Immune therapy in respiratory disease

Pharmacologic manipulation of pulmonary immunity plays an important role in primary and adjunct therapy for equine respiratory disease. Frequent exposure to respiratory viral pathogens, strenuous exercise, long distance transport, and inhalation of harmful substances destroy various aspects of the pulmonary defense system and predispose performance horses to development of infectious and noninfectious respiratory disease. Pulmonary immunity may be bolstered by nonspecific immunostimulants to combat primary or secondary immunodeficiency. State of the art technology improves active and passive-specific immunity for prevention of common infectious respiratory diseases in horses. Immuno-suppressive therapy can attenuate hyperreactive pulmonary immune responses in horses with allergic airway disease.     

Pharmacological activity and safety profile of P10358, a novel, orally active acetylcholinesterase inhibitor for Alzheimer's disease

1-[(3-Fluoro-4-pyridinyl)amino]-3-methyl-1(H)-indol-5-yl methyl carbamate (P10358) is a potent, reversible acetylcholinesterase inhibitor that produces central cholinergic stimulation after oral and parental administration in rats and mice. P10358 is a 2.5 times more potent acetylcholinesterase inhibitor than THA in vitro (IC50 = 0.10 +/- 0.02 microM vs. IC50 = 0.25 +/- 0.03 microM). It also inhibits butyrylcholinesterase activity as potently as THA (IC50 = 0.08 +/- 0.05 microM vs. IC50 = 0.07 +/- 0.01 microM). Ex vivo, P10358 (0.2 - 20 mg/kg, p.o.) produced dose-dependent inhibition of brain acetylcholinesterase activity. At 10 and 20 mg/ kg, it produced profound and long-lasting hypothermia in mice. P10358 enhanced performance in rats in a step-down passive avoidance task (0.62 and 1.25 mg/kg) and in a social recognition paradigm (0.32, 0.64 and 1.25 mg/kg) in mice. It reversed scopolamine-induced deficits in the Morris Water maze in rats (1.25 and 2.5 mg/kg) and a higher dose elevated striatal homovanillic acid levels. These behavioral and biochemical effects are consistent with central cholinergic stimulation. Hemodynamic studies in the rat demonstrated a 16-fold separation between behaviorally active doses (1.25 mg/kg) and those that elevated arterial pressure (20 mg/kg). Lethality in rats occurred at an oral dose of 80 mg/kg, but not at lower doses. Chemically, P10358 is an N-aminoindole and may not have the hepatotoxic liability associated with aminoacridine structure of tacrine. P10358 had weak affinity (>10 microM) at a variety of aminergic and peptidergic receptors and uptake carriers. These properties suggest that P10358 may be a safe and promising symptomatic treatment for Alzheimer's disease.     

Endogenous neurotrophin-3 supports the survival of a subpopulation of sensory neurons in neonatal rat

Neurotrophin-3 promotes the differentiation and supports the survival of neuroblasts derived from the neural crest in early development. Neurotrophin-3 also plays an important role in the differentiation and survival of a subpopulation of large sensory neurons after their axons arrive at their targets. Proprioception and mechanoception are lost after gene deletion of neurotrophin-3 or its high-affinity receptor, TrkC. However, the function of neurotrophin-3 during late development and in mature animals is not clear. We have used an antiserum, specific for neurotrophin-3, to neutralize endogenous neurotrophin-3 in postnatal rats to determine its role in late sensory neuron development. Administration of the antiserum for a period of two weeks, but not one week, resulted in a 20% reduction in the number of primary sensory neurons in the dorsal root ganglia and a 19% reduction in the number of myelinated axons in the saphenous nerve. The size distribution histogram also indicated that a subpopulation of large neurons was lost by the neurotrophin-3 antiserum treatment. This neuronal loss was accompanied by reduced cell soma sizes and weights of the ganglia. Immunoreactivities for calbindin and calretinin were reduced in the trigeminal and dorsal root ganglia and nerve fibres surrounding whisker hair follicles. The number of Merkel cells in touch domes labelled with quinacrine and the number of parvalbumin-immunoreactive neurons in the dorsal root ganglia were significantly reduced by the antibody treatment. In contrast, the number of muscle spindles in the gastrocnemius muscle is not reduced by the neurotrophin-3 antiserum. Together, these results indicate that a subpopulation of primary sensory neurons in the neonatal rat requires neurotrophin-3 for their survival and expression of calcium binding proteins. In addition, Merkel cells in touch domes also require neurotrophin-3 for their survival. Thus, endogenous neurotrophin-3 in neonatal rats is critical for the survival and function of a subpopulation of primary sensory neurons and Merkel cells.     

Nutritional alterations and the effect of fish oil supplementation in dogs with heart failure

Alterations in body composition and nutritional status are common in humans with heart failure and are related, in part, to increases in cytokine concentrations. Cytokines have not been studied previously in dogs with naturally occurring cardiac disease nor has fish oil administration been used in this population to decrease cytokine production. The purposes of this study were to characterize nutritional and cytokine alterations in dogs with heart failure and to test the ability of fish oil to reduce cytokines and improve clinical outcome. Body composition, insulinlike growth factor-1, fatty acids, and cytokines were measured in 28 dogs with heart failure and in 5 healthy controls. Dogs with heart failure then were randomized to receive either fish oil or placebo for 8 weeks. All parameters were measured again at the end of the study period. At baseline, 54% of dogs with heart failure were cachectic and the severity of cachexia correlated with circulating tumor necrosis factor-alpha concentrations (P = .05). Cytokine concentrations at baseline, however, were not significantly increased in dogs with heart failure compared to controls. Baseline plasma arachidonic acid (P = .02), eicosapentaenoic acid (P = .03), and docosahexaenoic acid (P = .004) concentrations were lower in dogs with heart failure than in controls. Fish oil supplementation decreased interleukin-1 beta (IL-1) concentrations (P = .02) and improved cachexia (P = .01) compared to the placebo group. The mean caloric intake of the heart failure dogs as a group was below the maintenance energy requirement (P < .001), but no difference was found in food intake between the fish oil and placebo groups. Insulinlike growth factor-1 concentrations (P = .01) and reductions in circulating IL-1 concentrations over the study period (P = .02) correlated with survival. These data demonstrate that canine heart failure is associated with cachexia, alterations in fatty acids, and reduced caloric intake. Fish oil supplementation decreased IL-1 concentrations and improved cachexia. In addition, reductions in IL-1 predicted survival, suggesting that anticytokine strategies may benefit patients with heart failure.     

Cocaine improves inhibitory control in a human model of response conflict.

The present study was designed to test the acute effects of cocaine on behavioral control in the presence and absence of motivational conflict. Adults (N=14) with a history of stimulant use received oral cocaine hydrogen chloride (0, 100, 200, and 300 mg) and performed a cue-dependent go/no-go task to measure inhibitory and activational mechanisms of behavioral control either with or without motivated conflict between the inhibition and the activation of responses. Cocaine improved response inhibition in both conflict conditions, as evident by a decrease in inhibitory failures following active doses. The current study provides a useful model to investigate the effects of other drugs reported to have performance-enhancing effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

B<Emphasis Type="SmallCaps">ench</Emphasis>IP: Benchmarking Intelligence Processors

The increasing attention on deep learning has tremendously spurred the design of intelligence processing hardware. The variety of emerging intelligence processors requires standard benchmarks for fair comparison and system optimization (in both software and hardware). However, existing benchmarks are unsuitable for benchmarking intelligence processors due to their non-diversity and nonrepresentativeness. Also, the lack of a standard benchmarking methodology further exacerbates this problem. In this paper, we propose BenchIP, a benchmark suite and benchmarking methodology for intelligence processors. The benchmark suite in BenchIP consists of two sets of benchmarks: microbenchmarks and macrobenchmarks. The microbenchmarks consist of single-layer networks. They are mainly designed for bottleneck analysis and system optimization. The macrobenchmarks contain state-of-the-art industrial networks, so as to offer a realistic comparison of different platforms. We also propose a standard benchmarking methodology built upon an industrial software stack and evaluation metrics that comprehensively reflect various characteristics of the evaluated intelligence processors. BenchIP is utilized for evaluating various hardware platforms, including CPUs, GPUs, and accelerators. BenchIP will be open-sourced soon.     

Multi-Wire Proportional Counters for Low-Energy Particles

We have constructed multi-wire proportional-counter arrays in which only every second wire operates as an anode, the others being held at the cathode potential, and have investigated their response to a particles. The variation of the sensitivity and amplification with voltage and with different geometrical arrangements is described.     

On the Independence of Magnetic and Electric Body Surface Recordings

Recent papers have shown that the ECG depends on the flow sources of the impressed field in the heart while the MCG is a function of its vortex source distribution. It has consequently been suggested that body surface electric and magnetic recordings yield completely independent information about the physiological generators. Such independence would be of enormous significance wherever present diagnostic procedures rely heavily on the ECG or EEG. This paper points out that the independence of the flow and vortex sources is only a mathematical possibility. It demonstrates that two important physical constraints are operating which require the flow and vortex sources to be, in effect, one-to-one with each other. Consequently, the electric and magnetic fields arising from excitable tissue in an assumed homogeneous volume conductor are fundamentally interdependent.