Hemodynamic Assay of Hind Limb in Multiple Animal Models.

INTRODUCTION: Measuring hemodynamic characteristics of injured limbs is paramount to early identification of potentially damaging ischemic conditions, but can often prove difficult attributable to a multitude of factors. Here, we present an in vivo optical imaging technique to characterize pulsatile blood flow quality through the distal extremity in multiple animal models that replicate the signs of distal extremity ischemia. The purpose of this study is to examine the feasibility of the optical imaging technique and relevance to hemodynamic complications such as acute compartment syndrome (ACS) and nonobvious hemorrhage. MATERIALS AND METHODS: In one pig and six mice, three different methods were used to create ischemic conditions in the lower extremity, producing symptoms similar to what is observed in ACS. In each condition, perfusion to the distal extremity was measured with the hemodynamic detection device (HDD; Odin Technologies), an optical assessment tool for perfusion and blood flow quality. RESULTS: We observed a profound decrease in extremity perfusion immediately after onset of ischemia in all three models. In the porcine model, the HDD's measurements demonstrated similar characteristic flow between the various measurement locations. After the tourniquet was applied, the HDD revealed a 95% decrease in normalized perfusion value (npv) while the intracompartmental pressure rose from 5 to 52 mmHg (a 47mmHg increase). After the tourniquet was removed during reperfusion, the normalized blood flow returned to baseline and the intracompartmental pressure dropped from 20 to 6 mmHg in less than 5 minutes. For each mouse, the HDD test leg demonstrated a measurement of 0.97 npv before femoral ligation and 0.05 npv after femoral ligation, an 89% decrease (P < .01) in flow. Pulsed-wave Doppler ultrasound (PWDU) measurements on the test leg had pre-ligation measurement of 0.84 npv and a post-ligation measurement of 0.001 npv, a 99% decrease. These PWDU measurements revealed almost complete stoppage of blood flow during ischemia, followed by a substantial increase after the femoral artery ligation was removed. CONCLUSIONS: Here, we show that a novel, optics-based sensing system can be used to diagnose and assess ACS in animal models. This technology is comparable to other standards used to monitor ACS and nonobvious hemorrhage and may also be a plausible alternative to prolonged invasive monitoring of patients with sustained extremity trauma.

Understanding the Attachment Dimension of Human-animal Bond within A Homeless Population: A One-Health Initiative in the Student Health Outreach for Wellness (SHOW) Clinic.

In response to a gap in veterinary care for low-income, under-served populations, the Student Health Outreach for Wellness (SHOW) Clinic in Phoenix, AZ took a One-Health initiative to establish a pilot veterinary care program to serve the veterinary needs of the local homeless pet owners receiving human medical care at the clinic. The study examines the pilot program through the lens of the human-animal bond (HAB) and focuses specifically on the attachment dimension of the bond as measured by the Lexington Attachment to Pets Scale (LAPS). Data was collected from the homeless pet owners, and Rasch modeling was used to investigate the importance of various factors of the owner attachment to pet as described in LAPS items. The results demonstrate the perceptions of the homeless pet owners of ownership. The findings also provide psychometric evidence for revising the LAPS to better serve future research on human-animal relationships. Limitations and possible extensions of the research as related to the HAB and owner attachment to pets are discussed and enhancements proposed for the pilot program to better serve the local homeless people.

Chemical profiling of the synthetic cannabinoid MDMB-CHMICA: Identification, assessment, and stability study of synthesis-related impurities in seized and synthesized samples.

In this work, the most discriminating synthesis-related impurities found in samples from seizures and controlled synthesis of the synthetic cannabinoid MDMB-CHMICA (methyl (S)-2-(1-(cyclohexylmethyl)-1H-indole-3-carboxamido)-3,3-dimethylbutanoate) were characterized. Based on 61 available powder samples of MDMB-CHMICA, 15 key-impurities were assessed, isolated in larger quantities via flash chromatography and structurally elucidated and characterized via high resolution mass spectrometry and nuclear magnetic resonance spectroscopy. Apart from verifying the relation of the impurities to the major component, the interpretation of their chemical structures with distinct structural elements provided first insights into the manufacturing process and the precursor compounds used. Following liquid chromatography mass spectrometry analysis of the 15 key-impurities, the 61 seized samples of MDMB-CHMICA were evaluated and classified via multivariate data analysis based on the corresponding relative peak areas. In a second part of this work, stability tests and multiple controlled syntheses of MDMB-CHMICA were carried out to better understand variations in impurity signatures and to assess the significance of variations in the impurity patterns of seized samples. The last coupling step of the amino acid with 1-(cyclohexylmethyl)-1H-indole-3-carboxylic acid was performed using the coupling agents oxalyl chloride, thionyl chloride, and HATU. Furthermore, the impact of reaction time and temperature on the impurity profile were investigated. Overall, eight new impurities were found in the controlled syntheses and two degradation products of MDMB-CHIMCA were found in the course of the stability tests. Replicates of a synthesis conducted on the same day showed similar impurity signatures; on different days they showed discriminable signatures. The use of different coupling reagents or conditions gave clearly distinguishable impurity signatures.

Modelling the N400 brain potential as change in a probabilistic representation of meaning.

The N400 component of the event-related brain potential has aroused much interest because it is thought to provide an online measure of meaning processing in the brain. However, the underlying process remains incompletely understood and actively debated. Here we present a computationally explicit account of this process and the emerging representation of sentence meaning. We simulate N400 amplitudes as the change induced by an incoming stimulus in an implicit and probabilistic representation of meaning captured by the hidden unit activation pattern in a neural network model of sentence comprehension, and we propose that the process underlying the N400 also drives implicit learning in the network. The model provides a unified account of 16 distinct findings from the N400 literature and connects human language comprehension with recent deep learning approaches to language processing.

Synthesis and biological evaluation of a D-ring-contracted analogue of lamellarin D.

A D-ring contracted analogue of the strongly cytotoxic marine pyrrole alkaloid lamellarin D was synthesized and investigated for its antiproliferative action towards a wild type and a multidrug resistant (MDR) cancer cell line. The compound was found to inhibit tumor cell growth at submicromolar concentrations and showed a lower relative resistance in the MDR cell line than the antitumor drug camptothecin to which lamellarin D shows cross resistance and with which lamellarin D shares the same binding site.

Building on prior knowledge without building it in.

Lake et al. propose that people rely on "start-up software," "causal models," and "intuitive theories" built using compositional representations to learn new tasks more efficiently than some deep neural network models. We highlight the many drawbacks of a commitment to compositional representations and describe our continuing effort to explore how the ability to build on prior knowledge and to learn new tasks efficiently could arise through learning in deep neural networks.

Synthesis of Lamellarin D Trimethyl Ether and Lamellarin H via 6π-Electrocyclization.

An electrocyclic ring closure of a 2-azapentadienyl anion generated in situ from a chalcone and glycine ester is the key step of an efficient synthesis of the pyrrole core of the lamellarin alkaloids. A recently developed scalable one-pot procedure provides multigram quantities of a 3,5-diaryl-4-iodopyrrole-2-carboxylate intermediate which is transformed in four further high-yielding operations including a one-pot Pomeranz-Fritsch alkylation/cyclization and an Ullmann-type lactone ring closure into the pentacyclic lamellarin skeleton.

Effectiveness and adverse effects of the use of apomorphine and 3% hydrogen peroxide solution to induce emesis in dogs.

OBJECTIVE: To determine the effectiveness and adverse effects of apomorphine and 3% hydrogen peroxide solution used for emesis in dogs. DESIGN: Prospective observational study. ANIMALS: 147 dogs that received apomorphine (IV or placed in the conjunctival sac) or 3% hydrogen peroxide solution (PO) to induce emesis after exposure to toxic agents. PROCEDURES: Data regarding signalment; agent information; type, dose, route, and number of emetic administrations; whether emesis was successful; number of times emesis occurred; percentage of ingested agent recovered; and adverse effects were collected via telephone during American Society for the Prevention of Cruelty to Animals Animal Poison Control Center operations and stored in a database for analysis. Mann-Whitney and Fisher exact tests were used to evaluate emetic success rates. RESULTS: Apomorphine and 3% hydrogen peroxide solution successfully induced emesis in 59 of 63 (94%) and 76 of 84 (90%) of dogs, respectively. Mean time to onset of emesis after the first dose of emetic was 14.5 and 18.6 minutes when hydrogen peroxide (n = 37) and apomorphine (31) were used, respectively, with mean durations of 42 and 27 minutes, respectively. Mean estimates for recovery of ingested agents were 48% for hydrogen peroxide and 52% for apomorphine. Adverse effects were reported in 16 of 112 (14%) dogs for which information was available. CONCLUSIONS AND CLINICAL RELEVANCE: 3% hydrogen peroxide solution and apomorphine effectively induced emesis in dogs when used as directed. Emesis occurred within minutes after administration and helped recover substantial amounts of ingested agents. Adverse effects of both emetics were considered mild and self-limiting.

An overview of trends in animal poisoning cases in the United States: 2002-2010.

Veterinary toxicology is a constantly evolving field. The authors use the ASPCA Animal Poison Control Center's medical record database to examine recent trends in veterinary toxicology/animal poisoning incidents received from 2002 to 2010. The demographics of animals exposed to potentially harmful substances, the types of substances ingested, changes/emerging trends in substance exposures, and trends in therapies used to treat exposures are discussed.

Toxicokinetic profile of N-(2-aminoethyl)ethanolamine in the female Wistar rat and distribution into the late gestation fetus and milk.

N-(2-aminoethyl)ethanolamine (AEEA) caused aneurysms of the great vessels in rats exposed in utero and during the first days post partum, exacerbated by postnatal treatment of the lactating dams (Moore et al., 2012). The purpose of this work was to examine the systemic availability of AEEA during gestation and early lactation. The absorption of AEEA was determined following oral administration to nonpregnant and pregnant female Wistar rats. A single dose administered by gavage (0.5 or 50 mg/kg) on gestation day 18 was rapidly and extensively (>90%) absorbed from the gastrointestinal tract (absorption t(1/2) = 0.1-0.2 hr). Elimination from the plasma followed a biphasic pattern, with a rapid elimination phase (t(1/2 α) = 1.6-1.8 hr) followed by a slower phase (t(1/2 ß) = 16.7-17.3 hr). Following repeated gavage administration during gestation day 17 to 19, (14) C-AEEA-derived radioactivity readily partitioned into the fetus and was evenly distributed therein, but cleared approximately twofold slower from the fetal blood and tissues than the maternal blood and chorioallantoic placenta. When administered to lactating dams during lactation days 1 to 12, (14) C-AEEA-derived radioactivity preferentially partitioned into the milk reaching levels that were between 1.6- and 2.5-fold higher than the maternal blood. Although the concentration of AEEA equivalents in the maternal blood remained quite consistent, the concentration in the milk fell by almost 40% between lactation days 4 and 12, probably reflecting an increase in milk production over this same period. We confirm exposure of the offspring to AEEA both in utero and during lactation, but that AEEA does not appear to specifically concentrate in the great vessels.

Carrier-mediated electrodialysis.

Supported liquid membranes containing valinomycin or a calix[4]arene carrier can support electrodialysis under an imposed transmembrane potential. Under optimal conditions both transmembrane flux and carrier-based cation selectivity are enhanced relative to simple dialysis mediated by the same carriers.

Assessment of targeting accuracy of a low-energy stereotactic radiosurgery treatment for age-related macular degeneration.

Age-related macular degeneration (AMD), a leading cause of blindness in the United States, is a neovascular disease that may be controlled with radiation therapy. Early patient outcomes of external beam radiotherapy, however, have been mixed. Recently, a novel multimodality treatment was developed, comprising external beam radiotherapy and concomitant treatment with a vascular endothelial growth factor inhibitor. The radiotherapy arm is performed by stereotactic radiosurgery, delivering a 16 Gy dose in the macula (clinical target volume, CTV) using three external low-energy x-ray fields while adequately sparing normal tissues. The purpose of our study was to test the sensitivity of the delivery of the prescribed dose in the CTV using this technique and of the adequate sparing of normal tissues to all plausible variations in the position and gaze angle of the eye. Using Monte Carlo simulations of a 16 Gy treatment, we varied the gaze angle by ±5° in the polar and azimuthal directions, the linear displacement of the eye ±1 mm in all orthogonal directions, and observed the union of the three fields on the posterior wall of spheres concentric with the eye that had diameters between 20 and 28 mm. In all cases, the dose in the CTV fluctuated <6%, the maximum dose in the sclera was <20 Gy, the dose in the optic disc, optic nerve, lens and cornea were <0.7 Gy and the three-field junction was adequately preserved. The results of this study provide strong evidence that for plausible variations in the position of the eye during treatment, either by the setup error or intrafraction motion, the prescribed dose will be delivered to the CTV and the dose in structures at risk will be kept far below tolerance doses.

Kilovoltage stereotactic radiosurgery for age-related macular degeneration: assessment of optic nerve dose and patient effective dose.

Age-related macular degeneration (AMD) is a leading cause for vision loss for people over the age of 65 in the United States and a major health problem worldwide. Research for new treatments of the wet form of the disease using kilovoltage stereotactic radiosurgery is currently underway at Oraya Therapeutics, Inc. In the present study, the authors extend their previous computational stylized model of a single treated eye [Med. Phys. 35, 5151-5160 (2008)] to include full NURBS-based reference head phantoms of the adult male and female using anatomical data from ICRP Publication 89. The treatment was subsequently modeled in MCNPX 2.5 using a 1 x 1 x 1 mm3 voxelized version of the NURBS models. These models incorporated several organs of interest including the brain, thyroid, salivary glands, cranium, mandible, and cervical vertebrae. A higher resolution eye section at 0.5 x 0.5 x 0.5 mm3 voxel resolution was extracted from the head phantoms to model smaller eye structures including the macula target, cornea, lens, vitreous humor, sclera/retina layer, and optic nerve. Due to lack of literature data on optic nerve pathways, a CT imaging study was undertaken to quantify the anatomical position of the optic nerve. The average absorbed doses to the organs of interest were below generally accepted thresholds for radiation safety. The estimated effective dose was 0.28 mSv which is comparable to diagnostic procedures such as a head radiograph and a factor of 10 lower than a head CT scan.

Dosimetry characterization of a multibeam radiotherapy treatment for age-related macular degeneration.

Age-related macular degeneration (ARMD) is a major health problem worldwide. Advanced ARMD, which ultimately leads to profound vision loss, has dry and wet forms, which account for 20% and 80% of cases involving severe vision loss, respectively. A new device and approach for radiation treatment of ARMD has been recently developed by Oraya Therapeutics, Inc. (Newark, CA). The goal of the present study is to provide a initial dosimetry characterization of the proposed radiotherapy treatment via Monte Carlo radiation transport simulation. A 3D eye model including cornea, anterior chamber, lens, orbit, fat, sclera, choroid, retina, vitreous, macula, and optic nerve was carefully designed. The eye model was imported into the MCNPX2.5 Monte Carlo code and radiation transport simulations were undertaken to obtain absorbed doses and dose volume histograms (DVH) to targeted and nontargeted structures within the eye. Three different studies were undertaken to investigate (1) available beam angles that maximized the dose to the macula target tissue, simultaneously minimizing dose to normal tissues, (2) the energy dependency of the DVH for different x-ray energies (80, 100, and 120 kVp), and (3) the optimal focal spot size among options of 0.0, 0.4, 1.0, and 5.5 mm. All results were scaled to give 8 Gy to the macula volume, which is the current treatment requirement. Eight beam treatment angles are currently under investigation. In all eight beam angles, the source-to-target distance is 13 cm, and the polar angle of entry is 300 from the geometric axis of the eye. The azimuthal angle changes in eight increments of 45 degrees in a clockwise fashion, such that an azimuthal angle of 0 degreee corresponds to the 12 o'clock position when viewing the treated eye. Based on considerations of nontarget tissue avoidance, as well as facial-anatomical restrictions on beam delivery, treatment azimuthal angles between 135 degrees and 225 degrees would be available for this treatment system (i.e., directly upward and entering the eye from below). At beam directions approaching 225 degrees and higher, some dose contribution to the optic nerve would result under the assumption that the optic nerve is tilted cranially above the geometric axis in a given patient, a feature not typically seen in past studies. A total treatment dose of 24 Gy would be delivered in three 8 Gy treatments at these selected azimuthal angles. Dose coefficients, defined as the macula radiation absorbed dose per unit air kerma in units of Gy/Gy, were 16% higher for 120 kVp x-ray beams in comparison to those at 80 kVp, thus requiring only 86% of the integrated tube current (mAs) for equivalent dose delivery. When 0.0, 0.4, and 1.0 mm focal spot sizes were used, the dose profiles in the macula are very similar and relatively uniform, whereas a 5.5 mm focal spot size produced a more nonuniform dose profile. The results of this study dem onstrate the therapeutic promise of this device and provide important information for further design and clinical implementation for radiotherapy treatments for ARMD.

The effect of route, vehicle, and divided doses on the pharmacokinetics of chlorpyrifos and its metabolite trichloropyridinol in neonatal Sprague-Dawley rats.

There is a paucity of data on neonatal systemic exposure using different dosing paradigms. Male CD (Sprague-Dawley derived) rats at postnatal day (PND) 5 were dosed with chlorpyrifos (CPF, 1 mg/kg) using different routes of exposure, vehicles, and single versus divided doses. Blood concentrations of CPF and its primary metabolite, trichloropyridinol, were measured at multiple times through 24 h. Groups included were single gavage bolus versus divided gavage doses in corn oil (one vs. three times in 24h), single gavage bolus versus divided gavage doses in rat milk, and sc administration in dimethyl sulfoxide (DMSO). These data were compared with lactational exposure of PND 5 pups from dams exposed to CPF in the diet at 5 mg/kg/day for 4 weeks or published data from dams exposed to daily gavage with CPF at 5 mg/kg/day. Maternal blood CPF levels were an order of magnitude lower from dietary exposure than gavage (1.1 vs. 14.8 ng/g), and blood CPF levels in PND 5 pups that nursed dietary-exposed or gavage-exposed dams were below the limit of detection. Single gavage doses of 1 mg/kg CPF in corn oil vehicle in pups resulted in CPF blood levels of 49 ng/g and in milk vehicle about 9 ng/g. Divided doses led to lower peak CPF levels. A bolus dose of 1 mg/kg CPF in DMSO administered sc appeared to have substantially altered pharmacokinetics from orally administered CPF. To be meaningful for risk assessment, neonatal studies require attention to the exposure scenario, since route, vehicle, dose, and frequency of administration result in different systemic exposure to the test chemical and its metabolites.

Learning to optimize speed, accuracy, and energy expenditure: a framework for understanding speed-accuracy relations in goal-directed aiming.

Over the last century, investigators have developed a number of models to explain the relation between speed and accuracy in target-directed manual aiming. The models vary in the extent to which they stress the importance of feedforward processes and the online use of sensory information (see D. Elliott, W. F. Helsen, & R. Chua, 2001, for a recent review). A common feature of those models is that the role of practice in optimizing speed, accuracy, and energy expenditure in goal-directed aiming is either ignored or minimized. The authors present a theoretical framework for understanding speed-accuracy tradeoffs that takes into account the strategic, trial-to-trial behavior of the performer. The strategic behavior enables individuals to maximize movement speed while minimizing error and energy expenditure.

The bioconcentration and metabolism of chlorpyrifos by the eastern oyster, Crassostrea virginica.

Eastern oysters (Crassostrea virginica) were exposed to [14C]chlorpyrifos (O,O-diethyl-O-[3,5,6-trichloro-2-pyridyl] phosphorothioate) at an average measured seawater concentration of 0.6 microg/L under flow-through conditions for 28 d. The compound O,O-diethyl-O-(3,5-dichloro-6-methylthio-2-pyridyl)phosphorothioate (DMP) was extracted and identified as the single metabolite observed, and this metabolite constituted the majority of the total [14C] activity in the oyster at all sampling times. Once oysters were exposed to clean water, both chlorpyrifos and DMP residues cleared rapidly from whole oysters, with elimination half-lives of <3 d. A simple two-compartment uptake/elimination model was adequate to describe total [14C] activity in whole oysters, edible tissue, and oyster liquor. The average bioconcentration factors (BCFs) for total [14C] activity in whole oysters, edible tissue, and oyster liquor were 565, 1,400, and 35 ml/g, respectively. The parent [14C]chlorpyrifos accumulated to a peak residue concentration of 135 microg/kg in whole oyster tissue, representing an empirical [14C]chlorpyrifos BCF value in the oyster of approximately 225 ml/ g; the BCF value for [14C]chlorpyrifos was lower than the BCF for total [14C] activity in whole oysters and edible tissue because of extensive metabolism to DMP and oyster elimination processes.