Current therapeutic approaches to equine protozoal myeloencephalitis

Equine protozoal myeloencephalitis is the most important infectious neurologic disease of horses in the Western Hemisphere. Equine protozoal myeloencephalitis can interfere with a horse\u27s ability to race, work, and perform; untreated, EPM can be lethal. Antemortem diagnosis of EPM is challenging, requiring careful evaluation of the animal\u27s history, clinical signs, and laboratory data, with rigorous exclusion of other causes. Therapeutic approaches to EPM are evolving. First-generation therapeutic approaches for EPM were based on the classic anti–Toxoplasma gondii pyrimethamine–sulfonamide combinations; treatment is prolonged and can be associated with a considerable relapse rate, which may be associated with the difficulty in maintaining effective CNS concentrations of pyrimethamine. Second-generation therapeutic approaches are based on diclazuril and related triazine agentsa; in 2001, toltrazuril sulfoneb (ponazuril) became the first FDA-approved treatment for EPM. Triazine agents may have prolonged plasma half-lives, and their therapeutic efficacy would likely be enhanced by application of loading-dose schedules. A pyrimethamine-sulfonamide combination formulationc received FDA approval in 2004 for the treatment of EPM. Additionally, a diclazuril-based topical feed dressing formulationd received FDA approval in 2011. The ideal therapeutic agents for use against EPM would be effective when administered orally, with high efficacy against Sarcocystis neurona and minimal toxicity for horses. This article reviews the current information available for EPM, including the clinical pharmacology and efficacy of FDA-approved and nonapproved investigational medications for the treatment or prophylaxis of EPM. Equine protozoal myeloencephalitis is caused by 2 apicomplexan protozoal parasites: S neurona and, much less commonly, Neospora hughesi. Location of the causative organism in the CNS is random, so clinical signs of EPM are highly variable. Any combination of neurologic signs is possible, although spinal cord involvement is most common. Onset may be gradual or acute, with the usual pattern being mild clinical signs that progress with time. Furthermore, the intracellular localization of the causative organisms in the CNS creates difficulties for chemotherapeutic approaches and may also interfere with host-based immunologic defenses. Antemortem diagnosis of EPM is particularly challenging, requiring careful evaluation of the animal\u27s history, clinical signs, and laboratory data, with rigorous exclusion of other causes. Definitive diagnosis of EPM is dependent on necropsy detection of typical CNS lesions of the disease or presence of the appropriate causative organisms. Although careful clinical examination remains the most important antemortem diagnostic technique for EPM, laboratory methods have been developed to assist clinical diagnosis. As such, for horses with clinical signs consistent with EPM, it is optimal to perform immunoblotting, an indirect florescent antibody test, or ELISA analyses on blood and CSF samples prior to diagnosis and initiation of treatment. Preventative approaches to EPM are not well defined. Prevention of EPM with daily pyrantel tartratee administration at the current labeled dose has not been effective in immunocompetent horses1 or in interferon-γ knockout mice,2 even though the compound is active against S neurona in vitro.3 An EPM vaccine based on homogenates of S neurona merozoites with conditional licensure has been marketed for prevention of EPM, but this vaccine was removed from the market due to lack of efficacy data in prospective studies

Guanabenz in the horse – A preliminary report on clinical effects and comparison to clonidine and other alpha-2 adrenergic agonists

In veterinary medicine, a number of alpha-2 receptor agonists are marketed as sedatives/hypnotics and analgesics, with their principal use being the chemical restraint of large and small animals. Guanabenz (Wytensin®) is an alpha-2 adrenergic receptor agonist marketed for use in humans as an anti-hypertensive agent. Recent reports indicate that guanabenz has been administered to horses in small doses (0.04 mg/kg) for its anti-hypertensive effects. While this offers both benefits of sedation of the horse as well as amelioration of pulmonary hypertension during running exercise and consequent Exercise-Induced Pulmonary Hemorrhage (EIPH), guanabenz is currently proscribed in most racing jurisdictions and its administration to a racing horse can lead to penalties. The Association of Racing Commissioners International (ARCI) lists guanabenz as an ARCI Class 3 agent; Class 3 agents include bronchodilators, anabolic steroids and other drugs with primary effects on the autonomic nervous system, procaine, antihistamines with sedative properties and diuretics and includes amitraz, clonidine, xylazine, detomidine, medetomidine, and romifidine. Guanabenz is unique among alpha-2 agonists in that it differentiates into E- and Z-forms (Fig. 1), with the Z-form lacking hypotensive properties, yet with both E- and Z-forms able to afford relief to cellular stresses related to inflammation or degenerative diseases. The objective of the study was a preliminary description of the pharmacological properties of guanabenz in comparison with clonidine and a number of other alpha-2 agonists. The goal was clinical evaluation of their sedative, analgesic and related activities with the goal of increasing our understanding of the clinical use of such medications and also as a possible prophylaxis for Exercise- Induced Pulmonary Hemorrhage. The clinical study of guanabenz and clonidine was performed in a complete crossover strategy using quantitative markers of sedation, antinociception, heart rate, blood and urine glucose following administration of each compound in five horses. Amitraz, detomidine, medetomidine, romifidine, and xylazine were studied in one horse each. The sedation was quantified by measuring head droop and locomotor activity, while antinociception was measured by Hoof Withdrawal Reflex Latency. Heart rates, urine glucose, urine production and urine specific gravities were also determined by standard clinical chemistry techniques. Guanabenz serum levels and related urinary guanabenz glucuronide levels were determined by established Liquid Chromatography-tandem Mass Spectrometric (LC-MS) methods. In result the clinically effective doses (0.2 mg/kg) of guanabenz produced a rapid and intense sedative effect, with sagging of the lower lip, sunken eyelids, and marked head droop corresponding to plasma guanabenz concentrations that peaked at 120 ng/mL at 2.5 min post-injection (Fig. 2). The initial head height above the ground is considered 100 %, and head heights fell to values ranging 18–40 % with guanabenz, all of which are greater than a 50 % reduction in head height, considered a full clinically useful sedative effect. Despite the intensity of the sedation, all horses remained standing and were able to walk, and the sedation and head droop responses were rapidly reversed by intravenous administration of the alpha-2 receptor antagonist yohimbine, reversals occurring within 10 min of administration. As a pilot investigation this study was extended to six other members of the alpha-2 agonist group, clonidine administered to five horses, and amitraz, detomidine, medetomidine, romifidine, and xylazine to one horse each. Hoof Withdrawal Reflex Latency evaluation demonstrated the considerable analgesic properties of guanabenz, greater than the corresponding potencies among clonidine, detomidine, romifidine, medetomidine and xylazine. Heart rate monitoring showed guanabenz as possessing capacity for prolonged bradycardia, with effects of a single dose lasting for up to 3.5 hr, in contrast with clonidine (1 hr), amitraz (2 hr), detomidine (\u3c1 hr), medetomidine (1 hr), romifidine (2 hr), and xylazine (\u3c1 hr). Peak urine production following guanabenz administration occurred between 1.5 and 3.0 hr after administration (Fig. 6), as indicated by the steeper decline of the urine volume curve during that period. Urine specific gravity dropped to a low of about 1.006 at 2.0 hr after administration and remained at this level for ~1.0 hr. Urine pH remained at 8, and urine protein was negative throughout testing. The other alpha-2 agonists evaluated also caused an increased urine production with a concomitant decrease in specific gravity. The effect of guanabenz had the longest duration on increased urine volume, lasting about 3.0 hr. Xylazine had the shortest diuretic effect, persisting for only about 1.0 hr. Guanabenz along with romifidine and detomidine induced glucosuria whereas other alpha-2 agonists did not. Hyperglycemia and the corresponding glucosuria resulted in a significant diuresis, as shown by the cumulative urine volume. Guanabenz along with amitraz, detomidine and xylazine also produced measurable sedation presenting as reduced locomotor activity (Table 1). While all alpha-2 agonists showed qualitatively similar pharmacological responses, only guanabenz produced an intense and relatively prolonged antinociceptive response. The study is limited by the number of horses examined (five each for guanabenz and clonidine, five for repeat studies that included yohimbine antagonism, and one each for the other agonists). Study design was focused on clinical evaluation of agonist similarities and differences and thus did not specifically generate data for detailed statistical evaluation. In conclusion these studies show that a 100 mg IV dose of guanabenz rapidly induces clinically useful sedation, analgesia and antinociception effects that are more intense and considerably longer-lasting than those produced by other alpha-2 receptor agonists evaluated. Guanabenz also remains detectable in serum up to 8-hours following administration at doses as low as 0.04 mg/kg. In the work reported here, guanabenz administered at 0.2 mg/kg IV showed peak concentrations in serum of 120 ng/ mL at 2.5 min and was detectable for up to 4 hr with its glucuronide metabolite peaking at 120 min post-administration. Although we did not investigate the combination of guanabenz with opioid drugs such as butorphanol for pain management, guanabenz may well be a drug of choice among the other alpha-2 agonists evaluated in this study for administration with opioids for pain management based on maintaining maximum levels of analgesia for longer periods of time. These experiments suggest considerable clinical potential for guanabenz as a sedative and a relatively long-lasting analgesic in equine medicine. Based on these pharmacological properties, guanabenz and related alpha-2 agonists also have considerable potential for clinical use in equine medicine

Improving Loss Estimation for Woodframe Buildings. Volume 2: Appendices

This report documents Tasks 4.1 and 4.5 of the CUREE-Caltech Woodframe Project. It presents a theoretical and empirical methodology for creating probabilistic relationships between seismic shaking severity and physical damage and loss for buildings in general, and for woodframe buildings in particular. The methodology, called assembly-based vulnerability (ABV), is illustrated for 19 specific woodframe buildings of varying ages, sizes, configuration, quality of construction, and retrofit and redesign conditions. The study employs variations on four basic floorplans, called index buildings. These include a small house and a large house, a townhouse and an apartment building. The resulting seismic vulnerability functions give the probability distribution of repair cost as a function of instrumental ground-motion severity. These vulnerability functions are useful by themselves, and are also transformed to seismic fragility functions compatible with the HAZUS software. The methods and data employed here use well-accepted structural engineering techniques, laboratory test data and computer programs produced by Element 1 of the CUREE-Caltech Woodframe Project, other recently published research, and standard construction cost-estimating methods. While based on such well established principles, this report represents a substantially new contribution to the field of earthquake loss estimation. Its methodology is notable in that it calculates detailed structural response using nonlinear time-history structural analysis as opposed to the simplifying assumptions required by nonlinear pushover methods. It models physical damage at the level of individual building assemblies such as individual windows, segments of wall, etc., for which detailed laboratory testing is available, as opposed to two or three broad component categories that cannot be directly tested. And it explicitly models uncertainty in ground motion, structural response, component damageability, and contractor costs. Consequently, a very detailed, verifiable, probabilistic picture of physical performance and repair cost is produced, capable of informing a variety of decisions regarding seismic retrofit, code development, code enforcement, performance-based design for above-code applications, and insurance practices

HOPS 383: An Outbursting Class 0 Protostar in Orion

We report the dramatic mid-infrared brightening between 2004 and 2006 of HOPS 383, a deeply embedded protostar adjacent to NGC 1977 in Orion. By 2008, the source became a factor of 35 brighter at 24 microns with a brightness increase also apparent at 4.5 microns. The outburst is also detected in the submillimeter by comparing APEX/SABOCA to SCUBA data, and a scattered-light nebula appeared in NEWFIRM K_s imaging. The post-outburst spectral energy distribution indicates a Class 0 source with a dense envelope and a luminosity between 6 and 14 L_sun. Post-outburst time-series mid- and far-infrared photometry shows no long-term fading and variability at the 18% level between 2009 and 2012. HOPS 383 is the first outbursting Class 0 object discovered, pointing to the importance of episodic accretion at early stages in the star formation process. Its dramatic rise and lack of fading over a six-year period hint that it may be similar to FU Ori outbursts, although the luminosity appears to be significantly smaller than the canonical luminosities of such objects.Comment: Accepted by ApJ Letters, 6 pages, 4 figures; v2 has an updated email address for the lead autho

Pleistocene/Holocene Cave Fossils From Grand Canyon National Park: Ice Age (Pleistocene) Flora, Fauna, Environments, and Climate of the Grand Canyon, Arizona

The Colorado Plateau is a distinct physiographic province in western North America covering an area of roughly 337,000 km2 (130,115 mi2) across parts of Arizona, Colorado, New Mexico, and Utah. Elevations range from about 360 m (1,180 ft) in the overall Grand Canyon (GC; which includes the Grand Canyon National Park, GRCA) river corridor to an average at the eastern South Rim of 2,072 m (6,800 ft) to 3,850 m (12,630 ft) on the nearby San Francisco Peaks at Flagstaff, Arizona, with an average elevation of 1,525 m (5,000 ft). The Colorado River of Grand Canyon is located along the southwestern portion of the Colorado Plateau in Arizona and is renowned for its dramatic display of geomorphic effects created by fluvial incision and its unique dry-preservation of fossils from the Ice Age (late Pleistocene and Holocene [Quaternary]; most recent 2.58 million years). Although there were at least 22 glacial-interglacial cycles during the Ice Age, this discussion is limited to the most recent episode (called the Wisconsinan Glaciation), which includes the transition to the modern climate (latest Pleistocene and Holocene; the most recent 50,000 years of geologic history)

Bovine Colostrum Supplementation Optimises Earnings, Performance and Recovery in Racing Thoroughbreds

Bovine colostrum (BC) is the first milk produced by cows after calving and contains numerous beneficial substances for the immunity and development of the newborn calf. Because of the growth and immune factors in BC, it has become an attractive supplement for use by athletes to support immunity and health during athletic performance. In order to evaluate the effects of oral BC supplementation on equine athletes, this study evaluated the earnings, performance, recovery and incidence of upper respiratory infections (URTI) in racing horses. The study design was a randomized cross-over racing performance study. 21 horses in race training were randomly assigned to train and compete with or without BC supplementation. After each horse competed in three races, it was crossed over to the other group, allowed a three week washout period, and then competed in three additional races. Horses in public training stables of 3 participating trainers were used. Race performance as determined by earnings, Bloodstock Research Information System (BRIS) speed figures, recovery as determined by number of days between races and incidence of upper respiratory tract disease was recorded. 11 horses completed the study. There was no effect of the order of BC supplementation on the measured variables. Horses on BC supplementation earned $ 2,088 more purse money per race, than when unsupplemented (P = 0.016), and ran an average of 5 BRIS speed points higher (P = 0.03). Horses returned to racing on average 7.5 days faster (16.9 days vs 24.4 days, P = 0.048). There were no URTI among the horses on BC supplementation and two infections while not on BC supplementation (z-test, P = 0.11). Statistical analysis showed that horses recovered more quickly, earned three times more money and raced better as judged by BRIS scores while competing with BC supplementation. BC supplemented horses also experienced fewer URTI, although this effect was not significant

Pemoline and Tetramisole \u27Positives\u27 in English Racehorses Following Levamisole Administration

Pemoline is a central nervous system stimulant that has been used to treat attention-deficit hyperactivity disorder and narcolepsy in humans; its identification in horses could be considered evidence of attempts to influence performance. Two recent pemoline \u27positives\u27 in English racehorses led us to review the chemical relationships between tetramisole, levamisole, aminorex and pemoline. Pemoline is a simple oxidation product of aminorex, which has been shown in the United States and elsewhere to be an equine metabolite of levamisole. Based on the clear structural relationships between aminorex and pemoline, we conclude that levamisole can metabolise to pemoline in horses and that pemoline identifications in horses post levamisole administration are likely to be associated with levamisole administration. Levamisole should not be administered to horses about to compete because of its ability to metabolise to two central nervous system stimulants, aminorex and pemoline

Benefit-Cost Analysis of FEMA Hazard Mitigation Grants

Mitigation ameliorates the impact of natural hazards on communities by reducing loss of life and injury, property and environmental damage, and social and economic disruption. The potential to reduce these losses brings many benefits, but every mitigation activity has a cost that must be considered in our world of limited resources. In principle benefit-cost analysis (BCA) can be used to assess a mitigation activity’s expected net benefits (discounted future benefits less discounted costs), but in practice this often proves difficult. This paper reports on a study that refined BCA methodologies and applied them to a national statistical sample of FEMA mitigation activities over a ten-year period for earthquake, flood, and wind hazards. The results indicate that the overall benefit-cost ratio for FEMA mitigation grants is about 4 to 1, though the ratio varies according to hazard and mitigation type.

Multiwavelength Observations of V2775 Ori, an Outbursting Protostar in L 1641: Exploring the Edge of the FU Orionis Regime

Individual outbursting young stars are important laboratories for studying the physics of episodic accretion and the extent to which this phenomenon can explain the luminosity distribution of protostars. We present new and archival data for V2775 Ori (HOPS 223), a protostar in the L 1641 region of the Orion molecular clouds that was discovered by Caratti o Garatti et al. to have recently undergone an order-of-magnitude increase in luminosity. Our near-infrared spectra of the source have strong blueshifted He I λ10830 absorption, strong H_(2)O and CO absorption, and no H I emission, all typical of FU Orionis sources. With data from the Infrared Telescope Facility, the Two Micron All Sky Survey, the Hubble Space Telescope, Spitzer, the Wide-field Infrared Survey Explorer, Herschel, and the Atacama Pathfinder Experiment that span from 1 to 70 μm pre-outburst and from 1 to 870 μm post-outburst, we estimate that the outburst began between 2005 April and 2007 March. We also model the pre- and post-outburst spectral energy distributions of the source, finding it to be in the late stages of accreting its envelope with a disk-to-star accretion rate that increased from ~2 × 10^(–6) M_☉ yr^(–1) to ~10^(–5) M_☉ yr^(–1) during the outburst. The post-outburst luminosity at the epoch of the FU Orionis-like near-IR spectra is 28 L_☉, making V2775 Ori the least luminous documented FU Orionis outburster with a protostellar envelope. The existence of low-luminosity outbursts supports the notion that a range of episiodic accretion phenomena can partially explain the observed spread in protostellar luminosities