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Sample records for awake intranasal insulin

  1. Intranasal Administration of CNS Therapeutics to Awake Mice

    PubMed Central

    Hanson, Leah R.; Fine, Jared M.; Svitak, Aleta L.; Faltesek, Katherine A.

    2013-01-01

    Intranasal administration is a method of delivering therapeutic agents to the central nervous system (CNS). It is non-invasive and allows large molecules that do not cross the blood-brain barrier access to the CNS. Drugs are directly targeted to the CNS with intranasal delivery, reducing systemic exposure and thus unwanted systemic side effects1. Delivery from the nose to the CNS occurs within minutes along both the olfactory and trigeminal neural pathways via an extracellular route and does not require drug to bind to any receptor or axonal transport2. Intranasal delivery is a widely publicized method and is currently being used in human clinical trials3. Intranasal delivery of drugs in animal models allows for initial evaluation of pharmacokinetic distribution and efficacy. With mice, it is possible to administer drugs to awake (non-anesthetized) animals on a regular basis using a specialized intranasal grip. Awake delivery is beneficial because it allows for long-term chronic dosing without anesthesia, it takes less time than with anesthesia, and can be learned and done by many people so that teams of technicians can dose large numbers of mice in short periods. Efficacy of therapeutics administered intranasally in this way to mice has been demonstrated in a number of studies including insulin in diabetic mouse models 4-6 and deferoxamine in Alzheimer's mouse models. 7,8 The intranasal grip for mice can be learned, but is not easy and requires practice, skill, and a precise grip to effectively deliver drug to the brain and avoid drainage to the lung and stomach. Mice are restrained by hand using a modified scruff in the non-dominant hand with the neck held parallel to the floor, while drug is delivered with a pipettor using the dominant hand. It usually takes 3-4 weeks of acclimating to handling before mice can be held with this grip without a stress response. We have prepared this JoVE video to make this intranasal delivery technique more accessible. PMID

  2. Position on zinc delivery to olfactory nerves in intranasal insulin phase I-III clinical trials.

    PubMed

    Hamidovic, A

    2015-11-01

    Zinc in pancreatic insulin is essential for processing and action of the peptide, while in commercial preparations zinc promotes hexameric structure and prevents aggregate formation. In 2002, for the first time, insulin was delivered to humans intranasally with resulting cerebrospinal fluid insulin increases, but steady peripheral insulin levels. The novel method of increasing brain insulin levels without changes in the periphery resulted in an expansion of brain insulin research in clinical trials. As pre-clinical research has shown that brain insulin modulates a number functions, including food cravings and eating behavior, learning and memory functions, stress and mood regulation; realization of beneficial effects of insulin in modulating these functions in clinical populations became a possibility with the new direct-to-brain insulin delivery methodology. However, zinc, being integral to insulin structure and function, is neurotoxic, and has resulted in adverse effects to human health. In the last century, intranasal zinc was given preventively during the time of polio outbreak, and in the 21st century intranasal zinc was widely used over the counter to prevent common cold. In both cases, patients experienced partial or complete loss of smell. This paper is the first one to analyze zinc salts and concentrations of those two epidemiological adversities and directly compare formulations distributed to the public with animal toxicity data. The information gained from animal and epidemiological data provides a foundation for the formation of opinion given in this paper regarding safety of intranasal zinc in emerging clinical trials with intranasal insulin.

  3. Postprandial Administration of Intranasal Insulin Intensifies Satiety and Reduces Intake of Palatable Snacks in Women

    PubMed Central

    Hallschmid, Manfred; Higgs, Suzanne; Thienel, Matthias; Ott, Volker; Lehnert, Hendrik

    2012-01-01

    The role of brain insulin signaling in the control of food intake in humans has not been thoroughly defined. We hypothesized that the hormone contributes to the postprandial regulation of appetite for palatable food, and assessed the effects on appetite and snack intake of postprandial versus fasted intranasal insulin administration to the brain in healthy women. Two groups of subjects were intranasally administered 160 IU insulin or vehicle after lunch. Two hours later, consumption of cookies of varying palatability was measured under the pretext of a taste test. In a control study, the effects of intranasal insulin administered to fasted female subjects were assessed. Compared with placebo, insulin administration in the postprandial but not in the fasted state decreased appetite as well as intake and rated palatability of chocolate chip cookies (the most palatable snack offered). In both experiments, intranasal insulin induced a slight decrease in plasma glucose but did not affect serum insulin concentrations. Data indicate that brain insulin acts as a relevant satiety signal during the postprandial period, in particular reducing the intake of highly palatable food, and impacts peripheral glucose homeostasis. Postprandial intranasal insulin administration might be useful in curtailing overconsumption of snacks with accentuated rewarding value. PMID:22344561

  4. Postprandial administration of intranasal insulin intensifies satiety and reduces intake of palatable snacks in women.

    PubMed

    Hallschmid, Manfred; Higgs, Suzanne; Thienel, Matthias; Ott, Volker; Lehnert, Hendrik

    2012-04-01

    The role of brain insulin signaling in the control of food intake in humans has not been thoroughly defined. We hypothesized that the hormone contributes to the postprandial regulation of appetite for palatable food, and assessed the effects on appetite and snack intake of postprandial versus fasted intranasal insulin administration to the brain in healthy women. Two groups of subjects were intranasally administered 160 IU insulin or vehicle after lunch. Two hours later, consumption of cookies of varying palatability was measured under the pretext of a taste test. In a control study, the effects of intranasal insulin administered to fasted female subjects were assessed. Compared with placebo, insulin administration in the postprandial but not in the fasted state decreased appetite as well as intake and rated palatability of chocolate chip cookies (the most palatable snack offered). In both experiments, intranasal insulin induced a slight decrease in plasma glucose but did not affect serum insulin concentrations. Data indicate that brain insulin acts as a relevant satiety signal during the postprandial period, in particular reducing the intake of highly palatable food, and impacts peripheral glucose homeostasis. Postprandial intranasal insulin administration might be useful in curtailing overconsumption of snacks with accentuated rewarding value.

  5. Enhancement of Vasoreactivity and Cognition by Intranasal Insulin in Type 2 Diabetes

    PubMed Central

    Novak, Vera; Milberg, William; Hao, Ying; Munshi, Medha; Novak, Peter; Galica, Andrew; Manor, Bradley; Roberson, Paula; Craft, Suzanne; Abduljalil, Amir

    2014-01-01

    OBJECTIVE To determine acute effects of intranasal insulin on regional cerebral perfusion and cognition in older adults with type 2 diabetes mellitus (DM). RESEARCH DESIGN AND METHODS This was a proof-of-concept, randomized, double-blind, placebo-controlled intervention evaluating the effects of a single 40-IU dose of insulin or saline on vasoreactivity and cognition in 15 DM and 14 control subjects. Measurements included regional perfusion, vasodilatation to hypercapnia with 3-Tesla MRI, and neuropsychological evaluation. RESULTS Intranasal insulin administration was well tolerated and did not affect systemic glucose levels. No serious adverse events were reported. Across all subjects, intranasal insulin improved visuospatial memory (P ≤ 0.05). In the DM group, an increase of perfusion after insulin administration was greater in the insular cortex compared with the control group (P = 0.0003). Cognitive performance after insulin administration was related to regional vasoreactivity. Improvements of visuospatial memory after insulin administration in the DM group (R2adjusted = 0.44, P = 0.0098) and in the verbal fluency test in the control group (R2adjusted = 0.64, P = 0.0087) were correlated with vasodilatation in the middle cerebral artery territory. CONCLUSIONS Intranasal insulin administration appears safe, does not affect systemic glucose control, and may provide acute improvements of cognitive function in patients with type 2 DM, potentially through vasoreactivity mechanisms. Intranasal insulin-induced changes in cognitive function may be related to vasodilatation in the anterior brain regions, such as insular cortex that regulates attention-related task performance. Larger studies are warranted to identify long-term effects and predictors of positive cognitive response to intranasal insulin therapy. PMID:24101698

  6. Intranasal Insulin Therapy for Cognitive Impairment and Neurodegeneration: Current State of the Art

    PubMed Central

    de la Monte, Suzanne M.

    2015-01-01

    Introduction Growing evidence supports the concept that insulin resistance plays an important role in the pathogenesis of cognitive impairment and neurodegeneration, including in Alzheimer's disease (AD). The metabolic hypothesis has led to the development and utilization of insulin- and insulin agonist-based treatments. Therapeutic challenges faced include the ability to provide effective treatments that do not require repeated injections and also minimize potentially hazardous off-target effects. Areas covered This review covers the role of intra-nasal insulin therapy for cognitive impairment and neurodegeneration, particularly Alzheimer's disease. The literature reviewed focuses on data published within the past 5 years as this field is evolving rapidly. The author provides evidence that brain insulin resistance is an important and early abnormality in Alzheimer's disease, and that increasing brain supply and utilization of insulin improves cognition and memory. Emphasis was placed on discussing outcomes of clinical trials and interpreting discordant results to clarify the benefits and limitations of intranasal insulin therapy. Expert Opinion Intranasal insulin therapy can efficiently and directly target the brain to support energy metabolism, myelin maintenance, cell survival, and neuronal plasticity, which begin to fail in the early stages of neurodegeneration. Efforts must continue toward increasing the safety, efficacy, and specificity of intranasal insulin therapy. PMID:24215447

  7. Intranasal Insulin Enhanced Resting-State Functional Connectivity of Hippocampal Regions in Type 2 Diabetes

    PubMed Central

    Zhang, Hui; Hao, Ying; Manor, Bradley; Novak, Peter; Milberg, William; Zhang, Jue; Fang, Jing

    2015-01-01

    Type 2 diabetes mellitus (T2DM) alters brain function and manifests as brain atrophy. Intranasal insulin has emerged as a promising intervention for treatment of cognitive impairment. We evaluated the acute effects of intranasal insulin on resting-state brain functional connectivity in older adults with T2DM. This proof-of-concept, randomized, double-blind, placebo-controlled study evaluated the effects of a single 40 IU dose of insulin or saline in 14 diabetic and 14 control subjects. Resting-state functional connectivity between the hippocampal region and default mode network (DMN) was quantified using functional MRI (fMRI) at 3Tesla. Following insulin administration, diabetic patients demonstrated increased resting-state connectivity between the hippocampal regions and the medial frontal cortex (MFC) as compared with placebo (cluster size: right, P = 0.03) and other DMN regions. On placebo, the diabetes group had lower connectivity between the hippocampal region and the MFC as compared with control subjects (cluster size: right, P = 0.02), but on insulin, MFC connectivity was similar to control subjects. Resting-state connectivity correlated with cognitive performance. A single dose of intranasal insulin increases resting-state functional connectivity between the hippocampal regions and multiple DMN regions in older adults with T2DM. Intranasal insulin administration may modify functional connectivity among brain regions regulating memory and complex cognitive behaviors. PMID:25249577

  8. [Targeting the brain through the nose. Effects of intranasally administered insulin].

    PubMed

    Brünner, Y F; Benedict, C; Freiherr, J

    2013-08-01

    The assumption that the human brain is an insulin-independent organ was disproved with the discovery of insulin receptors in the central nervous system in the year 1978. Evidence has been provided for a high density of insulin receptors in brain regions responsible for cognitive memory processes (hippocampus) and for the regulation of appetite (hypothalamus). Accordingly, in animal studies an increased insulin level in the central nervous system leads to an improvement of hippocampal memory function and a decrease of food intake. Similar results were obtained in humans using the method of intranasal administration of insulin. Intranasal insulin reaches the brain and the cerebrospinal fluid via the olfactory epithelium and olfactory nerve fiber bundles leading through the lamina cribrosa to the olfactory bulb. Thus, this method renders the investigation of specific insulin effects in humans possible. The therapeutic potential of an intranasal insulin administration for the treatment of diseases for which an imbalance of the central nervous insulin metabolism is discussed (e.g. Alzheimer's disease, diabetes mellitus and obesity) can only be estimated with the help of further clinical studies. PMID:23760596

  9. Influence of hemorrhage on adrenal secretion, blood glucose and serum insulin in the awake pig.

    PubMed Central

    Carey, L C; Curtin, R; Sapira, J D

    1976-01-01

    A study was performed to quantitate the adrenal medullary and cortical response to hemorrhage in awake animals bled at different rates and to relate these responses to simultaneous changes in blood glucose and serum insulin. A series of awake pigs were bled either slowly or rapidly of 30% of their calculated blood volume. Infusions of exogenous epinephrine were performed in an additional series of unbled animals and infusions of epinephrine plus hydrocortisone were similarly performed in an additonal series. Increase in blood glucose and epinephrine secretion rate following hemorrhage were found to be significantly dependent upon the rate of initial hemorrhage. Cortisol secretion was found to rise significantly during and following hemorrhage in both rapidly and slowly bled animals. Serum insulin levels remained at baseline levels during shock, despite the presence of significant hyperglycemia. In unbled animals infused with epinephrine at rates comparable to those measured in shock, elevations in blood glucose were markedly lower, shifting to the right of the dose-response curve during hemorrhage. Simultaneous infusions of cortisol and epinephrine resulted in a dose-response curve which did not differ significantly from that following infusion of epinephrine alone. Images Fig. 2. PMID:1247317

  10. Effect of superfused insulin on cerebral cortical glucose utilization in awake goats

    SciTech Connect

    Pelligrino, D.A.; Miletich, D.J.; Albrecht, R.F. )

    1987-10-01

    The effect on cortical cerebral glucose utilization (CMR{sub glu}) of intracerebral insulin administration in awake goats was studied. The insulin was superfused in a mock cerebrospinal fluid (CSF) employing chronically implanted cranial windows. Two windows were implanted bilaterally: one window over an equivalent portion of each parietal cortex. With one window used to deliver insulin/CSF and the other used to simultaneously deliver CSF alone (control), changes in CMR{sub glu} were assessed using a modification of a sequential 2-({sup 3}H)- then 2({sup 14}C)deoxy-D-glucose (2DG) technique originally described by Altenau and Agranoff. Initial experiments employing {sup 125}I-insulin demonstrated that the superfusion procedure increased insulin levels only in the outer 1 mm of cortical tissue exposed to insulin containing perfusate. Additional preliminary evaluations, using conditions known to alter CMR{sub glu}, generally established that present methods were adequate to induce and detect CMR{sub glu} changes. However, it was also shown experimentally and using a mathematical model that 2-({sup 3}H)DG test/control tissue ratios could be influenced by subsequent changes in CMR{sub glu} and the dephosphorylation rate. Thus {sup 3}H ratios could not be used to establish preexperimental test/control CMR{sub glu} relationships as the originally devised model assumed but could be employed to indicate changes in dephosphorylation. The mathematical model allowed for improved estimates of CMR{sub glu} changes from 2({sup 14}C)DG/2-({sup 3}H)DG test over control tissue ratios. Even with these corrections, insulin was estimated to cause no more than an 8-15% increase in cortical CMR{sub glu}. A very limited role for insulin, at least in cerebral cortical metabolic regulation, is thus indicated.

  11. Intranasal Insulin Prevents Cognitive Decline, Cerebral Atrophy and White Matter Changes in Murine Type I Diabetic Encephalopathy

    ERIC Educational Resources Information Center

    Francis, George J.; Martinez, Jose A.; Liu, Wei Q.; Xu, Kevin; Ayer, Amit; Fine, Jared; Tuor, Ursula I.; Glazner, Gordon; Hanson, Leah R.; Frey, William H., II; Toth, Cory

    2008-01-01

    Insulin deficiency in type I diabetes may lead to cognitive impairment, cerebral atrophy and white matter abnormalities. We studied the impact of a novel delivery system using intranasal insulin (I-I) in a mouse model of type I diabetes (streptozotocin-induced) for direct targeting of pathological and cognitive deficits while avoiding potential…

  12. Pharmacokinetics and Pharmacodynamics of Intranasal Insulin Spray (Nasulin™) Administered to Healthy Male Volunteers:

    PubMed Central

    Leary, Andrew C.; Dowling, Muiris; Cussen, Kathleen; O'Brien, Jackie; Stote, Robert M.

    2008-01-01

    Background The pharmacokinetics and pharmacodynamics of a Bentley Pharmaceuticals proprietary intranasal (IN) insulin formulation (Nasulin™) were studied in healthy volunteers. Methods Thirteen fasting healthy male volunteers received five doses of medication (one dose of 4 international units [IU] subcutaneous (SC) regular insulin and four doses of 25 IU IN insulin) at least 48 h apart. Serum insulin, serum C-peptide, and plasma glucose were measured in the 4 h after dosing. Profiles were compared for IN insulin spray following administration into the dominant nostril (more open at time of dosing) and into the nondominant nostril (less open at time of dosing). Results The formulation was generally well tolerated. A rise in serum insulin levels accompanied by a decrease in plasma glucose was seen following all doses. For IN doses, peak insulin levels were generally attained in 10–20 min and remained elevated for approximately 40–50 min; the resultant effect on glucose peaked at 40 min and waned approximately 2 h postdosing. As reported in other studies, the interindividual response to insulin was variable. The comparative absorption of IN insulin relative to SC insulin was 12.0% (dominant nostril) or 15.4% (nondominant nostril) over 2 h. This increased somewhat if sneezers and volunteers with moderately blocked nostrils were removed from the analysis. Conclusions This IN formulation was generally well tolerated and relatively well absorbed. While both insulin data (maximal plasma concentration and area under the plasma concentration time curve) and glucose data (% fall) support a trend toward better absorption from the nondominant nostril, this did not reach statistical significance. Nasulin can be administered without reference to the nasal cycle. PMID:19885293

  13. Cortisol, but not intranasal insulin, affects the central processing of visual food cues.

    PubMed

    Ferreira de Sá, Diana S; Schulz, André; Streit, Fabian E; Turner, Jonathan D; Oitzl, Melly S; Blumenthal, Terry D; Schächinger, Hartmut

    2014-12-01

    Stress glucocorticoids and insulin are important endocrine regulators of energy homeostasis, but little is known about their central interaction on the reward-related processing of food cues. According to a balanced group design, healthy food deprived men received either 40IU intranasal insulin (n=13), 30mg oral cortisol (n=12), both (n=15), or placebo (n=14). Acoustic startle responsiveness was assessed during presentation of food and non-food pictures. Cortisol enhanced startle responsiveness during visual presentation of "high glycemic" food pictures, but not during presentation of neutral and pleasant non-food pictures. Insulin had no effect. Based on the "frustrative nonreward" model these results suggest that the reward value of high glycemic food items is specifically increased by cortisol.

  14. Neural correlates of olfactory and visual memory performance in 3D-simulated mazes after intranasal insulin application.

    PubMed

    Brünner, Yvonne F; Rodriguez-Raecke, Rea; Mutic, Smiljana; Benedict, Christian; Freiherr, Jessica

    2016-10-01

    This fMRI study intended to establish 3D-simulated mazes with olfactory and visual cues and examine the effect of intranasally applied insulin on memory performance in healthy subjects. The effect of insulin on hippocampus-dependent brain activation was explored using a double-blind and placebo-controlled design. Following intranasal administration of either insulin (40IU) or placebo, 16 male subjects participated in two experimental MRI sessions with olfactory and visual mazes. Each maze included two separate runs. The first was an encoding maze during which subjects learned eight olfactory or eight visual cues at different target locations. The second was a recall maze during which subjects were asked to remember the target cues at spatial locations. For eleven included subjects in the fMRI analysis we were able to validate brain activation for odor perception and visuospatial tasks. However, we did not observe an enhancement of declarative memory performance in our behavioral data or hippocampal activity in response to insulin application in the fMRI analysis. It is therefore possible that intranasal insulin application is sensitive to the methodological variations e.g. timing of task execution and dose of application. Findings from this study suggest that our method of 3D-simulated mazes is feasible for studying neural correlates of olfactory and visual memory performance. PMID:27492601

  15. Neural correlates of olfactory and visual memory performance in 3D-simulated mazes after intranasal insulin application.

    PubMed

    Brünner, Yvonne F; Rodriguez-Raecke, Rea; Mutic, Smiljana; Benedict, Christian; Freiherr, Jessica

    2016-10-01

    This fMRI study intended to establish 3D-simulated mazes with olfactory and visual cues and examine the effect of intranasally applied insulin on memory performance in healthy subjects. The effect of insulin on hippocampus-dependent brain activation was explored using a double-blind and placebo-controlled design. Following intranasal administration of either insulin (40IU) or placebo, 16 male subjects participated in two experimental MRI sessions with olfactory and visual mazes. Each maze included two separate runs. The first was an encoding maze during which subjects learned eight olfactory or eight visual cues at different target locations. The second was a recall maze during which subjects were asked to remember the target cues at spatial locations. For eleven included subjects in the fMRI analysis we were able to validate brain activation for odor perception and visuospatial tasks. However, we did not observe an enhancement of declarative memory performance in our behavioral data or hippocampal activity in response to insulin application in the fMRI analysis. It is therefore possible that intranasal insulin application is sensitive to the methodological variations e.g. timing of task execution and dose of application. Findings from this study suggest that our method of 3D-simulated mazes is feasible for studying neural correlates of olfactory and visual memory performance.

  16. Intranasal insulin protects against substantia nigra dopaminergic neuronal loss and alleviates motor deficits induced by 6-OHDA in rats.

    PubMed

    Pang, Y; Lin, S; Wright, C; Shen, J; Carter, K; Bhatt, A; Fan, L-W

    2016-03-24

    Protection of substantia nigra (SN) dopaminergic (DA) neurons by neurotrophic factors (NTFs) is one of the promising strategies in Parkinson's disease (PD) therapy. A major clinical challenge for NTF-based therapy is that NTFs need to be delivered into the brain via invasive means, which often shows limited delivery efficiency. The nose to brain pathway is a non-invasive brain drug delivery approach developed in recent years. Of particular interest is the finding that intranasal insulin improves cognitive functions in Alzheimer's patients. In vitro, insulin has been shown to protect neurons against various insults. Therefore, the current study was designed to test whether intranasal insulin could afford neuroprotection in the 6-hydroxydopamine (6-OHDA)-based rat PD model. 6-OHDA was injected into the right side of striatum to induce a progressive DA neuronal lesion in the ipsilateral SN pars compact (SNc). Recombinant human insulin was applied intranasally to rats starting from 24h post lesion, once per day, for 2 weeks. A battery of motor behavioral tests was conducted on day 8 and 15. The number of DA neurons in the SNc was estimated by stereological counting. Our results showed that 6-OHDA injection led to significant motor deficits and 53% of DA neuron loss in the ipsilateral side of injection. Treatment with insulin significantly ameliorated 6-OHDA-induced motor impairments, as shown by improved locomotor activity, tapered/ledged beam-walking performance, vibrissa-elicited forelimb-placing, initial steps, as well as methamphetamine-induced rotational behavior. Consistent with behavioral improvements, insulin treatment provided a potent protection of DA neurons in the SNc against 6-OHDA neurotoxicity, as shown by a 74.8% increase in tyrosine hydroxylase (TH)-positive neurons compared to the vehicle group. Intranasal insulin treatment did not affect body weight and blood glucose levels. In conclusion, our study showed that intranasal insulin provided strong

  17. Intranasal insulin protects against substantia nigra dopaminergic neuronal loss and alleviates motor deficits induced by 6-OHDA in rats.

    PubMed

    Pang, Y; Lin, S; Wright, C; Shen, J; Carter, K; Bhatt, A; Fan, L-W

    2016-03-24

    Protection of substantia nigra (SN) dopaminergic (DA) neurons by neurotrophic factors (NTFs) is one of the promising strategies in Parkinson's disease (PD) therapy. A major clinical challenge for NTF-based therapy is that NTFs need to be delivered into the brain via invasive means, which often shows limited delivery efficiency. The nose to brain pathway is a non-invasive brain drug delivery approach developed in recent years. Of particular interest is the finding that intranasal insulin improves cognitive functions in Alzheimer's patients. In vitro, insulin has been shown to protect neurons against various insults. Therefore, the current study was designed to test whether intranasal insulin could afford neuroprotection in the 6-hydroxydopamine (6-OHDA)-based rat PD model. 6-OHDA was injected into the right side of striatum to induce a progressive DA neuronal lesion in the ipsilateral SN pars compact (SNc). Recombinant human insulin was applied intranasally to rats starting from 24h post lesion, once per day, for 2 weeks. A battery of motor behavioral tests was conducted on day 8 and 15. The number of DA neurons in the SNc was estimated by stereological counting. Our results showed that 6-OHDA injection led to significant motor deficits and 53% of DA neuron loss in the ipsilateral side of injection. Treatment with insulin significantly ameliorated 6-OHDA-induced motor impairments, as shown by improved locomotor activity, tapered/ledged beam-walking performance, vibrissa-elicited forelimb-placing, initial steps, as well as methamphetamine-induced rotational behavior. Consistent with behavioral improvements, insulin treatment provided a potent protection of DA neurons in the SNc against 6-OHDA neurotoxicity, as shown by a 74.8% increase in tyrosine hydroxylase (TH)-positive neurons compared to the vehicle group. Intranasal insulin treatment did not affect body weight and blood glucose levels. In conclusion, our study showed that intranasal insulin provided strong

  18. Enhanced Absorption of Nasulin™, an Ultrarapid-Acting Intranasal Insulin Formulation, Using Single Nostril Administration in Normal Subjects

    PubMed Central

    Stote, Robert; Miller, Michael; Marbury, Thomas; Shi, Leon; Strange, Poul

    2011-01-01

    Background This pharmacokinetic (PK) study was designed to investigate the maximum intranasal insulin dose that could be achieved by repeated doses in a single nostril of a nasal spray of recombinant regular human insulin 1% in combination with cyclopentadecalactone (CPE-215) 2%, a compound that enhances absorption of molecules across mucous membranes (Nasulin™, CPEX Pharmaceuticals, Inc.). Method A nine-period crossover study of 8 healthy, nonsmoking subjects (ages 18–50, body mass index <33 kg/m2, weight >70 kg) were studied. In a fasted state, subjects were randomly given 25, 50, and 75 U in a single nostril on the first day and randomly given 50, 75, and 100 U doses utilizing both nostrils on two subsequent days. After a 45-minute PK assessment, subjects were given a meal. To determine the mechanism of enhanced absorption in a single nostril, a second study utilizing 24 subjects under similar conditions received 25 U, placebo (P) that included CPE-215 plus 25 U, and 50 U in a single nostril. Results Single nostril administration revealed enhanced absorption with maximum concentrations (Cmax) of 13, 65, and 96 µU/ml for the 25, 50, and 75 U doses, respectively. Dual nostril administration in two cohorts resulted in Cmax of 31/42, 65/52, and 88/79 µU/ml for the 50, 75, and 100 U, respectively. In the second cohort, Cmax was 23, 19, 56 µU/ml for the 25, P + 25, and 50 U doses, respectively. Conclusions Repeated dosing in a single nostril resulted in enhanced absorption; this was not due to the increased CPE-215 but to the increased insulin administered. PMID:21303633

  19. Intranasal Glucagon

    PubMed Central

    2014-01-01

    Prevention of diabetic complications is mainly obtained through optimal control of blood glucose levels. With hypoglycemic drugs like beta-cell stimulating drugs and especially insulin, the limit to treatment is represented by hypoglycemia, a life-threatening occurrence that is dangerous itself and can induce fear of other episodes. Glucagon, injected subcutaneously (SC) or intramuscularly (IM), is the treatment of choice for severe hypoglycemia outside of the hospital setting. However, due to practical aspects such as preparation of solutions for administration and injection by untrained persons, there are obstacles to its routine use. This review focuses on the current status of alternative routes of administration of peptide hormones, and in particular the intranasal (IN) route of glucagon, as a promising approach for the treatment of severe hypoglycemia. PMID:25385946

  20. The window of opportunity for treatment of focal cerebral ischemic damage with noninvasive intranasal insulin-like growth factor-I in rats.

    PubMed

    Liu, Xin-Feng; Fawcett, John R; Hanson, Leah R; Frey, William H

    2004-01-01

    Intracerebroventricular injection of insulin-like growth factor (IGF)-I has been shown to protect against stroke in rats. This method of delivery is not practical in human beings, as it requires an operation with risk of infection and other complications. Intranasal (i.n.) delivery offers a noninvasive method of bypassing the blood-brain barrier to deliver IGF-I to the brain. This study delineates the window of opportunity for treatment of focal cerebral ischemic damage using i.n. IGF-I after middle cerebral artery occlusion (MCAO). Rats were allowed to survive 7 days after 2 hours of MCAO. Infarct volume, apoptosis after 7 days, and neurologic deficit scores from the postural reflex and adhesive tape tests assessing motor-sensory and somatosensory functions, respectively, at 1 to 7 days were used to evaluate the efficacy of i.n. IGF-I (150 microg) administered at different times after MCAO. I.n. IGF-I significantly reduced infarct volume by 54%; and 39%; versus control when administered at 2 or 4 hours, respectively, after the onset of MCAO (P < .05) and improved motor-sensory and somatosensory functions (P < .05) when administered 2 hours after the onset of MCAO. In addition, treatment with i.n. IGF-I at 2, 4, or 6 hours after MCAO decreased apoptotic cell counts by more than 90%; in the hemisphere ipsilateral to the occlusion. I.n. IGF-I is a promising treatment for stroke with a therapeutic window of opportunity for up to 6 hours after the onset of ischemia. This noninvasive method provides a simpler, safer, and potentially more cost-effective method of delivery than other methods currently in use.

  1. Insulin

    MedlinePlus

    ... pump is connected to your body by a flexible tube that has a tip that sticks under your skin. A cartridge of insulin is put in the pump. The insulin flows through the tube into your body. The pump controls how much insulin goes into your body. The ...

  2. Comparison Pharmacokinetics of Two Concentrations (0.7% and 1.0%) of Nasulin™, an Ultra-Rapid-Acting Intranasal Insulin Formulation

    PubMed Central

    Stote, Robert; Marbury, Thomas; Shi, Leon; Miller, Michael; Strange, Poul

    2010-01-01

    Background This pharmacokinetic (PK) study was designed to characterize the dose response of two concentrations (0.7% and 1%) of a nasal spray of recombinant regular human insulin in combination with cyclopentadecalactone (CPE-215), a compound that enhances absorption of molecules across mucous membranes (Nasulin™, CPEX Pharmaceuticals). Nasulin has been effective in lowering blood glucose in both normal subjects and diabetes patients, and additional dosing options would allow greater titration flexibility. Method A five-period crossover study of 24 healthy, nonsmoking subjects (ages 18-50, basal metabolic index <33 kg/m2, weight >70 kg) were studied. Subjects were in a fasted state for 5 h before and 45 min after administration for PK assessment and were then given a meal. Each spray contained 100 μl. Doses tested were 25, 35, 50, 70, and 100 U. Maximum concentration (Cmax) and area under the curve (AUC) were estimated for each dose group. Glucose measurements were also performed. Results A dose response (slope of the natural log response versus dose) was demonstrated by baseline-adjusted Cmax of 22, 27, 56, 62, and 84 μU/ml for the 25, 35, 50, 70, and 100 U doses (p < .0001), respectively, and by baseline-adjusted AUC(0–45 min) values of 491, 592, 1231, 1310, and 1894 μU/ml/min (p < .0001). Glucose AUC(0–45 min) determinations also demonstrated a pharmacodynamic (PD) dose response. Conclusions Proportional and linear dose responses for both PK and PD parameters were demonstrated for the two concentrations, making multiple doses available for clinical development. PMID:20513326

  3. Awake right hemisphere brain surgery.

    PubMed

    Hulou, M Maher; Cote, David J; Olubiyi, Olutayo I; Smith, Timothy R; Chiocca, E Antonio; Johnson, Mark D

    2015-12-01

    We report the indications and outcomes of awake right hemispheric brain surgery, as well as a rare patient with crossed aphasia. Awake craniotomies are often performed to protect eloquent cortex. We reviewed the medical records for 35 of 96 patients, in detail, who had awake right hemisphere brain operations. Intraoperative cortical mapping of motor and/or language function was performed in 29 of the 35 patients. A preoperative speech impairment and left hand dominance were the main indicators for awake right-sided craniotomies in patients with right hemisphere lesions. Four patients with lesion proximity to eloquent areas underwent awake craniotomies without cortical mapping. In addition, one patient had a broncho-pulmonary fistula, and another had a recent major cardiac procedure that precluded awake surgery. An eloquent cortex representation was identified in 14 patients (48.3%). Postoperatively, seven of 17 patients (41.1%) who presented with weakness, experienced improvements in their motor functions, 11 of 16 (68.7%) with seizures became seizure-free, and seven of nine (77.7%) with moderate to severe headaches and one of two with a visual field deficit improved significantly. There were also improvements in speech and language functions in all patients who presented with speech difficulties. A right sided awake craniotomy is an excellent option for left handed patients, or those with right sided cortical lesions that result in preoperative speech impairments. When combined with intraoperative cortical mapping, both speech and motor function can be well preserved.

  4. Insulin

    NASA Technical Reports Server (NTRS)

    2004-01-01

    The manipulation of organic materials--cells, tissues, and even living organisms--offers many exciting possibilities for the future from organic computers to improved aquaculture. Commercial researchers are using the microgravity environment to produce large near perfect protein crystals Research on insulin has yielded crystals that far surpass the quality of insulin crystals grown on the ground. Using these crystals industry partners are working to develop new and improved treatments for diabetes. Other researchers are exploring the possibility of producing antibiotics using plant cell cultures which could lead to both orbital production and the improvement of ground-based antibiotic production.

  5. Pitfalls of Intranasal Naloxone

    PubMed Central

    Zuckerman, Matthew; Weisberg, Stacy N.; Boyer, Edward W.

    2016-01-01

    We present a case of failed prehospital treatment of fentanyl induced apnea with intranasal (IN) naloxone. While IN administration of naloxone is becoming more common in both lay and pre-hospital settings, older EMS protocols utilized intravenous (IV) administration. Longer-acting, higher potency opioids, such as fentanyl, may not be as easily reversed as heroin, and studies evaluating IN administration in this population are lacking. In order to contribute to our understanding of the strengths and limitations of IN administration of naloxone, we present a case where it failed to restore ventilation. We also describe peer reviewed literature that supports the use of IV naloxone following heroin overdose and explore possible limitations of generalizing this literature to opioids other than heroin and to IN routes of administration. PMID:24830404

  6. Awake transapical aortic valve implantation.

    PubMed

    Petridis, Francesco Dimitri; Savini, Carlo; Castelli, Andrea; Di Bartolomeo, Roberto

    2012-05-01

    Transapical aortic valve implantation is being employed as a less invasive alternative to open heart surgery in high-risk patients with severe aortic stenosis. Here we report the case of an awake transapical aortic valve implantation in a patient with severe chronic obstructive pulmonary disease.

  7. Intranasal scopolamine preparation and method

    NASA Technical Reports Server (NTRS)

    Putcha, Lakshmi (Inventor); Cintron, Nitza M. (Inventor)

    1991-01-01

    A new method and preparation for intranasal delivery of scopolamine provides a safe and effective treatment for motion sickness and other conditions requiring anticholinergic therapy. The preparation can be in the form of aqueous nasal drops, mist spray, gel or oinment. Intranasal delivery of scopolamine has similar bioavailability and effect of intravenous delivery and is far superior to oral dosage. Scopolamine is prepared in a buffered saline solution at the desired dosage rate for effective anticholinergic response.

  8. Evaluation of Gastrointestinal Motility in Awake Rats: A Learning Exercise for Undergraduate Biomedical Students

    ERIC Educational Resources Information Center

    Souza, M. A. N.; Souza, M. H. L. P.; Palheta, R. C., Jr.; Cruz, P. R. M.; Medeiros, B. A.; Rola, F. H.; Magalhaes, P. J. C.; Troncon, L. E. A.; Santos, A. A.

    2009-01-01

    Current medical curricula devote scarce time for practical activities on digestive physiology, despite frequent misconceptions about dyspepsia and dysmotility phenomena. Thus, we designed a hands-on activity followed by a small-group discussion on gut motility. Male awake rats were randomly submitted to insulin, control, or hypertonic protocols.…

  9. Associations of Sleep Quality and Awake Physical Activity with Fluctuations in Nocturnal Blood Pressure in Patients with Cardiovascular Risk Factors

    PubMed Central

    Kadoya, Manabu; Koyama, Hidenori; Kurajoh, Masafumi; Naka, Mariko; Miyoshi, Akio; Kanzaki, Akinori; Kakutani, Miki; Shoji, Takuhito; Moriwaki, Yuji; Yamamoto, Tetsuya; Inaba, Masaaki; Namba, Mitsuyoshi

    2016-01-01

    Background Sleep quality and awake physical activity are important behavioral factors involved in the occurrence of cardiovascular diseases, potentially through nocturnal blood pressure (BP) changes. However, the impacts of quantitatively measured sleep quality and awake physical activity on BP fluctuation, and their relationships with several candidate causal factors for nocturnal hypertension are not well elucidated. Methods This cross-sectional study included 303 patients registered in the HSCAA study. Measurements included quantitatively determined sleep quality parameters and awake physical activity obtained by actigraph, nocturnal systolic BP (SBP) fall [100 × (1- sleep SBP/awake SBP ratio)], apnea hypopnea index, urinary sodium and cortisol secretion, plasma aldosterone concentration and renin activity, insulin resistance index, parameters of heart rate variability (HRV), and plasma brain-derived neurotrophic factor (BDNF). Results Simple regression analysis showed that time awake after sleep onset (r = -0.150), a parameter of sleep quality, and awake physical activity (r = 0.164) were significantly correlated with nocturnal SBP fall. Among those, time awake after sleep onset (β = -0.179) and awake physical activity (β = 0.190) were significantly and independently associated with nocturnal SBP fall in multiple regression analysis. In a subgroup of patients without taking anti-hypertensive medications, both time awake after sleep onset (β = -0.336) and awake physical activity (β = 0.489) were more strongly and independently associated with nocturnal SBP falls. Conclusion Sleep quality and awake physical activity were found to be significantly associated with nocturnal SBP fall, and that relationship was not necessarily confounded by candidate causal factors for nocturnal hypertension. PMID:27166822

  10. Awake operative videothoracoscopic pulmonary resections.

    PubMed

    Pompeo, Eugenio; Mineo, Tommaso C

    2008-08-01

    The authors' initial experience with awake videothoracoscopic lung resection suggests that these procedures can be easily and safely performed under sole thoracic epidural anesthesia with no mortality and negligible morbidity. One major concern was that operating on a ventilating lung would render surgical maneuvers more difficult because of the lung movements and lack of a sufficient operating space. Instead, the open pneumothorax created after trocar insertion produces a satisfactory lung collapse that does not hamper surgical maneuvers. These results contradict the accepted assumption that the main prerequisite for allowing successful thoracoscopic lung surgery is general anesthesia with one-lung ventilation. No particular training is necessary to accomplish an awake pulmonary resection for teams experienced in thoracoscopic surgery, and conversions to general anesthesia are mainly caused by the presence of extensive fibrous pleural adhesions or the development of intractable panic attacks. Overall, awake pulmonary resection is easily accepted and well tolerated by patients, as confirmed by the high anesthesia satisfaction score, which was better than in nonawake control patients. Nonetheless, thoracic epidural anesthesia has potential complications, including epidural hematoma, spinal cord injury, and phrenic nerve palsy caused by inadvertently high anesthetic level, but these never occurred in the authors' experience. Further concerns relate to patient participation in operating room conversations or risk for development of perioperative panic attacks. However, the authors have found that reassuring the patient during the procedure, explaining step-by-step what is being performed, and even showing the ongoing procedure on the operating video can greatly improve the perioperative wellness and expectations of patients, particularly if the procedure is performed for oncologic diseases. Panic attacks occurred in few patients and could be usually managed through

  11. Intranasal sedatives in pediatric dentistry

    PubMed Central

    AlSarheed, Maha A.

    2016-01-01

    Objectives: To identify the intranasal (IN) sedatives used to achieve conscious sedation during dental procedures amongst children. Methods: A literature review was conducted by identifying relevant studies through searches on Medline. Search included IN of midazolam, ketamine, sufentanil, dexmedetomidine, clonidine, haloperidol and loranzepam. Studies included were conducted amongst individuals below 18 years, published in English, and were not restricted by year. Exclusion criteria were articles that did not focus on pediatric dentistry. Results: Twenty studies were included. The most commonly used sedatives were midazolam, followed by ketamine and sufentanil. Onset of action for IN midazolam was 5-15 minutes (min), however, IN ketamine was faster (mean 5.74 min), while both IN sufentanil (mean 20 min) and IN dexmedetomidine (mean 25 min) were slow in comparison. Midazolam was effective for modifying behavior in mild to moderately anxious children, however, for more invasive or prolonged procedures, stronger sedatives, such as IN ketamine, IN sufentanil were recommended. In addition, ketamine fared better in overall success rate (89%) when compared with IN midazolam (69%). Intranasal dexmedetomidine was only used as pre-medication amongst children. While its’ onset of action is longer when compared with IN midazolam, it produced deeper sedation at the time of separation from the parent and at the time of anesthesia induction. Conclusion: Intranasal midazolam, ketamine and sufentanil are effective and safe for conscious sedation, while intranasal midazolam, dexmedetomidine and sufentanil have proven to be effective premedications. PMID:27570849

  12. [Intranasal opioids for acute pain].

    PubMed

    Añez Simón, C; Rull Bartomeu, M; Rodríguez Pérez, A; Fuentes Baena, A

    2006-12-01

    Intranasal drug administration is an easy, well-tolerated, noninvasive transmucosal route that avoids first-pass metabolism in the liver. The nasal mucosa provides an extensive, highly vascularized surface of pseudostratified ciliated epithelium. It secretes mucus that is subjected to mucociliary movement that can affect the time of contact between the drug and the surface. Absorption is influenced by anatomical and physiological factors as well as by properties of the drug and the delivery system. We review the literature on intranasal administration of fentanyl, meperidine, diamorphine, and butorphanol to treat acute pain. The adverse systemic effects are similar to those described for intravenous administration, the most common being drowsiness, nausea, and vomiting. Local effects reported are a burning sensation with meperidine and a bad taste. PMID:17302079

  13. 21 CFR 874.4780 - Intranasal splint.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Intranasal splint. 874.4780 Section 874.4780 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Surgical Devices § 874.4780 Intranasal splint. (a)...

  14. 21 CFR 874.4780 - Intranasal splint.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Intranasal splint. 874.4780 Section 874.4780 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Surgical Devices § 874.4780 Intranasal splint. (a)...

  15. 21 CFR 874.4780 - Intranasal splint.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Intranasal splint. 874.4780 Section 874.4780 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Surgical Devices § 874.4780 Intranasal splint. (a)...

  16. Study of intranasal ostium external dacryocystorhinostomy.

    PubMed

    Linberg, J V; Anderson, R L; Bumsted, R M; Barreras, R

    1982-11-01

    A rigid endoscope was used to directly examine, measure, and photograph the intranasal ostium created by an external dacryocystorhinostomy (DCR). This technique was used to examine 19 patients who underwent 22 standard external DCRs. All patients had clinically successful results, documented by a positive Jone I dye test following surgery. The dimension of the bony opening created at surgery was measured and averaged 11.84 mm in diameter. The average diameter of the healed intranasal ostium was only 1.80 mm. No statistically valid correlation between the size of the bony opening and the final size of the healed intranasal ostium could be established. Thus, a large surgical anastomosis did not necessarily result in a large healed intranasal ostium. Excellent functional results were obtained even when the intranasal ostium was quite small. Other indications for the use of this technique are discussed.

  17. Evaluation of Language Function under Awake Craniotomy

    PubMed Central

    KANNO, Aya; MIKUNI, Nobuhiro

    2015-01-01

    Awake craniotomy is the only established way to assess patients’ language functions intraoperatively and to contribute to their preservation, if necessary. Recent guidelines have enabled the approach to be used widely, effectively, and safely. Non-invasive brain functional imaging techniques, including functional magnetic resonance imaging and diffusion tensor imaging, have been used preoperatively to identify brain functional regions corresponding to language, and their accuracy has increased year by year. In addition, the use of neuronavigation that incorporates this preoperative information has made it possible to identify the positional relationships between the lesion and functional regions involved in language, conduct functional brain mapping in the awake state with electrical stimulation, and intraoperatively assess nerve function in real time when resecting the lesion. This article outlines the history of awake craniotomy, the current state of pre- and intraoperative evaluation of language function, and the clinical usefulness of such functional evaluation. When evaluating patients’ language functions during awake craniotomy, given the various intraoperative stresses involved, it is necessary to carefully select the tasks to be undertaken, quickly perform all examinations, and promptly evaluate the results. As language functions involve both input and output, they are strongly affected by patients’ preoperative cognitive function, degree of intraoperative wakefulness and fatigue, the ability to produce verbal articulations and utterances, as well as perform synergic movement. Therefore, it is essential to appropriately assess the reproducibility of language function evaluation using awake craniotomy techniques. PMID:25925758

  18. Awake Craniotomy: A New Airway Approach.

    PubMed

    Sivasankar, Chitra; Schlichter, Rolf A; Baranov, Dimitry; Kofke, W Andrew

    2016-02-01

    Awake craniotomies have been performed regularly at the University of Pennsylvania since 2004. Varying approaches to airway management are described for this procedure, including intubation with an endotracheal tube and use of a laryngeal mask airway, simple facemask, or nasal cannula. In this case series, we describe the successful use (i.e., no need for endotracheal intubation related to inadequate gas exchange) of bilateral nasopharyngeal airways in 90 patients undergoing awake craniotomies. The use of nasopharyngeal airways can ease the transition between the asleep and awake phases of the craniotomy without the need to stimulate the airway. Our purpose was to describe our experience and report adverse events related to this technique. PMID:26579845

  19. Intranasal IGF-1 Reduced Rat Pup Germinal Matrix Hemorrhage.

    PubMed

    Lekic, Tim; Flores, Jerry; Klebe, Damon; Doycheva, Desislava; Rolland, William B; Tang, Jiping; Zhang, John H

    2016-01-01

    Germinal matrix hemorrhage (GMH) is the most devastating neurological problem of premature infants. Current treatment strategies are ineffective and brain injury is unpreventable. Insulin-like growth factor 1 (IGF-1) is an endogenous protein shown to have multiple neuroprotective properties. We therefore hypothesized that IGF-1 would reduce brain injury after GMH. Neonatal rats (P7 age) received stereotactic collagenase into the right ganglionic eminence. The following groups were studied: (1) sham, (2) GMH + vehicle, (3) GMH + intranasal IGF-1. Three days later, the animals were evaluated using the righting-reflex (early neurobehavior), Evans blue dye leakage (blood-brain barrier (BBB) permeability), brain water content (edema), and hemoglobin assay (extent of bleeding). Three weeks later, juvenile rats were tested using a water maze (delayed neurobehavior), and then were sacrificed on day 28 for assessment of hydrocephalus (ventricular size). Intranasal IGF-1 treated animals had improved neurological function, and amelioration of BBB permeability, edema, and re-bleeding. IGF-1 may play a part in protective brain signaling following GMH, and our observed protective effect may offer new promise for treatment targeting this vulnerable patient population. PMID:26463950

  20. Intranasal glucagon: a promising approach for treatment of severe hypoglycemia.

    PubMed

    Pontiroli, Antonio E

    2015-01-01

    Prevention of diabetic complications is mainly obtained through optimal control of blood glucose levels. With hypoglycemic drugs like beta-cell stimulating drugs and especially insulin, the limit to treatment is represented by hypoglycemia, a life-threatening occurrence that is dangerous itself and can induce fear of other episodes. Glucagon, injected subcutaneously (SC) or intramuscularly (IM), is the treatment of choice for severe hypoglycemia outside of the hospital setting. However, due to practical aspects such as preparation of solutions for administration and injection by untrained persons, there are obstacles to its routine use. This review focuses on the current status of alternative routes of administration of peptide hormones, and in particular the intranasal (IN) route of glucagon, as a promising approach for the treatment of severe hypoglycemia. PMID:25385946

  1. Live attenuated intranasal influenza vaccine.

    PubMed

    Esposito, Susanna; Montinaro, Valentina; Groppali, Elena; Tenconi, Rossana; Semino, Margherita; Principi, Nicola

    2012-01-01

    Annual vaccination is the most effective means of preventing and controlling influenza epidemics, and the traditional trivalent inactivated vaccine (TIV) is by far the most widely used. Unfortunately, it has a number of limitations, the most important of which is its poor immunogenicity in younger children and the elderly, the populations at greatest risk of severe influenza. Live attenuated influenza vaccine (LAIV) has characteristics that can overcome some of these limitations. It does not have to be injected because it is administered intranasally. It is very effective in children and adolescents, among whom it prevents significantly more cases of influenza than the traditional TIV. However, its efficacy in adults has not been adequately documented, which is why it has not been licensed for use by adults by the European health authorities. LAIV is safe and well tolerated by children aged > 2 y and adults, but some concerns arisen regarding its safety in younger children and subjects with previous asthma or with recurrent wheezing. Further studies are needed to solve these problems and to evaluate the possible role of LAIV in the annual vaccination of the general population.

  2. Path to AWAKE: Evolution of the concept

    DOE PAGESBeta

    Caldwell, A.; Adli, E.; Amorim, L.; Apsimon, R.; Argyropoulos, T.; Assmann, R.; Bachmann, A. -M.; Batsch, F.; Bauche, J.; Berglyd Olsen, V. K.; et al

    2016-01-02

    This study describes the conceptual steps in reaching the design of the AWAKE experiment currently under construction at CERN. We start with an introduction to plasma wakefield acceleration and the motivation for using proton drivers. We then describe the self-modulation instability – a key to an early realization of the concept. This is then followed by the historical development of the experimental design, where the critical issues that arose and their solutions are described. We conclude with the design of the experiment as it is being realized at CERN and some words on the future outlook. A summary of themore » AWAKE design and construction status as presented in this conference is given in Gschwendtner et al. [1] .« less

  3. Path to AWAKE: Evolution of the concept

    NASA Astrophysics Data System (ADS)

    Caldwell, A.; Adli, E.; Amorim, L.; Apsimon, R.; Argyropoulos, T.; Assmann, R.; Bachmann, A.-M.; Batsch, F.; Bauche, J.; Berglyd Olsen, V. K.; Bernardini, M.; Bingham, R.; Biskup, B.; Bohl, T.; Bracco, C.; Burrows, P. N.; Burt, G.; Buttenschön, B.; Butterworth, A.; Cascella, M.; Chattopadhyay, S.; Chevallay, E.; Cipiccia, S.; Damerau, H.; Deacon, L.; Dirksen, P.; Doebert, S.; Dorda, U.; Elsen, E.; Farmer, J.; Fartoukh, S.; Fedosseev, V.; Feldbaumer, E.; Fiorito, R.; Fonseca, R.; Friebel, F.; Geschonke, G.; Goddard, B.; Gorn, A. A.; Grulke, O.; Gschwendtner, E.; Hansen, J.; Hessler, C.; Hillenbrand, S.; Hofle, W.; Holloway, J.; Huang, C.; Hüther, M.; Jaroszynski, D.; Jensen, L.; Jolly, S.; Joulaei, A.; Kasim, M.; Keeble, F.; Kersevan, R.; Kumar, N.; Li, Y.; Liu, S.; Lopes, N.; Lotov, K. V.; Lu, W.; Machacek, J.; Mandry, S.; Martin, I.; Martorelli, R.; Martyanov, M.; Mazzoni, S.; Meddahi, M.; Merminga, L.; Mete, O.; Minakov, V. A.; Mitchell, J.; Moody, J.; Müller, A.-S.; Najmudin, Z.; Noakes, T. C. Q.; Norreys, P.; Osterhoff, J.; Öz, E.; Pardons, A.; Pepitone, K.; Petrenko, A.; Plyushchev, G.; Pozimski, J.; Pukhov, A.; Reimann, O.; Rieger, K.; Roesler, S.; Ruhl, H.; Rusnak, T.; Salveter, F.; Savard, N.; Schmidt, J.; von der Schmitt, H.; Seryi, A.; Shaposhnikova, E.; Sheng, Z. M.; Sherwood, P.; Silva, L.; Simon, F.; Soby, L.; Sosedkin, A. P.; Spitsyn, R. I.; Tajima, T.; Tarkeshian, R.; Timko, H.; Trines, R.; Tückmantel, T.; Tuev, P. V.; Turner, M.; Velotti, F.; Verzilov, V.; Vieira, J.; Vincke, H.; Wei, Y.; Welsch, C. P.; Wing, M.; Xia, G.; Yakimenko, V.; Zhang, H.; Zimmermann, F.

    2016-09-01

    This paper describes the conceptual steps in reaching the design of the AWAKE experiment currently under construction at CERN. We start with an introduction to plasma wakefield acceleration and the motivation for using proton drivers. We then describe the self-modulation instability - a key to an early realization of the concept. This is then followed by the historical development of the experimental design, where the critical issues that arose and their solutions are described. We conclude with the design of the experiment as it is being realized at CERN and some words on the future outlook. A summary of the AWAKE design and construction status as presented in this conference is given in Gschwendtner et al. [1].

  4. Awake, Offline Processing during Associative Learning

    PubMed Central

    Nestor, Adrian; Tarr, Michael J.; Creswell, J. David

    2016-01-01

    Offline processing has been shown to strengthen memory traces and enhance learning in the absence of conscious rehearsal or awareness. Here we evaluate whether a brief, two-minute offline processing period can boost associative learning and test a memory reactivation account for these offline processing effects. After encoding paired associates, subjects either completed a distractor task for two minutes or were immediately tested for memory of the pairs in a counterbalanced, within-subjects functional magnetic resonance imaging study. Results showed that brief, awake, offline processing improves memory for associate pairs. Moreover, multi-voxel pattern analysis of the neuroimaging data suggested reactivation of encoded memory representations in dorsolateral prefrontal cortex during offline processing. These results signify the first demonstration of awake, active, offline enhancement of associative memory and suggest that such enhancement is accompanied by the offline reactivation of encoded memory representations. PMID:27119345

  5. Population Pharmacokinetics of Intranasal Scopolamine

    NASA Technical Reports Server (NTRS)

    Wu, L.; Chow, D. S. L.; Putcha, L.

    2013-01-01

    Introduction: An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS).The bioavailability and pharmacokinetics (PK) was evaluated using data collected in Phase II IND protocols. We reported earlier statistically significant gender differences in PK parameters of INSCOP at a dose level of 0.4 mg. To identify covariates that influence PK parameters of INSCOP, we examined population covariates of INSCOP PK model for 0.4 mg dose. Methods: Plasma scopolamine concentrations versus time data were collected from 20 normal healthy human subjects (11 male/9 female) after a 0.4 mg dose. Phoenix NLME was employed for PK analysis of these data using gender, body weight and age as covariates for model selection. Model selection was based on a likelihood ratio test on the difference of criteria (-2LL). Statistical significance for base model building and individual covariate analysis was set at P less than 0.05{delta(-2LL)=3.84}. Results: A one-compartment pharmacokinetic model with first-order elimination best described INSCOP concentration ]time profiles. Inclusion of gender, body weight and age as covariates individually significantly reduced -2LL by the cut-off value of 3.84(P less than 0.05) when tested against the base model. After the forward stepwise selection and backward elimination steps, gender was selected to add to the final model which had significant influence on absorption rate constant (ka) and the volume of distribution (V) of INSCOP. Conclusion: A population pharmacokinetic model for INSCOP has been identified and gender was a significant contributing covariate for the final model. The volume of distribution and Ka were significantly higher in males than in females which confirm gender-dependent pharmacokinetics of scopolamine after administration of a 0.4 mg dose.

  6. Human Cortical Excitability Increases with Time Awake

    PubMed Central

    Huber, Reto; Mäki, Hanna; Rosanova, Mario; Casarotto, Silvia; Canali, Paola; Casali, Adenauer G.; Tononi, Giulio

    2013-01-01

    Prolonged wakefulness is associated not only with obvious changes in the way we feel and perform but also with well-known clinical effects, such as increased susceptibility to seizures, to hallucinations, and relief of depressive symptoms. These clinical effects suggest that prolonged wakefulness may be associated with significant changes in the state of cortical circuits. While recent animal experiments have reported a progressive increase of cortical excitability with time awake, no conclusive evidence could be gathered in humans. In this study, we combine transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to monitor cortical excitability in healthy individuals as a function of time awake. We observed that the excitability of the human frontal cortex, measured as the immediate (0–20 ms) EEG reaction to TMS, progressively increases with time awake, from morning to evening and after one night of total sleep deprivation, and that it decreases after recovery sleep. By continuously monitoring vigilance, we also found that this modulation in cortical responsiveness is tonic and not attributable to transient fluctuations of the level of arousal. The present results provide noninvasive electrophysiological evidence that wakefulness is associated with a steady increase in the excitability of human cortical circuits that is rebalanced during sleep. PMID:22314045

  7. Influenza (Flu) vaccine (Live, Intranasal): What you need to know

    MedlinePlus

    ... is taken in its entirety from the CDC Influenza Live, Intranasal Flu Vaccine Information Statement (VIS): www.cdc.gov/vaccines/ ... flulive.html . CDC review information for Live, Intranasal Influenza VIS: Vaccine Information Statement Influenza Page last reviewed: ...

  8. 21 CFR 874.4780 - Intranasal splint.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Surgical Devices § 874.4780 Intranasal splint. (a) Identification... septum and the nasal cavity. It is placed in the nasal cavity after surgery or trauma. The...

  9. 21 CFR 874.4780 - Intranasal splint.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES EAR, NOSE, AND THROAT DEVICES Surgical Devices § 874.4780 Intranasal splint. (a) Identification... septum and the nasal cavity. It is placed in the nasal cavity after surgery or trauma. The...

  10. Awake craniotomy and multilingualism: language testing during anaesthesia for awake craniotomy in a bilingual patient.

    PubMed

    Costello, T G

    2014-08-01

    An awake craniotomy for epilepsy surgery is presented where a bilingual patient post-operatively reported temporary aphasia of his first language (Spanish). This case report discusses the potential causes for this clinical presentation and methods to prevent the occurrence of this in future patients undergoing this form of surgery.

  11. State of awakeness during visual fixation in preterm infants.

    PubMed

    Hack, M; Muszynski, S Y; Miranda, S B

    1981-07-01

    To demonstrate the presence of discriminable awake states in preterm infants, facial behaviors and visual fixation to a single patterned stimulus were recorded. Five healthy preterm infants born at a mean of 29 weeks' gestation were followed from 30 to 35 weeks' postmenstrual age. Behaviors (eye openness, movements, mouthing, and vocalizations) were recorded simultaneously with visual fixation measured by the corneal reflection technique. Test time was determined by the duration of time the infant remained awake before crying or closing eyes. The presence of both quiet awakeness and drowsiness was demonstrated. Younger infants spent more time in drowsiness, whereas older infants had more quiet awakeness. Visual pattern fixation was observed as early as 30 weeks. Fixation time increased with increasing postmenstrual age. More fixation was observed during quiet awakeness than during drowsiness.

  12. Insulin and Insulin Resistance

    PubMed Central

    2005-01-01

    As obesity and diabetes reach epidemic proportions in the developed world, the role of insulin resistance and its consequences are gaining prominence. Understanding the role of insulin in wide-ranging physiological processes and the influences on its synthesis and secretion, alongside its actions from the molecular to the whole body level, has significant implications for much chronic disease seen in Westernised populations today. This review provides an overview of insulin, its history, structure, synthesis, secretion, actions and interactions followed by a discussion of insulin resistance and its associated clinical manifestations. Specific areas of focus include the actions of insulin and manifestations of insulin resistance in specific organs and tissues, physiological, environmental and pharmacological influences on insulin action and insulin resistance as well as clinical syndromes associated with insulin resistance. Clinical and functional measures of insulin resistance are also covered. Despite our incomplete understanding of the complex biological mechanisms of insulin action and insulin resistance, we need to consider the dramatic social changes of the past century with respect to physical activity, diet, work, socialisation and sleep patterns. Rapid globalisation, urbanisation and industrialisation have spawned epidemics of obesity, diabetes and their attendant co-morbidities, as physical inactivity and dietary imbalance unmask latent predisposing genetic traits. PMID:16278749

  13. Intranasal estradiol: new formulation. Intranasal oestrogen delivery system: just a gimmick.

    PubMed

    2002-12-01

    (1) Many oral and transdermal (patch and gel) estradiol preparations are already available for controlling menopausal symptoms due to oestrogen deficiency. (2) Marketing authorization has now been granted in Europe for an intranasal delivery system, which produces a high, brief plasma estradiol peak. (3) According to two clinical trials, the symptomatic effects of 300 micrograms of estradiol daily by the intranasal route is similar to that of 50 micrograms /day transdermally (unblinded trial) and 2 mg/day orally (double-blind trial). (4) The most frequent side effects are intranasal reactions (in approximately 50% of patients), breast pain (30-40% of patients), and metrorrhagia (approximately 7% of cycles). (5) The long-term consequences of such high plasma estradiol peaks, including the risk of breast cancer, are unknown. (6) Intranasal estradiol is not reimbursed in France, unlike other oestrogen preparations for use in menopausal women. (7) In practice, oral and transdermal delivery systems, with which we have lengthy experience, are adequate for relieving menopausal symptoms. The intranasal route offers no proven advantage, and its long-term risks are unknown.

  14. Intranasal Osteopontin for Rodent Germinal Matrix Hemorrhage.

    PubMed

    Malaguit, Jay; Casel, Darlene; Dixon, Brandon; Doycheva, Desislava; Tang, Jiping; Zhang, John H; Lekic, Tim

    2016-01-01

    Germinal matrix hemorrhage (GMH) is the most common and devastating neurological problem of premature infants. Current treatment is largely ineffective and GMH has been nonpreventable. Osteopontin (OPN) is an endogenous protein that has been shown to be neuroprotective, however, it has not been tested in GMH. P7 neonatal rats were subjected to stereotactic ganglionic eminence collagenase infusion. Groups were as follows: (1) sham, (2) GMH + vehicle, (3) GMH + intranasal OPN. Seventy-two hours later, the animals were evaluated using righting reflex, blood-brain barrier (BBB) permeability by Evans blue dye leakage, brain water content, and hemoglobin assay. Intranasal OPN improved outcomes after GMH by attenuation of brain swelling, BBB function, re-bleeding, and neurological outcomes. OPN may play an important role in enhancing neuroprotective brain signaling following GMH. These observed effects may offer novel possibilities for therapy in this patient population. PMID:26463952

  15. Intranasal versus subcutaneous rubella vaccination in schoolgirls.

    PubMed

    Midulla, M; Assensio, A M; Balducci, L; Vanni, O; Msstropasqua, S

    1976-01-01

    In this study a venous blood specimen was drawn and, at the same time, rubella vaccine was given to 1906 schoolgirls mostly in the pre-pubertal age. To assess the pre-vaccination immune status and the effect of the vaccine, a second blood sample was taken 6 weeks later and tested for rubella HAI antibody simultaneously with the first one. RA 27/3 rubella vaccine administered by intranasal route to 81 girls produced a 100% seroconversion rate and the same vaccine strain, given by subcutaneous route to 460 girls, produced a 94.73% seroconversion rate. Among the 1, 365 schoolgirls who received subcutaneous Cendehill vaccine, the seroconversion rate was 86.68%. Side effects were mild and transient and occurred, as headache, most frequently among the girls who received RA 27/3 vaccine by intranasal route.

  16. Evaluation of gastrointestinal motility in awake rats: a learning exercise for undergraduate biomedical students.

    PubMed

    Souza, M A N; Souza, M H L P; Palheta, R C; Cruz, P R M; Medeiros, B A; Rola, F H; Magalhães, P J C; Troncon, L E A; Santos, A A

    2009-12-01

    Current medical curricula devote scarce time for practical activities on digestive physiology, despite frequent misconceptions about dyspepsia and dysmotility phenomena. Thus, we designed a hands-on activity followed by a small-group discussion on gut motility. Male awake rats were randomly submitted to insulin, control, or hypertonic protocols. Insulin and control rats were gavage fed with 5% glucose solution, whereas hypertonic-fed rats were gavage fed with 50% glucose solution. Insulin treatment was performed 30 min before a meal. All meals (1.5 ml) contained an equal mass of phenol red dye. After 10, 15, or 20 min of meal gavage, rats were euthanized. Each subset consisted of six to eight rats. Dye recovery in the stomach and proximal, middle, and distal small intestine was measured by spectrophotometry, a safe and reliable method that can be performed by minimally trained students. In a separate group of rats, we used the same protocols except that the test meal contained (99m)Tc as a marker. Compared with control, the hypertonic meal delayed gastric emptying and gastrointestinal transit, whereas insulinic hypoglycemia accelerated them. The session helped engage our undergraduate students in observing and analyzing gut motor behavior. In conclusion, the fractional dye retention test can be used as a teaching tool to strengthen the understanding of basic physiopathological features of gastrointestinal motility.

  17. Intranasal Neuropeptide Administration To Target the Human Brain in Health and Disease.

    PubMed

    Spetter, Maartje S; Hallschmid, Manfred

    2015-08-01

    Central nervous system control of metabolic function relies on the input of endocrine messengers from the periphery, including the pancreatic hormone insulin and the adipokine leptin. This concept primarily derives from experiments in animals where substances can be directly applied to the brain. A feasible approach to study the impact of peptidergic messengers on brain function in humans is the intranasal (IN) route of administration, which bypasses the blood-brain barrier and delivers neuropeptides to the brain compartment, but induces considerably less, if any, peripheral uptake than other administration modes. Experimental IN insulin administration has been extensively used to delineate the role of brain insulin signaling in the control of energy homeostasis, but also cognitive function in healthy humans. Clinical pilot studies have found beneficial effects of IN insulin in patients with memory deficits, suggesting that the IN delivery of this and other peptides bears some promise for new, selectively brain-targeted pharmaceutical approaches in the treatment of metabolic and cognitive disorders. More recently, experiments relying on the IN delivery of the hypothalamic hormone oxytocin, which is primarily known for its involvement in psychosocial processes, have provided evidence that oxytocin influences metabolic control in humans. The IN administration of leptin has been successfully tested in animal models but remains to be investigated in the human setting. We briefly summarize the literature on the IN administration of insulin, leptin, and oxytocin, with a particular focus on metabolic effects, and address limitations and perspectives of IN neuropeptide administration.

  18. Awake tracheal intubation using the Airtraq laryngoscope: a case series.

    PubMed

    Dimitriou, V K; Zogogiannis, I D; Liotiri, D G

    2009-08-01

    The Airtraq laryngoscope (AL) is a new single use indirect laryngoscope designed to facilitate tracheal intubation in anaesthetised patients either with normal or difficult airway anatomy. It is designed to provide a view of the glottis without alignment of the oral, pharyngeal and tracheal axes. We report four cases of successful awake tracheal intubation using the AL. The first case is a patient with severe ankylosing spondylitis and the other three cases with anticipated difficult airway. An awake intubation under sedation and topical airway anaesthesia was chosen. We consider that the AL can be used effectively to accomplish an awake intubation in patients with a suspected or known difficult airway and may be a useful alternative where other methods for awake intubation have failed or are not available.

  19. Anaesthesia for awake craniotomy: A retrospective study of 54 cases

    PubMed Central

    Sokhal, Navdeep; Rath, Girija Prasad; Chaturvedi, Arvind; Dash, Hari Hara; Bithal, Parmod Kumar; Chandra, P Sarat

    2015-01-01

    Background and Aims: The anaesthetic challenge of awake craniotomy is to maintain adequate sedation, analgesia, respiratory and haemodynamic stability in an awake patient who should be able to co-operate during intraoperative neurological assessment. The current literature, sharing the experience on awake craniotomy, in Indian context, is minimal. Hence, we carried out a retrospective study with the aim to review and analyse the anaesthetic management and perioperative complications in patients undergoing awake craniotomy, at our centre. Methods: Medical records of 54 patients who underwent awake craniotomy for intracranial lesions over a period of 10 years were reviewed, retrospectively. Data regarding anaesthetic management, intraoperative complications and post-operative course were recorded. Results: Propofol (81.5%) and dexmedetomidine (18.5%) were the main agents used for providing conscious sedation to facilitate awake craniotomy. Hypertension (16.7%) was the most commonly encountered complication during intraoperative period, followed by seizures (9.3%), desaturation (7.4%), tight brain (7.4%), and shivering (5.6%). The procedure had to be converted to general anaesthesia in one of patients owing to refractory brain bulge. The incidence of respiratory and haemodynamic complications were comparable in the both groups (P > 0.05). There was less incidence of intraoperative seizures in patients who received propofol (P = 0.03). In post-operative period, 20% of patients developed new motor deficit. Mean intensive care unit stay was 2.8 ± 1.9 day (1–14 days) and mean hospital stay was 7.0 ± 5.0 day (3–30 days). Conclusions: ‘Conscious sedation’ was the technique of choice for awake craniotomy, at our institute. Fentanyl, propofol, and dexmedetomidine were the main agents used for this purpose. Patients receiving propofol had less incidence of intraoperative seizure. Appropriate selection of patients, understanding the procedure of surgery, and judicious

  20. Awake craniotomy: A qualitative review and future challenges

    PubMed Central

    Ghazanwy, Mahmood; Chakrabarti, Rajkalyan; Tewari, Anurag; Sinha, Ashish

    2014-01-01

    Neurosurgery in awake patients incorporates newer technologies that require the anesthesiologists to update their skills and evolve their methodologies. They need effective communication skills and knowledge of selecting the right anesthetic drugs to ensure adequate analgesia, akinesia, along with patient satisfaction with the anesthetic conduct throughout the procedure. The challenge of providing adequate anesthetic care to an awake patient for intracranial surgery requires more than routine vigilance about anesthetic management. PMID:25422613

  1. Molecular Imaging of Conscious, Unrestrained Mice with AwakeSPECT

    SciTech Connect

    Baba, Justin S.; Endres, Christopher J.; Foss, Catherine A.; Nimmagadda, Sridhar; Jung, Hyeyun; Goddard, James S.; Lee, Seung Joon; McKisson, John; Smith, Mark F.; Stolin, Alexander V.; Weisenberger, Andrew G.; Pomper, Martin G.

    2013-06-01

    We have developed a SPECT imaging system, AwakeSPECT, to enable molecular brain imaging of untrained mice that are conscious, unanesthetized, and unrestrained. We accomplished this with head tracking and motion correction techniques. Methods: The capability of the system for motion-corrected imaging was demonstrated with a ^99mTc-pertechnetate phantom, ^99mTc-methylene diphosphonate bone imaging, and measurement of the binding potential of the dopamine transporter radioligand ^123I-ioflupane in mouse brain in the awake and anesthetized (isoflurane) states. Stress induced by imaging in the awake state was assessed through measurement of plasma corticosterone levels. Results: AwakeSPECT provided high-resolution bone images reminiscent of those obtained from CT. The binding potential of ^123I-ioflupane in the awake state was on the order of 50% of that obtained with the animal under anesthesia, consistent with previous studies in nonhuman primates. Levels of stress induced were on the order of those seen in other behavioral tasks and imaging studies of awake animals. Conclusion: These results demonstrate the feasibility of SPECT molecular brain imaging of mice in the conscious, unrestrained state and demonstrate the effects of isoflurane anesthesia on radiotracer uptake.

  2. Molecular Imaging of Conscious, Unrestrained Mice with AwakeSPECT

    SciTech Connect

    Baba, Justin S; Endres, Christopher; Foss, Catherine; Nimmagadda, Sridhar; Jung, Hyeyun; Goddard Jr, James Samuel; Lee, Seung Joon; McKisson, John; Smith, Mark F.; Stolin, Alexander; Weisenberger, Andrew G.; Pomper, Martin

    2013-01-01

    We have developed a SPECT imaging system, AwakeSPECT, to enable molecular brain imaging of untrained mice that are conscious, unanesthetized, and unrestrained. We accomplished this with head tracking and motion correction techniques. Methods: The capability of the system for motion-corrected imaging was demonstrated with a 99mTc-pertechnetate phantom, 99mTcmethylene diphosphonate bone imaging, and measurement of the binding potential of the dopamine transporter radioligand 123I-ioflupane in mouse brain in the awake and anesthetized (isoflurane) states. Stress induced by imaging in the awake state was assessed through measurement of plasma corticosterone levels. Results: AwakeSPECT provided high-resolution bone images reminiscent of those obtained from CT. The binding potential of 123I-ioflupane in the awake state was on the order of 50% of that obtained with the animal under anesthesia, consistent with previous studies in nonhuman primates. Levels of stress induced were on the order of those seen in other behavioral tasks and imaging studies of awake animals. Conclusion: These results demonstrate the feasibility of SPECT molecular brain imaging of mice in the conscious, unrestrained state and demonstrate the effects of isoflurane anesthesia on radiotracer uptake.

  3. Trials of intranasally administered rubella vaccine.

    PubMed

    Hillary, I B

    1971-12-01

    No evidence of vaccine virus transmission was found in two studies where Wistar RA 27/3 rubella vaccine was administered intranasally. Vaccine was immunogenic in all of 23 vaccinated children in one study, while in the other only 5 of the 11 vaccinees developed antibody. The reduced seroconversion rate in the latter study appears to have been caused by one or a combination of factors, including the vaccination technique, the presence of infective nasal conditions in vaccinees and the titre of vaccine used.

  4. [Development of intranasal lactocin (oxytocin) drops technology].

    PubMed

    Klimas, Rimantas; Baranauskas, Algirdas; Gendrolis, Antanas

    2002-01-01

    Pure oxytocin substance was obtained from posterior part of cattle pituitary gland by high pressure liquid chromatography. Biological activity of the substance--450-500 IU/mg. Chromatographically pure Oxytocin substance was used in developing two different compositions of Lactocin intranasal drops (40 IU/ml). Stability evaluation was performed for 2 year period. The technical documentation was prepared on the basis of the research results. Lactocin is active preparation helping lactation and is indicated for lactostasis treatment and its prophylaxis after delivery. PMID:12474675

  5. Intranasal drug delivery in neuropsychiatry: focus on intranasal ketamine for refractory depression.

    PubMed

    Andrade, Chittaranjan

    2015-05-01

    Intranasal drug delivery (INDD) systems offer a route to the brain that bypasses problems related to gastrointestinal absorption, first-pass metabolism, and the blood-brain barrier; onset of therapeutic action is rapid, and the inconvenience and discomfort of parenteral administration are avoided. INDD has found several applications in neuropsychiatry, such as to treat migraine, acute and chronic pain, Parkinson disease, disorders of cognition, autism, schizophrenia, social phobia, and depression. INDD has also been used to test experimental drugs, such as peptides, for neuropsychiatric indications; these drugs cannot easily be administered by other routes. This article examines the advantages and applications of INDD in neuropsychiatry; provides examples of test, experimental, and approved INDD treatments; and focuses especially on the potential of intranasal ketamine for the acute and maintenance therapy of refractory depression.

  6. Intranasal medications for the treatment of migraine and cluster headache.

    PubMed

    Rapoport, Alan M; Bigal, Marcelo E; Tepper, Stewart J; Sheftell, Fred D

    2004-01-01

    Intranasal medications for the treatment of headache have recently received increased attention. This paper reviews intranasal formulations of a variety of available medications (dihydroergotamine mesylate [dihydroergotamine mesilate], sumatriptan, zolmitriptan, butorphanol, capsaicin and lidocaine [lignocaine]) and one experimental medication (civamide, a cis-isomer of capsaicin) for the treatment of migraine and cluster headache. Although the efficacy of intranasal agents varies with the product used, intranasal delivery may be both convenient and more effective than other modes of drug delivery for a variety of reasons: (i) intranasal administration bypasses small bowel gastrointestinal tract absorption, which is often significantly delayed during the acute phase of a migraine attack; (ii) nauseated patients may prefer non-oral formulations as they decrease the chance of vomiting and are more rapidly effective; (iii) intranasal administration causes no pain or injection site reaction and is easier and more convenient to administer than injection or suppository and so may be used earlier in a migraine attack, resulting in better efficacy; (iv) intranasal medication produces the same number or fewer adverse events than injections; and (v) intranasal formulations offer a more rapid onset of action than oral medications, for some of the above reasons and, as such, may be more useful in patients with cluster headache, although this needs to be verified. However, it is important to emphasise that a preference study showed that most patients prefer oral tablets to an intranasal formulation. Also, some nasal preparations have significant adverse effects or are not well absorbed and therefore do not work consistently; others are more challenging to administer as a result of their delivery apparatus. Nevertheless, it is our opinion that nasal preparations increase therapeutic options and may result in faster response times and better efficacy than oral formulations and

  7. Implantable electrode for recording nerve signals in awake animals

    NASA Technical Reports Server (NTRS)

    Ninomiya, I.; Yonezawa, Y.; Wilson, M. F.

    1976-01-01

    An implantable electrode assembly consisting of collagen and metallic electrodes was constructed to measure simultaneously neural signals from the intact nerve and bioelectrical noises in awake animals. Mechanical artifacts, due to bodily movement, were negligibly small. The impedance of the collagen electrodes, measured in awake cats 6-7 days after implantation surgery, ranged from 39.8-11.5 k ohms at a frequency range of 20-5 kHz. Aortic nerve activity and renal nerve activity, measured in awake conditions using the collagen electrode, showed grouped activity synchronous with the cardiac cycle. Results indicate that most of the renal nerve activity was from postganglionic sympathetic fibers and was inhibited by the baroceptor reflex in the same cardiac cycle.

  8. Coding odor identity and odor value in awake rodents.

    PubMed

    Nunez-Parra, Alexia; Li, Anan; Restrepo, Diego

    2014-01-01

    In the last decade, drastic changes in the understanding of the role of the olfactory bulb and piriform cortex in odor detection have taken place through awake behaving recording in rodents. It is clear that odor responses in mitral and granule cells are strikingly different in the olfactory bulb of anesthetized versus awake animals. In addition, sniff recording has evidenced that mitral cell responses to odors during the sniff can convey information on the odor identity and sniff phase. Moreover, we review studies that show that the mitral cell conveys information on not only odor identity but also whether the odor is rewarded or not (odor value). Finally, we discuss how the substantial increase in awake behaving recording raises questions for future studies.

  9. Dual-headed SPECT for awake animal brain imaging

    SciTech Connect

    S. Lee, B. Kross, D. Weisenberger, J. McKisson, J.S. Goddard, J.S. Baba, M.S. Smith

    2012-02-01

    Motion-corrected awake animal imaging is needed for normal-state investigations of models of neurological disease and brain activity. The awake animal brain SPECT/CT system, AwakeSPECT at Johns Hopkins University has in the past used a single gamma camera for imaging. Enhancements have been made by adding a pinhole collimator to the second gamma camera at the opposite side which has been previously equipped parallel hole collimator. Geometry calibration was performed using a custom built quality control phantom containing three Co-57 point sources and applied to the tomographic reconstruction code. Hot-rod phantom scans with Tc-99m were performed to test sensitivity and resolution improvements. The reconstruction results show significant resolution and sensitivity improvements.

  10. Dual-headed SPECT for awake animal brain imaging

    SciTech Connect

    Lee, Seung Joon; Weisenberger, A G; McKisson, J; Goddard Jr, James Samuel; Baba, Justin S; Smith, M F

    2011-01-01

    Abstract- Motion-corrected awake animal imaging is needed for normal-state investigations of models of neurological disease and brain activity. The awake animal brain SPECT/CT system, AwakeSPECT at Johns Hopkins University has in the past used a single gamma camera for imaging. Enhancements have been made by adding a pinhole collimator to the second gamma camera at the opposite side which has been previously equipped parallel hole collimator. Geometry calibration was performed using a custom built quality control phantom containing three Co-57 point sources and applied to the tomographic reconstruction code. Hot-rod phantom scans with Tc-99m were performed to test sensitivity and resolution improvements. The reconstruction results show significant resolution and sensitivity improvements.

  11. Central Nervous Insulin Signaling in Sleep-Associated Memory Formation and Neuroendocrine Regulation

    PubMed Central

    Feld, Gordon B; Wilhem, Ines; Benedict, Christian; Rüdel, Benjamin; Klameth, Corinna; Born, Jan; Hallschmid, Manfred

    2016-01-01

    The neurochemical underpinnings of sleep's contribution to the establishment and maintenance of memory traces are largely unexplored. Considering that intranasal insulin administration to the CNS improves memory functions in healthy and memory-impaired humans, we tested whether brain insulin signaling and sleep interact to enhance memory consolidation in healthy participants. We investigated the effect of intranasal insulin on sleep-associated neurophysiological and neuroendocrine parameters and memory consolidation in 16 men and 16 women (aged 18–30 years), who learned a declarative word-pair task and a procedural finger sequence tapping task in the evening before intranasal insulin (160 IU) or placebo administration and 8 h of nocturnal sleep. On the subsequent evening, they learned interfering word-pairs and a new finger sequence before retrieving the original memories. Insulin increased growth hormone concentrations in the first night-half and EEG delta power during the second 90 min of non-rapid-eye-movement sleep. Insulin treatment impaired the acquisition of new contents in both the declarative and procedural memory systems on the next day, whereas retrieval of original memories was unchanged. Results indicate that sleep-associated memory consolidation is not a primary mediator of insulin's acute memory-improving effect, but that the peptide acts on mechanisms that diminish the subsequent encoding of novel information. Thus, by inhibiting processes of active forgetting during sleep, central nervous insulin might reduce the interfering influence of encoding new information. PMID:26448203

  12. Virtual help for real surgery: the case of awake surgery.

    PubMed

    Albani, Giovanni; Cipresso, Pietro; Gaggioli, Andrea; Serino, Silvia; Vigna, Cinzia; Priano, Lorenzo; Mauro, Alessandro; Franzini, Angelo; Riva, Giuseppe

    2012-01-01

    Awake surgery can be highly stressful for patients. In fact, being awake, patients could perceive that the environmental demands are taxing or exceed their adaptive abilities. We proposed the use of Virtual Reality as a functional and effective tool for a new class of clinical applications aimed at helping patients to cope with these specific stressful situations. Using coping skills that have been learnt during the virtual experience, patients can reduce their psychological stress and improve their collaboration and - in general - the outcome of the intervention.

  13. Non-Clinical Safety Evaluation of Intranasal Iota-Carrageenan

    PubMed Central

    Hebar, Alexandra; Koller, Christiane; Seifert, Jan-Marcus; Chabicovsky, Monika; Bodenteich, Angelika; Bernkop-Schnürch, Andreas; Grassauer, Andreas; Prieschl-Grassauer, Eva

    2015-01-01

    Carrageenan has been widely used as food additive for decades and therefore, an extended oral data set is available in the public domain. Less data are available for other routes of administration, especially intranasal administration. The current publication describes the non-clinical safety and toxicity of native (non-degraded) iota-carrageenan when applied intranasally or via inhalation. Intranasally applied iota-carrageenan is a topically applied, locally acting compound with no need of systemic bioavailability for the drug’s action. Animal experiments included repeated dose local tolerance and toxicity studies with intranasally applied 0.12% iota-carrageenan for 7 or 28 days in New Zealand White rabbits and nebulized 0.12% iota-carrageenan administered to F344 rats for 7 days. Permeation studies revealed no penetration of iota-carrageenan across nasal mucosa, demonstrating that iota-carrageenan does not reach the blood stream. Consistent with this, no relevant toxic or secondary pharmacological effects due to systemic exposure were observed in the rabbit or rat repeated dose toxicity studies. Data do not provide any evidence for local intolerance or toxicity, when carrageenan is applied intranasally or by inhalation. No signs for immunogenicity or immunotoxicity have been observed in the in vivo studies. This is substantiated by in vitro assays showing no stimulation of a panel of pro-inflammatory cytokines by iota-carrageenan. In conclusion, 0.12% iota-carrageenan is safe for clinical use via intranasal application. PMID:25875737

  14. Insulin Signaling And Insulin Resistance

    PubMed Central

    Beale, Elmus G.

    2013-01-01

    Insulin resistance or its sequelae may be the common etiology of maladies associated with metabolic syndrome (e.g., hypertension, type 2 diabetes, atherosclerosis, heart attack, stroke and kidney failure). It is thus important to understand those factors that affect insulin sensitivity. This review stems from the surprising discovery that interference with angiotensin signaling improves insulin sensitivity and it provides a general overview of insulin action and factors that control insulin sensitivity. PMID:23111650

  15. Closing capacity in awake and anesthetized-paralyzed man.

    PubMed

    Juno, J; Marsh, H M; Knopp, T J; Rehder, K

    1978-02-01

    Functional residual capacity (FRC), closing capacity (CC), and (FRC--CC) were determined in 61 supine patients using the 133Xe bolus test. In 28 of the 61 patients measurements were made both while the patients were awake and during anesthesia-paralysis. Both FRC and CC decreased significantly after induction of anesthesia-paralysis. The magnitude of the reduction in CC, but not of FRC, was dependent on the relationship between FRC and CC in the awake state. Patients whose FRC was larger than their CC while awake (group I) showed less decrease in CC than FRC, i.e., (FRC--CC) decreased. By contrast, those patients whose CC was larger than their FRC while awake (group II) showed a greater decrease in CC than in FRC, i.e., (FRC--CC) became less negative. The reduction in CC after induction of anesthesia-paralysis may result from an increased elastic recoil of the lung. The larger reduction in CC in group II patients may have been due to a larger increase in elastic recoil, possibly due to the development of atelactasis.

  16. Awake craniotomy using electromagnetic navigation technology without rigid pin fixation.

    PubMed

    Morsy, Ahmed A; Ng, Wai Hoe

    2015-11-01

    We report our institutional experience using an electromagnetic navigation system, without rigid head fixation, for awake craniotomy patients. The StealthStation® S7 AxiEM™ navigation system (Medtronic, Inc.) was used for this technique. Detailed preoperative clinical and neuropsychological evaluations, patient education and contrast-enhanced MRI (thickness 1.5mm) were performed for each patient. The AxiEM Mobile Emitter was typically placed in a holder, which was mounted to the operating room table, and a non-invasive patient tracker was used as the patient reference device. A monitored conscious sedation technique was used in all awake craniotomy patients, and the AxiEM Navigation Pointer was used for navigation during the procedure. This offers the same accuracy as optical navigation, but without head pin fixation or interference with intraoperative neurophysiological techniques and surgical instruments. The application of the electromagnetic neuronavigation technology without rigid head fixation during an awake craniotomy is accurate, and offers superior patient comfort. It is recommended as an effective adjunctive technique for the conduct of awake surgery.

  17. Awake craniotomy using electromagnetic navigation technology without rigid pin fixation.

    PubMed

    Morsy, Ahmed A; Ng, Wai Hoe

    2015-11-01

    We report our institutional experience using an electromagnetic navigation system, without rigid head fixation, for awake craniotomy patients. The StealthStation® S7 AxiEM™ navigation system (Medtronic, Inc.) was used for this technique. Detailed preoperative clinical and neuropsychological evaluations, patient education and contrast-enhanced MRI (thickness 1.5mm) were performed for each patient. The AxiEM Mobile Emitter was typically placed in a holder, which was mounted to the operating room table, and a non-invasive patient tracker was used as the patient reference device. A monitored conscious sedation technique was used in all awake craniotomy patients, and the AxiEM Navigation Pointer was used for navigation during the procedure. This offers the same accuracy as optical navigation, but without head pin fixation or interference with intraoperative neurophysiological techniques and surgical instruments. The application of the electromagnetic neuronavigation technology without rigid head fixation during an awake craniotomy is accurate, and offers superior patient comfort. It is recommended as an effective adjunctive technique for the conduct of awake surgery. PMID:26249245

  18. Massive insulin overdose managed by monitoring daily insulin levels.

    PubMed

    Mork, Tyler A; Killeen, Colin T; Patel, Neel K; Dohnal, James M; Karydes, Harry C; Leikin, Jerrold B

    2011-09-01

    We present a case of a significant insulin overdose that was managed by monitoring daily plasma insulin levels. A 39-year-old male with poorly controlled diabetes mellitus presented to the Emergency Department via emergency medical services after an attempted suicide by insulin overdose. In the attempted suicide, he injected 800 U of insulin lispro and 3800 U of insulin glargine subcutaneously over several parts of his abdomen. The patient was conscious upon arrival to the emergency department. His vital parameters were within normal range. The abdominal examination, in particular, was nonfocal and showed no evidence of hematomas. He was awake, alert, conversant, tearful, and without any focal deficits. An infusion of 10% dextrose was begun at 100 mL/h with hourly blood glucose (BG) checks. The patient was transferred to the intensive care unit where his BG began to decrease and fluctuate between 50 and 80 mg/dL, and the rate of 10% dextrose was increased to 200 mL/h where it was maintained for the next 48 hours. The initial plasma insulin level was found to be 3712.6 uU/mL (reference range 2.6-31.1 uU/mL). At 10 hours, this had decreased to 1582.1 uU/ml. On five occasions, supplemental dextrose was needed when the BG was <70 mg/dL. Thirty-four hours after admission, the plasma insulin level was 724.8 uU/mL. Fifty-eight hours after admission, the plasma insulin level was 321.2 uU/mL, and the 10% dextrose infusion was changed to 5% dextrose solution at 200 mL/h. The plasma insulin levels continued to fall daily to 112.7 uU/mL at 80 hours and to 30.4 uU/mL at 108 hours. He was transferred to an inpatient psychiatric facility 109 hours after initial presentation. Monitoring daily plasma insulin levels and adjusting treatment on a day-to-day basis in terms of basal glucose infusions provides fewer opportunities for episodic hypoglycemia. Furthermore, it was easier to predict daily glucose requirements and eventual medical clearance based on the plasma levels.

  19. Intranasal oxytocin effects on social cognition: a critique

    PubMed Central

    Evans, Simon L.; Monte, Olga Dal; Noble, Pamela; Averbeck, Bruno B.

    2014-01-01

    The last decade has seen a large number of published findings supporting the hypothesis that intranasally delivered oxytocin (OT) can enhance the processing of social stimuli and regulate social emotion-related behaviors such as trust, memory, fidelity, and anxiety. The use of nasal spray for administering OT in behavioral research has become a standard method, but many questions still exist regarding its action. OT is a peptide that cannot cross the blood-brain barrier, and it has yet to be shown that it does indeed reach the brain when delivered intranasally. Given the evidence, it seems highly likely that OT does affect behavior when delivered as a nasal spray. These effects may be driven by at least three possible mechanisms. First, the intranasally delivered OT may diffuse directly into the CNS where it directly engages OT receptors. Second, the intranasally delivered OT may trigger increased central release via an indirect peripheral mechanism. And third, the indirect peripheral effects may directly lead to behavioral effects via some mechanism other than increased central release. Although intranasally delivered OT likely affects behavior, there are conflicting reports as to the exact nature of those behavioral changes: some studies suggest that OT effects are not always “pro-social” and others suggest effects on social behaviors are due to a more general anxiolytic effect. In this critique, we draw from work in healthy human populations and the animal literature to review the mechanistic aspects of intranasal OT delivery, and to discuss intranasal OT effects on social cognition and behavior. We conclude that future work should control carefully for anxiolytic and gender effects, which could underlie inconsistencies in the existing literature. PMID:24239931

  20. The use of Midazolam as an Intranasal Sedative in Dentistry.

    PubMed

    Greaves, Anwen

    2016-01-01

    The administration of midazolam intranasally exploits the unique structure of the nasopharynx thus ensuring rapid delivery to the systemic circulation (The Nose - Brain Pathway). The absorption of midazolam nasally is influenced by the volume and concentration of midazolam, its physicochemical properties and the characteristics of the nasal mucosa. Delivering midazolam intranasally is non-titratable. The level of conscious sedation may be equivalent to that achieved by intravenous routes but is approached in a less controlled manner. Randomised Control trials using intranasal sedation in children have shown the technique to be safe and effective in secondary care for dental procedures at concentrations varying from 0.2 mg/kg to 0.5 mg/kg. A combined technique of intranasal midazolam (to facilitate cannulation) and intravenous midazolam is used for adults with moderate to severe learning disabilities. This has revolutionised dental treatment for this group of patients as treatment under General Anaesthesia (GA) may be avoided. Intranasal delivery of midazolam is emerging as a significant tool in our dental armamentarium for the treatment of anxious children, phobic adult patients and patients with learning disabilities.

  1. The use of Midazolam as an Intranasal Sedative in Dentistry.

    PubMed

    Greaves, Anwen

    2016-01-01

    The administration of midazolam intranasally exploits the unique structure of the nasopharynx thus ensuring rapid delivery to the systemic circulation (The Nose - Brain Pathway). The absorption of midazolam nasally is influenced by the volume and concentration of midazolam, its physicochemical properties and the characteristics of the nasal mucosa. Delivering midazolam intranasally is non-titratable. The level of conscious sedation may be equivalent to that achieved by intravenous routes but is approached in a less controlled manner. Randomised Control trials using intranasal sedation in children have shown the technique to be safe and effective in secondary care for dental procedures at concentrations varying from 0.2 mg/kg to 0.5 mg/kg. A combined technique of intranasal midazolam (to facilitate cannulation) and intravenous midazolam is used for adults with moderate to severe learning disabilities. This has revolutionised dental treatment for this group of patients as treatment under General Anaesthesia (GA) may be avoided. Intranasal delivery of midazolam is emerging as a significant tool in our dental armamentarium for the treatment of anxious children, phobic adult patients and patients with learning disabilities. PMID:27145560

  2. Pharmacokinetics of Intranasal Scopolamine Gel Formulation (Inscop)

    NASA Technical Reports Server (NTRS)

    Boyd, Jason L.; Du, Brian; Daniels, Vernie; Simmons, Rita; Buckey, Jay; Putcha, Lakshmi

    2009-01-01

    Space Motion Sickness (SMS) is commonly experienced by astronauts and often requires treatment with medications during early flight days of space missions. Orally administered scopolamine is commonly used by astronauts to prevent SMS. Bioavailability of oral (PO) SMS medications is often low and highly variable. Intranasal (IN) administration of medications achieves higher and more reliable bioavailability than from an equivalent PO dose. Methods: To test the safety and reliability of INSCOP, two clinical studies were performed, a dose escalation study and a comparison study administering INSCOP during normal ambulation and head down tilt bedrest. Efficacy was evaluated by testing INSCOP with two, different motion sickness inducing paradigms. Results: Preliminary results indicate that INSCOP demonstrates linear pharmacokinetics and a low side effect profile. In head down tilt bedrest, relative bioavailability of INSCOP was increased for females at both doses (0.2 and 0.4 mg) and for males at the higher dose (0.4 mg) but is reduced at the lower dose (0.2 mg) compared to normal ambulation. INSCOP displays gender specific differences during ABR. One of the treatment efficacy trials conducted at Dartmouth Hitchcock Medical Center demonstrated that INSCOP is efficacious at both doses (0.2 and 0.4 mg) in suppressing motion sickness symptoms as indicated by longer chair ride times with INSCOP administration than with placebo, and efficacy increases with dose. Similar results were seen using another motion sickness simulator, the motion simulator dome, at the Naval Aerospace Medical Research Laboratory, with significantly increased time in the dome in motion-susceptible subjects when using INSCOP compared to untreated controls. Conclusion: Higher bioavailability, linear pharmacokinetics, a low incidence of side effects, and a favorable efficacy profile make INSCOP a desirable formulation for prophylactic and rescue treatment of astronauts in space and military personnel on

  3. Aerosol characterization of nebulized intranasal glucocorticoid formulations.

    PubMed

    Berlinski, A; Waldrep, J C

    2001-01-01

    Inhaled glucocorticoids (GCs) are the mainstay of long-term therapy for asthma. The lack of suitable preparations in the United States has induced clinicians to use intranasal (IN) GC formulations as "nebulizer suspensions" for off-label therapy. However, no data are available regarding aerosol production and characteristics. The aim of this study was to characterize drug outputs and aerodynamic profiles of four nebulized IN GC formulations with further analysis of flunisolide (Flu), and to test the influence of different delivery system/formulation combinations. The aerodynamic profiles and drug outputs were determined by impaction and chemical analysis. The solution output was determined by the gravimetric technique. Triamcinole acetonide (TAA), fluticasone propionate (Flut), beclomethasone dipropionate (Bec), and Flu (550, 500, 840, and 250 microg, respectively) diluted to 4 mL with saline solution were tested with the Sidestream (SID) and Aero-Tech II (AT2) nebulizers. Subsequently, Flu was tested with four additional nebulizers (Pari LC + [PARI] Acorn II, Hudson T Up-draft II, and Raindrop). All the aerosols were heterodisperse and had a particle size range optimal for peripheral airway deposition (1.85 to 3.67 microm). Flu had the highest drug output in the respirable range (22.8 and 20.3 microg/min with the AT and SID, respectively). Flu was 5-11 times more efficiently nebulized than the other formulations tested. No differences were detected in the solution outputs (0.25 to 0.3 mL/min). In subsequent testing of Flu, the PARI, AT, and SID showed the best performances. The LC+ achieved the highest drug and solution output (27.4 microg/min and 0.89 mL/min, respectively). In conclusion, Flu showed the best aerosol performance characteristics. These data do not endorse the off-label utilization of nebulized IN GC, but underscores the importance of in vitro testing before selecting any formulation/nebulizer combinations for clinical use.

  4. [Novel insulins].

    PubMed

    Eriksson, Johan G; Laine, Merja K

    2016-01-01

    Novel insulins have entered the market during recent years. The ultra-long acting insulins, insulin degludek and insulin glargine, the latter having a strength of 300 U/ml, exhibit a steady and predictable action curve. Studies have indicated that significantly fewer hypoglycemiae occur when using degludek in patients with either type 1 or type 2 diabetes, whereas similar evidence about glargine (300 U/mI) has been obtained in the treatment of type 2 diabetes. The long duration of action of both insulins brings long-needed flexibility to.their dosing. PMID:27089618

  5. Enclosure for small animals during awake animal imaging

    DOEpatents

    Goddard, Jr., James S

    2013-11-26

    An enclosure or burrow restrains an awake animal during an imaging procedure. A tubular body, made from a radiolucent material that does not attenuate x-rays or gamma rays, accepts an awake animal. A proximal end of the body includes an attachment surface that corresponds to an attachment surface of an optically transparent and optically uniform window. An anti-reflective coating may be applied to an inner surface, an outer surface, or both surfaces of the window. Since the window is a separate element of the enclosure and it is not integrally formed as part of the body, it can be made with optically uniform thickness properties for improved motion tracking of markers on the animal with a camera during the imaging procedure. The motion tracking information is then used to compensate for animal movement in the image.

  6. Aberrant insulin signaling in Alzheimer's disease: current knowledge

    PubMed Central

    Bedse, Gaurav; Di Domenico, Fabio; Serviddio, Gaetano; Cassano, Tommaso

    2015-01-01

    Alzheimer's disease (AD) is the most common form of dementia affecting elderly people. AD is a multifaceted pathology characterized by accumulation of extracellular neuritic plaques, intracellular neurofibrillary tangles (NFTs) and neuronal loss mainly in the cortex and hippocampus. AD etiology appears to be linked to a multitude of mechanisms that have not been yet completely elucidated. For long time, it was considered that insulin signaling has only peripheral actions but now it is widely accepted that insulin has neuromodulatory actions in the brain. Insulin signaling is involved in numerous brain functions including cognition and memory that are impaired in AD. Recent studies suggest that AD may be linked to brain insulin resistance and patients with diabetes have an increased risk of developing AD compared to healthy individuals. Indeed insulin resistance, increased inflammation and impaired metabolism are key pathological features of both AD and diabetes. However, the precise mechanisms involved in the development of AD in patients with diabetes are not yet fully understood. In this review we will discuss the role played by aberrant brain insulin signaling in AD. In detail, we will focus on the role of insulin signaling in the deposition of neuritic plaques and intracellular NFTs. Considering that insulin mitigates beta-amyloid deposition and phosphorylation of tau, pharmacological strategies restoring brain insulin signaling, such as intranasal delivery of insulin, could have significant therapeutic potential in AD treatment. PMID:26136647

  7. Methylphenidate-induced awake bruxism: a case report.

    PubMed

    Sivri, Rukiye Çolak; Bilgiç, Ayhan

    2015-01-01

    Methylphenidate (MPH) is a stimulant that is commonly used in the treatment of attention-deficit/hyperactivity disorder in children and adults. Several reports are available regarding the relationship of MPH use and sleep bruxism. We report the case of a 9-year-old boy who presented with severe awake bruxism after his second dose of sustained release form of MPH treatment, which was confirmed on rechallenge. This is the first report of its kind showing such relationship in the literature.

  8. [A Case of Psychogenic Tremor during Awake Craniotomy].

    PubMed

    Kujirai, Kazumasa; Kamata, Kotoe; Uno, Toshihiro; Hamada, Keiko; Ozaki, Makoto

    2016-01-01

    A 31-year-old woman with a left frontal and parietal brain tumor underwent awake craniotomy. Propofol/remifentanil general anesthesia was induced. Following craniotomy, anesthetic administrations ceased. The level of consciousness was sufficient and she was not agitated. However, the patient complained of nausea 70 minutes into the awake phase. Considering the adverse effects of antiemetics and the upcoming surgical strategy, we did not give any medications. Nausea disappeared spontaneously while the operation was suspended. When surgical intervention extended to the left caudate nucleus, involuntary movement, classified as a tremor, with 5-6 Hz frequency, abruptly occurred on her left forearm. The patient showed emotional distress. Tremor appeared on her right forearm and subsequently spread to her lower extremities. Intravenous midazolam and fentanyl could not reduce her psychological stress. Since the tremor disturbed microscopic observation, general anesthesia was induced. Consequently, the tremor disappeared and did not recur. Based on the anatomical ground and the medication status, her involuntary movement was diagnosed as psychogenic tremor. Various factors can induce involuntary movements. In fact, intraoperative management of nausea and vomiting takes priority during awake craniotomy, but we should be reminded that some antiemetics potentially induce involuntary movement that could be caused by surgery around basal ganglia. PMID:27004392

  9. Presurgical Rehearsals for Patients Considering "Awake" Deep Brain Stimulation.

    PubMed

    Falconer, Ramsey A; Rogers, Sean L; Brewer, Cristie M; Piscitani, Franco; Shenai, Mahesh B

    2016-01-01

    Simulated surgical environments are rapidly gaining adoption in training students, residents, and members of specialized surgical teams. However, minimal attention has been given to the use of simulated surgical environments to educate patients on surgical processes, particularly procedures that require the active participation of the patient. "Awake" neurosurgery provides a unique situation in which patients openly participate in their operation. We describe a case report, in which a 62-year-old male was referred for "awake" deep brain stimulation implantation, in relation to medically refractory Parkinson's disease. The patient had significant concerns regarding anxiety and claustrophobia, and toleration of the "awake" procedure. Consequently, we designed a simulated OR environment and process, to recreate the physical experience of the procedure, with minimal cost or risk. This experience was crucial in determining the care plan, as after this experience, the patient opted for an "asleep" alternative. Thus, in certain settings, presurgical rehearsals may have a dramatic impact in the overall course of care. PMID:27532036

  10. Real-time dopamine measurement in awake monkeys.

    PubMed

    Schluter, Erik W; Mitz, Andrew R; Cheer, Joseph F; Averbeck, Bruno B

    2014-01-01

    Fast-scan cyclic voltammetry (FSCV) is often used to measure real-time dopamine (DA) concentrations in awake, behaving rodents. Extending this technique to work in monkeys would provide a platform for advanced behavioral studies and a primate model for preclinical research. The present study demonstrates the feasibility of DA recordings in two awake monkeys (Macaca mulatta) using a mixture of techniques adapted from rodent, primate and brain slice work. We developed a long carbon fiber electrode to operate in the larger primate brain. This electrode was lowered into the striatum each day using a recording chamber and a detachable micromanipulator system. A manipulator also moved one or more tungsten stimulating electrodes into either the nearby striatum or the ventral tegmental area/substantia nigra pars compacta (VTA/SNc). We developed an electrical stimulation controller to reduce artifacts during electrical stimulation. We also introduce a stimulation-based methodology for estimating distances between electrodes in the brain. Dopamine responses within the striatum were evoked by either stimulation of the striatum near the FSCV electrode, or stimulation within the VTA/SNc. Unexpected juice rewards also evoked dopamine responses in the ventral striatum. Thus, we demonstrate that robust dopamine responses can be recorded from awake, behaving primates with FSCV. In addition, we describe how a stimulation technique borrowed from the neuroprosthetics field can activate the distributed monkey midbrain dopamine system in a way that mimics rodent VTA stimulation. PMID:24921937

  11. Real-Time Dopamine Measurement in Awake Monkeys

    PubMed Central

    Schluter, Erik W.; Mitz, Andrew R.; Cheer, Joseph F.; Averbeck, Bruno B.

    2014-01-01

    Fast-scan cyclic voltammetry (FSCV) is often used to measure real-time dopamine (DA) concentrations in awake, behaving rodents. Extending this technique to work in monkeys would provide a platform for advanced behavioral studies and a primate model for preclinical research. The present study demonstrates the feasibility of DA recordings in two awake monkeys (Macaca mulatta) using a mixture of techniques adapted from rodent, primate and brain slice work. We developed a long carbon fiber electrode to operate in the larger primate brain. This electrode was lowered into the striatum each day using a recording chamber and a detachable micromanipulator system. A manipulator also moved one or more tungsten stimulating electrodes into either the nearby striatum or the ventral tegmental area/substantia nigra pars compacta (VTA/SNc). We developed an electrical stimulation controller to reduce artifacts during electrical stimulation. We also introduce a stimulation-based methodology for estimating distances between electrodes in the brain. Dopamine responses within the striatum were evoked by either stimulation of the striatum near the FSCV electrode, or stimulation within the VTA/SNc. Unexpected juice rewards also evoked dopamine responses in the ventral striatum. Thus, we demonstrate that robust dopamine responses can be recorded from awake, behaving primates with FSCV. In addition, we describe how a stimulation technique borrowed from the neuroprosthetics field can activate the distributed monkey midbrain dopamine system in a way that mimics rodent VTA stimulation. PMID:24921937

  12. Hour-long adaptation in the awake early visual system

    PubMed Central

    Stoelzel, Carl R.; Huff, Joseph M.; Bereshpolova, Yulia; Zhuang (庄骏), Jun; Hei (黑晓娟), Xiaojuan; Alonso, Jose-Manuel

    2015-01-01

    Sensory adaptation serves to adjust awake brains to changing environments on different time scales. However, adaptation has been studied traditionally under anesthesia and for short time periods. Here, we demonstrate in awake rabbits a novel type of sensory adaptation that persists for >1 h and acts on visual thalamocortical neurons and their synapses in the input layers of the visual cortex. Following prolonged visual stimulation (10–30 min), cells in the dorsal lateral geniculate nucleus (LGN) show a severe and prolonged reduction in spontaneous firing rate. This effect is bidirectional, and prolonged visually induced response suppression is followed by a prolonged increase in spontaneous activity. The reduction in thalamic spontaneous activity following prolonged visual activation is accompanied by increases in 1) response reliability, 2) signal detectability, and 3) the ratio of visual signal/spontaneous activity. In addition, following such prolonged activation of an LGN neuron, the monosynaptic currents generated by thalamic impulses in layer 4 of the primary visual cortex are enhanced. These results demonstrate that in awake brains, prolonged sensory stimulation can have a profound, long-lasting effect on the information conveyed by thalamocortical inputs to the visual cortex. PMID:26108950

  13. The evolution of brain surgery on awake patients.

    PubMed

    Surbeck, Werner; Hildebrandt, Gerhard; Duffau, Hugues

    2015-01-01

    In the early days of modern neurological surgery, the inconveniences and potential dangers of general anesthesia by chloroform and ether using the so-called "open-drop technique" led to the quest for alternative methods of anesthesia. Besides preventing the feared side effects, the introduction of regional anesthesia revealed another decisive advantage over general anesthesia in neurosurgery: While intraoperative direct cortical stimulation under general anesthesia could only delineate the motor area (by evocation of contralateral muscular contraction), now, the awake patients were able to report sensations elicited by this method. These properties advanced regional anesthesia to the regimen of choice for cranial surgeries in the first half of the 20th century. While technical advances and new drugs led to a progressive return to general anesthesia for neurosurgical procedures, the use of regional anesthesia for epilepsy surgery has only decreased in recent decades. Meanwhile, awake craniotomies regained popularity in oncologically motivated surgeries, especially in craniotomies for diffuse low-grade gliomas. Intraoperative mapping of brain functions using electrical stimulation in awake patients enables not only for increased tumor removal while preserving the functional status of the patients but also opens a window to cognitive neuroscience. Observations during such interventions and their correlation with both pre - and postoperative neuropsychological examinations and functional neuroimaging is progressively leading to new insights into the complex functional anatomy of the human brain. Furthermore, it broadens our knowledge on cerebral network reorganization in the presence of disease-with implications for all disciplines of clinical neuroscience.

  14. Demystifying FluMist, a new intranasal, live influenza vaccine.

    PubMed

    Mossad, Sherif B

    2003-09-01

    FluMist--a cold-adapted, live-attenuated, trivalent, intranasal influenza virus vaccine approved by the US Food and Drug Administration on June 17, 2003--has been shown to be safe and effective, but its role in the general prevention of influenza is yet to be defined. Intranasal administration is expected to be more acceptable than parenteral, particularly in children, but the potential for the shedding of live virus may pose a risk to anyone with a compromised immune system. PMID:14518575

  15. Biosimilar Insulins

    PubMed Central

    Hompesch, Marcus

    2014-01-01

    Until now most of the insulin used in developed countries has been manufactured and distributed by a small number of multinational companies. Beyond the established insulin manufacturers, a number of new players have developed insulin manufacturing capacities based on modern biotechnological methods. Because the patents for many of the approved insulin formulations have expired or are going to expire soon, these not yet established companies are increasingly interested in seeking market approval for their insulin products as biosimilar insulins (BI) in highly regulated markets like the EU and the United States. Differences in the manufacturing process (none of the insulin manufacturing procedures are 100% identical) can lead to insulins that to some extent may differ from the originator insulin. The key questions are if subtle differences in the structure of the insulins, purity, and so on are clinically relevant and may result in different biological effects. The aim of this article is to introduce and discuss basic aspects that may be of relevance with regard to BI. PMID:24876530

  16. Intranasal H5N1 vaccines, adjuvanted with chitosan derivatives, protect ferrets against highly pathogenic influenza intranasal and intratracheal challenge.

    PubMed

    Mann, Alex J; Noulin, Nicolas; Catchpole, Andrew; Stittelaar, Koert J; de Waal, Leon; Veldhuis Kroeze, Edwin J B; Hinchcliffe, Michael; Smith, Alan; Montomoli, Emanuele; Piccirella, Simona; Osterhaus, Albert D M E; Knight, Alastair; Oxford, John S; Lapini, Giulia; Cox, Rebecca; Lambkin-Williams, Rob

    2014-01-01

    We investigated the protective efficacy of two intranasal chitosan (CSN and TM-CSN) adjuvanted H5N1 Influenza vaccines against highly pathogenic avian Influenza (HPAI) intratracheal and intranasal challenge in a ferret model. Six groups of 6 ferrets were intranasally vaccinated twice, 21 days apart, with either placebo, antigen alone, CSN adjuvanted antigen, or TM-CSN adjuvanted antigen. Homologous and intra-subtypic antibody cross-reacting responses were assessed. Ferrets were inoculated intratracheally (all treatments) or intranasally (CSN adjuvanted and placebo treatments only) with clade 1 HPAI A/Vietnam/1194/2004 (H5N1) virus 28 days after the second vaccination and subsequently monitored for morbidity and mortality outcomes. Clinical signs were assessed and nasal as well as throat swabs were taken daily for virology. Samples of lung tissue, nasal turbinates, brain, and olfactory bulb were analysed for the presence of virus and examined for histolopathological findings. In contrast to animals vaccinated with antigen alone, the CSN and TM-CSN adjuvanted vaccines induced high levels of antibodies, protected ferrets from death, reduced viral replication and abrogated disease after intratracheal challenge, and in the case of CSN after intranasal challenge. In particular, the TM-CSN adjuvanted vaccine was highly effective at eliciting protective immunity from intratracheal challenge; serologically, protective titres were demonstrable after one vaccination. The 2-dose schedule with TM-CSN vaccine also induced cross-reactive antibodies to clade 2.1 and 2.2 H5N1 viruses. Furthermore ferrets immunised with TM-CSN had no detectable virus in the respiratory tract or brain, whereas there were signs of virus in the throat and lungs, albeit at significantly reduced levels, in CSN vaccinated animals. This study demonstrated for the first time that CSN and in particular TM-CSN adjuvanted intranasal vaccines have the potential to protect against significant mortality and

  17. Insulin oedema.

    PubMed Central

    Evans, D. J.; Pritchard-Jones, K.; Trotman-Dickenson, B.

    1986-01-01

    A 35 year old markedly underweight woman presented with uncontrolled diabetes. Following insulin therapy she developed gross fluid retention with extensive peripheral oedema, bilateral pleural effusions and weight gain of 18.8 kg in 22 days, accompanied by a fall in plasma albumin. She responded well to treatment with diuretics and salt-poor albumin, losing 10.3 kg in 6 days without recurrence of oedema. Severe insulin oedema is an uncommon complication of insulin therapy and may be due to effects of insulin on both vascular permeability and the renal tubule. Images Figure 2 PMID:3529068

  18. Ready-to-use colloidal adjuvant systems for intranasal immunization.

    PubMed

    Lee, Jeong-Jun; Shim, Aeri; Lee, Song Yi; Kwon, Bo-Eun; Kim, Seong Ryeol; Ko, Hyun-Jeong; Cho, Hyun-Jong

    2016-04-01

    Adjuvant systems based on oil-in-water (o/w) microemulsions (MEs) for vaccination via intranasal administration were prepared and evaluated. A ready-to-use blank ME system composed of mineral oil (oil), Labrasol (surfactant), Tween 80 (cosurfactant), and water was prepared and blended with antigen (Ag) solution prior to use. The o/w ME system developed exhibited nano-size droplets within the tested range of Ag concentrations and dilution factors. The maintenance of primary, secondary, and tertiary structural stability of ovalbumin (OVA) in ME, compared with OVA in solution, was demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), circular dichroism (CD), and fluorescence intensity measurements, respectively. The uptake efficiency in RAW 264.7 cells, evaluated by flow cytometry, of OVA in the ME group was significantly higher than that of the OVA solution group (p<0.05). In an intranasal immunization study with OVA ME in mice, elevated adjuvant effects in terms of mucosal immunization and Th1-dominant cell-mediated immune responses were identified. Given the convenience of use (simply mixing with Ag solution prior to use) and the adjuvant effects after intranasal immunization, the new o/w ME may be a practical and efficient adjuvant system for intranasal vaccination. PMID:26775242

  19. Pharmacodynamics and toxicity of vasoactive intestinal peptide for intranasal administration.

    PubMed

    Cui, Xu; Cao, De-Ying; Wang, Zhi-Min; Zheng, Ai-Ping

    2013-01-01

    The aim of this work was to study the nasal route for the delivery of vasoactive intestinal peptide (VIP) to the brain and to evaluate the toxicity of VIP nasal spray. Mice were injected intracerebroventricularly with the aggregated Abeta25-35 to mimic Alzheimer's disease. Following administration, different groups of mice were treated over one week, and their spatial learning and memory capacities were evaluated by the Morris water maze test. The toxicity of VIP nasal spray was evaluated by examining the morphology of individual rat nasal mucosa cilia and the pathology of rat nasal mucosa. Rats receiving intranasal VIP (40 microg/ml) showed good spatial memory relative to the Abeta25-35 model group, but the escape latency did not show any statistically significant difference. Intranasal administration of VIP nasal spray (200 microg/ml) improved deficits in spatial memory to the point that test animals receiving intranasal VIP showed no statistically significant differences from the normal control group in escape latency. This indicated that the nasal spray method could increase the quantity of VIP entering the brain and protect the central nervous systems of mice. Toxicity evaluation showed that the preparation could cause minor irritation, which resolved spontaneously within a week at the end of treatment. In conclusion, VIP can be delivered successfully to the brain using the intranasal route. PMID:23444784

  20. Distinct BOLD Activation Profiles Following Central and Peripheral Oxytocin Administration in Awake Rats

    PubMed Central

    Ferris, Craig F.; Yee, Jason R.; Kenkel, William M.; Dumais, Kelly Marie; Moore, Kelsey; Veenema, Alexa H.; Kulkarni, Praveen; Perkybile, Allison M.; Carter, C. Sue

    2015-01-01

    A growing body of literature has suggested that intranasal oxytocin (OT) or other systemic routes of administration can alter prosocial behavior, presumably by directly activating OT sensitive neural circuits in the brain. Yet there is no clear evidence that OT given peripherally can cross the blood–brain barrier at levels sufficient to engage the OT receptor. To address this issue we examined changes in blood oxygen level-dependent (BOLD) signal intensity in response to peripheral OT injections (0.1, 0.5, or 2.5 mg/kg) during functional magnetic resonance imaging (fMRI) in awake rats imaged at 7.0 T. These data were compared to OT (1 μg/5 μl) given directly to the brain via the lateral cerebroventricle. Using a 3D annotated MRI atlas of the rat brain segmented into 171 brain areas and computational analysis, we reconstructed the distributed integrated neural circuits identified with BOLD fMRI following central and peripheral OT. Both routes of administration caused significant changes in BOLD signal within the first 10 min of administration. As expected, central OT activated a majority of brain areas known to express a high density of OT receptors, e.g., lateral septum, subiculum, shell of the accumbens, bed nucleus of the stria terminalis. This profile of activation was not matched by peripheral OT. The change in BOLD signal to peripheral OT did not show any discernible dose–response. Interestingly, peripheral OT affected all subdivisions of the olfactory bulb, in addition to the cerebellum and several brainstem areas relevant to the autonomic nervous system, including the solitary tract nucleus. The results from this imaging study do not support a direct central action of peripheral OT on the brain. Instead, the patterns of brain activity suggest that peripheral OT may interact at the level of the olfactory bulb and through sensory afferents from the autonomic nervous system to influence brain activity. PMID:26441574

  1. Methylphenidate-induced awake bruxism: a case report.

    PubMed

    Sivri, Rukiye Çolak; Bilgiç, Ayhan

    2015-01-01

    Methylphenidate (MPH) is a stimulant that is commonly used in the treatment of attention-deficit/hyperactivity disorder in children and adults. Several reports are available regarding the relationship of MPH use and sleep bruxism. We report the case of a 9-year-old boy who presented with severe awake bruxism after his second dose of sustained release form of MPH treatment, which was confirmed on rechallenge. This is the first report of its kind showing such relationship in the literature. PMID:25768854

  2. UPPER AIRWAY BLOCKS FOR AWAKE DIFFICULT AIRWAY MANAGEMENT.

    PubMed

    Pintaric, Tatjana Stopar

    2016-03-01

    Airway anesthesia is pivotal for successful awake intubation provided either topically or by blocks. Airway blocks are considered technically more difficult to perform and carry a higher risk of complications. However, in experienced hands, they can be useful as they provide excellent intubating conditions. For complete upper airway anesthesia, bilateral glossopharyngeal and superior laryngeal nerve blocks with translaryngeal injection are required. Superior laryngeal nerve block and translaryngeal injection can be performed easily, safely and with a high success rate in patients with normal anatomy. In those with difficult landmarks, ultrasound can be of assistance. For the superior laryngeal nerve block, other targets than the nerve itself must be established to make the technique consistently successful, easy to teach, learn and perform. The same applies to the translaryngeal injection, where the use of ultrasound is necessary for correct midline identification. Intraoral glossopharyngeal nerve block is also safe and easy to perform, but associated with long lasting discomfort. Bilateral extraoral peristyloid approach should be discouraged since inadvertent blocks of the closely adjacent vagus nerve cannot be prevented in this location. A safe and easy method of blocking the distal portions of the glossopharyngeal nerve for awake intubation is therefore required. PMID:27276778

  3. Realignment strategies for awake-monkey fMRI data.

    PubMed

    Stoewer, Steffen; Goense, Jozien; Keliris, Georgios A; Bartels, Andreas; Logothetis, Nikos K; Duncan, John; Sigala, Natasha

    2011-12-01

    Functional magnetic resonance imaging (fMRI) experiments with awake nonhuman primates (NHPs) have recently seen a surge of applications. However, the standard fMRI analysis tools designed for human experiments are not optimal for NHP data collected at high fields. One major difference is the experimental setup. Although real head movement is impossible for NHPs, MRI image series often contain visible motion artifacts. Animal body movement results in image position changes and geometric distortions. Since conventional realignment methods are not appropriate to address such differences, algorithms tailored specifically for animal scanning become essential. We have implemented a series of high-field NHP specific methods in a software toolbox, fMRI Sandbox (http://kyb.tuebingen.mpg.de/~stoewer/), which allows us to use different realignment strategies. Here we demonstrate the effect of different realignment strategies on the analysis of awake-monkey fMRI data acquired at high field (7 T). We show that the advantage of using a nonstandard realignment algorithm depends on the amount of distortion in the dataset. While the benefits for less distorted datasets are minor, the improvement of statistical maps for heavily distorted datasets is significant.

  4. Intrinsic Feature Pose Measurement for Awake Animal SPECT Imaging

    SciTech Connect

    Goddard Jr, James Samuel; Baba, Justin S; Lee, Seung Joon; Weisenberger, A G; Stolin, A; McKisson, J; Smith, M F

    2009-01-01

    New developments have been made in optical motion tracking for awake animal imaging that measures 3D position and orientation (pose) for a single photon emission computed tomography (SPECT) imaging system. Ongoing SPECT imaging research has been directed towards head motion measurement for brain studies in awake, unrestrained mice. In contrast to previous results using external markers, this work extracts and tracks intrinsic features from multiple camera images and computes relative pose from the tracked features over time. Motion tracking thus far has been limited to measuring extrinsic features such as retro-reflective markers applied to the mouse s head. While this approach has been proven to be accurate, the additional animal handling required to attach the markers is undesirable. A significant improvement in the procedure is achieved by measuring the pose of the head without extrinsic markers using only the external surface appearance. This approach is currently being developed with initial results presented here. The intrinsic features measurement extracts discrete, sparse natural features from 2D images such as eyes, nose, mouth and other visible structures. Stereo correspondence between features for a camera pair is determined for calculation of 3D positions. These features are also tracked over time to provide continuity for surface model fitting. Experimental results from live images are presented.

  5. Ventilation and respiratory pattern and timing in resting awake cats.

    PubMed

    Jennings, D B; Szlyk, P C

    1985-02-01

    The purpose of this study was to characterize the variability and patterns of spontaneous respiratory behaviour in awake cats. Respiration was measured in six cats over 80 or 90 min by the plethysmographic technique. In three cats, arterial blood gases were measured. Breath frequency (f) and tidal volume (VT) varied considerably breath-to-breath, although on average, these measurements as well as average ventilation remained relatively constant. The incidence of breath ventilation (VT X 60/TTOT) and VT were distributed unimodally but the incidence of breath f had a bimodal distribution. In the low f range, average f was 22.5 breaths/min, and in the high f range, average f was 41.6 breaths/min. The latter range appeared to be associated with purring. Inspiratory duration (TI) was less than expiratory duration (TE) at low f but exceeded TE at high f. For a given breath ventilation there was a predictable f and VT. At shorter TI (higher f) mean inspiratory flow, an index of central respiratory drive, increased but VT decreased. This study indicates that "normal" control respiratory behaviour in awake cats is better described by the range and pattern of breathing than by average values.

  6. Mapping oxygen concentration in the awake mouse brain

    PubMed Central

    Lyons, Declan G; Parpaleix, Alexandre; Roche, Morgane; Charpak, Serge

    2016-01-01

    Although critical for brain function, the physiological values of cerebral oxygen concentration have remained elusive because high-resolution measurements have only been performed during anesthesia, which affects two major parameters modulating tissue oxygenation: neuronal activity and blood flow. Using measurements of capillary erythrocyte-associated transients, fluctuations of oxygen partial pressure (Po2) associated with individual erythrocytes, to infer Po2 in the nearby neuropil, we report the first non-invasive micron-scale mapping of cerebral Po2 in awake, resting mice. Interstitial Po2 has similar values in the olfactory bulb glomerular layer and the somatosensory cortex, whereas there are large capillary hematocrit and erythrocyte flux differences. Awake tissue Po2 is about half that under isoflurane anesthesia, and within the cortex, vascular and interstitial Po2 values display layer-specific differences which dramatically contrast with those recorded under anesthesia. Our findings emphasize the importance of measuring energy parameters non-invasively in physiological conditions to precisely quantify and model brain metabolism. DOI: http://dx.doi.org/10.7554/eLife.12024.001 PMID:26836304

  7. Assessment of the pharmacodynamics of intranasal, intravenous and oral scopolamine

    NASA Technical Reports Server (NTRS)

    Tietze, Karen J.

    1990-01-01

    Space motion sickness is an important issue in the space medical sciences program. One of the objectives of the ongoing clinical experimental protocol Pharmacokinetics of Intranasal Scopolamine in Normal Subjects is to evaluate the pharmacodynamics of scopolamine using salivary flow rate and pH profiles and cognitive performance tests as pharmacodynamic parameters. Normal volunteers collected saliva and performed the NTI Multiresource Performance Battery tests at designed time intervals to establish control saliva flow rates, salivary pH profiles, and the characteristics of the learning curve for the performance program under normal conditions. In the clinical part of the study, saliva samples and performance test scores are collected from healthy nonsmoking subjects after receiving a single 0.4 mg dose of either intranasal, intravenous, or oral scopolamine.

  8. Intranasal midazolam for seizure cessation in the community setting

    PubMed Central

    Zelcer, Michal; Goldman, Ran D.

    2016-01-01

    Question There are times when parents arrive to my clinic after their child has had a seizure and a second seizure takes place in the clinic. While waiting for transport to the hospital, are there ways to stop the seizures without the need to obtain intravenous access in the clinic? Answer Intravenous diazepam has been a first-line therapy to stop seizures in children for many years. Other routes of drug administration such as intramuscular, rectal, and buccal are available but have several limitations. More evidence suggests that the intranasal route to administer drugs is quick and effective in children, and the use of midazolam has been continuing to show promise in seizure cessation. With its good safety profile, intranasal midazolam can be used in the clinic and prehospital setting for seizure cessation in children. PMID:27412207

  9. Targeting glioblastoma via intranasal administration of Ff bacteriophages

    PubMed Central

    Dor-On, Eyal; Solomon, Beka

    2015-01-01

    Bacteriophages (phages) are ubiquitous viruses that control the growth and diversity of bacteria. Although they have no tropism to mammalian cells, accumulated evidence suggests that phages are not neutral to the mammalian macro-host and can promote immunomodulatory and anti-tumorigenic activities. Here we demonstrate that Ff phages that do not display any proteins or peptides could inhibit the growth of subcutaneous glioblastoma tumors in mice and that this activity is mediated in part by lipopolysaccharide molecules attached to their virion. Using the intranasal route, a non-invasive approach to deliver therapeutics directly to the CNS, we further show that phages rapidly accumulate in the brains of mice and could attenuate progression of orthotopic glioblastoma. Taken together, this study provides new insight into phages non-bacterial activities and demonstrates the feasibility of delivering Ff phages intranasally to treat brain malignancies. PMID:26074908

  10. Targeting glioblastoma via intranasal administration of Ff bacteriophages.

    PubMed

    Dor-On, Eyal; Solomon, Beka

    2015-01-01

    Bacteriophages (phages) are ubiquitous viruses that control the growth and diversity of bacteria. Although they have no tropism to mammalian cells, accumulated evidence suggests that phages are not neutral to the mammalian macro-host and can promote immunomodulatory and anti-tumorigenic activities. Here we demonstrate that Ff phages that do not display any proteins or peptides could inhibit the growth of subcutaneous glioblastoma tumors in mice and that this activity is mediated in part by lipopolysaccharide molecules attached to their virion. Using the intranasal route, a non-invasive approach to deliver therapeutics directly to the CNS, we further show that phages rapidly accumulate in the brains of mice and could attenuate progression of orthotopic glioblastoma. Taken together, this study provides new insight into phages non-bacterial activities and demonstrates the feasibility of delivering Ff phages intranasally to treat brain malignancies.

  11. Insulin Test

    MedlinePlus

    ... people with type 2 diabetes , polycystic ovarian syndrome (PCOS) , prediabetes or heart disease , or metabolic syndrome . A ... resistance), especially in obese individuals and those with PCOS . This test involves an IV-infusion of insulin, ...

  12. Gene therapy prospects--intranasal delivery of therapeutic genes.

    PubMed

    Podolska, Karolina; Stachurska, Anna; Hajdukiewicz, Karolina; Małecki, Maciej

    2012-01-01

    Gene therapy is recognized to be a novel method for the treatment of various disorders. Gene therapy strategies involve gene manipulation on broad biological processes responsible for the spreading of diseases. Cancer, monogenic diseases, vascular and infectious diseases are the main targets of gene therapy. In order to obtain valuable experimental and clinical results, sufficient gene transfer methods are required. Therapeutic genes can be administered into target tissues via gene carriers commonly defined as vectors. The retroviral, adenoviral and adeno-associated virus based vectors are most frequently used in the clinic. So far, gene preparations may be administered directly into target organs or by intravenous, intramuscular, intratumor or intranasal injections. It is common knowledge that the number of gene therapy clinical trials has rapidly increased. However, some limitations such as transfection efficiency and stable and long-term gene expression are still not resolved. Consequently, great effort is focused on the evaluation of new strategies of gene delivery. There are many expectations associated with intranasal delivery of gene preparations for the treatment of diseases. Intranasal delivery of therapeutic genes is regarded as one of the most promising forms of pulmonary gene therapy research. Gene therapy based on inhalation of gene preparations offers an alternative way for the treatment of patients suffering from such lung diseases as cystic fibrosis, alpha-1-antitrypsin defect, or cancer. Experimental and first clinical trials based on plasmid vectors or recombinant viruses have revealed that gene preparations can effectively deliver therapeutic or marker genes to the cells of the respiratory tract. The noninvasive intranasal delivery of gene preparations or conventional drugs seems to be very encouraging, although basic scientific research still has to continue.

  13. Pharmacokinetic Modeling of Intranasal Scopolamine in Plasma Saliva and Urine

    NASA Technical Reports Server (NTRS)

    Wu, L.; Tam, V.; Chow, Diana S. L.; Putcha, Lakshmi

    2014-01-01

    An intranasal gel formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness. The bioavailability and pharmacokinetics (PK) were evaluated under the Food and Drug Administration guidelines for clinical trials with an Investigative New Drug (IND). The aim of this project was to develop a PK model that can predict the relationship between plasma, saliva and urinary scopolamine concentrations using data collected from the IND clinical trial with INSCOP.

  14. Pharmaceutical Product Development: Intranasal Scopolamine (INSCOP) Metered Dose Spray

    NASA Technical Reports Server (NTRS)

    Putcha, Lakshmi; Crady, Camille; Putcha, Lakshmi

    2012-01-01

    Motion sickness (MS) has been a problem associated with space flight, the modern military and commercial air and water transportation for many years. Clinical studies have shown that scopolamine is the most effective medication for the prevention of motion sickness (Dornhoffer et al, 2004); however, the two most common methods of administration (transdermal and oral) have performance limitations that compromise its utility. Intranasal administration offers a noninvasive treatment modality, and has been shown to counter many of the problems associated with oral and transdermal administration. With the elimination of the first pass effect by the liver, intranasal delivery achieves higher and more reliable bioavailability than an equivalent oral dose. This allows for the potential of enhanced efficacy at a reduced dose, thus minimizing the occurrence of untoward side effects. An Intranasal scopolamine (INSCOP) gel formulation was prepared and tested in four ground-based clinical trials under an active Investigational New Drug (IND) application with the Food and Drug Administration (FDA). Although there were early indicators that the intranasal gel formulation was effective, there were aspects of formulation viscosity and the delivery system that were less desirable. The INSCOP gel formulation has since been reformulated into an aqueous spray dosage form packaged in a precise, metered dose delivery system; thereby enhancing dose uniformity, increased user satisfaction and palatability, and a potentially more rapid onset of action. Recent reports of new therapeutic indications for scopolamine has prompted a wide spread interest in new scopolamine dosage forms. The novel dosage form and delivery system of INSCOP spray shows promise as an effective treatment for motion sickness targeted at the armed forces, spaceflight, and commercial sea, air, and space travel markets, as well as prospective psychotherapy for mental and emotional disorders.

  15. [Intranasal meningocele presenting as a nasal polyp--case report].

    PubMed

    Kosztyła-Hojna, Bozena; Popko, Mariola

    2008-01-01

    Intranasal meningocele occurs rarely. It is difficult to diagnose because its appearance resembles common polyps. If it coexists with other inborn cranio-facial malformation they are easier to diagnose. In the case investigated by us, the 32 year-old woman's ailments suggested intranasal polyps and we discovered the meningocele localized intranasal on the right. The CT scan of the nasal sinuses is the most reliable examination for the developing diagnosis. The CT findings revealed the meningocele protruding from the anterior cranial fosse through the lamina cribrosa to the right nasal cavity. During the operation the meningocele was removed and the durra mater was sutured. The bony-mucosal lesion was covered with composite graft taken from bony part of nasal septum and mucosal part of the inferior turbinate. The graft has been incorporated into the surrounding tissue. Neither a cerebrospinal fluid leak nor any other complications have been reported within the past 6 years. Therefore, we consider this a successful procedure. PMID:18634248

  16. Preparation and evaluation of fexofenadine microemulsion for intranasal delivery.

    PubMed

    Piao, Hong-Mei; Balakrishnan, Prabagar; Cho, Hyun Jong; Kim, Hyunjun; Kim, You Sun; Chung, Suk-Jae; Shim, Chang-Koo; Kim, Dae-Duk

    2010-06-01

    To enhance the solubility and bioavailability of poorly absorbable fexofenadine, microemulsion system composed of oil, surfactant and co-surfactant was developed for intranasal delivery. Phase behavior, particle size, viscosity and solubilization capacity of the microemulsion system were characterized. Histopathology and in vivo nasal absorption of the optimized microemulsion formulations were also investigated in rats. A single isotropic region was found in the pseudo-ternary phase diagrams developed at various ratios with Lauroglycol 90 as oil, Labrasol as surfactant and Plurol oleiqueCC49 or its mixture with PEG-400 (1:1) as cosurfactant. An increase in the microemulsion region in pseudo-ternary phase systems was observed with increased surfactant concentration. The optimized microemulsion formulations showed higher solubulization of fexofenadine, i.e., F1 (22.64mg/mL) and F2 (22.98mg/mL), compared to its intrinsic water solubility (1.51mg/mL). Nasal absorption of fexofenadine from these microemulsions was found to be fairly rapid. T(max) was observed within 5min after intranasal administration at 1.0mg/kg dose, and the absolute bioavailability (0-4h) was about 68% compared to the intravenous administration in rats. Our results suggested that these microemulsion formulations could be used as an effective intranasal dosage form for the rapid-onset delivery of fexofenadine. PMID:20685383

  17. Preparation and evaluation of fexofenadine microemulsions for intranasal delivery.

    PubMed

    Piao, Hong-Mei; Balakrishnan, Prabagar; Cho, Hyun-Jong; Kim, Hyunjun; Kim, You-Sun; Chung, Suk-Jae; Shim, Chang-Koo; Kim, Dae-Duk

    2010-08-16

    To enhance the solubility and bioavailability of poorly absorbable fexofenadine, microemulsion system composed of oil, surfactant and co-surfactant was developed for intranasal delivery. Phase behavior, particle size, viscosity and solubilization capacity of the microemulsion system were characterized. Histopathology and in vivo nasal absorption of the optimized microemulsion formulations were also investigated in rats. A single isotropic region was found in the pseudo-ternary phase diagrams developed at various ratios with Lauroglycol 90 as oil, Labrasol as surfactant and Plurol Oleique CC49 or its mixture with PEG-400 (1:1) as cosurfactant. An increase in the microemulsion region in pseudo-ternary phase systems was observed with increased surfactant concentration. The optimized microemulsion formulations showed higher solubulization of fexofenadine, i.e., F1 (22.64 mg/mL) and F2 (22.98 mg/mL), compared to its intrinsic water solubility (1.51 mg/mL). Nasal absorption of fexofenadine from these microemulsions was found to be fairly rapid. Tmax was observed within 5 min after intranasal administration at 1.0 mg/kg dose, and the absolute bioavailability (0-4 h) was about 68% compared to the intravenous administration in rats. Our results suggested that these microemulsion formulations could be used as an effective intranasal dosage form for the rapid-onset delivery of fexofenadine PMID:20635476

  18. Preparation and evaluation of fexofenadine microemulsions for intranasal delivery.

    PubMed

    Piao, Hong-Mei; Balakrishnan, Prabagar; Cho, Hyun-Jong; Kim, Hyunjun; Kim, You-Sun; Chung, Suk-Jae; Shim, Chang-Koo; Kim, Dae-Duk

    2010-08-16

    To enhance the solubility and bioavailability of poorly absorbable fexofenadine, microemulsion system composed of oil, surfactant and co-surfactant was developed for intranasal delivery. Phase behavior, particle size, viscosity and solubilization capacity of the microemulsion system were characterized. Histopathology and in vivo nasal absorption of the optimized microemulsion formulations were also investigated in rats. A single isotropic region was found in the pseudo-ternary phase diagrams developed at various ratios with Lauroglycol 90 as oil, Labrasol as surfactant and Plurol Oleique CC49 or its mixture with PEG-400 (1:1) as cosurfactant. An increase in the microemulsion region in pseudo-ternary phase systems was observed with increased surfactant concentration. The optimized microemulsion formulations showed higher solubulization of fexofenadine, i.e., F1 (22.64 mg/mL) and F2 (22.98 mg/mL), compared to its intrinsic water solubility (1.51 mg/mL). Nasal absorption of fexofenadine from these microemulsions was found to be fairly rapid. Tmax was observed within 5 min after intranasal administration at 1.0 mg/kg dose, and the absolute bioavailability (0-4 h) was about 68% compared to the intravenous administration in rats. Our results suggested that these microemulsion formulations could be used as an effective intranasal dosage form for the rapid-onset delivery of fexofenadine

  19. Spike timing and synaptic dynamics at the awake thalamocortical synapse.

    PubMed

    Swadlow, Harvey A; Bezdudnaya, Tatiana; Gusev, Alexander G

    2005-01-01

    Thalamocortical (TC) neurons form only a small percentage of the synapses onto neurons of cortical layer 4, but the response properties of these cortical neurons are arguably dominated by thalamic input. This discrepancy is explained, in part, by studies showing that TC synapses are of high efficacy. However, TC synapses display activity-dependent depression. Because of this, in vitro measures of synaptic efficacy will not reflect the situation in vivo, where different neuronal populations have widely varying levels of "spontaneous" activity. Indeed, TC neurons of awake subjects generate high rates of spontaneous activity that would be expected, in a depressing synapse, to result in a chronic state of synaptic depression. Here, we review recent work in the somatosensory thalamocortical system of awake rabbits in which the relationship between TC spike timing and TC synaptic efficacy was examined during both thalamic "relay mode" (alert state) and "burst mode" (drowsy state). Two largely independent methodological approaches were used. First, we employed cross-correlation methods to examine the synaptic impact of single TC "barreloid" neurons on a single neuronal subtype in the topographically aligned layer 4 "barrel" - putative fast-spike inhibitory interneurons. We found that the initial spike of a TC burst, as well as isolated TC spikes with long preceding interspike intervals (ISIs) elicited postsynaptic action potentials far more effectively than did TC impulses with short ISIs. Our second approach took a broader view of the postsynaptic impact of TC impulses. In these experiments we examined spike-triggered extracellular field potentials and synaptic currents (using current source-density analysis) generated through the depths of a cortical barrel column by the impulses of single topographically aligned TC neurons. We found that (a) closely neighboring TC neurons may elicit very different patterns of monosynaptic activation within layers 4 and 6 of the aligned

  20. Comparison of incidence of hyponatremia between intranasal and oral desmopressin in patients with central diabetes insipidus.

    PubMed

    Kataoka, Yuko; Nishida, Sachi; Hirakawa, Akihiro; Oiso, Yutaka; Arima, Hiroshi

    2015-01-01

    Central diabetes insipidus (CDI), which is characterized by polyuria and polydipsia, is caused by a deficiency of the antidiuretic hormone arginine vasopressin (AVP). While CDI is treated with desmopressin, an analogue of AVP, the intranasal formulation is inconvenient and CDI patients reportedly prefer the oral formulation to the intranasal one. In Japan, intranasal desmopressin had been the only formulation for the treatment of CDI until 2012, when the desmopressin orally disintegrating tablet (ODT) was approved for treatment. In this study we analyzed 26 patients with CDI in whom intranasal desmopressin was switched to desmopressin ODT. The mean daily dose of intranasal desmopressin was 10 ± 8 μg/day, and that of desmopressin ODT was 142 ± 59 μg/day. The mean serum sodium levels were 140 ± 5 mmol/L and 140 ± 3 mmol/L with intranasal desmopressin and desmopressin ODT, respectively, and there were no significant differences between these values. The frequency of hyponatremia (<135 mmol/L) with intranasal desmopressin was 11.7% and that with desmopressin ODT was 7.6%, while the frequency of hyponatremia (<130 mmol/L) with intranasal desmopressin was 4.2% and that with desmopressin ODT was 1.3%. Statistical analyses revealed that incidence of hyponatremia was significantly decreased after the switch to desmopressin ODT. Thus, it is suggested that water balance is better controlled with desmopressin ODT than with intranasal desmopressin in patients with CDI.

  1. Sleep bruxism, awake bruxism and sleep quality among Brazilian dental students: a cross-sectional study.

    PubMed

    Serra-Negra, Júnia Maria; Scarpelli, Ana Carolina; Tirsa-Costa, Débora; Guimarães, Flávia Helena; Pordeus, Isabela Almeida; Paiva, Saul Martins

    2014-01-01

    The aim of the study was to evaluate the association of sleep bruxism, awake bruxism and sleep quality among dental students of the Federal University of Minas Gerais, Belo Horizonte, Brazil. A cross-sectional study was performed including 183 Brazilian dental students aged from 17 to 46 years old. The complete course curriculum consists of 9 semesters. Students enrolled in the first semester, the middle semester and the final semester of the course participated in the survey. The PSQI-BR (the Brazilian version of the Pittsburgh Sleep Questionnaire Index) was used for data collection. The PSQI-BR was distributed during lecture classes. Sleep bruxism and awake bruxism diagnosis was based on self-reported data. Descriptive analysis, Kruskal-Wallis, Mann-Whitney and Poisson regression with robust estimator were the statistical tests used. Sleep bruxism prevalence was 21.5% and awake bruxism prevalence was 36.5%. Sleep duration components were associated with sleep bruxism (PR=1.540; 95% CI: 1.00-2.37) and awake bruxism (PR=1.344; 95% CI: 1,008-1,790). There was an association between awake bruxism and habitual sleep efficiency component (PR=1.323; 95% CI: 1.03-1.70). Sleep disturbance component and awake bruxism were associated (PR=1.533; 95% CI: 1.03-2.27). Poor sleep quality was an important factor among dental students, who reported sleep bruxism as well as among those who presented awake bruxism.

  2. The electron accelerator for the AWAKE experiment at CERN

    NASA Astrophysics Data System (ADS)

    Pepitone, K.; Doebert, S.; Burt, G.; Chevallay, E.; Chritin, N.; Delory, C.; Fedosseev, V.; Hessler, Ch.; McMonagle, G.; Mete, O.; Verzilov, V.; Apsimon, R.

    2016-09-01

    The AWAKE collaboration prepares a proton driven plasma wakefield acceleration experiment using the SPS beam at CERN. A long proton bunch extracted from the SPS interacts with a high power laser and a 10 m long rubidium vapour plasma cell to create strong wakefields allowing sustained electron acceleration. The electron bunch to probe these wakefields is supplied by a 20 MeV electron accelerator. The electron accelerator consists of an RF-gun and a short booster structure. This electron source should provide beams with intensities between 0.1 and 1 nC, bunch lengths between 0.3 and 3 ps and an emittance of the order of 2 mm mrad. The wide range of parameters should cope with the uncertainties and future prospects of the planned experiments. The layout of the electron accelerator, its instrumentation and beam dynamics simulations are presented.

  3. Awake hippocampal reactivations project onto orthogonal neuronal assemblies.

    PubMed

    Malvache, Arnaud; Reichinnek, Susanne; Villette, Vincent; Haimerl, Caroline; Cossart, Rosa

    2016-09-16

    The chained activation of neuronal assemblies is thought to support major cognitive processes, including memory. In the hippocampus, this is observed during population bursts often associated with sharp-wave ripples, in the form of an ordered reactivation of neurons. However, the organization and lifetime of these assemblies remain unknown. We used calcium imaging to map patterns of synchronous neuronal activation in the CA1 region of awake mice during runs on a treadmill. The patterns were composed of the recurring activation of anatomically intermingled, but functionally orthogonal, assemblies. These assemblies reactivated discrete temporal segments of neuronal sequences observed during runs and could be stable across consecutive days. A binding of these assemblies into longer chains revealed temporally ordered replay. These modules may represent the default building blocks for encoding or retrieving experience. PMID:27634534

  4. Awake hippocampal reactivations project onto orthogonal neuronal assemblies.

    PubMed

    Malvache, Arnaud; Reichinnek, Susanne; Villette, Vincent; Haimerl, Caroline; Cossart, Rosa

    2016-09-16

    The chained activation of neuronal assemblies is thought to support major cognitive processes, including memory. In the hippocampus, this is observed during population bursts often associated with sharp-wave ripples, in the form of an ordered reactivation of neurons. However, the organization and lifetime of these assemblies remain unknown. We used calcium imaging to map patterns of synchronous neuronal activation in the CA1 region of awake mice during runs on a treadmill. The patterns were composed of the recurring activation of anatomically intermingled, but functionally orthogonal, assemblies. These assemblies reactivated discrete temporal segments of neuronal sequences observed during runs and could be stable across consecutive days. A binding of these assemblies into longer chains revealed temporally ordered replay. These modules may represent the default building blocks for encoding or retrieving experience.

  5. Default-mode-like network activation in awake rodents.

    PubMed

    Upadhyay, Jaymin; Baker, Scott J; Chandran, Prasant; Miller, Loan; Lee, Younglim; Marek, Gerard J; Sakoglu, Unal; Chin, Chih-Liang; Luo, Feng; Fox, Gerard B; Day, Mark

    2011-01-01

    During wakefulness and in absence of performing tasks or sensory processing, the default-mode network (DMN), an intrinsic central nervous system (CNS) network, is in an active state. Non-human primate and human CNS imaging studies have identified the DMN in these two species. Clinical imaging studies have shown that the pattern of activity within the DMN is often modulated in various disease states (e.g., Alzheimer's, schizophrenia or chronic pain). However, whether the DMN exists in awake rodents has not been characterized. The current data provides evidence that awake rodents also possess 'DMN-like' functional connectivity, but only subsequent to habituation to what is initially a novel magnetic resonance imaging (MRI) environment as well as physical restraint. Specifically, the habituation process spanned across four separate scanning sessions (Day 2, 4, 6 and 8). At Day 8, significant (p<0.05) functional connectivity was observed amongst structures such as the anterior cingulate (seed region), retrosplenial, parietal, and hippocampal cortices. Prior to habituation (Day 2), functional connectivity was only detected (p<0.05) amongst CNS structures known to mediate anxiety (i.e., anterior cingulate (seed region), posterior hypothalamic area, amygdala and parabracial nucleus). In relating functional connectivity between cingulate-default-mode and cingulate-anxiety structures across Days 2-8, a significant inverse relationship (r = -0.65, p = 0.0004) was observed between these two functional interactions such that increased cingulate-DMN connectivity corresponded to decreased cingulate anxiety network connectivity. This investigation demonstrates that the cingulate is an important component of both the rodent DMN-like and anxiety networks.

  6. Diabetes and Insulin

    MedlinePlus

    ... years, but may eventually need insulin to maintain glucose control. What are the different types of insulin? Different ... glulisine • Short-acting: regular human insulin Basal insulin. Controls blood glucose levels between meals and throughout the night. This ...

  7. New intranasal formulations for the treatment of allergic rhinitis.

    PubMed

    Meltzer, Eli O; Bensch, Greg W; Storms, William W

    2014-01-01

    Intranasal corticosteroids (INSs) have been effectively used for >40 years for the treatment of seasonal allergic rhinitis (SAR) and perennial AR (PAR). Following the Montreal Protocol, the initial aerosol formulations using chlorofluorocarbon (CFC) propellants were phased out. For the past 20 years, aqueous solutions have been the only available option for INS treatment. In 2012, the U.S. Food and Drug Administration approved two new nonaqueous aerosol AR treatments that use a hydrofluoroalkane (HFA) propellant. In 2012, the first intranasal aqueous combination product was also approved. This article reviews the clinical profiles of HFA beclomethasone dipropionate (BDP) and HFA ciclesonide (CIC) and the aqueous combination intranasal antihistamine (INA)/INS formulation of azelastine hydrochloride/fluticasone propionate (AZE/FP). The medical literature was searched for clinical trials investigating the use of BDP, CIC, and AZE/FP in SAR and PAR. Clinical trials involving aqueous solutions and CFC propellant or HFA propellant delivery were included. Data from prescribing information and published efficacy and safety data were presented as part of the clinical profile for the reviewed agents. AZE/FP has shown efficacy and safety comparable or greater with the current AR treatment options. Although efficacy comparisons of new HFA formulations have not been investigated in head-to-head clinical trials with aqueous formulations, HFA formulations have shown similar efficacy rates. Furthermore, HFA formulations may have some additional benefits, including a preferable sensory profile for some patients. These new formulations will provide additional options for clinicians and patients to better individualize therapy for control of AR. PMID:25582157

  8. Computed Intranasal Spray Penetration: Comparisons Before and After Nasal Surgery

    PubMed Central

    Frank, Dennis O.; Kimbell, Julia S.; Cannon, Daniel; Rhee, John S.

    2012-01-01

    Background Quantitative methods for comparing intranasal drug delivery efficiencies pre- and postoperatively have not been fully utilized. The objective of this study is to use computational fluid dynamics techniques to evaluate aqueous nasal spray penetration efficiencies before and after surgical correction of intranasal anatomic deformities. Methods Ten three-dimensional models of the nasal cavities were created from pre- and postoperative computed tomography scans in five subjects. Spray simulations were conducted using a particle size distribution ranging from 10–110μm, a spray speed of 3m/s, plume angle of 68°, and with steady state, resting inspiratory airflow present. Two different nozzle positions were compared. Statistical analysis was conducted using Student T-test for matched pairs. Results On the obstructed side, posterior particle deposition after surgery increased by 118% and was statistically significant (p-value=0.036), while anterior particle deposition decreased by 13% and was also statistically significant (p-value=0.020). The fraction of particles that by-passed the airways either pre- or post-operatively was less than 5%. Posterior particle deposition differences between obstructed and contralateral sides of the airways were 113% and 30% for pre- and post-surgery, respectively. Results showed that nozzle positions can influence spray delivery. Conclusions Simulations predicted that surgical correction of nasal anatomic deformities can improve spray penetration to areas where medications can have greater effect. Particle deposition patterns between both sides of the airways are more evenly distributed after surgery. These findings suggest that correcting anatomic deformities may improve intranasal medication delivery. For enhanced particle penetration, patients with nasal deformities may explore different nozzle positions. PMID:22927179

  9. Insulin Injection

    MedlinePlus

    ... to control blood sugar in people who have type 1 diabetes (condition in which the body does not make insulin and therefore cannot control the amount of sugar in the blood) or in people who have type 2 diabetes (condition in which the blood sugar ...

  10. Serospecific protection of mice against intranasal infection with Bordetella pertussis.

    PubMed

    Robinson, A; Gorringe, A R; Funnell, S G; Fernandez, M

    1989-08-01

    The ability of purified serospecific agglutinogens from Bordetella pertussis to protect mice against intranasal infection has been examined. Immunization with agglutinogen 2 protected mice against infection with 1.2.0 or 1.2.3 serotypes of B. pertussis, whereas immunization with agglutinogen 3 protected mice against infection with all serotypes. More importantly immunization with serospecific agglutinogen resulted in immune selection so that organisms recovered following infection did not express the immunizing antigen. The results are consistent with the suggestions that protection of children with whole cell pertussis vaccine is to some extent serospecific and that agglutinogens should be considered as constituents of acellular pertussis vaccines. PMID:2573215

  11. Intranasal Delivery of pGDNF Nanoparticles for Parkinson's Disease

    NASA Astrophysics Data System (ADS)

    Harmon, Brendan Trevor

    Parkinson's disease (PD) is a progressive neurodegenerative disorder that primarily affects the dopaminergic A9 nigrostriatal tract. For dopamine neurons specifically, glial cell-derived neurotrophic factor (GDNF) has been shown to promote their survival and proliferation both in culture and in vivo. GDNF has also proven to be neuroprotective and restorative in various animal models of PD and some human clinical trials. However, its delivery to the brain has required invasive surgical routes which are not clinically practical for many patients. The main objective of this project was to test intranasal delivery to the brain of a nanoparticle vector incorporating an expression plasmid for GDNF (pGDNF). The intranasal route circumvents the blood-brain barrier, allowing larger sized vectors into the central nervous system while avoiding peripheral distribution. This approach would provide a renewable source of GDNF within the target areas of the brain, the striatum and the substantia nigra (SN) without the need for surgical injections or frequent re-dosing. A PEGylated polylysine compacted plasmid nanoparticle vector (PEG-CK30), developed by Copernicus Therapeutics, Inc., has been shown to transfect neurons and glial cells in vivo while lacking the safety issues present with other vectors. The first goal of this work was to determine if these PEG-CK30 compacted plasmid nanoparticles can successfully transfect cells and express the reporter protein, enhanced green fluorescent protein (eGFP) in the rat brain after intranasal administration. Initial in vivo experiments utilized the expression plasmid pCG, expressing eGFP under the fast-acting cytomegalovirus (CMV) promoter. Intranasal administration of pCG nanoparticles resulted in evidence of transfection of brain cells, as shown both qualitatively, by GFP-immunohistochemistry, and quantitatively, by GFP-ELISA. Expression was detected throughout the rat brain two days post-administration. Following the proof

  12. Pediatric awake craniotomy for seizure focus resection with dexmedetomidine sedation-a case report.

    PubMed

    Sheshadri, Veena; Chandramouli, B A

    2016-08-01

    Resection of lesions near the eloquent cortex of brain necessitates awake craniotomy to reduce the risk of permanent neurologic deficits during surgery. There are limited reports of anesthetic management of awake craniotomy in pediatric patients. This report is on use of dexmedetomidine sedation for awake craniotomy in a 11-year-old child, without any airway adjuncts throughout the procedure. Dexmedetomidine infusion administered at a dosage of 0.2 to 0.7μg kg(-1) h(-1) provided adequate sedation for the entire procedure. There were no untoward incidents or any interference with electrocorticography, intraoperative stimulation, and functional mapping. Adequate preoperative visits and counseling of patient and parents regarding course and nature of events along with well-planned intraoperative management are of utmost importance in a pediatric age group for successful intraoperative awake craniotomy. PMID:27290976

  13. Pediatric awake craniotomy for seizure focus resection with dexmedetomidine sedation-a case report.

    PubMed

    Sheshadri, Veena; Chandramouli, B A

    2016-08-01

    Resection of lesions near the eloquent cortex of brain necessitates awake craniotomy to reduce the risk of permanent neurologic deficits during surgery. There are limited reports of anesthetic management of awake craniotomy in pediatric patients. This report is on use of dexmedetomidine sedation for awake craniotomy in a 11-year-old child, without any airway adjuncts throughout the procedure. Dexmedetomidine infusion administered at a dosage of 0.2 to 0.7μg kg(-1) h(-1) provided adequate sedation for the entire procedure. There were no untoward incidents or any interference with electrocorticography, intraoperative stimulation, and functional mapping. Adequate preoperative visits and counseling of patient and parents regarding course and nature of events along with well-planned intraoperative management are of utmost importance in a pediatric age group for successful intraoperative awake craniotomy.

  14. Long-term imaging in awake mice using removable cranial windows

    PubMed Central

    Glickfeld, Lindsey L.; Kerlin, Aaron M.; Reid, R. Clay; Bonin, Vincent; Schafer, Dorothy P.; Andermann, Mark L.

    2015-01-01

    Cranial window implants in head-fixed rodents are becoming a preparation of choice for stable optical access to large areas of cortex over extended periods of time. Here, we provide a highly detailed and reliable surgical protocol for a cranial window implantation procedure for chronic widefield and cellular imaging in awake, head-fixed mice, which enables subsequent window removal and replacement in the weeks and months following the initial craniotomy. This protocol has facilitated awake, chronic imaging in adolescent as well as adult mice over several months from a large number of cortical brain regions; targeted virus and tracer injections from data obtained using prior awake functional mapping; and functionally-targeted two-photon imaging across all cortical layers in awake mice using a microprism attachment to the cranial window. Collectively, these procedures extend the reach of chronic imaging of cortical function and dysfunction in behaving animals. PMID:25275789

  15. Anti-insulin antibody test

    MedlinePlus

    Insulin antibodies - serum; Insulin Ab test; Insulin resistance - insulin antibodies; Diabetes - insulin antibodies ... Normally, there are no antibodies against insulin in your blood. ... different laboratories. Some labs use different measurements or ...

  16. Chronic multiscale imaging of neuronal activity in the awake common marmoset

    PubMed Central

    Yamada, Yoshiyuki; Matsumoto, Yoshifumi; Okahara, Norio; Mikoshiba, Katsuhiko

    2016-01-01

    We report a methodology to chronically record in vivo brain activity in the awake common marmoset. Over a month, stable imaging revealed macroscopic sensory maps in the somatosensory cortex and their underlying cellular activity with a high signal-to-noise ratio in the awake but not anesthetized state. This methodology is applicable to other brain regions, and will be useful for studying cortical activity and plasticity in marmosets during learning, development, and in neurological disorders. PMID:27786241

  17. Language testing during awake "anesthesia" in a bilingual patient with brain lesion adjacent to Wernicke's area.

    PubMed

    Bilotta, Federico; Stazi, Elisabetta; Delfini, Roberto; Rosa, Giovanni

    2011-04-01

    Awake "anesthesia" is the preferable anesthetic approach for neurosurgical procedures that require intraoperative localization of eloquent brain areas. We describe intraoperative inducible selective English aphasia in a bilingual (English and Italian) patient undergoing awake anesthesia for excision of a brain lesion adjacent to Wernicke's area with no postoperative neurological sequelae. We discuss the importance of intraoperative brain mapping and intraoperative language testing in bilingual patients to prevent iatrogenic-related morbidity.

  18. The efficacy of combined regional nerve blocks in awake orotracheal fiberoptic intubation

    PubMed Central

    Chatrath, Veena; Sharan, Radhe; Jain, Payal; Bala, Anju; Ranjana; Sudha

    2016-01-01

    Aims of Study: To evaluate the efficacy, hemodynamic changes, and patient comfort during awake fiberoptic intubation done under combined regional blocks. Materials and Methods: In the present observational study, 50 patients of American Society of Anesthesiologists ( ASA) Grade I–II, Mallampati Grade I–IV were given nerve blocks - bilateral glossopharyngeal nerve block, bilateral superior laryngeal nerve block, and recurrent laryngeal nerve block before awake fiberoptic intubation using 2% lidocaine. Results: Procedure was associated with minimal increases in hemodynamic parameters during the procedure and until 3 min after it. Most of the intubations were being carried out within 3 min. Patient comfort was satisfactory with 90% of patients having favorable grades. Discussion: The most common cause of mortality and serious morbidity due to anesthesia is from airway problems. One-third of all anesthetic deaths are due to failure to intubate and ventilate. Awake flexible fiberoptic intubation under local anesthesia is now an accepted technique for managing such situations. In awake patient's anatomy, muscle tone, airway protection, and ventilation are preserved, but it is essential to sufficiently anesthetize the upper airway before the performance of awake fiberoptic bronchoscope-guided intubation to ensure patient comfort and cooperation for which in our study we used the nerve block technique. Conclusion: A properly performed technique of awake fiberoptic intubation done under combined regional nerve blocks provides good intubating conditions, patient comfort and safety and results in minimal hemodynamic changes. PMID:27212757

  19. Comparison of intranasal azelastine to intranasal fluticasone propionate for symptom control in moderate-to-severe seasonal allergic rhinitis.

    PubMed

    Carr, Warner W; Ratner, Paul; Munzel, Ullrich; Murray, Ruth; Price, David; Canonica, G Walter; Mullol, Joaquim; Virchow, J Christian; Lieberman, Phil; Meltzer, Eli; Bachert, Claus

    2012-01-01

    Intranasal corticosteroids are considered the most effective therapy for moderate-to-severe seasonal allergic rhinitis (SAR) and recommended first line in guidelines. It is uncertain whether intranasal antihistamines have comparable efficacy. This study was designed to compare the efficacy of azelastine (AZE; 137 μg/spray) and fluticasone propionate (FP; 50 μg/spray), both given as 1 spray/nostril bid (i.e., approved dosing regimen in the United States), in SAR via a post hoc analysis of data from a previously published direct-comparison study. Six hundred ten moderate-to-severe SAR patients (≥12 years old) were randomized into a double-blind, placebo-controlled, parallel-group trial. The primary efficacy variable was change from baseline in reflective total nasal symptom score (rTNSS (morning and evening), over 14 days. Reflective total ocular symptom score (rTOSS) was a key secondary variable. Reflective total of seven symptom scores (rT7SS [nasal plus ocular symptoms]) and time to ≥50% reduction from baseline in these key parameters were also analyzed. AZE and FP reduced rTNSS from baseline by a similar degree (-3.25 versus -3.84; p = 0.2014). Patients experienced comparable improvement in rTOSS (-2.62 versus -2.17; p = 0.2371) and rT7SS (-5.83 versus -6.05; p = 0.7820). FP was superior to AZE in alleviating rhinorrhea (-1.15 versus -0.87; p = 0.0433), but AZE showed comparable efficacy for all other nasal and ocular symptoms. There was no clinically or statistically significant difference between AZE (-1.17) and FP (-1.43) for reduction in the overall rhinitis quality of life questionnaire score (although FP, but not AZE, significantly differed from placebo). A similar proportion of patients in the AZE and FP groups achieved a 50% reduction in rTNSS. However, more AZE patients (53.0%) exhibited a 50% reduction in rTOSS by day 14 versus FP (39.6%), and ≤3 days faster (p = 0.028). Intranasal AZE (137 micrograms/spray) and intranasal FP (50 micrograms

  20. Intranasally Administered Adjunctive Dexmedetomidine Reduces Perioperative Anesthetic Requirements in General Anesthesia

    PubMed Central

    Wu, Xiang; Hang, Li-Hua; Wang, Hong; Shao, Dong-Hua; Xu, Yi-Guo; Cui, Wei

    2016-01-01

    Purpose Intranasal dexmedetomidine is an effective sedative for premedication and is regularly used to reduce preoperative tension and anxiety in children. This study aimed to assess the effect of intranasally adjunctive dexmedetomidine on perioperative sedative and analgesic requirements in adults. Materials and Methods Patients were randomly divided into four groups to receive preoperative administration of saline, intranasal dexmedetomidine 1 µg/kg and 2 µg/kg, and intravenous dexmedetomidine 1 µg/kg, respectively. Propofol and remifentanil were target-controlled infused to maintain intraoperative bispectral index at 45–55 and blood pressure at baseline value±20%. Sufentanil was administered to maintain postoperative visual analogue scale ≤3. Perioperative anesthetics requirements were compared using nonparametric tests. Results Intranasal dexmedetomidine significantly attenuated propofol requirements for anesthesia induction and maintenance in a dose-dependent manner. Patients given intranasal dexmedetomidine 2 µg/kg required less remifentanil for anesthesia maintenance. The first postoperative request for sufentanil analgesia was delayed in patients given intranasal dexmedetomidine 2 µg/kg. The anesthetics-sparing effect of intranasal dexmedetomidine was significantly weaker than intravenous dexmedetomidine at the same dose of 1 µg/kg. The incidences of adverse events, including hemodynamic instability and delayed recovery, were comparable with and without intranasal dexmedetomidine. Conclusion Intranasal administration of dexmedetomidine can reduce perioperative anesthetic requirements, and a dose of dexmedetomidine 2 µg/kg produces a better effect in adults. The anesthetics-sparing effect of intranasal dexmedetomidine 1 µg/kg is less than that with the same intravenous dose of dexmedetomidine. PMID:27189297

  1. Intranasal scopolamine affects the semicircular canals centrally and peripherally.

    PubMed

    Weerts, Aurélie P; Putcha, Lakshmi; Hoag, Stephen W; Hallgren, Emma; Van Ombergen, Angelique; Van de Heyning, Paul H; Wuyts, Floris L

    2015-08-01

    Space motion sickness (SMS), a condition caused by an intravestibular conflict, remains an important obstacle that astronauts encounter during the first days in space. Promethazine is currently the standard treatment of SMS, but scopolamine is used by some astronauts to prevent SMS. However, the oral and transdermal routes of administration of scopolamine are known to have substantial drawbacks. Intranasal administration of scopolamine ensures a fast absorption and rapid onset of therapeutic effect, which might prove to be suitable for use during spaceflights. The aim of this study was to evaluate the effects of intranasally administered scopolamine (0.4 mg) on the semicircular canals (SCCs) and the otoliths. This double-blind, placebo-controlled study was performed on 19 healthy male subjects. The function of the horizontal SCC and the vestibulo-ocular reflex, as well as the saccular function and utricular function, were evaluated. Scopolamine turned out to affect mainly the SCCs centrally and peripherally but also the utricles to a lesser extent. Centrally, the most probable site of action is the medial vestibular nucleus, where the highest density of muscarinic receptors has been demonstrated and afferent fibers from the SCCs and utricles synapse. Furthermore, our results suggest the presence of muscarinic receptors in the peripheral vestibular system on which scopolamine has a suppressive effect. Given the depressant actions on the SCCs, it is suggested that the pharmacodynamic effect of scopolamine may be attributed to the obliteration of intravestibular conflict that arises during (S)MS.

  2. The effect of intranasal administration of oxytocin on fear recognition.

    PubMed

    Fischer-Shofty, M; Shamay-Tsoory, S G; Harari, H; Levkovitz, Y

    2010-01-01

    The oxytocinergic system has recently been placed amongst the most promising targets for various psychiatric treatments due to its role in prosocial behavior and anxiety reduction. Although recent studies have demonstrated a general effect of administration of oxytocin on emotion recognition, no study to date has examine the effect of oxytocin on each emotion separately. In the present study, a double-blind placebo-controlled crossover design was used in a dynamic facial expression task, in order to assess the effects of administration of oxytocin on emotion recognition. A single dose of oxytocin or a placebo was administered intranasally to 27 healthy male subjects 45 min prior to task performance. The results showed that a single intranasal administration of oxytocin, as opposed to the placebo, improved the subjects' ability to recognize fear, but not other emotions. These results suggest a specific role for oxytocin in fear recognition, which could be relevant for clinical disorders that manifest deficits in processing emotional facial expressions, particularly fear. PMID:19747930

  3. The effects of intranasal oxytocin on contagious yawning.

    PubMed

    Gallup, Andrew C; Church, Allyson M

    2015-10-21

    Contagious yawning is thought to represent a basic form of empathy involved in state matching. Despite recent evidence in support of this connection, the neurochemical basis of contagious yawning remains largely unknown. Here, we investigate whether intranasal oxytocin, a hormone and neuropeptide involved in empathic processing, bonding and social affiliation, influences contagious yawning among human participants in a laboratory setting. Using a double blind procedure, 60 male college students received 30 IU of intranasal oxytocin or placebo and were then recorded during exposure to a contagious yawning video stimulus. Contrary to the empathic modeling hypothesis, oxytocin did not increase contagious yawning but rather appeared to modulate its expression in ways indicative of an enhanced awareness of the social stigma associated with this behavior. In particular, individuals in the oxytocin condition were more likely to conceal their yawns and less likely to display overt cues associated with the behavior. Follow-up research could explore how social context and affiliation with the target stimulus alter this response.

  4. Intranasal scopolamine affects the semicircular canals centrally and peripherally.

    PubMed

    Weerts, Aurélie P; Putcha, Lakshmi; Hoag, Stephen W; Hallgren, Emma; Van Ombergen, Angelique; Van de Heyning, Paul H; Wuyts, Floris L

    2015-08-01

    Space motion sickness (SMS), a condition caused by an intravestibular conflict, remains an important obstacle that astronauts encounter during the first days in space. Promethazine is currently the standard treatment of SMS, but scopolamine is used by some astronauts to prevent SMS. However, the oral and transdermal routes of administration of scopolamine are known to have substantial drawbacks. Intranasal administration of scopolamine ensures a fast absorption and rapid onset of therapeutic effect, which might prove to be suitable for use during spaceflights. The aim of this study was to evaluate the effects of intranasally administered scopolamine (0.4 mg) on the semicircular canals (SCCs) and the otoliths. This double-blind, placebo-controlled study was performed on 19 healthy male subjects. The function of the horizontal SCC and the vestibulo-ocular reflex, as well as the saccular function and utricular function, were evaluated. Scopolamine turned out to affect mainly the SCCs centrally and peripherally but also the utricles to a lesser extent. Centrally, the most probable site of action is the medial vestibular nucleus, where the highest density of muscarinic receptors has been demonstrated and afferent fibers from the SCCs and utricles synapse. Furthermore, our results suggest the presence of muscarinic receptors in the peripheral vestibular system on which scopolamine has a suppressive effect. Given the depressant actions on the SCCs, it is suggested that the pharmacodynamic effect of scopolamine may be attributed to the obliteration of intravestibular conflict that arises during (S)MS. PMID:25953832

  5. Bioavailability of intranasal promethazine dosage forms in dogs

    NASA Technical Reports Server (NTRS)

    Ramanathan, R.; Geary, R. S.; Bourne, D. W.; Putcha, L.

    1998-01-01

    Intramuscular promethazine (PMZ) is used aboard the US Space Shuttle to ameliorate symptoms of space motion sickness. Bioavailability after an oral dose of PMZ during space flight is thought to be impaired because of gastrointestinal disturbances associated with weightlessness and space motion sickness. In an attempt to find an alternative dosage form for use in space, we evaluated two intranasal (i.n.) dosage forms of PMZ in dogs for absorption and bioavailability relative to that of an equivalent intramuscular dose. Promethazine (5 mg kg-1) was administered as two intranasal dosage forms and as an intramuscular (i.m.) dose to three dogs in a randomised cross-over design. Serial blood samples were taken and analysed for PMZ concentrations and the absorption and bioavailability of PMZ were calculated for the three dosage forms. PMZ absorption from the carboxymethyl cellulose microsphere i.n. dosage form was more rapid and complete than from the myverol cubic gel formulation or from an i.m. injection. Bioavailability of the microsphere formulation was also greater than that of the gel formulation (AUC 3009 vs 1727 ng h ml-1). The bioavailability of the two i.n. dosage forms (relative to that of the i.m. injection) were 94% (microsphere) and 54% (gel). The i.n. microsphere formulation of PMZ offers great promise as an effective non-invasive alternative for treating space motion sickness due to its rapid absorption and bioavailability equivalent to the i.m. dose.

  6. Clinical implications for breath-powered powder sumatriptan intranasal treatment.

    PubMed

    Tepper, Stewart J

    2013-09-01

    The acute treatment of migraine requires matching patient need to drug and formulation. In particular, nausea and vomiting, quick time to peak intensity, and the common gastroparesis of migraineurs, all call for a variety of non-oral formulations for treatment of attacks. A novel breath-powered powder sumatriptan intranasal treatment offers an improvement, at least in pharmacokinetics, over conventional liquid nasal sumatriptan spray. The device for delivery in this breath-powered nasal sumatriptan uses natural nose anatomy to close the soft palate and propel the sumatriptan high up in the nasal cavity on one side with bidirectional airflow coming out the other side. This approach has the potential to reduce adverse events and improve efficacy. Phase 3 data on this system are in press at the time of this writing and results appear promising. The clinical role for a fast acting non-oral nasal formulation will be in those for whom tablets are bound to fail, that is, in the setting of nausea and vomiting or when the time to central sensitization, allodynia, and disabling migraine is too short for the patient to respond to a tablet. This review provides a clinical perspective on the breath-powered powder sumatriptan intranasal treatment. PMID:23809006

  7. Influenza virus vaccine live intranasal--MedImmune vaccines: CAIV-T, influenza vaccine live intranasal.

    PubMed

    2003-01-01

    submitting a licence application in Europe, a $US27.5 million payment for approval of a refrigerator-stable liquid formulation of FluMist and as much as $US50 million for licensing of FluMist internationally. In July 2003 MedImmune announced that it had received approximately $US28 million in milestone payments during Q2 of 2003 for the approval of FluMist. CSL Ltd of Australia will collaborate on the development, sale and distribution of MedImmune Vaccine's vaccine in Australia, New Zealand and certain countries in the South Pacific. MedImmune is to acquire vaccine research programmes in respiratory syncytial virus and cytomegalovirus from MedImmune Vaccines. The company's primary interest is in FluMist. In May 2002, MedImmune licensed exclusive rights to Crucell's proprietary human cell line PER.C6 for use in its influenza vaccine programmes. On 11 March 2002, American Home Products changed its name and the names of its subsidiaries Wyeth-Ayerst and Wyeth-Lederle to Wyeth. Wyeth's vaccines division is called Wyeth Vaccines. On 29 September 2000, Aviron announced that it had been awarded a $US2.7 million Challenge Grant from NIAID for development of vaccines against pandemic strains of influenza based on FluMist intranasal technology. The cold-adapted live influenza vaccine has been widely evaluated in the US and Japan since 1975 in clinical trials involving several thousand people. Aviron completed phase II clinical trials in adults in the US and phase III trials in US children aged 15-71 months. Additional phase III trials in adults and the elderly are ongoing. Aviron also commenced phase III trials to test the safety of its intranasal live vaccine in children with moderate to severe asthma. The vaccine is delivered using the AccuSpray nasal delivery system by Becton Dickinson, which will supply the system for FluMist through the 2001-2002 influenza season under an agreement with Aviron made in August 1998. On 7 March 2000, Aviron announced that Wyeth-Lederle Vaccines

  8. Influenza virus vaccine live intranasal--MedImmune vaccines: CAIV-T, influenza vaccine live intranasal.

    PubMed

    2003-01-01

    submitting a licence application in Europe, a $US27.5 million payment for approval of a refrigerator-stable liquid formulation of FluMist and as much as $US50 million for licensing of FluMist internationally. In July 2003 MedImmune announced that it had received approximately $US28 million in milestone payments during Q2 of 2003 for the approval of FluMist. CSL Ltd of Australia will collaborate on the development, sale and distribution of MedImmune Vaccine's vaccine in Australia, New Zealand and certain countries in the South Pacific. MedImmune is to acquire vaccine research programmes in respiratory syncytial virus and cytomegalovirus from MedImmune Vaccines. The company's primary interest is in FluMist. In May 2002, MedImmune licensed exclusive rights to Crucell's proprietary human cell line PER.C6 for use in its influenza vaccine programmes. On 11 March 2002, American Home Products changed its name and the names of its subsidiaries Wyeth-Ayerst and Wyeth-Lederle to Wyeth. Wyeth's vaccines division is called Wyeth Vaccines. On 29 September 2000, Aviron announced that it had been awarded a $US2.7 million Challenge Grant from NIAID for development of vaccines against pandemic strains of influenza based on FluMist intranasal technology. The cold-adapted live influenza vaccine has been widely evaluated in the US and Japan since 1975 in clinical trials involving several thousand people. Aviron completed phase II clinical trials in adults in the US and phase III trials in US children aged 15-71 months. Additional phase III trials in adults and the elderly are ongoing. Aviron also commenced phase III trials to test the safety of its intranasal live vaccine in children with moderate to severe asthma. The vaccine is delivered using the AccuSpray nasal delivery system by Becton Dickinson, which will supply the system for FluMist through the 2001-2002 influenza season under an agreement with Aviron made in August 1998. On 7 March 2000, Aviron announced that Wyeth-Lederle Vaccines

  9. Insulin pumps.

    PubMed

    Pickup, J

    2010-02-01

    Insulin pump therapy is now more than 30 years old, and is an established part of the routine care of selected people with type 1 diabetes. Nevertheless, there are still significant areas of concern, particularly how pumps compare with modern injection therapy, whether the increasingly sophisticated pump technologies like onboard calculators and facility for computer download offer any real benefit, and whether we have a consensus on the clinical indications. The following papers offer some insight into these and other current questions.

  10. Optogenetic manipulation of neural circuits in awake marmosets.

    PubMed

    MacDougall, Matthew; Nummela, Samuel U; Coop, Shanna; Disney, Anita; Mitchell, Jude F; Miller, Cory T

    2016-09-01

    Optogenetics has revolutionized the study of functional neuronal circuitry (Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K. Nat Neurosci 8: 1263-1268, 2005; Deisseroth K. Nat Methods 8: 26-29, 2011). Although these techniques have been most successfully implemented in rodent models, they have the potential to be similarly impactful in studies of nonhuman primate brains. Common marmosets (Callithrix jacchus) have recently emerged as a candidate primate model for gene editing, providing a potentially powerful model for studies of neural circuitry and disease in primates. The application of viral transduction methods in marmosets for identifying and manipulating neuronal circuitry is a crucial step in developing this species for neuroscience research. In the present study we developed a novel, chronic method to successfully induce rapid photostimulation in individual cortical neurons transduced by adeno-associated virus to express channelrhodopsin (ChR2) in awake marmosets. We found that large proportions of neurons could be effectively photoactivated following viral transduction and that this procedure could be repeated for several months. These data suggest that techniques for viral transduction and optical manipulation of neuronal populations are suitable for marmosets and can be combined with existing behavioral preparations in the species to elucidate the functional neural circuitry underlying perceptual and cognitive processes. PMID:27334951

  11. Brainstem areas activated by intermittent apnea in awake unrestrained rats.

    PubMed

    Ferreira, C B; Schoorlemmer, G H; Rossi, M V; Takakura, A C; Barna, B F; Moreira, T S; Cravo, S L

    2015-06-25

    We investigated the role of the autonomic nervous system to cardiovascular responses to obstructive apnea in awake, unrestrained rats, and measured expression of Fos induced by apnea in the brainstem. We implanted a tracheal balloon contained in a rigid tube to allow the induction of apnea without inducing pain in the trachea. During bouts of 15s of apnea, heart rate fell from 371±8 to 161±11bpm (mean±SEM, n=15, p<0.01) and arterial pressure increased from 115±2 to 131±4mmHg (p<0.01). Bradycardia was due to parasympathetic activity because it was blocked by the muscarinic antagonist, methylatropine. The pressor response was due to vasoconstriction caused by sympathetic activation because it was blocked by the α1 antagonist, prazosin. Apnea induced Fos expression in several brainstem areas involved in cardiorespiratory control such as the nucleus of the solitary tract (NTS), ventrolateral medulla (VLM), and pons. Ligation of the carotid body artery reduced apnea-induced bradycardia, blocked heart rate responses to i.v. injection of cyanide, reduced Fos expression in the caudal NTS, and increased Fos expression in the rostral VLM. In conclusion, apnea activates neurons in regions that process signals from baroreceptors, chemoreceptors, pulmonary receptors, and regions responsible for autonomic and respiratory activity both in the presence and absence of carotid chemoreceptors.

  12. Functional Connectivity Hubs and Networks in the Awake Marmoset Brain

    PubMed Central

    Belcher, Annabelle M.; Yen, Cecil Chern-Chyi; Notardonato, Lucia; Ross, Thomas J.; Volkow, Nora D.; Yang, Yihong; Stein, Elliot A.; Silva, Afonso C.; Tomasi, Dardo

    2016-01-01

    In combination with advances in analytical methods, resting-state fMRI is allowing unprecedented access to a better understanding of the network organization of the brain. Increasing evidence suggests that this architecture may incorporate highly functionally connected nodes, or “hubs”, and we have recently proposed local functional connectivity density (lFCD) mapping to identify highly-connected nodes in the human brain. Here, we imaged awake nonhuman primates to test whether, like the human brain, the marmoset brain contains FC hubs. Ten adult common marmosets (Callithrix jacchus) were acclimated to mild, comfortable restraint using individualized helmets. Following restraint training, resting BOLD data were acquired during eight consecutive 10 min scans for each subject. lFCD revealed prominent cortical and subcortical hubs of connectivity across the marmoset brain; specifically, in primary and secondary visual cortices (V1/V2), higher-order visual association areas (A19M/V6[DM]), posterior parietal and posterior cingulate areas (PGM and A23b/A31), thalamus, dorsal and ventral striatal areas (caudate, putamen, lateral septal nucleus, and anterior cingulate cortex (A24a). lFCD hubs were highly connected to widespread areas of the brain, and further revealed significant network-network interactions. These data provide a baseline platform for future investigations in a nonhuman primate model of the brain’s network topology. PMID:26973476

  13. Spontaneous cortical activity in awake monkeys composed of neuronal avalanches.

    PubMed

    Petermann, Thomas; Thiagarajan, Tara C; Lebedev, Mikhail A; Nicolelis, Miguel A L; Chialvo, Dante R; Plenz, Dietmar

    2009-09-15

    Spontaneous neuronal activity is an important property of the cerebral cortex but its spatiotemporal organization and dynamical framework remain poorly understood. Studies in reduced systems--tissue cultures, acute slices, and anesthetized rats--show that spontaneous activity forms characteristic clusters in space and time, called neuronal avalanches. Modeling studies suggest that networks with this property are poised at a critical state that optimizes input processing, information storage, and transfer, but the relevance of avalanches for fully functional cerebral systems has been controversial. Here we show that ongoing cortical synchronization in awake rhesus monkeys carries the signature of neuronal avalanches. Negative LFP deflections (nLFPs) correlate with neuronal spiking and increase in amplitude with increases in local population spike rate and synchrony. These nLFPs form neuronal avalanches that are scale-invariant in space and time and with respect to the threshold of nLFP detection. This dimension, threshold invariance, describes a fractal organization: smaller nLFPs are embedded in clusters of larger ones without destroying the spatial and temporal scale-invariance of the dynamics. These findings suggest an organization of ongoing cortical synchronization that is scale-invariant in its three fundamental dimensions--time, space, and local neuronal group size. Such scale-invariance has ontogenetic and phylogenetic implications because it allows large increases in network capacity without a fundamental reorganization of the system.

  14. Fiber optic based multisensor to brain neurons in awake animals

    NASA Astrophysics Data System (ADS)

    Shen, Zheng; Lin, Shuzhi

    1995-02-01

    The fibeated broptic-based multisensor was made of quartz optic fiber capillary with an outer diameter of 250 micrometers and an inner diameter of 10 micrometers through two methods: a capillary and the parallel capillary with another piece of optic fiber. There was a thin layer of tungsten membrane (thickness 1 micrometers ) around the outer surface of the optic fiber or capillary. The metal membrane worked as a micro electrode or an electro-osmosis electrode. Nitrogen laser beam and laser-fluorescent pulses were guided in two ways through optic fiber or the wall of the capillary. The advantage of one capillary was its small tip and measurement of different physiological indices in the same site, but the intensity of laser-fluorescent pulses was diminished by electro-osmosis flow; the parallel optic fiber and capillary avoided the shortage, but the device tip was bigger than a capillary. The multisensor was used to inquire into cognitive brain mechanism in awake animals by simultaneous recording of neuron activities (neuron firing), neuron metabolism rate (laser-fluorescent pulses), and biochemical events through microelectrophore in vivo and field effect electro-osmosis analysis at situ. The effects of nitric oxide biosynthesis-related compounds on neuron efficiency of the cortex were investigated by the multisensor.

  15. Cognitive outcome after awake surgery for tumors in language areas.

    PubMed

    Santini, B; Talacchi, A; Squintani, G; Casagrande, F; Capasso, R; Miceli, G

    2012-06-01

    In surgery for tumors of the dominant hemisphere, the attention devoted to quality of resection and preservation of language function has not been accompanied by comparable interest in preservation of cognitive abilities which may affect quality of life. We studied 22 patients undergoing awake surgery for glioma removal in the language areas of the brain. Besides monitoring tumor variables (size, location, histology, edema), we used a multifaceted battery of tests to investigate mood, cognition, and language in an attempt to assess the burden of disease and treatment, and the relationships between these three dimensions. Baseline assessment showed that 45% of the patients were depressed and 23% anxious; some cognitive and language impairment was noted for 59 and 50%, respectively. A general decline in postoperative cognitive performance (significant for memory and attention only) and language function (significant for picture naming) was observed, whereas depression was unchanged and anxiety decreased. Tumor histology, but not demographic variables or extent of resection, correlated with postoperative cognitive changes: patients undergoing surgery for high-grade tumors were more likely to improve. No correlation was observed between scores for mood, cognition, and language function. A subset of patients with low-grade glioma was followed up for 3-6 months; although some improvement was observed they did not always regain their preoperative performance. In conclusion, we believe that cognitive assessment performed in conjunction with language testing is a necessary step in the global evaluation of brain tumor patients both before and after surgery.

  16. Intranasal administration of IGF-1 attenuates hypoxic-ischemic brain injury in neonatal rats

    PubMed Central

    Lin, Shuying; Fan, Lir-Wan; Rhodes, Philip G.; Cai, Zhengwei

    2009-01-01

    To determine whether intranasal administration (iN) of recombinant human insulin-like growth factor-1 (rhIGF-1) provides neuroprotection to the neonatal rat brain following cerebral hypoxia-ischemia (HI), two doses of rhIGF-1 (50 μg at a 1 h interval) were infused into the right naris of postnatal day 7 (P7) rat pups with or without a prior HI insult (right common carotid artery ligation, followed by an exposure to 8% oxygen for 2 h). Our result showed that rhIGF-1 administered via iN was successfully delivered into the brain 30 min after the second dose. In the following studies rhIGF-1 was administered to P7 rat pups at 0, 1 or 2 h after HI at the dose described above. Pups in the control group received cerebral HI and vehicle treatment. Pups that underwent sham operation and vehicle treatment served as the sham group. Brain pathological changes were evaluated 2 and 15 d after HI. Our results showed that rhIGF-1 treatment up to 1 hr after cerebral HI effectively reduced brain injury as compared to that in the vehicle-treated rats. Moreover, rhIGF-1 treatment improved neurobehavioral performance (tested on P5-P21) in juvenile rats subjected to HI. Our results further showed that rhIGF-1 inhibited apoptotic cell death, possibly through activating the Akt signal transduction pathway. rhIGF-1 enhanced proliferation of neuronal and oligodendroglial progenitors after cerebral HI as well. These data suggest that iN administration of IGF-1 has the potential to be used for clinical treatment. PMID:19332057

  17. Intranasal oxytocin increases social grooming and food sharing in the common vampire bat Desmodus rotundus.

    PubMed

    Carter, Gerald G; Wilkinson, Gerald S

    2015-09-01

    Intranasal oxytocin (OT) delivery has been used to non-invasively manipulate mammalian cooperative behavior. Such manipulations can potentially provide insight into both shared and species-specific mechanisms underlying cooperation. Vampire bats are remarkable for their high rates of allogrooming and the presence of regurgitated food sharing among adults. We administered intranasal OT to highly familiar captive vampire bats of varying relatedness to test for an effect on allogrooming and food sharing. We found that intranasal OT did not have a detectable effect on food-sharing occurrence, but it did increase the size of regurgitated food donations when controlling for dyad and amount of allogrooming. Intranasal OT in females increased the amount of allogrooming per partner and across all partners per trial, but not the number of partners. We also found that the peak effect of OT treatments occurred 30-50min after administration, which is consistent with the reported latency for intranasal OT to affect relevant brain areas in rats and mice. Our results suggest that intranasal OT is a potential tool for influencing dyadic cooperative investments, but measuring prior social relationships may be necessary to interpret the results of hormonal manipulations of cooperative behavior and it may be difficult to alter partner choice in vampire bats using intranasal OT alone.

  18. Intranasal oxytocin increases social grooming and food sharing in the common vampire bat Desmodus rotundus.

    PubMed

    Carter, Gerald G; Wilkinson, Gerald S

    2015-09-01

    Intranasal oxytocin (OT) delivery has been used to non-invasively manipulate mammalian cooperative behavior. Such manipulations can potentially provide insight into both shared and species-specific mechanisms underlying cooperation. Vampire bats are remarkable for their high rates of allogrooming and the presence of regurgitated food sharing among adults. We administered intranasal OT to highly familiar captive vampire bats of varying relatedness to test for an effect on allogrooming and food sharing. We found that intranasal OT did not have a detectable effect on food-sharing occurrence, but it did increase the size of regurgitated food donations when controlling for dyad and amount of allogrooming. Intranasal OT in females increased the amount of allogrooming per partner and across all partners per trial, but not the number of partners. We also found that the peak effect of OT treatments occurred 30-50min after administration, which is consistent with the reported latency for intranasal OT to affect relevant brain areas in rats and mice. Our results suggest that intranasal OT is a potential tool for influencing dyadic cooperative investments, but measuring prior social relationships may be necessary to interpret the results of hormonal manipulations of cooperative behavior and it may be difficult to alter partner choice in vampire bats using intranasal OT alone. PMID:26475061

  19. Comparative efficacy of intranasal and oral vaccines against Bordetella bronchiseptica in dogs.

    PubMed

    Ellis, J A; Gow, S P; Waldner, C L; Shields, S; Wappel, S; Bowers, A; Lacoste, S; Xu, Z; Ball, E

    2016-06-01

    In order to determine the comparative efficacy of vaccines administered intranasally or orally to protect puppies from disease subsequent to experimental infection with Bordetella bronchiseptica (Bb), a randomized controlled trial was performed using 48 approximately 8-week-old specific pathogen free, Bb naive Beagle puppies. Puppies were randomized into three groups and administered vaccines containing Bb intranasally or orally, or a placebo intranasally. Twenty-one days later, all dogs were challenge exposed via aerosol administration of Bb. Clinical signs, nasal bacterial shedding and immune responses were monitored for 28 days after challenge. Intranasally vaccinated puppies had significantly lower rates of coughing, nasal discharge, retching and sneezing (i.e. were less sick clinically) than control puppies. The distinction between the orally vaccinated puppies and the control puppies was less consistent. The orally vaccinated puppies had less coughing and less retching than the control puppies, but nasal discharge and sneezing did not differ from control animals. Orally vaccinated puppies had higher rates of coughing, nasal discharge, retching and sneezing than the intranasally vaccinated puppies. Although both intranasal and oral Bb vaccines stimulated immune responses associated with disease sparing following Bb infection, the intranasal route of delivery conferred superior clinical outcomes. The observed difference in clinical efficacy suggests the need to question the rationale for the use of currently available orally administered Bb vaccines. PMID:27256028

  20. Comparative efficacy of intranasal and oral vaccines against Bordetella bronchiseptica in dogs.

    PubMed

    Ellis, J A; Gow, S P; Waldner, C L; Shields, S; Wappel, S; Bowers, A; Lacoste, S; Xu, Z; Ball, E

    2016-06-01

    In order to determine the comparative efficacy of vaccines administered intranasally or orally to protect puppies from disease subsequent to experimental infection with Bordetella bronchiseptica (Bb), a randomized controlled trial was performed using 48 approximately 8-week-old specific pathogen free, Bb naive Beagle puppies. Puppies were randomized into three groups and administered vaccines containing Bb intranasally or orally, or a placebo intranasally. Twenty-one days later, all dogs were challenge exposed via aerosol administration of Bb. Clinical signs, nasal bacterial shedding and immune responses were monitored for 28 days after challenge. Intranasally vaccinated puppies had significantly lower rates of coughing, nasal discharge, retching and sneezing (i.e. were less sick clinically) than control puppies. The distinction between the orally vaccinated puppies and the control puppies was less consistent. The orally vaccinated puppies had less coughing and less retching than the control puppies, but nasal discharge and sneezing did not differ from control animals. Orally vaccinated puppies had higher rates of coughing, nasal discharge, retching and sneezing than the intranasally vaccinated puppies. Although both intranasal and oral Bb vaccines stimulated immune responses associated with disease sparing following Bb infection, the intranasal route of delivery conferred superior clinical outcomes. The observed difference in clinical efficacy suggests the need to question the rationale for the use of currently available orally administered Bb vaccines.

  1. Intranasal Location and Immunohistochemical Characterization of the Equine Olfactory Epithelium

    PubMed Central

    Kupke, Alexandra; Wenisch, Sabine; Failing, Klaus; Herden, Christiane

    2016-01-01

    The olfactory epithelium (OE) is the only body site where neurons contact directly the environment and are therefore exposed to a broad variation of substances and insults. It can serve as portal of entry for neurotropic viruses which spread via the olfactory pathway to the central nervous system. For horses, it has been proposed and concluded mainly from rodent studies that different viruses, e.g., Borna disease virus, equine herpesvirus 1 (EHV-1), hendra virus, influenza virus, rabies virus, vesicular stomatitis virus can use this route. However, little is yet known about cytoarchitecture, protein expression and the intranasal location of the equine OE. Revealing differences in cytoarchitecture or protein expression pattern in comparison to rodents, canines, or humans might help to explain varying susceptibility to certain intranasal virus infections. On the other hand, disclosing similarities especially between rodents and other species, e.g., horses would help to underscore transferability of rodent models. Analysis of the complete noses of five adult horses revealed that in the equine OE two epithelial subtypes with distinct marker expression exist, designated as types a and b which resemble those previously described in dogs. Detailed statistical analysis was carried out to confirm the results obtained on the descriptive level. The equine OE was predominantly located in caudodorsal areas of the nasal turbinates with a significant decline in rostroventral direction, especially for type a. Immunohistochemically, olfactory marker protein and doublecortin (DCX) expression was found in more cells of OE type a, whereas expression of proliferating cell nuclear antigen and tropomyosin receptor kinase A was present in more cells of type b. Accordingly, type a resembles the mature epithelium, in contrast to the more juvenile type b. Protein expression profile was comparable to canine and rodent OE but equine types a and b were located differently within the nose and

  2. Intranasal delivery of obidoxime to the brain prevents mortality and CNS damage from organophosphate poisoning.

    PubMed

    Krishnan, Jishnu K S; Arun, Peethambaran; Appu, Abhilash P; Vijayakumar, Nivetha; Figueiredo, Taíza H; Braga, Maria F M; Baskota, Sudikshya; Olsen, Cara H; Farkas, Natalia; Dagata, John; Frey, William H; Moffett, John R; Namboodiri, Aryan M A

    2016-03-01

    Intranasal delivery is an emerging method for bypassing the blood brain barrier (BBB) and targeting therapeutics to the CNS. Oximes are used to counteract the effects of organophosphate poisoning, but they do not readily cross the BBB. Therefore, they cannot effectively counteract the central neuropathologies caused by cholinergic over-activation when administered peripherally. For these reasons we examined intranasal administration of oximes in an animal model of severe organophosphate poisoning to determine their effectiveness in reducing mortality and seizure-induced neuronal degeneration. Using the paraoxon model of organophosphate poisoning, we administered the standard treatment (intramuscular pralidoxime plus atropine sulphate) to all animals and then compared the effectiveness of intranasal application of obidoxime (OBD) to saline in the control groups. Intranasally administered OBD was effective in partially reducing paraoxon-induced acetylcholinesterase inhibition in the brain and substantially reduced seizure severity and duration. Further, intranasal OBD completely prevented mortality, which was 41% in the animals given standard treatment plus intranasal saline. Fluoro-Jade-B staining revealed extensive neuronal degeneration in the surviving saline-treated animals 24h after paraoxon administration, whereas no detectable degenerating neurons were observed in any of the animals given intranasal OBD 30min before or 5min after paraoxon administration. These findings demonstrate that intranasally administered oximes bypass the BBB more effectively than those administered peripherally and provide an effective method for protecting the brain from organophosphates. The addition of intranasally administered oximes to the current treatment regimen for organophosphate poisoning would improve efficacy, reducing both brain damage and mortality. PMID:26751814

  3. Giving an insulin injection

    MedlinePlus

    ... want. Put the needle into and through the rubber top of the insulin bottle. Push the plunger ... longer-acting insulin. Put the needle into the rubber top of that insulin bottle. Push the plunger ...

  4. Topical and Intranasal Analgesic Therapy in a Woman with Refractory Postherpetic Neuralgia

    PubMed Central

    Hohmeier, Kenneth C.; Almon, Lyndsey M.

    2015-01-01

    A patient-specific, stepped approach to topical and intranasal analgesic pharmacotherapy was effective in reducing refractory postherpetic neuralgia (PHN) not responding to the current standard of care for PHN. The use of topical analgesic therapy allowed for higher concentrations of medication locally while reducing the likelihood of systemic side effects common to the drugs used. No adverse effects were noted for either topical or intranasal drug therapy. The patient-specific, stepped approach resulted in clinically significant decreases in pain on visual analog scale (VAS), with the use of intranasal ketamine 10% solution and topical gabapentin 6%, ketoprofen 10%, lidocaine 5%, and ketamine 10% cream. PMID:25949241

  5. Spectral analysis of ventilation in elderly subjects awake and asleep.

    PubMed

    Pack, A I; Silage, D A; Millman, R P; Knight, H; Shore, E T; Chung, D C

    1988-03-01

    We studied the periodicities of ventilation in elderly subjects using digital comb filtering. Two groups of subjects were studied, those with and without sleep apnea. Measurements were made in wakefulness, stage 1-2 sleep, and where possible in stage 3-4 sleep. For each of the digital filters we calculated the average power of the oscillatory output. To compare subject groups we first specifically determined the average power in the filter with the maximum output. The mean of this measurement was greater in elderly subjects with apnea compared with those without apnea, both during wakefulness and stage 1-2 sleep. In both groups of subjects the cycle time of the major ventilatory oscillations was on the order of 40-60 s. There was no difference in this cycle time between the two groups of subjects in wakefulness or stage 1-2 sleep. Thus, whereas similar oscillatory processes occur in subjects with and without apnea, it is the magnitude of the oscillation that differs between the two groups. These conclusions are supported by analysis of the output of individual filters of the digital comb filter. In both groups, stage 1-2 sleep produced significantly increased oscillations in ventilation. Both in wakefulness and stage 1-2 sleep, significantly greater periodicities occurred in the apneic compared with the nonapneic group. In the few subjects who had sufficient data in stage 3-4 sleep for spectral analysis, ventilatory oscillations were virtually absent in this state. Our data suggest that subjects who develop apnea during sleep have an increased propensity for periodic breathing even while awake.

  6. Stability of thalamocortical synaptic transmission across awake brain states.

    PubMed

    Stoelzel, Carl R; Bereshpolova, Yulia; Swadlow, Harvey A

    2009-05-27

    Sensory cortical neurons are highly sensitive to brain state, with many neurons showing changes in spatial and/or temporal response properties and some neurons becoming virtually unresponsive when subjects are not alert. Although some of these changes are undoubtedly attributable to state-related filtering at the thalamic level, another likely source of such effects is the thalamocortical (TC) synapse, where activation of nicotinic receptors on TC terminals have been shown to enhance synaptic transmission in vitro. However, monosynaptic TC synaptic transmission has not been directly examined during different states of alertness. Here, in awake rabbits that shifted between alert and non-alert EEG states, we examined the monosynaptic TC responses and short-term synaptic dynamics generated by spontaneous impulses of single visual and somatosensory TC neurons. We did this using spike-triggered current source-density analysis, an approach that enables assessment of monosynaptic extracellular currents generated in different cortical layers by impulses of single TC afferents. Spontaneous firing rates of TC neurons were higher, and burst rates were much lower in the alert state. However, we found no state-related changes in the amplitude of monosynaptic TC responses when TC spikes with similar preceding interspike interval were compared. Moreover, the relationship between the preceding interspike interval of the TC spike and postsynaptic response amplitude was not influenced by state. These data indicate that TC synaptic transmission and dynamics are highly conserved across different states of alertness and that observed state-related changes in receptive field properties that occur at the cortical level result from other mechanisms.

  7. Clinical utility of insulin and insulin analogs

    PubMed Central

    Sanlioglu, Ahter D.; Altunbas, Hasan Ali; Balci, Mustafa Kemal; Griffith, Thomas S.; Sanlioglu, Salih

    2013-01-01

    Diabetes is a pandemic disease characterized by autoimmune, genetic and metabolic abnormalities. While insulin deficiency manifested as hyperglycemia is a common sequel of both Type-1 and Type-2 diabetes (T1DM and T2DM), it does not result from a single genetic defect—rather insulin deficiency results from the functional loss of pancreatic β cells due to multifactorial mechanisms. Since pancreatic β cells of patients with T1DM are destroyed by autoimmune reaction, these patients require daily insulin injections. Insulin resistance followed by β cell dysfunction and β cell loss is the characteristics of T2DM. Therefore, most patients with T2DM will require insulin treatment due to eventual loss of insulin secretion. Despite the evidence of early insulin treatment lowering macrovascular (coronary artery disease, peripheral arterial disease and stroke) and microvascular (diabetic nephropathy, neuropathy and retinopathy) complications of T2DM, controversy exists among physicians on how to initiate and intensify insulin therapy. The slow acting nature of regular human insulin makes its use ineffective in counteracting postprandial hyperglycemia. Instead, recombinant insulin analogs have been generated with a variable degree of specificity and action. Due to the metabolic variability among individuals, optimum blood glucose management is a formidable task to accomplish despite the presence of novel insulin analogs. In this article, we present a recent update on insulin analog structure and function with an overview of the evidence on the various insulin regimens clinically used to treat diabetes. PMID:23584214

  8. [Inhaled insulin, new perspective for insulin therapy].

    PubMed

    Radermecker, R P; Sélam, J L

    2005-01-01

    Since the discovery of insulin and its use in diabetes care, patients, physicians and nurses dream of another way of insulin administration than the subcutaneous injections actually used. Different types of insulin administration have been evaluated and, particularly, that using the pulmonary route. The use of this alternative method to deliver insulin may result in improved patient compliance, facilitate intensified therapies and avoid the delay of initiating insulin administration because patient's reluctance. The different insulin pulmonary delivering devices actually studied will be presented. Preliminary data comparing this way of administration and the subcutaneous injection of human regular insulin are good, but sufficient data comparing inhaled insulin with the new short-acting insulin analogues are not yet available. Among various difficulties of the pulmonary insulin delivery, the finding of an effective promoter, capable of increasing the bioavailability of insulin, is a crucial issue. The cost of such insulin administration might also be a problem. Finally, careful studies concerning the safety of this kind of administration, particularly potential long-term pulmonary toxicity, are mandatory. Nevertheless, inhaled insulin is an attractive topic in which most important pharmaceutical companies are currently involved.

  9. Effects of intranasal cocaine on sympathetic nerve discharge in humans.

    PubMed Central

    Jacobsen, T N; Grayburn, P A; Snyder, R W; Hansen, J; Chavoshan, B; Landau, C; Lange, R A; Hillis, L D; Victor, R G

    1997-01-01

    Cocaine-induced cardiovascular emergencies are mediated by excessive adrenergic stimulation. Animal studies suggest that cocaine not only blocks norepinephrine reuptake peripherally but also inhibits the baroreceptors, thereby reflexively increasing sympathetic nerve discharge. However, the effect of cocaine on sympathetic nerve discharge in humans is unknown. In 12 healthy volunteers, we recorded blood pressure and sympathetic nerve discharge to the skeletal muscle vasculature using intraneural microelectrodes (peroneal nerve) during intranasal cocaine (2 mg/kg, n = 8) or lidocaine (2%, n = 4), an internal local anesthetic control, or intravenous phenylephrine (0.5-2.0 microg/kg, n = 4), an internal sympathomimetic control. Experiments were repeated while minimizing the cocaine-induced rise in blood pressure with intravenous nitroprusside to negate sinoaortic baroreceptor stimulation. After lidocaine, blood pressure and sympathetic nerve discharge were unchanged. After cocaine, blood pressure increased abruptly and remained elevated for 60 min while sympathetic nerve discharge initially was unchanged and then decreased progressively over 60 min to a nadir that was only 2+/-1% of baseline (P < 0.05); however, plasma venous norepinephrine concentrations (n = 5) were unchanged up to 60 min after cocaine. Sympathetic nerve discharge fell more rapidly but to the same nadir when blood pressure was increased similarly with phenylephrine. When the cocaine-induced increase in blood pressure was minimized (nitroprusside), sympathetic nerve discharge did not decrease but rather increased by 2.9 times over baseline (P < 0.05). Baroreflex gain was comparable before and after cocaine. We conclude that in conscious humans the primary effect of intranasal cocaine is to increase sympathetic nerve discharge to the skeletal muscle bed. Furthermore, sinoaortic baroreflexes play a pivotal role in modulating the cocaine-induced sympathetic excitation. The interplay between these

  10. Guinea Pig Lung Lavage Cells After Intranasal BCG Sensitization

    PubMed Central

    Terai, T.; Ganguly, Rama; Waldman, Robert H.

    1979-01-01

    Recent studies have suggested that intranasal administration of antigen can induce local cell-mediated immunity in lung lavage cells. The present study was designed to examine the changes in composition of lung lavage cells and their capacity to produce the lymphokine migration inhibitory factor after intranasal immunization with BCG in guinea pigs. Results indicate that guinea pigs responded to respiratory tract BCG infection with an increase in immunocompetent cells in the bronchoalveolar tract and with production of migration inhibitory factor. After local pulmonary BCG administration, the total number of cells increased as compared with that of the uninfected animals, the increase being statistically significant within 2 weeks. This marked increase in the total cell population is due to a more than doubling of the number of macrophages in the lavage fluid. Animals also developed at this time positive delayed hypersensitivity to intradermally administered purified protein derivative. A significant increase in the total lymphoid cells and macrophage population was observed again at 6 weeks after sensitization, suggesting that the response is biphasic in nature. At 6 weeks, however, there was also a significant rise in total lymphocytes and T cell population in addition to macrophage numbers. This increase in T cells correlated with an increase in production of migration inhibitory factor in the presence of purified protein derivative. These data suggest that the immune response of the respiratory tract after BCG challenge involves increased recruitment of immunocompetent cells locally at the site of infection and that these cells are capable of producing effector molecules in terms of the elaboration of migration inhibitory factor. PMID:387595

  11. Thermoreversible nanoethosomal gel for the intranasal delivery of Eletriptan hydrobromide.

    PubMed

    Shelke, Santosh; Shahi, Sadhana; Jadhav, Kiran; Dhamecha, Dinesh; Tiwari, Roshan; Patil, Hemlata

    2016-06-01

    The objective of the current study was to formulate and characterize thermoreversible gel of Eletriptan Hydrobromide for brain targeting via the intranasal route. Ethosomes were prepared by 3(2) factorial design with two independent variables (concentration of soya lecithin and ethanol) and two response variables [percent entrapment efficiency and vesicle size (nm)] using ethanol injection method. Formulated ethosomes were evaluated for preliminary microscopic examination followed by percent drug entrapment efficiency, vesicle size analysis, zeta potential, polydispersibility index and Transmission electron microscopy (TEM). TEM confirms spherical morphology of ethosomes, whereas Malvern zeta sizer confirms that the vesicle size was in the range of 191 ± 6.55-381.3 ± 61.0 nm. Ethosomes were incorporated in gel using poloxamer 407 and carbopol 934 as thermoreversible and mucoadhesive polymers, respectively. Ethosomal gels were evaluated for their pH, viscosity, mucoadhesive strength, in vitro drug release and ex vivo drug permeation through the sheep nasal mucosa. Mucoadhesive strength and pH was found to be 4400 ± 45 to 5500 ± 78.10 dynes/cm(2) and 6.0 ± 0.3 to 6.2 ± 0.1, respectively. In-vitro drug release from the optimized ethosomal gel formulation (G4) was found to be almost 100 % and ex vivo permeation of 4980 µg/ml with a permeability coefficient of 11.94 ± 0.04 × 10(-5) cm/s after 24 h. Histopathological study of the nasal mucosa confirmed non-toxic nature of ethosomal gels. Formulated EH loaded ethosomal thermoreversible gel could serve as the better alternative for the brain targeting via the intranasal route which in turn could subsequently improve its bioavailability. PMID:27091045

  12. Thermoreversible nanoethosomal gel for the intranasal delivery of Eletriptan hydrobromide.

    PubMed

    Shelke, Santosh; Shahi, Sadhana; Jadhav, Kiran; Dhamecha, Dinesh; Tiwari, Roshan; Patil, Hemlata

    2016-06-01

    The objective of the current study was to formulate and characterize thermoreversible gel of Eletriptan Hydrobromide for brain targeting via the intranasal route. Ethosomes were prepared by 3(2) factorial design with two independent variables (concentration of soya lecithin and ethanol) and two response variables [percent entrapment efficiency and vesicle size (nm)] using ethanol injection method. Formulated ethosomes were evaluated for preliminary microscopic examination followed by percent drug entrapment efficiency, vesicle size analysis, zeta potential, polydispersibility index and Transmission electron microscopy (TEM). TEM confirms spherical morphology of ethosomes, whereas Malvern zeta sizer confirms that the vesicle size was in the range of 191 ± 6.55-381.3 ± 61.0 nm. Ethosomes were incorporated in gel using poloxamer 407 and carbopol 934 as thermoreversible and mucoadhesive polymers, respectively. Ethosomal gels were evaluated for their pH, viscosity, mucoadhesive strength, in vitro drug release and ex vivo drug permeation through the sheep nasal mucosa. Mucoadhesive strength and pH was found to be 4400 ± 45 to 5500 ± 78.10 dynes/cm(2) and 6.0 ± 0.3 to 6.2 ± 0.1, respectively. In-vitro drug release from the optimized ethosomal gel formulation (G4) was found to be almost 100 % and ex vivo permeation of 4980 µg/ml with a permeability coefficient of 11.94 ± 0.04 × 10(-5) cm/s after 24 h. Histopathological study of the nasal mucosa confirmed non-toxic nature of ethosomal gels. Formulated EH loaded ethosomal thermoreversible gel could serve as the better alternative for the brain targeting via the intranasal route which in turn could subsequently improve its bioavailability.

  13. Plasma oxytocin concentrations following MDMA or intranasal oxytocin in humans.

    PubMed

    Kirkpatrick, Matthew G; Francis, Sunday M; Lee, Royce; de Wit, Harriet; Jacob, Suma

    2014-08-01

    MDMA (±3,4-methylenedioxymethamphetamine, 'ecstasy') is reportedly used recreationally because it increases feelings of sociability and interpersonal closeness. Prior work suggests that the pro-social effects of MDMA may be mediated by release of oxytocin. A direct examination of plasma levels of oxytocin after acute doses of oxytocin and MDMA, in the same individuals, would provide further evidence for the idea that MDMA produces its pro-social effects by increasing oxytocin. Fourteen healthy MDMA users participated in a 4-session, double-blind study in which they received oral MDMA (0.75 and 1.5mg/kg), intranasal oxytocin (20IU or 40IU), and placebo. Plasma oxytocin concentrations, as well as cardiovascular and subjective effects were assessed before and at several time points after drug administration. MDMA (1.5mg/kg only) increased plasma oxytocin levels to a mean peak of 83.7pg/ml at approximately 90-120min, compared to 18.6pg/ml after placebo. Intranasal oxytocin (40IU, but not 20IU) increased plasma oxytocin levels to 48.0pg/ml, 30-60min after nasal spray administration. MDMA dose-dependently increased heart rate, blood pressure, feelings of euphoria (e.g., 'High' and 'Like Drug'), and feelings of sociability, whereas oxytocin had no cardiovascular or subjective effects. The subjective and cardiovascular responses to MDMA were not related to plasma oxytocin levels, although the N was small for this analysis. Future studies examining the effects of oxytocin antagonists on responses to MDMA will help to determine the mechanism by which MDMA produces pro-social effects.

  14. Awake Measures of Nasal Resistance and Upper Airway Resistance on CPAP during Sleep

    PubMed Central

    Masdeu, Maria J.; Seelall, Vijay; Patel, Amit V.; Ayappa, Indu; Rapoport, David M.

    2011-01-01

    Study Objectives: Since on CPAP, the nose is the primary determinant of upper airway resistance, we assess utility of noninvasive measures of nasal resistance during wakefulness as a predictor of directly assessed upper airway resistance on CPAP during sleep in patients with obstructive sleep apnea/hypopnea syndrome. Methods: Patients with complaints of snoring and excessive daytime sleepiness were recruited. 14 subjects underwent daytime evaluations including clinical assessment, subjective questionnaires to assess nasal symptoms and evaluation of nasal resistance with acoustic rhinometry (AR) and active anterior rhinomanometry (RM) in the sitting and supine positions. Patients underwent nocturnal polysomnography on optimal CPAP with measurements of supraglottic pressure to evaluate upper airway resistance. Comparisons were made between nasal resistance using AR and RM during wakefulness, and between AR and RM awake and upper airway resistance during sleep. Results: Our study shows that measures of awake nasal resistance using AR and RM had little or no correlation to each other in the sitting position, whereas there was significant but weak correlation in the supine position. Upper airway resistance measured while on CPAP during sleep did not show significant relationships to any of the awake measures of nasal resistance (AR or RM). Conclusion: Awake measurements of nasal resistance do not seem to be predictive of upper airway resistance during sleep on CPAP. Citation: Masdeu MJ; Seelall V; Patel AV; Ayappa I; Rapoport DM. Awake Measures of Nasal Resistance and Upper Airway Resistance on CPAP during Sleep. J Clin Sleep Med 2011;7(1):31-40. PMID:21344056

  15. Awake brain tumor resection during pregnancy: Decision making and technical nuances.

    PubMed

    Meng, Lingzhong; Han, Seunggu J; Rollins, Mark D; Gelb, Adrian W; Chang, Edward F

    2016-02-01

    The co-occurrence of primary brain tumor and pregnancy poses unique challenges to the treating physician. If a rapidly growing lesion causes life-threatening mass effect, craniotomy for tumor debulking becomes urgent. The choice between awake craniotomy versus general anesthesia becomes complicated if the tumor is encroaching on eloquent brain because considerations pertinent to both patient safety and oncological outcome, in addition to fetal wellbeing, are involved. A 31-year-old female at 30 weeks gestation with twins presented to our hospital seeking awake craniotomy to resect a 7 × 6 × 5 cm left frontoparietal brain tumor with 7 mm left-to-right subfalcine herniation on imaging that led to word finding difficulty, dysfluency, right upper extremity paralysis, and right lower extremity weakness. She had twice undergone tumor debulking under general anesthesia during the same pregnancy at an outside hospital at 16 weeks and 28 weeks gestation. There were considerations both for and against awake brain tumor resection over surgery under general anesthesia. The decision-making process and the technical nuances related to awake brain tumor resection in this neurologically impaired patient are discussed. Awake craniotomy benefits the patient who harbors a tumor that encroaches on the eloquent brain by allowing a greater extent of resection while preserving the language and sensorimotor function. It can be successfully done in pregnant patients who are neurologically impaired. The patient should be motivated and well informed of the details of the process. A multidisciplinary and collaborative effort is also crucial.

  16. Awake brain tumor resection during pregnancy: Decision making and technical nuances.

    PubMed

    Meng, Lingzhong; Han, Seunggu J; Rollins, Mark D; Gelb, Adrian W; Chang, Edward F

    2016-02-01

    The co-occurrence of primary brain tumor and pregnancy poses unique challenges to the treating physician. If a rapidly growing lesion causes life-threatening mass effect, craniotomy for tumor debulking becomes urgent. The choice between awake craniotomy versus general anesthesia becomes complicated if the tumor is encroaching on eloquent brain because considerations pertinent to both patient safety and oncological outcome, in addition to fetal wellbeing, are involved. A 31-year-old female at 30 weeks gestation with twins presented to our hospital seeking awake craniotomy to resect a 7 × 6 × 5 cm left frontoparietal brain tumor with 7 mm left-to-right subfalcine herniation on imaging that led to word finding difficulty, dysfluency, right upper extremity paralysis, and right lower extremity weakness. She had twice undergone tumor debulking under general anesthesia during the same pregnancy at an outside hospital at 16 weeks and 28 weeks gestation. There were considerations both for and against awake brain tumor resection over surgery under general anesthesia. The decision-making process and the technical nuances related to awake brain tumor resection in this neurologically impaired patient are discussed. Awake craniotomy benefits the patient who harbors a tumor that encroaches on the eloquent brain by allowing a greater extent of resection while preserving the language and sensorimotor function. It can be successfully done in pregnant patients who are neurologically impaired. The patient should be motivated and well informed of the details of the process. A multidisciplinary and collaborative effort is also crucial. PMID:26498092

  17. Intranasal Delivery of pGDNF Nanoparticles for Parkinson's Disease

    NASA Astrophysics Data System (ADS)

    Harmon, Brendan Trevor

    Parkinson's disease (PD) is a progressive neurodegenerative disorder that primarily affects the dopaminergic A9 nigrostriatal tract. For dopamine neurons specifically, glial cell-derived neurotrophic factor (GDNF) has been shown to promote their survival and proliferation both in culture and in vivo. GDNF has also proven to be neuroprotective and restorative in various animal models of PD and some human clinical trials. However, its delivery to the brain has required invasive surgical routes which are not clinically practical for many patients. The main objective of this project was to test intranasal delivery to the brain of a nanoparticle vector incorporating an expression plasmid for GDNF (pGDNF). The intranasal route circumvents the blood-brain barrier, allowing larger sized vectors into the central nervous system while avoiding peripheral distribution. This approach would provide a renewable source of GDNF within the target areas of the brain, the striatum and the substantia nigra (SN) without the need for surgical injections or frequent re-dosing. A PEGylated polylysine compacted plasmid nanoparticle vector (PEG-CK30), developed by Copernicus Therapeutics, Inc., has been shown to transfect neurons and glial cells in vivo while lacking the safety issues present with other vectors. The first goal of this work was to determine if these PEG-CK30 compacted plasmid nanoparticles can successfully transfect cells and express the reporter protein, enhanced green fluorescent protein (eGFP) in the rat brain after intranasal administration. Initial in vivo experiments utilized the expression plasmid pCG, expressing eGFP under the fast-acting cytomegalovirus (CMV) promoter. Intranasal administration of pCG nanoparticles resulted in evidence of transfection of brain cells, as shown both qualitatively, by GFP-immunohistochemistry, and quantitatively, by GFP-ELISA. Expression was detected throughout the rat brain two days post-administration. Following the proof

  18. Concentrated insulins: the new basal insulins

    PubMed Central

    Lamos, Elizabeth M; Younk, Lisa M; Davis, Stephen N

    2016-01-01

    Introduction Insulin therapy plays a critical role in the treatment of type 1 and type 2 diabetes mellitus. However, there is still a need to find basal insulins with 24-hour coverage and reduced risk of hypoglycemia. Additionally, with increasing obesity and insulin resistance, the ability to provide clinically necessary high doses of insulin at low volume is also needed. Areas covered This review highlights the published reports of the pharmacokinetic (PK) and glucodynamic properties of concentrated insulins: Humulin-R U500, insulin degludec U200, and insulin glargine U300, describes the clinical efficacy, risk of hypoglycemic, and metabolic changes observed, and finally, discusses observations about the complexity of introducing a new generation of concentrated insulins to the therapeutic market. Conclusion Humulin-R U500 has a similar onset but longer duration of action compared with U100 regular insulin. Insulin glargine U300 has differential PK/pharmacodynamic effects when compared with insulin glargine U100. In noninferiority studies, glycemic control with degludec U200 and glargine U300 is similar to insulin glargine U100 and nocturnal hypoglycemia is reduced. Concentrated formulations appear to behave as separate molecular entities when compared with earlier U100 insulin analog compounds. In the review of available published data, newer concentrated basal insulins may offer an advantage in terms of reduced intraindividual variability as well as reducing the injection burden in individuals requiring high-dose and large volume insulin therapy. Understanding the PK and pharmacodynamic properties of this new generation of insulins is critical to safe dosing, dispensing, and administration. PMID:27022271

  19. Anti-obesity effect of intranasal administration of galanin-like peptide (GALP) in obese mice

    PubMed Central

    Kageyama, Haruaki; Shiba, Kanako; Hirako, Satoshi; Wada, Nobuhiro; Yamanaka, Satoru; Nogi, Yukinori; Takenoya, Fumiko; Nonaka, Naoko; Hirano, Tsutomu; Inoue, Shuji; Shioda, Seiji

    2016-01-01

    Galanin-like peptide (GALP) has an anti-obesity effect in rats and mice. It has been reported that the uptake of GALP by the brain is higher after intranasal administration than with intravenous injection. This study therefore aimed to clarify the effect of intranasal administration of GALP on the feeding behavior of lean and obese mice. Autoradiography revealed the presence of 125I-GALP in the olfactory bulb and the brain microcirculation. The body weights of ob/ob mice gradually increased during vehicle treatment, but remained unchanged in response to repeated intranasal administration of GALP, with both ob/ob and diet-induced obese mice displaying significantly decreased food intake, water intake and locomotor activity when treated with GALP. These results suggest that intranasal administration is an effective route whereby GALP can exert its effect as an anti-obesity drug. PMID:27323911

  20. Anti-obesity effect of intranasal administration of galanin-like peptide (GALP) in obese mice.

    PubMed

    Kageyama, Haruaki; Shiba, Kanako; Hirako, Satoshi; Wada, Nobuhiro; Yamanaka, Satoru; Nogi, Yukinori; Takenoya, Fumiko; Nonaka, Naoko; Hirano, Tsutomu; Inoue, Shuji; Shioda, Seiji

    2016-01-01

    Galanin-like peptide (GALP) has an anti-obesity effect in rats and mice. It has been reported that the uptake of GALP by the brain is higher after intranasal administration than with intravenous injection. This study therefore aimed to clarify the effect of intranasal administration of GALP on the feeding behavior of lean and obese mice. Autoradiography revealed the presence of (125)I-GALP in the olfactory bulb and the brain microcirculation. The body weights of ob/ob mice gradually increased during vehicle treatment, but remained unchanged in response to repeated intranasal administration of GALP, with both ob/ob and diet-induced obese mice displaying significantly decreased food intake, water intake and locomotor activity when treated with GALP. These results suggest that intranasal administration is an effective route whereby GALP can exert its effect as an anti-obesity drug. PMID:27323911

  1. The effect of long-term use of intranasal steroids on intraocular pressure.

    PubMed

    Şimşek, Ali; Bayraktar, Cem; Doğan, Sedat; Karataş, Mehmet; Sarıkaya, Yasin

    2016-01-01

    Long-term use of topical nasal steroids (especially older generation steroids) has been shown to elevate intraocular pressure (IOP), but newer intranasal steroids are thought to have a minimal effect on IOP because of their low bioavailability. This study aimed to investigate alterations in IOP with two commonly used intranasal steroids for a 6-month period of time. One-hundred allergic rhinitis patients, divided equally into two groups, used mometasone furoate and fluticasone furoate intranasal steroids for 6 months. IOPs were measured before treatment and repeated at the 3rd, 6th, 12th, and 24th weeks of treatment. The IOPs of the groups were then compared. No statistically significant alteration was observed between the groups during the treatment time period. It was found that new generation intranasal steroids can be used safely, and there may not be an increased risk of IOP elevation in prolonged use in normal healthy people. PMID:27354761

  2. [Successful airway management using i-gel in 7 patients undergoing awake craniotomy].

    PubMed

    Matsunami, Katsuaki; Sanuki, Michiyoshi; Yasuuji, Masakazu; Nakanuno, Ryuichi; Kato, Takahiro; Kawamoto, Masashi

    2014-07-01

    In order to secure airway during awake craniotomy, we used i-gel to perform positive-pressure ventilation in 7 patients for their anesthetic management. During removal of a tumor around the motor speech center, anesthetic management including asleep-awake-asleep technique was applied for speech testing. The technique, insertion and re-insertion of i-gel, was needed and it was easy in all the patients. During positive-pressure ventilation, peak pressure, tidal volume both for inspiration and expiration, and endtidal-CO2 were not markedly altered. Leakage around i-gel, and its differences between inspiration and expiration were negligible, while the tidal volume was adequate. We conclude that i-gel is useful for anesthetic management for awake craniotomy procedure for both securing airway and ventilation.

  3. AWAKE, The Advanced Proton Driven Plasma Wakefield Acceleration Experiment at CERN

    NASA Astrophysics Data System (ADS)

    Gschwendtner, E.; Adli, E.; Amorim, L.; Apsimon, R.; Assmann, R.; Bachmann, A.-M.; Batsch, F.; Bauche, J.; Berglyd Olsen, V. K.; Bernardini, M.; Bingham, R.; Biskup, B.; Bohl, T.; Bracco, C.; Burrows, P. N.; Burt, G.; Buttenschön, B.; Butterworth, A.; Caldwell, A.; Cascella, M.; Chevallay, E.; Cipiccia, S.; Damerau, H.; Deacon, L.; Dirksen, P.; Doebert, S.; Dorda, U.; Farmer, J.; Fedosseev, V.; Feldbaumer, E.; Fiorito, R.; Fonseca, R.; Friebel, F.; Gorn, A. A.; Grulke, O.; Hansen, J.; Hessler, C.; Hofle, W.; Holloway, J.; Hüther, M.; Jaroszynski, D.; Jensen, L.; Jolly, S.; Joulaei, A.; Kasim, M.; Keeble, F.; Li, Y.; Liu, S.; Lopes, N.; Lotov, K. V.; Mandry, S.; Martorelli, R.; Martyanov, M.; Mazzoni, S.; Mete, O.; Minakov, V. A.; Mitchell, J.; Moody, J.; Muggli, P.; Najmudin, Z.; Norreys, P.; Öz, E.; Pardons, A.; Pepitone, K.; Petrenko, A.; Plyushchev, G.; Pukhov, A.; Rieger, K.; Ruhl, H.; Salveter, F.; Savard, N.; Schmidt, J.; Seryi, A.; Shaposhnikova, E.; Sheng, Z. M.; Sherwood, P.; Silva, L.; Soby, L.; Sosedkin, A. P.; Spitsyn, R. I.; Trines, R.; Tuev, P. V.; Turner, M.; Verzilov, V.; Vieira, J.; Vincke, H.; Wei, Y.; Welsch, C. P.; Wing, M.; Xia, G.; Zhang, H.

    2016-09-01

    The Advanced Proton Driven Plasma Wakefield Acceleration Experiment (AWAKE) aims at studying plasma wakefield generation and electron acceleration driven by proton bunches. It is a proof-of-principle R&D experiment at CERN and the world's first proton driven plasma wakefield acceleration experiment. The AWAKE experiment will be installed in the former CNGS facility and uses the 400 GeV/c proton beam bunches from the SPS. The first experiments will focus on the self-modulation instability of the long (rms ~12 cm) proton bunch in the plasma. These experiments are planned for the end of 2016. Later, in 2017/2018, low energy (~15 MeV) electrons will be externally injected into the sample wakefields and be accelerated beyond 1 GeV. The main goals of the experiment will be summarized. A summary of the AWAKE design and construction status will be presented.

  4. The development of one-stop wide-awake dupuytren's fasciectomy service: a retrospective review

    PubMed Central

    Bismil, QMK; Bismil, MSK; Bismil, Annamma; Neathey, Julia; Gadd, Judith; Roberts, Sue; Brewster, Jennifer

    2012-01-01

    Objectives To detail the transition to a totally one-stop wide-awake (OSWA) Dupuytren's contracture surgical service. Design Retrospective review of Dupuytren's component of last 1000 OSWA cases. Setting The UK's first totally one-stop wide-awake orthopaedic service. Participants 270 patients with Dupuytren's contracture out of the last 1000 OSWA cases. Main outcome measures Surgical outcomes, patient satisfaction and cost-effectiveness and efficiency. Results The OSWA Dupuytren's model is safe, efficient and effective; with a low complication rate, extremely high patient satisfaction; and cost-savings to the nhs of £2500 per case treated. The service saved the NHS approximately £675,000 for the 270 cases presented. Conclusions A totally one-stop wide-awake Dupuytren's Contracture service is practicable and feasible alternative to the conventional treatment pathway, with benefits in terms of efficiency and cost-effectiveness. PMID:22908029

  5. Intranasal live attenuated seasonal influenza vaccine: does not challenge current practice.

    PubMed

    2013-09-01

    Influenza vaccination of children is only justified when there is a risk of serious influenza complications. In 2012, a live attenuated vaccine for intranasal administration was authorised in the European Union for influenza prevention in individuals aged from 2 to less than 18 years. This type of vaccine has been available in the United States since 2003. Clinical evaluation of this live vaccine is based on three non-inferiority trials versus an injected inactivated vaccine. There are no specific trials in children at risk of serious influenza complications. Only one of these trials was double-blinded. Two trials involved children with a history of respiratory problems. Symptomatic influenza confirmed by viral culture was less frequent in these three trials after intranasal vaccination than after injection of the conventional vaccine (about 3 to 5% and 6 to 10%, respectively). There was no difference between the vaccines in terms of clinical complications of influenza, especially asthma exacerbations. Adverse effects attributed to the intranasal vaccine mainly consisted of local reactions such as rhinorrhoea and nasal congestion, as well as flu-like syndromes. Wheezing, respiratory tract infections and hospitalisation were more frequent with the intranasal vaccine than with the injected vaccine in children aged less than 1 year and in children with a history of severe respiratory illness. The intranasal vaccine is contraindicated in these children. The intranasal vaccine contains live attenuated virus strains and is therefore contraindicated in immunocompromised patients. US pharmacovigilance data suggest that severe allergic reactions to the intranasal vaccine, Guillain-Barré syndrome, and transmission of vaccine viruses to contacts are very rare. Intranasal administration seems to be more practical, especially for children. In practice, there is no firm evidence that this live attenuated influenza vaccine has any clinical advantages over injected vaccines

  6. [Awake Nasotracheal Intubation for a 4-Year-old Boy with an Oral Penetrating Toothbrush Injury].

    PubMed

    Kobayashi, Naoya; Ando, Kokichi; Saito, Kazutomo; Toyama, Hiroaki; Fudeta, Hiroto; Yamauchi, Masanori

    2015-09-01

    We report a case of an oral penetrating injury caused by a toothbrush in a 4-year-old 17-kg boy. The toothbrush was lodged in the right cervical region through the oral cavity, and emergency surgery for removal was planned under general anesthesia. Although mask ventilation was not possible because of the protruding toothbrush handle, awake nasotracheal intubation was successfully performed with a fiber-scope and intravenous fentanyl 25 μg. We conclude that appropriate analgesics could facilitate awake intubation in pediatric patients.

  7. Photoacoustic detection of functional responses in the motor cortex of awake behaving monkey during forelimb movement

    NASA Astrophysics Data System (ADS)

    Jo, Janggun; Zhang, Hongyu; Cheney, Paul D.; Yang, Xinmai

    2012-11-01

    Photoacoustic (PA) imaging was applied to detect the neuronal activity in the motor cortex of an awake, behaving monkey during forelimb movement. An adult macaque monkey was trained to perform a reach-to-grasp task while PA images were acquired through a 30-mm diameter implanted cranial chamber. Increased PA signal amplitude results from an increase in regional blood volume and is interpreted as increased neuronal activity. Additionally, depth-resolved PA signals enabled the study of functional responses in deep cortical areas. The results demonstrate the feasibility of utilizing PA imaging for studies of functional activation of cerebral cortex in awake monkeys performing behavioral tasks.

  8. Sampling phasic dopamine signaling with fast-scan cyclic voltammetry in awake behaving rats

    PubMed Central

    Fortin, SM; Cone, JJ; Ng-Evans, S; McCutcheon, JE; Roitman, MF

    2015-01-01

    Fast-scan cyclic voltammetry (FSCV) is an electrochemical technique which permits the in vivo measurement of extracellular fluctuations in multiple chemical species. The technique is frequently utilized to sample sub-second (phasic) concentration changes of the neurotransmitter dopamine in awake and behaving rats. Phasic dopamine signaling is implicated in reinforcement, goal-directed behavior, and locomotion and FSCV has been used to investigate how rapid changes in striatal dopamine concentration contribute to these and other behaviors. This unit describes the instrumentation and construction, implantation, and use of necessary components required to sample and analyze dopamine concentration changes in awake rats with FSCV. PMID:25559005

  9. Intranasal delivery of nanomicelle curcumin promotes corneal epithelial wound healing in streptozotocin-induced diabetic mice.

    PubMed

    Guo, Chuanlong; Li, Mengshuang; Qi, Xia; Lin, Guiming; Cui, Fenghua; Li, Fengjie; Wu, Xianggen

    2016-01-01

    Corneal nerves are mainly derived from the ophthalmic branch of the trigeminal ganglion (TG). Corneal neuropathy contributes to epithelial degenerative changes in diabetic keratopathy. Efficient drug delivery to TG may be beneficial for the treatment of diabetic keratopathy. This article described intranasal delivery of nanomicelle curcumin to correct pathophysiological conditions in TG to promote corneal epithelial/nerve wound healing in streptozotocin-induced diabetic mice. A diabetic mice model with corneal epithelium abrasion was established. Ocular topical and/or intranasal nanomicelle curcumin treatments were performed, and treatment efficacy and mechanisms of action were explored. Results showed that intranasal nanomicelle curcumin treatment promoted corneal epithelial wound healing and recovery of corneal sensation. Enhanced accumulation of reactive oxygen species, reduced free radical scavengers, increased mRNA expressions of inflammatory cytokines, and decreased mRNA expressions of neurotrophic factors in the cornea and TG neuron were observed in diabetic mice with corneal epithelium abrasions. Intranasal nanomicelle curcumin treatment effectively recovered these pathophysiological conditions, especially that of the TG neuron, and a strengthened recovery was observed with ocular topical combined with intranasal treatment. These findings indicated that intranasal curcumin treatment effectively helped promote diabetic corneal epithelial/nerve wound healing. This novel treatment might be a promising strengthened therapy for diabetic keratopathy. PMID:27405815

  10. Does insulin therapy for type 1 diabetes mellitus protect against Alzheimer's disease?

    PubMed

    Rdzak, Grzegorz M; Abdelghany, Osama

    2014-12-01

    Alzheimer's disease is the most common cause of dementia in the United States. A better understanding of the disease's underlying pathways may provide novel treatment and/or prevention strategies for this progressive chronic neurodegenerative disorder. In recent years, there has been a growing interest in the possible links between insulin and Alzheimer's disease. Insulin-induced hypoglycemia causes adaptive changes in the brain, including an improved ability to use alternative fuels. Insulin has been shown to facilitate reduction of intracellular amyloid plaque and downregulation of amyloid-β-derived diffusible ligand-binding sites. Insulin also promotes tau hypophosphorylation, which stabilizes microtubules and promotes tubulin polymerization. Excess exogenous insulin may also play a role in overcoming the decreased utilization and transport of glucose in patients with Alzheimer's disease. Intranasal insulin therapy may have beneficial effects on cognition and function in patients with Alzheimer's disease, as well as having only minor adverse effects, and this route of administration been the focus in clinical trials. These data support the mechanistic pathways that might link excess exogenous insulin administered to patients with type 1 diabetes mellitus to possible protection from Alzheimer's disease and provide a rationale for using insulin to prevent the disease in high-risk patients.

  11. Microsphere translocation and immunopotentiation in systemic tissues following intranasal administration.

    PubMed

    Eyles, J E; Bramwell, V W; Williamson, E D; Alpar, H O

    2001-09-14

    With a view to developing improved mucosal immunisation strategies, we have quantitatively investigated the uptake of fluorescent polystyrene carboxylate microspheres (1.1 microm diameter), using histology and fluorescence-activated cell sorting, following intranasal delivery to BALB/c mice. To qualify these biodistribution data, antigen specific memory and effector responses in the spleens of mice immunised nasally with Yersinia pestis V antigen loaded poly(lactide) (PLA) microspheres (1.5 microm diameter) were assessed at 4, 7 and 11 days. Irrespective of administration vehicle volume (10 or 50 microl), appreciable numbers of fluorescent microspheres were detected within nasal associated lymphoid tissues (NALT) and draining cervical lymph nodes. Nasal administration of the particles suspended in 50 microl volumes of phosphate-buffered saline (PBS) served to deposit the fluorescent microspheres throughout the respiratory tract (P<0.05). In these animals, appreciable particle uptake into the mediastinal lymph node was noted (P<0.05). Also, spleens removed from mice 10 days after fluorescent particle application contained significantly more microspheres if the suspension had been nasally instilled using a 50 microl volume (P<0.05). Appreciable memory (and effector from day 7) responses were detected in mediastinal lymph nodes removed from mice immunised nasally with 50 microl volumes of microparticulated or soluble V antigen. Immunological responses in splenic tissue removed 7 days after intranasal immunisation corroborated the thesis that the spleen can act as an inductive site following bronchopulmonary deposition of particulated antigen: upon exposure to V in vitro, splenic T-cells from mice nasally immunised with 50 microl volumes of microspheres incorporated statistically greater (P<0.05) quantities of [3H]thymidine into newly synthesised DNA than did T-cells from cohorts nasally immunised with 50 microl volumes of V in solution. Similarly, significant numbers

  12. Intranasal administration of oxytocin: behavioral and clinical effects, a review.

    PubMed

    Veening, Jan G; Olivier, Berend

    2013-09-01

    The intranasal (IN-) administration of substances is attracting attention from scientists as well as pharmaceutical companies. The effects are surprisingly fast and specific. The present review explores our current knowledge about the routes of access to the cranial cavity. 'Direct-access-pathways' from the nasal cavity have been described but many additional experiments are needed to answer a variety of open questions regarding anatomy and physiology. Among the IN-applied substances oxytocin (OT) has an extensive history. Originally applied in women for its physiological effects related to lactation and parturition, over the last decade most studies focused on their behavioral 'prosocial' effects: from social relations and 'trust' to treatment of 'autism'. Only very recently in a microdialysis study in rats and mice, the 'direct-nose-brain-pathways' of IN-OT have been investigated directly, implying that we are strongly dependent on results obtained from other IN-applied substances. Especially the possibility that IN-OT activates the 'intrinsic' OT-system in the hypothalamus as well needs further clarification. We conclude that IN-OT administration may be a promising approach to influence human communication but that the existing lack of information about the neural and physiological mechanisms involved is a serious problem for the proper understanding and interpretation of the observed effects.

  13. Development of risperidone liposomes for brain targeting through intranasal route.

    PubMed

    Narayan, Reema; Singh, Mohan; Ranjan, OmPrakash; Nayak, Yogendra; Garg, Sanjay; Shavi, Gopal V; Nayak, Usha Y

    2016-10-15

    The present paper is aimed at development of functionalized risperidone liposomes for brain targeting through nasal route for effective therapeutic management of schizophrenia. The risperidone liposomes were prepared by thin film hydration method. Various parameters such as lipid ratio and lipid to drug ratio were optimized by using Design-Expert(®) Software to obtain high entrapment with minimum vesicle size. The surface of the optimized liposomes was modified by coating stearylamine and MPEG-DSPE for enhanced penetration to the brain. The formulations were evaluated for vesicle size, zeta potential, and entrapment efficiency. The morphology was studied by Transmission Electron Microscopy (TEM). In vivo efficacy was assessed by performing pharmacokinetic study in Wistar albino rats following intranasal administration of the formulations in comparison to intravenous bolus administration of pure drug. The mean vesicle size of optimized liposomes ranged from 90 to 100nm with low polydispersity index (<0.5). The entrapment efficiency of optimized liposomes was between 50 and 60%, functionalized liposomes showed maximum entrapment. The TEM images showed predominantly spherical vesicles with smooth bilayered surface. All formulations showed prolonged diffusion controlled drug release. The in vivo results showed that liposomal formulations provided enhanced brain exposure. Among the formulations studied, PEGylated liposomes (LP-16) had shown greater uptake of risperidone into the brain than plasma. High brain targeting efficiency index for LP-16 indicating preferential transport of the drug to brain. The study demonstrated successful formulation of surface modified risperidone liposomes for nasal delivery with brain targeting potential.

  14. Development of risperidone liposomes for brain targeting through intranasal route.

    PubMed

    Narayan, Reema; Singh, Mohan; Ranjan, OmPrakash; Nayak, Yogendra; Garg, Sanjay; Shavi, Gopal V; Nayak, Usha Y

    2016-10-15

    The present paper is aimed at development of functionalized risperidone liposomes for brain targeting through nasal route for effective therapeutic management of schizophrenia. The risperidone liposomes were prepared by thin film hydration method. Various parameters such as lipid ratio and lipid to drug ratio were optimized by using Design-Expert(®) Software to obtain high entrapment with minimum vesicle size. The surface of the optimized liposomes was modified by coating stearylamine and MPEG-DSPE for enhanced penetration to the brain. The formulations were evaluated for vesicle size, zeta potential, and entrapment efficiency. The morphology was studied by Transmission Electron Microscopy (TEM). In vivo efficacy was assessed by performing pharmacokinetic study in Wistar albino rats following intranasal administration of the formulations in comparison to intravenous bolus administration of pure drug. The mean vesicle size of optimized liposomes ranged from 90 to 100nm with low polydispersity index (<0.5). The entrapment efficiency of optimized liposomes was between 50 and 60%, functionalized liposomes showed maximum entrapment. The TEM images showed predominantly spherical vesicles with smooth bilayered surface. All formulations showed prolonged diffusion controlled drug release. The in vivo results showed that liposomal formulations provided enhanced brain exposure. Among the formulations studied, PEGylated liposomes (LP-16) had shown greater uptake of risperidone into the brain than plasma. High brain targeting efficiency index for LP-16 indicating preferential transport of the drug to brain. The study demonstrated successful formulation of surface modified risperidone liposomes for nasal delivery with brain targeting potential. PMID:27593571

  15. Intranasal trigeminal sensitivity in subjects with allergic rhinitis.

    PubMed

    Doerfler, H; Hummel, T; Klimek, L; Kobal, G

    2006-01-01

    Trigeminal nerve endings of the human nasal mucosa are activated by chemical, physical or thermal stimuli. Activation of these A(delta) and C fibers can be quantified through the recording of chemo-somatosensory event-related potentials (ERP). The aim of this study was to investigate whether allergy-related activation of trigeminal nerve endings leads to changes in their responsiveness to intranasal trigeminal stimulation. Gaseous carbon dioxide (CO(2)) stimuli were applied in three sessions (baseline, after NaCl solution and after allergen application) to the nasal mucosa of 13 subjects with allergic rhinitis. Chemo-somatosensory ERP were recorded, and subjects rated the intensity of rhinitis symptoms. Administration of allergen produced a significant shortening of chemo-somatosensory ERP peak latencies P1 and N1. Observed changes of latencies were in line with rhinitis symptoms subjects indicated during the session. In addition, there was a negative relation between the general symptom score and ERP peak latencies, obtained both at baseline and after allergen exposure. In conclusion, it is hypothesized that in patients suffering from allergic rhinitis, nasal itching and sneezing after allergen exposure are, at least in part, clinical correlates of the activation of trigeminal nerve endings due to local inflammatory mechanisms. The correlations between ERP latencies and the patients' symptoms indicate that ERP latencies may possess a predictive value of the subjects' responsiveness to allergens.

  16. Intranasal Midazolam Sedation in a Pediatric Emergency Dental Clinic.

    PubMed

    Peerbhay, Fathima; Elsheikhomer, Ahmed Mahgoub

    2016-01-01

    The purpose of this study was to compare the effectiveness and recovery times of 0.3 and 0.5 mg/kg intranasal midazolam (INM) administered with a mucosal atomizer device (MAD) in a pediatric emergency dental hospital clinic. One hundred eighteen children aged from 4 to 6 years were randomly administered either 0.3 or 0.5 mg/kg INM via an MAD in a triple-blinded randomized controlled trial. Sedation was achieved to some degree in 100% of the sample. The pulse rate and oxygen saturation were within the normal range in 99% of the patients. A burning sensation was reported in 9% of children. The recovery time of the 0.5 mg/kg group was statistically longer than that of the 0.3 mg/kg group (16.5 vs 18.8 minutes) but the difference was not clinically significant. The findings of this study show that 0.3 or 0.5 mg/kg doses of INM resulted in safe and effective sedation. The 0.5 mg/kg dose was more effective than the 0.3 mg/kg dose in reducing anxiety. PMID:27585415

  17. Stimulus Selection for Intranasal Sensory Isolation: Eugenol Is an Irritant

    PubMed Central

    Wise, Paul M.; Lundström, Johan N.

    2012-01-01

    Both the olfactory and the trigeminal systems are able to respond to intranasal presentations of chemical vapor. Accordingly, when the nose detects a volatile chemical, it is often unclear whether we smell it, feel it, or both. The distinction may often be unimportant in our everyday perception of fragrances or aromas, but it can matter in experiments that purport to isolate olfactory processes or study the interaction between olfaction and chemesthesis. Researchers turn to a small pool of compounds that are believed to be “pure olfactory” stimuli with little or no trigeminal impact. The current report reexamines one such commonly used compound, namely eugenol, a flavor and fragrance ingredient that has anesthetic properties under some conditions. Using a standard method involving many trials during an experimental session (Experiment 1), subjects were unable to reliably lateralize eugenol, consistent with claims that this compound is detected primarily through olfaction. However, with more limited exposure (Experiments 2 and 3), subjects were able to lateralize eugenol. We speculate that anesthetic properties of eugenol could blunt its trigeminal impact in some paradigms. Regardless, the current experiments suggest that eugenol can in fact stimulate the trigeminal nerve but in a complex concentration–dependent manner. Implications and strategies for selection of model odorants are discussed. PMID:22293937

  18. Pharmacokinetic Modeling of Intranasal Scopolamine in Plasma Saliva and Urine

    NASA Technical Reports Server (NTRS)

    Wu, L.; Tam, V. H.; Chow, D. S. L.; Putcha, L.

    2015-01-01

    An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS). The bioavailability and pharmacokinetics (PK) were evaluated under IND (Investigational New Drug) guidelines. The aim of the project was to develop a PK model that can predict the relationships among plasma, saliva and urinary scopolamine concentrations using data collected from the IND clinical trial protocol with INSCOP. Twelve healthy human subjects were administered at three dose levels (0.1, 0.2 and 0.4 mg) of INSCOP. Serial blood, saliva and urine samples were collected between 5 min to 24 h after dosing and scopolamine concentrations were measured by using a validated LC-MS-MS assay. PK compartmental models, using actual dosing and sampling time, were established using Phoenix (version 1.2). Model selection was based on a likelihood ratio test on the difference of criteria (-2LL (i.e. log-likelihood ratio test)) and comparison of the quality of fit plots. The results: Predictable correlations among scopolamine concentrations in compartments of plasma, saliva and urine were established, and for the first time the model satisfactorily predicted the population and individual PK of INSCOP in plasma, saliva and urine. The model can be utilized to predict the INSCOP plasma concentration by saliva and urine data, and it will be useful for monitoring the PK of scopolamine in space and other remote environments using non-invasive sampling of saliva and/or urine.

  19. Intranasal epidermal growth factor treatment rescues neonatal brain injury

    NASA Astrophysics Data System (ADS)

    Scafidi, Joseph; Hammond, Timothy R.; Scafidi, Susanna; Ritter, Jonathan; Jablonska, Beata; Roncal, Maria; Szigeti-Buck, Klara; Coman, Daniel; Huang, Yuegao; McCarter, Robert J.; Hyder, Fahmeed; Horvath, Tamas L.; Gallo, Vittorio

    2014-02-01

    There are no clinically relevant treatments available that improve function in the growing population of very preterm infants (less than 32 weeks' gestation) with neonatal brain injury. Diffuse white matter injury (DWMI) is a common finding in these children and results in chronic neurodevelopmental impairments. As shown recently, failure in oligodendrocyte progenitor cell maturation contributes to DWMI. We demonstrated previously that the epidermal growth factor receptor (EGFR) has an important role in oligodendrocyte development. Here we examine whether enhanced EGFR signalling stimulates the endogenous response of EGFR-expressing progenitor cells during a critical period after brain injury, and promotes cellular and behavioural recovery in the developing brain. Using an established mouse model of very preterm brain injury, we demonstrate that selective overexpression of human EGFR in oligodendrocyte lineage cells or the administration of intranasal heparin-binding EGF immediately after injury decreases oligodendroglia death, enhances generation of new oligodendrocytes from progenitor cells and promotes functional recovery. Furthermore, these interventions diminish ultrastructural abnormalities and alleviate behavioural deficits on white-matter-specific paradigms. Inhibition of EGFR signalling with a molecularly targeted agent used for cancer therapy demonstrates that EGFR activation is an important contributor to oligodendrocyte regeneration and functional recovery after DWMI. Thus, our study provides direct evidence that targeting EGFR in oligodendrocyte progenitor cells at a specific time after injury is clinically feasible and potentially applicable to the treatment of premature children with white matter injury.

  20. Biomineralized vaccine nanohybrid for needle-free intranasal immunization.

    PubMed

    Wang, Xiaoyu; Yang, Dong; Li, Shihua; Xu, Xurong; Qin, Cheng-Feng; Tang, Ruikang

    2016-11-01

    Frequent outbreaks and the rapid global spread of infectious diseases have increased the urgent need for massive vaccination especially in countries with limited resources. Intranasal vaccination facilitates the mass vaccination via needle-free delivery of vaccine through nasal mucosal surfaces. Inspired by the strong capability of calcium phosphate (CaP) materials to adhere to cells and tissues, we propose to improve nasal vaccination by using a biomineralization-based strategy. The vaccine nanohybrid was obtained by covering the viral surface with CaP nanoshell, which changed the physiochemical properties of original vaccine, resulting in the increase of mucosal adhesion to the nasal tissues. The core-shell structure was beneficial for the receptor-independent uptake and the induction of elevated local IgA response within the nasal cavity. Moreover, the vaccine complex elicited enhanced systemic antibody response that neutralized wild type of dengue virus and promoted the systemic cellular immune responses. This achievement presents the potential of CaP based vaccine biomineralization for the fabrication of needle-free vaccine formulation. PMID:27575530

  1. Systemic and Behavioral Effects of Intranasal Administration of Silver Nanoparticles

    PubMed Central

    Davenport, Laurie L.; Hsieh, Heidi; Eppert, Bryan L.; Carreira, Vinicius S.; Krishan, Mansi; Ingle, Taylor; Howard, Paul C.; Williams, Michael T.; Vorhees, Charles V.; Genter, Mary Beth

    2015-01-01

    Use of silver nanoparticles (AgNPs) for their antimicrobial properties is widespread. Much of the previous work on the toxicity of AgNPs has been conducted in vitro or following oral or intravenous administration in vivo. Intranasal (IN) instillation of AgNPs mimics inhalation exposure and allows further exploration of the toxicity of these particles via respiratory tract exposure. The present study involved 1) single-dose exposures to assess tissue distribution and toxicity and 2) repeated exposures to assess behavioral effects of IN AgNP exposure (nominally uncoated 25 nm AgNP). AgNP deposition was localized in the liver, gut-associated lymphoid tissue, and brain. Decrease cellularity in spleen follicles was observed in treated mice, along with changes in cell number and populations in the spleen. The splenic GSH:GSSG ratio was also reduced following AgNP exposure. Expression of the oxidative stress-responsive gene Hmox1 was elevated in the hippocampus, but not cortex of treated mice, as was the level of HMOX1 protein. Mice receiving 7 days of IN exposure to 50 mg/kg AgNPs exhibited similar learning- and memory-related behaviors to control mice, except that treated mice spent significantly less time in the target quadrant of the Morris Water Maze during the acquisition phase probe trial. These findings indicate systemic distribution and toxicity following IN administration of AgNPs. PMID:26340819

  2. The Sleep Elaboration-Awake Pruning (SEAP) theory of memory: long term memories grow in complexity during sleep and undergo selection while awake. Clinical, psychopharmacological and creative implications.

    PubMed

    Charlton, Bruce G; Andras, Peter

    2009-07-01

    Long term memory (LTM) systems need to be adaptive such that they enhance an organism's reproductive fitness and self-reproducing in order to maintain their complexity of communications over time in the face of entropic loss of information. Traditional 'representation-consolidation' accounts conceptualize memory adaptiveness as due to memories being 'representations' of the environment, and the longevity of memories as due to 'consolidation' processes. The assumption is that memory representations are formed while an animal is awake and interacting with the environment, and these memories are consolidated mainly while the animal is asleep. So the traditional view of memory is 'instructionist' and assumes that information is transferred from the environment into the brain. By contrast, we see memories as arising endogenously within the brain's LTM system mainly during sleep, to create complex but probably maladaptive memories which are then simplified ('pruned') and selected during the awake period. When awake the LTM system is brought into a more intense interaction with past and present experience. Ours is therefore a 'selectionist' account of memory, and could be termed the Sleep Elaboration-Awake Pruning (or SEAP) theory. The SEAP theory explains the longevity of memories in the face of entropy by the tendency for memories to grow in complexity during sleep; and explains the adaptiveness of memory by selection for consistency with perceptions and previous memories during the awake state. Sleep is therefore that behavioural state during which most of the internal processing of the system of LTM occurs; and the reason sleep remains poorly understood is that its primary activity is the expansion of long term memories. By re-conceptualizing the relationship between memory, sleep and the environment; SEAP provides a radically new framework for memory research, with implications for the measurement of memory and the design of empirical investigations in clinical

  3. Differential Effects of Cocaine on Dopamine Neuron Firing in Awake and Anesthetized Rats

    PubMed Central

    Koulchitsky, Stanislav; De Backer, Benjamin; Quertemont, Etienne; Charlier, Corinne; Seutin, Vincent

    2012-01-01

    Cocaine (benzoylmethylecgonine), a natural alkaloid, is a powerful psychostimulant and a highly addictive drug. Unfortunately, the relationships between its behavioral and electrophysiological effects are not clear. We investigated the effects of cocaine on the firing of midbrain dopaminergic (DA) neurons, both in anesthetized and awake rats, using pre-implanted multielectrode arrays and a recently developed telemetric recording system. In anesthetized animals, cocaine (10 mg/kg, intraperitoneally) produced a general decrease of the firing rate and bursting of DA neurons, sometimes preceded by a transient increase in both parameters, as previously reported by others. In awake rats, however, injection of cocaine led to a very different pattern of changes in firing. A decrease in firing rate and bursting was observed in only 14% of DA neurons. Most of the other DA neurons underwent increases in firing rate and bursting: these changes were correlated with locomotor activity in 52% of the neurons, but were uncorrelated in 29% of them. Drug concentration measurements indicated that the observed differences between the two conditions did not have a pharmacokinetic origin. Taken together, our results demonstrate that cocaine injection differentially affects the electrical activity of DA neurons in awake and anesthetized states. The observed increases in neuronal activity may in part reflect the cocaine-induced synaptic potentiation found ex vivo in these neurons. Our observations also show that electrophysiological recordings in awake animals can uncover drug effects, which are masked by general anesthesia. PMID:22298123

  4. Awake nasotracheal fiberoptic intubation and self-positioning followed by anesthesia induction in prone patients

    PubMed Central

    Heng, Lei; Wang, Ming-Yu; Sun, Hou-Liang; Zhu, Shan-Shan

    2016-01-01

    Abstract Anesthesia followed by placement in the prone position takes time and may result in complications. This study aimed to evaluate the feasibility of awake nasotracheal fiberoptic intubation and self-positioning followed by anesthesia induction in prone-positioned patients under general anesthesia. Sixty-two patients (ASA physical status I–II) scheduled for awake nasotracheal fiberoptic intubation and prone self-positioning before surgery under general anesthesia were selected. Patient preparation began with detailed preoperative counseling regarding the procedure. Premedication with sedative and antisialagogue was followed by airway anesthesia with topical lidocaine; then, awake nasotracheal fiberoptic intubation was carried out. The patients then positioned themselves comfortably before induction of general anesthesia. The changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), incidence of coughing or gagging, and rate pressure product (RPP) were assessed. Statistical analysis was performed with repeated-measures one-way analysis of variance. Fifty-eight of the 62 patients completed prone self-positioning smoothly. Compared with values before intubation, SBP, DBP, HR, and RPP were slightly increased after intubation, although the difference was not statistically significant (P > 0.05). One patient had moderate coughing and 1 patient had gagging during prone self-positioning, which were tolerable. These findings indicated that awake nasotracheal fiberoptic intubation and self-positioning followed by induction of anesthesia is safe and feasible alternative to routine prone positioning after induction of general anesthesia. PMID:27512858

  5. a-Band Oscillations in Intracellular Membrane Potentials of Dentate Gyrus Neurons in Awake Rodents

    ERIC Educational Resources Information Center

    Anderson, Ross W.; Strowbridge, Ben W.

    2014-01-01

    The hippocampus and dentate gyrus play critical roles in processing declarative memories and spatial information. Dentate granule cells, the first relay in the trisynaptic circuit through the hippocampus, exhibit low spontaneous firing rates even during locomotion. Using intracellular recordings from dentate neurons in awake mice operating a…

  6. Noninvasive high-speed photoacoustic tomography of cerebral hemodynamics in awake-moving rats

    PubMed Central

    Tang, Jianbo; Xi, Lei; Zhou, Junli; Huang, Hua; Zhang, Tao; Carney, Paul R; Jiang, Huabei

    2015-01-01

    We present a noninvasive method of photoacoustic tomography (PAT) for imaging cerebral hemodynamics in awake-moving rats. The wearable PAT (wPAT) system has a size of 15 mm in height and 33 mm in diameter, and a weight of ~8 g (excluding cabling). The wPAT achieved an imaging rate of 3.33 frames/s with a lateral resolution of 243 μm. Animal experiments were designed to show wPAT feasibility for imaging cerebral hemodynamics on awake-moving animals. Results showed that the cerebral oxy-hemoglobin and deoxy-hemoglobin changed significantly in response to hyperoxia; and, after the injection of pentylenetetrazol (PTZ), cerebral blood volume changed faster over time and larger in amplitude for rats in awake-moving state compared with rats under anesthesia. By providing a light-weight, high-resolution technology for in vivo monitoring of cerebral hemodynamics in awake-behaving animals, it will be possible to develop a comprehensive understanding on how activity alters hemodynamics in normal and diseased states. PMID:26082016

  7. Awake craniotomy in a patient with ejection fraction of 10%: considerations of cerebrovascular and cardiovascular physiology.

    PubMed

    Meng, Lingzhong; Weston, Stephen D; Chang, Edward F; Gelb, Adrian W

    2015-05-01

    A 37-year-old man with nonischemic 4-chamber dilated cardiomyopathy and low-output cardiac failure (estimated ejection fraction of 10%) underwent awake craniotomy for a low-grade oligodendroglioma resection under monitored anesthesia care. The cerebrovascular and cardiovascular physiologic challenges and our management of this patient are discussed.

  8. Brain Uptake of Neurotherapeutics after Intranasal versus Intraperitoneal Delivery in Mice

    PubMed Central

    Chauhan, Mihir B.; Chauhan, Neelima B.

    2015-01-01

    There is a growing global prevalence of neurodegenerative diseases such as Alzheimer’s disease and dementia. Current treatment for neurodegenerative diseases is limited due to the blood brain barrier’s ability to restrict the entry of therapeutics to the brain. In that context, direct delivery of drugs from nose to brain has gained emerging interest as an important alternative to oral and parenteral routes of administration. Although there are considerable reports showing promising results after intranasal drug delivery in various disease-models and investigatory human clinical trials, there are very few studies showing a detailed pharmacokinetics with regard to the uptake and retention of intranasally delivered material(s) within specific brain regions, which are critical determining factors for dosing conditions and optimal treatment regimen. This investigation compared a time-dependent brain uptake and resident time of various radiolabeled candidate neurotherapeutics after a single bolus intranasal or intraperitoneal administration in mice. Results indicate that the brain uptake of intranasally delivered therapeutic(s) is > 5 times greater than that after intraperitoneal delivery. The peak uptake and resident time of all intranasally delivered test therapeutics for all brain regions is observed to be between 30min-12h, depending upon the distance of brain region from the site of administration, followed by gradual fading of radioactive counts by 24h post intranasal administration. Current study confirms the usefulness of intranasal administration as a non- invasive and efficient means of delivering therapeutics to the brain to treat neurodegenerative diseases including Alzheimer’s disease. PMID:26366437

  9. Characterization of Scale-Free Properties of Human Electrocorticography in Awake and Slow Wave Sleep States

    PubMed Central

    Zempel, John M.; Politte, David G.; Kelsey, Matthew; Verner, Ryan; Nolan, Tracy S.; Babajani-Feremi, Abbas; Prior, Fred; Larson-Prior, Linda J.

    2012-01-01

    Like many complex dynamic systems, the brain exhibits scale-free dynamics that follow power-law scaling. Broadband power spectral density (PSD) of brain electrical activity exhibits state-dependent power-law scaling with a log frequency exponent that varies across frequency ranges. Widely divergent naturally occurring neural states, awake and slow wave sleep (SWS), were used to evaluate the nature of changes in scale-free indices of brain electrical activity. We demonstrate two analytic approaches to characterizing electrocorticographic (ECoG) data obtained during awake and SWS states. A data-driven approach was used, characterizing all available frequency ranges. Using an equal error state discriminator (EESD), a single frequency range did not best characterize state across data from all six subjects, though the ability to distinguish awake and SWS ECoG data in individual subjects was excellent. Multi-segment piecewise linear fits were used to characterize scale-free slopes across the entire frequency range (0.2–200 Hz). These scale-free slopes differed between awake and SWS states across subjects, particularly at frequencies below 10 Hz and showed little difference at frequencies above 70 Hz. A multivariate maximum likelihood analysis (MMLA) method using the multi-segment slope indices successfully categorized ECoG data in most subjects, though individual variation was seen. In exploring the differences between awake and SWS ECoG data, these analytic techniques show that no change in a single frequency range best characterizes differences between these two divergent biological states. With increasing computational tractability, the use of scale-free slope values to characterize ECoG and EEG data will have practical value in clinical and research studies. PMID:22701446

  10. Induction of systemic immune responses to measles virus synthetic peptides administered intranasally.

    PubMed

    Hathaway, L J; Partidos, C D; Vohra, P; Steward, M W

    1995-11-01

    A systemic antibody response was induced when a chimeric peptide containing two copies of a promiscuous T-cell epitope and one copy of a B-cell epitope (TTB) from the fusion protein of measles virus (MV) was administered to mice intranasally without adjuvant. A higher antibody titre was produced when the peptide was administered intranasally with cholera toxin B subunit (CTB) as an adjuvant and these antibodies crossreacted with the MV. Furthermore, splenocytes from intranasally immunized mice proliferated in vitro in the presence of the TTB peptide. The immune response following intranasal immunization with the peptide was influenced by the MHC haplotype of the strain of mice used. Thus CBA and BALB/c mice were high responders whereas C57BL/6 mice were low responders. Although peptide administered intranasally with CTB to CBA mice induced an immune response, no significant protection was observed against intra-cranial challenge with canine distemper virus which is antigenically related to MV. PMID:8578832

  11. Intranasal immunization with protective antigen of Bacillus anthracis induces a long-term immunological memory response.

    PubMed

    Woo, Sun-Je; Kang, Seok-Seong; Park, Sung-Moo; Yang, Jae Seung; Song, Man Ki; Yun, Cheol-Heui; Han, Seung Hyun

    2015-10-01

    Although intranasal vaccination has been shown to be effective for the protection against inhalational anthrax, establishment of long-term immunity has yet to be achieved. Here, we investigated whether intranasal immunization with recombinant protective antigen (rPA) of Bacillus anthracis induces immunological memory responses in the mucosal and systemic compartments. Intranasal immunization with rPA plus cholera toxin (CT) sustained PA-specific antibody responses for 6 months in lung, nasal washes, and vaginal washes as well as serum. A significant induction of PA-specific memory B cells was observed in spleen, cervical lymph nodes (CLNs) and lung after booster immunization. Furthermore, intranasal immunization with rPA plus CT remarkably generated effector memory CD4(+) T cells in the lung. PA-specific CD4(+) T cells preferentially increased the expression of Th1- and Th17-type cytokines in lung, but not in spleen or CLNs. Collectively, the intranasal immunization with rPA plus CT promoted immunologic memory responses in the mucosal and systemic compartments, providing long-term immunity.

  12. Iatrogenic Cushing's Syndrome Due to Intranasal Usage of Ophthalmic Dexamethasone: A Case Report.

    PubMed

    Orton, Sarah; Censani, Marisa

    2016-05-01

    Iatrogenic Cushing's syndrome (ICS) is caused by exogenous corticosteroid administration with suppression of the hypothalamic-pituitary-adrenal axis. It has been commonly described with oral and topical steroid use, but scarce reports have documented intranasal steroid usage as the etiology in infancy. In this article, we describe a case of a 4-month-old infant who developed ICS after 6 weeks of intranasal dexamethasone ophthalmic solution administration for nasal obstruction. To our knowledge, this is the youngest patient reported with ICS due to intranasal use of a prescribed dose of an ophthalmic steroid. His hypothalamic-pituitary-adrenal axis recovered fully 4.5 months after steroid discontinuation. Because of the small body surface area and supine position during administration, infants are particularly susceptible to ICS. Given that intranasal steroids are commonly prescribed to infants and children for a variety of diagnoses, this case highlights the risks inherent in the use of intranasal steroid drops, particularly in young infants, for both adrenal suppression and linear growth deceleration, even with short-term use. Close monitoring of these patients' height and weight should occur while on steroid treatment, with every effort made to decrease or discontinue steroid use when possible. PMID:27244810

  13. Intranasal hydroxypropyl-β-cyclodextrin-adjuvanted influenza vaccine protects against sub-heterologous virus infection.

    PubMed

    Kusakabe, Takato; Ozasa, Koji; Kobari, Shingo; Momota, Masatoshi; Kishishita, Natsuko; Kobiyama, Kouji; Kuroda, Etsushi; Ishii, Ken J

    2016-06-01

    Intranasal vaccination with inactivated influenza viral antigens is an attractive and valid alternative to currently available influenza (flu) vaccines; many of which seem to need efficient and safe adjuvant, however. In this study, we examined whether hydroxypropyl-β-cyclodextrin (HP-β-CD), a widely used pharmaceutical excipient to improve solubility and drug delivery, can act as a mucosal adjuvant for intranasal flu vaccines. We found that intranasal immunization of mice with hemagglutinin split- as well as inactivated whole-virion influenza vaccine with HP-β-CD resulted in secretion of antigen-specific IgA and IgGs in the airway mucosa and the serum as well. As a result, both HP-β-CD adjuvanted-flu intranasal vaccine protected mice against lethal challenge with influenza virus, equivalent to those induced by experimental cholera toxin-adjuvanted ones. Of note, intranasal use of HP-β-CD as an adjuvant induced significantly lower antigen-specific IgE responses than that induced by aluminum salt adjuvant. These results suggest that HP-β-CD may be a potent mucosal adjuvant for seasonal and pandemic influenza vaccine. PMID:27160037

  14. Preparation of lorazepam-loaded microemulsions for intranasal delivery and its pharmacokinetics.

    PubMed

    Yao, J; Hou, L; Zhou, J P; Zhang, Z Q; Sun, L

    2009-10-01

    The purpose of this study was to develop a microemulsion system for intranasal delivery of lorazepam. The phase behavior and properties of microemulsions were characterized in a pseudo-ternary system composed of Cremophor EL 35/Transcutol P/Lauroglycol FCC or Labrafil M 1944CS/water, and intranasal absorption of lorazepam from microemulsions was investigated in rabbit. The microemulsions, comprising of FCC, Cremophor EL 35/Transcutol P (1.5:1) and water, were optimal for intranasal delivery of lorazepam. These systems had a higher solubilization capacity with the particle size of <150 nm, and were stable at ambient conditions for at least six months. In vivo absorption studies showed that intranasal absorption of lorazepam from microemulsions at 0.38 mg/kg had the larger AUC(0-t), the longer half-life and the prolonged circulation time with the mean bioavailability of 80.84% for ME2 and 63.48% for ME8 as compared to the intramuscular injection at 0.16 mg/kg. These results indicate that microemulsions may bea promising approach for the intranasal delivery of lorazepam. PMID:19947165

  15. Evaluation of the effectiveness and safety of chitosan derivatives as adjuvants for intranasal vaccines.

    PubMed

    Kobayashi, Takashi; Fukushima, Kenji; Sannan, Takanori; Saito, Noriko; Takiguchi, Yasuyuki; Sato, Yuko; Hasegawa, Hideki; Ishikawa, Koichi

    2013-04-01

    Intranasal immunization is currently used to deliver live virus vaccines such as influenza. However, to develop an intranasal vaccine to deliver inactivated virus, a safe and effective adjuvant is necessary to enhance the mucosal immune response. Here, we demonstrate the effectiveness of a chitosan microparticle (1-20 μm, 50 kDa, degree of deacetylation=85%) and a cationized chitosan (1000 kDa, degree of deacetylation=85%) derived from natural crab shells as adjuvants for an intranasal vaccine candidate. We examined the effectiveness of chitosan derivatives as an adjuvant by co-administering them with ovalbumin (OVA) intranasally in BALB/c mice, polymeric Ig receptor knockout (pIgR-KO) mice, and cynomolgus monkeys (Macaca fascicularis). pIgR-KO mice were used to evaluate S-IgA production on the mucosal surface without nasal swab collection. Administration of OVA with chitosan microparticles or cationized chitosan induced a high OVA-specific IgA response in the serum of pIgR-KO mice and a high IgG response in the serum of BALB/c mice and cynomolgus monkeys. We also found that administration of chitosan derivatives did not have a detrimental effect on cynomolgus monkeys as determined by complete blood count, blood chemistries, and gross pathology results. These results suggest that chitosan derivatives are safe and effective mucosal adjuvants for intranasal vaccination.

  16. Nanogel antigenic protein-delivery system for adjuvant-free intranasal vaccines.

    PubMed

    Nochi, Tomonori; Yuki, Yoshikazu; Takahashi, Haruko; Sawada, Shin-ichi; Mejima, Mio; Kohda, Tomoko; Harada, Norihiro; Kong, Il Gyu; Sato, Ayuko; Kataoka, Nobuhiro; Tokuhara, Daisuke; Kurokawa, Shiho; Takahashi, Yuko; Tsukada, Hideo; Kozaki, Shunji; Akiyoshi, Kazunari; Kiyono, Hiroshi

    2010-07-01

    Nanotechnology is an innovative method of freely controlling nanometre-sized materials. Recent outbreaks of mucosal infectious diseases have increased the demands for development of mucosal vaccines because they induce both systemic and mucosal antigen-specific immune responses. Here we developed an intranasal vaccine-delivery system with a nanometre-sized hydrogel ('nanogel') consisting of a cationic type of cholesteryl-group-bearing pullulan (cCHP). A non-toxic subunit fragment of Clostridium botulinum type-A neurotoxin BoHc/A administered intranasally with cCHP nanogel (cCHP-BoHc/A) continuously adhered to the nasal epithelium and was effectively taken up by mucosal dendritic cells after its release from the cCHP nanogel. Vigorous botulinum-neurotoxin-A-neutralizing serum IgG and secretory IgA antibody responses were induced without co-administration of mucosal adjuvant. Importantly, intranasally administered cCHP-BoHc/A did not accumulate in the olfactory bulbs or brain. Moreover, intranasally immunized tetanus toxoid with cCHP nanogel induced strong tetanus-toxoid-specific systemic and mucosal immune responses. These results indicate that cCHP nanogel can be used as a universal protein-based antigen-delivery vehicle for adjuvant-free intranasal vaccination. PMID:20562880

  17. Nanogel antigenic protein-delivery system for adjuvant-free intranasal vaccines

    NASA Astrophysics Data System (ADS)

    Nochi, Tomonori; Yuki, Yoshikazu; Takahashi, Haruko; Sawada, Shin-Ichi; Mejima, Mio; Kohda, Tomoko; Harada, Norihiro; Kong, Il Gyu; Sato, Ayuko; Kataoka, Nobuhiro; Tokuhara, Daisuke; Kurokawa, Shiho; Takahashi, Yuko; Tsukada, Hideo; Kozaki, Shunji; Akiyoshi, Kazunari; Kiyono, Hiroshi

    2010-07-01

    Nanotechnology is an innovative method of freely controlling nanometre-sized materials. Recent outbreaks of mucosal infectious diseases have increased the demands for development of mucosal vaccines because they induce both systemic and mucosal antigen-specific immune responses. Here we developed an intranasal vaccine-delivery system with a nanometre-sized hydrogel (`nanogel') consisting of a cationic type of cholesteryl-group-bearing pullulan (cCHP). A non-toxic subunit fragment of Clostridium botulinum type-A neurotoxin BoHc/A administered intranasally with cCHP nanogel (cCHP-BoHc/A) continuously adhered to the nasal epithelium and was effectively taken up by mucosal dendritic cells after its release from the cCHP nanogel. Vigorous botulinum-neurotoxin-A-neutralizing serum IgG and secretory IgA antibody responses were induced without co-administration of mucosal adjuvant. Importantly, intranasally administered cCHP-BoHc/A did not accumulate in the olfactory bulbs or brain. Moreover, intranasally immunized tetanus toxoid with cCHP nanogel induced strong tetanus-toxoid-specific systemic and mucosal immune responses. These results indicate that cCHP nanogel can be used as a universal protein-based antigen-delivery vehicle for adjuvant-free intranasal vaccination.

  18. Intranasal T-LysYal® as adjunctive therapy for patients after functional endoscopic sinus surgery.

    PubMed

    Gelardi, M; Taliente, S; Fiorella, M L; Quaranta, N; De Candia, N; Russo, C; Mola, P; Ciofalo, A; Zambetti, G; Cantone, E; Arnone, F; Macchi, A; Rosso, P; Ciprandi, G

    2016-01-01

    Functional Endoscopic Sinus Surgery (FESS) is a common day surgery technique for upper airway disorders. Hyaluronic acid (HA) is a fundamental component of the human connective tissue. HA may exert reparative, anti-inflammatory and immune-modulating activities. Recently, a new intranasal HA formulation has been proposed: a supramolecular system containing lysine hyaluronate, thymine and sodium chloride (T-LysYal®). This randomized study investigated whether intranasal T-LysYal® (RinoLysYal®, Farmigea, Italy) was able to reduce symptom severity, endoscopic features, and nasal cytology in 83 patients (49 males and 34 females mean age 45.4±6.2 years) treated with FESS. All patients were treated with isotonic saline solution for 4 weeks, and a sub-group (active group) was also treated with intranasal T-LysYal®. Patients were visited at baseline, after treatment, and after 4-week follow-up. Intranasal T-LysYal® treatment significantly reduced the quote of patients with symptoms, endoscopic features, and inflammatory cells in comparison to isotonic solution. In conclusion, the present study demonstrates that intranasal T-LysYal® is able to significantly improve patients after FESS and its effect is long lasting. PMID:27049103

  19. Intranasal inhalation of oxytocin improves face processing in developmental prosopagnosia.

    PubMed

    Bate, Sarah; Cook, Sarah J; Duchaine, Bradley; Tree, Jeremy J; Burns, Edwin J; Hodgson, Timothy L

    2014-01-01

    Developmental prosopagnosia (DP) is characterised by a severe lifelong impairment in face recognition. In recent years it has become clear that DP affects a substantial number of people, yet little work has attempted to improve face processing in these individuals. Intriguingly, recent evidence suggests that intranasal inhalation of the hormone oxytocin can improve face processing in unimpaired participants, and we investigated whether similar findings might be noted in DP. Ten adults with DP and 10 matched controls were tested using a randomized placebo-controlled double-blind within-subject experimental design (AB-BA). Each participant took part in two testing sessions separated by a 14-25 day interval. In each session, participants inhaled 24 IU of oxytocin or placebo spray, followed by a 45 min resting period to allow central oxytocin levels to plateau. Participants then completed two face processing tests: one assessing memory for a set of newly encoded faces, and one measuring the ability to match simultaneously presented faces according to identity. Participants completed the Multidimensional Mood Questionnaire (MMQ) at three points in each testing session to assess the possible mood-altering effects of oxytocin and to control for attention and wakefulness. Statistical comparisons revealed an improvement for DP but not control participants on both tests in the oxytocin condition, and analysis of scores on the MMQ indicated that the effect cannot be attributed to changes in mood, attention or wakefulness. This investigation provides the first evidence that oxytocin can improve face processing in DP, and the potential neural underpinnings of the findings are discussed alongside their implications for the treatment of face processing disorders.

  20. Pharmacokinetics of Scopolamine Intranasal Gel Formulation (INSCOP) During Antiorthostatic Bedrest

    NASA Technical Reports Server (NTRS)

    Putcha, L.; Du, B.; Daniels, V.

    2010-01-01

    Space Motion Sickness (SMS) is experienced during early flight days of space missions and on reduced gravity simulation flights which require treatment with medications. Oral administration of scopolamine tablets is still a common practice to prevent SMS symptoms. Bioavailability of medications taken by mouth for SMS is often low and variable. Intranasal (IN) administration of medications has been reported to achieve higher and more reliable bioavailability than from an equivalent oral dose. In this FDA reviewed phase II clinical trial, we evaluated pharmacokinetics of an investigative new drug formulation, INSCOP during ambulatory (AMB) and antiorthostatic bedrest (HBR), a ground-based microgravity analog. Twelve subjects including 6 males and 6 females received 0.2 and 0.4 mg doses of INSCOP on separate days during AMB and ABR in a randomized, double blind cross over experimental design. Blood samples were collected at regular time intervals for 24 h post dose and analyzed for free scopolamine concentrations by an LC-MS-MS method. Pharmacokinetic parameters were calculated using concentration versus time data and compared between AMB and ABR conditions. Results indicated that maximum concentration and relative bioavailability increased marginally during ABR compared to AMB; differences in PK parameters between AMB and ABR were greater with 0.2 mg than with 0.4 mg dose. Gender specific differences in PK parameters was observed both during AMB and ABR with differences higher in females between the two conditions than in males. A significant observation is that while gender differences in PK appear to exist, the differences in primary PK parameters between AMB and ABR after IN administration, unlike oral administration, are minimal and may not be clinically significant for both genders.

  1. Pharmacokinetic Modeling of Intranasal Scopolamine in Plasma Saliva and Urine

    NASA Technical Reports Server (NTRS)

    Wu, L.; Chow, D. S. L.; Tam, V.; Putcha, L.

    2014-01-01

    An intranasal gel formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness. The bioavailability and pharmacokinetics (PK) were evaluated under the Food and Drug Administration guidelines for clinical trials for an Investigative New Drug (IND). The aim of this project was to develop a PK model that can predict the relationship between plasma, saliva and urinary scopolamine concentrations using data collected from the IND clinical trial with INSCOP. METHODS: Twelve healthy human subjects were administered three dose levels (0.1, 0.2 and 0.4 mg) of INSCOP. Serial blood, saliva and urine samples were collected between 5 min to 24 h after dosing and scopolamine concentrations measured by using a validated LC-MS-MS assay. Pharmacokinetic Compartmental models, using actual dosing and sampling times, were built using Phoenix (version 1.2). Model discrimination was performed, by minimizing the Akaike Information Criteria (AIC), maximizing the coefficient of determination (r²) and by comparison of the quality of fit plots. RESULTS: The best structural model to describe scopolamine disposition after INSCOP administration (minimal AIC =907.2) consisted of one compartment for plasma, saliva and urine respectively that were inter-connected with different rate constants. The estimated values of PK parameters were compiled in Table 1. The model fitting exercises revealed a nonlinear PK for scopolamine between plasma and saliva compartments for K21, Vmax and Km. CONCLUSION: PK model for INSCOP was developed and for the first time it satisfactorily predicted the PK of scopolamine in plasma, saliva and urine after INSCOP administration. Using non-linear PK yielded the best structural model to describe scopolamine disposition between plasma and saliva compartments, and inclusion of non-linear PK resulted in a significant improved model fitting. The model can be utilized to predict scopolamine plasma concentration using saliva and/or urine data that

  2. Promnestic effects of intranasally applied pregnenolone in rats.

    PubMed

    Abdel-Hafiz, Laila; Chao, Owen Y; Huston, Joseph P; Nikolaus, Susanne; Spieler, Richard E; de Souza Silva, Maria A; Mattern, Claudia

    2016-09-01

    The neurosteroid pregnenolone (PREG) has been shown to have memory-enhancing and anti-depressant action. The present study addresses the question of whether intranasally applied pregnenolone (IN-PREG) also has promnestic properties in the rat. We examined the effects of IN-PREG at doses of 0.187 and 0.373mg/kg on memory for objects and their location on learning and retention of escape in a water maze, and on behavior on the elevated plus maze. The main findings were: (a) Pre-trial, but not post-trial, administration of IN-PREG facilitated long-term memory in a novel object-preference test and a novel object-location preference test when tested 48h after dosing. (b) Over the duration of 5days of extinction trials, after learning to escape onto a hidden platform in a water maze, the animals treated with IN-PREG spent more time in searching for the absent platform, indicating either, or both, superior memory for the former position of the escape platform, or a higher resistance to extinction. (c) Administration of the anticholinergic, scopolamine, disrupted learning to escape from the water maze in the vehicle-treated group. The IN-PREG treated groups exhibited superior escape learning in comparison with vehicle controls, indicating that the treatment countered the scopolamine effect. IN-PREG treatment had no influence on behaviors on the elevated plus maze. Our results demonstrate that IN-PREG is behaviorally active with cognitive enhancing properties comparable to those known from studies employing systemic PREG administration. PMID:27423520

  3. Insulin Human Inhalation

    MedlinePlus

    ... insulin and therefore cannot control the amount of sugar in the blood). It is also used in ... normally and, therefore, cannot control the amount of sugar in the blood) who need insulin to control ...

  4. Insulin Lispro Injection

    MedlinePlus

    ... insulin and therefore cannot control the amount of sugar in the blood). It is also used to ... normally and therefore cannot control the amount of sugar in the blood) who need insulin to control ...

  5. Insulin pump (image)

    MedlinePlus

    The catheter at the end of the insulin pump is inserted through a needle into the abdominal ... with diabetes. Dosage instructions are entered into the pump's small computer and the appropriate amount of insulin ...

  6. High-mix insulins

    PubMed Central

    Kalra, Sanjay; Farooqi, Mohammad Hamed; El-Houni, Ali E.

    2015-01-01

    Premix insulins are commonly used insulin preparations, which are available in varying ratios of different molecules. These drugs contain one short- or rapid-acting, and one intermediate- or long-acting insulin. High-mix insulins are mixtures of insulins that contain 50% or more than 50% of short-acting insulin. This review describes the clinical pharmacology of high-mix insulins, including data from randomized controlled trials. It suggests various ways, in which high-mix insulin can be used, including once daily, twice daily, thrice daily, hetero-mix, and reverse regimes. The authors provide a rational framework to help diabetes care professionals, identify indications for pragmatic high-mix use. PMID:26425485

  7. Insulin, insulin analogues and diabetic retinopathy.

    PubMed

    Chantelau, Ernst; Kimmerle, Renate; Meyer-Schwickerath, Rolf

    2008-02-01

    Insulin is absolutely vital for living beings. It is not only involved in metabolism, but also in the regulation of growth factors, e.g. IGF-1. In this review we address the role insulin has in the natural evolution of diabetic retinopathy. On the one hand, chronic deficiency of insulin and IGF-1 at the retina is thought to cause capillary degeneration, with subsequent ischaemia. On the other hand, acute abundance of (exogenously administered) insulin and IGF-1 enhances ischaemia-induced VEGF expression. A critical ratio of tissue VEGF-susceptibility: VEGF-availability triggers vascular proliferation (i.e. of micro-aneurysms and/or abnormal vessels). The patent-protected insulin analogues Lispro, Glulisine, Aspart, Glargine and Detemir are artificial insulin derivatives with altered biological responses compared to natural insulin (e.g. divergent insulin and /or IGF-1 receptor-binding characteristics, signalling patterns, and mitogenicity). Their safety profiles concerning diabetic retinopathy remain to be established by randomised controlled trials. Anecdotal reports and circumstantial evidence suggest that Lispro and Glargine might worsen diabetic retinopathy.

  8. Adherence to Insulin Therapy.

    PubMed

    Sarbacker, G Blair; Urteaga, Elizabeth M

    2016-08-01

    IN BRIEF Six million people with diabetes use insulin either alone or in combination with an oral medication. Many barriers exist that lead to poor adherence with insulin. However, there is an underwhelming amount of data on interventions to address these barriers and improve insulin adherence. Until pharmacological advancements create easier, more acceptable insulin regimens, it is imperative to involve patients in shared decision-making. PMID:27574371

  9. Hypothalamic orexin prevents hepatic insulin resistance via daily bidirectional regulation of autonomic nervous system in mice.

    PubMed

    Tsuneki, Hiroshi; Tokai, Emi; Nakamura, Yuya; Takahashi, Keisuke; Fujita, Mikio; Asaoka, Takehiro; Kon, Kanta; Anzawa, Yuuki; Wada, Tsutomu; Takasaki, Ichiro; Kimura, Kumi; Inoue, Hiroshi; Yanagisawa, Masashi; Sakurai, Takeshi; Sasaoka, Toshiyasu

    2015-02-01

    Circadian rhythm is crucial for preventing hepatic insulin resistance, although the mechanism remains uncovered. Here we report that the wake-active hypothalamic orexin system plays a key role in this regulation. Wild-type mice showed that a daily rhythm in blood glucose levels peaked at the awake period; however, the glucose rhythm disappeared in orexin knockout mice despite normal feeding rhythm. Central administration of orexin A during nighttime awake period acutely elevated blood glucose levels but subsequently lowered daytime glucose levels in normal and diabetic db/db mice. The glucose-elevating and -lowering effects of orexin A were suppressed by adrenergic antagonists and hepatic parasympathectomy, respectively. Moreover, the expression levels of hepatic gluconeogenic genes, including Pepck, were increased and decreased by orexin A at nanomolar and femtomolar doses, respectively. These results indicate that orexin can bidirectionally regulate hepatic gluconeogenesis via control of autonomic balance, leading to generation of the daily blood glucose oscillation. Furthermore, during aging, orexin deficiency enhanced endoplasmic reticulum (ER) stress in the liver and caused impairment of hepatic insulin signaling and abnormal gluconeogenic activity in pyruvate tolerance test. Collectively, the daily glucose rhythm under control of orexin appears to be important for maintaining ER homeostasis, thereby preventing insulin resistance in the liver.

  10. Insulin therapy in pregnancy.

    PubMed

    Kalra, Sanjay; Jawad, Fatema

    2016-09-01

    Insulin is the mainstay of pharmacotherapy in pregnancy complicated by diabetes. This review covers the various insulin regimes and preparations, explaining how to use them, and decide appropriate doses in pregnancy. It approaches insulin treatment from a patient - centred, as well as physician and obstetrician friendly viewpoint, providing pragmatic guidance for management of diabetes in pregnancy. PMID:27582152

  11. Autonomic control of bronchial circulation in awake sheep during rest and behaviour.

    PubMed

    McIlveen, S; White, S; Parsons, G

    1997-12-01

    1. We tested the hypothesis that the pattern and the intensity of autonomic mechanisms causing vasoconstriction in the resting bronchial circulation of awake dogs also exists in awake sheep. It was also postulated that sighing behaviour and the associated bronchovascular dilatation induced by non-adrenergic, non-cholinergic (NANC) mechanisms observed in the dog exist in sheep. 2. Bronchial arterial blood flow to lower airways of both lungs of awake sheep was measured continuously using pulsed Doppler flow probes mounted on the bronchial artery at prior thoracotomy. 3. Cumulative and factorial analysis of responses to randomized combinations of autonomic alpha 1-, alpha 2-, beta 1- and beta 2-adrenoceptors and cholinoceptor autonomic blockade suggests that resting vasoconstrictor activity is less in sheep than in dogs. At normal aortic pressure, the autonomic activity of these receptor groups in the sheep lowers bronchial blood flow and conductance by 30%, whereas in the awake dog, the corresponding autonomic effect is 50%. 4. Tonic autonomic control of bronchial conductance can be partitioned in sheep to show significant and separate alpha- and beta-adrenoceptor vasoconstrictor activity at a ratio of 1.8:1, an effect normally offset by a weaker vasodilator alpha-/beta-adrenoceptor interaction. In contrast to the situation in awake dogs, cholinoceptors do not play a role in awake sheep. 5. Nitric oxide (NO) synthase inhibition in sheep using NG-nitro-L-arginine following blockade of alpha- and beta-adrenoceptors and cholinoceptors causes hypertension, but minor changes, if any, in pulmonary pressures or heart rate. Bronchial flow and conductance, however, fall from a higher resting conductance by approximately 50%, suggesting that, normally, resting bronchial flow conductance is dominated by strong tonic NO vasodilator effects that interact with weaker tonic autonomic vasoconstrictor effects. 6. Superimposed (respiratory) behaviours of sighing, sneezing and coughing

  12. Combination of Continuous Dexmedetomidine Infusion with Titrated Ultra-Low-Dose Propofol-Fentanyl for an Awake Craniotomy.

    PubMed

    Das, Samaresh; Al-Mashani, Ali; Suri, Neelam; Salhotra, Neeraj; Chatterjee, Nilay

    2016-08-01

    An awake craniotomy is a continuously evolving technique used for the resection of brain tumours from the eloquent cortex. We report a 29-year-old male patient who presented to the Khoula Hospital, Muscat, Oman, in 2016 with a two month history of headaches and convulsions due to a space-occupying brain lesion in close proximity with the left motor cortex. An awake craniotomy was conducted using a scalp block, continuous dexmedetomidine infusion and a titrated ultra-low-dose of propofolfentanyl. The patient remained comfortable throughout the procedure and the intraoperative neuropsychological tests, brain mapping and tumour resection were successful. This case report suggests that dexmedetomidine in combination with titrated ultra-low-dose propofolfentanyl are effective options during an awake craniotomy, ensuring optimum sedation, minimal disinhibition and a rapid recovery. To the best of the authors' knowledge, this is the first awake craniotomy conducted successfully in Oman. PMID:27606116

  13. Combination of Continuous Dexmedetomidine Infusion with Titrated Ultra-Low-Dose Propofol-Fentanyl for an Awake Craniotomy

    PubMed Central

    Das, Samaresh; Al-Mashani, Ali; Suri, Neelam; Salhotra, Neeraj; Chatterjee, Nilay

    2016-01-01

    An awake craniotomy is a continuously evolving technique used for the resection of brain tumours from the eloquent cortex. We report a 29-year-old male patient who presented to the Khoula Hospital, Muscat, Oman, in 2016 with a two month history of headaches and convulsions due to a space-occupying brain lesion in close proximity with the left motor cortex. An awake craniotomy was conducted using a scalp block, continuous dexmedetomidine infusion and a titrated ultra-low-dose of propofolfentanyl. The patient remained comfortable throughout the procedure and the intraoperative neuropsychological tests, brain mapping and tumour resection were successful. This case report suggests that dexmedetomidine in combination with titrated ultra-low-dose propofolfentanyl are effective options during an awake craniotomy, ensuring optimum sedation, minimal disinhibition and a rapid recovery. To the best of the authors’ knowledge, this is the first awake craniotomy conducted successfully in Oman. PMID:27606116

  14. Anesthetic agents modulate ECoG potentiation after spreading depression, and insulin-induced hypoglycemia does not modify this effect.

    PubMed

    de Souza, Thays Kallyne Marinho; E Silva-Gondim, Mariana Barros; Rodrigues, Marcelo Cairrão Araújo; Guedes, Rubem Carlos Araújo

    2015-04-10

    Cortical spreading depression (CSD) is characterized by reversible reduction of spontaneous and evoked electrical activity of the cerebral cortex. Experimental evidence suggests that CSD may modulate neural excitability and synaptic activity, with possible implications for long-term potentiation. Systemic factors like anesthetics and insulin-induced hypoglycemia can influence CSD propagation. In this study, we examined whether the post-CSD ECoG potentiation can be modulated by anesthetics and insulin-induced hypoglycemia. We found that awake adult rats displayed increased ECoG potentiation after CSD, as compared with rats under urethane+chloralose anesthesia or tribromoethanol anesthesia. In anesthetized rats, insulin-induced hypoglycemia did not modulate ECoG potentiation. Comparison of two cortical recording regions in awake rats revealed a similarly significant (p<0.05) potentiation effect in both regions, whereas in the anesthetized groups the potentiation was significant only in the recording region nearer to the stimulating point. Our data suggest that urethane+chloralose and tribromoethanol anesthesia modulate the post-CSD potentiation of spontaneous electrical activity in the adult rat cortex, and insulin-induced hypoglycemia does not modify this effect. Data may help to gain a better understanding of excitability-dependent mechanisms underlying CSD-related neurological diseases. PMID:25681772

  15. Oral Insulin Reloaded

    PubMed Central

    Heinemann, Lutz; Plum-Mörschel, Leona

    2014-01-01

    Optimal coverage of insulin needs is the paramount aim of insulin replacement therapy in patients with diabetes mellitus. To apply insulin without breaking the skin barrier by a needle and/or to allow a more physiological provision of insulin are the main reasons triggering the continuous search for alternative routes of insulin administration. Despite numerous attempts over the past 9 decades to develop an insulin pill, no insulin for oral dosing is commercially available. By way of a structured approach, we aim to provide a systematic update on the most recent developments toward an orally available insulin formulation with a clear focus on data from clinical-experimental and clinical studies. Thirteen companies that claim to be working on oral insulin formulations were identified. However, only 6 of these companies published new clinical trial results within the past 5 years. Interestingly, these clinical data reports make up a mere 4% of the considerably high total number of publications on the development of oral insulin formulations within this time period. While this picture clearly reflects the rising research interest in orally bioavailable insulin formulations, it also highlights the fact that the lion’s share of research efforts is still allocated to the preclinical stages. PMID:24876606

  16. Impact of Gender on Pharmocokinetics of Intranasal Scopolamine

    NASA Technical Reports Server (NTRS)

    Putcha, L.; Lei, Wu.; S-L Chow, Diana

    2013-01-01

    Introduction: An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS), which is commonly experienced by astronauts during space missions. The bioavailability and pharmacokinetics (PK) were evaluated under IND guidelines. Since information is lacking on the effect of gender on the PK of Scopolamine, we examined gender differences in PK parameters of INSCOP at three dose levels of 0.1, 0.2 and 0.4 mg. Methods: Plasma scopolamine concentrations as a function of time data were collected from twelve normal healthy human subjects (6 male/6 female) who participated in a fully randomized double blind crossover study. The PK parameters were derived using WinNonlin. Covariate analysis of PK profiles was performed using NONMEN and statistically compared using a likelihood ratio test on the difference of objective function value (OFV). Statistical significance for covariate analysis was set at P<0.05(?OFV=3.84). Results: No significant difference in PK parameters between male and female subjects was observed with 0.1 and 0.2 mg doses. However, CL and Vd were significantly different between male and female subjects at the 0.4 mg dose. Results from population covariate modeling analysis indicate that a onecompartment PK model with first-order elimination rate offers best fit for describing INSCOP concentration-time profiles. The inclusion of sex as a covariate enhanced the model fitting (?OFV=-4.1) owing to the genderdependent CL and Vd differences after the 0.4 mg dose. Conclusion: Statistical modeling of scopolamine concentration-time data suggests gender-dependent pharmacokinetics of scopolamine at the high dose level of 0.4 mg. Clearance of the parent compound was significantly faster and the volume of distribution was significantly higher in males than in females, As a result, including gender as a covariate to the pharmacokinetic model of scopolamine offers the best fit for PK modeling of the drug at dose

  17. 5-aminolevulinic acid guidance during awake craniotomy to maximise extent of safe resection of glioblastoma multiforme.

    PubMed

    Corns, Robert; Mukherjee, Soumya; Johansen, Anja; Sivakumar, Gnanamurthy

    2015-01-01

    Overall survival for patients with glioblastoma multiforme (GBM) has been consistently shown to improve when the surgeon achieves a gross total resection of the tumour. It has also been demonstrated that surgical adjuncts such as 5-aminolevulinic acid (5-ALA) fluorescence--which delineates malignant tumour tissue--normal brain tissue margin seen using violet-blue excitation under an operating microscope--helps achieve this. We describe the case of a patient with recurrent left frontal GBM encroaching on Broca's area (eloquent brain). Gross total resection of the tumour was achieved by combining two techniques, awake resection to prevent damage to eloquent brain and 5-ALA fluorescence guidance to maximise the extent of tumour resection.This technique led to gross total resection of all T1-enhancing tumour with the avoidance of neurological deficit. The authors recommend this technique in patients when awake surgery can be tolerated and gross total resection is the aim of surgery. PMID:26177997

  18. Evolving Models of Pavlovian Conditioning: Cerebellar Cortical Dynamics in Awake Behaving Mice

    PubMed Central

    ten Brinke, Michiel M.; Boele, Henk-Jan; Spanke, Jochen K.; Potters, Jan-Willem; Kornysheva, Katja; Wulff, Peer; IJpelaar, Anna C.H.G.; Koekkoek, Sebastiaan K.E.; De Zeeuw, Chris I.

    2015-01-01

    Summary Three decades of electrophysiological research on cerebellar cortical activity underlying Pavlovian conditioning have expanded our understanding of motor learning in the brain. Purkinje cell simple spike suppression is considered to be crucial in the expression of conditional blink responses (CRs). However, trial-by-trial quantification of this link in awake behaving animals is lacking, and current hypotheses regarding the underlying plasticity mechanisms have diverged from the classical parallel fiber one to the Purkinje cell synapse LTD hypothesis. Here, we establish that acquired simple spike suppression, acquired conditioned stimulus (CS)-related complex spike responses, and molecular layer interneuron (MLI) activity predict the expression of CRs on a trial-by-trial basis using awake behaving mice. Additionally, we show that two independent transgenic mouse mutants with impaired MLI function exhibit motor learning deficits. Our findings suggest multiple cerebellar cortical plasticity mechanisms underlying simple spike suppression, and they implicate the broader involvement of the olivocerebellar module within the interstimulus interval. PMID:26655909

  19. Behavioral effects of acclimatization to restraint protocol used for awake animal imaging.

    PubMed

    Reed, Michael D; Pira, Ashley S; Febo, Marcelo

    2013-07-15

    Functional MRI in awake rats involves acclimatization to restraint to minimize motion. We designed a study to examine the effects of an acclimatization protocol (5 days of restraint, 60 min per day) on the emission of 22-kHz ultrasonic vocalizations and performance in a forced swim test (FST). Our results showed that USV calls are reduced significantly by days 3, 4 and 5 of acclimatization. Although the rats showed less climbing activity (and more immobility) in FST on day 5 compared to the 1st day of restraint acclimatization, the difference was not detected once the animals were given a 2-week hiatus. Overall, we showed that animals adapt to the restraint over a five-day period; however, restraint may introduce confounding behavioral outcomes that may hinder the interpretation of results derived from awake rat imaging. The present data warrants further testing of the effects of MRI restraint on behavior.

  20. Episodic-like memory trace in awake replay of hippocampal place cell activity sequences.

    PubMed

    Takahashi, Susumu

    2015-01-01

    Episodic memory retrieval of events at a specific place and time is effective for future planning. Sequential reactivation of the hippocampal place cells along familiar paths while the animal pauses is well suited to such a memory retrieval process. It is, however, unknown whether this awake replay represents events occurring along the path. Using a subtask switching protocol in which the animal experienced three subtasks as 'what' information in a maze, I here show that the replay represents a trial type, consisting of path and subtask, in terms of neuronal firing timings and rates. The actual trial type to be rewarded could only be reliably predicted from replays that occurred at the decision point. This trial-type representation implies that not only 'where and when' but also 'what' information is contained in the replay. This result supports the view that awake replay is an episodic-like memory retrieval process. PMID:26481131

  1. [Single-port video-assisted thoracic surgery in an awake patient].

    PubMed

    Alonso-García, F J; Navarro-Martínez, J; Gálvez, C; Rivera-Cogollos, M J; Sgattoni, C; Tarí-Bas, I M

    2016-03-01

    Video-assisted thoracic surgery is traditionally carried out with general anaesthesia and endotracheal intubation with double lumen tube. However, in the last few years procedures, such as lobectomies, are being performed with loco-regional anaesthesia, with and without sedation, maintaining the patient awake and with spontaneous breathing, in order to avoid the inherent risks of general anaesthesia, double lumen tube intubation and mechanical ventilation. This surgical approach has also shown to be effective in that it allows a good level of analgesia, maintaining a correct oxygenation and providing a better post-operative recovery. Two case reports are presented in which video-assisted thoracic surgery was used, a lung biopsy and a lung resection, both with epidural anaesthesia and maintaining the patient awake and with spontaneous ventilation, as part of a preliminary evaluation of the anaesthetic technique in this type of surgery.

  2. Hemispheric specialization in the primary auditory area of awake and anesthetized starlings (Sturnus vulgaris).

    PubMed

    George, Isabella; Vernier, Baptiste; Richard, Jean-Pierre; Hausberger, Martine; Cousillas, Hugo

    2004-06-01

    Although evidence exists for a lateralization of song production, few studies have focused on the perceptual aspect of lateralization in songbirds. In the present study, the authors recorded neuronal responses to a variety of species-specific and artificial, nonspecific stimuli in both hemispheres of awake and anesthetized male starlings (Sturnus vulgaris). Recordings were made in the primary auditory area of the songbird brain, the Field L complex. The right hemisphere exhibited significantly more responsive units than the left hemisphere in awake birds, and this difference was significantly reduced in anesthetized birds. Furthermore, clear hemispheric specialization toward categories of behaviorally relevant stimuli and precise parameters of these stimuli were found. The main auditory area of the starling's brain thus appears to show some degree of lateralization. PMID:15174938

  3. Episodic-like memory trace in awake replay of hippocampal place cell activity sequences.

    PubMed

    Takahashi, Susumu

    2015-01-01

    Episodic memory retrieval of events at a specific place and time is effective for future planning. Sequential reactivation of the hippocampal place cells along familiar paths while the animal pauses is well suited to such a memory retrieval process. It is, however, unknown whether this awake replay represents events occurring along the path. Using a subtask switching protocol in which the animal experienced three subtasks as 'what' information in a maze, I here show that the replay represents a trial type, consisting of path and subtask, in terms of neuronal firing timings and rates. The actual trial type to be rewarded could only be reliably predicted from replays that occurred at the decision point. This trial-type representation implies that not only 'where and when' but also 'what' information is contained in the replay. This result supports the view that awake replay is an episodic-like memory retrieval process.

  4. Insulin-derived amyloidosis

    PubMed Central

    Gupta, Yashdeep; Singla, Gaurav; Singla, Rajiv

    2015-01-01

    Amyloidosis is the term for diseases caused by the extracellular deposition of insoluble polymeric protein fibrils in tissues and organs. Insulin-derived amyloidosis is a rare, yet significant complication of insulin therapy. Insulin-derived amyloidosis at injection site can cause poor glycemic control and increased insulin dose requirements because of the impairment in insulin absorption, which reverse on change of injection site and/or excision of the mass. This entity should be considered and assessed by histopathology and immunohistochemistry, in patients with firm/hard local site reactions, which do not regress after cessation of insulin injection at the affected site. Search strategy: PubMed was searched with terms “insulin amyloidosis”. Full text of articles available in English was reviewed. Relevant cross references were also reviewed. Last search was made on October 15, 2014. PMID:25593849

  5. Retrospective evaluation of airway management with blind awake intubation in temporomandibular joint ankylosis patients: A review of 48 cases

    PubMed Central

    Sankar, Duraiswamy; Krishnan, Radhika; Veerabahu, Muthusubramanian; Vikraman, Bhaskara Pandian; Nathan, J. A.

    2016-01-01

    Aim: The aim was to determine the morbidity or mortality associated with the blind awake intubation technique in temporomandibular ankylosis patients. Settings and Design: A total of 48 cases with radiographically and clinically confirmed cases of temporomandibular joint (TMJ) ankylosis were included in the study for evaluation of anesthetic management and its complications. Materials and Methods: Airway assessment was done with standard proforma including Look externally, evaluate 3-3-2 rule, Mallampati classification, Obstruction, Neck mobility (LEMON) score assessment in all TMJ ankylosis patients. The intubation was carried out with the standard departmental anesthetic protocol in all the patients. The preoperative difficulty assessment and postoperative outcome were recorded. Results: Blind awake intubation was done in 92% of cases, 6% of cases were intubated by fiberoptic awake intubation, and 2% patient required surgical airway. Ninety-eight percent of the patients were cooperative during the awake intubation. The frequent complications encountered during the blind awake intubation were epistaxis and sore throat. Conclusion: In an anesthetic setup, where fiberoptic intubation is not available, blind awake intubation could be considered in the anesthetic management algorithm. PMID:27563608

  6. Development of a simultaneous optical/PET imaging system for awake mice.

    PubMed

    Takuwa, Hiroyuki; Ikoma, Yoko; Yoshida, Eiji; Tashima, Hideaki; Wakizaka, Hidekatsu; Shinaji, Tetsuya; Yamaya, Taiga

    2016-09-01

    Simultaneous measurements of multiple physiological parameters are essential for the study of brain disease mechanisms and the development of suitable therapies to treat them. In this study, we developed a measurement system for simultaneous optical imaging and PET for awake mice. The key elements of this system are the OpenPET, optical imaging and fixation apparatus for an awake mouse. The OpenPET is our original open-type PET geometry, which can be used in combination with another device because of the easily accessible open space of the former. A small prototype of the axial shift single-ring OpenPET was used. The objective lens for optical imaging with a mounted charge-coupled device camera was placed inside the open space of the AS-SROP. Our original fixation apparatus to hold an awake mouse was also applied. As a first application of this system, simultaneous measurements of cerebral blood flow (CBF) by laser speckle imaging (LSI) and [(11)C]raclopride-PET were performed under control and 5% CO2 inhalation (hypercapnia) conditions. Our system successfully obtained the CBF and [(11)C]raclopride radioactivity concentration simultaneously. Accumulation of [(11)C]raclopride was observed in the striatum where the density of dopamine D2 receptors is high. LSI measurements could be stably performed for more than 60 minutes. Increased CBF induced by hypercapnia was observed while CBF under the control condition was stable. We concluded that our imaging system should be useful for investigating the mechanisms of brain diseases in awake animal models. PMID:27514436

  7. Development of a simultaneous optical/PET imaging system for awake mice

    NASA Astrophysics Data System (ADS)

    Takuwa, Hiroyuki; Ikoma, Yoko; Yoshida, Eiji; Tashima, Hideaki; Wakizaka, Hidekatsu; Shinaji, Tetsuya; Yamaya, Taiga

    2016-09-01

    Simultaneous measurements of multiple physiological parameters are essential for the study of brain disease mechanisms and the development of suitable therapies to treat them. In this study, we developed a measurement system for simultaneous optical imaging and PET for awake mice. The key elements of this system are the OpenPET, optical imaging and fixation apparatus for an awake mouse. The OpenPET is our original open-type PET geometry, which can be used in combination with another device because of the easily accessible open space of the former. A small prototype of the axial shift single-ring OpenPET was used. The objective lens for optical imaging with a mounted charge-coupled device camera was placed inside the open space of the AS-SROP. Our original fixation apparatus to hold an awake mouse was also applied. As a first application of this system, simultaneous measurements of cerebral blood flow (CBF) by laser speckle imaging (LSI) and [11C]raclopride-PET were performed under control and 5% CO2 inhalation (hypercapnia) conditions. Our system successfully obtained the CBF and [11C]raclopride radioactivity concentration simultaneously. Accumulation of [11C]raclopride was observed in the striatum where the density of dopamine D2 receptors is high. LSI measurements could be stably performed for more than 60 minutes. Increased CBF induced by hypercapnia was observed while CBF under the control condition was stable. We concluded that our imaging system should be useful for investigating the mechanisms of brain diseases in awake animal models.

  8. The kinematic architecture of the Active Headframe: A new head support for awake brain surgery.

    PubMed

    Malosio, Matteo; Negri, Simone Pio; Pedrocchi, Nicola; Vicentini, Federico; Cardinale, Francesco; Tosatti, Lorenzo Molinari

    2012-01-01

    This paper presents the novel hybrid kinematic structure of the Active Headframe, a robotic head support to be employed in brain surgery operations for an active and dynamic control of the patient's head position and orientation, particularly addressing awake surgery requirements. The topology has been conceived in order to satisfy all the installation, functional and dynamic requirements. A kinetostatic optimization has been performed to obtain the actual geometric dimensions of the prototype currently being developed. PMID:23366166

  9. "Awake Veno-arterial Extracorporeal Membrane Oxygenation" in Pediatric Cardiogenic Shock: A Single-Center Experience.

    PubMed

    Schmidt, F; Jack, T; Sasse, M; Kaussen, T; Bertram, H; Horke, A; Seidemann, K; Beerbaum, P; Koeditz, H

    2015-12-01

    In pediatric patients with acute refractory cardiogenic shock (CS), extracorporeal membrane oxygenation (ECMO) remains an established procedure to maintain adequate organ perfusion. In this context, ECMO can be used as a bridging procedure to recovery, VAD or transplantation. While being supported by ECMO, most centers tend to keep their patients well sedated and supported by invasive ventilation. This may be associated with an increased risk of therapy-related morbidity and mortality. In order to optimize clinical management in pediatric patients with ECMO therapy, we report our strategy of veno-arterial ECMO (VA-ECMO) in extubated awake and conscious patients. We therefore present data of six of our patients with CS, who were treated by ECMO being awake without continuous analgosedation and invasive ventilation. Of these six patients, four were <1 year and two >14 years of age. Median time on ECMO was 17.4 days (range 6.9-94.2 days). Median time extubated, while receiving ECMO support was 9.5 days. Mean time extubated was 78 % of the total time on ECMO. Three patients reached full recovery of cardiac function on "Awake-VA-ECMO," whereas the other three were successfully bridged to destination therapy (VAD, heart transplantation, withdrawal). Four out of our six patients are still alive. Complications related to ECMO therapy (i.e., severe bleeding, site infection or dislocation of cannulas) were not observed. We conclude that "Awake-VA-ECMO" in extubated, spontaneously breathing conscious pediatric patients is feasible and safe for the treatment of acute CS and can be used as a "bridging therapy" to recovery, VAD implantation or transplantation.

  10. A chronic cannula for obtaining CSF from the cisterna magna of awake dogs.

    PubMed

    Jennings, D B; Tobin, P

    1979-01-01

    We have designed a cannula system that can be chronically implanted to end above the dura of the cisterna magna of the dog. During experiments in the awake dog, a screw cap with stylet is removed from the cannula and a spinal needle inserted for the withdrawal of samples of cisternal cerebrospinal fluid (CSF) or for making continuous measurements of pressure. The system can be used for repeated experiments extending over several weeks.

  11. The kinematic architecture of the Active Headframe: A new head support for awake brain surgery.

    PubMed

    Malosio, Matteo; Negri, Simone Pio; Pedrocchi, Nicola; Vicentini, Federico; Cardinale, Francesco; Tosatti, Lorenzo Molinari

    2012-01-01

    This paper presents the novel hybrid kinematic structure of the Active Headframe, a robotic head support to be employed in brain surgery operations for an active and dynamic control of the patient's head position and orientation, particularly addressing awake surgery requirements. The topology has been conceived in order to satisfy all the installation, functional and dynamic requirements. A kinetostatic optimization has been performed to obtain the actual geometric dimensions of the prototype currently being developed.

  12. Added impact of obesity and insulin resistance in nocturnal blood pressure elevation in children and adolescents.

    PubMed

    Lurbe, Empar; Torro, Isabel; Aguilar, Francisco; Alvarez, Julio; Alcon, Jose; Pascual, Jose Maria; Redon, Josep

    2008-03-01

    The aim of the present study was to analyze the relationship between insulin resistance and the ambulatory blood pressure components in obese children and adolescents. Eighty-seven overweight and obese white children and adolescents of both sexes, of European origin from 6 to 18 years of age (mean age: 10.9+/-2.7 years), were selected. Obesity was defined on the basis of a threshold body mass index z score >2 (Cole's least mean square method) and overweight with a body mass index from the 85th to 97th percentile. A validated oscillometric method was used to measure ambulatory BP (Spacelabs 90207) during 24 hours. Fasting glucose and insulin were measured, and the homeostasis model assessment index was calculated. Subjects were grouped into tertiles of homeostasis model assessment index. No significant differences in terms of age, sex, and body mass index z score distribution were observed among groups. When adjusted by age, sex, and height, nocturnal systolic blood pressure and heart rate were significantly higher in subjects in the highest homeostasis model assessment index tertile (>4.7) as compared with those of the other groups, whereas no differences were observed for awake systolic blood pressure or heart rate. Whereas body mass index z score was more closely related with blood pressure and heart rate values, waist circumference was strongly related with insulin resistance. Moreover, both waist circumference and insulin resistance were mainly associated with higher nocturnal but not with awake blood pressure. The early increment of nocturnal blood pressure and heart rate associated with hyperinsulinemia may be a harbinger of hypertension-related insulin resistance and may contribute to heightened cardiovascular risk associated with this condition. PMID:18195166

  13. Information flow and coherence of EEG during awake, meditation and drowsiness.

    PubMed

    Dissanayaka, Chamila; Ben-Simon, Eti; Gruberger, Michal; Maron-Katz, Adi; Hendler, Talma; Chaparro-Vargas, Ramiro; Cvetkovic, Dean

    2014-01-01

    A comparison of coupling (information flow) and coherence (connectedness) of the brain regions between human awake, meditation and drowsiness states was carried out in this study. The Directed Transfer Function (DTF) method was used to estimate the coupling or brain's flow of information between different regions during each condition. Welch and Minimum Variance Distortionless Response (MVDR) methods were utilised to estimate the coherence between brain areas. Analysis was conducted using the EEG data of 30 subjects (10 awake, 10 drowsiness and 10 meditating) with 6 EEG electrodes. The EEG data was recorded for each subject during 5 minutes baseline and 15 minutes of three specific conditions (awake, meditation or drowsiness). Statistical analysis was carried out which consisted of the Kruskal-Wallis (KW) non-parametric analysis of variance followed by post-hoc tests with Bonferroni alpha-correction. The results of this study revealed that a change in external awareness led to substantial differences in the spectral profile of the brain's information flow as well as it's connectedness.

  14. Some effects of vagal blockade on abdominal muscle activation and shortening in awake dogs.

    PubMed Central

    Leevers, A M; Road, J D

    1995-01-01

    1. The mechanisms of abdominal muscle activation are thought to be different during expiratory threshold loading (ETL) compared with hypercapnia. Our objectives in the present study were to determine the effects of removing excitatory vagal feedback on abdominal muscle activation, shortening and pattern of recruitment during ETL and hypercapnia. Six tracheotomized dogs were chronically implanted with sonomicrometer transducers and fine wire EMG electrodes in each of the four abdominal muscles. Muscle length changes and EMG activity were studied in the awake dog during ETL (6 dogs) and CO2 rebreathing (3 dogs), before and after vagal blockade. 2. Following vagal blockade, the change in volume (increase in functional residual capacity, FRC) during ETL was greater and active phasic shortening of all the abdominal muscles was reduced, when shortening was compared with a similar change in lung volume. Similarly, at comparable minute ventilation, abdominal muscle active shortening was also reduced during hypercapnia. The internal muscle layer was recruited preferentially in both control and vagally blocked dogs during both ETL and hypercapnia. 3. The degree of recruitment of the abdominal muscles during ETL and hypercapnia in awake dogs is influenced by vagal feedback, but less so than in anaesthetized dogs. These results illustrate the importance of the vagi and abdominal muscle activation in load compensation. However, vagal reflexes are apparently not contributing to the preferential recruitment of the internal muscle layer. In awake dogs during vagal blockade abdominal muscle recruitment still occurs by extravagal mechanisms. PMID:8568685

  15. Imaging Circulating Tumor Cells in Freely Moving Awake Small Animals Using a Miniaturized Intravital Microscope

    PubMed Central

    Sasportas, Laura Sarah; Gambhir, Sanjiv Sam

    2014-01-01

    Metastasis, the cause for 90% of cancer mortality, is a complex and poorly understood process involving the invasion of circulating tumor cells (CTCs) into blood vessels. These cells have potential prognostic value as biomarkers for early metastatic risk. But their rarity and the lack of specificity and sensitivity in measuring them render their interrogation by current techniques very challenging. How and when these cells are circulating in the blood, on their way to potentially give rise to metastasis, is a question that remains largely unanswered. In order to provide an insight into this "black box" using non-invasive imaging, we developed a novel miniature intravital microscopy (mIVM) strategy capable of real-time long-term monitoring of CTCs in awake small animals. We established an experimental 4T1-GL mouse model of metastatic breast cancer, in which tumor cells express both fluorescent and bioluminescent reporter genes to enable both single cell and whole body tumor imaging. Using mIVM, we monitored blood vessels of different diameters in awake mice in an experimental model of metastasis. Using an in-house software algorithm we developed, we demonstrated in vivo CTC enumeration and computation of CTC trajectory and speed. These data represent the first reported use we know of for a miniature mountable intravital microscopy setup for in vivo imaging of CTCs in awake animals. PMID:24497977

  16. Intranasal sirna targeting c-kit reduces airway inflammation in experimental allergic asthma.

    PubMed

    Wu, Wei; Chen, Hui; Li, Ya-Ming; Wang, Sheng-Yu; Diao, Xin; Liu, Kai-Ge

    2014-01-01

    Allergic asthma is characterized by airway inflammation caused by infiltration and activation of inflammatory cells that produce cytokines. Many studies have revealed that c-kit, a proto-oncogene, and its ligand, stem cell factor (SCF), play an important role in the development of asthmatic inflammation. Intranasal small interference RNA (siRNA) nanoparticles targeting specific viral gene could inhibit airway inflammation. In this study, we assessed whether silencing of c-kit with intranasal small interference RNA could reduce inflammation in allergic asthma. A mouse model of experimental asthma was treated with intranasal administration of anti-c-kit siRNA to inhibit the expression of the c-kit gene. We assessed the inflammatory response in both anti-c-kit siRNA-treated and control mice. Local administration of siRNA effectively inhibited the expression of the c-kit gene and reduced airway mucus secretion and the infiltration of eosinophils in bronchoalveolar lavage fluid. Moreover, c-kit siRNA reduced the production of SCF, interleukin-4 (IL-4), and IL-5, but had no effect on interferon-γ (IFN-γ) generation. These results show that intranasal siRNA nanoparticles targeting c-kit can decrease the inflammatory response in experimental allergic asthma.

  17. Early experience of radio frequency coblation in the management of intranasal and sinus tumors.

    PubMed

    Syed, Mohammed Iqbal; Mennie, Joanna; Williams, Alun T

    2012-02-01

    The purpose of this study was to evaluate the safety and efficacy of the use of radiofrequency coblation for endoscopic resection of intranasal and sinus tumors. A review was conducted of 15 adult patients with intranasal and or sinus tumors endoscopically treated with radio frequency coblation between November 2008 and November 2010 at St. John's Hospital at Livingston, a tertiary referral center that covers otolaryngology services for the southeast of Scotland. Fifteen patients with intranasal and sinus tumors were treated with transnasal endoscopic resection using radiofrequency coblation. The tumors included inverted papilloma (seven), paraganglioma (one), glomangiopericytoma (one), capillary hemangioma (one), hemangiopericytoma (one), juvenile angiofibroma (one), juvenile ossifying fibroma (one), oncocytic adenoma (one), and transitional cell carcinoma (one). We found that radiofrequency coblation is a useful and safe tool associated with minimal blood loss (<200 mL to 600 mL) in the resection of these tumors, and the average operating time was 1.67 hours. Radio frequency is a rapidly evolving technique and in the future will have an increasing role to play in the endoscopic resection of intranasal and sinus tumors.

  18. Development of an Intranasal Vaccine To Prevent Urinary Tract Infection by Proteus mirabilis

    PubMed Central

    Li, Xin; Lockatell, C. Virginia; Johnson, David E.; Lane, M. Chelsea; Warren, John W.; Mobley, Harry L. T.

    2004-01-01

    Proteus mirabilis commonly infects the complicated urinary tract and is associated with urolithiasis. Stone formation is caused by bacterial urease, which hydrolyzes urea to ammonia, causing local pH to rise, and leads to the subsequent precipitation of magnesium ammonium phosphate (struvite) and calcium phosphate (apatite) crystals. To prevent these infections, we vaccinated CBA mice with formalin-killed bacteria or purified mannose-resistant, Proteus-like (MR/P) fimbriae, a surface antigen expressed by P. mirabilis during experimental urinary tract infection, via four routes of immunization: subcutaneous, intranasal, transurethral, and oral. We assessed the efficacy of vaccination using the CBA mouse model of ascending urinary tract infection. Subcutaneous or intranasal immunization with formalin-killed bacteria and intranasal or transurethral immunization with purified MR/P fimbriae significantly protected CBA mice from ascending urinary tract infection by P. mirabilis (P < 0.05). To investigate the potential of MrpH, the MR/P fimbrial tip adhesin, as a vaccine, the mature MrpH peptide (residues 23 to 275, excluding the signal peptide), and the N-terminal receptor-binding domain of MrpH (residues 23 to 157) were overexpressed as C-terminal fusions to maltose-binding protein (MBP) and purified on amylose resins. Intranasal immunization of CBA mice with MBP-MrpH (residues 23 to 157) conferred effective protection against urinary tract infection by P. mirabilis (P < 0.002). PMID:14688082

  19. Effects of nasal-airway volume and body temperature on intranasal chemosensitivity.

    PubMed

    Nordin, S; Lötsch, J; Kobal, G; Murphy, C

    1998-02-01

    Interrelations between intranasal detection sensitivity for odor (H2S) and pain (CO2), nasal-airway volume (acoustic rhinometry), and body temperature were studied in young, healthy men across the diurnal cycle. The results showed a weak but statistically significant negative correlation between nasal volume and odor threshold and a weak but positive correlation between body temperature and odor threshold.

  20. Abuse potential of intranasal buprenorphine versus buprenorphine/naloxone in buprenorphine-maintained heroin users.

    PubMed

    Jones, Jermaine D; Sullivan, Maria A; Vosburg, Suzanne K; Manubay, Jeanne M; Mogali, Shanthi; Metz, Verena; Comer, Sandra D

    2015-07-01

    In spite of the clinical utility of buprenorphine, parenteral abuse of this medication has been reported in several laboratory investigations and in the real world. Studies have demonstrated lower abuse liability of the buprenorphine/naloxone combination relative to buprenorphine alone. However, clinical research has not yet examined the utility of the combined formulation to deter intranasal use in a buprenorphine-maintained population. Heroin-using volunteers (n = 12) lived in the hospital for 8-9 weeks and were maintained on each of three sublingual buprenorphine doses (2, 8, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intranasal doses of buprenorphine (8, 16 mg), buprenorphine/naloxone (8/2, 8/8, 8/16, 16/4 mg) and controls (placebo, heroin 100 mg, naloxone 4 mg) were assessed. Intranasal buprenorphine alone typically produced increases in positive subjective effects and the 8 mg dose was self-administered above the level of placebo. The addition of naloxone dose dependently reduced positive subjective effects and increased aversive effects. No buprenorphine/naloxone combination dose was self-administered significantly more than placebo. These data suggest that within a buprenorphine-dependent population, intranasal buprenorphine/naloxone has reduced abuse potential in comparison to buprenorphine alone. These data strongly argue in favor of buprenorphine/naloxone rather than buprenorphine alone as the more reasonable option for managing the risk of buprenorphine misuse. PMID:25060839

  1. CSF and blood oxytocin concentration changes following intranasal delivery in macaque.

    PubMed

    Dal Monte, Olga; Noble, Pamela L; Turchi, Janita; Cummins, Alex; Averbeck, Bruno B

    2014-01-01

    Oxytocin (OT) in the central nervous system (CNS) influences social cognition and behavior, making it a candidate for treating clinical disorders such as schizophrenia and autism. Intranasal administration has been proposed as a possible route of delivery to the CNS for molecules like OT. While intranasal administration of OT influences social cognition and behavior, it is not well established whether this is an effective means for delivering OT to CNS targets. We administered OT or its vehicle (saline) to 15 primates (Macaca mulatta), using either intranasal spray or a nebulizer, and measured OT concentration changes in the cerebral spinal fluid (CSF) and in blood. All subjects received both delivery methods and both drug conditions. Baseline samples of blood and CSF were taken immediately before drug administration. Blood was collected every 10 minutes after administration for 40 minutes and CSF was collected once post-delivery, at the 40 minutes time point. We found that intranasal administration of exogenous OT increased concentrations in both CSF and plasma compared to saline. Both delivery methods resulted in similar elevations of OT concentration in CSF, while the changes in plasma OT concentration were greater after nasal spray compared to nebulizer. In conclusion our study provides evidence that both nebulizer and nasal spray OT administration can elevate CSF OT levels. PMID:25133536

  2. Preclinical evaluation of dual action intranasal formulation intended for postoperative/cancer associated therapies.

    PubMed

    El-Setouhy, Doaa Ahmed; Ahmed, Sami; Badawi, Alia Abd El-Latif; El-Nabarawi, Mohamed Ahmed; Sallam, Nada

    2015-08-30

    Granisetron hydrochloride is a potent antiemetic yet experiencing first pass metabolism. Ketorolac tromethamine is a potent analgesic NSAID that is known to cause gastrointestinal complications. The purpose of this study is to prepare combined in situ nasal copolymer thermal gel combining both drugs for the management of postoperative and cancer associated nausea, vomiting and pain while avoiding the problems associated with their therapy. In situ gelling nasal formulations with/without different mucoadhesive polymers were prepared and evaluated. Viscosity of different formulations was measured and correlated to in-vitro drug release. Selected formulae were evaluated for in-vivo mucociliary transit time. Based on in-vitro release pattern and mucociliary transit time, the selected formula F4 was evaluated for chemical and thermal anti-nociception activity in rats following intranasal or intraperitoneal administration. Only the intra-nasal administration of the selected formulation F4 showed significant analgesia against chemical nociception during both the early and late phases. Also, intranasal administration of the selected formulation F4 showed significant analgesia against thermal nociception. F4 intranasal formulation may offer higher therapeutic value than oral administration as it may not only avoid granisetron first pass metabolism but may also minimize ketorolac gastrointestinal adverse effects as well. PMID:25917526

  3. Abuse Potential of Intranasal Buprenorphine versus Buprenorphine/Naloxone in Buprenorphine-Maintained Heroin Users

    PubMed Central

    Jones, Jermaine D.; Sullivan, Maria A.; Vosburg, Suzanne K.; Manubay, Jeanne M.; Mogali, Shanthi; Metz, Verena; Comer, Sandra D.

    2014-01-01

    In spite of the clinical utility of buprenorphine, parenteral abuse of this medication has been reported in several laboratory investigations and in the real world. Studies have demonstrated lower abuse liability of the buprenorphine/naloxone combination relative to buprenorphine alone. However, clinical research has not yet examined the utility of the combined formulation to deter intranasal use in a buprenorphine-maintained population. Heroin-using volunteers (n = 12) lived in the hospital for 8–9 weeks and were maintained on each of three sublingual buprenorphine doses (2, 8, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intranasal doses of buprenorphine (8, 16 mg), buprenorphine/naloxone (8/2, 8/8, 8/16, 16/4 mg) and controls (placebo, heroin 100 mg, naloxone 4 mg) were assessed. Intranasal buprenorphine alone typically produced increases in positive subjective effects and the 8 mg dose was self-administered above the level of placebo. The addition of naloxone dose-dependently reduced positive subjective effects and increased aversive effects. No buprenorphine/naloxone combination dose was self-administered significantly more than placebo. These data suggest that within a buprenorphine-dependent population, intranasal buprenorphine/naloxone has reduced abuse potential in comparison to buprenorphine alone. These data strongly argue in favor of buprenorphine/naloxone rather than buprenorphine alone as the more reasonable option for managing the risk of buprenorphine misuse. PMID:25060839

  4. Anaesthesia Management for Awake Craniotomy: Systematic Review and Meta-Analysis

    PubMed Central

    Rossaint, Rolf; Veldeman, Michael

    2016-01-01

    Background Awake craniotomy (AC) renders an expanded role in functional neurosurgery. Yet, evidence for optimal anaesthesia management remains limited. We aimed to summarise the latest clinical evidence of AC anaesthesia management and explore the relationship of AC failures on the used anaesthesia techniques. Methods Two authors performed independently a systematic search of English articles in PubMed and EMBASE database 1/2007-12/2015. Search included randomised controlled trials (RCTs), observational trials, and case reports (n>4 cases), which reported anaesthetic approach for AC and at least one of our pre-specified outcomes: intraoperative seizures, hypoxia, arterial hypertension, nausea and vomiting, neurological dysfunction, conversion into general anaesthesia and failure of AC. Random effects meta-analysis was used to estimate event rates for four outcomes. Relationship with anaesthesia technique was explored using logistic meta-regression, calculating the odds ratios (OR) and 95% confidence intervals [95%CI]. Results We have included forty-seven studies. Eighteen reported asleep-awake-asleep technique (SAS), twenty-seven monitored anaesthesia care (MAC), one reported both and one used the awake-awake-awake technique (AAA). Proportions of AC failures, intraoperative seizures, new neurological dysfunction and conversion into general anaesthesia (GA) were 2% [95%CI:1–3], 8% [95%CI:6–11], 17% [95%CI:12–23] and 2% [95%CI:2–3], respectively. Meta-regression of SAS and MAC technique did not reveal any relevant differences between outcomes explained by the technique, except for conversion into GA. Estimated OR comparing SAS to MAC for AC failures was 0.98 [95%CI:0.36–2.69], 1.01 [95%CI:0.52–1.88] for seizures, 1.66 [95%CI:1.35–3.70] for new neurological dysfunction and 2.17 [95%CI:1.22–3.85] for conversion into GA. The latter result has to be interpreted cautiously. It is based on one retrospective high-risk of bias study and significance was

  5. Intranasal DNA vaccination induces potent mucosal and systemic immune responses and cross-protective immunity against influenza viruses.

    PubMed

    Torrieri-Dramard, Lea; Lambrecht, Bénédicte; Ferreira, Helena Lage; Van den Berg, Thierry; Klatzmann, David; Bellier, Bertrand

    2011-03-01

    The induction of potent virus-specific immune responses at mucosal surfaces where virus transmission occurs is a major challenge for vaccination strategies. In the case of influenza vaccination, this has been achieved only by intranasal delivery of live-attenuated vaccines that otherwise pose safety problems. Here, we demonstrate that potent mucosal and systemic immune responses, both cellular and humoral, are induced by intranasal immunization using formulated DNA. We show that formulation with the DNA carrier polyethylenimine (PEI) improved by a 1,000-fold the efficiency of gene transfer in the respiratory track following intranasal administration of luciferase-coding DNA. Using PEI formulation, intranasal vaccination with DNA-encoding hemagglutinin (HA) from influenza A H5N1 or (H1N1)2009 viruses induced high levels of HA-specific immunoglobulin A (IgA) antibodies that were detected in bronchoalveolar lavages (BALs) and the serum. No mucosal responses could be detected after parenteral or intranasal immunization with naked-DNA. Furthermore, intranasal DNA vaccination with HA from a given H5N1 virus elicited full protection against the parental strain and partial cross-protection against a distinct highly pathogenic H5N1 strain that could be improved by adding neuraminidase (NA) DNA plasmids. Our observations warrant further investigation of intranasal DNA as an effective vaccination route.

  6. Biosimilar Insulin and Costs

    PubMed Central

    Heinemann, Lutz

    2015-01-01

    The costs for insulin treatment are high, and the steady increase in the number of patients with diabetes on insulin presents a true challenge to health care systems. Therefore, all measures to lower these costs are welcomed by patients, physicians, and health care providers. The market introduction of biosimilar insulins presents an option to lower treatment costs as biosimilars are usually offered at a lower price than the originator product. However, the assumption that a drastic reduction in insulin prices will take place, as was observed with many generic drugs, is most probably not realistic. As the first biosimilar insulin has now been approved in the EU, this commentary discusses a number of aspects that are relevant when it comes to the potential cost reduction we will see with the use of biosimilar insulins. PMID:26350722

  7. Intranasal steroids: managing allergic rhinitis and tailoring treatment to patient preference.

    PubMed

    Meltzer, Eli O

    2005-01-01

    Allergic rhinitis (AR) can have a significant impact on patient quality of life (QoL), affecting learning ability and work productivity. Both the consequences of the impairment and the costs of treatment are associated with a large economic burden. The management of AR includes allergen avoidance, pharmacotherapy, and immunotherapy. Current pharmacotherapy options are oral and intranasal antihistamines, intranasal corticosteroids (INS), intranasal chromones, oral and intranasal decongestants, oral and intranasal anticholinergic agents, and antileukotrienes. A number of guidelines recommend INS as first-line treatment for persistent and moderate-to-severe AR. Although both patient and physician concern over the long-term safety of oral systemic steroids has previously prevented widespread use of INS, it is important to note that they have a superior risk/benefit ratio compared with other monotherapies. Indeed, the limited systemic bioavailability of INS agents, when used at recommended doses, has resulted in very low rates of systemic adverse effects, as shown by a lack of either hypothalamic-pituitary-adrenal axis or growth suppression. Large, controlled clinical studies have shown comparable efficacy and safety among the newer INS; therefore, clinicians may need to consider other factors, such as good patient compliance, when selecting an appropriate INS agent for a patient. In addition, patients often prefer one agent over another, and compliance may be improved by selecting the preferred agent. The development of two new questionnaires, the Clinical Practice Patient Preference Questionnaire and the Clinical Trial Patient Preference Questionnaire, may prove useful in selecting the optimal treatment regimen for patients.

  8. Intranasal vaccination with adjuvant-free S. aureus antigens effectively protects mice against experimental sepsis.

    PubMed

    Stegmiller, Nataly Pescinalli; Barcelos, Estevão Carlos; Leal, Janine Miranda; Covre, Luciana Polaco; Donatele, Dirlei Molinari; de Matos Guedes, Herbet Leonel; Cunegundes, Marco Cesar; Rodrigues, Rodrigo Ribeiro; Gomes, Daniel Cláudio Oliviera

    2016-06-24

    Staphylococcus aureus (S. aureus) is a Gram-positive coccal bacterium comprising part of the human skin, nares and gastrointestinal tract normal microbiota. It is also an important cause of nosocomial/community-acquired infections in humans and animals, which can cause a diverse array of infections, including sepsis, which is a progressive systemic inflammation response syndrome that is frequently fatal. The emergence of drug-resistant strains and the high toxicity of the treatments used for these infections point out the need to develop an effective, inexpensive and safe vaccine that can be used prophylactically. In this work, we used an experimental sepsis model to evaluate the effectiveness of whole antigens from S. aureus (SaAg) given by the intranasal route to induce protective immunity against S. aureus infection in mice. BALB/c mice were vaccinated via intranasal or intramuscular route with two doses of SaAg, followed by biocompatibility and immunogenicity evaluations. Vaccinated animals did not show any adverse effects associated with the vaccine, as determined by transaminase and creatinine measurements. Intranasal, but not intramuscular vaccination with SaAg led to a significant reduction in IL-10 production and was associated with increased level of IFN-γ and NO. SaAg intranasal vaccination was able to prime cellular and humoral immune responses and inducing a higher proliferation index and increased production of specific IgG1/IgG2, which contributed to decrease the bacterial load in both liver and the spleen and improve survival during sepsis. These findings present the first evidence of the effectiveness of whole Ag intranasal-based vaccine administration, which expands the vaccination possibilities against S. aureus infection. PMID:27091687

  9. Intranasal Corticosteroids in Management of Acute Sinusitis: A Systematic Review and Meta-Analysis

    PubMed Central

    Hayward, Gail; Heneghan, Carl; Perera, Rafael; Thompson, Matthew

    2012-01-01

    PURPOSE Acute sinusitis is a common condition in ambulatory care, where it is frequently treated with antibiotics, despite little evidence of their benefit. Intranasal corticosteroids might relieve symptoms; however, evidence for this benefit is currently unclear. We performed a systematic review and meta-analysis of the effects of intranasal corticosteroids on the symptoms of acute sinusitis. METHODS We searched MEDLINE, EMBASE, the Cochrane Central register of Controlled Trials (CENTRAL), and Centre for Reviews and Dissemination databases until February 2011 for studies comparing intranasal corticosteroids with placebo in children or adults having clinical symptoms and signs of acute sinusitis or rhinosinusitis in ambulatory settings. We excluded chronic/allergic sinusitis. Two authors independently extracted data and assessed the studies’ methodologic quality. RESULTS We included 6 studies having a total of 2,495 patients. In 5 studies, antibiotics were prescribed in addition to corticosteroids or placebo. Intranasal corticosteroids resulted in a significant, small increase in resolution of or improvement in symptoms at days 14 to 21 (risk difference [RD] = 0.08; 95% CI, 0.03–0.13). Analysis of individual symptom scores revealed most consistently significant benefits for facial pain and congestion. Subgroup analysis by time of reported outcomes showed a significant beneficial effect at 21 days (RD = 0.11; 95% CI, 0.06–0.17), but not at 14 to 15 days (RD = 0.05; 95% CI, −0.01 to 0.11). Meta-regression analysis of trials using different doses of mometasone furoate showed a significant dose-response relationship (P=.02). CONCLUSIONS Intranasal corticosteroids offer a small therapeutic benefit in acute sinusitis, which may be greater with high doses and with courses of 21 days’ duration. Further trials are needed in antibiotic-naïve patients. PMID:22585889

  10. In vivo visualization of olfactory pathophysiology induced by intranasal cadmium instillation in mice

    PubMed Central

    Czarnecki, Lindsey A.; Moberly, Andrew H.; Rubinstein, Tom; Turkel, Daniel J.; Pottackal, Joseph; McGann, John P.

    2013-01-01

    Intranasal exposure to cadmium has been related to olfactory dysfunction in humans and to nasal epithelial damage and altered odorant-guided behavior in rodent models. The pathophysiology underlying these deficits has not been fully elucidated. Here we use optical imaging techniques to visualize odorant-evoked neurotransmitter release from the olfactory nerve into the brain’s olfactory bulbs in vivo in mice. Intranasal cadmium chloride instillations reduced this sensory activity by up to 91% in a dose-dependent manner. In the olfactory bulbs, afferents from the olfactory epithelium could be quantified by their expression of a genetically-encoded fluorescent marker for olfactory marker protein. At the highest dose tested, cadmium exposure reduced the density of these projections by 20%. In a behavioral psychophysical task, mice were trained to sample from an odor port and make a response when they detected an odorant against a background of room air. After intranasal cadmium exposure, mice were unable to detect the target odor. These experiments serve as proof of concept for a new approach to the study of the neural effects of inhaled toxicants. The use of in vivo functional imaging of the neuronal populations exposed to the toxicant permits the direct observation of primary pathophysiology. In this study optical imaging revealed significant reductions in odorant-evoked release from the olfactory nerve at a cadmium chloride dose two orders of magnitude less than that required to induce morphological changes in the nerve in the same animals, demonstrating that it is a more sensitive technique for assessing the consequences of intranasal neurotoxicant exposure. This approach is potentially useful in exploring the effects of any putative neurotoxicant that can be delivered intranasally. PMID:21443902

  11. Long-term exposure to intranasal oxytocin in a mouse autism model.

    PubMed

    Bales, K L; Solomon, M; Jacob, S; Crawley, J N; Silverman, J L; Larke, R H; Sahagun, E; Puhger, K R; Pride, M C; Mendoza, S P

    2014-01-01

    Oxytocin (OT) is a neuropeptide involved in mammalian social behavior. It is currently in clinical trials for the treatment of autism spectrum disorder (ASD). Previous studies in healthy rodents (prairie voles and C57BL/6J mice) have shown that there may be detrimental effects of long-term intranasal administration, raising the questions about safety and efficacy. To investigate the effects of OT on the aspects of ASD phenotype, we conducted the first study of chronic intranasal OT in a well-validated mouse model of autism, the BTBR T+ Itpr3tf/J inbred strain (BTBR), which displays low sociability and high repetitive behaviors. BTBR and C57BL/6J (B6) mice (N=94) were administered 0.8  IU/kg of OT intranasally, daily for 30 days, starting on day 21. We ran a well-characterized set of behavioral tasks relevant to diagnostic and associated symptoms of autism, including juvenile reciprocal social interactions, three-chambered social approach, open-field exploratory activity, repetitive self-grooming and fear-conditioned learning and memory, some during and some post treatment. Intranasal OT did not improve autism-relevant behaviors in BTBR, except for female sniffing in the three-chambered social interaction test. Male saline-treated BTBR mice showed increased interest in a novel mouse, both in chamber time and sniffing time, whereas OT-treated male BTBR mice showed a preference for the novel mouse in sniffing time only. No deleterious effects of OT were detected in either B6 or BTBR mice, except possibly for the lack of a preference for the novel mouse's chamber in OT-treated male BTBR mice. These results highlight the complexity inherent in understanding the effects of OT on behavior. Future investigations of chronic intranasal OT should include a wider dose range and early developmental time points in both healthy rodents and ASD models to affirm the efficacy and safety of OT. PMID:25386957

  12. Long-term exposure to intranasal oxytocin in a mouse autism model

    PubMed Central

    Bales, K L; Solomon, M; Jacob, S; Crawley, J N; Silverman, J L; Larke, R H; Sahagun, E; Puhger, K R; Pride, M C; Mendoza, S P

    2014-01-01

    Oxytocin (OT) is a neuropeptide involved in mammalian social behavior. It is currently in clinical trials for the treatment of autism spectrum disorder (ASD). Previous studies in healthy rodents (prairie voles and C57BL/6J mice) have shown that there may be detrimental effects of long-term intranasal administration, raising the questions about safety and efficacy. To investigate the effects of OT on the aspects of ASD phenotype, we conducted the first study of chronic intranasal OT in a well-validated mouse model of autism, the BTBR T+ Itpr3tf/J inbred strain (BTBR), which displays low sociability and high repetitive behaviors. BTBR and C57BL/6J (B6) mice (N=94) were administered 0.8  IU/kg of OT intranasally, daily for 30 days, starting on day 21. We ran a well-characterized set of behavioral tasks relevant to diagnostic and associated symptoms of autism, including juvenile reciprocal social interactions, three-chambered social approach, open-field exploratory activity, repetitive self-grooming and fear-conditioned learning and memory, some during and some post treatment. Intranasal OT did not improve autism-relevant behaviors in BTBR, except for female sniffing in the three-chambered social interaction test. Male saline-treated BTBR mice showed increased interest in a novel mouse, both in chamber time and sniffing time, whereas OT-treated male BTBR mice showed a preference for the novel mouse in sniffing time only. No deleterious effects of OT were detected in either B6 or BTBR mice, except possibly for the lack of a preference for the novel mouse's chamber in OT-treated male BTBR mice. These results highlight the complexity inherent in understanding the effects of OT on behavior. Future investigations of chronic intranasal OT should include a wider dose range and early developmental time points in both healthy rodents and ASD models to affirm the efficacy and safety of OT. PMID:25386957

  13. Effects of intranasal and peripheral oxytocin or gastrin-releasing peptide administration on social interaction and corticosterone levels in rats.

    PubMed

    Kent, Pamela; Awadia, Alisha; Zhao, Leah; Ensan, Donna; Silva, Dinuka; Cayer, Christian; James, Jonathan S; Anisman, Hymie; Merali, Zul

    2016-02-01

    The intranasal route of drug administration has gained increased popularity as it is thought to allow large molecules, such as peptide hormones, more direct access to the brain, while limiting systemic exposure. Several studies have investigated the effects of intranasal oxytocin administration in humans as this peptide is associated with prosocial behavior. There are, however, few preclinical studies investigating the effects of intranasal oxytocin administration in rodents. Oxytocin modulates hypothalamic-pituitary-adrenal (HPA) axis functioning and it has been suggested that oxytocin's ability to increase sociability may occur through a reduction in stress reactivity. Another peptide that appears to influence both social behavior and HPA axis activity is gastrin-releasing peptide (GRP), but it is not known if these GRP-induced effects are related. With this in mind, in the present study, we assessed the effects of intranasal and intraperitoneal oxytocin and GRP administration on social interaction and release of corticosterone in rats. Intranasal and intraperitoneal administration of 20, but not 5 μg, of oxytocin significantly increased social interaction, whereas intranasal and peripheral administration of GRP (20 but not 5 μg) significantly decreased levels of social interaction. In addition, while intranasal oxytocin (20 μg) had no effect on blood corticosterone levels, a marked increase in blood corticosterone levels was observed following intraperitoneal oxytocin administration. With GRP, intranasal (20 μg) but not peripheral administration increased corticosterone levels. These findings provide further evidence that intranasal peptide delivery can induce behavioral alterations in rodents which is consistent with findings from human studies. In addition, the peptide-induced changes in social interaction were not linked to fluctuations in corticosterone levels.

  14. The pharmacodynamic and pharmacokinetic profile of intranasal crushed buprenorphine and buprenorphine/naloxone tablets in opioid abusers

    PubMed Central

    Middleton, L.S.; Nuzzo, P.A.; Lofwall, M.R.; Moody, D.E.; Walsh, S.L.

    2011-01-01

    Aims Sublingual buprenorphine and buprenorphine/naloxone are efficacious opioid dependence pharmacotherapies, but there are reports of their diversion and misuse by the intranasal route. The study objectives were to characterize and compare their intranasal pharmacodynamic and pharmacokinetic profiles. Design A randomized, double-blind, placebo-controlled, crossover study. Setting An in-patient research unit at the University of Kentucky. Participants Healthy adults (n=10) abusing, but not physically dependent on, intranasal opioids. Measurements Six sessions (72 hours apart) tested five intranasal doses [0/0, crushed buprenorphine (2, 8 mg), crushed buprenorphine/naloxone (2/0.5, 8/2 mg)] and one intravenous dose (0.8 mg buprenorphine/0.2 mg naloxone for bioavailability assessment). Plasma samples, physiological, subject- and observer-rated measures were collected before and for up to 72 hours after drug administration. Findings Both formulations produced time- and dose-dependent increases on subjective and physiological mu-opioid agonist effects (e.g. ‘liking’, miosis). Subjects reported higher subjective ratings and street values for 8 mg compared to 8/2 mg, but these differences were not statistically significant. No significant formulation differences in peak plasma buprenorphine concentration or time-course were observed. Buprenorphine bioavailability was 38–44% and Tmax was 35–40 minutes after all intranasal doses. Naloxone bioavailability was 24% and 30% following 2/0.5 and 8/2 mg, respectively. Conclusions It is difficult to determine if observed differences in abuse potential between intranasal buprenorphine and buprenorphine/naloxone are clinically relevant at the doses tested. Greater bioavailability and faster onset of pharmacodynamic effects compared to sublingual administration suggests a motivation for intranasal misuse in non-dependent opioid abusers. However, significant naloxone absorption from intranasal buprenorphine

  15. Tea enhances insulin activity.

    PubMed

    Anderson, Richard A; Polansky, Marilyn M

    2002-11-20

    The most widely known health benefits of tea relate to the polyphenols as the principal active ingredients in protection against oxidative damage and in antibacterial, antiviral, anticarcinogenic, and antimutagenic activities, but polyphenols in tea may also increase insulin activity. The objective of this study was to determine the insulin-enhancing properties of tea and its components. Tea, as normally consumed, was shown to increase insulin activity >15-fold in vitro in an epididymal fat cell assay. Black, green, and oolong teas but not herbal teas, which are not teas in the traditional sense because they do not contain leaves of Camellia senensis, were all shown to increase insulin activity. High-performance liquid chromatography fractionation of tea extracts utilizing a Waters SymmetryPrep C18 column showed that the majority of the insulin-potentiating activity for green and oolong teas was due to epigallocatechin gallate. For black tea, the activity was present in several regions of the chromatogram corresponding to, in addition to epigallocatechin gallate, tannins, theaflavins, and other undefined compounds. Several known compounds found in tea were shown to enhance insulin with the greatest activity due to epigallocatechin gallate followed by epicatechin gallate, tannins, and theaflavins. Caffeine, catechin, and epicatechin displayed insignificant insulin-enhancing activities. Addition of lemon to the tea did not affect the insulin-potentiating activity. Addition of 5 g of 2% milk per cup decreased the insulin-potentiating activity one-third, and addition of 50 g of milk per cup decreased the insulin-potentiating activity approximately 90%. Nondairy creamers and soy milk also decreased the insulin-enhancing activity. These data demonstrate that tea contains in vitro insulin-enhancing activity and the predominant active ingredient is epigallocatechin gallate. PMID:12428980

  16. Pathophysiology of insulin secretion.

    PubMed

    Scheen, A J

    2004-02-01

    Defects in pancreatic islet beta-cell function play a major role in the development of diabetes mellitus. Type 1 diabetes is caused by a more or less rapid destruction of pancreatic beta cells, and the autoimmune process begins years before the beta-cell destruction becomes complete, thereby providing a window of opportunity for intervention. During the preclinical period and early after diagnosis, much of the insulin deficiency may be the result of functional inhibition of insulin secretion that may be at least partially and transiently reversible. Type 2 diabetes is characterized by a progressive loss of beta-cell function throughout the course of the disease. The pattern of loss is an initial (probably of genetic origin) defect in acute or first-phase insulin secretion, followed by a decreasing maximal capacity of insulin secretion. Last, a defective steady-state and basal insulin secretion develops, leading to almost complete beta-cell failure requiring insulin treatment. Because of the reciprocal relation between insulin secretion and insulin sensitivity, valid representation of beta-cell function requires interpretation of insulin responses in the context of the prevailing degree of insulin sensitivity. This appropriate approach highlights defects in insulin secretion at the various stages of the natural history of type 2 diabetes and already present in individuals at risk to develop the disease. To date none of the available therapies can stop the progressive beta-cell defect and the progression of the metabolic disorder. The better understanding of the pathophysiology of the disease should lead to the development of new strategies to preserve beta-cell function in both type 1 and type 2 diabetes mellitus.

  17. Mapping the Functional Network of Medial Prefrontal Cortex by Combining Optogenetics and fMRI in Awake Rats

    PubMed Central

    Liang, Zhifeng; Watson, Glenn D.R.; Alloway, Kevin D.; Lee, Gangchea; Neuberger, Thomas; Zhang, Nanyin

    2015-01-01

    The medial prefrontal cortex (mPFC) plays a critical role in multiple cognitive and limbic functions. Given its vital importance, investigating the function of individual mPFC circuits in animal models has provided critical insight into the neural basis underlying different behaviors and psychiatric conditions. However, our knowledge regarding the mPFC whole-brain network stays largely at the anatomical level, while the functional network of mPFC, which can be dynamic in different conditions or following manipulations, remains elusive especially in awake rodents. Here we combined optogenetic stimulation and functional magnetic resonance imaging (opto-fMRI) to reveal the network of brain regions functionally activated by mPFC outputs in awake rodents. Our data showed significant increases in blood-oxygenation-level dependent (BOLD) signals in prefrontal, striatal and limbic regions when mPFC was optically stimulated. This activation pattern was robust, reproducible, and did not depend on the stimulation period in awake rats. BOLD signals, however, were substantially reduced when animals were anesthetized. In addition, regional brain activation showing increased BOLD signals during mPFC stimulation was corroborated by electrophysiological recordings. These results expand the applicability of the opto-fMRI approach from sensorimotor processing to cognition-related networks in awake rodents. Importantly, it may help elucidate the circuit mechanisms underlying numerous mPFC-related functions and behaviors that need to be assessed in the awake state. PMID:26002727

  18. Mapping the functional network of medial prefrontal cortex by combining optogenetics and fMRI in awake rats.

    PubMed

    Liang, Zhifeng; Watson, Glenn D R; Alloway, Kevin D; Lee, Gangchea; Neuberger, Thomas; Zhang, Nanyin

    2015-08-15

    The medial prefrontal cortex (mPFC) plays a critical role in multiple cognitive and limbic functions. Given its vital importance, investigating the function of individual mPFC circuits in animal models has provided critical insight into the neural basis underlying different behaviors and psychiatric conditions. However, our knowledge regarding the mPFC whole-brain network stays largely at the anatomical level, while the functional network of mPFC, which can be dynamic in different conditions or following manipulations, remains elusive especially in awake rodents. Here we combined optogenetic stimulation and functional magnetic resonance imaging (opto-fMRI) to reveal the network of brain regions functionally activated by mPFC outputs in awake rodents. Our data showed significant increases in blood-oxygenation-level dependent (BOLD) signals in prefrontal, striatal and limbic regions when mPFC was optically stimulated. This activation pattern was robust, reproducible, and did not depend on the stimulation period in awake rats. BOLD signals, however, were substantially reduced when animals were anesthetized. In addition, regional brain activation showing increased BOLD signals during mPFC stimulation was corroborated by electrophysiological recordings. These results expand the applicability of the opto-fMRI approach from sensorimotor processing to cognition-related networks in awake rodents. Importantly, it may help elucidate the circuit mechanisms underlying numerous mPFC-related functions and behaviors that need to be assessed in the awake state.

  19. Importance of transcapillary insulin transport on insulin action in vivo

    SciTech Connect

    Yang, Y.J.

    1989-01-01

    The relationship between transcapillary insulin transport and insulin action was examined in normal conscious dogs. Plasma and thoracic duct lymph insulin, and insulin action were simultaneously measured during euglycemic clamps and intravenous glucose tolerance tests. During the clamps, while {sup 14}C-inulin reached an equilibrium, steady-state (ss) plasma insulin was higher than lymph and the ratio of 3:2 was maintained during basal, activation and deactivation phases: 18 {+-} 2 vs. 12 {+-} 1, 51 {+-} 2 vs. 32 {+-} 1, and 18 {+-} 3 vs. 13 {+-} 1 {mu}U/ml. In addition, it took longer for lymph insulin to reach ss than plasma insulin during activation and deactivation: 11 {+-} 2 vs. 31 {+-} 5 and 8 {+-} 2 vs. 32 {+-} 6 min. During IVGTT, plasma insulin peaked within 5 {+-} 2 min; lymph insulin rose slowly to a lower peak. The significant gradient and delay between plasma and lymph insulin concentrations suggest a restricted transcapillary insulin transport.

  20. Protein Crystal Bovine Insulin

    NASA Technical Reports Server (NTRS)

    1991-01-01

    The comparison of protein crystal, Bovine Insulin space-grown (left) and earth-grown (right). Facilitates the incorporation of glucose into cells. In diabetics, there is either a decrease in or complete lack of insulin, thereby leading to several harmful complications. Principal Investigator is Larry DeLucas.

  1. Murine intranasal challenge model for the study of Campylobacter pathogenesis and immunity.

    PubMed Central

    Baqar, S; Bourgeois, A L; Applebee, L A; Mourad, A S; Kleinosky, M T; Mohran, Z; Murphy, J R

    1996-01-01

    Campylobacter jejuni infection of mice initiated by intranasal administration was investigated as a potential model for studies of pathogenesis and immunity. By using a standard challenge (5 x 10(9) CFU), C. jejuni 81-176 was more virulent for BALB/c (72% mortality) than for C3H/Hej (50%), CBA/CAJ (30%), or C58/J (0%). Intranasal challenge of BALB/c was used to compare the relative virulence of three reference strains; C.jejuni 81-176 was more virulent (killing 83% of challenged mice) than C. jejuni HC (0%) or C. coli VC-167 (0%). The course of intranasally initiated C. jejuni 81-176 infection in BALB/c was determined. C. jejuni was recovered from the lungs, intestinal tract, liver, and spleen at 4 h after challenge, the first interval evaluated. After this initial interval, three distinct patterns of infection were recognized: (i) a progressive decline in number of C. jejuni CFU (stomach, blood, lungs), (ii) decline followed by a second peak in the number of organisms recovered at 2 or 3 days postchallenge (intestine, liver, mesenteric lymph nodes), and (iii) persistence of approximately the same number of C.jejuni CFU during the course of the experiment (spleen). Intranasally induced infection initiated with a sublethal number of bacteria or intranasal immunization with killed Campylobacter preparations resulted in both the generation of Campylobacter antigen-specific immune responses and an acquired resistance to homologous rechallenge. The model was used to evaluate the relative virulence of nine low-in vitro-passage (no more than five passages) isolates of C. jejuni species from patients with diarrhea. The patient isolates were differentially virulent for mice; one killed all exposed mice, three were avirulent (no deaths) and the remainder showed an intermediate virulence, killing 17 to 33%. Mouse virulence of Campylobacter strains showed a trend toward isolates originating from individuals with watery diarrhea; however, no association was found between mouse

  2. Functional recordings from awake, behaving rodents through a microchannel based regenerative neural interface

    PubMed Central

    Gore, Russell K.; Choi, Yoonsu; Bellamkonda, Ravi; English, Arthur

    2015-01-01

    Objective Neural interface technologies could provide controlling connections between the nervous system and external technologies, such as limb prosthetics. The recording of efferent, motor potentials is a critical requirement for a peripheral neural interface, as these signals represent the user-generated neural output intended to drive external devices. Our objective was to evaluate structural and functional neural regeneration through a microchannel neural interface and to characterize potentials recorded from electrodes placed within the microchannels in awake and behaving animals. Approach Female rats were implanted with muscle EMG electrodes and, following unilateral sciatic nerve transection, the cut nerve was repaired either across a microchannel neural interface or with end-to-end surgical repair. During a 13-week recovery period, direct muscle responses to nerve stimulation proximal to the transection were monitored weekly. In two rats repaired with the neural interface, four wire electrodes were embedded in the microchannels and recordings were obtained within microchannels during proximal stimulation experiments and treadmill locomotion. Main results In these proof-of-principle experiments, we found that axons from cut nerves were capable of functional reinnervation of distal muscle targets, whether regenerating through a microchannel device or after direct end-to-end repair. Discrete stimulation-evoked and volitional potentials were recorded within interface microchannels in a small group of awake and behaving animals and their firing patterns correlated directly with intramuscular recordings during locomotion. Of 38 potentials extracted, 19 were identified as motor axons reinnervating tibialis anterior or soleus muscles using spike triggered averaging. Significance These results are evidence for motor axon regeneration through microchannels and are the first report of in vivo recordings from regenerated motor axons within microchannels in a small

  3. Functional recordings from awake, behaving rodents through a microchannel based regenerative neural interface

    NASA Astrophysics Data System (ADS)

    Gore, Russell K.; Choi, Yoonsu; Bellamkonda, Ravi; English, Arthur

    2015-02-01

    Objective. Neural interface technologies could provide controlling connections between the nervous system and external technologies, such as limb prosthetics. The recording of efferent, motor potentials is a critical requirement for a peripheral neural interface, as these signals represent the user-generated neural output intended to drive external devices. Our objective was to evaluate structural and functional neural regeneration through a microchannel neural interface and to characterize potentials recorded from electrodes placed within the microchannels in awake and behaving animals. Approach. Female rats were implanted with muscle EMG electrodes and, following unilateral sciatic nerve transection, the cut nerve was repaired either across a microchannel neural interface or with end-to-end surgical repair. During a 13 week recovery period, direct muscle responses to nerve stimulation proximal to the transection were monitored weekly. In two rats repaired with the neural interface, four wire electrodes were embedded in the microchannels and recordings were obtained within microchannels during proximal stimulation experiments and treadmill locomotion. Main results. In these proof-of-principle experiments, we found that axons from cut nerves were capable of functional reinnervation of distal muscle targets, whether regenerating through a microchannel device or after direct end-to-end repair. Discrete stimulation-evoked and volitional potentials were recorded within interface microchannels in a small group of awake and behaving animals and their firing patterns correlated directly with intramuscular recordings during locomotion. Of 38 potentials extracted, 19 were identified as motor axons reinnervating tibialis anterior or soleus muscles using spike triggered averaging. Significance. These results are evidence for motor axon regeneration through microchannels and are the first report of in vivo recordings from regenerated motor axons within microchannels in a small

  4. In Vivo Tumour Mapping Using Electrocorticography Alterations During Awake Brain Surgery: A Pilot Study.

    PubMed

    Boussen, Salah; Velly, Lionel; Benar, Christian; Metellus, Philippe; Bruder, Nicolas; Trébuchon, Agnès

    2016-09-01

    During awake brain surgery for tumour resection, in situ EEG recording (ECoG) is used to identify eloquent areas surrounding the tumour. We used the ECoG setup to record the electrical activity of cortical and subcortical tumours and then performed frequency and connectivity analyses in order to identify ECoG impairments and map tumours. We selected 16 patients with cortical (8) and subcortical (8) tumours undergoing awake brain surgery. For each patient, we computed the spectral content of tumoural and healthy areas in each frequency band. We computed connectivity of each electrode using connectivity markers (linear and non-linear correlations, phase-locking and coherence). We performed comparisons between healthy and tumour electrodes. The ECoG alterations were used to implement automated classification of the electrodes using clustering or neural network algorithms. ECoG alterations were used to image cortical tumours.Cortical tumours were found to profoundly alter all frequency contents (normalized and absolute power), with an increase in the δ activity and a decreases for the other bands (P < 0.05). Cortical tumour electrodes showed high level of connectivity compared to surrounding electrodes (all markers, P < 0.05). For subcortical tumours, a relative decrease in the γ1 band and in the alpha band in absolute amplitude (P < 0.05) were the only abnormalities. The neural network algorithm classification had a good performance: 93.6 % of the electrodes were classified adequately on a test subject. We found significant spectral and connectivity ECoG changes for cortical tumours, which allowed tumour recognition. Artificial neural algorithm pattern recognition seems promising for electrode classification in awake tumour surgery. PMID:27324381

  5. MATLAB-based automated patch-clamp system for awake behaving mice

    PubMed Central

    Siegel, Jennifer J.; Taylor, William; Chitwood, Raymond A.; Johnston, Daniel

    2015-01-01

    Automation has been an important part of biomedical research for decades, and the use of automated and robotic systems is now standard for such tasks as DNA sequencing, microfluidics, and high-throughput screening. Recently, Kodandaramaiah and colleagues (Nat Methods 9: 585–587, 2012) demonstrated, using anesthetized animals, the feasibility of automating blind patch-clamp recordings in vivo. Blind patch is a good target for automation because it is a complex yet highly stereotyped process that revolves around analysis of a single signal (electrode impedance) and movement along a single axis. Here, we introduce an automated system for blind patch-clamp recordings from awake, head-fixed mice running on a wheel. In its design, we were guided by 3 requirements: easy-to-use and easy-to-modify software; seamless integration of behavioral equipment; and efficient use of time. The resulting system employs equipment that is standard for patch recording rigs, moderately priced, or simple to make. It is written entirely in MATLAB, a programming environment that has an enormous user base in the neuroscience community and many available resources for analysis and instrument control. Using this system, we obtained 19 whole cell patch recordings from neurons in the prefrontal cortex of awake mice, aged 8–9 wk. Successful recordings had series resistances that averaged 52 ± 4 MΩ and required 5.7 ± 0.6 attempts to obtain. These numbers are comparable with those of experienced electrophysiologists working manually, and this system, written in a simple and familiar language, will be useful to many cellular electrophysiologists who wish to study awake behaving mice. PMID:26084901

  6. MATLAB-based automated patch-clamp system for awake behaving mice.

    PubMed

    Desai, Niraj S; Siegel, Jennifer J; Taylor, William; Chitwood, Raymond A; Johnston, Daniel

    2015-08-01

    Automation has been an important part of biomedical research for decades, and the use of automated and robotic systems is now standard for such tasks as DNA sequencing, microfluidics, and high-throughput screening. Recently, Kodandaramaiah and colleagues (Nat Methods 9: 585-587, 2012) demonstrated, using anesthetized animals, the feasibility of automating blind patch-clamp recordings in vivo. Blind patch is a good target for automation because it is a complex yet highly stereotyped process that revolves around analysis of a single signal (electrode impedance) and movement along a single axis. Here, we introduce an automated system for blind patch-clamp recordings from awake, head-fixed mice running on a wheel. In its design, we were guided by 3 requirements: easy-to-use and easy-to-modify software; seamless integration of behavioral equipment; and efficient use of time. The resulting system employs equipment that is standard for patch recording rigs, moderately priced, or simple to make. It is written entirely in MATLAB, a programming environment that has an enormous user base in the neuroscience community and many available resources for analysis and instrument control. Using this system, we obtained 19 whole cell patch recordings from neurons in the prefrontal cortex of awake mice, aged 8-9 wk. Successful recordings had series resistances that averaged 52 ± 4 MΩ and required 5.7 ± 0.6 attempts to obtain. These numbers are comparable with those of experienced electrophysiologists working manually, and this system, written in a simple and familiar language, will be useful to many cellular electrophysiologists who wish to study awake behaving mice.

  7. In Vivo Tumour Mapping Using Electrocorticography Alterations During Awake Brain Surgery: A Pilot Study.

    PubMed

    Boussen, Salah; Velly, Lionel; Benar, Christian; Metellus, Philippe; Bruder, Nicolas; Trébuchon, Agnès

    2016-09-01

    During awake brain surgery for tumour resection, in situ EEG recording (ECoG) is used to identify eloquent areas surrounding the tumour. We used the ECoG setup to record the electrical activity of cortical and subcortical tumours and then performed frequency and connectivity analyses in order to identify ECoG impairments and map tumours. We selected 16 patients with cortical (8) and subcortical (8) tumours undergoing awake brain surgery. For each patient, we computed the spectral content of tumoural and healthy areas in each frequency band. We computed connectivity of each electrode using connectivity markers (linear and non-linear correlations, phase-locking and coherence). We performed comparisons between healthy and tumour electrodes. The ECoG alterations were used to implement automated classification of the electrodes using clustering or neural network algorithms. ECoG alterations were used to image cortical tumours.Cortical tumours were found to profoundly alter all frequency contents (normalized and absolute power), with an increase in the δ activity and a decreases for the other bands (P < 0.05). Cortical tumour electrodes showed high level of connectivity compared to surrounding electrodes (all markers, P < 0.05). For subcortical tumours, a relative decrease in the γ1 band and in the alpha band in absolute amplitude (P < 0.05) were the only abnormalities. The neural network algorithm classification had a good performance: 93.6 % of the electrodes were classified adequately on a test subject. We found significant spectral and connectivity ECoG changes for cortical tumours, which allowed tumour recognition. Artificial neural algorithm pattern recognition seems promising for electrode classification in awake tumour surgery.

  8. BOLD fMRI in awake prairie voles: A platform for translational social and affective neuroscience.

    PubMed

    Yee, J R; Kenkel, W M; Kulkarni, P; Moore, K; Perkeybile, A M; Toddes, S; Amacker, J A; Carter, C S; Ferris, C F

    2016-09-01

    The advancement of neuroscience depends on continued improvement in methods and models. Here, we present novel techniques for the use of awake functional magnetic resonance imaging (fMRI) in the prairie vole (Microtus ochrogaster) - an important step forward in minimally-invasive measurement of neural activity in a non-traditional animal model. Imaging neural responses in prairie voles, a species studied for its propensity to form strong and selective social bonds, is expected to greatly advance our mechanistic understanding of complex social and affective processes. The use of ultra-high-field fMRI allows for recording changes in region-specific activity throughout the entire brain simultaneously and with high temporal and spatial resolutions. By imaging neural responses in awake animals, with minimal invasiveness, we are able to avoid the confound of anesthesia, broaden the scope of possible stimuli, and potentially make use of repeated scans from the same animals. These methods are made possible by the development of an annotated and segmented 3D vole brain atlas and software for image analysis. The use of these methods in the prairie vole provides an opportunity to broaden neuroscientific investigation of behavior via a comparative approach, which highlights the ethological relevance of pro-social behaviors shared between voles and humans, such as communal breeding, selective social bonds, social buffering of stress, and caregiving behaviors. Results using these methods show that fMRI in the prairie vole is capable of yielding robust blood oxygen level dependent (BOLD) signal changes in response to hypercapnic challenge (inhaled 5% CO2), region-specific physical challenge (unilateral whisker stimulation), and presentation of a set of novel odors. Complementary analyses of repeated restraint sessions in the imaging hardware suggest that voles do not require acclimation to this procedure. Taken together, awake vole fMRI represents a new arena of neurobiological

  9. Electrical stimulation of the midbrain increases heart rate and arterial blood pressure in awake humans

    PubMed Central

    Thornton, Judith M; Aziz, Tipu; Schlugman, David; Paterson, David J

    2002-01-01

    Electrical stimulation of the hypothalamus, basal ganglia or pedunculopontine nucleus in decorticate animals results in locomotion and a cardiorespiratory response resembling that seen during exercise. This has led to the hypothesis that parallel activation of cardiorespiratory and locomotor systems from the midbrain could form part of the ‘central command’ mechanism of exercise. However, the degree to which subcortical structures play a role in cardiovascular activation in awake humans has not been established. We studied the effects on heart rate (HR) and mean arterial blood pressure (MAP) of electrically stimulating the thalamus and basal ganglia in awake humans undergoing neurosurgery for movement disorders (n = 13 Parkinson's disease, n = 1 myoclonic dystonia, n = 1 spasmodic torticollis). HR and MAP increased during high frequency (> 90 Hz) electrical stimulation of the thalamus (HR 5 ± 3 beats min−1, P = 0.002, MAP 4 ± 3 mmHg, P = 0.05, n = 9), subthalamic nucleus (HR 5 ± 3 beats min−1, P = 0.002, MAP 5 ± 3 mmHg, P = 0.006, n = 8) or substantia nigra (HR 6 ± 3 beats min−1, P = 0.001, MAP 5 ± 2 mmHg, P = 0.005, n = 8). This was accompanied by the facilitation of movement, but without the movement itself. Stimulation of the internal globus pallidus did not increase cardiovascular variables but did facilitate movement. Low frequency (< 20 Hz) stimulation of any site did not affect cardiovascular variables or movement. Electrical stimulation of the midbrain in awake humans can cause a modest increase in cardiovascular variables that is not dependent on movement feedback from exercising muscles. The relationship between this type of response and that occurring during actual exercise is unclear, but it indicates that subcortical command could be involved in ‘parallel activation’ of the locomotor and cardiovascular systems and thus contribute to the neurocircuitry of ‘central command’. PMID:11882692

  10. Insulin Resistance of Puberty.

    PubMed

    Kelsey, Megan M; Zeitler, Philip S

    2016-07-01

    Puberty is a time of considerable metabolic and hormonal change. Notably, puberty is associated with a marked decrease in insulin sensitivity, on par with that seen during pregnancy. In otherwise healthy youth, there is a nadir in insulin sensitivity in mid-puberty, and then it recovers at puberty completion. However, there is evidence that insulin resistance (IR) does not resolve in youth who are obese going into puberty and may result in increased cardiometabolic risk. Little is known about the underlying pathophysiology of IR in puberty, and how it might contribute to increased disease risk (e.g., type 2 diabetes). In this review, we have outlined what is known about the IR in puberty in terms of pattern, potential underlying mechanisms and other mediating factors. We also outline other potentially related metabolic changes that occur during puberty, and effects of underlying insulin resistant states (e.g., obesity) on pubertal changes in insulin sensitivity. PMID:27179965

  11. Insulin and glucose regulation.

    PubMed

    Ralston, Sarah L

    2002-08-01

    Abnormally high or low blood glucose and insulin concentrations after standardized glucose tolerance tests can reflect disorders such as pituitary dysfunction, polysaccharide storage myopathies, and other clinical disorders. Glucose and insulin responses, however, are modified by the diet to which the animal has adapted, time since it was last fed, and what it was fed. Body fat (obesity), fitness level, physiologic status, and stress also alter glucose and insulin metabolism. Therefore, it is important to consider these factors when evaluating glucose and insulin tests, especially if only one sample it taken. This article describes the factors affecting glucose and insulin metabolism in horses and how they might influence the interpretation of standardized tests of glucose tolerance.

  12. Algorithmic complexity as an index of cortical function in awake and pentobarbital-anesthetized rats.

    PubMed

    Shaw, F Z; Chen, R F; Tsao, H W; Yen, C T

    1999-11-15

    This study introduces algorithmic complexity to measure characteristics of brain functions. The EEG of the rat was recorded with implanted electrodes. The normalized complexity value was relatively independent of data length, and it showed a simpler and easier calculation characteristic than other non-linear indexes. The complexity index revealed significant differences among awake, asleep, and anesthetized states. It may be useful in tracking short-term and long-term changes in brain functions, such as anesthetized depth, drug effects, or sleep-wakefulness.

  13. Awake GlideScope intubation in a critically ill pediatric patient.

    PubMed

    Fraser-Harris, Eva; Patel, Yash

    2012-04-01

    We report a challenging case of a 10-year-old boy with history of biventricular heart failure, pulmonary hypertension, severe asthma, and obesity with a BMI of 37. He presented to our hospital in acute decompensated heart failure. Our anesthesia team was consulted by the pediatric intensivist for urgent airway management in this rapidly deteriorating, premorbid patient. We describe here the use of the GlideScope(®) in an awake pediatric patient of ASA 4E status with a potentially difficult airway who required to remain in the seated position and thus necessitating a face-to-face approach. PMID:22268524

  14. Classification of awake, REM, and NREM from EEG via singular spectrum analysis.

    PubMed

    Mohammadi, Sara Mahvash; Enshaeifar, Shirin; Ghavami, Mohammad; Sanei, Saeid

    2015-01-01

    In this study, a single-channel electroencephalography (EEG) analysis method has been proposed for automated 3-state-sleep classification to discriminate Awake, NREM (non-rapid eye movement) and REM (rapid eye movement). For this purpose, singular spectrum analysis (SSA) is applied to automatically extract four brain rhythms: delta, theta, alpha, and beta. These subbands are then used to generate the appropriate features for sleep classification using a multi class support vector machine (M-SVM). The proposed method provided 0.79 agreement between the manual and automatic scores.

  15. Laser pulse propagation in a meter scale rubidium vapor/plasma cell in AWAKE experiment

    NASA Astrophysics Data System (ADS)

    Joulaei, A.; Moody, J.; Berti, N.; Kasparian, J.; Mirzanejhad, S.; Muggli, P.

    2016-09-01

    We present the results of numerical studies of laser pulse propagating in a 3.5 cm Rb vapor cell in the linear dispersion regime by using a 1D model and a 2D code that has been modified for our special case. The 2D simulation finally aimed at finding laser beam parameters suitable to make the Rb vapor fully ionized to obtain a uniform, 10 m-long, at least 1 mm in radius plasma in the next step for the AWAKE experiment.

  16. Acute functional reactivation of the language network during awake intraoperative brain mapping.

    PubMed

    Spena, Giannantonio; Costi, Emanuele; Panciani, Pier Paolo; Roca, Elena; Migliorati, Karol; Fontanella, Marco Maria

    2015-01-01

    Acute brain plasticity during resection of central lesions has been recently described. In the cases reported, perilesional latent networks, useful to preserve the neurological functions, were detected in asymptomatic patients. In this paper, we presented a case of acute functional reactivation (AFR) of the language network in a symptomatic patient. Tumor resection allowed to acutely restore the neurological deficit. Intraoperative direct cortical stimulation (DCS) and functional neuroimaging showed new epicentres of activation of the language network after tumor excision. DCS in awake surgery is mandatory to reveal AFR needful to improve the extent of resection preserving the quality of life.

  17. Resting state functional connectivity magnetic resonance imaging integrated with intraoperative neuronavigation for functional mapping after aborted awake craniotomy

    PubMed Central

    Batra, Prag; Bandt, S. Kathleen; Leuthardt, Eric C.

    2016-01-01

    Background: Awake craniotomy is currently the gold standard for aggressive tumor resections in eloquent cortex. However, a significant subset of patients is unable to tolerate this procedure, particularly the very young or old or those with psychiatric comorbidities, cardiopulmonary comorbidities, or obesity, among other conditions. In these cases, typical alternative procedures include biopsy alone or subtotal resection, both of which are associated with diminished surgical outcomes. Case Description: Here, we report the successful use of a preoperatively obtained resting state functional connectivity magnetic resonance imaging (MRI) integrated with intraoperative neuronavigation software in order to perform functional cortical mapping in the setting of an aborted awake craniotomy due to loss of airway. Conclusion: Resting state functional connectivity MRI integrated with intraoperative neuronavigation software can provide an alternative option for functional cortical mapping in the setting of an aborted awake craniotomy. PMID:26958419

  18. Preoperative saline-filled computed tomography thoracography for awake video-assisted thoracic surgery: report of three cases.

    PubMed

    Watanabe, Tatsuaki; Noda, Masafumi; Okazaki, Toshimasa; Tsukidate, Hisakatsu; Sato, Kota; Notsuda, Hirotsugu; Niikawa, Hiromichi; Okada, Yoshinori; Matsumura, Yuji; Kondo, Takashi

    2015-12-01

    Awake video-assisted thoracic surgery (VATS) is a therapeutic option for patients with intractable secondary spontaneous pneumothorax (SSP) complicated by impaired pulmonary function. The preoperative identification of air leak points is one of the keys to the success of this procedure. We describe how we performed saline-filled computed tomography (CT) thoracography to detect pleural fistulae in three patients with intractable SSP. Saline-filled CT thoracography showed bubble signs in two patients and an air-water level in bulla in one patient. The preoperative identification of air leak points resulted in successful awake VATS for all three patients. Our experience demonstrates that saline-filled CT thoracography is a useful diagnostic tool for SSP, especially when used in preparation for awake VATS when minimally invasive procedures are desirable. PMID:26070908

  19. Salivary Oxytocin Concentrations in Males following Intranasal Administration of Oxytocin: A Double-Blind, Cross-Over Study.

    PubMed

    Daughters, Katie; Manstead, Antony S R; Hubble, Kelly; Rees, Aled; Thapar, Anita; van Goozen, Stephanie H M

    2015-01-01

    The use of intranasal oxytocin (OT) in research has become increasingly important over the past decade. Although researchers have acknowledged a need for further investigation of the physiological effects of intranasal administration, few studies have actually done so. In the present double-blind cross-over study we investigated the longevity of a single 24 IU dose of intranasal OT measured in saliva in 40 healthy adult males. Salivary OT concentrations were significantly higher in the OT condition, compared to placebo. This significant difference lasted until the end of testing, approximately 108 minutes after administration, and peaked at 30 minutes. Results showed significant individual differences in response to intranasal OT administration. To our knowledge this is the largest and first all-male within-subjects design study to demonstrate the impact of intranasal OT on salivary OT concentrations. The results are consistent with previous research in suggesting that salivary OT is a valid matrix for OT measurement. The results also suggest that the post-administration 'wait-time' prior to starting experimental tasks could be reduced to 30 minutes, from the 45 minutes typically used, thereby enabling testing during peak OT concentrations. Further research is needed to ascertain whether OT concentrations after intranasal administration follow similar patterns in females, and different age groups. PMID:26669935

  20. Intranasal Delivery of Granulocyte Colony-Stimulating Factor Enhances Its Neuroprotective Effects Against Ischemic Brain Injury in Rats.

    PubMed

    Sun, Bao-liang; He, Mei-qing; Han, Xiang-yu; Sun, Jing-yi; Yang, Ming-feng; Yuan, Hui; Fan, Cun-dong; Zhang, Shuai; Mao, Lei-lei; Li, Da-wei; Zhang, Zong-yong; Zheng, Cheng-bi; Yang, Xiao-yi; Li, Yang V; Stetler, R Anne; Chen, Jun; Zhang, Feng

    2016-01-01

    Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor with strong neuroprotective properties. However, it has limited capacity to cross the blood-brain barrier and thus potentially limiting its protective capacity. Recent studies demonstrated that intranasal drug administration is a promising way in delivering neuroprotective agents to the central nervous system. The current study therefore aimed at determining whether intranasal administration of G-CSF increases its delivery to the brain and its neuroprotective effect against ischemic brain injury. Transient focal cerebral ischemia in rat was induced with middle cerebral artery occlusion. Our resulted showed that intranasal administration is 8-12 times more effective than subcutaneous injection in delivering G-CSF to cerebrospinal fluid and brain parenchyma. Intranasal delivery enhanced the protective effects of G-CSF against ischemic injury in rats, indicated by decreased infarct volume and increased recovery of neurological function. The neuroprotective mechanisms of G-CSF involved enhanced upregulation of HO-1 and reduced calcium overload following ischemia. Intranasal G-CSF application also promoted angiogenesis and neurogenesis following brain ischemia. Taken together, G-CSF is a legitimate neuroprotective agent and intranasal administration of G-CSF is more effective in delivery and neuroprotection and could be a practical approach in clinic.

  1. The effect of intranasal oxytocin on perceiving and understanding emotion on the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT).

    PubMed

    Cardoso, Christopher; Ellenbogen, Mark A; Linnen, Anne-Marie

    2014-02-01

    Evidence suggests that intranasal oxytocin enhances the perception of emotion in facial expressions during standard emotion identification tasks. However, it is not clear whether this effect is desirable in people who do not show deficits in emotion perception. That is, a heightened perception of emotion in faces could lead to "oversensitivity" to the emotions of others in nonclinical participants. The goal of this study was to assess the effects of intranasal oxytocin on emotion perception using ecologically valid social and nonsocial visual tasks. Eighty-two participants (42 women) self-administered a 24 IU dose of intranasal oxytocin or a placebo in a double-blind, randomized experiment and then completed the perceiving and understanding emotion components of the Mayer-Salovey-Caruso Emotional Intelligence Test. In this test, emotion identification accuracy is based on agreement with a normative sample. As expected, participants administered intranasal oxytocin rated emotion in facial stimuli as expressing greater emotional intensity than those given a placebo. Consequently, accurate identification of emotion in faces, based on agreement with a normative sample, was impaired in the oxytocin group relative to placebo. No such effect was observed for tests using nonsocial stimuli. The results are consistent with the hypothesis that intranasal oxytocin enhances the salience of social stimuli in the environment, but not nonsocial stimuli. The present findings support a growing literature showing that the effects of intranasal oxytocin on social cognition can be negative under certain circumstances, in this case promoting "oversensitivity" to emotion in faces in healthy people.

  2. Visualization of murine intranasal dosing efficiency using luminescent Francisella tularensis: effect of instillation volume and form of anesthesia.

    PubMed

    Miller, Mark A; Stabenow, Jennifer M; Parvathareddy, Jyothi; Wodowski, Andrew J; Fabrizio, Thomas P; Bina, Xiaowen R; Zalduondo, Lillian; Bina, James E

    2012-01-01

    Intranasal instillation is a widely used procedure for pneumonic delivery of drugs, vaccine candidates, or infectious agents into the respiratory tract of research mice. However, there is a paucity of published literature describing the efficiency of this delivery technique. In this report we have used the murine model of tularemia, with Francisella tularensis live vaccine strain (FTLVS) infection, to evaluate the efficiency of pneumonic delivery via intranasal dosing performed either with differing instillation volumes or different types of anesthesia. FTLVS was rendered luminescent via transformation with a reporter plasmid that constitutively expressed the Photorhabdus luminescens lux operon from a Francisella promoter. We then used an IVIS Spectrum whole animal imaging system to visualize FT dissemination at various time points following intranasal instillation. We found that instillation of FT in a dose volume of 10 µl routinely resulted in infection of the upper airways but failed to initiate infection of the pulmonary compartment. Efficient delivery of FT into the lungs via intranasal instillation required a dose volume of 50 µl or more. These studies also demonstrated that intranasal instillation was significantly more efficient for pneumonic delivery of FTLVS in mice that had been anesthetized with inhaled (isoflurane) vs. parenteral (ketamine/xylazine) anesthesia. The collective results underscore the need for researchers to consider both the dose volume and the anesthesia type when either performing pneumonic delivery via intranasal instillation, or when comparing studies that employed this technique. PMID:22384012

  3. Salivary Oxytocin Concentrations in Males following Intranasal Administration of Oxytocin: A Double-Blind, Cross-Over Study

    PubMed Central

    Daughters, Katie; Manstead, Antony S. R.; Hubble, Kelly; Rees, Aled; Thapar, Anita; van Goozen, Stephanie H. M.

    2015-01-01

    The use of intranasal oxytocin (OT) in research has become increasingly important over the past decade. Although researchers have acknowledged a need for further investigation of the physiological effects of intranasal administration, few studies have actually done so. In the present double-blind cross-over study we investigated the longevity of a single 24 IU dose of intranasal OT measured in saliva in 40 healthy adult males. Salivary OT concentrations were significantly higher in the OT condition, compared to placebo. This significant difference lasted until the end of testing, approximately 108 minutes after administration, and peaked at 30 minutes. Results showed significant individual differences in response to intranasal OT administration. To our knowledge this is the largest and first all-male within-subjects design study to demonstrate the impact of intranasal OT on salivary OT concentrations. The results are consistent with previous research in suggesting that salivary OT is a valid matrix for OT measurement. The results also suggest that the post-administration ‘wait-time’ prior to starting experimental tasks could be reduced to 30 minutes, from the 45 minutes typically used, thereby enabling testing during peak OT concentrations. Further research is needed to ascertain whether OT concentrations after intranasal administration follow similar patterns in females, and different age groups. PMID:26669935

  4. Brain Transit and Ameliorative Effects of Intranasally Delivered Anti-Amyloid-β Oligomer Antibody in 5XFAD Mice

    PubMed Central

    Xiao, Chun; Davis, Francesca J.; Chauhan, Balwantsinh C.; Viola, Kirsten L.; Lacor, Pascale N.; Velasco, Pauline T.; Klein, William L.; Chauhan, Neelima B.

    2013-01-01

    Alzheimer’s disease (AD) is a global health crisis with limited treatment options. Despite major advances in neurotherapeutics, poor brain penetration due to the blood-brain barrier continues to pose a big challenge in overcoming the access of therapeutics to the central nervous system. In that regard, the non-invasive intranasal route of brain targeting is gaining considerable attention. The nasal mucosa offers a large surface area, rapid absorption, and avoidance of first-pass metabolism increasing drug bioavailability with less systemic side effects. Intranasal delivery is known to utilize olfactory, rostral migratory stream, and trigeminal routes to reach the brain. This investigation confirmed that intranasal delivery of oligomeric amyloid-β antibody (NU4) utilized all three routes to enter the brain with a resident time of 96 hours post single bolus intranasal administration, and showed evidence of perikaryal and parenchymal uptake of NU4 in 5XFAD mouse brain, confirming the intranasal route as a non-invasive and efficient way of delivering therapeutics to the brain. In addition, this study demonstrated that intranasal delivery of NU4 antibody lowered cerebral amyloid-β and improved spatial learning in 5XFAD mice. PMID:23542865

  5. Effects of Adverse Childhood Experiences on the Association between Intranasal Oxytocin and Social Stress Reactivity among Individuals with Cocaine Dependence

    PubMed Central

    Flanagan, Julianne C.; Baker, Nathaniel L.; McRae-Clark, Aimee L.; Brady, Kathleen T.; Moran-Santa Maria, Margaret M.

    2015-01-01

    Background Drug dependence and adverse childhood experiences (ACE) are commonly reflected by dysregulation of the hypothalamic-pituitary-adrenal axis (HPA). Accumulating research indicates that the neuropeptide oxytocin may regulate HPA function, resulting in reductions in neuroendocrine reactivity to social stress among individuals with drug dependence. However, emerging literature suggests that individual differences may differentially impact intranasal oxytocin’s effects on human social behaviors. Methods This study employed a double-blind, placebo-controlled design to examine the extent to which ACE influenced the effects of intranasal oxytocin (40 IU) on neuroendocrine reactivity to a laboratory social stress paradigm in a sample of 31 cocaine-dependent individuals. Results ACE scores modified the relationship between intranasal oxytocin and cortisol reactivity. While ACE modified the relationship between intranasal oxytocin and DHEA response in a similar direction to what was seen in cortisol, it did not reach statistical significance. Conclusions Findings are congruent with the emerging hypothesis that intranasal oxytocin may differentially attenuate social stress reactivity among individuals with specific vulnerabilities. Future research examining the nuances of intranasal oxytocin’s therapeutic potential is necessary. PMID:26231584

  6. Intranasal administration of nanostructured lipid carriers containing CNS acting drug: pharmacodynamic studies and estimation in blood and brain.

    PubMed

    Alam, M Intakhab; Baboota, Sanjula; Ahuja, Alka; Ali, Mushir; Ali, Javed; Sahni, Jasjeet K

    2012-09-01

    The present study was aimed to investigate and compare the efficacy of duloxetine (DLX) loaded nanostructured lipid carriers (NLC) with DLX solution pharmacodynamically following intranasal administration. The study was further conducted to estimate DLX concentration in brain and blood. DLX was administered to albino Wistar rats either intranasally or orally in solution form (DLX solution) or encapsulated in NLC (DLX-NLC). These were evaluated in-vivo for pharmacodynamic studies for depression by forced swimming test and locomotor activity test. Intranasal DLX-NLC treatment exhibited improved behavioural analysis results (swimming, climbing, and immobility) than the DLX solution after 24 h of study. Furthermore, DLX-NLC significantly increased the total swimming and climbing time when compared with control and significantly reduced the immobility period. The intranasal DLX-NLC demonstrated improved locomotor activity when compared with DLX solution. Amount of DLX was quantified in blood and brain after the forced swimming test. The intranasal DLX-NLC demonstrated higher concentration in brain compared with DLX solution. Thus, intranasal DLX-NLC was found to be a promising formulation for the treatment of depression.

  7. Brain Targeting of a Water Insoluble Antipsychotic Drug Haloperidol via the Intranasal Route Using PAMAM Dendrimer.

    PubMed

    Katare, Yogesh K; Daya, Ritesh P; Sookram Gray, Christal; Luckham, Roger E; Bhandari, Jayant; Chauhan, Abhay S; Mishra, Ram K

    2015-09-01

    Delivery of therapeutics to the brain is challenging because many organic molecules have inadequate aqueous solubility and limited bioavailability. We investigated the efficiency of a dendrimer-based formulation of a poorly aqueous soluble drug, haloperidol, in targeting the brain via intranasal and intraperitoneal administration. Aqueous solubility of haloperidol was increased by more than 100-fold in the developed formulation. Formulation was assessed via different routes of administration for behavioral (cataleptic and locomotor) responses, and for haloperidol distribution in plasma and brain tissues. Dendrimer-based formulation showed significantly higher distribution of haloperidol in the brain and plasma compared to a control formulation of haloperidol administered via intraperitoneal injection. Additionally, 6.7 times lower doses of the dendrimer-haloperidol formulation administered via the intranasal route produced behavioral responses that were comparable to those induced by haloperidol formulations administered via intraperitoneal injection. This study demonstrates the potential of dendrimer in improving the delivery of water insoluble drugs to brain.

  8. Photodynamic therapy for the treatment of intranasal tumors in 3 dogs and 1 cat.

    PubMed

    Lucroy, Michael D; Long, Kevin R; Blaik, Margaret A; Higbee, Russell G; Ridgway, Tisha D

    2003-01-01

    Three dogs and 1 cat with intranasal tumors were treated with pyropheophorbide-a-hexyl ether-based photodynamic therapy (PDT). PDT was well tolerated by all the animals, and no adverse effects from photosensitizer injection, such as cutaneous photosensitization, were observed. Facial swelling was observed in all animals after each PDT treatment but resolved spontaneously within 72 hours after treatment. All animals had a decrease in severity of epistaxis, frequency of sneezing, and amount of nasal discharge after PDT. Clinical signs were controlled for variable time, although long-term responses were comparable with radiation therapy in 2 animals. This small case series demonstrates another application for PDT in veterinary medicine. On the basis of these findings. further studies are warranted to define the role of PDT in the management of intranasal tumors in dogs and cats.

  9. Respiratory and hemodynamic outcomes following exchange extubation with laryngeal mask airway as compared to traditional awake extubation

    PubMed Central

    Suppiah, Ramanathan Kannan; Rajan, Sunil; Paul, Jerry; Kumar, Lakshmi

    2016-01-01

    Background: Traditional awake extubation leads to respiratory complications and hemodynamic response which are detrimental in neurosurgery, ENT surgery and patients with comorbidities. Aims: The primary objective was to compare the respiratory complications and hemodynamic stress response between traditional awake extubation of a endotracheal tube (ETT) and that following exchange extubation of ETT by using a laryngeal mask airway (LMA). Settings and Design: This prospective randomized study was conducted in a Tertiary Care Centre in 60 American Society of Anesthesiologists I and II patients coming for general surgery. Materials and Methods: Patients were randomized by permuted blocks into traditional awake extubation group and exchange extubation group. At the end of surgery in traditional group, awake extubation of ETT was done. In exchange group, 0.3 mg/kg propofol was administered, and the ETT was exchanged for a LMA. Awake extubation of LMA was then performed. Respiratory complications such as bucking, coughing, desaturation and the need for airway maneuvers and hemodynamic response were noted in both groups. Analysis Tools: Chi-square test, independent sample t- and paired t-tests were used as applicable. Results: Incidence of respiratory complication was 93.3% in traditional extubation while it was only 36.7% in exchange extubation group (P < 0.001). Hemodynamic response measured immediately at extubation in terms of heart rate, systolic blood pressure (BP), diastolic BP, mean arterial pressure, and rate pressure product were all significantly lesser in exchange group when compared to traditional extubation. Conclusion: Exchange extubation with LMA decreases respiratory complications and hemodynamic stress response when compared to traditional awake extubation. PMID:27212749

  10. The importance of the diluent for airway transport of toluene diisocyanate following intranasal dosing of mice.

    PubMed

    Ebino, K; Lemus, R; Karol, M H

    1999-03-01

    Uncertainty of the transport of reactive chemicals to the lung is a major concern when using intranasal dosing of animals. In a preliminary study using mice, intranasal instillation of the dyes methylene blue (in water) and Sudan black B (in 1:4 ethyl acetate:olive oil), indicated that the following conditions were necessary to achieve transport to the lung: (1) aqueous diluent, (2) light anesthesia prior to dosing, (3) holding the animal in a supine position during chemical application, and (4) maintaining the animal in the same position postdosing. Using these conditions, we investigated the distribution of toluene diisocyanate (TDI), a major industrial asthmogen, to the lung following intranasal administration. Female C57BL/6 mice received 20 microl of 1% TDI in ethyl acetate:olive oil (1:4). Group 1 received a single application on day 1; group 2, single applications on 2 consecutive days; group 3, single applications on 4 consecutive days; and group 4, a single application of the vehicle on 2 consecutive days. All mice were necropsied 24 h after the final application. The nasal passages, upper pharynx, trachea, lungs, and olfactory bulbs of each animal were examined with hematoxylin-eosin and immunohistochemical staining, the latter using a rabbit anti-TDI antiserum. Histopathology revealed desquamation of ciliated epithelial cells as well as inflammatory cell debris in the nasal cavity and upper pharynx of animals in groups 1-3. The intensity of these changes was dependent on the number of applications. No inflammation was observed in the trachea, lungs, or olfactory bulbs in any of the groups. Immunohistochemical examination revealed positive staining for the TDI moiety in epithelial cells of the nasal cavity and upper pharynx in animals of groups 1-3. No staining was observed in the trachea, lungs, or olfactory bulbs of any animal. These results suggest that TDI, when dissolved in olive oil:ethyl acetate and applied intranasally, does not reach the trachea

  11. A Randomized Controlled Trial of Intranasal Ketamine in Major Depressive Disorder

    PubMed Central

    Lapidus, Kyle A.B.; Levitch, Cara F.; Perez, Andrew M.; Brallier, Jess W.; Parides, Michael K.; Soleimani, Laili; Feder, Adriana; Iosifescu, Dan V.; Charney, Dennis S.; Murrough, James W.

    2014-01-01

    Background The N-methyl-d-aspartate glutamate receptor antagonist ketamine, delivered via an intravenous route, has shown rapid antidepressant effects in patients with treatment-resistant depression. The current study was designed to test the safety, tolerability and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial. Methods Twenty patients with major depression were randomized and 18 completed two treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution in a randomized, double-blind, crossover study. The primary efficacy outcome measure was change in depression severity 24 hours following ketamine or placebo, measured using the Montgomery-Asberg Depression Rating Scale. Secondary outcomes included persistence of benefit, changes in self-reports of depression, changes in anxiety, and proportion of responders. Potential psychotomimetic, dissociative, hemodynamic, and general adverse effects associated with ketamine were also measured. Results Patients showed significant improvement in depressive symptoms at 24 hours following ketamine compared to placebo [t=4.39, p<0.001; estimated mean MADRS score difference of 7.6 ± 3.7 (95% CI: 3.9 – 11.3)]. Eight of 18 patients (44%) met response criteria 24 hours following ketamine administration, compared to 1 of 18 (6%) following placebo (p=0.033). Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinically significant changes in hemodynamic parameters. Conclusions This study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with major depression. Trial Registration clinicaltrials.gov identifier NCT01304147 PMID:24821196

  12. Nanoemulsion-based intranasal drug delivery system of saquinavir mesylate for brain targeting.

    PubMed

    Mahajan, Hitendra S; Mahajan, Milind S; Nerkar, Pankaj P; Agrawal, Anshuman

    2014-03-01

    The central nervous system (CNS) is an immunological privileged sanctuary site-providing reservoir for HIV-1 virus. Current anti-HIV drugs, although effective in reducing plasma viral levels, cannot eradicate the virus completely from the body. The low permeability of anti-HIV drugs across the blood-brain barrier (BBB) leads to insufficient delivery. Therefore, developing a novel approaches enhancing the CNS delivery of anti-HIV drugs are required for the treatment of neuro-AIDS. The aim of this study was to develop intranasal nanoemulsion (NE) for enhanced bioavailability and CNS targeting of saquinavir mesylate (SQVM). SQVM is a protease inhibitor which is a poorly soluble drug widely used as antiretroviral drug, with oral bioavailability is about 4%. The spontaneous emulsification method was used to prepare drug-loaded o/w nanoemulsion, which was characterized by droplet size, zeta potential, pH, drug content. Moreover, ex-vivo permeation studies were performed using sheep nasal mucosa. The optimized NE showed a significant increase in drug permeation rate compared to the plain drug suspension (PDS). Cilia toxicity study on sheep nasal mucosa showed no significant adverse effect of SQVM-loaded NE. Results of in vivo biodistribution studies show higher drug concentration in brain after intranasal administration of NE than intravenous delivered PDS. The higher percentage of drug targeting efficiency (% DTE) and nose-to-brain drug direct transport percentage (% DTP) for optimized NE indicated effective CNS targeting of SQVM via intranasal route. Gamma scintigraphy imaging of the rat brain conclusively demonstrated transport of drug in the CNS at larger extent after intranasal administration as NE.

  13. Mouse Model of Cat Allergic Rhinitis and Intranasal Liposome-Adjuvanted Refined Fel d 1 Vaccine.

    PubMed

    Tasaniyananda, Natt; Chaisri, Urai; Tungtrongchitr, Anchalee; Chaicumpa, Wanpen; Sookrung, Nitat

    2016-01-01

    Cats (Felis domesticus) are rich source of airborne allergens that prevailed in the environment and sensitized a number of people to allergy. In this study, a mouse model of allergic rhinitis caused by the cat allergens was developed for the first time and the model was used for testing therapeutic efficacy of a novel intranasal liposome-entrapped vaccines made of native Fel d 1 (major cat allergen) in comparison with the vaccine made of crude cat hair extract (cCE). BALB/c mice were sensitized with cCE mixed with alum intraperitoneally and intranasally. The allergic mice were treated with eight doses of either liposome (L)-entrapped native Fel d 1 (L-nFD1), L-cCE), or placebo on every alternate day. Vaccine efficacy evaluation was performed one day after provoking the treated mice with aerosolic cCE. All allergenized mice developed histological features of allergic rhinitis with rises of serum specific-IgE and Th2 cytokine gene expression. Serum IgE and intranasal mucus production of allergic mice reduced significantly after vaccination in comparison with the placebo mice. The vaccines also caused a shift of the Th2 response (reduction of Th2 cytokine expressions) towards the non-pathogenic responses: Th1 (down-regulation of the Th1 suppressive cytokine gene, IL-35) and Treg (up-regulation of IL-10 and TGF-β). In conclusions, a mouse model of allergic rhinitis to cat allergens was successfully developed. The intranasal, liposome-adjuvanted vaccines, especially the refined single allergen formulation, assuaged the allergic manifestations in the modeled mice. The prototype vaccine is worthwhile testing further for clinical use in the pet allergic patients. PMID:26954254

  14. Awareness and Attitudes Toward Intranasal Naloxone Rescue for Opioid Overdose Prevention.

    PubMed

    Kirane, Harshal; Ketteringham, Michael; Bereket, Sewit; Dima, Richie; Basta, Ann; Mendoza, Sonia; Hansen, Helena

    2016-10-01

    Opioid overdose prevention is a pressing public health concern and intranasal naloxone rescue kits are a useful tool in preventing fatal overdose. We evaluated the attitudes, knowledge, and experiences of patients and providers related to overdose and naloxone rescue. Over a six month period, patients and providers within a large community hospital in Staten Island were recruited to complete tailored questionnaires for their respective groupings. 100 patients and 101 providers completed questionnaires between August, 2014 and January, 2015. Patient participants were primarily Caucasian males with a mean age of 37.7 years, of which 65% accurately identified naloxone for opioid overdose, but only 21% knew more specific clinical features. 68% of patients had previously witnessed a drug overdose. Notably, 58% of patients anticipated their behavior would change if provided access to an intranasal naloxone rescue kit, of which 83% predicted an increase in opioid use. Prior overdose was significantly correlated with anticipating no change in subsequent opioid use pattern (p=0.02). 99% of patients reported that their rapport with their health-care provider would be enhanced if offered an intranasal naloxone rescue kit. As for providers, 24% had completed naloxone rescue kit training, and 96% were able to properly identify its clinical application. 50% of providers felt naloxone access would decrease the likelihood of an overdose occurring, and 58% felt it would not contribute to high-risk behavior. Among providers, completion of naloxone training was correlated with increased awareness of where to access kits for patients (p<0.001). This study suggests that patients and providers have distinct beliefs and attitudes toward overdose prevention. Patient-Provider discussion of overdose prevention enhances patients' rapport with providers. However, access to an intranasal naloxone rescue kit may make some patients more vulnerable to high-risk behavior. Future research efforts

  15. Intranasal Vaccination with AAV5 and 9 Vectors Against Human Papillomavirus Type 16 in Rhesus Macaques

    PubMed Central

    Nieto, Karen; Stahl-Hennig, Christiane; Leuchs, Barbara; Müller, Martin; Gissmann, Lutz

    2012-01-01

    Abstract Cervical cancer is the second most common cancer in women worldwide. Persistent high-risk human papillomavirus (HPV) infection has been identified as the causative event for the development of this type of cancer. Recombinant adeno-associated viruses (rAAVs) are currently being developed and evaluated as vaccine vector. In previous work, we demonstrated that rAAVs administered intranasally in mice induced high titers and long-lasting neutralizing antibodies against HPV type 16 (HPV16). To extend this approach to a more human-related species, we immunized rhesus macaques (Macaca mulatta) with AAVs expressing an HPV16 L1 protein using rAAV5 and 9 vectors in an intranasal prophylactic setting. An rAAV5-L1 vector followed by a boost with rAAV9-L1 induced higher titers of L1-specific serum antibodies than a single rAAV5-L1 immunization. L1-specific antibodies elicited by AAV9 vector neutralized HPV16 pseudovirions and persisted for at least 7 months post immunization. Interestingly, nasal application of rAAV9 was immunogenic even in the presence of high AAV9 antibody titers, allowing reimmunization with the same serotype without prevention of the transgene expression. Two of six animals did not respond to AAV-mediated intranasal vaccination, although they were not tolerant, as both developed antibodies after intramuscular vaccination with HPV16 virus-like particles. These data clearly show the efficacy of an intranasal immunization using rAAV9-L1 vectors without the need of an adjuvant. We conclude from our results that rAAV9 vector is a promising candidate for a noninvasive nasal vaccination strategy. PMID:22401308

  16. Mouse Model of Cat Allergic Rhinitis and Intranasal Liposome-Adjuvanted Refined Fel d 1 Vaccine

    PubMed Central

    Tasaniyananda, Natt; Chaisri, Urai; Tungtrongchitr, Anchalee; Chaicumpa, Wanpen; Sookrung, Nitat

    2016-01-01

    Cats (Felis domesticus) are rich source of airborne allergens that prevailed in the environment and sensitized a number of people to allergy. In this study, a mouse model of allergic rhinitis caused by the cat allergens was developed for the first time and the model was used for testing therapeutic efficacy of a novel intranasal liposome-entrapped vaccines made of native Fel d 1 (major cat allergen) in comparison with the vaccine made of crude cat hair extract (cCE). BALB/c mice were sensitized with cCE mixed with alum intraperitoneally and intranasally. The allergic mice were treated with eight doses of either liposome (L)-entrapped native Fel d 1 (L-nFD1), L-cCE), or placebo on every alternate day. Vaccine efficacy evaluation was performed one day after provoking the treated mice with aerosolic cCE. All allergenized mice developed histological features of allergic rhinitis with rises of serum specific-IgE and Th2 cytokine gene expression. Serum IgE and intranasal mucus production of allergic mice reduced significantly after vaccination in comparison with the placebo mice. The vaccines also caused a shift of the Th2 response (reduction of Th2 cytokine expressions) towards the non-pathogenic responses: Th1 (down-regulation of the Th1 suppressive cytokine gene, IL-35) and Treg (up-regulation of IL-10 and TGF-β). In conclusions, a mouse model of allergic rhinitis to cat allergens was successfully developed. The intranasal, liposome-adjuvanted vaccines, especially the refined single allergen formulation, assuaged the allergic manifestations in the modeled mice. The prototype vaccine is worthwhile testing further for clinical use in the pet allergic patients. PMID:26954254

  17. Chemoprevention of lung tumorigenesis by intranasally administered diindolylmethane in A/J mice

    PubMed Central

    Kassie, Fekadu

    2013-01-01

    The main reasons for the failure of most chemopreventive agents during clinical trials are poor in vivo bioavailability and dose-limiting side effects. One potential approach to surmount these problems in lung cancer chemoprevention trials could be direct delivery of agents into the pulmonary tissue. In this study, we assessed the efficacy of intranasally delivered bio-response diindolylmethane (BRD) against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in mice. Mice treated with NNK (two doses of 50mg/kg at an interval of a week, intraperitoneal) developed 16.3±2.9 lung tumors per mouse. Post-carcinogen administration of BRD, via intranasal instillation, for 24 weeks, twice a week, at a dose of 2mg per mouse (0.6mg pure diindolylmethane per mouse) reduced the lung tumor multiplicity to 4.6±2.2 tumors per mouse (72% reduction). Likewise, large tumors (>1mm) were almost completely abolished and multiplicities of tumors with a size of 0.5–1mm were reduced by 74%. Tumor volume was also reduced by 82%. Further studies using an in vitro model of lung tumorigenesis showed that BRD exhibited pronounced antiproliferative and apoptotic effects in premalignant and malignant bronchial cells but only minimal effects in parental immortalized cells through, at least in part, suppression of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. These results showed the potent lung tumor inhibitory activities of low doses of BRD given via intranasal instillation and, therefore, intranasal delivery of BRD holds a great promise for lung cancer chemoprevention in subjects at high risk to develop lung cancer. PMID:23239747

  18. Mouse Model of Cat Allergic Rhinitis and Intranasal Liposome-Adjuvanted Refined Fel d 1 Vaccine.

    PubMed

    Tasaniyananda, Natt; Chaisri, Urai; Tungtrongchitr, Anchalee; Chaicumpa, Wanpen; Sookrung, Nitat

    2016-01-01

    Cats (Felis domesticus) are rich source of airborne allergens that prevailed in the environment and sensitized a number of people to allergy. In this study, a mouse model of allergic rhinitis caused by the cat allergens was developed for the first time and the model was used for testing therapeutic efficacy of a novel intranasal liposome-entrapped vaccines made of native Fel d 1 (major cat allergen) in comparison with the vaccine made of crude cat hair extract (cCE). BALB/c mice were sensitized with cCE mixed with alum intraperitoneally and intranasally. The allergic mice were treated with eight doses of either liposome (L)-entrapped native Fel d 1 (L-nFD1), L-cCE), or placebo on every alternate day. Vaccine efficacy evaluation was performed one day after provoking the treated mice with aerosolic cCE. All allergenized mice developed histological features of allergic rhinitis with rises of serum specific-IgE and Th2 cytokine gene expression. Serum IgE and intranasal mucus production of allergic mice reduced significantly after vaccination in comparison with the placebo mice. The vaccines also caused a shift of the Th2 response (reduction of Th2 cytokine expressions) towards the non-pathogenic responses: Th1 (down-regulation of the Th1 suppressive cytokine gene, IL-35) and Treg (up-regulation of IL-10 and TGF-β). In conclusions, a mouse model of allergic rhinitis to cat allergens was successfully developed. The intranasal, liposome-adjuvanted vaccines, especially the refined single allergen formulation, assuaged the allergic manifestations in the modeled mice. The prototype vaccine is worthwhile testing further for clinical use in the pet allergic patients.

  19. [Insulin and physical exercise].

    PubMed

    Louis-Sylvestre, J

    1987-04-01

    Secretion of some pituitary hormones and sympatho-adrenal activity increase very early during exercise. Sympathetic activation is of major importance in cardiovascular adaptation, thermoregulation, etc. Furthermore among the hormonal consequences of such activation those related to insulin are capital. In animal and human subjects basal insulin level decrease during prolonged and progressive exercise. With habitual exercise, both basal and stimulated insulin levels are reduced. It seems that the reduced basal level could be due to alpha-adrenergic inhibition of the islets of Langerhans, while the reduced stimulated response could be the consequence of increased clearance. In trained subjects, in spite of reduced insulin secretion tolerance to glucose is normal due to increased sensitivity to insulin. Sensitivity to insulin is particularly enhanced at the muscular tissue level; it is accompanied by increased hexokinase and glycogen synthetase activity. As a consequence glucose uptake remains optimal at the muscular level. In the liver, both insulin sensitivity and glucokinase activity are reduced, so that glucose is spared and the muscular glycogen store can be restored. At the adipocyte level, metabolic adaptations are such that triglyceride turnover is greatly increased, favouring fuel supply and resaturation of stores.

  20. [Alleged suicide by insulin].

    PubMed

    Birngruber, Christoph G; Krüll, Ralf; Dettmeyer, Reinhard; Verhoff, Marcel A

    2015-01-01

    A 26-year-old man, who was on probation, was found dead in his home by his mother. Insulin vials and 2 insulin pens, which the man's stepfather (an insulin-dependent diabetic) had been missing for over a week, were found next to the deceased. The circumstances suggested suicide by an injected insulin overdose. At the time of the autopsy, the corpse showed already marked signs of autolysis. Clinical chemical tests confirmed the injection of insulin, but indicated hyperglycemia at the time of death. Toxicological analyses revealed that the man had consumed amphetamine, cannabinoids, and tramadol in the recent past. Histological examination finally revealed extensive bronchopneumonia as the cause of death. The most plausible explanation for the results of the autopsy and the additional examinations was an injection of insulin as a failed attempt of self-treatment. It is conceivable that the man had discovered by a rapid test that he was a diabetic, but had decided not to go to a doctor to avoid disclosure of parole violation due to continued drug abuse. He may have misinterpreted the symptoms caused by his worsening bronchitis and the developing bronchopneumonia as symptoms of a diabetic metabolic status and may have felt compelled to treat himself with insulin. PMID:26419091

  1. Tagging insulin in microgravity

    NASA Technical Reports Server (NTRS)

    Dobeck, Michael; Nelson, Ronald S.

    1992-01-01

    Knowing the exact subcellular sites of action of insulin in the body has the potential to give basic science investigators a basis from which a cause and cure for this disease can be approached. The goal of this project is to create a test reagent that can be used to visualize these subcellular sites. The unique microgravity environment of the Shuttle will allow the creation of a reagent that has the possibility of elucidating the subcellular sites of action of insulin. Several techniques have been used in an attempt to isolate the sites of action of items such as insulin. One of these is autoradiography in which the test item is obtained from animals fed radioactive materials. What is clearly needed is to visualize individual insulin molecules at their sites of action. The insulin tagging process to be used on G-399 involves the conjugation of insulin molecules with ferritin molecules to create a reagent that will be used back on Earth in an attempt to elucidate the sites of action of insulin.

  2. Awake and unable to move: what can perioperative practitioners do to avoid accidental awareness under general anaesthesia?

    PubMed

    Almeida, D

    2015-12-01

    I thought the last thing I would remember about my surgery was counting up to 10 ... but that didn't happen... I could hear people talking, instruments banging, the sound of my heart beat coming from the anaesthetic machine and all of a sudden, that horrible pain digging inside my body. Oh my God! I thought. I'm awake! I tried to tell someone but no sound came out of my mouth. I tried to kick my legs, shake my arms, blink, breathe... Nothing!! I couldn't move a muscle. I was paralysed and awake during my operation... I thought I was going to die!!!

  3. Optimization of combinational intranasal drug delivery system for the management of migraine by using statistical design.

    PubMed

    Kumar, Animesh; Garg, Tarun; Sarma, Ganti S; Rath, Goutam; Goyal, Amit Kumar

    2015-04-01

    Migraine is a chronic disorder characterized by significant headache and various associated symptoms which worsen with exertion. Zolmitriptan approved for use in the acute treatment of migraine and related vascular headaches but are limited by high pain recurrence due to rapid drug elimination. Combinationalformulationof triptans and a nonsteroidal anti-inflammatory drug may provide a quicker and longer duration of relief from the subsequent pain during the attack. In this study, we formulate a Zolmitriptan (ZT) & ketorolac tromethamine (KT) loaded thermo reversible in-situ mucoadhesive intranasal gel (TMISG) formulation which gels at the nasal mucosal temperature and contains a bioadhesive polymer (Xyloglucan) that lengthens the residence time will enhance the bioavailability of the combinational drugs. This study uses Box-Behnken design for the first time to develop, optimize the TMISG and assess factors affecting the critical quality attributes. Histopathological study of the nasal mucosa suggested that the formulation was safe for nasal administration. The statistical difference in absolute bioavailability between oral and intranasal route suggested that intranasal route had almost 21% increases in bioavailability for ZT and for KT there was 16% increase over oral formulations. Optimized formulation would help mitigate migraine associated symptoms much better over the currently available formulations.

  4. Promotion of allergic immune responses by intranasally-administrated nanosilica particles in mice

    NASA Astrophysics Data System (ADS)

    Yoshida, Tokuyuki; Yoshioka, Yasuo; Fujimura, Maho; Yamashita, Kohei; Higashisaka, Kazuma; Morishita, Yuki; Kayamuro, Hiroyuki; Nabeshi, Hiromi; Nagano, Kazuya; Abe, Yasuhiro; Kamada, Haruhiko; Tsunoda, Shin-Ichi; Itoh, Norio; Yoshikawa, Tomoaki; Tsutsumi, Yasuo

    2011-12-01

    With the increase in use of nanomaterials, there is growing concern regarding their potential health risks. However, few studies have assessed the role of the different physical characteristics of nanomaterials in allergic responses. Here, we examined whether intranasally administered silica particles of various sizes have the capacity to promote allergic immune responses in mice. We used nanosilica particles with diameters of 30 or 70 nm (nSP30 or nSP70, respectively), and conventional micro-sized silica particles with diameters of 300 or 1000 nm (nSP300 or mSP1000, respectively). Mice were intranasally exposed to ovalbumin (OVA) plus each silica particle, and the levels of OVA-specific antibodies (Abs) in the plasma were determined. Intranasal exposure to OVA plus smaller nanosilica particles tended to induce a higher level of OVA-specific immunoglobulin (Ig) E, IgG and IgG1 Abs than did exposure to OVA plus larger silica particles. Splenocytes from mice exposed to OVA plus nSP30 secreted higher levels of Th2-type cytokines than mice exposed to OVA alone. Taken together, these results indicate that nanosilica particles can induce allergen-specific Th2-type allergic immune responses in vivo. This study provides the foundations for the establishment of safe and effective forms of nanosilica particles.

  5. Midazolam Premedication in Children: A Pilot Study Comparing Intramuscular and Intranasal Administration

    PubMed Central

    Lam, Christy; Udin, Richard D; Malamed, Stanley F; Good, David L; Forrest, Jane L

    2005-01-01

    The purpose of this study was to compare the effectiveness of intramuscular and intranasal midazolam used as a premedication before intravenous conscious sedation. Twenty-three children who were scheduled to receive dental treatment under intravenous sedation participated. The patients ranged in age from 2 to 9 years (mean age, 5.13 years) and were randomly assigned to receive a dose of 0.2 mg/kg of midazolam premedication via either intramuscular or intranasal administration. All patients received 50% nitrous oxide and 50% oxygen inhalation sedation and local anesthetic (0.2 mL of 4% prilocaine hydrochloride) before venipuncture. The sedation level, movement, and crying were evaluated at the following time points: 10 minutes after drug administration and at the times of parental separation, passive papoose board restraint, nitrous oxide nasal hood placement, local anesthetic administration, and initial venipuncture attempt. Mean ratings for the behavioral parameters of sedation level, degree of movement, and degree of crying were consistently higher but not significant in the intramuscular midazolam group at all 6 assessment points. Intramuscular midazolam was found to be statistically more effective in providing a better sedation level and less movement at the time of venipuncture than intranasal administration. Our findings indicate a tendency for intramuscular midazolam to be more effective as a premedication before intravenous sedation. PMID:16048152

  6. Midazolam premedication in children: a pilot study comparing intramuscular and intranasal administration.

    PubMed

    Lam, Christy; Udin, Richard D; Malamed, Stanley F; Good, David L; Forrest, Jane L

    2005-01-01

    The purpose of this study was to compare the effectiveness of intramuscular and intranasal midazolam used as a premedication before intravenous conscious sedation. Twenty-three children who were scheduled to receive dental treatment under intravenous sedation participated. The patients ranged in age from 2 to 9 years (mean age, 5.13 years) and were randomly assigned to receive a dose of 0.2 mg/kg of midazolam premedication via either intramuscular or intranasal administration. All patients received 50% nitrous oxide and 50% oxygen inhalation sedation and local anesthetic (0.2 mL of 4% prilocaine hydrochloride) before venipuncture. The sedation level, movement, and crying were evaluated at the following time points: 10 minutes after drug administration and at the times of parental separation, passive papoose board restraint, nitrous oxide nasal hood placement, local anesthetic administration, and initial venipuncture attempt. Mean ratings for the behavioral parameters of sedation level, degree of movement, and degree of crying were consistently higher but not significant in the intramuscular midazolam group at all 6 assessment points. Intramuscular midazolam was found to be statistically more effective in providing a better sedation level and less movement at the time of venipuncture than intranasal administration. Our findings indicate a tendency for intramuscular midazolam to be more effective as a premedication before intravenous sedation.

  7. Effects of PAMAM dendrimers in the mouse brain after a single intranasal instillation.

    PubMed

    Win-Shwe, Tin-Tin; Sone, Hideko; Kurokawa, Yoshika; Zeng, Yang; Zeng, Qin; Nitta, Hiroshi; Hirano, Seishiro

    2014-08-01

    Dendrimers are highly branched spherical nanomaterials produced for use in diagnostic and therapeutic applications such as a drug delivery system. The toxicological profiles of dendrimers are largely unknown. We investigated the in vivo effects of nasal exposure to polyamidoamine (PAMAM) dendrimers on their effects on neurological biomarkers in the mouse brain. A single dose of PAMAM dendrimers (3 or 15μg/mouse) was intranasally administered to 8-week old male BALB/c mice. Twenty-four hours after administration, the olfactory bulb, hippocampus, and cerebral cortex were collected and potential biomarkers in the blood and brain were examined using blood marker, microarray and real-time RT-PCR analyses. No remarkable changes in standard serum biochemical markers were observed in the blood. A microarray analysis showed the alterations of the genes expression level related to pluripotent network, serotonin-anxiety pathway, TGF-beta receptor signaling, prostaglandin synthesis-regulation, complement-coagulation cascades, and chemokine-signaling pathway and non-odorant GPCR signaling pathways in brain tissues. Brain derived-neurotrophic factor mRNA was up-regulated in the hippocampus and cerebral cortex in mice treated with a high dose of dendrimers. These findings suggest that PAMAM dendrimers may reach the brain via the systemic circulation or an olfactory nerve route after intranasal instillation, and indicate that a single intranasal administration of PAMAM dendrimers may potentially lead to neuronal effects by modulating the gene expression of brain-derived neurotrophic factor signaling pathway.

  8. Preparation, characterization, and in vivo evaluation of intranasally administered liposomal formulation of donepezil.

    PubMed

    Al Asmari, Abdulrahman K; Ullah, Zabih; Tariq, Mohammad; Fatani, Amal

    2016-01-01

    The adequate amount of drug delivery to the brain in neurological patients is a major problem faced by the physicians. Recent studies suggested that intranasal administration of liposomal formulation may improve the drug delivery to the brain. In the present study, an attempt was made to study the brain bioavailability of commonly used anti-Alzheimer drug donepezil (DNP) liposomal formulation by intranasal route in rats. We adopted the thin layer hydration technique for the preparation of liposomes by using cholesterol, polyethylene glycol, and 1,2-distearyl-sn-glycero-3-phosphocholine (DSPC). The prepared liposomes were characterized by determining particle size, shape, surface morphology, zeta potential, encapsulation efficiency, and in vitro release of DNP. The pharmacokinetic parameters of liposomal DNP in plasma and brain of rats were determined following oral and nasal administration. The results of this study showed that the DNP liposomal formulation was stable with a consistent size (102 ± 3.3 nm) and shape. The prepared liposomes showed high encapsulation efficiency (84.91% ±3 .31%) and sustained-release behavior. The bioavailability of DNP in plasma and brain increased significantly (P<0.05) after administration of liposomal formulation by the intranasal route. Histopathological examination showed that the formulation was safe and free from toxicity. It can be concluded that the nasal administration of liposomal preparation may provide an efficient and reliable mode of drug delivery to the central nervous system.

  9. Attenuation of histamine-induced airway effects by intranasal application of levocetirizine in mice.

    PubMed

    Kitayama-Sugiyama, Chie; Mochizuki, Naoko; Murata, Hitomi; Katsura, Masashi; Kamei, Chiaki

    2013-10-01

    The present study was performed to investigate the histamine-induced airway effect of levocetirizine, an active enantiomer of cetirizine, by intranasal application using ddY mice. Nasal rubbing and sneezing after histamine application into the nasal cavity were used as an index of histamine-induced airway effect in mice. Intranasal application of levocetirizine inhibited both nasal rubbing and sneezing concentration-dependently, and the ED50 values were 0.62 (0.51-0.77) and 0.70 (0.51-1.02) %/site for nasal rubbing and sneezing, respectively. ED50 values of cetirizine were 1.24 (1.02-1.59) and 1.35 (1.02-2.08) %/site for nasal rubbing and sneezing, respectively. Levocetirizine also inhibited nasal rubbing and sneezing when administered orally. These results clearly indicate that levocetirizine was about two times more potent than cetirizine by intranasal application, similar to the findings of the former's affinity for human histamine H1 receptors. In addition, the present findings raise the expectation of the development of levocetirizine nasal drops. PMID:23855419

  10. Intranasal curcumin attenuates airway remodeling in murine model of chronic asthma.

    PubMed

    Chauhan, Preeti S; Subhashini; Dash, D; Singh, Rashmi

    2014-07-01

    Curcumin, phytochemical present in turmeric, rhizome of Curcuma longa, a known anti-inflammatory molecule with variety of pharmacological activities is found effective in murine model of chronic asthma characterized by structural alterations and airway remodeling. Here, we have investigated the effects of intranasal curcumin in chronic asthma where animals were exposed to allergen for longer time. In the present study Balb/c mice were sensitized by an intraperitoneal injection of ovalbumin (OVA) and subsequently challenged with 2% OVA in aerosol twice a week for five consecutive weeks. Intranasal curcumin (5mg/kg) was administered from days 21 to 55, an hour before every nebulization and inflammatory cells recruitment, levels of IgE, EPO, IL-4 and IL-5 were found suppressed in bronchoalveolar lavage fluid (BALF). Intranasal curcumin administration prevented accumulation of inflammatory cells to the airways, structural alterations and remodeling associated with chronic asthma like peribronchial and airway smooth muscle thickening, sloughing off of the epithelial lining and mucus secretion in ovalbumin induced murine model of chronic asthma.

  11. Preparation, characterization, and in vivo evaluation of intranasally administered liposomal formulation of donepezil.

    PubMed

    Al Asmari, Abdulrahman K; Ullah, Zabih; Tariq, Mohammad; Fatani, Amal

    2016-01-01

    The adequate amount of drug delivery to the brain in neurological patients is a major problem faced by the physicians. Recent studies suggested that intranasal administration of liposomal formulation may improve the drug delivery to the brain. In the present study, an attempt was made to study the brain bioavailability of commonly used anti-Alzheimer drug donepezil (DNP) liposomal formulation by intranasal route in rats. We adopted the thin layer hydration technique for the preparation of liposomes by using cholesterol, polyethylene glycol, and 1,2-distearyl-sn-glycero-3-phosphocholine (DSPC). The prepared liposomes were characterized by determining particle size, shape, surface morphology, zeta potential, encapsulation efficiency, and in vitro release of DNP. The pharmacokinetic parameters of liposomal DNP in plasma and brain of rats were determined following oral and nasal administration. The results of this study showed that the DNP liposomal formulation was stable with a consistent size (102 ± 3.3 nm) and shape. The prepared liposomes showed high encapsulation efficiency (84.91% ±3 .31%) and sustained-release behavior. The bioavailability of DNP in plasma and brain increased significantly (P<0.05) after administration of liposomal formulation by the intranasal route. Histopathological examination showed that the formulation was safe and free from toxicity. It can be concluded that the nasal administration of liposomal preparation may provide an efficient and reliable mode of drug delivery to the central nervous system. PMID:26834457

  12. Characterization of a murine model of intranasal infection suitable for testing vaccines against C. abortus.

    PubMed

    Buendía, A J; Nicolás, L; Ortega, N; Gallego, M C; Martinez, C M; Sanchez, J; Caro, M R; Navarro, J A; Salinas, J

    2007-01-15

    Mouse models have been widely used to test candidate vaccines against Chlamydophila abortus infection in mice. Although the induction of a systemic infection by endogenous or intraperitoneal inoculation is a useful tool for understanding the immune mechanism involved in the protection conferred by the vaccination, a different approach is necessary to understand other factors of the infection, such as mucosal immunity or the colonization of target organs. To test whether C. abortus intranasal model of infection in mice is a useful tool for testing vaccines in a first group of experiments mice, were infected intranasally with C. abortus to characterize the model of infection. When this model was used to test vaccines, two inactivated experimental vaccines, one of them adjuvated with QS-21 and another with aluminium hydroxide, and a live attenuated vaccine (strain 1B) were used. Non-vaccinated control mice died within the first 8 days, after displaying substantial loss of weight. Histologically, the mice showed lobar fibrinopurulent bronchointerstitial pneumonia. Prior immunization with QS-21 adjuvated vaccine or 1B vaccine presented mortality and the recipients showed a greater number of T cells in the lesions, especially CD8(+) T cells, than the control mice and mice immunized with vaccine adjuvated with aluminium hydroxide. The results confirm that the C. abortus intranasal model of infection in mice is a useful tool for testing vaccines.

  13. Intranasal microemulsion for targeted nose to brain delivery in neurocysticercosis: Role of docosahexaenoic acid.

    PubMed

    Shinde, Rajshree L; Bharkad, Gopal P; Devarajan, Padma V

    2015-10-01

    Intranasal Microemulsions (MEs) for nose to brain delivery of a novel combination of Albendazole sulfoxide (ABZ-SO) and Curcumin (CUR) for Neurocysticercosis (NCC), a brain infection are reported. MEs prepared by simple solution exhibited a globule size <20nm, negative zeta potential and good stability. The docosahexaenoic acid (DHA) ME revealed high and rapid ex vivo permeation of drugs through sheep nasal mucosa. Intranasal DHA ME resulted in high brain concentrations and 10.76 (ABZ-SO) and 3.24 (CUR) fold enhancement in brain area-under-the-curve (AUC) compared to intravenous DHA MEs at the same dose. Direct nose to brain transport (DTP) of >95% was seen for both drugs. High drug targeting efficiency (DTE) to the brain compared to Capmul ME and drug solution (P<0.05) suggested the role of DHA in aiding nose to brain delivery. Histopathology study confirmed no significant changes. High efficacy of ABZ-SO: CUR (100:10ng/mL) DHA ME in vitro on Taenia solium cysts was confirmed by complete ALP inhibition and disintegration of cysts at 96h. Considering that the brain concentration at 24h was 1400±160.1ng/g (ABZ-SO) and 120±35.2ng/g (CUR), the in vitro efficacy seen at a 10 fold lower concentration of the drugs strongly supports the assumption of clinical efficacy. The intranasal DHA ME is a promising delivery system for targeted nose to brain delivery.

  14. [Perioperative management of an obese patient complicated with sleep apnea syndrome (SAS) undergoing awake craniotomy].

    PubMed

    Komayama, Noriaki; Kamata, Kotoe; Maruyama, Takashi; Nitta, Masayuki; Muragaki, Yoshihiro; Ozaki, Makoto

    2014-10-01

    Both obesity (BMI over 30) and SAS are risks for Supper airway maintenance. We report an obese patient (BMI 33.5) with SAS who underwent awake craniotomy. Weight reduction was instructed 1 month before the operation, and the patient lost enough weight to use intraoperative MRI. Under general anesthesia, surgical pads containing 2% lidocaine with adrenaline were inserted into the nasal cavities. The patient's airway S was secured by i-gel® until dura was opened. A nasal airway was then inserted to confirm the upper airway patency and anesthetics were terminated The patient regained consciousness and started respiration. The i-gel® was removed. The nasal airway was changed to an RAE tracheal tube ; the tube was fixed above the vocal cords under bronchofiberscopic observation. Continuous positive airway pressure (CPAP) via RAE tube was started. Neither coughing nor epistaxis was observed.The RAE tube prevented glossoptosis and did not disturb speech mapping. Emergent endotracheal intubation was easily managed because the tube was close to the glottis. The RAE tube was removed and nasal CP AP was applied overnight Carefully prepared CP AP support via nasal RAE tube was practical in keeping upper airway patency for an obese patient complicated with SAS undergoing awake craniotomy.

  15. The discriminatory value of cardiorespiratory interactions in distinguishing awake from anaesthetised states: a randomised observational study.

    PubMed

    Kenwright, D A; Bernjak, A; Draegni, T; Dzeroski, S; Entwistle, M; Horvat, M; Kvandal, P; Landsverk, S A; McClintock, P V E; Musizza, B; Petrovčič, J; Raeder, J; Sheppard, L W; Smith, A F; Stankovski, T; Stefanovska, A

    2015-12-01

    Depth of anaesthesia monitors usually analyse cerebral function with or without other physiological signals; non-invasive monitoring of the measured cardiorespiratory signals alone would offer a simple, practical alternative. We aimed to investigate whether such signals, analysed with novel, non-linear dynamic methods, would distinguish between the awake and anaesthetised states. We recorded ECG, respiration, skin temperature, pulse and skin conductivity before and during general anaesthesia in 27 subjects in good cardiovascular health, randomly allocated to receive propofol or sevoflurane. Mean values, variability and dynamic interactions were determined. Respiratory rate (p = 0.0002), skin conductivity (p = 0.03) and skin temperature (p = 0.00006) changed with sevoflurane, and skin temperature (p = 0.0005) with propofol. Pulse transit time increased by 17% with sevoflurane (p = 0.02) and 11% with propofol (p = 0.007). Sevoflurane reduced the wavelet energy of heart (p = 0.0004) and respiratory (p = 0.02) rate variability at all frequencies, whereas propofol decreased only the heart rate variability below 0.021 Hz (p < 0.05). The phase coherence was reduced by both agents at frequencies below 0.145 Hz (p < 0.05), whereas the cardiorespiratory synchronisation time was increased (p < 0.05). A classification analysis based on an optimal set of discriminatory parameters distinguished with 95% success between the awake and anaesthetised states. We suggest that these results can contribute to the design of new monitors of anaesthetic depth based on cardiovascular signals alone. PMID:26350998

  16. Prolonged wakefulness alters neuronal responsiveness to local electrical stimulation of the neocortex in awake rats

    PubMed Central

    Vyazovskiy, Vladyslav V.; Olcese, Umberto; Cirelli, Chiara; Tononi, Giulio

    2012-01-01

    Summary Prolonged wakefulness or a lack of sleep lead to cognitive deficits, but little is known about the underlying cellular mechanisms. We recently found that sleep deprivation affects spontaneous neuronal activity in the neocortex of sleeping and awake rats. While it is well known that synaptic responses are modulated by ongoing cortical activity, it remains unclear whether prolonged waking affects responsiveness of cortical neurons to incoming stimuli. By applying local electrical microstimulation to the frontal area of the neocortex, we found that after a 4-hour period of waking the initial neuronal response in the contralateral frontal cortex was stronger and more synchronous, and was followed by a more profound inhibition of neuronal spiking as compared to the control condition. These changes in evoked activity suggest increased neuronal excitability and indicate that after staying awake cortical neurons become transiently bistable. We propose that some of the detrimental effects of sleep deprivation may be a result of altered neuronal responsiveness to incoming intrinsic and extrinsic inputs. PMID:23607417

  17. Detergent inhibits 70-90% of responses to intravenous endotoxin in awake sheep.

    PubMed

    Staub, N C; Longworth, K E; Serikov, V; Jerome, E H; Elsasser, T

    2001-05-01

    Sheep have reactive pulmonary intravascular macrophages, which are essential for the marked pulmonary vascular response to infusions of small quantities of endotoxin. In another species with reactive pulmonary intravascular macrophages, horses, our laboratory found that an intravenous biosafe detergent, tyloxapol, inhibited some systemic and pulmonary responses to endotoxin (Longworth KE, Smith BL, Staub NC, Steffey EP, and Serikov V. Am J Vet Res 57: 1063-1066, 1996). We determined whether the same detergent would inhibit endotoxin responses in awake sheep. In 10 awake, instrumented sheep with chronic lung lymph fistulas, we did a control experiment by intravenously infusing 1 microg/kg Escherichia coli endotoxin. One week later, we gave 40 micromol/kg tyloxapol intravenously 1-4 h before infusing the same dose of endotoxin. In these paired studies, we compared pulmonary hemodynamics, lung lymph dynamics, body temperature, circulating leukocyte concentrations, and circulating tumor necrosis factor for 6 h. In all 10 sheep, tyloxapol blocked 80-90% of the pulmonary responses and 70-90% of the systemic responses. Tyloxapol is safe, inexpensive, easy to use, and effective immediately. It may be a clinically useful approach to contravening many of the effects of endotoxemia, in humans as well as animals.

  18. Technical and Conceptual Considerations for Performing and Interpreting Functional MRI Studies in Awake Rats

    PubMed Central

    Febo, Marcelo

    2011-01-01

    Functional neuroimaging studies in rodents have the potential to provide insight into neurodevelopmental and psychiatric conditions. The strength of the technique lies in its non-invasive nature that can permit longitudinal functional studies in the same animal over its adult life. The relatively good spatial and temporal resolution and the ever-growing database on the biological and biophysical basis of the blood oxygen level dependent (BOLD) signal make it a unique technique in preclinical neuroscience research. Our laboratory has used imaging to investigate brain activation in awake rats following cocaine administration and during the presentation of lactation-associated sensory stimuli. Factors that deserve attention when planning functional magnetic resonance imaging studies in rats include technical issues, animal physiology and interpretability of the resulting data. The present review discusses the pros and cons of animal imaging with a particular focus on the technical aspects of studies with awake rats. Overall, the benefits of the technique outweigh its limitations and the rapidly evolving methods will open the way for more laboratories to employ the technique in neuroscience research. PMID:21808625

  19. Indirect self-modulation instability measurement concept for the AWAKE proton beam

    NASA Astrophysics Data System (ADS)

    Turner, M.; Petrenko, A.; Biskup, B.; Burger, S.; Gschwendtner, E.; Lotov, K. V.; Mazzoni, S.; Vincke, H.

    2016-09-01

    AWAKE, the Advanced Proton-Driven Plasma Wakefield Acceleration Experiment, is a proof-of-principle R&D experiment at CERN using a 400 GeV / c proton beam from the CERN SPS (longitudinal beam size σz = 12 cm) which will be sent into a 10 m long plasma section with a nominal density of ≈ 7 ×1014 atoms /cm3 (plasma wavelength λp = 1.2 mm). In this paper we show that by measuring the time integrated transverse profile of the proton bunch at two locations downstream of the AWAKE plasma, information about the occurrence of the self-modulation instability (SMI) can be inferred. In particular we show that measuring defocused protons with an angle of 1 mrad corresponds to having electric fields in the order of GV/m and fully developed self-modulation of the proton bunch. Additionally, by measuring the defocused beam edge of the self-modulated bunch, information about the growth rate of the instability can be extracted. If hosing instability occurs, it could be detected by measuring a non-uniform defocused beam shape with changing radius. Using a 1 mm thick Chromox scintillation screen for imaging of the self-modulated proton bunch, an edge resolution of 0.6 mm and hence an SMI saturation point resolution of 1.2 m can be achieved.

  20. Status of the proton and electron transfer lines for the AWAKE Experiment at CERN

    NASA Astrophysics Data System (ADS)

    Schmidt, J. S.; Bauche, J.; Biskup, B.; Bracco, C.; Doebert, S.; Goddard, B.; Gschwendtner, E.; Jensen, L. K.; Jones, O. R.; Mazzoni, S.; Meddahi, M.; Pepitone, K.; Petrenko, A.; Velotti, F. M.; Vorozhtsov, A.

    2016-09-01

    The AWAKE project at CERN is planned to study proton driven plasma wakefield acceleration with an externally injected electron beam. Therefore two transfer lines are being designed in order to provide the proton beam from the SPS and the electron beam from an RF gun to the plasma cell. The commissioning of the proton line will take place in 2016 for the first phase of the experiment, which is focused on the self-modulation of a 12 cm long proton bunch in the plasma. The electron line will be added for the second phase of AWAKE in 2017, when the wakefield will be probed with an electron beam of 10-20 MeV/c. The challenge for these transfer lines lies in the parallel operation of the proton, electron and laser beam used to ionize the plasma and seed the self-modulation. These beams, of different characteristics, need to be synchronized and positioned for optimized injection conditions into the wakefield. This task requires great flexibility in the transfer line optics. The status of these designs will be presented in this paper.

  1. The stimulus-evoked population response in visual cortex of awake monkey is a propagating wave.

    PubMed

    Muller, Lyle; Reynaud, Alexandre; Chavane, Frédéric; Destexhe, Alain

    2014-04-28

    Propagating waves occur in many excitable media and were recently found in neural systems from retina to neocortex. While propagating waves are clearly present under anaesthesia, whether they also appear during awake and conscious states remains unclear. One possibility is that these waves are systematically missed in trial-averaged data, due to variability. Here we present a method for detecting propagating waves in noisy multichannel recordings. Applying this method to single-trial voltage-sensitive dye imaging data, we show that the stimulus-evoked population response in primary visual cortex of the awake monkey propagates as a travelling wave, with consistent dynamics across trials. A network model suggests that this reliability is the hallmark of the horizontal fibre network of superficial cortical layers. Propagating waves with similar properties occur independently in secondary visual cortex, but maintain precise phase relations with the waves in primary visual cortex. These results show that, in response to a visual stimulus, propagating waves are systematically evoked in several visual areas, generating a consistent spatiotemporal frame for further neuronal interactions.

  2. Language mapping with verbs and sentences in awake surgery: a review.

    PubMed

    Rofes, Adrià; Miceli, Gabriele

    2014-06-01

    Intraoperative language mapping in awake surgery is typically conducted by asking the patient to produce automatic speech and to name objects. These tasks might not map language with sufficient accuracy, as some linguistic processes can only be triggered by tasks that use verbs and sentences. Verb and sentence processing tasks are currently used during surgery, albeit sparsely. Medline, PubMed, and Web of Science records were searched to retrieve studies focused on language mapping with verbs/sentences in awake surgery. We review the tasks reported in the published literature, spell out the language processes assessed by each task, list the cortical and subcortical regions whose stimulation inhibited language processing, and consider the types of errors elicited by stimulation in each region. We argue that using verb tasks allows a more thorough evaluation of language functions. We also argue that verb tasks are preferable to object naming tasks in the case of frontal lesions, as lesion and neuroimaging data demonstrate that these regions play a critical role in verb and sentence processing. We discuss the clinical value of these tasks and the current limitations of the procedure, and provide some guidelines for their development. Future research should aim toward a differentiated approach to language mapping - one that includes the administration of standardized and customizable tests and the use of longitudinal neurocognitive follow-up studies. Further work will allow researchers and clinicians to understand brain and language correlates and to improve the current surgical practice.

  3. Membrane Potential Dynamics of Spontaneous and Visually Evoked Gamma Activity in V1 of Awake Mice

    PubMed Central

    Perrenoud, Quentin; Pennartz, Cyriel M. A.; Gentet, Luc J.

    2016-01-01

    Cortical gamma activity (30–80 Hz) is believed to play important functions in neural computation and arises from the interplay of parvalbumin-expressing interneurons (PV) and pyramidal cells (PYRs). However, the subthreshold dynamics underlying its emergence in the cortex of awake animals remain unclear. Here, we characterized the intracellular dynamics of PVs and PYRs during spontaneous and visually evoked gamma activity in layers 2/3 of V1 of awake mice using targeted patch-clamp recordings and synchronous local field potentials (LFPs). Strong gamma activity patterned in short bouts (one to three cycles), occurred when PVs and PYRs were depolarizing and entrained their membrane potential dynamics regardless of the presence of visual stimulation. PV firing phase locked unconditionally to gamma activity. However, PYRs only phase locked to visually evoked gamma bouts. Taken together, our results indicate that gamma activity corresponds to short pulses of correlated background synaptic activity synchronizing the output of cortical neurons depending on external sensory drive. PMID:26890123

  4. No short-term effects of digital mobile radio telephone on the awake human electroencephalogram

    SciTech Connect

    Roeschke, J.; Mann, K.

    1997-05-01

    A recent study reported the results of an exploratory study of alterations of the quantitative sleep profile due to the effects of a digital mobile radio telephone. Rapid eye movement (REM) was suppressed, and the spectral power density in the 8--13 Hz frequency range during REM sleep was altered. The aim of the present study was to illuminate the influence of digital mobile radio telephone on the awake electroencephalogram (EEG) of healthy subjects. For this purpose, the authors investigated 34 male subjects in a single-blind cross-over design experiment by measuring spontaneous EEGs under closed-eyes condition from scalp positions C{sub 3} and C{sub 4} and comparing the effects of an active and an inactive digital mobile radio telephone (GSM) system. During exposure of nearly 3.5 min to the 900 MHz electromagnetic field pulsed at a frequency of 217 Hz and with a pulse width of 580 {micro}s, the authors could not detect any difference in the awake EEGs in terms of spectral power density measures.

  5. Disrupting neural activity related to awake-state sharp wave-ripple complexes prevents hippocampal learning

    PubMed Central

    Nokia, Miriam S.; Mikkonen, Jarno E.; Penttonen, Markku; Wikgren, Jan

    2012-01-01

    Oscillations in hippocampal local-field potentials (LFPs) reflect the crucial involvement of the hippocampus in memory trace formation: theta (4–8 Hz) oscillations and ripples (~200 Hz) occurring during sharp waves are thought to mediate encoding and consolidation, respectively. During sharp wave-ripple complexes (SPW-Rs), hippocampal cell firing closely follows the pattern that took place during the initial experience, most likely reflecting replay of that event. Disrupting hippocampal ripples using electrical stimulation either during training in awake animals or during sleep after training retards spatial learning. Here, adult rabbits were trained in trace eyeblink conditioning, a hippocampus-dependent associative learning task. A bright light was presented to the animals during the inter-trial interval (ITI), when awake, either during SPW-Rs or irrespective of their neural state. Learning was particularly poor when the light was presented following SPW-Rs. While the light did not disrupt the ripple itself, it elicited a theta-band oscillation, a state that does not usually coincide with SPW-Rs. Thus, it seems that consolidation depends on neuronal activity within and beyond the hippocampus taking place immediately after, but by no means limited to, hippocampal SPW-Rs. PMID:23316148

  6. Novel method for functional brain imaging in awake minimally restrained rats.

    PubMed

    Chang, Pei-Ching; Procissi, Daniel; Bao, Qiyuan; Centeno, Maria Virginia; Baria, Alex; Apkarian, A Vania

    2016-07-01

    Functional magnetic resonance imaging (fMRI) in rodents holds great promise for advancing our knowledge about human brain function. However, the use of anesthetics to immobilize rodents during fMRI experiments has restricted the type of questions that can be addressed using this technique. Here we describe an innovative procedure to train rats to be constrained without the need of any anesthesia during the whole procedure. We show that with 8-10 days of acclimation rats can be conscious and remain still during fMRI experiments under minimal stress. In addition, we provide fMRI results of conscious rodents in a variety of commonly used fMRI experimental paradigms, and we demonstrate the improved quality of these scans by comparing results when the same rodents were scanned under anesthesia. We confirm that the awake scanning procedure permits an improved evaluation of brain networks and brain response to external stimuli with minimal movement artifact. The present study further advances the field of fMRI in awake rodents, which provide more direct, forward and reverse, translational opportunities regarding brain functional correspondences between human and rodent research.

  7. A novel tablet computer platform for advanced language mapping during awake craniotomy procedures.

    PubMed

    Morrison, Melanie A; Tam, Fred; Garavaglia, Marco M; Golestanirad, Laleh; Hare, Gregory M T; Cusimano, Michael D; Schweizer, Tom A; Das, Sunit; Graham, Simon J

    2016-04-01

    A computerized platform has been developed to enhance behavioral testing during intraoperative language mapping in awake craniotomy procedures. The system is uniquely compatible with the environmental demands of both the operating room and preoperative functional MRI (fMRI), thus providing standardized testing toward improving spatial agreement between the 2 brain mapping techniques. Details of the platform architecture, its advantages over traditional testing methods, and its use for language mapping are described. Four illustrative cases demonstrate the efficacy of using the testing platform to administer sophisticated language paradigms, and the spatial agreement between intraoperative mapping and preoperative fMRI results. The testing platform substantially improved the ability of the surgeon to detect and characterize language deficits. Use of a written word generation task to assess language production helped confirm areas of speech apraxia and speech arrest that were inadequately characterized or missed with the use of traditional paradigms, respectively. Preoperative fMRI of the analogous writing task was also assistive, displaying excellent spatial agreement with intraoperative mapping in all 4 cases. Sole use of traditional testing paradigms can be limiting during awake craniotomy procedures. Comprehensive assessment of language function will require additional use of more sophisticated and ecologically valid testing paradigms. The platform presented here provides a means to do so.

  8. α1-Adrenergic receptors mediate coordinated Ca2+ signaling of cortical astrocytes in awake, behaving mice.

    PubMed

    Ding, Fengfei; O'Donnell, John; Thrane, Alexander S; Zeppenfeld, Douglas; Kang, Hongyi; Xie, Lulu; Wang, Fushun; Nedergaard, Maiken

    2013-12-01

    Astrocyte Ca2+ signals in awake behaving mice are widespread, coordinated and differ fundamentally from the locally restricted Ca2+ transients observed ex vivo and in anesthetized animals. Here we show that the synchronized release of norepinephrine (NE) from locus coeruleus (LC) projections throughout the cerebral cortex mediate long-ranging Ca2+ signals by activation of astrocytic α1-adrenergic receptors. When LC output was triggered by either physiological sensory (whisker) stimulation or an air-puff startle response, astrocytes responded with fast Ca2+ transients that encompassed the entire imaged field (positioned over either frontal or parietal cortex). The application of adrenergic inhibitors, including α1-adrenergic antagonist prazosin, potently suppressed both evoked, as well as the frequently observed spontaneous astroglial Ca2+ signals. The LC-specific neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), which reduced cortical NE content by >90%, prevented nearly all astrocytic Ca2+ signals in awake mice. The observations indicate that in adult, unanesthetized mice, astrocytes do not respond directly to glutamatergic signaling evoked by sensory stimulation. Instead astrocytes appear to be the primary target for NE, with astrocytic Ca2+ signaling being triggered by the α1-adrenergic receptor. In turn, astrocytes may coordinate the broad effects of neuromodulators on neuronal activity.

  9. Intact skull chronic windows for mesoscopic wide-field imaging in awake mice

    PubMed Central

    Silasi, Gergely; Xiao, Dongsheng; Vanni, Matthieu P.; Chen, Andrew C. N.; Murphy, Timothy H.

    2016-01-01

    Background Craniotomy-based window implants are commonly used for microscopic imaging, in head-fixed rodents, however their field of view is typically small and incompatible with mesoscopic functional mapping of cortex. New Method We describe a reproducible and simple procedure for chronic through-bone wide-field imaging in awake head-fixed mice providing stable optical access for chronic imaging over large areas of the cortex for months. Results The preparation is produced by applying clear-drying dental cement to the intact mouse skull, followed by a glass coverslip to create a partially transparent imaging surface. Surgery time takes about 30 minutes. A single set-screw provides a stable means of attachment for mesoscale assessment without obscuring the cortical field of view. Comparison with Existing Methods We demonstrate the utility of this method by showing seed-pixel functional connectivity maps generated from spontaneous cortical activity of GCAMP6 signals in both awake and anesthetized mice. Conclusions We propose that the intact skull preparation described here may be used for most longitudinal studies that do not require micron scale resolution and where cortical neural or vascular signals are recorded with intrinsic sensors. PMID:27102043

  10. Episodic-like memory trace in awake replay of hippocampal place cell activity sequences

    PubMed Central

    Takahashi, Susumu

    2015-01-01

    Episodic memory retrieval of events at a specific place and time is effective for future planning. Sequential reactivation of the hippocampal place cells along familiar paths while the animal pauses is well suited to such a memory retrieval process. It is, however, unknown whether this awake replay represents events occurring along the path. Using a subtask switching protocol in which the animal experienced three subtasks as ‘what’ information in a maze, I here show that the replay represents a trial type, consisting of path and subtask, in terms of neuronal firing timings and rates. The actual trial type to be rewarded could only be reliably predicted from replays that occurred at the decision point. This trial-type representation implies that not only ‘where and when’ but also ‘what’ information is contained in the replay. This result supports the view that awake replay is an episodic-like memory retrieval process. DOI: http://dx.doi.org/10.7554/eLife.08105.001 PMID:26481131

  11. The linearity and selectivity of neuronal responses in awake visual cortex

    PubMed Central

    Chen, Yao; Anand, Sanjiv; Martinez-Conde, Susana; Macknik, Stephen L.; Bereshpolova, Yulia; Swadlow, Harvey A.; Alonso, Jose-Manuel

    2011-01-01

    Neurons in primary visual cortex (V1) are frequently classified based on their response linearity: the extent in which their visual responses to drifting gratings resemble a linear replica of the stimulus. This classification is supported by the finding that response linearity is bimodally distributed across neurons in area V1 of anesthetized animals. However, recent studies suggest that such bimodal distribution may not reflect two neuronal types but a nonlinear relationship between the membrane potential and the spike output. A main limitation of these previous studies is that they measured response linearity in anesthetized animals, where the distance between the neuronal membrane potential and spike threshold is artificially increased by anesthesia. Here, we measured V1 response linearity in the awake brain and its correlation with the neuronal spontaneous firing rate, which is related to the distance between membrane potential and threshold. Our results demonstrate that response linearity is bimodally distributed in awake V1 but that it is poorly correlated with spontaneous firing rate. In contrast, the spontaneous firing rate is best correlated to the response selectivity and response latency to stimuli. PMID:19761345

  12. The stimulus-evoked population response in visual cortex of awake monkey is a propagating wave

    PubMed Central

    Muller, Lyle; Reynaud, Alexandre; Chavane, Frédéric; Destexhe, Alain

    2014-01-01

    Propagating waves occur in many excitable media and were recently found in neural systems from retina to neocortex. While propagating waves are clearly present under anaesthesia, whether they also appear during awake and conscious states remains unclear. One possibility is that these waves are systematically missed in trial-averaged data, due to variability. Here we present a method for detecting propagating waves in noisy multichannel recordings. Applying this method to single-trial voltage-sensitive dye imaging data, we show that the stimulus-evoked population response in primary visual cortex of the awake monkey propagates as a travelling wave, with consistent dynamics across trials. A network model suggests that this reliability is the hallmark of the horizontal fibre network of superficial cortical layers. Propagating waves with similar properties occur independently in secondary visual cortex, but maintain precise phase relations with the waves in primary visual cortex. These results show that, in response to a visual stimulus, propagating waves are systematically evoked in several visual areas, generating a consistent spatiotemporal frame for further neuronal interactions. PMID:24770473

  13. A novel tablet computer platform for advanced language mapping during awake craniotomy procedures.

    PubMed

    Morrison, Melanie A; Tam, Fred; Garavaglia, Marco M; Golestanirad, Laleh; Hare, Gregory M T; Cusimano, Michael D; Schweizer, Tom A; Das, Sunit; Graham, Simon J

    2016-04-01

    A computerized platform has been developed to enhance behavioral testing during intraoperative language mapping in awake craniotomy procedures. The system is uniquely compatible with the environmental demands of both the operating room and preoperative functional MRI (fMRI), thus providing standardized testing toward improving spatial agreement between the 2 brain mapping techniques. Details of the platform architecture, its advantages over traditional testing methods, and its use for language mapping are described. Four illustrative cases demonstrate the efficacy of using the testing platform to administer sophisticated language paradigms, and the spatial agreement between intraoperative mapping and preoperative fMRI results. The testing platform substantially improved the ability of the surgeon to detect and characterize language deficits. Use of a written word generation task to assess language production helped confirm areas of speech apraxia and speech arrest that were inadequately characterized or missed with the use of traditional paradigms, respectively. Preoperative fMRI of the analogous writing task was also assistive, displaying excellent spatial agreement with intraoperative mapping in all 4 cases. Sole use of traditional testing paradigms can be limiting during awake craniotomy procedures. Comprehensive assessment of language function will require additional use of more sophisticated and ecologically valid testing paradigms. The platform presented here provides a means to do so. PMID:26473779

  14. Distinct spatiotemporal activity in principal neurons of the mouse olfactory bulb in anesthetized and awake states

    PubMed Central

    Blauvelt, David G.; Sato, Tomokazu F.; Wienisch, Martin; Murthy, Venkatesh N.

    2013-01-01

    The acquisition of olfactory information and its early processing in mammals are modulated by brain states through sniffing behavior and neural feedback. We imaged the spatiotemporal pattern of odor-evoked activity in a population of output neurons (mitral/tufted cells, MTCs) in the olfactory bulb (OB) of head-restrained mice expressing a genetically-encoded calcium indicator. The temporal dynamics of MTC population activity were relatively simple in anesthetized animals, but were highly variable in awake animals. However, the apparently irregular activity in awake animals could be predicted well using sniff timing measured externally, or inferred through fluctuations in the global responses of MTC population even without explicit knowledge of sniff times. The overall spatial pattern of activity was conserved across states, but odor responses had a diffuse spatial component in anesthetized mice that was less prominent during wakefulness. Multi-photon microscopy indicated that MTC lateral dendrites were the likely source of spatially disperse responses in the anesthetized animal. Our data demonstrate that the temporal and spatial dynamics of MTCs can be significantly modulated by behavioral state, and that the ensemble activity of MTCs can provide information about sniff timing to downstream circuits to help decode odor responses. PMID:23543674

  15. Ultra-minimally invasive cardiac surgery: robotic surgery and awake CABG.

    PubMed

    Ishikawa, Norihiko; Watanabe, Go

    2015-01-01

    The recognition of the significant advantages of minimizing surgical trauma has resulted in the development of minimally invasive surgical procedures. Endoscopic surgery confers the benefits of minimally invasive surgery upon patients, and surgical robots have enhanced the ability and precision of surgeons. Consequently, technological advances have facilitated totally endoscopic robotic cardiac surgery, which has allowed surgeons to operate endoscopically, rather than through a median sternotomy, during cardiac surgery. Thus, repairs for structural heart conditions, including mitral valve plasty, atrial septal defect closure, multivessel minimally invasive direct coronary artery bypass grafting and totally endoscopic coronary artery bypass graft surgery (CABG), can be totally endoscopic. On the other hand, general anesthesia remains a risk in patients who have severe carotid artery stenosis before surgery, as well as in those with a history of severe cerebral infarction or respiratory failure. In this study, the potential of a new awake CABG protocol using only epidural anesthesia was investigated for realizing day surgery and was found to be a promising modality for ultra-minimally invasive cardiac surgery. We herein review robot-assisted cardiac surgery and awake off-pump coronary artery bypass grafting as ultra-minimally invasive cardiac surgeries. PMID:25274467

  16. Insulin and the law.

    PubMed

    Marks, Vincent

    2015-11-01

    Hypoglycaemia, if it can be proved, may be used as a defence against almost any criminal charge provided it can be established that the perpetrator was in a state of neuroglycopenic (hypoglycaemic) automatism at the time of the offence. Hypoglycaemia produced by exogenous insulin can also be used as a suicidal or homicidal weapon. This paper discusses some of the pitfalls confronting the investigator of suspected insulin misuse including problems arising from the increasing prevalence of insulin analogues and the unreliability of immunoassays for their detection and measurement in the forensic context. PMID:26092979

  17. Insulin inhalation: NN 1998.

    PubMed

    2004-01-01

    Aradigm Corporation has developed an inhaled form of insulin using its proprietary AERx drug delivery system. The system uses liquid insulin that is converted into an aerosol containing very small particles (1-3 micro in diameter), and an electronic device suitable for either the rapid transfer of molecules of insulin into the bloodstream or localised delivery within the lung. The AERx insulin Diabetes Management System (iDMS), AERx iDMS, instructs the user on breathing technique to achieve the best results. Aradigm Corporation and Novo Nordisk have signed an agreement to jointly develop a pulmonary delivery system for insulin [AERx iDMS, NN 1998]. Under the terms of the agreement, Novo Nordisk has exclusive rights for worldwide marketing of any products resulting from the development programme. Aradigm Corporation will initially manufacture the product covered by the agreement, and in return will receive a share of the overall gross profits from Novo Nordisk's sales. Novo Nordisk will cover all development costs incurred by Aradigm Corporation while both parties will co-fund final development of the AERx device. Both companies will explore the possibilities of the AERx platform to deliver other compounds for the regulation of blood glucose levels. Additionally, the agreement gives Novo Nordisk an option to develop the technology for delivery of agents outside the diabetes area. In April 2001, Aradigm Corporation received a milestone payment from Novo Nordisk related to the completion of certain clinical and product development stages of the AERx drug delivery system. Profil, a CRO in Germany, is cooperating with Aradigm and Novo Nordisk in the development of inhaled insulin. Aradigm and Novo Nordisk initiated a pivotal phase III study with inhaled insulin formulation in September 2002. This 24-month, 300-patient trial is evaluating inhaled insulin in comparison with insulin aspart. Both medications will be given three times daily before meals in addition to basal

  18. [(11)C]Raclopride binding in the striatum of minimally restrained and free-walking awake mice in a positron emission tomography study.

    PubMed

    Takuwa, Hiroyuki; Maeda, Jun; Ikoma, Yoko; Tokunaga, Masaki; Wakizaka, Hidekatsu; Uchida, Shouko; Kanno, Iwao; Taniguchi, Junko; Ito, Hiroshi; Higuchi, Makoto

    2015-12-01

    Anesthesia and restraint stress have profound impacts on brain functions, including neural activity and cerebrovascular function, possibly influencing functional and neurochemical positron emission tomography (PET) imaging data. For circumventing this effect, we developed an experimental system enabling PET imaging of free-walking awake mice with minimal restraints by fixing the head to a holder. The applicability of this system was investigated by performing PET imaging of D2 dopamine receptors with [(11)C]raclopride under the following three different conditions: (1) free-walking awake state; (2) 1.5% isoflurane anesthesia; and (3) whole-body restraint without anesthesia. [(11)C]raclopride binding potential (BP(ND)) values under isoflurane anesthesia and restrained awake state were significantly lower than under free-walking awake state (P < 0.01). Heart rates in restrained awake mice were significantly higher than those in free-walking awake mice (P < 0.01), suggesting that free-walking awake state minimized restraint stress during the PET scan. [(11)C] raclopride-PET with methamphetamine (METH) injection was also performed in awake and anesthetized mice. METH-induced reduction of [(11)C]raclopride BP(ND) in anesthetized mice showed a trend to be less than that in free-walking awake mice, implying that pharmacological modulation of dopaminergic transmissions could be sensitively captured by PET imaging of free-walking awake mice. We concluded that our system is of utility as an in vivo assaying platform for studies of brain functions and neurotransmission elements in small animals, such as those modeling neuropsychiatric disorders.

  19. Intranasal administration of retinyl palmitate with a respiratory virus vaccine corrects impaired mucosal IgA response in the vitamin A-deficient host.

    PubMed

    Surman, Sherri L; Jones, Bart G; Rudraraju, Rajeev; Sealy, Robert E; Hurwitz, Julia L

    2014-04-01

    Our previous studies showed that intranasal vaccination of vitamin A-deficient (VAD) mice failed to induce normal levels of upper respiratory tract IgA, a first line of defense against respiratory virus infection. Here we demonstrate that the impaired responses in VAD animals are corrected by a single intranasal application of retinyl palmitate with the vaccine. Results encourage the clinical testing of intranasal vitamin A supplements to improve protection against respiratory viral disease in VAD populations. PMID:24554696

  20. Reduced phosphorylation of brain insulin receptor substrate and Akt proteins in apolipoprotein-E4 targeted replacement mice.

    PubMed

    Ong, Qi-Rui; Chan, Elizabeth S; Lim, Mei-Li; Cole, Gregory M; Wong, Boon-Seng

    2014-01-17

    Human ApoE4 accelerates memory decline in ageing and in Alzheimer's disease. Although intranasal insulin can improve cognition, this has little effect in ApoE4 subjects. To understand this ApoE genotype-dependent effect, we examined brain insulin signaling in huApoE3 and huApoE4 targeted replacement (TR) mice. At 32 weeks, lower insulin receptor substrate 1 (IRS1) at S636/639 and Akt phosphorylation at T308 were detected in fasting huApoE4 TR mice as compared to fasting huApoE3 TR mice. These changes in fasting huApoE4 TR mice were linked to lower brain glucose content and have no effect on plasma glucose level. However, at 72 weeks of age, these early changes were accompanied by reduction in IRS2 expression, IRS1 phosphorylation at Y608, Akt phosphorylation at S473, and MAPK (p38 and p44/42) activation in the fasting huApoE4 TR mice. The lower brain glucose was significantly associated with higher brain insulin in the aged huApoE4 TR mice. These results show that ApoE4 reduces brain insulin signaling and glucose level leading to higher insulin content.

  1. Insulin Delivery System

    NASA Technical Reports Server (NTRS)

    1988-01-01

    When Programmable Implantable Medication System (PIMS) is implanted in human body, it delivers precise programmed amounts of insulin over long periods of time. Mini-Med Technologies has been refining the Technologies since initial development at APL. The size of a hockey puck, and encased in titanium shell, PIMS holds about 2 1/2 teaspoons of insulin at a programmed basal rate. If a change in measured blood sugar level dictates a different dose, the patient can vary the amount of insulin delivered by holding a small radio transceiver over the implanted system and dialing in a specific program held in the PIMS computer memory. Insulin refills are accomplished approximately 4 times a year by hypodermic needle.

  2. All about Insulin Resistance

    MedlinePlus

    ... news is that cutting calories, being active, and losing weight can reverse insulin resistance and lower your ... you’ll lose weight. Studies have shown that losing even 7% of your weight, may help. For ...

  3. Insulin signaling and addiction

    PubMed Central

    Daws, Lynette C.; Avison, Malcolm J.; Robertson, Sabrina D.; Niswender, Kevin D.; Galli, Aurelio; Saunders, Christine

    2012-01-01

    Across species, the brain evolved to respond to natural rewards such as food and sex. These physiological responses are important for survival, reproduction and evolutionary processes. It is no surprise, therefore, that many of the neural circuits and signaling pathways supporting reward processes are conserved from Caenorhabditis elegans to Drosophilae, to rats, monkeys and humans. The central role of dopamine (DA) in encoding reward and in attaching salience to external environmental cues is well recognized. Less widely recognized is the role of reporters of the “internal environment”, particularly insulin, in the modulation of reward. Insulin has traditionally been considered an important signaling molecule in regulating energy homeostasis and feeding behavior rather than a major component of neural reward circuits. However, research over recent decades has revealed that DA and insulin systems do not operate in isolation from each other, but instead, work together to orchestrate both the motivation to engage in consummatory behavior and to calibrate the associated level of reward. Insulin signaling has been found to regulate DA neurotransmission and to affect the ability of drugs that target the DA system to exert their neurochemical and behavioral effects. Given that many abused drugs target the DA system, the elucidation of how dopaminergic, as well as other brain reward systems, are regulated by insulin will create opportunities to develop therapies for drug and potentially food addiction. Moreover, a more complete understanding of the relationship between DA neurotransmission and insulin may help to uncover etiological bases for “food addiction” and the growing epidemic of obesity. This review focuses on the role of insulin signaling in regulating DA homeostasis and DA signaling, and the potential impact of impaired insulin signaling in obesity and psychostimulant abuse. PMID:21420985

  4. Moving toward the ideal insulin for insulin pumps.

    PubMed

    Cengiz, Eda; Bode, Bruce; Van Name, Michelle; Tamborlane, William V

    2016-01-01

    Advances in insulin formulations have been important for diabetes management and achieving optimal glycemic control. Rapid-acting insulin analogs provide a faster time-action profile than regular insulin and are approved for use in pumps. However, the need remains for therapy to deliver a more physiologic insulin profile. New insulin formulations and delivery methods are in development, with the aim of accelerating insulin absorption to accomplish ultra-fast-acting insulin time-action profiles. Furthermore, the integration of continuous glucose monitoring with insulin pump therapy enables on-going adjustment of insulin delivery to optimize glycemic control throughout the day and night. These technological and pharmacological advances are likely to facilitate the development of closed-loop pump systems (i.e., artificial pancreas), and improve glycemic control and quality of life for patients with diabetes. PMID:26560137

  5. REAL-TIME MEASUREMENT OF AIRWAY RESPONSES TO SULOFUR DIOXIDE (SO2) IN AN INTACT, AWAKE GUINEA PIG MODEL

    EPA Science Inventory

    Real-time measurment of airway responses to Sulfur Dioxide (SO2) in an intact, awake guinea pig model. J Stanek1,2, Q Krantz2, J Nolan2, D Winsett2, W Watkinson2, and D Costa2. 1College of Veterinary Medicine, NCSU, Raleigh, NC, USA; 2Pulmonary Toxicology Branch, ETD, NHEERL, US...

  6. Coding of Electric Pulse Trains Presented through Cochlear Implants in the Auditory Midbrain of Awake Rabbit: Comparison with Anesthetized Preparations

    PubMed Central

    Hancock, Kenneth E.; Nam, Sung-Il; Delgutte, Bertrand

    2014-01-01

    Cochlear implant (CI) listeners show limits at high frequencies in tasks involving temporal processing such as rate pitch and interaural time difference discrimination. Similar limits have been observed in neural responses to electric stimulation in animals with CI; however, the upper limit of temporal coding of electric pulse train stimuli in the inferior colliculus (IC) of anesthetized animals is lower than the perceptual limit. We hypothesize that the upper limit of temporal neural coding has been underestimated in previous studies due to the confound of anesthesia. To test this hypothesis, we developed a chronic, awake rabbit preparation for single-unit studies of IC neurons with electric stimulation through CI. Stimuli were periodic trains of biphasic pulses with rates varying from 20 to 1280 pulses per second. We found that IC neurons in awake rabbits showed higher spontaneous activity and greater sustained responses, both excitatory and suppressive, at high pulse rates. Maximum pulse rates that elicited synchronized responses were approximately two times higher in awake rabbits than in earlier studies with anesthetized animals. Here, we demonstrate directly that anesthesia is a major factor underlying these differences by monitoring the responses of single units in one rabbit before and after injection of an ultra-short-acting barbiturate. In general, the physiological rate limits of IC neurons in the awake rabbit are more consistent with the psychophysical limits in human CI subjects compared with limits from anesthetized animals. PMID:24381283

  7. Insulin pump therapy in pregnancy.

    PubMed

    Kesavadev, Jothydev

    2016-09-01

    Control of blood glucose during pregnancy is difficult because of wide variations, ongoing hormonal changes and mood swings. The need for multiple injections, pain at the injection site, regular monitoring and skillful handling of the syringes/pen further makes insulin therapy inconvenient. Insulin pump is gaining popularity in pregnancy because it mimics the insulin delivery of a healthy human pancreas. Multiple guidelines have also recommended the use of insulin pump in pregnancy to maintain the glycaemic control. The pump can release small doses of insulin continuously (basal), or a bolus dose close to mealtime to control the spike in blood glucose after a meal and the newer devices can shut down insulin delivery before the occurrence of hypoglycaemia. Pump insulin of choice is rapid acting analogue insulin. This review underscores the role of insulin pump in pregnancy, their usage, advantages and disadvantages in the light of existing literature and clinic experience. PMID:27582150

  8. Influence of anti-insulin antibodies on insulin immunoassays in the autoimmune insulin syndrome.

    PubMed

    Casesnoves, A; Mauri, M; Dominguez, J R; Alfayate, R; Picó, A M

    1998-11-01

    The autoimmune insulin syndrome (AIS) is a rare, benign syndrome characterized by hyperinsulinaemia and hypoglycaemia associated with the presence of autoantibodies to insulin in patients who have not been treated with insulin. We report here the case of a 52-year-old patient with recurrent attacks of severe postprandial hypoglycaemia and we also present the effect of anti-insulin antibodies on insulin immunoassays. The patient was submitted to the following diagnostic tests: 5-h oral glucose tolerance test (OGTT), a prolonged 72-h fast and an insulin tolerance test (ITT). Serum glucose, total and free insulin, C-peptide, proinsulin, insulin antibodies and other autoantibodies were measured. Insulin concentrations were measured by two methods: a double antibody radioimmunoassay (RIA) and an immunoradiometric assay (IRMA). Insulin concentration measured by RIA was extremely high in the OGTT and 72-h fast. In contrast, insulin concentrations measured by IRMA were between 120 and 888 pmol/L in the OGTT and between 37 and 133 pmol/L during the 72-h fast. Fasting free-insulin concentrations measured by RIA were between 2224 and 2669 pmol/L, whereas free-insulin concentrations measured by IRMA ranged between 93 and 237 pmol/L. Total insulin concentrations measured by RIA and IRMA were 57,615 and 94,021 pmol/L, respectively. The C-peptide concentrations were moderately high in the three tests. Serum insulin antibody concentrations were extremely high (62-71%), compared with less than 3% in normal serum samples. In conclusion, the high insulin concentrations measured by RIA were caused by insulin autoantibodies. However, insulin concentrations measured by IRMA were not influenced by them. We conclude that IRMA is the more accurate method for measuring insulin concentrations in such cases.

  9. Insulin-producing cells.

    PubMed

    Schroeder, Insa S; Kania, Gabriela; Blyszczuk, Przemyslaw; Wobus, Anna M

    2006-01-01

    Embryonic stem (ES) cells offer great potential for cell replacement and tissue engineering therapies because of their almost unlimited proliferation capacity and the potential to differentiate into cellular derivatives of all three primary germ layers. This chapter describes a strategy for the in vitro differentiation of mouse ES cells into insulin-producing cells. The three-step protocol does not select for nestin-expressing cells as performed in previous differentiation systems. It includes (1) the spontaneous differentiation of ES cells via embryoid bodies and (2) the formation of progenitor cells of all three primary germ layers (multilineage progenitors) followed by (3) directed differentiation into the pancreatic lineage. The application of growth and extracellular matrix factors, including laminin, nicotinamide, and insulin, leads to the development of committed pancreatic progenitors, which subsequently differentiate into islet-like clusters that release insulin in response to glucose. During differentiation, transcript levels of pancreas-specific transcription factors (i.e., Pdx1, Pax4) and of genes specific for early and mature beta cells, including insulin, islet amyloid pancreatic peptide, somatostatin, and glucagon, are upregulated. C-peptide/insulin-positive islet-like clusters are formed, which release insulin in response to high glucose concentrations at terminal stages. The differentiated cells reveal functional properties with respect to voltage-activated Na+ and ATP-modulated K+ channels and normalize blood glucose levels in streptozotocin-treated diabetic mice. In conclusion, we demonstrate the efficient differentiation of murine ES cells into insulin-producing cells, which may help in the future to establish ES cell-based therapies in diabetes mellitus.

  10. Effect of aminated gelatin on the nasal absorption of insulin in rats.

    PubMed

    Seki, Toshinobu; Kanbayashi, Hiroshi; Nagao, Tomonobu; Chono, Sumio; Tomita, Mikio; Hayashi, Masahiro; Tabata, Yasuhiko; Morimoto, Kazuhiro

    2005-03-01

    Absorption enhancers, which increase the permeability of drugs through epithelial membranes without damaging them, are especially useful for intranasal administration of peptide drugs. In this study, aminated gelatins, candidate enhancers, having different numbers of amino groups were prepared from gelatin (H-gelatin, isoelectric point = 9.0, MW 100 kDa) and a partial gelatin hydrolysate (L-gelatin, isoelectric point = 8.0, MW 5 kDa), and the enhancing effects on the nasal absorption of insulin, used as a model peptide drug, and 5(6)-carboxyfluorescein (CF), a paracellular marker, were examined in rats. The enhancing effect on insulin and CF depends on the MW and number of amino groups. A high correlation between the enhancing effects on insulin and CF was observed and this suggests that an increase in the paracellular permeability is the mechanism governing the nasal absorption-enhancement of aminated gelatins, at least as far as insulin and CF are concerned. The enhancing mechanism might be shared with other cationic polymers having absorption-enhancing effects.

  11. A novel permeation enhancer: N-succinyl chitosan on the intranasal absorption of isosorbide dinitrate in rats.

    PubMed

    Na, Lidong; Wang, Juan; Wang, Linlin; Mao, Shirui

    2013-01-23

    The purpose of this paper is to study the potential of N-succinyl chitosan as a novel permeation enhancer for the intranasal absorption of isosorbide dinitrate (ISDN). A series of N-succinyl chitosan (NSCS) with different degree of succinylation (DS) and molecular weight were synthesized. An in situ nasal perfusion technique in rats was utilized to investigate the effect of NSCS substitution degree, NSCS molecular weight and concentration on the intranasal absorption of ISDN. The absorption enhancing effect of NSCS was compared with that of chitosan. It was found that all the NSCS investigated improved the intranasal absorption of ISDN remarkably. Better promoting effect was observed for 0.1% NSCS 50 (63) compared with 0.5% chitosan 50. In nasal ciliotoxicity test, both NSCS and chitosan investigated showed good safety profiles. Thereafter, in vivo studies of the selected formulations were carried out in rats and the pharmacokinetic parameters were calculated and compared with that of intravenous injection. Both in situ and in vivo studies demonstrated that NSCS is more effective than chitosan in promoting intranasal absorption of ISDN. Taking both absorption enhancing and safety reason into account, we suggest NSCS is a promising intranasal absorption enhancer.

  12. Intranasal nerve growth factor bypasses the blood-brain barrier and affects spinal cord neurons in spinal cord injury

    PubMed Central

    Aloe, Luigi; Bianchi, Patrizia; De Bellis, Alberto; Soligo, Marzia; Rocco, Maria Luisa

    2014-01-01

    The purpose of this work was to investigate whether, by intranasal administration, the nerve growth factor bypasses the blood-brain barrier and turns over the spinal cord neurons and if such therapeutic approach could be of value in the treatment of spinal cord injury. Adult Sprague-Dawley rats with intact and injured spinal cord received daily intranasal nerve growth factor administration in both nostrils for 1 day or for 3 consecutive weeks. We found an increased content of nerve growth factor and enhanced expression of nerve growth factor receptor in the spinal cord 24 hours after a single intranasal administration of nerve growth factor in healthy rats, while daily treatment for 3 weeks in a model of spinal cord injury improved the deficits in locomotor behaviour and increased spinal content of both nerve growth factor and nerve growth factor receptors. These outcomes suggest that the intranasal nerve growth factor bypasses blood-brain barrier and affects spinal cord neurons in spinal cord injury. They also suggest exploiting the possible therapeutic role of intranasally delivered nerve growth factor for the neuroprotection of damaged spinal nerve cells. PMID:25206755

  13. Sedation and physiologic response to manual restraint after intranasal administration of midazolam in Hispaniolan Amazon parrots (Amazona ventralis).

    PubMed

    Mans, Christoph; Guzman, David Sanchez-Migallon; Lahner, Lesanna L; Paul-Murphy, Joanne; Sladky, Kurt K

    2012-09-01

    Administration of intranasal midazolam (2 mg/kg) was evaluated for sedation and effects on cloacal temperature, respiratory rate, and heart rate in manually restrained Hispaniolan Amazon parrots (Amazona ventralis). Adult parrots (n=9) were administered either midazolam (2 mg/kg) or an equal volume of saline solution intranasally before a 15-minute manual restraint in a complete crossover study. Respiratory rate and sedation scores were recorded before and during capture and during and after 15 minutes of manual restraint. Heart rate and cloacal temperature were recorded during manual restraint. After restraint, the parrots received intranasal flumazenil (0.05 mg/kg) or an equal volume of saline solution, and the recovery time was recorded. In those birds that received midazolam, sedation was observed within 3 minutes of administration, and vocalization, flight, and defense responses were significantly reduced during capture. During manual restraint, the mean rate of cloacal temperature increase was significantly slower and remained significantly lower in birds that received midazolam compared with controls. Mean respiratory rates were significantly lower for up to 12 minutes in parrots that received midazolam compared with those receiving saline solution. Flumazenil antagonized the effects of midazolam within 10 minutes. No overt clinical adverse effects to intranasal midazolam and flumazenil administration were observed. Further studies on the safety of intranasal midazolam and flumazenil in this species are warranted.

  14. Intranasal Inoculation of White-Tailed Deer (Odocoileus virginianus) with Lyophilized Chronic Wasting Disease Prion Particulate Complexed to Montmorillonite Clay

    PubMed Central

    Nichols, Tracy A.; Spraker, Terry R.; Rigg, Tara D.; Meyerett-Reid, Crystal; Hoover, Clare; Michel, Brady; Bian, Jifeng; Hoover, Edward; Gidlewski, Thomas; Balachandran, Aru; O'Rourke, Katherine; Telling, Glenn C.; Bowen, Richard

    2013-01-01

    Chronic wasting disease (CWD), the only known prion disease endemic in wildlife, is a persistent problem in both wild and captive North American cervid populations. This disease continues to spread and cases are found in new areas each year. Indirect transmission can occur via the environment and is thought to occur by the oral and/or intranasal route. Oral transmission has been experimentally demonstrated and although intranasal transmission has been postulated, it has not been tested in a natural host until recently. Prions have been shown to adsorb strongly to clay particles and upon oral inoculation the prion/clay combination exhibits increased infectivity in rodent models. Deer and elk undoubtedly and chronically inhale dust particles routinely while living in the landscape while foraging and rutting. We therefore hypothesized that dust represents a viable vehicle for intranasal CWD prion exposure. To test this hypothesis, CWD-positive brain homogenate was mixed with montmorillonite clay (Mte), lyophilized, pulverized and inoculated intranasally into white-tailed deer once a week for 6 weeks. Deer were euthanized at 95, 105, 120 and 175 days post final inoculation and tissues examined for CWD-associated prion proteins by immunohistochemistry. Our results demonstrate that CWD can be efficiently transmitted utilizing Mte particles as a prion carrier and intranasal exposure. PMID:23671598

  15. Ancillary therapy of intranasal T-LysYal® for patients with allergic, non-allergic, and mixed rhinitis.

    PubMed

    Gelardi, M; Taliente, S; Fiorella, M L; Quaranta, N; Ciancio, G; Russo, C; Mola, P; Ciofalo, A; Zambetti, G; Caruso Armone, A; Cantone, E; Ciprandi, G

    2016-01-01

    Allergic rhinitis (AR) is caused by an IgE-mediated inflammatory reaction. Non-allergic rhinitis (NAR) is characterized by a non-IgE-mediated pathogenesis. Frequently, patients have the two disorders associated: such as mixed rhinitis (MR). Hyaluronic acid (HA) is a fundamental component of the human connective tissue. HA may exert anti-inflammatory and immune-modulating activities. Recently, an intranasal HA formulation was proposed: a supramolecular system containing lysine hyaluronate, thymine and sodium chloride (T-LysYal®). This randomized study investigated whether intranasal T-LysYal® (rinoLysYal®, Farmigea, Italy) was able to reduce symptom severity, endoscopic features, and nasal cytology in 89 patients (48 males and 41 females, mean age 36.3±7.1 years) with AR, NAR, and MR. Patients were treated with intranasal T-LysYal® or isotonic saline solution as adjunctive therapy to nasal corticosteroid and oral antihistamine for 4 weeks. Patients were visited at baseline, after treatment and after 4-week follow-up. Intranasal T-LysYal® treatment significantly reduced the quote of patients with symptoms, endoscopic features, and inflammatory cells. In conclusion, the present study demonstrates that intranasal T-LysYal® is able, as ancillary therapy, to significantly improve patients with AR, NAR, and MR, and its effect is long lasting. PMID:27049100

  16. Epidural anaesthesia through caudal catheters for inguinal herniotomies in awake ex-premature babies.

    PubMed

    Peutrell, J M; Hughes, D G

    1993-02-01

    Ex-premature babies are at risk of apnoea after surgery. Regional anaesthesia has been used as an alternative to general anaesthesia for some surgical procedures in the belief that it may be safer. However, single dose caudal epidural and subarachnoid anaesthetics have a duration of action which may be insufficient for some operations. The level and duration of anaesthesia can be extended if local anaesthetic is given through an epidural catheter. In addition, the dose needed to provide adequate anaesthesia may be lower because the local anaesthetic is given at an appropriate segmental level. We report our experience of caudal epidural anaesthesia in nine, awake ex-premature babies who were having inguinal herniotomies. The anaesthesia was excellent in six babies. Two babies cried briefly with peritoneal or spermatic cord traction. One other baby needed supplementation with nitrous oxide in oxygen in order to complete the surgery. The majority of babies slept throughout surgery. There were no reported postoperative complications.

  17. Neurons Differentiated from Transplanted Stem Cells Respond Functionally to Acoustic Stimuli in the Awake Monkey Brain.

    PubMed

    Wei, Jing-Kuan; Wang, Wen-Chao; Zhai, Rong-Wei; Zhang, Yu-Hua; Yang, Shang-Chuan; Rizak, Joshua; Li, Ling; Xu, Li-Qi; Liu, Li; Pan, Ming-Ke; Hu, Ying-Zhou; Ghanemi, Abdelaziz; Wu, Jing; Yang, Li-Chuan; Li, Hao; Lv, Long-Bao; Li, Jia-Li; Yao, Yong-Gang; Xu, Lin; Feng, Xiao-Li; Yin, Yong; Qin, Dong-Dong; Hu, Xin-Tian; Wang, Zheng-Bo

    2016-07-26

    Here, we examine whether neurons differentiated from transplanted stem cells can integrate into the host neural network and function in awake animals, a goal of transplanted stem cell therapy in the brain. We have developed a technique in which a small "hole" is created in the inferior colliculus (IC) of rhesus monkeys, then stem cells are transplanted in situ to allow for investigation of their integration into the auditory neural network. We found that some transplanted cells differentiated into mature neurons and formed synaptic input/output connections with the host neurons. In addition, c-Fos expression increased significantly in the cells after acoustic stimulation, and multichannel recordings indicated IC specific tuning activities in response to auditory stimulation. These results suggest that the transplanted cells have the potential to functionally integrate into the host neural network.

  18. Statistical Modeling and Analysis of Laser-Evoked Potentials of Electrocorticogram Recordings from Awake Humans

    PubMed Central

    Chen, Zhe; Ohara, Shinji; Cao, Jianting; Vialatte, François; Lenz, Fred A.; Cichocki, Andrzej

    2007-01-01

    This article is devoted to statistical modeling and analysis of electrocorticogram (ECoG) signals induced by painful cutaneous laser stimuli, which were recorded from implanted electrodes in awake humans. Specifically, with statistical tools of factor analysis and independent component analysis, the pain-induced laser-evoked potentials (LEPs) were extracted and investigated under different controlled conditions. With the help of wavelet analysis, quantitative and qualitative analyses were conducted regarding the LEPs' attributes of power, amplitude, and latency, in both averaging and single-trial experiments. Statistical hypothesis tests were also applied in various experimental setups. Experimental results reported herein also confirm previous findings in the neurophysiology literature. In addition, single-trial analysis has also revealed many new observations that might be interesting to the neuroscientists or clinical neurophysiologists. These promising results show convincing validation that advanced signal processing and statistical analysis may open new avenues for future studies of such ECoG or other relevant biomedical recordings. PMID:18369410

  19. Endocytic structures and synaptic vesicle recycling at a central synapse in awake rats.

    PubMed

    Körber, Christoph; Horstmann, Heinz; Sätzler, Kurt; Kuner, Thomas

    2012-12-01

    The synaptic vesicle (SV) cycle has been studied extensively in cultured cells and slice preparations, but not much is known about the roles and relative contributions of endocytic pathways and mechanisms of SV recycling in vivo, under physiological patterns of activity. We employed horseradish peroxidase (HRP) as an in vivo marker of endocytosis at the calyx of Held synapse in the awake rat. Ex vivo serial section scanning electron microscopy and 3D reconstructions revealed two categories of labelled structures: HRP-filled SVs and large cisternal endosomes. Inhibition of adaptor protein complexes 1 and 3 (AP-1, AP-3) by in vivo application of Brefeldin A (BFA) disrupted endosomal SV budding while SV recycling via clathrin-mediated endocytosis (CME) remained unaffected. In conclusion, our study establishes cisternal endosomes as an intermediate of the SV cycle and reveals CME and endosomal budding as the predominant mechanisms of SV recycling in a tonically active central synapse in vivo.

  20. The Dutch Linguistic Intraoperative Protocol: a valid linguistic approach to awake brain surgery.

    PubMed

    De Witte, E; Satoer, D; Robert, E; Colle, H; Verheyen, S; Visch-Brink, E; Mariën, P

    2015-01-01

    Intraoperative direct electrical stimulation (DES) is increasingly used in patients operated on for tumours in eloquent areas. Although a positive impact of DES on postoperative linguistic outcome is generally advocated, information about the neurolinguistic methods applied in awake surgery is scarce. We developed for the first time a standardised Dutch linguistic test battery (measuring phonology, semantics, syntax) to reliably identify the critical language zones in detail. A normative study was carried out in a control group of 250 native Dutch-speaking healthy adults. In addition, the clinical application of the Dutch Linguistic Intraoperative Protocol (DuLIP) was demonstrated by means of anatomo-functional models and five case studies. A set of DuLIP tests was selected for each patient depending on the tumour location and degree of linguistic impairment. DuLIP is a valid test battery for pre-, intraoperative and postoperative language testing and facilitates intraoperative mapping of eloquent language regions that are variably located.

  1. The Dutch Linguistic Intraoperative Protocol: a valid linguistic approach to awake brain surgery.

    PubMed

    De Witte, E; Satoer, D; Robert, E; Colle, H; Verheyen, S; Visch-Brink, E; Mariën, P

    2015-01-01

    Intraoperative direct electrical stimulation (DES) is increasingly used in patients operated on for tumours in eloquent areas. Although a positive impact of DES on postoperative linguistic outcome is generally advocated, information about the neurolinguistic methods applied in awake surgery is scarce. We developed for the first time a standardised Dutch linguistic test battery (measuring phonology, semantics, syntax) to reliably identify the critical language zones in detail. A normative study was carried out in a control group of 250 native Dutch-speaking healthy adults. In addition, the clinical application of the Dutch Linguistic Intraoperative Protocol (DuLIP) was demonstrated by means of anatomo-functional models and five case studies. A set of DuLIP tests was selected for each patient depending on the tumour location and degree of linguistic impairment. DuLIP is a valid test battery for pre-, intraoperative and postoperative language testing and facilitates intraoperative mapping of eloquent language regions that are variably located. PMID:25526520

  2. Neurons Differentiated from Transplanted Stem Cells Respond Functionally to Acoustic Stimuli in the Awake Monkey Brain.

    PubMed

    Wei, Jing-Kuan; Wang, Wen-Chao; Zhai, Rong-Wei; Zhang, Yu-Hua; Yang, Shang-Chuan; Rizak, Joshua; Li, Ling; Xu, Li-Qi; Liu, Li; Pan, Ming-Ke; Hu, Ying-Zhou; Ghanemi, Abdelaziz; Wu, Jing; Yang, Li-Chuan; Li, Hao; Lv, Long-Bao; Li, Jia-Li; Yao, Yong-Gang; Xu, Lin; Feng, Xiao-Li; Yin, Yong; Qin, Dong-Dong; Hu, Xin-Tian; Wang, Zheng-Bo

    2016-07-26

    Here, we examine whether neurons differentiated from transplanted stem cells can integrate into the host neural network and function in awake animals, a goal of transplanted stem cell therapy in the brain. We have developed a technique in which a small "hole" is created in the inferior colliculus (IC) of rhesus monkeys, then stem cells are transplanted in situ to allow for investigation of their integration into the auditory neural network. We found that some transplanted cells differentiated into mature neurons and formed synaptic input/output connections with the host neurons. In addition, c-Fos expression increased significantly in the cells after acoustic stimulation, and multichannel recordings indicated IC specific tuning activities in response to auditory stimulation. These results suggest that the transplanted cells have the potential to functionally integrate into the host neural network. PMID:27425612

  3. Astrocyte and microvascular imaging in awake animals using two-photon microscopy.

    PubMed

    Tran, Cam Ha T; Gordon, Grant R

    2015-04-01

    Neurovascular coupling is an important control mechanism in CBF regulation. New insights into the integrated relationship between synaptic activity, astrocytes Ca(2+) , and cerebral blood vessels using two-photon fluorescence imaging are slowly emerging. Here, we provide a brief overview of the current understandings and controversies regarding astrocytes in activity-dependent vasodilation. We highlight the key advantages and disadvantages of the in vitro and in vivo methodologies used to study this topic. In particular, we emphasize some of the drawbacks of acute brain slices as well as the confounding effects of anesthesia in in vivo preparations. To overcome these limitations, we discuss an emerging and important trend in imaging cell Ca(2+) and blood flow control in awake and behaving animals. This new approach may help resolve existing controversies on astrocyte control of arteriole diameter by providing a more physiologically relevant preparation to study CBF regulation.

  4. Irregular spiking of pyramidal neurons organizes as scale-invariant neuronal avalanches in the awake state.

    PubMed

    Bellay, Timothy; Klaus, Andreas; Seshadri, Saurav; Plenz, Dietmar

    2015-07-07

    Spontaneous fluctuations in neuronal activity emerge at many spatial and temporal scales in cortex. Population measures found these fluctuations to organize as scale-invariant neuronal avalanches, suggesting cortical dynamics to be critical. Macroscopic dynamics, though, depend on physiological states and are ambiguous as to their cellular composition, spatiotemporal origin, and contributions from synaptic input or action potential (AP) output. Here, we study spontaneous firing in pyramidal neurons (PNs) from rat superficial cortical layers in vivo and in vitro using 2-photon imaging. As the animal transitions from the anesthetized to awake state, spontaneous single neuron firing increases in irregularity and assembles into scale-invariant avalanches at the group level. In vitro spike avalanches emerged naturally yet required balanced excitation and inhibition. This demonstrates that neuronal avalanches are linked to the global physiological state of wakefulness and that cortical resting activity organizes as avalanches from firing of local PN groups to global population activity.

  5. Epidural anaesthesia through caudal catheters for inguinal herniotomies in awake ex-premature babies.

    PubMed

    Peutrell, J M; Hughes, D G

    1993-02-01

    Ex-premature babies are at risk of apnoea after surgery. Regional anaesthesia has been used as an alternative to general anaesthesia for some surgical procedures in the belief that it may be safer. However, single dose caudal epidural and subarachnoid anaesthetics have a duration of action which may be insufficient for some operations. The level and duration of anaesthesia can be extended if local anaesthetic is given through an epidural catheter. In addition, the dose needed to provide adequate anaesthesia may be lower because the local anaesthetic is given at an appropriate segmental level. We report our experience of caudal epidural anaesthesia in nine, awake ex-premature babies who were having inguinal herniotomies. The anaesthesia was excellent in six babies. Two babies cried briefly with peritoneal or spermatic cord traction. One other baby needed supplementation with nitrous oxide in oxygen in order to complete the surgery. The majority of babies slept throughout surgery. There were no reported postoperative complications. PMID:8460759

  6. Long-term optical imaging of intrinsic signals in anesthetized and awake monkeys

    NASA Astrophysics Data System (ADS)

    Roe, Anna W.

    2007-04-01

    Some exciting new efforts to use intrinsic signal optical imaging methods for long-term studies in anesthetized and awake monkeys are reviewed. The development of such methodologies opens the door for studying behavioral states such as attention, motivation, memory, emotion, and other higher-order cognitive functions. Long-term imaging is also ideal for studying changes in the brain that accompany development, plasticity, and learning. Although intrinsic imaging lacks the temporal resolution offered by dyes, it is a high spatial resolution imaging method that does not require application of any external agents to the brain. The bulk of procedures described here have been developed in the monkey but can be applied to the study of surface structures in any in vivo preparation.

  7. Pleural liquid clearance rate measured in awake sheep by the volume of dilution method

    SciTech Connect

    Broaddus, V.C.; Wiener-Kronish, J.P.; Berthiaume, Y.; Staub, N.C.

    1986-03-01

    The authors reported 24h clearance of mock pleural effusions measured terminally in sheep. To measure effusion volume at different times in the same sheep, they injected /sup 111/In-transferrin and measured its dilution. In 5 sheep with effusions of known sizes, the method was accurate to +/-10%. In 5 awake sheep, the authors injected 10 ml/kg of a 1% protein solution via a non-penetrating rib capsule. At 6h, the authors measured the volume by the dilution method and at 24h by direct recovery. The clearance rate in each animal was constant at 2.9-6.0%/h (average 4.8 +/- 1.3%/h). This new method gives a reliable two point clearance rate and requires fewer animals.

  8. Replicability and Heterogeneity of Awake Unrestrained Canine fMRI Responses

    PubMed Central

    Berns, Gregory S.; Brooks, Andrew; Spivak, Mark

    2013-01-01

    Previously, we demonstrated the possibility of fMRI in two awake and unrestrained dogs. Here, we determined the replicability and heterogeneity of these results in an additional 11 dogs for a total of 13 subjects. Based on an anatomically placed region-of-interest, we compared the caudate response to a hand signal indicating the imminent availability of a food reward to a hand signal indicating no reward. 8 of 13 dogs had a positive differential caudate response to the signal indicating reward. The mean differential caudate response was 0.09%, which was similar to a comparable human study. These results show that canine fMRI is reliable and can be done with minimal stress to the dogs. PMID:24324719

  9. Millisecond Coupling of Local Field Potentials to Synaptic Currents in the Awake Visual Cortex.

    PubMed

    Haider, Bilal; Schulz, David P A; Häusser, Michael; Carandini, Matteo

    2016-04-01

    The cortical local field potential (LFP) is a common measure of population activity, but its relationship to synaptic activity in individual neurons is not fully established. This relationship has been typically studied during anesthesia and is obscured by shared slow fluctuations. Here, we used patch-clamp recordings in visual cortex of anesthetized and awake mice to measure intracellular activity; we then applied a simple method to reveal its coupling to the simultaneously recorded LFP. LFP predicted membrane potential as accurately as synaptic currents, indicating a major role for synaptic currents in the relationship between cortical LFP and intracellular activity. During anesthesia, cortical LFP predicted excitation far better than inhibition; during wakefulness, it predicted them equally well, and visual stimulation further enhanced predictions of inhibition. These findings reveal a central role for synaptic currents, and especially inhibition, in the relationship between the subthreshold activity of individual neurons and the cortical LFP during wakefulness. PMID:27021173

  10. Irregular spiking of pyramidal neurons organizes as scale-invariant neuronal avalanches in the awake state.

    PubMed

    Bellay, Timothy; Klaus, Andreas; Seshadri, Saurav; Plenz, Dietmar

    2015-01-01

    Spontaneous fluctuations in neuronal activity emerge at many spatial and temporal scales in cortex. Population measures found these fluctuations to organize as scale-invariant neuronal avalanches, suggesting cortical dynamics to be critical. Macroscopic dynamics, though, depend on physiological states and are ambiguous as to their cellular composition, spatiotemporal origin, and contributions from synaptic input or action potential (AP) output. Here, we study spontaneous firing in pyramidal neurons (PNs) from rat superficial cortical layers in vivo and in vitro using 2-photon imaging. As the animal transitions from the anesthetized to awake state, spontaneous single neuron firing increases in irregularity and assembles into scale-invariant avalanches at the group level. In vitro spike avalanches emerged naturally yet required balanced excitation and inhibition. This demonstrates that neuronal avalanches are linked to the global physiological state of wakefulness and that cortical resting activity organizes as avalanches from firing of local PN groups to global population activity. PMID:26151674

  11. Imaging large-scale neural activity with cellular resolution in awake, mobile mice.

    PubMed

    Dombeck, Daniel A; Khabbaz, Anton N; Collman, Forrest; Adelman, Thomas L; Tank, David W

    2007-10-01

    We report a technique for two-photon fluorescence imaging with cellular resolution in awake, behaving mice with minimal motion artifact. The apparatus combines an upright, table-mounted two-photon microscope with a spherical treadmill consisting of a large, air-supported Styrofoam ball. Mice, with implanted cranial windows, are head restrained under the objective while their limbs rest on the ball's upper surface. Following adaptation to head restraint, mice maneuver on the spherical treadmill as their heads remain motionless. Image sequences demonstrate that running-associated brain motion is limited to approximately 2-5 microm. In addition, motion is predominantly in the focal plane, with little out-of-plane motion, making the application of a custom-designed Hidden-Markov-Model-based motion correction algorithm useful for postprocessing. Behaviorally correlated calcium transients from large neuronal and astrocytic populations were routinely measured, with an estimated motion-induced false positive error rate of <5%.

  12. Neural oscillation, network, eloquent cortex and epileptogenic zone revealed by magnetoencephalography and awake craniotomy

    PubMed Central

    Idris, Zamzuri; Kandasamy, Regunath; Reza, Faruque; Abdullah, Jafri M.

    2014-01-01

    Background: Magnetoencephalography (MEG) is a method of functional neuroimaging. The concomitant use of MEG and electrocorticography has been found to be useful in elucidating neural oscillation and network, and to localize epileptogenic zone and functional cortex. We describe our early experience using MEG in neurosurgical patients, emphasizing on its impact on patient management as well as the enrichment of our knowledge in neurosciences. Materials and Methods: A total of 10 subjects were included; five patients had intraaxial tumors, one with an extraaxial tumor and brain compression, two with arteriovenous malformations, one with cerebral peduncle hemorrhage and one with sensorimotor cortical dysplasia. All patients underwent evoked and spontaneous MEG recordings. MEG data was processed at band-pass filtering frequency of between 0.1 and 300 Hz with a sampling rate of 1 kHz. MEG source localization was performed using either overdetermined equivalent current dipoles or underdetermined inversed solution. Neuromag collection of events software was used to study brain network and epileptogenic zone. The studied data were analyzed for neural oscillation in three patients; brain network and clinical manifestation in five patients; and for the location of epileptogenic zone and eloquent cortex in two patients. Results: We elucidated neural oscillation in three patients. One demonstrated oscillatory phenomenon on stimulation of the motor-cortex during awake surgery, and two had improvement in neural oscillatory parameters after surgery. Brain networks corresponding to clinico-anatomical relationships were depicted in five patients, and two networks were illustrated here. Finally, we demonstrated epilepsy cases in which MEG data was found to be useful in localizing the epileptogenic zones and functional cortices. Conclusion: The application of MEG while enhancing our knowledge in neurosciences also has a useful role in epilepsy and awake surgery. PMID:25685205

  13. Long-term facilitation of ventilation following repeated hypoxic episodes in awake goats.

    PubMed Central

    Turner, D L; Mitchell, G S

    1997-01-01

    1. This study tested two hypotheses: (1) that episodic hypoxia elicits long-term facilitation (LTF) in respiratory neurons that is manifest as an increase in ventilation in awake goats; and (2) that LTF causes complex changes in respiratory pattern which are responsible for the increase in ventilation. 2. Each goat participated in two protocols. In the first, inspired gas mixtures were alternated between isocapnic normoxia and hypoxia (arterial partial pressure of oxygen, Pa,O2 = 47 mmHg) for ten cycles. Each hypoxic episode lasted 3 min and normoxic intervals were 5 min. Ventilatory variables were measured during the last minute of each episode and periodically for up to 1 h following the last hypoxic episode. The second, sham protocol was undertaken at least 2 weeks later and was identical to the first, except that isocapnic hypoxia was replaced with normoxia. 3. Inspired ventilation (VI) increased during the first isocapnic hypoxic episode and reached progressively higher levels in subsequent hypoxic episodes. VI also increased progressively among normoxic intervals, such that by the tenth normoxic interval, it had increased 68% relative to the comparable sham value (P < 0.05). Respiratory frequency (FR), tidal volume and mean inspiratory flow all contributed to the augmented VI during both isocapnic normoxia and hypoxia. The increase in VI lasted up to 40 min after the final hypoxic episode, with an increased FR making the greatest contribution. The persistent increase in VI strongly suggests that episodic hypoxia elicits LTF in respiratory neurons in the awake goat. Complex changes in respiratory pattern underpin the ventilatory manifestation of LTF. PMID:9080380

  14. Activity patterns of the diaphragm during voluntary movements in awake cats.

    PubMed

    Uga, Minako; Niwa, Masatoshi; Ochiai, Naoyuki; Sasaki, Sei-Ichi

    2010-05-01

    The diaphragm is an important inspiratory muscle, and is also known to participate in the postural function. However, the activity of the diaphragm during voluntary movements has not been fully investigated in awake animals. In order to investigate the diaphragmatic activity during voluntary movements such as extending or rotating their body, we analyzed the electromyogram (EMG) of the diaphragm and trunk muscles in the cat using a technique for simultaneous recordings of EMG signals and video images. Periodic respiratory discharges occurred in the left and right costal diaphragm when the cat kept still. However, once the cat moved, their periodicity and/or synchrony were sometimes buried by non-respiratory activity. Such non-periodic diaphragmatic activities during voluntary movements are considered as the combination of respiratory activity and non-respiratory activity. Most of the diaphragmatic activities started shortly after the initiation of standing-up movements and occurred after the onset of trunk muscle activities. Those activities were more active compared to the normal respiratory activity. During rotation movements, left and right diaphragmatic activities showed asymmetrical discharge patterns and higher discharges than those during the resting situation. This asymmetrical activity may be caused by taking different lengths of each side of the diaphragm and trunk muscles. During reaching movements, the diaphragmatic activity occurred prior to or with the onset of trunk muscle activities. It is likely that diaphragmatic activities during reaching movements and standing-up movements may have been controlled by some different control mechanisms of the central nervous system. This study will suggest that the diaphragmatic activity is regulated not only by the respiratory center but also by inputs from the center for voluntary movements and/or sensory reflex pathways under the awake condition.

  15. Continuous thoracic epidural anesthesia induces segmental sympathetic block in the awake rat.

    PubMed

    Freise, Hendrik; Anthonsen, Sören; Fischer, Lars G; Van Aken, Hugo K; Sielenkämper, Andreas W

    2005-01-01

    Thoracic epidural anesthesia (TEA) is used increasingly in critical care, especially for cardiac and intestinal sympathetic block. In this study we evaluated cardiorespiratory function and sympathetic activity in a new model of continuous TEA in awake rats. Thirteen rats received epidural saline control (CON) or bupivacaine 0.5% epidural infusion (EPI) at 15 microl/h for 2 h on day 1 and day 3. Mean arterial blood pressure, heart rate, respiration rate, arterial PCO2, and motor score were recorded at baseline and after 30, 60, 90, and 120 min. Skin temperature was measured at front paws, high-thoracic, mid-thoracic, and low-thoracic, hind paws, and the proximal and distal tail. Changes in sympathetic activity were assessed by skin temperature changes from baseline (DeltaT). In the EPI group, hemodynamics and respiration remained unchanged and only mild motor deficits occurred. DeltaT in thoracic segments was higher in the EPI than in the CON group (P <0.001 at all times at high-thoracic, mid-thoracic, and low-thoracic segments). Skin temperature decreased in the distal tail in the EPI group, e.g., after 90 min DeltaT=-0.86 +/- 0.25 degrees C (EPI) versus 0.4 +/- 0.12 degrees C (CON) (P <0.05 at 60, 90, and 120 min). DeltaT on day 3 was comparable to day 1. TEA induced stable segmental sympathetic block without cardiorespiratory and motor side effects in awake rats. This new technique may be applied in prolonged models of critical illness. PMID:15616087

  16. New Insulins and New Aspects in Insulin Delivery.

    PubMed

    Woo, Vincent C

    2015-08-01

    The major abnormality in both type 1 and type 2 diabetes is insulin deficiency. The methods of replacing insulin have improved throughout the decades, but hypoglycemia is still the limiting factor for many individuals with diabetes, and it prevents them from achieving ideal glycemic targets. New insulin and newer delivery systems are being developed that can improve some of the limitations of current insulins or make the delivery of insulins more acceptable for some patients. Extending the duration of action of basal insulins and shortening the peak of fast-acting insulins may have advantages for individuals with diabetes. Different delivery systems may make insulin more acceptable to patients and may have other advantages, which may aid in attaining better glycemic control.

  17. New Insulins and New Aspects in Insulin Delivery.

    PubMed

    Woo, Vincent C

    2015-08-01

    The major abnormality in both type 1 and type 2 diabetes is insulin deficiency. The methods of replacing insulin have improved throughout the decades, but hypoglycemia is still the limiting factor for many individuals with diabetes, and it prevents them from achieving ideal glycemic targets. New insulin and newer delivery systems are being developed that can improve some of the limitations of current insulins or make the delivery of insulins more acceptable for some patients. Extending the duration of action of basal insulins and shortening the peak of fast-acting insulins may have advantages for individuals with diabetes. Different delivery systems may make insulin more acceptable to patients and may have other advantages, which may aid in attaining better glycemic control. PMID:26233724

  18. Molecular Mechanisms of Insulin Secretion and Insulin Action.

    ERIC Educational Resources Information Center

    Flatt, Peter R.; Bailey, Clifford J.

    1991-01-01

    Information and current ideas on the factors regulating insulin secretion, the mechanisms underlying the secretion and biological actions of insulin, and the main characteristics of diabetes mellitus are presented. (Author)

  19. Intranasal nanoparticles of basic fibroblast growth factor for brain delivery to treat Alzheimer's disease.

    PubMed

    Zhang, Chi; Chen, Jie; Feng, Chengcheng; Shao, Xiayan; Liu, Qingfeng; Zhang, Qizhi; Pang, Zhiqing; Jiang, Xinguo

    2014-01-30

    Disabilities caused by neurodegeneration have become one of the main causes of mortality in elderly population, with drug distribution to the brain remaining one of the most difficult challenges in the treatment of the central nervous system (CNS) diseases due to the existence of blood-brain barrier. Lectins modified polyethylene glycol-polylactide-polyglycolide (PEG-PLGA) nanoparticles could enhance the drug delivery to the brain following intranasal administration. In this study, basic fibroblast growth factor (bFGF) was entrapped in nanoparticles conjugated with Solanum tuberosum lectin (STL), which selectively binds to N-acetylglucosamine on the nasal epithelial membrane for its brain delivery. The resulting nanoparticles had uniform particle size and negative zeta potential. The brain distribution of the formulations following intranasal administration was assessed using radioisotopic tracing method. The areas under the concentration-time curve of (125)I-bFGF in the olfactory bulb, cerebrum, and cerebellum of rats following nasal application of STL modified nanoparticles (STL-bFGF-NP) were 1.79-5.17 folds of that of rats with intravenous administration, and 0.61-2.21 and 0.19-1.07 folds higher compared with intranasal solution and unmodified nanoparticles, respectively. Neuroprotective effect was evaluated using Mirror water maze task in rats with intracerebroventricular injection of β-amyloid25-35 and ibotenic acid. The spatial learning and memory of Alzheimer's disease (AD) rats in STL-bFGF-NP group were significantly improved compared with AD model group, and were also better than other preparations. The results were consistent with the value of choline acetyltransferase activity of rat hippocampus as well as the histological observations of rat hippocampal region. The histopathology assays also confirmed the in vivo safety of STL-bFGF-NP. These results clearly indicated that STL-NP was a promising drug delivery system for peptide and protein drugs such as

  20. Comparison of Oral Montelukast and Intranasal Fluticasone in Patients with Asthma and Allergic Rhinitis

    PubMed Central

    Jindal, Apar; Sagadevan, Suresh; Narasimhan, Meenakshi; Shanmuganathan, Aruna; Vallabhaneni, Viswambhar; Rajalingam, Ragulan

    2016-01-01

    Introduction Even though the links between upper and lower airway had been of interest to clinicians since long back, it has not attracted the attention of the researchers till recent past. But the evidence is still far from conclusive, due to limited number of randomized controlled trials available on subjects with concomitant allergic rhinitis and asthma. This gap in the knowledge is even more conspicuous in Indian population. Aim The current study is conducted with an objective of comparing the efficacy and tolerability of intranasal Fluticasone and oral Montelukast in treatment of allergic rhinitis and bronchial asthma. Materials and Methods The study was a prospective randomized, single blinded, comparative, parallel group study, with two intervention groups conducted in a tertiary teaching hospital in Chennai, Southern India. One hundred and twenty patients diagnosed with concomitant diagnosis of allergic rhinitis and bronchial asthma was randomly allocated to either Fluticasone propionate aqueous nasal spray or oral Montelukast group. Results Out of total 120 subjects recruited, 108 subjects were included in the final analysis. The mean reduction in asthma and rhinitis symptom scores and improvement in PEFR was higher for Group A, compared to Group B during all the follow-up periods. No statistically significant difference was observed in proportion of subjects reporting exacerbations in the current study. Both the treatments were well tolerated. Conclusion Addition of intranasal Fluticasone propionate to Salmeterol plus Fluticasone is beneficial in improving asthma control, allergic rhinitis control and lung functions as compared to oral Montelukast. Thereby the use of intranasal Fluticasone Propionate in comparison to oral Montelukast in control of Allergic Rhinitis is justified as per the significant improvement in outcome measures. PMID:27656477

  1. Responses to olfactory and intranasal trigeminal stimuli: relation to the respiratory cycle.

    PubMed

    Haehner, A; Gruenewald, G; Dibenedetto, M; Hummel, T

    2011-02-23

    The aim of the study was to investigate whether the perception of intranasal chemosensory stimuli changes in relation to the respiratory cycle. We investigated 40 healthy subjects with normal olfactory function who participated in four sessions. The first session was used to adapt subjects to the experimental conditions, and, specifically, to train a certain breathing technique (velopharyngeal closure) which prevents intranasal respiratory air-flow. In each of the following three sessions one of three stimulants was tested, namely phenyl ethyl alcohol (PEA), hydrogen sulfide (H(2)S), or the trigeminal stimulant carbon dioxide (CO(2)). The sequence of testing the three stimulants was randomized across all participants. Sessions were separated by at least 1 day. Chemosensory event-related potentials (ERP) were recorded in response to 80 stimuli each. Following each stimulus subjects rated its intensity using a computerized visual analogue scale. Respiration was recorded using a probe in front of the subjects' mouth. While presentation of chemosensory stimuli was performed independent of the respiratory cycle, responses were averaged off-line according to the subjects' respiratory phase when the stimuli had been presented. Intensity of olfactory or trigeminal stimuli did not differ significantly in relation to the respiratory cycle. Olfactory ERP to phenylethyl alcohol were larger when stimuli were presented during inspiration. Similarly, responses to H(2)S tended to be larger when stimuli were presented during inspiratory phases. In addition, responses to CO(2) were larger when stimuli were presented during inspiration. Differences in relation to the respiratory cycle were found specifically for early ERP components. It is important to note that the changes of chemosensory information processing were found in the absence of changes of intranasal airflow. These data indicate on an electrophysiological level that there is priming of both olfactory and trigeminally

  2. Comparison of preanesthetic sedation in pediatric patients with oral and intranasal midazolam

    PubMed Central

    Deshmukh, Purvashree Vijay; Kulkarni, Sadhana Sudhir; Parchandekar, Mukund Kachru; Sikchi, Sneha Purshottam

    2016-01-01

    Background and Aims: Preoperative anxiety in children leading to postoperative negative changes and long-term behavioral problems needs better preanesthetic sedation. Across the world, midazolam is the most commonly used premedicant in pediatric patients. The fact that no single route has achieved universal acceptance for its administration suggests that each route has its own merits and demerits. This study compares oral midazolam syrup and intranasal midazolam spray as painless and needleless systems of drug administration for preanesthetic sedation in children. Material and Methods: With randomization, Group O (30 children): Received oral midazolam syrup 0.5 mg/kg and Group IN (30 children): Received intranasal midazolam spray 0.2 mg/kg. Every child was observed for acceptance of drug, response to drug administration, sedation scale, separation score, acceptance to mask, recovery score and side effects of drug. Data were analyzed using Student's t-test, standard error of the difference between two means and Chi-square test. Results: In Group O and IN, 15/30 children (50%) and 7/30 children (23%) accepted drug easily (P < 0.05); 4/22 children (18%) in Group O and 11/20 children (55%) in Group IN cried after drug administration (P < 0.05). In both the groups, sedation at 20 min after premedication (Group O [80%] 24/30 vs. Group IN [77%] 23/30), parental separation and acceptance to mask were comparable (P > 0.05); 12/30 children (40%) in Group IN showed transient nasal irritation. Conclusion: Oral midazolam and intranasal midazolam spray produce similar anxiolysis and sedation, but acceptance of drug and response to drug administration is better with oral route. PMID:27625485

  3. Intranasal nanoparticles of basic fibroblast growth factor for brain delivery to treat Alzheimer's disease.

    PubMed

    Zhang, Chi; Chen, Jie; Feng, Chengcheng; Shao, Xiayan; Liu, Qingfeng; Zhang, Qizhi; Pang, Zhiqing; Jiang, Xinguo

    2014-01-30

    Disabilities caused by neurodegeneration have become one of the main causes of mortality in elderly population, with drug distribution to the brain remaining one of the most difficult challenges in the treatment of the central nervous system (CNS) diseases due to the existence of blood-brain barrier. Lectins modified polyethylene glycol-polylactide-polyglycolide (PEG-PLGA) nanoparticles could enhance the drug delivery to the brain following intranasal administration. In this study, basic fibroblast growth factor (bFGF) was entrapped in nanoparticles conjugated with Solanum tuberosum lectin (STL), which selectively binds to N-acetylglucosamine on the nasal epithelial membrane for its brain delivery. The resulting nanoparticles had uniform particle size and negative zeta potential. The brain distribution of the formulations following intranasal administration was assessed using radioisotopic tracing method. The areas under the concentration-time curve of (125)I-bFGF in the olfactory bulb, cerebrum, and cerebellum of rats following nasal application of STL modified nanoparticles (STL-bFGF-NP) were 1.79-5.17 folds of that of rats with intravenous administration, and 0.61-2.21 and 0.19-1.07 folds higher compared with intranasal solution and unmodified nanoparticles, respectively. Neuroprotective effect was evaluated using Mirror water maze task in rats with intracerebroventricular injection of β-amyloid25-35 and ibotenic acid. The spatial learning and memory of Alzheimer's disease (AD) rats in STL-bFGF-NP group were significantly improved compared with AD model group, and were also better than other preparations. The results were consistent with the value of choline acetyltransferase activity of rat hippocampus as well as the histological observations of rat hippocampal region. The histopathology assays also confirmed the in vivo safety of STL-bFGF-NP. These results clearly indicated that STL-NP was a promising drug delivery system for peptide and protein drugs such as

  4. Clinical development of an advanced intranasal delivery system of azelastine hydrochloride and fluticasone propionate.

    PubMed

    Derendorf, H; Meltzer, E O; Hermann, R; Canonica, G W

    2014-01-01

    There is no shortage of pharmacologic treatments available for the management of allergic rhinitis (AR), but none regularly provide full relief from all symptoms. MP29-02 (Dymista®) is a novel intranasal formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP), benefiting from an enhanced formulation and improved device characteristics compared to marketed intranasal corticosteroid (INS) formulations. Results from large, randomized, double-blind, placebo-controlled, head-to-head trials versus first-line therapies, confirmed MP29-02 as the evidence-based drug-of-choice for AR treatment. MP29-02 was twice as effective as AZE or FP for nasal and ocular symptom relief in moderate to severe seasonal AR patients, with superiority documented regardless of season, and in more severe patients. More MP29-02-treated patients experienced clinically relevant responses (i.e., halving of nasal symptom burden and complete/near-to-complete relief) days faster than those on INS or intranasal antihistamine monotherapy. MP29-02's efficacy was sustained long-term versus FP (up to 52 weeks) in chronic rhinitis patients (perennial AR or nonallergic rhinitis), with 7 out of 10 patients first becoming symptom-free following 1 month's treatment with MP29-02, and days faster than with the INS. These results confirm MP29-02's superiority over the historical gold-standard therapy for AR (i.e., INS), and position it now as first-line treatment for moderate to severe AR patients, the majority of whom are uncontrolled on existing medications. PMID:24524103

  5. Intrinsic intranasal chemosensory brain networks shown by resting-state functional MRI.

    PubMed

    Tobia, Michael J; Yang, Qing X; Karunanayaka, Prasanna

    2016-05-01

    The human brain is organized into functional networks for sensory-motor and cognitive processing. Intrinsic networks are detectable in the absence of stimulation or task demands, whereas extrinsic networks are detectable when stimulated by sensory or cognitive demands. Intranasal chemosensory processing relies on two dissociable networks for processing incoming trigeminal and olfactory stimulation, but it is not known whether these networks are intrinsically organized. The aim of this study was to identify whether brain networks for intranasal chemosensory processing are detectable in functional connectivity resting-state functional MRI (fMRI). Sixteen healthy adults participated in a 5-min resting-state fMRI study. Functional connectivity seeds were defined from coordinates that anchor olfactory (i.e. bilateral piriform and orbitofrontal cortex) and trigeminal (bilateral anterior insula and cingulate cortex) networks in published task activation studies, and the resulting networks were thresholded at P less than 0.001. The olfactory network showed extended functional connectivity to the thalamus, medial prefrontal cortex, caudate, nucleus accumbens, parahippocampal gyrus, and hippocampus. The trigeminal network showed extended functional connectivity to the precuneus, thalamus, caudate, brainstem, and cerebellum. Both networks overlapped in the thalamus, caudate, medial prefrontal cortex, and insula. These results show that brain networks for intranasal chemosensory processing are intrinsically organized, not just extrinsically instantiated in response to task demands, and resemble networks for processing olfactory and trigeminal stimulation. As such, it may be possible to study the functional organization and dynamics of the olfactory network in resting-state fMRI as well as its implications for aging and disease.

  6. Differential effects of intranasal oxytocin on sexual experiences and partner interactions in couples.

    PubMed

    Behnia, Behnoush; Heinrichs, Markus; Bergmann, Wiebke; Jung, Stefanie; Germann, Janine; Schedlowski, Manfred; Hartmann, Uwe; Kruger, Tillmann H C

    2014-03-01

    Knowledge about the effects of the neuropeptide oxytocin (OXT) on human sexual behaviors and partner interactions remains limited. Based on our previous studies, we hypothesize that OXT should be able to positively influence parameters of sexual function and couple interactions. Employing a naturalistic setting involving 29 healthy heterosexual couples (n=58 participants), we analyzed the acute effects of intranasally administered OXT (24IU) on sexual drive, arousal, orgasm and refractory aspects of sexual behavior together with partner interactions. Data were assessed by psychometric instruments (Acute Sexual Experiences Scale, Arizona Sexual Experience Scale) as well as biomarkers, such as cortisol, α-amylase and heart rate. Intranasal OXT administration did not alter "classical" parameters of sexual function, such as sexual drive, arousal or penile erection and lubrication. However, analysis of variance and a hierarchical linear model (HLM) revealed specific effects related to the orgasmic/post-orgasmic interval as well as parameters of partner interactions. According to HLM analysis, OXT increased the intensity of orgasm, contentment after sexual intercourse and the effect of study participation. According to ANOVA analysis, these effects were more pronounced in men. Men additionally indicated higher levels of sexual satiety after sexual intercourse with OXT administration. Women felt more relaxed and subgroups indicated better abilities to share sexual desires or to empathize with their partners. The effect sizes were small to moderate. Biomarkers indicated moderate psychophysiological activation but were not affected by OXT, gender or method of contraception. Using a naturalistic setting, intranasal OXT administration in couples exerted differential effects on parameters of sexual function and partner interactions. These results warrant further investigations, including subjects with sexual and relationship problems.

  7. Effect of intranasal manganese administration on neurotransmission and spatial learning in rats

    SciTech Connect

    Blecharz-Klin, Kamilla; Piechal, Agnieszka; Joniec-Maciejak, Ilona; Pyrzanowska, Justyna; Widy-Tyszkiewicz, Ewa

    2012-11-15

    The effect of intranasal manganese chloride (MnCl{sub 2}·4H{sub 2}O) exposure on spatial learning, memory and motor activity was estimated in Morris water maze task in adult rats. Three-month-old male Wistar rats received for 2 weeks MnCl{sub 2}·4H{sub 2}O at two doses the following: 0.2 mg/kg b.w. (Mn0.2) or 0.8 mg/kg b.w. (Mn0.8) per day. Control (Con) and manganese-exposed groups were observed for behavioral performance and learning in water maze. ANOVA for repeated measurements did not show any significant differences in acquisition in the water maze between the groups. However, the results of the probe trial on day 5, exhibited spatial memory deficits following manganese treatment. After completion of the behavioral experiment, the regional brain concentrations of neurotransmitters and their metabolites were determined via HPLC in selected brain regions, i.e. prefrontal cortex, hippocampus and striatum. ANOVA demonstrated significant differences in the content of monoamines and metabolites between the treatment groups compared to the controls. Negative correlations between platform crossings on the previous platform position in Southeast (SE) quadrant during the probe trial and neurotransmitter turnover suggest that impairment of spatial memory and cognitive performance after manganese (Mn) treatment is associated with modulation of the serotonergic, noradrenergic and dopaminergic neurotransmission in the brain. These findings show that intranasally applied Mn can impair spatial memory with significant changes in the tissue level and metabolism of monoamines in several brain regions. -- Highlights: ► Intranasal exposure to manganese in rats impairs spatial memory in the water maze. ► Regional changes in levels of neurotransmitters in the brain have been identified. ► Cognitive disorder correlates with modulation of 5-HT, NA and DA neurotransmission.

  8. Pharmacokinetics and brain uptake of diazepam after intravenous and intranasal administration in rats and rabbits.

    PubMed

    Kaur, Paramjeet; Kim, Kwonho

    2008-11-19

    The purpose of this study was to investigate the plasma pharmacokinetics and brain uptake of a lipophilic benzodiazepine anticonvulsant, diazepam in New Zealand white rabbits and Sprague-Dawley rats to evaluate the possible absorption pathways after intravenous and intranasal administration. The intranasal formulation was prepared by dissolving DZ and 1% sodium glycocholate into microemulsion system composed of 15% ethyl laurate, 25% Labrasol, 37.5% Transcutol P, 12.5% ethanol, and 10% water. Diazepam was administered intravenously (1 mg/kg) or intranasally (2 mg/kg) to rats and rabbits. Drug concentrations in the plasma and six different regions of the brain tissues, i.e., olfactory bulb, olfactory tract, anterior, middle, and posterior segments of cerebrum and cerebellum were analyzed by LC/MS method after solid phase extraction. After i.n. administration, DZ was rapidly absorbed into the systemic circulation, and readily and homogeneously distributed into the different regions of brain tissues with a t(max) of 5 and 10 min in rats and rabbits, respectively. The bioavailability of DZ in rat plasma (68.4%) and brain (67.7%) were 32-47% higher than those observed in rabbit plasma (51.6%) and brain (45.9%). The AUC(brain)/AUC(plasma) ratios in rabbits after i.n. administration (3.77+/-0.17) were slightly lower than from i.v. administration (4.23+/-0.08). However, in rats the AUC(brain)/AUC(plasma) ratios after i.v. (3.03+/-0.07) and i.n. (3.00+/-0.32) administration were nearly identical. The plasma pharmacokinetic and distribution studies in the two animal models clearly showed that lipophilic DZ molecules reached the brain predominantly from the blood by crossing the blood-brain barrier after i.n. administration with no significant direct nose-to-brain transport via olfactory epithelium.

  9. Development and evaluation of brain targeted intranasal alginate nanoparticles for treatment of depression.

    PubMed

    Haque, Shadabul; Md, Shadab; Sahni, Jasjeet Kaur; Ali, Javed; Baboota, Sanjula

    2014-01-01

    The purpose of the present study was to investigate the potential of Venlafaxine loaded alginate nanoparticles (VLF AG-NPs) for treatment of depression via intranasal (i.n.) nose to brain delivery route. The VLF AG-NPs were prepared and optimized on the basis of various physio-chemical characteristics. Pharmacodynamic studies of the VLF AG-NPs for antidepressant activity were carried in-vivo by forced swimming test and locomotor activity test on albino Wistar rats. VLF AG-NPsi.n. treatment significantly improved the behavioural analysis parameters i.e. swimming, climbing, and immobility in comparison to the VLF solutioni.n. and VLF tabletoral. The intranasal VLF AG-NPs also improved locomotor activity when compared with VLF solutioni.n. and VLF tabletoral. Confocal laser scanning fluorescence microscopy studies were performed on isolated organs of rats after intravenous and intranasal administrations of Rodamine-123 loaded alginate nanoparticles to determine its efficacy for nose to brain delivery and also for its qualitative distribution to other organs. Brain uptake and pharmacokinetic studies were performed by determination of VLF concentration in blood and brain respectively for VLF AG-NPsi.n., VLF solutioni.n. and VLF solutioni.v. The greater brain/blood ratios for VLF AG-NPsi.n. in comparison to VLF solutioni.n. and VLF solutioni.v. respectively at 30 min are indicative of superiority of alginate nanoparticles for direct nose to brain transport of VLF. Thus, VLF AG-NPsi.n. delivered greater VLF to the brain in comparison to VLF solution which indicates that VLF AG-NPs could be a promising approach for the treatment of depression.

  10. Locus coeruleus response to single-prolonged stress and early intervention with intranasal neuropeptide Y.

    PubMed

    Sabban, Esther L; Laukova, Marcela; Alaluf, Lishay G; Olsson, Emelie; Serova, Lidia I

    2015-12-01

    Dysregulation of the central noradrenergic system is a core feature of post-traumatic stress disorder (PTSD). Here, we examined molecular changes in locus coeruleus (LC) triggered by single-prolonged stress (SPS) PTSD model at a time when behavioral symptoms are manifested, and the effect of early intervention with intranasal neuropeptide Y (NPY). Immediately following SPS stressors, male SD rats were administered intranasal NPY (SPS/NPY) or vehicle (SPS/V). Seven days later, TH protein, but not mRNA, was elevated in LC only of the SPS/V group. Although 90% of TH positive cells expressed GR, its levels were unaltered. Compared to unstressed controls, LC of SPS/V, but not SPS/NPY, expressed less Y2 receptor mRNA with more CRHR1 mRNA in subset of animals, and elevated corticotropin-releasing hormone (CRH) in central nucleus of amygdala. Following testing for anxiety on elevated plus maze (EPM), there were significantly increased TH, DBH and NPY mRNAs in LC of SPS-treated, but not previously unstressed animals. Their levels highly correlated with each other but not with behavioral features on EPM. Thus, SPS triggers long-term noradrenergic activation and higher sensitivity to mild stressors, perhaps mediated by the up-regulation influence of amygdalar CRH input and down-regulation of Y2R presynaptic inhibition in LC. Results also demonstrate the therapeutic potential of early intervention with intranasal NPY for traumatic stress-elicited noradrenergic impairments. Single-prolonged stress (SPS)-triggered long-term changes in the locus coeruleus/norepinephrine (LC/NE) system with increased tyrosine hydroxylase (TH) protein and CRH receptor 1(CRHR1) mRNA and lower neuropeptide Y receptor 2 (Y2R) mRNA levels as well as elevated corticotropin-releasing hormone (CRH) in the central nucleus of amygdala (CeA) that were prevented by early intervention with intranasal neuropeptide Y (NPY). SPS treatment led to increased sensitivity of LC to mild stress of elevated plus maze

  11. No relevant modulation of TRPV1-mediated trigeminal pain by intranasal carbon dioxide in healthy humans

    PubMed Central

    2013-01-01

    Background Nasal insufflation of CO2 has been shown to exert antinociceptive respectively antihyperalgesic effects in animal pain models using topical capsaicin with activation of TRPV1-receptor positive nociceptive neurons. Clinical benefit from CO2 inhalation in patients with craniofacial pain caused by a putative activation of TRPV1 receptor positive trigeminal neurons has also been reported. These effects are probably mediated via an activation of TRPV1 receptor - positive neurons in the nasal mucosa with subsequent central inhibitory effects (such as conditioned pain modulation). In this study, we aimed to examine the effects of intranasal CO2 on a human model of craniofacial pain elicited by nasal application of capsaicin. Methods In a first experiment, 48 healthy volunteers without previous craniofacial pain received intranasal capsaicin to provoke trigeminal pain elicited by activation of TRVP1 positive nociceptive neurons. Then, CO2 or air was insufflated alternatingly into the nasal cavity at a flow rate of 1 l/min for 60 sec each. In the subsequent experiment, all participants were randomized into 2 groups of 24 each and received either continuous nasal insufflation of CO2 or placebo for 18:40 min after nociceptive stimulation with intranasal capsaicin. In both experiments, pain was rated on a numerical rating scale every 60 sec. Results Contrary to previous animal studies, the effects of CO2 on experimental trigeminal pain were only marginal. In the first experiment, CO2 reduced pain ratings only minimally by 5.3% compared to air if given alternatingly with significant results for the main factor GROUP (F1,47 = 4.438; p = 0.041) and the interaction term TIME*GROUP (F2.6,121.2 = 3.3; p = 0.029) in the repeated-measures ANOVA. However, these effects were abrogated after continuous insufflation of CO2 or placebo with no significant changes for the main factors or the interaction term. Conclusions Although mild modulatory effects of low

  12. Nasal vasomotor responses in man to breath holding and hyperventilation recorded by means of intranasal balloons.

    PubMed

    Babatola, F D; Eccles, R

    1986-12-01

    Nasal vasomotor responses were recorded in conscious human subjects by means of water filled balloons. Hyperventilation caused an increase in intranasal balloon pressure associated with vasodilatation whereas breath holding caused a decrease associated with vasoconstriction. The amplitude of the nasal vasomotor response was influenced by the nasal cycle with the greatest response always observed on the congested or low airflow side of the nose. The results suggest that an elevated arterial level of carbon dioxide causes a pronounced vasoconstruction of the nasal blood vessels and that this response may be clinically relevant in controlling nasal bleeding.

  13. Locus coeruleus response to single-prolonged stress and early intervention with intranasal neuropeptide Y.

    PubMed

    Sabban, Esther L; Laukova, Marcela; Alaluf, Lishay G; Olsson, Emelie; Serova, Lidia I

    2015-12-01

    Dysregulation of the central noradrenergic system is a core feature of post-traumatic stress disorder (PTSD). Here, we examined molecular changes in locus coeruleus (LC) triggered by single-prolonged stress (SPS) PTSD model at a time when behavioral symptoms are manifested, and the effect of early intervention with intranasal neuropeptide Y (NPY). Immediately following SPS stressors, male SD rats were administered intranasal NPY (SPS/NPY) or vehicle (SPS/V). Seven days later, TH protein, but not mRNA, was elevated in LC only of the SPS/V group. Although 90% of TH positive cells expressed GR, its levels were unaltered. Compared to unstressed controls, LC of SPS/V, but not SPS/NPY, expressed less Y2 receptor mRNA with more CRHR1 mRNA in subset of animals, and elevated corticotropin-releasing hormone (CRH) in central nucleus of amygdala. Following testing for anxiety on elevated plus maze (EPM), there were significantly increased TH, DBH and NPY mRNAs in LC of SPS-treated, but not previously unstressed animals. Their levels highly correlated with each other but not with behavioral features on EPM. Thus, SPS triggers long-term noradrenergic activation and higher sensitivity to mild stressors, perhaps mediated by the up-regulation influence of amygdalar CRH input and down-regulation of Y2R presynaptic inhibition in LC. Results also demonstrate the therapeutic potential of early intervention with intranasal NPY for traumatic stress-elicited noradrenergic impairments. Single-prolonged stress (SPS)-triggered long-term changes in the locus coeruleus/norepinephrine (LC/NE) system with increased tyrosine hydroxylase (TH) protein and CRH receptor 1(CRHR1) mRNA and lower neuropeptide Y receptor 2 (Y2R) mRNA levels as well as elevated corticotropin-releasing hormone (CRH) in the central nucleus of amygdala (CeA) that were prevented by early intervention with intranasal neuropeptide Y (NPY). SPS treatment led to increased sensitivity of LC to mild stress of elevated plus maze

  14. Intranasal administration of neuropeptide Y in man: systemic absorption and functional effects.

    PubMed Central

    Lacroix, J. S.; Ricchetti, A. P.; Morel, D.; Mossimann, B.; Waeber, B.; Grouzmann, E.

    1996-01-01

    1. Exogenous neuropeptide Y (NPY, 10 nmol, 50 nmol and 100 nmol) and its vehicle (NaCl 0.9%) were administered in a double blind, randomized and controlled manner by intranasal spray in 7 healthy volunteers. Variations of plasma NPY concentration over time were measured during 120 min. Forty min after the administration of 50 nmol and 100 nmol of exogenous NPY, plasma NPY increased from 5.5 +/- 1.1 pM to 9.8 +/- 2.3 pM (P < 0.05) and from 9.06 +/- 5.1 pM to 20.8 +/- 6.16 pM (P < 0.001), respectively. There was no significant modification of the mean arterial blood pressure and no subjective discomfort was reported. 2. Nasal airway resistance (NAR) was measured by anterior rhinomanometry and was reduced by 25 +/- 3% and 32 +/- 5% after the spray of 50 nmol and 100 nmol, respectively, for about 90 min. 3. Double-blind, randomized, placebo-controlled and 3-way crossover design experiments were performed in 8 healthy volunteers to evaluate the influence of intranasal pretreatment with NPY (20 nmol) and the mixed alpha 1/alpha 2-adrenoceptor agonist oxymetazoline (20 nmol) on the functional effects of subsequent local irritation evoked by capsaicin (3.3 x 10(-4) mol). Subjective evaluation of NAR and local intensity of discomfort were evaluated by means of a visual analogue scale. Nasal secretions were collected and objective NAR was recorded by rhinomanometry. 4. Subjective NAR, nasal secretions and rhinomanometry recordings were not modified by intranasal application of saline, NPY or oxymetazoline. Subjective nasal obstruction, local discomfort, nasal secretions and NAR increase evoked by capsaicin were markedly reduced by NPY pretreatment (P < 0.05) when compared to saline or oxymetazoline. 5. It is concluded that intranasal application of exogenous NPY has very low systemic absorption but induced long lasting nasal vasoconstriction without cardiovascular effects. Pretreatment of the nasal mucosa with exogenous NPY reduces both secretagogue and vasodilator responses

  15. Validation of a Best-Fit Pharmacokinetic Model for Scopolamine Disposition after Intranasal Administration

    NASA Technical Reports Server (NTRS)

    Wu, L.; Chow, D. S-L.; Tam, V.; Putcha, L.

    2015-01-01

    An intranasal gel formulation of scopolamine (INSCOP) was developed for the treatment of Motion Sickness. Bioavailability and pharmacokinetics (PK) were determined per Investigative New Drug (IND) evaluation guidance by the Food and Drug Administration. Earlier, we reported the development of a PK model that can predict the relationship between plasma, saliva and urinary scopolamine (SCOP) concentrations using data collected from an IND clinical trial with INSCOP. This data analysis project is designed to validate the reported best fit PK model for SCOP by comparing observed and model predicted SCOP concentration-time profiles after administration of INSCOP.

  16. Brain delivery of intranasal in situ gel of nanoparticulated polymeric carriers containing antidepressant drug: behavioral and biochemical assessment.

    PubMed

    Kaur, Prabhjot; Garg, Tarun; Vaidya, Bhuvaneshwar; Prakash, Atish; Rath, Goutam; Goyal, Amit K

    2015-04-01

    This study was aimed for brain delivery of Tramadol HCl (centrally acting synthetic opioid) following intranasal administration for treatment of depression. Chitosan nanoparticles (NPs) were prepared by ionic gelation method followed by the addition of developed NPs with in the Pluronic and HPMC-based mucoadhesive thermo-reversible gel. Developed formulation optimized based on the various parameters such as particle size, entrapment efficiency, in vitro release study. Depression induction was done by forced swim test and evaluated by various behavioral and biochemical parameters. Furthermore, results showed significantly increased in locomotors activity, body weight as compared to control group. It also showed alteration in biochemical parameters such glutathione level and catalase levels significantly increased other than lipid peroxidation and nitrite level was found to be decreased after intranasal administration of formulation. Thus, intranasal TRM HCl NP-loaded in situ gel was found to be a promising formulation for the treatment of depression.

  17. Immune response of poults following intranasal inoculation with Artvax vaccine and a formalin-inactivated Bordetella avium bacterin.

    PubMed

    Hofstad, M S; Jeska, E L

    1985-01-01

    Poults 3 weeks and older developed temporary tracheal resistance to intranasal challenge following inoculation of either Artvax vaccine or formalin-inactivated Bordetella avium bacterin by the intranasal and eyedrop routes. Resistance usually persisted for 3-4 weeks after B. avium challenge. However, with constant exposure to infected controls, the vaccinated birds eventually developed tracheal infection. Day-old poults did not respond to either the Artvax or the bacterin and were completely susceptible to challenge. Two-week-old poults responded to some degree, but poults 3 weeks old and older responded best. Poults inoculated with bacterin by aerosol or by drinking water did not respond as well as those inoculated by the intranasal and eyedrop routes. When poults were given a single subcutaneous injection at 3 weeks of age and challenged 2 weeks later, three of five resisted infection for 18 days.

  18. Insulin C-peptide test

    MedlinePlus

    C-peptide ... the test depends on the reason for the C-peptide measurement. Ask your health care provider if ... C-peptide is measured to tell the difference between insulin the body produces and insulin someone injects ...

  19. Brief Report: Oxytocin Enhances Paternal Sensitivity to a Child with Autism--A Double-Blind Within-Subject Experiment with Intranasally Administered Oxytocin

    ERIC Educational Resources Information Center

    Naber, Fabienne B. A.; Poslawsky, Irina E.; van Ijzendoorn, Marinus H.; van Engeland, Herman; Bakermans-Kranenburg, Marian J.

    2013-01-01

    Oxytocin seems associated with parenting style, and experimental work showed positive effects of intranasally administered oxytocin on parenting style of fathers. Here, the first double-blind, placebo-controlled, within-subject experiment with intranasal oxytocin administration to fathers of children with autism spectrum disorder (ASD) is…

  20. Early intervention with intranasal NPY prevents single prolonged stress-triggered impairments in hypothalamus and ventral hippocampus in male rats.

    PubMed

    Laukova, Marcela; Alaluf, Lishay G; Serova, Lidia I; Arango, Victoria; Sabban, Esther L

    2014-10-01

    Intranasal administration of neuropeptide Y (NPY) is a promising treatment strategy to reduce traumatic stress-induced neuropsychiatric symptoms of posttraumatic stress disorder (PTSD). We evaluated the potential of intranasal NPY to prevent dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, a core neuroendocrine feature of PTSD. Rats were exposed to single prolonged stress (SPS), a PTSD animal model, and infused intranasally with vehicle or NPY immediately after SPS stressors. After 7 days undisturbed, hypothalamus and hippocampus, 2 structures regulating the HPA axis activity, were examined for changes in glucocorticoid receptor (GR) and CRH expression. Plasma ACTH and corticosterone, and hypothalamic CRH mRNA, were significantly higher in the vehicle but not NPY-treated group, compared with unstressed controls. Although total GR levels were not altered in hypothalamus, a significant decrease of GR phosphorylated on Ser232 and increased FK506-binding protein 5 mRNA were observed with the vehicle but not in animals infused with intranasal NPY. In contrast, in the ventral hippocampus, only vehicle-treated animals demonstrated elevated GR protein expression and increased GR phosphorylation on Ser232, specifically in the nuclear fraction. Additionally, SPS-induced increase of CRH mRNA in the ventral hippocampus was accompanied by apparent decrease of CRH peptide particularly in the CA3 subfield, both prevented by NPY. The results show that early intervention with intranasal NPY can prevent traumatic stress-triggered dysregulation of the HPA axis likely by restoring HPA axis proper negative feedback inhibition via GR. Thus, intranasal NPY has a potential as a noninvasive therapy to prevent negative effects of traumatic stress.

  1. Direct nose-to-brain transfer of a growth hormone releasing neuropeptide, hexarelin after intranasal administration to rabbits.

    PubMed

    Yu, Hui; Kim, Kwonho

    2009-08-13

    The purpose of this study was to investigate the olfactory transfer of a growth hormone releasing neuropeptide, hexarelin to the brain tissues by comparing brain uptake levels after intranasal administration with those after intravenous administration. The hexarelin nasal formulation was prepared using an aqueous cosolvent vehicle consisting of ethanol, propylene glycol, and n-tridecyl-beta-D-maltoside as a permeation enhancer. Hexarelin was administered intravenously or intranasally to male rabbits at a dose of 1 mg/kg. Drug concentrations in the plasma, cerebrospinal fluid and six different regions of the brain, i.e., olfactory bulb (OB), olfactory tract (OT), anterior (CB1), middle (CB2), posterior (CB3) cerebrum, and cerebellum (CL) were analyzed by LC/MS method after solid phase extraction. The brain and cerebrospinal fluid levels achieved following intranasal administration were approximately 1.6 times greater than those attained after intravenous administration despite the intranasal plasma levels being significantly lower than the intravenous plasma levels. Intranasal administration resulted in significantly different spatial distribution patterns in various regions of brain with the rank order of C(OB)>C(OT)>C(CB1, CB2, CB3)>C(CL) at 10, 20, and 40 min post-dosing, whereas intravenous administration yielded nearly similar distribution patterns in the brain. The intranasal administration into one nostril (left or right) exhibited markedly greater hexarelin concentrations in olfactory bulb and olfactory tract on the treated-side of brain tissues than those on the non-treated-side of the brain hemisphere. It was demonstrated that the hydrophilic neuropeptide hexarelin was transferred via olfactory pathway to the brain hemispheres and the drug transfer via this route significantly contributed to high brain concentrations after nasal administration to rabbits.

  2. Insulin tolerance in laminitic ponies.

    PubMed Central

    Coffman, J R; Colles, C M

    1983-01-01

    Sensitivity to insulin was assessed in ponies episodically affected with chronic laminitis by measurement of blood glucose and arterial blood pressure during insulin tolerance tests. In terms of blood glucose values, laminitic ponies were significantly less sensitive to insulin than controls. Conversely, a post-insulin decline in diastolic, systolic and mean blood pressure values was significantly greater in laminitic ponies than in controls. PMID:6357412

  3. Oral Insulin and Buccal Insulin: A Critical Reappraisal

    PubMed Central

    Heinemann, Lutz; Jacques, Yves

    2009-01-01

    Despite the availability of modern insulin injection devices with needles that are so sharp and thin that practically no injection pain takes place, it is still the dream of patients with diabetes to, for example, swallow a tablet with insulin. This is not associated with any pain and would allow more discretion. Therefore, availability of oral insulin would not only ease insulin therapy, it would certainly increase compliance. However, despite numerous attempts to develop such a “tablet” in the past 85 years, still no oral insulin is commercially available. Buccal insulin is currently in the last stages of clinical development by one company and might become available in the United States and Europe in the coming years (it is already on the market in some other countries). The aim of this review is to critically describe the different approaches that are currently under development. Optimal coverage of prandial insulin requirements is the aim with both routes of insulin administration (at least with most approaches). The speed of onset of metabolic effect seen with some oral insulin approaches is rapid, but absorption appears to be lower when the tablet is taken immediately prior to a meal. With all approaches, considerable amounts of insulin have to be applied in order to induce therapeutically relevant increases in the metabolic effect because of the low relative biopotency of buccal insulin. Unfortunately, the number of publications about clinical–experimental and clinical studies is surprisingly low. In addition, there is no study published in which the variability of the metabolic effect induced (with and without a meal) was studied adequately. In summary, after the failure of inhaled insulin, oral insulin and buccal insulin are hot candidates to come to the market as the next alternative routes of insulin administration. PMID:20144297

  4. Influenza vaccination for the pediatric patient: a focus on the new intranasal, cold-adapted, live attenuated vaccine.

    PubMed

    Ellis, Jennifer M; Reilly, Joan C; Salazar, Juan C

    2004-04-01

    FluMist is the first live attenuated, cold-adapted intranasal influenza vaccine (LAIV) approved for the prevention of influenza A and B. Clinical trials have shown that annual vaccination with LAIV is effective for the prevention of influenza. LAIV appears well tolerated in healthy patients 5-49 years of age. The most common adverse events are abdominal pain, chills, cough, diarrhea, headache, irritability, lethargy, muscle aches, otitis media, rhinitis, sinusitis, sore throat, and vomiting. FluMist has a novel intranasal route of administration that allows for influenza prevention without a painful intramuscular injection. Barriers preventing acceptance of LAIV include defining the appropriate patient population, cost, and insurance coverage.

  5. A role for the intranasal formulation of azelastine hydrochloride/fluticasone propionate in the treatment of allergic rhinitis.

    PubMed

    Ridolo, Erminia; Montagni, Marcello; Melli, Valerie; Bonzano, Laura; Incorvaia, Cristoforo; Canonica, Giorgio Walter

    2015-01-01

    Rhinitis is a very common disease and represents a health problem for both children and adults globally. Rhinitis can be allergic or occur without any IgE-mediated sensitization to aeroallergens. Common symptoms include nasal congestion, postnasal drainage, nasal itching, rhinorrhea and sneezing. The most effective drugs for the treatment of rhinitis are antihistamines and topical glucocorticoids. MP29-02 (Dymista(®)) is a novel intranasal formulation combining the second-generation antihistamine, azelastine hydrochloride, with fluticasone propionate in a single device that has recently been developed. Here, we review the efficacy and safety profile of this intranasal formulation in the treatment of allergic and nonallergic rhinitis. PMID:25913181

  6. Insulin Resistance in Alzheimer's Disease

    PubMed Central

    Dineley, Kelly T; Jahrling, Jordan B; Denner, Larry

    2014-01-01

    Insulin is a key hormone regulating metabolism. Insulin binding to cell surface insulin receptors engages many signaling intermediates operating in parallel and in series to control glucose, energy, and lipids while also regulating mitogenesis and development. Perturbations in the function of any of these intermediates, which occur in a variety of diseases, cause reduced sensitivity to insulin and insulin resistance with consequent metabolic dysfunction. Chronic inflammation ensues which exacerbates compromised metabolic homeostasis. Since insulin has a key role in learning and memory as well as directly regulating ERK, a kinase required for the type of learning and memory compromised in early Alzheimer's disease (AD), insulin resistance has been identified as a major risk factor for the onset of AD. Animal models of AD or insulin resistance or both demonstrate that AD pathology and impaired insulin signaling form a reciprocal relationship. Of note are human and animal model studies geared toward improving insulin resistance that have led to the identification of the nuclear receptor and transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) as an intervention tool for early AD. Strategic targeting of alternate nodes within the insulin signaling network has revealed disease-stage therapeutic windows in animal models that coalesce with previous and ongoing clinical trial approaches. Thus, exploiting the connection between insulin resistance and AD provides powerful opportunities to delineate therapeutic interventions that slow or block the pathogenesis of AD. PMID:25237037

  7. Insulin resistance in the liver: Deficiency or excess of insulin?

    PubMed Central

    Bazotte, Roberto B; Silva, Lorena G; Schiavon, Fabiana PM

    2014-01-01

    In insulin-resistant states (obesity, pre-diabetes, and type 2 diabetes), hepatic production of glucose and lipid synthesis are heightened in concert, implying that insulin deficiency and insulin excess coexists in this setting. The fact that insulin may be inadequate or excessive at any one point in differing organs and tissues has many biologic ramifications. In this context the concept of metabolic compartmentalization in the liver is offered herein as one perspective of this paradox. In particular, we focus on the hypothesis that insulin resistance accentuates differences in periportal and perivenous hepatocytes, namely periportal glucose production and perivenous lipid synthesis. Subsequently, excessive production of glucose and accumulation of lipids could be expected in the livers of patients with obesity and insulin resistance. Overall, in this review, we provide our integrative perspective regarding how excessive production of glucose in periportal hepatocytes and accumulation of lipids in perivenous hepatocytes interact in insulin resistant states. PMID:25486190

  8. Poly-ε-caprolactone/Chitosan and Chitosan Particles: Two Recombinant Antigen Delivery Systems for Intranasal Vaccination.

    PubMed

    Jesus, Sandra; Soares, Edna; Borges, Olga

    2016-01-01

    Several evidences converge on the idea that among the mucosal administration routes, the nasal mucosa is the most attractive site for the delivery of vaccines. Mucoadhesive particulate adjuvants should be able to increase the residence time of antigens in nasal cavity in order to increase their probability of being taken up by nasopharynx-associated lymphoid tissue (NALT) cells and subsequently to initiate the innate and adaptive immune response. Focusing on chitosan, a mucoadhesive biopolymer, we describe in this chapter a method to prepare antigen loaded chitosan nanoparticles and a second method to prepare antigen loaded poly-ε-caprolactone/chitosan nanoparticles. Additionally the methodology for the assessment of mucoadhesivity of the delivery system is also described. The two critical procedures in mice intranasal immunization experiments include challenges in the intranasal administration itself due to the small mouse nose, and the other is related with the collection of mucosal secretions to assess the sIgA. The techniques are difficult to perform without advanced training. Therefore, protocols followed in our laboratory, as well as some tips, are described in this chapter.

  9. Study of sodium hyaluronate-based intranasal formulations containing micro- or nanosized meloxicam particles.

    PubMed

    Bartos, Csilla; Ambrus, Rita; Sipos, Péter; Budai-Szűcs, Mária; Csányi, Erzsébet; Gáspár, Róbert; Márki, Árpád; Seres, Adrienn B; Sztojkov-Ivanov, Anita; Horváth, Tamás; Szabó-Révész, Piroska

    2015-08-01

    This article reports on the micro- and nanonization of meloxicam (MEL) with the aim of developing pre-dispersions as intermediates for the design of intranasal formulations. As a new approach, combined wet milling technology was developed in order to reduce the particle size of the MEL. Different milling times resulted in micro- or nanosized MEL in the pre-dispersions with polyvinyl alcohol as stabilizer agent, which were directly used for preparing intranasal liquid formulations with the addition of sodium hyaluronate as mucoadhesive agent. Reduction of the MEL particle size into the nano range led to increased saturation solubility and dissolution velocities, and increased adhesiveness to surfaces as compared with microsized MEL particles. A linear correlation was demonstrated between the specific surface area of MEL and the AUC. The in vitro and in vivo studies indicated that the longer residence time and the uniform distribution of nano MEL spray throughout an artificial membrane and the nasal mucosa resulted in better diffusion and a higher AUC. Nanosized MEL may be suggested for the development of an innovative dosage form with a different dose of the drug, as a possible administration route for pain management. PMID:26142244

  10. Gene silencing of SOCS3 by siRNA intranasal delivery inhibits asthma phenotype in mice.

    PubMed

    Zafra, Ma Paz; Mazzeo, Carla; Gámez, Cristina; Rodriguez Marco, Ainara; de Zulueta, Ana; Sanz, Veronica; Bilbao, Izaskun; Ruiz-Cabello, Jesús; Zubeldia, Jose M; del Pozo, Victoria

    2014-01-01

    Suppresors of cytokine signaling (SOCS) proteins regulate cytokine responses and control immune balance. Several studies have confirmed that SOCS3 is increased in asthmatic patients, and SOCS3 expression is correlated with disease severity. The objective of this study was to evaluate if delivering of SOCS3 short interfering RNA (siRNA) intranasally in lungs could be a good therapeutic approach in an asthma chronic mouse model. Our results showed that intranasal treatment with SOCS3-siRNA led to an improvement in the eosinophil count and the normalization of hyperresponsiveness to methacholine. Concomitantly, this treatment resulted in an improvement in mucus secretion, a reduction in lung collagen, which are prominent features of airway remodeling. The mechanism implies JAK/STAT and RhoA/Rho-kinase signaling pathway, because we found a decreasing in STAT3 phosphorylation status and down regulation of RhoA/Rho-kinase protein expression. These results might lead to a new therapy for the treatment of chronic asthma.

  11. Intranasal nanoemulsion-based inactivated respiratory syncytial virus vaccines protect against viral challenge in cotton rats

    PubMed Central

    O'Konek, Jessica J; Makidon, Paul E; Landers, Jeffrey J; Cao, Zhengyi; Malinczak, Carrie-Anne; Pannu, Jessie; Sun, Jennifer; Bitko, Vira; Ciotti, Susan; Hamouda, Tarek; Wojcinski, Zbigniew W; Lukacs, Nicholas W; Fattom, Ali; Baker, James R

    2015-01-01

    Respiratory Syncytial Virus is a leading cause of bronchiolitis and pneumonia in infants, the elderly and individuals with compromised immune systems. Despite decades of research, there is currently no available vaccine for RSV. Our group has previously demonstrated that intranasal immunization of mice with RSV inactivated by and adjuvanted with W805EC nanoemulsion elicits robust humoral and cellular immune responses, resulting in protection against RSV infection. This protection was achieved without the induction of airway hyper-reactivity or a Th2-skewed immune response. The cotton rat Sigmodon hispidus has been used for years as an excellent small animal model of RSV disease. Thus, we extended these rodent studies to the more permissive cotton rat model. Intranasal immunization of the nanoemulsion-adjuvanted RSV vaccines induced high antibody titers and a robust Th1-skewed cellular response. Importantly, vaccination provided sterilizing cross-protective immunity against a heterologous RSV challenge and did not induce marked or severe histological effects or eosinophilia in the lung after viral challenge. Overall, these data demonstrate that nanoemulsion-formulated whole RSV vaccines are both safe and effective for immunization in multiple animal models. PMID:26307915

  12. Gene Silencing of SOCS3 by siRNA Intranasal Delivery Inhibits Asthma Phenotype in Mice

    PubMed Central

    Mazzeo, Carla; Gámez, Cristina; Rodriguez Marco, Ainara; de Zulueta, Ana; Sanz, Veronica; Bilbao, Izaskun; Ruiz-Cabello, Jesús; Zubeldia, Jose M.; del Pozo, Victoria

    2014-01-01

    Suppresors of cytokine signaling (SOCS) proteins regulate cytokine responses and control immune balance. Several studies have confirmed that SOCS3 is increased in asthmatic patients, and SOCS3 expression is correlated with disease severity. The objective of this study was to evaluate if delivering of SOCS3 short interfering RNA (siRNA) intranasally in lungs could be a good therapeutic approach in an asthma chronic mouse model. Our results showed that intranasal treatment with SOCS3-siRNA led to an improvement in the eosinophil count and the normalization of hyperresponsiveness to methacholine. Concomitantly, this treatment resulted in an improvement in mucus secretion, a reduction in lung collagen, which are prominent features of airway remodeling. The mechanism implies JAK/STAT and RhoA/Rho-kinase signaling pathway, because we found a decreasing in STAT3 phosphorylation status and down regulation of RhoA/Rho-kinase protein expression. These results might lead to a new therapy for the treatment of chronic asthma. PMID:24637581

  13. Intranasal Delivery of Recombinant NT4-NAP/AAV Exerts Potential Antidepressant Effect.

    PubMed

    Ma, Xian-Cang; Chu, Zheng; Zhang, Xiao-Ling; Jiang, Wen-Hui; Jia, Min; Dang, Yong-Hui; Gao, Cheng-Ge

    2016-06-01

    The present study was designed to construct a recombinant adeno-associated virus (rAAV) which can express NAP in the brain and examine whether this virus can produce antidepressant effects on C57 BL/6 mice that had been subjected to open field test and forced swimming test, via nose-to-brain pathway. When the recombinant plasmid pGEM-T Easy/NT4-NAP was digested by EcoRI, 297 bp fragments can be obtained and NT4-NAP sequence was consistent with the designed sequence confirmed by DNA sequencing. When the recombinant plasmid pSSCMV/NT4-NAP was digested by EcoRI, 297 bp fragments is visible. Immunohistochemical staining of fibroblasts revealed that expression of NAP was detected in NT4-NAP/AAV group. Intranasal delivery of NT4-NAP/AAV significantly reduced immobility time when the FST was performed after 1 day from the last administration. The effects observed in the FST could not be attributed to non-specific increases in activity since intranasal delivery of NT4-NAP/AAV did not alter the behavior of the mice during the open field test. The results indicated that a recombinant AAV vector which could express NAP in cells was successfully constructed and NAP may be a potential target for therapeutic action of antidepressant treatment. PMID:26846142

  14. Ribavirin Protects Syrian Hamsters against Lethal Hantavirus Pulmonary Syndrome — After Intranasal Exposure to Andes Virus

    PubMed Central

    Ogg, Monica; Jonsson, Colleen B.; Camp, Jeremy V.; Hooper, Jay W.

    2013-01-01

    Andes virus, ANDV, harbored by wild rodents, causes the highly lethal hantavirus pulmonary syndrome (HPS) upon transmission to humans resulting in death in 30% to 50% of the cases. As there is no treatment for this disease, we systematically tested the efficacy of ribavirin in vitro and in an animal model. In vitro assays confirmed antiviral activity and determined that the most effective doses were 40 µg/mL and above. We tested three different concentrations of ribavirin for their capability to prevent HPS in the ANDV hamster model following an intranasal challenge. While the highest level of ribavirin (200 mg/kg) was toxic to the hamster, both the middle (100 mg/kg) and the lowest concentration (50 mg/kg) prevented HPS in hamsters without toxicity. Specifically, 8 of 8 hamsters survived intranasal challenge for both of those groups whereas 7 of 8 PBS control-treated animals developed lethal HPS. Further, we report that administration of ribavirin at 50 mg/kg/day starting on days 6, 8, 10, or 12 post-infection resulted in significant protection against HPS in all groups. Administration of ribavirin at 14 days post-infection also provided a significant level of protection against lethal HPS. These data provide in vivo evidence supporting the potential use of ribavirin as a post-exposure treatment to prevent HPS after exposure by the respiratory route. PMID:24217424

  15. Protective Efficacy and Pulmonary Immune Response Following Subcutaneous and Intranasal BCG Administration in Mice.

    PubMed

    Uranga, Santiago; Marinova, Dessislava; Martin, Carlos; Aguilo, Nacho

    2016-01-01

    Despite global coverage of intradermal BCG vaccination, tuberculosis remains one of the most prevalent infectious diseases in the world. Preclinical data have encouraged pulmonary tuberculosis vaccines as a promising strategy to prevent pulmonary disease, which is responsible for transmission. In this work, we describe the methodology used to demonstrate in the mouse model the benefits of intranasal BCG vaccination when compared to subcutaneous. Our data revealed greater protective efficacy following intranasal BCG administration. In addition, our results indicate that pulmonary vaccination triggers a higher immune response in lungs, including Th1 and Th17 responses, as well as an increase of immunoglobulin A (IgA) concentration in respiratory airways. Our data show correlation between protective efficacy and the presence of IL17-producing cells in lungs post-Mycobacterium tuberculosis challenge, suggesting a role for this cytokine in the protective response conferred by pulmonary vaccination. Finally, we detail the global workflow we have developed to study respiratory vaccination in the mouse model, which could be extrapolated to other tuberculosis vaccines, apart from BCG, targeting the mucosal response or other pulmonary routes of administration such as the intratracheal or aerosol. PMID:27684521

  16. Intranasal Immunization of Mice to Avoid Interference of Maternal Antibody against H5N1 Infection.

    PubMed

    Zhang, Fenghua; Peng, Bo; Chang, Haiyan; Zhang, Ran; Lu, Fangguo; Wang, Fuyan; Fang, Fang; Chen, Ze

    2016-01-01

    Maternally-derived antibodies (MDAs) can protect offspring against influenza virus infection but may also inhibit active immune responses. To overcome MDA- mediated inhibition, active immunization of offspring with an inactivated H5N1 whole-virion vaccine under the influence of MDAs was explored in mice. Female mice were vaccinated twice via the intraperitoneal (IP) or intranasal (IN) route with the vaccine prior to mating. One week after birth, the offspring were immunized twice via the IP or IN route with the same vaccine and then challenged with a lethal dose of a highly homologous virus strain. The results showed that, no matter which immunization route (IP or IN) was used for mothers, the presence of MDAs severely interfered with the active immune response of the offspring when the offspring were immunized via the IP route. Only via the IN immunization route did the offspring overcome the MDA interference. These results suggest that intranasal immunization could be a suitable inoculation route for offspring to overcome MDA interference in the defense against highly pathogenic H5N1 virus infection. This study may provide references for human and animal vaccination to overcome MDA-induced inhibition. PMID:27280297

  17. Protection against feline infectious peritonitis by intranasal inoculation of a temperature-sensitive FIPV vaccine.

    PubMed

    Gerber, J D; Ingersoll, J D; Gast, A M; Christianson, K K; Selzer, N L; Landon, R M; Pfeiffer, N E; Sharpee, R L; Beckenhauer, W H

    1990-12-01

    Cats vaccinated intranasally (i.n.) with a temperature sensitive feline infectious peritonitis virus (ts-FIPV) vaccine were protected against an FIP-inducing challenge. Seventeen of 20 vaccinated cats (85%) survived a rigorous virulent FIPV challenge that caused FIP in 12 of 12 non-vaccinated cats (100%), 10 (83%) of which died. Intranasal vaccination stimulated serum IgG and serum and salivary IgA antibody responses (measured by ELISA), FIPV-neutralizing antibody (VN), and a cell-mediated immune (CMI) response as measured by lymphocyte proliferation. The serum antibody response to vaccination was not associated with protection. In fact, the IgG, IgA and VN titres were much higher in control cats than in vaccinated cats following challenge suggesting an immune-mediated pathogenesis. In contrast, stimulation of a mucosal IgA response to vaccination was related to protection. The in vitro proliferation of peripheral blood lymphocytes in response to virulent FIPV was observed in vaccinated cats, in vaccinated and challenged cats but not in non-vaccinated challenged cats.

  18. Intranasal nanoemulsion-based inactivated respiratory syncytial virus vaccines protect against viral challenge in cotton rats.

    PubMed

    O'Konek, Jessica J; Makidon, Paul E; Landers, Jeffrey J; Cao, Zhengyi; Malinczak, Carrie-Anne; Pannu, Jessie; Sun, Jennifer; Bitko, Vira; Ciotti, Susan; Hamouda, Tarek; Wojcinski, Zbigniew W; Lukacs, Nicholas W; Fattom, Ali; Baker, James R

    2015-01-01

    Respiratory Syncytial Virus is a leading cause of bronchiolitis and pneumonia in infants, the elderly and individuals with compromised immune systems. Despite decades of research, there is currently no available vaccine for RSV. Our group has previously demonstrated that intranasal immunization of mice with RSV inactivated by and adjuvanted with W805EC nanoemulsion elicits robust humoral and cellular immune responses, resulting in protection against RSV infection. This protection was achieved without the induction of airway hyper-reactivity or a Th2-skewed immune response. The cotton rat Sigmodon hispidus has been used for years as an excellent small animal model of RSV disease. Thus, we extended these rodent studies to the more permissive cotton rat model. Intranasal immunization of the nanoemulsion-adjuvanted RSV vaccines induced high antibody titers and a robust Th1-skewed cellular response. Importantly, vaccination provided sterilizing cross-protective immunity against a heterologous RSV challenge and did not induce marked or severe histological effects or eosinophilia in the lung after viral challenge. Overall, these data demonstrate that nanoemulsion-formulated whole RSV vaccines are both safe and effective for immunization in multiple animal models. PMID:26307915

  19. Formulation, optimization and evaluation of spray-dried mucoadhesive microspheres as intranasal carriers for Valsartan.

    PubMed

    Pardeshi, Chandrakant V; Rajput, Pravin V; Belgamwar, Veena S; Tekade, Avinash R

    2012-01-01

    This investigation deals with the intranasal delivery of Valsartan, encapsulated in HPMC-based spray-dried mucoadhesive microspheres, with an aim to provide rapid absorption and quick onset of action for treating hypertension. A 2³-factorial design has been employed for the assessment of influence of three independent variables, namely inlet temperature, feed-flow rate and drug-polymer ratio on production yield, particle size and in vitro drug diffusion of the prepared microspheres. Microspheres were evaluated for particle size, entrapment efficiency, swelling property, in vitro mucoadhesion, in vitro drug diffusion, ex vivo drug permeation, histopathological examination and stability studies. The results of differential scanning calorimetry, X-ray diffraction and scanning electron microscopy revealed molecular dispersion of Valsartan into microspheres with spherical shape and smooth surface. Optimized formulation indicated good mucoadhesion with no severe sign of damage on nasal mucosa. Results of the non-invasive animal studies in dexamethasone-induced hypertensive rat model suggested the suitability of investigated drug delivery system for intranasal administration.

  20. Intranasal immunisation with inactivated RSV and bacterial adjuvants induces mucosal protection and abrogates eosinophilia upon challenge.

    PubMed

    Etchart, Nathalie; Baaten, Bas; Andersen, Svein Rune; Hyland, Lisa; Wong, Simon Y C; Hou, Sam

    2006-05-01

    We have previously shown that following intranasal exposure to influenza virus, specific plasma cells are generated in the nasal-associated lymphoid tissue (NALT) and maintained for the life of the animal. However, we also showed that following infection with respiratory syncytial virus (RSV), specific plasma cells are generated in the NALT but wane quickly and are not maintained even after challenge, even though RSV-specific serum antibody responses remain robust. Only infection with influenza virus generated sterilising immunity, implying a role for these long-lived plasma cells in protection. We show here that the RSV-specific IgA NALT plasma cell population and lung antibody levels can be substantially boosted, both at acute and memory time points, by intranasal immunisation with inactivated RSV (iRSV) in combination with bacterial outer membrane vesicles (OMV) compared to live RSV alone. Finally, challenge with live RSV showed that immunisation with iRSV and OMV protect against both virus replication in the lung and the eosinophil infiltrate generated by either live RSV or iRSV alone. These data show that immunisation with iRSV and OMV maintains a NALT RSV-specific plasma cell population and generates an efficient protective immune response following RSV infection. PMID:16619288

  1. Pharmacokinetics of Intranasal Scopolamine Gel Formation During Antiorthostatic Bedrest - A Microgravity Analog

    NASA Technical Reports Server (NTRS)

    Lakshmi, Putcha; Singh, R. P.; Crady, V. A.; Derendorf, H.

    2011-01-01

    Space Motion sickness (SMS) is an age old problem for astronauts on both short and long duration space flights. Scopolamine (SCOP) is the most frequently used drug for the treatment of motion sickness (MS) which is currently available in transdermal patch and tablet dosage forms. These formulations of SCOP are ineffective for the treatment of SMS. Intranasal dosage forms are noninvasive with rapid absorption and enhanced bioavailability thus allowing precise and reduced dosing options in addition to offering rescue and treatment options. As such, an intranasal gel dosage formulation of scopolamine (INSCOP) was developed and Pharmacokinetics (PK) and bioavailability were determined under IND guidelines. The present clinical trial compares PK and bioavailability of INSCOP in 12 normal, healthy subjects (6 male/ 6 female) during ambulation (AMB) and antiorthostatic bedrest (ABR) used as a ground-based microgravity analog. Subjects received 0.2 and 0.4 mg doses of INSCOP during AMB and ABR in a four-way crossover design. Results indicated no difference between AMB and ABR in PK parameters after 0.2 mg dose. Clearance (Cls) decreased with a concomitant increase in maximum concentration and area under concentration versus time curve (AUC) during ABR after the 0.4 mg dose. This difference in AUC and Cls at the higher but not the lower dose during ABR may suggest that ABR may affect metabolism and/or clearance at higher doses of INSCOP. These results indicate that dosing adjustment may be required for treatment of SMS with INSCOP in space.

  2. Intranasal Immunization of Mice to Avoid Interference of Maternal Antibody against H5N1 Infection

    PubMed Central

    Zhang, Fenghua; Peng, Bo; Chang, Haiyan; Zhang, Ran; Lu, Fangguo; Wang, Fuyan; Fang, Fang

    2016-01-01

    Maternally-derived antibodies (MDAs) can protect offspring against influenza virus infection but may also inhibit active immune responses. To overcome MDA- mediated inhibition, active immunization of offspring with an inactivated H5N1 whole-virion vaccine under the influence of MDAs was explored in mice. Female mice were vaccinated twice via the intraperitoneal (IP) or intranasal (IN) route with the vaccine prior to mating. One week after birth, the offspring were immunized twice via the IP or IN route with the same vaccine and then challenged with a lethal dose of a highly homologous virus strain. The results showed that, no matter which immunization route (IP or IN) was used for mothers, the presence of MDAs severely interfered with the active immune response of the offspring when the offspring were immunized via the IP route. Only via the IN immunization route did the offspring overcome the MDA interference. These results suggest that intranasal immunization could be a suitable inoculation route for offspring to overcome MDA interference in the defense against highly pathogenic H5N1 virus infection. This study may provide references for human and animal vaccination to overcome MDA-induced inhibition. PMID:27280297

  3. Optimization of curcumin nanoemulsion for intranasal delivery using design of experiment and its toxicity assessment.

    PubMed

    Sood, Sumeet; Jain, Kunal; Gowthamarajan, K

    2014-01-01

    The objective of the study was to optimize curcumin nanoemulsion for intranasal delivery using design of experiment. Box-Behnken design was constructed using oil, surfactant and co-surfactant concentration as independent variables and their affect on response y1 (globule size) and y2 (zeta potential) were studied. The ANOVA test identified the significant factors that affected the responses. For globule size, percentage of oil, surfactant and co-surfactant were identified as significant model terms whereas for zeta potential, oil and co-surfactant were found to be significant. Critical factors affecting the responses were identified using perturbation and contour plots. The derived polynomial equation and contour graph aid in predicting the values of selected independent variables for preparation of optimum nanoemulsion with desired properties. Further, 2(4) factorial design was used to study influence of chitosan on particle size and zeta potential. The formulations were subjected to in vitro cytotoxicity using SK-N-SH cell line and nasal ciliotoxicity studies. The developed formulations did not show any toxicity and were safe for intranasal delivery for brain targeting. In vitro diffusion studies revealed that nanoemulsions had a significantly higher release compared to drug solution. Ex vivo diffusion studies were carried out using sheep nasal mucosa fixed onto Franz diffusion cells. Mucoadhesive nanoemulsion showed higher flux and permeation across sheep nasal mucosa.

  4. Prevention or early cure of type 1 diabetes by intranasal administration of gliadin in NOD mice.

    PubMed

    Funda, David P; Fundova, Petra; Hansen, Axel Kornerup; Buschard, Karsten

    2014-01-01

    Induction of long-term tolerance to β-cell autoantigens has been investigated both in animal models and in human type 1 diabetes (T1D) in order to prevent the disease. As regards external compounds, the dietary plant protein fraction has been associated with high penetrance of the disease, whereas gluten-free diets prevent T1D in animal models. Herewith we investigated whether intranasal (i.n.) administration of gliadin or gluten may arrest the diabetogenic process. I.n. administration of gliadin to 4-week-old NOD mice significantly reduced the diabetes incidence. Similarly, the insulitis was lowered. Intranasal gliadin also rescued a fraction of prediabetic 13-week-old NOD mice from progressing to clinical onset of diabetes compared to OVA-treated controls. Vaccination with i.n. gliadin led to an induction of CD4(+)Foxp3(+) T cells and even more significant induction of γδ T cells in mucosal, but not in non-mucosal lymphoid compartments. This prevention strategy was characterized by an increased proportion of IL-10 and a decreased proportion of IL-2, IL-4 and IFN-γ-positive CD4(+)Foxp3(+) T cells, and IFN-γ-positive γδ T cells, preferentially in mucosal lymphoid organs. In conclusion, i.n. vaccination with gliadin, an environmental antigen with possible etiological influence in T1D, may represent a novel, safer strategy for prevention or even early cure of T1D.

  5. Intranasal DNA Vaccine for Protection against Respiratory Infectious Diseases: The Delivery Perspectives

    PubMed Central

    Xu, Yingying; Yuen, Pak-Wai; Lam, Jenny Ka-Wing

    2014-01-01

    Intranasal delivery of DNA vaccines has become a popular research area recently. It offers some distinguished advantages over parenteral and other routes of vaccine administration. Nasal mucosa as site of vaccine administration can stimulate respiratory mucosal immunity by interacting with the nasopharyngeal-associated lymphoid tissues (NALT). Different kinds of DNA vaccines are investigated to provide protection against respiratory infectious diseases including tuberculosis, coronavirus, influenza and respiratory syncytial virus (RSV) etc. DNA vaccines have several attractive development potential, such as producing cross-protection towards different virus subtypes, enabling the possibility of mass manufacture in a relatively short time and a better safety profile. The biggest obstacle to DNA vaccines is low immunogenicity. One of the approaches to enhance the efficacy of DNA vaccine is to improve DNA delivery efficiency. This review provides insight on the development of intranasal DNA vaccine for respiratory infections, with special attention paid to the strategies to improve the delivery of DNA vaccines using non-viral delivery agents. PMID:25014738

  6. New Insulin Delivery Recommendations.

    PubMed

    Frid, Anders H; Kreugel, Gillian; Grassi, Giorgio; Halimi, Serge; Hicks, Debbie; Hirsch, Laurence J; Smith, Mike J; Wellhoener, Regine; Bode, Bruce W; Hirsch, Irl B; Kalra, Sanjay; Ji, Linong; Strauss, Kenneth W

    2016-09-01

    Many primary care professionals manage injection or infusion therapies in patients with diabetes. Few published guidelines have been available to help such professionals and their patients manage these therapies. Herein, we present new, practical, and comprehensive recommendations for diabetes injections and infusions. These recommendations were informed by a large international survey of current practice and were written and vetted by 183 diabetes experts from 54 countries at the Forum for Injection Technique and Therapy: Expert Recommendations (FITTER) workshop held in Rome, Italy, in 2015. Recommendations are organized around the themes of anatomy, physiology, pathology, psychology, and technology. Key among the recommendations are that the shortest needles (currently the 4-mm pen and 6-mm syringe needles) are safe, effective, and less painful and should be the first-line choice in all patient categories; intramuscular injections should be avoided, especially with long-acting insulins, because severe hypoglycemia may result; lipohypertrophy is a frequent complication of therapy that distorts insulin absorption, and, therefore, injections and infusions should not be given into these lesions and correct site rotation will help prevent them; effective long-term therapy with insulin is critically dependent on addressing psychological hurdles upstream, even before insulin has been started; inappropriate disposal of used sharps poses a risk of infection with blood-borne pathogens; and mitigation is possible with proper training, effective disposal strategies, and the use of safety devices. Adherence to these new recommendations should lead to more effective therapies, improved outcomes, and lower costs for patients with diabetes. PMID:27594187

  7. [Insulin therapy of diabetes].

    PubMed

    Lechleitner, Monika; Roden, Michael; Weitgasser, Raimund; Ludvik, Bernhard; Fasching, Peter; Hoppichler, Friedrich; Kautzky-Willer, Alexandra; Schernthaner, Guntram; Prager, Rudolf; Wascher, Thomas C

    2016-04-01

    Hyperglycemia contributes to morbidity and mortality in patients with diabetes. Thus, reaching treatment targets with regard to control of glycemia is a central goal in the therapy of diabetic patients. The present article represents the recommendations of the Austrian Diabetes Association for the practical use of insulin according to current scientific evidence and clinical studies. PMID:27052221

  8. New Insulin Delivery Recommendations.

    PubMed

    Frid, Anders H; Kreugel, Gillian; Grassi, Giorgio; Halimi, Serge; Hicks, Debbie; Hirsch, Laurence J; Smith, Mike J; Wellhoener, Regine; Bode, Bruce W; Hirsch, Irl B; Kalra, Sanjay; Ji, Linong; Strauss, Kenneth W

    2016-09-01

    Many primary care professionals manage injection or infusion therapies in patients with diabetes. Few published guidelines have been available to help such professionals and their patients manage these therapies. Herein, we present new, practical, and comprehensive recommendations for diabetes injections and infusions. These recommendations were informed by a large international survey of current practice and were written and vetted by 183 diabetes experts from 54 countries at the Forum for Injection Technique and Therapy: Expert Recommendations (FITTER) workshop held in Rome, Italy, in 2015. Recommendations are organized around the themes of anatomy, physiology, pathology, psychology, and technology. Key among the recommendations are that the shortest needles (currently the 4-mm pen and 6-mm syringe needles) are safe, effective, and less painful and should be the first-line choice in all patient categories; intramuscular injections should be avoided, especially with long-acting insulins, because severe hypoglycemia may result; lipohypertrophy is a frequent complication of therapy that distorts insulin absorption, and, therefore, injections and infusions should not be given into these lesions and correct site rotation will help prevent them; effective long-term therapy with insulin is critically dependent on addressing psychological hurdles upstream, even before insulin has been started; inappropriate disposal of used sharps poses a risk of infection with blood-borne pathogens; and mitigation is possible with proper training, effective disposal strategies, and the use of safety devices. Adherence to these new recommendations should lead to more effective therapies, improved outcomes, and lower costs for patients with diabetes.

  9. Insulin Resistance and Prediabetes

    MedlinePlus

    ... to be used in most health care providers' offices. The clamp is a research tool used by scientists to learn more about glucose metabolism. Research has shown that if blood tests indicate prediabetes, insulin ... care provider's office or commercial facility and sending the sample to ...

  10. Insulin therapy and exercise.

    PubMed

    Kourtoglou, Georgios I

    2011-08-01

    Medical nutrition therapy and physical exercise are the cornerstones of the diabetes management. Patients with type 1 DM always need exogenous insulin administration, recently available in the form of insulin analogs. In type 2 DM, characterized by increased insulin resistance and progressive decline of the beta-cell function, various antidiabetic medications are used. Most of the subjects with type 2 DM will finally need insulin. The main site of insulin action is the skeletal muscle, while the liver is the main site of glucose storage in the form of glycogen. With the modern diabetes therapies it is possible to rapidly reach and maintain normoglycemia in both types of DM but with the cost of higher incidence of hypoglycemia, especially related to exercise. Regular physical exercise causes a lot of beneficial effects in healthy as well as diabetic subjects of all age groups. In type 1 DM physical exercise is a fundamental element for both physical and mental development. In type 2 DM it has a main role in diabetes control. The increased hepatic glucose production and the increased muscular glucose uptake during exercise are closely interrelated in all exercise intensities. In diabetes mellitus there is a disturbed energy substrate use during exercise leading to either hypo- or hyperglycemia. The influence of low or moderate intensity aerobic exercise on diabetes control has been well studied. The inappropriately high insulinemia combined with the low glucose levels can lead to severe hypoglycemia if proper measures are not taken. Prolonged exercise can also predispose to decreased glucose counter regulation. It is better for the type 1 diabetic subject to postpone the exercise session in very high (>300 mg/dl) or very low (<70 mg/dl) BG levels. Every insulin treated subject is recommended to be checked for any existing diabetic complication before the start of every exercise program. Glucose measurement with glucose meters or sometimes with Continuous Glucose

  11. Use of extracorporeal membrane oxygenation in an awake patient after a major trauma with an incidental finding of tuberculosis.

    PubMed

    Haneke, F; Schildhauer, T A; Strauch, J; Swol, J

    2016-05-01

    We report the use of extracorporeal membrane oxygenation (ECMO) in a trauma patient with an incidental finding of open tuberculosis (TB). Sedation was reduced during extracorporeal support and awake veno-venous ECMO was successfully performed. Subsequently, accidental cannula removal caused major blood loss which required the administration of cardiopulmonary resuscitation (CPR). Our case report demonstrates that the incidental finding of open TB is an important hint for differential diagnosis and that it should still be considered in high-income countries. In addition, awake ECMO appears to be a feasible therapeutic option in non-transplant patients, although the described case demonstrates that patient compliance and nursing care are important for therapeutic success to avoid complications, for example, inadvertent decannulation. PMID:26498750

  12. Evidence against extrapancreatic insulin synthesis.

    PubMed Central

    Eng, J; Yalow, R S

    1981-01-01

    Labeled and unlabeled insulin in acid/ethanol tissue extracts can be concentrated up to 100-fold by using a hydrophobic adsorption technique. After adsorption to and elution from an octadecylsilyl silica column, insulin is recovered in yields greater than 75%. By using this method of concentration, insulin in brain tissues of three of four fed rats and one rabbit was found to be less than 20% of plasma concentration. The kidney is the only extrapancreatic organ in which insulin is observed to be markedly above plasma levels. Porcine-insulin-like material was not detectable in guinea pig tissues (less than 0.02 ng/g). It is concluded that insulin is not synthesized in brain or other extrapancreatic tissues and that other mammalian insulins are not found in guinea pig tissues. PMID:6270683

  13. Insulin degludec for diabetes mellitus.

    PubMed

    2013-07-01

    Over the last few years there has been a steady increase in the number of prescriptions dispensed in primary care for intermediate and long-acting insulin analogues and a reduction in prescriptions for biphasic isophane insulin. For example, in England, the volume of intermediate and long-acting insulin analogues in general practice has risen from approximately 650,000 prescriptions per quarter in 2007 to over 850,000 per quarter in 2012.(1) ▾Insulin degludec (Tresiba, Novo Nordisk) is a new long acting basal insulin analogue for the management of diabetes mellitus in adults.(2) Two strengths of insulin degludec (100 units/mL and 200 units/mL) were launched in the UK in February 2013. Here we discuss evidence for the effectiveness and safety of insulin degludec. PMID:23842634

  14. Effects of Optogenetic Activation of Corticothalamic Terminals in the Motor Thalamus of Awake Monkeys

    PubMed Central

    Hu, Xing; Smith, Yoland; Wichmann, Thomas

    2016-01-01

    The role of the corticothalamic projection in the ventral motor thalamus remains poorly understood. Therefore, we studied the electrophysiological responses of neurons in the basal ganglia and cerebellar receiving-territories of the motor thalamus (BGMT and CbMT, respectively) using optogenetic activation of corticothalamic projections in awake rhesus macaques. After injections of viral vectors carrying the excitatory opsins ChR2 or C1V1 into the primary motor and premotor cortices of two monkeys, we used optrodes to light activate opsin-expressing neurons in cortex or their terminals in the thalamus while simultaneously recording the extracellular activity of neurons in the vicinity of the stimulation sites. As expected, light activation of opsins in the cerebral cortex evoked robust, short-latency increases in firing of cortical neurons. In contrast, light stimulation of corticothalamic terminals induced small-amplitude, long-latency increases and/or decreases of activity in thalamic neurons. In postmortem material, opsins were found to be expressed in cell bodies and dendrites of cortical neurons and along their corticothalamic projections. At the electron microscopic level, opsin labeling was confined to unmyelinated preterminal axons and small terminals that formed asymmetric synapses with dendrites of projection neurons or GABAergic interneurons in BGMT and CbMT and with neurons in the reticular thalamic nucleus. The morphological features of the transfected terminals, along with the long latency and complex physiological responses of thalamic neurons to their activation, suggest a modulatory role of corticothalamic afferents upon the primate ventral motor thalamus. SIGNIFICANCE STATEMENT This study provides the first analysis of the physiological effects of cortical inputs on the activity of neurons in the primate ventral motor thalamus using light activation of opsin-containing corticothalamic terminals in awake monkeys. We found that selective light

  15. Optical methods and integrated systems for brain imaging in awake, untethered animals

    NASA Astrophysics Data System (ADS)

    Murari, Kartikeya

    Imaging is a powerful tool for biomedical research offering non-contact and minimally or non-invasive means of investigating at multiple scales---from single molecules to large populations of cells. Imaging in awake, behaving animals is an emerging field that offers the additional advantage of being able to study physiological processes and structures in a more natural state than what is possible in tissue slices or even in anesthetized animals. To date, most imaging in awake animals has used optical fiber bundles or electrical cables to transfer signals to traditional imaging-system components. However, the fibers or cables tether the animal and greatly limit the kind and duration of animal behavior that can be studied using imaging methods. This work involves three distinct yet related approaches to fulfill the goal of imaging in unanesthetized, unrestrained animals---optical techniques for functional and structural imaging, development of novel photodetectors and the design of miniaturized imaging systems. I hypothesized that the flow within vessels might act as a contrast-enhancing agent and improve the visualization of vascular architecture using laser speckle imaging. When imaging rodent cerebral vasculature I saw a two to four fold increase in the contrast-to-noise ratios and was able to visualize 10--30% more vascular features over reflectance techniques. I designed a complementary metal oxide semiconductor (CMOS) photodetector array that was comparable in sensitivity and noise performance to cooled CCD sensors, able to image fluorescence from a single cell, while running at faster frame rates. Next, I designed an imaging system weighing under 6 grams and occupying less than 4 cm3. The system incorporated multispectral illumination, adjustable focusing optics and the high-sensitivity CMOS imager. I was able to implement a variety of optical modalities with the system and performed reflectance, fluorescence, spectroscopic and laser speckle imaging with my

  16. Biofeedback for treatment of awake and sleep bruxism in adults: systematic review protocol

    PubMed Central

    2014-01-01

    Background Bruxism is a disorder of jaw-muscle activity characterised by repetitive clenching or grinding of the teeth which results in discomfort and damage to dentition. The two clinical manifestations of the condition (sleep and awake bruxism) are thought to have unrelated aetiologies but are palliated using similar techniques. The lack of a definitive treatment has prompted renewed interest in biofeedback, a behaviour change method that uses electronic detection to provide a stimulus whenever bruxism occurs. This systematic review aims to provide a comprehensive overview of the state of research into biofeedback for bruxism; to assess the efficacy and acceptability of biofeedback therapy in management of awake bruxism and, separately, sleep bruxism in adults; and to compare findings between the two variants. Methods A systematic review of published literature examining biofeedback as an intervention directed at controlling primary bruxism in adults. We will search electronic databases and the grey literature using a predefined search strategy to identify randomised and non-randomised studies, technical reports and patents. Searches will not be restricted by language or date and will be expanded through contact with authors and experts, and by following up reference lists and citations. Two authors, working independently, will conduct screening of search results, study selection, data extraction and quality assessment and a third will resolve any disagreements. The primary outcomes of acceptability and effectiveness will be assessed using only randomised studies, segregated by bruxism subtype. A meta-analysis of these data will be conducted only if pre-defined conditions for quality and heterogeneity are met, otherwise the data will be summarized in narrative form. Data from non-randomised studies will be used to augment a narrative synthesis of the state of technical developments and any safety-related issues. PROSPERO registration number: CRD42013006880

  17. Significance of time awake for predicting pilots' fatigue on short-haul flights: implications for flight duty time regulations.

    PubMed

    Vejvoda, Martin; Elmenhorst, Eva-Maria; Pennig, Sibylle; Plath, Gernot; Maass, Hartmut; Tritschler, Kristjof; Basner, Mathias; Aeschbach, Daniel

    2014-10-01

    European regulations restrict the duration of the maximum daily flight duty period for pilots as a function of the duty start time and the number of scheduled flights. However, late duty end times that may include long times awake are not specifically regulated. In this study, fatigue levels in pilots finishing their duty late at night (00:00-01:59 hour) were analysed and compared with pilots starting their duty early (05:00-06:59 hour). Fatigue levels of 40 commercial short-haul pilots were studied during a total of 188 flight duty periods, of which 87 started early and 22 finished late. Pilots used a small handheld computer to maintain a duty and sleep log, and to indicate fatigue levels immediately after each flight. Sleep logs were checked with actigraphy. Pilots on late-finishing flight duty periods were more fatigued at the end of their duty than pilots on early-starting flight duty periods, despite the fact that preceding sleep duration was longer by 1.1 h. Linear mixed-model regression identified time awake as a preeminent factor predicting fatigue. Workload had a minor effect. Pilots on late-finishing flight duty periods were awake longer by an average of 5.5 h (6.6 versus 1.1 h) before commencing their duty than pilots who started early in the morning. Late-finishing flights were associated with long times awake at a time when the circadian system stops promoting alertness, and an increased, previously underestimated fatigue risk. Based on these findings, flight duty limitations should consider not only duty start time, but also the time of the final landing. PMID:25040665

  18. Significance of time awake for predicting pilots' fatigue on short-haul flights: implications for flight duty time regulations.

    PubMed

    Vejvoda, Martin; Elmenhorst, Eva-Maria; Pennig, Sibylle; Plath, Gernot; Maass, Hartmut; Tritschler, Kristjof; Basner, Mathias; Aeschbach, Daniel

    2014-10-01

    European regulations restrict the duration of the maximum daily flight duty period for pilots as a function of the duty start time and the number of scheduled flights. However, late duty end times that may include long times awake are not specifically regulated. In this study, fatigue levels in pilots finishing their duty late at night (00:00-01:59 hour) were analysed and compared with pilots starting their duty early (05:00-06:59 hour). Fatigue levels of 40 commercial short-haul pilots were studied during a total of 188 flight duty periods, of which 87 started early and 22 finished late. Pilots used a small handheld computer to maintain a duty and sleep log, and to indicate fatigue levels immediately after each flight. Sleep logs were checked with actigraphy. Pilots on late-finishing flight duty periods were more fatigued at the end of their duty than pilots on early-starting flight duty periods, despite the fact that preceding sleep duration was longer by 1.1 h. Linear mixed-model regression identified time awake as a preeminent factor predicting fatigue. Workload had a minor effect. Pilots on late-finishing flight duty periods were awake longer by an average of 5.5 h (6.6 versus 1.1 h) before commencing their duty than pilots who started early in the morning. Late-finishing flights were associated with long times awake at a time when the circadian system stops promoting alertness, and an increased, previously underestimated fatigue risk. Based on these findings, flight duty limitations should consider not only duty start time, but also the time of the final landing.

  19. Restraint training for awake functional brain scanning of rodents can cause long-lasting changes in pain and stress responses.

    PubMed

    Low, Lucie A; Bauer, Lucy C; Pitcher, Mark H; Bushnell, M Catherine

    2016-08-01

    With the increased interest in longitudinal brain imaging of awake rodents, it is important to understand both the short-term and long-term effects of restraint on sensory and emotional processing in the brain. To understand the effects of repeated restraint on pain behaviors and stress responses, we modeled a restraint protocol similar to those used to habituate rodents for magnetic resonance imaging scanning, and studied sensory sensitivity and stress hormone responses over 5 days. To uncover lasting effects of training, we also looked at responses to the formalin pain test 2 weeks later. We found that while restraint causes acute increases in the stress hormone corticosterone, it can also cause lasting reductions in nociceptive behavior in the formalin test, coupled with heightened corticosterone levels and increased activation of the "nociceptive" central nucleus of the amygdala, as seen by Fos protein expression. These results suggest that short-term repeated restraint, similar to that used to habituate rats for awake functional brain scanning, could potentially cause long-lasting changes in physiological and brain responses to pain stimuli that are stress-related, and therefore could potentially confound the functional activation patterns seen in awake rodents in response to pain stimuli.

  20. [Incidence and causes of early end in awake surgery for language mapping not directly related to eloquence].

    PubMed

    Villalba, Gloria; Pacreu, Susana; Fernández-Candil, Juan Luis; León, Alba; Serrano, Laura; Conesa, Gerardo

    2016-01-01

    The incidence and causes that may lead to an early end (unfinished cortical/subcortical mapping) of awake surgery for language mapping are little known. A study was conducted on 41 patients with brain glioma located in the language area that had awake surgery under conscious sedation. Surgery was ended early in 6 patients. The causes were: tonic-clonic seizure (1), lack of cooperation due to fatigue/sleep (4), whether or not word articulation was involved, a decreased level of consciousness for ammonia encephalopathy that required endotracheal intubation (1). There are causes that could be expected and in some cases avoided. Tumour size, preoperative aphasia, valproate treatment, and type of anaesthesia used are variables to consider to avoid failure in awake surgery for language mapping. With these results, the following measures are proposed: l) If the tumour is large, perform surgery in two times to avoid fatigue, 2) if patient has a preoperative aphasia, do not use sedation during surgery to ensure that sleepiness does not cause worse word articulation, 3) if the patient is on valproate treatment, it is necessary to rule out the pre-operative symptoms that are not due to ammonia encephalopathy.

  1. Noradrenergic inhibitory modulation in the caudal commissural NTS of the pressor response to chemoreflex activation in awake rats.

    PubMed

    Silva de Oliveira, Luciana C; Bonagamba, Leni G H; Machado, Benedito H

    2007-10-30

    In the present study we evaluated the possible modulatory role of noradrenaline on the neurotransmission of the peripheral chemoreflex afferents in the caudal commissural NTS of awake rats. To reach this goal we performed a dose-response curve to microinjection of increasing dose of noradrenaline into the caudal commissural NTS of awake rats and then the threshold dose, which produces minor changes in the baseline mean arterial pressure, was selected to be used in the chemoreflex experiment. The peripheral chemoreflex was activated with KCN before and after bilateral microinjections of noradrenaline (5 nMol/50 nL, threshold dose) into the NTS. The data show that microinjection of noradrenaline into the caudal NTS produced a significant reduction in the pressor response to the chemoreflex 30 s after the injection when compared to the control response (30+/-6 vs. 49+/-3 mm Hg) but no significant changes in the bradycardic response. The data indicate that noradrenaline in the caudal commissural NTS of awake rats may play an important inhibitory neuromodulatory role on the processing of the pressor/sympathoexcitatory component of the chemoreflex.

  2. Interhemispheric transfalcine approach and awake cortical mapping for resection of peri-atrial gliomas associated with the central lobule.

    PubMed

    Malekpour, Mahdi; Cohen-Gadol, Aaron A

    2015-02-01

    Medial posterior frontal and parietal gliomas extending to the peri-atrial region are difficult to reach surgically because of the working angle required to expose the lateral aspect of the tumor and the proximity of the tumor to the sensorimotor lobule; retraction of the sensorimotor cortex may lead to morbidity. The interhemispheric transfalcine approach is favorable and safe for resection of medial hemispheric tumors adjacent to the falx cerebri, but the literature on this approach is scarce. Awake cortical mapping using this operative route for tumors associated with the sensorimotor cortex has not been previously reported to our knowledge. We present the first case of a right medial posterior frontoparietal oligoastrocytoma that was resected through the interhemispheric transfalcine approach using awake cortical and subcortical mapping. Through a contralateral frontoparietal craniotomy, we excised a section of the falx and exposed the contralateral medial hemisphere. Cortical stimulation allowed localization of the supplementary motor cortex, and suprathreshold stimulation mapping excluded the primary motor cortex corresponding to the leg area. Gross total tumor resection was accomplished without any intraoperative or postoperative deficits. Awake cortical mapping using the contralateral transfalcine approach allows a "cross-court" operative route to map functional cortices and resect peri-atrial low-grade gliomas. This technique can minimize the otherwise necessary retraction on the ipsilateral hemisphere through an ipsilateral craniotomy.

  3. Restraint training for awake functional brain scanning of rodents can cause long-lasting changes in pain and stress responses

    PubMed Central

    Low, Lucie A.; Bauer, Lucy C.; Pitcher, Mark H.; Bushnell, M. Catherine

    2016-01-01

    Abstract With the increased interest in longitudinal brain imaging of awake rodents, it is important to understand both the short-term and long-term effects of restraint on sensory and emotional processing in the brain. To understand the effects of repeated restraint on pain behaviors and stress responses, we modeled a restraint protocol similar to those used to habituate rodents for magnetic resonance imaging scanning, and studied sensory sensitivity and stress hormone responses over 5 days. To uncover lasting effects of training, we also looked at responses to the formalin pain test 2 weeks later. We found that while restraint causes acute increases in the stress hormone corticosterone, it can also cause lasting reductions in nociceptive behavior in the formalin test, coupled with heightened corticosterone levels and increased activation of the “nociceptive” central nucleus of the amygdala, as seen by Fos protein expression. These results suggest that short-term repeated restraint, similar to that used to habituate rats for awake functional brain scanning, could potentially cause long-lasting changes in physiological and brain responses to pain stimuli that are stress-related, and therefore could potentially confound the functional activation patterns seen in awake rodents in response to pain stimuli. PMID:27058679

  4. [Incidence and causes of early end in awake surgery for language mapping not directly related to eloquence].

    PubMed

    Villalba, Gloria; Pacreu, Susana; Fernández-Candil, Juan Luis; León, Alba; Serrano, Laura; Conesa, Gerardo

    2016-01-01

    The incidence and causes that may lead to an early end (unfinished cortical/subcortical mapping) of awake surgery for language mapping are little known. A study was conducted on 41 patients with brain glioma located in the language area that had awake surgery under conscious sedation. Surgery was ended early in 6 patients. The causes were: tonic-clonic seizure (1), lack of cooperation due to fatigue/sleep (4), whether or not word articulation was involved, a decreased level of consciousness for ammonia encephalopathy that required endotracheal intubation (1). There are causes that could be expected and in some cases avoided. Tumour size, preoperative aphasia, valproate treatment, and type of anaesthesia used are variables to consider to avoid failure in awake surgery for language mapping. With these results, the following measures are proposed: l) If the tumour is large, perform surgery in two times to avoid fatigue, 2) if patient has a preoperative aphasia, do not use sedation during surgery to ensure that sleepiness does not cause worse word articulation, 3) if the patient is on valproate treatment, it is necessary to rule out the pre-operative symptoms that are not due to ammonia encephalopathy. PMID:26260205

  5. Effects of the endogenous clock and sleep time on melatonin, insulin, glucose and lipid metabolism.

    PubMed

    Morgan, L; Arendt, J; Owens, D; Folkard, S; Hampton, S; Deacon, S; English, J; Ribeiro, D; Taylor, K

    1998-06-01

    This study was undertaken to determine whether the internal clock contributes to the hormone and metabolic responses following food, in an experiment designed to dissociate internal clock effects from other factors. Nine female subjects participated. They lived indoors for 31 days with normal time cues, including the natural light: darkness cycle. For 7 days they retired to bed from 0000 h to 0800 h. They then underwent a 26-h 'constant routine' (CR) starting at 0800 h, being seated awake in dim light with hourly 88 Kcal drinks. They then lived on an imposed 27-h day (18 h of wakefulness, 9 h allowed for sleep), for a total of 27 days. A second 26-h CR, starting at 2200 h, was completed. During each CR salivary melatonin and plasma glucose, triacylglycerol (TAG), non-essential fatty acids (NEFA), insulin, gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1) were measured hourly. Melatonin and body temperature data indicated no shift in the endogenous clock during the 27-h imposed schedule. Postprandial NEFA, GIP and GLP-1 showed no consistent effects. Glucose, TAG and insulin increased during the night in the first CR. There was a significant effect of both the endogenous clock and sleep for glucose and TAG, but not for insulin. These findings may be relevant to the known increased risk of cardiovascular disease amongst shift workers.

  6. Ameliorating treatment-refractory depression with intranasal ketamine: potential NMDA receptor actions in the pain circuitry representing mental anguish.

    PubMed

    Opler, Lewis A; Opler, Mark G A; Arnsten, Amy F T

    2016-02-01

    This article reviews the antidepressant actions of ketamine, an N-methyl-D-aspartame glutamate receptor (NMDAR) antagonist, and offers a potential neural mechanism for intranasal ketamine's ultra-rapid actions based on the key role of NMDAR in the nonhuman primate prefrontal cortex (PFC). Although intravenous ketamine infusions can lift mood within hours, the current review describes how intranasal ketamine administration can have ultra-rapid antidepressant effects, beginning within minutes (5-40 minutes) and lasting hours, but with repeated treatments needed for sustained antidepressant actions. Research in rodents suggests that increased synaptogenesis in PFC may contribute to the prolonged benefit of ketamine administration, beginning hours after administration. However, these data cannot explain the relief that occurs within minutes of intranasal ketamine delivery. We hypothesize that the ultra-rapid effects of intranasal administration in humans may be due to ketamine blocking the NMDAR circuits that generate the emotional representations of pain (eg, Brodmann Areas 24 and 25, insular cortex), cortical areas that can be overactive in depression and which sit above the nasal epithelium. In contrast, NMDAR blockade in the dorsolateral PFC following systemic administration of ketamine may contribute to cognitive deficits. This novel view may help to explain how intravenous ketamine can treat the symptoms of depression yet worsen the symptoms of schizophrenia. PMID:25619798

  7. Safety, tolerability, pharmacokinetics, and pharmacodynamics of compound SFDAC by intranasal administration of multiple escalating dose in healthy male subjects.

    PubMed

    Thennati, Rajamannar; Khanna, Aman; Khanna, Mallika; Sonaiya, Tushar; Mehta, Tejas; Mehta, Kalpana; Shahi, Pradeep; Patel, Jigneshkumar

    2014-11-01

    A novel corticosteroid compound (short form of IUPAC name: SFDAC) has been discovered by Sun Pharma Advanced Research Company (SPARC) Ltd. A randomized, observer-blind, active-controlled, parallel-groups, intranasal multiple escalating dose study was conducted in healthy male subjects to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of compound SFDAC formulated as an aqueous suspension for intranasal administration. Intranasal sprays of SFDAC, active control fluticasone propionate (FP) and placebo were administered once in a day for 14 days as per randomization. Various clinical evaluations including 24-hour serum cortisol and urinary free cortisol (UFC) profiles were carried out. Blood samples were collected at pre-defined time-points and analyzed using a validated chromatographic method for estimation of SFDAC and its metabolite. The results of the study indicate that multiple dose of SFDAC intranasal spray upto 3,200 µg is safe and tolerated. Clinically significant suppression of hypothalamic pituitary adrenal (HPA) axis was not observed. The plasma concentration of SFDAC was found to be below the lower limit of quantification (LLQ) at most time-points for all subjects. SFDAC M1 metabolite was detected only at picogram level in plasma. The safety and pharmacokinetic characteristics of SFDAC observed in this study support further clinical development of the SFDAC nasal spray.

  8. Immune Responses of Dairy Cattle to Parainfluenza-3 Virus in Intranasal Infectious Bovine Rhinotracheitis-Parainfluenza-3 Virus Vaccines

    PubMed Central

    Burroughs, A.L.; Morrill, J.L.; Bostwick, J.L.; Ridley, R.K.; Fryer, H.C.

    1982-01-01

    Two hundred and fifty dairy heifers were vaccinated at three to six months of age with an intranasal infectious bovine rhinotracheitis-parainfluenza-3 vaccine. Eighteen additional heifers were tested prior to vaccination and again three to four weeks after vaccination. Neither cell-mediated nor humoral immunity was significantly raised to parainfluenza-3 virus in either group of cattle. PMID:6290012

  9. Intranasal Vaccination Affords Localization and Persistence of Antigen-Specific CD8+ T Lymphocytes in the Female Reproductive Tract

    PubMed Central

    Singh, Shailbala; Schluns, Kimberly S.; Yang, Guojun; Anthony, Scott M.; Barry, Michael A.; Sastry, K. Jagannadha

    2016-01-01

    Immunization strategies generating large numbers of antigen-specific T cells in the female reproductive tract (FRT) can provide barrier protection against sexually-transmitted pathogens, such as the human immunodeficiency virus (HIV) and human papillomaviruses (HPV). The kinetics and mechanisms of regulation of vaccine-induced adaptive T cell-mediated immune responses in FRT are less well defined. We present here evidence for intranasal delivery of the model antigen ovalbumin (OVA) along with alpha-galactosylceramide adjuvant as a protein vaccine to induce significantly higher levels of antigen-specific effector and memory CD8+ T cells in the FRT, relative to other systemic and mucosal tissues. Antibody blocking of the CXCR3 receptor significantly reduced antigen-specific CD8+ T cells subsequent to intranasal delivery of the protein vaccine suggesting an important role for the CXCR3 chemokine-receptor signaling for T cell trafficking. Further, intranasal vaccination with an adenoviral vector expressing OVA or HIV-1 envelope was as effective as intramuscular vaccination for generating OVA- or ENV-specific immunity in the FRT. These results support the application of the needle-free intranasal route as a practical approach to delivering protein as well as DNA/virus vector-based vaccines for efficient induction of effector and memory T cell immunity in the FRT. PMID:26999228

  10. Effects of cold pressor pain on the abuse liability of intranasal oxycodone in male and female prescription opioid abusers

    PubMed Central

    Lofwall, Michelle R.; Nuzzo, Paul A.; Walsh, Sharon L.

    2012-01-01

    Background Approximately 1.9 million persons in the U.S. have prescription opioid use disorders often with concomitant bodily pain, but systematic data on the impact of pain on abuse liability of opioids is lacking. The purpose of this study was to determine whether pain alters the intranasal abuse liability of oxycodone, a commonly prescribed and abused analgesic, in males and females. Methods Sporadic prescription opioid abusers (10 females, 10 males) participated in this mixed (between and within-subject), randomized inpatient study. Experimental sessions (n=6) tested intranasal placebo, oxycodone 15 or 30 mg/70 kg during cold pressor testing (CPT) and a warm water control. Observer- and subject-rated drug effect measures, analgesia, physiologic and cognitive effects were assessed. Results The CPT significantly increased blood pressure, heart rate, pain, stress, and “opiate desire” compared to the no-pain control but did not alter opioid liking, high or street value. Intranasal oxycodone produced effects within 10 minutes, significantly decreasing pain and significantly increasing subjective measures of abuse liability (e.g., high). Females had higher ratings of street value, high, and liking for one or both active doses. Conclusions The CPT was a reliably painful and stressful stimulus that did not diminish the abuse liability of intranasal Oxycodone®. Females were more sensitive to oxycodone on several abuse liability measures that warrant further follow-up. Snorting oxycodone rapidly produced psychoactive effects indicative of substantial abuse liability. PMID:22209386

  11. A common oxytocin receptor gene (OXTR) polymorphism modulates intranasal oxytocin effects on the neural response to social cooperation in humans

    PubMed Central

    Feng, Chunliang; Lori, Adriana; Waldman, Irwin D.; Binder, Elisabeth B.; Haroon, Ebrahim; Rilling, James K.

    2015-01-01

    Intranasal oxytocin (OT) can modulate social-emotional functioning and related brain activity in humans. Consequently, OT has been discussed as a potential treatment for psychiatric disorders involving social behavioral deficits. However, OT effects are often heterogeneous across individuals. Here we explore individual differences in OT effects on the neural response to social cooperation as a function of the rs53576 polymorphism of the oxytocin receptor gene (OXTR). Previously, we conducted a double-blind, placebo-controlled study in which healthy men and women were randomized to treatment with intranasal OT or placebo. Afterwards, they were imaged with fMRI while playing an iterated Prisoner’s Dilemma Game with same-sex partners. Within the left ventral caudate nucleus, intranasal OT treatment increased activation to reciprocated cooperation in men, but tended to decrease activation in women. Here, we show that these sex differences in OT effects are specific to individuals with the rs53576 GG genotype, and are not found for other genotypes (rs53576 AA/AG). Thus, OT may increase the reward or salience of positive social interactions for male GG homozygotes, while decreasing those processes for female GG homozygotes. These results suggest that rs53576 genotype is an important variable to consider in future investigations of the clinical efficacy of intranasal OT treatment. PMID:26178189

  12. Ameliorating treatment-refractory depression with intranasal ketamine: potential NMDA receptor actions in the pain circuitry representing mental anguish.

    PubMed

    Opler, Lewis A; Opler, Mark G A; Arnsten, Amy F T

    2016-02-01

    This article reviews the antidepressant actions of ketamine, an N-methyl-D-aspartame glutamate receptor (NMDAR) antagonist, and offers a potential neural mechanism for intranasal ketamine's ultra-rapid actions based on the key role of NMDAR in the nonhuman primate prefrontal cortex (PFC). Although intravenous ketamine infusions can lift mood within hours, the current review describes how intranasal ketamine administration can have ultra-rapid antidepressant effects, beginning within minutes (5-40 minutes) and lasting hours, but with repeated treatments needed for sustained antidepressant actions. Research in rodents suggests that increased synaptogenesis in PFC may contribute to the prolonged benefit of ketamine administration, beginning hours after administration. However, these data cannot explain the relief that occurs within minutes of intranasal ketamine delivery. We hypothesize that the ultra-rapid effects of intranasal administration in humans may be due to ketamine blocking the NMDAR circuits that generate the emotional representations of pain (eg, Brodmann Areas 24 and 25, insular cortex), cortical areas that can be overactive in depression and which sit above the nasal epithelium. In contrast, NMDAR blockade in the dorsolateral PFC following systemic administration of ketamine may contribute to cognitive deficits. This novel view may help to explain how intravenous ketamine can treat the symptoms of depression yet worsen the symptoms of schizophrenia.

  13. Subacute intranasal administration of tissue plasminogen activator promotes neuroplasticity and improves functional recovery following traumatic brain injury in rats.

    PubMed

    Meng, Yuling; Chopp, Michael; Zhang, Yanlu; Liu, Zhongwu; An, Aaron; Mahmood, Asim; Xiong, Ye

    2014-01-01

    Traumatic brain injury (TBI) is a major cause of death and long-term disability worldwide. To date, there are no effective pharmacological treatments for TBI. Recombinant human tissue plasminogen activator (tPA) is the effective drug for the treatment of acute ischemic stroke. In addition to its thrombolytic effect, tPA is also involved in neuroplasticity in the central nervous system. However, tPA has potential adverse side effects when administered intravenously including brain edema and hemorrhage. Here we report that tPA, administered by intranasal delivery during the subacute phase after TBI, provides therapeutic benefit. Animals with TBI were treated intranasally with saline or tPA initiated 7 days after TBI. Compared with saline treatment, subacute intranasal tPA treatment significantly 1) improved cognitive (Morris water maze test) and sensorimotor (footfault and modified neurological severity score) functional recovery in rats after TBI, 2) reduced the cortical stimulation threshold evoking ipsilateral forelimb movement, 3) enhanced neurogenesis in the dentate gyrus and axonal sprouting of the corticospinal tract originating from the contralesional cortex into the denervated side of the cervical gray matter, and 4) increased the level of mature brain-derived neurotrophic factor. Our data suggest that subacute intranasal tPA treatment improves functional recovery and promotes brain neurogenesis and spinal cord axonal sprouting after TBI, which may be mediated, at least in part, by tPA/plasmin-dependent maturation of brain-derived neurotrophic factor.

  14. Intratracheal administration of influenza virus is superior to intranasal administration as a model of acute lung injury.

    PubMed

    Morales-Nebreda, Luisa; Chi, Monica; Lecuona, Emilia; Chandel, Navdeep S; Dada, Laura A; Ridge, Karen; Soberanes, Saul; Nigdelioglu, Recep; Sznajder, Jacob I; Mutlu, Gökhan M; Budinger, G R Scott; Radigan, Kathryn A

    2014-12-01

    Infection of mice with human or murine adapted influenza A viruses results in a severe pneumonia. However, the results of studies from different laboratories show surprising variability, even in genetically similar strains. Differences in inoculum size related to the route of viral delivery (intranasal vs. intratracheal) might explain some of this variability. To test this hypothesis, mice were infected intranasally or intratracheally with different doses of influenza A virus (A/WSN/33 [H1N1]). Daily weights, a requirement for euthanasia, viral load in the lungs and brains, inflammatory cytokines, wet-to-dry ratio, total protein and histopathology of the infected mice were examined. With all doses of influenza tested, intranasal delivery resulted in less severe lung injury, as well as smaller and more variable viral loads in the lungs when compared with intratracheal delivery. Virus was not detected in the brain following either method of delivery. It is concluded that compared to intranasal infection, intratracheal infection with influenza A virus is a more reliable method to deliver virus to the lungs.

  15. High-throughput mapping of brain-wide activity in awake and drug-responsive vertebrates.

    PubMed

    Lin, Xudong; Wang, Shiqi; Yu, Xudong; Liu, Zhuguo; Wang, Fei; Li, Wai Tsun; Cheng, Shuk Han; Dai, Qiuyun; Shi, Peng

    2015-02-01

    The reconstruction of neural activity across complete neural circuits, or brain activity mapping, has great potential in both fundamental and translational neuroscience research. Larval zebrafish, a vertebrate model, has recently been demonstrated to be amenable to whole brain activity mapping in behaving animals. Here we demonstrate a microfluidic array system ("Fish-Trap") that enables high-throughput mapping of brain-wide activity in awake larval zebrafish. Unlike the commonly practiced larva-processing methods using a rigid gel or a capillary tube, which are laborious and time-consuming, the hydrodynamic design of our microfluidic chip allows automatic, gel-free, and anesthetic-free processing of tens of larvae for microscopic imaging with single-cell resolution. Notably, this system provides the capability to directly couple pharmaceutical stimuli with real-time recording of neural activity in a large number of animals, and the local and global effects of pharmacoactive drugs on the nervous system can be directly visualized and evaluated by analyzing drug-induced functional perturbation within or across different brain regions. Using this technology, we tested a set of neurotoxin peptides and obtained new insights into how to exploit neurotoxin derivatives as therapeutic agents. The novel and versatile "Fish-Trap" technology can be readily unitized to study other stimulus (optical, acoustic, or physical) associated functional brain circuits using similar experimental strategies.

  16. PET measured evoked cerebral blood flow responses in an awake monkey

    SciTech Connect

    Perlmutter, J.S.; Lich, L.L.; Margenau, W.; Buchholz, S. )

    1991-03-01

    We have developed a method to measure task-related regional cerebral blood flow (BF) responses in an awake, trained monkey using positron emission tomography (PET) and H215O. We trained an animal with operant conditioning using only positive reinforcement to climb unassisted into a modified primate chair that was then positioned in the PET scanner. A special headholder and acrylic skull cap permitted precise placement and accurate repositioning. We measured BF qualitatively with bolus injection of H215O and 40-s scan. Each session included scans at rest interposed with scans during vibration of a forepaw. Regional responses were identified using subtraction image analysis. After global normalization, a resting image was subtracted on a pixel-by-pixel basis from a comparable image collected during vibration. The region of peak response occurred in contralateral sensorimotor cortex with a mean magnitude of 11.6% (+/- 3.2%) of the global mean value for 10 separate experiments, significantly greater than the mean qualitative BF change (0.4 +/- 3.6%; p less than 0.00001) in the same region for seven rest-rest pairs. This newly developed technique forms the basis for a wide variety of experiments.

  17. Evaluation of a closed loop inductive power transmission system on an awake behaving animal subject.

    PubMed

    Kiani, Mehdi; Kwon, Ki Yong; Zhang, Fei; Oweiss, Karim; Ghovanloo, Maysam

    2011-01-01

    This paper presents in vivo experimental results for a closed loop wireless power transmission system to implantable devices on an awake behaving animal subject. In this system, wireless power transmission takes place across an inductive link, controlled by a commercial off-the-shelf (COTS) radio frequency identification (RFID) transceiver (TRF7960) operating at 13.56 MHz. Induced voltage on the implantable secondary coil is rectified, digitized by a 10-bit analog to digital converter, and transmitted back to the primary via back telemetry. Transmitter (Tx) and receiver (Rx) circuitry were mounted on the back of an adult rat with a nominal distance of ~7 mm between their coils. Our experiments showed that the closed loop system was able to maintain the Rx supply voltage at the designated 3.8 V despite changes in the coils' relative distance and alignment due to animal movements. The Tx power consumption changed between 410 ~ 560 mW in order to deliver 27 mW to the receiver. The open loop system, on the other hand, showed undesired changes in the Rx supply voltage while the Tx power consumption was constant at 660 mW. PMID:22256112

  18. Neurobehavioral evidence for individual differences in canine cognitive control: an awake fMRI study.

    PubMed

    Cook, Peter F; Spivak, Mark; Berns, Gregory

    2016-09-01

    Based on behavioral evidence, the domestic dog has emerged as a promising comparative model of human self-control. However, while research on human inhibition has probed heterogeneity and neuropathology through an integration of neural and behavioral evidence, there are no parallel data exploring the brain mechanisms involved in canine inhibition. Here, using a combination of cognitive testing and awake neuroimaging in domestic dogs, we provide evidence precisely localizing frontal brain regions underpinning response inhibition in this species and demonstrate the dynamic relationship between these regions and behavioral measures of control. Thirteen dogs took part in an in-scanner go/no-go task and an out-of-scanner A-not-B test. A frontal brain region was identified showing elevated neural activity for all subjects during successful inhibition in the scanner, and dogs showing greater mean brain activation in this region produced fewer false alarms. Better performance in the go/no-go task was also correlated with fewer errors in the out-of-scanner A-not-B test, suggesting that dogs show consistent neurobehavioral individual differences in cognitive control, as is seen in humans. These findings help establish parity between human and canine mechanisms of self-control and pave the way for future comparative studies examining their function and dysfunction. PMID:27062134

  19. Sodium bicarbonate treatment prevents gastric emptying delay caused by acute exercise in awake rats.

    PubMed

    Silva, Moisés T B; Palheta-Junior, Raimundo C; Sousa, Daniel F; Fonseca-Magalhães, Patrícia A; Okoba, Willy; Campos, Caio P S; Oliveira, Ricardo B; Magalhães, Pedro J C; Santos, Armenio A

    2014-05-01

    Physical exercise, mainly after vigorous activity, may induce gastrointestinal dysmotility whose mechanisms are still unknown. We hypothesized that physical exercise and ensuing lactate-related acidemia alter gastrointestinal motor behavior. In the present study, we evaluated the effects of short-term exercise on gastric emptying rate in awake rats subjected to 15-min swimming sessions against a load equivalent to 5% of their body weight. After 0, 10, or 20 min of exercise testing, the rats were gavage fed with 1.5 ml of a liquid test meal (0.5 mg/ml of phenol red in 5% glucose solution) and euthanized 10 min postprandially to measure fractional gastric dye recovery. In addition to inducing acidemia and increasing blood lactate levels, acute exercise increased (P < 0.05) gastric retention. Such a phenomenon presented a positive correlation (P < 0.001) between blood lactate levels and fractional gastric dye recovery. Gastric retention and other acidbase-related changes were all prevented by NaHCO3 pretreatment. Additionally, exercise enhanced (P < 0.05) the marker's progression through the small intestine. In anesthetized rats, exercise increased (P < 0.05) gastric volume, measured by a balloon catheter in a barostat system. Compared with sedentary control rats, acute exercise also inhibited (P < 0.05) the contractility of gastric fundus strips in vitro. In conclusion, acute exercise delayed the gastric emptying of a liquid test meal by interfering with the acid-base balance. PMID:24557800

  20. Areas of the brain concerned with ventilatory load compensation in awake man

    PubMed Central

    Isaev, Gennadi; Murphy, Kevin; Guz, Abraham; Adams, Lewis

    2002-01-01

    There is broad agreement that the awake human ventilatory response to a moderate inspiratory load consists of a prolongation of inspiratory time (TI) with a maintenance of tidal volume (VT) and end-tidal PCO2 (PET,CO2), the response being severely blunted in sleep. There is no agreement on the mechanisms underlying this ventilatory response. Six naive healthy males (aged 39–44) were studied supine with their heads in a positron emission tomography (PET) scanner to allow relative regional cerebral blood flow (rCBF) to be measured with H215O given intravenously. A linearised resistive load (24 cmH2O (l s−1)−1) could be added to the inspiratory limb of a breathing valve inserted into a tightly fitting facemask; inspiratory flow was measured with a pneumotachograph. The load was applied, without alerting the subject, when the radioactivity first reached the head. Six scans were performed with and without the load, in each subject. Relative rCBF contrasts between the loaded and unloaded breathing states showed significant activations in inferior parietal cortex, prefrontal cortex, midbrain, basal ganglia and multiple cerebellar sites. No activations were found in the primary sensorimotor cortex. The findings suggest that there is a pattern of motor behavioural response to the uncomfortable sensation that inspiration is impeded. This results in a prolongation of TI, the maintenance of VT and a reduction in the degree of discomfort, presumably because of the reduction of mean negative pressure in the airways. PMID:11897862

  1. Awake dynamics and brain-wide direct inputs of hypothalamic MCH and orexin networks

    PubMed Central

    González, J. Antonio; Iordanidou, Panagiota; Strom, Molly; Adamantidis, Antoine; Burdakov, Denis

    2016-01-01

    The lateral hypothalamus (LH) controls energy balance. LH melanin-concentrating-hormone (MCH) and orexin/hypocretin (OH) neurons mediate energy accumulation and expenditure, respectively. MCH cells promote memory and appropriate stimulus-reward associations; their inactivation disrupts energy-optimal behaviour and causes weight loss. However, MCH cell dynamics during wakefulness are unknown, leaving it unclear if they differentially participate in brain activity during sensory processing. By fiberoptic recordings from molecularly defined populations of LH neurons in awake freely moving mice, we show that MCH neurons generate conditional population bursts. This MCH cell activity correlates with novelty exploration, is inhibited by stress and is inversely predicted by OH cell activity. Furthermore, we obtain brain-wide maps of monosynaptic inputs to MCH and OH cells, and demonstrate optogenetically that VGAT neurons in the amygdala and bed nucleus of stria terminalis inhibit MCH cells. These data reveal cell-type-specific LH dynamics during sensory integration, and identify direct neural controllers of MCH neurons. PMID:27102565

  2. Automated working distance adjustment enables optical coherence tomography of the human larynx in awake patients

    PubMed Central

    Donner, Sabine; Bleeker, Sebastian; Ripken, Tammo; Ptok, Martin; Jungheim, Michael; Krueger, Alexander

    2015-01-01

    Abstract. Optical coherence tomography (OCT) provides structural information of laryngeal tissue which is comparable to histopathological analysis of biopsies taken under general anesthesia. In awake patients, movements impede clinically useful OCT acquisition. Therefore, an automatic compensation of movements was implemented into a swept source OCT-laryngoscope. Video and OCT beam path were combined in one tube of 10-mm diameter. Segmented OCT images served as distance sensor and a feedback control adjusted the working distance between 33 and 70 mm by synchronously translating the reference mirror and focusing lens. With this motion compensation, the tissue was properly visible in up to 88% of the acquisition time. During quiet respiration, OCT contrasted epithelium and lamina propria. Mean epithelial thickness was measured to be 109 and 135  μm in female and male, respectively. Furthermore, OCT of mucosal wave movements during phonation enabled estimation of the oscillation frequency and amplitude. Regarding clinical issues, the OCT-laryngoscope with automated working distance adjustment may support the estimation of the depth extent of epithelial lesions and contribute to establish an indication for a biopsy. Moreover, OCT of the vibrating vocal folds provides functional information, possibly giving further insight into mucosal behavior during the vibratory cycle. PMID:26158116

  3. Neural correlates of sensorimotor gating: a metabolic positron emission tomography study in awake rats.

    PubMed

    Rohleder, Cathrin; Jung, Fabienne; Mertgens, Hanna; Wiedermann, Dirk; Sué, Michael; Neumaier, Bernd; Graf, Rudolf; Leweke, F Markus; Endepols, Heike

    2014-01-01

    Impaired sensorimotor gating occurs in neuropsychiatric disorders such as schizophrenia and can be measured using the prepulse inhibition (PPI) paradigm of the acoustic startle response. This assay is frequently used to validate animal models of neuropsychiatric disorders and to explore the therapeutic potential of new drugs. The underlying neural network of PPI has been extensively studied with invasive methods and genetic modifications. However, its relevance for healthy untreated animals and the functional interplay between startle- and PPI-related areas during a PPI session is so far unknown. Therefore, we studied awake rats in a PPI paradigm, startle control and background noise control, combined with behavioral [(18)F]fluoro-2-deoxyglucose positron emission tomography (FDG-PET). Subtractive analyses between conditions were used to identify brain regions involved in startle and PPI processing in well-hearing Black hooded rats. For correlative analysis with regard to the amount of PPI we also included hearing-impaired Lister hooded rats that startled more often, because their hearing threshold was just below the lowest prepulses. Metabolic imaging showed that the brain areas proposed for startle and PPI mediation are active during PPI paradigms in healthy untreated rats. More importantly, we show for the first time that the whole PPI modulation network is active during "passive" PPI sessions, where no selective attention to prepulse or startle stimulus is required. We conclude that this reflects ongoing monitoring of stimulus significance and constant adjustment of sensorimotor gating.

  4. Salicylate induced tinnitus: behavioral measures and neural activity in auditory cortex of awake rats.

    PubMed

    Yang, Guang; Lobarinas, Edward; Zhang, Liyan; Turner, Jeremy; Stolzberg, Daniel; Salvi, Richard; Sun, Wei

    2007-04-01

    Neurophysiological studies of salicylate-induced tinnitus have generally been carried out under anesthesia, a condition that abolishes the perception of tinnitus and depresses neural activity. To overcome these limitations, measurement of salicylate induced tinnitus were obtained from rats using schedule induced polydipsia avoidance conditioning (SIPAC) and gap pre-pulse inhibition of acoustic startle (GPIAS). Both behavioral measures indicated that tinnitus was present after treatment with 150 and 250 mg/kg of salicylate; measurements with GPIAS indicated that the pitch of the tinnitus was near 16 kHz. Chronically implanted microwire electrode arrays were used to monitor the local field potentials and spontaneous discharge rate from multiunit clusters in the auditory cortex of awake rats before and after treatment with 150 mg/kg of salicylate. The amplitude of the local field potential elicited with 60 dB SPL tone bursts increased significantly 2h after salicylate treatment particularly at 16-20 kHz; frequencies associated with the tinnitus pitch. Field potential amplitudes had largely recovered 1-2 days post-salicylate when behavioral results showed that tinnitus was absent. The mean spontaneous spike recorded from the same multiunit cluster pre- and post-salicylate decreased from 22 spikes/s before treatment to 14 spikes/s 2h post-salicylate and recovered 1 day post-treatment. These preliminary physiology data suggest that salicylate induced tinnitus is associated with sound evoked hyperactivity in auditory cortex and spontaneous hypoactivity.

  5. Irregular spiking of pyramidal neurons organizes as scale-invariant neuronal avalanches in the awake state

    PubMed Central

    Bellay, Timothy; Klaus, Andreas; Seshadri, Saurav; Plenz, Dietmar

    2015-01-01

    Spontaneous fluctuations in neuronal activity emerge at many spatial and temporal scales in cortex. Population measures found these fluctuations to organize as scale-invariant neuronal avalanches, suggesting cortical dynamics to be critical. Macroscopic dynamics, though, depend on physiological states and are ambiguous as to their cellular composition, spatiotemporal origin, and contributions from synaptic input or action potential (AP) output. Here, we study spontaneous firing in pyramidal neurons (PNs) from rat superficial cortical layers in vivo and in vitro using 2-photon imaging. As the animal transitions from the anesthetized to awake state, spontaneous single neuron firing increases in irregularity and assembles into scale-invariant avalanches at the group level. In vitro spike avalanches emerged naturally yet required balanced excitation and inhibition. This demonstrates that neuronal avalanches are linked to the global physiological state of wakefulness and that cortical resting activity organizes as avalanches from firing of local PN groups to global population activity. DOI: http://dx.doi.org/10.7554/eLife.07224.001 PMID:26151674

  6. Effects of lesions of the caudal cerebellar vermis on cardiovascular regulation in awake cats

    NASA Technical Reports Server (NTRS)

    Holmes, M. J.; Cotter, L. A.; Arendt, H. E.; Cass, S. P.; Yates, B. J.

    2002-01-01

    The vestibular system is known to participate in cardiovascular regulation during movement and postural alterations. The present study considered whether lesions of two regions of the posterior cerebellar vermis (the nodulus and uvula) that provide inputs to vestibular nucleus regions that affect control of blood pressure would alter cardiovascular responses during changes in posture. Blood pressure and heart rate were monitored in awake cats during nose-up tilts up to 60 degrees in amplitude before and following aspiration lesions of the nodulus or uvula; in most animals, cardiovascular responses were also recorded following the subsequent removal of vestibular inputs. Lesions of the nodulus or uvula did not affect baseline blood pressure or heart rate, although cardiovascular responses during nose-up tilts were altered. Increases in heart rate that typically occurred during 60 degrees nose-up tilt were attenuated in all three animals with lesions affecting both dorsal and ventral portions of the uvula; in contrast, the heart rate responses were augmented in the two animals with lesions mainly confined to the nodulus. Furthermore, following subsequent removal of vestibular inputs, uvulectomized animals, but not those with nodulus lesions, experienced more severe orthostatic hypotension than has previously been reported in cerebellum-intact animals with bilateral labyrinthectomies. These data suggest that the cerebellar nodulus and uvula modulate vestibulo-cardiovascular responses, although the two regions play different roles in cardiovascular regulation.

  7. Effect of geometric and motion tracking errors on awake small animal SPECT

    SciTech Connect

    Lee, Seung Joon; Baba, Justin S; Goddard Jr, James Samuel; Weisenberger, A G; Stolin, A; McKisson, J; Smith, M F

    2009-01-01

    A series of simulation studies were performed to evaluate the effects of geometric and motion tracking errors on reconstruction image quality for a single pinhole collimator awake animal imaging SPECT system. List-mode SPECT data generated using a custom Monte Carlo program that incorporated experimental mouse motion data were reconstructed by MLEM with Siddon's ray tracing. To better understand the impact of motion tracking and system geometric parameter errors on reconstructed system data, an offset of up to 1 mm or degree was separately applied to each for evaluation. In the absence of motion tracking or system geometric error, the applied motion compensation algorithm successfully reconstructed volumes without any degradation or distortion. Presented results reveal that motion tracking errors propagate through the SPECT reconstruction process. However, it is confirmed that the impact of tracking errors in the currently employed motion tracking system, is minimal because of their accuracy. The results also reveal the direct and indirect impact of geometric errors to motion compensated reconstruction quality and that a wrong assumption of pinhole transaxial position produces the most amount of distortion of all the investigated errors. Finally, system geometric errors are shown to have a greater impact on reconstruction quality than equivalent tracking errors.

  8. Awake dynamics and brain-wide direct inputs of hypothalamic MCH and orexin networks.

    PubMed

    González, J Antonio; Iordanidou, Panagiota; Strom, Molly; Adamantidis, Antoine; Burdakov, Denis

    2016-01-01

    The lateral hypothalamus (LH) controls energy balance. LH melanin-concentrating-hormone (MCH) and orexin/hypocretin (OH) neurons mediate energy accumulation and expenditure, respectively. MCH cells promote memory and appropriate stimulus-reward associations; their inactivation disrupts energy-optimal behaviour and causes weight loss. However, MCH cell dynamics during wakefulness are unknown, leaving it unclear if they differentially participate in brain activity during sensory processing. By fiberoptic recordings from molecularly defined populations of LH neurons in awake freely moving mice, we show that MCH neurons generate conditional population bursts. This MCH cell activity correlates with novelty exploration, is inhibited by stress and is inversely predicted by OH cell activity. Furthermore, we obtain brain-wide maps of monosynaptic inputs to MCH and OH cells, and demonstrate optogenetically that VGAT neurons in the amygdala and bed nucleus of stria terminalis inhibit MCH cells. These data reveal cell-type-specific LH dynamics during sensory integration, and identify direct neural controllers of MCH neurons.

  9. Effects of hypercapnia on variability of normal respiratory behavior in awake cats.

    PubMed

    Szlyk, P C; Jennings, D B

    1987-03-01

    Resting quiet awake cats breathing air in a steady state have a range of respiratory behavior, and this encompasses nonpurring and purring (D. B. Jennings and P. C. Szlyk, Can. J. Physiol. Pharmacol. 63: 148-154, 1985). On a given study day, individual cats usually breathed in a limited part of their potential respiratory range. Respiratory pattern, such as average breath frequency (f) and average tidal volume (VT) utilized for a given level of ventilation (V), could be predicted when cats breathed air; as well, inspiratory (TI) and expiratory (TE) times were specific for a given breath f. Inhalation of 2% and 4% CO2 in air caused an average increase in ventilation of 16 and 100%, respectively but breath-to-breath variability of V, f, and VT persisted at each fractional concentration of inspired CO2 (FICO2). The range of different V utilized breath to breath when breathing 2% CO2 overlapped with V during air control studies. Substantial overlap with control V also occurred in three of six cats when breathing 4% CO2. The most consistent effect of progressive hypercapnia was to increase VT and decrease f at a given level of V; increase in V during hypercapnia was accounted for by an increase in mean inspiratory flow (VT/TI). Hypercapnia also caused the fraction of breathing cycle devoted to inspiration (TI/TT) to increase at low f but not at high f.

  10. The role of awake craniotomy in reducing intraoperative visual field deficits during tumor surgery

    PubMed Central

    Wolfson, Racheal; Soni, Neil; Shah, Ashish H.; Hosein, Khadil; Sastry, Ananth; Bregy, Amade; Komotar, Ricardo J.

    2015-01-01

    Objective: Homonymous hemianopia due to damage to the optic radiations or visual cortex is a possible consequence of tumor resection involving the temporal or occipital lobes. The purpose of this review is to present and analyze a series of studies regarding the use of awake craniotomy (AC) to decrease visual field deficits following neurosurgery. Materials and Methods: A literature search was performed using the Medline and PubMed databases from 1970 and 2014 that compared various uses of AC other than intraoperative motor/somatosensory/language mapping with a focus on visual field mapping. Results: For the 17 patients analyzed in this study, 14 surgeries resulted in quadrantanopia, 1 in hemianopia, and 2 without visual deficits. Overall, patient satisfaction with AC was high, and AC was a means to reduce surgery-related complications and cost related with the procedure. Conclusion AC is a safe and tolerable procedure that can be used effectively to map optic radiations and the visual cortices in order to preserve visual function during resection of tumors infiltrating the temporal and occipital lobes. In the majority of cases, a homonymous hemianopia was prevented and patients were left with a quadrantanopia that did not interfere with daily function. PMID:26396597

  11. Neural correlates of sensorimotor gating: a metabolic positron emission tomography study in awake rats

    PubMed Central

    Rohleder, Cathrin; Jung, Fabienne; Mertgens, Hanna; Wiedermann, Dirk; Sué, Michael; Neumaier, Bernd; Graf, Rudolf; Leweke, F. Markus; Endepols, Heike

    2014-01-01

    Impaired sensorimotor gating occurs in neuropsychiatric disorders such as schizophrenia and can be measured using the prepulse inhibition (PPI) paradigm of the acoustic startle response. This assay is frequently used to validate animal models of neuropsychiatric disorders and to explore the therapeutic potential of new drugs. The underlying neural network of PPI has been extensively studied with invasive methods and genetic modifications. However, its relevance for healthy untreated animals and the functional interplay between startle- and PPI-related areas during a PPI session is so far unknown. Therefore, we studied awake rats in a PPI paradigm, startle control and background noise control, combined with behavioral [18F]fluoro-2-deoxyglucose positron emission tomography (FDG-PET). Subtractive analyses between conditions were used to identify brain regions involved in startle and PPI processing in well-hearing Black hooded rats. For correlative analysis with regard to the amount of PPI we also included hearing-impaired Lister hooded rats that startled more often, because their hearing threshold was just below the lowest prepulses. Metabolic imaging showed that the brain areas proposed for startle and PPI mediation are active during PPI paradigms in healthy untreated rats. More importantly, we show for the first time that the whole PPI modulation network is active during “passive” PPI sessions, where no selective attention to prepulse or startle stimulus is required. We conclude that this reflects ongoing monitoring of stimulus significance and constant adjustment of sensorimotor gating. PMID:24904330

  12. Effect of geometric and motion tracking error for awake small animal SPECT

    SciTech Connect

    S.J. Lee, J.S. Baba, J. S. Goddard, A. Stolin, J. McKisson, A.G. Weisenberger, M.F. Smith

    2010-01-01

    A series of simulation studies were performed to evaluate the effects of geometric and motion tracking errors on reconstruction image quality for a single pinhole collimator awake animal imaging SPECT system. List-mode SPECT data generated using a custom Monte Carlo program that incorporated experimental mouse motion data were reconstructed by MLEM with Siddon's ray tracing. To better understand the impact of motion tracking and system geometric parameter errors on reconstructed system data, an offset of up to 1 mm or degree was separately applied to each for evaluation. In the absence of motion tracking or system geometric error, the applied motion compensation algorithm successfully reconstructed volumes without any degradation or distortion. Presented results reveal that motion tracking errors propagate through the SPECT reconstruction process. However, it is confirmed that the impact of tracking errors in the currently employed motion tracking system, is minimal because of their accuracy. The results also reveal the direct and indirect impact of geometric errors to motion compensated reconstruction quality and that a wrong assumption of pinhole transaxial position produces the most amount of distortion of all the investigated errors. Finally, system geometric errors are shown to have a greater impact on reconstruction quality than equivalent tracking errors.

  13. Validation of a Modified Algometer to Measure Mechanical Nociceptive Thresholds in Awake Dogs

    PubMed Central

    Chen, Hui Cheng; Goh, Yong Meng; Abubakar, Adamu Abdul; Fakurazi, Sharida

    2015-01-01

    This study was conducted to validate the use of a modified algometer device to measure mechanical nociceptive thresholds in six dogs. Dogs were administered morphine intravenously (IV) at 1 mg/kg or saline at equivolume in a crossover design with one-week washout period. Mechanical nociceptive thresholds were determined before, after the administration of treatments at 5 minutes, and hourly for 8 hours. Thresholds were recorded at the carpal pad, metacarpal foot pad, tibia, femur, and abdomen. Heart rates, body temperature, and respiration were recorded at similar time points. Thresholds increased significantly (P < 0.05) from baseline values for up to 3 hours at tibia and abdomen, 4 hours at metacarpal pad, and 5 hours at the carpal pad and femur. Hypothermia, bradycardia, and change in respiration were observed in all dogs after morphine injection. Saline did not alter any threshold levels during the eight-hour study period, indicating no evidence of tolerance, learned avoidance, or local hyperaesthesia. The device and methods of testing were well tolerated by all the dogs. Results suggest that the modified algometer and method of application are useful to measure nociceptive mechanical thresholds in awake dogs. PMID:26075236

  14. RESPONSE PROPERTIES OF LOCAL FIELD POTENTIALS AND NEIGHBORING SINGLE NEURONS IN AWAKE PRIMARY VISUAL CORTEX

    PubMed Central

    Lashgari, Reza; Li, Xiaobing; Chen, Yao; Kremkow, Jens; Bereshpolova, Yulia; Swadlow, Harvey A.; Alonso, Jose M.

    2012-01-01

    Recordings from local field potentials (LFPs) are becoming increasingly common in research and clinical applications, however, we still have a poor understanding of how LFP stimulus selectivity originates from the combined activity of single neurons. Here, we systematically compared the stimulus selectivity of LFP and neighboring single unit activity (SUA) recorded in area V1 of awake primates. We demonstrate that LFP and SUA have similar stimulus preferences for orientation, direction of motion, contrast, size, temporal frequency and even spatial phase. However, the average SUA had 50 times better signal to noise, 20% higher contrast sensitivity, 45% higher direction selectivity and 15% more tuning depth than the average LFP. Low LFP frequencies (< 30 Hz) were most strongly correlated with the spiking frequencies of neurons with non-linear spatial summation and poor orientation/direction selectivity that were located near cortical current sinks (negative LFPs). In contrast, LFP gamma frequencies (> 30 Hz) were correlated with a more diverse group of neurons located near cortical sources (positive LFPs). In summary, our results indicate that low- and high-frequency LFP pools signals from V1 neurons with similar stimulus preferences but different response properties and cortical depths. PMID:22895722

  15. PET measured evoked cerebral blood flow responses in an awake monkey.

    PubMed

    Perlmutter, J S; Lich, L L; Margenau, W; Buchholz, S

    1991-03-01

    We have developed a method to measure task-related regional cerebral blood flow (BF) responses in an awake, trained monkey using positron emission tomography (PET) and H215O. We trained an animal with operant conditioning using only positive reinforcement to climb unassisted into a modified primate chair that was then positioned in the PET scanner. A special headholder and acrylic skull cap permitted precise placement and accurate repositioning. We measured BF qualitatively with bolus injection of H215O and 40-s scan. Each session included scans at rest interposed with scans during vibration of a forepaw. Regional responses were identified using subtraction image analysis. After global normalization, a resting image was subtracted on a pixel-by-pixel basis from a comparable image collected during vibration. The region of peak response occurred in contralateral sensorimotor cortex with a mean magnitude of 11.6% (+/- 3.2%) of the global mean value for 10 separate experiments, significantly greater than the mean qualitative BF change (0.4 +/- 3.6%; p less than 0.00001) in the same region for seven rest-rest pairs. This newly developed technique forms the basis for a wide variety of experiments.

  16. Coherent 25- to 35-Hz Oscillations in the Sensorimotor Cortex of Awake Behaving Monkeys

    NASA Astrophysics Data System (ADS)

    Murthy, Venkatesh N.; Fetz, Eberhard E.

    1992-06-01

    Synchronous 25- to 35-Hz oscillations were observed in local field potentials and unit activity in sensorimotor cortex of awake rhesus monkeys. The oscillatory episodes occurred often when the monkeys retrieved raisins from a Kluver board or from unseen locations using somatosensory feedback; they occurred less often during performance of repetitive wrist flexion and extension movements. The amplitude, duration, and frequency of oscillations were not directly related to movement parameters in behaviors studied so far. The occurrence of the oscillations was not consistently related to bursts of activity in forearm muscles, but cycle-triggered averages of electromyograms revealed synchronous modulation in flexor and extensor muscles. The phase of the oscillations changed continuously from the surface to the deeper layers of the cortex, reversing their polarity completely at depths exceeding 800 μm. The oscillations could become synchronized over a distance of 14 mm mediolaterally in precentral cortex. Coherent oscillations could also occur at pre- and postcentral sites separated by an estimated tangential intracortical distance of 20 mm. Activity of single units was commonly seen to burst in synchrony with field potential oscillations. These findings suggest that such oscillations may facilitate interactions between cells during exploratory and manipulative movements, requiring attention to sensorimotor integration.

  17. Inhibition shapes selectivity to vocalizations in the inferior colliculus of awake mice

    PubMed Central

    Mayko, Zachary M.; Roberts, Patrick D.; Portfors, Christine V.

    2012-01-01

    The inferior colliculus (IC) is a major center for integration of auditory information as it receives ascending projections from a variety of brainstem nuclei as well as descending projections from the thalamus and auditory cortex. The ascending projections are both excitatory and inhibitory and their convergence at the IC results in a microcircuitry that is important for shaping responses to simple, binaural, and modulated sounds in the IC. Here, we examined the role inhibition plays in shaping selectivity to vocalizations in the IC of awake, normal-hearing adult mice (CBA/CaJ strain). Neurons in the IC of mice show selectivity in their responses to vocalizations, and we hypothesized that this selectivity is created by inhibitory microcircuitry in the IC. We compared single unit r