D-lactate is not a reliable marker of gut ischemia-reperfusion in a rat model of supraceliac aortic clamping

OBJECTIVE: D-lactate is the dextrorotatory form of L-lactate. L-lactate is the isomer routinely tested in clinical practice to assess cell hypoxemia. D-lactate has been recently proposed as a specific marker of gut ischemia-reperfusion (IR), particularly after surgery for ruptured aortic aneurysms. We sought to assess D-lactate as a reliable marker of gut IR in a rat model of supraceliac aortic clamping. DESIGN: Prospective, randomized trial. SETTING: Animal research center. SUBJECTS: Male Wistar rats. INTERVENTIONS: After general anesthesia, rats were randomized into two groups (n = 8 in each). The IR group underwent a laparotomy, aortic clamping for 40 mins, and 1 hr of reperfusion. The control group underwent the same procedure, except for aortic clamping. MEASUREMENTS AND MAIN RESULTS: The following variables were tested after 1 hr of reperfusion (IR group) or after the equivalent time (control group): 1) tissue and cell insult via ileum morphometry and electron microscopy, serum glutamic transaminases (serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase), pH, and L-lactate; 2) systemic inflammatory response via tumor necrosis factor-alpha; and 3) D-lactate levels. After IR, mucous membrane thickness and villi height decreased significantly, respectively by 30% and 45%, and electron-microscopic examination showed typical IR mucous membrane cell insult. IR also caused lactic acidosis (pH = 7.16 +/- 0.05 vs. 7.31 +/- 0.02, p < .01; L-lactate = 7.1 +/- 1.6 vs. 1.6 +/- 0.4 mmol/L, p = .001) and increased blood levels of transaminases. Concurrently, the inflammatory response was characterized by an increase in tumor necrosis factor-alpha (213 +/- 129 vs. 47 +/- 32 pg/mL, p < .05). However, blood levels of D-lactate never increased after IR. CONCLUSIONS: D-lactate is not a reliable marker of gut IR in our model of supraceliac aortic clamping in rats.     

Neural Mechanisms Supporting Robust Discrimination of Spectrally and Temporally Degraded Speech

Cochlear implants provide good speech discrimination ability despite highly limited amount of information they transmit compared with normal cochlea. Noise vocoded speech, simulating cochlear implants in normal hearing listeners, have demonstrated that spectrally and temporally degraded speech contains sufficient cues to provide accurate speech discrimination. We hypothesized that neural activity patterns generated in the primary auditory cortex by spectrally and temporally degraded speech sounds will account for the robust behavioral discrimination of speech. We examined the behavioral discrimination of noise vocoded consonants and vowels by rats and recorded neural activity patterns from rat primary auditory cortex (A1) for the same sounds. We report the first evidence of behavioral discrimination of degraded speech sounds by an animal model. Our results show that rats are able to accurately discriminate both consonant and vowel sounds even after significant spectral and temporal degradation. The degree of degradation that rats can tolerate is comparable to human listeners. We observed that neural discrimination based on spatiotemporal patterns (spike timing) of A1 neurons is highly correlated with behavioral discrimination of consonants and that neural discrimination based on spatial activity patterns (spike count) of A1 neurons is highly correlated with behavioral discrimination of vowels. The results of the current study indicate that speech discrimination is resistant to degradation as long as the degraded sounds generate distinct patterns of neural activity.     

Improvement in psoriasis after intradermal administration of delipidated, deglycolipidated Mycobacterium vaccae (PVAC™): results of an open-label trial

The aim of new treatments for psoriasis is to induce extended remissions with fewer side-effects. Previous studies suggest that Mycobacterium vaccae, a harmless organism prepared as a heat-killed suspension, may induce periods of remission in some psoriasis patients after intradermal administration. To assess a more potent derivative of M. vaccae, we conducted an open-label study in which 20 patients with moderate to severe psoriasis (Psoriasis Area and Severity Index of 12-35) received two intradermal inoculations of heat-killed, delipidated, deglycolipidated M. vaccae (DD-MVAC or 'PVAC') in lesion-free deltoid skin, separated by a period of 3 weeks. Twelve weeks after the injections, 13 out of 20 patients (65%) showed marked improvement in the PASI score (> 50% reduction), three were unchanged (< 25% reduction), three had worsened (> 5% increase), and one was withdrawn from the trial because of an exfoliative flare. At 24 weeks, 13 out of 19 patients continued to show > 50% improvement that, in some, lasted for 6 months or longer. Patients classified as good responders at 12 or 24 weeks were then offered additional PVAC injections after 24 weeks if the PASI reached 8 or higher. Intra-dermal administration of PVAC was safe, well tolerated, and induced clinically significant improvement in many psoriasis patients. A randomized, double-blind, controlled study is warranted.     

Varenicline decreases nicotine self-administration and cue-induced reinstatement of nicotine-seeking behaviour in rats when a long pretreatment time is used

Effects of varenicline (Champix), a nicotinic partial agonist, were evaluated on subjective effects of nicotine (drug discrimination), motivation for nicotine taking (progressive-ratio schedule of intravenous nicotine self-administration) and reinstatement (cue-induced reinstatement of previously extinguished nicotine-seeking behaviour). Effects on motor performance were assessed in rats trained to discriminate nicotine (0.4 mg/kg) from saline under a fixed-ratio (FR 10) schedule of food delivery and in rats trained to respond for food under a progressive-ratio schedule. At short pretreatment times (5-40 min), varenicline produced full or high levels of partial generalization to nicotine's discriminative-stimulus effects and disrupted responding for food, while there were low levels of partial generalization and no disruption of responding for food at 2- or 4-h pretreatment times. Varenicline (1 and 3 mg/kg, 2-h pretreatment time) enhanced discrimination of low doses of nicotine and to a small extent decreased discrimination of the training dose of nicotine. It also dose-dependently decreased nicotine-taking behaviour, but had no effect on food-taking behaviour under progressive-ratio schedules. Finally, varenicline significantly reduced the ability of a nicotine-associated cue to reinstate extinguished nicotine-seeking behaviour. The ability of varenicline to reduce both nicotine-taking and nicotine-seeking behaviour can contribute to its relatively high efficacy in treating human smokers.     

Solid-state nanoparticle coated emulsions for encapsulation and improving the chemical stability of all-trans-retinol

Submicron oil-in-water (o/w) emulsions stabilised with conventional surfactants and silica nanoparticles were prepared and freeze-dried to obtain free-flowing powders with good redispersibility and a three-dimensional porous matrix structure. Solid-state emulsions were characterised for visual appearance, particle size distribution, zeta potential and reconstitution properties after freeze-drying with various sugars and at a range of sugar to oil ratios. Comparative degradation kinetics of all-trans-retinol from freeze-dried and liquid emulsions was investigated as a function of storage temperatures. Optimum stability was observed for silica-coated oleylamine emulsions at 4 °C in their wet state. The half-life of all-trans-retinol was 25.66 and 22.08 weeks for silica incorporation from the oil and water phases respectively. This was ∼4 times higher compared to the equivalent solid-state emulsions with drug half-life of 6.18 and 6.06 weeks at 4 °C. Exceptionally, at a storage temperature of 40 °C, the chemical stability of the drug was 3 times higher in the solid-state compared to the wet emulsions which confirmed that freeze-drying is a promising approach to improve the chemical stability of water-labile compounds provided that the storage conditions are optimised.     

Blockade of Dopamine D4 Receptors Attenuates Reinstatement of Extinguished Nicotine-Seeking Behavior in Rats

Since cloning of the dopamine receptor D4 (DRD4), its role in the brain has remained unclear. It has been reported that polymorphism of the DRD4 gene in humans is associated with reactivity to cues related to tobacco smoking. However, the role of DRD4 in animal models of nicotine addiction has seldom been explored. In our study, male Long-Evans rats learned to intravenously self-administer nicotine under a fixed-ratio (FR) schedule of reinforcement. Effects of the selective DRD4 antagonist L-745,870 were evaluated on nicotine self-administration behavior and on reinstatement of extinguished nicotine-seeking behavior induced by nicotine-associated cues or by priming injections of nicotine. L-745,870 was also tested on reinstatement of extinguished food-seeking behavior as a control. In addition, the selective DRD4 agonist PD 168,077 was tested for its ability to reinstate extinguished nicotine-seeking behavior. Finally, L-745,870 was tested in Sprague Dawley rats trained to discriminate administration of 0.4 mg/kg nicotine from vehicle under an FR schedule of food delivery. L-745,870 significantly attenuated reinstatement of nicotine-seeking induced by both nicotine-associated cues and nicotine priming. In contrast, L-745,870 did not affect established nicotine self-administration behavior or reinstatement of food-seeking behavior induced by food cues or food priming. L-745,870 did not produce nicotine-like discriminative-stimulus effects and did not alter discriminative-stimulus effects of nicotine. PD 168,077 did not reinstate extinguished nicotine-seeking behavior. As DRD4 blockade by L-745,870 selectively attenuated both cue- and nicotine-induced reinstatement of nicotine-seeking behavior, without affecting cue- or food-induced reinstatement of food-seeking behavior, DRD4 antagonists are potential therapeutic agents against tobacco smoking relapse.     

Novel Use of a Lipid-Lowering Fibrate Medication to Prevent Nicotine Reward and Relapse: Preclinical Findings

Experimental drugs that activate α-type peroxisome proliferator-activated receptors (PPARα) have recently been shown to reduce the rewarding effects of nicotine in animals, but these drugs have not been approved for human use. The fibrates are a class of PPARα-activating medications that are widely prescribed to improve lipid profiles and prevent cardiovascular disease, but these drugs have not been tested in animal models of nicotine reward. Here, we examine the effects of clofibrate, a representative of the fibrate class, on reward-related behavioral, electrophysiological, and neurochemical effects of nicotine in rats and squirrel monkeys. Clofibrate prevented the acquisition of nicotine-taking behavior in naive animals, substantially decreased nicotine taking in experienced animals, and counteracted the relapse-inducing effects of re-exposure to nicotine or nicotine-associated cues after a period of abstinence. In the central nervous system, clofibrate blocked nicotine''s effects on neuronal firing in the ventral tegmental area and on dopamine release in the nucleus accumbens shell. All of these results suggest that fibrate medications might promote smoking cessation. The fact that fibrates are already approved for human use could expedite clinical trials and subsequent implementation of fibrates as a treatment for tobacco dependence, especially in smokers with abnormal lipid profiles.     

Selected integrative medicine treatments for depression: considerations for women

This review evaluates the research published between 1966 and 2004 on several integrative treatments for depression, including omega-3 fatty acids, Hypericum perforatum (St. John's Wort), S-adenosyl-methionine, folate, 5-Hydroxytryptophan, acupuncture, exercise, and light therapy, with a particular emphasis on issues pertinent to women. Data from double-blind, placebo-controlled trials support each of these as treatment interventions for depression. We discuss both the strength of the evidence for each treatment and methodological issues related to interpretation of efficacy. Available data pertaining to considerations in women, including use during pregnancy and breastfeeding and interactions with hormonal therapies are discussed. The reviewed treatments deserve further research. Their appropriate place in the armamentarium of depression treatments for women must be defined. An evidence-based integrative medicine approach brings together treatment options with proven efficacy and the public's desire for complementary and alternative medicine treatments.