An Ultra-Low Dose of ∆9-Tetrahydrocannabinol Alleviates Alzheimer’s Disease-Related Cognitive Impairments and Modulates TrkB Receptor Expression in a 5XFAD Mouse Model

Alzheimer’s disease (AD) is the most common form of dementia, but there is still no available treatment. Δ9-tetrahydrocannabinol (THC) is emerging as a promising therapeutic agent. Using THC in conventional high doses may have deleterious effects. Therefore, we propose to use an ultra-low dose of THC (ULD-THC). We previously published that a single injection of ULD-THC ameliorated cognitive functioning in several models of brain injuries as well as in naturally aging mice. Here, 5xFAD AD model mice received a single treatment of ULD-THC (0.002 mg/kg) after disease onset and were examined in two separate experiments for cognitive functions, neurotropic, and inflammatory factors in the hippocampus. We show that a single injection of ULD-THC alleviated cognitive impairments in 6- and 12-month-old 5xFAD mice. On the biochemical level, our results indicate an imbalance between the truncated TrkB receptor isoform and the full receptor, with AD mice showing a greater tendency to express the truncated receptor, and ULD-THC improved this imbalance. We also investigated the expression of three AD-related inflammatory markers and found an ameliorating effect of ULD-THC. The current research demonstrates for the first time the beneficial effects of a single ultra-low dose of THC in a mouse model of AD after disease onset.     

Principles of psychotherapeutic strategy.

Argues that strategy fills a real need in psychotherapeutic thinking. An attempt is made to define strategic rules for (1) choosing and defining goals, (2) locating strategic points, (3) actively searching for the client's responses, (4) dealing with resistance, (5) exploiting or creating propitious timings, (6) mobilizing allies, (7) concentrating the therapeutic influence, (8) stabilizing partial achievements, (9) dealing with competing demands, (10) retreating after failure, and (11) changing the therapeutic framework when needed. Each principle is illustrated by interventions from different therapeutic orientations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Burnout and risk of cardiovascular disease: Evidence, possible causal paths, and promising research directions.

Burnout is characterized by emotional exhaustion, physical fatigue, and cognitive weariness, resulting from prolonged exposure to work-related stress. The authors review the accumulated evidence suggesting that burnout and the related concept of vital exhaustion are associated with increased risk of cardiovascular disease and cardiovascular-related events. The authors present evidence supporting several potential mechanisms linking burnout with ill health, including the metabolic syndrome, dysregulation of the hypothalamic-pituitary-adrenal axis along with sympathetic nervous system activation, sleep disturbances, systemic inflammation, impaired immunity functions, blood coagulation and fibrinolysis, and poor health behaviors. The association of burnout and vital exhaustion with these disease mediators suggests that their impact on health may be more extensive than currently indicated. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Lipopolysaccharide isolated from Porphyromonas gingivalis grown in hemin-limited chemostat conditions has a reduced capacity for human neutrophil priming

One way prokaryotes respond to environmental stresses is by modifying selected outer membrane components. Iron, in the form of hemin, has been shown to be a significant regulator of Porphyromonas gingivalis growth and virulence and of the expression of outer membrane proteins and lipopoly saccharide. Since lipopoly saccharide has profound effects on host immune cells, this study compared the effect of hemin-restricted and hemin-normal P. gingivalis growth conditions on lipopolysaccharide priming of N-formylmethionyl-leucyl-phenylalanine-induced superoxide generation by human neutrophils. P. gingivalis was grown in a chemostat under normal (5 micrograms hemin/ml) and hemin-restricted (0.08 microgram hemin/ml) conditions. Purified lipopolysaccharide from both P. gingivalis normal and hemin-limited environments increased N-formylmethionyl-leucyl-phenylalanine-induced superoxide release by neutrophils in a dose-dependent manner. Lipopolysaccharide isolated from the hemin-normal conditions was a significantly more potent neutrophil priming agent than the lipopolysaccharide isolated from hemin-restricted conditions. Addition of normal human serum enhanced the priming effect of both lipopolysaccharide preparations; this effect, however, was more evident with the hemin-normal lipopolysaccharide. Further, this enhancing effect of serum was partly reduced in the presence of antibodies raised against the serum lipopolysaccharide-binding protein. The differences in the biological activity of the two lipopolysaccharide preparations could be associated with structural differences detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis. These results indicate that hemin availability affects regulation of an aspect of P. gingivalis virulence, lipopolysaccharide-human neutrophils priming. The reduced capacity for neutrophil priming by hemin-restricted lipopolysaccharide appears to be related to lipopolysaccharide-neutrophil interactions and not to serum factors Targeting bacterial cell-surface components involved in hemin transport might be effective therapy for P. gingivalis-associated periodontal diseases.     

The dose-dependent effects of oral premedication with midazolam

OBJECTIVE: The aim of this study was to examine the psychological effects, well-being and side effects after various doses of oral midazolam medication. METHODS: After informed consent has been obtained and following the approval by the institutional ethical committee, 80 adult patients in the ASA physical status I and II were randomly assigned to one of five different premedication groups: 3.75, 7.5, 11.25, 15 mg midazolam, and placebo. The medication was given in a double-blind fashion 60 min before induction of general anaesthesia for various surgical procedures. At 3 definite stages (before premedication, 30 and 60 min after premedication), blood pressure, heart rate, transcutaneous oxygen saturation and respiratory rate were measured. Sedation and well-being were graded according to a 5-point scale, and the subjective anxiety level was assessed according a visual analogue scale (range 0-100 mm). Anterograde and retrograde amnesia were measured by recall of auditive and visual stimuli. Finally, patients were asked whether in case of future surgery they would prefer the same or a different medication. RESULTS: Demographic data were similar in all groups. There was no significant difference in respiratory rate, oxygen saturation, blood pressure or heart rate. Alertness declined only after 60 min in the groups treated with 7.5 mg and more midazolam. During the entire measurement period, anxiolysis was not different from placebo in any of the midazolam groups. In comparison to placebo, all midazolam groups showed a statistically significant and dose dependent anterograde amnesia for visual stimuli. Subjective well-being scores showed no differences between the groups. Only few side effects were seen following doses of 7.5 mg and higher, including ptosis, strabismus, diplopia, speech disorders, disorientation and vertigo. The majority of patients in all groups indicated a wish for the same medication in case of future anaesthesia for surgical interventions. CONCLUSIONS: Midazolam administered orally prior to surgical procedures showed marked interindividual variability. Sedation and amnesia were dose-dependent and were evaluated by the patients as acceptable. Anxiolysis was not significantly different from placebo. A dose of 7.5 mg midazolam showed the best relation between desirable and undesirable effects. Adequate attention given to the patient by the anaesthesiologist prior to surgery seems to be as important and beneficial as oral medication with midazolam.     

Shape blending using the star-skeleton representation

Shape blending, the metamorphosis of one shape into another, is a central problem in two-dimensional computer animation. In spite of impressive uses of morphing in film and video productions, the problem is far from solved. In particular, shape blending still requires considerable manual effort. By decomposing two polygons into equivalent star-shaped pieces and a connecting skeleton, the paper presents a blending method which can represent polygon interiors, not just boundaries, and generate high-quality results with minimal user intervention     

Improved parallel approximation of a class of integer programming problems

We present a method to derandomizeRNC algorithms, converting them toNC algorithms. Using it, we show how to approximate a class of NP-hard integer programming problems inNC, to within factors better than the current-bestNC algorithms (of Berger and Rompel and Motwaniet al.); in some cases, the approximation factors are as good as the best-known sequential algorithms, due to Raghavan. This class includes problems such as global wire-routing in VLSI gate arrays and a generalization of telephone network planning in SONET rings. Also for a subfamily of the “packing” integer programs, we provide the firstNC approximation algorithms; this includes problems such as maximum matchings in hypergraphs, and generalizations. The key to the utility of our method is that it involves sums ofsuperpolynomially many terms, which can however be computed inNC; this superpolynomiality is the bottleneck for some earlier approaches, due to Berger and Rompel and Motwaniet al. A preliminary version of this work appeared inProc. International Colloquim on Automata, Languages and Programming, 1996, pages 562–573. Work done in parts at DIMACS (supported in part by NSF-STC91-19999 and by support from the N.J. Commission on Science and Technology), at the Institute for Advanced Study, Princeton (supported in part by Grant 93-6-6 of the Alfred P. Sloan Foundation), and at the National University of Singapore.