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Background: The Stroke & Vascular Neurology Section of the American Academy of Neurology was charged to identify challenges to the recruitment and retention of stroke neurologists and to make recommendations to address any identified problems. The Section initiated this effort by determining the impact of stroke on-call requirements as a barrier to the recruitment and retention of vascular neurologists.Methods: This is a cross-sectional survey of a sample of US Neurologists providing acute stroke care.Results: Of the 900 neurologists who were sent surveys, 313 (35%) responded. Of respondents from institutions providing stroke coverage, 71% indicated that general neurologists and 45% indicated that vascular neurologists provided that service. Of those taking stroke call, 36% agreed with the statement, "I spent too much time on stroke call," a perception that was less common among those who took less than 12-hour shifts (P < .0001); 21% who participated in stroke call were dissatisfied with their current job. Forty-six percent indicated that their stroke call duties contributed to their personal feeling of "burnout."Conclusions: Although the reasons are likely multifactorial, our survey of neurologists providing stroke care suggests that over-burdensome on-call responsibilities may be contributing to the vascular neurology workforce burnout and could be affecting recruitment and retention of vascular neurologists. Strategies to reduce the lifestyle impact of stroke call may help address this problem. [ABSTRACT FROM AUTHOR]

Evolved gas analysis (EGA) mass-spectrometry (MS) is used to characterize the solid state pyrolysis decomposition pathways of air- and moisture-sensitive organometallic compounds. In this study, the single-source GaAs compounds (Et 2 AsGaEt 2 ) 3 ( 1) , ( t -Bu 2 AsGaEt 2 ) 2 ( 2) , and [ t -Bu(H)AsGaEt 2 ] 2 ( 3) were heated in capillary tubes under inert condition and the volatile products were analyzed by MS. In addition, the relative ratios of evolved gases were characterized using gas chromatography (GC), while the solid state pyrolysis products were analyzed by EDS, 1 H NMR and XRD. Pyrolysis of GaAs single-source materials in the solid state reveals chemical information on the stability of the Ga As bond, an observation masked in gas-phase analysis of single-source materials during chemical vapor deposition. Information on Ga As bond stability may be elucidated due to the volatility of the by-products formed during Ga-As precursor pyrolysis. Loss of Ga As bond integrity in materials with alkyl substitution on Ga and As leads to formation of mobile and volatile alkyl diarsine species, as was observed for the pyrolysis of 1. An in-situ method to monitor solid-state pyrolysis by mass spectrometry identified the loss of a tetraalkyl-diarsine as the critical factor that drives formation of sub-stoichiometric GaAs products from single-source precursors. Replacing a single alkyl group on the As atom with a H (precursor 3 ) leads to the loss of an alkane instead of tetraalkyl-diarsine formation. Solid-state pyrolysis precursor 3 results in the formation of polycrystalline GaAs in up to 58% yield with a 52:48 Ga:As stoichiometry. [ABSTRACT FROM AUTHOR]

Abstract: This electrophysiological study investigated the relationship between language and nonverbal socio-spatial context for demonstrative use in speech communication. Adult participants from an English language group and a Japanese language group were asked to make congruency judgment for simultaneous presentation of an audio demonstrative phrase in their native language and a picture that included two human figures as speaker and hearer, as well as a referent object in different spatial arrangements. The demonstratives (“this” and “that” in English, and “ko,” “so,” and “a” in Japanese) were varied for the visual scenes to produce expected and unexpected combinations to refer to an object based on its relative spatial distances to the speaker and hearer. Half of the trials included an accompanying pointing gesture in the picture, and the other half did not. Behavioral data showed robust congruency effects with longer reaction time for the incongruent trials in both subject groups irrespective of the presence or absence of the pointing gesture. Both subject groups also showed a significant N400-like congruency effect in the event-related potential responses for the gesture trials, a finding predicted from previous work (Stevens & Zhang, 2013). In the no-gesture trials, the English data alone showed a P600 congruency effect preceded by a negative deflection. These results provide evidence for shared brain mechanisms for processing demonstrative expression congruency, as well as language-specific neural sensitivity to encoding the co-expressivity of gesture and speech. [Copyright &y& Elsevier]

Abstract: The daily variation in air temperature is large compared with the temperature changes a short distance below the surface of the ground. In theory, a heat engine can be arranged to produce electricity from this temperature difference. In practice, the thermal efficiency of such a device will be low because of the small temperature differences involved. One example of such an energy harvesting device that can produce a small amount of electrical power uses a thermoelectric generator operating between the air and ground temperatures. The low thermal efficiency means that accurately predicting thermal resistances throughout the device and at the air-side and ground-side heat exchangers is critical to the creation of a useful device. Advantages of this device include high reliability, no acoustic emissions, low visibility, significant night-time power production, ruggedness, and long life. With appropriate external power conditioning components, the device could be used to power remote sensors and communications systems. The design of a pair of milliwatt-scale ground source heat engines is described. The devices were fabricated using custom heat exchangers and off-the-shelf thermoelectric modules and other supplies. Both systems were tested over an extended period in order to quantitatively assess effects of sunlight and precipitation on system performance and life. Exhaustive analysis of air-side average heat transfer coefficients, system thermal resistances, and ground-side thermal resistances provides quantitative design information for future applications. Finned and unfinned versions of otherwise identical prototypes permits assessment of fin performance on both ground-side and air-side heat transfer. [Copyright &y& Elsevier]

Abstract: How linguistic expressions are contextually constrained is of vital importance to our understanding of language as a formal representational system and a vehicle of social communication. This study collected behavioral and event-related potential (ERP) data to investigate neural processing of two entity-referring spatial demonstrative expressions, this one and that one, in different contexts involving the speaker, the hearer and the referred-to object. Stimulus presentation varied distance and gaze conditions with either semantically congruent or incongruent audiovisual pairings. Behavioral responses showed that distance determined the demonstrative form only in joint gaze conditions. The ERP data for the joint gaze conditions further indicated significant congruent vs. incongruent differences in the post-stimulus window of 525–725 ms for the hearer-associated spatial context. Standardized Low Resolution Brain Electromagnetic Tomography (sLORETA) showed left temporal and bilateral parietal activations for the effect. The results provide the first neural evidence that the use of spatial demonstratives in English is obligatorily influenced by two factors: (1) shared gaze of speaker and hearer, and (2) the relative distance of the object to the speaker and hearer. These findings have important implications for cognitive-linguistic theories and studies on language development and social discourse. [Copyright &y& Elsevier]

Abstract: For a thermoelectric device driven by the temperature difference between soil and ambient air, previous analytical work has been performed wherein a sinusoidal surface boundary condition was imposed; the results suggested that optimal placement of the lower terminal of the device should be at a nondimensional depth of x∗ =2.28, resulting in a 7% increase in power over placement at a much greater depth. Analysis of temperature data taken in conjunction with operation of a thermoelectric device has shown that the optimal depth for the lower thermal reservoir is much shallower than originally thought (x ∗ ∼1), with increases in performance approaching 70% over that experienced at greater depths. Representative data are presented and interpreted, along with recommendations for future work. [Copyright &y& Elsevier]

Drug safety remains a high profile issue at a time when the cost and time required to develop a new drug are at an all time high. Balancing risk against the expected clinical benefit is the primary purpose of preclinical and clinical testing. We offer an expanded view on the application of predictive strategies and technologies to early safety decisions and suggestions to narrow the focus for improving preclinical safety testing to the problems that contribute most to adverse drug reactions. [Copyright &y& Elsevier]

Productivity issues facing the pharmaceutical industry are numerous, and the current challenges come in the face of an aging population and a demand for new and better medications. These challenges call for improvement in the drug discovery and development process, which paradoxically comes on the heels of remarkable scientific advances and in an era of great opportunity in medical science. Despite these advances, the pharmaceutical industry has yet to translate breakthroughs in new technologies, including genomics, into new drug therapies for unmet medical needs. The strategic application of toxicogenomics to the earliest stages of a drug discovery program offers a valuable opportunity to identify potential safety hurdles earlier than is the norm today. We propose that using genomics predictively (in vitro to predict outcomes in vivo and short-term studies in vivo to predict safety issues in longer studies) can assist in reducing inefficiency in the current paradigm, which is still heavily weighted on traditional endpoints from lengthy in vivo studies. Implementation of these strategies will assist in solving the current pharmaceutical pipeline productivity dilemma of long cycle times and unacceptable attrition rates in the preclinical drug discovery process. [Copyright &y& Elsevier]

The year 2009 is the 100th anniversary of the founding of the first inbred strain of mouse, called DBA. During the last 100 years, inbred strains have proved their value for biomedical research and the number of such strains has mushroomed to over 450, each with different genotypic and phenotypic characteristics and useful for the study of disease and normal function. However, although inbred strains are stable, they are not fixed entities and researchers need to be aware of the phenomena of new mutations and of genetic drift, which occur within all mouse colonies. If the mutations are what we term in this review ‘quiet mutations’, then they might result in rather unexpected and sometimes tremendously valuable results. Here, we discuss these phenomena and look at how new genomic technologies might help us to detect ‘quiet mutations’ and use them to our advantage. [Copyright &y& Elsevier]

Abstract: Our first aim was to determine whether an isocaloric intervention using α-linolenic acid (ALA) in the form of flaxseed oil would alter adiponectin levels among overweight, otherwise healthy, males and females, and our second aim was to test for any potential modification of this intervention by 2 single nucleotide polymorphisms (276 and 45) in the adiponectin gene. Subjects included healthy adult males and females (∼81% female; average age, 38 years) with increased waist circumference (mean, 99 cm) and body mass index (mean, 30 kg/m2) who were free of chronic disease, not taking medications, and sedentary. Subjects met weekly with a registered dietician for 8 weeks. The control subjects (n = 27) were instructed not to alter their habitual diet and the ALA group (n = 30) was instructed to follow an enriched ALA diet by using flaxseed oil capsules (increasing ALA to 5% of total energy intake) and to lower their dietary fat consumption by a commensurate amount. Diets were analyzed using the Food Intake and Analysis System (v. 3.0, University of Texas School of Public Health, 1998). Fasting blood samples were obtained before and after the 8-week intervention. We found significant decreases (P = .02) in adiponectin (10.12 μg/mL pre, 9.23 μg/mL post) in the ALA group as compared with the control group (7.93 μg/mL pre, 8.10 μg/mL post) after the intervention. We also saw a decline in adiponectin in all genotype groups with the greatest decline among those carrying the rare T allele of single nucleotide polymorphism 276. There were no significant changes in fasting insulin, glucose, or quantitative insulin sensitivity check index values as a result of this intervention. In conclusion, this study suggests that supplementing with ALA for 8 weeks may lower adiponectin levels among healthy individuals, and this effect appears to be independent of polymorphisms in the adiponectin gene. Although the change in adiponectin in response to the ω-3 fatty acids was not accompanied by any change in glucose, insulin, or quantitative insulin sensitivity check index, long-term implications of such a decrease should be considered in future studies. [Copyright &y& Elsevier]

Abstract: The propagation of uncertainty in non-linear cases can be handled accurately and easily with a piecewise linear approach to propagating the probability density function through the analysis equation. Previous work outlined this method but did not examine the effects of parameters on the accuracy of the results. Parameters to be chosen in this approach include the number of evaluation points and the distribution of those points over the range of interest. The effects of these parameters are explored for three elementary functions. It is found that for the functions examined, the piecewise linear approach always converged with increasing numbers of points. For the cases examined, 30–200 evaluation points were required for convergence. A uniform distribution of points was both the simplest to implement and converged the fastest. [Copyright &y& Elsevier]

Objective: To analyze the long-term outcomes in pediatric liver transplant recipients after they have transferred to an adult provider and assess for racial disparities in health outcomes.Study Design: This is a single-center, retrospective review of pediatric patients who underwent liver transplantation between July 1990 and August 2015 at a tertiary healthcare system with a large transplant center. Patient mortality and retransplantation were assessed after transfer to adult care.Results: There were 120 patients who were transferred, of whom 19 did not meet the inclusion criteria. Of the remaining 101 patients, 64 (63%) transferred care to a nearby affiliated tertiary adult facility, 29 (29%) were followed by other healthcare systems, and 8 (8%) were lost to follow-up. Of the patients followed at our affiliated adult center, 18 of the 64 (28%) died. Of those 18 deaths, 4 (22%) occurred within the first 2 years after transfer, and 10 (55%) within 5 years of transfer. Four patients were retransplanted by an adult provider, of whom 2 eventually received a third transplant. African Americans had higher rates of death after transfer than patients of other races (44% mortality vs 16%, representing 67% of all cases of death; P = .032), with nearly 50% mortality at 20 years from time of transplantation.Conclusions: Death is common in pediatric liver transplant recipients after transfer to adult care, with African Americans having disproportionately higher mortality. This period of transition of care is a vulnerable time, and measures must be taken to ensure the safe transfer of young adults with chronic health care needs. [ABSTRACT FROM AUTHOR]

Complications from esophageal button battery impactions remain a real fear for practicing pediatric gastroenterologists and surgeons. This case describes a child who developed an aorto-esophageal fistula 25 days after initial battery ingestion and survived due to prompt placement of an aortic stent via minimally invasive surgery, avoiding an open procedure. A 6-year-old female presented acutely with a mid-esophageal button battery impaction witnessed by her parents. Presenting symptoms included chest pain and emesis. Button battery location and size were confirmed on X-ray. She underwent removal with flexible esophagogastroduodenoscopy (EGD) and rigid esophagoscopy. She was admitted to the hospital and received conservative medical management, with serial cross-sectional imaging via chest MRIs to assess the evolution of her injury according to available national guidelines, and was discharged after 12 days of close inpatient monitoring. Despite these measures the patient re-presented 25 days post-ingestion with hematemesis from a new aorto-esophageal fistula, requiring emergent cardiac catheterization with successful, life-saving aortic stent placement. She remained admitted for an additional 12 days of monitoring as her diet was advanced slowly post-catheterization. Since this second hospitalization she continues to do well, with outpatient follow-up by multiple subspecialists. This case highlights the continued uncertainty regarding the risk of developing this complication, as well as gaps in the current literature and guidelines for managing these patients following ingestion and esophageal injury. It also details the unique course following development of this complication and its surgical repair. • Button battery ingestions with esophageal impaction can lead to life-threatening complications. • These complications can occur several weeks after the initial ingestion despite conservative medical management. • Multidisciplinary teamwork resulted in prompt life-saving treatment for this patient. • Minimally invasive aortic stent placement is a possible life-saving intervention in arterio-esophageal fistula development. [ABSTRACT FROM AUTHOR]

We investigated the role of the endoplasmic reticulum (ER) stress response in intracellular Ca[sup 2+] regulation, MAPK activation, and cytoprotection in LLC-PK[sub 1] renal epithelial cells in an attempt to identify the mechanisms of protection afforded by ER stress. Cells preconditioned with trans-4,5-dihydroxy-1,2-dithiane, tunicamycin, thapsigargin, or A23187 expressed ER stress proteins and were resistant to subsequent H[sub 2]O[sub 2]-induced cell injury. In addition, ER stress preconditioning prevented the increase in intracellular Ca[sup 2+] concentration that normally follows H[sub 2]O[sub 2] exposure. Stable transfection of cells with antisense RNA targeted against GRP78 (pkASgrp78 cells) prevented GRP78 induction, disabled the ER stress response, sensitized cells to H[sub 2]O[sub 2]-induced injury, and prevented the development of tolerance to H[sub 2]O[sub 2] that normally occurs with preconditioning. ERK and JNK were transiently (30-60 min) phosphorylated in response to H[sub 2]O[sub 2]. ER stress-preconditioned cells had more ERK and less JNK phosphorylation than control cells in response to H[sub 2]O[sub 2] exposure. Preincubation with a specific inhibitor of JNK activation or adenoviral infection with a construct that encodes constitutively active MEK1, the upstream activator of ERKs, also protected cells against H[sub 2]O[sub 2] toxicity. In contrast, the pkASgrp78 cells had less ERK and more JNK phosphorylation upon H[sub 2]O[sub 2] exposure. Expression of constitutively active ERK also conferred protection on native as well as pkASgrp78 cells. These results indicate that GRP78 plays an important role in the ER stress response and cytoprotection. ER stress preconditioning attenuates H[sub 2]O[sub 2]-induced cell injury in LLC-PK[sub 1] cells by preventing an increase in intracellular Ca[sup 2+] concentration, potentiating ERK activation, and decreasing JNK activation. Thus, the ER stress response modulates the balance between ERK and JNK... [ABSTRACT FROM AUTHOR]

Abstract Annual vaccination is routinely used in organ transplant recipients for immunization against seasonal influenza. However, detailed analysis of the kinetics of vaccine-induced immune responses in this population is lacking. In this study, we investigated the kinetics of vaccine strains-specific antibody responses to trivalent influenza vaccine in a group of renal transplant recipients and a control group. First, we found that the geometric mean hemagglutination inhibition titer against all 3 vaccine strains in the transplant cohort was significantly low when compared to control subjects. Next, whereas the control group sera showed significantly higher HA-specific IgG and isotype IgG1 antibodies at all four time points, a similar increase in the transplant group was delayed until day 28. Interestingly, within the transplant group, subjects receiving belatacept/MMF/prednisone-based regimen had significantly lower levels of total IgG and HA-specific IgG when compared to tacrolimus/MMF/prednisone-based regimen. Even though IgG-ASC response in both cohorts peaked at day 7 post-vaccination, the frequency of IgG-ASC was significantly low in the transplant group. Taken together, our studies show delayed kinetics and lower levels of influenza vaccine-specific antibody responses in renal transplant recipients and, more importantly, indicate the need to probe and improve current vaccination strategies in renal transplant recipients. [ABSTRACT FROM AUTHOR]

Characterization of the epitopes on antigen recognized by monoclonal antibodies (mAb) is useful for the development of therapeutic antibodies, diagnostic tools, and vaccines. Epitope mapping also provides functional information for sequence-based repertoire analysis of antibody response to pathogen infection and/or vaccination. However, development of mapping strategies has lagged behind mAb discovery. We have developed a site-directed mutagenesis approach that can be used in conjunction with bio-layer interferometry (BLI) biosensors to map mAb epitopes. By generating a panel of single point mutants in the recombinant hemagglutinin (HA) and neuraminidase (NA) proteins of influenza A viruses, we have characterized the epitopes of hundreds of mAbs targeting the H1 and H3 subtypes of HA and the N9 subtype of NA. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (steatosis) is the most prevalent liver disease in the Western world. One of the advanced pathologies is nonalcoholic steatohepatitis (NASH), which is associated with induction of the unfolded protein response (UPR) and disruption of autophagic flux. However, the mechanisms by which these processes contribute to the pathogenesis of human diseases are unclear. Herein, we identify theα isoform of the inhibitor of Bruton's tyrosine kinase (IBTKα) as a member of the UPR, whose expression is preferentially translated during endoplasmic reticulum (ER) stress. We found that IBTKα is located in the ER and associates with proteins LC3b, SEC16A and SEC31A and plays a previously unrecognized role in phagophore initiation from ER exit sites. Depletion of IBTKα helps prevent accumulation of autophagosome intermediates stemming from exposure to saturated free fatty acids and rescues hepatocytes from death. Of note, induction of IBTKα and the UPR, along with inhibition of autophagic flux, was associated with progression from steatosis to NASH in liver biopsies. These results indicate a function for IBTKα in NASH that links autophagy with activation of the UPR. [ABSTRACT FROM AUTHOR]

Zoonotic A(H7N9) avian influenza viruses emerged in China in 2013 and continue to be a threat to human public health, having infected over 800 individuals with a mortality rate approaching 40%. Treatment options for people infected with A(H7N9) include the use of neuraminidase (NA) inhibitors. However, like other influenza viruses, A(H7N9) can become resistant to these drugs. The use of monoclonal antibodies is a rapidly developing strategy for controlling influenza virus infection. Here we generated a murine monoclonal antibody (3c10-3) directed against the NA of A(H7N9) and show that prophylactic systemic administration of 3c10-3 fully protected mice from lethal challenge with wild-type A/Anhui/1/2013 (H7N9). Further, post-infection treatment with a single systemic dose of 3c10-3 at either 24, 48 or 72 h post A(H7N9) challenge resulted in both dose- and time-dependent protection of up to 100% of mice, demonstrating therapeutic potential for 3c10-3. Epitope mapping revealed that 3c10-3 binds near the enzyme active site of NA, and functional characterization showed that 3c10-3 inhibits the enzyme activity of NA and restricts the cell-to-cell spread of the virus in cultured cells. Affinity analysis also revealed that 3c10-3 binds equally well to recombinant NA of wild-type A/Anhui/1/2013 and to a variant NA carrying a R289K mutation known to infer NAI resistance. These results suggest that 3c10-3 has the potential to be used as a therapeutic to treat A(H7N9) infections either as an alternative to, or in combination with, current NA antiviral inhibitors. [ABSTRACT FROM AUTHOR]

Since the first case of human infection in March 2013, continued reports of H7N9 cases highlight a potential pandemic threat. Highly immunogenic vaccines to this virus are urgently needed to protect vulnerable populations who lack protective immunity. In this study, an egg- and adjuvant-independent adenoviral vector-based, hemagglutinin H7 subtype influenza vaccine (HAd-H7HA) demonstrated enhanced cell-mediated immunity as well as serum antibody responses in a mouse model. Most importantly, this vaccine provided complete protection against homologous A/H7N9 viral challenge suggesting its potential utility as a pandemic vaccine. [ABSTRACT FROM AUTHOR]

Summary: Background: Three small trials suggest that intravenous immunoglobulin can affect biomarkers and symptoms of mild-to-moderate Alzheimer''s disease. We tested the safety, effective dose, and infusion interval of intravenous immunoglobulin in such patients. Methods: We did a multicentre, placebo-controlled phase 2 trial at seven sites in the USA and five in Germany. Participants with probable Alzheimer''s disease aged 50–85 years were randomly assigned (by a computer-generated randomisation sequence, with block sizes of eight) to infusions every 4 weeks (0·2, 0·5, or 0·8 g intravenous immunoglobulin per kg bodyweight, or placebo) or infusions every 2 weeks (0·1, 0·25, or 0·4 g/kg, or placebo). Patients, caregivers, investigators assessing outcomes, and staff at imaging facilities and the clinical research organisation were masked to treatment allocation, but dispensing pharmacists, the statistician, and the person responsible for final PET analyses were not. Treatment was masked with opaque pouches and infusion lines. The primary endpoint was median area under the curve (AUC) of plasma amyloid β (Aβ)1–40 between the last infusion and the final visit (2 weeks or 4 weeks depending on infusion interval) in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT00812565) and controlled-trials.com (ISRCTN64846759). Findings: 89 patients were assessed for eligibility, of whom 58 were enrolled and 55 included in the primary analysis. Median AUC of plasma Aβ1–40 was not significantly different for intravenous immunoglobulin compared with placebo for five of the six intervention groups (–18·0 [range −1347·0 to 1068·5] for 0·2 g/kg, −364·3 [–5834·5 to 1953·5] for 0·5 g/kg, and −351·8 [–1084·0 to 936·5] for 0·8 g/kg every 4 weeks vs −116·3 [–1379·0 to 5266·0] for placebo; and −13·8 [–1729·0 to 307·0] for 0·1 g/kg, and −32·5 [–1102·5 to 451·5] for 0·25 g/kg every 2 weeks vs 159·5 [51·5 to 303·0] for placebo; p>0·05 for all). The difference in median AUC of plasma Aβ1–40 between the 0·4 g/kg every 2 weeks group (47·0 [range −341·0 to 72·5]) and the placebo group was significant (p=0·0216). 25 of 42 (60%) patients in the intervention group versus nine of 14 (64%) receiving placebo had an adverse event. Four of 42 (10%) patients in the intravenous immunoglobulin group versus four of 14 (29%) receiving placebo had a serious adverse event, including one stroke in the intervention group. Interpretation: Intravenous immunoglobulin may have an acceptable safety profile. Our results did not accord with those from previous studies. Longer trials with greater power are needed to assess the cognitive and functional effects of intravenous immunoglobulin in patients with Alzheimer''s disease. Funding: Octapharma AG. [Copyright &y& Elsevier]

Abstract: A major challenge facing the future Hydrogen Economy is the issue of hydrogen fuel delivery and distribution. In the near term, it may be necessary to deliver high-density hydrocarbon fuels (e.g., diesel fuel) directly to the end-user (e.g., a fueling station) wherein it is reformed to hydrogen, on demand. This approach has the advantages of utilizing the existing fuel delivery infrastructure, and the fact that more energy can be delivered per trip when the tanker is filled with diesel instead of liquefied or compressed hydrogen gas. Reforming high-sulfur hydrocarbon fuels (e.g., diesel, JP-8, etc.) is particularly challenging due to rapid deactivation of conventional reforming catalysts by sulfurous compounds. A new on-demand hydrogen production technology for distributed hydrogen production is reported. In this process, first, the diesel fuel is catalytically pre-reformed to shorter chain hydrocarbons (C1–C6) before being fed to the steam reformer, where it is converted to syngas and further to high-purity hydrogen gas. In the pre-reformer, most sulfurous species present in the fuel are converted to H2S. Desulfurization of the pre-reformate gas is carried out in a special regenerative redox system, which includes an iron-based scrubber coupled with an electrolyzer. The integrated pre-reformer and sulfur-scrubbing unit operated successfully for 100h at desulfurization efficiency of greater than 95%. [Copyright &y& Elsevier]

: ObjectiveTo evaluate visual performance and resolution through night vision goggles (NVG) before and after photorefractive keratectomy (PRK).: DesignNonrandomized, comparative (self-controlled) trial.: ParticipantsNineteen patients (38 eyes) of active-duty US Army Special Forces soldiers.: InterventionPRK for myopia and astigmatism.: Main outcome measuresVisual acuity with best optical correction was measured preoperatively and postoperatively (3 months) using acuity charts of various contrast (100%, 10%, 2.5%, 1.25%). Preoperative and postoperative (3 month) uncorrected and best-corrected visual resolutions through NVGs were assessed using a high contrast tribar chart presented at four light levels (3.44 × 10−3, 1.08 × 10−3, 1.04 × 10−4, 1.09 × 10−5 foot Lamberts) simulating a range of night sky conditions. Subjects were trained before testing.: ResultsUncorrected visual acuity at the 3-month postoperative assessment was greater than or equal to 20/20 in 33 of 38 (86.8%) eyes. No eyes lost 2 or more lines of best spectacle-corrected visual acuity. Preoperative and 3-month postoperative best-corrected low-contrast acuity measurements showed no significant differences at all levels of resolution. Preoperative visual resolution through NVGs decreased systematically with decreasing night sky condition. Visual acuities before PRK were reduced without optical correction. Postoperative visual performance with NVGs (without optical correction) equaled or exceeded performance preoperatively with best correction.: ConclusionsThis prospective case series provides data on the safety and efficacy of PRK with respect to visual performance under night sky conditions using NVGs. There was no significant loss of visual acuity across a range of contrast levels 3 months postoperatively. There was no change in best-corrected NVG visual resolution postoperatively, whereas uncorrected visual resolution was significantly enhanced compared with preoperative levels. This improvement may translate into better function for soldiers who are unable to or choose not to use optical correction in operational environments. [Copyright &y& Elsevier]

The Food Quality Protection Act (FQPA) of 1996 requires the United States Environmental Protection Agency to consider the cumulative effects of exposure to pesticides having a ‘common mechanism of toxicity.’ This paper reviews the information available on the acute neurotoxicity and mechanisms of toxic action of pyrethroid insecticides in mammals from the perspective of the ‘common mechanism’ statute of the FQPA. The principal effects of pyrethroids as a class are various signs of excitatory neurotoxicity. Historically, pyrethroids were grouped into two subclasses (Types I and II) based on chemical structure and the production of either the T (tremor) or CS (choreoathetosis with salivation) intoxication syndrome following intravenous or intracerebral administration to rodents. Although this classification system is widely employed, it has several shortcomings for the identification of common toxic effects. In particular, it does not reflect the diversity of intoxication signs found following oral administration of various pyrethroids. Pyrethroids act in vitro on a variety of putative biochemical and physiological target sites, four of which merit consideration as sites of toxic action. Voltage-sensitive sodium channels, the sites of insecticidal action, are also important target sites in mammals. Unlike insects, mammals have multiple sodium channel isoforms that vary in their biophysical and pharmacological properties, including their differential sensitivity to pyrethroids. Pyrethroids also act on some isoforms of voltage-sensitive calcium and chloride channels, and these effects may contribute to the toxicity of some compounds. Effects on peripheral-type benzodiazepine receptors are unlikely to be a principal cause of pyrethroid intoxication but may contribute to or enhance convulsions caused by actions at other target sites. In contrast, other putative target sites that have been identified in vitro do not appear to play a major role in pyrethroid intoxication. The diverse toxic actions and pharmacological effects of pyrethroids suggest that simple additivity models based on combined actions at a single target are not appropriate to assess the risks of cumulative exposure to multiple pyrethroids. [Copyright &y& Elsevier]

[Display omitted] Drug-induced liver injury (DILI) is the most prevalent adversity encountered in drug development and clinical settings leading to urgent needs to understand the underlying mechanisms. In this study, we have systematically investigated the dynamics of the activation of cellular stress response pathways and cell death outcomes upon exposure of a panel of liver toxicants using live cell imaging of fluorescent reporter cell lines. We established a comprehensive temporal dynamic response profile of a large set of BAC-GFP HepG2 cell lines representing the following components of stress signaling: i) unfolded protein response (UPR) [ATF4, XBP1, BIP and CHOP]; ii) oxidative stress [NRF2, SRXN1, HMOX1]; iii) DNA damage [P53, P21, BTG2, MDM2]; and iv) NF-κB pathway [A20, ICAM1]. We quantified the single cell GFP expression as a surrogate for endogenous protein expression using live cell imaging over > 60 h upon exposure to 14 DILI compounds at multiple concentrations. Using logic-based ordinary differential equation (Logic-ODE), we modelled the dynamic profiles of the different stress responses and extracted specific descriptors potentially predicting the progressive outcomes. We identified the activation of ATF4-CHOP axis of the UPR as the key pathway showing the highest correlation with cell death upon DILI compound perturbation. Knocking down main components of the UPR provided partial protection from compound-induced cytotoxicity, indicating a complex interplay among UPR components as well as other stress pathways. Our results suggest that a systematic analysis of the temporal dynamics of ATF4-CHOP axis activation can support the identification of DILI risk for new candidate drugs. [ABSTRACT FROM AUTHOR]