General Anesthesia and Altered States of Arousal: A Systems Neuroscience Analysis

Placing a patient in a state of general anesthesia is crucial for safely and humanely performing most surgical and many nonsurgical procedures. How anesthetic drugs create the state of general anesthesia is considered a major mystery of modern medicine. Unconsciousness, induced by altered arousal and/or cognition, is perhaps the most fascinating behavioral state of general anesthesia. We perform a systems neuroscience analysis of the altered arousal states induced by five classes of intravenous anesthetics by relating their behavioral and physiological features to the molecular targets and neural circuits at which these drugs are purported to act. The altered states of arousal are sedation-unconsciousness, sedation-analgesia, dissociative anesthesia, pharmacologic non-REM sleep, and neuroleptic anesthesia. Each altered arousal state results from the anesthetic drugs acting at multiple targets in the central nervous system. Our analysis shows that general anesthesia is less mysterious than currently believed.Massachusetts General Hospital. Dept. of Anesthesia and Critical CareNational Institutes of Health (U.S.) (Director's Pioneer Award DP10D003646)National Institutes of Health (U.S.) (New Innovator Award DP2OD006454)National Institutes of Health (U.S.) (Grant K25-NS057580)National Institutes of Health (U.S.) (Training Program in Sleep, Circadian and Respiratory Neurobiology HL07901

Effects of PCB on Reproductive Success in Sprague-Dawley Rats Exposed to Aroclor 1254 for One Year

Author Institution: Department of Biological Sciences, Bowling Green State UniversityPolychlorinated biphenyls (PCB) are environmental contaminants that have been a problem since the 1960s. PCB are a serious concern because they are widespread, lipophilic, and bioaccumulate through food webs concentrating in adipose tissue. PCB are a threat to both wildlife and humans because they elicit metabolic and endocrine disruptions with some problems including hypothyroxinemia, spatial learning and memory deficits, neurochemical and neurobehavioral alterations, and reproductive alterations. Sprague-Dawley rats were obtained that had been exposed to Aroclor 1254® in the diet at 1.25 ppni or 25.0 ppm dosage for one year before being mated. Males and females were placed together in a cage and females were tested each day for a sperm-positive vaginal smear. After a sperm positive vaginal smear, females were housed separately, maintained on their respective diets, and weighed daily until weight gain reversal or miscarriage. All animals in the present study that were fed PCB had weight gain reversal or miscarriage, whereas controls of a similar age all carried pregnancy to term. The results of the present study indicate that continuous ingestion of Aroclor 1254® at low doses has a depressive effect on reproductive success

Negligible risk of inducing resistance in Mycobacterium tuberculosis with single-dose rifampicin as post-exposure prophylaxis for leprosy

Post-exposure prophylaxis (PEP) for leprosy is administered as one single dose of rifampicin (SDR) to the contacts of newly diagnosed leprosy patients. SDR reduces the risk of developing leprosy among contacts by around 60 % in the first 2-3 years after receiving SDR. In countries where SDR is currently being implemented under routine programme conditions in defined areas, questions were raised by health authorities and professional bodies about the possible risk of inducing rifampicin resistance among the M. tuberculosis strains circulating in these areas. This issue has not been addressed in scientific literature to date. To produce an authoritative consensus statement about the risk that SDR would induce rifampicin-resistant tuberculosis, a meeting was convened with tuberculosis (TB) and leprosy experts. The experts carefully reviewed and discussed the available evidence regarding the mechanisms and risk factors for the development of (multi) drug-resistance in M. tuberculosis with a view to the special situation of the use of SDR as PEP for leprosy. They concluded that SDR given to contacts of leprosy patients, in the absence of symptoms of active TB, poses a negligible risk of generating resistance in M. tuberculosis in individuals and at the population level. Thus, the benefits of SDR prophylaxis in reducing the risk of developing leprosy in contacts of new leprosy patients far outweigh the risks of generating drug resistance in M. tuberculosis

Effectiveness and Feasibility of the Workout on Wheels Internet Intervention (WOWii) for Individuals With Spinal Cord Injury: A Randomized Controlled Trial

STUDY DESIGN: Randomized-controlled trial (RCT) with immediate intervention (IMM) and wait-list control (WLC) groups; WLC participants received the intervention during delivery to subsequent cohorts. OBJECTIVES: Investigate the effectiveness and feasibility of a virtually-delivered exercise intervention. SETTING: Home and community. METHODS: A total of 168 middle-aged (49.6 [12.3] years old) men (57%) and women (43%) who lived an average 15.5 (12.3) years with spinal cord injury (SCI) participated. The 16-week program provides users (a) website access with exercise information, resources, and 16 skill-building modules; (b) virtual 60-minute, group-based weekly meetings; and (c) a starter package of exercise equipment. Primary outcomes included subjective physical activity (IPAQ) and objective exercise (Polar A300 wrist-based activity monitor and H7 heart rate strap). Secondary outcomes included fitness indices during a maximal arm crank test, plus self-reported exercise barriers, exercise self-efficacy, and goal-directed thinking. RESULTS: RCT results indicate significant between group differences in participants\u27 self-reported weekly time spent in vigorous-intensity PA and goal directed thinking but not for fitness changes. Data combined for IMM and WLC participants from Polar monitoring show participants performed 150 min per week of aerobic exercise plus reported significantly greater time spent in moderate-PA, vigorous-PA, self-efficacy for exercise and nutrition, goal directed thinking, and exercise barriers. Oxygen uptake (V̇O CONCLUSION: This virtually-delivered program offers a promising approach to increase exercise among those with SCI and may help participants perceive fewer motivational barriers and greater self-efficacy

Synthesis of 2,6-disubstituted dihydropyrans via an efficient BiBr3-initiated three component, one-pot cascade

The rapid synthesis of cis-2,6-disubstituted dihydropyrans is achieved in a three-component, one-pot cascade reaction. BiBr3-mediated addition of ketene silyl acetals or silyl enol ethers to beta,gamma-unsaturated cis-4-trimethylsilyl-3-butenal provides a Mukaiyama aldol adduct containing a vinylsilane moiety tethered to a silyl ether. Addition of a second aldehyde initiates a domino sequence involving intermolecular addition followed by an intramolecular silyl-modified Sakurai (ISMS) reaction. Isolated yields of this one-pot reaction vary from 44 to 80% and all compounds were isolated as the cis-diastereomers (10 examples). (C) 2009 Elsevier Ltd. All rights reserved

Description of normal pulmonary radiographic findings in 55 apparently healthy juvenile Kemp's ridley sea turtles (Lepidochelys kempii)

A total of 55 digital radiographic studies from 53 individual juvenile Kemp's ridley sea turtles (Lepidochelys kempii) were retrospectively used to determine the normal radiographic anatomy of the lower respiratory tract in sea turtles that had been stranded due to hook-and-line injury and were otherwise clinically healthy. There were three or four projections available for each study: dorsoventral (DV), rostrocaudal (RoCd), and left and/or right lateral. The DV and RoCd were most conducive for assessing global lung volume and symmetry of lung volume. The DV and lateral views were most helpful for evaluating the main bronchus and its branching channels and for assessing lung margination. The RoCd view was most useful for assessing the symmetry of the lung opacity. The lateral views were most helpful for assessing the ventral margin of each lung lobe. On the lateral view, the main bronchus lay ventrally and coursed horizontally through the lung from cranial to caudal. On the DV view, the bronchus lay medially and was observed to be curvilinear coursing caudomedially. On the RoCd view, the main bronchus was located ventromedially. The RoCd view demonstrated the channels and niches end-on resulting in a reticulated or honeycomb appearance. The channels were seen as uniform striations coursing perpendicular to the main bronchus on the lateral views (vertical striations coursing dorsal to ventral) and DV views (horizontal striations coursing medially to laterally)

Effort-related motivational effects of the pro-inflammatory cytokine interleukin 1-beta: studies with the concurrent fixed ratio 5/ chow feeding choice task

Rationale. Effort-related motivational symptoms such as anergia and fatigue are common in patients with depression and other disorders. Research implicates pro-inflammatory cytokines in depression, and administration of cytokines can induce effort-related motivational symptoms in humans. Objectives. The present experiments focused on the effects of the pro-inflammatory cytokine interleukin 1-beta (IL-1β) on effort-related choice behavior. Methods. Rats were tested on a concurrent fixed ratio 5 lever pressing/chow feeding choice procedure, which assesses the tendency of rats to work for a preferred food (high carbohydrate pellets) in the presence of a concurrently available but less preferred substitute (laboratory chow). Results. IL-1β (1.0–4.0 μg/kg IP) shifted choice behavior, significantly decreasing lever pressing and increasing intake of the freely available chow. The second experiment assessed the ability of the adenosine A2A antagonist (E)-phosphoric acid mono-[3-[8-[2-(3-methoxyphenyl)vinyl]-7-methyl-2,6-dioxo-1-prop-2-ynyl-1,2,6,7-tetrahydropurin-3-yl] propyl] ester disodium salt (MSX-3) to reverse the behavioral effects of IL-1β. MSX-3 attenuated the effort-related impairments produced by IL-1β, increasing lever pressing and also decreasing chow intake. In the same dose range that shifted effort-related choice behavior, IL-1β did not alter food intake or preference in parallel free-feeding choice studies, indicating that these low doses were not generally suppressing appetite or altering preference for the high carbohydrate pellets. In addition, IL-1β did not affect core body temperature. Conclusions. These results indicate that IL-1β can reduce the tendency to work for food, even at low doses that do not produce a general sickness, malaise, or loss of appetite. This research has implications for the involvement of cytokines in motivational symptoms such as anergia and fatigue

Optogenetic activation of dopamine neurons in the ventral tegmental area induces reanimation from general anesthesia

Dopamine (DA) promotes wakefulness, and DA transporter inhibitors such as dextroamphetamine and methylphenidate are effective for increasing arousal and inducing reanimation, or active emergence from general anesthesia. DA neurons in the ventral tegmental area (VTA) are involved in reward processing, motivation, emotion, reinforcement, and cognition, but their role in regulating wakefulness is less clear. The current study was performed to test the hypothesis that selective optogenetic activation of VTA DA neurons is sufficient to induce arousal from an unconscious, anesthetized state. Floxed-inverse (FLEX)-Channelrhodopsin2 (ChR2) expression was targeted to VTA DA neurons in DA transporter (DAT)-cre mice (ChR2+ group; n = 6). Optical VTA stimulation in ChR2+ mice during continuous, steady-state general anesthesia (CSSGA) with isoflurane produced behavioral and EEG evidence of arousal and restored the righting reflex in 6/6 mice. Pretreatment with the D1 receptor antagonist SCH-23390 before optical VTA stimulation inhibited the arousal responses and restoration of righting in 6/6 ChR2+ mice. In control DAT-cre mice, the VTA was targeted with a viral vector lacking the ChR2 gene (ChR2− group; n = 5). VTA optical stimulation in ChR2− mice did not restore righting or produce EEG changes during isoflurane CSSGA in 5/5 mice. These results provide compelling evidence that selective stimulation of VTA DA neurons is sufficient to induce the transition from an anesthetized, unconscious state to an awake state, suggesting critical involvement in behavioral arousal.United States. National Institutes of Health (TR01-GM104948)United States. National Institutes of Health (T32-GM07592