We present rapid, multiwavelength photometry of the low-mass X-ray binary Swift J1357.2-0933 during its 2017 outburst. Using several sets of quasi-simultaneous ULTRACAM/NTT (optical), NuSTAR (X-ray), ...XRT/Swift (X-ray), SALT (optical) and ATCA (radio) observations taken during outburst decline, we confirm the frequent optical dipping that has previously been noted both in outburst and in quiescence. We also find: 1) that the dip frequency decreases as the outburst decays, similar to what was seen in the previous outburst, 2) that the dips produce a shape similar to that in binary systems with partial disc occultations, 3) that the source becomes significantly bluer during these dips, indicating an unusual geometry compared to other LMXB dippers, and 4) that dip superposition analysis confirms the lack of an X-ray response to the optical dips. These very unusual properties appear to be unique to Swift J1357.2-0933, and are likely the result of a high binary inclination, as inferred from features such as its very low outburst X-ray luminosity. From this analysis as well as X-ray/optical timing correlations, we suggest a model with multi-component emission/absorption features with differing colours. This could include the possible presence of a sporadically occulted jet base and a recessed disc. This source still hosts many puzzling features, with consequences for the very faint X-ray transients population.
The mechanisms of death and neurologic sequelae in African children with cerebral malaria are undetermined. Because pathologic features are confined to the cerebral vasculature, perturbations in ...cerebral hemodynamics may be responsible. We compared the transcranial Doppler findings in 50 children with cerebral malaria with those of 115 conscious Kenyan children. In addition, 10 children with cerebral malaria were studied during intracranial pressure monitoring and nine children were studied during the agonal stages. In the children with cerebral malaria, cerebral blood flow velocity was increased in 30%, usually associated with seizures. Of the 11 children who developed neurologic sequelae, six had sonographic abnormalities associated with lateralizing deficits, including four children with hemiparesis (in two children the contralateral middle cerebral artery could not be insonated and two had transient increases in blood flow velocity associated with seizures). In the children with severe intracranial hypertension, there was a significant linear relationship between the cerebral perfusion pressure and blood flow velocity, suggesting that autoregulation was impaired. Sonographic features of progressive intracranial hypertension, were observed in three children with cerebral malaria who died. Perturbations of cerebral hemodynamics are associated with a poor outcome in Kenyan children with cerebral malaria.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Gastroesophageal reflux disease (GERD) often is associated with pulmonary problems such as asthma as well as recurrent and nocturnal cough. Dual-probe 24-hr pH monitoring may assist in establishing a ...correlation between these symptoms and GERD-related symptoms. To determine if any specific symptom was predictive of aspiration, this study was undertaken. Ambulatory dual-probe esophageal pH monitoring was performed on 133 patients who had upper airway and additional symptoms for GERD. All patients had esophageal manometric studies of the lower esophageal sphincter (LES), the upper esophageal sphincter (UES), and the esophageal body before dual-probe pH monitoring was performed. Using two assembled glass probes, the distal and the proximal sensors were placed 5 cm above the proximal border of the LES and 1 cm below the lower border of the UES, respectively. Patients were classified into three groups: proximal and distal probe positive (group I), proximal probe negative and distal probe positive (group II) and proximal and distal probe negative (Group III) Upper airway and additional symptoms plus manometry results of the LES, body and UES study were compared between groups. In addition, positive distal probe patients (groups I and II) were compared for distal fraction of time at pH < 4 and number of reflux episodes at each probe position. A positive distal probe result was defined as an abnormal DeMeester score (> 14.8). A proximal probe test result was considered positive if percent time pH < 4.0 was > 1.1 for total, 1.7 for upright, and 0.6 for supine positions. The ages of the subjects ranged from 18 to 83 years (mean age: 50.5 +/- 1.5 years). Groups I, II, and III included 16 patients, 38 patients, and 79 patients, respectively. Group I had a significantly higher incidence of nocturnal cough than the other two groups. (P < 0.05). The manometric data revealed between groups that LES pressure (LESP) for groups I and II was significantly lower than LESP for group III (P = 0.003). Cricoid pressure, pharyngeal pressure, length, and relaxation of UES were not different between groups. Fraction of reflux time for group I was significantly higher than for group II in the supine position and at mealtime (P < 0.05). The number of reflux episodes for group I was significantly higher at meal time (P < 0.01). In conclusion, nocturnal cough is strongly predictive of proximal esophageal reflux. Proximal reflux episodes are significantly more frequent in the supine position and correlate well with the high predictive value of nocturnal cough.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
B-cell lymphoproliferative disorders (BLPD*) caused by Epstein-Barr virus (EBV) occurring after allogeneic bone marrow transplantation (BMT) are usually of donor origin. Treatment such as ...discontinuation of immunosuppression may be successful in some cases, but infusion of donor T cells results in successful eradication of EBV BLPD in most cases.
We report a case of EBV positive aggressive BLPD after HLA matched sibling BMT for aplastic anaemia. The tumour completely regressed after withdrawal of cyclosporin and donor lymphocyte infusion. However, although the tumor was of donor origin, the donor serum was negative for antibodies to EBV antigens and no EBV-specific cytotoxicity was detected in donor peripheral blood mononuclear cells. The recipient was seropositive for EBV before BMT.
We speculate that a 'second primary' EBV infection occurred involving donor cells in the recipient during BMT immunosuppression, with subsequent outgrowth of donor-derived BLPD. EBV infection may have been by an endogenous EBV isolate, from external sources, or from third party transfusions.
During the past two decades of research, the ultra-relativistic beam-driven plasma wakefield accelerator (PWFA) concept has achieved many significant milestones. These include the demonstration of ...ultra-high gradient acceleration of electrons over meter-scale plasma accelerator structures, efficient acceleration of a narrow energy spread electron bunch at high-gradients, positron acceleration using wakes in uniform plasmas and in hollow plasma channels, and demonstrating that highly nonlinear wakes in the 'blow-out regime' have the electric field structure necessary for preserving the emittance of the accelerating bunch. A new 10 GeV electron beam facility, Facilities for Accelerator Science and Experimental Test (FACET) II, is currently under construction at SLAC National Accelerator Laboratory for the next generation of PWFA research and development. The FACET II beams will enable the simultaneous demonstration of substantial energy gain of a small emittance electron bunch while demonstrating an efficient transfer of energy from the drive to the trailing bunch. In this paper we first describe the capabilities of the FACET II facility. We then describe a series of PWFA experiments supported by numerical and particle-in-cell simulations designed to demonstrate plasma wake generation where the drive beam is nearly depleted of its energy, high efficiency acceleration of the trailing bunch while doubling its energy and ultimately, quantifying the emittance growth in a single stage of a PWFA that has optimally designed matching sections. We then briefly discuss other FACET II plasma-based experiments including in situ positron generation and acceleration, and several schemes that are promising for generating sub-micron emittance bunches that will ultimately be needed for both an early application of a PWFA and for a plasma-based future linear collider.
Overexpression of the prosurvival Bcl-2 family members (Bcl-2, Bcl-xL, and Mcl-1) is commonly associated with tumor maintenance, progression, and chemoresistance. We previously reported the discovery ...of ABT-737, a potent, small-molecule Bcl-2 family protein inhibitor. A major limitation of ABT-737 is that it is not orally bioavailable, which would limit chronic single agent therapy and flexibility to dose in combination regimens. Here we report the biological properties of ABT-263, a potent, orally bioavailable Bad-like BH3 mimetic (K(i)'s of <1 nmol/L for Bcl-2, Bcl-xL, and Bcl-w). The oral bioavailability of ABT-263 in preclinical animal models is 20% to 50%, depending on formulation. ABT-263 disrupts Bcl-2/Bcl-xL interactions with pro-death proteins (e.g., Bim), leading to the initiation of apoptosis within 2 hours posttreatment. In human tumor cells, ABT-263 induces Bax translocation, cytochrome c release, and subsequent apoptosis. Oral administration of ABT-263 alone induces complete tumor regressions in xenograft models of small-cell lung cancer and acute lymphoblastic leukemia. In xenograft models of aggressive B-cell lymphoma and multiple myeloma where ABT-263 exhibits modest or no single agent activity, it significantly enhances the efficacy of clinically relevant therapeutic regimens. These data provide the rationale for clinical trials evaluating ABT-263 in small-cell lung cancer and B-cell malignancies. The oral efficacy of ABT-263 should provide dosing flexibility to maximize clinical utility both as a single agent and in combination regimens.
Vanilloid receptor type 1 (TRPV1) is a ligand-gated nonselective cation channel that is considered to be an important integrator of various pain stimuli such as endogenous lipids, capsaicin, heat, ...and low pH. In addition to expression in primary afferents, TRPV1 is also expressed in the CNS. To test the hypothesis that the CNS plays a differential role in the effect of TRPV1 antagonists in various types of pain, the analgesic effects of two TRPV1 antagonists with similar in vitro potency but different CNS penetration were compared in vivo. Oral administration of either A-784168 (1-3-(trifluoromethyl)pyridin-2-yl-N-4-(trifluoromethylsulfonyl)phenyl-1,2,3,6-tetrahydropyridine-4-carboxamide) (good CNS penetration) or A-795614 (N-1H-indazol-4-yl-N'-(1R)-5-piperidin-1-yl-2,3-dihydro-1H-inden-1-ylurea) (poor CNS penetration) blocked capsaicin-induced acute pain with the same potency. In complete Freund's adjuvant (CFA)-induced chronic inflammatory pain, oral administration of either compound blocked thermal hyperalgesia with similar potency. Furthermore, intraplantar or intrathecal administration of A-784168 blocked CFA-induced thermal hyperalgesia, suggesting that both peripheral and CNS TRPV1 receptors may play a role in inflammatory thermal hyperalgesia. The effects of the two TRPV1 antagonists were further assessed in models presumably mediated by central sensitization, including CFA- and capsaicin-induced mechanical allodynia and osteoarthritic pain. In these models, the potency of the two compounds was similar after intrathecal administration. However, when administered orally, A-784168, with good CNS penetration, was much more potent than A-795614. Together, these results demonstrate that TRPV1 receptors in the CNS play an important role in pain mediated by central sensitization. In addition, these results demonstrate that significant CNS penetration is necessary for a TRPV1 antagonist to produce broad-spectrum analgesia.
Summary
Background
There is limited understanding of how maternal diet affects breastmilk food allergen concentrations, and whether exposure to allergens through this route influences the development ...of infant oral tolerance or sensitization.
Objective
To investigate how maternal dietary egg ingestion during early lactation influences egg protein (ovalbumin) levels detected in human breastmilk.
Methods
In a randomized controlled trial, women were allocated to a dietary group for the first six weeks of lactation: high‐egg diet (> 4 eggs per week), low‐egg diet (one‐three eggs per week) or an egg‐free diet. Breastmilk samples were collected at 2, 4 and 6 weeks of lactation for the measurement of ovalbumin. The permeability of the mammary epithelium was assessed by measuring the breastmilk sodium : potassium ratio. Egg‐specific IgE and IgG4 were measured in infant plasma at 6 weeks, and prior to the introduction of egg in solids at 16 weeks.
Results
Average maternal egg ingestion was associated with breastmilk ovalbumin concentration. Specifically, for each additional egg ingested per week, there was an average 25% increase in ovalbumin concentration (95% CI: 5–48%, P = 0.01). Breastmilk ovalbumin concentrations were significantly higher in the ‘high‐egg’ group (> 4 eggs per week) compared with the ‘egg‐free’ group (P = 0.04). However, one‐third of women had no breastmilk ovalbumin detected. No detectable associations were found between mammary epithelium permeability and breastmilk ovalbumin concentrations. Infant plasma egg‐specific IgG4 levels were also positively associated with maternal egg ingestion, with an average 22% (95% CI: 3–45%) increase in infant egg‐specific IgG4 levels per additional egg consumed per week (P = 0.02).
Conclusions and Clinical Relevance
Increased maternal egg ingestion is associated with increased breastmilk ovalbumin, and markers of immune tolerance in infants. These results highlight the potential for maternal diet to benefit infant oral tolerance development during lactation.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The concentrations and distribution of polycyclic aromatic hydrocarbons (PAHs) were assessed in sediment cores from among 14 lakes from three regions comprising a transect across the central ...Mackenzie Delta. PAHs were consistently found in the lake sediments, with parent concentrations in the 20-200 ng/g range. Concentrations were generally independent of depth in the sediment cores and this pattern was similar among the 3 regions of the delta. Concentrations increased in a westerly direction among the regions. For some lakes, the concentration of PAHs decreased with decreasing flooding frequency, and decreasing sedimentation rates. For the latter, maximum concentrations occurred at shallower depths within the sediment cores as flooding frequency among the lakes decreased. The distributions of C
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alkylated 2- and 3- ring PAHs were consistent with a petrogenic origin, while the corresponding distribution of 4-ring PAHs appears to be more consistent with a biogenic or pyrogenic origin. Based on relative contributions to the overall PAH budget, a petrogenic source appears to be dominant. However, the pyrene/fluoranthene ratio is more consistent with a source derived from peat. The alkylated PAH profiles are inconsistent with those in the Athabasca River system, and supports a previously published hypothesis that the contribution of PAHs from the Athabasca oil sands to the lower Mackenzie River is minimal. A double ratio plot of chrysene vs dibenzothiophene, diagnostic of weathering, suggests most weathering occurred before the sediments were deposited in the lakes, while a double ratio plot of dibenzothiophene vs phenanthrene suggests a common source of PAHs across the delta, despite differing water sources from east to west across the delta. PAH inputs to the delta appear to mirror sediment inputs documented in previous work, where high sediment input from the Mackenzie mainstem during high floods dominates the delta sediment influx and masks any influence of the Peel River.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
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