A Mouse Model Of Toluene Abstinence-Induced Pathology

The intentional misuse of volatile solvents is a persistent public health concern. Limited self-report data suggests that chronic inhalant abusers experience withdrawal symptoms including anxiety and seizure symptoms. However, these symptoms have never been explored in a preclinical model and are not considered part of the DSM-V criteria for an Inhalant Use Disorder. For this experiment, 76 young adult male Swiss Webster mice were exposed to either 5,000 ppm toluene vapor or air (0 ppm) for 24 consecutive hours beginning on postnatal day (PND) 30. Following the 24 hour exposure, mice were allowed to recover for 3 hours before behavioral testing began. In the 1st experiment, mice were tested for handling-induced seizure activity every hour for 6 hours (and again at 24 hours). As compared to controls, toluene-abstinent animals showed persistent clonic seizure activity throughout the 6 hour period. In the 2nd experiment, mice were given a single i.p. injection of pentylenetetrazole (PTZ; 42 or 48 mg/kg) to induce seizure activity. Mice were observed for 30 min and seizure activity was scored for severity using criteria adapted from the Functional Observational Battery. As compared to air controls, toluene-abstinent mice displayed a significant increase in seizure symptoms. In the 3rd experiment, previously exposed toluene mice were re-exposed to toluene vapor for 30 min following the three hour abstinence period. Following toluene re-exposure, these mice were tested for seizure severity with 42 or 48 mg/kg PTZ. Toluene re-exposure significantly reduced the severity of the seizure response. Next, we examined anxiety-like behavior arising 24 hours following 24 hour toluene exposure. Mice were tested in the Elevated Plus Maze, Open Field Test, Light/Dark Box, and Marble Burying task at either 24 or 72 hours of abstinence. Mice 24, but not 72 hours abstinent from toluene displayed increased anxiety-like behavior. Taken together, these results suggest that toluene abstinence lowers seizure threshold in mice and increases anxiety and that toluene re-exposure ameliorates these effects. These findings provide support for clinical reports of a physical withdrawal syndrome from inhalants, which has implications for the successful diagnosis and subsequent treatment of Inhalant Use Disorders

The Effect Of Gaba A Antagonism On Locomotor Activity And Dopamine Release In The Mouse Caudate Putamen Following Acute Toluene Inhalation: An In-Vivo Microdialysis Study

Toluene is ubiquitous solvent commonly inhaled recreationally. Despite its frequency of misuse, there is little understanding of how toluene acts within the brain. To examine this, this master\u27s thesis examined the impact of acutely inhaled toluene on dopamine (DA) release in the mouse CPu in vivo using microdialysis techniques. Toluene inhalation produced dose-dependent increases in DA levels as well as changes in locomotor activity. These effects were potentiated by pre-treatment with the GABAA antagonist bicuculline via reverse microdialysis delivery. These results suggest that the DA dynamics of toluene abuse are related to toluene\u27s previously explored effects on the GABA system. It is possible that the action of toluene on GABA in the caudate actually inhibits toluene\u27s action on DA. Another theory is that toluene activates multiple GABA receptor sites, and blocking GABAA blocked a primarily inhibitory pathway

The Distributional Implications of a Carbon Tax in Ireland. ESRI WP250. July 2008

We study the effects of carbon tax and revenue recycling across the income distribution in the Republic of Ireland. In absolute terms, a carbon tax of €20/tCO2 would cost the poorest households less than €3/week and the richest households more than €4/week. A carbon tax is regressive, therefore. However, if the tax revenue is used to increase social benefits and tax credits, households across the income distribution can be made better off without exhausting the total carbon tax revenue

The Naas Motorway Bypass - A Cost Benefit Analysis. Quarterly Economic Commentary Special Article, January 1984

The paper examines the Naas Motorway Bypass which cost £16m at 1983 prices. Twelve thousand vehicles a day using the bypass save over 10 minutes between 8 am and 8 pm and 6 minutes at other times. Five thousand vehicles a day using the present route through Naas also benefit by saving 4 minutes due to reduced congestion in the town. In addition to time savings, the bypass reduces accidents and fuel costs. Ninety-one per cent of the benefits accrue in time savings. The internal rate of return on the project is estimated at 20.51 per cent, assuming 2 per cent annual traffic and income growth. The sensitivity tests of the results show that even with zero growth in incomes and traffic for twenty years, a high proportion of leisure time savings with zero value and no increase in the value of fuel savings the project would have an internal rate of return which meets the test discount rate used by the Department of Finance. The environmental aspects of the bypass are positive in terms of noise and smoke and lead pollution reduction. The impact on farm severence and natural amenities on the motorway route has been mitigated by several design features of the bypass

Dilatonic wormholes: construction, operation, maintenance and collapse to black holes

The CGHS two-dimensional dilaton gravity model is generalized to include a ghost Klein-Gordon field, i.e. with negative gravitational coupling. This exotic radiation supports the existence of static traversible wormhole solutions, analogous to Morris-Thorne wormholes. Since the field equations are explicitly integrable, concrete examples can be given of various dynamic wormhole processes, as follows. (i) Static wormholes are constructed by irradiating an initially static black hole with the ghost field. (ii) The operation of a wormhole to transport matter or radiation between the two universes is described, including the back-reaction on the wormhole, which is found to exhibit a type of neutral stability. (iii) It is shown how to maintain an operating wormhole in a static state, or return it to its original state, by turning up the ghost field. (iv) If the ghost field is turned off, either instantaneously or gradually, the wormhole collapses into a black hole.Comment: 9 pages, 7 figure

Orally administered oxygen nanobubbles enhance tumor response to sonodynamic therapy

Suspensions of oxygen-filled bubbles are under active investigation as potential means of relieving tissue hypoxia. Intravenous administration of large quantities of bubbles is, however, undesirable. Previous work by the authors has demonstrated that tumor oxygen levels can be increased following oral administration of phospholipid stabilized oxygen nanobubbles. The aim of this study was to determine whether this would enhance the efficacy of sonodynamic therapy (SDT), which is known to be inhibited in hypoxic tissue. Experiments were conducted in a murine model of pancreatic cancer. Animals were treated with SDT (intratumoural injection of 1 mM Rose Bengal followed by exposure to 1 MHz ultrasound, 0.1 kHz pulse repetition frequency, 30% duty cycle, 3.5 W cm−2 for 3.5 minutes) either with or without a prior gavage of oxygen bubbles. A statistically significant reduction in the rate of tumor growth was observed in the groups receiving oxygen nanobubbles either 5 or 20 minutes before SDT. Separate measurements of tumor oxygen using a fiber optic probe and expression of hypoxia inducible factor (HIF)1α following tumor excision, confirmed the change in tumor oxygen levels. These findings offer a potentially promising new approach to relieving tissue hypoxia in order to facilitate cancer therapy

Product labeling accuracy and contamination analysis of commercially available cannabidiol product samples

Background and objective: Commercially available cannabidiol (CBD) products are increasingly being used for medicinal purposes, including for the treatment of various neurological conditions, but there are growing concerns around adherence to quality control measures that protect consumers. This study was conducted to assess the purity and label accuracy of commercially available CBD products.Methods: Commercially available CBD products were chosen from the open stream of commerce in the United States based on formulations as a tincture, gummy, vape, or topical product. Cannabinoid concentrations were analyzed to verify label accuracy including “full spectrum,” “broad spectrum,” and “CBD isolate” claims on the product label. Analysis for the presence of contaminants included evaluation for heavy metals, pesticides, and residual solvents. Labeled and actual total amounts of CBD and levels of impurities such as heavy metals, residual solvents, and pesticides were measured.Results: A total of 202 CBD products (100 tinctures, 48 gummies, 34 vape products, and 20 topicals) were chosen to represent a broad sample in the United States. Of the products tested (full spectrum, n = 84; broad spectrum, n = 28; CBD isolate, n = 37), 26% did not meet the definition for product type claimed on the packaging. The majority of products (74%) deviated from their label claim of CBD potency by at least 10%. Heavy metals were detected 52 times across 44 of the 202 products tested, with lead being the most prevalent heavy metal. Residual solvents were detected 446 times across 181 of 202 products, with the highest concentrations reported for hexane, m/p-xylene, methanol, and o-xylene. Of 232 pesticides tested, 26 were found 55 times across 30 products. A total of 3% of heavy metals, 1% of residual solvents, and 1% of pesticides violated >1 regulatory threshold.Discussion: This study demonstrated that the majority of commercially available CBD products tested within the current study are inaccurately labeled. Heavy metals, residual solvents, and pesticides were found in several products, some of which violated regulatory thresholds. Thus, uniform compliance with CBD quality control measures is lacking and raises consumer protection concerns. Improved regulatory oversight of this industry is recommended

Ultrasound Mediated Gemcitabine Delivery Reduces the Normal-Tissue Toxicity of Chemoradiation Therapy in a Muscle-Invasive Bladder Cancer Model

Purpose: Chemoradiation is the standard of care in muscle-invasive bladder. While agents such as gemcitabine can enhance tumour radiosensitisation, their side effects can limit patient eligibility and treatment efficacy. Here we investigate ultrasound and microbubbles for targeting gemcitabine delivery to reduce normal tissue toxicity in a murine orthotopic MIBC model. Materials and Methods: CD1-nude mice were injected orthotopically with RT112 bladder tumour cells. Conventional chemoradiation involved injecting gemcitabine (10 mg/kg) before 6 Gy targeted irradiation of the bladder area using a Small Animal Radiation Research Platform (SARRP). Ultrasound-mediated gemcitabine delivery (10 mg/kg gemcitabine) involved either co-administration of microbubbles with gemcitabine or conjugating gemcitabine onto microbubbles followed by exposure to ultrasound (1.1 MHz centre frequency, 1 MPa peak negative pressure, 1% duty cycle and 0.5 Hz pulse repetition frequency), prior to SARRP irradiation. The effect of ultrasound and microbubbles alone was also tested. Tumour volumes were measured by 3D ultrasound imaging. Acute normal tissue toxicity from 12 Gy to the lower bowel area was assessed using an intestinal crypt assay in mice culled. 3.75 days post-treatment. Results: Significant tumour growth delay was observed with conventional chemoradiation and both microbubble groups (p Conclusions: Ultrasound and microbubbles offer a promising new approach for improving chemoradiation therapy in muscle-invasive bladder cancer, maintaining tumour growth delay but with reduced acute intestinal toxicity compared to conventional chemoradiation therapy.</p

A General Black String and its Microscopics

Using G2(2) dualities we construct the most general black string solution of minimal five-dimensional ungauged supergravity. The black string has five independent parameters, namely, the magnetic one-brane charge, smeared electric zero-brane charge, boost along the string direction, energy above the BPS bound, and rotation in the transverse space. In one extremal limit it reduces to the three parameter supersymmetric string of five-dimensional minimal supergravity; in another extremal limit it reduces to the three parameter non-supersymmetric extremal string of five-dimensional minimal supergravity. It also admits an extremal limit when it has maximal rotation in the four-dimensional transverse space. The decoupling limit of our general black string is a BTZ black hole times a two sphere. The macroscopic entropy of the string is reproduced by the Maldacena-Strominger-Witten CFT in appropriate ranges of the parameters. When the pressureless condition is imposed, our string describes the infinite radius limit of the most general class of black rings of minimal supergravity. We discuss implications our solution has for extremal and non-extremal black rings of minimal supergravity.Comment: 35 pages; 3 figures; v2 section 4.1.1 rewritten + minor changes + ref adde