such as familial exudative vitreoretinopathy, do not adequately communicate the potential spectrum of severity of this disorder to affected or carrier family members.

Do injections of 5-fluorouracil after trabeculectomy have toxic effects on the anterior segment?

OBJECTIVE: To discourage fibrosis of the filtering bleb, 5 fluorouracil (5-FU) may be injected after trabeculectomy. 5-FU is an antimetabolite that also can damage extraocular tissues at concentrations as low as 0.5%. This study ascertained whether repeated injection of 5-FU has toxic effects on intraocular structures. METHODS: After unilateral trabeculectomy in anesthetized New Zealand rabbits, 5-FU (5.0 mg/0.1 mL) was injected at the trabeculectomy site every 5 days for 15 days. Evaluation included slit-lamp examination, confocal microscopy, and intraocular pressure (IOP). After sacrifice, aqueous humor (AH) was drawn and eyes excised for scanning electron microscopy (SEM) and light microscopy. RESULTS: The 5-FU injection not decrease IOP beyond trabeculectomy alone. Bleb height remained constant, thickness increased, and vascularity decreased. No changes in cornea or anterior segment were observed. No inflammation was observed in the bleb or surrounding tissues by slit-lamp or histologic examination. Protein in AH increased from 0.6 +/- 0.5 microg/mL at baseline to 19.8 +/- 4.4 microg/mL after trabeculectomy but only to 0.9 +/- 0.6 microg/mL after trabeculectomy plus 5-FU. Both in vivo confocal microscopy and SEM revealed deleterious effects on corneal epithelial and endothelial cells with a minor shift toward smaller cells. CONCLUSIONS: In this study 5-FU did not provoke an intraocular inflammatory response and had minimal effect on extraocular structures. Changes in corneal epithelium and endothelium detectable by confocal microscopy suggest a small toxic effect. These in vivo measurements by confocal microscopy were confirmed by SEM. Repeated administration did not cause additional cumulative toxic effects in the anterior segment. Therefore, multiple injections of 5- FU into the filtering bleb pose minimal risk to intraocular structures.

PET imaging of implanted human retinal pigment epithelial cells in the MPTP-induced primate model of Parkinson's disease.

Human retinal pigment epithelial (hRPE) cells produce L-dopa, are easily harvested and expanded in culture, and, attached to microcarriers, can survive in the brain without immunosuppression. Studies in rats, primates, and parkinsonian patients have demonstrated that striatally implanted hRPE cells attached to gelatin microcarriers (RPE-GM) are able to improve parkinsonian symptoms and are well tolerated for extended periods. In moderately to severely impaired monkeys with bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced parkinsonism receiving a unilateral RPE-GM implant in the putamen, there was a 39% improvement in clinical scores over the first 2 months post-implant. Positron emission tomography (PET) with [18F]fluoro-L-dopa (FDOPA) showed increased accumulation in the implanted putamen and a concomitant decrease in [11C]raclopride binding in the same area, suggesting increased dopamine release compared to the contralateral putamen. We report the first in vivo visualization of hRPE cells and their effects, implicating a dopaminergic mechanism of action.

Stereotaxic intrastriatal implantation of human retinal pigment epithelial (hRPE) cells attached to gelatin microcarriers: a potential new cell therapy for Parkinson's disease.

Human retinal pigment epithelial (hRPE) cells are dopaminergic support cells in the neural retina. Stereotaxic intrastriatal implantation of hRPE cells attached to gelatin microcarriers (Spheramine) in rodent and non-human primate models of Parkinson's disease (PD) produces long term amelioration of motor and behavioral deficits, with histological and PET evidence of cell survival without immunosuppression. Long-term safety in cynomologous monkeys has also been demonstrated. Six H&Y stage III/IV PD patients were enrolled in a one-year, open-label, single center study to evaluate the safety and efficacy of Spheramine (approximately 325,000 cells) implanted in the most affected post-commissural putamen. All patients tolerated the implantation of Spheramine well and demonstrated improvement. At 6, 9, and 12 months post-operatively, the mean UPDRS-Motor score "off", the primary outcome measure, improved 33%, (n = 6), 42% (n = 6), and 48% (n = 3), respectively. No "off-state" dyskinesias have been observed. Based on these preliminary results, Spheramine appears to show promise in treating late stage PD patients.

Reducing the impact of rheumatic diseases in childhood.

Reducing the impact of rheumatic diseases in childhood is the fundamental objective of every member of the multi-disciplinary team involved in the care of affected children and families. The means by which this objective may be achieved are broad and include the implementation of a range of non-pharmacological therapies to address the effects of rheumatic diseases on the physical development of the child. In addition, the treating team must be aware of the psychosocial impact that these diseases may have and the ways in which this may be minimized. This chapter is devoted to an examination of some of the non-pharmacological issues that arise in the management of the commonest rheumatic disease found in children, juvenile idiopathic arthritis (JIA). Aspects of physical rehabilitation, schooling, medication compliance, pain management and family dynamics are discussed, as are interventions to reduce the impact of this disease and its sequelae, utilizing, where possible, evidence-based principles from the literature. Although specific issues applicable to children with arthritis will be discussed, the broad principles of much of what follows applies to all of the rheumatic diseases in childhood.

Direct evidence for neutrino flavor transformation from neutral-current interactions in the Sudbury Neutrino Observatory.

Observations of neutral-current nu interactions on deuterium in the Sudbury Neutrino Observatory are reported. Using the neutral current (NC), elastic scattering, and charged current reactions and assuming the standard 8B shape, the nu(e) component of the 8B solar flux is phis(e) = 1.76(+0.05)(-0.05)(stat)(+0.09)(-0.09)(syst) x 10(6) cm(-2) s(-1) for a kinetic energy threshold of 5 MeV. The non-nu(e) component is phi(mu)(tau) = 3.41(+0.45)(-0.45)(stat)(+0.48)(-0.45)(syst) x 10(6) cm(-2) s(-1), 5.3sigma greater than zero, providing strong evidence for solar nu(e) flavor transformation. The total flux measured with the NC reaction is phi(NC) = 5.09(+0.44)(-0.43)(stat)(+0.46)(-0.43)(syst) x 10(6) cm(-2) s(-1), consistent with solar models.

Measurement of day and night neutrino energy spectra at SNO and constraints on neutrino mixing parameters.

The Sudbury Neutrino Observatory (SNO) has measured day and night solar neutrino energy spectra and rates. For charged current events, assuming an undistorted 8B spectrum, the night minus day rate is 14.0%+/-6.3%(+1.5%)(-1.4%) of the average rate. If the total flux of active neutrinos is additionally constrained to have no asymmetry, the nu(e) asymmetry is found to be 7.0%+/-4.9%(+1.3%)(-1.2%). A global solar neutrino analysis in terms of matter-enhanced oscillations of two active flavors strongly favors the large mixing angle solution.

Molecular characterization and ophthalmic investigation of a large family with type 2A Von Hippel-Lindau Disease.

BACKGROUND: Von Hippel-Lindau (VHL) disease is a dominantly inherited cancer syndrome. Since the identification of the VHL gene, at least 3 clinical-genetic subtypes of the disease have been recognized. OBJECTIVES: To identify the specific abnormality in the VHL gene and to correlate it with the prevalence and severity of ocular involvement in a large family with VHL disease. METHODS: A longitudinal clinical study and DNA analysis of 24 family members. RESULTS: All 14 affected family members exhibited a thymine-to-cysteine change at nucleotide 505 (T505C) in exon 1 of the VHL gene, consistent with the clinical diagnosis of VHL disease subtype 2A. Two asymptomatic gene carriers were also identified. Seventy-five percent (12/16) of the gene carriers had 1 or more ocular angiomas. The mean number of ocular angiomas per gene carrier was 3.3. Six eyes had optic disc angioma. Five gene carriers (31%) had lost vision because of angiomatosis. Cerebellar hemangioblastomas were present in 4 patients (25%) and pheochromocytomas in 11 (69%). No patient was found to have a renal cell carcinoma. CONCLUSIONS: The family shows a low susceptibility to renal carcinoma consistent with the clinical diagnosis of VHL disease type 2A. The prevalence and severity of ocular angiomatosis in this subtype do not significantly differ from those of the other more common subtypes of VHL. Recognition of the VHL disease 2A phenotype suggests the presence of a specific mutation (T505C) in the VHL gene. Confirmation of this genotype increases the clinician's ability to provide favorable prognostic information to affected family members.

Plastibell template circumcision: a new technique.

A novel circumcision technique using the Plastibell as a template is described. This technique is fast and ensures excellent cosmesis compared with the standard sleeve circumcision. It is easy to perform and allows the urologist to achieve consistently excellent cosmetic results. We describe the technique in detail.

Measurement of the rate of nu(e) + d --> p + p + e(-) interactions produced by (8)B solar neutrinos at the Sudbury Neutrino Observatory.

Solar neutrinos from (8)B decay have been detected at the Sudbury Neutrino Observatory via the charged current (CC) reaction on deuterium and the elastic scattering (ES) of electrons. The flux of nu(e)'s is measured by the CC reaction rate to be straight phi(CC)(nu(e)) = 1.75 +/- 0.07(stat)(+0.12)(-0.11)(syst) +/- 0.05(theor) x 10(6) cm(-2) s(-1). Comparison of straight phi(CC)(nu(e)) to the Super-Kamiokande Collaboration's precision value of the flux inferred from the ES reaction yields a 3.3 sigma difference, assuming the systematic uncertainties are normally distributed, providing evidence of an active non- nu(e) component in the solar flux. The total flux of active 8B neutrinos is determined to be 5.44+/-0.99 x 10(6) cm(-2) s(-1).