BepiColombo mission confirms stagnation region of Venus and reveals its large extent.

The second Venus flyby of the BepiColombo mission offer a unique opportunity to make a complete tour of one of the few gas-dynamics dominated interaction regions between the supersonic solar wind and a Solar System object. The spacecraft pass through the full Venusian magnetosheath following the plasma streamlines, and cross the subsolar stagnation region during very stable solar wind conditions as observed upstream by the neighboring Solar Orbiter mission. These rare multipoint synergistic observations and stable conditions experimentally confirm what was previously predicted for the barely-explored stagnation region close to solar minimum. Here, we show that this region has a large extend, up to an altitude of 1900 km, and the estimated low energy transfer near the subsolar point confirm that the atmosphere of Venus, despite being non-magnetized and less conductive due to lower ultraviolet flux at solar minimum, is capable of withstanding the solar wind under low dynamic pressure.

Advances in the treatment of relapsed/refractory chronic lymphocytic leukemia.

Treatment of chronic lymphocytic leukemia (CLL) has advanced with the introduction of chemoimmunotherapy (CIT) agents that have improved the outcomes of frontline therapy. However, most treated patients will relapse and require subsequent therapy. This review focuses on recent advances in the treatment of relapsed or refractory CLL. Until recently, treatment options for relapsed CLL were of limited efficacy. Retreatment with fludarabine, cyclophosphamide, and rituximab (FCR) was recommended for patients with a durable response to first-line FCR, although acquired genetic aberrations, impaired marrow reserve, and comorbidities often made this suboptimal therapy for many patients. New options include two agents targeting B cell receptor (BCR) signaling pathways (ibrutinib and idelalisib) and a B cell lymphoma-2 (BCL-2) inhibitor (venetoclax). Allogeneic hematopoietic stem cell transplantation (HSCT) remains a potentially curative option for younger patients with a suitable donor.

Simultaneous Remote Observations of Intense Reconnection Effects by DMSP and MMS Spacecraft During a Storm Time Substorm.

During a magnetic storm on 23 June 2015, several very intense substorms took place, with signatures observed by multiple spacecraft including DMSP and Magnetospheric Multiscale (MMS). At the time of interest, DMSP F18 crossed inbound through a poleward expanding auroral bulge boundary at 23.5 h magnetic local time (MLT), while MMS was located duskward of 22 h MLT during an inward crossing of the expanding plasma sheet boundary. The two spacecraft observed a consistent set of signatures as they simultaneously crossed the reconnection separatrix layer during this very intense reconnection event. These include (1) energy dispersion of the energetic ions and electrons traveling earthward, accompanied with high electron energies in the vicinity of the separatrix; (2) energy dispersion of polar rain electrons, with a high-energy cutoff; and (3) intense inward convection of the magnetic field lines at the MMS location. The high temporal resolution measurements by MMS provide unprecedented observations of the outermost electron boundary layer. We discuss the relevance of the energy dispersion of the electrons, and their pitch angle distribution, to the spatial and temporal evolution of the boundary layer. The results indicate that the underlying magnetotail magnetic reconnection process was an intrinsically impulsive and the active X-line was located relatively close to the Earth, approximately at 16-18 RE.

Statistical characterization of the growth and spatial scales of the substorm onset arc.

We present the first multievent study of the spatial and temporal structuring of the aurora to provide statistical evidence of the near-Earth plasma instability which causes the substorm onset arc. Using data from ground-based auroral imagers, we study repeatable signatures of along-arc auroral beads, which are thought to represent the ionospheric projection of magnetospheric instability in the near-Earth plasma sheet. We show that the growth and spatial scales of these wave-like fluctuations are similar across multiple events, indicating that each sudden auroral brightening has a common explanation. We find statistically that growth rates for auroral beads peak at low wave number with the most unstable spatial scales mapping to an azimuthal wavelength λ≈ 1700-2500 km in the equatorial magnetosphere at around 9-12 RE . We compare growth rates and spatial scales with a range of theoretical predictions of magnetotail instabilities, including the Cross-Field Current Instability and the Shear Flow Ballooning Instability. We conclude that, although the Cross-Field Current instability can generate similar magnitude of growth rates, the range of unstable wave numbers indicates that the Shear Flow Ballooning Instability is the most likely explanation for our observations.

In situ spatiotemporal measurements of the detailed azimuthal substructure of the substorm current wedge.

The substorm current wedge (SCW) is a fundamental component of geomagnetic substorms. Models tend to describe the SCW as a simple line current flowing into the ionosphere toward dawn and out of the ionosphere toward dusk, linked by a westward electrojet. We use multispacecraft observations from perigee passes of the Cluster 1 and 4 spacecraft during a substorm on 15 January 2010, in conjunction with ground-based observations, to examine the spatial structuring and temporal variability of the SCW. At this time, the spacecraft traveled east-west azimuthally above the auroral region. We show that the SCW has significant azimuthal substructure on scales of 100 km at altitudes of 4000-7000 km. We identify 26 individual current sheets in the Cluster 4 data and 34 individual current sheets in the Cluster 1 data, with Cluster 1 passing through the SCW 120-240 s after Cluster 4 at 1300-2000 km higher altitude. Both spacecraft observed large-scale regions of net upward and downward field-aligned current, consistent with the large-scale characteristics of the SCW, although sheets of oppositely directed currents were observed within both regions. We show that the majority of these current sheets were closely aligned to a north-south direction, in contrast to the expected east-west orientation of the preonset aurora. Comparing our results with observations of the field-aligned current associated with bursty bulk flows (BBFs), we conclude that significant questions remain for the explanation of SCW structuring by BBF-driven "wedgelets." Our results therefore represent constraints on future modeling and theoretical frameworks on the generation of the SCW. KEY POINTS: The substorm current wedge (SCW) has significant azimuthal structureCurrent sheets within the SCW are north-south alignedThe substructure of the SCW raises questions for the proposed wedgelet scenario.

Plasma jet braking: energy dissipation and nonadiabatic electrons.

We report in situ observations by the Cluster spacecraft of wave-particle interactions in a magnetic flux pileup region created by a magnetic reconnection outflow jet in Earth's magnetotail. Two distinct regions of wave activity are identified: lower-hybrid drift waves at the front edge and whistler-mode waves inside the pileup region. The whistler-mode waves are locally generated by the electron temperature anisotropy, and provide evidence for ongoing betatron energization caused by magnetic flux pileup. The whistler-mode waves cause fast pitch-angle scattering of electrons and isotropization of the electron distribution, thus making the flow braking process nonadiabatic. The waves strongly affect the electron dynamics and thus play an important role in the energy conversion chain during plasma jet braking.

Observations of slow electron holes at a magnetic reconnection site.

We report in situ observations of high-frequency electrostatic waves in the vicinity of a reconnection site in the Earth's magnetotail. Two different types of waves are observed inside an ion-scale magnetic flux rope embedded in a reconnecting current sheet. Electron holes (weak double layers) produced by the Buneman instability are observed in the density minimum in the center of the flux rope. Higher frequency broadband electrostatic waves with frequencies extending up to f(pe) are driven by the electron beam and are observed in the denser part of the rope. Our observations demonstrate multiscale coupling during the reconnection: Electron-scale physics is induced by the dynamics of an ion-scale flux rope embedded in a yet larger-scale magnetic reconnection process.

Formation of inner structure of a reconnection separatrix region.

We present multipoint spacecraft observations at the dayside magnetopause of a magnetic reconnection separatrix region. This region separates two plasmas with significantly different temperatures and densities, at a large distance from the X line. We identify which terms in the generalized Ohm's law balance the observed electric field throughout the separatrix region. The electric field inside a thin approximately c/omega pi Hall layer is balanced by the j x B/ne term while other terms dominate elsewhere. On the low density side of the region we observe a density cavity which forms due to the escape of magnetospheric electrons along the newly opened field lines. The perpendicular electric field inside the cavity constitutes a potential jump of several kV. The observed potential jump and field aligned currents can be responsible for strong aurora.

A haplotype of the CYP27B1 promoter is associated with autoimmune Addison's disease but not with Graves' disease in a UK population.

Previous studies have suggested an association between alleles of the CYP27B1 (1-alpha hydroxylase) gene and autoimmune conditions. We have examined three single nucleotide polymorphisms (SNPs) that are located in the 5' region and promoter of the CYP27B1 gene for association in a cohort of Graves' disease and autoimmune Addison's disease subjects from the UK. Genomic DNA samples from white patients with autoimmune Addison's disease (n = 104) and healthy controls (n = 464) were genotyped by PCR-RFLP analysis for the SNPs at positions -1260 and -1077 5' of the coding CYP27B1 sequences. The -1260 SNP was also examined in a cohort of patients with Graves' disease (n = 446). Chi 2 testing of contingency tables was used to determine the significance of genotypes and alleles. Haplotype frequencies and linkage disequilibrium measures were estimated using the UNPHASED and HAPLOVIEW packages. Alleles at the three CYP27B1 markers were in tight linkage disequilibrium with each other and all showed association with autoimmune Addison's disease. The maximum evidence for association was with the -1260 C allele (76.0% in Addison's subjects versus 64.9% in controls; P = 0.003; odds ratio 1.71 (5-95% confidence intervals, 1.20-2.44). A global test of significance for the common -1918 T, -1260 C and -1077 G haplotype was significant in Addison's subjects compared with controls (P = 0.01). In contrast, there was no association of alleles at the -1260 SNP with Graves' disease. We are able to confirm that a CYP27B1 promoter allele is associated with autoimmune Addison's disease, and extend this finding to include an associated promoter haplotype.

The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves' disease.

The lymphoid tyrosine phosphatase (LYP), encoded by the protein tyrosine phosphatase-22 (PTPN22) gene, is a powerful inhibitor of T cell activation. Recently, a single nucleotide polymorphism (SNP), encoding a functional arginine to tryptophan residue change at LYP codon 620 has been shown to be associated with type 1 diabetes and other autoimmune disorders. We have used a PCR-restriction fragment (XcmI) assay to examine genotypes at the codon 620 polymorphism in 549 unrelated probands with Graves' disease, 104 unrelated subjects with autoimmune Addison's disease and 429 controls. The T nucleotide at the SNP, encoding the tryptophan 620 residue, was present in 151 of 1098 (13.8%) Graves' disease alleles compared to 67 of 858 (7.8%) control alleles (chi(2) = 17.2, p = 3.4 x 10(-5)' odds ratio = 1.88, 5-95% confidence intervals [CI] 1.39 to 2.55). Similarly, the T nucleotide at the codon 620 SNP was present in 26 of 208 (12.5%) Addison's disease alleles vs 7.8% of controls (chi(2) = 4.63, p = 0.031; odds ratio = 1.69, 5-95% CI 1.04 to 2.73). These data suggest that this LYP polymorphism is a susceptibility allele for Graves' disease with a major effect, and which is likely to have a role in many other autoimmune conditions.

Prevalence of maternal dietary iodine insufficiency in the north east of England: implications for the fetus.

BACKGROUND: Maternal subclinical hypothyroidism is a cause of poor neurodevelopment outcome in the offspring. Although iodine deficiency is the most common cause of hypothyroidism world wide, there are no screening programmes for it in the United Kingdom where the population is assumed to be iodine replete. OBJECTIVE: To determine the prevalence of reduced iodine intake by measuring urinary iodide concentrations in pregnant and non-pregnant women from the north east of England. METHODS: Urinary iodide excretion (UIE) rate was estimated using inductively coupled mass spectrometry in 227 women at 15 weeks gestation and in 227 non-pregnant age matched controls. A reduced intake of iodine is indicated by a concentration in urine of less than 50 microg/l or less than 0.05 microg iodine/mmol creatinine. RESULTS: Eight (3.5%) pregnant women and 13 (5.7%) controls had a reduced iodine/creatinine ratio. These values were higher when UIE was expressed as iodine concentration: 16 (7%) and 20 (8.8%) respectively. Ninety (40%) of the pregnant women had a UIE of 0.05-0.10, which is consistent with borderline deficiency. CONCLUSION: In this study, 3.5% of pregnant women had evidence of iodine deficiency, and 40% may be borderline deficient. Larger scale studies are required to estimate the true prevalence of iodine deficiency in the United Kingdom.

Treatment of vasospasm with a 480-nm pulsed-dye laser.

Laser energy at a wavelength of 480 nm was applied in 1-microseconds pulses of 3 to 10 mJ to two models of vasospasm. Rabbit common carotid arteries (CCA's) were constricted chronically by the application of human blood within a silicone sheath. Peak vasospasm developed 24 to 48 hours later, and persisted for up to 6 days. Endovascular laser treatment was delivered to 40 CCA's via a 200-microns diameter silica quartz fiber introduced through the femoral artery. The CCA caliber increased from 60% of the pre-vasospasm control diameter to a minimum post-laser diameter of 83% of control. No instances of laser-induced perforation or of arterial thrombosis were observed for up to 60 days after treatment. Prophylactic laser application to nine normal vessels was able to attenuate the development of vasospasm if blood was applied immediately thereafter (88% vs. 59% of control diameter, p less than 0.02), but not if blood was applied 7 days later. Studies in 16 normal CCA's established that there was a considerable margin between the laser energy required to induce dilatation and that which caused perforation, providing that the fiber remained relatively central within the artery. Morphological examination demonstrated focal loss of endothelial cells immediately after laser application, followed approximately 7 days later by the development of areas of intimal hyperplasia. Only minimal changes were observed in the medial or adventitial layers. In a second study, the basilar artery of seven dogs was constricted chronically by two intracisternal injections of autologous blood 3 days apart. Five dogs received endovascular laser treatment 7 or 10 days after the first injection, when basilar artery diameter was reduced to a mean of 61% and 77% of control, respectively. Immediately following treatment, basilar artery diameter increased to 104% and 102% of resting diameter, respectively. Both untreated and laser-treated arteries were smaller than the control diameter at 30 days (80% and 82%, respectively), but in each group the vasodilatory response to hypercapnia was preserved. These findings indicate that 1-microsecond laser pulses are well tolerated by systemic and cerebral arteries in two different animal models, and suggest that the 480-nm pulsed-dye laser may have an application for the treatment or prophylaxis of cerebral vasospasm.

Application of the 1-microsecond pulsed-dye laser to the treatment of experimental cerebral vasospasm.

Laser energy of 480 nm was applied in 1-microsecond pulses varying between 2.2 and 10 mJ to in vitro and in vivo models of cerebral vasospasm. First, the pulsed-dye laser was applied intravascularly via a 320-microns fiber to basilar artery segments from six dogs. The segments were mounted in a vessel-perfusion apparatus and constricted to, on average, 70% of resting diameter by superfusion with dog hemolysate. Immediate increase in basilar artery diameter occurred to a mean of 83% of control. In a second model, the basilar artery was exposed transclivally in the rabbit. In three normal animals, superfusion of the artery with rabbit hemolysate resulted in a reduction of mean vessel diameter to 81% of control. Following extravascular application of the laser, vessels returned to an average of 106% of the resting state. In six rabbits, the basilar artery was constricted by two intracisternal injections of autologous blood. 3 days apart. Two to 4 days after the second injection, the basilar artery was exposed. Extravascular laser treatment from a quartz fiber placed perpendicular to the vessel adventitia resulted in an immediate 53% average increase in caliber to an estimated 107% of control. No reconstriction was observed over a period of up to 5 hours. Morphologically, damage to the arterial wall was slight. This preliminary investigation suggests that the 1-microsecond pulsed-dye laser may be of benefit in the treatment of cerebral vasospasm.

Evidence of the role of hemolysis in experimental cerebral vasospasm.

The short-term (less than or equal to 72-hour) reaction to subarachnoid injections of various blood components was determined in a canine model of cerebral vasospasm. Platelet-rich plasma (PRP) formed durable clots in the basal cistern surrounding the basilar artery and provoked no vascular reaction in 72 hours or more. Freshly isolated autologous erythrocytes resuspended in PRP likewise provoked no vasoconstriction in 72 hours although a second injection of fresh erythrocytes in PRP induced significant reaction, as in the conventional "double subarachnoid hemorrhage (SAH)" canine model. Hemolysate of fresh erythrocytes led to a severe immediate vascular reaction after introduction into the basal cistern using PRP as the carrier/clotting medium, as did the injection of intact erythrocytes incubated ex vivo for 72 hours. Resolution of the initial reaction was rapid for hemolysate, but slow and (depending on hematocrit) incomplete for intact "aged" erythrocytes. In vitro measurements of erythrocyte lysis in these media and histological examination indicate that the production of erythrocyte lysate was responsible for the vascular reaction observed, suggesting that the rate of lysis of erythrocytes in the subarachnoid clot is a major factor in the genesis of vasospasm after SAH.