Ice stream activity scaled to ice sheet volume during Laurentide Ice Sheet deglaciation.

The contribution of the Greenland and West Antarctic ice sheets to sea level has increased in recent decades, largely owing to the thinning and retreat of outlet glaciers and ice streams. This dynamic loss is a serious concern, with some modelling studies suggesting that the collapse of a major ice sheet could be imminent or potentially underway in West Antarctica, but others predicting a more limited response. A major problem is that observations used to initialize and calibrate models typically span only a few decades, and, at the ice-sheet scale, it is unclear how the entire drainage network of ice streams evolves over longer timescales. This represents one of the largest sources of uncertainty when predicting the contributions of ice sheets to sea-level rise. A key question is whether ice streams might increase and sustain rates of mass loss over centuries or millennia, beyond those expected for a given ocean-climate forcing. Here we reconstruct the activity of 117 ice streams that operated at various times during deglaciation of the Laurentide Ice Sheet (from about 22,000 to 7,000 years ago) and show that as they activated and deactivated in different locations, their overall number decreased, they occupied a progressively smaller percentage of the ice sheet perimeter and their total discharge decreased. The underlying geology and topography clearly influenced ice stream activity, but--at the ice-sheet scale--their drainage network adjusted and was linked to changes in ice sheet volume. It is unclear whether these findings can be directly translated to modern ice sheets. However, contrary to the view that sees ice streams as unstable entities that can accelerate ice-sheet deglaciation, we conclude that ice streams exerted progressively less influence on ice sheet mass balance during the retreat of the Laurentide Ice Sheet.

Assessing Class 1 Integron Presence in Poultry Litter Amended with Wood Biochar and Wood Vinegar.

Class 1 integrons are mobile genetic elements that facilitate the spread of antibiotic resistance genes among bacteria. The use of prophylactic antibiotics has resulted in the rise of antibiotic resistance genes accumulating in a wide range of settings, including poultry houses and the agricultural fields where poultry litter is applied as a fertilizer. Biochar and wood vinegar are forest products wastes that have generated increasing attention as additives to agricultural soils. The objectives of this study were to observe the prevalence of class 1 integrons in poultry litter blended with biochar and wood vinegar over time and to verify a modified class 1 integron screening assay. Poultry litter blends were sampled and screened for class 1 integrons using polymerase chain reaction, and 80 products, 79 of which showed positive, were sent for DNA sequencing. The GenBank® BLAST database was used to verify the presence of the class 1 integron-integrase gene (intI1). There was no change in prevalence over time in poultry litter blends. Out of 79 PCR products that were intI1 positive, 78 showed at least 95% sequence identity to intI1 encoding bacteria and 64 showed at least 97% sequence identity. This indicates that this method was effective for conducting baseline surveillance of class 1 integrons in poultry litter and poultry litter-blended biochar and/or wood vinegar. Most significantly, class 1 integron prevalence did not decrease over time, further supporting the recalcitrance of these elements and the need for improved monitoring systems.

Rapid, climate-driven changes in outlet glaciers on the Pacific coast of East Antarctica.

Observations of ocean-terminating outlet glaciers in Greenland and West Antarctica indicate that their contribution to sea level is accelerating as a result of increased velocity, thinning and retreat. Thinning has also been reported along the margin of the much larger East Antarctic ice sheet, but whether glaciers are advancing or retreating there is largely unknown, and there has been no attempt to place such changes in the context of localized mass loss or climatic or oceanic forcing. Here we present multidecadal trends in the terminus position of 175 ocean-terminating outlet glaciers along 5,400 kilometres of the margin of the East Antarctic ice sheet, and reveal widespread and synchronous changes. Despite large fluctuations between glaciers--linked to their size--three epochal patterns emerged: 63 per cent of glaciers retreated from 1974 to 1990, 72 per cent advanced from 1990 to 2000, and 58 per cent advanced from 2000 to 2010. These trends were most pronounced along the warmer western South Pacific coast, whereas glaciers along the cooler Ross Sea coast experienced no significant changes. We find that glacier change along the Pacific coast is consistent with a rapid and coherent response to air temperature and sea-ice trends, linked through the dominant mode of atmospheric variability (the Southern Annular Mode). We conclude that parts of the world's largest ice sheet may be more vulnerable to external forcing than recognized previously.

Fungal Communities and Functional Guilds Shift Along an Elevational Gradient in the Southern Appalachian Mountains.

Nitrogen deposition alters forest ecosystems particularly in high elevation, montane habitats where nitrogen deposition is greatest and continues to increase. We collected soils across an elevational (788-1940 m) gradient, encompassing both abiotic (soil chemistry) and biotic (vegetation community) gradients, at eight locations in the southern Appalachian Mountains of southwestern North Carolina and eastern Tennessee. We measured soil chemistry (total N, C, extractable PO4, soil pH, cation exchange capacity [ECEC], percent base saturation [% BS]) and dissected soil fungal communities using ITS2 metabarcode Illumina MiSeq sequencing. Total soil N, C, PO4, % BS, and pH increased with elevation and plateaued at approximately 1400 m, whereas ECEC linearly increased and C/N decreased with elevation. Fungal communities differed among locations and were correlated with all chemical variables, except PO4, whereas OTU richness increased with total N. Several ecological guilds (i.e., ectomycorrhizae, saprotrophs, plant pathogens) differed in abundance among locations; specifically, saprotroph abundance, primarily attributable to genus Mortierella, was positively correlated with elevation. Ectomycorrhizae declined with total N and soil pH and increased with total C and PO4 where plant pathogens increased with total N and decreased with total C. Our results demonstrate significant turnover in taxonomic and functional fungal groups across elevational gradients which facilitate future predictions on forest ecosystem change in the southern Appalachians as nitrogen deposition rates increase and regional temperature and precipitation regimes shift.

Quantitative Assessment of Population Variability in Hepatic Drug Metabolism Using a Perfused Three-Dimensional Human Liver Microphysiological System.

In this work, we first describe the population variability in hepatic drug metabolism using cryopreserved hepatocytes from five different donors cultured in a perfused three-dimensional human liver microphysiological system, and then show how the resulting data can be integrated with a modeling and simulation framework to accomplish in vitro-in vivo translation. For each donor, metabolic depletion profiles of six compounds (phenacetin, diclofenac, lidocaine, ibuprofen, propranolol, and prednisolone) were measured, along with metabolite formation, mRNA levels of 90 metabolism-related genes, and markers of functional viability [lactate dehydrogenase (LDH) release, albumin, and urea production]. Drug depletion data were analyzed with mixed-effects modeling. Substantial interdonor variability was observed with respect to gene expression levels, drug metabolism, and other measured hepatocyte functions. Specifically, interdonor variability in intrinsic metabolic clearance ranged from 24.1% for phenacetin to 66.8% for propranolol (expressed as coefficient of variation). Albumin, urea, LDH, and cytochrome P450 mRNA levels were identified as significant predictors of in vitro metabolic clearance. Predicted clearance values from the liver microphysiological system were correlated with the observed in vivo values. A population physiologically based pharmacokinetic model was developed for lidocaine to illustrate the translation of the in vitro output to the observed pharmacokinetic variability in vivo. Stochastic simulations with this model successfully predicted the observed clinical concentration-time profiles and the associated population variability. This is the first study of population variability in drug metabolism in the context of a microphysiological system and has important implications for the use of these systems during the drug development process.

A genetic variant in the promoter of phosphate-activated glutaminase is associated with hepatic encephalopathy.

BACKGROUND: Hepatic encephalopathy (HE) is a serious complication of liver cirrhosis. Recently, a microsatellite in the promoter region of the phosphate-activated glutaminase (GLS ) gene was associated with the risk of HE. The aim of the present study was to investigate, using the critical flicker frequency (CFF) test, whether the described GLS variant increases the risk of developing HE in patients with cirrhosis. METHODS: We recruited 158 patients (66% men; mean age 59 years, range 23-86) with liver cirrhosis. Mean model for end-stage liver disease score was 13.8 (range 5-35); 48% of patients presented with Child-Pugh score B or C. The presence and severity of HE were determined by the CFF test, with frequencies ≤39 Hz denoting cases. GLS variants were genotyped by sequencing the microsatellite in the promoter region and were classified as short, long or short-long forms (depending on the length of the macrosatellite alleles). RESULTS: In total, 53% of patients had abnormal CFF results (i.e. ≤39 Hz; range for entire cohort 26-57). The GLS microsatellite distribution amongst patients was short form (20%), long form (32%) and short-long form (48%) and was consistent with Hardy-Weinberg equilibrium. CFF values differed significantly between groups (P = 0.043). Carriers of the GLS long microsatellite had a significantly higher risk of HE according to multivariate analyses (odds ratio 3.23, 95% confidence interval 1.46-7.13, P = 0.004). CONCLUSION: CFF results were significantly lower amongst carriers of the GLS long microsatellite. Our findings support the role of the GLS long microsatellite in the development of HE; this could be important for identifying susceptible patients and for the prevention of this condition.

Rare human nicotinic acetylcholine receptor α4 subunit (CHRNA4) variants affect expression and function of high-affinity nicotinic acetylcholine receptors.

Nicotine, the primary psychoactive component in tobacco smoke, produces its behavioral effects through interactions with neuronal nicotinic acetylcholine receptors (nAChRs). α4ß2 nAChRs are the most abundant in mammalian brain, and converging evidence shows that this subtype mediates the rewarding and reinforcing effects of nicotine. A number of rare variants in the CHRNA4 gene that encode the α4 nAChR subunit have been identified in human subjects and appear to be underrepresented in a cohort of smokers. We compared three of these variants (α4R336C, α4P451L, and α4R487Q) to the common variant to determine their effects on α4ß2 nAChR pharmacology. We examined [(3)H]epibatidine binding, interacting proteins, and phosphorylation of the α4 nAChR subunit with liquid chromatography and tandem mass spectrometry (LC-MS/MS) in HEK 293 cells and voltage-clamp electrophysiology in Xenopus laevis oocytes. We observed significant effects of the α4 variants on nAChR expression, subcellular distribution, and sensitivity to nicotine-induced receptor upregulation. Proteomic analysis of immunopurified α4ß2 nAChRs incorporating the rare variants identified considerable differences in the intracellular interactomes due to these single amino acid substitutions. Electrophysiological characterization in X. laevis oocytes revealed alterations in the functional parameters of activation by nAChR agonists conferred by these α4 rare variants, as well as shifts in receptor function after incubation with nicotine. Taken together, these experiments suggest that genetic variation at CHRNA4 alters the assembly and expression of human α4ß2 nAChRs, resulting in receptors that are more sensitive to nicotine exposure than those assembled with the common α4 variant. The changes in nAChR pharmacology could contribute to differences in responses to smoked nicotine in individuals harboring these rare variants.

Rhinoviral infection and asthma: the detection and management of rhinoviruses by airway epithelial cells.

Human rhinoviruses (HRV) have been linked to the development of childhood asthma and recurrent acute asthma exacerbations throughout life, and contribute considerably to the healthcare and economic burden of this disease. However, the ability of HRV infections to trigger exacerbations, and the link between allergic status and HRV responsiveness, remains incompletely understood. Whilst the receptors on human airway cells that detect and are utilized by most HRV group A and B, but not C serotypes are known, how endosomal pattern recognition receptors (PRRs) detect HRV replication products that are generated within the cytoplasm remains somewhat of an enigma. In this article, we explore a role for autophagy, a cellular homeostatic process that allows the cell to encapsulate its own cytosolic constituents, as the crucial mechanism controlling this process and regulating the innate immune response of airway epithelial cells to viral infection. We will also briefly describe some of the recent insights into the immune responses of the airway to HRV, focusing on neutrophilic inflammation that is a potentially unwanted feature of the acute response to viral infection, and the roles of IL-1 and Pellinos in the regulation of responses to HRV.

First Report of Pseudomonas syringae pv. actinidiae the Causal Agent of Bacterial Canker of Kiwifruit on Actinidia arguta Vines in New Zealand.

Actinidia arguta is commercially grown in New Zealand and few other countries; the fruit are sometimes sold as kiwiberry or hardy kiwi. In New Zealand, two biovars of Pseudomonas syringae pv. actinidiae have recently been found to cause bacterial canker on both A. chinensis and A. deliciosa, which produce the yellow and green fleshed kiwifruit, respectively (4). In November 2011, in a commercial orchard in the Bay of Plenty, New Zealand, A. arguta 'Tahi' and 'Rua' showed small angular necrotic leaf spots. About 50% of the vines randomly located throughout the orchard showed symptoms. Canker or shoot dieback were not detected on any of the infected plants. Four strains, labeled 13093 to 13096, were isolated onto King's B medium (KB) from leaves selected from four different plants showing symptoms. These four strains were gram-negative, induced a hypersensitive reaction when infiltrated in tobacco plants, lacked cytochrome c oxidase, arginine dehydrolase, and urease activity, and were unable to hydrolyze esculin, starch, and gelatine, and to induce ice nucleation. When plated on KB, these strains showed the same weak fluorescence associated with some strains of P. syringae pv. actinidiae (4). All these characteristics support identification of the strains as P. syringae pv. actinidiae. Using P. syringae pv. actinidiae-specific primers PsaF1/R2 (2), the expected 280-bp fragment was amplified by PCR from genomic DNA extracted from the four strains. The four amplicons were sequenced (GenBank Accession Nos. KF206138 to 41) and found to be 100% identical to each other and to the corresponding DNA fragment of the pathotype strain, ICMP 9617 (AY342165). A similar conclusion was reached using the duplex PCR targeting the ompP1 and the avrD genes (1); two amplicons of 492 and 226 bp were obtained with each of the four strains as expected for P. syringae pv. actinidiae. The DNA sequence of the 492-bp amplicon (KF206134 to 37) was 100% identical to that of strains of P. syringae pv. actinidiae, such as Psa 10627 (JQ934475.1). Strain 13094 isolated from A. arguta and pathotype strain ICMP 9617 were sprayed at a concentration of 3 × 109 cfu/ml on to the undersides of leaves of three 6- to 8-week-old seedlings of A. chinensis'Hort16A' and three similar seedlings of A. deliciosa 'Bruno.' Those are the conditions under which the pathogenicity of strains of P. syringae pv. actinidiae is usually evaluated (4). After 2 weeks of incubation, small necrotic angular spots were observed on all plants inoculated with 13094 or ICMP 9617 but not on the water-treated control plants. The bacteria isolated from those necrotic spots had the same morphological characteristics on KB as P. syringae pv. actinidiae and gave a 280-bp amplicon after PCR with the PsaF1/R2 primers. Leaves of two rooted cuttings of A. arguta'Tahi' were spray inoculated with strain 13094 at a concentration of 2.7 × 109 cfu/ml or with water. Necrotic spots developed on leaves 1 week after inoculation. No spots developed on the water-treated plants. The bacteria isolated from those necrotic spots had the same morphological characteristics on KB as P. syringae pv. actinidiae and gave a 280-bp amplicon after PCR with the PsaF1/R2 primers. Isolation of P. syringae pv. actinidiae from A. arguta has been reported only once before (3). This is this is the first report of P. syringae pv. actinidiae being isolated from A. arguta vines in New Zealand. This limited outbreak did not lead to any loss of production and since then only very few symptoms have been observed in this particular orchard. References: (1) A. Gallelli et al. J. Plant Pathol 93:425, 2011. (2) J. Rees-Gorge et al. Plant Pathol. 59:453, 2010. (3) K. Ushiyama et al. Ann. Phytopath. Soc. Japan 58:476, 1992. (4) J. L. Vanneste et al. Plant Dis. 97:708, 2013.

Muckle-Wells syndrome without mutation in exon 3 of the NLRP3 gene, identified by evidence of excessive monocyte production of functional interleukin 1ß and rapid response to anakinra.

We report a man with lifelong urticaria, night sweats, arthralgia and lethargy. He had high levels of inflammatory markers and serum amyloid A, but no identifiable mutation in exon 3 of the NLRP3 (NOD-like receptor family, pyrin domain-1 containing 3) gene, and no relevant family history. We found marked production of functional interleukin (IL)-1 by the patient's monocytes at baseline and after stimulation with lipopolysaccharide. The patient made an immediate response to treatment with an IL-1ß receptor antagonist. We propose that this patient has Muckle-Wells syndrome without deafness, occurring de novo. Functional screening for IL-1 production could aid diagnosis in future similar cases.

Extended Detection Window for Gamma-Hydroxybutyrate in the Urine of an Elderly Woman.

Gamma-hydroxybutyrate (GHB) is a central nervous system depressant that has gained popularity as an illicit recreational drug. We describe a case of an elderly woman who was found unconscious in her home. The paramedics initially suspected an intracranial incident. A head computed tomography was negative, as was the initial urinary drug screening. The diagnosis of GHB intoxication was made with the detection of GHB in a urine sample obtained 28-29 hours after the assumed time of intake. Our case underscores the importance of considering drug testing in a broad range of patients and shows that elderly patients may have an extended detection window of GHB.

The Influence of Minor Aortic Branches in Patient-Specific Flow Simulations of Type-B Aortic Dissection.

Type-B aortic dissection (TBAD) is a disease in which a tear develops in the intimal layer of the descending aorta forming a true lumen and false lumen (FL). Because disease outcomes are thought to be influenced by haemodynamic quantities such as pressure and wall shear stress (WSS), their analysis via numerical simulations may provide valuable clinical insights. Major aortic branches are routinely included in simulations but minor branches are virtually always neglected, despite being implicated in TBAD progression and the development of complications. As minor branches are estimated to carry about 7-21% of cardiac output, neglecting them may affect simulation accuracy. We present the first simulation of TBAD with all pairs of intercostal, subcostal and lumbar arteries, using 4D-flow MRI (4DMR) to inform patient-specific boundary conditions. Compared to an equivalent case without minor branches, their inclusion improved agreement with 4DMR velocities, reduced time-averaged WSS (TAWSS) and transmural pressure and elevated oscillatory shear in regions where FL dilatation and calcification were observed in vivo. Minor branch inclusion resulted in differences of 60-75% in these metrics of potential clinical relevance, indicating a need to account for minor branch flow loss if simulation accuracy is sought.

Increased warm water intrusions could cause mass loss in East Antarctica during the next 200 years.

The East Antarctic Ice Sheet (EAIS) is currently surrounded by relatively cool water, but climatic shifts have the potential to increase basal melting via intrusions of warm modified Circumpolar Deep Water (mCDW) onto the continental shelf. Here we use an ice sheet model to show that under the current ocean regime, with only limited intrusions of mCDW, the EAIS will likely gain mass over the next 200 years due to the increased precipitation from a warming atmosphere outweighing increased ice discharge due to ice-shelf melting. However, if the ocean regime were to become dominated by greater mCDW intrusions, the EAIS would have a negative mass balance, contributing up to 48 mm of SLE over this time period. Our modelling finds George V Land to be particularly at risk to increased ocean induced melting. With warmer oceans, we also find that a mid range RCP4.5 emissions scenario is likely to result in a more negative mass balance than a high RCP8.5 emissions scenario, as the relative difference between increased precipitation due to a warming atmosphere and increased ice discharge due to a warming ocean is more negative in the mid range RCP4.5 emission scenario.

Aneurysmal growth in type-B aortic dissection: assessing the impact of patient-specific inlet conditions on key haemodynamic indices.

Type-B aortic dissection is a cardiovascular disease in which a tear develops in the intimal layer of the descending aorta, allowing pressurized blood to delaminate the layers of the vessel wall. In medically managed patients, long-term aneurysmal dilatation of the false lumen (FL) is considered virtually inevitable and is associated with poorer disease outcomes. While the pathophysiological mechanisms driving FL dilatation are not yet understood, haemodynamic factors are believed to play a key role. Computational fluid dynamics (CFD) and 4D-flow MRI (4DMR) analyses have revealed correlations between flow helicity, oscillatory wall shear stress and aneurysmal dilatation of the FL. In this study, we compare CFD simulations using a patient-specific, three-dimensional, three-component inlet velocity profile (4D IVP) extracted from 4DMR data against simulations with flow rate-matched uniform and axial velocity profiles that remain widely used in the absence of 4DMR. We also evaluate the influence of measurement errors in 4DMR data by scaling the 4D IVP to the degree of imaging error detected in prior studies. We observe that oscillatory shear and helicity are highly sensitive to inlet velocity distribution and flow volume throughout the FL and conclude that the choice of IVP may greatly affect the future clinical value of simulations.

Laryngeal transplantation in minipigs: early immunological outcomes.

Despite recent tissue-engineering advances, there is no effective way of replacing all the functions of the larynx in those requiring laryngectomy. A recent clinical transplant was a success. Using quantitative immunofluorescence targeted at immunologically relevant molecules, we have studied the early (48 h and 1 week) immunological responses within larynxes transplantated between seven pairs of National Institutes of Health (NIH) minipigs fully homozygous at the major histocompatibility complex (MHC) locus. There were only small changes in expression of some molecules (relative to interindividual variation) and these were clearest in samples from the subglottic region, where the areas of co-expression of CD25(+) CD45RC(-) CD8(-) and of CD163(+) CD172(+) MHC-II(-) increased at 1 week after transplant. In one case, infiltration by recipient T cells was analysed by T cell receptor (TCR) Vß spectratype analysis; this suggested that changes in the T cell repertoire occur in the donor subglottis mucosal tissues from day 0 to day 7, but that the donor and recipient mucosal Vß repertoires remain distinct. The observed lack of strong immunological responses to the trauma of surgery and ischaemia provides encouraging evidence to support clinical trials of laryngeal transplantation, and a basis on which to interpret future studies involving mismatches.

Practicing medicine without borders: tele-consultations and tele-mentoring for improving paediatric care in a conflict setting in Somalia?

OBJECTIVES: In a district hospital in conflict-torn Somalia, we assessed (i) the impact of introducing telemedicine on the quality of paediatric care, and (ii) the added value as perceived by local clinicians. METHODS: A 'real-time' audio-visual exchange of information on paediatric cases (Audiosoft Technologies, Quebec, Canada) took place between clinicians in Somalia and a paediatrician in Nairobi. The study involved a retrospective analysis of programme data, and a perception study among the local clinicians. RESULTS: Of 3920 paediatric admissions, 346 (9%) were referred for telemedicine. In 222 (64%) children, a significant change was made to initial case management, while in 88 (25%), a life-threatening condition was detected that had been initially missed. There was a progressive improvement in the capacity of clinicians to manage complicated cases as demonstrated by a significant linear decrease in changes to initial case management for meningitis and convulsions (92-29%, P = 0.001), lower respiratory tract infection (75-45%, P = 0.02) and complicated malnutrition (86-40%, P = 0.002). Adverse outcomes (deaths and lost to follow-up) fell from 7.6% in 2010 (without telemedicine) to 5.4% in 2011 with telemedicine (30% reduction, odds ratio 0.70, 95% CI: 0.57-0.88, P = -0.001). The number needed to be treated through telemedicine to prevent one adverse outcome was 45. All seven clinicians involved with telemedicine rated it to be of high added value. CONCLUSION: The introduction of telemedicine significantly improved quality of paediatric care in a remote conflict setting and was of high added value to distant clinicians.

Interprofessional Collaborative Care Skills and Behaviors: Perception Differences Between Allied Health Students and an Independent Observer.

Interprofessional practice and education (IPE) is incorporated into pre-licensure healthcare programs to prepare students for collaboration in clinical practice and to improve patient outcomes. The use of interprofessional simulation as a teaching strategy is increasing, but most literature involves medical and nursing students, and outcomes measure students' knowledge, perceptions, or attitudes. The purpose of this study was to compare allied health students' self-assessment of their team's interprofessional collaborative care (IPCC) skills and behaviors with an independent observer's perception during an interprofessional simulation discharge planning event with standardized patients. Students (n = 177) were recruited from the Departments of Occupational Therapy (OT), Physical Therapy (PT), and Physician Assistant Studies (PA). Students reflected on their team's performance, and an independent observer assessed each team's IPCC skills and behaviors with a valid and reliable tool developed from the IPEC Core Competencies. The results showed that students' assessments of their teams' IPCC were significantly greater than the independent observer's ratings. Additionally, the observer found that the students demonstrated higher levels of interprofessional collaboration during a team huddle without a standardized patient present. This study suggests that IPE program evaluation should include observations of interprofessional skills and behaviors and that students involved in interprofessional simulation may benefit from a team huddle prior to team interactions with a standardized patient.

The pros and cons of drug 'trafficking'.

Internalization of targeted therapeutics is often needed for efficacy, but also alters drug penetration of a tissue. A new model explores the trade-offs of intracellular drug trafficking.