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Background: Focused ultrasound (FUS) activation of microbubbles (MBs) for blood-brain (BBB) and blood-tumor barrier (BTB) opening permits targeted therapeutic delivery. While the effects of FUS+MBs mediated BBB opening have been investigated for normal brain tissue, no such studies exist for intracranial tumors. As this technology advances into clinical immunotherapy trials, it will be crucial to understand how FUS+MBs modulates the tumor immune microenvironment. Methods and Results: Bulk RNA sequencing revealed that FUS+MBs BTB/BBB opening (1 MHz, 0.5 MPa peak-negative pressure) of intracranial B16F1cOVA tumors increases the expression of genes related to proinflammatory cytokine and chemokine signaling, pattern recognition receptor signaling, and antigen processing and presentation. Flow cytometry revealed increased maturation (i.e. CD86) of dendritic cells (DCs) in the meninges and altered antigen loading of DCs in both the tumor and meninges. For DCs in tumor draining lymph nodes, FUS+MBs had no effect on maturation and elicited only a trend towards increased presentation of tumor-derived peptide by MHC. Neither tumor endothelial cell adhesion molecule expression nor homing of activated T cells was affected by FUS+MBs. Conclusion: FUS+MBs-mediated BTB/BBB opening elicits signatures of inflammation; however, the response is mild, transient, and unlikely to elicit a systemic response independent of administration of immune adjuvants.

Significance Focused ultrasound (FUS) is a targeted and noninvasive technique that can be used to activate gas-filled microbubbles (MBs) to oscillate within the bloodstream. This technique has been used previously to open the blood–brain barrier (BBB) to facilitate the delivery of therapeutics to the surrounding brain tissue. However, disruption of the BBB may be contraindicated in certain disease contexts. Here, we utilize low-pressure FUS to oscillate the MBs just enough to transfect endothelial cells, without opening the BBB. The low-pressure FUS regimen results in enhanced gene delivery to endothelial cells, with none of the inflammatory or immune pathway up-regulation observed at higher FUS pressures., Treatment of many pathologies of the brain could be improved markedly by the development of noninvasive therapeutic approaches that elicit robust, endothelial cell-selective gene expression in specific brain regions that are targeted under MR image guidance. While focused ultrasound (FUS) in conjunction with gas-filled microbubbles (MBs) has emerged as a noninvasive modality for MR image-guided gene delivery to the brain, it has been used exclusively to transiently disrupt the blood–brain barrier (BBB), which may induce a sterile inflammation response. Here, we introduce an MR image-guided FUS method that elicits endothelial-selective transfection of the cerebral vasculature (i.e., “sonoselective” transfection), without opening the BBB. We first determined that activating circulating, cationic plasmid-bearing MBs with pulsed low-pressure (0.1 MPa) 1.1-MHz FUS facilitates sonoselective gene delivery to the endothelium without MRI-detectable disruption of the BBB. The degree of endothelial selectivity varied inversely with the FUS pressure, with higher pressures (i.e., 0.3-MPa and 0.4-MPa FUS) consistently inducing BBB opening and extravascular transfection. Bulk RNA sequencing analyses revealed that the sonoselective low-pressure regimen does not up-regulate inflammatory or immune responses. Single-cell RNA sequencing indicated that the transcriptome of sonoselectively transfected brain endothelium was unaffected by the treatment. The approach developed here permits targeted gene delivery to blood vessels and could be used to promote angiogenesis, release endothelial cell-secreted factors to stimulate nerve regrowth, or recruit neural stem cells.

The observation of 236 MeV muon neutrinos from kaon-decay-at-rest (KDAR) originating in the core of the Sun would provide a unique signature of dark matter annihilation. Since excellent angle and energy reconstruction are necessary to detect this monoenergetic, directional neutrino flux, DUNE with its vast volume and reconstruction capabilities, is a promising candidate for a KDAR neutrino search. In this work, we evaluate the proposed KDAR neutrino search strategies by realistically modeling both neutrino-nucleus interactions and the response of DUNE. We find that, although reconstruction of the neutrino energy and direction is difficult with current techniques in the relevant energy range, the superb energy resolution, angular resolution, and particle identification offered by DUNE can still permit great signal/background discrimination. Moreover, there are non-standard scenarios in which searches at DUNE for KDAR in the Sun can probe dark matter interactions.

Global warming is leading to range shifts of marine species, threatening the structure and functioning of ecological communities and human populations that rely on them. The largest changes are seen in biogeographic transition zones, such as subtropical reef communities, where species range shifts are already causing substantial community reorganisation. This causes functional changes in communities over subtropical latitudes, though a baseline functional understanding remains elusive for many taxa. One key marine taxon are molluscs, which provide many ecosystem services, are important prey for fishes and are also fisheries targets themselves, but remain largely unstudied. Here, we examine the trait composition, functional diversity, and functional redundancy of mollusc assemblages along the tropical-to-temperate transition in Japan (25° to 35° Northern latitude). Specifically, we use a trait database of 88 mollusc species from 31 subtropical reefs along the Pacific coast of Japan to show that trait composition of mollusc assemblages changes continuously along the latitudinal gradient. We discover that functional diversity of mollusc assemblages decreases with increasing latitude, a pattern associated with declines in functional dispersion. Moreover, we find a clear distinction between tropical and subtropical mollusc assemblages, with substrate-attached, suspension feeding bivalves more abundant in the tropics and free-living gastropod grazers more prevalent at higher latitudes. Our trait-based evidence in this study shows a contraction and almost complete shift in the functioning of marine mollusc assemblages at biogeographic transition zones and our trait database facilitates further study. Our findings provide evidence of the changing taxonomic and functional composition of extant mollusc communities with latitude, pointing to potential pertinent changes and tropicalisation of these communities with rapid ocean warming.

Strong similarities in Holocene climate reconstructions derived from multiple proxies (BSi, TOC – total organic carbon, δ13C, C∕N, MS – magnetic susceptibility, δ15N) preserved in sediments from both glacial and non-glacial lakes across Iceland indicate a relatively warm early to mid Holocene from 10 to 6 ka, overprinted with cold excursions presumably related to meltwater impact on North Atlantic circulation until 7.9 ka. Sediment in lakes from glacial catchments indicates their catchments were ice-free during this interval. Statistical treatment of the high-resolution multi-proxy paleoclimate lake records shows that despite great variability in catchment characteristics, the sediment records document more or less synchronous abrupt, cold departures as opposed to the smoothly decreasing trend in Northern Hemisphere summer insolation. Although all lake records document a decline in summer temperature through the Holocene consistent with the regular decline in summer insolation, the onset of significant summer cooling occurs ∼5 ka at high-elevation interior sites but is variably later at sites closer to the coast, suggesting that proximity to the sea may modulate the impact from decreasing summer insolation. The timing of glacier inception during the mid Holocene is determined by the descent of the equilibrium line altitude (ELA), which is dominated by the evolution of summer temperature as summer insolation declined as well as changes in sea surface temperature for coastal glacial systems. The glacial response to the ELA decline is also highly dependent on the local topography. The initial ∼5 ka nucleation of Langjökull in the highlands of Iceland defines the onset of neoglaciation in Iceland. Subsequently, a stepwise expansion of both Langjökull and northeast Vatnajökull occurred between 4.5 and 4.0 ka, with a second abrupt expansion ∼3 ka. Due to its coastal setting and lower topographic threshold, the initial appearance of Drangajökull in the NW of Iceland was delayed until ∼2.3 ka. All lake records reflect abrupt summer temperature and catchment disturbance at ∼4.5 ka, statistically indistinguishable from the global 4.2 ka event, and a second widespread abrupt disturbance at 3.0 ka, similar to the stepwise expansion of Langjökull and northeast Vatnajökull. Both are intervals characterized by large explosive volcanism and tephra distribution in Iceland resulting in intensified local soil erosion. The most widespread increase in glacier advance, landscape instability, and soil erosion occurred shortly after 2 ka, likely due to a complex combination of increased impact from volcanic tephra deposition, cooling climate, and increased sea ice off the coast of Iceland. All lake records indicate a strong decline in temperature ∼1.5 ka, which culminated during the Little Ice Age (1250–1850 CE) when the glaciers reached their maximum Holocene dimensions.

An inexpensive and radiolucent elbow can be built with a PVC pipe available at any home center or hardware store for less than $25 that allows elbow arthroscopy or open elbow surgery such as open reductions and internal fixation to be performed in the prone, "sloppy" lateral, or decubitus position.

SummaryThe Japanese Murrelet Synthliboramphus wumizusume is a rare, globally ‘Vulnerable’ seabird, endemic to Japan and South Korea. However, little is known of its at-sea distribution, habitat or threats. We conducted several years of at-sea surveys around Japan to model Japanese Murrelet density in relation to habitat parameters, and make spatial predictions to assess the adequacy of the current Japanese marine Important Bird and Biodiversity Area (IBA) network for the species. During a five-year period, 3,485 km of at-sea surveys recorded 3,161 Japanese Murrelets around four breeding locations. Maximum murrelet group size was 90 individuals with a mean group size of 2.9 ± 4.2 individuals. Models of Japanese Murrelet at-sea density around the two largest breeding locations predicted that almost all murrelets occur within 30 km of the breeding colony and most within 10 km. Murrelets were predicted closer to the colony in May than in April and closer to the colony at a neritic colony than at an offshore island colony. Additionally, murrelets breeding on an offshore island colony also commuted to mainland neritic habitat for foraging. The marine habitat used by Japanese Murrelets differed between each of the four surveyed colonies, however oceanographic variables offered little explanatory power in models. Models with colony, month and year generated four foraging radii (9–39 km wide) containing murrelet densities of > 0.5 birds/km2. Using these radii the Japanese marine IBA network was found to capture between 95% and 25% of Japanese Murrelet at-sea habitat while breeding and appears appropriately configured to protect near-colony murrelet distributions. Given the range of marine habitats that breeding murrelets inhabit, our simple models offer an applicable method for predicting to unsampled colonies and generating ecologically-informed seaward extension radii. However, data on colony populations and further at-sea surveys are necessary to refine models and improve predictions.

Large efforts have been deployed in developing methods to estimate methane emissions from cattle. For large scale applications, accurate and inexpensive methane predictors are required. Within a livestock precision farming context, the objective of this work was to integrate real-time data on animal feeding behaviour with anin silicomodel for predicting the individual dynamic pattern of methane emission in cattle. The integration of real-time data with a mathematical model to predict variables that are not directly measured constitutes a software sensor. We developed a dynamic parsimonious grey-box model that uses as predictor variables either dry matter intake (DMI) or the intake time (IT). The model is described by ordinary differential equations. Model building was supported by experimental data of methane emissions from respiration chambers. The data set comes from a study with finishing beef steers (cross-bred Charolais and purebred Luing finishing). DMI and IT were recorded with load cells. A total of 37 individual dynamic patterns of methane production were analysed. Model performance was assessed by concordance analysis between the predicted methane output and the methane measured in respiration chambers. The model predictors DMI and IT performed similarly with a Lin’s concordance correlation coefficient (CCC) of 0.78 on average. When predicting the daily methane production, the CCC was 0.99 for both DMI and IT predictors. Consequently, on the basis of concordance analysis, our model performs very well compared with reported literature results for methane proxies and predictive models. Since IT measurements are easier to obtain than DMI measurements, this study suggests that a software sensor that integrates ourin silicomodel with a real-time sensor providing accurate IT measurements is a viable solution for predicting methane output in a large scale context.ImplicationsReducing methane emissions from ruminants is a major target for sustainable and efficient livestock farming. For the animal, methane production represents a loss of feed energy. For the environment, methane exerts a potent greenhouse effect. Methane mitigation strategies require accurate, non-invasive and inexpensive techniques for estimating individual methane emissions on farm. In this study, we integrate measurements of feeding behaviour in cattle and a mathematical model to estimate individual methane production. Together, model and measurements form a software sensor that efficiently predicts methane output. Our software sensor is a promising approach for estimating methane emissions at large scale.

Objective To analyze factors associated with changes in prescription drug use and expenditures in the United States from 1999 to 2016, a period of rapid growth, deceleration, and resumed above-average growth. Data sources/study setting The Medical Expenditure Panel Survey (MEPS), containing household and pharmacy information on over five million prescription drug fills. Study design We use nonparametric decomposition to analyze drug use, average payment per fill, and per capita expenditure, tracking the contributions over time of socioeconomic characteristics, health status and treated conditions, insurance coverage, and market factors surrounding the patent cycle. Data collection/extraction methods Medical Expenditure Panel Survey data were combined with information on drug approval dates and patent status. Principal findings Per capita utilization increased by nearly half during 1999-2016, with changes in health status and treated conditions accounting for four-fifths of the increase. In contrast, per capita expenditures more than doubled, with individual characteristics only explaining one-third of the change. Other drivers of spending during this period include the changing pipeline of new drugs, drugs losing exclusivity, and changes in generic competition. Conclusions Long-term trends in treated conditions were the fundamental drivers of medication use, whereas factors involving the patent cycle accelerated and decelerated spending growth relative to trends in use.

International audience; Our understanding of the niche concept will remain limited while the quantity and range of different food types eaten remain a dominant proxy for niche breadth, as this does not account for the broad ecological context that governs diet. Linking nutrition, physiology and behaviour is critical to predict the extent to which a species adjusts its nutritional niche breadth at the levels of prey (“prey composition niche,” defined as the range of prey compositions eaten) and diet (“realized nutritional niche” is the range of diets composed through feeding on the prey).Here, we studied adult chick‐rearing Australasian gannets Morus serrator to propose an integrative approach using sea surface temperature anomalies (SSTa), geographic location and bathymetry over different years, to explore their relationship with the nutritional composition of prey and diets (i.e. prey composition and nutritional niche breadth), habitat use and foraging behaviour.We found that gannets feed on prey that varied widely in their nutritional composition (have a broad prey composition niche), and composed diets from these prey that likewise varied in composition (have a broad realized nutritional niche), suggesting generalism at two levels of macronutrient selection.Across seasons, we established “nutritional landscapes” (hereafter nutriscapes), linking the nutritional content of prey (wet mass protein‐to‐lipid ratio—P:L) to the most likely geographic area of capture and bathymetry. Nutriscapes varied in their P:L from 6.06 to 15.28, over time, space and bathymetry (0–150 m).During warm water events (strong positive SSTa), gannets expanded their foraging habitat, increased their foraging trip duration and consumed prey and diets with low macronutrient content (wet mass proportions of P and L). They were also constrained to the smallest prey composition and realized nutritional niche breadths.Our findings are consistent with previous suggestions that dietary generalism evolves in heterogeneous environments, and provide a framework for understanding the nutritional goals in wild marine predators and how these goals drive ecological interactions and are, in turn, ultimately shaped by environmental fluctuations.

Most countries have committed to protect 17% of their terrestrial area by 2020 through Aichi Target 11 of the Convention on Biological Diversity, with a focus on protecting areas of particular importance for biodiversity. This means national-scale spatial conservation prioritisations are needed to help meet this target and guide broader conservation and land-use policy development. However, to ensure these assessments are adopted by policy makers, they must also consider national priorities. This situation is exemplified by Guyana, a corner of Amazonia that couples high biodiversity with low economic development. In recent years activities that threaten biodiversity conservation have increased, and consequently, protected areas are evermore critical to achieving the Aichi targets. Here we undertake a cost-effective approach to protected area planning in Guyana that accounts for in-country conditions. To do this we conducted a stakeholder-led spatial conservation prioritisation based on meeting targets for 17 vegetation types and 329 vertebrate species, while minimising opportunity costs for forestry, mining, agriculture and urbanisation. Our analysis identifies 3 million ha of priority areas for conservation, helping inform government plans to double the current protected area network from 8.5 to 17%. As part of this, we also develop a new technique to prioritise engagement with local communities whose lands are identified as important to conservation. Our study both provides a scientifically robust, politically acceptable protected area expansion strategy for Guyana, and illustrates the importance of conservation planning at the country-scale to translate international commitments into national action.

OBJECTIVEUltrasound can be precisely focused through the intact human skull to target deep regions of the brain for stereotactic ablations. Acoustic energy at much lower intensities is capable of both exciting and inhibiting neural tissues without causing tissue heating or damage. The objective of this study was to demonstrate the effects of low-intensity focused ultrasound (LIFU) for neuromodulation and selective mapping in the thalamus of a large-brain animal.METHODSTen Yorkshire swine (Sus scrofa domesticus) were used in this study. In the first neuromodulation experiment, the lemniscal sensory thalamus was stereotactically targeted with LIFU, and somatosensory evoked potentials (SSEPs) were monitored. In a second mapping experiment, the ventromedial and ventroposterolateral sensory thalamic nuclei were alternately targeted with LIFU, while both trigeminal and tibial evoked SSEPs were recorded. Temperature at the acoustic focus was assessed using MR thermography. At the end of the experiments, all tissues were assessed histologically for damage.RESULTSLIFU targeted to the ventroposterolateral thalamic nucleus suppressed SSEP amplitude to 71.6% ± 11.4% (mean ± SD) compared with baseline recordings. Second, we found a similar degree of inhibition with a high spatial resolution (∼ 2 mm) since adjacent thalamic nuclei could be selectively inhibited. The ventromedial thalamic nucleus could be inhibited without affecting the ventrolateral nucleus. During MR thermography imaging, there was no observed tissue heating during LIFU sonications and no histological evidence of tissue damage.CONCLUSIONSThese results suggest that LIFU can be safely used to modulate neuronal circuits in the central nervous system and that noninvasive brain mapping with focused ultrasound may be feasible in humans.

Background Ethanol (EtOH) intake correlates with increased risk-taking, and sex differences exist in both EtOH use and risk-taking in humans and rats. However, the interaction of sex and gonadal hormones to affect risk-taking under the influence of EtOH has not been determined. This was the focus of the current study. Methods Adult Long-Evans rats (n = 18 males and females) were gonadectomized and received hormone replacement at physiologic levels or blank implants (n = 7-9/group). Risk-taking was assessed with probability discounting, requiring rats to choose between a small/certain reward and a large/uncertain reward delivered with decreasing probability throughout each daily session. Before testing, rats received saline or EtOH (0.5 or 1.0 g/kg) ip. Results In males, EtOH increased preference for the large/uncertain reward lever (F2,28 = 10.462, p 0.05). At baseline, ORCHX+T males showed a greater preference for the large/uncertain reward lever then ORCHX males (F1,14 = 13.805, p Conclusions These results show that EtOH, sex, and hormones interact to influence decision making. EtOH increases risk taking in males, but not in females. However, EtOH selectively decreases choice latency in females, and decreases loss sensitivity in both sexes. These findings are relevant to understanding human behavior, particularly in adolescents who experience increased hormone levels and often drink EtOH and engage in risky behavior.

International audience; Niche divergence is expected for species that compete for shared resources, including migrants that occupy similar regions during the non-breeding season. Studies of temperate seabirds indicate that both spatial and behavioural segregation can be important mechanisms for reducing competition, but there have been few investigations of resource partitioning by closely related taxa in low productivity, tropical environments. We investigated niche partitioning in 3 gadfly petrel taxa, Pterodroma leucoptera leucoptera (n = 22), P. leucoptera caledonica (n = 7) and P. pycrofti (n = 12), during their non-breeding season in the eastern tropical Pacific Ocean by combining tracking data from geolocator-immersion loggers with remotely sensed environmental data in species distribution models (SDMs), and by comparing feather stable isotope ratios. The 3 taxa showed spatial partitioning: two foraged in the North Equatorial Counter Current and one in the South Equatorial Current. This reflected differences in their realised habitat niches, with significant taxon-specific responses to thermocline depth, sea surface temperature and bathymetry. There were also differences among taxa in activity patterns, and all birds spent a much larger proportion of time in flight at night than during the day, suggesting predominance of nocturnal foraging behaviour. Comparison of stable isotope ratios in feathers suggests that P. l. leucoptera and P. pycrofti mainly consume vertically migrating mesopelagic fishes, whereas the diet of P. l. caledonica also includes some lower trophic levels including crustaceans and squid. Unique insights can be gained from studies of the foraging ecology of tropical pelagic seabirds, in comparison with temperate and polar waters, and are urgently required for understanding and protecting tropical avifauna in key marine habitats.

Background During high-intensity focused ultrasound (HIFU) surgical procedures, there is a need to rapidly ablate pathological tissue while minimizing damage to healthy tissue. Current techniques are limited by relatively long procedure times and risks of off-target heating of healthy tissue. One possible solution is the use of microbubbles, which can improve the efficiency of thermal energy delivery during HIFU procedures. However, microbubbles also suffer from limitations such as low spatial selectivity and short circulation time in vivo. In this study, the use of a dual-perfluorocarbon nanodroplet that can enhance thermal ablation, yet retains high spatial selectivity and circulation half-life, was evaluated in vivo and compared to traditional microbubble agents during HIFU ablations of rat liver. Methods High-intensity focused ultrasound (1.1 MHz, 4.1 MPa, 15-s continuous wave) was applied to rat liver in vivo, and heating was monitored during sonication by magnetic resonance thermometry. Thermometry data were analyzed to quantify temperature rise and ablated area, both at the target and prefocally, for HIFU applied 5, 15, or 95 min after intravenous injection of either nanodroplet or microbubble agents. Sham control experiments (no injected agents) were also performed. Results At all three time points, nanodroplets significantly enhanced thermal delivery to the target, achieving temperatures 130 % higher and ablated areas 30 times larger than no-agent control sonications. Nanodroplets did not significantly enhance off-target surface heating. Microbubbles also resulted in significantly greater thermal delivery, but heating was concentrated at the proximal surface of the animal, causing skin burns. Furthermore, microbubbles resulted in lower thermal delivery to the desired target than even the control case, with the notable exception of the 95-min time point. Conclusions Results indicate that the nanodroplet formulation studied here can substantially increase thermal delivery at the acoustic focus while avoiding prefocal heating. In contrast, microbubbles resulted in greater prefocal heating and less heating at the target. Furthermore, nanodroplets are sufficiently stable to enhance HIFU ablation in vivo for at least 1.5 h after injection. The use of a dual-perfluorocarbon nanodroplet formulation as described herein could substantially reduce HIFU procedure times without increasing the risk of skin burns.

Objectives To use the most recently available population-based data to estimate potentially inappropriate medication (PIM) prevalence under the 2012 update of the Beers list of PIMs and to provide a benchmark from which to measure future changes. Design Retrospective cohort study using nationally representative data. Setting 2006–2010 Medical Expenditure Panel Survey (MEPS). Participants Community-dwelling sample of U.S. older adults (N = 18,475). Measurements The updated Beers criteria were operationalized, generating a “broad” PIM definition that incorporated form, route, or dose restrictions where clearly specified and a “qualified” definition that applied specific exceptions where mentioned in the rationale associated with each drug category. Bivariate analyses described PIM prevalence, comparing the two operational definitions, and examined time trends. Results Of older adults with prescription medications, 42.6% had at least one medication fill that met the broad definition, with nonsteroidal anti-inflammatory drugs (NSAIDs) having the highest prevalence (10.9%). The rate declined from 45.5% in 2006–2007 to 40.8% in 2009–2010. The categories with the largest absolute decline were NSAIDs, selected sulfonylureas, and estrogens. PIM prevalence was 30.9% using the qualified definition. Conclusion Despite the overall high use of PIMs, there has been a decline observed in recent years. Future studies should test the effect of educational and clinical interventions on changes in PIM use and outcomes. The current study results can aid in targeting these interventions.

In this work we present a spectral and multifractal study of the electric self-potential fluctuations registered in an electroseismic station located at 100km from the epicenter of an earthquake (EQ) with Mw=6.5 in the Pacific coast of Mexico. Our study suggests that in general the time series analyzed displays a persistent behavior. Our results show an anticorrelation between the spectral exponent β and the width of the multifractal spectrum Δα, when they are calculated during a time interval of five months (four months before the EQ and one month after the EQ). In addition, we also calculate the time evolution of the correlation coefficient finding that it has a very similar behavior that the time evolution of Δα.

Investigation of volitional animal models of resistance training has been instrumental in our understanding of adaptive training. However, these studies have lacked reactive force measurements, a precise performance measure, and morphological analysis at a distinct phase of training - when initial strength gains precede muscle hypertrophy. Our aim was to expose rats to one month of training (70 or 700 g load) on a custom-designed weight-lifting apparatus for analysis of reactive forces and muscle morphology prior to muscle hypertrophy. Exclusively following 700 g load training, forces increased by 21% whereas muscle masses remained unaltered. For soleus (SOL) and tibialis anterior (TA) muscles, 700 g load training increased muscle fiber number per unit area by ~20% and decreased muscle fiber area by ~20%. Additionally, number of muscle fibers per section increased by 18% for SOL muscles. These results establish that distinct morphological alterations accompany early strength gains in a volitional animal model of load-dependent adaptive resistance training.

Work rotation schedules may be used to reduce the negative effects of vibration on vascular function. This study determined how long it takes vascular function to recover after a single exposure to vibration in rats (125 Hz, acceleration 5 g). The responsiveness of rat-tail arteries to the vasoconstricting factor UK14304, an α2C-adrenoreceptor agonist, and the vasodilating factor acetylcholine (ACh) were measured ex vivo 1, 2, 7, or 9 d after exposure to a single bout of vibration. Vasoconstriction induced by UK14304 returned to control levels after 1 d of recovery. However, re-dilation induced by ACh did not return to baseline until after 9 d of recovery. Exposure to vibration exerted prolonged effects on peripheral vascular function, and altered vascular responses to a subsequent exposure. To optimize the positive results of work rotation schedules, it is suggested that studies assessing recovery of vascular function after exposure to a single bout of vibration be performed in humans.

Information regarding the contributions of the authors was not included in the original publication. In the original format of the paper submitted for review, the author order was Phillips, Puett, Sheeran, Miller, Matsunaga, and Dayton. This order was agreed on by all authors to properly acknowledge levels of contribution according to standard biomedical convention with primary contributor first and senior author last. However, the authors wish to note that because of the standard format style of JASA, the authors in the published document are grouped by institution. Dr. Phillips, as first author, conducted all of the studies in the manuscript, analyzed data, wrote the manuscript, and performed editing. Mr. Puett and Mr. Sheeran assisted with data collection and analysis, as did Dr. Miller. Dr. Matsunaga provided expertise as to the nanodroplet formulations. Dr. Dayton was the senior author on this work, contributed to study concept and design, applied for the funding, and edited the manuscript.

Occupational exposure to hand-transmitted vibration can result in damage to nerves and sensory loss. The goal of this study was to assess the frequency-dependent effects of repeated bouts of vibration on sensory nerve function and associated changes in nerves.The tails of rats were exposed to vibration at 62.5, 125, or 250 Hz (constant acceleration of 49 m/s2) for 10 days. The effects on sensory nerve function, nerve morphology, and transcript expression in ventral tail nerves were measured.Vibration at all frequencies had effects on nerve function and physiology. However, the effects tended to be more prominent with exposure at 250 Hz.Exposure to vibration has detrimental effects on sensory nerve function and physiology. However, many of these changes are more prominent at 250-Hz exposure than at lower frequencies.

Planets orbiting post-common envelope binaries provide fundamental information on planet formation and evolution, especially for the yet nearly unexplored class of circumbinary planets. We searched for such planets in \odp, an eclipsing short-period binary, which shows long-term eclipse-time variations. Using published, reanalysed, and new mid-eclipse times of the white dwarf in DP\,Leo, obtained between 1979 and 2010, we find agreement with the light-travel-time effect produced by a third body in an elliptical orbit. In particular, the measured binary period in 2009/2010 and the implied radial velocity coincide with the values predicted for the motion of the binary and the third body around the common center of mass. The orbital period, semi-major axis, and eccentricity of the third body are P_c = 28.0 +/- 2.0 yrs, a_c = 8.2 +/- 0.4 AU, and e_c = 0.39 +/- 0.13. Its mass of M_c sin(i_c) = 6.1 +/- 0.5 M_J qualifies it as a giant planet. It formed either as a first generation object in a protoplanetary disk around the original binary or as a second generation object in a disk formed in the common envelope shed by the progenitor of the white dwarf. Even a third generation origin in matter lost from the present accreting binary can not be entirely excluded. We searched for, but found no evidence for a fourth body., Comment: Accepted by A&A

Despite a myriad of technical advances in medical imaging, as well as the growing need to address the global impact of pulmonary diseases, such as asthma and chronic obstructive pulmonary disease, on health and quality of life, it remains challenging to obtain in vivo regional depiction and quantification of the most basic physiological functions of the lung—gas delivery to the airspaces and gas uptake by the lung parenchyma and blood—in a manner suitable for routine application in humans. We report a method based on MRI of hyperpolarized xenon-129 that permits simultaneous observation of the 3D distributions of ventilation (gas delivery) and gas uptake, as well as quantification of regional gas uptake based on the associated ventilation. Subjects with lung disease showed variations in gas uptake that differed from those in ventilation in many regions, suggesting that gas uptake as measured by this technique reflects such features as underlying pathological alterations of lung tissue or of local blood flow. Furthermore, the ratio of the signal associated with gas uptake to that associated with ventilation was substantially altered in subjects with lung disease compared with healthy subjects. This MRI-based method provides a way to quantify relationships among gas delivery, exchange, and transport, and appears to have significant potential to provide more insight into lung disease.

We have made the first measurements of the virtual Compton scattering (VCS) process via the H$(e,e'p)\gamma$ exclusive reaction in the nucleon resonance region, at backward angles. Results are presented for the $W$-dependence at fixed $Q^2=1$ GeV$^2$, and for the $Q^2$-dependence at fixed $W$ near 1.5 GeV. The VCS data show resonant structures in the first and second resonance regions. The observed $Q^2$-dependence is smooth. The measured ratio of H$(e,e'p)\gamma$ to H$(e,e'p)\pi^0$ cross sections emphasizes the different sensitivity of these two reactions to the various nucleon resonances. Finally, when compared to Real Compton Scattering (RCS) at high energy and large angles, our VCS data at the highest $W$ (1.8-1.9 GeV) show a striking $Q^2$- independence, which may suggest a transition to a perturbative scattering mechanism at the quark level., Comment: 20 pages, 8 figures. To appear in Phys.Rev.C

Purpose To investigate short- and long-time-scale 3He diffusion in asthma. Materials and Methods A hybrid MRI sequence was developed to obtain coregistered short- and long-time-scale apparent diffusion coefficient (ADC) maps during a single breath-hold. The study groups were: asthma (n = 14); healthy (n = 14); chronic obstructive pulmonary disease (COPD) (n = 9). Correlations were made between mean-ADC and %ADC-abn (abnormal) (%pixels with ADC > mean +2 SD of healthy) at both time scales and spirometry. Sensitivities were determined using receiver operating characteristic (ROC) analysis. Results For asthmatics, the short- and long-time-scale group-mean ADCs were 0.254 ± 0.032 cm2/s and 0.0237 ± 0.0055 cm2/s, respectively, representing a 9% and 27% (P = 0.038 and P = 0.005) increase compared to the healthy group. The group-mean %ADC-abn were 6.4% ± 3.7% and 17.5% ± 14.2%, representing a 107% and 272% (P = 0.004 and P = 0.006) increase. For COPD much greater elevations were observed. %ADC-abn provided better discrimination than mean-ADC between asthmatic and healthy subjects. In asthmatics ADC did not correlate with spirometry. Conclusion With long-time scale 3He diffusion magnetic resonance imaging (MRI) changes in lung microstructure were detected in asthma that more conspicuous regionally than at the short time scale. The hybrid diffusion method is a novel means of identifying small airway disease. J. Magn. Reson. Imaging 2008;28:80–88. © 2008 Wiley-Liss, Inc.

The Sudbury Neutrino Observatory (SNO) used an array of 3He proportional counters to measure the rate of neutral-current interactions in heavy water and precisely determined the total active (nu_x) 8B solar neutrino flux. This technique is independent of previous methods employed by SNO. The total flux is found to be 5.54_-0.31;+0.33(stat)-0.34+0.36(syst)x10(6) cm(-2) s(-1), in agreement with previous measurements and standard solar models. A global analysis of solar and reactor neutrino results yields Deltam2=7.59_-0.21;+0.19x10(-5) eV2 and theta=34.4_-1.2;+1.3 degrees. The uncertainty on the mixing angle has been reduced from SNO's previous results.

Necrotising fasciitis (‘synergic gangrene’) is a serious bacterial soft tissue infection with a rapidly progressive course and high mortality. It is caused by a variable combination of obligate anaerobes, streptococci, staphylococci, and Gram-negative bacilli. Histologically, it is characterised by obliterative endarteritis and thrombosis of the subcutaneous vessels, leukocyte infiltration, and fascial necrosis.1 It predominantly occurs in patients who are debilitated by a co-morbid condition such as diabetes, alcoholic liver disease, or intravenous drug use. We have described a case of necrotising fasciitis secondary to a locally advanced carcinoma of the lower rectum, as a likely consequence of perforation into the surrounding extraperitoneal tissues. The patient had no other identifiable predisposing factors.

The potential role of new drugs in reducing expenditures for non-drug health services has received considerable attention in recent policy debates. We estimate expenditure models to determine whether the use of newer drugs to treat cardiovascular conditions is associated with lower (or higher) non-drug expenditures for these conditions. We fail to substantiate the findings of previous research that newer drugs are associated with reductions in non-drug expenditures. We find, however, that increases in the number of drugs used, or the mix of drugs of different ages, are associated with increased non-drug expenditures and find that the number or mix of drugs used are important confounders in the estimated association between drug age and non-drug expenditures.

The Sudbury Neutrino Observatory has precisely determined the total active (nu(x)) 8B solar neutrino flux without assumptions about the energy dependence of the nu(e) survival probability. The measurements were made with dissolved NaCl in heavy water to enhance the sensitivity and signature for neutral-current interactions. The flux is found to be 5.21 +/- 0.27(stat)+/-0.38(syst) x 10(6) cm(-2) s(-1), in agreement with previous measurements and standard solar models. A global analysis of these and other solar and reactor neutrino results yields Deltam(2)=7.1(+1.2)(-0.6) x 10(-5) eV(2) and theta=32.5(+2.4)(-2.3) degrees. Maximal mixing is rejected at the equivalent of 5.4 standard deviations.

The Sudbury Neutrino Observatory (SNO) has measured day and night solar neutrino energy spectra and rates. For charged current events, assuming an undistorted $^8$B spectrum, the night minus day rate is $14.0% \pm 6.3% ^{+1.5}_{-1.4}%$ of the average rate. If the total flux of active neutrinos is additionally constrained to have no asymmetry, the $\nu_e$ asymmetry is found to be $7.0% \pm 4.9% ^{+1.3}_{-1.2}%$. A global solar neutrino analysis in terms of matter-enhanced oscillations of two active flavors strongly favors the Large Mixing Angle (LMA) solution., Comment: 5 pages, 4 figures; very minor revisions, accepted by Physical Review Letters

Observations of neutral current neutrino interactions on deuterium in the Sudbury Neutrino Observatory are reported. Using the neutral current, elastic scattering, and charged current reactions and assuming the standard 8B shape, the electron-neutrino component of the 8B solar flux is 1.76 +/-0.05(stat.)+/-0.09(syst.) x10^6/(cm^2 s), for a kinetic energy threshold of 5 MeV. The non-electron neutrino component is 3.41+/-0.45(stat.)+0.48,-0.45(syst.) x10^6/(cm^2 s), 5.3 standard deviations greater than zero, providing strong evidence for solar electron neutrino flavor transformation. The total flux measured with the NC reaction is 5.09 +0.44,-0.43(stat.)+0.46,-0.43(syst.)x10^6/(cm^2 s), consistent with solar models., Comment: 6 pages, 3 figures, correction to author list and minor typographical corrections to references

By means of the box counting method we calculate the fractal dimension D of the distribution of faults, fractures and lineaments in a region of the southern Mexican Pacific coast. The results suggest that in the spatial sense the b-value of the Gutenberg-Richter law and the fractal dimension are positively correlated. We also suggest that D depends on the depth of the seismogenic zone.

This study characterises the somatostatin binding site in human gastrointestinal cancer and mucosa in terms of cationic specificity and relative affinity for three somatostatin analogues. Competitive displacement assays were performed on plasma membranes from human gastric and colonic tissues using radiolabelled somatostatin-14 as ligand. Comparison was made with the somatostatin binding site in rat cerebral cortex. In gastrointestinal tissue, magnesium decreased and sodium increased specific binding. By contrast, in rat cerebral cortex, the converse cationic effect was seen. These changes resulted from alterations in receptor density, with no change in receptor affinity. Displacement studies were then performed with somatostatin-14 and somatostatin analogues RC-160, somatuline, and octreotide. RC-160 and somatuline displaced radiolabel from binding sites in gastric and colonic cancer and mucosa with 10-fold lower affinity than the native peptide. Octreotide did not displace radioligand in gastric or colonic cancer at any concentration tested. By contrast, in rat cortex, although all three analogues displaced with a lower affinity than the native peptide, there was no difference between analogues. These data suggest a distinct somatostatin receptor subtype in gastrointestinal tissues.

A multilaboratory study was undertaken to reassess the amount of calcium and magnesium that should be added to Mueller-Hinton broth when testing Pseudomonas aeruginosa against amikacin, gentamicin, isepamicin, netilmicin, and tobramycin. To achieve parity with agar dilution tests, cation-adjusted broth should contain 20 to 25 mg of calcium and 10 to 12.5 mg of magnesium per liter rather than the 50- and 25-mg/liter supplements recommended previously. For quality control of tests with contemporary media, MIC control limits should be adjusted by lowering the current MIC limits by at least 1 doubling-dilution interval.

Treatment of BALB/c mice with purified pig anti-(BALB/c anti-nuclease) anti-idiotypic antibodies has been found to induce the appearance of idiotype-bearing immunoglobulins (Id') in the serum of these mice in the absence of detectable antigen binding activity. This phenomenon appeared to require T cells in the hosts because no Id' was detected in the serum of nude mice similarly treated. Furthermore, the spleens of BALB/c mice treated with anti-idiotype were found to contain helper T cells capable of providing help in an in vitro plaque-forming cell response to trinitrophenyl-nuclease equivalent to that provided by helper T cells from the spleens of nuclease-primed animals. Helper T cells from both anti-idiotype-treated and nuclease-treated animals were found to be antigen-specific and to be similarly susceptible to elimination by treatment with anti-idiotype plus complement. Therefore, treatment with both antigen and anti-idiotype appeared to prime similar populations of antigen-specific helper T cells, while having different effects on the induction of antibody. These findings are consistent with the network theory of receptor interactions in the immune response, and may provide a means for studying individual cell populations involved in such interactions.

We report 26 individuals from ten unrelated families who exhibit variable expression and/or incomplete penetrance of epilepsy, learning difficulties, intellectual disabilities, and/or neurobehavioral abnormalities as a result of a heterozygous microdeletion distally adjacent to the Williams-Beuren syndrome region on chromosome 7q11.23. In six families with a common recurrent ∼1.2 Mb deletion that includes the Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (YWHAG) genes and that is flanked by large complex low-copy repeats, we identified sites for nonallelic homologous recombination in two patients. There were no cases of this ∼1.2 Mb distal 7q11.23 deletion copy number variant identified in over 20,000 control samples surveyed. Three individuals with smaller, nonrecurrent deletions (∼180-500 kb) that include HIP1 but not YWHAG suggest that deletion of HIP1 is sufficient to cause neurological disease. Mice with targeted mutation in the Hip1 gene (Hip1⁻(/)⁻) develop a neurological phenotype characterized by failure to thrive, tremor, and gait ataxia. Overall, our data characterize a neurodevelopmental and epilepsy syndrome that is likely caused by recurrent and nonrecurrent deletions, including HIP1. These data do not exclude the possibility that YWHAG loss of function is also sufficient to cause neurological phenotypes. Based on the current knowledge of Hip1 protein function and its proposed role in AMPA and NMDA ionotropic glutamate receptor trafficking, we believe that HIP1 haploinsufficiency in humans will be amenable to rational drug design for improved seizure control and cognitive and behavioral function.

Chlorinated hydrocarbons as one group of synthetic pesticides have been in common use since 1945. They are characterized by their stability, residual effect, insolubility in water, and relative specific action. Dieldrin is a widely used pesticide which has been employed for the control of termites and agricultural insects in corn, alfalfa, lawns, turfs, and flowers, and also in household sprays.' Although the use of dieldrin has been restricted in New York State to the control of termites, lumber insects, sod and soil, potential contamination of food items still exists. Chlorinated hydrocarbons are known to last for long periods in the environment, not necessarily at the site of application. Food represents the most important carrier of chemical contamination, including pesticides, being an end product of the three components of the environment-air, water and soil. Unavoidable bactericidal operations, environmental pollution, natural sources, and human error often result in such contamination. The major sources of chlorinated hydrocarbons in food are those of animal origin, namely, milk and dairy products, meat, fish and poultry. Studies conducted by the Food and Drug Administration and other agencies during the 1960s have indicated that these foods are the source of approximately one-half of the total intake of chlorinated hydrocarbon residues.2 Pesticide residues in milk and dairy prod