Rapid, buoyancy-driven ice-sheet retreat of hundreds of metres per day.

Rates of ice-sheet grounding-line retreat can be quantified from the spacing of corrugation ridges on deglaciated regions of the seafloor1,2, providing a long-term context for the approximately 50-year satellite record of ice-sheet change3-5. However, the few existing examples of these landforms are restricted to small areas of the seafloor, limiting our understanding of future rates of grounding-line retreat and, hence, sea-level rise. Here we use bathymetric data to map more than 7,600 corrugation ridges across 30,000 km2 of the mid-Norwegian shelf. The spacing of the ridges shows that pulses of rapid grounding-line retreat, at rates ranging from 55 to 610 m day-1, occurred across low-gradient (±1°) ice-sheet beds during the last deglaciation. These values far exceed all previously reported rates of grounding-line retreat across the satellite3,4,6,7 and marine-geological1,2 records. The highest retreat rates were measured across the flattest areas of the former bed, suggesting that near-instantaneous ice-sheet ungrounding and retreat can occur where the grounding line approaches full buoyancy. Hydrostatic principles show that pulses of similarly rapid grounding-line retreat could occur across low-gradient Antarctic ice-sheet beds even under present-day climatic forcing. Ultimately, our results highlight the often-overlooked vulnerability of flat-bedded areas of ice sheets to pulses of extremely rapid, buoyancy-driven retreat.

Mouse maternal protein restriction during preimplantation alone permanently alters brain neuron proportion and adult short-term memory.

Maternal protein malnutrition throughout pregnancy and lactation compromises brain development in late gestation and after birth, affecting structural, biochemical, and pathway dynamics with lasting consequences for motor and cognitive function. However, the importance of nutrition during the preimplantation period for brain development is unknown. We have previously shown that maternal low-protein diet (LPD) confined to the preimplantation period (Emb-LPD) in mice, with normal nutrition thereafter, is sufficient to induce cardiometabolic and locomotory behavioral abnormalities in adult offspring. Here, using a range of in vivo and in vitro techniques, we report that Emb-LPD and sustained LPD reduce neural stem cell (NSC) and progenitor cell numbers at E12.5, E14.5, and E17.5 through suppressed proliferation rates in both ganglionic eminences and cortex of the fetal brain. Moreover, Emb-LPD causes remaining NSCs to up-regulate the neuronal differentiation rate beyond control levels, whereas in LPD, apoptosis increases to possibly temper neuron formation. Furthermore, Emb-LPD adult offspring maintain the increase in neuron proportion in the cortex, display increased cortex thickness, and exhibit short-term memory deficit analyzed by the novel-object recognition assay. Last, we identify altered expression of fragile X family genes as a potential molecular mechanism for adverse programming of brain development. Collectively, these data demonstrate that poor maternal nutrition from conception is sufficient to cause abnormal brain development and adult memory loss.

A model of the recruitment-derecruitment and volume of lung units in an excised lung as it is inflated-deflated between minimum and maximum lung volume.

The role of the recruitment-derecruitment of small structures in the lung (lung units) as the lung increases and decreases in volume has been debated. The objective of this study was to develop a model to estimate the change in the number and volume of open lung units as an excised lung is inflated-deflated between minimum and maximum lung volume. The model was formulated based on the observation that the compliance of the slowly changing quasi-static pressure-volume (P-V) curve of an excised rat lung can differ from the compliance of a faster changing small sinusoidal pressure volume perturbations superimposed on the curve. In those regions of the curve where differences in compliance occur, the lung tissue properties exhibit nonlinear characteristics, which cannot be linearized using "incremental" or "small signal" analysis. The model attributes the differences between the perturbation and quasi-static compliance to an additional nonlinear compliance term that results from the sequential opening and closing of lung units. Using this approach, it was possible to calculate the normalized average volume and the normalized number of open units as the lung is slowly inflated-deflated. Results indicate that the normalized average volume and the normalized number of open units are not linearly related to normalized lung volume, and at equal lung volumes the normalized number of open units is greater and the normalized average lung unit volume is smaller during lung deflation when compared to lung inflation. In summary, a model was developed to describe the recruitment-derecruitment process in excised lungs based on the differences between small signal perturbation compliance and quasi-static compliance. Values of normalized lung unit volume and the normalized number of open lung units were shown to be nonlinear functions of both transpulmonary pressure and normalized lung volume.

Mutations in cornea-specific keratin K3 or K12 genes cause Meesmann's corneal dystrophy.

The intermediate filament cytoskeleton of corneal epithelial cells is composed of cornea-specific keratins K3 and K12 (refs 1,2). Meesmann's corneal dystrophy (MCD) is an autosomal dominant disorder causing fragility of the anterior corneal epithelium, where K3 and K12 are specifically expressed. We postulated that dominant-negative mutations in these keratins might be the cause of MCD. K3 was mapped to the type-II keratin gene cluster on 12q; and K12 to the type-I keratin cluster on 17q using radiation hybrids. We obtained linkage to the K12 locus in Meesmann's original German kindred (Zmax = 7.53; theta = 0) and we also showed that the phenotype segregated with either the K12 or the K3 locus in two Northern Irish pedigrees. Heterozygous missense mutations in K3 (E509K) and in K12 (V143L; R135T) completely co-segregated with MCD in the families and were not found in 100 normal unrelated chromosomes. All mutations occur in the highly conserved keratin helix boundary motifs, where dominant mutations in other keratins have been found to severely compromise cytoskeletal function, leading to keratinocyte fragility phenotypes. Our results demonstrate for the first time the molecular basis of Meesmann's corneal dystrophy.

Inter-decadal climate variability induces differential ice response along Pacific-facing West Antarctica.

West Antarctica has experienced dramatic ice losses contributing to global sea-level rise in recent decades, particularly from Pine Island and Thwaites glaciers. Although these ice losses manifest an ongoing Marine Ice Sheet Instability, projections of their future rate are confounded by limited observations along West Antarctica's coastal perimeter with respect to how the pace of retreat can be modulated by variations in climate forcing. Here, we derive a comprehensive, 12-year record of glacier retreat around West Antarctica's Pacific-facing margin and compare this dataset to contemporaneous estimates of ice flow, mass loss, the state of the Southern Ocean and the atmosphere. Between 2003 and 2015, rates of glacier retreat and acceleration were extensive along the Bellingshausen Sea coastline, but slowed along the Amundsen Sea. We attribute this to an interdecadal suppression of westerly winds in the Amundsen Sea, which reduced warm water inflow to the Amundsen Sea Embayment. Our results provide direct observations that the pace, magnitude and extent of ice destabilization around West Antarctica vary by location, with the Amundsen Sea response most sensitive to interdecadal atmosphere-ocean variability. Thus, model projections accounting for regionally resolved ice-ocean-atmosphere interactions will be important for predicting accurately the short-term evolution of the Antarctic Ice Sheet.

Pulmonary and cardiovascular responses of rats to inhalation of a commercial antimicrobial spray containing titanium dioxide nanoparticles.

Our laboratory has previously demonstrated that application of an antimicrobial spray product containing titanium dioxide (TiO(2)) generates an aerosol of titanium dioxide in the breathing zone of the applicator. The present report describes the design of an automated spray system and the characterization of the aerosol delivered to a whole body inhalation chamber. This system produced stable airborne levels of TiO(2) particles with a median count size diameter of 110 nm. Rats were exposed to 314 mg/m(3) min (low dose), 826 mg/m(3) min (medium dose), and 3638 mg/m(3) min (high dose) of TiO(2) under the following conditions: 2.62 mg/m(3) for 2 h, 1.72 mg/m(3) 4 h/day for 2 days, and 3.79 mg/m(3) 4 h/day for 4 days, respectively. Pulmonary (breathing rate, specific airway resistance, inflammation, and lung damage) and cardiovascular (the responsiveness of the tail artery to constrictor or dilatory agents) endpoints were monitored 24 h post-exposure. No significant pulmonary or cardiovascular changes were noted at low and middle dose levels. However, the high dose caused significant increases in breathing rate, pulmonary inflammation, and lung cell injury. Results suggest that occasional consumer use of this antimicrobial spray product should not be a hazard. However, extended exposure of workers routinely applying this product to surfaces should be avoided. During application, care should be taken to minimize exposure by working under well ventilated conditions and by employing respiratory protection as needed. It would be prudent to avoid exposure to children or those with pre-existing respiratory disease.

Antarctic Seabed Assemblages in an Ice-Shelf-Adjacent Polynya, Western Weddell Sea.

Ice shelves cover ~1.6 million km2 of the Antarctic continental shelf and are sensitive indicators of climate change. With ice-shelf retreat, aphotic marine environments transform into new open-water spaces of photo-induced primary production and associated organic matter export to the benthos. Predicting how Antarctic seafloor assemblages may develop following ice-shelf loss requires knowledge of assemblages bordering the ice-shelf margins, which are relatively undocumented. This study investigated seafloor assemblages, by taxa and functional groups, in a coastal polynya adjacent to the Larsen C Ice Shelf front, western Weddell Sea. The study area is rarely accessed, at the frontline of climate change, and located within a CCAMLR-proposed international marine protected area. Four sites, ~1 to 16 km from the ice-shelf front, were explored for megabenthic assemblages, and potential environmental drivers of assemblage structures were assessed. Faunal density increased with distance from the ice shelf, with epifaunal deposit-feeders a surrogate for overall density trends. Faunal richness did not exhibit a significant pattern with distance from the ice shelf and was most variable at sites closest to the ice-shelf front. Faunal assemblages significantly differed in composition among sites, and those nearest to the ice shelf were the most dissimilar; however, ice-shelf proximity did not emerge as a significant driver of assemblage structure. Overall, the study found a biologically-diverse and complex seafloor environment close to an ice-shelf front and provides ecological baselines for monitoring benthic ecosystem responses to environmental change, supporting marine management.

Nanoparticle inhalation impairs endothelium-dependent vasodilation in subepicardial arterioles.

Exposure to fine particulate matter (PM, mean aerodynamic diameter

Increased susceptibility of the lungs of hyperthyroid rats to oxidant injury: specificity of effects.

Results from previous studies indicate that hyperthyroidism increases the risk of ozone-induced lung toxicity. This observation raised the possibility that pulmonary damage from other oxidant substances might be greater in a hyperthyroid state. To address this hypothesis, pulmonary responses to crystalline silica, a particulate with oxidant properties, were evaluated in normal or hyperthyroid adult male rats. To induce a hyperthyroid condition, time-release pellets containing thyroxine were implanted subcutaneously; control rats received placebo pellets. After 7 days, the animals were exposed to saline or silica (0.1mg/100g BW or 1.0mg/100g BW) by intratracheal instillation. Following silica treatment, there was a dose-related increase in bronchoalveolar lavage (BAL) albumin levels and neutrophil numbers. However, the effects of silica were similar in both normal and hyperthyroid rats. These findings were confirmed and contrasted with those regarding ozone (1ppm, 4h inhalation) in a subsequent experiment. The results indicated that, although exposure to either ozone or silica resulted in increases in BAL albumin levels and neutrophil numbers, only responses to ozone were enhanced in hyperthyroid rats. These findings suggest that specificity exists in regards to the modulation of oxidant-induced lung damage and inflammation by thyroid hormones.

Increased susceptibility of hyperthyroid rats to ozone: early events and mechanisms.

Previous studies demonstrated that ozone-induced lung damage and inflammation are much greater in hyperthyroid rats, compared to normal rats, at 18 h postexposure. The purpose of the present investigation was to study early events and mechanisms underlying the increased sensitivity to ozone in a hyperthyroid state. Specifically, the degree of lung epithelial cell barrier disruption, the antioxidant status of the extracellular lining fluid, and the release of inflammatory mediators were examined. To induce a hyperthyroid state, mature male Sprague-Dawley rats were implanted with time-release pellets containing thyroxine; control rats received placebo pellets. After 7 d, the animals were exposed to air or ozone (2 ppm, 3 h). Immediately following the end of the exposure, bronchoalveolar lavage (BAL) fluid and cells were harvested. BAL fluid albumin levels and total antioxidant status were examined. In addition, levels of prostaglandin E2 (PGE2), macrophage inflammatory protein (MIP)-2, MCP-1, and tumor necrosis factor (TNF)-alpha were determined in BAL fluid and in media samples following ex vivo culture of BAL cells harvested after in vivo inhalation exposures. The results of this study are consistent with the following hypotheses: (1) A marked increase in the permeability of the alveolar-capillary barrier is an early event following ozone exposure in a hyperthyroid state; however this does not appear to be due to overall changes in BAL fluid antioxidant potential. (2) Early increases in MIP-2, but not PGE2, are involved in the enhanced lung response to ozone in a hyperthyroid state. (3) Inflammatory mediator production (i.e., PGE2, MIP-2, MCP-1, and TNF-alpha) by alveolar macrophages plays a minimal role in the initial responses to ozone in a hyperthyroid state.

Inhibition of stimulant-induced activation of phagocytic cells with tetrandrine.

Tetrandrine is an alkaloid obtained from the root of a medicinal herb which is employed in China as a treatment for silicosis. One proposed mechanism for the development of silica-induced fibrosis is lung damage resulting from particle-induced inflammation and secretion of reactive compounds from alveolar phagocytes. Therefore, the objective of the present study was to determine if tetrandrine exhibited the ability to inhibit respiratory burst activity of pulmonary phagocytes. The data indicate that although tetrandrine is not cytotoxic to phagocytic cells, it is a potent inhibitor in vitro of zymosan-stimulated oxygen consumption, superoxide anion release, and hydrogen peroxide secretion by alveolar macrophages. Tetrandrine is also effective in vivo in preventing activation of alveolar macrophages after inhalation or intratracheal instillation of silica. Tetrandrine also inhibits stimulant-induced chemiluminescence by polymorphonuclear leukocytes. Since tetrandrine does not alter stimulant-induced depolarization of phagocytic cells, its inhibitory action is not via interference with receptor-ligand binding but rather must occur elsewhere in the stimulus-secretion coupling scheme.

Pulmonary reactions to organic dust exposures: development of an animal model.

Acute inhalation of organic dusts such as cotton, hay, silage, grain, animal confinement, or compost dust can result in illness characterized by fever, pulmonary inflammation, chest tightness, and airway obstruction. These agricultural materials are complex mixtures of plant, bacterial, and fungal products. Elucidation of the time course of disease onset, the mechanisms of disease progression, and the identity of etiologic agents is essential for effective prevention and treatment. Toward this end, animal models for acute organic dust-induced reactions have been developed and characterized. Information concerning the applicability of various animal models to humans and progress toward elucidation of causative agents and mechanisms of action is presented.

Comparison of lung sounds and gas trapping in the study of airway mechanics.

We have previously shown that gas is trapped in isolated animal lungs and have proposed that this gas-trapping process is related to meniscus formation in the small airways of the lung. The purpose of this investigation was to compare how the lung sound-generation process and the gas-trapping process are related to airway mechanics and each other. Rats were anesthetized, the heart and lungs were removed en bloc and placed in a liquid-filled plethysmograph. Lung sounds were recorded by using a microphone acoustically coupled to the tracheal cannula. The results show that discontinuous lung sounds in the form of crackles occur during lung inflation at the same time gas trapping takes place.

Risks of keratitis and patterns of use with disposable contact lenses.

Disposable soft contact lenses have been marketed as a safer alternative to conventional soft lenses. We undertook a case-control study of patients attending the casualty unit of an eye hospital to quantify the relative risk of keratitis in disposable lens wear and to establish associated patterns of use. All eligible contact lens users were identified and asked to complete a questionnaire (n=242). Keratitis, microbial or sterile, was the most common complication in disposable lens users, occurring in 16 of 41 subjects. The relative risks for all lens types were estimated by comparison with rigid lenses (the referent). Both extended- and daily-wear disposable lenses were associated with higher risks of keratitis than other lens types including conventional extended-wear lenses. Poor hygiene, disinfectant system failure, and lens type may all account for these statistically significant trends.

Ventilation heterogeneity does not change following pulmonary microembolism.

By using the multiple-breath helium washout technique, ventilation heterogeneity (VH) after embolic injury in the lung can be quantitatively partitioned into the conductive and acinar components. Total VH, represented by the normalized slope of the phase III alveolar plateau, Sn(III (total)), was studied for 120 min in three groups of anesthetized and paralyzed mongrel dogs. Group 1 (n = 3) received only normal saline and served as controls. Group 2 (n = 4) received repeated infusions of polystyrene beads (250 microm) into the right atrium at 10, 40, 80, and 120 min. Group 3 (n = 3) was similarly treated, except that the embolic beads used were 1,000 microm in diameter. The data show that, despite repeated embolic injury by polystyrene beads of different diameters, there was no significant increase in total VH. The acinar component of Sn(III), which represents VH in the distal airways, accounts for over 90% of the total VH. The conductive component of Sn(III), which represents VH between larger conductive airways, remains relatively constant and a minor component. We conclude that pulmonary microembolism does not result in significant redistribution of ventilation.

Role of intrinsic airway neurons in ozone-induced airway hyperresponsiveness in ferret trachea.

Exposure to ozone (O(3)) enhances airway responsiveness, which is mediated partly by the release of substance P (SP) from airway neurons. In this study, the role of intrinsic airway neurons in O(3)-induced airway responses was examined. Ferrets were exposed to 2 ppm O(3) or air for 1 h. Reactivity of isolated tracheal smooth muscle to cholinergic agonists was significantly increased after O(3) exposure, as were contractions to electrical field stimulation at 10 Hz. Pretreatment with CP-99994, a neurokinin type 1 receptor antagonist, partially abolished the O(3)-induced reactivity to cholinergic agonists and electrical field stimulation. The O(3)-enhanced airway responses were present in tracheal segments cultured for 24 h, a procedure shown to deplete sensory nerves while maintaining viability of intrinsic airway neurons, and all the enhanced smooth muscle responses were also diminished by CP-99994. Immunocytochemistry showed that the percentage of SP-containing neurons in longitudinal trunk and the percentage of neurons innervated by SP-positive nerve fibers in superficial muscular plexus were significantly increased at 1 h after exposure to O(3). These results suggest that enhanced SP levels in airway ganglia contribute to O(3)-induced airway hyperresponsiveness.

Determination of regional ventilation and perfusion in the lung using xenon and computed tomography.

We propose a model to measure both regional ventilation (V) and perfusion (Q) in which the regional radiodensity (RD) in the lung during xenon (Xe) washin is a function of regional V (increasing RD) and Q (decreasing RD). We studied five anesthetized, paralyzed, mechanically ventilated, supine sheep. Four 2.5-mm-thick computed tomography (CT) images were simultaneously acquired immediately cephalad to the diaphragm at end inspiration for each breath during 3 min of Xe breathing. Observed changes in RD during Xe washin were used to determine regional V and Q. For 16 mm(3), Q displayed more variance than V: the coefficient of variance of Q (CV(Q)) = 1.58 +/- 0.23, the CV of V (CV(V)) = 0.46 +/- 0.07, and the ratio of CV(Q) to CV(V) = 3.5 +/- 1.1. CV(Q) (1.21 +/- 0.37) and the ratio of CV(Q) to CV(V) (2.4 +/- 1.2) were smaller at 1,000-mm(3) scale, but CV(V) (0.53 +/- 0.09) was not. V/Q distributions also displayed scale dependence: log SD of V and log SD of Q were 0.79 +/- 0.05 and 0.85 +/- 0.10 for 16-mm(3) and 0.69 +/- 0.20 and 0.67 +/- 0.10 for 1,000-mm(3) regions of lung, respectively. V and Q measurements made with CT and Xe also demonstrate vertically oriented and isogravitational heterogeneity, which are described using other methodologies. Sequential images acquired by CT during Xe breathing can be used to determine both regional V and Q noninvasively with high spatial resolution.

Comparative pulmonary toxicity of 6 abrasive blasting agents.

Inhalation of silica dust is associated with pulmonary fibrosis. Therefore, substitute abrasive materials have been suggested for use in abrasive blasting operations. To date, toxicological evaluation of most substitute abrasives has been incomplete. Therefore, the objective of this study was to compare the pulmonary toxicity of a set of substitute abrasives (garnet, staurolite, coal slag, specular hematite, and treated sand) to that of blasting sand. Rats were exposed to blasting sand or an abrasive substitute by intratracheal instillation and pulmonary responses to exposure were monitored 4 weeks postexposure. Pulmonary damage was monitored as lactate dehydrogenase (LDH) in the acellular lavage fluid. Pulmonary inflammation was evaluated from the yield of polymorphonuclear leukocytes (PMN) obtained by bronchoalveolar lavage. The activity of alveolar macrophages was determined by measuring zymosan-stimulated chemiluminescence. Blasting sand caused lung damage and showed histologic evidence for inflammation and fibrosis. Garnet, staurolite, and treated sand exhibited toxicity and inflammation that were similar to blasting sand, while coal slag caused greater pulmonary damage and inflammation than blasting sand. In contrast, specular hematite did not significantly elevate LDH or PMN levels and did not stimulate macrophage activity 4 weeks postexposure.

Psychopathy and conduct problems in children: II. Implications for subtyping children with conduct problems.

OBJECTIVE: To test whether the presence of callous and unemotional (CU) traits designates a unique subgroup of children with conduct problems that corresponds more closely to adult conceptualizations of psychopathy. METHOD: A clinic-referred sample of 120 children between the ages of 6 and 13 years were assessed using parent and teacher ratings of CU traits, as well as parent and teacher report on a structured interview assessing oppositional defiant disorder (ODD) and conduct disorder (CD) symptoms. RESULTS: A cluster analysis of the ratings of CU traits and ODD/ CD symptoms revealed four clusters of children, two of which had high rates of ODD and CD symptoms. One of these conduct problem clusters also exhibited high levels of CU traits (n = 11). These children had a greater number and variety of conduct problems, a stronger history of police contacts, and a stronger parental history of antisocial personality disorder, despite being of higher intelligence than other children with significant conduct problems (n = 29). CONCLUSION: The presence of CU traits with significant conduct problems seems to designate a unique subgroup of antisocial children who show a very severe pattern of antisocial behavior and who correspond more closely to adult conceptualizations of psychopathy.

Reactivity of guinea-pig isolated trachea to methacholine, histamine and isoproterenol applied serosally versus mucosally.

Guinea-pig tracheas were perfused with recirculating modified Krebs-Henseleit solution while monitoring changes in inflow-outflow pressure difference, which is an index of trachealis muscle tone. The reactivities of the trachealis muscle to methacholine, histamine and isoproterenol applied separately to the mucosal (intraluminal, IL) or serosal (extraluminal, EL) compartments were compared, and evidence for the agonist-induced release of epithelium-derived relaxing factor (EpDRF) was sought. All agents were more potent when added to the EL compartment, but the IL/EL EC50 ratios were different: 100 for methacholine, 41 for histamine and 25 for isoproterenol. Methacholine or histamine added to the IL compartment, after the preparations were pre-contracted with the same concentration of the agonist or 30 mM KCl added EL, did not result in relaxation. Likewise, IL isoproterenol did not evoke contraction. IL KCl evoked relaxation. The results indicate that the epithelium reduces access of bronchoactive agents to the muscle, while an immediate relaxant effect of EpDRF released by agonists could not be demonstrated.