WorldWideScience

Sample records for awake intranasal insulin

  1. Intranasal insulin therapy

    DEFF Research Database (Denmark)

    Hilsted, J; Madsbad, S; Hvidberg, A;

    1995-01-01

    To evaluate metabolic control and safety parameters (hypoglycaemia frequency and nasal mucosa physiology), 31 insulin-dependent diabetic patients were treated with intranasal insulin at mealtimes for 1 month and with subcutaneous fast-acting insulin at meals for another month in an open, crossover...... randomized trial. During both treatment periods the patients were treated with intermediate-acting insulin at bedtime. Six of the patients were withdrawn from the study during intranasal insulin therapy due to metabolic dysregulation. Serum insulin concentrations increased more rapidly and decreased more...... quickly during intranasal as compared with subcutaneous insulin administration. Metabolic control deteriorated, as assessed by haemoglobin A1c concentrations, slightly but significantly after intranasal as compared with subcutaneous insulin therapy. The bioavailability of intranasally applied insulin...

  2. Intranasal insulin therapy: the clinical realities

    DEFF Research Database (Denmark)

    Hilsted, J; Madsbad, Sten; Hvidberg, A;

    1995-01-01

    To evaluate metabolic control and safety parameters (hypoglycaemia frequency and nasal mucosa physiology), 31 insulin-dependent diabetic patients were treated with intranasal insulin at mealtimes for 1 month and with subcutaneous fast-acting insulin at meals for another month in an open, crossover...... randomized trial. During both treatment periods the patients were treated with intermediate-acting insulin at bedtime. Six of the patients were withdrawn from the study during intranasal insulin therapy due to metabolic dysregulation. Serum insulin concentrations increased more rapidly and decreased more...... quickly during intranasal as compared with subcutaneous insulin administration. Metabolic control deteriorated, as assessed by haemoglobin A1c concentrations, slightly but significantly after intranasal as compared with subcutaneous insulin therapy. The bioavailability of intranasally applied insulin...

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

    Science.gov (United States)

    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.

  4. Intranasal Insulin Improves Age-Related Cognitive Deficits and Reverses Electrophysiological Correlates of Brain Aging.

    Science.gov (United States)

    Maimaiti, Shaniya; Anderson, Katie L; DeMoll, Chris; Brewer, Lawrence D; Rauh, Benjamin A; Gant, John C; Blalock, Eric M; Porter, Nada M; Thibault, Olivier

    2016-01-01

    Peripheral insulin resistance is a key component of metabolic syndrome associated with obesity, dyslipidemia, hypertension, and type 2 diabetes. While the impact of insulin resistance is well recognized in the periphery, it is also becoming apparent in the brain. Recent studies suggest that insulin resistance may be a factor in brain aging and Alzheimer's disease (AD) whereby intranasal insulin therapy, which delivers insulin to the brain, improves cognition and memory in AD patients. Here, we tested a clinically relevant delivery method to determine the impact of two forms of insulin, short-acting insulin lispro (Humalog) or long-acting insulin detemir (Levemir), on cognitive functions in aged F344 rats. We also explored insulin effects on the Ca(2+)-dependent hippocampal afterhyperpolarization (AHP), a well-characterized neurophysiological marker of aging which is increased in the aged, memory impaired animal. Low-dose intranasal insulin improved memory recall in aged animals such that their performance was similar to that seen in younger animals. Further, because ex vivo insulin also reduced the AHP, our results suggest that the AHP may be a novel cellular target of insulin in the brain, and improved cognitive performance following intranasal insulin therapy may be the result of insulin actions on the AHP.

  5. Reduction of smoking urges with intranasal insulin: a randomized, crossover, placebo-controlled clinical trial.

    Science.gov (United States)

    Hamidovic, A; Khafaja, M; Brandon, V; Anderson, J; Ray, G; Allan, A M; Burge, M R

    2017-02-28

    Many cigarette smokers express a desire to quit smoking, but ~85% of cessation attempts fail. In our attempt to delineate genetic modulators of smoking persistence, we have earlier shown that a locus within an ~250 kb haplotype block spanning the 5' untranslated region region of insulin-degrading enzyme is associated with serum cotinine levels; the study's measure of smoking quantity. Based on our findings, and coupled with recent preclinical studies showing the importance of multiple neuropeptides in reinstatement of drug use, we formulated intranasal insulin to evaluate its efficacy during acute abstinence from smoking. Our original study was a crossover trial including 19 otherwise healthy smokers who abstained from smoking for 36 h. The morning following their second night of abstinence, in random order, study participants received intranasal insulin (60 IU) or placebo (8.7% sodium chloride). The goal of our second study was to replicate the craving findings from the original trial and expand this research by including additional stress-related measures. Thirty-seven study participants abstained from smoking overnight. The next day, they were administered either intranasal insulin (60 IU) or placebo, following which they participated in the Trier Social Stress Test Task. This was a parallel design study focusing on the standard stress subjective, hormonal and cardiovascular measures. We also evaluated any changes in circulating glucose, insulin and c-peptide (a marker of endogenous insulin). In the original study, intranasal insulin significantly reduced morning nicotine craving (b=3.65, P⩽0.05). Similarly, in the second study, intranasal insulin reduced nicotine cravings over time (b=0.065, P⩽0.05) and the effect lasted through the psychosocial stress period. Intranasal insulin also increased circulating cortisol levels (F=12.78, P⩽0.001). No changes in insulin or c-peptide were detected. A significant treatment × time interaction (P⩽0.05) was

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

    Science.gov (United States)

    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.

  7. Intranasal insulin prevents anesthesia-induced hyperphosphorylation of tau in 3xTg-AD mice

    Directory of Open Access Journals (Sweden)

    Yanxing eChen

    2014-05-01

    Full Text Available Background: It is well documented that elderly individuals are at increased risk of cognitive decline after anesthesia. General anesthesia is believed to be a risk factor for Alzheimer’s disease (AD. Recent studies suggest that anesthesia may increase the risk for cognitive decline and AD through promoting abnormal hyperphosphorylation of tau, which is crucial to neurodegeneration seen in AD. Methods: We treated 3xTg-AD mice, a commonly used transgenic mouse model of AD, with daily intranasal administration of insulin (1.75U/day for one week. The insulin- and control-treated mice were then anesthetized with single intraperitoneal injection of propofol (250 mg/kg body weight. Tau phosphorylation and tau protein kinases and phosphatases in the brains of mice 30 min and two hours after propofol injection were then investigated by using Western blots and immunohistochemistry.Results: Propofol strongly promoted hyperphosphorylation of tau at several AD-related phosphorylation sites. Intranasal administration of insulin attenuated propofol-induced hyperphosphorylation of tau, promoted brain insulin signaling, and led to up-regulation of protein phosphatase 2A, a major tau phosphatase in the brain. Intranasal insulin also resulted in down-regulation of several tau protein kinases, including cyclin-dependent protein kinase 5, calcium/calmodulin-dependent protein kinase II, and c-Jun N-terminal kinase. Conclusion: Our results demonstrate that pretreatment with intranasal insulin prevents AD-like tau hyperphosphorylation. These findings provide the first evidence supporting that intranasal insulin administration might be used for the prevention of anesthesia-induced cognitive decline and increased risk for AD and dementia.

  8. Effect of hepatic glucose production on acute insulin resistance induced by lipid-infusion in awake rats

    Institute of Scientific and Technical Information of China (English)

    Ling Li; Gang-Yi Yang

    2004-01-01

    AIM: To explore the influence of hepatic glucose production on acute insulin resistance induced by a lipid infusion in awake rats.METHODS: A hyperinsulinaemic-euglycaemic clamp was established in awake chronically catheterized rats. Two groups of rats were studied either with a 4-h intraarterial infusion of lipid/heparin or saline. Insulin-mediated peripheral and hepatic glucose metabolism was assessed by hyperinsulinaemiceuglycaemic clamp combined with [3-3H]-glucose infusion.RESULTS: During hyperinsulinaemic-euglycaemic clamp,there was a significant increase in plasma free fatty acid (FFA, from 741.9±50.6 to 2346.4±238.5 μmol/L, P<0.01) in lipid-infused group. The glucose infusion rates (GIR) in the lipid infusion rats, compared to control rats, were significantly reduced (200-240 min average: lipid infusion; 12.6±1.5 vs control; 34.0±1.6 mg/kg.min, P<0.01), declining to - 35%of the corresponding control values during the last time of the clamp (240 min: lipid infusion; 12.0±1.9 vs control;34.7±1.7 mg/kg.min, P<0.0001). At the end of clamp study,the hepatic glucose production (HGP) in control rats was significantly suppressed (88%) from 19.0±4.5 (basal) to 2.3±0.9 mg/kg.min (P<0.01). The suppressive effect of insulin on HGP was significantly blunted in the lipid-infused (P<0.05). The rate of glucose disappearance (GRd) was a slight decrease in the lipid-infused rats compared with controls during the clamp.CONCLUSION: These data suggest that lipid infusion could induces suppression of hepatic glucose production, impairs the abilities of insulin to suppress lipolysis and mediate glucose utilization in peripheral tissue. Therefore, we conclude that lipid-infusion induces an acute insulin resistance in vivo.

  9. 胰岛素鼻黏膜给药系统的研究进展%Progress of the intranasal administration of insulin

    Institute of Scientific and Technical Information of China (English)

    李莹; 段晓品; 毛世瑞

    2012-01-01

    Objective To review the new administration routes of insulin and the development of intranasal delivery system. Methods According to thirty-six recent relevant literatures, the new routes and the development of intranasal delivery system of insulin were summarized. The new routes of insulin administration,the characteristics of intranasal delivery and some strategies to improve the bioavailability of insulin after nasal administration were summarized. Results It seems that the addition of safe absorption enhancers or water-insoluble powders into insulin formulation can dramatically improve the bioavailability of insulin after nasal administration. Conclusions The intranasal administration of insulin in the pharmaceutical field is promising.%目的 综述胰岛素近年来鼻黏膜给药的相关信息.方法 查阅国内外相关文献36篇,进行相关分析、归纳和总结.结果 综述出鼻黏膜给药的特点以及提高鼻黏膜生物利用度的诸多方法.在胰岛素制剂中加入安全高效的吸收促进剂或水不溶性粉末将会很大程度上提高其生物利用度.结论 胰岛素鼻黏膜给药在药学领域将会有广阔的发展前景.

  10. ADMINISTRACIÓN DE INSULINA POR VÍA INTRANASAL Y MEMORIA DECLARATIVA: REVISIÓN SISTEMÁTICA DE LA LITERATURA Intranasal insulin administration and declarative memory: A systematic review

    Directory of Open Access Journals (Sweden)

    Andrés Jagua Gualdrón

    2008-12-01

    Full Text Available Antecedentes. La insulina participa de los procesos de formación de la memoria y los defectos en su señalización podrían estar relacionados con el déficit cognitivo y las enfermedades neurode-generativas como la enfermedad de Alzheimer. Objetivo. Evaluar la relación entre la administración de la insulina por vía intranasal y la memoria declarativa en estudios en humanos. Material y métodos. Se realizó una búsqueda intensiva y sistemática de estudios publicados entre enero de 1997 y diciembre del 2008 a través de las bases de datos MEDLINE, Cochrane, DynaMed y LILACS. Los estudios fueron sometidos a dos pruebas de calidad metodológica, se les realizó un análisis crítico y se aplicó estadística básica. Resultados. Se hallaron cinco artículos que incluían 252 personas. De ellos 143 tenían diagnóstico probable de la enfermedad de Alzheimer o alteración cognitiva leve. Los estudios reportan mejoría en las tareas de la memoria a corto y largo plazo en los grupos que recibieron la insulina comparados con quienes recibieron el placebo. Conclusión. Los estudios son pocos y difíciles de comparar. Sin embargo tras este análisis puede sugerirse que la insulina actúa durante la formación de la memoria declarativa y podría emplearse en el tratamiento de los trastornos de la memoria.Background. Insulin acts in memory formation and its signal impairment can be related with mild cognitive impairment and neurodegenerative diseases like Alzheimer's disease. Objective. To evaluate the relationship between intranasal insulin administration and declarative memory in studies with human. Materials and methods. A systematic search of studies published from January 1997 to december 2008 through electronic databases MEDLINE, DynaMed, Cochrane and LIlACS. Articles were evaluated with two tests for methodological validity and a basic statistical analysis was performed. Results. We find five articles that include 252 persons. 143 have

  11. Kliniske konsekvenser af intranasal insulinbehandling ved insulinkraevende diabetes mellitus

    DEFF Research Database (Denmark)

    Hilsted, J C; Madsbad, S; Rasmussen, M H;

    1996-01-01

    Metabolic control, hypoglycaemia frequency and nasal mucosal physiology were evaluated in 31 insulin-dependent diabetics treated with intranasal insulin at mealtimes for one month and with subcutaneous fast-acting insulin for another month in a randomized crossover trial. During both periods...

  12. [BETA-ADRENERGIC REGULATION OF THE ADENYLYL CYCLASE SIGNALING SYSTEM IN MYOCARDIUM AND BRAIN OF RATS WITH OBESITY AND TYPES 2 DIABETES MELLITUS AND THE EFFECT OF LONG-TERM INTRANASAL INSULIN TREATMENT].

    Science.gov (United States)

    Kuznetsova, L A; Sharova, T S; Pertseva, M N; Shpakov, A O

    2015-01-01

    The stimulating effect of norepinephrine, isoproterenol and selective β-adrenoceptor (β3-AR) agonists BRL 37344 and CL 316.243 on the adenylyl cyclase signaling system (ACSS) in the brain and myocardium of young and mature rats (disease induction at 2 and 4 months, respectively) with experimental obesity and type 2 diabetes mellitus (DM2), and the influence of long-term treatment of animals with intranasal insulin (I-I) were studied. The AC stimulatory effects of β-agonist isoproterenol in animals with obesity and DM2 was shown to be practically unchanged. The respective effects of norepinephrine on the AC activity were attenuated in the brain of young and mature rats and in the myocardium if mature rats, and the I-I treatment led to their partial recovery. In the brain and myocardium of mature rats with obesity and DM2, the enhancement of the AC stimulatory effects of β3-AR agonists was observed, white in young rats the influence of the same pathological conditions was lacking. The I-I treatment decreased the AC stimulatory effects of β3-agonists to their levels in the control. Since functional disruption of the adrenergic agonist-sensitive ACSS can lead to metabolic syndrome and DM2, the recovery of this system by the I-I treatment offers one of the ways to correct these diseases and their complications in the nervous and cardiovascular systems.

  13. Awake craniotomy for tumor resection

    Directory of Open Access Journals (Sweden)

    Mohammadali Attari

    2013-01-01

    Full Text Available Surgical treatment of brain tumors, especially those located in the eloquent areas such as anterior temporal, frontal lobes, language, memory areas, and near the motor cortex causes high risk of eloquent impairment. Awake craniotomy displays major rule for maximum resection of the tumor with minimum functional impairment of the Central Nervous System. These case reports discuss the use of awake craniotomy during the brain surgery in Alzahra Hospital, Isfahan, Iran. A 56-year-old woman with left-sided body hypoesthesia since last 3 months and a 25-year-old with severe headache of 1 month duration were operated under craniotomy for brain tumors resection. An awake craniotomy was planned to allow maximum tumor intraoperative testing for resection and neurologic morbidity avoidance. The method of anesthesia should offer sufficient analgesia, hemodynamic stability, sedation, respiratory function, and also awake and cooperative patient for different neurological test. Airway management is the most important part of anesthesia during awake craniotomy. Tumor surgery with awake craniotomy is a safe technique that allows maximal resection of lesions in close relationship to eloquent cortex and has a low risk of neurological deficit.

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

    Science.gov (United States)

    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.…

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

    Directory of Open Access Journals (Sweden)

    Manabu Kadoya

    Full Text Available 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.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.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.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.

  16. Awake operative videothoracoscopic pulmonary resections.

    Science.gov (United States)

    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

  17. Neurosurgical complications after intranasal ethmoidectomy.

    OpenAIRE

    Toselli, R M; dePapp, A; Harbaugh, R E; Saunders, R. L.

    1991-01-01

    Intranasal ethmoidectomy is a common otolaryngological procedure. Despite the potential for serious intracranial complications, there is a paucity of reports describing the neurosurgical complications of the procedure. Two patients with intracranial complications of intranasal ethmoidectomy, and the relevant medical literature, are reviewed. The anatomy of the ethmoid air cells and their relation to the intracranial cavity are described. The importance of definitive, emergent repair with atte...

  18. Awake fiberoptic or awake video laryngoscopic tracheal intubation in patients with anticipated difficult airway management

    DEFF Research Database (Denmark)

    Rosenstock, Charlotte Vallentin; Thøgersen, Bente; Afshari, Arash;

    2012-01-01

    Awake flexible fiberoptic intubation (FFI) is the gold standard for management of anticipated difficult tracheal intubation. The purpose of this study was to compare awake FFI to awake McGrath® video laryngoscope, (MVL), (Aircraft Medical, Edinburgh, Scotland, United Kingdom) intubation in patien...

  19. Intranasal Oxytocin: Myths and Delusions.

    Science.gov (United States)

    Leng, Gareth; Ludwig, Mike

    2016-02-01

    Despite widespread reports that intranasal application of oxytocin has a variety of behavioral effects, very little of the huge amounts applied intranasally appears to reach the cerebrospinal fluid. However, peripheral concentrations are increased to supraphysiologic levels, with likely effects on diverse targets including the gastrointestinal tract, heart, and reproductive tract. The wish to believe in the effectiveness of intranasal oxytocin appears to be widespread and needs to be guarded against with scepticism and rigor. Preregistering trials, declaring primary and secondary outcomes in advance, specifying the statistical methods to be applied, and making all data openly available should minimize problems of publication bias and questionable post hoc analyses. Effects of intranasal oxytocin also need proper dose-response studies, and such studies need to include control subjects for peripheral effects, by administering oxytocin peripherally and by blocking peripheral actions with antagonists. Reports in the literature of oxytocin measurements include many that have been made with discredited methodology. Claims that peripheral measurements of oxytocin reflect central release are questionable at best.

  20. Intranasal sedatives in pediatric dentistry

    Science.gov (United States)

    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

  1. AWAKE starts the equipment installation phase

    CERN Multimedia

    Antonella Del Rosso

    2015-01-01

    AWAKE is the proof-of-principle experiment whose aim is to use protons to generate powerful wakefields to accelerate an electron beam. With accelerator gradients hundreds of times higher than those used in current systems, this technique could revolutionise the field of particle acceleration. Installed in the tunnel previously used by the CNGS facility, AWAKE is completing the service installation phase and will receive the plasma cell in the coming months.   The AWAKE proton line with all the magnets installed. (Image: AWAKE collaboration.) AWAKE is the world’s first proton-driven plasma wakefield acceleration experiment. In AWAKE, a beam of protons from the SPS will be travelling through a plasma cell and this will generate a wakefield that, in turn, will accelerate an electron beam. A laser will ionise the gas in the plasma cell and seed the self-modulation instability that will trigger the wakefield in the plasma. The project aims to prove that the plasma wakefield can be driv...

  2. Intranasal sedatives in pediatric dentistry

    OpenAIRE

    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 art...

  3. The Role of Insulin, Insulin Growth Factor, and Insulin-Degrading Enzyme in Brain Aging and Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Claude Messier

    2005-01-01

    Full Text Available Most brain insulin comes from the pancreas and is taken up by the brain by what appears to be a receptor-based carrier. Type 2 diabetes animal models associated with insulin resistance show reduced insulin brain uptake and content. Recent data point to changes in the insulin receptor cascade in obesity-related insulin resistance, suggesting that brain insulin receptors also become less sensitive to insulin, which could reduce synaptic plasticity. Insulin transport to the brain is reduced in aging and in some animal models of type 2 diabetes; brain insulin resistance may be present as well. Studies examining the effect of the hyperinsulinic clamp or intranasal insulin on cognitive function have found a small but consistent improvement in memory and changes in brain neuroelectric parameters in evoked brain potentials consistent with improved attention or memory processing. These effects appear to be due to raised brain insulin levels. Peripheral levels of Insulin Growth Factor-I (IGF-I are associated with glucose regulation and influence glucose disposal. There is some indication that reduced sensitivity to insulin or IGF-I in the brain, as observed in aging, obesity, and diabetes, decreases the clearance of Aβ amyloid. Such a decrease involves the insulin receptor cascade and can also increase amyloid toxicity. Insulin and IGF-I may modulate brain levels of insulin degrading enzyme, which would also lead to an accumulation of Aβ amyloid.

  4. Intranasal siRNA administration reveals IGF2 deficiency contributes to impaired cognition in Fragile X syndrome mice

    Science.gov (United States)

    Pardo, Marta; Cheng, Yuyan; Velmeshev, Dmitry; Magistri, Marco; Martinez, Ana; Faghihi, Mohammad A.; Jope, Richard S.; Beurel, Eleonore

    2017-01-01

    Molecular mechanisms underlying learning and memory remain imprecisely understood, and restorative interventions are lacking. We report that intranasal administration of siRNAs can be used to identify targets important in cognitive processes and to improve genetically impaired learning and memory. In mice modeling the intellectual deficiency of Fragile X syndrome, intranasally administered siRNA targeting glycogen synthase kinase-3β (GSK3β), histone deacetylase-1 (HDAC1), HDAC2, or HDAC3 diminished cognitive impairments. In WT mice, intranasally administered brain-derived neurotrophic factor (BDNF) siRNA or HDAC4 siRNA impaired learning and memory, which was partially due to reduced insulin-like growth factor-2 (IGF2) levels because the BDNF siRNA– or HDAC4 siRNA–induced cognitive impairments were ameliorated by intranasal IGF2 administration. In Fmr1–/– mice, hippocampal IGF2 was deficient, and learning and memory impairments were ameliorated by IGF2 intranasal administration. Therefore intranasal siRNA administration is an effective means to identify mechanisms regulating cognition and to modulate therapeutic targets. PMID:28352664

  5. Awake, Offline Processing during Associative Learning.

    Directory of Open Access Journals (Sweden)

    James K Bursley

    Full Text Available 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.

  6. Path to AWAKE: Evolution of the concept

    Science.gov (United States)

    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].

  7. Path to AWAKE: Evolution of the concept

    CERN Document Server

    Caldwell, A; 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.

    2016-01-01

    This report 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 [1].

  8. Path to AWAKE: Evolution of the concept

    OpenAIRE

    Caldwell, Allen; Adli, E.; Bernardini, M.; Soby, L.; Sosedkin, A. P.; Spitsyn, R. I.; Tajima, T.; Tarkeshian, R.; Timko, H.; Trines, R; Tückmantel, T.; Tuev, P. V.; Turner, M.; Bingham, R.; Velotti, F.

    2016-01-01

    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 w...

  9. Path to AWAKE: Evolution of the concept

    Energy Technology Data Exchange (ETDEWEB)

    Caldwell, A. [Max Planck Institute for Physics, Föhringer Ring 6, 80805 München (Germany); Adli, E. [University of Oslo, 0316 Oslo (Norway); Amorim, L. [GoLP/Instituto de Plasmas e Fusão Nuclear, Instituto Superior Técnico, Universidade de Lisboa, Lisbon (Portugal); Apsimon, R. [Cockcroft Institute, Warrington WA4 4AD (United Kingdom); Lancaster University, Lancaster LA1 4YR (United Kingdom); Argyropoulos, T. [CERN, Geneva (Switzerland); Assmann, R. [DESY, Notkestrasse 85, 22607 Hamburg (Germany); Bachmann, A.-M.; Batsch, F. [Max Planck Institute for Physics, Föhringer Ring 6, 80805 München (Germany); Bauche, J. [CERN, Geneva (Switzerland); Berglyd Olsen, V.K. [University of Oslo, 0316 Oslo (Norway); Bernardini, M. [CERN, Geneva (Switzerland); Bingham, R. [STFC Rutherford Appleton Laboratory, Didcot OX11 0QX (United Kingdom); Biskup, B. [CERN, Geneva (Switzerland); Czech Technical University, Zikova 1903/4, 166 36 Praha 6 (Czech Republic); Bohl, T.; Bracco, C. [CERN, Geneva (Switzerland); Burrows, P.N. [John Adams Institute for Accelerator Science, Oxford (United Kingdom); University of Oxford, Oxford OX1 2JD (United Kingdom); Burt, G. [Cockcroft Institute, Warrington WA4 4AD (United Kingdom); Lancaster University, Lancaster LA1 4YR (United Kingdom); Buttenschön, B. [Max Planck Institute for Plasma Physics, Wendelsteinstr. 1, 17491 Greifswald (Germany); Butterworth, A. [CERN, Geneva (Switzerland); Cascella, M. [UCL, Gower Street, London WC1E 6BT (United Kingdom); and others

    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]. - Highlights: • Proton-driven plasma wakefield acceleration is proposed to bring electron bunches to high energies. • The self-modulation instability allows the use of existing proton bunches. • Schemes for overcoming the varying wake phase velocity were developed. • AWAKE will demonstrate proton-driven plasma wakefield acceleration for the first time.

  10. Intranasal Insulin: A Novel Treatment for Gulf War Multisymptom Illness

    Science.gov (United States)

    2015-10-01

    pump twice daily through the nose . The placebo group will administer saline through a nasal infusion pump twice daily as well. The primary outcome...level sarin and cyclosarin exposure and Gulf War Illness on Brain Structure and Function: A study at 4T. Neurotoxicology. Chao LL, Rothlind JC...Cardenas VA, Meyerhoff DJ, Weiner MW. (2010). Effects of low-level exposure to sarin and cyclosarin during the 1991 Gulf War on brain function and brain

  11. Live attenuated intranasal influenza vaccine.

    Science.gov (United States)

    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.

  12. CERN AWAKE Facility Readiness for First Beam

    CERN Document Server

    Bracco, Chiara; Butterworth, Andrew; Damerau, Heiko; Döbert, Steffen; Fedosseev, Valentin; Feldbaumer, Eduard; Gschwendtner, Edda; Höfle, Wolfgang; Pardons, Ans; Shaposhnikova, Elena; Vincke, Helmut

    2016-01-01

    The AWAKE project at CERN was approved in August 2013 and since then a big effort was made to be able to probe the acceleration of electrons before the "2019-2020 Long Shutdown". The next steps in this challenging schedule will be a dry run of all the beam line systems, at the end of the HW commissioning in June 2016, and the first proton beam sent to the plasma cell one month later. The current status of the project is presented together with an outlook over the foreseen works for operation with electrons in 2018.

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

    Science.gov (United States)

    ... 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: ...

  14. INTRANASAL DEXMEDETOMIDINE VS. INTRANASAL MIDAZOLAM FOR PREMEDICATION OF PAEDIATRIC SURGERY PATIENTS

    Directory of Open Access Journals (Sweden)

    Revi N

    2016-06-01

    Full Text Available AIM Preoperative anxiety is one of the most common problems faced by anyone practising paediatric anaesthesia. Various drugs have been used in various routes to get a calm but cooperative child before induction of anaesthesia. Midazolam and dexmedetomidine have already proved their value in paediatric premedication. This study was conducted to compare the effects of these two drugs given intranasally. MATERIALS AND METHODS 100 children falling under the inclusion criteria were assigned to groups of 50 each. They received either intranasal midazolam 0.2 mg/kg (group M or intranasal dexmedetomidine 2 mcg/kg (Group D as premedication. They were compared with regards to the sedation status, anxiety levels and cardiovascular status every 10 minutes, at parental separation and at face mask application. RESULTS The mean sedation score obtained at all-time intervals, at parental separation and more importantly at mask induction were much lower for the midazolam group compared to the dexmedetomidine group. The mean anxiety levels, in general, were lower in the midazolam group, but they attained statistical significance only at 10 minutes and at mask induction. The heart rate measured up to 20 minutes after drug administration did not show much difference between both groups, but at 30 minutes, 40 minutes and at parental separation, heart rate was found to be lower in the dexmedetomidine group. CONCLUSION Intranasal dexmedetomidine and intranasal midazolam are equally effective in providing satisfactory parental separation, but intranasal midazolam produced superior conditions for mask acceptance than intranasal dexmedetomidine.

  15. Population Pharmacokinetics of Intranasal Scopolamine

    Science.gov (United States)

    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.

  16. Preparing to perform an awake fiberoptic intubation.

    LENUS (Irish Health Repository)

    Walsh, M E

    2012-02-03

    Fiberoptically guided tracheal intubation represents one of the most important advances in airway management to occur in the past thirty years. Perhaps its most important role is in management of the anticipated difficult airway. This is a situation in which the dangers of encountering the life-threatening "can\\'t intubate, can\\'t ventilate" situation can be avoided by placement of an endotracheal tube while the patient is awake. Although skill at the procedure of endoscopy is obviously necessary in this setting, these authors hold that success or failure of the technique frequently depends on the adequacy of preparation. These measures include 1) pre-operative assessment of the patient; 2) careful explanation of what lies in store; 3) "setting the stage"; 4) preparing the equipment to be used; and 5) preparing the patient (antisialogue, sedation, application of topical anesthesia to the upper airway). If these preparatory measures are carried out meticulously, the likelihood of performing a successful and comfortable awake fiberoptic tracheal intubation is greatly increased.

  17. Lung function measurement in awake young children

    DEFF Research Database (Denmark)

    Bisgaard, H; Klug, B

    1995-01-01

    The aim of the study was to evaluate methods applicable in a clinical setting for monitoring of changes in lung function in awake young children. Impedance measurements by the impulse oscillation technique (ZIOS), respiratory resistance measurements by the interrupter technique (Rint) and transcu......The aim of the study was to evaluate methods applicable in a clinical setting for monitoring of changes in lung function in awake young children. Impedance measurements by the impulse oscillation technique (ZIOS), respiratory resistance measurements by the interrupter technique (Rint......, with suspected asthma. Measurements with each technique were repeated after each challenge step. A special face-mask was developed with an integrated mouthpiece which ensured mouth breathing during the measurements. The order of sensitivity of the techniques to assess methacholine-induced changes in lung...... to methacholine in young children aged 4-6 yrs. This implies that ZIOS, Rint and Ptc,O2 provide convenient indices of changes in lung function. Their combined use will be useful for monitoring airway diseases of young children....

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

    NARCIS (Netherlands)

    A.J. Mann (Alex); N. Noulin (Nicolas); A. Catchpole (Andrew); K.J. Stittelaar (Koert); L. de Waal (Leon); E.J.B. Veldhuis Kroeze (Edwin); M. Hinchcliffe (Michael); A. Smith (Alan); E. Montomoli (Emanuele); S. Piccirella (Simona); A.D.M.E. Osterhaus (Albert); A. Knight (Alastair); J. Oxford; G. Lapini (Giulia); R. Cox (Ruben); R. Lambkin-Williams (Rob)

    2014-01-01

    textabstractWe 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

  19. Insulin Secretagogues

    Science.gov (United States)

    ... Your Body in Balance › Insulin Secretagogues Fact Sheet Insulin Secretagogues March, 2012 Download PDFs English Espanol Editors ... medicines can help you stay healthy. What are insulin secretagogues? Insulin secretagogues (pronounced seh-KREET-ah-gogs) ...

  20. Brain processing of biologically relevant odors in the awake rat, as revealed by manganese-enhanced MRI.

    Directory of Open Access Journals (Sweden)

    Benoist Lehallier

    Full Text Available BACKGROUND: So far, an overall view of olfactory structures activated by natural biologically relevant odors in the awake rat is not available. Manganese-enhanced MRI (MEMRI is appropriate for this purpose. While MEMRI has been used for anatomical labeling of olfactory pathways, functional imaging analyses have not yet been performed beyond the olfactory bulb. Here, we have used MEMRI for functional imaging of rat central olfactory structures and for comparing activation maps obtained with odors conveying different biological messages. METHODOLOGY/PRINCIPAL FINDINGS: Odors of male fox feces and of chocolate flavored cereals were used to stimulate conscious rats previously treated by intranasal instillation of manganese (Mn. MEMRI activation maps showed Mn enhancement all along the primary olfactory cortex. Mn enhancement elicited by male fox feces odor and to a lesser extent that elicited by chocolate odor, differed from that elicited by deodorized air. This result was partly confirmed by c-Fos immunohistochemistry in the piriform cortex. CONCLUSION/SIGNIFICANCE: By providing an overall image of brain structures activated in awake rats by odorous stimulation, and by showing that Mn enhancement is differently sensitive to different stimulating odors, the present results demonstrate the interest of MEMRI for functional studies of olfaction in the primary olfactory cortex of laboratory small animals, under conditions close to natural perception. Finally, the factors that may cause the variability of the MEMRI signal in response to different odor are discussed.

  1. Cilioretinal artery occlusion following intranasal cocaine insufflations

    Directory of Open Access Journals (Sweden)

    Balaji Kannan

    2011-01-01

    Full Text Available Cocaine is used to produce a euphoric effect by abusers, who may be unaware of the devastating systemic and ocular side effects of this drug. We describe the first known case of cilioretinal artery occlusion after intranasal cocaine abuse.

  2. Insulin and Insulin Resistance

    OpenAIRE

    Wilcox, Gisela

    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, stru...

  3. Anesthesia management of awake craniotomy performed under asleep-awake-asleep technique using laryngeal mask airway: Report of two cases

    Directory of Open Access Journals (Sweden)

    Vitthal Shrinivas

    2008-01-01

    Full Text Available Asleep-awake-asleep technique of anesthesia is used during awake craniotomy with or without securing airway. We assessed this technique using laryngeal mask airway (LMA in two patients. Patients underwent awake craniotomy for epilepsy surgery and the removal of a frontotemporal glioma. After anesthesia induction, airway was secured using LMA. Anesthesia was maintained using oxygen, nitrous oxide and sevoflurane, supplemented with an infusion of propofol and remifentanil. Twenty minutes before corticography, anesthesia was discontinued and LMA removed. Both patients were awake and cooperative during the neurological assessment and surgery on eloquent areas. The LMA was reinserted before the closure of the dura and remained in place until the end of surgery. Both patients had no recall of events under anesthesia, although experienced mild pain and discomfort during awake phase of surgery. Both expressed complete satisfaction over the anesthetic management. Asleep-awake-asleep technique using LMA offers airway protection. The painful aspect of surgery can be performed under anesthesia, hence minimizing the duration of stress and pain. Patients remained awake and cooperative throughout the time of neurological testing.

  4. Visualization and Quantitative Assessment of the Brain Distribution of Insulin through Nose-to-Brain Delivery Based on the Cell-Penetrating Peptide Noncovalent Strategy.

    Science.gov (United States)

    Kamei, Noriyasu; Shingaki, Tomotaka; Kanayama, Yousuke; Tanaka, Misa; Zochi, Riyo; Hasegawa, Koki; Watanabe, Yasuyoshi; Takeda-Morishita, Mariko

    2016-03-07

    Our recent work suggested that intranasal coadministration with the cell-penetrating peptide (CPP) penetratin increased the brain distribution of the peptide drug insulin. The present study aimed to distinctly certify the ability of penetratin to facilitate the nose-to-brain delivery of insulin by quantitatively evaluating the distribution characteristics in brain using radioactive (64)Cu-NODAGA-insulin. Autoradiography and analysis using a gamma counter of brain areas demonstrated that the accumulation of radioactivity was greatest in the olfactory bulb, the anterior part of the brain closest to the administration site, at 15 min after intranasal administration of (64)Cu-NODAGA-insulin with l- or d-penetratin. The brain accumulation of (64)Cu-NODAGA-insulin with penetratin was confirmed by ELISA using unlabeled insulin in which intact insulin was delivered to the brain after intranasal coadministration with l- or d-penetratin. By contrast, quantification of cerebrospinal fluid (CSF) samples showed increased insulin concentration in only the anterior portion of the CSF at 15 min after intranasal coadministration with l-penetratin. This study gives the first concrete proof that penetratin can accelerate the direct transport of insulin from the nasal cavity to the brain parenchyma. Further optimization of intranasal administration with CPP may increase the efficacy of delivery of biopharmaceuticals to the brain while reducing the risk of systemic drug exposure.

  5. The insulin-mediated modulation of visually evoked magnetic fields is reduced in obese subjects.

    Directory of Open Access Journals (Sweden)

    Martina Guthoff

    Full Text Available BACKGROUND: Insulin is an anorexigenic hormone that contributes to the termination of food intake in the postprandial state. An alteration in insulin action in the brain, named "cerebral insulin resistance", is responsible for overeating and the development of obesity. METHODOLOGY/PRINCIPAL FINDINGS: To analyze the direct effect of insulin on food-related neuronal activity we tested 10 lean and 10 obese subjects. We conducted a magnetencephalography study during a visual working memory task in both the basal state and after applying insulin or placebo spray intranasally to bypass the blood brain barrier. Food and non-food pictures were presented and subjects had to determine whether or not two consecutive pictures belonged to the same category. Intranasal insulin displayed no effect on blood glucose, insulin or C-peptide concentrations in the periphery; however, it led to an increase in the components of evoked fields related to identification and categorization of pictures (at around 170 ms post stimuli in the visual ventral stream in lean subjects when food pictures were presented. In contrast, insulin did not modulate food-related brain activity in obese subjects. CONCLUSIONS/SIGNIFICANCE: We demonstrated that intranasal insulin increases the cerebral processing of food pictures in lean whereas this was absent in obese subjects. This study further substantiates the presence of a "cerebral insulin resistance" in obese subjects and might be relevant in the pathogenesis of obesity.

  6. Intranasal glukagon til behandling af hypoglykaemi. En fremtidig behandlingsmulighed

    DEFF Research Database (Denmark)

    Carstens, S; Andersen, I; Gustafsson, Ida

    1994-01-01

    or glucose administered intravenously by a physician. These are however not optimal treatments. Obtaining intravenous access requires a medical doctor and glucagon injection is not always properly done by family members. Glucagon administered intranasally has been proven to raise blood glucose levels...... in volunteers. The effect of intranasal glucagon on blood glucose is similar to that seen after intramuscular administration for the first 15 minutes following administration. However, intranasal glucagon seems more physiological in that is stabilizes blood glucose concentrations at nearfasting levels, whereas...... glucagon given intramuscularly tends to give hyperglycaemia. Intranasal glucagon is easy to administer, and can thus prevent serious hypoglycaemic crises and thereby make diabetics and their families more secure....

  7. Patient experiences during awake mechanical ventilation

    Directory of Open Access Journals (Sweden)

    Danille Prime

    2016-02-01

    Full Text Available Background: Sedation practices in an ICU have shifted significantly in the past 20 years toward the use of minimizing sedation in mechanically ventilated patients. While minimizing sedation is clearly in the best interest of patients, data are lacking about how this approach affects patients’ experiences. Methods: We interviewed mechanically ventilated patients receiving minimal sedation, over a 6-month period in an ICU, in order to explore their emotional, comfort, and communication experiences. Their responses were compared with the responses of their available family members regarding their attitudes and perceptions of the patients’ experiences. Results: Seventy-five percent of the patients agreed or strongly agreed that they experienced pain, and 50% agreed or strongly agreed that they were comfortable. Half of the patients agreed or strongly agreed that they preferred to be kept awake. Five patients (31% indicated that they were frustrated while 17 relatives (89% agreed or strongly agreed that the patients were frustrated. When controlling for age and gender of respondents, family members perceived higher levels of patient pain (least square [LS] mean [95% CI]: 4.2 [3.7, 4.7] vs. 3.1 [2.5, 3.8]; p=0.022, frustration (LS mean [95% CI]: 4.2 [3.7, 4.6] vs. 3.2 [2.6, 3.9]; p=0.031, and adequate communication with nurses and doctors (LS mean [95% CI]: 3.9 [3.5, 4.4] vs. 3.1 [2.4, 3.7]; p=0.046 than the patients themselves. Conclusion: Patients tolerated minimal sedation without significant frustration while mechanically ventilated despite experiencing discomfort. Patient and family member perceptions of the patient experience may differ, especially in regards to pain and frustration. The use of a communication tool can facilitate understanding of patient experiences and preferences.

  8. Preparation of the patient and the airway for awake intubation

    Directory of Open Access Journals (Sweden)

    Venkateswaran Ramkumar

    2011-01-01

    Full Text Available Awake intubation is usually performed electively in the presence of a difficult airway. A detailed airway examination is time-consuming and often not feasible in an emergency. A simple 1-2-3 rule for airway examination allows one to identify potential airway difficulty within a minute. A more detailed airway examination can give a better idea about the exact nature of difficulty and the course of action to be taken to overcome it. When faced with an anticipated difficult airway, the anaesthesiologist needs to consider securing the airway in an awake state without the use of anaesthetic agents or muscle relaxants. As this can be highly discomforting to the patient, time and effort must be spent to prepare such patients both psychologically and pharmacologically for awake intubation. Psychological preparation is best initiated by an anaesthesiologist who explains the procedure in simple language. Sedative medications can be titrated to achieve patient comfort without compromising airway patency. Additional pharmacological preparation includes anaesthetising the airway through topical application of local anaesthetics and appropriate nerve blocks. When faced with a difficult airway, one should call for the difficult airway cart as well as for help from colleagues who have interest and expertise in airway management. Preoxygenation and monitoring during awake intubation is important. Anxious patients with a difficult airway may need to be intubated under general anaesthesia without muscle relaxants. Proper psychological and pharmacological preparation of the patient by an empathetic anaesthesiologist can go a long way in making awake intubation acceptable for all concerned.

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

    Science.gov (United States)

    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.

  10. Distinct BOLD activation profiles following central and peripheral oxytocin administration in awake rats

    Directory of Open Access Journals (Sweden)

    Craig F Ferris

    2015-09-01

    Full Text Available 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 (fMRI in awake rats imaged at 7.0 tesla. These data were compared to OT (1ug/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.

  11. Awake transapical aortic valve implantation using thoracic epidural anesthesia.

    Science.gov (United States)

    Mukherjee, Chirojit; Walther, Thomas; Borger, Michael Andrew; Kempfert, Joerg; Schuler, Gerhard; Mohr, Friedrich Wilhelm; Ender, Joerg

    2009-09-01

    Transapical aortic valve implantation is a minimally invasive, beating-heart procedure that normally requires a general anesthetic. We herein report an 85-year-old patient with impaired pulmonary function who underwent successful transapical aortic valve implantation while awake, using a thoracic epidural anesthetic.

  12. Insulin Injection

    Science.gov (United States)

    ... or buttocks. Do not inject insulin into muscles, scars, or moles. Use a different site for each ... you are using insulin.Alcohol may cause a decrease in blood sugar. Ask your doctor about the ...

  13. Non-clinical safety evaluation of intranasal iota-carrageenan.

    Directory of Open Access Journals (Sweden)

    Alexandra Hebar

    Full Text Available 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.

  14. Cytotoxic Effects of Intranasal Midazolam on Nasal Mucosal Tissue.

    Science.gov (United States)

    Ozbay, I; Kucur, C; Değer, A; Ital, I; Kasim, Cayci M; Oghan, F

    2015-09-01

    The aim of this experimental study was to investigate the cytotoxic effects of intranasal midazolam on nasal mucosal tissue in rats. Forty healthy rats were randomly divided into 5 groups. Group 1 (n = 8) was the control group, group 2 (n = 8) received intranasal saline, group 3 (n = 8) received intranasal midazolam, group 4 (n = 8) received intraperitoneal saline, and group 5 received intraperitoneal midazolam (n = 8). Midazolam and saline were administered via intraperitoneal and intranasal routes at doses of 200 μg/kg. Nasal septal mucosal stripe tissues were removed at the 6th hour. All materials were evaluated according to Ki67 and p53 staining to evaluate proliferation and apoptosis, respectively, and hemotoxylin and eosin staining was performed for histopathology evaluation. Ki67 values and inflammation in group 3 were statistically higher compared to group 1, group 2, and group 4. P53 values in group 3 were statistically higher compared to group 1. Assessment of subepithelial edema between group 3 and the other groups revealed no statistically significant differences. Assessment of cilia loss between group 3 and group 1, group 2, and group 4 revealed no statistically significant difference. The evaluation of goblet cell loss between group 3 and group 1 revealed a statistically significant difference. Intranasal midazolam had adverse effects on nasal mucosa. However, intranasal midazolam is as safe as systemic midazolam administration with respect to nasal mucosa.

  15. Intranasal mucoadhesive microemulsion of mirtazapine: Pharmacokinetic and pharmacodynamic studies

    Directory of Open Access Journals (Sweden)

    Hetal P Thakkar

    2013-01-01

    Full Text Available The aim of this investigation was to prepare and characterize mirtazapine microemulsion for intranasal delivery, to determine its brain drug delivery using pharmacokinetic studies, and assess its performance pharmacodynamically for the antidepressant activity. Mirtazapine microemulsion of different compositions were prepared by water titration method and characterized for globule size and zeta potential. Microemulsion with maximum drug solubilization, lowest globule size and lowest zeta potential was considered optimal and taken for further studies with or without addition of chitosan, a mucoadhesive agent. Pharmacokinetics of optimized mirtazapine microemulsion, mucoadhesive microemulsion and mirtazapine solution were studied in brain and blood of male Wistar rats post intranasal and oral administration. Despair Swim test, locomotor activity and plus maze test were carried out in rats in order to compare therapeutic activity of the drug formulation for oral and intranasal route. Brain/blood uptake ratios were found to be highest for mirtazapine mucoadhesive microemulsion (MMME followed by mirtazapine microemulsion (MME post-intranasal administration compared to oral delivery of microemulsion. Significant ( P < 0.05 reduction in assessed pharmacodynamic parameters was observed after intranasal administration of MMME against control group. This investigation demonstrates a more rapid and larger extent of transport of mirtazapine into the brain with intranasal MMME, which may prove useful in treating depression.

  16. Enclosure for small animals during awake animal imaging

    Science.gov (United States)

    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.

  17. Insulin allergy.

    Science.gov (United States)

    Ghazavi, Mohammad K; Johnston, Graham A

    2011-01-01

    Insulin reactions occur rarely but are of tremendous clinical importance. The first was reported in 1922 as a callus reaction at the injection site of insufficiently purified bovine insulin. Porcine insulin was subsequently found to be less allergenic than bovine insulin. Increasingly pure insulins have decreased the risk of adverse reactions, and the production of recombinant insulin with the same amino sequence as human insulin saw a large decrease in adverse reactions. Currently, the prevalence of allergic reactions to insulin products appears to be approximately 2%, and less than one-third of these events have been considered related to the insulin itself. Other reactions occur due to the preservatives added to insulin, including zinc, protamine, and meta-cresol. Allergic reactions can be type I or immunoglobulin E-mediated, type III or Arthus, and type IV or delayed-type hypersensitivity reactions. Type I reactions are the most common and can, rarely, cause anaphylaxis. In contrast, type IV reactions can occur after a delay of several days. Investigations include skin prick testing, patch testing, intradermal testing, and occasionally, skin biopsy.

  18. The influence of awake craniotomy on postoperative neuropsychology

    Directory of Open Access Journals (Sweden)

    YANG Ming-yuan

    2012-12-01

    Full Text Available Objective To assess the neuropsychological function and quality of life of the patients after awake craniotomy (AC. Methods A case-control study was conducted among 81 patients who underwent awake craniotomy, and a 1-to-1 control group (matched by age, gender, degree of education, tumor location and characteristic undergoing general anesthesia (GA in glioma resections was assembled. The incidence of postoperative neurological deficits, psychological disorders and recurrence were investigated during telephone follow-ups, and Medical Outcomes Study Short Form 36 (SF-36 was adopted to evaluate the life quality of patients. Results Almost 73 pairs of patients fulfilled the survey of AC and GA group respectively. There were 21 patients and 28 patients with postoperative neurological deficits, and 12 patients and 8 patients with psychological disorders in AC and GA group respectively. Thirty patients of AC group had the recollection of being awake during the surgery. There were 9 patients in CA group having long-term ( > 6 months neurological deficits, which was less than the number of GA group (18 patients, P = 0.038. According to the assessment in short-term, medium-term and long-term postoperative neurological deficits, there was no significant difference in the quality-of-life scores between the two groups (P > 0.05, for all. Conclusion Awake craniotomy can be the main method for removing the lesions located in or close to functional areas with lower incidence of long?term postoperative neurological deficits, and it has no significant impact on the psychological status and the quality of life postoperatively.

  19. Modeling of an Electron Injector for the AWAKE Project

    CERN Document Server

    Mete, O; Apsimon, R; Burt, G; Doebert, S; Fiorito, R; Welsch, C

    2015-01-01

    Particle-in-cell simulations were performed by using PARMELA to characterise an electron injector with a booster linac for the AWAKE project in order to provide the baseline specifications required by the plasma wakefield experiments. Tolerances and errors were investigated. A 3 GHz travelling wave structure designed by using CST code. Particles were tracked by using the field maps acquired from these electromagnetic simulations. These results are pre- sented in comparison with the generic accelerating structure model within PARMELA.

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

    Science.gov (United States)

    Stoelzel, Carl R; Huff, Joseph M; Bereshpolova, Yulia; Zhuang, Jun; Hei, Xiaojuan; Alonso, Jose-Manuel; Swadlow, Harvey A

    2015-08-01

    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.

  1. Proinflammatory responses in the murine brain after intranasal delivery of cholera toxin: implications for the use of AB toxins as adjuvants in intranasal vaccines.

    Science.gov (United States)

    Armstrong, Michelle E; Lavelle, Ed C; Loscher, Christine E; Lynch, Marina A; Mills, Kingston H G

    2005-11-01

    Intranasal delivery of vaccines provides an attractive alternative to parenteral delivery, but it requires appropriate mucosal adjuvants. Cholera toxin (CT) is a powerful mucosal adjuvant, but it can undergo retrograde transport to the brain via the olfactory system after intranasal delivery. We demonstrate that intranasal delivery of CT increases the expression of interleukin-1 beta , cyclooxygenase-2, and chemokine messenger RNA in the murine hypothalamus, whereas parenterally delivered CT has little effect. Our findings suggest that CT can induce proinflammatory mediators in the brain when it is administered intranasally but not parenterally, and they raise concerns about the use of AB toxins as adjuvants in intranasal vaccines.

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

    Science.gov (United States)

    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.

  3. Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers.

    NARCIS (Netherlands)

    Knoester, P.D.; Jonker, D.M.; Hoeven, R.T. van der; Vermeij, T.A.; Edelbroek, P.M.; Brekelmans, G.J.; Haan, G.J. de

    2002-01-01

    AIMS: To investigate the pharmacokinetic and pharmacodynamic profile of midazolam administered as a concentrated intranasal spray, compared with intravenous midazolam, in healthy adult subjects. METHODS: Subjects were administered single doses of 5 mg midazolam intranasally and intravenously in a cr

  4. Pharmacokinetics of Intranasal Scopolamine Gel Formulation (Inscop)

    Science.gov (United States)

    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

  5. The safety and tolerability of intranasal midazolam in epilepsy.

    Science.gov (United States)

    Mula, Marco

    2014-07-01

    Midazolam is a short-acting benzodiazepine that has clearly demonstrated to be an effective option for the acute management of epileptic seizures. It has the advantage of being water-soluble, with a rapid onset of action and it can be administered orally or intranasally, implementing an early intervention at the pre-hospital setting. This article aims to provide an overview of intranasal midazolam in the acute management of epileptic seizures. Available data suggest that midazolam 0.2 mg/kg is as effective as diazepam 0.5 mg/kg, especially in children with febrile or afebrile seizures. Local mucosal irritation seems to occur in less than one-third of cases while serious side effects such as respiratory depression in about 1%. Future studies need to be focused on adults and optimized technologies for intranasal delivery. Moreover, comparisons with buccal midazolam are warranted.

  6. ENHANCED BIOAVAILABILITY OF DRUGS VIA INTRANASAL DRUG DELIVEY SYSTEM

    Directory of Open Access Journals (Sweden)

    kumar Brajesh

    2012-07-01

    Full Text Available The aim of present investigation is to explain the enhancement of bioavailability of drug through intranasal drug delivery system. Intranasal Therapy has been an accepted form of treatment in the Ayurvedic system of Indian Medicine. Recently, it has been shown that many drugs have better bioavailability by nasal route than the oral route. This has been attributed to rich vasculature and a highly permeable structure of the nasal mucosa coupled with avoidance of hepatic first-pass elimination, gut wall metabolism and/or destruction in the gastrointestinal tract. Intranasal microemulsion, gels, nanoparticles, liposome and microspheres have gained increased interest in recent years as a delivery system for protein and peptides through the nasal route. Thus this review focuses on nasal drug delivery, nasal drug absorption mechanisms, various mechanisms for increasing the bioavailability of drug, and their applications in drug delivery.

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

    Directory of Open Access Journals (Sweden)

    Alex J Mann

    Full Text Available 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

  8. Critical Neural Networks in Awake Surgery for Gliomas

    Science.gov (United States)

    KINOSHITA, Masashi; MIYASHITA, Katsuyoshi; TSUTSUI, Taishi; FURUTA, Takuya; NAKADA, Mitsutoshi

    2016-01-01

    From the embarrassing character commonly infiltrating eloquent brain regions, the surgical resection of glioma remains challenging. Owing to the recent development of in vivo visualization techniques for the human brain, white matter regions can be delineated using diffusion tensor imaging (DTI) as a routine clinical practice in neurosurgery. In confirmation of the results of DTI tractography, a direct electrical stimulation (DES) substantially influences the investigation of cortico-subcortical networks, which can be identified via specific symptoms elicited in the concerned white matter tracts (eg., the arcuate fascicle, superior longitudinal fascicles, inferior fronto-occipital fascicle, inferior longitudinal fascicle, frontal aslant tract, sensori-motor tracts, optic radiation, and so forth). During awake surgery for glioma using DES, it is important to identify the anatomo-functional structure of white matter tracts to identify the surgical boundaries of brain regions not only to achieve maximal resection of the glioma but also to maximally preserve quality of life. However, the risk exists that neurosurgeons may be misled by the inability of DTI to visualize the actual anatomy of the white matter fibers, resulting in inappropriate decisions regarding surgical boundaries. This review article provides information of the critical neuronal network that is necessary to identify and understand in awake surgery for glioma, with special references to white matter tracts and the author’s experiences. PMID:27250817

  9. AWAKE: Advanced Proton Driven Plasma Wakefield Acceleration Experiment at CERN

    CERN Document Server

    Gschwendtner, E

    2014-01-01

    Plasma wakefield acceleration is a promising alternative reaching accelerating fields a magnitude of up to 3 higher (GV/m) when compared to conventional RF acceleration. AWAKE, world’s first proton-driven plasma wakefield experiment, was launched at CERN to verify this concept. In this experiment proton bunches at 400 GeV/c will be extracted from the CERN SPS and sent to the plasma cell, where the proton beam drives the plasma wakefields and creates a large accelerating field. This large gradient of ~GV/m can be achieved by relying on the self-modulation instability (SMI) of the proton beam; when seeded by ionization through a short laser pulse, a train of micro-bunches with a period on the order of the plasma wavelength (~mm) develops, which can drive such a large amplitude wake from a long proton bunch (~12 cm). An electron beam will be injected into the plasma to probe the accelerating wakefield. The AWAKE experiment is being installed at CERN in the former CNGS facility, which must be modified to mat...

  10. The pharmacokinetics of intravenous fenoldopam in healthy, awake cats.

    Science.gov (United States)

    O'Neill, K E; Labato, M A; Court, M H

    2016-04-01

    Fenoldopam is a selective dopamine-1 receptor agonist that improves diuresis by increasing renal blood flow and perfusion and causing peripheral vasodilation. Fenoldopam has been shown to induce diuresis and be well-tolerated in healthy cats. It is used clinically in cats with oliguric kidney injury at doses extrapolated from human medicine and canine studies. The pharmacokinetics in healthy beagle dogs has been reported; however, pharmacokinetic data in cats are lacking. The goal of this study was to determine pharmacokinetic data for healthy, awake cats receiving an infusion of fenoldopam. Six healthy, awake, client-owned cats aged 2-6 years old received a 120-min constant rate infusion of fenoldopam at 0.8 μg/kg/min followed by a 20-min washout period. Ascorbate stabilized plasma samples were collected during and after the infusion for the measurement of fenoldopam concentration by HPLC with mass spectrometry detection. This study showed that the geometric mean of the volume of distribution, clearance, and half-life (198 mL/kg, 46 mL/kg/min, and 3.0 mins) is similar to pharmacokinetic parameters for humans. No adverse events were noted. Fenoldopam at a constant rate infusion of 0.8 μg/kg per min was well tolerated in healthy cats. Based on the results, further evaluation of fenoldopam in cats with kidney disease is recommended.

  11. Realignment strategies for awake-monkey fMRI data.

    Science.gov (United States)

    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.

  12. Endotracheal Administration of Sufentanil and Tetracaine During Awake Fiberoptic Intubation.

    Science.gov (United States)

    Ji, Meng; Tao, Jun; Cheng, Min; Wang, Qingli

    2016-01-01

    Combined use of local anesthetics and low-dose opioids enhances the effects of local anesthetics. This study aimed to evaluate the efficacy of combined administration of sufentanil and tetracaine through the cricothyroid membrane during awake nasal intubation using fiberoptic bronchoscopy in patients with difficult airways. Forty patients were divided into 2 groups: group A received endotracheal administration of 25 μg of sufentanil and 2 mL of 1% tetracaine mixture; group B received endotracheal administration of 2 mL 1% tetracaine and routine local anesthetic sprays followed by slow intravenous injection of 25 μg of sufentanil. The results showed that endotracheal intubation was safely completed in all patients and vital signs including blood pressure, heart rate, and pulse oxygen saturation were not significantly different between groups A and B. However, time required for local anesthesia to take effect, time required to complete intubation, cough reflex, patient tolerance during intubation, and hemodynamic indices were significantly better in group A than in group B. In conclusion, our results suggest that endotracheal administration of sufentanil combined with tetracaine is safe, effective, and feasible in the context of awake nasal intubation using fiberoptic bronchoscopy.

  13. Markerless motion tracking of awake animals in positron emission tomography.

    Science.gov (United States)

    Kyme, Andre; Se, Stephen; Meikle, Steven; Angelis, Georgios; Ryder, Will; Popovic, Kata; Yatigammana, Dylan; Fulton, Roger

    2014-11-01

    Noninvasive functional imaging of awake, unrestrained small animals using motion-compensation removes the need for anesthetics and enables an animal's behavioral response to stimuli or administered drugs to be studied concurrently with imaging. While the feasibility of motion-compensated radiotracer imaging of awake rodents using marker-based optical motion tracking has been shown, markerless motion tracking would avoid the risk of marker detachment, streamline the experimental workflow, and potentially provide more accurate pose estimates over a greater range of motion. We have developed a stereoscopic tracking system which relies on native features on the head to estimate motion. Features are detected and matched across multiple camera views to accumulate a database of head landmarks and pose is estimated based on 3D-2D registration of the landmarks to features in each image. Pose estimates of a taxidermal rat head phantom undergoing realistic rat head motion via robot control had a root mean square error of 0.15 and 1.8 mm using markerless and marker-based motion tracking, respectively. Markerless motion tracking also led to an appreciable reduction in motion artifacts in motion-compensated positron emission tomography imaging of a live, unanesthetized rat. The results suggest that further improvements in live subjects are likely if nonrigid features are discriminated robustly and excluded from the pose estimation process.

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

    Science.gov (United States)

    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.

  15. Median effective dose of remifentanil for awake laryngoscopy and intudation

    Institute of Scientific and Technical Information of China (English)

    XU Ya-chao; XUE Fu-shan; LUO Mad-ping; YANG Quan-yong; LIAO Xu; LU Yi; ZHANG Yan-ming

    2009-01-01

    Background Awake intubation requires an anesthetic management that provides sufficient patient safety and comfort, adequate intubating conditions, and stable hemodynamics. In this prospective clinical study, our aim was to determine the median effective dose (ED50) of remifentanil in combination with midazolam and airway topical anesthesia for awake laryngoscopy and intubation.Methods Thirty-six female adult patients, scheduled for elective plastic surgery under general anesthesia requiring orotracheal intubation were included in this study. Ten minutes after intravenous administration of midazolam 0.1 mg/kg, patients were assigned to receive remifentanil in bolus, followed by a continuous infusion. The bolus dose and infusion rate of remifentanil were adjusted by a modified Dixon's up-and-down method. Patient's reaction score at laryngoscopy and an Observer's Assessment of Alertness/Sedation Scale (OAA/S) were used to determine whether the remifentanil dosage regimen was accepted. During laryngoscopy, 2% lidocaine was sprayed into the airway to provide the topical anesthesia. EDso of remifentanil was calculated by the modified Dixon up-and-clown method, and the probit analysis was then used to confirm the results obtained from the modified Dixon's up-and-down method. In the patients who were scored as "accept", patient's OAA/S and reaction scores at different observed points, intubating condition score and patient's tolerance to the endotracheal tube after intubation were evaluated and recorded. Blood pressure and heart rate at different measuring points were also noted.Results ED50 of remifentanil for awake laryngoscopy and intubation obtained by the modified Dixon's up-and-down method was (0.62±0.02) pg/kg. Using probit analysis, ED50 and ED95 of remifentanil were 0.63 μg/kg (95% Cl, 0.54-0.70) and 0.83 μg/kg (95% Cl, 0.73-2.59), respectively. Nineteen patients who were scored as =accept" had an OAA/S of 15 and tolerated well laryngoscopy without significant

  16. Intranasal administration of oxytocin: Behavioral and clinical effects, a review

    NARCIS (Netherlands)

    Veening, J.G.; Olivier, B.

    2013-01-01

    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'

  17. Intranasal clobazam delivery in the treatment of status epilepticus.

    Science.gov (United States)

    Florence, Kiruba; Manisha, Lalan; Kumar, Babbar Anil; Ankur, Kaul; Kumar, Mishra Anil; Ambikanandan, Misra

    2011-02-01

    The aim of the present investigation was to prepare and characterize clobazam mucoadhesive microemulsion (CZMME) to assess brain drug uptake and protection against pentylenetetrazole (PTZ)-induced convulsions in mice. Clobazam microemulsion (CZME) and CZMME were prepared by titration method and characterized. Brain uptake and pharmacokinetic parameters were calculated from drug concentration in mice brain versus time plots following intranasal administration of radiolabeled CZME and CZMME, intravenous and intranasal administration of radiolabeled clobazam solution. Gamma scintigraphy imaging of rabbit brain following intranasal administration was performed. Formulations were investigated for the onset of seizures in PTZ-challenged mice. Brain targeting efficiency and direct nose-to-brain transport percentage for mucoadhesive microemulsion suggested an improved brain uptake following intranasal administration. The findings were supported by gamma scintigraphy images. Delay in onset of PTZ-induced seizures with CZMME compared with positive control and placebo-treated groups confirmed the improved brain uptake. However, extensive animal studies followed by clinical trials are necessary to develop a product suitable for emergencies of acute seizures in status epilepticus and patients suffering from drug tolerance and hepatic impairment on long-term use in treatment of epilepsy, schizophrenia, and anxiety.

  18. Anti-insulin antibody test

    Science.gov (United States)

    Insulin antibodies - serum; Insulin Ab test; Insulin resistance - insulin antibodies; Diabetes - insulin antibodies ... You appear to have an allergic response to insulin Insulin no longer seems to control your diabetes

  19. Comparison of intranasal hypertonic dead sea saline spray and intranasal aqueous triamcinolone spray in seasonal allergic rhinitis.

    Science.gov (United States)

    Cordray, Scott; Harjo, Jim B; Miner, Linda

    2005-07-01

    Intranasal corticosteroids are well known to be efficacious in the treatment of allergic rhinitis. Nasal irrigation with saline, including hypertonic saline, has long been recommended for the treatment of sinonasal disease, and it has been shown to have a positive effect on the physiology of the nasal mucosa. Until now, no study of the clinical efficacy of intranasal hypertonic Dead Sea saline as a monotherapy for seasonal allergic rhinitis has been reported. We conducted a prospective, randomized, single-blind, placebo-controlled comparison of intranasal hypertonic Dead Sea saline spray and intranasal aqueous triamcinolone spray in 15 patients with seasonal allergic rhinitis. Results were based on a 7-day regimen. Based on Rhinoconjunctivitis Quality of Life Questionnaire scores, clinically and statistically significant (p Dead Sea saline solution can be an effective alternative in mild-to-moderate allergic rhinitis, particularly with respect to nasal and eye symptoms. The hypertonicity of the Dead Sea solution may have a positive effect on the physiology of the nasal mucosa by improving mucociliary clearance. In addition, the dominant cation in the Dead Sea solution--magnesium--probably exerts anti-inflammatory effects on the nasal mucosa and on the systemic immune response.

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

    Science.gov (United States)

    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

  1. Central Nervous Insulin Administration before Nocturnal Sleep Decreases Breakfast Intake in Healthy Young and Elderly Subjects

    Science.gov (United States)

    Santiago, João C. P.; Hallschmid, Manfred

    2017-01-01

    Peripheral insulin acts on the brain to regulate metabolic functions, in particular decreasing food intake and body weight. This concept has been supported by studies in humans relying on the intranasal route of administration, a method that permits the direct permeation of insulin into the CNS without substantial absorption into the blood stream. We investigated if intranasal insulin administration before nocturnal sleep, a period of reduced metabolic activity and largely absent external stimulation, affects food intake and energy turnover on the subsequent morning. Healthy participants who were either young (16 men and 16 women; mean age ± SEM, 23.68 ± 0.40 years, mean BMI ± SEM, 22.83 ± 0.33 kg/m2) or elderly (10 men, 9 women; 70.79 ± 0.81 years, 25.27 ± 0.60 kg/m2) were intranasally administered intranasal insulin (160 IU) or placebo before a night of regular sleep that was polysomnographically recorded. Blood was repeatedly sampled for the determination of circulating glucose, insulin, leptin and total ghrelin. In the morning, energy expenditure was assessed via indirect calorimetry and subjects were offered a large standardized breakfast buffet from which they could eat ad libitum. Insulin compared to placebo reduced breakfast size by around 110 kcal (1,054.43 ± 50.91 vs. 1,162.36 ± 64.69 kcal, p = 0.0095), in particular decreasing carbohydrate intake (502.70 ± 25.97 vs. 589.82 ± 35.03 kcal, p = 0.0080). This effect was not dependent on sex or age (all p > 0.11). Sleep architecture, blood glucose and hormonal parameters as well as energy expenditure were not or only marginally affected. Results show that intranasal insulin administered to healthy young and elderly humans before sleep exerts a delayed inhibitory effect on energy intake that is not compensated for by changes in energy expenditure. While the exact underlying mechanisms cannot be derived from our data, findings indicate a long-lasting catabolic effect of central nervous insulin delivery

  2. Diabetes and Insulin

    Science.gov (United States)

    ... in the abdomen just behind the stomach, produces insulin. Insulin is a hormone that takes glucose from the ... occurs when the pancreas does not produce enough insulin or when the body doesn’t use insulin ...

  3. AWAKE CRANIOTOMY USING DEXMEDETOMIDINE INFUSION AND SCALP BLOCK: OUR EXPERIENCE IN SERIES OF CASES

    Directory of Open Access Journals (Sweden)

    Annapurna Sarma

    2015-06-01

    Full Text Available BACKGROUND: Awake craniotomy is an important technique used for brain tumour excision from eloquent cortex. Awake craniotomy allows maximum resection of the tumor with minimum functional impairment . The critical aspect is to maintain adequate analgesia and sedation, hemodynamic stability, airway safety, while keeping the patient awake and cooperative for neurological testing. AIM OF THE STUDY: We are reporting cases series of awake craniotomy under monito red anesthesia care using dexmedetomidine infusion as an adjuvant to scalp block, titrating the sedation level by BIS monitoring. MATERIALS AND METHODS: After careful patient selection and psychological preparation Monitored Anesthesia Care was provided by continuous infusion of dexmedetomidine at a rate of 0.2 - 0.5ug/kg/min titrating sedation score to BIS value of 70 - 90. Bilateral scalp block was administered using 0.5% bupivacaine. For dura mater incision, a pad with 2% lidocaine was applied for 3 minutes . The tumor removal was complete with no neurological deficiency. All the patients were discharged on 5 th postoperative day without complications and with full patient satisfaction. CONCLUSION: We conclude that monitored anesthesia care with dexmedetomidine infusion and scalp block for awake craniotomy is safe and efficacious. Absence of complications and high patient satisfaction score makes this technique close to an ideal technique for awake craniotomy. KEYWORDS: Awake craniotomy; Dexmedetomidine; Scalp b lock; BIS index

  4. Nociceptive responses to thermal and mechanical stimulations in awake pigs

    DEFF Research Database (Denmark)

    di Giminiani, Pierpaolo; Petersen, Lars Jelstrup; Herskin, Mette S

    2013-01-01

    BACKGROUND: Porcine skin exhibits a high degree of homology to human skin, and the pig has recently been used as a cutaneous pain model. However, before the full potential of this novel in vivo cutaneous pain model can be achieved, several methodological aspects related to the management of awake...... animal studies in a large species require further examination. This manuscript describes the initial development of a porcine model of cutaneous nociception and focuses on interactions between the sensory modality, body size and the anatomical location of the stimulation site. METHODS: Pigs of different...... body sizes (30 and 60 kg) were exposed to thermal (CO(2) laser) and mechanical (pressure application measurement device) stimulations to the flank and the hind legs in a balanced order. The median response latency and the type of behavioural response were recorded. RESULTS: Small pigs exhibited...

  5. The electron accelerator for the AWAKE experiment at CERN

    Energy Technology Data Exchange (ETDEWEB)

    Pepitone, K., E-mail: kevin.pepitone@cern.ch [CERN, Geneva (Switzerland); Doebert, S., E-mail: steffen.doebert@cern.ch [CERN, Geneva (Switzerland); Burt, G. [The University of Lancaster, Lancaster (United Kingdom); Chevallay, E.; Chritin, N.; Delory, C.; Fedosseev, V.; Hessler, Ch.; McMonagle, G. [CERN, Geneva (Switzerland); Mete, O. [The University of Manchester, Manchester (United Kingdom); Verzilov, V. [Triumf, Vancouver (Canada); Apsimon, R. [The University of Lancaster, Lancaster (United Kingdom)

    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.

  6. Replicability and heterogeneity of awake unrestrained canine FMRI responses.

    Directory of Open Access Journals (Sweden)

    Gregory S Berns

    Full Text Available 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.

  7. Replicability and heterogeneity of awake unrestrained canine FMRI responses.

    Science.gov (United States)

    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.

  8. Insulin Resistance

    DEFF Research Database (Denmark)

    Jensen, Benjamin Anderschou Holbech

    Insulin resistance (IR) is escalating with alarming pace and is no longer restricted to westernized countries. As a forerunner for some of the most serious threats to human health including metabolic syndrome, cardiovascular diseases, and type 2-diabetes, the need for new treatment modalities...... interventions. We further show that improving the inflammatory toning, using fish oil as fat source, protects mice against diet induced obesity and -inflammation while preserving insulin sensitivity, even in the absence of free fatty acid receptor 4. Conversely, HFD-induced intestinal dysbiosis is associated...

  9. Targeting glioblastoma via intranasal administration of Ff bacteriophages

    Science.gov (United States)

    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

    Directory of Open Access Journals (Sweden)

    Eyal eDor-On

    2015-05-01

    Full Text Available 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. Targeting glioblastoma via intranasal administration of Ff bacteriophages.

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  13. Intranasal delivery of antiepileptic medications for treatment of seizures.

    Science.gov (United States)

    Wermeling, Daniel P

    2009-04-01

    Acute isolated seizure, repetitive or recurrent seizures, and status epilepticus are all deemed medical emergencies. Mortality and worse neurologic outcome are directly associated with the duration of seizure activity. A number of recent reviews have described consensus statements regarding the pharmacologic treatment protocols for seizures when patients are in pre-hospital, institutional, and home-bound settings. Benzodiazepines, such as lorazepam, diazepam, midazolam, and clonazepam are considered to be medications of first choice. The rapidity by which a medication can be delivered to the systemic circulation and then to the brain plays a significant role in reducing the time needed to treat seizures and reduce opportunity for damage to the CNS. Speed of delivery, particularly outside of the hospital, is enhanced when transmucosal routes of delivery are used in place of an intravenous injection. Intranasal transmucosal delivery of benzodiazepines is useful in reducing time to drug administration and cessation of seizures in the pre-hospital setting, when actively seizing patients arrive in the emergency room, and at home where caregivers treat their dependents. This review summarizes factors to consider when choosing a benzodiazepine for intranasal administration, including formulation and device considerations, pharmacology and pharmacokinetic/pharmacodynamic profiles. A review of the most relevant clinical studies in epilepsy patients will provide context for the relative success of this technique with a number of benzodiazepines and relatively less sophisticated nasal preparations. Neuropeptides delivered intranasally, crossing the blood-brain barrier via the olfactory system, may increase the availability of medications for treatment of epilepsy. Consequently, there remains a significant unmet medical need to serve the pharamcotherapeutic requirements of epilepsy patients through commercial development and marketing of intranasal antiepileptic products.

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

    Science.gov (United States)

    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.

  15. Delivery of cefotaxime to the brain via intranasal administration.

    Science.gov (United States)

    Manda, Prashanth; Hargett, Jamie K; Vaka, Siva Ram Kiran; Repka, Michael A; Murthy, S Narasimha

    2011-11-01

    The purpose of this study was to investigate the plausibility of delivery of cefotaxime to the brain via intranasal administration. In vitro permeation studies were carried out using Franz diffusion cells, and the effect of different concentrations of chitosan (0.1% w/v and 0.25% w/v) on drug permeation across the bovine olfactory mucosa was determined. Samples were collected from the receiver compartment at different time points and analyzed using HPLC. The amount of cefotaxime that permeated across the olfactory mucosa when 0.25% w/v of chitosan was used as a permeation enhancer was ~1.5- and ~2-fold higher at the end of the first hour and second hour, respectively, over control (29.56 ± 6.18 µg/cm(2)). There was no significant enhancement in drug permeation when 0.1% w/v chitosan was used as the permeation enhancer. Pharmacokinetic studies were carried out using Sprague-Dawley rats. Cefotaxime solution with 0.25% w/v chitosan (40 mg/kg) was administered intravenously (i.v.) to rats in groups 1 and 3 and intranasally to those in group 2 and 4. The time course of drug in the brain was investigated by performing microdialysis in rats of groups 1 and 2. Blood samples were withdrawn from rats in groups 3 and 4, and cefotaxime in plasma was analyzed using HPLC after extraction with a hydrochloric acid-chloroform:1-pentanol (3:1) and phosphate buffer solvent system. Pharmacokinetic parameters were calculated using the trapezoidal rule. The results imply that the drug levels attained in the brain following i.v. and intranasal administrations were comparable. These results suggest that intranasal administration of cefotaxime could be a potential method of delivering antibacterial agents because of it being noninvasive and patient compliant.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  18. Identification of cortical lamination in awake monkeys by high resolution magnetic resonance imaging

    OpenAIRE

    Chen, Gang; Wang, Feng; Gore, John C.; Roe, Anna W.

    2011-01-01

    Brodman divided the neocortex into 47 different cortical areas based on histological differences in laminar myeloarchitectonic and cytoarchitectonic defined structure. The ability to do so in vivo with anatomical magnetic resonance (MR) methods in awake subjects would be extremely advantageous for many functional studies. However, due to the limitations of spatial resolution and contrast, this has been difficult to achieve in awake subjects. Here, we report that by using a combination of MR m...

  19. Urgent awake thoracoscopic treatment of retained haemothorax associated with respiratory failure

    OpenAIRE

    Pompeo, Eugenio; Cristino, Benedetto; Rogliani, Paola; Dauri, Mario

    2015-01-01

    A number of video-assisted thoracoscopic surgery (VATS) procedures are being increasingly performed by awake anesthesia in an attempt of minimizing the surgical- and anesthesia-related traumas. However, so far the usefulness of awake VATS for urgent management of retained haemothorax has been scarcely investigated. Herein we present two patients with retained haemothorax following previous thoracentesis and blunt chest trauma, respectively, who developed acute respiratory failure and underwen...

  20. Awake tracheal intubation using Pentax airway scope in 30 patients: A Case series

    Directory of Open Access Journals (Sweden)

    Payal Kajekar

    2014-01-01

    Full Text Available Background and Aims: Pentax airway scope (AWS has been successfully used for managing difficult intubations. In this case series, we aimed to evaluate the success rate and time taken to complete intubation, when AWS was used for awake tracheal intubation. Methods: We prospectively evaluated the use of AWS for awake tracheal intubation in 30 patients. Indication for awake intubation, intubation time, total time to complete tracheal intubation, laryngoscopic view (Cormack and Lehane grade, total dose of local anaesthetic used, anaesthetists rating and patient′s tolerance of the procedure were recorded. Results: The procedure was successful in 25 out of the 30 patients (83%. The mean (standard deviation intubation time and total time to complete the tracheal intubation was 5.4 (2.4 and 13.9 (3.7 min, respectively in successful cases. The laryngeal view was grade 1 in 24 and grade 2 in one of 25 successful intubations. In three out of the five patients where the AWS failed, awake tracheal intubation was successfully completed with the assistance of flexible fibre optic scope (FOS. Conclusion: Awake tracheal intubation using AWS was successful in 83% of patients. Success rate can be further improved using a combination of AWS and FOS. Anaesthesiologists who do not routinely use FOS may find AWS easier to use for awake tracheal intubation using an oral route.

  1. Alteration in insulin action

    DEFF Research Database (Denmark)

    Tanti, J F; Gual, P; Grémeaux, T;

    2004-01-01

    Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterised by a decrease in insulin effect on glucose transport in muscle and adipose tIssue. Tyrosine phosphorylation of insulin receptor substrate 1 (IR...

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

    Directory of Open Access Journals (Sweden)

    Annabelle Marie Belcher

    2016-03-01

    Full Text Available In combination with advances in analytical methods, resting-state fMRI is allowing unprecedented access to achieve 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 functional connectivity 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.

  3. Dexmedetomidine versus Remifentanil for Sedation during Awake Fiberoptic Intubation

    Directory of Open Access Journals (Sweden)

    Davide Cattano

    2012-01-01

    Full Text Available This study compared remifentanil and dexmedetomidine as awake fiberoptic intubation (AFOI anesthetics. Thirty-four adult ASA I-III patients were enrolled in a double-blinded randomized pilot study to receive remifentanil (REM or dexmedetomidine (DEX for sedation during AFOI (nasal and oral. Thirty patients completed the study and received 2 mg midazolam IV and topical anesthesia. The REM group received a loading dose of 0.75 mcg/kg followed by an infusion of 0.075 mcg/kg/min. The DEX group received a loading dose of 0.4 mcg/kg followed by an infusion of 0.7 mcg/kg/hr. Time to sedation, number of intubation attempts, Ramsay sedation scale (RSS score, bispectral index (BIS, and memory recall were recorded. All thirty patients were successfully intubated by AFOI (22 oral intubations/8 nasal. First attempt success rate with AFOI was higher in the REM group than the DEX group, 72% and 38% (P=0.02, respectively. The DEX group took longer to attain RSS of ≥3 and to achieve BIS <80, as compared to the REM group. Postloading dose verbal recall was poorer in the DEX group. Dexmedetomidine seems a useful adjunct for patients undergoing AFOI but is dependent on dosage and time. Further studies in the use of dexmedetomidine for AFOI are warranted.

  4. Effect of an Enhanced Nose-to-Brain Delivery of Insulin on Mild and Progressive Memory Loss in the Senescence-Accelerated Mouse.

    Science.gov (United States)

    Kamei, Noriyasu; Tanaka, Misa; Choi, Hayoung; Okada, Nobuyuki; Ikeda, Takamasa; Itokazu, Rei; Takeda-Morishita, Mariko

    2017-03-06

    Insulin is now considered to be a new drug candidate for treating dementias, such as Alzheimer's disease, whose pathologies are linked to insulin resistance in the brain. Our recent work has clarified that a noncovalent strategy involving cell-penetrating peptides (CPPs) can increase the direct transport of insulin from the nasal cavity into the brain parenchyma. The present study aimed to determine whether the brain insulin level increased by intranasal coadministration of insulin with the CPP penetratin has potential for treating dementia. The pharmacological actions of insulin were investigated at different stages of memory impairment using a senescence-accelerated mouse-prone 8 (SAMP8) model. The results of spatial learning tests suggested that chronic intranasal administration of insulin with l-penetratin to SAMP8 slowed the progression of memory loss in the early stage of memory impairment. However, contrary to expectations, this strategy using penetratin was ineffective in recovering the severe cognitive dysfunction in the progressive stage, which involves brain accumulation of amyloid β (Aβ). Immunohistological examination of hippocampal regions of samples from SAMP8 in the progressive stage suggested that accelerated nose-to-brain insulin delivery had a partial neuroprotective function but unexpectedly increased Aβ plaque deposition in the hippocampus. These findings suggest that the efficient nose-to-brain delivery of insulin combined with noncovalent CPP strategy has different effects on dementia during the mild and progressive stages of cognitive dysfunction.

  5. Insulin glargine overdose

    Directory of Open Access Journals (Sweden)

    Fatma Sari Dogan

    2012-01-01

    Full Text Available Insulin glargine is a long acting novel recombinant human insulin analogue indicated to improve glycemic control, in adults and children with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. The time course of action of insulins including insulin glargine may vary between individuals and/or within the same individual. Insulin glargine is given as a 24-h dosing regimen and has no documented half-life or peak effect. Hypoglycemia is the most common adverse effect of insulin, including insulin glargine. As with all insulins, the timing of hypoglycemia may differ among various insulin formulations. We present a case of a 76-year-old male insulin-dependent diabetic patient with refractory hypoglycemia secondary to an intentional overdose of insulin glargine. We would like to highlight the necessity of prolonging IV glucose infusion, for a much longer period than expected from pharmacokinetic properties of these insulin analogues after intentional massive overdose.

  6. Insulin Human Inhalation

    Science.gov (United States)

    Insulin inhalation is used in combination with a long-acting insulin to treat type 1 diabetes (condition in which the body does not produce insulin and therefore cannot control the amount of sugar ...

  7. Concentrated insulins: the new basal insulins

    Directory of Open Access Journals (Sweden)

    Lamos EM

    2016-03-01

    Full Text Available Elizabeth M Lamos,1 Lisa M Younk,2 Stephen N Davis3 1Division of Endocrinology, Diabetes and Nutrition, 2Department of Medicine, University of Maryland School of Medicine, 3Department of Medicine, University of Maryland Medical Center, Baltimore, MD, USA 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

  8. Intranasal mesenchymal stem cell treatment for neonatal brain damage : long-term cognitive and sensorimotor improvement

    NARCIS (Netherlands)

    Donega, Vanessa; van Velthoven, Cindy T J; Nijboer, Cora H; van Bel, Frank; Kas, Martien J H; Kavelaars, Annemieke; Heijnen, Cobi J

    2013-01-01

    Mesenchymal stem cell (MSC) administration via the intranasal route could become an effective therapy to treat neonatal hypoxic-ischemic (HI) brain damage. We analyzed long-term effects of intranasal MSC treatment on lesion size, sensorimotor and cognitive behavior, and determined the therapeutic wi

  9. Thermoreversible biogels for intranasal delivery of rizatriptan benzoate

    Directory of Open Access Journals (Sweden)

    Chand Renuka

    2009-01-01

    Full Text Available The objective of the present study was to formulate and evaluate a thermoreversible formulation containing rizatriptan benzoate for intranasal administration. Chitosan and aqueous β-glycerolphosphate were mixed in cold condition to obtain chitosan-β-glycerolphosphate mixtures, which served as the thermoreversible systems. Rizatriptan benzoate was incorporated at a final strength of 25 mg/ml. Both in vitro release and ex vivo permeation of rizatriptan from gels were measured at 37º using Franz diffusion cells Formulations were tested in vivo in mice for reduction in locomotor activity using digital actophotometer and nasal mucosal tissues were examined histopathologically.

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

    Science.gov (United States)

    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

  11. A new minimal-stress freely-moving rat model for preclinical studies on intranasal administration of CNS drugs

    NARCIS (Netherlands)

    Stevens, Jasper; Suidgeest, Ernst; van der Graaf, Piet Hein; Danhof, Meindert; de Lange, Elizabeth C M

    2009-01-01

    PURPOSE: To develop a new minimal-stress model for intranasal administration in freely moving rats and to evaluate in this model the brain distribution of acetaminophen following intranasal versus intravenous administration. METHODS: Male Wistar rats received one intranasal cannula, an intra-cerebra

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

    Science.gov (United States)

    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.

  13. Central nervous insulin administration does not potentiate the acute glucoregulatory impact of concurrent mild hyperinsulinemia.

    Science.gov (United States)

    Ott, Volker; Lehnert, Hendrik; Staub, Josefine; Wönne, Kathrin; Born, Jan; Hallschmid, Manfred

    2015-03-01

    Experiments in rodents suggest that hypothalamic insulin signaling essentially contributes to the acute control of peripheral glucose homeostasis. Against this background, we investigated in healthy humans whether intranasal (IN) insulin, which is known to effectively reach the brain compartment, impacts systemic glucose metabolism. Twenty overnight-fasted healthy, normal-weight men were IN administered 210 and 420 international units [IU] (10 and 20 IU every 15 min) of the insulin analog aspart (ins-asp) and placebo, respectively, during experimental sessions lasting 6 h. The use of ins-asp rather than human insulin enabled us to disentangle exogenous and endogenous insulin kinetics. IN insulin dose-dependently decreased plasma glucose concentrations while reducing C-peptide and attenuating endogenous insulin levels. However, we also observed a slight dose-dependent permeation of ins-asp into the circulation. In control experiments mimicking the systemic but not the central nervous uptake of the IN 210 IU dose via intravenous infusion of ins-asp at a dose of 0.12 IU/kg/24 h (n = 10), we obtained essentially identical effects on fasting plasma glucose concentrations. This pattern indicates that sustained IN insulin administration to the human brain to enhance central nervous insulin signaling does not acutely alter systemic glucose homeostasis beyond effects accounted for by concurrent mild hyperinsulinemia.

  14. AWAKE CRANIOTOMY USING DEXMEDETOMIDINE INFUSION AND SCALP BLOCK: OUR EXPERIENCE IN SERIES OF CASES

    Directory of Open Access Journals (Sweden)

    MSSV Prasad

    2015-11-01

    Full Text Available BACKGROUND: Awake craniotomy for removal of intracranial tumors is most challenging procedure. The critical aspect of awake craniotomy is to maintain adequate analgesia and sedation, hemodynamic stability, airway safety, while keeping the patient immobile for duration of surgery, cooperative for neurological testing. AIM OF THE STUDY: Dexmedetomidine is good analgesic, sedative and has anaesthetic-sparing properties without causing significant respiratory depression. [1] We are reporting cases series of awake craniotomy under monitored anesthesia care using dexmedetomidine infusion as an adjuvant to scalp block, titrating the sedation level by BIS monitoring. MATERIALS AND METHODS: after careful patient selection and psychological preparation Monitored Anesthesia care(MAC was provided by continuous infusion of Dexmedetomidine at a rate of 0.2-0.5 mcg/kg/min titrating sedation level to a BIS value of 70-90%. Bilateral scalp block was administered using 0.5% bupivacaine. For dura mater incision, a pad with 2% lidocaine was applied for 3 minutes. The tumor removal was complete with no neurological deficiency. All the patients were discharged on 5th postoperative day without complications and with full patient satisfaction. CONCLUSION: We conclude that monitored anesthesia care with dexmedetomidine infusion and scalp block for awake craniotomy is a safe and efficacious. Absence of complications and high patient satisfaction score makes this technique close to an ideal technique for awake craniotomy.

  15. Intranasal oxytocin administration is reflected in human saliva.

    Science.gov (United States)

    Weisman, Omri; Zagoory-Sharon, Orna; Feldman, Ruth

    2012-09-01

    Following the discovery that intranasal administration of neuropeptides can reach the central nervous system, a growing number of studies applied intranasal oxytocin (OT) paradigms to demonstrate the positive effects of OT on social and emotional processes. The three-step paradigm typically included: OT administration, a 45-min waiting period, and approximately 1-h period of active drug effects when experimental manipulations are applied. Yet, this schedule has not been put to systematic validation. Utilizing a double-blind placebo-control within-subject design, ten individuals were administered OT or placebo and salivary OT was measured ten times, at baseline and nine times over four consecutive hours. OT administration induced substantial increases in salivary OT across the entire period. OT rose dramatically 15 min after administration (from 6.9 pg/ml at baseline to 1265.4 pg/ml), reached plateau at 45-120 min (range=131.6 and 105.3 pg/ml), and did not return to baseline by 4h. Results contribute to discussion on brain-periphery coordination of OT and highlight the need for further research on the temporal dynamics and durations of OT administration effects.

  16. [Effectiveness of intranasal salmon calcitonin treatment in postmenopausal osteoporosis].

    Science.gov (United States)

    Kopaliani, M

    2005-04-01

    The aim of this study was to assess clinical efficacy of intranasal salmon calcitonin (Miacalcic, Novartis pharma) treatment in women with established postmenopausal osteoporosis. 30 women of the main group with established postmenopausal osteoporosis(T-score salmon calcitonin: 200 IU daily for 2 months with subsequent pause of 2 months (3 cycles), 12 months in total. Age matched control group was formed by 25 postmenopausal women with similar clinical status. SOS (speed of sound) of cortical bone was measured in the middle of the tibia by ultrasound densitometer--Sound Scan Compact (Myriad-Israel). Patients of both groups received 500 mg Ca and 200 IU vit.D3 (CaD3 Nycomed) two times daily in the same regimen (two months treatment--two months pause). Our results showed that intranasal treatment with 200 IU daily effectively influence the back pain, reduces bone turnover and significantly increases cortical BMD. Significant changes were not observed in patients of the control group, who received only CaD3 Nycomed, that showed that Calcium and vitamin D supplementation is more effective for prevention of bone lose in postmenopausal women, rather for treatment of established osteoporosis.

  17. Intranasal midazolam vs rectal diazepam in acute childhood seizures.

    Science.gov (United States)

    Bhattacharyya, Madhumita; Kalra, Veena; Gulati, Sheffali

    2006-05-01

    One hundred eighty-eight seizure episodes in 46 children were randomly assigned to receive treatment with rectal diazepam and intranasal midazolam with doses of 0.3 mg/kg body weight and 0.2 mg/kg body weight, respectively. Efficacy of the drugs was assessed by drug administration time and seizure cessation time. Heart rate, blood pressure, respiratory rate, and oxygen saturation were measured before and after 5, 10, and 30 minutes following administration of the drugs in both groups. Mean time from arrival of doctor to drug administration was 68.3 +/- 55.12 seconds in the diazepam group and 50.6 +/- 14.1 seconds in the midazolam group (P = 0.002). Mean time from drug administration to cessation of seizure was significantly less in the midazolam group than the diazepam group (P = 0.005). Mean heart rate and blood pressure did not vary significantly between the two drug groups. However, mean respiratory rate and oxygen saturation differed significantly between the two drug groups at 5, 10, and 30 minutes after drug administration. Intranasal midazolam is preferable to rectal diazepam in the treatment of acute seizures in children. Its administration is easy, it has rapid onset of action, has no significant effect on respiration and oxygen saturation, and is socially acceptable.

  18. Intranasal sufentanil for cancer-associated breakthrough pain.

    Science.gov (United States)

    Good, P; Jackson, K; Brumley, D; Ashby, M

    2009-01-01

    The objective of this study was to demonstrate the efficacy, safety and patient acceptability of the use of intranasal sufentanil for cancer-associated breakthrough pain. This was a prospective, open label, observational study of patients in three inpatient palliative care units in Australia. Patients on opioids with cancer-associated breakthrough pain and clinical evidence of opioid responsiveness to their breakthrough pain were given intranasal (IN) Sufentanil via a GO Medical patient controlled IN analgesia device. The main outcome measures were pain scores, need to revert to previous breakthrough opioid after 30 min, number of patients who chose to continue using IN sufentanil, and adverse effects. There were 64 episodes of use of IN sufentanil for breakthrough pain in 30 patients. There was a significant reduction in pain scores at 15 (P < 0.0001) and 30 min (P < 0.0001). In only 4/64 (6%) episodes of breakthrough pain did the participants choose to revert to their prestudy breakthrough medication. Twenty-three patients (77%) rated IN sufentanil as better than their prestudy breakthrough medication. The incidence of adverse effects was low and most were mild. Our study showed that IN sufentanil can provide relatively rapid onset, intense but relatively short lasting analgesia and in the palliative care setting it is an effective, practical, and safe option for breakthrough pain.

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

    Science.gov (United States)

    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.

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

    CERN Document Server

    Gschwendtner, 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.; Buttenschon, 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.; Huther, 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.; Oz, 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.

    2016-01-01

    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 to sample the 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Gschwendtner, E. [CERN, Geneva (Switzerland); Adli, E. [University of Oslo, Oslo 0316 (Norway); Amorim, L. [GoLP/Instituto de Plasmas e Fusão Nuclear, Instituto Superior Técnico, Universidade de Lisboa, Lisbon (Portugal); Apsimon, R. [Cockcroft Institute, Warrington WA4 4AD (United Kingdom); Lancaster University, Lancaster LA1 4YR (United Kingdom); Assmann, R. [DESY, Notkestrasse 85, 22607 Hamburg (Germany); Bachmann, A.-M.; Batsch, F. [Max Planck Institute for Physics, Föhringer Ring 6, München 80805 (Germany); Bauche, J. [CERN, Geneva (Switzerland); Berglyd Olsen, V.K. [University of Oslo, Oslo 0316 (Norway); Bernardini, M. [CERN, Geneva (Switzerland); Bingham, R. [STFC Rutherford Appleton Laboratory, Didcot OX11 0QX (United Kingdom); Biskup, B. [CERN, Geneva (Switzerland); Czech Technical University, Zikova 1903/4, 166 36 Praha 6 (Czech Republic); Bohl, T.; Bracco, C. [CERN, Geneva (Switzerland); Burrows, P.N. [John Adams Institute for Accelerator Science, Oxford (United Kingdom); University of Oxford, Oxford OX1 2JD (United Kingdom); Burt, G. [Cockcroft Institute, Warrington WA4 4AD (United Kingdom); Buttenschön, B. [Max Planck Institute for Plasma Physics, Wendelsteinstr. 1, Greifswald 17491 (Germany); Butterworth, A. [CERN, Geneva (Switzerland); Caldwell, A. [Max Planck Institute for Physics, Föhringer Ring 6, München 80805 (Germany); Cascella, M. [UCL, Gower Street, London WC1E 6BT (United Kingdom); and others

    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.

  2. [Non-verbal communication of patients submitted to heart surgery: from awaking after anesthesia to extubation].

    Science.gov (United States)

    Werlang, Sueli da Cruz; Azzolin, Karina; Moraes, Maria Antonieta; de Souza, Emiliane Nogueira

    2008-12-01

    Preoperative orientation is an essential tool for patient's communication after surgery. This study had the objective of evaluating non-verbal communication of patients submitted to cardiac surgery from the time of awaking from anesthesia until extubation, after having received preoperative orientation by nurses. A quantitative cross-sectional study was developed in a reference hospital of the state of Rio Grande do Sul, Brazil, from March to July 2006. Data were collected in the pre and post operative periods. A questionnaire to evaluate non-verbal communication on awaking from sedation was applied to a sample of 100 patients. Statistical analysis included Student, Wilcoxon, and Mann Whittney tests. Most of the patients responded satisfactorily to non-verbal communication strategies as instructed on the preoperative orientation. Thus, non-verbal communication based on preoperative orientation was helpful during the awaking period.

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

    Science.gov (United States)

    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.

  4. Indirect Self-Modulation Instability Measurement Concept for the AWAKE Proton Beam

    OpenAIRE

    Turner, M.; Petrenko, A.; Biskup, B.; Burger, S; Gschwendtner, E; Lotov, K. V.; S. Mazzoni; Vincke, H.

    2015-01-01

    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 sigma_z = 12 cm) which will be sent into a 10 m long plasma section with a nominal density of approx. 7x10^14 atoms/cm3 (plasma wavelength lambda_p = 1.2mm). In this paper we show that by measuring the time integrated transverse profile of the proton bunch at two locations downstream of the AWAKE plas...

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

    OpenAIRE

    Gschwendtner, E; Adli, E.; Bingham, R.; Biskup, B.; Bohl, T.; Bracco, C.; Burrows, P.N.; Burt, G.; Buttenschon, B.; Butterworth, A.(CERN, Geneva, Switzerland); Caldwell, A.; Cascella, M.; AMORIM, L.; Chevallay, E.; Cipiccia, S.

    2016-01-01

    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 ...

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

    Science.gov (United States)

    Fortin, S M; Cone, J J; Ng-Evans, S; McCutcheon, J E; Roitman, M F

    2015-01-05

    Fast-scan cyclic voltammetry (FSCV) is an electrochemical technique that 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 components required to sample and analyze dopamine concentration changes in awake rats with FSCV.

  7. Inflammatory Profile of Awake Function-Controlled Craniotomy and Craniotomy under General Anesthesia

    Directory of Open Access Journals (Sweden)

    Markus Klimek

    2009-01-01

    Results. Plasma IL-6 level significantly increased with time similarly in both groups. No significant plasma IL-8 and IL-10 change was observed in both experimental groups. The VAS pain score was significantly lower in the awake group compared to the anesthesia group at 12 hours postoperative. Postoperative anxiety and stress declined similarly in both groups. Conclusion. This study suggests that awake function-controlled craniotomy does not cause a significantly different inflammatory response than craniotomy performed under general anesthesia. It is also likely that function-controlled craniotomy does not cause a greater emotional challenge than tumor resection under general anesthesia.

  8. Awake surgery between art and science. Part I: clinical and operative settings.

    Science.gov (United States)

    Talacchi, Andrea; Santini, Barbara; Casagrande, Francesca; Alessandrini, Franco; Zoccatelli, Giada; Squintani, Giovanna M

    2013-01-01

    Awake surgery requires coordinated teamwork and communication between the surgeon and the anesthesiologist, as he monitors the patient, the neuroradiologist as he interprets the images for intraoperative confirmation, and the neuropsychologist and neurophysiologist as they evaluate in real-time the patient's responses to commands and questions. To improve comparison across published studies on clinical assessment and operative settings in awake surgery, we reviewed the literature, focusing on methodological differences and aims. In complex, interdisciplinary medical care, such differences can affect the outcome and the cost-benefit ratio of the treatment. Standardization of intraoperative mapping and related controversies will be discussed in Part II.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  12. Intranasal location and immunohistochemical characterization of the equine olfactory epithelium

    Directory of Open Access Journals (Sweden)

    Alexandra Kupke

    2016-10-01

    Full Text Available 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 (CNS. For horses, it has been proposed and concluded mainly from rodent studies that different viruses, e.g. Borna disease virus (BoDV, equine herpesvirus 1 (EHV-1, hendra virus, influenza virus, rabies virus, vesicular stomatitis virus (VSV 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 5 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 (OMP and doublecortin (DCX expression was found in more cells of OE type a, whereas expression of proliferating cell nuclear antigen (PCNA and tropomyosin receptor kinase A (TrkA 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 type a and b were

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    Kenneth C. Hohmeier

    2015-01-01

    Full Text Available 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.

  15. Nanoemulsion based intranasal delivery of antimigraine drugs for nose to brain targeting

    Directory of Open Access Journals (Sweden)

    Bhanushali R

    2009-01-01

    Full Text Available The objective of this study was to develop intranasal nanoemulsion and gel formulations for rizatriptan benzoate for prolonged action. Nanoemulsion formulations were prepared by constructing pseudo-ternary phase diagrams using lipophilic and hydrophilic surfactants and water. Various mucoadhesive agents were tried out to form thermo-triggered mucoadhesive nanoemulsions. Mucoadhesive gel formulations of rizatriptan were prepared using different ratios of HPMC and Carbopol 980. Comparative evaluation of intranasal nanoemulsions and intranasal mucoadhesive gels indicated that greater brain-targeting could be achieved with nanoemulsions.

  16. Case presentation of an intranasal ectopic tooth in a pediatric patient.

    Science.gov (United States)

    Yu, Chao; Gu, Deying; An, Junnan; Tang, Yuedi

    2015-01-01

    An ectopic tooth in the nasal cavity is a rare phenomenon, especially on the inferior turbinate. In most of the reported cases, no etiological explanation of the intranasal teeth has been suggested or found. In children, intranasal ectopic teeth are usually associated with cleft lip and alveolus. Here, we report a rare case of a pediatric patient with unilateral nasal obstruction due to an intranasal ectopic tooth originating from the inferior turbinate without any facial and dental deformities. This case is unique due to the unusual location of the ectopic tooth and its presentation in a child without facial and dental deformities.

  17. Formulation and kinetic modeling of curcumin loaded intranasal mucoadhesive microemulsion

    Directory of Open Access Journals (Sweden)

    B Mikesh Patel

    2012-01-01

    Full Text Available It is a challenge to develop the optimum dosage form of poorly water-soluble drugs and to target them due to limited bioavailability, intra and inter subject variability. In this investigation, mucoadhesive microemulsion of curcumin was developed by water titration method taking biocompatible components for intranasal delivery and was characterized. Nasal ciliotoxicity studies were carried out using excised sheep nasal mucosa. in vitro release studies of formulations and PDS were performed. Labrafil M 1944 CS based microemulsion was transparent, stable and nasal non-ciliotoxic having particle size 12.32±0.81nm (PdI=0.223 and from kinetic modeling, the release was found to be Fickian diffusion for mucoadhesive microemulsion.

  18. Formulation and characterization of nanoemulsion of olanzapine for intranasal delivery.

    Science.gov (United States)

    Kumar, Mukesh; Misra, Ambikanandan; Pathak, Kamla

    2009-01-01

    The objective was to formulate an olanzapine nanoemulsion that could potentially deliver the drug directly to the brain following intranasal administration. The nanoemulsions were prepared using the water titration method. The mucoadhesive character was imparted by the addition of 0.5%w/w chitosan and 0.5%w/w polycarbophil and was characterized for drug content, pH, percentage transmittance, globule size, zeta potential, and PDI. The composition (%w/w) of the optimized olanzapine nanoemulsion was capmul MCM, tween 80, and a mixture of 1:1 ratio of polyethylene glycol 400 and ethanol, and aqueous phase in a ratio of 15:35:17.5:32.5. The optimized olanzapine nanoemulsion exhibited a high diffusion coefficient and no nasal cilio-toxicity. The drug release followed the Higuchi model. The optimized nanoemulsions were found to be stable for 3 months.

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

    Science.gov (United States)

    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.

  20. INTRANASAL LIPOSOMES : AN APPROACH FOR DRUG DELIVERY TO BRAIN

    Directory of Open Access Journals (Sweden)

    Mr. Jatin B. Trivedi

    2012-05-01

    Full Text Available Targeting drug molecules to brain is one of the most challenging research areas in pharmaceuticalsciences. Drugs that are effective against diseases in the CNS and reach the brain via the bloodcompartment must pass the BBB. The blood-brain barrier (BBB represents an insurmountable obstaclefor a large number of drugs, including antibiotics, anti-neoplastic agents, and a variety of central nervoussystem (CNS-active drugs. Therefore, various strategies have been proposed to improve the delivery ofdifferent drugs to this tissue which includes liposomes, colloidal drug carriers, micelles, chimericpeptide technology, intranasal and olfactory route of administration and nano technology. The discoveryof liposome or lipid vesicle emerged from self forming enclosed lipid bi-layer upon hydration; liposomedrug delivery systems have played a significant role in formulation of potent drug to improvetherapeutics Liposomes have been investigated as carriers of various pharmacologically active agentssuch as antineoplastic, antimicrobial drugs, chelating agents, steroids, vaccines, and genetic materials.Liposomes provide an efficient drug delivery system because they can alter the pharmacokinetics andpharmacodynamics of the entrapped drugs. Liposomes have been widely used for brain delivery in vivo.Nowadays, the nasal route for systemic drug delivery has gained great interest. It provides severaladvantages over other routes of drug administrations, which includes rapid absorption, avoids intestinaland hepatic presystemic disposition and high potential for drug transfer to the CSF. Moreover, the nasalroute is a potential alternative route for systemic availability of drugs restricted to intravenousadministration, viz. peptide and protein drugs and vaccines. As well, intranasal route has also beensuccessfully exploited for bypassing the blood brain barrier [BBB] and subsequently delivering drugmolecules to central nervous system [CNS].

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

    Science.gov (United States)

    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.

  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.

    Science.gov (United States)

    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. Nociception-related somatosensory evoked potentials in awake dogs recorded after intra epidermal electrical stimulation

    NARCIS (Netherlands)

    van Oostrom, H.; Stienen, P.J.; Doornenbal, A.; Hellebrekers, L.J.

    2009-01-01

    Eur J Pain. 2009 Feb;13(2):154-60. Epub 2008 May 16. Nociception-related somatosensory evoked potentials in awake dogs recorded after intra epidermal electrical stimulation. van Oostrom H, Stienen PJ, Doornenbal A, Hellebrekers LJ. Department of Clinical Sciences of Companion Animals, Division Anest

  4. Stay Awake Behind the Wheel (A Minute of Health with CDC)

    Centers for Disease Control (CDC) Podcasts

    2016-11-10

    Being a safe driver requires complete focus on the road and the cars around you. This podcast discusses the importance of staying awake while driving.  Created: 11/10/2016 by MMWR.   Date Released: 11/10/2016.

  5. Awake insertion of the laryngeal mask airway using topical lidocaine and intravenous remifentanil

    NARCIS (Netherlands)

    Lee, MC; Absalom, AR; Menon, DK; Smith, HL

    2006-01-01

    We assessed the use of intravenous remifentanil for the insertion of the laryngeal mask airway in 10 healthy awake volunteers, a technique primarily developed to facilitate functional magnetic resonance imaging studies of anaesthesia. Each volunteer received 200 mu g glycopyrronium intravenously. To

  6. Comparison of jaw muscle EMG activity in awake and sleep bruxers

    DEFF Research Database (Denmark)

    Castrillon, Eduardo; Dreyer Nielsen, Patricia; Haugland, Morten;

    2015-01-01

    TITLE: Comparison of Jaw Muscle EMG Activity in Awake and Sleep Bruxers AUTHORS: E. E. Castrillon, P. Dreyer, M. Haugland, W. Yachida, T. Arima, P. Svensson AUTHORS/INSTITUTIONS: E.E. Castrillon, P. Dreyer, P. Svensson, Aarhus School of Dentistry, Aarhus C, DENMARK; E.E. Castrillon, P. Svensson, ...

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

    Science.gov (United States)

    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. Membrane Potential Dynamics of Spontaneous and Visually Evoked Gamma Activity in V1 of Awake Mice

    NARCIS (Netherlands)

    Perrenoud, Q.; Pennartz, C.M.A.; Gentet, L.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 unc

  9. RELATIONSHIP BETWEEN ANALGESIA AND EXTRACELLULAR MORPHINE IN BRAIN AND SPINAL-CORD IN AWAKE RATS

    NARCIS (Netherlands)

    MATES, FF; ROLLEMA, H; TAIWO, YO; LEVINE, JD; BASBAUM, AI

    1995-01-01

    Extracellular concentrations of morphine from the dorsal spinal cord, the periaqueductal gray (FAG) including the dorsal raphe, and the lateral hypothalamus were measured by microdialysis in awake rats after intraperitoneal (i.p.) administration of 2.5, 5.0 and 10 mg/kg morphine. Morphine concentrat

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

    Science.gov (United States)

    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…

  11. Intravenous ketamine plus midazolam is superior to intranasal midazolam for emergency paediatric procedural sedation

    OpenAIRE

    Acworth, J; Purdie, D.; Clark, R

    2001-01-01

    Objectives—This study compared intranasal midazolam (INM) with a combination of intravenous ketamine and intravenous midazolam (IVKM) for sedation of children requiring minor procedures in the emergency department.

  12. Intranasal epidermoid cyst causing upper airway obstruction in three brachycephalic dogs.

    Science.gov (United States)

    Murgia, D; Pivetta, M; Bowlt, K; Volmer, C; Holloway, A; Dennis, R

    2014-08-01

    This case report describes three brachycephalic dogs with intranasal epidermoid cysts that were causing additional upper airway obstruction. Although epidermoid cysts have been described in several locations in dogs, to the authors' knowledge intranasal epidermoid cysts have not been previously reported. All dogs had mucopurulent to haemorrhagic nasal discharge. Magnetic resonance imaging of the head revealed the presence of unilateral or bilateral intranasal cystic lesions obstructing the nasal cavities partially or completely, with atrophy of the ipsilateral nasal turbinates. The cystic lesions were surgically excised in all dogs using a modified lateral alveolar mucosal approach to the affected nasal cavity. Aerobic, anaerobic and fungal culture of the cystic contents were negative and histology of the excised tissue was consistent with a benign intranasal epidermoid cyst in each dog. Upper airway obstruction was clinically improved in two dogs.

  13. Optimised motion tracking for positron emission tomography studies of brain function in awake rats.

    Directory of Open Access Journals (Sweden)

    Andre Z Kyme

    Full Text Available Positron emission tomography (PET is a non-invasive molecular imaging technique using positron-emitting radioisotopes to study functional processes within the body. High resolution PET scanners designed for imaging rodents and non-human primates are now commonplace in preclinical research. Brain imaging in this context, with motion compensation, can potentially enhance the usefulness of PET by avoiding confounds due to anaesthetic drugs and enabling freely moving animals to be imaged during normal and evoked behaviours. Due to the frequent and rapid motion exhibited by alert, awake animals, optimal motion correction requires frequently sampled pose information and precise synchronisation of these data with events in the PET coincidence data stream. Motion measurements should also be as accurate as possible to avoid degrading the excellent spatial resolution provided by state-of-the-art scanners. Here we describe and validate methods for optimised motion tracking suited to the correction of motion in awake rats. A hardware based synchronisation approach is used to achieve temporal alignment of tracker and scanner data to within 10 ms. We explored the impact of motion tracker synchronisation error, pose sampling rate, rate of motion, and marker size on motion correction accuracy. With accurate synchronisation (20 Hz, and a small head marker suitable for awake animal studies, excellent motion correction results were obtained in phantom studies with a variety of continuous motion patterns, including realistic rat motion (<5% bias in mean concentration. Feasibility of the approach was also demonstrated in an awake rat study. We conclude that motion tracking parameters needed for effective motion correction in preclinical brain imaging of awake rats are achievable in the laboratory setting. This could broaden the scope of animal experiments currently possible with PET.

  14. Enhanced brain targeting efficiency of intranasally administered plasmid DNA: an alternative route for brain gene therapy.

    Science.gov (United States)

    Han, In-Kwon; Kim, Mi Young; Byun, Hyang-Min; Hwang, Tae Sun; Kim, Jung Mogg; Hwang, Kwang Woo; Park, Tae Gwan; Jung, Woon-Won; Chun, Taehoon; Jeong, Gil-Jae; Oh, Yu-Kyoung

    2007-01-01

    Recently, nasal administration has been studied as a noninvasive route for delivery of plasmid DNA encoding therapeutic or antigenic genes. Here, we examined the brain targeting efficiency and transport pathways of intranasally administered plasmid DNA. Quantitative polymerase chain reaction (PCR) measurements of plasmid DNA in blood and brain tissues revealed that intranasally administered pCMVbeta (7.2 kb) and pN2/CMVbeta (14.1 kb) showed systemic absorption and brain distribution. Following intranasal administration, the beta-galactosidase protein encoded by these plasmids was significantly expressed in brain tissues. Kinetic studies showed that intranasally administered plasmid DNA reached the brain with a 2,595-fold higher efficiency than intravenously administered plasmid DNA did, 10 min post-dose. Over 1 h post-dose, the brain targeting efficiencies were consistently higher for intranasally administered plasmid DNA than for intravenously administered DNA. To examine how plasmid DNA enters the brain and moves to the various regions, we examined tissues from nine brain regions, at 5 and 10 min after intranasal or intravenous administration of plasmid DNA. Intravenously administered plasmid DNA displayed similar levels of plasmid DNA in the nine different regions, whereas, intranasally administered plasmid DNA exhibited different levels of distribution among the regions, with the highest plasmid DNA levels in the olfactory bulb. Moreover, plasmid DNA was mainly detected in the endothelial cells, but not in glial cells. Our results suggest that intranasally applied plasmid DNA may reach the brain through a direct route, possibly via the olfactory bulb, and that the nasal route might be an alternative method for efficiently delivering plasmid DNA to the brain.

  15. Comparative pharmacokinetics of single doses of doxylamine succinate following intranasal, oral and intravenous administration in rats.

    Science.gov (United States)

    Pelser, Andries; Müller, Douw G; du Plessis, Jeanetta; du Preez, Jan L; Goosen, Colleen

    2002-09-01

    The intranasal route of administration provides a potential useful way of administering a range of systemic drugs. In order to assess the feasibility of this approach for the treatment of nausea and vomiting, doxylamine succinate was studied in rats for the pharmacokinetics (AUC, C(max), t(max)) following intranasal, oral and intravenous administrations. Subjects (six male Sprague-Dawley rats per time interval for each route of administration) received 2-mg doses of doxylamine succinate orally and I-mg doses intranasally and intravenously, respectively. The various formulations were formulated in isotonic saline (0.9% w/v) at 25 +/- 1 degrees C. Doxylamine succinate concentrations in plasma were determined with a high-performance liquid chromatographic assay and a liquid-liquid extraction procedure. Intranasal and oral bioavailabilities were determined from AUC values relative to those after intravenous dosing. Intranasal bioavailability was greater than that of oral doxylamine succinate (70.8 vs 24.7%). The intranasal and oral routes of administration differed significantly from the intravenous route of administration. Peak plasma concentration (C(max)) was 887.6 ng/ml (S.D. 74.4), 281.4 ng/ml (S.D. 24.6) and 1296.4 ng/ml (S.D. 388.9) for the intranasal, oral and intravenous routes, respectively. The time to achieve C(max) for the intranasal route (t(max)=0.5 h) was faster than for the oral route (t(max)=1.5 h), but no statistically significant differences between the C(max) values were found using 95% confidence intervals. The results of this study show that doxylamine succinate is rapidly and effectively absorbed from the nasal mucosa.

  16. The rostral migratory stream plays a key role in intranasal delivery of drugs into the CNS.

    Directory of Open Access Journals (Sweden)

    Robert A Scranton

    Full Text Available BACKGROUND: The blood brain barrier (BBB is impermeable to most drugs, impeding the establishment of novel neuroprotective therapies and strategies for many neurological diseases. Intranasal administration offers an alternative path for efficient drug delivery into the CNS. So far, the anatomical structures discussed to be involved in the transport of intranasally administered drugs into the CNS include the trigeminal nerve, olfactory nerve and the rostral migratory stream (RMS, but the relative contributions are debated. METHODS AND FINDINGS: In the present study we demonstrate that surgical transection, and the resulting structural disruption of the RMS, in mice effectively obstructs the uptake of intranasally administered radioligands into the CNS. Furthermore, using a fluorescent cell tracer, we demonstrate that intranasal administration in mice allows agents to be distributed throughout the entire brain, including olfactory bulb, hippocampus, cortex and cerebellum. CONCLUSIONS: This study provides evidence of the vital role the RMS has in the CNS delivery of intranasally administered agents. The identification of the RMS as the major access path for intranasally administered drugs into the CNS may contribute to the development of treatments that are tailored for efficient transport within this structure. Research into the RMS needs to continue to elucidate its limitations, capabilities, mechanisms of transport and potential hazards before we are able to advance this technique into human research.

  17. Insulin, insulin analogues and diabetic retinopathy.

    Science.gov (United States)

    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.

  18. Glycosphingolipids and insulin resistance

    NARCIS (Netherlands)

    M. Langeveld; J.F.M.G. Aerts

    2009-01-01

    Obesity is associated with an increased risk for insulin resistance, a state characterized by impaired responsiveness of liver, muscle and adipose tissue to insulin. One class of lipids involved in the development of insulin resistance are the (glyco)sphingolipids. Ceramide, the most simple sphingol

  19. Carcinogenicity of insulin analogues

    NARCIS (Netherlands)

    Braak, Sebastiaan Johannes ter

    2015-01-01

    There is epidemiological evidence that the use of some insulin analogues by diabetic patients is correlated with an increased cancer risk. In vitro exposure experiments revealed that insulin glargine (LANTUS) was the only commercial insulin analogue with an increased mitogenic potential. In the huma

  20. Clinical assessment of awake endotracheal intubation using the lightwand technique alone in patients with difficult airways

    Institute of Scientific and Technical Information of China (English)

    XUE Fu-shan; HE Nong; LIAO Xu; XU Xiu-Zheng; XU Yachao; YANG Quan-yong; LUO Mao-ping; ZHANG Yan-ming

    2009-01-01

    Background There is few study to determine whether the use of the lightwand technique alone could achieve effective, safe and successful awake endotracheal intubation (ETI), therefore we designed a prospective clinical study to systematically evaluate the feasibility, safety and efficacy of awake ETI using the lightwand alone in patients with difficult airways.Methods Seventy adult patients with difficult airways were enrolled in this study. After the desired sedation with fentanyl and midazolam, airway topical anesthesia was performed with 9 ml of 2% lidocaine, which were in order sprayed in three aliquots at 5 minutes intervals into the supraglottic (two doses) and laryngotracheal areas (one dose) using a combined unit of the lightwand and MADgic atomizer. After airway topical anesthesia, awake ETI was performed using a Lightwand. Subjective assessments by patients and operators using the visual analogue scores (VAS), and objective assessments by an independent investigator using patients' tolerance and reaction scores, coughing severity, intubating conditions and cardiovascular variables were taken as the observed parameters.Results Of 210 airway sprays, 197 (93.8%) were successfully completed on the first attempt. The total time for airway spray was (14.6±1.5) minutes. During airway topical anesthesia, the average patients' tolerance scores were 1.7-2.3. After airway topical anesthesia, the mean VAS for discomfort levels that the patients reported was 6.5. Also airway topical anesthesia procedure was rated as acceptable and no discomfort by 94.3% of patients. The lightwand-guided awake ETI was successfully completed on first attempt within 29 seconds in all patients. During awake ETI, patients' reaction and coughing scores were 1.9 and 1.6, respectively. All patients exhibited excellent or acceptable intubating conditions. Cardiovascular monitoring revealed that changes of systolic blood pressure and heart rate at each stage of airway manipulations were less

  1. Metformin and insulin receptors

    Energy Technology Data Exchange (ETDEWEB)

    Vigneri, R.; Gullo, D.; Pezzino, V.

    The authors evaluated the effect of metformin (N,N-dimethylbiguanide), a biguanide known to be less toxic than phenformin, on insulin binding to its receptors, both in vitro and in vivo. Specific /sup 125/I-insulin binding to cultured IM-9 human lymphocytes and MCF-7 human breast cancer cells was determined after preincubation with metformin. Specific /sup 125/I-insulin binding to circulating monocytes was also evaluated in six controls, eight obese subjects, and six obese type II diabetic patients before and after a short-term treatment with metformin. Plasma insulin levels and blood glucose were also measured on both occasions. Metformin significantly increased insulin binding in vitro to both IM-9 lymphocytes and MCF-7 cells; the maximum increment was 47.1% and 38.0%, respectively. Metformin treatment significantly increased insulin binding in vivo to monocytes of obese subjects and diabetic patients. Scatchard analysis indicated that the increased binding was mainly due to an increase in receptor capacity. Insulin binding to monocytes of normal controls was unchanged after metformin as were insulin levels in all groups; blood glucose was significantly reduced after metformin only in diabetic patients. These data indicate that metformin increases insulin binding to its receptors in vitro and in vivo. The effect in vivo is observed in obese subjects and in obese type II diabetic patients, paralleling the clinical effectiveness of this antidiabetic agent, and is not due to receptor regulation by circulating insulin, since no variation in insulin levels was recorded.

  2. Use of movable high-field-strength intraoperative magnetic resonance imaging with awake craniotomies for resection of gliomas: preliminary experience.

    LENUS (Irish Health Repository)

    Leuthardt, Eric C

    2011-07-01

    Awake craniotomy with electrocortical mapping and intraoperative magnetic resonance imaging (iMRI) are established techniques for maximizing tumor resection and preserving function, but there has been little experience combining these methodologies.

  3. Influence of intranasal and carotid cooling on cerebral temperature balance and oxygenation

    Directory of Open Access Journals (Sweden)

    Lars eNybo

    2014-02-01

    Full Text Available The present study evaluated the influence of intranasal cooling with balloon catheters, increased nasal ventilation, or percutaneous cooling of the carotid arteries on cerebral temperature balance and oxygenation in six healthy male subjects. Aortic arch and internal jugular venous blood temperatures were measured to assess the cerebral heat balance and corresponding paired blood samples were obtained to evaluate cerebral metabolism and oxygenation at rest, following 60 min of intranasal cooling, 5 min of nasal ventilation, and 15 min with carotid cooling. Intranasal cooling induced a parallel drop in jugular venous and arterial blood temperatures by 0.30 ± 0.08 ºC (mean ± SD, whereas nasal ventilation and carotid cooling failed to lower the jugular venous blood temperature. The magnitude of the arterio-venous temperature difference across the brain remained unchanged at - 0.33 ± 0.05 ºC following intranasal and carotid cooling, but increased to - 0.44 ± 0.11 ºC (P< 0.05 following nasal ventilation. Calculated cerebral capillary oxygen tension was 43 ± 3 mmHg at rest and remained unchanged during intranasal and carotid cooling, but decreased to 38 ± 2 mmHg (P< 0.05 following increased nasal ventilation. In conclusion, percutaneous cooling of the carotid arteries and intranasal cooling with balloon catheters are insufficient to influence cerebral oxygenation in normothermic subjects as the cooling rate is only 0.3 ºC per hour and neither intranasal nor carotid cooling is capable of inducing selective brain cooling.

  4. Distribution of nimodipine in brain following intranasal administration in rats

    Institute of Scientific and Technical Information of China (English)

    Qi-zhi ZHANG; Xin-guo JIANG; Chun-hua WU

    2004-01-01

    AIM: To determine whether nasally applied nimodipine (NM) could improve its systemic bioavailability and be transported directly from the nasal cavity to the brain. METHODS: NM was administered nasally, intravenously (iv), and orally to male Sprague-Dawley rats. At different times post dose, blood, cerebrospinal fluid (CSF), and brain tissue samples were collected, and the concentrations of NM in the samples were analyzed by HPLC. RESULTS:Oral systemic bioavailability of NM in rats was 1.17 %, nasal dosing improved bioavailibility to 67.4 %. Following intranasal administration, NM concentrations in olfactory bulb (OB) within 30 min post dose were found significant higher than in the other brain tissues. However, similar NM levels in different brain regions were observed after iv injection. AUC in CSF and OB from the nasal route was 1.26 and 1.39 fold compared with the iv route, respectively.The brain-to-plasma AUC ratios were significantly higher after nasal administration than after iv administration (P<0.01). CONCLUSION: Nasally administered NM could markedly improve the bioavailability and a fraction of the NM dose could be transported into brain via the olfactory pathway in rats.

  5. Bioavailability enhancement of verapamil HCl via intranasal chitosan microspheres.

    Science.gov (United States)

    Abdel Mouez, Mamdouh; Zaki, Noha M; Mansour, Samar; Geneidi, Ahmed S

    2014-01-23

    Chitosan microspheres are potential drug carriers for maximizing nasal residence time, circumventing rapid mucociliary clearance and enhancing nasal absorption. The aim of the present study was to develop and characterize chitosan mucoadhesive microspheres of verapamil hydrochloride (VRP) for intranasal delivery as an alternative to oral VRP which suffers low bioavailability (20%) due to extensive first pass effect. The microspheres were produced using a spray-drying and precipitation techniques and characterized for morphology (scanning electron microscopy), particle size (laser diffraction method), drug entrapment efficiency, thermal behavior (differential scanning calorimetry) and crystallinity (X-ray diffractometric studies) as well as in vitro drug release. Bioavailability of nasal VRP microspheres was studied in rabbits and the results were compared to those obtained after nasal, oral and intravenous administration of VRP solution. Results demonstrated that the microspheres were spherical with size 21-53 μm suitable for nasal deposition. The spray-drying technique was superior over precipitation technique in providing higher VRP entrapment efficiency and smaller burst release followed by a more sustained one over 6h. The bioavailability study demonstrated that the nasal microspheres exhibited a significantly higher bioavailability (58.6%) than nasal solution of VRP (47.8%) and oral VRP solution (13%). In conclusion, the chitosan-based nasal VRP microspheres are promising for enhancing VRP bioavailability by increasing the nasal residence time and avoiding the first-pass metabolism of the drug substance.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  8. Intranasal epidermal growth factor treatment rescues neonatal brain injury

    Science.gov (United States)

    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.

  9. Beam Transfer Line Design for a Plasma Wakefield Acceleration Experiment (AWAKE) at the CERN SPS

    CERN Document Server

    Bracco, C; Brethoux, D; Clerc, V; Goddard, B; Gschwendtner, E; Jensen, L K; Kosmicki, A; Le Godec, G; Meddahi, M; Muggli, P; Mutin, C; Osborne, O; Papastergiou, K; Pardons, A; Velotti, F M; Vincke, H

    2013-01-01

    The world’s first proton driven plasma wakefield acceleration experiment (AWAKE) is presently being studied at CERN. The experimentwill use a high energy proton beam extracted from the SPS as driver. Two possible locations for installing the AWAKE facility were considered: the West Area and the CNGS beam line. The previous transfer line from the SPS to the West Area was completely dismantled in 2005 and would need to be fully re-designed and re-built. For this option, geometric constraints for radiation protection reasons would limit the maximum proton beam energy to 300 GeV. The existing CNGS line could be used by applying only minor changes to the lattice for the final focusing and the interface between the proton beam and the laser, required for plasma ionisation and bunch-modulation seeding. The beam line design studies performed for the two options are presented.

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

    Directory of Open Access Journals (Sweden)

    Michiel M. ten Brinke

    2015-12-01

    Full Text Available 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.

  11. Layer-specific high-frequency spiking in the prefrontal cortex of awake rats

    Directory of Open Access Journals (Sweden)

    Zimbo Saroeni Raymond Maria Boudewijns

    2013-06-01

    Full Text Available Cortical pyramidal neurons show irregular in vivo action potential (AP spiking with high frequency bursts occurring on sparse background activity. Somatic APs can backpropagate from soma into basal and apical dendrites and locally generate dendritic calcium spikes. The critical AP frequency for generation of such dendritic calcium spikes can be very different depending on cell-type or brain area involved. Previously, it was shown in vitro that calcium electrogenesis can also be induced in L(ayer 5 pyramidal neurons of prefrontal cortex (PFC. It remains an open question whether somatic burst spiking and resulting dendritic calcium electrogenesis also occur in morphologically more compact L2/3 pyramidal neurons. Furthermore, it is not known whether critical frequencies that trigger dendritic calcium electrogenesis occur in PFC under awake conditions in vivo. Here, we addressed these issues and found that pyramidal neurons in both PFC L2/3 and L5 in awake rats spike APs in short bursts, but with different probabilities. The critical frequency for calcium electrogenesis in vitro was layer-specific and lower in L5 neurons compared to L2/3. Taking the in vitro critical frequency as predictive measure for dendritic electrogenesis during in vivo spontaneous activity, supracritical bursts in vivo were observed in a larger fraction of L5 neurons compared to L2/3 neurons but with similar incidence within these subpopulations. Together, these results show that in PFC of awake rats, AP spiking occurs at frequencies that are relevant for dendritic calcium electrogenesis and suggest that in awake rat PFC, dendritic calcium electrogenesis may be involved in neuronal computation.

  12. Laryngeal Radiation Fibrosis: A Case of Failed Awake Flexible Fibreoptic Intubation

    Directory of Open Access Journals (Sweden)

    Johannes M. Huitink

    2011-01-01

    Full Text Available Awake fibreoptic intubation is accepted as the gold standard for intubation of patients with an anticipated difficult airway. Radiation fibrosis may cause difficulties during the intubation procedure. We present an unusual severe case of radiation induced changes to the larynx, with limited clinical symptoms, that caused failure of the fibreoptic intubation technique. A review of the known literature on radiation fibrosis and airway management is presented.

  13. Millisecond Coupling of Local Field Potentials to Synaptic Currents in the Awake Visual Cortex

    OpenAIRE

    Haider, Bilal; Schulz, David P.A.; Häusser, Michael; Carandini, Matteo

    2016-01-01

    Summary 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 ...

  14. Millisecond Coupling of Local Field Potentials to Synaptic Currents in the Awake Visual Cortex

    OpenAIRE

    Haider, B; Schulz, D. P.; Häusser, M.; Carandini, M.

    2016-01-01

    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...

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

    Science.gov (United States)

    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.

  16. On the "Awake Lion "Culture%“醒狮”文化

    Institute of Scientific and Technical Information of China (English)

    姜喜平; 黎宇

    2012-01-01

    2006年“狮舞”作为民间舞蹈列入国务院确定的第一批国家级非物质文化遗产名录,狮舞包括徐水舞狮、天塔狮舞、黄沙狮子、广东醒狮。广东醒狮指佛山市、遂溪县、广州市的舞狮活动。文章通过田野调查法对广东省的广州市、佛山市、东莞市的醒狮历史文化进行阐述,并走访多名民间艺人和“醒狮”专家,发现“醒狮”存在发展不均衡,其主要原因为:风俗各异、经济状况、部门重视程度不同。%In 2006 "lion-dancing " as a folk dance was by the State Department identified the first batch of national intangible cultural heritage list, which includes the Xushui lion -dancing, Tianta lion-dancing, Huangsha lion -dancing and awake lion of Guangdong Province. Awake lion of Guangdong Province is lion-dancing in Foshan City, Suixi County, Guangzhou County. The article based on the field investigation of Guangdong Province in Guangzhou, Foshan, Dongguan about the awake lion history culture, and many folk artists and" Lion" experts were visited, the study found that " awake lion " development is not balanced. The main reasons are: different customs, economic status, departments emphasis.

  17. Characterization of scale-free properties of human electrocorticography in awake and slow wave sleep states

    Directory of Open Access Journals (Sweden)

    John M Zempel

    2012-06-01

    Full Text Available 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 periods, were used evaluate the nature of changes in scale-free indices. 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 states in individual subjects was excellent. Multisegment 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 multisegment slope indices successfully categorized ECoG data in most subjects, though individual variation was seen. The ECoG spectrum is not well characterized by a single linear fit across a defined set of frequencies, but is best described by a set of discrete linear fits across the full range of available frequencies. With increasing computational tractability, the use of scale-free slope values to characterize EEG data will have practical value in clinical and research EEG studies.

  18. GHz modulation detection using a streak camera: Suitability of streak cameras in the AWAKE experiment

    Science.gov (United States)

    Rieger, K.; Caldwell, A.; Reimann, O.; Muggli, P.

    2017-02-01

    Using frequency mixing, a modulated light pulse of ns duration is created. We show that, with a ps-resolution streak camera that is usually used for single short pulse measurements, we can detect via an FFT detection approach up to 450 GHz modulation in a pulse in a single measurement. This work is performed in the context of the AWAKE plasma wakefield experiment where modulation frequencies in the range of 80-280 GHz are expected.

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

    Science.gov (United States)

    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 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.

  20. Estradiol Binds to Insulin and Insulin Receptor Decreasing Insulin Binding in vitro

    Directory of Open Access Journals (Sweden)

    Robert eRoot-Bernstein

    2014-07-01

    Full Text Available Rationale: Insulin resistance associated with hyperestrogenemias occurs in gestational diabetes mellitus, polycystic ovary syndrome, ovarian hyperstimulation syndrome, estrogen therapies, metabolic syndrome and obesity. The mechanism by which insulin and estrogen interact is unknown. We hypothesize that estrogen binds directly to insulin and the insulin receptor producing insulin resistance.Objectives: To determine the binding constants of steroid hormones to insulin, the insulin receptor, and insulin-like peptides derived from the insulin receptor; and to investigate the effect of estrogens on the binding of insulin to its receptor.Methods: Ultraviolet spectroscopy, capillary electrophoresis and NMR demonstrated estrogen binding to insulin and its receptor. Horse-radish peroxidase-linked insulin was used in an ELISA-like procedure to measure the effect of estradiol on binding of insulin to its receptor. Measurements: Binding constants for estrogens to insulin and the insulin receptor were determined by concentration-dependent spectral shifts. The effect of estradiol on insulin-HRP binding to its receptor was determined by shifts in the insulin binding curve. Main Results: Estradiol bound to insulin with a Kd of 12 x 10-9 M and to the insulin receptor with a Kd of 24 x 10-9 M, while other hormones had significantly less affinity. 200 nM estradiol shifted the binding curve of insulin to its receptor 0.8 log units to the right. Conclusions: Estradiol concentrations in many hyperestrogenemic syndromes are sufficient to interfere with insulin binding to its receptor producing significant insulin resistance.

  1. Imaging circulating tumor cells in freely moving awake small animals using a miniaturized intravital microscope.

    Directory of Open Access Journals (Sweden)

    Laura Sarah Sasportas

    Full Text Available 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.

  2. [Difficult Ventilation Requiring Emergency Endotracheal Intubation during Awake Craniotomy Managed by Laryngeal Mask Airway].

    Science.gov (United States)

    Matsuda, Asako; Mizota, Toshiyuki; Tanaka, Tomoharu; Segawa, Hajime; Fukuda, Kazuhiko

    2016-04-01

    We report a case of difficult ventilation requiring emergency endotracheal intubation during awake craniotomy managed by laryngeal mask airway (LMA). A 45-year-old woman was scheduled to receive awake craniotomy for brain tumor in the frontal lobe. After anesthetic induction, airway was secured using ProSeal LMA and patient was mechanically ventilated in pressure-control mode. Patient's head was fixed with head-pins at anteflex position, and the operation started. About one hour after the start of the operation, tidal volume suddenly decreased. We immediately started manual ventilation, but the airway resistance was extremely high and we could not adequately ventilate the patient. We administered muscle relaxant for suspected laryngospasm, but ventilatory status did not improve; so we decided to conduct emergency endotracheal intubation. We tried to intubate using Airwayscope or LMA-Fastrach, but they were not effective in our case. Finally trachea was intubated using transnasal fiberoptic bronchoscopy. We discuss airway management during awake craniotomy, focusing on emergency endotracheal intubation during surgery.

  3. Auditory ERPs to stimulus deviance in an awake chimpanzee (Pan troglodytes: towards hominid cognitive neurosciences.

    Directory of Open Access Journals (Sweden)

    Ari Ueno

    Full Text Available BACKGROUND: For decades, the chimpanzee, phylogenetically closest to humans, has been analyzed intensively in comparative cognitive studies. Other than the accumulation of behavioral data, the neural basis for cognitive processing in the chimpanzee remains to be clarified. To increase our knowledge on the evolutionary and neural basis of human cognition, comparative neurophysiological studies exploring endogenous neural activities in the awake state are needed. However, to date, such studies have rarely been reported in non-human hominid species, due to the practical difficulties in conducting non-invasive measurements on awake individuals. METHODOLOGY/PRINCIPAL FINDINGS: We measured auditory event-related potentials (ERPs of a fully awake chimpanzee, with reference to a well-documented component of human studies, namely mismatch negativity (MMN. In response to infrequent, deviant tones that were delivered in a uniform sound stream, a comparable ERP component could be detected as negative deflections in early latencies. CONCLUSIONS/SIGNIFICANCE: The present study reports the MMN-like component in a chimpanzee for the first time. In human studies, various ERP components, including MMN, are well-documented indicators of cognitive and neural processing. The results of the present study validate the use of non-invasive ERP measurements for studies on cognitive and neural processing in chimpanzees, and open the way for future studies comparing endogenous neural activities between humans and chimpanzees. This signifies an essential step in hominid cognitive neurosciences.

  4. A VLSI Neural Monitoring System With Ultra-Wideband Telemetry for Awake Behaving Subjects.

    Science.gov (United States)

    Greenwald, E; Mollazadeh, M; Hu, C; Wei Tang; Culurciello, E; Thakor, V

    2011-04-01

    Long-term monitoring of neuronal activity in awake behaving subjects can provide fundamental information about brain dynamics for neuroscience and neuroengineering applications. Here, we present a miniature, lightweight, and low-power recording system for monitoring neural activity in awake behaving animals. The system integrates two custom designed very-large-scale integrated chips, a neural interface module fabricated in 0.5 μm complementary metal-oxide semiconductor technology and an ultra-wideband transmitter module fabricated in a 0.5 μm silicon-on-sapphire (SOS) technology. The system amplifies, filters, digitizes, and transmits 16 channels of neural data at a rate of 1 Mb/s. The entire system, which includes the VLSI circuits, a digital interface board, a battery, and a custom housing, is small and lightweight (24 g) and, thus, can be chronically mounted on small animals. The system consumes 4.8 mA and records continuously for up to 40 h powered by a 3.7-V, 200-mAh rechargeable lithium-ion battery. Experimental benchtop characterizations as well as in vivo multichannel neural recordings from awake behaving rats are presented here.

  5. Prospective pilot trial of dexmedetomidine sedation for awake diagnostic flexible bronchoscopy.

    Science.gov (United States)

    Lee, Keat; Orme, Ruari; Williams, Daryl; Segal, Reny

    2010-10-01

    Dexmedetomidine has the favorable properties of sedation, sympatholysis, analgesia, and a low risk of apnea. These properties suggest that dexmedetomidine may be useful in procedural sedation. In view of this, we conducted a pilot trial to determine the feasibility of using dexmedetomidine as a sole agent for providing sedation during awake diagnostic flexible bronchoscopy. Patients presenting for awake diagnostic flexible bronchoscopy consented to participate in a trial of dexmedetomidine sedation for the procedure. In addition to local anesthetic topicalization of the airways, dexmedetomidine was infused at 0.5 μg/kg over 10 minutes followed by an infusion of 0.2 to 0.7 μg/kg/h titrating to a Ramsay Sedation Scale score of 3. Hemodynamic parameters (heart rate, blood pressure), oxygenation status (pulse oximetry), adverse events, use of rescue sedation, and patient and proceduralist satisfaction were recorded during the trial. Five of 9 recruited patients required rescue sedation to allow the procedure to proceed. Dexmedetomidine as a sole agent at an infusion of 0.5 μg/kg over 10 minutes followed by an infusion of 0.2 to 0.7 μg/kg/h is unable to provide adequate sedation for awake diagnostic flexible bronchoscopy without the need for rescue sedation in a large proportion of patients.

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

    Energy Technology Data Exchange (ETDEWEB)

    Joulaei, A. [Max-Planck Institute for Physics, Munich (Germany); University of Mazandaran (Iran, Islamic Republic of); Moody, J. [Max-Planck Institute for Physics, Munich (Germany); Berti, N.; Kasparian, J. [University of Geneva (Switzerland); Mirzanejhad, S. [University of Mazandaran (Iran, Islamic Republic of); Muggli, P. [Max-Planck Institute for Physics, Munich (Germany)

    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. - Highlights: • Discussion the AWAKE plasma source based on photoionization of rubidium vapor with a TW/cm^2 Intensity laser with a spectrum across valence ground state transition resonances. • Examines the propagation of the AWAKE ionization laser through rubidium vapor at design density on a small scale and reduced intensity with a linear numerical model compared to experimental results. • Discusses physics of pulse propagation through the vapor at high intensity regime where strong ionization occurs within the laser pulse.

  7. Blockade of STAT3 in T Cells Inhibits Germinal Center Reactions against Intranasal Allergens.

    Science.gov (United States)

    Choi, Garam; Chung, Yeonseok

    2016-05-01

    Understanding the developmental mechanisms of humoral immunity against intranasal antigens is essential for the development of therapeutic approaches against air-borne pathogens as well as allergen-induced pulmonary inflammation. Follicular helper T (Tfh) cells expressing CXCR5 are required for humoral immunity by providing IL-21 and ICOS costimulation to activated B cells. However, the regulation of Tfh cell responses against intranasal antigens remains unclear. Here, we found that the generation of Tfh cells and germinal center B cells in the bronchial lymph node against intranasal proteinase antigens was independent of TGF-β. In contrast, administration of STAT3 inhibitor STA-21 suppressed the generation of Tfh cells and germinal center B cells. Compared with wild-type OT-II T cells, STAT3-deficient OT-II T cells transferred into recipients lacking T cells not only showed significantly reduced frequency Tfh cells, but also induced diminished IgG as well as IgE specific for the intranasal antigens. Cotransfer study of wild-type OT-II and STAT3-deficient OT-II T cells revealed that the latter failed to differentiate into Tfh cells. These findings demonstrate that T cell-intrinsic STAT3 is required for the generation of Tfh cells to intranasal antigens and that targeting STAT3 might be an effective approach to ameliorate antibody-mediated pathology in the lung.

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

    Science.gov (United States)

    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.

  9. Intranasal Rapamycin Rescues Mice from Staphylococcal Enterotoxin B-Induced Shock

    Directory of Open Access Journals (Sweden)

    Teresa Krakauer

    2012-09-01

    Full Text Available Staphylococcal enterotoxin B (SEB and related exotoxins produced by Staphylococcus aureus are potent activators of the immune system and cause toxic shock in humans. Currently there is no effective treatment except for the use of intravenous immunoglobulins administered shortly after SEB exposure. Intranasal SEB induces long-lasting lung injury which requires prolonged drug treatment. We investigated the effects of rapamycin, an immunosuppressive drug used to prevent graft rejection, by intranasal administration in a lethal mouse model of SEB-induced shock. The results show that intranasal rapamycin alone delivered as late as 17 h after SEB protected 100% of mice from lethal shock. Additionally, rapamycin diminished the weight loss and temperature fluctuations elicited by SEB. Intranasal rapamycin attenuated lung MCP-1, IL-2, IL-6, and IFNγ by 70%, 30%, 64%, and 68% respectively. Furthermore, short courses (three doses of rapamycin were sufficient to block SEB-induced shock. Intranasal rapamycin represents a novel use of an immunosuppressant targeting directly to site of toxin exposure, reducing dosages needed and allowing a wider therapeutic window.

  10. Comparison of desmopressin (DDAVP tablet and intranasal spray in the treatment of central diabetes insipidus

    Directory of Open Access Journals (Sweden)

    "Bagher Larijani

    2005-07-01

    Full Text Available Desmoperssin is the drug of choice for treatment of central diabetes insipidus and most commonly it is used as intranasal spray. In this study, efficacy and side effects of oral desmopressin was compared with the intranasal spray. This study was before -after clinical trial on 14 outpatients (9 F, 5 M, age 14 -50 Y with central diabetes insipidus who had been treated with intranasal spray of desmopressin previously. Weight, pulse rate and blood pressure (sitting -standing, biochemical profile, serum electrolytes, 24h urine volume, specific gravity of urine and LFT was measured before and after 1 month study. Starting dose for each patient was one oral tablet of DDAVP (0.1 mg per 8 hours. Paired Samples T-Test was used for data analysis. No clinically significant changes were found as regard to weight, pulse rate, blood pressure, blood chemistry, electrolyte and urinalysis. Single reported adverse effect was headache (43% in tablet group and dyspnea (7% in spray group. Both dosage forms were able to control diurnal polyuria and nocturnal polyuria. The antidiuretic dose - equivalence ratio for intranasal to oral desmopressin was 1: 18. Spray was superior in terms of rapid onset of action and duration of antidiuretic action in 100% and 78% of cases (not significant, respectively. Tablets were more available and much more easily consumed as reported by patients, in 86% (P=0.0006. Treatment with tablets offers a good alternative to the intranasal route, especially in patients with chronic rhinitis or common cold and similar conditions.

  11. Biosimilar Insulin and Costs

    Science.gov (United States)

    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

  12. Diabetes, insulin and exercise

    DEFF Research Database (Denmark)

    Richter, Erik; Galbo, H

    1986-01-01

    The metabolic and hormonal adaptations to single exercise sessions and to exercise training in normal man and in patients with insulin-dependent as well as non-insulin-dependent diabetes mellitus are reviewed. In insulin-dependent (type I) diabetes good metabolic control is best obtained...... of the patient's reaction to exercise is desirable, which necessitates frequent self-monitoring of plasma glucose. It may often be necessary to diminish the insulin dose before exercise, and/or to ingest additional carbohydrate during or after exercise. In non-insulin-dependent (type II) diabetes, exercise...... by a regular pattern of life which will lead to a fairly constant demand for insulin from day to day. Exercise is by nature a perturbation that makes treatment of diabetes difficult: Muscle contractions per se tend to decrease the plasma glucose concentration whereas the exercise-induced response of the so...

  13. Insulin aspart pharmacokinetics

    DEFF Research Database (Denmark)

    Rasmussen, Christian Hove; Roge, Rikke Meldgaard; Ma, Zhulin;

    2014-01-01

    Background: Insulin aspart (IAsp) is used by many diabetics as a meal-time insulin to control postprandial glucose levels. As is the case with many other insulin types, the pharmacokinetics (PK), and consequently the pharmacodynamics (PD), is associated with clinical variability, both between...... to investigate and quantify the properties of the subcutaneous depot. Data from Brange et al. (1990) are used to determine the effects of insulin chemistry in subcutis on the absorption rate. Intravenous (i.v.) bolus and infusion PK data for human insulin are used to understand and quantify the systemic...... distribution and elimination (Porksen et al., 1997; Sjostrand et al., 2002). PK and PD profiles for type 1 diabetics from Chen et al. (2005) are analyzed to demonstrate the effects of IAsp antibodies in terms of bound and unbound insulin. PK profiles from Thorisdottir et al. (2009) and Ma et al. (2012b...

  14. Intranasal oxytocin enhances socially-reinforced learning in rhesus monkeys

    Directory of Open Access Journals (Sweden)

    Lisa A Parr

    2014-09-01

    Full Text Available There are currently no drugs approved for the treatment of social deficits associated with autism spectrum disorders (ASD. One hypothesis for these deficits is that individuals with ASD lack the motivation to attend to social cues because those cues are not implicitly rewarding. Therefore, any drug that could enhance the rewarding quality of social stimuli could have a profound impact on the treatment of ASD, and other social disorders. Oxytocin (OT is a neuropeptide that has been effective in enhancing social cognition and social reward in humans. The present study examined the ability of OT to selectively enhance learning after social compared to nonsocial reward in rhesus monkeys, an important species for modeling the neurobiology of social behavior in humans. Monkeys were required to learn an implicit visual matching task after receiving either intranasal (IN OT or Placebo (saline. Correct trials were rewarded with the presentation of positive and negative social (play faces/threat faces or nonsocial (banana/cage locks stimuli, plus food. Incorrect trials were not rewarded. Results demonstrated a strong effect of socially-reinforced learning, monkeys’ performed significantly better when reinforced with social versus nonsocial stimuli. Additionally, socially-reinforced learning was significantly better and occurred faster after IN-OT compared to placebo treatment. Performance in the IN-OT, but not Placebo, condition was also significantly better when the reinforcement stimuli were emotionally positive compared to negative facial expressions. These data support the hypothesis that OT may function to enhance prosocial behavior in primates by increasing the rewarding quality of emotionally positive, social compared to emotionally negative or nonsocial images. These data also support the use of the rhesus monkey as a model for exploring the neurobiological basis of social behavior and its impairment.

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

    Science.gov (United States)

    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.

  16. History of insulin

    Directory of Open Access Journals (Sweden)

    Celeste C. Quianzon

    2012-07-01

    Full Text Available The advancement of diabetes treatment has gone from crude extracts of insulin and accidental discovery of sulfa-like drugs in antibiotics to the development of drugs based on improved understanding of the pathophysiology of diabetes mellitus. This article will review the history of the discovery and development of insulin. A companion focusing on non-insulin diabetes agents will follow in the next issue of JCHIMP.

  17. Landmarks in Insulin Research

    OpenAIRE

    Ward, Colin W.; Lawrence, Michael C.

    2011-01-01

    Ever since the discovery of insulin and its role in the regulation of glucose uptake and utilization, there has been great interest in insulin, its structure and the way in which it interacts with its receptor and effects signal transduction. As the 90th anniversary of the discovery of insulin approaches, it is timely to provide an overview of the landmark discoveries relating to the structure and function of this remarkable molecule and its receptor.

  18. Buccal, intranasal or intravenous lorazepam for the treatment of acute convulsions in children in Malawi: An open randomized trial

    Directory of Open Access Journals (Sweden)

    Samantha Lissauer

    2015-09-01

    Conclusions: Intravenous lorazepam effectively treats most childhood seizures in this setting. Intranasal and buccal routes are less effective but may be useful in pre-hospital care or when intravenous access cannot be obtained. Further studies comparing intranasal lorazepam to other benzodiazepines, or alternative doses by a non-intravenous route are warranted.

  19. AMPK and insulin action

    DEFF Research Database (Denmark)

    Frøsig, Christian; Jensen, Thomas Elbenhardt; Jeppesen, Jacob

    2013-01-01

    The 5'-AMP-activated protein kinase (AMPK) is considered "a metabolic master-switch" in skeletal muscle reducing ATP- consuming processes whilst stimulating ATP regeneration. Within recent years, AMPK has also been proposed as a potential target to attenuate insulin resistance, although the exact...... and insulin stimulated glucose uptake in both the soleus and extensor digitorum longus muscle, coinciding with reduced insulin signaling at the level of Akt (pSer473 and pThr308), TBC1D1 (pThr590) and TBC1D4 (pThr642). In contrast to our hypothesis, the impact of ageing and high fat diet on insulin action...

  20. Insulin sensitivity and albuminuria

    DEFF Research Database (Denmark)

    Pilz, Stefan; Rutters, Femke; Nijpels, Giel;

    2014-01-01

    was assessed by hyperinsulinemic-euglycemic clamps, expressed as the M/I value. Oral glucose tolerance test-based insulin sensitivity (OGIS), homeostasis model assessment of insulin resistance (HOMA-IR), and urinary albumin-to-creatinine ratio (UACR) were determined at baseline and follow-up. RESULTS...... AND METHODS: We investigated 1,415 healthy, nondiabetic participants (mean age 43.9 ± 8.3 years; 54.3% women) from the RISC (Relationship between Insulin Sensitivity and Cardiovascular Disease) study, of whom 852 participated in a follow-up examination after 3 years. At baseline, insulin sensitivity...

  1. A randomized controlled trial of intranasal-midazolam versus intravenous-diazepam for acute childhood seizures.

    Science.gov (United States)

    Thakker, Arpita; Shanbag, Preeti

    2013-02-01

    The objective of this study is to compare the safety and efficacy of midazolam given intranasally with diazepam given intravenously in the treatment of acute childhood seizures. A randomized controlled study was conducted in a pediatric emergency department in a tertiary general hospital. Fifty children aged from 1 month to 12 years presenting with acute seizures of at least 10 min duration were enrolled during a 12 month period. Intranasal midazolam (0.2 mg/kg) and intravenous diazepam (0.3 mg/kg) were administered. The main outcome measures were interval between arrival at hospital and starting treatment and interval between arrival at hospital and cessation of seizures. Intranasal midazolam and intravenous diazepam were equally effective. Overall 18 of 27 seizures were controlled with midazolam and 15 of 23 with diazepam. The mean interval between arrival at hospital and starting treatment was significantly shorter in the midazolam group [3.37 min (SD 2.46)] as compared to the diazepam group [14.13 min (SD 3.39)]. The mean interval between cessation of seizures and arrival at hospital was significantly shorter in the midazolam group [6.67 min (SD 3.12)] as compared to the diazepam group [17.18 min (SD 5.09)]. The mean interval between control of seizures and administration of the drug was shorter in the diazepam group [2.67 min (SD 2.31)] as compared to the midazolam group [3.01 min (SD 2.79)]. No significant side effects were observed in either group. Seizures were controlled more quickly with intravenous diazepam than with intranasal midazolam. Midazolam was as safe and effective as diazepam. The overall interval between arrival at hospital and cessation of seizures was shorter with intranasal midazolam than with intravenous diazepam. The intranasal route can be possibly used not only in medical centres, but with appropriate instruction by the parents of children with acute seizures at home.

  2. Comparison of Nanoemulsion and Aqueous Micelle Systems of Paliperidone for Intranasal Delivery.

    Science.gov (United States)

    Pidaparthi, Kartika; Suares, Divya

    2016-10-06

    The objective of the study was to develop and compare the efficiency of nanoemulsion and aqueous micelle system of Paliperidone on intranasal administration. Both the formulations were evaluated for physical parameters such as globule size, pH, viscosity, conductivity and in vitro drug release studies. The reduction in spontaneous motor activity of L-dopa and Carbidopa-treated Swiss Albino mice on intranasal administration of nanoemulsion and micellar system of Paliperidone was compared with plain drug suspension. Histopathological evaluation of formulation treated nasal mucosal membrane was performed. Nasal spray device was evaluated for spray pattern and volume per actuation. Globule size of micellar system and nanoemulsion was found to be 16.14 & 38.25 nm, respectively. In vitro release of drug from micellar system was found to be 1.8-fold higher than nanoemulsion. The loading of drug in nanoemulsion was found to be superior (2.5 mg/mL) when compared to micellar system (0.41 mg/mL). The spray pattern of micellar system and nanoemulsion from the device was elliptical and circular, respectively. The locomotor activity of L-dopa and Carbidopa-treated Swiss albino mice was found to be 1096.5±78.49, 551.5±13.43 and 535.5±24.75 counts/min in case of plain drug suspension, micellar system and nanoemulsion, respectively. The intranasal administration of developed formulations showed significant difference (p<0.01) in the locomotor activity when compared to intranasal administration of plain drug. Thus it can be concluded that both the developed formulations have shown improved in vivo activity on intranasal administration and pose great potential for delivery of Paliperidone through intranasal route.

  3. Insulin and the Lung

    DEFF Research Database (Denmark)

    Singh, Suchita; Prakash, Y S; Linneberg, Allan;

    2013-01-01

    Obesity, metabolic syndrome, and asthma are all rapidly increasing globally. Substantial emerging evidence suggests that these three conditions are epidemiologically and mechanistically linked. Since the link between obesity and asthma appears to extend beyond mechanical pulmonary disadvantage......, molecular understanding is necessary. Insulin resistance is a strong, independent risk factor for asthma development, but it is unknown whether a direct effect of insulin on the lung is involved. This review summarizes current knowledge regarding the effect of insulin on cellular components of the lung...... and highlights the molecular consequences of insulin-related metabolic signaling cascades that could adversely affect lung structure and function. Examples include airway smooth muscle proliferation and contractility and regulatory signaling networks that are associated with asthma. These aspects of insulin...

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  6. Methemoglobinemia induced by exposure to topical benzocaine for an awake nasal intubation--a case report.

    Science.gov (United States)

    Lin, Shih-Kai; Wu, Ji-Leih; Lee, Yung-Lung; Tsao, Shao-Lun

    2007-06-01

    Topical benzocaine and lidocaine are widely used in general anesthesia to minimize the stimulation by awake intubation and in very rare occasion they may induce methemoglobinemia. Although this complication is uncommon, it may be potentially lethal. Here we report a 29-year-old female who was scheduled to receive correction of malocclusion and developed acute methemoglobinemia soon after induction of general anesthesia. Three weeks ago, she had received open reduction for fracture of mandible with intermaxillary fixation under general anesthesia, for which awake fiberoptic intubation was smoothly performed after premedication with 2% topical lidocaine and intravenous fentanyl. This time, trachomucosal block with 4 mL of 4% topical lidocaine and spray of 20% topical benzocaine over the oral cavity and nostrils were carried out before intubation. Awake blind intubation was performed because she could not open her mouth for more than 1 cm. A 6.5 mm-sized nasal endotracheal tube was smoothly placed in first attempt. About 10 min later, an unexplained cyanosis occurred and SpO2 fell to about 70%. Based on a high oxygen tension by arterial blood gas analysis (PaO2) with a contradictory fall of oxygen saturation by pulse oximetry (SpO2), acute methemoglobinemia was highly suspected. The diagnosis was confirmed by multiple-wavelength CO-oximetry. The methemoglobinemia was resolved gradually after methylene blue was given. In conclusion, we must always take the possibility of methemoglobinemia into consideration for differential diagnosis in case of unexplained cyanosis, particularly when patients have prior exposure to methemoglobin-inducing agents.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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.

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

    CERN Document Server

    Joulaei, Atefeh; Berti, Nicolas; Kasparian, Jerome; Mirzanejhad, Saeed; Muggli, Patric

    2016-01-01

    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.

  10. Methemoglobinemia with the use of benzocaine spray for awake fiberoptic intubation.

    Science.gov (United States)

    Abdel-Aziz, Samer; Hashmi, Nazish; Khan, Sabina; Ismaeil, Mohamed

    2013-10-01

    We report a case in which the use of benzocaine spray to facilitate awake fiber optic intubation (FOI) in a patient with a difficult airway caused methemoglobinemia intraoperatively. Local benzocaine was sprayed to numb the patient's airway for a total time of one second, fifteen minutes later SpO2 decreased to 85% on the pulse oximeter. Arterial blood gas (ABG) showed a MetHb of 24.6% of total Hemoglobin. The patient was successfully treated with methylene blue intravenously and recovered uneventfully. Small amounts of local benzocaine sprayed to numb the airway can cause significant methemoglobinemia that requires immediate recognition and appropriate management.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  13. Cost analysis of awake versus asleep deep brain stimulation: a single academic health center experience.

    Science.gov (United States)

    Jacob, R Lorie; Geddes, Jonah; McCartney, Shirley; Burchiel, Kim J

    2016-05-01

    OBJECT The objective of this study was to compare the cost of deep brain stimulation (DBS) performed awake versus asleep at a single US academic health center and to compare costs across the University HealthSystem Consortium (UHC) Clinical Database. METHODS Inpatient and outpatient demographic and hospital financial data for patients receiving a neurostimulator lead implant (from the first quarter of 2009 to the second quarter of 2014) were collected and analyzed. Inpatient charges included those associated with International Classification of Diseases, Ninth Revision (ICD-9) procedure code 0293 (implantation or replacement of intracranial neurostimulator lead). Outpatient charges included all preoperative charges ≤ 30 days prior to implant and all postoperative charges ≤ 30 days after implant. The cost of care based on reported charges and a cost-to-charge ratio was estimated. The UHC database was queried (January 2011 to March 2014) with the same ICD-9 code. Procedure cost data across like hospitals (27 UHC hospitals) conducting similar DBS procedures were compared. RESULTS Two hundred eleven DBS procedures (53 awake and 158 asleep) were performed at a single US academic health center during the study period. The average patient age ( ± SD) was 65 ± 9 years old and 39% of patients were female. The most common primary diagnosis was Parkinson's disease (61.1%) followed by essential and other forms of tremor (36%). Overall average DBS procedure cost was $39,152 ± $5340. Asleep DBS cost $38,850 ± $4830, which was not significantly different than the awake DBS cost of $40,052 ± $6604. The standard deviation for asleep DBS was significantly lower (p ≤ 0.05). In 2013, the median cost for a neurostimulator implant lead was $34,052 at UHC-affiliated hospitals that performed at least 5 procedures a year. At Oregon Health & Science University, the median cost was $17,150 and the observed single academic health center cost for a neurostimulator lead implant was

  14. Intranasal oxytocin administration in relationship to social behaviour in domestic pigs

    NARCIS (Netherlands)

    Camerlink, Irene; Reimert, Inonge; Bolhuis, Liesbeth

    2016-01-01

    Intranasal administration of oxytocin has been shown to alter positive and negative social behaviour. Positive social behaviour in pigs (Sus scrofa) may be expressed through gentle social nosing, and greater insight in the specific expression hereof might contribute to the current search for posi

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

    Science.gov (United States)

    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.

  16. Comparative Study of Intranasal Midazolam and Intravenous Benzodiazepines in Control of Seizures in Children

    Directory of Open Access Journals (Sweden)

    Janki Panchal

    2013-02-01

    Full Text Available Background: Seizures are very common in pediatric patients. As duration of seizures impacts morbidity and mortality to child’s life, control of seizures should be achieved as early as possible, preferably at home. Rectal diazepam and intranasal midazolam are available methods for control of seizures and can be learnt by parents. Methods: We assessed safety and efficacy of intranasal midazolam for control of seizures and also compared its effect with other benzodiazepines given by intravenous route. Results: Among 84 patients, success rate of treatment with Midazolam (intranasal was 45.5% and success rate with Benzodiazepines (intravenous was 90%. The difference is statistically significant. In present study, average time recorded to give drug after arrival at hospital in IN Midazolam group was 0.379 min, where as it was 1.598 min in IV Benzodiazepine group. Average time for cessation of seizures after giving drug was 3.001 min in IN Midazolam group, where as it was 1.009 min in IV Benzodiazepine group. Conclusion: Intra-venous route for control of seizures is most effective compare to Inta-nasal Midazolam. However intranasal Midazolam can be use full when IV access is not available at home or during transport of patient to health care centre. [Natl J of Med Res 2013; 3(1.000: 30-33

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

    Directory of Open Access Journals (Sweden)

    Olga Dal Monte

    Full Text Available 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.

  18. Direct nose-to-brain delivery of lamotrigine following intranasal administration to mice.

    Science.gov (United States)

    Serralheiro, Ana; Alves, Gilberto; Fortuna, Ana; Falcão, Amílcar

    2015-07-25

    Pharmacoresistance is considered one of the major causes underlying the failure of the anticonvulsant therapy, demanding the development of alternative and more effective therapeutic approaches. Due to the particular anatomical features of the nasal cavity, intranasal administration has been explored as a means of preferential drug delivery to the brain. The purpose of the present study was to assess the pharmacokinetics of lamotrigine administered by the intranasal route to mice, and to investigate whether a direct transport of the drug from nose to brain could be involved. The high bioavailability achieved for intranasally administered lamotrigine (116.5%) underscored the fact that a substantial fraction of the drug has been absorbed to the systemic circulation. Nonetheless, the heterogeneous biodistribution of lamotrigine in different brain regions, with higher concentration levels attained in the olfactory bulb comparatively to the frontal cortex and the remaining portion of the brain, strongly suggest that lamotrigine was directly transferred to the brain via the olfactory neuronal pathway, circumventing the blood-brain barrier. Therefore, it seems that intranasal route can be assumed as a suitable and valuable drug delivery strategy for the chronic treatment of epilepsy, also providing a promising alternative approach for a prospective management of pharmacoresistance.

  19. Intranasal delivery of liposomal indole-3-carbinol improves its pulmonary bioavailability.

    Science.gov (United States)

    Song, Jung Min; Kirtane, Ameya R; Upadhyaya, Pramod; Qian, Xuemin; Balbo, Silvia; Teferi, Fitsum; Panyam, Jayanth; Kassie, Fekadu

    2014-12-30

    Indole-3-carbinol (I3C), a constituent of commonly consumed Brassica vegetables, has been shown to have anticancer effects in a variety of preclinical models of lung cancer. However, it has shown only limited efficacy in clinical trials, likely due to its poor oral bioavailability. Intranasal administration of I3C has the potential to enhance the pulmonary accumulation of the drug, thereby improving its availability at the target site of action. In this study, we developed a liposomal formulation of I3C and evaluated its lung delivery and chemopreventive potential in tobacco smoke carcinogen [4-(methylnitro-samino)-1-(3-pyridyl)-1-butanone (NNK)]-treated mice. Intranasal administration of I3C liposomes led to a ∼100-fold higher lung exposure of I3C than the oral route of administration. Further, intranasal delivery of liposomal I3C led to a significant reduction (37%; pLiposomal I3C also significantly increased (by 10-fold) the expression of CYP1A1, a cytochrome P450 enzyme known to increase the detoxification of chemical carcinogens by enhancing their metabolism. Overall, our findings demonstrate that intranasal administration of liposomal I3C has the potential to significantly improve the efficacy of I3C for lung cancer chemoprevention.

  20. Limited evidence for effects of intranasal corticosteroids on symptom relief for recurrent acute rhinosinusitis

    NARCIS (Netherlands)

    van Loon, J.W.L.; van Harn, R.P.; Venekamp, R.P.; Kaper, N.M.; Sachs, A.P.E.; van der Heijden, G.J.M.G.

    2013-01-01

    Objective To systematically review the evidence base on the effectiveness of intranasal corticosteroids in adult patients with recurrent acute rhinosinusitis. Data Sources Pubmed, EMBASE, and the Cochrane Library. Review Methods A comprehensive search was performed up to March 20, 2013. Two reviewer

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

    Science.gov (United States)

    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 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.

  2. Prevention or early cure of type 1 diabetes by intranasal administration of gliadin in NOD mice

    DEFF Research Database (Denmark)

    Funda, David; Fundova, Petra; Hansen, Axel Kornerup

    2014-01-01

    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...

  3. Intranasal LH-RH treatment of cryptorchidism. A clinical trial and 5 years follow-up

    DEFF Research Database (Denmark)

    Thorup, Jørgen Mogens; Mauritzen, K; Skakkebaek, N E

    1987-01-01

    The effect of intranasal LH-RH on cryptorchidism was investigated in 45 prepubertal boys with 68 undescended testes. A daily dose of 1.2 mg LH-RH was given for 4 weeks. A total of 16 testes (24%) descended. Follow-up examination 5 years later showed that relapse had occurred in two cases. Fifty-t...

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

    Science.gov (United States)

    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.

  5. Simultaneous intramammary and intranasal inoculation of lactating cows with bovine herpesvirus 4 induce subclinical mastitis

    NARCIS (Netherlands)

    Wellenberg, G.J.; Bruschke, C.J.M.; Wisselink, H.J.; Barkema, H.W.; Oirschot, van J.T.

    2002-01-01

    In this study, we examined whether an experimental bovine herpesvirus 4 (BHV4) infection can induce bovine mastitis, or can enhance bovine mastitis induced by Streptococcus uberis (S. uberis). Four lactating cows were inoculated intramammarily and intranasally with BHV4, and four lactating control c

  6. Intranasal Rapamycin Rescues Mice from Staphylococcal Enterotoxin B-Induced Shock

    Science.gov (United States)

    2012-09-18

    Mice from Staphylococcal Enterotoxin B-Induced Shock Teresa Krakauer * and Marilyn Buckley Integrated Toxicology Division, U.S. Army Medical...2012 / Published: 18 September 2012 Abstract: Staphylococcal enterotoxin B (SEB) and related exotoxins produced by Staphylococcus aureus are...allowing a wider therapeutic window. Keywords: intranasal rapamycin; staphylococcal enterotoxin B; shock 1. Introduction Staphylococcal

  7. Safety of Intranasal Fentanyl in the Out-of-Hospital Setting

    DEFF Research Database (Denmark)

    Karlsen, Anders P H; Pedersen, Danny M B; Trautner, Sven

    2014-01-01

    : In this prospective observational study, we administered intranasal fentanyl in the out-of-hospital setting to adults and children older than 8 years with severe pain resulting from orthopedic conditions, abdominal pain, or acute coronary syndrome refractory to nitroglycerin spray. Patients received 1 to 3 doses...

  8. Direct nose-brain transport of benzoylecgonine following intranasal administration in rats.

    Science.gov (United States)

    Chow, H H; Anavy, N; Villalobos, A

    2001-11-01

    In our previous research, cocaine applied intranasally in rats diffused or was transported directly from the nasal cavity to the brain. However, the direct nose-brain cocaine transport only contributes to an initial increase in the relative cocaine brain exposure. In this study, we have determined the nose-brain transport of a polar metabolite of cocaine, benzoylecgonine, to help understand factors affecting drug transport via this novel pathway. The nasal cavity of male Sprague-Dawley rats was isolated to prevent drainage of nasally applied dosing solution to non-nasal regions. Benzoylecgonine was then administered, either by intranasal administration or by intravenous (iv) injection. At different times postdose, blood and tissues from different regions of the brain were collected from groups of rats (n = 4 for each collection time) and benzoylecgonine concentrations in these samples were analyzed by high-performance liquid chromatography. Benzoylecgonine concentrations in plasma were at maximal levels immediately after iv dosing and declined as a function of time. Following intranasal administration, benzoylecgonine concentrations in plasma reached maximal levels between 15 and 30 min after dosing and declined as a function of time. To allow comparison of brain benzoylecgonine content after iv and intranasal administration, brain benzoylecgonine contents were normalized by plasma benzoylecgonine concentrations. The ratios of the area under the benzoylecgonine concentration-time curve (AUC) between the olfactory bulb and plasma following intranasal administration were 10-100 times higher than those obtained after iv dosing. The olfactory tract-to-plasma benzoylecgonine AUC ratios after intranasal administration were significantly higher than those after iv dosing up to 120 min following dosing. The brain tissue-to-plasma AUC ratios in cerebellum, brain stem, and cerebral cortex after intranasal administration were significantly higher than the corresponding ratios

  9. Assessment of pharmacokinetics and tolerability of intranasal diazepam relative to rectal gel in healthy adults.

    Science.gov (United States)

    Henney, Herbert R; Sperling, Michael R; Rabinowicz, Adrian L; Bream, Gary; Carrazana, Enrique J

    2014-09-01

    Diazepam rectal gel (RG) is currently the only approved rescue therapy for outpatient management of seizure clusters in the United States. There is an unmet medical need for an alternative rescue therapy for seizure clusters that is effective, and more convenient to administer with a socially acceptable method of delivery. An intranasal diazepam formulation has been developed, and this study evaluates the tolerability and bioavailability of diazepam nasal spray (NS) relative to an equivalent dose of diazepam-RG in healthy adults. Twenty-four healthy adults were enrolled in a phase 1, open-label, 3-period crossover study. Plasma diazepam and metabolite concentrations were measured by serial sampling. Dose proportionality for 5- and 20-mg intranasal doses and the bioavailability of 20mg diazepam-NS relative to 20mg diazepam-RG were assessed by maximum plasma concentration (Cmax) and systemic exposure parameters (AUC0-∞ and AUC0-24). The mean Cmax values for 20mg diazepam-NS and 20mg diazepam-RG were 378 ± 106 and 328 ± 152 ng/mL, achieved at 1.0 and 1.5h, respectively. Subjects administered intranasal and rectal gel formulations experienced nasal and rectal leakage, respectively. Diazepam absorption following intranasal administration was consistent but 3 subjects with diazepam-RG had low plasma drug levels at the earliest assessment of 5 min, due to poor retention, and were excluded from analysis. Excluding them, the treatment ratios (20mg diazepam-NS:20mg diazepam-RG) and 90% confidence intervals for diazepam Cmax and AUC0-24 were 0.98 (0.85-1.14) and 0.89 (0.80-0.98), respectively, suggesting that the bioavailability was comparable between the two formulations. Dose proportionality was observed between the lowest and highest dose-strengths of intranasal formulation. Both intranasal and rectal treatments were well tolerated with mild to moderate adverse events. Results suggest that a single-dose of 20mg diazepam-NS is tolerable and comparable in bioavailability

  10. Insulin Resistance and Hypertension

    Institute of Scientific and Technical Information of China (English)

    张建华; 张春秀

    2002-01-01

    Summary: The insulin sensitivity in hypertensive patients with normal glucose tolerance (NGT),impaired glucose tolerance (IGT) and type 2 diabetes mellitus (DM) and the insulin resistance(IR) under the disorder of glucose metabolism and hypertension were studied. By glucose toler-ance test and insulin release test, insulin sensitivity index (ISI) and the ratio of area under glucosetolerance curve (AUCG) to area under insulin release curve (AUC1) were calculated and analyzed.The results showed that ISI was decreased to varying degrees in the patients with hypertension,the mildest in the group of NGT with hypertension, followed by the group of IGT without hyper-tension, the group of IGT with hypertension and DM (P=0). There was very significant differ-ence in the ratio of AUCG/AUC1 between the hypertensive patients with NGT and controls (P=0). It was concluded that a significant IR existed during the development of IGT both in hyperten-sion and nonhypertension. The increase of total insulin secretion (AUC1) was associated with non-hypertension simultaneously. IR of the hypertensive patients even existed in NGT and was wors-ened with the deterioration of glucose metabolism disorder, but the AUC1 in the HT groupchanged slightly. A relative deficiency of insulin secretion or dysfunction of β-cell of islet existed inIGT and DM of the hypertensive patients.

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

    Science.gov (United States)

    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.

  12. Drug brain distribution following intranasal administration of Huperzine A in situ gel in rats

    Institute of Scientific and Technical Information of China (English)

    Yan ZHAO; Peng YUE; Tao TAO; Qing-hua CHEN

    2007-01-01

    Aim: To determine the uptake extent of Huperzine A (Hup A) into the brain after intranasal administration of Hup A in situ gel to rats, and to compare the pharma-cokinetic parameters between intranasal administration and iv and po. Methods: Hup A was administered to male Sprague-Dawley rats via nasal, iv and oral routes at the dose of 166.7, 166.7, and 500μg/kg, respectively. Blood and brain tissue samples including the cerebrum, hippocampus, cerebellum and olfactory bulb were collected, and the concentrations of Hup A in the samples were assayed by HPLC. The area under the concentration-time curve (AUC,0→6h) and the ratio of the AUC,brain, to the AUC,plasma (drug targeting efficiency, DTE) were calculated toevaluate the brain targeting efficiency of the drug via 3 administration routes. Results: The AUC,0→6h of the drug in the cerebrum, hippocampus, cerebellum, left olfactory bulb and right olfactory bulb after intranasal administration of the Hup A in situ gel were 1.5, 1.3, 1.0, 1.2, and 1.0 times of those after iv administration of the injection, and 2.7, 2.2, 1.9, 3.1, and 2.6 times of those after administration of the oral formulation. The AUC,brain0→6h/AUC,plasma0→6h of Hup A in the cerebrum, hippocampus and left olfactory bulb following the intranasal administration dose were significantly higher (P0.05) than the iv dose. Conclusion: Intranasal delivery showed a viable, non-invasive strategy for delivering the drug into brain.

  13. Molecular mechanism of insulin resistance

    Indian Academy of Sciences (India)

    Samir Bhattacharya; Debleena Dey; Sib Sankar Roy

    2007-03-01

    Free fatty acids are known to play a key role in promoting loss of insulin sensitivity, thereby causing insulin resistance and type 2 diabetes. However, the underlying mechanism involved is still unclear. In searching for the cause of the mechanism, it has been found that palmitate inhibits insulin receptor (IR) gene expression, leading to a reduced amount of IR protein in insulin target cells. PDK1-independent phosphorylation of PKCε causes this reduction in insulin receptor gene expression. One of the pathways through which fatty acid can induce insulin resistance in insulin target cells is suggested by these studies. We provide an overview of this important area, emphasizing the current status.

  14. Case Report: Emergency awake craniotomy for cerebral abscess in a patient with unrepaired cyanotic congenital heart disease

    Science.gov (United States)

    Fassl, Jens; Tobler, Daniel; Zumofen, Daniel; Steiner, Luzius A.; Goettel, Nicolai

    2017-01-01

    We report the case of a 39-year-old male with complex cyanotic congenital heart disease undergoing emergency craniotomy for a cerebral abscess. Maintenance of intraoperative hemodynamic stability and adequate tissue oxygenation during anesthesia may be challenging in patients with cyanotic congenital heart disease. In this case, we decided to perform the surgery as an awake craniotomy after interdisciplinary consensus. We discuss general aspects of anesthetic management during awake craniotomy and specific concerns in the perioperative care of patients with congenital heart disease. PMID:27928498

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

    Science.gov (United States)

    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!!!

  16. Association of Awake Bruxism with Khat, Coffee, Tobacco, and Stress among Jazan University Students

    Science.gov (United States)

    Quadri, Mir Faeq Ali; Mahnashi, Ali; Al Almutahhir, Ayman; Tubayqi, Hamzah; Hakami, Abdullah; Arishi, Mohamed; Alamir, Abdulwahab

    2015-01-01

    Objective. The objective is to assess the prevalence of bruxism among the university students and to check its association with their khat chewing habit. Materials and Methods. A cross-sectional descriptive study is designed using cluster random sampling. Pretested questionnaire was administered by a trained interviewer to assess awake bruxism and the use of variables like khat, coffee, tobacco, and stress. Chi-square test at 5% significance was used for assessing the association. Logistic regression was also performed after adjusting for covariates. Results. A high response rate (95%) was obtained as the distribution and collection of questionnaire was within an hour interval. 85% (63%, males; 22%, females) experienced an episode of bruxism at least one time in the past six months. Regression analysis revealed an association of stress (P = 0.00; OR = 5.902, 95% CI 2.614–13.325) and khat use (P = 0.05; OR = 1.629, 95% CI 0.360–7.368) with bruxism. Interestingly, it is observed that the one who chew khat experienced 3.56 times (95% CI; 2.62–11.22) less pain when compared to the nonusers. Conclusion. This study is the first of its kind to assess the association of bruxism with khat chewing. High amount of stress and khat use can be considered as important risk indicators for awake bruxism. PMID:26491448

  17. Association of Awake Bruxism with Khat, Coffee, Tobacco, and Stress among Jazan University Students

    Directory of Open Access Journals (Sweden)

    Mir Faeq Ali Quadri

    2015-01-01

    Full Text Available Objective. The objective is to assess the prevalence of bruxism among the university students and to check its association with their khat chewing habit. Materials and Methods. A cross-sectional descriptive study is designed using cluster random sampling. Pretested questionnaire was administered by a trained interviewer to assess awake bruxism and the use of variables like khat, coffee, tobacco, and stress. Chi-square test at 5% significance was used for assessing the association. Logistic regression was also performed after adjusting for covariates. Results. A high response rate (95% was obtained as the distribution and collection of questionnaire was within an hour interval. 85% (63%, males; 22%, females experienced an episode of bruxism at least one time in the past six months. Regression analysis revealed an association of stress (P=0.00; OR = 5.902, 95% CI 2.614–13.325 and khat use (P=0.05; OR = 1.629, 95% CI 0.360–7.368 with bruxism. Interestingly, it is observed that the one who chew khat experienced 3.56 times (95% CI; 2.62–11.22 less pain when compared to the nonusers. Conclusion. This study is the first of its kind to assess the association of bruxism with khat chewing. High amount of stress and khat use can be considered as important risk indicators for awake bruxism.

  18. Disrupting neural activity related to awake-state sharp wave-ripple complexes prevents hippocampal learning

    Directory of Open Access Journals (Sweden)

    Miriam Shirin Nokia

    2012-12-01

    Full Text Available Oscillations in hippocampal local-field potentials 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, 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.

  19. Awake fi beroptic intubation of a patient with amyotrophic lateral sclerosis: case report

    Directory of Open Access Journals (Sweden)

    Elif Bakı

    2012-12-01

    Full Text Available Amyotrophic Lateral Sclerosis is a rapidly progressive disease from the fi fth to sixth decades of life causing degeneration and death of the upper and lower motor neurons and no effective treatment. The diagnosis isdependent on the clinical presentation and consistent electrodiagnostic studies. Progressive denervation affects the muscles, causing muscular weakness and atrophy, when the ventilation muscles are affected deathdue to respiratory failure occurs within a few years. We present the case of a 54 years old, 180 cm height and 94 kg weight male patient with amyotrophic lateral sclerosis who underwent surgical treatment of thyroidcancer. Fiberoptic intubation was orally performed providing spontaneus breathing. Propofol was applied after passing vocal cords. Anesthesia was maintained with sevofl orane (%2 and a mixture of oxygen and airunder volume controlled ventilation. Rocuronium was used 20 mg at the beginning of the surgery. At the end of surgery, he wasn’t extubated and transferred to anesthesia intensive care unit. He was extubated after tenhours and he was awaked perfectly. The patient was discharged from intensive care unit after 24 hours and from hospital after ten days. We reported that amyotrophic lateral sclerosis patient with limited mouth opening who underwent thyroid surgery, using awake intubation.

  20. Indirect self-modulation instability measurement concept for the AWAKE proton beam

    Science.gov (United States)

    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.

  1. Indirect Self-Modulation Instability Measurement Concept for the AWAKE Proton Beam

    CERN Document Server

    Turner, M; Biskup, B; Burger, S; Gschwendtner, E; Lotov, K V; Mazzoni, S; Vincke, H

    2016-01-01

    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 sigma_z = 12 mm) which will be sent into a 10 m long plasma section with a nominal density of approx. 7x10^14 atoms/cm3 (plasma wavelength lambda_p = 1.2mm). 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 defo...

  2. Response Patterns of GABAergic Neurons in the Anterior Piriform Cortex of Awake Mice.

    Science.gov (United States)

    Hu, Rongfeng; Zhang, Juen; Luo, Minmin; Hu, Ji

    2016-06-01

    Local inhibition by γ-amino butyric acid (GABA)-containing neurons is of vital importance for the operation of sensory cortices. However, the physiological response patterns of cortical GABAergic neurons are poorly understood, especially in the awake condition. Here, we utilized the recently developed optical tagging technique to specifically record GABAergic neurons in the anterior piriform cortex (aPC) in awake mice. The identified aPC GABAergic neurons were stimulated with robotic delivery of 32 distinct odorants, which covered a broad range of functional groups. We found that aPC GABAergic neurons could be divided into 4 types based on their response patterns. Type I, type II, and type III neurons displayed broad excitatory responses to test odorants with different dynamics. Type I neurons were constantly activated during odorant stimulation, whereas type II neurons were only transiently activated at the onset of odorant delivery. In addition, type III neurons displayed transient excitatory responses both at the onset and termination of odorant presentation. Interestingly, type IV neurons were broadly inhibited by most of the odorants. Taken together, aPC GABAergic neurons adopt different strategies to affect the cortical circuitry. Our results will allow for better understanding of the role of cortical GABAergic interneurons in sensory information processing.

  3. Status of the proton and electron transfer lines for the AWAKE Experiment at CERN

    Energy Technology Data Exchange (ETDEWEB)

    Schmidt, J.S., E-mail: janet.schmidt@cern.ch [CERN, Geneva (Switzerland); Bauche, J. [CERN, Geneva (Switzerland); Biskup, B. [CERN, Geneva (Switzerland); Czech Technical University, Prague (Czech Republic); 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. [CERN, Geneva (Switzerland)

    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.

  4. Status of the proton and electron transfer lines for the AWAKE Experiment at CERN

    Science.gov (United States)

    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.

  5. The stimulus-evoked population response in visual cortex of awake monkey is a propagating wave.

    Science.gov (United States)

    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.

  6. Mismatch responses in the awake rat: evidence from epidural recordings of auditory cortical fields.

    Directory of Open Access Journals (Sweden)

    Fabienne Jung

    Full Text Available Detecting sudden environmental changes is crucial for the survival of humans and animals. In the human auditory system the mismatch negativity (MMN, a component of auditory evoked potentials (AEPs, reflects the violation of predictable stimulus regularities, established by the previous auditory sequence. Given the considerable potentiality of the MMN for clinical applications, establishing valid animal models that allow for detailed investigation of its neurophysiological mechanisms is important. Rodent studies, so far almost exclusively under anesthesia, have not provided decisive evidence whether an MMN analogue exists in rats. This may be due to several factors, including the effect of anesthesia. We therefore used epidural recordings in awake black hooded rats, from two auditory cortical areas in both hemispheres, and with bandpass filtered noise stimuli that were optimized in frequency and duration for eliciting MMN in rats. Using a classical oddball paradigm with frequency deviants, we detected mismatch responses at all four electrodes in primary and secondary auditory cortex, with morphological and functional properties similar to those known in humans, i.e., large amplitude biphasic differences that increased in amplitude with decreasing deviant probability. These mismatch responses significantly diminished in a control condition that removed the predictive context while controlling for presentation rate of the deviants. While our present study does not allow for disambiguating precisely the relative contribution of adaptation and prediction error processing to the observed mismatch responses, it demonstrates that MMN-like potentials can be obtained in awake and unrestrained rats.

  7. A novel tablet computer platform for advanced language mapping during awake craniotomy procedures.

    Science.gov (United States)

    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. Membrane Potential Dynamics of Spontaneous and Visually Evoked Gamma Activity in V1 of Awake Mice.

    Directory of Open Access Journals (Sweden)

    Quentin Perrenoud

    2016-02-01

    Full Text Available 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.

  9. Intact skull chronic windows for mesoscopic wide-field imaging in awake mice

    Science.gov (United States)

    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. Does Global Astrocytic Calcium Signaling Participate in Awake Brain State Transitions and Neuronal Circuit Function?

    Science.gov (United States)

    Kjaerby, Celia; Rasmussen, Rune; Andersen, Mie; Nedergaard, Maiken

    2017-02-16

    We continuously need to adapt to changing conditions within our surrounding environment, and our brain needs to quickly shift between resting and working activity states in order to allow appropriate behaviors. These global state shifts are intimately linked to the brain-wide release of the neuromodulators, noradrenaline and acetylcholine. Astrocytes have emerged as a new player participating in the regulation of brain activity, and have recently been implicated in brain state shifts. Astrocytes display global Ca(2+) signaling in response to activation of the noradrenergic system, but whether astrocytic Ca(2+) signaling is causative or correlative for shifts in brain state and neural activity patterns is not known. Here we review the current available literature on astrocytic Ca(2+) signaling in awake animals in order to explore the role of astrocytic signaling in brain state shifts. Furthermore, we look at the development and availability of innovative new methodological tools that are opening up for new ways of visualizing and perturbing astrocyte activity in awake behaving animals. With these new tools at hand, the field of astrocyte research will likely be able to elucidate the causal and mechanistic roles of astrocytes in complex behaviors within a very near future.

  11. [Perioperative management of an obese patient complicated with sleep apnea syndrome (SAS) undergoing awake craniotomy].

    Science.gov (United States)

    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.

  12. AMPK and insulin action

    DEFF Research Database (Denmark)

    Frøsig, Christian; Jensen, Thomas Elbenhardt; Jeppesen, Jacob;

    2013-01-01

    The 5'-AMP-activated protein kinase (AMPK) is considered "a metabolic master-switch" in skeletal muscle reducing ATP- consuming processes whilst stimulating ATP regeneration. Within recent years, AMPK has also been proposed as a potential target to attenuate insulin resistance, although the exact...... role of AMPK is not well understood. Here we hypothesized that mice lacking a2AMPK activity in muscle would be more susceptible to develop insulin resistance associated with ageing alone or in combination with high fat diet. Young (~4 month) or old (~18 month) wild type and muscle specific a2AMPK...... kinase-dead mice on chow diet as well as old mice on 17 weeks of high fat diet were studied for whole body glucose homeostasis (OGTT, ITT and HOMA-IR), insulin signaling and insulin-stimulated glucose uptake in muscle. We demonstrate that high fat diet in old mice results in impaired glucose homeostasis...

  13. Inhaled insulin: overview of a novel route of insulin administration

    Directory of Open Access Journals (Sweden)

    Lucy D Mastrandrea

    2010-01-01

    Full Text Available Lucy D MastrandreaDepartment of Pediatrics, School of Medicine and Biochemical Sciences, University at Buffalo, Buffalo, NY, USAAbstract: Diabetes is a chronic disease characterized by inadequate insulin secretion with resulting hyperglycemia. Diabetes complications include both microvascular and macrovascular disease, both of which are affected by optimal diabetes control. Many individuals with diabetes rely on subcutaneous insulin administration by injection or continuous infusion to control glucose levels. Novel routes of insulin administration are an area of interest in the diabetes field, given that insulin injection therapy is burdensome for many patients. This review will discuss pulmonary delivery of insulin via inhalation. The safety of inhaled insulin as well as the efficacy in comparison to subcutaneous insulin in the various populations with diabetes are covered. In addition, the experience and pitfalls that face the development and marketing of inhaled insulin are discussed.Keywords: glycemic control, hemoglobin A1c, inhalation, insulin, type 1 diabetes, type 2 diabetes

  14. Reduced phosphorylation of brain insulin receptor substrate and Akt proteins in apolipoprotein-E4 targeted replacement mice.

    Science.gov (United States)

    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.

  15. Insulin pump therapy in pregnancy.

    Science.gov (United States)

    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.

  16. A VEP study in sleeping and awake one-month-old infants and its relation with social behavior.

    Science.gov (United States)

    Cruz, Sara; Crego, Alberto; Ribeiro, Eugénia; Gonçalves, Óscar; Sampaio, Adriana

    2015-04-01

    With the present study we aimed to analyze the relationship between infants' behavior and their visual evoked-potential (VEPs) response. Specifically, we want to verify differences regarding the VEP response in sleeping and awake infants and if an association between VEP components, in both groups, with neurobehavioral outcome could be identified. To do so, thirty-two full-term and healthy infants, approximately 1-month of age, were assessed through a VEP unpatterned flashlight stimuli paradigm, offered in two different intensities, and were assessed using a neurobehavioral scale. However, only 18 infants have both assessments, and therefore, these is the total included in both analysis. Infants displayed a mature neurobehavioral outcome, expected for their age. We observed that P2 and N3 components were present in both sleeping and awake infants. Differences between intensities were found regarding the P2 amplitude, but only in awake infants. Regression analysis showed that N3 amplitude predicted an adequate social interactive and internal regulatory behavior in infants who were awake during the stimuli presentation. Taking into account that social orientation and regulatory behaviors are fundamental keys for social-like behavior in 1-month-old infants, this study provides an important approach for assessing physiological biomarkers (VEPs) and its relation with social behavior, very early in postnatal development. Moreover, we evidence the importance of the infant's state when studying differences regarding visual threshold processing and its association with behavioral outcome.

  17. NCOG-06. Usability and validity of a phone battery to assess language functions in brain tumor patients undergoing awake surgery

    NARCIS (Netherlands)

    Witte, E. de; Piai, V.; Dronkers, N.F.; Berger, M.S.

    2016-01-01

    Introduction: A wake surgery in eloquent brain regions is performed to preserve language functions. Although in general no major permanent language deficits are found after awake brain surgery, clinically relevant impairments are detected (Satoer et al., 2014). Unfortunately, follow-up of tum

  18. Laser speckle imaging identification of increases in cortical microcirculatory blood flow induced by motor activity during awake craniotomy ; Clinical article

    NARCIS (Netherlands)

    E. Klijn (Elko); M.E.J.L. Hulscher (Marlies); R.K. Balvers (Rutger); W.P.J. Holland (Wim); J. Bakker (Jan); A.J.P.E. Vincent (Arnoud); C.M.F. Dirven (Clemens); C. Ince (Can)

    2013-01-01

    textabstractObject. The goal of awake neurosurgery is to maximize resection of brain lesions with minimal injury to functional brain areas. Laser speckle imaging (LSI) is a noninvasive macroscopic technique with high spatial and temporal resolution used to monitor changes in capillary perfusion. In

  19. REAL-TIME MEASUREMENT OF AIRWAY RESPONSES TO SULOFUR DIOXIDE (SO2) IN AN INTACT, AWAKE GUINEA PIG MODEL

    Science.gov (United States)

    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...

  20. Spiking in primary somatosensory cortex during natural whisking in awake head-restrained rats is cell-type specific

    NARCIS (Netherlands)

    C.P.J. de Kock (Christiaan); B. Sakmann (Bert)

    2009-01-01

    textabstractSensation involves active movement of sensory organs, but it remains unknown how position or movement of sensory organs is encoded in cortex. In the rat whisker system, each whisker is represented by an individual cortical (barrel) column. Here, we quantified in awake, head-fixed rats th

  1. Measurement of lung function in awake 2-4-year-old asthmatic children during methacholine challenge and acute asthma

    DEFF Research Database (Denmark)

    Klug, B; Bisgaard, H

    1996-01-01

    This study evaluated three techniques for testing of lung function in young awake children. We compared measurements by the forced or impulse oscillation technique (IOS), the interrupter technique (IT), and transcutaneous measurements of oxygen (tcPo2) with concomitant measurements of specific...

  2. Ex vivo evaluation of the serotonin 1A receptor partial agonist [³H]CUMI-101 in awake rats

    DEFF Research Database (Denmark)

    Palner, Mikael; Underwood, Mark D; Kumar, Dileep J S;

    2011-01-01

    [³H]CUMI-101 is a 5-HT(1A) partial agonist, which has been evaluated for use as a positron emission tracer in baboon and humans. We sought to evaluate the properties of [³H]CUMI-101 ex vivo in awake rats and determine if [³H]CUMI-101 can measure changes in synaptic levels of serotonin after...

  3. SIMULTANEOUS MEASUREMENT OF EXTRACELLULAR MORPHINE AND SEROTONIN IN BRAIN-TISSUE AND CSF BY MICRODIALYSIS IN AWAKE RATS

    NARCIS (Netherlands)

    MATOS, FF; ROLLEMA, H; BASBAUM, AI

    1992-01-01

    In this report, we describe an HPLC with electrochemical detection assay for the simultaneous measurement of levels of morphine, serotonin, 5-hydroxyindole-3-acetic acid, and homovanillic acid in dialysates of various brain areas and CSF in the awake rat. Morphine could be detected in the dialysates

  4. Molecular biocoding of insulin

    Directory of Open Access Journals (Sweden)

    Lutvo Kuric

    2010-07-01

    Full Text Available Lutvo KuricNovi Travnik, Kalinska, Bosnia and Herzegovina Abstract: This paper discusses cyberinformation studies of the amino acid composition of insulin, in particular the identification of scientific terminology that could describe this phenomenon, ie, the study of genetic information, as well as the relationship between the genetic language of proteins and theoretical aspects of this system and cybernetics. The results of this research show that there is a matrix code for insulin. It also shows that the coding system within the amino acid language gives detailed information, not only on the amino acid “record”, but also on its structure, configuration, and various shapes. The issue of the existence of an insulin code and coding of the individual structural elements of this protein are discussed. Answers to the following questions are sought. Does the matrix mechanism for biosynthesis of this protein function within the law of the general theory of information systems, and what is the significance of this for understanding the genetic language of insulin? What is the essence of existence and functioning of this language? Is the genetic information characterized only by biochemical principles or it is also characterized by cyberinformation principles? The potential effects of physical and chemical, as well as cybernetic and information principles, on the biochemical basis of insulin are also investigated. This paper discusses new methods for developing genetic technologies, in particular more advanced digital technology based on programming, cybernetics, and informational laws and systems, and how this new technology could be useful in medicine, bioinformatics, genetics, biochemistry, and other natural sciences.Keywords: human insulin, insulin model, biocode, genetic code, amino acids

  5. Investigation of cross-species translatability of pharmacological MRI in awake nonhuman primate - a buprenorphine challenge study.

    Directory of Open Access Journals (Sweden)

    Stephanie Seah

    Full Text Available BACKGROUND: Pharmacological MRI (phMRI is a neuroimaging technique where drug-induced hemodynamic responses can represent a pharmacodynamic biomarker to delineate underlying biological consequences of drug actions. In most preclinical studies, animals are anesthetized during image acquisition to minimize movement. However, it has been demonstrated anesthesia could attenuate basal neuronal activity, which can confound interpretation of drug-induced brain activation patterns. Significant efforts have been made to establish awake imaging in rodents and nonhuman primates (NHP. Whilst various platforms have been developed for imaging awake NHP, comparison and validation of phMRI data as translational biomarkers across species remain to be explored. METHODOLOGY: We have established an awake NHP imaging model that encompasses comprehensive acclimation procedures with a dedicated animal restrainer. Using a cerebral blood volume (CBV-based phMRI approach, we have determined differential responses of brain activation elicited by the systemic administration of buprenorphine (0.03 mg/kg i.v., a partial µ-opioid receptor agonist, in the same animal under awake and anesthetized conditions. Additionally, region-of-interest analyses were performed to determine regional drug-induced CBV time-course data and corresponding area-under-curve (AUC values from brain areas with high density of µ-opioid receptors. PRINCIPAL FINDINGS: In awake NHPs, group-level analyses revealed buprenorphine significantly activated brain regions including, thalamus, striatum, frontal and cingulate cortices (paired t-test, versus saline vehicle, p<0.05, n = 4. This observation is strikingly consistent with µ-opioid receptor distribution depicted by [6-O-[(11C]methyl]buprenorphine ([(11C]BPN positron emission tomography imaging study in baboons. Furthermore, our findings are consistent with previous buprenorphine phMRI studies in humans and conscious rats which collectively

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

    Directory of Open Access Journals (Sweden)

    Mark A Miller

    Full Text Available 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.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  9. Levamisole induced necrosis of the skin and neutropenia following intranasal cocaine use: a newly recognized syndrome.

    Science.gov (United States)

    Mouzakis, John; Somboonwit, Charurut; Lakshmi, Seetha; Rumbak, Mark; Sinnott, John; Cherpelis, Basil; Keshishian, Jonathan

    2011-10-01

    Levamisole is a veterinary anti-helminthic used to treat several autoimmune conditions but also commonly utilized as an additive in cocaine distribution. Toxicity resulting in agranulocytosis and cutaneous necrosis in association with cocaine use is an infrequently described phenomenon of an emerging problem. Although levamisole is found extensively in the cocaine supply of the United States, relatively few cases of necrotic skin lesions associated with intranasal use have been reported. The skin necrosis secondary to levamisole toxicity is characterized by variable findings on biopsy, ranging from leukocytoclastic vasculitis to occlusive vasculopathy. The following case describes a 54-year-old male who developed fever, agranulocytosis, p-ANCA autoantibodies and extensive skin necrosis following heavy intranasal cocaine use. Necrosis of greater than 50% of the patient's total body surface area resulted and was followed by thorough wound debridement.

  10. Prevention or early cure of type 1 diabetes by intranasal administration of gliadin in NOD mice

    DEFF Research Database (Denmark)

    Funda, David; Fundova, Petra; Hansen, Axel Kornerup;

    2014-01-01

    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......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...... 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...

  11. PPS nanoparticles as versatile delivery system to induce systemic and broad mucosal immunity after intranasal administration.

    Science.gov (United States)

    Stano, Armando; van der Vlies, André J; Martino, Mikael M; Swartz, Melody A; Hubbell, Jeffrey A; Simeoni, Eleonora

    2011-01-17

    Degradable polymer nanoparticles (NPs, 50 nm) based on polypropylene sulfide (PPS) were conjugated to thiolated antigen and adjuvant proteins by reversible disulfide bonds and evaluated in mucosal vaccination. Ovalbumin was used as a model antigen, and antigen-conjugated NPs were administered intranasally in the mouse. We show penetration of nasal mucosae, transit via M cells, and uptake by antigen-presenting cells in the nasal-associated lymphoid tissue. Ovalbumin-conjugated NPs induced cytotoxic T lymphocytic responses in lung and spleen tissues, as well as humoral response in mucosal airways. Co-conjugation of the TLR5 ligand flagellin further enhanced humoral responses in the airways as well as in the distant vaginal and rectal mucosal compartments and induced cellular immune responses with a Th1 bias, in contrast with free flagellin. The PPS NP platform thus appears interesting as a platform for intranasally-administered mucosal vaccination for inducing broad mucosal immunity.

  12. Intranasal oxytocin attenuates the human acoustic startle response independent of emotional modulation.

    Science.gov (United States)

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

    2014-11-01

    Oxytocin promotes social affiliation in humans. However, the mechanisms underlying this phenomenon require further elucidation. The present study investigated the influence of intranasal oxytocin on basic emotional processing in men and women, using an emotion-modulated startle response paradigm. Eighty-four participants self-administered 24 IU of intranasal oxytocin or saline and completed an assessment of the acoustic startle reflex, using electromyography (EMG), with varying emotional foregrounds. Oxytocin had no impact on the affective modulation of the startle eye blink response, but significantly diminished the acoustic startle reflex irrespective of the emotional foreground. The results suggest that oxytocin facilitates prosocial behavior, in part, by attenuating basic physiological arousal. The dampening effect of oxytocin on EMG startle could possibly be used as an inexpensive marker of oxytocin's effect on limbic brain circuits.

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

    Science.gov (United States)

    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.

  14. Synthetic polyacrylate polymers as particulate intranasal vaccine delivery systems for the induction of mucosal immune response.

    Science.gov (United States)

    Zaman, Mehfuz; Simerska, Pavla; Toth, Istvan

    2010-04-01

    The nasal route as a site of vaccine delivery for both local and systemic effect is currently of considerable interest. The administration of vaccines to mucosal surfaces such as the nasopharynx associated lymphoid tissues confers many advantages since the nasal mucosa is a primary site through which most inhaled antigens are encountered. However, the success of intranasally delivered mucosal vaccines is limited by lack of effective vaccine formulations or delivery systems suitable for use in humans. This review provides a brief overview of the mucosal immune system at the nasal surface, enhancement techniques for induction of mucosal immune response after intranasal administration of particulate systems and an explanation of the inherent properties of polyacrylate polymer-based particulate systems that may facilitate mucosal immune responses.

  15. A Comparison of Visual Response Properties in the Lateral Geniculate Nucleus and Primary Visual Cortex of Awake and Anesthetized Mice.

    Science.gov (United States)

    Durand, Séverine; Iyer, Ramakrishnan; Mizuseki, Kenji; de Vries, Saskia; Mihalas, Stefan; Reid, R Clay

    2016-11-30

    The cerebral cortex of the mouse has become one of the most important systems for studying information processing and the neural correlates of behavior. Multiple studies have examined the first stages of visual cortical processing: primary visual cortex (V1) and its thalamic inputs from the dorsal lateral geniculate nucleus (dLGN), but more rarely in the lateral posterior nucleus (LP) in mice. Multiple single-unit surveys of dLGN and V1, both with electrophysiology and two-photon calcium imaging, have described receptive fields in anesthetized animals. Increasingly, awake animals are being used in physiological studies, so it is important to compare neuronal responses between awake and anesthetized state. We have performed a comprehensive survey of spatial and temporal response properties in V1, dLGN, and lateral posterior nucleus of both anesthetized and awake animals, using a common set of stimuli: drifting sine-wave gratings spanning a broad range of spatial and temporal parameters, and sparse noise stimuli consisting of flashed light and dark squares. Most qualitative receptive field parameters were found to be unchanged between the two states, such as most aspects of spatial processing, but there were significant differences in several parameters, most notably in temporal processing. Compared with anesthetized animals, the temporal frequency that evoked the peak response was shifted toward higher values in the dLGN of awake mice and responses were more sustained. Further, the peak response to a flashed stimulus was earlier in all three areas. Overall, however, receptive field properties in the anesthetized animal remain a good model for those in the awake animal.

  16. Classifying Multiple Types of Hand Motions Using Electrocorticography During Intraoperative Awake Craniotomy & Seizure Monitoring Processes - Case Studies

    Directory of Open Access Journals (Sweden)

    Tao eXie

    2015-10-01

    Full Text Available In this work, some case studies were conducted toclassify several kinds of hand motions from electrocorticography(ECoG signals during intraoperative awake craniotomy &extraoperative seizure monitoring processes. Four subjects (P1,P2 with intractable epilepsy during seizure monitoring and P3,P4 with brain tumor during awake craniotomy participatedin the experiments. Subjects performed three types of handmotions (Grasp, Thumb-finger motion and Index-finger motioncontralateral to the motor cortex covered with ECoG electrodes.Two methods were used for signal processing. Method I:autoregressive (AR model with burg method was applied toextract features, and additional waveform length (WL featurehas been considered, finally the linear discriminative analysis(LDA was used as the classifier. Method II: stationary subspaceanalysis (SSA was applied for data preprocessing, and thecommon spatial pattern (CSP was used for feature extractionbefore LDA decoding process. Applying method I, the threeclassaccuracy of P1□P4 were 90.17%, 96.00%, 91.77% and92.95% respectively. For method II, the three-class accuracy ofP1□P4 were 72.00%, 93.17%, 95.22% and 90.36% respectively.This study verified the possibility of decoding multiple handmotion types during an awake craniotomy, which is the firststep towards dexterous neuroprosthetic control during surgicalimplantation, in order to verify the optimal placement of electrodes.The accuracy during awake craniotomy was comparableto results during seizure monitoring. This study also indicatedthat ECoG was a promising approach for precise identificationof eloquent cortex during awake craniotomy, and might forma promising BCI system that could benefit both patients andneurosurgeons.

  17. Neurons Differentiated from Transplanted Stem Cells Respond Functionally to Acoustic Stimuli in the Awake Monkey Brain.

    Science.gov (United States)

    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. The Dutch Linguistic Intraoperative Protocol: a valid linguistic approach to awake brain surgery.

    Science.gov (United States)

    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.

  19. Does Global Astrocytic Calcium Signaling Participate in Awake Brain State Transitions and Neuronal Circuit Function?

    DEFF Research Database (Denmark)

    Kjaerby, Celia; Rasmussen, Rune; Andersen, Mie

    2017-01-01

    We continuously need to adapt to changing conditions within our surrounding environment, and our brain needs to quickly shift between resting and working activity states in order to allow appropriate behaviors. These global state shifts are intimately linked to the brain-wide release...... of the neuromodulators, noradrenaline and acetylcholine. Astrocytes have emerged as a new player participating in the regulation of brain activity, and have recently been implicated in brain state shifts. Astrocytes display global Ca2+ signaling in response to activation of the noradrenergic system, but whether...... astrocytic Ca2+ signaling is causative or correlative for shifts in brain state and neural activity patterns is not known. Here we review the current available literature on astrocytic Ca2+ signaling in awake animals in order to explore the role of astrocytic signaling in brain state shifts. Furthermore, we...

  20. Endocytic structures and synaptic vesicle recycling at a central synapse in awake rats.

    Science.gov (United States)

    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.

  1. Long-term optical imaging of intrinsic signals in anesthetized and awake monkeys

    Science.gov (United States)

    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.

  2. Sensory-Driven Enhancement of Calcium Signals in Individual Purkinje Cell Dendrites of Awake Mice

    Directory of Open Access Journals (Sweden)

    Farzaneh Najafi

    2014-03-01

    Full Text Available Climbing fibers (CFs are thought to contribute to cerebellar plasticity and learning by triggering a large influx of dendritic calcium in the postsynaptic Purkinje cell (PC to signal the occurrence of an unexpected sensory event. However, CFs fire about once per second whether or not an event occurs, raising the question of how sensory-driven signals might be distinguished from a background of ongoing spontaneous activity. Here, we report that in PC dendrites of awake mice, CF-triggered calcium signals are enhanced when the trigger is a sensory event. In addition, we show that a large fraction of the total enhancement in each PC dendrite can be accounted for by an additional boost of calcium provided by sensory activation of a non-CF input. We suggest that sensory stimulation may modulate dendritic voltage and calcium concentration in PCs to increase the strength of plasticity signals during cerebellar learning.

  3. Characterization of nociceptive behavioural responses in the awake pig following UV-B-induced inflammation

    DEFF Research Database (Denmark)

    di Giminiani, Pierpaolo; Petersen, L J; Herskin, Mette S.

    2014-01-01

    Background Among the current translational inflammatory pain models, the ultraviolet (UV) irradiation is of rapidly growing interest. The development of primary thermal and mechanical hyperalgesia has been observed in humans and rodents. The pig as a translational animal model might be advantageous...... of irradiation compared with the control skin at both 24 and 48 h (P thermal hyperalgesia following UV-B inflammation in porcine skin, but they were not capable of providing a clear indication...... due to its great homology with humans. Methods The skin in the flank of awake pigs was irradiated by a UV-B light source (1 J/cm2) and changes in thermal and mechanical sensitivity 24 and 48 h following irradiation were measured via assessment of nociceptive behaviours. Results Thermal sensitivity...

  4. Awake caudal anesthesia for inguinal hernia operations: successful use in low birth weight neonates.

    Science.gov (United States)

    Geze, S; Imamoğlu, M; Cekic, B

    2011-09-01

    Neonates with inguinal hernia face a relatively high risk of incarcerated hernia and bowel obstruction and this therefore requires surgical treatment. Complications following general anesthesia even for minor surgery are more common in low birth weight neonates than in term neonates. Caudal epidural anesthesia without adjunct general anesthesia has been recommended for neonates to reduce the risk of postoperative complications. The successful application of awake caudal anesthesia with levobupivacaine for inguinal hernia repair in 15 low birth weight neonates is reported. Single dose caudal epidural anesthesia was administered for inguinal hernia surgery to avoid complications associated with general anesthesia. Caudal block was performed with 2.5 mg/kg body weight (BW) levobupivacaine. Caudal anesthesia can be recommended as an effective technique for avoiding postoperative anesthetic complications in low birth weight neonates.

  5. Effect of aminated gelatin on the nasal absorption of insulin in rats.

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Al Asmari AK

    2016-01-01

    Full Text Available Abdulrahman K Al Asmari,1 Zabih Ullah,1 Mohammad Tariq,1 Amal Fatani21Department of Research, Prince Sultan, Military Medical City, 2Department of Pharmacy, King Saud University, Riyadh, Saudi ArabiaAbstract: 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.Keywords: donepezil, intranasal, liposomes, bioavailability, blood–brain barrier

  7. Intranasal delivery of Natesto® testosterone gel and its effects on doping markers.

    Science.gov (United States)

    Miller, Geoffrey D; Nair, Vinod; Morrison, M Scott; Summers, Maggie; Willick, Stuart E; Eichner, Daniel

    2016-11-01

    The laboratory profile of intranasal testosterone gel has not been previously reported from an anti-doping perspective. Because intranasal testosterone gel is newly available as a commercial product, we sought to examine the laboratory parameters following administration of this formulation, with particular attention to anti-doping guidelines. Five healthy and active male subjects were administered testosterone intranasal gel three times daily for four weeks, using a pattern of five consecutive days on, two days off. Urine was collected after each five-day round of drug administration and analyzed using a full steroid screen and isotope ratio mass spectrometry (IRMS). Windows of detection for elevated testosterone/epitestosterone (T/E) and other steroid ratios, World Anti-Doping Agency (WADA) athlete biological passport (ABP) findings, and IRMS results were analyzed in this study. In the 0-24 h window post-administration, 70% of samples were flagged with a suspicious steroid profile and 85% were flagged as atypical passport findings according to the WADA ABP steroid module. In the 24-48 h window, 0% of samples displayed suspicious steroid profiles while 40% resulted in atypical passport findings. IRMS testing confirmed the presence of exogenous testosterone in 90% and 40% of samples in the 0-24 h and 24-48 h windows post-administration, respectively. Additionally, IRMS data were analyzed to determine commonalities in the population changes in δ(13) C values of testosterone, androsterone, etiocholanolone, 5αAdiol, and 5βAdiol. Though no discernible metabolic trend of the route of administration was identified, we discovered that intranasal gel testosterone is detectable using conventional anti-doping tests. Copyright © 2016 John Wiley & Sons, Ltd.

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

    Directory of Open Access Journals (Sweden)

    Natt Tasaniyananda

    Full Text Available 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.

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

    Science.gov (United States)

    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.

  10. Recurrent epistaxis caused by an intranasal supernumerary tooth in a young adult

    OpenAIRE

    Al Dhafeeri, Hamed O.; Kavarodi, Abdulmajid; Shaikh, Khalil Al; Bukhari, Ahmed; Hussain, Omair Al; Baramawy, Ahmed El

    2014-01-01

    Patient: Male, 27 Final Diagnosis: Recurrent epistaxis Symptoms: Nasal bleeding Medication: — Clinical Procedure: — Specialty: Pediatrics and Neonatology Objective: Congenital defects/diseases Background: Recurrent epistaxis is a common disorder among children and young adults. We report an unusual cause, intranasal supernumerary tooth causing friction with Little’s area of the nasal septum. Case Report: A 22-year-old male presented with recurrent, mild, unilateral left-sided epistaxis once t...

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

    Science.gov (United States)

    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

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

    OpenAIRE

    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 ...

  13. INTRANASAL DELIVERY OF NERVE GROWTH FACTOR TO PROTECT THE CENTRAL NERVOUS SYSTEM AGAINST ACUTE CEREBRAL INFARCTION

    Institute of Scientific and Technical Information of China (English)

    Hong-mei Zhao; Xin-feng Liu; Xiao-wei Mao; Chun-fu Chen

    2004-01-01

    Objective To confirmed reliability and feasibility of intranasal nerve growth factor (NGF) bypassing the blood-brain barrier and its potential neuroprotective effects on acute cerebral ischemia.Methods (1) To assay NGF concentrations in different brain regions after middle cerebral artery occlusion (MCAO).Rats were randomly divided into intranasal (IN) NGF, intravenous (Ⅳ) NGF, and untreated group (n =4). The concentrations of NGF of different brain regions in the three groups after MCAO were measured by ELISA. (2) To observe neuroprotective action of NGF on focal cerebral ischemic damage. Rats were randomly assigned to 4 groups: IN vehicle, IN NGF,Ⅳ vehicle, Ⅳ NGF (n = 8). Treatment was initiated 30 minutes after onset of MCAO and given again 24 hours later. Three neurologic behavioral tests were performed 24 and 48 hours following onset of MCAO. Corrected infarct volumes were determined 48 hours after onset of MCAO.Results The olfactory bulb in IN NGF group obtained the highest concentration (3252 pg/g) of NGF among all regions, followed by the hippocumpus. The NGF concentrations in the olfactory bulb and hippocampus in IN NGF group were markedly higher than that in Ⅳ NGF and control groups. The infarct volume in IN NGF group was markedly reduced by 38.8% compared with IN vehicle group. IN NGF group vestibulum function markedly improved compared with IN vehicle group at 24 and 48 hours after onset of MCAO (P24h = 0.02 and P48h = 0.04, respectively).Conclusion Intranasal NGF could pass through the blood-brain barrier, reach the central nervous system, reduce infarct volume, and improve neurologic function in rats following MCAO. Intranasal delivery of NGF may be a promising treatment for stroke.

  14. Motion compensation using origin ensembles in awake small animal positron emission tomography

    Science.gov (United States)

    Gillam, John E.; Angelis, Georgios I.; Kyme, Andre Z.; Meikle, Steven R.

    2017-02-01

    In emission tomographic imaging, the stochastic origin ensembles algorithm provides unique information regarding the detected counts given the measured data. Precision in both voxel and region-wise parameters may be determined for a single data set based on the posterior distribution of the count density allowing uncertainty estimates to be allocated to quantitative measures. Uncertainty estimates are of particular importance in awake animal neurological and behavioral studies for which head motion, unique for each acquired data set, perturbs the measured data. Motion compensation can be conducted when rigid head pose is measured during the scan. However, errors in pose measurements used for compensation can degrade the data and hence quantitative outcomes. In this investigation motion compensation and detector resolution models were incorporated into the basic origin ensembles algorithm and an efficient approach to computation was developed. The approach was validated against maximum liklihood—expectation maximisation and tested using simulated data. The resultant algorithm was then used to analyse quantitative uncertainty in regional activity estimates arising from changes in pose measurement precision. Finally, the posterior covariance acquired from a single data set was used to describe correlations between regions of interest providing information about pose measurement precision that may be useful in system analysis and design. The investigation demonstrates the use of origin ensembles as a powerful framework for evaluating statistical uncertainty of voxel and regional estimates. While in this investigation rigid motion was considered in the context of awake animal PET, the extension to arbitrary motion may provide clinical utility where respiratory or cardiac motion perturb the measured data.

  15. Insulin Glargine (rDNA origin) Injection

    Science.gov (United States)

    Lantus® ... Insulin glargine is used to treat type 1 diabetes (condition in which the body does not produce insulin and ... diabetes. In patients with type 1 diabetes, insulin glargine must be used with another type of insulin ( ...

  16. Chemical and thermal stability of insulin

    DEFF Research Database (Denmark)

    Huus, Kasper; Havelund, Svend; Olsen, Helle B;

    2006-01-01

    To study the correlation between the thermal and chemical stability of insulin formulations with various insulin hexamer ligands.......To study the correlation between the thermal and chemical stability of insulin formulations with various insulin hexamer ligands....

  17. Dente intranasal em portador de fissura de lábio e palato: relato de caso Intranasal tooth in patient with cleft lip and palate: case report

    Directory of Open Access Journals (Sweden)

    Aline Rogéria F. de Castilho

    2004-12-01

    Full Text Available A presença de dentes na cavidade nasal é rara e inclui alguns sinais e sintomas característicos, como obstrução nasal, rinite casual e odor fétido, entre outros, que podem ser confundidos com outras patologias. Por esta razão, o diagnóstico diferencial deve ser bem executado, por meio dos exames clínico e radiográfico da região. O tratamento, geralmente, é cirúrgico e pode prevenir complicações secundárias. O presente trabalho apresenta um caso de dente intranasal e seu respectivo tratamento cirúrgico para remoção.The presence of teeth at the nasal cavity is rare and involves some characteristic signs and symptoms, such as nasal obstruction, eventual rhinitis and fetid smell, and also others that may be confused with other pathologies. Therefore, differential diagnosis should be carefully accomplished by means of clinical and radiographic examinations of the area. Treatment is usually surgical and may prevent secondary complications. The present paper presents a case of intranasal tooth and the respective surgical treatment for its removal.

  18. Intranasal, siRNA Delivery to the Brain by TAT/MGF Tagged PEGylated Chitosan Nanoparticles

    Directory of Open Access Journals (Sweden)

    Meenakshi Malhotra

    2013-01-01

    Full Text Available Neurodegeneration is characterized by progressive loss of structure and function of neurons. Several therapeutic methods and drugs are available to alleviate the symptoms of these diseases. The currently used delivery strategies such as implantation of catheters, intracarotid infusions, surgeries, and chemotherapies are invasive in nature and pose a greater risk of postsurgical complications, which can have fatal side effects. The current study utilizes a peptide (TAT and MGF tagged PEGylated chitosan nanoparticle formulation for siRNA delivery, administered intranasally, which can bypass the blood brain barrier. The study investigates the optimal dose, duration, biodistribution, and toxicity, of the nanoparticle-siRNA formulation, in-vivo. The results indicate that 0.5 mg/kg of siRNA is delivered successfully to the hippocampus, thalamus, hypothalamus, and Purkinje cells in the cerebellum after 4 hrs of post intranasal delivery. The results indicate maximum delivery to the brain in comparison to other tissues with no cellular toxic effects. This study shows the potential of peptide-tagged PEGylated chitosan nanoparticles to be delivered intranasally and target brain tissue for the treatment of neurological disorders.

  19. Cellular immune responses to nine Mycobacterium tuberculosis vaccine candidates following intranasal vaccination.

    Directory of Open Access Journals (Sweden)

    Suraj B Sable

    Full Text Available BACKGROUND: The identification of Mycobacterium tuberculosis vaccines that elicit a protective immune response in the lungs is important for the development of an effective vaccine against tuberculosis. METHODS AND PRINCIPAL FINDINGS: In this study, a comparison of intranasal (i.n. and subcutaneous (s.c. vaccination with the BCG vaccine demonstrated that a single moderate dose delivered intranasally induced a stronger and sustained M. tuberculosis-specific T-cell response in lung parenchyma and cervical lymph nodes of BALB/c mice than vaccine delivered subcutaneously. Both BCG and a multicomponent subunit vaccine composed of nine M. tuberculosis recombinant proteins induced strong antigen-specific T-cell responses in various local and peripheral immune compartments. Among the nine recombinant proteins evaluated, the alanine proline rich antigen (Apa, Rv1860 was highly antigenic following i.n. BCG and immunogenic after vaccination with a combination of the nine recombinant antigens. The Apa-induced responses included induction of both type 1 and type 2 cytokines in the lungs as evaluated by ELISPOT and a multiplexed microsphere-based cytokine immunoassay. Of importance, i.n. subunit vaccination with Apa imparted significant protection in the lungs and spleen of mice against M. tuberculosis challenge. Despite observed differences in the frequencies and location of specific cytokine secreting T cells both BCG vaccination routes afforded comparable levels of protection in our study. CONCLUSION AND SIGNIFICANCE: Overall, our findings support consideration and further evaluation of an intranasally targeted Apa-based vaccine to prevent tuberculosis.

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

    Science.gov (United States)

    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.

  1. Intranasal Delivery of Camptothecin-Loaded Tat-Modified Nanomicells for Treatment of Intracranial Brain Tumors

    Directory of Open Access Journals (Sweden)

    Yuuki Takashima

    2012-10-01

    Full Text Available The blood-brain barrier is a substantial obstacle for delivering anticancer agents to brain tumors, and new strategies for bypassing it are sorely needed for brain tumor therapy. Intranasal delivery provides a practical, noninvasive method for delivering therapeutic agents to the brain. Intranasal application of nano-sized micelles that have been modified with Tat peptide facilitates brain delivery of fluorescent model materials. In this study, we evaluated a nose-to-brain delivery system for brain tumor therapy. We nasally administered the anti-tumor drug camptothecin (CPT in solution and in methoxy poly(ethylene glycol (MPEG/poly(e-caprolactone (PCL amphiphilic block copolymers (MPEG-PCL and cell penetrating peptide, Tat analog-modified MPEG-PCL (MPEG-PCL-Tat MPEG-PCL-Tat to rats bearing intracranial glioma tumors and quantified the cytotoxicity against glioma cells, and the therapeutic effects. CPT-loaded MPEG-PCL-Tat micelles showed higher cytotoxicity than CPT-loaded MPEG-PCL. CPT-free MPEG-PCL-Tat didn’t show any cytotoxicity, even at high concentrations (2 mmol/mL. CPT-loaded MPEG-PCL-Tat micelles significantly prolonged the median survival of rats. These results indicate that intranasal delivery of anti-cancer drugs with cell penetrating peptide-modified nanomicelles might be an effective therapy for brain tumors.

  2. Mexico City air pollution adversely affects olfactory function and intranasal trigeminal sensitivity.

    Science.gov (United States)

    Guarneros, Marco; Hummel, Thomas; Martínez-Gómez, Margaríta; Hudson, Robyn

    2009-11-01

    Surprisingly little is known about the effects of big-city air pollution on olfactory function and even less about its effects on the intranasal trigeminal system, which elicits sensations like burning, stinging, pungent, or fresh and contributes to the overall chemosensory experience. Using the Sniffin' Sticks olfactory test battery and an established test for intranasal trigeminal perception, we compared the olfactory performance and trigeminal sensitivity of residents of Mexico City, a region with high air pollution, with the performance of a control population from the Mexican state of Tlaxcala, a geographically comparable but less polluted region. We compared the ability of 30 young adults from each location to detect a rose-like odor (2-phenyl ethanol), to discriminate between different odorants, and to identify several other common odorants. The control subjects from Tlaxcala detected 2-phenyl ethanol at significantly lower concentrations than the Mexico City subjects, they could discriminate between odorants significantly better, and they performed significantly better in the test of trigeminal sensitivity. We conclude that Mexico City air pollution impairs olfactory function and intranasal trigeminal sensitivity, even in otherwise healthy young adults.

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

    Science.gov (United States)

    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.

  4. Thermo-sensitive gels containing lorazepam microspheres for intranasal brain targeting.

    Science.gov (United States)

    Jose, S; Ansa, C R; Cinu, T A; Chacko, A J; Aleykutty, N A; Ferreira, S V; Souto, E B

    2013-01-30

    Thermo-sensitive gels containing lorazepam microspheres were developed and characterized for intranasal brain targeting. Pluronics (PF-127 and PF-68) have been selected since they are thermo-reversible polymers with the property of forming a solution at low temperatures (4-5 °C), and a gel at body temperature (37 °C). This property makes them an interesting material to work with, especially in case of controlled release formulations. The present study focuses on the development of an intranasal formulation for lorazepam, as an alternative route of drug delivery to the brain. Direct transport of drugs to the brain circumventing the brain barrier, following intranasal administration, provides a unique feature and better option to target brain. The presence of mucoadhesive microspheres in the gel vehicle via nasal route can achieve a dual purpose of prolonged drug release and enhanced bioavailability. To optimise the microsphere formulation, Box Behnken design was employed by investigating the effect of three factors, polymer concentration (chitosan), emulsifier concentration (Span 80) and cross-linking agent (glutaraldehyde) on the response variable which is the mean particle size. The concentration of 21% PF-127 and 1% PF-68 were found to be promising gel vehicles. The results showed that the release rate followed a prolonged profile dispersion of the microspheres in the viscous media, in comparison to the microspheres alone. Histopathological studies proved that the optimised formulation does not produce any toxic effect on the microscopic structure of nasal mucosa.

  5. Mucoadhesive microemulsion of ibuprofen: design and evaluation for brain targeting efficiency through intranasal route

    Directory of Open Access Journals (Sweden)

    Surjyanarayan Mandal

    2015-09-01

    Full Text Available This study aimed at designing mucoadhesive microemulsion gel to enhance the brain uptake of Ibuprofen through intranasal route. Ibuprofen loaded mucoadhesive microemulsion (MMEI was developed by incorporating polycarbophil as mucoadhesive polymer into Capmul MCM based optimal microemulsion (MEI and was subjected to characterization, stability, mucoadhesion and naso-ciliotoxicity study. Brain uptake of ibuprofen via nasal route was studied by performing biodistribution study in Swiss albino rats. MEI was found to be transparent, stable and non ciliotoxic with 66.29 ± 4.15 nm, -20.9 ± 3.98 mV and 98.66 ± 1.01% as average globule size, zeta potential and drug content respectively. Transmission Electron Microscopy (TEM study revealed the narrow globule size distribution of MEI. Following single intranasal administration of MMEI and MEI at a dose of 2.86 mg/kg, uptake of ibuprofen in the olfactory bulb was around 3.0 and 1.7 folds compared with intravenous injection of ibuprofen solution (IDS. The ratios of AUC in brain tissues to that in plasma obtained after nasal administration of MMEI were significantly higher than those after intravenous administration of IDS. Findings of the present investigation revealed that the developed mucoadhesive microemulsion gel could be a promising approach for brain targeting of ibuprofen through intranasal route.

  6. Intranasal vaccination with leishmanial antigens protects golden hamsters (Mesocricetus auratus against Leishmania (Viannia Braziliensis infection.

    Directory of Open Access Journals (Sweden)

    Luzinei da Silva-Couto

    2015-01-01

    Full Text Available Previous results have shown that oral and intranasal administration of particulate Leishmania (Leishmania amazonensis antigens (LaAg partially protects mice against L. amazonensis infection. However, vaccination studies on species of the subgenus Viannia, the main causative agent of cutaneous and mucosal leishmaniasis in the Americas, have been hampered by the lack of easy-to-handle bio-models that accurately mimic the human disease. Recently, we demonstrated that the golden hamster is an appropriate model for studying the immunopathogenesis of cutaneous leishmaniasis caused by L. (Viannia braziliensis. Using the golden hamster model, our current study investigated whether the protective effect of intranasal immunisation with LaAg can be extended to L. braziliensis infection.Golden hamsters vaccinated with either two intranasal (IN doses of LaAg (10 µg or two intramuscular doses of LaAg (20 µg were challenged 2 weeks post-vaccination with L. braziliensis. The results showed that IN immunisation with LaAg significantly reduced lesion growth and parasitic load as well as serum IgG and IgG2 levels. At the experimental endpoint on day 114 post-infection, IN-immunised hamsters that were considered protected expressed IFN-γ and IL10 mRNA levels that returned to uninfected skin levels. In contrast to the nasal route, intramuscular (IM immunisation failed to provide protection.These results demonstrate for the first time that the nasal route of immunisation can induce cross protection against L. braziliensis infection.

  7. Insulin C-peptide test

    Science.gov (United States)

    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 ...

  8. [Treatment by external insulin pump].

    Science.gov (United States)

    Clavel, Sylvaine

    2010-12-01

    Since the recent recommendations by the French speaking association for research on diabetes and metabolic illnesses (Alfediam), treatment by insulin pump has found itself in competition with basal-bolus, a procedure using similar injections of insulin which has become a benchmark treatment. The latest Alfediam guidelines focus on defining ways of treating diabetics with an external insulin pump.

  9. Early insulin therapy Coordination Council

    Directory of Open Access Journals (Sweden)

    Marina Vladimirovna Shestakova

    2012-12-01

    Full Text Available Coordination Council has denoted the importance of adherence to Russian and international guidelines and prominent role of insulin therapy in management of type 2 diabetes mellitus (T2DM. Insulin therapy in T2DM preserves endogenous insulin secretion, prevents or decelerates development of microvascular complications and is known to be the most effective glucose-lowering treatment.

  10. Insulin Resistance and Prediabetes

    Science.gov (United States)

    ... symptoms. Scientists have found that complex interactions in fat tissue draw immune cells to the area and trigger low-level chronic inflammation. This inflammation can contribute to the development of insulin resistance, type 2 diabetes, and CVD. Studies show that losing ...

  11. New Insulin Delivery Recommendations.

    Science.gov (United States)

    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.

  12. Insulin som trickster

    DEFF Research Database (Denmark)

    Lassen, Aske Juul

    2011-01-01

    grænser nedbrydes i en konstant penetrering af huden, når blodsukkeret måles eller insulinen indsprøjtes. Insulin analyseres som en tricksterfigur, der udøver et grænsearbejde på kroppen, leger med dens kategorier og vender forholdet mellem gift og medicin, frihed og ufrihed, kunstighed og naturlighed...

  13. Predictors of Failure of Awake Regional Anesthesia for Neonatal Hernia Repair : Data from the General Anesthesia Compared to Spinal Anesthesia Study-Comparing Apnea and Neurodevelopmental Outcomes

    NARCIS (Netherlands)

    Frawley, Geoff; Bell, Graham; Disma, Nicola; Withington, Davinia E; de Graaff, Jurgen C; Morton, Neil S; McCann, Mary Ellen; Arnup, Sarah J; Bagshaw, Oliver; Wolfler, Andrea; Bellinger, David; Davidson, Andrew J; Absalom, Anthony

    2015-01-01

    BACKGROUND: Awake regional anesthesia (RA) is a viable alternative to general anesthesia (GA) for infants undergoing lower abdominal surgery. Benefits include lower incidence of postoperative apnea and avoidance of anesthetic agents that may increase neuroapoptosis and worsen neurocognitive outcomes

  14. Predictors of Failure of Awake Regional Anesthesia for Neonatal Hernia Repair : Data from the General Anesthesia Compared to Spinal Anesthesia Study--Comparing Apnea and Neurodevelopmental Outcomes

    NARCIS (Netherlands)

    Frawley, Geoff; Bell, Graham; Disma, Nicola; Withington, Davinia E; de Graaff, Jurgen C; Morton, Neil S; McCann, Mary Ellen; Arnup, Sarah J; Bagshaw, Oliver; Wolfler, Andrea; Bellinger, David; Davidson, Andrew J

    2015-01-01

    BACKGROUND: Awake regional anesthesia (RA) is a viable alternative to general anesthesia (GA) for infants undergoing lower abdominal surgery. Benefits include lower incidence of postoperative apnea and avoidance of anesthetic agents that may increase neuroapoptosis and worsen neurocognitive outcomes

  15. Insulin Signalling: The Inside Story.

    Science.gov (United States)

    Posner, Barry I

    2017-02-01

    Insulin signalling begins with binding to its cell surface insulin receptor (IR), which is a tyrosine kinase. The insulin receptor kinase (IRK) is subsequently autophosphorylated and activated to tyrosine phosphorylate key cellular substrates that are essential for entraining the insulin response. Although IRK activation begins at the cell surface, it is maintained and augmented following internalization into the endosomal system (ENS). The peroxovanadium compounds (pVs) were discovered to activate the IRK in the absence of insulin and lead to a full insulin response. Thus, IRK activation is both necessary and sufficient for insulin signalling. Furthermore, this could be shown to occur with activation of only the endosomal IRK. The mechanism of pV action was shown to be the inhibition of IRK-associated phosphotyrosine phosphatases (PTPs). Our studies showed that the duration and intensity of insulin signalling are modulated within ENS by the recruitment of cellular substrates to ENS; intra-endosomal acidification, which promotes dissociation of insulin from the IRK; an endosomal acidic insulinase, which degrades intra-endosomal insulin; and IRK-associated PTPs, which dephosphorylate and, hence, deactivate the IRK. Therefore, the internalization of IRKs is central to insulin signalling and its regulation.

  16. Intranasal nerve growth factor bypasses the blood-brain barrier and affects spinal cord neurons in spinal cord injur y

    Institute of Scientific and Technical Information of China (English)

    Luigi Aloe; Patrizia Bianchi; Alberto De Bellis; Marzia Soligo; Maria Luisa Rocco

    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 in-creased 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 deifcits 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.

  17. Sedation and physiologic response to manual restraint after intranasal administration of midazolam in Hispaniolan Amazon parrots (Amazona ventralis).

    Science.gov (United States)

    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.

  18. Intranasal inoculation of white-tailed deer (Odocoileus virginianus with lyophilized chronic wasting disease prion particulate complexed to montmorillonite clay.

    Directory of Open Access Journals (Sweden)

    Tracy A Nichols

    Full Text Available 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.

  19. Insulin resistance and hepatitis C

    Institute of Scientific and Technical Information of China (English)

    Manuel Romero-Gómez

    2006-01-01

    Insulin resistance is the major feature of the metabolic syndrome and depends on insulin secretion and insulin sensitivity. In chronic hepatitis C, insulin resistance and type 2 diabetes mellitus are more often seen than in healthy controls or chronic hepatitis B patients.Hepatitis C virus (HCV) infection promotes insulin resistance, mainly by increased TNF production together with enhancement of suppressor of cytokine (SOC-3); both events block PI3K and Akt phosphorylation. Two types of insulin resistance could be found in chronic hepatitis C patients: "viral" and "metabolic" insulin resistance. Insulin resistance in chronic hepatitis C is relevant because it promotes steatosis and fibrosis. The mechanisms by which insulin resistance promotes fibrosis progression include: (1) steatosis, (2) hyperleptinemia, (3) increased TNF production, (4) impaired expression of PPARy receptors. Lastly, insulin resistance has been found as a common denominator in patients difficult-to-treat like cirrhotics, overweight, HIV coinfected and Afro-American.Insulin resistance together with fibrosis and genotype has been found to be independently associated with impaired response rate to peginterferon plus ribavirin.Indeed, in genotype 1, the sustained response rate was twice (60%) in patients with HOMA ≤ 2 than patients with HOMA > 2. In experiments carried out on Huh-7cells transfected by full length HCVRNA, interferon alpha blocks HCV replication. However, when insulin (at doses of 128 μU/mL, similar that seen in the hyperinsulinemic state) was added to interferon, the ability to block HCV replication disappeared, and the PKR synthesis was abolished. In summary, hepatitis C promotes insulin resistance and insulin resistance induces interferon resistance,steatosis and fibrosis progression.

  20. Biofeedback for treatment of awake and sleep bruxism in adults: systematic review protocol

    Science.gov (United States)

    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

  1. A 4-channel 3 Tesla phased array receive coil for awake rhesus monkey fMRI and diffusion MRI experiments

    OpenAIRE

    Khachaturian, Mark Haig

    2010-01-01

    Awake monkey fMRI and diffusion MRI combined with conventional neuroscience techniques has the potential to study the structural and functional neural network. The majority of monkey fMRI and diffusion MRI experiments are performed with single coils which suffer from severe EPI distortions which limit resolution. By constructing phased array coils for monkey MRI studies, gains in SNR and anatomical accuracy (i.e., reduction of EPI distortions) can be achieved using parallel imaging. The major...

  2. Markerless rat head motion tracking using structured light for brain PET imaging of unrestrained awake small animals

    Science.gov (United States)

    Miranda, Alan; Staelens, Steven; Stroobants, Sigrid; Verhaeghe, Jeroen

    2017-03-01

    Preclinical positron emission tomography (PET) imaging in small animals is generally performed under anesthesia to immobilize the animal during scanning. More recently, for rat brain PET studies, methods to perform scans of unrestrained awake rats are being developed in order to avoid the unwanted effects of anesthesia on the brain response. Here, we investigate the use of a projected structure stereo camera to track the motion of the rat head during the PET scan. The motion information is then used to correct the PET data. The stereo camera calculates a 3D point cloud representation of the scene and the tracking is performed by point cloud matching using the iterative closest point algorithm. The main advantage of the proposed motion tracking is that no intervention, e.g. for marker attachment, is needed. A manually moved microDerenzo phantom experiment and 3 awake rat [18F]FDG experiments were performed to evaluate the proposed tracking method. The tracking accuracy was 0.33 mm rms. After motion correction image reconstruction, the microDerenzo phantom was recovered albeit with some loss of resolution. The reconstructed FWHM of the 2.5 and 3 mm rods increased with 0.94 and 0.51 mm respectively in comparison with the motion-free case. In the rat experiments, the average tracking success rate was 64.7%. The correlation of relative brain regional [18F]FDG uptake between the anesthesia and awake scan reconstructions was increased from on average 0.291 (not significant) before correction to 0.909 (p  <  0.0001) after motion correction. Markerless motion tracking using structured light can be successfully used for tracking of the rat head for motion correction in awake rat PET scans.

  3. Only a whisper away. A philosophical view of the awake patient's situation during regional anaesthetics and surgery.

    Science.gov (United States)

    Karlsson, Ann-Christin; Ekebergh, Margaretha; Larsson Mauléon, Annika; Almerud Österberg, Sofia

    2012-10-01

    In this study the awake patient's intraoperative situation and experiences during regional anaesthetics and surgery are reflected upon by using the work of the French philosopher Maurice Merleau-Ponty. Merleau-Ponty's phenomenological idea of the body as being at the centre of the world highlights the patient's embodied position and bestows significance onto the body as a whole, as a lived body. A case, based on the findings from a previous interview study, is presented as a contextual starting point where a patient goes from having a familiar body recognized as her own to having a partially anaesthetized body experienced as an unknown object. The intraoperative caring space is described in this context as the mutual ground where the awake patient and the nurse anaesthetist (NA) can interact to create meaning. The NA can act as the patient's bodily extension to bridge the gap between the patient's experiences and the situation. This calls for the NA's proximity and genuine presence in order to meet and understand the patient's awake experiences. Learning from the patient's situatedness gives information that is valuable for NAs to share with patients who are less experienced with this contextual situation. The challenge for the NA is not to perform routine-based care, but to acknowledge every patient's lifeworld and uniqueness thus enabling the patient to move easily along the mind-body-world continuum. The core of intraoperative care is to provide support and promote well-being of awake patients in the intraoperative environment. The use of a philosophical perspective is relevant for nurses who work in an intraoperative setting where patients undergo regional anaesthetics. This study shows how nursing research using phenomenological philosophy can help uncover new meanings known only to the patients living the experience.

  4. Examination of Rapid Dopamine Dynamics with Fast Scan Cyclic Voltammetry During Intra-oral Tastant Administration in Awake Rats.

    Science.gov (United States)

    Wickham, Robert J; Park, Jinwoo; Nunes, Eric J; Addy, Nii A

    2015-08-12

    Rapid, phasic dopamine (DA) release in the mammalian brain plays a critical role in reward processing, reinforcement learning, and motivational control. Fast scan cyclic voltammetry (FSCV) is an electrochemical technique with high spatial and temporal (sub-second) resolution that has been utilized to examine phasic DA release in several types of preparations. In vitro experiments in single-cells and brain slices and in vivo experiments in anesthetized rodents have been used to identify mechanisms that mediate dopamine release and uptake under normal conditions and in disease models. Over the last 20 years, in vivo FSCV experiments in awake, freely moving rodents have also provided insight of dopaminergic mechanisms in reward processing and reward learning. One major advantage of the awake, freely moving preparation is the ability to examine rapid DA fluctuations that are time-locked to specific behavioral events or to reward or cue presentation. However, one limitation of combined behavior and voltammetry experiments is the difficulty of dissociating DA effects that are specific to primary rewarding or aversive stimuli from co-occurring DA fluctuations that mediate reward-directed or other motor behaviors. Here, we describe a combined method using in vivo FSCV and intra-oral infusion in an awake rat to directly investigate DA responses to oral tastants. In these experiments, oral tastants are infused directly to the palate of the rat--bypassing reward-directed behavior and voluntary drinking behavior--allowing for direct examination of DA responses to tastant stimuli.

  5. The Use of the Target Cancellation Task to Identify Eloquent Visuospatial Regions in Awake Craniotomies: Technical Note.

    Science.gov (United States)

    Conner, Andrew K; Glenn, Chad; Burks, Joshua D; McCoy, Tressie; Bonney, Phillip A; Chema, Ahmed A; Case, Justin L; Brunner, Scott; Baker, Cordell; Sughrue, Michael

    2016-11-17

    The success of awake craniotomies relies on the patient's performance of function-specific tasks that are simple, quick, and reproducible. Intraoperative identification of visuospatial function through cortical and subcortical mapping has utilized a variety of intraoperative tests, each with its own benefits and drawbacks. In light of this, we developed a simple software program that aids in preventing neglect by simulating a target-cancellation task on a portable electronic device. In this report, we describe the interactive target cancellation task and have reviewed seven consecutive patients who underwent awake craniotomy for parietal and/or posterior temporal infiltrating brain tumors of the non-dominant hemisphere. Each of these patients performed target cancellation and line bisection tasks intraoperatively. The outcomes of each patient and testing scenario are described. Positive intraoperative cortical and subcortical sites involved with visuospatial processing were identified in three of the seven patients using the target cancellation and confirmed utilizing the line-bisection task. No identification of visuospatial function was accomplished utilizing the line-bisection task alone. Complete visuospatial function mapping was completed in less than 10 minutes in all patients. No patients had preoperative or postoperative hemineglect. Our findings highlight the feasibility of the target cancellation technique for use during awake craniotomy to aid in avoiding postoperative hemineglect. Target cancellation may offer an alternative method of cortical and subcortical visuospatial mapping in patients unable to perform other commonly used modalities.

  6. Interhemispheric transfalcine approach and awake cortical mapping for resection of peri-atrial gliomas associated with the central lobule.

    Science.gov (United States)

    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.

  7. Noradrenergic inhibitory modulation in the caudal commissural NTS of the pressor response to chemoreflex activation in awake rats.

    Science.gov (United States)

    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.

  8. Insulin and insulin mutants stimulate glucose uptake in rat adipocytes

    Institute of Scientific and Technical Information of China (English)

    姚矢音; 张新堂; 许英镐; 张信娜; 朱尚权

    1999-01-01

    A simple method to determine the in vitro biological activity of insulin by measuring glucose uptake in the rat adipocytes is presented here. In the presence of insulin, the glucose uptake is 5-6 times more than the basal control. And the uptake of D-[3-3H]-glucose is linear as the logarithm of insulin concentration from 0.2 μg/L to 1.0 μg/L. Glucose and 3-O-methyl-glucose inhibit D-[3-3H]-glucose uptake into adipocytes. By this method, the in vitro biological activity of [B2-Lys]-insulin and [B3-Lys]-insulin was measured to be 61.6% and 154% respectively, relative to that of insulin.

  9. Intranasal immunization of lambs with serine/threonine phosphatase 2A against gastrointestinal nematodes.

    Science.gov (United States)

    Mohamed Fawzi, Elshaima; Cruz Bustos, Teresa; Gómez Samblas, Mercedes; González-González, Gloria; Solano, Jenifer; González-Sánchez, María Elena; De Pablos, Luis Miguel; Corral-Caridad, María Jesús; Cuquerella, Montserrat; Osuna, Antonio; Alunda, José María

    2013-09-01

    Seven 3-month-old, female, helminth-free lambs were immunized intranasally with three doses (1 mg total) of a recombinant part of the catalytic region of the serine/threonine phosphatase 2A (PP2Ar) (group 1 [G1]). In addition, four lambs were used as an adjuvant control group (G2), four as unimmunized, infected controls (G3), and four as unimmunized, uninfected controls (G4). Fifteen days after the last immunization, lambs from G1, G2, and G3 were challenged with 10,000 larval stage 3 (L3) organisms in a plurispecific nematode infection composed of ca. 40% Trichostrongylus colubriformis, 40% Haemonchus contortus, and 20% Teladorsagia circumcincta. All the lambs were clinically monitored throughout the experiment. Parasitological (fecal egg output and immunological response), biopathological (packed-cell volume and leukocyte and eosinophil counts), and zootechnical (live-weight gain) analyses were conducted. On day 105 of the experiment, all the animals were slaughtered and the adult worm population in their abomasa examined. Intranasal administration of PP2Ar with bacterial walls as an adjuvant elicited a strong immune response in the immunized lambs, as evidenced by their humoral immune response. Immunized animals and animals receiving the adjuvant shed significantly (P 68%), protection being provided against both Haemonchus and Teladorsagia. Live-weight gain in the immunized lambs was similar to that in the uninfected controls versus the infected or adjuvanted animal groups. Our results suggest that heterologous immunization of ruminants by intranasal administration may be efficacious in the struggle to control gastrointestinal helminths in these livestock.

  10. Intranasal oxytocin administration in relationship to social behaviour in domestic pigs.

    Science.gov (United States)

    Camerlink, Irene; Reimert, Inonge; Bolhuis, J Elizabeth

    2016-09-01

    Intranasal administration of oxytocin has been shown to alter positive and negative social behaviour. Positive social behaviour in pigs (Sus scrofa) may be expressed through gentle social nosing, and greater insight in the specific expression hereof might contribute to the current search for positive indicators of animal welfare. We investigated whether oxytocin alters social nosing and whether this is specific to nose-body or nose-nose contact. Sixty-four focal female pigs of 13weeks of age (out of 16 groups) were given oxytocin (24IU dose) and saline (placebo) intranasally once on two consecutive days. The frequency of nose-to-nose contact and nose-to-body contact was recorded upon pigs' return in the home pen after being for 10min located in a separate area near pen mates undergoing a positive or negative event or not. The effect of intranasal oxytocin depended on the social context in which pigs were studied. Control pigs, which were not exposed to positively or negatively aroused pen mates, gave and received less nose-nose contact after oxytocin administration than after saline administration. Pigs exposed to positively aroused pen mates also tended to give less nose contact when given oxytocin compared to saline, whereas pigs exposed to negatively aroused pen mates and administered oxytocin tended to receive more nose contact. Nose-body contact was lowest in groups of negative social context, suggesting an effect of emotional state on social nosing. In contrast to nose-nose contact, nose-body contact was unaffected by oxytocin treatment. The relationship between social nosing and oxytocin merits further research.

  11. Development and evaluation of brain targeted intranasal alginate nanoparticles for treatment of depression.

    Science.gov (United States)

    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.

  12. Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis

    Directory of Open Access Journals (Sweden)

    Greiff Lennart

    2012-06-01

    Full Text Available Abstract Background Interactions between Th1 and Th2 immune responses are of importance to the onset and development of allergic disorders. A Toll-like receptor 7 agonist such as AZD8848 may have potential as a treatment for allergic airway disease by skewing the immune system away from a Th2 profile. Objective To evaluate the efficacy and safety of intranasal AZD8848. Methods In a placebo-controlled single ascending dose study, AZD8848 (0.3-600 μg was given intranasally to 48 healthy subjects and 12 patients with allergic rhinitis (NCT00688779. In a placebo-controlled repeat challenge/treatment study, AZD8848 (30 and 60 μg was given once weekly for five weeks to 74 patients with allergic rhinitis out of season: starting 24 hours after the final dose, daily allergen challenges were given for seven days (NCT00770003. Safety, tolerability, pharmacokinetics, and biomarkers were monitored. During the allergen challenge series, nasal symptoms and lavage fluid levels of tryptase and α2-macroglobulin, reflecting mast cell activity and plasma exudation, were monitored. Results AZD8848 produced reversible blood lymphocyte reductions and dose-dependent flu-like symptoms: 30–100 μg produced consistent yet tolerable effects. Plasma interleukin-1 receptor antagonist was elevated after administration of AZD8848, reflecting interferon production secondary to TLR7 stimulation. At repeat challenge/treatment, AZD8848 reduced nasal symptoms recorded ten minutes after allergen challenge up to eight days after the final dose. Tryptase and α2-macroglobulin were also reduced by AZD8848. Conclusions Repeated intranasal stimulation of Toll-like receptor 7 by AZD8848 was safe and produced a sustained reduction in the responsiveness to allergen in allergic rhinitis. Trial registration NCT00688779 and NCT00770003 as indicated above.

  13. Effect of intranasal manganese administration on neurotransmission and spatial learning in rats

    Energy Technology Data Exchange (ETDEWEB)

    Blecharz-Klin, Kamilla; Piechal, Agnieszka; Joniec-Maciejak, Ilona; Pyrzanowska, Justyna; Widy-Tyszkiewicz, Ewa, E-mail: etyszkiewicz@wum.edu.pl

    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.

  14. Preparation of ESAT-6 Nanoparticles and Evaluation of Humoral Immunity after Intranasal Administration

    Directory of Open Access Journals (Sweden)

    H Najminezhad

    2013-01-01

    Full Text Available Introduction: Among several tuberculosis vaccine candidates for replacement of BCG, ESAT-6 protein has a special role. Since mycobacterium tuberculosis infection most often attacks the lungs, intranasal rout can be regarded as appropriate methods for tuberculosis vaccines and drug delivery. One of the appropriate systems for intranasal vaccine delivery is using biodegradable nanoparticles. Among biodegradable polymers, chitosan polymer has great features to increase the response of immunity system. This study aimed to investigate the specific humoral immune response of mice model after encapsulation of recombinant ESAT-6 antigen in chitosan nanoparticles. Methods: The chitosan nanoparticles containing ESAT-6 antigen were synthesized by ionic gelation. Nanoparticle properties including morphology, particle size, zeta potential, encapsulation rates, and protein release were measured in vitro. The immunization was performed through the nose for 3 times on days 0 and 14 and 28. 2 weeks after last administration, blood samples were collected and specific IgG titers were measured by indirect ELISA. Results: The nanoparticles synthesized had appropriate properties. The mean size of resulting nanoparticles was 242.8 nm by excellent antigen loading capacity (95.23 %. The vitro release of antigen from nanoparticles after 200 hours was detected as 67.5%. The Level of IgG antibody showed significant increase in the group that had received chitosan nanoparticles containing ESAT-6 compared with other groups. Conclusion: ESAT-6 protein was encapsulated in chitosan nanoparticles successfully. Administration of chitosan nanoparticles can be a suitable method for administration of humoral immunity antigens of Mycobacterium tuberculosis through intranasal rout.

  15. Intranasal vaccination promotes detrimental Th17-mediated immunity against influenza infection.

    Directory of Open Access Journals (Sweden)

    Asher Maroof

    2014-01-01

    Full Text Available Influenza disease is a global health issue that causes significant morbidity and mortality through seasonal epidemics. Currently, inactivated influenza virus vaccines given intramuscularly or live attenuated influenza virus vaccines administered intranasally are the only approved options for vaccination against influenza virus in humans. We evaluated the efficacy of a synthetic toll-like receptor 4 agonist CRX-601 as an adjuvant for enhancing vaccine-induced protection against influenza infection. Intranasal administration of CRX-601 adjuvant combined with detergent split-influenza antigen (A/Uruguay/716/2007 (H3N2 generated strong local and systemic immunity against co-administered influenza antigens while exhibiting high efficacy against two heterotypic influenza challenges. Intranasal vaccination with CRX-601 adjuvanted vaccines promoted antigen-specific IgG and IgA antibody responses and the generation of polyfunctional antigen-specific Th17 cells (CD4(+IL-17A(+TNFα(+. Following challenge with influenza virus, vaccinated mice transiently exhibited increased weight loss and morbidity during early stages of disease but eventually controlled infection. This disease exacerbation following influenza infection in vaccinated mice was dependent on both the route of vaccination and the addition of the adjuvant. Neutralization of IL-17A confirmed a detrimental role for this cytokine during influenza infection. The expansion of vaccine-primed Th17 cells during influenza infection was also accompanied by an augmented lung neutrophilic response, which was partially responsible for mediating the increased morbidity. This discovery is of significance in the field of vaccinology, as it highlights the importance of both route of vaccination and adjuvant selection in vaccine development.

  16. Intranasal Vaccination Promotes Detrimental Th17-Mediated Immunity against Influenza Infection

    Science.gov (United States)

    Maroof, Asher; Yorgensen, Yvonne M.; Li, Yufeng; Evans, Jay T.

    2014-01-01

    Influenza disease is a global health issue that causes significant morbidity and mortality through seasonal epidemics. Currently, inactivated influenza virus vaccines given intramuscularly or live attenuated influenza virus vaccines administered intranasally are the only approved options for vaccination against influenza virus in humans. We evaluated the efficacy of a synthetic toll-like receptor 4 agonist CRX-601 as an adjuvant for enhancing vaccine-induced protection against influenza infection. Intranasal administration of CRX-601 adjuvant combined with detergent split-influenza antigen (A/Uruguay/716/2007 (H3N2)) generated strong local and systemic immunity against co-administered influenza antigens while exhibiting high efficacy against two heterotypic influenza challenges. Intranasal vaccination with CRX-601 adjuvanted vaccines promoted antigen-specific IgG and IgA antibody responses and the generation of polyfunctional antigen-specific Th17 cells (CD4+IL-17A+TNFα+). Following challenge with influenza virus, vaccinated mice transiently exhibited increased weight loss and morbidity during early stages of disease but eventually controlled infection. This disease exacerbation following influenza infection in vaccinated mice was dependent on both the route of vaccination and the addition of the adjuvant. Neutralization of IL-17A confirmed a detrimental role for this cytokine during influenza infection. The expansion of vaccine-primed Th17 cells during influenza infection was also accompanied by an augmented lung neutrophilic response, which was partially responsible for mediating the increased morbidity. This discovery is of significance in the field of vaccinology, as it highlights the importance of both route of vaccination and adjuvant selection in vaccine development PMID:24465206

  17. Brief Report: Oxytocin Enhances Paternal Sensitivity to a Child with Autism--A Double-Blind Within-Subject Experiment with Intranasally Administered Oxytocin

    Science.gov (United States)

    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…

  18. Brain delivery of intranasal in situ gel of nanoparticulated polymeric carriers containing antidepressant drug: behavioral and biochemical assessment.

    Science.gov (United States)

    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.

  19. Validation of a Best-Fit Pharmacokinetic Model for Scopolamine Disposition after Intranasal Administration

    Science.gov (United States)

    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.

  20. Locus coeruleus response to single-prolonged stress and early intervention with intranasal neuropeptide Y.

    Science.gov (United States)

    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

  1. Intranasal fentanyl in the treatment of acute pain--a systematic review

    DEFF Research Database (Denmark)

    Hansen, M S; Mathiesen, O; Trautner, S;

    2012-01-01

    population. The objective of this systematic review was to evaluate the current evidence of IN fentanyl in the treatment of acute pain. Reports of randomized controlled trials (RCTs) of IN fentanyl in treatment of pain were systematically sought using the PubMed database, Embase, Google scholar, Cochrane......Due to its non-invasive mode of administration, intranasal (IN) application of drugs may be a valuable alternative to non-invasive pain management. With characteristics that appear to be ideal for IN application, IN fentanyl may have a place in the out-of-hospital treatment and the paediatric...

  2. Validation of a Modified Algometer to Measure Mechanical Nociceptive Thresholds in Awake Dogs

    Directory of Open Access Journals (Sweden)

    Ubedullah Kaka

    2015-01-01

    Full Text Available 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.

  3. A regenerative microchannel device for recording multiple single-unit action potentials in awake, ambulatory animals.

    Science.gov (United States)

    Srinivasan, Akhil; Tipton, John; Tahilramani, Mayank; Kharbouch, Adel; Gaupp, Eric; Song, Chao; Venkataraman, Poornima; Falcone, Jessica; Lacour, Stéphanie P; Stanley, Garrett B; English, Arthur W; Bellamkonda, Ravi V

    2016-02-01

    Despite significant advances in robotics, commercially advanced prosthetics provide only a small fraction of the functionality of the amputated limb that they are meant to replace. Peripheral nerve interfacing could provide a rich controlling link between the body and these advanced prosthetics in order to increase their overall utility. Here, we report on the development of a fully integrated regenerative microchannel interface with 30 microelectrodes and signal extraction capabilities enabling evaluation in an awake and ambulatory rat animal model. In vitro functional testing validated the capability of the microelectrodes to record neural signals similar in size and nature to those that occur in vivo. In vitro dorsal root ganglia cultures revealed striking cytocompatibility of the microchannel interface. Finally, in vivo, the microchannel interface was successfully used to record a multitude of single-unit action potentials through 63% of the integrated microelectrodes at the early time point of 3 weeks. This marks a significant advance in microchannel interfacing, demonstrating the capability of microchannels to be used for peripheral nerve interfacing.

  4. Hypoxia-induced vasodilation and effects of regional phentolamine in awake patients with sleep apnea.

    Science.gov (United States)

    Moradkhan, Raman; Spitnale, Brett; McQuillan, Patrick; Hogeman, Cynthia; Gray, Kristen S; Leuenberger, Urs A

    2010-05-01

    Obstructive sleep apnea (OSA) is associated with increased sympathetic nerve activity, endothelial dysfunction, and premature cardiovascular disease. To determine whether hypoxia is associated with impaired skeletal muscle vasodilation, we compared femoral artery blood flow (ultrasound) and muscle sympathetic nerve activity (peroneal microneurography) during exposure to acute systemic hypoxia (fraction of inspired oxygen 0.1) in awake patients with OSA (n=10) and controls (n=8). To assess the role of elevated sympathetic nerve activity, in a separate group of patients with OSA (n=10) and controls (n=10) we measured brachial artery blood flow during hypoxia before and after regional alpha-adrenergic block with phentolamine. Despite elevated sympathetic activity, in OSA the vascular responses to hypoxia in the leg did not differ significantly from those in controls [P=not significant (NS)]. Following regional phentolamine, in both groups the hypoxia-induced increase in brachial blood flow was markedly enhanced (OSA pre vs. post, 84+/-13 vs. 201+/-34 ml/min, Pphentolamine, the increase of brachial blood flow above baseline was similar (OSA vs. controls +61+/-16 vs. +48+/-6%; P=NS). We conclude that despite high sympathetic vasoconstrictor tone and prominent sympathetic responses to acute hypoxia, hypoxia-induced limb vasodilation is preserved in OSA.

  5. Characterizing Alzheimer's disease severity via resting-awake EEG amplitude modulation analysis.

    Directory of Open Access Journals (Sweden)

    Francisco J Fraga

    Full Text Available Changes in electroencephalography (EEG amplitude modulations have recently been linked with early-stage Alzheimer's disease (AD. Existing tools available to perform such analysis (e.g., detrended fluctuation analysis, however, provide limited gains in discriminability power over traditional spectral based EEG analysis. In this paper, we explore the use of an innovative EEG amplitude modulation analysis technique based on spectro-temporal signal processing. More specifically, full-band EEG signals are first decomposed into the five well-known frequency bands and the envelopes are then extracted via a Hilbert transform. Each of the five envelopes are further decomposed into four so-called modulation bands, which were chosen to coincide with the delta, theta, alpha and beta frequency bands. Experiments on a resting-awake EEG dataset collected from 76 participants (27 healthy controls, 27 diagnosed with mild-AD, and 22 with moderate-AD showed significant differences in amplitude modulations between the three groups. Most notably, i delta modulation of the beta frequency band disappeared with an increase in disease severity (from mild to moderate AD, ii delta modulation of the theta band appeared with an increase in severity, and iii delta modulation of the beta frequency band showed to be a reliable discriminant feature between healthy controls and mild-AD patients. Taken together, it is hoped that the developed tool can be used to assist clinicians not only with early detection of Alzheimer's disease, but also to monitor its progression.

  6. Inhibition shapes selectivity to vocalizations in the inferior colliculus of awake mice

    Directory of Open Access Journals (Sweden)

    Zachary eMayko

    2012-10-01

    Full Text Available The inferior colliculus (IC is a major center for integration of auditory information as itreceives ascending projections from a variety of brainstem nuclei as well as descending projectionsfrom the thalamus and auditory cortex. The ascending projections are both excitatory andinhibitory and their convergence at the IC results in a microcircuitry that is important forshaping responses to simple, binaural, and modulated sounds in the IC. Here, we examined therole inhibition plays in shaping selectivity to vocalizations in the IC of awake, normal-hearingadult mice (CBA/CaJ strain. Neurons in the IC of mice show selectivity in their responses tovocalizations, and we hypothesized that this selectivity is created by inhibitory microcircuitryin the IC. We compared single unit responses in the IC to pure tones and a variety of ultrasonicmouse vocalizations before and after iontophoretic application of GABAA receptor (GABAARand glycine receptor (GlyR antagonists. The most pronounced effects of blocking GABAAR andGlyR on IC neurons were to increase spike rates and broaden excitatory frequency tuning curvesin response to pure tone stimuli, and to decrease selectivity to vocalizations. Thus, inhibitionplays an important role in creating selectivity to vocalizations in the inferior colliculus.

  7. Neural correlates of sensorimotor gating: A metabolic positron emission tomography study in awake rats

    Directory of Open Access Journals (Sweden)

    Cathrin eRohleder

    2014-05-01

    Full Text Available 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.

  8. Baroreceptor control of heart rate in the awake toad: peripheral autonomic effectors and arterial baroreceptor areas.

    Science.gov (United States)

    Bianchi-da-Silva, L M; Menescal-de-Oliveira, L; Hoffmann, A

    2000-04-12

    Systemic injection of sodium nitroprusside (30 microg/kg, i.v.) in the awake Bufo paracnemis toad induced a fall in arterial blood pressure and tachycardia. This tachycardia, but not the hypotension, was significantly reduced in toads with bilateral electrolytic lesion of the caudal and commissural regions of the solitary tract nucleus and in animals with transection of the spinal cord, 2 mm below the obex. This indicates that the tachycardia is reflex, depends on the integrity of the solitary tract nucleus and is due to descending spinal autonomic activation. Pretreatment with propranolol (4 mg/kg, i.v.) significantly reduced the tachycardia but did not block it completely, showing the importance of beta-adrenoceptors in its genesis. The reflex increase in heart rate induced by nitroprusside was not statistically significant in animals with bilateral section of the laryngeal nerve, whose baroreceptor fibers originate from the pulmocutaneous artery or in animals in which the bilateral section of the laryngeal nerve was performed together with section of the glossopharyngeal nerves, which incorporate fibers originating from the carotid labyrinth. The reduction of the reflex tachycardia was significant in toads with aortic arch denervation alone or combined with section of the laryngeal nerves or in animals with complete denervation of the three baroreceptors areas. These results suggest that the region of the aortic arch, when submitted to unloading, is the most important baroreceptor zone for cardiac compensation in toads.

  9. Auditory response properties of neurons in the putamen and globus pallidus of awake cats.

    Science.gov (United States)

    Zhong, Renjia; Qin, Ling; Sato, Yu

    2014-05-01

    Several decades of research have provided evidence that the basal ganglia are closely involved in motor processes. Recent clinical, electrophysiological, behavioral data have revealed that the basal ganglia also receive afferent input from the auditory system, but the detailed auditory response characteristics have not yet reported. The present study aimed to reveal the acoustic response properties of neurons in parts of the basal ganglia. We recorded single-unit activities from the putamen (PU) and globus pallidus (GP) of awake cats passively listening to pure tones, click trains, and natural sounds. Our major findings were: 1) responses in both PU and GP neurons were elicited by pure-tone stimuli, whereas PU neurons had lower intensity thresholds, shorter response latencies, shorter excitatory duration, and larger response magnitudes than GP neurons. 2) Some GP neurons showed a suppressive response lasting throughout the stimulus period. 3) Both PU and GP did not follow periodically repeated click stimuli well, and most neurons only showed a phasic response at the stimulus onset and offset. 4) In response to natural sounds, PU also showed a stronger magnitude and shorter duration of excitatory response than GP. The selectivity for natural sounds was low in both nuclei. 5) Nonbiological environmental sounds more efficiently evoked responses in PU and GP than the vocalizations of conspecifics and other species. Our results provide insights into how acoustic signals are processed in the basal ganglia and revealed the distinction of PU and GP in sensory representation.

  10. High-throughput mapping of brain-wide activity in awake and drug-responsive vertebrates.

    Science.gov (United States)

    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.

  11. Salicylate induced tinnitus: behavioral measures and neural activity in auditory cortex of awake rats.

    Science.gov (United States)

    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.

  12. The Challenge of Interfacing the Primary Beam Lines for the AWAKE Project at CERN

    CERN Document Server

    Bracco, C; Gschwendtner, E; Meddahi, M; Petrenko, A; Velotti, FM

    2014-01-01

    The Proton Driven Plasma Wakefield Acceleration Experiment (AWAKE) at CERN foresees the simultaneous operation of a proton, a laser and an electron beam. The first stage of the experiment will consist in proving the self-modulation, in the plasma, of a long proton bunch into micro-bunches. The success of this experiment requires an almost perfect concentricity of the proton and laser beam, over the full length of the plasma cell. The complexity of integrating the laser into the proton beam line and fulfilling the strict requirements in terms of pointing precision of the proton beam at the plasma cell are described. The second stage of the experiment foresees also the injection of electron bunches to probe the accelerating wakefields driven by the proton beam. Studies were performed to evaluate the possibility of injecting the electron beam parallel and with an offset to the beam axis. This option would imply that protons and electrons will have to share the last few meters of a common beam line. Issues and po...

  13. Effects of hypercapnia on variability of normal respiratory behavior in awake cats.

    Science.gov (United States)

    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.

  14. Characterization of flexible ECoG electrode arrays for chronic recording in awake rats.

    Science.gov (United States)

    Yeager, John D; Phillips, Derrick J; Rector, David M; Bahr, David F

    2008-08-30

    We developed a 64-channel flexible polyimide ECoG electrode array and characterized its performance for long-term implantation, chronic cortical recording and high resolution mapping of surface-evoked potentials in awake rats. To achieve the longest possible recording periods, the flexibility of the electrode array, adhesion between the metals and carrier substrate, and biocompatibility were critical for maintaining the signal integrity. Experimental testing of thin film adhesion was applied to a gold-polyimide system in order to characterize relative interfacial fracture energies for several different adhesion layers, yielding an increase in overall device reliability. We tested several different adhesion techniques including the following: gold alone without an adhesion layer, titanium-tungsten, tantalum and chromium. We found titanium-tungsten to be a suitable adhesion layer considering the biocompatibility requirements as well as stability and delamination resistance. While chromium and tantalum produced stronger gold adhesion, concerns over biocompatibility of these materials require further testing. We implanted the polyimide ECoG electrode arrays through a slit made in the skull of rats and recorded cortical surface evoked responses. The arrays performed reliably over a period of at least 100 days and signals compared well with traditional screw electrodes, with better high frequency response characteristics. Since the ultimate goal of chronically implanted electrode arrays is for neural prosthetic devices that need to last many decades, other adhesion layers that would prove safe for implantation may be tested in the same way in order to improve the device reliability.

  15. Nitric oxide modulates the cardiovascular effects elicited by acetylcholine in the NTS of awake rats.

    Science.gov (United States)

    da Silva, Liana Gouveia; Dias, Ana Carolina Rodrigues; Furlan, Elaina; Colombari, Eduardo

    2008-12-01

    Microinjection of acetylcholine chloride (ACh) in the nucleus of the solitary tract (NTS) of awake rats caused a transient and dose-dependent hypotension and bradycardia. Because it is known that cardiovascular reflexes are affected by nitric oxide (NO) produced in the NTS, we investigated whether these ACh-induced responses depend on NO in the NTS. Responses to ACh (500 pmol in 100 nl) were strongly reduced by ipsilateral microinjection of the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10 nmol in 100 nl) in the NTS: mean arterial pressure (MAP) fell by 50 +/- 5 mmHg before L-NAME to 9 +/- 4 mmHg, 10 min after L-NAME, and HR fell by 100 +/- 26 bpm before L-NAME to 20 +/- 10 bpm, 10 min after L-NAME (both P NTS also reduced responses to ACh: MAP fell from 42 +/- 3 mmHg before TRIM to 27 +/- 6 mmHg, 10 min after TRIM (P NTS of conscious rats induces hypotension and bradycardia, and these effects may be mediated at least partly by NO produced in NTS neurons.

  16. Efficacy of "Awake ECMO" for critical respiratory failure after pediatric open-heart surgery.

    Science.gov (United States)

    Higashida, Akihiko; Hoashi, Takaya; Kagisaki, Koji; Shimada, Masatoshi; Takahashi, Yuzo; Hayashi, Teruyuki; Ichikawa, Hajime

    2016-06-01

    A 4-year-old boy with atrioventricular discordance, double-outlet right ventricle, pulmonary stenosis, and mitral regurgitation, was undergoing anatomical repair consisting of Senning, Rastelli, Damus-Kaye-Stansel procedures, and a mitral valve repair, complained of post-operative excessive airway tract secretion, which ultimately developed into acute respiratory distress syndrome (ARDS) 28 days after the operation. The cause of the ARDS was thought to be frequent manual positive pressure recruitment and prolonged inhalation of pure oxygen. At 45 days after the operation, hypercapnia and respiratory acidosis turned out to be irreversible, and therefore, veno-arterial extracorporeal membrane oxygenation (ECMO) was established utilizing the Endumo(®)4000 system. Pulmonic interstitial inflammation gradually improved while resting the lung under ECMO support; however, effective ventilation volume decreased critically because a massive pulmonary hemorrhage occurred at 2 and 9 days after the initiation of ECMO. To maximize the effectiveness of respiratory physical therapy, "Awake ECMO" was started and tidal volume dramatically increased with a regained cough reflex. Five days later, he was successfully weaned off from ECMO, and discharged 7 months after the operation without any neurological and physiological sequelae.

  17. Coherent 25- to 35-Hz Oscillations in the Sensorimotor Cortex of Awake Behaving Monkeys

    Science.gov (United States)

    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.

  18. Early intervention with intranasal NPY prevents single prolonged stress-triggered impairments in hypothalamus and ventral hippocampus in male rats.

    Science.gov (United States)

    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.

  19. Prevalence and potential factors associated with probable sleep or awake bruxism and dentin hypersensitivity in undergraduate students

    Directory of Open Access Journals (Sweden)

    Neusa Barros DANTAS-NETA

    Full Text Available OBJECTIVE: To measure the prevalence of probable sleep or awake bruxism and cervical dentin hypersensitivity of undergraduate students and to determine the symptoms associated with these conditions.METHODOLOGY: This was a cross-sectional study. A diagnosis of probable bruxism was reached when students reported clenching or grinding of the teeth during sleep and/or wakefulness, and when they also presented some of the signs and symptoms of bruxism and masseter muscle pain on palpation. Cervical dentinal hypersensitivity was diagnosed by testing for sensitivity to pain in the cervical region of the teeth. Pain was triggered either by touch (using a #5 probe or by an air jet spray. The sample consisted of 306 university students aged between 19 and 35 years old. The data were stored and analysed using SPSS software, version 15.0 for Windows.RESULT: The prevalence of probable bruxism was 34.3%, with no predominance regarding sex. Probable awake bruxism was more prevalent (61.9%, mostly occurring when the individual reported being in a state of mental concentration (63.1%. There was no association between probable sleep or awake bruxism and dentin hypersensitivity (p = 0.195. Individuals with probable sleep bruxism had increased odds of having muscular pain in the face upon waking (OR = 14.14, 95% CI 5.06-39.55, and those with probable awake bruxism had a increased odds of having facial muscle fatigue when chewing or talking for a long time (OR = 2.88, 95% CI 1.53-5.43 and muscular pain in the face upon waking (OR = 5.31, 95% CI 1.93-14.62.CONCLUSION: The prevalence of probable bruxism was 34.3% and that of HDC was 57.8%, with 22.2% of these subjects also showing probable bruxism. Individuals with probable bruxism tended to have a higher odds of facial pain when they awakened and when chewing or talking for long periods. There were no associations between probable sleep and awake bruxism and cervical dentin hypersensitivity.

  20. Insulin Neuroprotection and the Mechanisms

    Institute of Scientific and Technical Information of China (English)

    Li-Yun Yu; Yu Pei

    2015-01-01

    Objective:To analyze the mechanism of neuroprotection of insulin and which blood glucose range was benefit for insulin exerting neuroprotective action.Data Sources:The study is based on the data from PubMed.Study Selection:Articles were selected with the search terms "insulin","blood glucose","neuroprotection","brain","glycogen","cerebral ischemia","neuronal necrosis","glutamate","γ-aminobutyric acid".Results:Insulin has neuroprotection.The mechanisms include the regulation of neurotransmitter,promoting glycogen synthesis,and inhibition of neuronal necrosis and apoptosis.Insulin could play its role in neuroprotection by avoiding hypoglycemia and hyperglycemia.Conclusions:Intermittent and long-term infusion insulin may be a benefit for patients with ischemic brain damage at blood glucose 6-9 mmol/L.

  1. Use of intranasal corticosteroids in the management of congestion and sleep disturbance in pediatric patients with allergic rhinitis.

    Science.gov (United States)

    Lanier, Bob Q

    2008-06-01

    Allergic rhinitis affects a large number of children and exerts a considerable socioeconomic impact. It is underdiagnosed and inadequately treated, which predisposes children to potentially serious comorbidities. Allergic rhinitis symptoms may create nighttime breathing problems and sleep disturbances and have a negative effect on a child's ability to learn in the classroom. Although antihistamines have shown efficacy in relieving many symptoms, they have little effect on nasal congestion. This article summarizes the advantages of intranasal corticosteroids, including their effectiveness against congestion and excellent safety profile. Intranasal corticosteroids with minimal systemic bioavailability provide topical drug delivery that minimizes the potential for systemic side-effects.

  2. Diabetic lipohypertrophy delays insulin absorption.

    Science.gov (United States)

    Young, R J; Hannan, W J; Frier, B M; Steel, J M; Duncan, L J

    1984-01-01

    The effect of lipohypertrophy at injection sites on insulin absorption has been studied in 12 insulin-dependent diabetic patients. The clearance of 125I-insulin from sites with lipohypertrophy was significantly slower than from complementary nonhypertrophied sites (% clearance in 3 h, 43.8 +/- 3.5 +/- SEM) control; 35.3 +/- 3.9 lipohypertrophy, P less than 0.05). The degree of the effect was variable but sufficient in several patients to be of clinical importance. Injection-site lipohypertrophy is another factor that modifies the absorption of subcutaneously injected insulin.

  3. Insulin aspart in diabetic pregnancy

    DEFF Research Database (Denmark)

    Mathiesen, Elisabeth R

    2008-01-01

    Pregnancy in women with diabetes is associated with an increased risk of obstetric complications and perinatal mortality. Maintenance of near-normal glycemia during pregnancy can bring the prevalence of fetal, neonatal and maternal complications closer to that of the nondiabetic population. Changes...... hyperglycemia with a tendency towards fewer episodes of severe hypoglycemia compared with human insulin. Treatment with insulin aspart was associated with a tendency toward fewer fetal losses and preterm deliveries than treatment with human insulin. Insulin aspart could not be detected in the fetal circulation...

  4. TLR4 and Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Jane J. Kim

    2010-01-01

    Full Text Available Chronic inflammation is a key feature of insulin resistance and obesity. Toll-Like Receptor 4 (TLR4, involved in modulating innate immunity, is an important mediator of insulin resistance and its comorbidities. TLR4 contributes to the development of insulin resistance and inflammation through its activation by elevated exogenous ligands (e.g., dietary fatty acids and enteric lipopolysaccharide and endogenous ligands (e.g., free fatty acids which are elevated in obese states. TLR4, expressed in insulin target tissues, activates proinflammatory kinases JNK, IKK, and p38 that impair insulin signal transduction directly through inhibitory phosphorylation of insulin receptor substrate (IRS on serine residues. TLR4 activation also leads to increased transcription of pro-inflammatory genes, resulting in elevation of cytokine, chemokine, reactive oxygen species, and eicosanoid levels that promote further insulin-desensitization within the target cell itself and in other cells via paracrine and systemic effects. Increased understanding of cell type-specific TLR4-mediated effects on insulin action present the opportunity and challenge of developing related therapeutic approaches for improving insulin sensitivity while preserving innate immunity.

  5. Cluster headache with ptosis responsive to intranasal lidocaine application: a case report

    Directory of Open Access Journals (Sweden)

    Bakbak Berker

    2012-02-01

    Full Text Available Abstract Introduction The application of lidocaine to the nasal mucosal area corresponding to the sphenopalatine fossa has been shown to be effective at extinguishing pain attacks in patients with a cluster headache. In this report, the effectiveness of local administration of lidocaine on cluster headache attacks as a symptomatic treatment of this disorder is discussed. Cases presentation A 22-year-old Turkish man presented with a five-year history of severe, repeated, unilateral periorbital pain and headache, diagnosed as a typical cluster headache. He suffered from rhinorrhea, lacrimation and ptosis during headaches. He had tried several unsuccessful daily medications. We applied a cotton tip with lidocaine hydrochloride into his left nostril for 10 minutes. The ptosis responded to the treatment and the intensity of his headache decreased. Conclusion Intranasal lidocaine is a useful treatment for the acute management of a cluster headache. Intranasal lidocaine blocks the neural transmission of the sphenopalatine ganglion, which contributes to the trigeminal nerve as well as containing both parasympathetic and sympathetic fibers.

  6. Study of sodium hyaluronate-based intranasal formulations containing micro- or nanosized meloxicam particles.

    Science.gov (United States)

    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.

  7. Development, characterization and application of in situ gel systems for intranasal delivery of tacrine.

    Science.gov (United States)

    Qian, Shuai; Wong, Yin Cheong; Zuo, Zhong

    2014-07-01

    The present study aimed to develop an in situ gel formulation for intranasal delivery of tacrine (THA), an anti-Alzheimer's drug. Thermosensitive polymer Pluronic F-127 was used to prepare THA in situ gels. Sol-gel transition temperature (Tsol-gel), rheological properties, in vitro release, and in vivo nasal mucociliary transport time were optimized. The pharmacokinetics and brain dispositions of in situ gel were compared with that from THA oral solution in rats. The in situ gel demonstrated a liquid state with Newtonian fluid behavior under 20 °C, while it exhibited as non-flowing gel with pseudoplastic fluid behavior beyond its Tsol-gel of 28.5 °C. Based on nasal mucociliary transport time, the in situ gel significantly prolonged its retention in nasal cavity compared to solution form. Moreover, the in situ gel achieved 2-3 fold higher peak plasma concentration (Cmax) and area under the curve (AUC) of THA in plasma and brain tissue, but lowered Cmax and AUC of the THA metabolites compared to that of oral solution. The enhanced nasal residence time, improved bioavailability, increased brain uptake of parent drug and decreased exposure of metabolites suggested that the in situ gel could be an effective intranasal formulation for THA.

  8. Intranasal DNA Vaccine for Protection against Respiratory Infectious Diseases: The Delivery Perspectives

    Directory of Open Access Journals (Sweden)

    Yingying Xu

    2014-07-01

    Full Text Available 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.

  9. Intranasal microemulsion for targeted nose to brain delivery in neurocysticercosis: Role of docosahexaenoic acid.

    Science.gov (United States)

    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 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 (Pnose 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.

  10. Prehospital Medication Administration: A Randomised Study Comparing Intranasal and Intravenous Routes

    Directory of Open Access Journals (Sweden)

    Cian McDermott

    2012-01-01

    Full Text Available Introduction. Opioid overdose is an ever-increasing problem globally. Recent studies have demonstrated that intranasal (IN naloxone is a safe and effective alternative to traditional routes of naloxone administration for reversal of opioid overdose. Aims. This randomised controlled trial aimed to compare the time taken to deliver intranasal medication with that of intravenous (IV medication by advanced paramedic trainees. Methods. 18 advanced paramedic trainees administered either an IN or IV medication to a mannequin model in a classroom-based setting. The time taken for medication delivery was compared. End-user satisfaction was assessed using a 5-point questionnaire regarding ease of use and safety for both routes. Results. The mean time taken for the IN and IV group was 87.1 seconds and 178.2 seconds respectively. The difference in mean time taken was 91.1 seconds (95% confidence interval 55.2 seconds to 126.9 seconds, P≤0.0001. 89% of advanced paramedic trainees reported that the IN route was easier and safer to use than the IV route. Conclusion. This study demonstrates that, amongst advanced paramedic trainees, the IN route of medication administration is significantly faster, better accepted and perceived to be safer than using the IV route. Thus, IN medication administration could be considered more frequently when administering emergency medications in a pre-hospital setting.

  11. Pharmacokinetics of Intranasal Scopolamine Gel Formation During Antiorthostatic Bedrest - A Microgravity Analog

    Science.gov (United States)

    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.

  12. Intranasal oxytocin and salivary cortisol concentrations during social rejection in university students.

    Science.gov (United States)

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

    2012-07-01

    Oxytocin facilitates pro-social behaviour and is proposed as a regulatory factor controlling stress reactivity. Previous research on oxytocin and stress has focused on achievement-related stressors among male participants. The aims of the study were to (1) examine the influence of oxytocin on the affective and cortisol response to the Yale Interpersonal Stressor (YIPS), a live social rejection paradigm, and (2) to replicate the finding that women exhibit a greater cortisol response to interpersonal stress than men (Stroud et al. 2002). Sex differences in stress responses: Social rejection versus achievement stress. Biol Psychiat 53:318-327. Ninety-six undergraduate students underwent the YIPS, where participants were excluded from two separate conversations by two same-sex confederates. Salivary cortisol concentrations and mood were repeatedly measured throughout the study. Participants were administered, in a double-blind design, a single dose of intranasal oxytocin (24 IU) or placebo prior to beginning the YIPS. The YIPS elicited a significant negative mood response that was more pronounced in females than in males. However, no significant cortisol response to the stressor and no sex difference in cortisol reactivity were observed. A significant effect of drug condition on cortisol levels was observed. Participants who were administered oxytocin exhibited a decrease in cortisol levels, relative to placebo, during the YIPS, F (4, 184)=4.50, pstress reported by Stroud et al. (2002). Intranasal oxytocin, however, appeared to reduce cortisol concentrations during an interpersonal challenge.

  13. Effects of single dose intranasal oxytocin on social cognition in schizophrenia.

    Science.gov (United States)

    Davis, Michael C; Lee, Junghee; Horan, William P; Clarke, Angelika D; McGee, Mark R; Green, Michael F; Marder, Stephen R

    2013-07-01

    Deficits in social cognition are common in schizophrenia and predict poor community functioning. Given the current limitations of psychosocial treatments and the lack of pharmacological treatments for social cognitive deficits, the development of novel therapeutic agents could greatly enhance functional recovery in schizophrenia. This study evaluated whether a single dose of intranasal oxytocin acutely improves social cognitive functioning in schizophrenia. Twenty-three male veterans with schizophrenia completed baseline assessments of social cognition that were divided into lower-level (facial affect perception, social perception, detection of lies) and higher-level (detection of sarcasm and deception, empathy) processes. One week later, patients received the same battery after being randomized to a single dose of 40 IU intranasal oxytocin or placebo. Though the groups did not differ significantly on the social cognition composite score, oxytocin improved performance for the higher-level social cognitive tasks (Cohen's d=1.0, p=0.045). Subjects were unable to accurately guess which treatment they had received. The improvements found in higher-level social cognition encourage further studies into the therapeutic potential of oxytocin in schizophrenia.

  14. The effect of topical sodium cromoglycate on intranasal histamine challenge in allergic rhinitis.

    Science.gov (United States)

    Birchall, M A; Henderson, J C; Studham, J M; Pride, N B; Fuller, R W

    1994-12-01

    Topical sodium cromoglycate is used to treat allergic diseases of the upper and lower airways. To investigate its mechanisms of action, intranasal histamine challenge was used in nine subjects with perennial allergic rhinitis. After a preliminary day where subjects' reactivity thresholds (D100) for histamine were determined, intranasal sodium cromoglycate was administered in a double-blind, placebo-controlled fashion. Graded (D100/3, D100, D100X3), sequential challenges were performed on days 1 and 21 of each course, and responses measured by changes in nasal airway resistance, sneezes, secretion volume and secretion content: total protein, lysozyme and mucin. After a single dose of sodium cromoglycate, there was no change in resistance, but secretion volumes fell significantly (3.12 ml/5 min c.i. 2.83-3.4; placebo 3.61, c.i. 3.32-3.90: P = 0.026). After a 3-week-course, there was a significant fall in resistance (4.29 cm H2O/l/s, c.i. 3.85-4.72; placebo 5.45, c.i. 5.01-5.88: P sodium cromoglycate has both short- and long-term effects on nasal reactivity to histamine challenge. Acutely, there is a reduction in nasal lavage fluid volume which may be the result of reduced irritant receptor activity. After a 3-week course, there is a reduction in nasal resistance responses, a possible anti-inflammatory effect.

  15. Prevention or early cure of type 1 diabetes by intranasal administration of gliadin in NOD mice.

    Directory of Open Access Journals (Sweden)

    David P Funda

    Full Text Available 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.

  16. Intranasal Immunization of Mice to Avoid Interference of Maternal Antibody against H5N1 Infection.

    Directory of Open Access Journals (Sweden)

    Fenghua Zhang

    Full Text Available 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.

  17. Cerebral insulin, insulin signaling pathway, and brain angiogenesis.

    Science.gov (United States)

    Zeng, Yi; Zhang, Le; Hu, Zhiping

    2016-01-01

    Insulin performs unique non-metabolic functions within the brain. Broadly speaking, two major areas of these functions are those related to brain endothelial cells and the blood-brain barrier (BBB) function, and those related to behavioral effects, like cognition in disease states (Alzheimer's disease, AD) and in health. Recent studies showed that both these functions are associated with brain angiogenesis. These findings raise interesting questions such as how they are linked to each other and whether modifying brain angiogenesis by targeting certain insulin signaling pathways could be an effective strategy to treat dementia as in AD, or even to help secure healthy longevity. The two canonical downstream pathways involved in mediating the insulin signaling pathway, the phosphoinositide-3 kinase (PI3K), and mitogen-activated protein kinase (MAPK) cascades, in the brain are supposed to be similar to those in the periphery. PI3K and MAPK pathways play important roles in angiogenesis. Both are involved in stimulating hypoxia inducible factor (HIF) in angiogenesis and could be activated by the insulin signaling pathway. This suggests that PI3K and MAPK pathways might act as cross-talk between the insulin signaling pathway and the angiogenesis pathway in brain. But the cerebral insulin, insulin signaling pathway, and the detailed mechanism in the connection of insulin signaling pathway, brain angiogenesis pathway, and healthy aging or dementias are still mostly not clear and need further studies.

  18. Improved insulin sensitivity after exercise: focus on insulin signaling

    DEFF Research Database (Denmark)

    Frøsig, Christian; Richter, Erik

    2009-01-01

    of the mechanism relates to an improved ability of insulin to stimulate translocation of glucose transporters (GLUT4) to the muscle membrane after exercise. How this is accomplished is still unclear; however, an obvious possibility is that exercise interacts with the insulin signaling pathway to GLUT4...

  19. Intensive Insulin Therapy: Tight Blood Sugar Control

    Science.gov (United States)

    ... insulin therapy can help you achieve desired blood sugar control and what intensive insulin therapy requires of ... aggressive treatment approach designed to control your blood sugar levels. Intensive insulin therapy requires close monitoring of ...

  20. Classifying insulin regimens

    DEFF Research Database (Denmark)

    Neu, A; Lange, K; Barrett, T;

    2015-01-01

    diabetes there is little distinctiveness about concepts and the nomenclature is confusing. Even among experts similar terms are used for different strategies. The aim of our review--based on the experiences of the Hvidoere Study Group (HSG)--is to propose comprehensive definitions for current insulin...... regimens reflecting current diabetes management in childhood and adolescence. The HSG--founded in 1994--is an international group representing 24 highly experienced pediatric diabetes centers, from Europe, Japan, North America and Australia. Different benchmarking studies of the HSG revealed a broad...

  1. Insulin resistance, insulin sensitization and inflammation in polycystic ovarian syndrome

    Directory of Open Access Journals (Sweden)

    Dhindsa G

    2004-04-01

    Full Text Available It is estimated that 5-10% of women of reproductive age have polycystic ovarian syndrome (PCOS. While insulin resistance is not part of the diagnostic criteria for PCOS, its importance in the pathogenesis of PCOS cannot be denied. PCOS is associated with insulin resistance independent of total or fat-free body mass. Post-receptor defects in the action of insulin have been described in PCOS which are similar to those found in obesity and type 2 diabetes. Treatment with insulin sensitizers, metformin and thiazolidinediones, improve both metabolic and hormonal patterns and also improve ovulation in PCOS. Recent studies have shown that PCOS women have higher circulating levels of inflammatory mediators like C-reactive protein, tumour necrosis factor- , tissue plasminogen activator and plasminogen activator inhibitor-1 (PAI-1 . It is possible that the beneficial effect of insulin sensitizers in PCOS may be partly due to a decrease in inflammation.

  2. Nicotine effects on regional cerebral blood flow in awake, resting tobacco smokers.

    Science.gov (United States)

    Domino, E F; Minoshima, S; Guthrie, S; Ohl, L; Ni, L; Koeppe, R A; Zubieta, J K

    2000-12-01

    The hypothesis for this research was that regional cerebral blood flow (rCBF) would increase following nasal nicotine administration to overnight abstinent tobacco smokers in relationship to the known brain distribution of nicotinic cholinergic receptors (nAChRs). Nine male and nine female healthy adult smokers were studied. They abstained overnight from tobacco products for 10 or more hours prior to study the next morning. Nicotine nasal spray was given in doses of 1-2.5 mg total with half in each nostril while the subject was awake and resting in a supine position. Oleoresin of pepper solution in a similar volume was used as an active placebo to control for the irritating effects of nicotine. Both substances were given single blind to the subjects. Positron emission tomography (PET) with H(2)(15)O was used to measure rCBF. The data from each subject volunteer were normalized to global activity to better assess regional brain changes. Both nasal nicotine and pepper spray produced similar increases in CBF in somesthetic area II, consistent with the irritant effects of both substances. The mean rCBF effects of nasal pepper were subtracted from those of nasal nicotine to determine the actions of nicotine alone. The latter produced increases in rCBF in the thalamus, pons, Brodman area 17 of the visual cortex, and cerebellum. Some brain areas that contain a large number of nAChRs, such as the thalamus, showed an increase in CBF. Other areas that have few nAChRs, such as the cerebellum, also showed an increase in relative CBF. The hippocampal/parahippocampal areas showed greater regional decreases (left) and lesser increases (right) in CBF that correlated with the increase in plasma arterial nicotine concentrations. The results obtained indicate complex primary and secondary effects of nicotine in which only some regional brain CBF changes correlate with the known distribution of nAChR. No gender differences were noted.

  3. The conjugacy of the vestibulo-ocular reflex evoked by single labyrinth stimulation in awake monkeys.

    Science.gov (United States)

    Tang, Xuehui; Xu, Youguo; Simpson, Ivra; Jeffcoat, Ben; Mustain, William; Zhou, Wu

    2010-10-01

    It is well known that the vestibulo-ocular reflex (VOR) is conjugate when measured in the dark with minimal vergence. But the neural basis of the VOR conjugacy remains to be identified. In the present study, we measured the VOR conjugacy during single labyrinth stimulation to examine whether the VOR conjugacy depends on reciprocal stimulation of the two labyrinths. There are conflicting views on this issue. First, since the vestibular signals carried by the ascending tract of Deiters' are distributed exclusively to the motoneurons of the ipsilateral eye, the neural innervations after single labyrinth stimulation are not symmetrical for the two eyes. Thus, single labyrinth stimulation may generate disjunctive VOR responses. Second, the only published study on this issue was an electrooculography (EOG) study that reported disjunctive VOR responses during unilateral caloric irrigation (Wolfe in Ann Otol 88:79-85, 1979). Third, the VOR during unilateral caloric stimulation performed in clinical vestibular tests is routinely perceived to be conjugate. To resolve these conflicting views, the present study examined the VOR conjugacy during single labyrinth stimulation by recording binocular eye position signals in awake monkeys with a search coil technique. In contradiction to the previous EOG study and the prediction based on the asymmetry of the unilateral brainstem VOR circuits, we found that the VOR during unilateral caloric irrigation was conjugate over a wide range of conditions. We conclude that the net neural innervations received by the two eyes are symmetrical after single labyrinth stimulation, despite the apparent asymmetry in the unilateral VOR pathways. A novel role for the ascending tract of Deiters' in the VOR conjugacy is proposed.

  4. Awake reactivation of emotional memory traces through hippocampal-neocortical interactions.

    Science.gov (United States)

    de Voogd, Lycia D; Fernández, Guillén; Hermans, Erno J

    2016-07-01

    Emotionally arousing experiences are typically well remembered not only due to immediate effects at encoding, but also through further strengthening of subsequent consolidation processes. A large body of research shows how neuromodulatory systems promote synaptic consolidation. However, how emotionally arousing experiences alter systems-level interactions, presumably a consequence of modifications at a synaptic level, remains unclear. Animal models predict that memory traces are maintained by spontaneous reactivations across hippocampal-neocortical circuits during "offline" periods such as post-learning rest, and suggest this might be stronger for emotional memories. The present study was designed to test this hypothesis in humans using functional Magnetic Resonance Imaging. Participants underwent a two-category localizer paradigm followed by a categorical differential delay fear conditioning paradigm interleaved with blocks of awake rest. Counterbalanced across participants, exemplars of one category (CS+), but not the other (CS-), were paired with mild electrical shocks. Fear recall (differential conditioned pupil dilation) was tested 24h later. Analyses of the localizer paradigm replicate earlier work showing category-specific response patterns in neocortical higher-order visual regions. Critically, we show that during post-learning rest, spontaneous reactivation of these neocortical patterns was stronger for the CS+ than the CS- category. Furthermore, hippocampal connectivity with the regions exhibiting these reactivations predicted strength of fear recall 24h later. We conclude that emotional arousal during learning promotes spontaneous post-learning reactivation of neocortical representations of recent experiences, which leads to better memory when coinciding with hippocampal connectivity. Our findings reveal a systems-level mechanism that may explain the persistence of long-term memory for emotional experiences.

  5. Measurement of Electroretinograms and Visually Evoked Potentials in Awake Moving Mice.

    Directory of Open Access Journals (Sweden)

    Yusuke Tomiyama

    Full Text Available The development of new treatments for intractable retinal diseases requires reliable functional assessment tools for animal models. In vivo measurements of neural activity within visual pathways, including electroretinogram (ERG and visually evoked potential (VEP recordings, are commonly used for such purposes. In mice, the ERG and VEPs are usually recorded under general anesthesia, a state that may alter sensory transduction and neurotransmission, but seldom in awake freely moving mice. Therefore, it remains unknown whether the electrophysiological assessment of anesthetized mice accurately reflects the physiological function of the visual pathway. Herein, we describe a novel method to record the ERG and VEPs simultaneously in freely moving mice by immobilizing the head using a custom-built restraining device and placing a rotatable cylinder underneath to allow free running or walking during recording. Injection of the commonly used anesthetic mixture xylazine plus ketamine increased and delayed ERG oscillatory potentials by an average of 67.5% and 36.3%, respectively, compared to unanesthetized mice, while having minimal effects on the a-wave and b-wave. Similarly, components of the VEP were enhanced and delayed by up to 300.2% and 39.3%, respectively, in anesthetized mice. Our method for electrophysiological recording in conscious mice is a sensitive and robust means to assess visual function. It uses a conventional electrophysiological recording system and a simple platform that can be built in any laboratory at low cost. Measurements using this method provide objective indices of mouse visual function with high precision and stability, unaffected by anesthetics.

  6. Acute blood volume expansion delays the gastrointestinal transit of a charcoal meal in awake rats

    Directory of Open Access Journals (Sweden)

    de-Oliveira G.R.

    1998-01-01

    Full Text Available The present study evaluates the effect of blood volume expansion on the gastrointestinal transit of a charchoal meal (2.5 ml of an aqueous suspension consisting of 5% charcoal and 5% gum arabic in awake male Wistar rats (200-270 g. On the day before the experiments, the rats were anesthetized with ether, submitted to left jugular vein cannulation and fasted with water ad libitum until 2 h before the gastrointestinal transit measurement. Blood volume expansion by iv infusion of 1 ml/min Ringer bicarbonate in volumes of 3, 4 or 5% body weight delayed gastrointestinal transit at 10 min after test meal administration by 21.3-26.7% (P<0.05, but no effect was observed after 1 or 2% body weight expansion. The effect of blood volume expansion (up to 5% body weight on gastrointestinal transit lasted for at least 60 min (P<0.05. Mean arterial pressure increased transiently and central venous pressure increased and hematocrit decreased (P<0.05. Subdiaphragmatic vagotomy and yohimbine (3 mg/kg prevented the delay caused by expansion on gastrointestinal transit, while atropine (0.5 mg/kg, L-NAME (2 mg/kg, hexamethonium (10 mg/kg, prazosin (1 mg/kg or propranolol (2 mg/kg were ineffective. These data show that blood volume expansion delays the gastrointestinal transit of a charcoal meal and that vagal and yohimbine-sensitive pathways appear to be involved in this phenomenon. The delay in gastrointestinal transit observed here, taken together with the modifications of gastrointestinal permeability to salt and water reported by others, may be part of the mechanisms involved in liquid excess management.

  7. Vincristine delays gastric emptying and gastrointestinal transit of liquid in awake rats

    Directory of Open Access Journals (Sweden)

    A.A. Peixoto Júnior

    2009-06-01

    Full Text Available We evaluated the effects of vincristine on the gastrointestinal (GI motility of awake rats and correlated them with the course of vincristine-induced peripheral neuropathy. Vincristine or saline was injected into the tail vein of male Wistar rats (180-250 g on alternate days: 50 µg/kg (5 doses, N = 10, 100 µg/kg (2, 3, 4 and 5 doses, N = 49 or 150 µg/kg (1, 2, or 5 doses, N = 37. Weight and stool output were measured daily for each animal. One day after completing the vincristine treatment, the animals were fasted for 24 h, gavage-fed with a test meal and sacrificed 10 min later to measure gastric emptying (GE, GI transit and colon weight. Sensory peripheral neuropathy was evaluated by hot plate testing. Chronic vincristine treatments with total cumulative doses of at least 250 µg/kg significantly decreased GE by 31-59% and GI transit by 55-93%. The effect of 5 doses of vincristine (150 µg/kg on GE did not persist for more than 1 week. Colon weight increased after 2 and 5 doses of vincristine (150 µg/kg. Fecal output decreased up to 48 h after the fifth dose of vincristine (150 µg/kg. Vincristine decreased the heat pain threshold 1 day after 5 doses of 50-100 µg/kg or after 3-5 doses of 150 µg/kg. This effect lasted for at least 2 weeks after the fifth dose. Chronic intravenous vincristine treatment delayed GE and GI transit of liquid. This effect correlated with the peak increase in colon weight but not with the pain threshold changes.

  8. Fast transmission from the dopaminergic ventral midbrain to the sensory cortex of awake primates.

    Science.gov (United States)

    Mylius, Judith; Happel, Max F K; Gorkin, Alexander G; Huang, Ying; Scheich, Henning; Brosch, Michael

    2015-11-01

    Motivated by the increasing evidence that auditory cortex is under control of dopaminergic cell structures of the ventral midbrain, we studied how the ventral tegmental area and substantia nigra affect neuronal activity in auditory cortex. We electrically stimulated 567 deep brain sites in total within and in the vicinity of the two dopaminergic ventral midbrain structures and at the same time, recorded local field potentials and neuronal discharges in cortex. In experiments conducted on three awake macaque monkeys, we found that electrical stimulation of the dopaminergic ventral midbrain resulted in short-latency (~35 ms) phasic activations in all cortical layers of auditory cortex. We were also able to demonstrate similar activations in secondary somatosensory cortex and superior temporal polysensory cortex. The electrically evoked responses in these parts of sensory cortex were similar to those previously described for prefrontal cortex. Moreover, these phasic responses could be reversibly altered by the dopamine D1-receptor antagonist SCH23390 for several tens of minutes. Thus, we speculate that the dopaminergic ventral midbrain exerts a temporally precise, phasic influence on sensory cortex using fast-acting non-dopaminergic transmitters and that their effects are modulated by dopamine on a longer timescale. Our findings suggest that some of the information carried by the neuronal discharges in the dopaminergic ventral midbrain, such as the motivational value or the motivational salience, is transmitted to auditory cortex and other parts of sensory cortex. The mesocortical pathway may thus contribute to the representation of non-auditory events in the auditory cortex and to its associative functions.

  9. Stimulation of the cardiopulmonary baroreflex enhances ventricular contractility in awake dogs: a mathematical analysis study.

    Science.gov (United States)

    Sala-Mercado, Javier A; Moslehpour, Mohsen; Hammond, Robert L; Ichinose, Masashi; Chen, Xiaoxiao; Evan, Sell; O'Leary, Donal S; Mukkamala, Ramakrishna

    2014-08-15

    The cardiopulmonary baroreflex responds to an increase in central venous pressure (CVP) by decreasing total peripheral resistance and increasing heart rate (HR) in dogs. However, the direction of ventricular contractility change is not well understood. The aim was to elucidate the cardiopulmonary baroreflex control of ventricular contractility during normal physiological conditions via a mathematical analysis. Spontaneous beat-to-beat fluctuations in maximal ventricular elastance (Emax), which is perhaps the best available index of ventricular contractility, CVP, arterial blood pressure (ABP), and HR were measured from awake dogs at rest before and after β-adrenergic receptor blockade. An autoregressive exogenous input model was employed to jointly identify the three causal transfer functions relating beat-to-beat fluctuations in CVP to Emax (CVP → Emax), which characterizes the cardiopulmonary baroreflex control of ventricular contractility, ABP to Emax, which characterizes the arterial baroreflex control of ventricular contractility, and HR to Emax, which characterizes the force-frequency relation. The CVP → Emax transfer function showed a static gain of 0.037 ± 0.010 ml(-1) (different from zero; P < 0.05) and an overall time constant of 3.2 ± 1.2 s. Hence, Emax would increase and reach steady state in ∼16 s in response to a step increase in CVP, without any change to ABP or HR, due to the cardiopulmonary baroreflex. Following β-adrenergic receptor blockade, the CVP → Emax transfer function showed a static gain of 0.0007 ± 0.0113 ml(-1) (different from control; P < 0.10). Hence, Emax would change little in steady state in response to a step increase in CVP. Stimulation of the cardiopulmonary baroreflex increases ventricular contractility through β-adrenergic receptor system mediation.

  10. Techniques for collecting saliva from awake, unrestrained, adult monkeys for cortisol assay.

    Science.gov (United States)

    Lutz, C K; Tiefenbacher, S; Jorgensen, M J; Meyer, J S; Novak, M A

    2000-10-01

    Cortisol levels serve as an index of pituitary-adrenal activity in nonhuman primates. In adult monkeys, cortisol is normally measured in blood (typically requiring restraint or sedation) or urine (reflecting a state rather than point estimate). In contrast, saliva collection is less invasive than drawing blood and allows for repeated sampling within a short period of time. Although protocols exist for collecting saliva from young monkeys, these procedures are inadequate for awake, unrestrained adult animals. Our laboratory has developed two methods for collecting saliva from adult rhesus monkeys: a "screen" method, which involves licking screen-covered gauze, and a "pole" method, which involves sucking and chewing on an attached rope. Twenty-three adult male rhesus monkeys were used to evaluate these two methods. After a period of adaptation, saliva samples were collected from 21 of 23 subjects. Saliva collection was faster with the pole than with the screen method (P method was not suitable for some animals because of their tendency to bite off the attached rope. An analysis of 19 saliva samples revealed a mean cortisol concentration of 0.84 microg/dl (range 0.27-1.77 microg/dl). There was no statistically significant difference in cortisol value between methods used (P > 0.22). The influence of the flavoring on the cortisol assay was tested, and was found to have no significant effect (P > 0.28). Our results indicate that either technique can be used to safely collect saliva from unrestrained adult monkeys. Choice of technique will depend on the proclivities of individual monkeys.

  11. Neuropeptides in the posterodorsal medial amygdala modulate central cardiovascular reflex responses in awake male rats

    Energy Technology Data Exchange (ETDEWEB)

    Quagliotto, E. [Departamento de Ciências Básicas da Saúde/Fisiologia, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS (Brazil); Programa de Pós-Graduação em Neurociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil); Casali, K.R. [Instituto de Ciência e Tecnologia, Universidade Federal de São Paulo, São José dos Campos, SP (Brazil); Dal Lago, P. [Departamento de Fisioterapia, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS (Brazil); Rasia-Filho, A.A. [Departamento de Ciências Básicas da Saúde/Fisiologia, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS (Brazil); Programa de Pós-Graduação em Neurociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS (Brazil)

    2014-11-21

    The rat posterodorsal medial amygdala (MePD) links emotionally charged sensory stimuli to social behavior, and is part of the supramedullary control of the cardiovascular system. We studied the effects of microinjections of neuroactive peptides markedly found in the MePD, namely oxytocin (OT, 10 ng and 25 pg; n=6/group), somatostatin (SST, 1 and 0.05 μM; n=8 and 5, respectively), and angiotensin II (Ang II, 50 pmol and 50 fmol; n=7/group), on basal cardiovascular activity and on baroreflex- and chemoreflex-mediated responses in awake adult male rats. Power spectral and symbolic analyses were applied to pulse interval and systolic arterial pressure series to identify centrally mediated sympathetic/parasympathetic components in the heart rate variability (HRV) and arterial pressure variability (APV). No microinjected substance affected basal parameters. On the other hand, compared with the control data (saline, 0.3 µL; n=7), OT (10 ng) decreased mean AP (MAP{sub 50}) after baroreflex stimulation and increased both the mean AP response after chemoreflex activation and the high-frequency component of the HRV. OT (25 pg) increased overall HRV but did not affect any parameter of the symbolic analysis. SST (1 μM) decreased MAP{sub 50}, and SST (0.05 μM) enhanced the sympathovagal cardiac index. Both doses of SST increased HRV and its low-frequency component. Ang II (50 pmol) increased HRV and reduced the two unlike variations pattern of the symbolic analysis (P<0.05 in all cases). These results demonstrate neuropeptidergic actions in the MePD for both the increase in the range of the cardiovascular reflex responses and the involvement of the central sympathetic and parasympathetic systems on HRV and APV.

  12. GLUCOSE AND LACTATE METABOLISM IN THE AWAKE AND STIMULATED RAT: A 13C-NMR STUDY.

    Directory of Open Access Journals (Sweden)

    Denys eSampol

    2013-05-01

    Full Text Available Glucose is the major energetic substrate for the brain but evidence has accumulated during the last 20 years that lactate produced by astrocytes could be an additional substrate for neurons. However, little information exists about this lactate shuttle in vivo in activated and awake animals. We designed an experiment in which the cortical barrel field (S1BF was unilaterally activated during infusion of both glucose and lactate (alternatively labeled with 13C in rats. At the end of stimulation (1h, both S1BF areas were removed and analyzed by HR-MAS NMR spectroscopy to compare glucose and lactate metabolism in the activated area versus the non-activated one. In combination with microwave irradiation, HR-MAS spectroscopy is a powerful technical approach to study brain lactate metabolism in vivo.Using in vivo 14C-2-deoxyglucose and autoradiography, we confirmed that whisker stimulation was effective since we observed a 40% increase in glucose uptake in the activated S1BF area compared to the ipsilateral one.We first determined that lactate observed on spectra of biopsies did not arise from post-mortem metabolism. 1H-NMR data indicated that during brain activation, there was an average 2.4-fold increase in lactate content in the activated area. When [1-13C]glucose+lactate were infused, 13C-NMR data showed an increase in 13C-labeled lactate during brain activation, as well as an increase in lactate C3-specific enrichment. This result demonstrates that the increase in lactate observed on 1H-NMR spectra originates from newly synthesized lactate from the labeled precursor ([1-13C]glucose. It also shows that this additional lactate does not arise from an increase in blood lactate uptake since it would otherwise be unlabeled. These results are in favor of intracerebral lactate production during brain activation in vivo, which could be a supplementary fuel for neurons.

  13. Role of insulin and insulin receptor in learning and memory.

    Science.gov (United States)

    Zhao, W Q; Alkon, D L

    2001-05-25

    As one of the most extensively studied protein hormones, insulin and its receptor have been known to play key roles in a variety of important biological functions. Until recent years, the functions of insulin and insulin receptor (IR) in the central nervous system (CNS) have largely remained unclear. IR is abundantly expressed in several specific brain regions that govern fundamental behaviors such as food intake, reproduction and high cognition. The IR from the periphery and CNS exhibit differences in both structure and function. In addition to that from the peripheral system, locally synthesized insulin in the brain has also been identified. Accumulated evidence has demonstrated that insulin/IR plays important roles in associative learning, as suggested by results from both interventive and correlative studies. Interruption of insulin production and IR activity causes deficits in learning and memory formation. Abnormal insulin/IR levels and activities are seen in Alzheimer's dementia, whereas administration of insulin significantly improves the cognitive performance of these patients. The synaptic bases for the action of insulin/IR include modifying neurotransmitter release processes at various types of presynaptic terminals and modulating the activities of both excitatory and inhibitory postsynaptic receptors such as NMDA and GABA receptors, respectively. At the molecular level, insulin/IR participates in regulation of learning and memory via activation of specific signaling pathways, one of which is shown to be associated with the formation of long-term memory and is composed of intracellular molecules including the shc, Grb-r/SOS, Ras/Raf, and MEK/MAP kinases. Cross-talk with another IR pathway involving IRS1, PI3 kinase, and protein kinase C, as well as with the non-receptor tyrosine kinase pp60c-src, may also be associated with memory processing.

  14. Insulin Signaling and Heart Failure.

    Science.gov (United States)

    Riehle, Christian; Abel, E Dale

    2016-04-01

    Heart failure is associated with generalized insulin resistance. Moreover, insulin-resistant states such as type 2 diabetes mellitus and obesity increases the risk of heart failure even after adjusting for traditional risk factors. Insulin resistance or type 2 diabetes mellitus alters the systemic and neurohumoral milieu, leading to changes in metabolism and signaling pathways in the heart that may contribute to myocardial dysfunction. In addition, changes in insulin signaling within cardiomyocytes develop in the failing heart. The changes range from activation of proximal insulin signaling pathways that may contribute to adverse left ventricular remodeling and mitochondrial dysfunction to repression of distal elements of insulin signaling pathways such as forkhead box O transcriptional signaling or glucose transport, which may also impair cardiac metabolism, structure, and function. This article will review the complexities of insulin signaling within the myocardium and ways in which these pathways are altered in heart failure or in conditions associated with generalized insulin resistance. The implications of these changes for therapeutic approaches to treating or preventing heart failure will be discussed.

  15. [Local lipohypertrophy in insulin treatment].

    Science.gov (United States)

    Herold, D A; Albrecht, G

    1993-01-01

    Local lipoatrophy and lipohypertrophy at injection sites are well known side effects of treatment with insulin. Conditions favouring these local complications are created when repeated or continuous injections are given into the same areas. We report on a 27-year-old female patient who suffered from persistent local swellings after use of an external pump which continuously injected human insulin via indwelling cannulas.

  16. Laksekalcitonin ved osteoporose. Effekten af intranasal applikation på knoglemineralindhold og frakturhyppighed hos postmenopausale kvinder med manifeste osteoporotiske forandringer

    DEFF Research Database (Denmark)

    Ravn, Pernille

    1993-01-01

    The objective was to study the dose-related response of intranasal salmon calcitonin (Salcatonin) on bone mass and bone turnover and the effect of salcatonin on rates of fracture in elderly women with moderate osteoporosis. A total of 208 healthy women aged 68-72 years, who had a bone mineral...

  17. A common oxytocin receptor gene (OXTR) polymorphism modulates intranasal oxytocin effects on the neural response to social cooperation in humans.

    Science.gov (United States)

    Feng, C; Lori, A; Waldman, I D; Binder, E B; Haroon, E; Rilling, J K

    2015-09-01

    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 functional magnetic resonance imaging 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.

  18. Intranasal pyrrolidine dithiocarbamate decreases brain inflammatory mediators and provides neuroprotection after brain hypoxia-ischemia in neonatal rats.

    Science.gov (United States)

    Wang, Zhi; Zhao, Huijuan; Peng, Shuling; Zuo, Zhiyi

    2013-11-01

    Brain injury due to birth asphyxia is the major cause of death and long-term disabilities in newborns. We determined whether intranasal pyrrolidine dithiocarbamate (PDTC) could provide neuroprotection in neonatal rats after brain hypoxia-ischemia (HI). Seven-day old male and female Sprague-Dawley rats were subjected to brain HI. They were then treated with intranasal PDTC. Neurological outcomes were evaluated 7 or 30 days after the brain HI. Brain tissues were harvested 6 or 24 h after the brain HI for biochemical analysis. Here, PDTC dose-dependently reduced brain HI-induced brain tissue loss with an effective dose (ED)50 at 27 mg/kg. PDTC needed to be applied within 45 min after the brain HI for this neuroprotection. This treatment reduced brain tissue loss and improved neurological and cognitive functions assessed 30 days after the HI. PDTC attenuated brain HI-induced lipid oxidative stress, nuclear translocation of nuclear factor κ-light-chain-enhancer of activated B cells, and various inflammatory mediators in the brain tissues. Inhibition of inducible nitric oxide synthase after brain HI reduced brain tissue loss. Our results suggest that intranasal PDTC provides neuroprotection possibly via reducing inflammation and oxidative stress. Intranasal PDTC may have a potential to provide neuroprotection to human neonates after birth asphyxia.

  19. Acute and repeated intranasal oxytocin administration exerts anti-aggressive and pro-affiliative effects in male rats

    NARCIS (Netherlands)

    Calcagnoli, Federica; Kreutzmann, Judith C.; de Boer, Sietse F.; Althaus, Monika; Koolhaas, Jaap M.

    2015-01-01

    Socio-emotional deficits and impulsive/aggressive outbursts are prevalent symptoms of many neuropsychiatric disorders, and intranasal administration of oxytocin (OXT) is emerging as a putative novel therapeutic approach to curb these problems. Recently, we demonstrated potent anti-aggressive and pro

  20. Systemic and direct nose-to-brain transport pharmacokinetic model for remoxipride after intravenous and intranasal administration

    NARCIS (Netherlands)

    Stevens, Jasper; Ploeger, Bart A; van der Graaf, Piet H; Danhof, Meindert; de Lange, Elizabeth C M

    2011-01-01

    Intranasal (IN) administration could be an attractive mode of delivery for drugs targeting the central nervous system, potentially providing a high bioavailability because of avoidance of a hepatic first-pass effect and rapid onset of action. However, controversy remains whether a direct transport r

  1. A prospective randomised double-blinded study of intranasal midazolam atomizer spray for procedural sedation in paediatric patients

    Directory of Open Access Journals (Sweden)

    Vijaykumara

    2016-09-01

    Conclusions: We can thereby say that administration of preservative free intranasal midazolam atomizer spray in dose of 0.2mg/kg as premedication in paediatric patients produces satisfactory level of sedation and anxiolysis with minimal adverse effects. [Int J Res Med Sci 2016; 4(9.000: 3850-3854

  2. Intranasal Immunization with Chitosan/pCAGGS-flaA Nanoparticles Inhibits Campylobacter jejuni in a White Leghorn Model

    Directory of Open Access Journals (Sweden)

    Jin-lin Huang

    2010-01-01

    Full Text Available Campylobacter jejuni is the most common zoonotic bacterium associated with human diarrhea, and chickens are considered to be one of the most important sources for human infection, with no effective prophylactic treatment available. We describe here a prophylactic strategy using chitosan-DNA intranasal immunization to induce specific immune responses. The chitosan used for intranasal administration is a natural mucus absorption enhancer, which results in transgenic DNA expression in chicken nasopharynx. Chickens immunized with chitosan-DNA nanoparticles, which carried a gene for the major structural protein FlaA, produced significantly increased levels of serum anti-Campylobacter jejuni IgG and intestinal mucosal antibody (IgA, compared to those treated with chitosan-DNA (pCAGGS. Chitosan-pCAGGS-flaA intranasal immunization induced reductions of bacterial expellation by 2-3 log10 and 2 log10 in large intestine and cecum of chickens, respectively, when administered with the isolated C. jejuni strain. This study demonstrated that intranasal delivery of chitosan-DNA vaccine successfully induced effective immune response and might be a promising vaccine candidate against C. jejuni infection.

  3. Immune Responses of Dairy Cattle to Parainfluenza-3 Virus in Intranasal Infectious Bovine Rhinotracheitis-Parainfluenza-3 Virus Vaccines

    OpenAIRE

    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.

  4. Formulation and evaluation of microemulsion-based in situ ion-sensitive gelling systems for intranasal administration of curcumin.

    Science.gov (United States)

    Wang, Shuang; Chen, Ping; Zhang, Lin; Yang, Chunfen; Zhai, Guangxi

    2012-12-01

    The purpose of our study was to develop a microemulsion-based in situ ion-sensitive gelling system for intranasal administration of curcumin. A new microemulsion composition for curcumin was optimized with the simple lattice design. And the microemulsion-based in situ ion-sensitive gelling system consisted of Capryol 90 as oil phase, Solutol HS15 as surfactant, Transcutol HP as cosurfactant and 0.3% DGG solution as water phase. The physicochemical properties such as morphology, droplet size distribution, zeta value and the in vitro release were investigated. In addition, the histological section studies on the reaction between the obtained formulation and nasal mucosa showed that the microemulsion-based in situ ion-sensitive gelling system could not produce obvious damage to nasal mucosa. The pharmacokinetics results showed that the absolute bioavailability of curcumin in the microemulsion-based in situ ion-sensitive gelling system was 55.82% by intranasal administration. And the brain targeting index (BTI) was 6.50, and in the tissue distribution experiment, the value of (AUC(brain)/AUC(blood)) following intranasal administration was higher than that following intravenous administration, suggesting that the obvious brain targeting property by nasal delivery be attributed to a direct nose-to-brain drug transport. It can be concluded that the microemulsion-based in situ gelling as an effective and safe vehicle could greatly enhance the in vivo absorption and facilitate the delivery of curcumin to brain by intranasal administration.

  5. Intranasal Vaccination Affords Localization and Persistence of Antigen-Specific CD8+ T Lymphocytes in the Female Reproductive Tract

    Directory of Open Access Journals (Sweden)

    Shailbala Singh

    2016-03-01

    Full Text Available 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.

  6. Intranasal BMP9 Ameliorates Alzheimer Disease-Like Pathology and Cognitive Deficits in APP/PS1 Transgenic Mice

    Science.gov (United States)

    Wang, Zigao; Xiong, Lu; Wan, Wenbin; Duan, Lijie; Bai, Xiaojing; Zu, Hengbing

    2017-01-01

    Alzheimer’s disease (AD) is the most common type of dementia and has no effective therapies. Previous studies showed that bone morphogenetic protein 9 (BMP9), an important factor in the differentiation and phenotype maintenance of cholinergic neurons, ameliorated the cholinergic defects resulting from amyloid deposition. These findings suggest that BMP9 has potential as a therapeutic agent for AD. However, the effects of BMP9 on cognitive function in AD and its underlying mechanisms remain elusive. In the present study, BMP9 was delivered intranasally to 7-month-old APP/PS1 mice for 4 weeks. Our data showed that intranasal BMP9 administration significantly improved the spatial and associative learning and memory of APP/PS1 mice. We also found that intranasal BMP9 administration significantly reduced the amyloid β (Aβ) plaques overall, inhibited tau hyperphosphorylation, and suppressed neuroinflammation in the transgenic mouse brain. Furthermore, intranasal BMP9 administration significantly promoted the expression of low-density lipoprotein receptor-related protein 1 (LRP1), an important membrane receptor involved in the clearance of amyloid β via the blood-brain barrier (BBB), and elevated the phosphorylation levels of glycogen synthase kinase-3β (Ser9), which is considered the main kinase involved in tau hyperphosphorylation. Our results suggest that BMP9 may be a promising candidate for treating AD by targeting multiple key pathways in the disease pathogenesis. PMID:28228716

  7. Abnormal nocturnal blood pressure fall in normotensive adolescents with insulin-dependent diabetes is ameliorated following glycemic improvement

    Directory of Open Access Journals (Sweden)

    S.R.G. Ferreira

    1998-04-01

    Full Text Available Lack of the physiological nocturnal fall in blood pressure (BP has been found in diabetics and it seems to be related to the presence of diabetic complications. The present study examined the changes in the nocturnal BP pattern of 8 normotensive insulin-dependent diabetic adolescents without nephropathy following improvement in glycemic control induced by an 8-day program of adequate diet and exercise. The same number of age- and sex-matched control subjects were studied. During the first and eighth nights of the program, BP was obtained by ambulatory BP monitoring. After a 10-min rest, 3 BP and heart rate (HR recordings were taken and the mean values were considered to represent their awake values. The monitor was programmed to cuff insufflation every 20 min from 10:00 p.m. to 7:00 a.m. The glycemic control of diabetics improved since glycemia (212.0 ± 91.5 to 140.2 ± 69.1 mg/dl, P<0.03, urine glucose (12.7 ± 11.8 to 8.6 ± 6.4 g/24 h, P = 0.08 and insulin dose (31.1 ± 7.7 to 16.1 ± 9.7 U/day, P<0.01 were reduced on the last day. The mean BP of control subjects markedly decreased during the sleeping hours of night 1 (92.3 ± 6.4 to 78.1 ± 5.0 mmHg, P<0.001 and night 8 (87.3 ± 6.7 to 76.9 ± 3.6 mmHg, P<0.001. Diabetic patients showed a slight decrease in mean BP during the first night. However, the fall in BP during the nocturnal period increased significantly on the eighth night. The average awake-sleep BP variation was significantly higher at the end of the study (4.2 vs 10.3%, P<0.05 and this ratio turned out to be similar to that found in the control group (10.3 vs 16.3%. HR variation also increased on the eighth night in the diabetics. Following the metabolic improvement obtained at the end of the period, the nocturnal BP variation of diabetics was close to the normal pattern. We suggest that amelioration of glycemic control may influence the awake-sleep BP and HR differences. This effect may be due at least in part to an attenuated

  8. Abnormal insulin levels and vertigo.

    Science.gov (United States)

    Proctor, C A

    1981-10-01

    Fifty patients with unexplained vertigo (36) or lightheadedness (14) are evaluated, all of whom had abnormal ENGs and normal audiograms. Five hour insulin glucose tolerance tests were performance on all patients, with insulin levels being obtained fasting and at one-half, one, two, and three hours. The results of this investigation were remarkable. Borderline or abnormal insulin levels were discovered in 82% of patients; 90% were found to have either an abnormal glucose tolerance test or at least borderline insulin levels. The response to treatment in these dizzy patients was also startling, with appropriate low carbohydrate diets improving the patient's symptoms in 90% of cases. It is, therefore, apparent that the earliest identification of carbohydrate imbalance with an insulin glucose tolerance test is extremely important in the work-up of the dizzy patients.

  9. Brain delivery of valproic acid via intranasal administration of nanostructured lipid carriers: in vivo pharmacodynamic studies using rat electroshock model

    Directory of Open Access Journals (Sweden)

    Sharareh Eskandari

    2011-02-01

    Full Text Available Sharareh Eskandari1, Jaleh Varshosaz1, Mohsen Minaiyan2, Majid Tabbakhian11Department of Pharmaceutics, 2Department of Pharmacology, School of Pharmacy and Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, IranAbstract: The treatment of brain disorders is one of the greatest challenges in drug delivery because of a variety of main barriers in effective drug transport and maintaining therapeutic concentrations in the brain for a prolonged period. The objective of this study was delivery of valproic acid (VPA to the brain by intranasal route. For this purpose, nanostructured lipid carriers (NLCs were prepared by solvent diffusion method followed by ultrasonication and characterized for size, zeta potential, drug-loading percentage, and release. Six groups of rats each containing six animals received drug-loaded NLCs intraperitoneally (IP or intranasally. Brain responses were then examined by using maximal electroshock (MES. The hind limb tonic extension:flexion inhibition ratio was measured at 15-, 30-, 60-, 90-, and 120-minute intervals. The drug concentration was also measured in plasma and brain at the most protective point using gas chromatography method. The particle size of NLCs was 154 ± 16 nm with drug-loading percentage of 47% ± 0.8% and drug release of 75% ± 1.9% after 21 days. In vivo results showed that there was a significant difference between protective effects of NLCs of VPA and control group 15, 30, 60, and 90 minutes after treatment via intranasal route (P < 0.05. Similar protective effect was observed in rats treated with NLCs of VPA in intranasal route and positive control in IP route (P > 0.05. Results of drug determination in brain and plasma showed that brain:plasma concentration ratio was much higher after intranasal administration of NLCs of VPA than the positive control group (IP route. In conclusion, intranasal administration of NLCs of VPA provided a better protection

  10. Influenza A Virus Challenge Models in Cynomolgus Macaques Using the Authentic Inhaled Aerosol and Intra-Nasal Routes of Infection.

    Directory of Open Access Journals (Sweden)

    Anthony C Marriott

    Full Text Available Non-human primates are the animals closest to humans for use in influenza A virus challenge studies, in terms of their phylogenetic relatedness, physiology and immune systems. Previous studies have shown that cynomolgus macaques (Macaca fascicularis are permissive for infection with H1N1pdm influenza virus. These studies have typically used combined challenge routes, with the majority being intra-tracheal delivery, and high doses of virus (> 107 infectious units. This paper describes the outcome of novel challenge routes (inhaled aerosol, intra-nasal instillation and low to moderate doses (103 to 106 plaque forming units of H1N1pdm virus in cynomolgus macaques. Evidence of virus replication and sero-conversion were detected in all four challenge groups, although the disease was sub-clinical. Intra-nasal challenge led to an infection confined to the nasal cavity. A low dose (103 plaque forming units did not lead to detectable infectious virus shedding, but a 1000-fold higher dose led to virus shedding in all intra-nasal challenged animals. In contrast, aerosol and intra-tracheal challenge routes led to infections throughout the respiratory tract, although shedding from the nasal cavity was less reproducible between animals compared to the high-dose intra-nasal challenge group. Intra-tracheal and aerosol challenges induced a transient lymphopaenia, similar to that observed in influenza-infected humans, and greater virus-specific cellular immune responses in the blood were observed in these groups in comparison to the intra-nasal challenge groups. Activation of lung macrophages and innate immune response genes was detected at days 5 to 7 post-challenge. The kinetics of infection, both virological and immunological, were broadly in line with human influenza A virus infections. These more authentic infection models will be valuable in the determination of anti-influenza efficacy of novel entities against less severe (and thus more common influenza

  11. A pilot study assessing the bioavailability and pharmacokinetics of diazepam after intranasal and intravenous administration in healthy volunteers.

    Science.gov (United States)

    Agarwal, Suresh K; Kriel, Robert L; Brundage, Richard C; Ivaturi, Vijay D; Cloyd, James C

    2013-08-01

    Diazepam rectal gel (Diastat(®)) is the only FDA-approved product indicated for acute repetitive seizures. Despite its proven efficacy, most older children and adults object to this route of administration. As a result, many patients do not realize the benefit of a therapy that can improve outcomes and decrease healthcare costs. Intranasal administration of benzodiazepines offers a potential alternative. The primary objective of this study was to compare the bioavailability and pharmacokinetics of two novel intranasal (IN) diazepam (DZP) formulations versus intravenous (IV) administration in healthy volunteers. Twenty-four healthy volunteers were randomized into an open-label, three-way crossover study. 10mg doses of two investigational intranasal DZP formulations (solution, suspension) and a 5mg IV dose of commercially available DZP injectable, USP were given. A two-week washout period separated treatments. Plasma samples for DZP analysis were collected pre-dose and at regular intervals up to 240 h post-dose. DZP concentration-time data were analyzed using a non-compartmental pharmacokinetics approach. Exposure following administration of DZP IN solution (absolute bioavailability - 97%) was greater than the IN suspension (absolute bioavailability - 67%). Mean Cmaxvalues for the suspension and solution formulations were 221 ng/mL and 272 ng/mL, respectively. Median time to maximum concentration (Tmax) was 1h and 1.5h for suspension and solution formulation, respectively. Both investigational intranasal formulations were well tolerated. The results of this pilot study indicate that development of an intranasal diazepam formulation with high bioavailability, reasonable variability, and good tolerability is feasible.

  12. EVALUATION OF EFFICACY OF INTRANASAL MIDAZOLAM SPRA Y FOR PREANAESTHETIC MEDICATION IN PAEDIATRIC PATIENTS

    Directory of Open Access Journals (Sweden)

    Sneha P.

    2013-05-01

    Full Text Available ABSTRACT: BACKGROUND: Preoperative anxiety and long-term behavioural pro blems are inevitable consequences in absence of preoperative sedation in paediatric patients undergoing surgery. An ideal premedicant removes fear and anxi ety in tender minds of children and achieves a calm, sedated child for smooth induction of anaesth esia and rapid recovery in postoperative period. Midazolam is the most commonly used premedicant in children as it satisfies most of the criteria of ideal premedicant but its route of administration i s a debatable issue in anaesthesia practice. AIMS: This study evaluated the efficacy of atomized intra nasal midazolam spray as a painless, user- friendly, needleless system of drug administration for pre-anaesthetic medication in paediatric patients. SETTINGS AND DESIGN: Tertiary hospital, a prospective, randomized, cont rolled, clinical study. METHODS AND MATERIAL: 60 ASA physical status I children of 2-5 years age group, weighing 10-18 kg scheduled for routine surgeries p articipated in the study. Children were randomly assigned to Group M: Received intranasal m idazolam spray in doses of 0.2 mg/kg and Group N: Received normal saline drops (1-2 drops/no stril. Patients were observed in preoperative room for 20 min. Acceptance of drug, response to dr ug administration, sedation scale, separation score, acceptance to mask, recovery score and side effects of drug were noted. STATISTICAL ANALYSIS: Student ‘t’ test, standard error of difference bet ween two means and Chi-square test. p value0.05. 20 min after p remedication 76.66% in group M and 10.00% group N, children showed satisfactory sedation (p<0 .05. 73.33% in group M while 26.66% in group N, children showed acceptable parental separa tion and 86.66% in group M while 23.33% group N, children showed satisfactory acceptance to mask (p<0.05. Transient nasal irritation in the form of rubbing of nose, watering, sneezing and lac rimation was observed in 40% children of

  13. Needle-free insulin drug delivery

    Directory of Open Access Journals (Sweden)

    Patni Preeti

    2006-01-01

    Full Text Available For most patients with type 1 diabetes, the worst part of the disease is to tolerate needle after needle, both for glucose measurement and to deliver insulin. In the last two decades, concept of insulin therapy by multiple-dose injection has undergone a miraculous change. Needle-free insulin delivery appeared to be a wonderful approach, and its allure rested in being comfortable and safe. In today′s era, insulin delivery by alternative route is a topic of current interest in the design of drug delivery system. Major global pharmaceutical companies are showing encouraging progress in their attempts to develop alternative insulin delivery technologies. Many such drug delivery systems have been developed for oral, buccal and nasal route. This review article discusses, in brief, the novel and emerging technologies that are in pipeline, including insulin inhalers, insulin spray, insulin pill, insulin analogues, insulin complement, islet cell transplant, implantable insulin pumps and guardian continuous glucose monitoring system.

  14. Best BETs from the Manchester Royal Infirmary. BET 1: intranasal lorazepam is an acceptable alternative to intravenous lorazepam in the control of acute seizures in children.

    Science.gov (United States)

    Allan, Anna; Cullen, Jayne

    2013-09-01

    A short-cut review was carried out to determine whether intranasal lorazepam was as effective as intravenous lorazepam in the control of seizures in children. Eighteen papers were found using the reported search, of which one was directly relevant and another compared intranasal lorazepam with intramuscular paraldehyde. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses are shown in table 1. It is concluded that intranasal lorazepam appears to be a safe and effective treatment for this condition.

  15. Fasting insulin has a stronger association with an adverse cardiometabolic risk profile than insulin resistance: the RISC study

    DEFF Research Database (Denmark)

    de Rooij, Susanne R; Dekker, Jacqueline M; Kozakova, Michaela;

    2009-01-01

    OBJECTIVE: Fasting insulin concentrations are often used as a surrogate measure of insulin resistance. We investigated the relative contributions of fasting insulin and insulin resistance to cardiometabolic risk and preclinical atherosclerosis. DESIGN AND METHODS: The Relationship between Insulin...

  16. Development of intranasal nanovehicles of itraconazole and their immunological activities for the therapy of rhinovirus infection.

    Science.gov (United States)

    Lee, Jeong-Jun; Shim, Aeri; Jeong, Jae Young; Lee, Song Yi; Ko, Hyun-Jeong; Cho, Hyun-Jong

    2016-07-01

    Itraconazole (ITZ)-loaded microemulsion (ME) systems for intranasal (IN) delivery were developed for the treatment of human rhinovirus serotype 1B (HRV1B) infection. ITZ was incorporated into the oil-in-water (o/w) ME formulation composed of benzyl alcohol (oil), Cremophor EL (surfactant), Solutol HS15 (cosurfactant), and water. The optimized composition of ME was determined by constructing pseudo-ternary phase diagram. ITZ ME formulation with about 150nm mean diameter and spherical shape was prepared and the solubility of ITZ in blank ME was markedly improved (up to 13.9mg/mL). The initial value of droplet size was maintained with four times dilution in the aqueous buffer and 72h incubation. Released amounts of drug from ME formulation were significantly enhanced compared to drug suspension group (prhinovirus infection.

  17. First clinical experience with intranasal cooling for hyperthermia in brain-injured patients

    DEFF Research Database (Denmark)

    Springborg, Jacob Bertram; Springborg, Karoline Kanstrup; Romner, Bertil

    2013-01-01

    Hyperthermia is common in brain-injured patients and associated with a worse outcome. As brain rather than body temperature reduction, theoretically, is the most important in cerebral protection, there is logic in targeting cooling at the brain. Selective brain cooling can, in theory, be obtained...... by cooling the skull or by heat loss from the upper airways. In this preliminary safety and efficacy study, we report clinical data from brain-injured patients who because of hyperthermia were treated with intranasal cooling.......Hyperthermia is common in brain-injured patients and associated with a worse outcome. As brain rather than body temperature reduction, theoretically, is the most important in cerebral protection, there is logic in targeting cooling at the brain. Selective brain cooling can, in theory, be obtained...

  18. Experimentally induced nasal hypersecretion does not reduce the efficacy of intranasal levocabastine

    DEFF Research Database (Denmark)

    Borum, Stefan; Nielsen, K; Bisgaard, H;

    1998-01-01

    In allergic rhinitis, a nasal H1-antihistamine spray seems to be well suited for usage on an as-needed basis, because it has a quick onset of action, and many patients prefer to take medicine only when they have symptoms. It is a prerequisite, however, that nasal hypersecretion during a rhinitis...... episode does not significantly reduce the efficacy of intranasal treatment by washing away the drug before it reaches the H1-histamine receptors. In order to investigate this problem, we have induced nasal hypersecretion with a methacholine challenge in one experiment and in four experiments we have......% (p antihistamine spray. We conclude that experimentally induced nasal hypersecretion does not reduce the efficacy...

  19. Intranasal delivery of nanoparticle-based vaccine increases protection against S. pneumoniae

    Science.gov (United States)

    Mott, Brittney; Thamake, Sanjay; Vishwanatha, Jamboor; Jones, Harlan P.

    2013-05-01

    Nanoparticle (NP) technologies are becoming commonplace in the development of vaccine delivery systems to protect against various diseases. The current study determined the efficacy of intranasal delivery of a 234 ± 87.5 nm poly lactic-co-glycolic acid nanoparticle vaccine construct in establishing protection against experimental respiratory pneumococcal infection. Nanoparticles encapsulating heat-killed Streptococcus pneumoniae (NP-HKSP) were retained in the lungs 11 days following nasal administration compared to empty NP. Immunization with NP-HKSP produced significant resistance against S. pneumoniae infection compared to administration of HKSP alone. Increased protection correlated with a significant increase in antigen-specific Th1-associated IFN-γ cytokine response by pulmonary lymphocytes. This study establishes the efficacy of NP-based technology as a non-invasive and targeted approach for nasal-pulmonary immunization against pulmonary infections.

  20. Antiglomerular basement membrane antibody-mediated glomerulonephritis after intranasal cocaine use.

    Science.gov (United States)

    Peces, R; Navascués, R A; Baltar, J; Seco, M; Alvarez, J

    1999-01-01

    We report a case of rapidly progressive glomerulonephritis due to antiglomerular basement membrane (anti-GBM) antibodies that progressed to end-stage renal disease in a 35-year-old man who used intranasal cocaine on an occasional basis. In contrast to many prior reports of acute renal failure occurring with cocaine-associated rhabdomyolysis, this patient did not have any evidence of acute muscle damage and myoglobin release. Circulating anti-GBM antibodies and renal biopsy with linear IgG and C3 deposits confirmed the diagnosis of anti-GBM disease. The possibility of anti-GBM must be considered in the differential diagnosis of acute renal failure in cocaine addicts. This unusual combination raises complex questions regarding the pathogenesis of this type of renal injury.

  1. Intranasal LPS-mediated Parkinson's model challenges the pathogenesis of nasal cavity and environmental toxins.

    Directory of Open Access Journals (Sweden)

    Qing He

    Full Text Available Accumulating evidence implicates the relationship between neuroinflammation and pathogenesis in idiopathic Parkinson's disease (iPD. The nose has recently been considered a gate way to the brain which facilitates entry of environmental neurotoxin into the brain. Our study aims to build a PD model by a natural exposure route. In this report, we establish a new endotoxin-based PD model in mice by unilateral intranasal (i.n. instillation of the lipopolysaccharides (LPS every other day for 5 months. These mice display a progressive hypokinesia, selective loss of dopaminergic neurons, and reduction in striatal dopamine (DA content, as well as α-synuclein aggregation in the SN, without systemic inflammatory and immune responses. This new PD model provides a tool for studying the inflammation-mediated chronic pathogenesis and searching for therapeutic intervention in glia-neuron pathway that will slow or halt neurodegeneration in PD.

  2. The relationship between temporal discounting and the prisoner's dilemma game in intranasal abusers of prescription opioids.

    Science.gov (United States)

    Yi, Richard; Buchhalter, August R; Gatchalian, Kirstin M; Bickel, Warren K

    2007-02-23

    Previous research on college students has found that cooperation in iterated prisoner's dilemma game is correlated with preference for delayed rewards in studies of temporal discounting. The present study attempted to replicate this finding in a drug-dependent population. Thirty-one individuals who intranasally abuse prescription opioids participated in temporal discounting and iterated prisoner's dilemma game procedures during intake for a treatment study. Rate of temporal discounting was determined for each participant at two hypothetical reward magnitudes, as well as proportion of cooperation in a 60-trial iterated prisoner's dilemma game versus a tit-for-tat strategy. Cooperation in the prisoner's dilemma game and temporal discounting rates were significantly correlated in the predicted direction: individuals who preferred delayed rewards in the temporal discounting task were more likely to cooperate in the prisoner's dilemma game.

  3. Intranasal delivery of nanoparticle-based vaccine increases protection against S. pneumoniae

    Energy Technology Data Exchange (ETDEWEB)

    Mott, Brittney [University of North Texas Health Science Center, Department of Molecular Biology and Immunology (United States); Thamake, Sanjay [Radio-Isotope Therapy of America Foundation (United States); Vishwanatha, Jamboor; Jones, Harlan P., E-mail: harlan.jones@unthsc.edu [University of North Texas Health Science Center, Department of Molecular Biology and Immunology (United States)

    2013-05-15

    Nanoparticle (NP) technologies are becoming commonplace in the development of vaccine delivery systems to protect against various diseases. The current study determined the efficacy of intranasal delivery of a 234 {+-} 87.5 nm poly lactic-co-glycolic acid nanoparticle vaccine construct in establishing protection against experimental respiratory pneumococcal infection. Nanoparticles encapsulating heat-killed Streptococcus pneumoniae (NP-HKSP) were retained in the lungs 11 days following nasal administration compared to empty NP. Immunization with NP-HKSP produced significant resistance against S. pneumoniae infection compared to administration of HKSP alone. Increased protection correlated with a significant increase in antigen-specific Th1-associated IFN-{gamma} cytokine response by pulmonary lymphocytes. This study establishes the efficacy of NP-based technology as a non-invasive and targeted approach for nasal-pulmonary immunization against pulmonary infections.

  4. No laughing matter: intranasal oxytocin administration changes functional brain connectivity during exposure to infant laughter.

    Science.gov (United States)

    Riem, Madelon M E; van IJzendoorn, Marinus H; Tops, Mattie; Boksem, Maarten A S; Rombouts, Serge A R B; Bakermans-Kranenburg, Marian J

    2012-04-01

    Infant laughter is a rewarding experience. It activates neural reward circuits and promotes parental proximity and care, thus facilitating parent-infant attachment. The neuropeptide oxytocin might enhance the incentive salience of infant laughter by modulating neural circuits related to the perception of infant cues. In a randomized controlled trial with functional magnetic resonance imaging we investigated the influence of intranasally administered oxytocin on functional brain connectivity in response to infant laughter. Blood oxygenation level-dependent responses to infant laughter were measured in 22 nulliparous women who were administered oxytocin and 20 nulliparous women who were administered a placebo. Elevated oxytocin levels reduced activation in the amygdala during infant laughter and enhanced functional connectivity between the amygdala and the orbitofrontal cortex, the anterior cingulate, the hippocampus, the precuneus, the supramarginal gyri, and the middle temporal gyrus. Increased functional connectivity between the amygdala and regions involved in emotion regulation may reduce negative emotional arousal while enhancing the incentive salience of the infant laughter.

  5. Metabolic regulation of insulin secretion.

    Science.gov (United States)

    Keane, Kevin; Newsholme, Philip

    2014-01-01

    Regulation of metabolic fuel homeostasis is a critical function of β-cells, which are located in the islets of Langerhans of the animal pancreas. Impairment of this β-cell function is a hallmark of pancreatic β-cell failure and may lead to development of type 2 diabetes mellitus. β-Cells are essentially "fuel sensors" that monitor and react to elevated nutrient load by releasing insulin. This response involves metabolic activation and generation of metabolic coupling factors (MCFs) that relay the nutrient signal throughout the cell and induce insulin biosynthesis and secretion. Glucose is the most important insulin secretagogue as it is the primary fuel source in food. Glucose metabolism is central to generation of MCFs that lead to insulin release, most notably ATP. In addition, other classes of nutrients are able to augment insulin secretion and these include members of the lipid and amino acid family of nutrients. Therefore, it is important to investigate the interplay between glucose, lipid, and amino acid metabolism, as it is this mixed nutrient sensing that generate the MCFs required for insulin exocytosis. The mechanisms by which these nutrients are metabolized to generate MCFs, and how they impact on β-cell insulin release and function, are discussed in detail in this article.

  6. Neural mechanisms of interstimulus interval-dependent responses in the primary auditory cortex of awake cats

    Directory of Open Access Journals (Sweden)

    Qin Ling

    2009-02-01

    Full Text Available Abstract Background Primary auditory cortex (AI neurons show qualitatively distinct response features to successive acoustic signals depending on the inter-stimulus intervals (ISI. Such ISI-dependent AI responses are believed to underlie, at least partially, categorical perception of click trains (elemental vs. fused quality and stop consonant-vowel syllables (eg.,/da/-/ta/continuum. Methods Single unit recordings were conducted on 116 AI neurons in awake cats. Rectangular clicks were presented either alone (single click paradigm or in a train fashion with variable ISI (2–480 ms (click-train paradigm. Response features of AI neurons were quantified as a function of ISI: one measure was related to the degree of stimulus locking (temporal modulation transfer function [tMTF] and another measure was based on firing rate (rate modulation transfer function [rMTF]. An additional modeling study was performed to gain insight into neurophysiological bases of the observed responses. Results In the click-train paradigm, the majority of the AI neurons ("synchronization type"; n = 72 showed stimulus-locking responses at long ISIs. The shorter cutoff ISI for stimulus-locking responses was on average ~30 ms and was level tolerant in accordance with the perceptual boundary of click trains and of consonant-vowel syllables. The shape of tMTF of those neurons was either band-pass or low-pass. The single click paradigm revealed, at maximum, four response periods in the following order: 1st excitation, 1st suppression, 2nd excitation then 2nd suppression. The 1st excitation and 1st suppression was found exclusively in the synchronization type, implying that the temporal interplay between excitation and suppression underlies stimulus-locking responses. Among these neurons, those showing the 2nd suppression had band-pass tMTF whereas those with low-pass tMTF never showed the 2nd suppression, implying that tMTF shape is mediated through the 2nd suppression. The

  7. Evaluation of subcutaneous versus mucosal (intranasal) allergen-specific rush immunotherapy in experimental feline asthma.

    Science.gov (United States)

    Lee-Fowler, Tekla M; Cohn, Leah A; DeClue, Amy E; Spinka, Christine M; Reinero, Carol R

    2009-05-15

    Rush immunotherapy (RIT) is effective for the treatment of experimental feline allergic asthma. In humans, the safety profile of immunotherapy is improved by delivering allergen by a mucosal route. We hypothesized that mucosal (intranasal) RIT would have similar efficacy to subcutaneous RIT with improved safety. Twelve cats sensitized and challenged with Bermuda grass allergen (BGA) were randomized to receive subcutaneous (SC) or intranasal (IN) RIT. Increasing doses of BGA (20-200 microg) were administered over 24h followed by 200 microg BGA weekly as maintenance. Adverse reactions were recorded. Clinical respiratory scores after BGA aerosol challenge, bronchoalveolar lavage fluid (BALF) % eosinophils, and cytokine concentrations were measured before RIT (day 1) and at months 1, 3 and 6 (M1, M3, M6). More adverse events were recorded with SC RIT (n=12) compared with IN RIT (n=6). Respiratory scores were lower by M6 compared with D1 in both the groups. The % BALF eosinophils declined significantly after RIT for both groups (mean+/-SEM, SC RIT D1 62+/-12, M6 9+/-4; IN RIT D1 54+/-9, M6 14+/-6). The BALF IL-4:IFN-gamma ratio significantly decreased over time in the IN RIT group (mean+/-SEM, D1 2.4+/-0.2, M6 1.0+/-0.2). While both protocols decreased eosinophilic airway inflammation, the SC RIT protocol did not cause life-threatening adverse events and demonstrated more consistent resolution of clinical signs after allergen challenge. Either protocol could be considered for the treatment of feline allergic asthma.

  8. Evaluation of Intranasal Midazolam as an Anesthetic Premedication in Preschool Children

    Directory of Open Access Journals (Sweden)

    Sh Behdad

    2005-10-01

    Full Text Available Introduction: Preoperative psycho emotional preparation of patients is one of the principle purposes of anesthesia which can be achieved by administration of premedications. Children should receive premedication before entering the operating room due to their dependence on parents and the fear and anxiety of separation from parents. Different drugs are administered for this purpose, but considering children's sensitivity, it is wise to use the most effective and comfortable medication with least side effects. Midazolam is a rapid onset, short acting and water soluble benzodiazapine which can be administered by oral, intravenous, intramuscular, rectal or intranasal routes. The purpose of this study was to evaluate the result of intranasal midazolam administration (0.2 mg/kg as a premedication in children aged 2-6 years.( Min dose and enough time Methods: In this randomized prospective study, 100 children aged between 2-6 years old in class ASA 1 and candidates of surgery were divided into two groups; case and control. The control group received several nasal drops of normal saline, while the case group received 0.2 mg/kg nasal midazolam 20 minutes before anesthesia induction. Results: Twenty minutes after administration of the nasal drops, 14% in the control group and 68% in the case group were alert and calm. (P value=0.0 . Mask acceptance during induction of anesthesia in control and case group was 14%and 72%, respectively (P value >0.00 The recovery time in the case group was longer (P value >0.5, but no complications (nausea, vomiting, respiratory and cardiovascular problems were seen in either group. Conclusion: Nasal midazolam with its anxiolytic, tranquilizing effects and no respiratory or cardiovascular complications is a safe drug and being better than parenteral drugs is acceptable by children.

  9. Protection of inactive intranasal ántrax vaccine to Bacillus anthracis infection

    Directory of Open Access Journals (Sweden)

    Adin Priadi

    2010-06-01

    Full Text Available Ánthrax is an endemic zoonotic disease distributed in many parts of Indonesia. Although vaccination program has been implemented in many areas, cases are still frequently reported. Farmers are reluctant to vaccinate their livestock since spore vaccine used in the field often cause side effects and death of the animals. To overcome this problem, an inactive vaccine composes of Bacillus anthracis toxins, cell wall and capsule subunits was developed. B. anthracis Sterne strain (34F2 was selected to produce toxins and cell walls. Local Bacillus anthracis isolated from Citaringgul was used to produce capsule as the Polymerase Chain Reaction (PCR revealed that this isolate poses cap gene encoding for capsule. Two vaccines compose of 15 μg toxoid, 30 μg of capsule, 15 μg of cell wall and 30 μg toxoid, 60 μg of capsule, 15 μg of cell walls were designated as vaccine I and vaccine II respectively. For each experiment, 10 mice were nasally immunized by placing 5 μl of vaccine into each nare 3 times at 2-week intervals. A group of 10 mice were unvaccinated and used as control. Blood was collected fortnightly to monitor antibody responses. All mice were challenged with 2 x 105 B. anthracis Sterne spores injected subcutaneously two weeks after the last vaccination. Two weeks after vaccination of antibodies to B. anthracis toxin, capsule and cell wall were detected in dot-blot assay. Mice that were immunised intranasally with chitosan adjuvanted vaccine developed high IgG responses in sera as detected by ELISA, and the response was dose dependent. Vaccine II gave better response than vaccine I. Vaccine I and II protected mice from challenge at a rate of 60 and 80% respectively. This results showed that intranasal B. anthracis vaccine composes of toxin, capsule and cell wall with chitosan as an adjuvant gave a good protection against B. anthracis Sterne spores challenge in mice.

  10. Formulation and evaluation of in situ gelling systems for intranasal administration of gastrodin.

    Science.gov (United States)

    Cai, Zheng; Song, Xiangrong; Sun, Feng; Yang, Zhaoxiang; Hou, Shixiang; Liu, Zhongqiu

    2011-12-01

    Gastrodin is the major bioactive constituent of the traditional Chinese drug "Tianma." It is used in the treatment of some nervous system diseases and can be transported to the brain via intranasal administration. In the current paper, the development of a novel ion-activated in situ gelling system for the nasal delivery of gastrodin is discussed. An in situ perfusion model was used to determine the absorption-rate constant of gastrodin through rat nasal mucosa. The optimal formulation was determined by measuring the critical cation concentration, anti-dilution capacity, gel expansion coefficient, water-holding capacity, and adhesive capacity. The best formulation consisted of 10% gastrodin, 0.5% deacetylated gellan gum as the gelatinizer, and 0.03% ethylparaben as the preservative. The rheological properties of gastrodin nasal in situ gels were also investigated. The viscosity and elasticity sharply increased at temperatures below 25°C. When physiological concentrations of cations were added into the preparation, the mixture gelled into a semi-solid. The results of an accelerated stability test show that gastrodin nasal in situ gels can be stable for more than 2 years. Mucociliary toxicity was evaluated using the in situ toad palate model and the rat nasal mucociliary method; both models demonstrated no measurable ciliotoxicity. Pharmacodynamic studies suggest that similar acesodyne and sedative effects were induced following intranasal administration of 50 mg/kg gastrodin nasal in situ gels or oral administration of 100 mg/kg gastrodin solution. The in situ gel preparation is a safe and effective nasal delivery system for gastrodin.

  11. Comparison of Preanesthetic Sedation after Intranasal Administration of Fentanyle, Ketamin and Midazolam

    Directory of Open Access Journals (Sweden)

    F Javaherforoosh

    2006-07-01

    Full Text Available Introduction & Objective: Induction of anesthesia in children can be a challenge for anesthetist. A stormy induction may increase the personality & behavioral changes. Therefore, it is desirable that they enter the operating room sedated. Many drugs are used for preanesthetic medication and there are many routes for administration. One route of administration is nasal mucous. In this study we compared the effect and side effect of three drugs (midazolam, ketamin and fentanyle after intra nasal administration. Materials & Methods: This is a double blind clinical trial. In this study we selected 60 patients (20 patients for every group A, B or C. We used 3 mg/kg ketamin or 3µg/kg fentanyle or 0.3 mg/kg midazolam by intranasal spray. After administration and in 5, 10 and 15 minutes, we observed the SPO2, PR and RR. After 15 min’s we separated children from parents and brought them to the operating room and controlled the acceptance of separation, depth of sedation with Ramsay score, acceptance of mask and tolerance of IV canulation. The data were then analyzed using K2 and kruskal-wallis test. Results: In our study we found that in SPO2 fentanyle had the highest rate of reduction even though none of the children had SPO2 lower than 90%. There were no differences between drugs in RR. In fentanyle group, we had the lowest rate and in ketamin group the highest rate. Midazolam had the medium rate. The rate of sedation for acceptance of separation from parents had no difference between the groups and all drugs with this dosage were effective for this aim. However, in Ramsay score, acceptance of mask and tolerance of IV canulation, the midazolam was more effective than the others. Conclusion: Intranasal administration of midazolam is a safe route for sedation in children in the pre-anesthetic time.

  12. A new brain drug delivery strategy: focused ultrasound-enhanced intranasal drug delivery.

    Directory of Open Access Journals (Sweden)

    Hong Chen

    Full Text Available Central nervous system (CNS diseases are difficult to treat because of the blood-brain barrier (BBB, which prevents most drugs from entering into the brain. Intranasal (i.n. administration is a promising approach for drug delivery to the brain, bypassing the BBB; however, its application has been restricted to particularly potent substances and it does not offer localized delivery to specific brain sites. Focused ultrasound (FUS in combination with microbubbles can deliver drugs to the brain at targeted locations. The present study proposed to combine these two different platform techniques (FUS+i.n. for enhancing the delivery efficiency of intranasally administered drugs at a targeted location. After i.n. administration of 40 kDa fluorescently-labeled dextran as the model drug, FUS targeted at one region within the caudate putamen of mouse brains was applied in the presence of systemically administered microbubbles. To compare with the conventional FUS technique, in which intravenous (i.v. drug injection is employed, FUS was also applied after i.v. injection of the same amount of dextran in another group of mice. Dextran delivery outcomes were evaluated using fluorescence imaging of brain slices. The results showed that FUS+i.n. enhanced drug delivery within the targeted region compared with that achieved by i.n. only. Despite the fact that the i.n. route has limited drug absorption across the nasal mucosa, the delivery efficiency of FUS+i.n. was not significantly different from that of FUS+i.v.. As a new drug delivery platform, the FUS+i.n. technique is potentially useful for treating CNS diseases.

  13. Pharmacokinetics of Intranasal Scopolamine Gel Formulation During Antiorthostatic Bed Rest, a Microgravity Analog

    Science.gov (United States)

    Singh, Rajendra P.; Daniels, Vernie R.; Crady, Camille J.; Derendorf, H.; Putcha, L.

    2011-01-01

    Statement of Purpose, Innovation or Hypothesis: Space Motion sickness (SMS) is a long-standing problem for astronauts on both short and long duration space flights. Scopolamine (SCOP) is frequently used for the treatment of motion sickness (MS), and is available as 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 in addition to offering rescue and treatment options. An intranasal gel dosage formulation of scopolamine (INSCOP) was developed and pharmacokinetics (PK) and bioavailability were determined in clinical trials with human subjects under IND guidelines.Description of Methods and Materials: The present clinical trial compares PK and bioavailability of INSCOP in 12 normal, healthy subjects (6 male/ 6 female) during ambulation (AMB) and antiorthostaticbed rest (ABR) used as a ground-based microgravity analog. Subjects received 0.2 mg and 0.4 mg doses of INSCOP during AMB and ABR in a 4-way crossover design.Data and Results: 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.Interpretation, Conclusion or Significance: The difference in AUC and Cls at the higher (0.4 mg) but not the lower dose (0.2 mg) during ABR suggests that ABR may affect metabolism and/or clearance of INSCOP at higher doses . These results indicate that dosing adjustment may be required for treatment of SMS with INSCOP in space.

  14. Pharmacokinetic evaluation of intranasally administered vinyl polymer-coated lorazepam microparticles in rabbits.

    Science.gov (United States)

    Zhao, Yanjun; Brown, Marc B; Khengar, Rajeshree H; Traynor, Matthew J; Barata, Pedro; Jones, Stuart A

    2012-06-01

    The intranasal (IN) administration of lorazepam is desirable in order to maximize speed of onset and minimise carry-over sedation; however, this benzodiazepine is prone to chemical hydrolysis and poor airway retention, and thus, innovative epithelial presentation is required. The aim of this study was to understand how the in situ self-assembly of a mucoretentive delivery system, formed by the dissolution of vinyl polymer-coated microparticles in the nasal mucosa, would influence lorazepam pharmacokinetics (PK). IN administration of the uncoated lorazepam powder (particle size, 6.7 ± 0.1 μm) generated a biphasic PK profile, which was indicative of sequential intranasal and oral absorption (n = 6; dose, 5 mg/kg). Coating the drug with the vinyl polymer, MP1 (9.9 ± 0.5 μm with 38.8 ± 14.0%, w/w lorazepam) and MP2 (10.7 ± 0.1 μm with 47.0 ± 1.0%, w/w lorazepam), allowed rapid systemic absorption (MP1, T (max) 14.2 ± 4.9 min; MP2, T (max) 9.3 ± 3.8 min) in rabbits and modified the PK profiles in a manner that suggested successful nasal retention. The poly(vinyl pyrrolidone)-rich MP2 system provided the best comparative bioavailability, it prolonged the early-phase nasal drug absorption and minimised drug mucociliary clearance, which correlated well with the intermolecular hydrogen-bond-driven vinyl polymer interactions observed in vitro.

  15. A new brain drug delivery strategy: focused ultrasound-enhanced intranasal drug delivery.

    Science.gov (United States)

    Chen, Hong; Chen, Cherry C; Acosta, Camilo; Wu, Shih-Ying; Sun, Tao; Konofagou, Elisa E

    2014-01-01

    Central nervous system (CNS) diseases are difficult to treat because of the blood-brain barrier (BBB), which prevents most drugs from entering into the brain. Intranasal (i.n.) administration is a promising approach for drug delivery to the brain, bypassing the BBB; however, its application has been restricted to particularly potent substances and it does not offer localized delivery to specific brain sites. Focused ultrasound (FUS) in combination with microbubbles can deliver drugs to the brain at targeted locations. The present study proposed to combine these two different platform techniques (FUS+i.n.) for enhancing the delivery efficiency of intranasally administered drugs at a targeted location. After i.n. administration of 40 kDa fluorescently-labeled dextran as the model drug, FUS targeted at one region within the caudate putamen of mouse brains was applied in the presence of systemically administered microbubbles. To compare with the conventional FUS technique, in which intravenous (i.v.) drug injection is employed, FUS was also applied after i.v. injection of the same amount of dextran in another group of mice. Dextran delivery outcomes were evaluated using fluorescence imaging of brain slices. The results showed that FUS+i.n. enhanced drug delivery within the targeted region compared with that achieved by i.n. only. Despite the fact that the i.n. route has limited drug absorption across the nasal mucosa, the delivery efficiency of FUS+i.n. was not significantly different from that of FUS+i.v.. As a new drug delivery platform, the FUS+i.n. technique is potentially useful for treating CNS diseases.

  16. Thermosensitive PLA based nanodispersion for targeting brain tumor via intranasal route

    Energy Technology Data Exchange (ETDEWEB)

    Jain, Darshana S., E-mail: darshanaj_cup@yahoo.com [C.U. Shah College of Pharmacy, S.N.D.T Women' s University, Juhu Tara Road, Santacruz (West), Mumbai 400 049 (India); Bajaj, Amrita N. [C.U. Shah College of Pharmacy, S.N.D.T Women' s University, Juhu Tara Road, Santacruz (West), Mumbai 400 049 (India); Athawale, Rajani B., E-mail: rajani.athawale@gmail.com [C.U. Shah College of Pharmacy, S.N.D.T Women' s University, Juhu Tara Road, Santacruz (West), Mumbai 400 049 (India); Shikhande, Shruti S. [C.U. Shah College of Pharmacy, S.N.D.T Women' s University, Juhu Tara Road, Santacruz (West), Mumbai 400 049 (India); Pandey, Abhijeet [H. R Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra (India); Goel, Peeyush N.; Gude, Rajiv P. [Gude Lab, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410 210 (India); Patil, Satish; Raut, Preeti [Cipla Pvt. Ltd., Vikhroli (West), Mumbai (India)

    2016-06-01

    Delivery of drugs to the brain via nasal route has been studied by many researchers. However, low residence time, mucociliary clearance and enzymatically active environment of nasal cavity pose many challenges to successful nasal delivery of drugs. We aim to deliver methotrexate by designing thermosensitive nanodispersion exhibiting enhanced residence time in nasal cavity and bypassing the blood brain barrier (BBB). PLA nanoparticles were developed using solvent evaporation technique. The developed nanoparticles were further dispersed in prepared thermosensitive vehicle of poloxamer 188 and Carbopol 934 to impart the property of increased residence time. The formulated nanoparticles demonstrated no interaction with the simulated nasal fluids (SNF), mucin, serum proteins and erythrocytes which demonstrate the safety of developed formulation for nasal administration. The penetration property of nanoparticles though the nasal mucosa was higher than the pure drug due to low mucociliary clearance. The developed nanoparticles diffused though the membrane pores and rapidly distributed into the brain portions compared to the pure drug. There was detectable and quantifiable amount of drug seen in the brain as demonstrated by in vivo brain distribution studies with considerably low amount of drug deposition in the lungs. The pharmacokinetic parameters demonstrated the enhancement in circulation half life, area under curve (AUC) and Cmax of the drug when administered intranasal in encapsulated form. Thus, the thermosensitive nanodispersions are surely promising delivery systems for delivering anticancer agents though the nasal route for potential treatment of brain tumors. - Highlights: • The present investigation explores intra-nasal route as potential route for targeting brain tumor. • Thermosensitive nanodispersion has been formulated for enhancing nasal residence time. • PLA nanoparticles enhance penetration into the brain owing to hydrophobic nature and small size

  17. Thiolated chitosan nanoparticles enhance anti-inflammatory effects of intranasally delivered theophylline

    Directory of Open Access Journals (Sweden)

    Mohapatra Shyam S

    2006-08-01

    Full Text Available Abstract Background Chitosan, a polymer derived from chitin, has been used for nasal drug delivery because of its biocompatibility, biodegradability and bioadhesiveness. Theophylline is a drug that reduces the inflammatory effects of allergic asthma but is difficult to administer at an appropriate dosage without causing adverse side effects. It was hypothesized that adsorption of theophylline to chitosan nanoparticles modified by the addition of thiol groups would improve theophylline absorption by the bronchial epithelium and enhance its anti-inflammatory effects. Objectives We sought to develop an improved drug-delivery matrix for theophylline based on thiolated chitosan, and to investigate whether thiolated chitosan nanoparticles (TCNs can enhance theophylline's capacity to alleviate allergic asthma. Methods A mouse model of allergic asthma was used to test the effects of theophylline in vivo. BALB/c mice were sensitized to ovalbumin (OVA and OVA-challenged to produce an inflammatory allergic condition. They were then treated intranasally with theophylline alone, chitosan nanoparticles alone or theophylline adsorbed to TCNs. The effects of theophylline on cellular infiltration in bronchoalveolar lavage (BAL fluid, histopathology of lung sections, and apoptosis of lung cells were investigated to determine the effectiveness of TCNs as a drug-delivery vehicle for theophylline. Results Theophylline alone exerts a moderate anti-inflammatory effect, as evidenced by the decrease in eosinophils in BAL fluid, the reduction of bronchial damage, inhibition of mucus hypersecretion and increased apoptosis of lung cells. The effects of theophylline were significantly enhanced when the drug was delivered by TCNs. Conclusion Intranasal delivery of theophylline complexed with TCNs augmented the anti-inflammatory effects of the drug compared to theophylline administered alone in a mouse model of allergic asthma. The beneficial effects of theophylline in

  18. Alternative routes of insulin delivery.

    Science.gov (United States)

    Krishnankutty, Ranjith K; Mathew, Aju; Sedimbi, Saikiran K; Suryanarayan, Shrikumar; Sanjeevi, Carani B

    2009-10-01

    Parenteral route of insulin administration has been the mode of treatment for all Type 1 diabetics and Type 2 diabetics with complications. Patient compliance has really been a major concern for this route of administration. Several alternative routes of administration are under consideration for effective glycemic control, including oral, inhaled, buccal, nasal, and patch routes. One of the approaches involving inhaled insulin has now reached the market. Several other candidates may reach the market in the near future, the promising one being oral insulin.

  19. Alternative routes of insulin delivery

    Institute of Scientific and Technical Information of China (English)

    Ranjith K. Krishnankutty; Aju Mathew; Saikiran K. Sedimbi; Shrikumar Suryanarayan; Carani B. Sanjeevi

    2009-01-01

    Parenteral route of insulin administration has been the mode of treatment for all Type 1 diabetics and Type 2 diabetics with complications. Patient compliance has really been a major concern for this route of administration. Several alternative routes of administration are under consideration for effective glycemic control, including oral, inhaled, buccal, nasal, and patch routes. One of the approaches involving inhaled insulin has now reached the market. Several other candidates may reach the market in the near future, the promising one being oral insulin.

  20. Additional disulfide bonds in insulin

    DEFF Research Database (Denmark)

    Vinther, Tine N; Pettersson, Ingrid; Huus, Kasper

    2015-01-01

    -chain is flexible and can adapt multiple conformations. We examined how well disulfide bond predictions algorithms could identify disulfide bonds in this region of insulin. In order to identify stable insulin analogues with additional disulfide bonds, which could be expressed, the Cβ cut-off distance had...... in comparison to analogues with additional disulfide bonds that were more difficult to predict. In contrast, addition of the fourth disulfide bond rendered all analogues resistant to fibrillation under stress conditions and all stable analogues bound to the insulin receptor with picomolar affinities. Thus...

  1. Case Report: Emergency awake craniotomy for cerebral abscess in a patient with unrepaired cyanotic congenital heart disease [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Corinne D’Antico

    2016-10-01

    Full Text Available We report the case of a 39-year-old male with complex cyanotic congenital heart disease undergoing emergency craniotomy for a cerebral abscess. Maintenance of intraoperative hemodynamic stability and adequate tissue oxygenation during anesthesia may be challenging in patients with cyanotic congenital heart disease. In this case, we decided to perform the surgery as an awake craniotomy after interdisciplinary consensus. We discuss general aspects of anesthetic management during awake craniotomy and specific concerns in the perioperative care of patients with congenital heart disease.

  2. New ways of insulin delivery.

    Science.gov (United States)

    Heinemann, L

    2010-02-01

    When Exubera (EXU), the first inhaled insulin formulation to make it through the clinical development process, was introduced to the market some years ago it was hoped that this would be the first in a series of novel insulin formulations applied by this route. In addition, it was hoped that inhaled insulin would pave the way for other alternative routes of insulin administration (ARIA), i.e. oral insulin, nasal insulin or transdermal insulin to mention only some of the different attempts that have been studied in the last 90 years. The failure of EXU, i.e. its withdrawal from the market due to insufficient market success, was followed by the cessation of nearly all other attempts to develop inhaled insulin formulations. Currently there is only one company (MannKind) which moves sturdily ahead with their Technosphere insulin. This company has submitted an NDA for their product recently and hopes to bring it to the market by the end of 2010 or early 2011. Even if the product is able to pass the approval hurdles in the USA and Europe, this does not guarantee that it will become a market success. Many diabetologists were sceptical about the need/advantages of inhaled insulin/EXU from the start and the introduction of this product has raised even more scepticism. Reports about 'side effects' (development of lung cancer in patients treated with EXU) of inhaled insulin are also not helpful, even if the causality of the appearance of cancer with this type of insulin therapy is not proven. One of the very negative consequences of stopping EXU are the huge financial losses to Pfizer. The managers in charge in other pharmaceutical companies and also most venture capitalists are reluctant to invest in ARIA nowadays. This in turn means that many of the small companies that try to develop new forms of insulin administration have issues when they try to find a big brother and/or sufficient financial support. Clearly the economic crisis has further aggravated this issue. One can

  3. Continuation versus discontinuation of insulin secretagogues when initiating insulin in type 2 diabetes

    NARCIS (Netherlands)

    S.G. Swinnen; M.P. Dain; D. Mauricio; J.H. Devries; J.B. Hoekstra; F. Holleman

    2010-01-01

    We compared the combined use of basal insulin, metformin and insulin secretagogues with a combination of basal insulin and metformin in patients with type 2 diabetes starting basal insulin analogue therapy. This analysis was part of a 24-week trial, in which 964 insulin-naive patients with type 2 di

  4. Whisking-Related Changes in Neuronal Firing and Membrane Potential Dynamics in the Somatosensory Thalamus of Awake Mice

    Directory of Open Access Journals (Sweden)

    Nadia Urbain

    2015-10-01

    Full Text Available The thalamus transmits sensory information to the neocortex and receives neocortical, subcortical, and neuromodulatory inputs. Despite its obvious importance, surprisingly little is known about thalamic function in awake animals. Here, using intracellular and extracellular recordings in awake head-restrained mice, we investigate membrane potential dynamics and action potential firing in the two major thalamic nuclei related to whisker sensation, the ventral posterior medial nucleus (VPM and the posterior medial group (Pom, which receive distinct inputs from brainstem and neocortex. We find heterogeneous state-dependent dynamics in both nuclei, with an overall increase in action potential firing during active states. Whisking increased putative lemniscal and corticothalamic excitatory inputs onto VPM and Pom neurons, respectively. A subpopulation of VPM cells fired spikes phase-locked to the whisking cycle during free whisking, and these cells may therefore signal whisker position. Our results suggest differential processing of whisking comparing thalamic nuclei at both sub- and supra-threshold levels.

  5. A method for closed-loop presentation of sensory stimuli conditional on the internal brain-state of awake animals.

    Science.gov (United States)

    Rutishauser, Ueli; Kotowicz, Andreas; Laurent, Gilles

    2013-04-30

    Brain activity often consists of interactions between internal-or on-going-and external-or sensory-activity streams, resulting in complex, distributed patterns of neural activity. Investigation of such interactions could benefit from closed-loop experimental protocols in which one stream can be controlled depending on the state of the other. We describe here methods to present rapid and precisely timed visual stimuli to awake animals, conditional on features of the animal's on-going brain state; those features are the presence, power and phase of oscillations in local field potentials (LFP). The system can process up to 64 channels in real time. We quantified its performance using simulations, synthetic data and animal experiments (chronic recordings in the dorsal cortex of awake turtles). The delay from detection of an oscillation to the onset of a visual stimulus on an LCD screen was 47.5ms and visual-stimulus onset could be locked to the phase of ongoing oscillations at any frequency ≤40Hz. Our software's architecture is flexible, allowing on-the-fly modifications by experimenters and the addition of new closed-loop control and analysis components through plugins. The source code of our system "StimOMatic" is available freely as open-source.

  6. Five-Minute Awake Snoring Test for Determining CPAP Pressures (Five-Minute CPAP Test): A Pilot Study

    Science.gov (United States)

    Camacho, Macario; Ruoff, Chad M.; Kawai, Makoto; Modi, Rahul; Arbee, Jabri; Hekmat, Anahid; Robertson, Matthew; Certal, Victor; Capasso, Robson; Kushida, Clete A.

    2016-01-01

    Objective. To develop a quick, simple, bedside test for determining continuous positive airway pressures (CPAP) for obstructive sleep apnea (OSA) patients. Study Design. Prospective case series at a tertiary medical center. Methods. The Five-Minute Awake Snoring Test for Determining CPAP (Five-Minute CPAP Test) was developed and tested. Patients wear a soft-gel nasal triangle mask while holding a tongue depressor with the wide section (1.75 cm) between the teeth. Fixed pressure nasal CPAP is applied while the patient simulates snoring at 4 centimeters of water pressure. The pressure is incrementally titrated up and then down to determine the lowest pressure at which the patient cannot snore (Quiet Pressure). Results. Overall, thirty-eight patients participated. All could simulate snoring. Correlation coefficients were statistically significant between Quiet Pressures and body mass index (rs = 0.60 [strong positive relationship], p = 0.0088), apnea-hypopnea index (rs = 0.49 [moderate positive relationship], p = 0.039), lowest oxygen saturation (rs = −0.47 [moderate negative relationship], p = 0.048), and oxygen desaturation index (rs = 0.62 [strong positive relationship], p = 0.0057). Conclusion. This pilot study introduces a new concept, which is the final product of over one year of exploration, development, and testing. Five-Minute CPAP Test is a quick, inexpensive, and safe bedside test based on supine awake simulated snoring with nasal CPAP. PMID:26881088

  7. Five-Minute Awake Snoring Test for Determining CPAP Pressures (Five-Minute CPAP Test: A Pilot Study

    Directory of Open Access Journals (Sweden)

    Macario Camacho

    2016-01-01

    Full Text Available Objective. To develop a quick, simple, bedside test for determining continuous positive airway pressures (CPAP for obstructive sleep apnea (OSA patients. Study Design. Prospective case series at a tertiary medical center. Methods. The Five-Minute Awake Snoring Test for Determining CPAP (Five-Minute CPAP Test was developed and tested. Patients wear a soft-gel nasal triangle mask while holding a tongue depressor with the wide section (1.75 cm between the teeth. Fixed pressure nasal CPAP is applied while the patient simulates snoring at 4 centimeters of water pressure. The pressure is incrementally titrated up and then down to determine the lowest pressure at which the patient cannot snore (Quiet Pressure. Results. Overall, thirty-eight patients participated. All could simulate snoring. Correlation coefficients were statistically significant between Quiet Pressures and body mass index (rs=0.60 [strong positive relationship], p=0.0088, apnea-hypopnea index (rs=0.49 [moderate positive relationship], p=0.039, lowest oxygen saturation (rs=-0.47 [moderate negative relationship], p=0.048, and oxygen desaturation index (rs=0.62 [strong positive relationship], p=0.0057. Conclusion. This pilot study introduces a new concept, which is the final product of over one year of exploration, development, and testing. Five-Minute CPAP Test is a quick, inexpensive, and safe bedside test based on supine awake simulated snoring with nasal CPAP.

  8. An Experimental Model of Vasovagal Syncope Induces Cerebral Hypoperfusion and Fainting-Like Behavior in Awake Rats

    Science.gov (United States)

    McBride, Devin W.; Reis, Cesar; Frank, Ethan; Klebe, Damon W.; Zhang, John H.; Applegate, Richard

    2016-01-01

    Vasovagal syncope, a contributing factor to elderly falls, is the transient loss of consciousness caused by decreased cerebral perfusion. Vasovagal syncope is characterized by hypotension, bradycardia, and reduced cerebral blood flow, resulting in fatigue, altered coordination, and fainting. The purpose of this study is to develop an animal model which is similar to human vasovagal syncope and establish an awake animal model of vasovagal syncope. Male Sprague-Dawley rats were subjected to sinusoidal galvanic vestibular stimulation (sGVS). Blood pressure, heart rate, and cerebral blood flow were monitored before, during, and post-stimulation. sGVS resulted in hypotension, bradycardia, and decreased cerebral blood flow. One cohort of animals was subjected to sGVS while freely moving. sGVS in awake animals produced vasovagal syncope-like symptoms, including fatigue and uncoordinated movements; two animals experienced spontaneous falling. Another cohort of animals was preconditioned with isoflurane for several days before being subjected to sGVS. Isoflurane preconditioning before sGVS did not prevent sGVS-induced hypotension or bradycardia, yet isoflurane preconditioning attenuated sGVS-induced cerebral blood flow reduction. The sGVS rat model mimics elements of human vasovagal syncope pathophysiology (hypotension, bradycardia, and decreased cerebral perfusion), including behavioral symptoms such as fatigue and altered balance. This study indicates that the sGVS rat model is similar to human vasovagal syncope and that therapies directed at preventing cerebral hypoperfusion may decrease syncopal episodes and reduce injuries from syncopal falls. PMID:27658057

  9. Five-Minute Awake Snoring Test for Determining CPAP Pressures (Five-Minute CPAP Test): A Pilot Study.

    Science.gov (United States)

    Camacho, Macario; Ruoff, Chad M; Kawai, Makoto; Modi, Rahul; Arbee, Jabri; Hekmat, Anahid; Robertson, Matthew; Zaghi, Soroush; Certal, Victor; Capasso, Robson; Kushida, Clete A

    2016-01-01

    Objective. To develop a quick, simple, bedside test for determining continuous positive airway pressures (CPAP) for obstructive sleep apnea (OSA) patients. Study Design. Prospective case series at a tertiary medical center. Methods. The Five-Minute Awake Snoring Test for Determining CPAP (Five-Minute CPAP Test) was developed and tested. Patients wear a soft-gel nasal triangle mask while holding a tongue depressor with the wide section (1.75 cm) between the teeth. Fixed pressure nasal CPAP is applied while the patient simulates snoring at 4 centimeters of water pressure. The pressure is incrementally titrated up and then down to determine the lowest pressure at which the patient cannot snore (Quiet Pressure). Results. Overall, thirty-eight patients participated. All could simulate snoring. Correlation coefficients were statistically significant between Quiet Pressures and body mass index (r s = 0.60 [strong positive relationship], p = 0.0088), apnea-hypopnea index (r s = 0.49 [moderate positive relationship], p = 0.039), lowest oxygen saturation (r s = -0.47 [moderate negative relationship], p = 0.048), and oxygen desaturation index (r s = 0.62 [strong positive relationship], p = 0.0057). Conclusion. This pilot study introduces a new concept, which is the final product of over one year of exploration, development, and testing. Five-Minute CPAP Test is a quick, inexpensive, and safe bedside test based on supine awake simulated snoring with nasal CPAP.

  10. A 4-channel 3 Tesla phased array receive coil for awake rhesus monkey fMRI and diffusion MRI experiments.

    Science.gov (United States)

    Khachaturian, Mark Haig

    2010-01-01

    Awake monkey fMRI and diffusion MRI combined with conventional neuroscience techniques has the potential to study the structural and functional neural network. The majority of monkey fMRI and diffusion MRI experiments are performed with single coils which suffer from severe EPI distortions which limit resolution. By constructing phased array coils for monkey MRI studies, gains in SNR and anatomical accuracy (i.e., reduction of EPI distortions) can be achieved using parallel imaging. The major challenges associated with constructing phased array coils for monkeys are the variation in head size and space constraints. Here, we apply phased array technology to a 4-channel phased array coil capable of improving the resolution and image quality of full brain awake monkey fMRI and diffusion MRI experiments. The phased array coil is that can adapt to different rhesus monkey head sizes (ages 4-8) and fits in the limited space provided by monkey stereotactic equipment and provides SNR gains in primary visual cortex and anatomical accuracy in conjunction with parallel imaging and improves resolution in fMRI experiments by a factor of 2 (1.25 mm to 1.0 mm isotropic) and diffusion MRI experiments by a factor of 4 (1.5 mm to 0.9 mm isotropic).

  11. Study protocol of a randomised controlled trial of intranasal ketamine compared with intranasal fentanyl for analgesia in children with suspected, isolated extremity fractures in the paediatric emergency department

    Science.gov (United States)

    Reynolds, Stacy L; Studnek, Jonathan R; Bryant, Kathleen; VanderHave, Kelly; Grossman, Eric; Moore, Charity G; Young, James; Hogg, Melanie; Runyon, Michael S

    2016-01-01

    Introduction Fentanyl is the most widely studied intranasal (IN) analgesic in children. IN subdissociative (INSD) ketamine may offer a safe and efficacious alternative to IN fentanyl and may decrease overall opioid use during the emergency department (ED) stay. This study examines the feasibility of a larger, multicentre clinical trial comparing the safety and efficacy of INSD ketamine to IN fentanyl and the potential role for INSD ketamine in reducing total opioid medication usage. Methods and analysis This double-blind, randomised controlled, pilot trial will compare INSD ketamine (1 mg/kg) to IN fentanyl (1.5 μg/kg) for analgesia in 80 children aged 4–17 years with acute pain from a suspected, single extremity fracture. The primary safety outcome for this pilot trial will be the frequency of cumulative side effects and adverse events at 60 min after drug administration. The primary efficacy outcome will be exploratory and will be the mean reduction of pain scale scores at 20 min. The study is not powered to examine efficacy. Secondary outcome measures will include the total dose of opioid pain medication in morphine equivalents/kg/hour (excluding study drug) required during the ED stay, number and reason for screen failures, time to consent, and the number and type of protocol deviations. Patients may receive up to 2 doses of study drug. Ethics and dissemination This study was approved by the US Food and Drug Administration, the local institutional review board and the study data safety monitoring board. This study data will be submitted for publication regardless of results and will be used to establish feasibility for a multicentre, non-inferiority trial. Trial registration number NCT02521415. PMID:27609854

  12. Assessing the Subjective and Physiological Effects of Intranasally Administered Crushed Extended-Release Morphine Formulations with and without a Sequestered Naltrexone Core in Recreational Opioid Users

    Directory of Open Access Journals (Sweden)

    Beatrice Setnik

    2013-01-01

    Full Text Available OBJECTIVE: To evaluate the pharmacodynamic (PD effects of morphine sulfate and naltrexone hydrochloride extended-release (MSN capsules compared with controlled-release morphine sulfate (MS and placebo when crushed and administered intranasally.

  13. New ways of insulin delivery.

    Science.gov (United States)

    Heinemann, L

    2011-02-01

    The predominant number of papers published from the middle of 2009 to the middle of 2010 about alternative routes of insulin administration (ARIA) were still about inhaled insulin. Long-term experience with Exubera was the topic of a number of publications that are also of relevance for inhaled insulin in general. The clinical trials performed with AIR insulin by Eli Lilly were published in a supplement issue of one diabetes technology journal and most of these will be presented. A number of other publications (also one in a high ranked journal) about their inhaled insulin were from another company: MannKind. The driving force behind Technosphere insulin (TI) - which is the only one still in clinical development - is Al Mann; he has put a lot of his personal fortune in this development. We will know the opinion of the regulatory authorities about TI in the near future; however, I am personally relatively confident that the Food and Drug Administration will provide TI with market approval. The more critical question for me is: will diabetologists and patients jump on this product once it becomes commercially available? Will it become a commercial success? In view of many negative feelings in the scientific community about inhaled insulin, it might be of help that MannKind publish their studies with TI systematically. Acknowledging being a believer in this route of insulin administration myself, one has to state that Exubera and AIR insulin had not offered profound advantages in terms of pharmacokinetic (PK) and pharmacodynamic (PD) properties in comparison with subcutaneously (SC) applied regular human insulin (RHI) and rapid-acting insulin analogues. The time-action profiles of these inhaled insulins were more or less comparable with that of rapid-acting insulin analogues. This is clearly different with TI which exhibits a strong metabolic effect shortly after application and a rapid decline in the metabolic effect thereafter; probably the duration of action is

  14. Insulin signaling meets mitochondria in metabolism

    OpenAIRE

    Cheng, Zhiyong; Tseng, Yolanda; White, Morris F.

    2010-01-01

    Insulin controls nutrient and metabolic homeostasis via the IRS–PI3K–AKT signaling cascade that targets FOXO1 and mTOR. Mitochondria, as the prime metabolic platform, malfunction during insulin resistance in metabolic diseases. However, the molecular link between insulin resistance and mitochondrial dysfunction remains undefined. Here we review recent studies on insulin action and the mechanistic association with mitochondrial metabolism. These studies suggest that insulin signaling underpins...

  15. Bioavailability and variability of biphasic insulin mixtures

    DEFF Research Database (Denmark)

    Søeborg, Tue; Rasmussen, Christian Hove; Mosekilde, Erik

    2012-01-01

    , the absorption kinetics for mixtures of insulins is described. This requires that the bioavailability of the different insulins is considered. A short review of insulin bioavailability and a description of the subcutaneous depot thus precede the presentation of possible mechanisms associated with subcutaneous...... mixtures. The results can be used in both the development of novel insulin products and in the planning of the treatment of insulin dependent diabetic patients....

  16. Insulin biosynthesis and diabetes mellitus.

    Science.gov (United States)

    Permutt, A; Chirgwin, J; Giddings, S; Kakita, K; Rotwein, P

    1981-10-01

    This review reports the use of recombinant DNA techniques in the study of the structure and regulation of expression of insulin genes in man and experimental animals. Insulin biosynthesis by pancreatic islet cells is predominantly regulated by change in plasma glucose concentration. Using a cell-free protein synthesizing system as an assay of functional proinsulin messenger RNA (mRNA), and hybridization analysis with a cloned DNA complementary to proinsulin mRNA, it has been determined that through changes in proinsulin mRNA levels. Insulin genes of the rat, chicken and human have been isolated and sequenced. The 5' ends of the genes have similar sequences suggesting areas important for regulation of transcription. There are two non-allelic insulin genes in the rat, but only one in chickens and humans. Intervening sequences, areas of DNA transcribed into precursor mRNA but which do not appear in mature mRNA, have been described within insulin genes. The insulin gene resides on chromosome 11 of humans as determined by DNA hybridization analysis of mouse human hybrid cells. The structure of the insulin gene in genomic DNA of humans has been analyzed in diabetics and non-diabetics. Insertions of DNA between 1500 and 3400 base pairs have been detected near the transcription initiation site in 65% of type II diabetics, and 25-30% of non-diabetics (this difference is significant at the p less than 0.001 level). Limitation of these insertions to this potential promotor region of the insulin gene suggests that they may alter gene expression in type II diabetes. These insertions of DNA may prove to be useful genetic markers for diabetes.

  17. In vivo toxicity and immunogenicity of wheat germ agglutinin conjugated poly(ethylene glycol)-poly(lactic acid) nanoparticles for intranasal delivery to the brain.

    Science.gov (United States)

    Liu, Qingfeng; Shao, Xiayan; Chen, Jie; Shen, Yehong; Feng, Chengcheng; Gao, Xiaoling; Zhao, Yue; Li, Jingwei; Zhang, Qizhi; Jiang, Xinguo

    2011-02-15

    Biodegradable polymer-based nanoparticles have been widely studied to deliver therapeutic agents to the brain after intranasal administration. However, knowledge as to the side effects of nanoparticle delivery system to the brain is limited. The aim of this study was to investigate the in vivo toxicity and immunogenicity of wheat germ agglutinin (WGA) conjugated poly(ethylene glycol)-poly(lactic acid) nanoparticles (WGA-NP) after intranasal instillation. Sprague-Dawley rats were intranasally given WGA-NP for 7 continuous days. Amino acid neurotransmitters, lactate dehydrogenase (LDH) activity, reduced glutathione (GSH), acetylcholine, acetylcholinesterase activity, tumor necrosis factor α (TNF-α) and interleukin-8 (IL-8) in rat olfactory bulb (OB) and brain were measured to estimate the in vivo toxicity of WGA-NP. Balb/C mice were intranasally immunized by WGA-NP and then WGA-specific antibodies in serum and nasal wash were detected by indirect ELISA. WGA-NP showed slight toxicity to brain tissue, as evidenced by increased glutamate level in rat brain and enhanced LDH activity in rat OB. No significant changes in acetylcholine level, acetylcholinesterase activity, GSH level, TNF-α level and IL-8 level were observed in rat OB and brain for the WGA-NP group. WGA-specific antibodies in mice serum and nasal wash were not increased after two intranasal immunizations of WGA-NP. These results demonstrate that WGA-NP is a safe carrier system for intranasal delivery of therapeutic agents to the brain.

  18. Comparación de la efectividad del midazolam en niños: via oral y via intranasal

    OpenAIRE

    Castro Jerí, Esmeralda Soledad; Facultad de Estomatología, Universidad Peruana Cayetano Heredia. Lima,; Díaz-Pizán, Maria Elena; Facultad de Estomatología, Universidad Peruana Cayetano Heredia. Lima,; Vargas Machuca, Mónica Valdivieso; Facultad de Estomatología, Universidad Peruana Cayetano Heredia. Lima,

    2014-01-01

    El propósito del presente estudio fue evaluar la efectividad de dos formas de administración demidazolam, vía oral e intranasal en la modificación de la conducta de niños en edad preescolarquienes recibieron tratamiento dental. Participaron 20 niños con edades entre los 22 a 68meses, quienes recibieron midazolam en dosis de 0,5mg/kg de peso administrado por vía oral y0,2 mg/kg de peso administrado por vía intranasal. A todos los niños se les registró la presiónarterial, frecuencia cardiaca y ...

  19. Brain delivery of small interfering ribonucleic acid and drugs through intranasal administration with nano-sized polymer micelles

    Directory of Open Access Journals (Sweden)

    Kanazawa T

    2015-01-01

    Full Text Available Takanori Kanazawa School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan Abstract: Recently, the development of effective strategies for enhancing drug delivery to the brain has been a topic of great interest in both clinical and pharmaceutical fields. In this review, we summarize our studies evaluating nose-to-brain delivery of drugs and small interfering ribonucleic acids in combination with cell-penetrating peptide-modified polymer micelles. Our findings show that the use of polymer micelles with surface modification with Tat peptide in the intranasal administration enables the non-invasive delivery of therapeutic agents to the brain by increasing the transfer of the administered drug or small interfering ribonucleic acid to the central nervous system from the nasal cavity. Keywords: nose-to-brain, polymer micelles, cell-penetrating peptide, intranasal administration, nucleic acid

  20. Limited evidence for intranasal fentanyl in the emergency department and the prehospital setting--a systematic review

    DEFF Research Database (Denmark)

    Hansen, Morten Sejer; Dahl, Jørgen Berg

    2013-01-01

    The intranasal (IN) mode of application may be a valuable asset in non-invasive pain management. Fentanyl demonstrates pharmacokinetic and pharmacodynamic properties that are desirable in the management of acute pain, and IN fentanyl may be of value in the prehospital setting. The aim of this sys......The intranasal (IN) mode of application may be a valuable asset in non-invasive pain management. Fentanyl demonstrates pharmacokinetic and pharmacodynamic properties that are desirable in the management of acute pain, and IN fentanyl may be of value in the prehospital setting. The aim...... of this systematic review was to evaluate the current evidence for the use of IN fentanyl in the emergency department (ED) and prehospital setting....

  1. Apnea after Awake Regional and General Anesthesia in Infants : The General Anesthesia Compared to Spinal Anesthesia Study-Comparing Apnea and Neurodevelopmental Outcomes, a Randomized Controlled Trial

    NARCIS (Netherlands)

    Davidson, Andrew J.; Morton, Neil S.; Arnup, Sarah J.; De Graaff, Jurgen C.; Disma, Nicola; Withington, Davinia E.; Frawley, Geoff; Hunt, Rodney W.; Hardy, Pollyanna; Khotcholava, Magda; Von Ungern Sternberg, Britta S.; Wilton, Niall; Tuo, Pietro; Salvo, Ida; Ormond, Gillian; Stargatt, Robyn; Locatelli, Bruno Guido; McCann, Mary Ellen; Lee, Katherine; Sheppard, Suzette; Hartmann, Penelope; Ragg, Philip; Backstrom, Marie; Costi, David; Von Ungern-Sternberg, Britta S.; Knottenbelt, Graham; Montobbio, Giovanni; Mameli, Leila; Giribaldi, Gaia; Prato, Alessio Pini; Mattioli, Girolamo; Wolfler, Andrea; Izzo, Francesca; Sonzogni, Valter; Van Gool, Jose T D G; Numan, Sandra C.; Kalkman, Cor J.; Hagenaars, J. H M; Absalom, Anthony R.; Hoekstra, Frouckje M.; Volkers, Martin J.; Furue, Koto; Gaudreault, Josee; Berde, Charles; Soriano, Sulpicio; Young, Vanessa; Sethna, Navil; Kovatsis, Pete; Cravero, Joseph P.; Bellinger, David; Marmor, Jacki; Lynn, Anne; Ivanova, Iskra; Hunyady, Agnes; Verma, Shilpa; Polaner, David; Thomas, Joss; Meuller, Martin; Haret, Denisa; Szmuk, Peter; Steiner, Jeffery; Kravitz, Brian; Suresh, Santhanam; Hays, Stephen R.; Taenzer, Andreas H.; Maxwell, Lynne G.; Williams, Robert K.; Bell, Graham T.; Dorris, Liam; Adey, Claire; Bagshaw, Oliver; Chisakuta, Anthony; Eissa, Ayman; Stoddart, Peter; Davis, Annette; Myles, Paul; Wolf, Andy; McIntosh, Neil; Carlin, John; Leslie, Kate; De Lima, Jonathan; Hammer, Greg; Field, David; Gebski, Val; Tibboel, Dick

    2015-01-01

    Background: Postoperative apnea is a complication in young infants. Awake regional anesthesia (RA) may reduce the risk; however, the evidence is weak. The General Anesthesia compared to Spinal anesthesia study is a randomized, controlled trial designed to assess the influence of general anesthesia (

  2. EXTRACELLULAR GAMMA-AMINOBUTYRIC-ACID IN THE SUBSTANTIA-NIGRA RETICULATA MEASURED BY MICRODIALYSIS IN AWAKE RATS - EFFECTS OF VARIOUS STIMULANTS

    NARCIS (Netherlands)

    TIMMERMAN, W; WESTERINK, BHC

    1995-01-01

    The gamma-aminobutyric acid (GABA)-ergic system in the substantia nigra reticulata (SNR) was challenged by local infusion of various receptor-specific agents to obtain additional information on the physiological significance of extracellular GABA levels as measured by microdialysis in awake rats. No

  3. Electrical stimulation of the substantia nigra reticulata : Detection of neuronal extracellular GABA in the ventromedial thalamus and its regulatory mechanism using microdialysis in awake rats

    NARCIS (Netherlands)

    Timmerman, W; Westerink, BHC

    1997-01-01

    A combination of electrical stimulation and microdialysis was used to study the nigrothalamic gamma aminobutyric acid (GABA)ergic system and its regulatory mechanisms in awake rats. Extracellular GABA levels in the ventromedial nucleus of the thalamus were detected in S-min fractions collected befor

  4. Apnea after Awake Regional and General Anesthesia in Infants : The General Anesthesia Compared to Spinal Anesthesia Study-Comparing Apnea and Neurodevelopmental Outcomes, a Randomized Controlled Trial

    NARCIS (Netherlands)

    Davidson, Andrew J; Morton, Neil S; Arnup, Sarah J; de Graaff, Jurgen C; Disma, Nicola; Withington, Davinia E; Frawley, Geoff; Hunt, Rodney W; Hardy, Pollyanna; Khotcholava, Magda; von Ungern Sternberg, Britta S; Wilton, Niall; Tuo, Pietro; Salvo, Ida; Ormond, Gillian; Stargatt, Robyn; Locatelli, Bruno Guido; McCann, Mary Ellen; Absalom, Anthony

    2015-01-01

    BACKGROUND: Postoperative apnea is a complication in young infants. Awake regional anesthesia (RA) may reduce the risk; however, the evidence is weak. The General Anesthesia compared to Spinal anesthesia study is a randomized, controlled trial designed to assess the influence of general anesthesia (

  5. Immunogenicity and protective efficacy of an elastase-dependent live attenuated swine influenza virus vaccine administered intranasally in pigs.

    Science.gov (United States)

    Masic, Aleksandar; Lu, Xinya; Li, Junwei; Mutwiri, George K; Babiuk, Lorne A; Brown, Earl G; Zhou, Yan

    2010-10-01

    Influenza A virus is an important respiratory pathogen of swine that causes significant morbidity and economic impact on the swine industry. Vaccination is the first choice for prevention and control of influenza infections. Live attenuated influenza vaccines (LAIV) are approved for use in humans and horses and their application provides broad protective immunity, however no LAIV against swine influenza virus (SIV) exists in the market. Previously we reported that an elastase-dependent mutant SIV A/Sw/Sk-R345V (R345V) derived from A/Sw/Saskatchewan/18789/02 (H1N1) (SIV/Sk02) is highly attenuated in pigs. Two intratracheal administrations of R345V induced strong cell-mediated and humoral immune responses and provided a high degree of protection to antigenically different SIV infection in pigs. Here we evaluated the immunogenicity and the protective efficacy of R345V against SIV infection by intranasal administration, the more practical route for vaccination of pigs in the field. Our data showed that intranasally administered R345V live vaccine is capable of inducing strong antigen-specific IFN-γ response from local tracheo-bronchial lymphocytes and antibody responses in serum and respiratory mucosa after two applications. Intranasal vaccination of R345V provided pigs with complete protection not only from parental wild type virus infection, but also from homologous antigenic variant A/Sw/Indiana/1726/88 (H1N1) infection. Moreover, intranasal administration of R345V conferred partial protection from heterologous subtypic H3N2 SIV infection in pigs. Thus, R345V elastase-dependent mutant SIV can serve as a live vaccine against antigenically different swine influenza viruses in pigs.

  6. Intranasal brain-derived neurotrophic factor protects brain from ischemic insult via modulating local inflammation in rats.

    Science.gov (United States)

    Jiang, Y; Wei, N; Lu, T; Zhu, J; Xu, G; Liu, X

    2011-01-13

    Inflammation plays a vital role in the pathogenesis of ischemic stroke. Brain-derived neurotrophic factor (BDNF) may protect brain tissues from ischemic injury. In this study, we investigated whether intranasal BDNF exerted neuroprotection against ischemic insult by modulating the local inflammation in rats with ischemic stroke. Rats were subjected to temporary occlusion of the right middle cerebral artery (120 min) and intranasal BDNF or vehicle was adminstrated 2 h after reperfusion. Infarct volume and neuron injury were measured using triphenyltetrazolium chloride, Nissl staining and TUNEL assay, respectively. Microglia were detected by immunohistofluorescence. Tumor necrosis factor-α, interleukin10 and mRNAs were evaluated by enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction. DNA-binding activity of nuclear factor-kappa B was measured by electrophoretic mobility shift assay. BDNF level in brain tissues was markedly raised following intranasal administration. There were more Nissl positive and less TUNEL positive neurons in BDNF group than in control group while intranasal BDNF did not reduce the infarct volume significantly (n=6, 0.27±0.04 vs. 0.24±0.05, P>0.05). BDNF increased the number of activated microglia (OX-42 positive) and phagocytotic microglia (ED1 positive). BDNF suppressed tumor necrosis factor-α and mRNA expression while increasing the interleukin10 and mRNA expression. BDNF also increased DNA-binding activity of nuclear factor-kappa B (n=6, 49.78±1.23 vs. 52.89±1.64, PBDNF might protect the brain against ischemic insult by modulating local inflammation via regulation of the levels of cellular, cytokine and transcription factor in the experimental stroke.

  7. MIDAZOLAM SEDATION IN PAEDIATRICS: COMPARATIVE STUDY OF INTRANASAL VERSUS SUBLINGUAL MIDAZOLAM ATOMIZER SPRAY IN PAEDIATRIC PATIENTS UNDERGOING MAGNETIC RESONANCE IMAGING

    Directory of Open Access Journals (Sweden)

    Santhisree

    2014-05-01

    Full Text Available INTRODUCTION: Magnetic Resonance Imaging (MRI causes a great amount of anxiety to both parents and child. Fear of unpleasant procedures and separation from parents may result in lasting and untoward psychological consequences in children. So sedation and anxiolysis is required for children undergoing even for minor diagnostic procedures. OBJECTIVES: The objectives of our study was to compare safety, onset of sedation, degree of sedation produced by intranasal and sublingual administration of midazolam for premedication in children of 4-10 years undergoing MRI. MATERIALS AND METHODS: In this prospective randomized double blind study, the intranasal and sublingual administration of midazolam in pediatric patients who were to undergo MRI was evaluated in 60 children who were aged between 4-10 years with ASA physical status I and II by using a newer midazolam spray. The patients were divided into two groups of 30 patients each and they received Midazolam 0.3 mg/kg. Either intranasally or sublingually in a randomized manner. The heart rate, oxygen saturation (SPO2, respiratory rate and the degree of sedation before and at 3 minutes intervals, recovery score, MRI image quality were recorded and compared. RESULTS: The respiratory rate, heart rate and the oxygen saturation was found from the baseline in both the groups (p >0.05. A sedation score of >3 (approx. was achieved in both the groups within 10 minutes of drug administration. The recovery score did not differ significantly between the two groups (p >0.05. CONCLUSION: Both the intranasal and sublingual administration of Midazolam as sedative is safe and equally effective in pediatric patients.

  8. Intranasal organic dust exposure-induced airway adaptation response marked by persistent lung inflammation and pathology in mice

    OpenAIRE

    Poole, Jill A.; Wyatt, Todd A; Oldenburg, Peter J.; Elliott, Margaret K.; West, William W.; Sisson, Joseph H.; Von Essen, Susanna G.; Romberger, Debra J.

    2009-01-01

    Organic dust exposure in agricultural environments results in an inflammatory response that attenuates over time, but repetitive exposures can result in chronic respiratory disease. Animal models to study these mechanisms are limited. This study investigated the effects of single vs. repetitive dust-induced airway inflammation in mice by intranasal exposure method. Mice were exposed to swine facility dust extract (DE) or saline once and once daily for 1 and 2 wk. Dust exposure resulted in inc...

  9. A Randomized, Controlled Trial of Intranasal Oxytocin as an Adjunct to Behavioral Therapy for Autism Spectrum Disorder

    Science.gov (United States)

    2015-10-01

    AWARD NUMBER: W81XWH-12-1-0543 TITLE: “A Randomized, Controlled Trial of Intranasal Oxytocin as an Adjunct to Behavioral Therapy for Autism... Behavioral Therapy for Autism Spectrum Disorder” 5b. GRANT NUMBER W81XWH-12-1-0543 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) John Gabrieli, Ph.D; Aude...Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT The primary objectives of this clinical study are test the hypotheses that (1) cognitive behavioral

  10. Intranasal administration of human umbilical cord mesenchymal stem cells-conditioned medium enhances vascular remodeling after stroke.

    Science.gov (United States)

    Zhao, Qiuchen; Hu, Jinxia; Xiang, Jie; Gu, Yuming; Jin, Peisheng; Hua, Fang; Zhang, Zunsheng; Liu, Yonghai; Zan, Kun; Zhang, Zuohui; Zu, Jie; Yang, Xinxin; Shi, Hongjuan; Zhu, Jienan; Xu, Yun; Cui, Guiyun; Ye, Xinchun

    2015-10-22

    Stem cell-based treatments have been reported to be a potential strategy for stroke. However, tumorigenic potential and low survival rates of transplanted cells could attenuate the efficacy of the stem cell-based treatments. The application of stem cell-condition medium (CM) may be a practicable approach to conquer these limitations. In this study, we investigated whether intranasal administration of human umbilical cord mesenchymal stem cells (hUCMSCs)-CM has the therapeutic effects in rats after stroke. Adult male rats were subjected to middle cerebral artery occlusion (MCAo) and were treated by intranasal routine with or without hUCMSCs-CM (1 ml/kg/d), starting 24h after MCAo and daily for 14 days. Neurological functional tests, blood brain barrier (BBB) leakage, were measured. Angiogenesis and angiogenic factor expression were measured by immunohistochemistry, and Western blot, respectively. hUCMSCs-CM treatment of stroke by intranasal routine starting 24h after MCAo in rats significantly enhances BBB functional integrity and promotes functional outcome but does not decrease lesion volume compared to rats in DMEM/F12 medium control group and saline control group. Treatment of ischemic rats with hUCMSCs-CM by intranasal routine also significantly decreases the levels of Ang2 and increases the levels of both Ang1 and Tie2 in the ischemic brain. To take together, increased expression of Ang1 and Tie2 and decreased expression of Ang2, induced by hUCMSCs-CM treatment, contribute to vascular remodeling in the ischemic brain which plays an important role in functional outcome after stroke.

  11. Protein engineering of insulin: Two novel fast-acting insulins [B16Ala]insulin and [B26Ala]insulin

    Institute of Scientific and Technical Information of China (English)

    ZHANG; Zhou; (张舟); TANG; Yuehua; (唐月华); YAO; Shiyin; (姚矢音); ZHU; Shangquan; (朱尚权); FENG; Youmin; (冯佑民)

    2003-01-01

    Blood glucose lowering assay proved that [B16Ala]insulin and [B26Ala]insulin exhibit potency of acute blood glucose lowering in normal pigs, which demonstrates that they are fast- acting insulin. Single-chain precursor of [B16Ala]insulin and [B26Ala]insulin is [B16Ala]PIP and [B26Ala]PIP, respectively, which are suitable for gene expression. Secretory expression level of the precursors in methylotrophic yeast Pichia pastoris was quite high, 650 mg/L and 130 mg/L, respectively. In vivo biological assay showed that the two fast-acting insulins have full or nearly full biological activity. So both [B16Ala]insulin and [B26Ala]insulin can be well developed as fast-acting insulin for clinic use.

  12. One time intranasal vaccination with a modified vaccinia Tiantan strain MVTT(ZCI) protects animals against pathogenic viral challenge.

    Science.gov (United States)

    Yu, Wenbo; Fang, Qing; Zhu, Weijun; Wang, Haibo; Tien, Po; Zhang, Linqi; Chen, Zhiwei

    2010-02-25

    To combat variola virus in bioterrorist attacks, it is desirable to develop a noninvasive vaccine. Based on the vaccinia Tiantan (VTT) strain, which was historically used to eradicate the smallpox in China, we generated a modified VTT (MVTT(ZCI)) by removing the hemagglutinin gene and an 11,944bp genomic region from HindIII fragment C2L to F3L. MVTT(ZCI) was characterized for its host cell range in vitro and preclinical safety and efficacy profiles in mice. Despite replication-competency in some cell lines, unlike VTT, MVTT(ZCI) did not cause death after intracranial injection or body weight loss after intranasal inoculation. MVTT(ZCI) did not replicate in mouse brain and was safe in immunodeficient mice. MVTT(ZCI) induced neutralizing antibodies via the intranasal route of immunization. One time intranasal immunization protected animals from the challenge of the pathogenic vaccinia WR strain. This study established proof-of-concept that the attenuated replicating MVTT(ZCI) may serve as a safe noninvasive smallpox vaccine candidate.

  13. Brain cytokine and chemokine mRNA expression in mice induced by intranasal instillation with ultrafine carbon black.

    Science.gov (United States)

    Tin-Tin-Win-Shwe; Yamamoto, Shoji; Ahmed, Sohel; Kakeyama, Masaki; Kobayashi, Takahiro; Fujimaki, Hidekazu

    2006-05-25

    Ambient air ultrafine particles (UFPs) have gained enormous attention to many researchers with recent evidence showing them to have more hazardous effects on human health than larger ambient particles. Studies focusing the possibility of effects on brain are quite limited. To examine the effect of ultrafine carbon black (ufCB) on mice brain, we instilled 125 microg of 14 nm or 95 nm CB into the nostrils of 8-week-old male BALB/c mice, once a week for 4 weeks. Four hours after the last instillation, we collected olfactory bulb and hippocampus and detected the expression of cytokine and chemokine mRNA by quantitative real-time PCR method. In this study, we found the induction of proinflammatory cytokines (interleukin-1 beta and tumor necrosis factor-alpha and chemokines (monocyte chemoattractant protein-1/CCL2, macrophage inflammatory protein-1 alpha/CCL3), and monokine induced interferon-gamma/CXC chemokine ligand (CXCL9) mRNA in brain olfactory bulb, not in the hippocampus of mice instilled with 14 nm ufCB intranasally. We suggest that the intranasal instillation of ufCB may influence the brain immune function depending on their size. To our knowledge, this is the first study to demonstrate region-specific brain cytokine and chemokine mRNA-induction in mice triggered by intranasal instillation of specific-sized ufCB, in a physiologically relevant condition.

  14. Using Gelatin Nanoparticle Mediated Intranasal Delivery of Neuropeptide Substance P to Enhance Neuro-Recovery in Hemiparkinsonian Rats.

    Directory of Open Access Journals (Sweden)

    Ying-Zheng Zhao

    Full Text Available Intranasal administration of phospholipid-based gelatin nanoparticles (GNP was prepared to investigate the neuro-recovery effects of neuropeptide Substance P (SP on hemiparkinsonian rats.The SP-loaded gelatin nanoparticles (SP-GNP were prepared by a water-in-water emulsion method and possessed high stability, encapsulating efficiency and loading capacity. PC-12 cells were used to examine the growth enhancement of SP-GNP in vitro by MTT assays and flow cytometry (FCM. The therapeutic effects of SP-GNP on 6-hydroxydopamine (6-OHDA induced hemiparkinsonian rats were assessed by quantifying rotational behavior and the levels of tyrosine hydroxylase (TH, phosphorylated c-Jun protein (p-c-Jun and Caspase-3 (Cas-3 expressed in substantia nigra (SN region of hemiparkinsonian rats.PC-12 cells under SP-GNP treatment showed better cell viability and lower degree of apoptosis than those under SP solution treatment. Hemiparkinsonian rats under intranasal SP-GNP administration demonstrated better behavioral improvement, higher level of TH in SN along with much lower extent of p-c-Jun and Cas-3 than those under intranasal SP solution administration and intravenous SP-GNP administration.With the advantages of GNP and nose-to-brain pathway, SP can be effectively delivered into the damaged SN region and exhibit its neuro-recovery function through the inhibition on JNK pathway and dopaminergic neuron apoptosis.

  15. Mucosal vaccination by the intranasal route. Nose-associated lymphoid tissue (NALT)-Structure, function and species differences.

    Science.gov (United States)

    Pabst, Reinhard

    2015-08-26

    The advantage of mucosal vaccination in viral and bacterial infections in different age groups is of enormous clinical relevance. The advantages and potential hazards of intranasal vaccination have always to be considered. The intranasal route for vaccination is very successful for some antigens. Specific adjuvants are necessary. In the nose of rodents there is a structured lymphoid tissue (nose-associated lymphoid tissue (NALT)). This abbreviation should not be used for nasopharynx-associated lymphoid tissue, as this includes parts of the tonsils. In children lymphoid tissue is more dispersed in the nose and not concentrated at the bottom of the dorsal nose ducts as in rodents. There are no data on organized lymphoid tissue in the nose of adults. In NALT of rodents there is a unique structure of adhesion molecule expression; the postnatal development and the different composition of T and B lymphocytes in comparison with Peyer's patches document the uniqueness of this lymphoid organ. There is also a mucosa in the nose with antigen-presenting dendritic cells. Thus, it is often unclear whether intranasal vaccination is initiated via NALT or the diffuse nasal mucosa. There are still many open questions e. g., which adjuvant is necessary for a specific virus, bacterium or other allergen, how many doses are critical for an effective nasal vaccination. Species differences are of major importance when extrapolating results from rodents to humans.

  16. Limited susceptibility and lack of systemic infection by an H3N2 swine influenza virus in intranasally inoculated chickens.

    Science.gov (United States)

    Thomas, Colleen; Manin, Timofey B; Andriyasov, Artem V; Swayne, David E

    2008-09-01

    Chickens were intranasally inoculated with the swine influenza virus (SIV) A/swine/NC/307408/04 (H3N2) (NC/04 SIV) to determine the infectivity of a North American SIV for chickens, as well as the possibility of chicken meat serving as a transmission vehicle for SIV. White leghorn (WL) layer-type chickens were used for initial pathotyping and infectivity tests, and a more comprehensive intranasal pathogenesis study was done with white Plymouth rock (WPR) broiler-type chickens. None of the NC/04 SIV-inoculated WL or WPR chickens displayed clinical signs. Serologic tests showed that the virus was able to infect both intranasally inoculated WL and WPR chickens, but the antibody titers were low, suggesting inefficient replication. Some of the NC/04 SIV-inoculated WL chickens shed low levels of virus, mostly from the alimentary tract, but viral shedding was not detected in NC/04 SIV-inoculated WPR chickens. The comprehensive pathogenesis study demonstrated that the virus did not cause systemic infections in WPR chickens, and feeding breast and thigh meat from the NC/04 SIV-inoculated WPR to WL chickens did not transmit NC/04 SIV.

  17. Intranasal Delivery of A Novel Amnion Cell Secretome Prevents Neuronal Damage and Preserves Function In A Mouse Multiple Sclerosis Model

    Science.gov (United States)

    Khan, Reas S.; Dine, Kimberly; Bauman, Bailey; Lorentsen, Michael; Lin, Lisa; Brown, Helayna; Hanson, Leah R.; Svitak, Aleta L.; Wessel, Howard; Brown, Larry; Shindler, Kenneth S.

    2017-01-01

    The ability of a novel intranasally delivered amnion cell derived biologic to suppress inflammation, prevent neuronal damage and preserve neurologic function in the experimental autoimmune encephalomyelitis animal model of multiple sclerosis was assessed. Currently, there are no existing optic nerve treatment methods for disease or trauma that result in permanent vision loss. Demyelinating optic nerve inflammation, termed optic neuritis, induces permanent visual dysfunction due to retinal ganglion cell damage in multiple sclerosis and experimental autoimmune encephalomyelitis. ST266, the biological secretome of Amnion-derived Multipotent Progenitor cells, contains multiple anti-inflammatory cytokines and growth factors. Intranasally administered ST266 accumulated in rodent eyes and optic nerves, attenuated visual dysfunction, and prevented retinal ganglion cell loss in experimental optic neuritis, with reduced inflammation and demyelination. Additionally, ST266 reduced retinal ganglion cell death in vitro. Neuroprotective effects involved oxidative stress reduction, SIRT1-mediated mitochondrial function promotion, and pAKT signaling. Intranasal delivery of neuroprotective ST266 is a potential novel, noninvasive therapeutic modality for the eyes, optic nerves and brain. The unique combination of biologic molecules in ST266 provides an innovative approach with broad implications for suppressing inflammation in autoimmune diseases, and for preventing neuronal damage in acute neuronal injury and chronic neurodegenerative diseases such as multiple sclerosis. PMID:28139754

  18. The Effect of Long-Term Intranasal Serotonin Treatment on Metabolic Parameters and Hormonal Signaling in Rats with High-Fat Diet/Low-Dose Streptozotocin-Induced Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Kira V. Derkach

    2015-01-01

    Full Text Available In the last years the treatment of type 2 diabetes mellitus (DM2 was carried out using regulators of the brain signaling systems. In DM2 the level of the brain serotonin is reduced. So far, the effect of the increase of the brain serotonin level on DM2-induced metabolic and hormonal abnormalities has been studied scarcely. The present work was undertaken with the aim of filling this gap. DM2 was induced in male rats by 150-day high-fat diet and the treatment with low dose of streptozotocin (25 mg/kg on the 70th day of experiment. From the 90th day, diabetic rats received for two months intranasal serotonin (IS at a daily dose of 20 μg/rat. The IS treatment of diabetic rats decreased the body weight, and improved glucose tolerance, insulin-induced glucose utilization, and lipid metabolism. Besides, it restored hormonal regulation of adenylyl cyclase (AC activity in the hypothalamus and normalized AC stimulation by β-adrenergic agonists in the myocardium. In nondiabetic rats the same treatment induced metabolic and hormonal alterations, some of which were similar to those in DM2 but expressed to a lesser extent. In conclusion, the elevation of the brain serotonin level may be regarded as an effective approach to treat DM2 and its complications.

  19. Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease.

    Science.gov (United States)

    Danielyan, Lusine; Schäfer, Richard; von Ameln-Mayerhofer, Andreas; Bernhard, Felix; Verleysdonk, Stephan; Buadze, Marine; Lourhmati, Ali; Klopfer, Tim; Schaumann, Felix; Schmid, Barbara; Koehle, Christoph; Proksch, Barbara; Weissert, Robert; Reichardt, Holger M; van den Brandt, Jens; Buniatian, Gayane H; Schwab, Matthias; Gleiter, Christoph H; Frey, William H

    2011-02-01

    Safe and effective cell delivery remains one of the main challenges in cell-based therapy of neurodegenerative disorders. Graft survival, sufficient enrichment of therapeutic cells in the brain, and avoidance of their distribution throughout the peripheral organs are greatly influenced by the method of delivery. Here we demonstrate for the first time noninvasive intranasal (IN) delivery of mesenchymal stem cells (MSCs) to the brains of unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. IN application (INA) of MSCs resulted in the appearance of cells in the olfactory bulb, cortex, hippocampus, striatum, cerebellum, brainstem, and spinal cord. Out of 1 × 10⁶ MSCs applied intranasally, 24% survived for at least 4.5 months in the brains of 6-OHDA rats as assessed by quantification of enhanced green fluorescent protein (EGFP) DNA. Quantification of proliferating cell nuclear antigen-positive EGFP-MSCs showed that 3% of applied MSCs were proliferative 4.5 months after application. INA of MSCs increased the tyrosine hydroxylase level in the lesioned ipsilateral striatum and substantia nigra, and completely eliminated the 6-OHDA-induced increase in terminal deoxynucleotidyl transferase (TdT)-mediated 2'-deoxyuridine, 5'-triphosphate (dUTP)-biotin nick end labeling (TUNEL) staining of these areas. INA of EGFP-labeled MSCs prevented any decrease in the dopamine level in the lesioned hemisphere, whereas the lesioned side of the control animals revealed significantly lower levels of dopamine 4.5 months after 6-OHDA treatment. Behavioral analyses revealed significant and substantial improvement of motor function of the Parkinsonian forepaw to up to 68% of the normal value 40-110 days after INA of 1 × 10⁶ cells. MSC-INA decreased the concentrations of inflammatory cytokines-interleukin-1β (IL-1β), IL-2, -6, -12, tumor necrosis factor (TNF), interferon-γ (IFN-γ, and granulocyte-macrophage colony-stimulating factor (GM-CSF)-in the lesioned side to their

  20. Selective CNS Uptake of the GCP-II Inhibitor 2-PMPA following Intranasal Administration.

    Directory of Open Access Journals (Sweden)

    Rana Rais

    Full Text Available Glutamate carboxypeptidase II (GCP-II is a brain metallopeptidase that hydrolyzes the abundant neuropeptide N-acetyl-aspartyl-glutamate (NAAG to NAA and glutamate. Small molecule GCP-II inhibitors increase brain NAAG, which activates mGluR3, decreases glutamate, and provide therapeutic utility in a variety of preclinical models of neurodegenerative diseases wherein excess glutamate is presumed pathogenic. Unfortunately no GCP-II inhibitor has advanced clinically, largely due to their highly polar nature resulting in insufficient oral bioavailability and limited brain penetration. Herein we report a non-invasive route for delivery of GCP-II inhibitors to the brain via intranasal (i.n. administration. Three structurally distinct classes of GCP-II inhibitors were evaluated including DCMC (urea-based, 2-MPPA (thiol-based and 2-PMPA (phosphonate-based. While all showed some brain penetration following i.n. administration, 2-PMPA exhibited the highest levels and was chosen for further evaluation. Compared to intraperitoneal (i.p. administration, equivalent doses of i.n. administered 2-PMPA resulted in similar plasma exposures (AUC0-t, i.n./AUC0-t, i.p. = 1.0 but dramatically enhanced brain exposures in the olfactory bulb (AUC0-t, i.n./AUC0-t, i.p. = 67, cortex (AUC0-t, i.n./AUC0-t, i.p. = 46 and cerebellum (AUC0-t, i.n./AUC0-t, i.p. = 6.3. Following i.n. administration, the brain tissue to plasma ratio based on AUC0-t in the olfactory bulb, cortex, and cerebellum were 1.49, 0.71 and 0.10, respectively, compared to an i.p. brain tissue to plasma ratio of less than 0.02 in all areas. Furthermore, i.n. administration of 2-PMPA resulted in complete inhibition of brain GCP-II enzymatic activity ex-vivo confirming target engagement. Lastly, because the rodent nasal system is not similar to humans, we evaluated i.n. 2-PMPA also in a non-human primate. We report that i.n. 2-PMPA provides selective brain delivery with micromolar concentrations. These studies

  1. Intranasal infection with Chlamydia abortus induces dose-dependent latency and abortion in sheep.

    Directory of Open Access Journals (Sweden)

    David Longbottom

    Full Text Available BACKGROUND: Latency is a key feature of the animal pathogen Chlamydia abortus, where infection remains inapparent in the non-pregnant animal and only becomes evident during a subsequent pregnancy. Often the first sign that an animal is infected is abortion occurring late in gestation. Despite this, little is understood of the underlying mechanisms that control latency or the recrudescence of infection that occurs during subsequent pregnancy. The aim of this study was to develop an experimental model of latency by mimicking the natural route of infection through the intranasal inoculation of non-pregnant sheep with C. abortus. METHODOLOGY/PRINCIPAL FINDINGS: Three groups of sheep (groups 1, 2 and 3 were experimentally infected with different doses of C. abortus (5×10(3, 5×10(5 and 5×10(7 inclusion forming units (IFU, respectively prior to mating and monitored over 2 breeding cycles for clinical, microbiological, pathological, immunological and serological outcomes. Two further groups received either negative control inoculum (group 4a,b or were inoculated subcutaneously on day 70 of gestation with 2×10(6 IFU C. abortus (group 5. Animals in groups 1, 2 and 5 experienced an abortion rate of 50-67%, while only one animal aborted in group 3 and none in group 4a,b. Pathological, microbiological, immunological and serological analyses support the view that the maternal protective immune response is influenced by initial exposure to the bacterium. CONCLUSIONS/SIGNIFICANCE: The results show that intranasal administration of non-pregnant sheep with a low/medium dose of C. abortus results in a latent infection that leads in a subsequent pregnancy to infection of the placenta and abortion. In contrast a high dose stimulates protective immunity, resulting in a much lower abortion rate. This model will be useful in understanding the mechanisms of infection underlying latency and onset of disease, as well as in the development of novel therapeutics and

  2. Insulin resistance: β-arrestin development

    Institute of Scientific and Technical Information of China (English)

    Joseph T Rodgers; Pere Puigserver

    2009-01-01

    @@ Insulin resistance is simply the in-ability of insulin to elicit a physiologic response. While insulin resistance is most commonly associated with the pathogenesis of metabolic disorders such as type II diabetes and obesity, it is also a predisposing factor to a number of other diseases such as cancer and car-diovascular disease . There are just as many theories as to the cause of insulin resistance as there are insulin signal-ing molecules and it is very unclear as to which are the actual molecular mechanisms of insulin resistance in diseased states.

  3. Clinical use of the co-formulation of insulin degludec and insulin aspart

    DEFF Research Database (Denmark)

    Kumar, A; Awata, T; Bain, S C;

    2016-01-01

    AIMS: To provide a review of the available data and practical use of insulin degludec with insulin aspart (IDegAsp). Premixed insulins provide basal and prandial glucose control; however, they have an intermediate-acting prandial insulin component and do not provide as effective basal coverage...... as true long-acting insulins, owing to the physicochemical incompatibility of their individual components, coupled with the inflexibility of adjustment. The molecular structure of the co-formulation of IDegAsp, a novel insulin preparation, allows these two molecules to coexist without affecting...... (HbA1c ) to current modern insulins, but with lower risk of nocturnal hypoglycaemia. In prior insulin users, glycaemic control was achieved with lower or equal insulin doses vs. other basal+meal-time or premix insulin regimens. In insulin-naïve patients with T2DM, IDegAsp can be started once or twice...

  4. Oxytocin and vasopressin modulation of the neural correlates of motivation and emotion: results from functional MRI studies in awake rats.

    Science.gov (United States)

    Febo, Marcelo; Ferris, Craig F

    2014-09-11

    Oxytocin and vasopressin modulate a range of species typical behavioral functions that include social recognition, maternal-infant attachment, and modulation of memory, offensive aggression, defensive fear reactions, and reward seeking. We have employed novel functional magnetic resonance mapping techniques in awake rats to explore the roles of these neuropeptides in the maternal and non-maternal brain. Results from the functional neuroimaging studies that are summarized here have directly and indirectly confirmed and supported previous findings. Oxytocin is released within the lactating rat brain during suckling stimulation and activates specific subcortical networks in the maternal brain. Both vasopressin and oxytocin modulate brain regions involved unconditioned fear, processing of social stimuli and the expression of agonistic behaviors. Across studies there are relatively consistent brain networks associated with internal motivational drives and emotional states that are modulated by oxytocin and vasopressin. This article is part of a Special Issue entitled Oxytocin and Social Behav.

  5. The neuropharmacology of upper airway motor control in the awake and asleep states: implications for obstructive sleep apnoea

    Directory of Open Access Journals (Sweden)

    Horner Richard L

    2001-08-01

    Full Text Available Abstract Obstructive sleep apnoea is a common and serious breathing problem that is caused by effects of sleep on pharyngeal muscle tone in individuals with narrow upper airways. There has been increasing focus on delineating the brain mechanisms that modulate pharyngeal muscle activity in the awake and asleep states in order to understand the pathogenesis of obstructive apnoeas and to develop novel neurochemical treatments. Although initial clinical studies have met with only limited success, it is proposed that more rational and realistic approaches may be devised for neurochemical modulation of pharyngeal muscle tone as the relevant neurotransmitters and receptors that are involved in sleep-dependent modulation are identified following basic experiments.

  6. [Venoarterial extracorporeal membrane oxygenation in an awake patient : Use of the mobile ECMO team for fulminant pulmonary embolism].

    Science.gov (United States)

    Keller, D; Lotz, C; Kippnich, M; Adami, P; Kranke, P; Roewer, N; Kredel, M; Schimmer, C; Leyh, R; Muellenbach, R M

    2015-05-01

    The current report highlights the use of venoarterial extracorporeal membrane oxygenation (va-ECMO) in a case of pulmonary embolism complicated by right ventricular failure. A 38-year-old woman was admitted to a secondary care hospital with dyspnea and systemic hypotension. Diagnostic testing revealed a massive pulmonary embolism. Thrombolytic therapy was unsuccessful necessitating thromboendarterectomy in the presence of cardiogenic shock. To allow the necessary transport of the highly unstable patient to a tertiary care center a mobile ECMO team was called in. The team immediately initiated awake va-ECMO as a bridge to therapy. Extracorporeal support subsequently allowed a safe transportation and successful completion of the surgical procedure with complete recovery.

  7. Oral insulin--a perspective.

    Science.gov (United States)

    Raj, N K Kavitha; Sharma, Chandra P

    2003-01-01

    Diabetes mellitus is generally controlled quite well with the administration of oral medications or by the use of insulin injections. The current practice is the use of one or more doses, intermediate or long acting insulin per day. Oral insulin is a promising yet experimental method providing tight glycemic control for patients with diabetes. A biologically adhesive delivery systems offer important advantage over conventional drug delivery systems. The engineered polymer microspheres made of erodable polymer display strong adhesive interactions with gastrointestinal mucus and cellular lining can traverse both the mucosal epithelium and the follicle associated epithelium covering the lymphoid tissue of Peyer's patches. Alginate, a natural polymer recovered from seaweed is being developed as a nanoparticle for the delivery of insulin without being destroyed in the stomach. Alginate is in fact finding application in biotechnology industry as thickening agent, a gelling agent and a colloid stabilizer. Alginate has in addition, several other properties that have enabled it to be used as a matrix for entrapment and for the delivery of a variety of proteins such as insulin and cells. These properties include: a relatively inert aqueous environment within the matrix; a mild room temperature encapsulation process free of organic solvents; a high gel porosity which allows for high diffusion rates of macromolecules; the ability to control this porosity with simple coating procedures and dissolution and biodegradation of the system under normal physiological conditions.

  8. Engineering of insulin receptor isoform-selective insulin analogues.

    Directory of Open Access Journals (Sweden)

    Tine Glendorf

    Full Text Available BACKGROUND: The insulin receptor (IR exists in two isoforms, A and B, and the isoform expression pattern is tissue-specific. The C-terminus of the insulin B chain is important for receptor binding and has been shown to contact the IR just adjacent to the region where the A and B isoforms differ. The aim of this study was to investigate the importance of the C-terminus of the B chain in IR isoform binding in order to explore the possibility of engineering tissue-specific/liver-specific insulin analogues. METHODOLOGY/PRINCIPAL FINDINGS: Insulin analogue libraries were constructed by total amino acid scanning mutagenesis. The relative binding affinities for the A and B isoform of the IR were determined by competition assays using scintillation proximity assay technology. Structural information was obtained by X-ray crystallography. Introduction of B25A or B25N mutations resulted in analogues with a 2-fold preference for the B compared to the A isoform, whereas the opposite was observed with a B25Y substitution. An acidic amino acid residue at position B27 caused an additional 2-fold selective increase in affinity for the receptor B isoform for analogues bearing a B25N mutation. Furthermore, the combination of B25H with either B27D or B27E also resulted in B isoform-preferential analogues (2-fold preference even though the corresponding single mutation analogues displayed no differences in relative isoform binding affinity. CONCLUSIONS/SIGNIFICANCE: We have discovered a new class of IR isoform-selective insulin analogues with 2-4-fold differences in relative binding affinities for either the A or the B isoform of the IR compared to human insulin. Our results demonstrate that a mutation at position B25 alone or in combination with a mutation at position B27 in the insulin molecule confers IR isoform selectivity. Isoform-preferential analogues may provide new opportunities for developing insulin analogues with improved clinical benefits.

  9. Intranasal sufentanil/midazolam versus ketamine/midazolam for analgesia/sedation in the pediatric population prior to undergoing multiple dental extractions under general anesthesia: a prospective, double-blind, randomized comparison.

    Science.gov (United States)

    Roelofse, J A; Shipton, E A; de la Harpe, C J; Blignaut, R J

    2004-01-01

    This article details a double-blind, randomized study evaluating the efficacy and safety of intranasal sufentanil and intranasal midazolam (S/M) when compared with intranasal ketamine and intranasal midazolam (K/M) for sedation and analgesia in pediatric patients undergoing dental surgery. Fifty healthy ASA status 1 children aged 5-7 years, weighing 15-20 kg, and having 6 or more teeth extracted, were randomly allocated to 2 groups of 25 patients each (n = 50). In the S/M group, 25 children received intranasal sufentanil 20 microg, and intranasal midazolam 0.3 mg/kg 20 minutes before the induction of anesthesia. In the K/M group, 25 children received intranasal ketamine 5 mg/kg and intranasal midazolam 0.3 mg/kg 20 minutes before the induction of anesthesia. Sevoflurane in nitrous oxide and oxygen was used for induction and maintenance of anesthesia. This study demonstrated the safety and efficacy of both methods with ease of administration, combined with a rapid onset of action. Both groups were equally sedated. A smooth mask induction of anesthesia was experienced in the majority of children. Effective postoperative analgesia for multiple dental extractions was provided. The intranasal administration of drugs for sedation and analgesia has some promising features in preschool children undergoing multiple dental extractions.

  10. Success rates and complications of awake caudal versus spinal block in preterm infants undergoing inguinal hernia repair: A prospective study

    Directory of Open Access Journals (Sweden)

    Mahin Seyedhejazi

    2015-01-01

    Full Text Available Background: Inguinal hernia is a common disease in preterm infants necessitating surgical repair. Despite the increased risk of postoperative apnea in preterm infants, the procedure was conventionally performed under general anesthesia. Recently, regional anesthesia approaches, including spinal and caudal blocks have been proposed as safe and efficient alternative anesthesia methods in this group of patients. The current study evaluates awake caudal and spinal blocks in preterm infants undergoing inguinal hernia repair. Materials and Methods: In a randomized clinical trial, 66 neonates and infants (weight <5 kg undergoing inguinal hernia repair were recruited in Tabriz Teaching Children Hospital during a 12-month period. They were randomly divided into two equal groups; receiving either caudal block by 1 ml/kg of 0.25% bupivacaine plus 20 μg adrenaline (group C or spinal block by 1 mg/kg of 0.5% bupivacaine plus 20 μg adrenaline (group S. Vital signs and pain scores were documented during operation and thereafter up to 24 h after operation. Results: Decrease in heart rate and systolic blood pressure was significantly higher in group C throughout the study period (P < 0.05. The mean recovery time was significantly higher in group S (27.3 ± 5.5 min vs. 21.8 ± 9.3 min; P = 0.03. Postoperative need for analgesia was significantly more frequent in group S (75.8% vs. 36.4%; P = 0.001. Failure in anesthesia was significantly higher in group S (24.4% vs. 6.1%; P = 0.04. Conclusion: More appropriate success rate, duration of recovery and postoperative need of analgesics could contribute to caudal block being a superior anesthesia technique compared to spinal anesthesia in awaked preterm infants undergoing inguinal hernia repair.

  11. Advantages and disadvantages of intraoperative language tasks in awake surgery: a three-task approach for prefrontal tumors.

    Science.gov (United States)

    Rofes, A; Spena, G; Miozzo, A; Fontanella, M M; Miceli, G

    2015-12-01

    Multidisciplinary efforts are being made to provide surgical teams with sensitive and specific tasks for language mapping in awake surgery. Researchers and clinicians have elaborated different tasks over time. A fair amount of work has been directed to study the neurofunctional correlates of some of these tasks, and there is recent interest in their standardization. However, little discussion exists on the advantages and disadvantages that each task poses from the perspective of the cognitive neuroscience of language. Such an approach may be a relevant step to assess task validity, to avoid using tasks that tap onto similar processes, and to provide patients with a surgical treatment that ensures maximal tumor resection while avoiding postoperative language deficits. An understanding of the language components that each task entails may also be relevant to improve the current assessments and the ways in which tasks are administered, and to disentangle neurofunctional questions. We reviewed 17 language mapping tasks that have been used in awake surgery. Overt production tasks have been a preferred choice over comprehension tasks. Tasks tapping lexico-semantic processes, particularly object-naming, maintain their role as gold standards. Automated speech tasks are used to detect speech errors and to set the amplitude of the stimulator. Comprehension tasks, reading and writing tasks, and tasks that assess grammatical aspects of language may be regularly administered in the near future. We provide examples of a three-task approach we are administering to patients with prefrontal lesions. We believe that future advances in this area are contingent upon reviewing gold standards and introducing new assessment tools.

  12. Topical airway anesthesia for awake fiberoptic intubation: Comparison between airway nerve blocks and nebulized lignocaine by ultrasonic nebulizer

    Directory of Open Access Journals (Sweden)

    Babita Gupta

    2014-01-01

    Full Text Available Overview: Awake fiberoptic bronchoscope (FOB guided intubation is the gold standard of airway management in patients with cervical spine injury. It is essential to sufficiently anesthetize the upper airway before the performance of awake FOB guided intubation in order to ensure patient comfort and cooperation. This randomized controlled study was performed to compare two methods of airway anesthesia, namely ultrasonic nebulization of local anesthetic and performance of airway blocks. Materials and Methods: A total of 50 adult patients with cervical spine injury were randomly allocated into two groups. Group L received airway anesthesia through ultrasonic nebulization of 10 ml of 4% lignocaine and Group NB received airway blocks (bilateral superior laryngeal and transtracheal recurrent laryngeal each with 2 ml of 2% lignocaine and viscous lignocaine gargles. FOB guided orotracheal intubation was then performed. Hemodynamic variables at baseline and during the procedure, patient recall, vocal cord visibility, ease of intubation, coughing/gagging episodes, and signs of lignocaine toxicity were noted. Results: The observations did not reveal any significant differences in demographics or hemodynamic parameters at any time during the study. However, the time taken for intubation was significantly lower in Group NB as compared with the Group L. Group L had an increased number of coughing/gagging episodes as compared with Group NB. Vocal cord visibility and ease of intubation were better in patients who received airway blocks and hence the amount of supplemental lignocaine used was less in this group. Overall patient comfort was better in Group NB with fewer incidences of unpleasant recalls as compared with Group L. Conclusion: Upper airway blocks provide better quality of anesthesia than lignocaine nebulization as assessed by patient recall of procedure, coughing/gagging episodes, ease of intubation, vocal cord visibility, and time taken to intubate.

  13. The role of the hypothalamic nitric oxide in the pressor responses elicited by acute environmental stress in awake rats.

    Science.gov (United States)

    Kawa, T; Takeda, K; Harada, S; Hatta, T; Moriguchi, J; Miki, S; Morimoto, S; Itoh, H; Nakata, T; Sasaki, S; Nakagawa, M

    2002-08-09

    We quantitatively investigated the change in nitric oxide (NO) in the hypothalamic paraventricular nucleus (PVN) and its effect on cardiovascular regulation during shaker stress (SS) using brain microdialysis in awake rats. Male Wistar rats were fed either N(G)-nitro-L-arginine methyl ester (L-NAME, 0.7 g/L) or tap water for 2 weeks. Two days after implantation of an arterial catheter and guide shaft, a microdialysis probe was placed to perfuse the PVN with degassed Ringer solution at 2 microl/min in awake normotensive Wistar (CONTROL) and chronic L-NAME-treated hypertensive rats. After the rat was placed in a plastic cage set on a shaker, the blood pressure and heart rate was monitored and 10-min SS was loaded at a frequency of 200 cycles/min. Dialysate samples were analyzed by NO analyzer (based on the Griess reaction) every 10 min, and NOx (NO(2)(-) + NO(3)(-)) was measured. Plasma NOx was also measured before and after SS. Pressor responses elicited by SS were significantly greater in L-NAME-treated rats than in the CONTROL. Although NOx in the PVN dialysate were increased by SS in the CONTROL, these responses were attenuated in chronic L-NAME-treated rats. Resting plasma NOx were higher in the CONTROL than in L-NAME-treated rats. SS elicited no difference between two groups in plasma NOx. These results indicated that NO within the PVN, but not in systemic circulation, may play a role on the attenuation of the pressor responses elicited by SS. The dysfunction of NO release within the PVN may, in part, play a role in the exaggerated pressor responses in acute environmental stress.

  14. An analysis approach for high-field fMRI data from awake non-human primates.

    Directory of Open Access Journals (Sweden)

    Steffen Stoewer

    Full Text Available fMRI experiments with awake non-human primates (NHP have seen a surge of applications in recent years. However, the standard fMRI analysis tools designed for human experiments are not optimal for analysis of NHP fMRI data collected at high fields. There are several reasons for this, including the trial-based nature of NHP experiments, with inter-trial periods being of no interest, and segmentation artefacts and distortions that may result from field changes due to movement. We demonstrate an approach that allows us to address some of these issues consisting of the following steps: 1 Trial-based experimental design. 2 Careful control of subject movement. 3 Computer-assisted selection of trials devoid of artefacts and animal motion. 4 Nonrigid between-trial and rigid within-trial realignment of concatenated data from temporally separated trials and sessions. 5 Linear interpolation of inter-trial intervals and high-pass filtering of temporally continuous data 6 Removal of interpolated data and reconcatenation of datasets before statistical analysis with SPM. We have implemented a software toolbox, fMRI Sandbox (http://code.google.com/p/fmri-sandbox/, for semi-automated application of these processing steps that interfaces with SPM software. Here, we demonstrate that our methodology provides significant improvements for the analysis of awake monkey fMRI data acquired at high-field. The method may also be useful for clinical applications with subjects that are unwilling or unable to remain motionless for the whole duration of a functional scan.

  15. Focused ultrasound-enhanced intranasal brain delivery of brain-derived neurotrophic factor

    Science.gov (United States)

    Chen, Hong; Yang, Georgiana Zong Xin; Getachew, Hoheteberhan; Acosta, Camilo; Sierra Sánchez, Carlos; Konofagou, Elisa E.

    2016-06-01

    The objective of this study was to unveil the potential mechanism of focused ultrasound (FUS)-enhanced intranasal (IN) brain drug delivery and assess its feasibility in the delivery of therapeutic molecules. Delivery outcomes of fluorescently-labeled dextrans to mouse brains by IN administration either before or after FUS sonication were compared to evaluate whether FUS enhances IN delivery by active pumping or passive diffusion. Fluorescence imaging of brain slices found that IN administration followed by FUS sonication achieved significantly higher delivery than IN administration only, while pre-treatment by FUS sonication followed by IN administration was not significantly different from IN administration only. Brain-derived neurotrophic factor (BDNF), a promising neurotrophic factor for the treatment of many central nervous system diseases, was delivered by IN followed by FUS to demonstrate the feasibility of this technique and compared with the established FUS technique where drugs are injected intravenously. Immunohistochemistry staining of BDNF revealed that FUS-enhanced IN delivery achieved similar locally enhanced delivery as the established FUS technique. This study suggested that FUS enhances IN brain drug delivery by FUS-induced active pumping of the drug and demonstrated that FUS-enhanced IN delivery is a promising technique for noninvasive and localized delivery of therapeutic molecules to the brain.

  16. Thermosensitive PLA based nanodispersion for targeting brain tumor via intranasal route.

    Science.gov (United States)

    Jain, Darshana S; Bajaj, Amrita N; Athawale, Rajani B; Shikhande, Shruti S; Pandey, Abhijeet; Goel, Peeyush N; Gude, Rajiv P; Patil, Satish; Raut, Preeti

    2016-06-01

    Delivery of drugs to the brain via nasal route has been studied by many researchers. However, low residence time, mucociliary clearance and enzymatically active environment of nasal cavity pose many challenges to successful nasal delivery of drugs. We aim to deliver methotrexate by designing thermosensitive nanodispersion exhibiting enhanced residence time in nasal cavity and bypassing the blood brain barrier (BBB). PLA nanoparticles were developed using solvent evaporation technique. The developed nanoparticles were further dispersed in prepared thermosensitive vehicle of poloxamer 188 and Carbopol 934 to impart the property of increased residence time. The formulated nanoparticles demonstrated no interaction with the simulated nasal fluids (SNF), mucin, serum proteins and erythrocytes which demonstrate the safety of developed formulation for nasal administration. The penetration property of nanoparticles though the nasal mucosa was higher than the pure drug due to low mucociliary clearance. The developed nanoparticles diffused though the membrane pores and rapidly distributed into the brain portions compared to the pure drug. There was detectable and quantifiable amount of drug seen in the brain as demonstrated by in vivo brain distribution studies with considerably low amount of drug deposition in the lungs. The pharmacokinetic parameters demonstrated the enhancement in circulation half life, area under curve (AUC) and Cmax of the drug when administered intranasal in encapsulated form. Thus, the thermosensitive nanodispersions are surely promising delivery systems for delivering anticancer agents though the nasal route for potential treatment of brain tumors.

  17. Intranasal immunisation with recombinant adenovirus vaccines protects against a lethal challenge with pneumonia virus of mice.

    Science.gov (United States)

    Maunder, Helen E; Taylor, Geraldine; Leppard, Keith N; Easton, Andrew J

    2015-11-27

    Pneumonia virus of mice (PVM) infection of BALB/c mice induces bronchiolitis leading to a fatal pneumonia in a dose-dependent manner, closely paralleling the development of severe disease during human respiratory syncytial virus infection in man, and is thus a recognised model in which to study the pathogenesis of pneumoviruses. This model system was used to investigate delivery of the internal structural proteins of PVM as a potential vaccination strategy to protect against pneumovirus disease. Replication-deficient recombinant human adenovirus serotype 5 (rAd5) vectors were constructed that expressed the M or N gene of PVM pathogenic strain J3666. Intranasal delivery of these rAd5 vectors gave protection against a lethal challenge dose of PVM in three different mouse strains, and protection lasted for at least 20 weeks post-immunisation. Whilst the PVM-specific antibody response in such animals was weak and inconsistent, rAd5N primed a strong PVM-specific CD8(+) T cell response and, to a lesser extent, a CD4(+) T cell response. These findings suggest that T-cell responses may be more important than serum IgG in the observed protection induced by rAd5N.

  18. The Phage Lysin PlySs2 Decolonizes Streptococcus suis from Murine Intranasal Mucosa

    Science.gov (United States)

    Gilmer, Daniel B.; Schmitz, Jonathan E.; Thandar, Mya; Euler, Chad W.; Fischetti, Vincent A.

    2017-01-01

    Streptococcus suis infects pigs worldwide and may be zoonotically transmitted to humans with a mortality rate of up to 20%. S. suis has been shown to develop in vitro resistance to the two leading drugs of choice, penicillin and gentamicin. Because of this, we have pursued an alternative therapy to treat these pathogens using bacteriophage lysins. The bacteriophage lysin PlySs2 is derived from an S. suis phage and displays potent lytic activity against most strains of that species including serotypes 2 and 9. At 64 μg/ml, PlySs2 reduced multiple serotypes of S. suis by 5 to 6-logs within 1 hour in vitro and exhibited a minimum inhibitory concentration (MIC) of 32 μg/ml for a S. suis serotype 2 strain and 64 μg/ml for a serotype 9 strain. Using a single 0.1-mg dose, the colonizing S. suis serotype 9 strain was reduced from the murine intranasal mucosa by >4 logs; a 0.1-mg dose of gentamicin reduced S. suis by 5-logs. While resistance to gentamicin was induced after systematically increasing levels of gentamicin in an S. suis culture, the same protocol resulted in no observable resistance to PlySs2. Thus, PlySs2 has both broad and high killing activity against multiple serotypes and strains of S. suis, making it a possible tool in the control and prevention of S. suis infections in pigs and humans. PMID:28046082

  19. Safety and efficacy of adjunctive intranasal mitomycin C and triamcinolone in endonasal endoscopic dacryocystorhinostomy.

    Science.gov (United States)

    Li, Emmy Y; Cheng, Andy C; Wong, Alex C; Sze, Amy M; Yuen, Hunter K

    2016-02-01

    One of the common causes of failure in dacryocystorhinostomy for nasolacrimal duct obstruction (NLDO) is mucosal scarring and fibrosis around the ostium. Steroid and mitomycin C (MMC) can potentially reduce scarring by their action on the inflammatory and proliferative phase of wound healing, respectively. The purpose of this study is to evaluate the safety and efficacy of combined usage of adjunctive MMC and intranasal triamcinolone (TA) in endonasal endoscopic dacryocystorhinostomy (EE-DCR). This is a retrospective interventional case series. All patients underwent mechanical EE-DCR in two regional hospitals in Hong Kong from January 2005 to December 2006 were included. All received intraoperative MMC application for 5 min and gelfoam soaked with TA onto the ostium. Main outcome measures include the anatomical and functional success rate at follow-up at least 6 months after operation. Other outcomes include complications occurred during and after operation. A total of 73 EE-DCR were performed in 69 patients. Three patients had simultaneous bilateral DCR; one had sequential DCRs for both sides. At the last follow-up, anatomical success was achieved in 68 cases (93 %) and both anatomical with functional success in 67 cases (92 %). No major complication was observed. Minor complications included asymptomatic mucosal adhesion between the nasal septum and lateral nasal wall in one patient and moderate secondary hemorrhage in another. EE-DCR with adjunctive MMC and TA is a safe and successful procedure for the treatment of NLDO.

  20. Intranasal immunization against dental caries with a Streptococcus mutans-enriched fimbrial preparation.

    Science.gov (United States)

    Fontana, M; Dunipace, A J; Stookey, G K; Gregory, R L

    1999-05-01

    Streptococcus mutans has been identified as the major etiological agent of human dental caries. The first step in the initiation of infection by this pathogenic bacterium is its attachment (i.e., through bacterial surface proteins such as glucosyltransferases, P1, glucan-binding proteins, and fimbriae) to a suitable receptor. It is hypothesized that a mucosal vaccine against a combination of S. mutans surface proteins would protect against dental caries by inducing specific salivary immunoglobulin A (IgA) antibodies which may reduce bacterial pathogenesis and adhesion to the tooth surface by affecting several adhesins simultaneously. Conventional Sprague-Dawley rats, infected with S. mutans at 18 to 20 days of age, were intranasally immunized with a mixture of S. mutans surface proteins, enriched for fimbriae and conjugated with cholera toxin B subunit (CTB) plus free cholera toxin (CT) at 13, 15, 22, 29, and 36 days of age (group A). Control rats were either not immunized (group B) or immunized with adjuvant alone (CTB and CT [group C]). At the termination of the study (when rats were 46 days of age), immunized animals (group A) had significantly (P dental caries.