Sex and ApoE Genotype Differences in Treatment Response to Two Doses of Intranasal Insulin in Adults with Mild Cognitive Impairment or Alzheimer’s Disease

PubMed Central

Claxton, Amy; Baker, Laura D.; Wilkinson, Charles W.; Trittschuh, Emily H.; Chapmana, Darla; Watson, G. Stennis; Cholerton, Brenna; Plymate, Stephen R.; Arbuckle, Matthew; Craft, Suzanne

2014-01-01

A previous clinical trial demonstrated that four months of treatment with intranasal insulin improves cognition and function for patients with Alzheimer’s disease (AD) or mild cognitive impairment (MCI), but prior studies suggest that response to insulin treatment may differ by sex and ApoE ε4 carriage. Thus, responder analyses using repeated measures analysis of covariance were completed on the trial’s 104 participants with MCI or AD who received either placebo or 20 or 40 IU of insulin for 4 months, administered by a nasal delivery device. Results indicate that men and women with memory impairment responded differently to intranasal insulin treatment. On delayed story memory, men and women showed cognitive improvement when taking 20 IU of intranasal insulin, but only men showed cognitive improvement for the 40 IU dose. The sex difference was most apparent for ApoE ε4 negative individuals. For the 40 IU dose, ApoE ε4 negative men improved while ApoE ε4 negative women worsened. Their ApoE ε4 positive counterparts remained cognitively stable. This sex effect was not detected in functional measures. However, functional abilities were relatively preserved for women on either dose of intranasal insulin compared with men. Unlike previous studies with young adults, neither men nor women taking intranasal insulin exhibited a significant change in weight over 4 months of treatment. PMID:23507773

Intranasal insulin modulates intrinsic reward and prefrontal circuitry of the human brain in lean women.

PubMed

Kullmann, Stephanie; Frank, Sabine; Heni, Martin; Ketterer, Caroline; Veit, Ralf; Häring, Hans-Ulrich; Fritsche, Andreas; Preissl, Hubert

2013-01-01

There is accumulating evidence that food consumption is controlled by a wide range of brain circuits outside of the homeostatic system. Activation in these brain circuits may override the homeostatic system and also contribute to the enormous increase of obesity. However, little is known about the influence of hormonal signals on the brain's non-homeostatic system. Thus, selective insulin action in the brain was investigated by using intranasal application. We performed 'resting-state' functional magnetic resonance imaging in 17 healthy lean female subjects to assess intrinsic brain activity by fractional amplitude of low-frequency fluctuations (fALFF) before, 30 and 90 min after application of intranasal insulin. Here, we showed that insulin modulates intrinsic brain activity in the hypothalamus and orbitofrontal cortex. Furthermore, we could show that the prefrontal and anterior cingulate cortex response to insulin is associated with body mass index. This demonstrates that hormonal signals as insulin may reduce food intake by modifying the reward and prefrontal circuitry of the human brain, thereby potentially decreasing the rewarding properties of food. Due to the alarming increase in obesity worldwide, it is of great importance to identify neural mechanisms of interaction between the homeostatic and non-homeostatic system to generate new targets for obesity therapy. Copyright © 2012 S. Karger AG, Basel.

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

ERIC Educational Resources Information Center

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

2008-01-01

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

Intranasal Insulin Prevents Anesthesia-Induced Cognitive Impairment and Chronic Neurobehavioral Changes.

PubMed

Chen, Yanxing; Dai, Chun-Ling; Wu, Zhe; Iqbal, Khalid; Liu, Fei; Zhang, Baorong; Gong, Cheng-Xin

2017-01-01

General anesthesia increases the risk for cognitive impairment post operation, especially in the elderly and vulnerable individuals. Recent animal studies on the impact of anesthesia on postoperative cognitive impairment have provided some valuable insights, but much remains to be understood. Here, by using mice of various ages and conditions, we found that anesthesia with propofol and sevoflurane caused significant deficits in spatial learning and memory, as tested using Morris Water Maze (MWM) 2-6 days after anesthesia exposure, in aged (17-18 months old) wild-type (WT) mice and in adult (7-8 months old) 3xTg-AD mice (a triple transgenic mouse model of Alzheimer's disease (AD)), but not in adult WT mice. Anesthesia resulted in long-term neurobehavioral changes in the fear conditioning task carried out 65 days after exposure to anesthesia in 3xTg-AD mice. Importantly, daily intranasal administration of insulin (1.75 U/mouse/day) for only 3 days prior to anesthesia completely prevented the anesthesia-induced deficits in spatial learning and memory and the long-term neurobehavioral changes tested 65 days after exposure to anesthesia in 3xTg-AD mice. These results indicate that aging and AD-like brain pathology increase the vulnerability to cognitive impairment after anesthesia and that intranasal treatment with insulin can prevent anesthesia-induced cognitive impairment.

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

PubMed

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

2014-12-01

Stress glucocorticoids and insulin are important endocrine regulators of energy homeostasis, but little is known about their central interaction on the reward-related processing of food cues. According to a balanced group design, healthy food deprived men received either 40IU intranasal insulin (n=13), 30mg oral cortisol (n=12), both (n=15), or placebo (n=14). Acoustic startle responsiveness was assessed during presentation of food and non-food pictures. Cortisol enhanced startle responsiveness during visual presentation of "high glycemic" food pictures, but not during presentation of neutral and pleasant non-food pictures. Insulin had no effect. Based on the "frustrative nonreward" model these results suggest that the reward value of high glycemic food items is specifically increased by cortisol. Copyright © 2014 Elsevier Ltd. All rights reserved.

Intranasal insulin treatment alleviates methamphetamine induced anxiety-like behavior and neuroinflammation.

PubMed

Beirami, Elmira; Oryan, Shahrbanoo; Seyedhosseini Tamijani, Seyedeh Masoumeh; Ahmadiani, Abolhassan; Dargahi, Leila

2017-11-01

Insulin, as a peptide hormone, has recently gained attention for its pro-cognitive, anti-inflammatory and neuroprotective effects in the central nervous system (CNS). Most studies have indicated anxiogenic and neuroinflammatory effects of methamphetamine (MA) and other psychostimulants, even after periods of abstinence. The present study aimed to examine whether intranasal (IN) insulin treatment with high CNS bioavailability and minimal systemic side effects, can reverse the anxiety-like behavior and neuroinflammation induced by repeated MA administration. In male wistar rats, escalating doses of MA (1-10mg/kg, i.p.) were administrated twice a day for 10 consecutive days. IN insulin treatment (0.5IU/day, for 7days after MA discontinuation) attenuated MA-induced anxiety-like behavior in the elevated plus maze task, and significantly decreased the levels of glial cell markers (GFAP and Iba1), pro-inflammatory cytokines (TNF-α and IL-6) as well as COX2 and NF-κB players of neuroinflammation, in the hippocampus of MA-treated animals. These findings introduce insulin as a potential therapeutic approach for the treatment of MA aversive symptoms. Copyright © 2017 Elsevier B.V. All rights reserved.

Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial.

PubMed

Craft, Suzanne; Baker, Laura D; Montine, Thomas J; Minoshima, Satoshi; Watson, G Stennis; Claxton, Amy; Arbuckle, Matthew; Callaghan, Maureen; Tsai, Elaine; Plymate, Stephen R; Green, Pattie S; Leverenz, James; Cross, Donna; Gerton, Brooke

2012-01-01

To examine the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease (AD). Randomized, double-blind, placebo-controlled trial. Clinical research unit of a Veterans Affairs medical center. The intent-to-treat sample consisted of 104 adults with amnestic mild cognitive impairment (n = 64) or mild to moderate AD (n = 40). Intervention  Participants received placebo (n = 30), 20 IU of insulin (n = 36), or 40 IU of insulin (n = 38) for 4 months, administered with a nasal drug delivery device (Kurve Technology, Bothell, Washington). Primary measures consisted of delayed story recall score and the Dementia Severity Rating Scale score, and secondary measures included the Alzheimer Disease's Assessment Scale-cognitive subscale (ADAS-cog) score and the Alzheimer's Disease Cooperative Study-activities of daily living (ADCS-ADL) scale. A subset of participants underwent lumbar puncture (n = 23) and positron emission tomography with fludeoxyglucose F 18 (n = 40) before and after treatment. Outcome measures were analyzed using repeated-measures analysis of covariance. Treatment with 20 IU of insulin improved delayed memory (P < .05), and both doses of insulin (20 and 40 IU) preserved caregiver-rated functional ability (P < .01). Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD (P < .05). Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the Aβ42 level and in the tau protein-to-Aβ42 ratio in cerebrospinal fluid. Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal, frontal, precuneus, and cuneus

Brain temperature in volunteers subjected to intranasal cooling.

PubMed

Covaciu, L; Weis, J; Bengtsson, C; Allers, M; Lunderquist, A; Ahlström, H; Rubertsson, S

2011-08-01

Intranasal cooling can be used to initiate therapeutic hypothermia. However, direct measurement of brain temperature is difficult and the intra-cerebral distribution of temperature changes with cooling is unknown. The purpose of this study was to measure the brain temperature of human volunteers subjected to intranasal cooling using non-invasive magnetic resonance (MR) methods. Intranasal balloons catheters circulated with saline at 20°C were applied for 60 min in ten awake volunteers. No sedation was used. Brain temperature changes were measured and mapped using MR spectroscopic imaging (MRSI) and phase-mapping techniques. Heart rate and blood pressure were monitored throughout the experiment. Rectal temperature was measured before and after the cooling. Mini Mental State Examination (MMSE) test and nasal inspection were done before and after the cooling. Questionnaires about the subjects' personal experience were completed after the experiment. Brain temperature decrease measured by MRSI was -1.7 ± 0.8°C and by phase-mapping -1.8 ± 0.9°C (n = 9) at the end of cooling. Spatial distribution of temperature changes was relatively uniform. Rectal temperature decreased by -0.5 ± 0.3°C (n = 5). The physiological parameters were stable and no shivering was reported. The volunteers remained alert during cooling and no cognitive dysfunctions were apparent in the MMSE test. Postcooling nasal examination detected increased nasal secretion in nine of the ten volunteers. Volunteers' acceptance of the method was good. Both MR techniques revealed brain temperature reductions after 60 min of intranasal cooling with balloons circulated with saline at 20°C in awake, unsedated volunteers.

A randomized, double-blind, placebo-controlled, crossover trial evaluating the effect of intranasal insulin on cognition and mood in individuals with treatment-resistant major depressive disorder.

PubMed

Cha, Danielle S; Best, Michael W; Bowie, Christopher R; Gallaugher, Laura Ashley; Woldeyohannes, Hanna O; Soczynska, Joanna K; Lewis, Gary; MacQueen, Glenda; Sahakian, Barbara J; Kennedy, Sidney H; Lui, Jane P; Mansur, Rodrigo B; McIntyre, Roger S

2017-03-01

Cognitive dysfunction in major depressive disorder (MDD) is identified as a primary therapeutic target; no current treatment is approved for the treatment of cognitive dysfunction in MDD. We examined whether intranasal insulin offered a beneficial effect across measures of cognitive function in adults with MDD. Thirty-five adults (18-65 years of age: 47.09±9.89) meeting criteria for a major depressive episode as per the Diagnostic and Statistical Manual (DSM)-IV-Treatment Revised were included in this randomized, double blind, placebo-controlled, crossover design study. Subjects were not stratified based on baseline cognitive deficit. Subjects were randomized to 4 weeks of either intranasal insulin 40 International Units (IU) taken four times a day (i.e., morning, afternoon, evening, and before bed) (QID) (n=19) or placebo (n=16). No between group differences were observed in change from baseline on total Montgomery Åsberg Depression Rating Scale (MADRS) score (25.98±2.81), in either of the Positive or Negative subscales of the Positive and Negative Affect Schedule (PANAS), or on a global index of neurocognition. The possibility of practice and/or carry over effect could not be excluded. Methodological refinement (e.g., stratification of subjects based on baseline cognitive deficit) may have augmented assay sensitivity. Intranasal insulin did not demonstrate statistically significant improvements on overall mood, aspects of emotional processing, neurocognitive function, or self-reported quality of life patient reported outcomes. Copyright © 2016 Elsevier B.V. All rights reserved.

Central insulin administration improves odor-cued reactivation of spatial memory in young men.

PubMed

Brünner, Yvonne F; Kofoet, Anja; Benedict, Christian; Freiherr, Jessica

2015-01-01

Insulin receptors are ubiquitously found in the human brain, comprising the olfactory bulb, essential for odor processing, and the hippocampus, important for spatial memory processing. The present study aimed at examining if intranasal insulin, which is known to transiently increase brain insulin levels in humans, would improve odor-cued reactivation of spatial memory in young men. We applied a double-blind, placebo-controlled, counterbalanced within-subject design. The study was conducted at the research unit of a university hospital. Interventions/Participants/Main Outcome Measures: Following intranasal administration of either insulin (40 I.U.) or placebo, male subjects (n = 18) were exposed to eight odors. During each odor exposure, a green-colored field was presented on a 17-in. computer screen. During immediate recall (comprising 3 runs), the participants were re-exposed to each odor cue, and were asked to select the corresponding field (with visual feedback after each response). The delayed recall was scheduled ∼10 min later (without feedback). To test if insulin's putative effect on odor-place memory would be domain-specific, participants also performed a separate place and odor recognition task. Intranasal insulin improved the delayed but not immediate odor-cued recall of spatial memory. This effect was independent of odor type and in the absence of systemic side effects (eg, fasting plasma glucose levels remained unaltered). Place and odor recognition were unaffected by the insulin treatment. These findings suggest that acute intranasal insulin improves odor-cued reactivation of spatial memory in young men.

[Awake craniotomy].

PubMed

2012-01-01

The article is a literature review on awake craniotomy. History of method, indications and contraindications, necessary conditions for successful application as well as complications and their prevention and correction are considered Outcomes in patients with neuro-oncological pathology and in patients with intractable epilepsy after awake craniotomy are also analyzed. It's also shown that awake craniotomy can make removal of tumors near eloquent cortex more radical and improve neurological outcome in such patients.

Changes in insulin and insulin signaling in Alzheimer’s disease: cause or consequence?

PubMed Central

Stanley, Molly; Macauley, Shannon L.

2016-01-01

Individuals with type 2 diabetes have an increased risk for developing Alzheimer’s disease (AD), although the causal relationship remains poorly understood. Alterations in insulin signaling (IS) are reported in the AD brain. Moreover, oligomers/fibrils of amyloid-β (Aβ) can lead to neuronal insulin resistance and intranasal insulin is being explored as a potential therapy for AD. Conversely, elevated insulin levels (ins) are found in AD patients and high insulin has been reported to increase Aβ levels and tau phosphorylation, which could exacerbate AD pathology. Herein, we explore whether changes in ins and IS are a cause or consequence of AD. PMID:27432942

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

PubMed Central

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

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

PubMed

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

2017-03-23

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.

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

PubMed

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

2016-05-01

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

Calcitonin intranasal--unigene: Salcatonin intranasal--unigene.

PubMed

2004-01-01

An intranasal spray formulation of recombinant salmon calcitonin [salcatonin] is in development with Unigene Laboratories as therapy for postmenopausal osteoporosis. Calcitonin is an endogenous polypeptide hormone that regulates calcium and bone metabolism. It is produced by the parafollicular cells of the thyroid gland in humans and other species. Calcitonin inhibits bone loss through the suppression of osteoclast activity. Salmon calcitonin is approximately 40-50 times more potent than natural human calcitonin at inhibiting osteoclast function. It can be obtained naturally from salmon or can be synthesised with the same chemical structure. Calcitonin was originally available only as an injectable formulation, but in recent years more convenient formulations have become available. Unigene is actively seeking to license its intranasal calcitonin product in Europe and other territories outside the US. nigene licensed its intranasal calcitonin product to Upsher-Smith Laboratories in December 2002, under a $US10 million exclusive US licensing agreement. Under the terms of the agreement, Unigene received an upfront payment of $US3 million from Upsher-Smith and will be eligible to receive milestone payments and royalty payments on product sales. Unigene will be responsible for manufacturing the product at its Boonton facility in New Jersey, USA, and will sell finished calcitonin product to Upsher-Smith. Upsher-Smith will package, market and distribute the product nationwide. Unigene granted an exclusive license to Faran Laboratories in September 2003 for its intranasal calcitonin osteoporosis product in Greece. Unigene will sell the finished product to Faran, who will promote and market it throughout the country after Unigene obtains European regulatory approval and local pricing approval. Unigene will receive an upfront payment and is eligible to receive milestone payments prior to product launch. Faran will pay Unigene a fixed price for each unit of product received

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

ERIC Educational Resources Information Center

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

2009-01-01

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

[Co-administration of intranasally delivered insulin and proinsulin C-peptide to rats with the types 1 and 2 diabetes mellitus restores their metabolic parameters.

PubMed

Derkach, K V; Bondareva, V M; Shpakov, A O

2017-01-01

The C-peptide, the product of proinsulin proteolysis, not only is a signal molecule, but also, forming a complex with insulin, is able to modulate the signaling functions of insulin. The signaling systems sensitive to insulin in the hypothalamus and other brain areas are among the targets of insulin. We hypothesized that in systemic deficiency of insulin and C-peptide in the type 1 diabetes mellitus (DM) and in severe forms of the type 2 DM, the increase in the level of C-peptide in the CNS will improve central effects of insulin, including its influence on peripheral metabolism. To verify this, the influence of separate and co-administration of intranasal insulin (II) and C-peptide (IP) on their metabolic parameters and sensitivity to insulin in rats with acute and mild type 1 DM induced by the treatment with streptozotocin at the doses of 60 and 35 mg/kg and in rats with neonatal type 2 DM corresponding to severe long-term form of type 2 DM in human was studied. The treatment of animals with II and IP was carried out for 7 days in the daily doses of 20 and 10 μg/rat, respectively. The co-administration of II and IP leading to an increase of insulin and C-peptide levels in the brain was most effective. In rats with type 1 DM treated with the combination of II plus IP, hyperglycemia was decreased and weight loss was prevented. In rats with type 2 DM, co-administration of II and IP led to the normalization of glucose homeostasis and the increase in insulin sensitivity, as shown by glucose-tolerance and insulin-glucose tolerance tests, and to improvement of lipid metabolism, as demonstrated by the decrease in the atherogenic index. The effectiveness of monotherapy with II was lower than in the case of a combination of II+IP, while monotherapy with C-peptide had little effect on the indicators studied. Thus, the simultaneous increase of insulin and C-peptide levels in the brain in the conditions of their deficiency in diabetic pathology can be considered as one of

Awake craniotomy

PubMed Central

Bajunaid, Khalid M.; Ajlan, Abdulrazag M.

2015-01-01

Objective: To report the personal experiences of patients undergoing awake craniotomy for brain tumor resection. Methods: We carried out a qualitative descriptive survey of patients’ experiences with awake craniotomies for brain tumor resection. The survey was conducted through a standard questionnaire form after the patient was discharged from the hospital. Results: Of the 9 patients who met the inclusion criteria and underwent awake craniotomy, 3 of those patients reported no recollection of the operation. Five patients had auditory recollections from the operation. Two-thirds (6/9) reported that they did not perceive pain. Five patients remembered the head clamp fixation, and 2 of those patients classified the pain from the clamp as moderate. None of the patients reported that the surgery was more difficult than anticipated. Conclusion: Awake craniotomy for surgical resection of brain tumors was well tolerated by patients. Most patients reported that they do not recall feeling pain during the operation. However, we feel that further work and exploration are needed in order to achieve better control of pain and discomfort during these types of operations. PMID:26166593

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

PubMed Central

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

2016-01-01

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

[Awake craniotomy for brain tumours].

PubMed

Milos, Peter; Metcalf, Kerstin; Vigren, Patrick; Lindehammar, Hans; Nilsson, Malin; Boström, Sverre

2016-10-11

Awake craniotomy for brain tumours  Awake neurosurgery is a useful method in lesions near eloquent brain areas, particularly low-grade gliomas.The aim is to maximise tumour resection and preserve neurological function. We performed 40 primary awake surgeries and 8 residual surgeries. Patients were operated awake throughout the procedure or with a laryngeal mask and general anaesthesia during the opening stage and then awake during intracerebral surgery. Language and motor function were mapped with direct cortical stimulation, motor evoked potential and standardised neurological testing. Radiologically, complete resection was achieved in 18 out of 40 patients in the primary surgeries. Full neurological recovery at three months was observed in 29 patients. Of the 11 patients with persisting neurological deficits at three months, symptoms were present preoperatively in 9 patients. We conclude that awake surgery, combined with intraoperative neurophysiological methods, is a safe method to improve treatment for low-grade gliomas.

[Anesthesiological management of awake craniotomy : Asleep-awake-asleep technique or without sedation].

PubMed

Seemann, M; Zech, N; Graf, B; Hansen, E

2015-02-01

Awake craniotomy is indicated in deep brain stimulation (DBS) for treatment of certain movement disorders, such as in Parkinson disease patients or in the surgery of brain tumors in close vicinity to the language area. The standard procedure is the asleep-awake-asleep technique where general anesthesia or analgosedation is intermittently interrupted for neurological testing. In DBS the intraoperative improvement of symptoms, stereotactic navigation and microelectrode reading guide to the optimal position. In brain tumor resection, reversible functional impairments during electrical stimulation on the brain surface (brain mapping) show the exact individual position of eloquent or motoric areas that should be protected.The anesthesiology procedures used are very variable. It is a balancing act between overdosing of anesthetics with impairment of respiration and alertness and underdosing with pain, strain and stress for the patient. For the asleep-awake-asleep technique high acceptance but also frequent and partly severe complications have been reported. The psychological stress for the patient can be immense. Obviously, a feeling of being left alone and being at someone's mercy is not adequately treated by drugs and performance of the neurological tests is undoubtedly better and more reliable with less pharmacological impairment. Cranial nerve blocks can reduce the amount of anesthetics as they provide analgesia of the scalp more efficiently than local infiltration. With these nerve blocks, a strong therapeutic relationship and a specific communication, sedatives can be avoided and the need for opioids markedly reduced or abolished. The suggestive communication promotes for instance dissociation to an inner safe refuge, as well as reframing of disturbing noises and sensations. Each of the methods applied for awake craniotomy can profit from the principles of this awake-awake-awake technique.

Surgeon-patient communication during awake procedures.

PubMed

Smith, Claire S; Guyton, Kristina; Pariser, Joseph J; Siegler, Mark; Schindler, Nancy; Langerman, Alexander

2017-06-01

Surgeons are increasingly performing procedures on awake patients. Communication during such procedures is complex and underexplored in the literature. Surgeons were recruited from the faculty of 2 hospitals to participate in an interview regarding their approaches to communication during awake procedures. Three researchers used the constant comparative method to transcribe, code, and review interviews until saturation was reached. Twenty-three surgeons described the advantages and disadvantages of awake procedures, their communication with the awake patient, their interactions with staff and with trainees, the environment of awake procedures, and how communication in this context is taught and learned. Surgeons recognized communication during awake procedures as important and reported varied strategies for ensuring patient comfort in this context. However, they also acknowledged challenges with multiparty communication during awake procedures, especially in balancing commitments to teaching with their duty to comfort the patient. Copyright © 2016 Elsevier Inc. All rights reserved.

Demonstration of analgesic effect of intranasal ketamine and intranasal fentanyl for postoperative pain after pediatric tonsillectomy.

PubMed

Yenigun, Alper; Yilmaz, Sinan; Dogan, Remzi; Goktas, Seda Sezen; Calim, Muhittin; Ozturan, Orhan

2018-01-01

Tonsillectomy is one of the oldest and most commonly performed surgical procedure in otolaryngology. Postoperative pain management is still an unsolved problem. In this study, our aim is to demonstrate the efficacy of intranasal ketamine and intranasal fentanyl for postoperative pain relief after tonsillectomy in children. This randomized-controlled study was conducted to evaluate the effects of intranasal ketamine and intranasal fentanyl in children undergoing tonsillectomy. Tonsillectomy performed in 63 children were randomized into three groups. Group I received: Intravenous paracetamol (10 mg/kg), Group II received intranasal ketamine (1.5 mg/kg ketamine), Group III received intranasal fentanyl (1.5 mcg/kg). The Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) and Wilson sedation scale scores were recorded at 15, 30, 60 min, 2 h, 6hr, 12 h and 24 h postoperatively. Patients were interviewed on the day after surgery to assess the postoperative pain, nightmares, hallucinations, nausea, vomiting and bleeding. Intranasal ketamine and intranasal fentanyl provided significantly stronger analgesic affects compared to intravenous paracetamol administration at postoperative 15, 30, 60 min and at 2, 6, 12 and 24 h in CHEOPS (p < 0.05). Sedative effects were observed in three patients in the intranasal ketamine administration group. No such sedative effect was seen in the groups that received intranasal fentanyl and intravenous paracetamol in Wilson Sedation Scale (p < 0.05). Cognitive impairment, constipation, nausea, vomiting and bleeding were not observed in any of the groups. This study showed that either intranasal ketamine and intranasal fentanyl were more effective than paracetamol for postoperative analgesia after pediatric tonsillectomy. Sedative effects were observed in three patients with the group of intranasal ketamine. There was no significant difference in the efficacy of IN Ketamine and IN Fentanyl for post-tonsillectomy pain

Awake craniotomy for tumor resection.

PubMed

Attari, Mohammadali; Salimi, Sohrab

2013-01-01

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.

Awake craniotomy for tumor resection

PubMed Central

Attari, Mohammadali; Salimi, Sohrab

2013-01-01

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. PMID:24223378

[Awake craniotomy].

PubMed

Kobyakov, G L; Lubnin, A Yu; Kulikov, A S; Gavrilov, A G; Goryaynov, S A; Poddubskiy, A A; Lodygina, K S

2016-01-01

Awake craniotomy is a neurosurgical intervention aimed at identifying and preserving the eloquent functional brain areas during resection of tumors located near the cortical and subcortical language centers. This article provides a review of the modern literature devoted to the issue. The anatomical rationale and data of preoperative functional neuroimaging, intraoperative electrophysiological monitoring, and neuropsychological tests as well as the strategy of active surgical intervention are presented. Awake craniotomy is a rapidly developing technique aimed at both preserving speech and motor functions and improving our knowledge in the field of speech psychophysiology.

Newer insulin therapies for management of type 1 and type 2 diabetes mellitus.

PubMed

Plum, Mary-Beth F; Sicat, Brigitte L; Brokaw, Deborah K

2003-05-01

To provide an overview of type 1 and type 2 diabetes mellitus and review newer insulin therapies used to manage patients with diabetes. A MEDLINE search covering articles published from 1985 to March 2003 was conducted to identify English-language literature available on the management of diabetes, specifically focusing on the newer insulin products insulin glargine and insulin aspart, and any other novel insulin therapies (Medical Subject Headings [MeSH] search terms used were: diabetes, insulin, insulin aspart, insulin glargine, inhaled insulin, intranasal insulin, oral insulin). These articles, abstracts, and data provided by the pharmaceutical manufacturers were reviewed to collect pertinent data. Additional references were obtained from the bibliographies of those publications. Human studies presenting safety or efficacy information on newer insulin formulations. Specific insulin formulations were reviewed with regard to background information, pharmacokinetic data, relevant clinical studies, U.S. Food and Drug Administration-approved indications, dosing and administration, adverse effects, storage, cost, and role in therapy. Insulin therapy is essential in the management of patients with type 1 diabetes, as well as in many patients with type 2 diabetes. No single insulin product currently on the U.S. market mimics natural endogenous insulin secretion. Problems encountered with traditional insulin products include variable absorption, peaks leading to hypoglycemic events, troughs leading to inadequate duration of response, and difficulty accurately timing injections in relation to meals. Insulin analogs such as insulin glargine and insulin aspart have been synthesized in an effort to overcome those difficulties. Novel insulin formulations (oral, intranasal, and inhaled) are also in various stages of investigation. Insulin glargine and insulin aspart are two of the newest insulin products approved for managing diabetes mellitus. Clinical trials have shown that

Awake right hemisphere brain surgery.

PubMed

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

2015-12-01

We report the indications and outcomes of awake right hemispheric brain surgery, as well as a rare patient with crossed aphasia. Awake craniotomies are often performed to protect eloquent cortex. We reviewed the medical records for 35 of 96 patients, in detail, who had awake right hemisphere brain operations. Intraoperative cortical mapping of motor and/or language function was performed in 29 of the 35 patients. A preoperative speech impairment and left hand dominance were the main indicators for awake right-sided craniotomies in patients with right hemisphere lesions. Four patients with lesion proximity to eloquent areas underwent awake craniotomies without cortical mapping. In addition, one patient had a broncho-pulmonary fistula, and another had a recent major cardiac procedure that precluded awake surgery. An eloquent cortex representation was identified in 14 patients (48.3%). Postoperatively, seven of 17 patients (41.1%) who presented with weakness, experienced improvements in their motor functions, 11 of 16 (68.7%) with seizures became seizure-free, and seven of nine (77.7%) with moderate to severe headaches and one of two with a visual field deficit improved significantly. There were also improvements in speech and language functions in all patients who presented with speech difficulties. A right sided awake craniotomy is an excellent option for left handed patients, or those with right sided cortical lesions that result in preoperative speech impairments. When combined with intraoperative cortical mapping, both speech and motor function can be well preserved. Copyright © 2015 Elsevier Ltd. All rights reserved.

The clinical management of awake bruxism.

PubMed

Goldstein, Ronald E; Auclair Clark, Wendy

2017-06-01

Awake bruxism is a common clinical condition that often goes undetected, often leading to pain or damaged teeth and restorations. The authors searched electronic databases regarding the treatment and effects of awake bruxism compared with those of sleep bruxism. The authors used the search terms diurnal bruxism and oral parafunction. The authors combined information from relevant literature with clinical experience to establish a recommended protocol for diagnosis and treatment. The authors found articles regarding the diagnosis and treatment of bruxism. The authors combined information from the articles with a review of clinical cases to establish a treatment protocol for awake bruxism. Literature and clinical experience indicate a lack of patient awareness and, thus, underreporting of awake bruxism. As a result, myriad dental consequences can occur from bruxism. The authors propose a need for increased awareness, for both patients and professionals, particularly of the number of conditions related to awake bruxism. Clinicians should look for clinical signs and symptoms of awake bruxism and use minimally invasive treatment modalities. Copyright © 2017 American Dental Association. Published by Elsevier Inc. All rights reserved.

How I do it: Awake craniotomy.

PubMed

Hill, Ciaran Scott; Severgnini, Flavio; McKintosh, Edward

2017-01-01

Awake craniotomy allows continuous assessment of a patient's clinical and neurological status during open brain surgery. This facilitates early detection of interference with eloquent cortex, and hence can allow a surgeon to maximize resection margins without compromising neurological function. Awake craniotomy requires an effective scalp blockade, intraoperative assessment, and a carefully co-ordinated theatre team. A variety of clinical and electrophysiological techniques can be used to assess cortical function. Effective scalp blockade and awake craniotomy provides the opportunity to intraoperatively assess cortical function in the awake patient, thus providing an important neurosurgical option for lesions near eloquent cortex.

History of intranasal splints.

PubMed

Lau, J; Elhassan, H A; Singh, N

2018-03-01

Intranasal splints have long been utilised as a post-operative adjunct in septoplasty, intended to reduce the risk of adhesions and haematoma formation, and to maintain alignment during healing. A Medline literature review of the history and evolution of intranasal splint materials and designs was performed. Advantages and disadvantages of various splints are discussed. Intranasal splints fashioned from X-ray film were first reported in 1955. Since then, a variety of materials have been utilised, including polyethylene coffee cup lids, samarium cobalt magnets and dental utility wax. Most contemporary splints are produced from silicon rubber or polytetrafluoroethylene (Teflon). Designs have varied in thickness, flexibility, shape, absorption and the inclusion of built-in airway tubes. Future directions in splint materials and designs are discussed. Intranasal splints have steadily evolved since 1955, with numerous novel innovations. Despite their simplicity, they play an important role in nasal surgery and will continue to evolve over time.

Awake craniotomy: improving the patient's experience.

PubMed

Potters, Jan-Willem; Klimek, Markus

2015-10-01

Awake craniotomy patients are exposed to various stressful stimuli while their attention and vigilance is important for the success of the surgery. We describe several recent findings on the perception of awake craniotomy patients and address nonpharmacological perioperative factors that enhance the experience of awake craniotomy patients. These factors could also be applicable to other surgical patients. Proper preoperative counseling gives higher patient satisfaction and should be individually tailored to the patient. Furthermore, there is a substantial proportion of patients who have significant pain or fear during an awake craniotomy procedure. There is a possibility that this could induce post-traumatic stress disorder or related symptoms. Preoperative preparation is of utmost importance in awake craniotomy patients, and a solid doctor-patient relationship is an important condition. Nonpharmacological intraoperative management should focus on reduction of fear and pain by adaptation of the environment and careful and well considered communication.

Effects of Regular and Long-Acting Insulin on Cognition and Alzheimer's Disease Biomarkers: A Pilot Clinical Trial.

PubMed

Craft, Suzanne; Claxton, Amy; Baker, Laura D; Hanson, Angela J; Cholerton, Brenna; Trittschuh, Emily H; Dahl, Deborah; Caulder, Erin; Neth, Bryan; Montine, Thomas J; Jung, Youngkyoo; Maldjian, Joseph; Whitlow, Christopher; Friedman, Seth

2017-01-01

Long acting insulin detemir administered intranasally for three weeks enhanced memory for adults with Alzheimer's disease dementia (AD) or amnestic mild cognitive impairment (MCI). The investigation of longer-term administration is necessary to determine whether benefits persist, whether they are similar to benefits provided by regular insulin, and whether either form of insulin therapy affects AD biomarkers. The present study aimed to determine whether four months of treatment with intranasal insulin detemir or regular insulin improves cognition, daily functioning, and AD biomarkers for adults with MCI or AD. This randomized, double-blind, placebo-controlled trial included an intent-to-treat sample consisting of 36 adults diagnosed with MCI or mild to moderate AD. Participants received placebo (n = 12), 40 IU of insulin detemir (n = 12), or 40 IU of regular insulin (n = 12) daily for four months, administered with a nasal delivery device. A cognitive battery was administered at baseline and after two and four months of treatment. MRI was administered for all participants and lumbar puncture for a subset (n = 20) at baseline and four months. The primary outcome was change from baseline to four months on a memory composite (sum of Z scores for delayed list and story recall). Secondary outcomes included: global cognition (Alzheimer's Disease Assessment Scale-Cognition), daily functioning (Dementia Severity Rating Scale), MRI volume changes in AD-related regions of interest, and cerebrospinal fluid AD markers. The regular insulin treated group had better memory after two and four months compared with placebo (p < 0.03). No significant effects were observed for the detemir-assigned group compared with the placebo group, or for daily functioning for either group. Regular insulin treatment was associated with preserved volume on MRI. Regular insulin treatment was also associated with reduction in the tau-P181/Aβ42 ratio. Future research is warranted

Predicting sleepiness during an awake craniotomy.

PubMed

Itoi, Chihiro; Hiromitsu, Kentaro; Saito, Shoko; Yamada, Ryoji; Shinoura, Nobusada; Midorikawa, Akira

2015-12-01

An awake craniotomy is a safe neurological surgical technique that minimizes the risk of brain damage. During the course of this surgery, the patient is asked to perform motor or cognitive tasks, but some patients exhibit severe sleepiness. Thus, the present study investigated the predictive value of a patient's preoperative neuropsychological background in terms of sleepiness during an awake craniotomy. Thirty-seven patients with brain tumor who underwent awake craniotomy were included in this study. Prior to craniotomy, the patient evaluated cognitive status, and during the surgery, each patient's performance and attitude toward cognitive tasks were recorded by neuropsychologists. The present findings showed that the construction and calculation abilities of the patients were moderately correlated with their sleepiness. These results indicate that the preoperative cognitive functioning of patients was related to their sleepiness during the awake craniotomy procedure and that the patients who exhibited sleepiness during an awake craniotomy had previously experienced reduced functioning in the parietal lobe. Copyright © 2015 Elsevier B.V. All rights reserved.

The Effects of Peripheral and Central High Insulin on Brain Insulin Signaling and Amyloid-β in Young and Old APP/PS1 Mice

PubMed Central

Stanley, Molly; Macauley, Shannon L.; Caesar, Emily E.; Koscal, Lauren J.; Moritz, Will; Robinson, Grace O.; Roh, Joseph; Keyser, Jennifer; Jiang, Hong

2016-01-01

Hyperinsulinemia is a risk factor for late-onset Alzheimer's disease (AD). In vitro experiments describe potential connections between insulin, insulin signaling, and amyloid-β (Aβ), but in vivo experiments are needed to validate these relationships under physiological conditions. First, we performed hyperinsulinemic-euglycemic clamps with concurrent hippocampal microdialysis in young, awake, behaving APPswe/PS1dE9 transgenic mice. Both a postprandial and supraphysiological insulin clamp significantly increased interstitial fluid (ISF) and plasma Aβ compared with controls. We could detect no increase in brain, ISF, or CSF insulin or brain insulin signaling in response to peripheral hyperinsulinemia, despite detecting increased signaling in the muscle. Next, we delivered insulin directly into the hippocampus of young APP/PS1 mice via reverse microdialysis. Brain tissue insulin and insulin signaling was dose-dependently increased, but ISF Aβ was unchanged by central insulin administration. Finally, to determine whether peripheral and central high insulin has differential effects in the presence of significant amyloid pathology, we repeated these experiments in older APP/PS1 mice with significant amyloid plaque burden. Postprandial insulin clamps increased ISF and plasma Aβ, whereas direct delivery of insulin to the hippocampus significantly increased tissue insulin and insulin signaling, with no effect on Aβ in old mice. These results suggest that the brain is still responsive to insulin in the presence of amyloid pathology but increased insulin signaling does not acutely modulate Aβ in vivo before or after the onset of amyloid pathology. Peripheral hyperinsulinemia modestly increases ISF and plasma Aβ in young and old mice, independent of neuronal insulin signaling. SIGNIFICANCE STATEMENT The transportation of insulin from blood to brain is a saturable process relevant to understanding the link between hyperinsulinemia and AD. In vitro experiments have found

Manipulating central nervous mechanisms of food intake and body weight regulation by intranasal administration of neuropeptides in man.

PubMed

Hallschmid, Manfred; Benedict, Christian; Born, Jan; Fehm, Horst-Lorenz; Kern, Werner

2004-10-30

Maintaining a stable body weight set-point is assumed to rely on a homeostatic central nervous system (CNS) regulation of body fat with the particular involvement of hypothalamic pathways. The peripheral adiposity signals insulin and leptin convey information on the amount of energy stored as body fat to the arcuate nucleus of the hypothalamus, where anabolic/orexigenic and catabolic/anorexigenic pathways interact to regulate food intake and energy expenditure. One of the most prominent orexigenic messengers is neuropeptide Y (NPY), whereas melanocortins, including alpha-melanocyte-stimulating hormone (alpha-MSH), are essential for inducing anorexigenic effects. The melanocortin receptor 4 (MC4-R) plays the most important role in mediating catabolic effects of alpha-MSH. In this review, we present a series of own studies on NPY, insulin and MSH/ACTH4-10, an MC4-R agonist. The studies were all based on the intranasal route of administration which enables a direct access of the peptides to hypothalamic functions. NPY acutely attenuated electrocortical signs of meal-related satiety. Prolonged intranasal administration of insulin as well as of MSH induced weight loss in healthy human subjects. However, overweight subjects did not lose body fat after MSH administration. The results corroborate in humans the significance of all three messengers for the central nervous regulation of adiposity and might contribute to the future development of medical strategies against body-weight-related disorders.

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

PubMed

Lehallier, Benoist; Rampin, Olivier; Saint-Albin, Audrey; Jérôme, Nathalie; Ouali, Christian; Maurin, Yves; Bonny, Jean-Marie

2012-01-01

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. 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. 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.

Ethical challenges with awake craniotomy for tumor.

PubMed

Kirsch, Brandon; Bernstein, Mark

2012-01-01

Awake brain surgery is useful for the treatment of a number of conditions such as epilepsy and brain tumor, as well as in functional neurosurgery. Several studies have been published regarding clinical results and outcomes of patients who have undergone awake craniotomy but few have dealt with related ethical issues. The authors undertake to explore broadly the ethical issues surrounding awake brain surgery for tumor resection to encourage further consideration and discussion. Based on a review of the literature related to awake craniotomy and in part from the personal experience of the senior author, we conducted an assessment of the ethical issues associated with awake brain tumor surgery. The major ethical issues identified relate to: (1) lack of data; (2) utilization; (3) conflict of interest; (4) informed consent; (5) surgical innovation; and (6) surgical training. The authors respectfully suggest that the selection of patients for awake craniotomy needs to be monitored according to more consistent, objective standards in order to avoid conflicts of interest and potential harm to patients.

Pediatric Awake Craniotomy for Brain Lesions.

PubMed

Akay, Ali; Rükşen, Mete; Çetin, H Yurday; Seval, H Özer; İşlekel, Sertaç

2016-01-01

Awake craniotomy is a special method to prevent motor deficits during the resection of lesions that are located in, or close to, functional areas. Although it is more commonly performed in adult patients, reports of pediatric cases undergoing awake craniotomy are limited in the literature. In our clinic, where we frequently use awake craniotomy in adult patients, we performed this method in 2 selected pediatric cases for lesion surgery. At an early age, these 2 cases diagnosed with epilepsy presented cerebral lesions, but since the lesions enclosed functional areas, surgical resection was not regarded as a treatment option at this time. In these 2 pediatric cases, we successfully completed lesion surgery with awake craniotomy. The method and the techniques employed during surgery are presented concomitant with other reports in the literature. © 2016 S. Karger AG, Basel.

[Awake craniotomy: analysis of complicated cases].

PubMed

Kulikov, A S; Kobyakov, G L; Gavrilov, A G; Lubnin, A Yu

2015-01-01

Awake craniotomy is recognized as method that can decrease the frequency of neurological complications after surgery for gliomas located near eloquent brain regions. Unfortunately good neurological outcome can't be ensured even by using of this technique. This paper discusses reasons and possible ways of prevention of such complications. 162 awake craniotomies were performed in our clinic. 152 of patients were discharged from the clinic with good outcome. In 10 (6%) cases sustained severe neurological deficit was noted. These complications were associated with anatomic or ischemic injury of subcortical pathways and internal capsule. Awake craniotomy is effective instrument of brain language mapping and prevention of neurological deterioration. Severe neurological complications of awake craniotomy are associated with underestimate neurosurgical risks, especially in terms of blood vessel injury and depth of resection. The main way of prevention of such complications is meticulous planning of operation and adequate using of mapping facilities.

Intranasal Oxytocin: Myths and Delusions.

PubMed

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. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Awake Craniotomy: First-Year Experiences and Patient Perception.

PubMed

Joswig, Holger; Bratelj, Denis; Brunner, Thomas; Jacomet, Alfred; Hildebrandt, Gerhard; Surbeck, Werner

2016-06-01

Awake craniotomy for brain lesions in or near eloquent brain regions enables neurosurgeons to assess neurologic functions of patients intraoperatively, reducing the risk of permanent neurologic deficits and increasing the extent of resection. A retrospective review was performed of a consecutive series of patients with awake craniotomies in the first year of their introduction to our tertiary non-university-affiliated neurosurgery department. Operation time, complications, and neurologic outcome were assessed, and patient perception of awake craniotomy was surveyed using a mailed questionnaire. There were 24 awake craniotomies performed in 22 patients for low-grade/high-grade gliomas, cavernomas, and metastases (average 2 cases per month). Mean operation time was 205 minutes. Failure of awake craniotomy because of intraoperative seizures with subsequent postictal impaired testing or limited cooperation occurred in 2 patients. Transient neurologic deficits occurred in 29% of patients; 1 patient sustained a permanent neurologic deficit. Of the 18 patients (82%) who returned the questionnaire, only 2 patients recalled significant fear during surgery. Introducing awake craniotomy to a tertiary non-university-affiliated neurosurgery department is feasible and resulted in reasonable operation times and complication rates and high patient satisfaction. Copyright © 2016 Elsevier Inc. All rights reserved.

Analysis of Navy Flight Scheduling Methods Using FlyAwake

DTIC Science & Technology

2009-09-01

28 Figure 4. FlyAwake Schedule Builder Screenshot..........................................................28...Figure 5. FlyAwake Work Schedule Builder Screenshot................................................29 Figure 6. FlyAwake Graphical Output Screenshot... disqualifies crewmembers from participating in the following day’s flight operations. These rules are subject to operational requirements and deviation

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

PubMed

Spetter, Maartje S; Hallschmid, Manfred

2015-08-03

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

Awake craniotomy. A patient`s perspective.

PubMed

Bajunaid, Khalid M; Ajlan, Abdulrazag M

2015-07-01

To report the personal experiences of patients undergoing awake craniotomy for brain tumor resection. We carried out a qualitative descriptive survey of patients` experiences with awake craniotomies for brain tumor resection. The survey was conducted through a standard questionnaire form after the patient was discharged from the hospital. Of the 9 patients who met the inclusion criteria and underwent awake craniotomy, 3 of those patients reported no recollection of the operation. Five patients had auditory recollections from the operation. Two-thirds (6/9) reported that they did not perceive pain. Five patients remembered the head clamp fixation, and 2 of those patients classified the pain from the clamp as moderate. None of the patients reported that the surgery was more difficult than anticipated. Awake craniotomy for surgical resection of brain tumors was well tolerated by patients. Most patients reported that they do not recall feeling pain during the operation. However, we feel that further work and exploration are needed in order to achieve better control of pain and discomfort during these types of operations.

Targeting Insulin Signaling for the Treatment of Alzheimer's Disease.

PubMed

Chen, Yanxing; Zhang, Jianfang; Zhang, Baorong; Gong, Cheng-Xin

2016-01-01

Sporadic Alzheimer's disease (AD) is caused by multiple etiological factors, among which impaired brain insulin signaling and decreased brain glucose metabolism are important metabolic factors. Contrary to previous belief that insulin would not act in the brain, studies in the last three decades have proven important roles of insulin and insulin signaling in various biological functions in the brain. Impaired brain insulin signaling or brain insulin resistance and its role in the molecular pathogenesis of sporadic AD have been demonstrated. Thus, targeting brain insulin signaling for the treatment of cognitive impairment and AD has now attracted much attention in the field of AD drug discovery. This article reviews recent studies that target brain insulin signaling, especially those investigations on intranasal insulin administration and drugs that improve insulin sensitivity, including incretins, dipeptidyl peptidase IV inhibitors, thiazolidinediones, and metformin. These drugs have been previously approved for the treatment of diabetes mellitus, which could expedite their development for the treatment of AD. Although larger clinical trials are needed for validating their efficacy for the treatment of cognitive impairment and AD, results of animal studies and clinical trials available to date are encouraging.

Awake Craniotomy: A New Airway Approach.

PubMed

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

2016-02-01

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

21 CFR 874.4780 - Intranasal splint.

Code of Federal Regulations, 2013 CFR

2013-04-01

... DEVICES EAR, NOSE, AND THROAT DEVICES Surgical Devices § 874.4780 Intranasal splint. (a) Identification... septum and the nasal cavity. It is placed in the nasal cavity after surgery or trauma. The intranasal splint is constructed from plastic, silicone, or absorbent material. (b) Classification. Class I (general...

21 CFR 874.4780 - Intranasal splint.

Code of Federal Regulations, 2011 CFR

2011-04-01

... DEVICES EAR, NOSE, AND THROAT DEVICES Surgical Devices § 874.4780 Intranasal splint. (a) Identification... septum and the nasal cavity. It is placed in the nasal cavity after surgery or trauma. The intranasal splint is constructed from plastic, silicone, or absorbent material. (b) Classification. Class I (general...

21 CFR 874.4780 - Intranasal splint.

Code of Federal Regulations, 2012 CFR

2012-04-01

... DEVICES EAR, NOSE, AND THROAT DEVICES Surgical Devices § 874.4780 Intranasal splint. (a) Identification... septum and the nasal cavity. It is placed in the nasal cavity after surgery or trauma. The intranasal splint is constructed from plastic, silicone, or absorbent material. (b) Classification. Class I (general...

21 CFR 874.4780 - Intranasal splint.

Code of Federal Regulations, 2010 CFR

2010-04-01

... DEVICES EAR, NOSE, AND THROAT DEVICES Surgical Devices § 874.4780 Intranasal splint. (a) Identification... septum and the nasal cavity. It is placed in the nasal cavity after surgery or trauma. The intranasal splint is constructed from plastic, silicone, or absorbent material. (b) Classification. Class I (general...

21 CFR 874.4780 - Intranasal splint.

Code of Federal Regulations, 2014 CFR

2014-04-01

... DEVICES EAR, NOSE, AND THROAT DEVICES Surgical Devices § 874.4780 Intranasal splint. (a) Identification... septum and the nasal cavity. It is placed in the nasal cavity after surgery or trauma. The intranasal splint is constructed from plastic, silicone, or absorbent material. (b) Classification. Class I (general...

Cinnamon extract (traditional herb) potentiates in vivo insulin-regulated glucose utilization via enhancing insulin signaling in rats.

PubMed

Qin, Bolin; Nagasaki, Masaru; Ren, Ming; Bajotto, Gustavo; Oshida, Yoshiharu; Sato, Yuzo

2003-12-01

Cinnamon has been shown to potentiate the insulin effect through upregulation of the glucose uptake in cultured adipocytes. In the present study, we evaluated the effect of the cinnamon extract on the insulin action in awaked rats by the euglycemic clamp and further analyzed possible changes in insulin signaling occurred in skeletal muscle. The rats were divided into saline and cinnamon extract (30 and 300 mg/kg BW-doses: C30 and C300) oral administration groups. After 3-weeks, cinnamon extract treated rats showed a significantly higher glucose infusion rate (GIR) at 3 mU/kg per min insulin infusions compared with controls (118 and 146% of controls for C30 and C300, respectively). At 30 mU/kg per min insulin infusions, the GIR in C300 rats was increased 17% over controls. There were no significant differences in insulin receptor (IR)-beta, IR substrate (IRS)-1, and phosphatidylinositol (PI) 3-kinase protein content between C300 rats and controls. However, the skeletal muscle insulin-stimulated IR-beta and the IRS-1 tyrosine phosphorylation levels in C300 rats were 18 and 33% higher, respectively, added to 41% higher IRS-1/PI 3-kinase association. These results suggest that the cinnamon extract would improve insulin action via increasing glucose uptake in vivo, at least in part through enhancing the insulin-signaling pathway in skeletal muscle.

Patient response to awake craniotomy - a summary overview.

PubMed

Milian, Monika; Tatagiba, Marcos; Feigl, Guenther C

2014-06-01

Awake craniotomy is a valuable procedure since it allows brain mapping and live monitoring of eloquent brain functions. The advantage of minimizing resource utilization is also emphasized by some physicians in North America. Data on how well an awake craniotomy is tolerated by patients and how much stress it creates is available from different studies, but this topic has not consequently been summarized in a review of the available literature. Therefore, it is the purpose of this review to shed more light on the still controversially discussed aspect of an awake craniotomy. We reviewed the available English literature published until December 2013 searching for studies that investigated patients' responses to awake craniotomies. Twelve studies, published between 1998 and 2013, including 396 patients with awake surgery were identified. Eleven of these 12 studies set the focus on the perioperative time, one study focused on the later postoperative time. The vast majority of patients felt well prepared and overall satisfaction with the procedure was high. In the majority of studies up to 30 % of the patients recalled considerable pain and 10-14 % experienced strong anxiety during the procedure. The majority of patients reported that they would undergo an awake craniotomy again. A post traumatic stress disorder was present neither shortly nor years after surgery. However, a normal human response to such an exceptional situation can for instance be the delayed appearance of unintentional distressing recollections of the event despite the patients' satisfaction concerning the procedure. For selected patients, an awake craniotomy presents the best possible way to reduce the risk of surgery related neurological deficits. However, benefits and burdens of this type of procedure should be carefully considered when planning an awake craniotomy and the decision should serve the interests of the patient.

Patient acceptance of awake craniotomy.

PubMed

Wrede, Karsten H; Stieglitz, Lennart H; Fiferna, Antje; Karst, Matthias; Gerganov, Venelin M; Samii, Madjid; von Gösseln, Hans-Henning; Lüdemann, Wolf O

2011-12-01

The aim of this study was to objectively assess the patients' acceptance for awake craniotomy in a group of neurosurgical patients, who underwent this procedure for removal of lesions in or close to eloquent brain areas. Patients acceptance for awake craniotomy under local anesthesia and conscious sedation was assessed by a formal questionnaire (PPP33), initially developed for general surgery patients. The results are compared to a group of patients who had brain surgery under general anesthesia and to previously published data. The awake craniotomy (AC) group consisted of 37 male and 9 female patients (48 craniotomies) with age ranging from 18 to 71 years. The general anesthesia (GA) group consisted of 26 male and 15 female patients (43 craniotomies) with age ranging from 26 to 83 years. All patients in the study were included in the questionnaire analysis. In comparison to GA the overall PPP33 score for AC was higher (p=0.07), suggesting better overall acceptance for AC. The subscale scores for AC were also significantly better compared to GA for the two subscales "postoperative pain" (p=0.02) and "physical disorders" (p=0.01) and equal for the other 6 subscales. The results of the overall mean score and the scores for the subscales of the PPP33 questionnaire verify good patients' acceptance for AC. Previous studies have shown good patients' acceptance for awake craniotomy, but only a few times using formal approaches. By utilizing a formal questionnaire we could verify good patient acceptance for awake craniotomy for the treatment of brain tumors in or close to eloquent areas. This is a novel approach that substantiates previously published experiences. Copyright © 2011 Elsevier B.V. All rights reserved.

Awake Craniotomy Anesthesia: A Comparison of the Monitored Anesthesia Care and Asleep-Awake-Asleep Techniques.

PubMed

Eseonu, Chikezie I; ReFaey, Karim; Garcia, Oscar; John, Amballur; Quiñones-Hinojosa, Alfredo; Tripathi, Punita

2017-08-01

Commonly used sedation techniques for an awake craniotomy include monitored anesthesia care (MAC), using an unprotected airway, and the asleep-awake-asleep (AAA) technique, using a partially or totally protected airway. We present a comparative analysis of the MAC and AAA techniques, evaluating anesthetic management, perioperative outcomes, and complications in a consecutive series of patients undergoing the removal of an eloquent brain lesion. Eighty-one patients underwent awake craniotomy for an intracranial lesion over a 9-year period performed by a single-surgeon and a team of anesthesiologists. Fifty patients were treated using the MAC technique, and 31 were treated using the AAA technique. A retrospective analysis evaluated anesthetic management, intraoperative complications, postoperative outcomes, pain management, and complications. The MAC and AAA groups had similar preoperative patient and tumor characteristics. Mean operative time was shorter in the MAC group (283.5 minutes vs. 313.3 minutes; P = 0.038). Hypertension was the most common intraoperative complication seen (8% in the MAC group vs. 9.7% in the AAA group; P = 0.794). Intraoperative seizure occurred at a rate of 4% in the MAC group and 3.2% in the AAA group (P = 0.858). Awake cases were converted to general anesthesia in no patients in the MAC group and in 1 patient (3.2%) in the AAA group (P = 0.201). No cases were aborted in either group. The mean hospital length of stay was 3.98 days in the MAC group and 3.84 days in the AAA group (P = 0.833). Both the MAC and AAA sedation techniques provide an efficacious and safe method for managing awake craniotomy cases and produce similar perioperative outcomes, with the MAC technique associated with shorter operative time. Copyright © 2017 Elsevier Inc. All rights reserved.

Awake craniotomy for supratentorial gliomas: why, when and how?

PubMed

Ibrahim, George M; Bernstein, Mark

2012-09-01

Awake craniotomy has become an increasingly utilized procedure in the treatment of supratentorial intra-axial tumors. The popularity of this procedure is partially attributable to improvements in intraoperative technology and anesthetic techniques. The application of awake craniotomy to the field of neuro-oncology has decreased iatrogenic postoperative neurological deficits, allowed for safe maximal tumor resection and improved healthcare resource stewardship by permitting early patient discharge. In this article, we review recent evidence for the utility of awake craniotomy in the resection of gliomas and describe the senior author's experience in performing this procedure. Furthermore, we explore innovative applications of awake craniotomy to outpatient tumor resections and the conduct of neurosurgery in resource-poor settings. We conclude that awake craniotomy is an effective and versatile neurosurgical procedure with expanding applications in neuro-oncology.

Absorption of clonazepam after intranasal and buccal administration.

PubMed Central

Schols-Hendriks, M W; Lohman, J J; Janknegt, R; Korten, J J; Merkus, F W; Hooymans, P M

1995-01-01

Serum concentrations of clonazepam after intranasal, buccal and intravenous administration were compared in a cross-over study in seven healthy male volunteers. Each subject received a 1.0 mg dose of clonazepam intranasally and buccally and 0.5 mg intravenously. A Cmax of 6.3 +/- 1.0 ng ml-1 (mean; +/- s.d.) was measured 17.5 min (median) (range 15-20 min) after intranasal administration. A second peak (4.6 +/- 1.3 ng ml-1) caused by oral absorption was seen after 1.7 h (range 0.7-3.0 h). After buccal administration a Cmax of 6.0 +/- 3.0 ng ml-1 was measured after 50 min (range 30-90 min) with a second peak of 6.5 +/- 2.5 ng ml-1 after 3.0 h (range 2.0-4.0 h). Two minutes after i.v. injection of 0.5 mg clonazepam the serum concentration was 27 +/- 18 ng ml-1. It is concluded that intranasal clonazepam is an alternative to buccal administration. However, the Cmax of clonazepam after intranasal administration is not high enough to recommend the intranasal route as an alternative to intravenous injection. PMID:7640154

Intranasal melatonin nanoniosomes: pharmacokinetic, pharmacodynamics and toxicity studies.

PubMed

Priprem, Aroonsri; Johns, Jeffrey R; Limsitthichaikoon, Sucharat; Limphirat, Wanwisa; Mahakunakorn, Pramote; Johns, Nutjaree Prateepawanit

2017-06-01

Intranasal melatonin encapsulated in nanosized niosomes was preclinically evaluated. A formula of melatonin niosomes (MN) was selected through physicochemical and cytotoxic data for pharmacokinetic, pharmacodynamics and toxicity studies in male Wistar rats. Intranasal MN was bioequivalent to intravenous injection of melatonin, providing therapeutic level doses. Acute and subchronic toxicity screening showed no abnormal signs, symptoms or hematological effects in any animals. Transient nasal irritations with no inflammation were observed with intranasal MN, leading it to be categorized as relatively harmless. The intranasal MN could deliver melatonin to the brain to induce sleep and provide delayed systemic circulation, relative to intravenous injection and also distribute to peripheral tissue.

Molecular Imaging of Conscious, Unrestrained Mice with AwakeSPECT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baba, Justin S; Endres, Christopher; Foss, Catherine

2013-01-01

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

Molecular Imaging of Conscious, Unrestrained Mice with AwakeSPECT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baba, Justin S.; Endres, Christopher J.; Foss, Catherine A.

2013-06-01

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

Intranasal scopolamine preparation and method

NASA Technical Reports Server (NTRS)

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

1991-01-01

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

Intranasal medications in pediatric emergency medicine.

PubMed

Del Pizzo, Jeannine; Callahan, James M

2014-07-01

Intranasal medication administration in the emergency care of children has been reported for at least 20 years and is gaining popularity because of ease of administration, rapid onset of action, and relatively little pain to the patient. The ability to avoid a needle stick is often attractive to practitioners, in addition to children and their parents. In time-critical situations for which emergent administration of medication is needed, the intranasal route may be associated with more rapid medication administration. This article reviews the use of intranasal medications in the emergency care of children. Particular attention will be paid to anatomy and its impact on drug delivery, pharmacodynamics, medications currently administered by this route, delivery devices available, tips for use, and future directions.

Nonopioid anesthesia for awake craniotomy: a case report.

PubMed

Wolff, Diane L; Naruse, Robert; Gold, Michele

2010-02-01

Awake craniotomy is becoming more popular as a neurosurgical technique that allows for increased tumor resection and decreased postoperative neurologic morbidity. This technique, however, presents many challenges to both the neurosurgeon and anesthetist. An ASA class II, 37-year-old man with recurrent oligodendroglioma presented for repeated craniotomy. Prior craniotomy under general anesthesia resulted in residual neurologic deficits. An awake craniotomy was planned to allow for intraoperative testing for maximum tumor resection and avoidance of neurologic morbidity. The patient was sedated with propofol, and bupivacaine was infiltrated for placement of Mayfield tongs and skin incision. Following exposure of brain tissue, propofol infusion was discontinued to allow for patient cooperation during the procedure. Speech, motor, and sensory testing occurred during tumor resection until resection stopped after onset of weakness in the right arm. The propofol infusion was resumed while the cranium was closed and Mayfield tongs removed. The patient was awake, alert, oriented, and able to move all extremities but had residual weakness in the right forearm. Awake craniotomy requires appropriate patient selection, knowledge of the surgeon's skill, and a thorough anesthesia plan. This case report discusses the clinical and anesthetic management for awake craniotomy and reviews the literature.

IGF-1 intranasal administration rescues Huntington's disease phenotypes in YAC128 mice.

PubMed

Lopes, Carla; Ribeiro, Márcio; Duarte, Ana I; Humbert, Sandrine; Saudou, Frederic; Pereira de Almeida, Luís; Hayden, Michael; Rego, A Cristina

2014-06-01

Huntington's disease (HD) is an autosomal dominant disease caused by an expansion of CAG repeats in the gene encoding for huntingtin. Brain metabolic dysfunction and altered Akt signaling pathways have been associated with disease progression. Nevertheless, conflicting results persist regarding the role of insulin-like growth factor-1 (IGF-1)/Akt pathway in HD. While high plasma levels of IGF-1 correlated with cognitive decline in HD patients, other data showed protective effects of IGF-1 in HD striatal neurons and R6/2 mice. Thus, in the present study, we investigated motor phenotype, peripheral and central metabolic profile, and striatal and cortical signaling pathways in YAC128 mice subjected to intranasal administration of recombinant human IGF-1 (rhIGF-1) for 2 weeks, in order to promote IGF-1 delivery to the brain. We show that IGF-1 supplementation enhances IGF-1 cortical levels and improves motor activity and both peripheral and central metabolic abnormalities in YAC128 mice. Moreover, decreased Akt activation in HD mice brain was ameliorated following IGF-1 administration. Upregulation of Akt following rhIGF-1 treatment occurred concomitantly with increased phosphorylation of mutant huntingtin on Ser421. These data suggest that intranasal administration of rhIGF-1 ameliorates HD-associated glucose metabolic brain abnormalities and mice phenotype.

Anaesthesia for awake craniotomy is safe and well-tolerated.

PubMed

Andersen, Jakob Hessel; Olsen, Karsten Skovgaard

2010-10-01

Awake craniotomy for tumour resection has been performed at Glostrup Hospital since 2004. We describe and discuss the various anaesthetic approaches for such surgery and retrospectively analyse the 44 planned awake craniotomies performed at Glostrup Hospital. The surgery falls into four phases: craniotomy, mapping, tumour resection and closing. Three methods are being used: monitored anaesthetic care, asleep-awake-asleep and asleep-awake (AA). Anaesthesia is induced and maintained with propofol and remifentanil. A laryngeal mask (LM) is used as an airway during the craniotomy phase. In the AA method, patients are mapped and the tumour is resected while the patient is awake. A total of 41 of 44 planned AA craniotomies were performed. Three had to be converted into general anaesthesia (GA) due to tight brain, leaking LM and tumour haemorrhage, respectively. The following complications were observed: bradycardia 10%, leaking LM 5%, nausea 10%, vomiting 5%, focal seizures 28%, generalized seizures 10%, hypoxia 2%, hypotension 5% and hypertension 2%. Our results comply well with the international literature in terms of complications related to haemodynamics, respiration, seizures, vomiting and nausea and in terms of patient satisfaction. Awake craniotomy is a well-tolerated procedure with potential benefits. More prospective randomized studies are required.

Ammonia encephalopathy and awake craniotomy for brain language mapping: cause of failed awake craniotomy.

PubMed

Villalba Martínez, G; Fernández-Candil, J L; Vivanco-Hidalgo, R M; Pacreu Terradas, S; León Jorba, A; Arroyo Pérez, R

2015-05-01

We report the case of an aborted awake craniotomy for a left frontotemporoinsular glioma due to ammonia encephalopathy on a patient taking Levetiracetam, valproic acid and clobazam. This awake mapping surgery was scheduled as a second-stage procedure following partial resection eight days earlier under general anesthesia. We planned to perform the surgery with local anesthesia and sedation with remifentanil and propofol. After removal of the bone flap all sedation was stopped and we noticed slow mentation and excessive drowsiness prompting us to stop and control the airway and proceed with general anesthesia. There were no post-operative complications but the patient continued to exhibit bradypsychia and hand tremor. His ammonia level was found to be elevated and was treated with an infusion of l-carnitine after discontinuation of the valproic acid with vast improvement. Ammonia encephalopathy should be considered in patients treated with valproic acid and mental status changes who require an awake craniotomy with patient collaboration. Copyright © 2014 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

Evaluation of Language Function under Awake Craniotomy

PubMed Central

KANNO, Aya; MIKUNI, Nobuhiro

2015-01-01

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

Evaluation of Language Function under Awake Craniotomy.

PubMed

Kanno, Aya; Mikuni, Nobuhiro

2015-01-01

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

Intranasal sedatives in pediatric dentistry

PubMed Central

AlSarheed, Maha A.

2016-01-01

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

Intranasal sedatives in pediatric dentistry.

PubMed

AlSarheed, Maha A

2016-09-01

To identify the intranasal (IN) sedatives used to achieve conscious sedation during dental procedures amongst children. 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.  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. Intranasal midazolam, ketamine, and sufentanil are effective and safe for conscious sedation, while intranasal midazolam, dexmedetomidine, and sufentanil have proven to be effective premedications.

Intranasal volume increases with age: Computed tomography volumetric analysis in adults.

PubMed

Loftus, Patricia A; Wise, Sarah K; Nieto, Daniel; Panella, Nicholas; Aiken, Ashley; DelGaudio, John M

2016-10-01

It is theorized that intranasal cavity volumes change throughout the aging process, possibly secondary to hormonal changes and atrophy of the sinonasal mucosa. Our objective is to compare intranasal volumes from different age groups to test the hypothesis that intranasal cavity volume increases with age. Case series. An analysis of computed tomography (CT) scans performed for reasons other than sinonasal complaints. Intranasal volumes of three groups (age 20-30 years, 40-50 years, and 70 years and above) were calculated using Vitrea software. The total intranasal volume was measured from the nasal vestibule anteriorly, the nasopharynx posteriorly, the olfactory cleft superiorly, and the nasal floor inferiorly. The total volume included the sum of the right and left sides. Sixty-two CT scans were analyzed. There was a progressive, relatively linear, increase in intranasal volume with increasing age: 20 to 30 years = 15.73 mL, 40 to 50 years = 17.30 mL, and 70 years and above = 18.38 mL. Mean intranasal volume for males was 19.07 mL, and for females was 15.23 mL. Analysis of variance demonstrated significant group differences in mean intranasal volume for age (P = .003) and gender (P < .001), with moderate-to-large effect size of 0.206 and 0.289 (partial η(2) ), respectively. Post hoc testing revealed a significant difference between the 20 to 30-year and >70-year age groups (P = .006). There was no significant difference in intranasal volume dependent upon body mass index. Intranasal volume increases with age and is larger in males. Specific etiologies responsible for increased intranasal cavity volume with age are actively being evaluated. 4 Laryngoscope, 126:2212-2215, 2016. © 2016 The American Laryngological, Rhinological and Otological Society, Inc.

Non-Clinical Safety Evaluation of Intranasal Iota-Carrageenan

PubMed Central

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

2015-01-01

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

Non-clinical safety evaluation of intranasal iota-carrageenan.

PubMed

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

2015-01-01

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

Teaching and sustainably implementing awake craniotomy in resource-poor settings.

PubMed

Howe, Kathryn L; Zhou, Guosheng; July, Julius; Totimeh, Teddy; Dakurah, Thomas; Malomo, Adefolarin O; Mahmud, Muhammad R; Ismail, Nasiru J; Bernstein, Mark A

2013-12-01

Awake craniotomy for brain tumor resection has the benefit of avoiding a general anesthetic and decreasing associated costs (e.g., intensive care unit beds and intravenous line insertion). In low- and middle-income countries, significant resource limitations for the system and individual make awake craniotomy an ideal tool, yet it is infrequently used. We sought to determine if awake craniotomy could be effectively taught and implemented safely and sustainably in low- and middle-income countries. A neurosurgeon experienced in the procedure taught awake craniotomy to colleagues in China, Indonesia, Ghana, and Nigeria during the period 2007-2012. Patients were selected on the basis of suspected intraaxial tumor, absence of major dysphasia or confusion, and ability to tolerate the positioning. Data were recorded by the local surgeons and included preoperative imaging, length of hospital admission, final pathology, postoperative morbidity, and mortality. Awake craniotomy was performed for 38 cases of suspected brain tumor; most procedures were completed independently. All patients underwent preoperative computed tomography or magnetic resonance imaging. In 64% of cases, patients remained in the hospital <10 days. The most common pathology was high-grade glioma, followed by meningioma, low-grade glioma, and metastasis. No deaths occurred, and no case required urgent intubation. The most common perioperative and postoperative issue was seizure, with 1 case of permanent postoperative deficit. Awake craniotomy was successfully taught and implemented in 6 neurosurgical centers in China, Indonesia, Ghana, and Nigeria. Awake craniotomy is safe, resource-sparing, and sustainable. The data suggest awake craniotomy has the potential to significantly improve access to neurosurgical care in resource-challenged settings. Copyright © 2013 Elsevier Inc. All rights reserved.

The neurolinguistic approach to awake surgery reviewed.

PubMed

De Witte, Elke; Mariën, Peter

2013-02-01

Intraoperative direct electrical stimulation (DES) is increasingly used in patients operated on for tumours in critical language areas. Although a positive impact of DES on postoperative linguistic outcome is generally advocated, the literature is only scantily documented with information about the linguistic methods applied in awake surgery. This article critically reviews the neurolinguistic procedures currently used in awake studies. Based on an extensive review of the literature, an overview is given of the language mapping techniques applied in brain tumour surgery. Studies investigating linguistic testing and outcome in awake surgery were analysed. Information about the timing of the assessment(s), the linguistic tasks, the linguistic stimuli and the indication for awake surgery was also discussed. Intraoperative DES remains the 'gold standard' for language mapping, but pre- and postoperative non-invasive mapping methods are important adjuncts. In the pre- and postoperative phase, standardised linguistic test batteries are generally used to assess language function. In the intraoperative phase, only naming and number counting are commonly applied. Most often no detailed information about the linguistic stimuli is provided and no standardised protocols measuring different linguistic levels have been described. Awake surgery with DES is a useful tool for preserving linguistic functions in patients undergoing surgery in critical brain regions. However, no studies exist that apply a well-balanced and standardised linguistic protocol to reliably identify the critical language zones. The availability of a standardised linguistic protocol might substantially increase intraoperative comfort and might improve outcome and quality of life. Copyright © 2012 Elsevier B.V. All rights reserved.

New twist on neuronal insulin receptor signaling in health, disease, and therapeutics.

PubMed

Wada, Akihiko; Yokoo, Hiroki; Yanagita, Toshihiko; Kobayashi, Hideyuki

2005-10-01

Long after the pioneering studies documenting the existence of insulin (year 1967) and insulin receptor (year 1978) in brain, the last decade has witnessed extraordinary progress in the understanding of brain region-specific multiple roles of insulin receptor signalings in health and disease. In the hypothalamus, insulin regulates food intake, body weight, peripheral fat deposition, hepatic gluconeogenesis, reproductive endocrine axis, and compensatory secretion of counter-regulatory hormones to hypoglycemia. In the hippocampus, insulin promotes learning and memory, independent of the glucoregulatory effect of insulin. Defective insulin receptor signalings are associated with the dementia in normal aging and patients with age-related neurodegenerative diseases (e.g., Alzheimer's disease); the cognitive impairment can be reversed with systemic administration of insulin in the euglycemic condition. Intranasal administration of insulin enhances memory and mood and decreases body weight in healthy humans, without causing hypoglycemia. In the hypothalamus, insulin-induced activation of the phosphoinositide 3-kinase pathway followed by opening of ATP-sensitive K+ channel has been shown to be related to multiple effects of insulin. However, the precise molecular mechanisms of insulin's pleiotropic effects still remain obscure. More importantly, much remains unknown about the quality control mechanisms ensuring correct conformational maturation of the insulin receptor, and the cellular mechanisms regulating density of cell surface functional insulin receptors.

Behavioral responses to two intranasal vaccine applicators in horses and ponies.

PubMed

Grogan, Elkanah H; McDonnell, Sue M

2005-05-15

To evaluate behavioral compliance of horses and ponies with simulated intranasal vaccination and assess development of generalized aversion to veterinary manipulations. Clinical trial. 28 light horse mares, 3 pony geldings, 2 light horse stallions, and 3 pony stallions that had a history of compliance with veterinary procedures. Behavioral compliance with 2 intranasal vaccine applicators was assessed. Compliance with standard physical examination procedures was assessed before and after a single experience with either of the applicators or a control manipulation to evaluate development of generalized aversion to veterinary manipulation. In all 30 horses, simulated intranasal vaccination or the control manipulation could be performed without problematic avoidance behavior, and simulated intranasal vaccination did not have any significant effect on duration of or compliance with a standardized physical examination that included manipulation of the ears, nose, and mouth. Results were similar for the 2 intranasal vaccine applicators, and no difference in compliance was seen between horses in which warm versus cold applicators were used. For 3 of the 6 ponies, substantial avoidance behavior was observed in association with simulated intranasal vaccination, and compliance with physical examination procedures decreased after simulated intranasal vaccination. Although some compliance problems were seen with ponies, neither problems with compliance with simulated intranasal vaccination nor adverse effects on subsequent physical examination were identified in any of the horses. Further study is needed to understand factors involved in practitioner reports of aversion developing in association with intranasal vaccination.

Intranasal dexmedetomidine for adrenergic crisis in familial dysautonomia.

PubMed

Spalink, Christy L; Barnes, Erin; Palma, Jose-Alberto; Norcliffe-Kaufmann, Lucy; Kaufmann, Horacio

2017-08-01

To report the use of intranasal dexmedetomidine, an α 2 -adrenergic agonist for the acute treatment of refractory adrenergic crisis in patients with familial dysautonomia. Case series. Three patients with genetically confirmed familial dysautonomia (case 1: 20-year-old male; case 2: 43-year-old male; case 3: 26-year-old female) received intranasal dexmedetomidine 2 mcg/kg, half of the dose in each nostril, for the acute treatment of adrenergic crisis. Within 8-17 min of administering the intranasal dose, the adrenergic crisis symptoms abated, and blood pressure and heart rate returned to pre-crises values. Adrenergic crises eventually resumed, and all three patients required hospitalization for investigation of the cause of the crises. Intranasal dexmedetomidine is a feasible and safe acute treatment for adrenergic crisis in patients with familial dysautonomia. Further controlled studies are required to confirm the safety and efficacy in this population.

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

PubMed

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

2015-05-01

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

Comparison of Conscious Sedation and Asleep-Awake-Asleep Techniques for Awake Craniotomy.

PubMed

Dilmen, Ozlem Korkmaz; Akcil, Eren Fatma; Oguz, Abdulvahap; Vehid, Hayriye; Tunali, Yusuf

2017-01-01

Since awake craniotomy (AC) has become a standard of care for supratentorial tumour resection, especially in the motor and language cortex, determining the most appropriate anaesthetic protocol is very important. The aim of this retrospective study is to compare the effectiveness of conscious sedation (CS) to "awake-asleep-awake" (AAA) techniques for supratentorial tumour resection. Forty-two patients undergoing CS and 22 patients undergoing AAA were included in the study. The primary endpoint was to compare the CS and AAA techniques with respect to intraoperative pain and agitation in patients undergoing supratentorial tumour resection. The secondary endpoint was comparison of the other intraoperative complications. This study results show that the incidence of intraoperative agitation and seizure were lower in the AAA group than in the CS group. Intraoperative blood pressures were significantly higher in the CS group than in the AAA group during the pinning and incision, but the level of blood pressures did not need antihypertensive treatment. Otherwise, blood pressures were significantly higher in the AAA group than in the CS group during the neurological examination and the severity of hypertension needed statistically significant more antihypertensive treatment in the AAA group. As a result of hypertension, the amount of intraoperative bleeding was higher in the AAA group than in the CS group. In conclusion, the AAA technique may provide better results with respect to agitation and seizure, but intraoperative hypertension needed a vigilant follow-up especially in the wake-up period. Copyright © 2016 Elsevier Ltd. All rights reserved.

Awake craniotomy in a depressed and agitated patient

PubMed Central

Al Shuaibi, Khalid M.

2010-01-01

Depressed patients with brain tumors are often not referred to awake craniotomy because of concern of uncooperation which may increase the risk of perioperative complications. This report describes an interesting case of awake craniotomy for frontal lobe glioma in a 41-year-old woman undergoing language and motor mapping intraoperatively. As she was fearful and apprehensive and was on antidepressant therapy to control depression, the author adopted general anesthesia with laryngeal mask airway during initial stage of skull pinning and craniotomy procedures. Then, the patient reverted to awake state to continue the intended neurosurgical procedure. The patient tolerated the situation satisfactorily and was cooperative till the finish, without any event. PMID:25885087

The History of Awake Craniotomy in Hospital Universiti Sains Malaysia

PubMed Central

WAN HASSAN, Wan Mohd Nazaruddin

2013-01-01

Awake craniotomy is a brain surgery performed on awake patients and is indicated for certain intracranial pathologies. These include procedures that require an awake patient for electrocorticographic mapping or precise electrophysiological recordings, resection of lesions located close to or in the motor and speech of the brain, or minor intracranial procedures that aim to avoid general anaesthesia for faster recovery and earlier discharge. This type of brain surgery is quite new and has only recently begun to be performed in a few neurosurgical centres in Malaysia. The success of the surgery requires exceptional teamwork from the neurosurgeon, neuroanaesthesiologist, and neurologist. The aim of this article is to briefly describe the history of awake craniotomy procedures at our institution. PMID:24643321

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

PubMed

Andrade, Chittaranjan

2015-05-01

Intranasal drug delivery (INDD) systems offer a route to the brain that bypasses problems related to gastrointestinal absorption, first-pass metabolism, and the blood-brain barrier; onset of therapeutic action is rapid, and the inconvenience and discomfort of parenteral administration are avoided. INDD has found several applications in neuropsychiatry, such as to treat migraine, acute and chronic pain, Parkinson disease, disorders of cognition, autism, schizophrenia, social phobia, and depression. INDD has also been used to test experimental drugs, such as peptides, for neuropsychiatric indications; these drugs cannot easily be administered by other routes. This article examines the advantages and applications of INDD in neuropsychiatry; provides examples of test, experimental, and approved INDD treatments; and focuses especially on the potential of intranasal ketamine for the acute and maintenance therapy of refractory depression. © Copyright 2015 Physicians Postgraduate Press, Inc.

Anaesthesia for awake craniotomy: A retrospective study of 54 cases

PubMed Central

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

2015-01-01

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

Awake craniotomy for brain tumor: indications, technique and benefits.

PubMed

Dziedzic, Tomasz; Bernstein, Mark

2014-12-01

Increasing interest in the quality of life of patients after treatment of brain tumors has led to the exploration of methods that can improve intraoperative assessment of neurological status to avoid neurological deficits. The only method that can provide assessment of all eloquent areas of cerebral cortex and white matter is brain mapping during awake craniotomy. This method helps ensure that the quality of life and the neuro-oncological result of treatment are not compromised. Apart from the medical aspects of awake surgery, its economic issues are also favorable. Here, we review the main aspects of awake brain tumor surgery. Neurosurgical, neuropsychological, neurophysiological and anesthetic issues are briefly discussed.

[AWAKE CRANIOTOMY: IN SEARCH FOR OPTIMAL SEDATION].

PubMed

Kulikova, A S; Sel'kov, D A; Kobyakov, G L; Shmigel'skiy, A V; Lubnin, A Yu

2015-01-01

Awake craniotomy is a "gold standard"for intraoperative brain language mapping. One of the main anesthetic challenge of awake craniotomy is providing of optimal sedation for initial stages of intervention. The goal of this study was comparison of different technics of anesthesia for awake craniotomy. Materials and methods: 162 operations were divided in 4 groups: 76 cases with propofol sedation (2-4mg/kg/h) without airway protection; 11 cases with propofol sedation (4-5 mg/kg/h) with MV via LMA; 36 cases of xenon anesthesia; and 39 cases with dexmedetomidine sedation without airway protection. Results and discussion: brain language mapping was successful in 90% of cases. There was no difference between groups in successfulness of brain mapping. However in the first group respiratory complications were more frequent. Three other technics were more safer Xenon anesthesia was associated with ultrafast awakening for mapping (5±1 min). Dexmedetomidine sedation provided high hemodynamic and respiratory stability during the procedure.

Intranasal Oxytocin and Vasopressin Modulate Divergent Brainwide Functional Substrates

PubMed Central

Galbusera, Alberto; De Felice, Alessia; Girardi, Stefano; Bassetto, Giacomo; Maschietto, Marta; Nishimori, Katsuhiko; Chini, Bice; Papaleo, Francesco; Vassanelli, Stefano; Gozzi, Alessandro

2017-01-01

The neuropeptides oxytocin (OXT) and vasopressin (AVP) have been identified as modulators of emotional social behaviors and associated with neuropsychiatric disorders characterized by social dysfunction. Experimental and therapeutic use of OXT and AVP via the intranasal route is the subject of extensive clinical research. However, the large-scale functional substrates directly engaged by these peptides and their functional dynamics remain elusive. By using cerebral blood volume (CBV) weighted fMRI in the mouse, we show that intranasal administration of OXT rapidly elicits the transient activation of cortical regions and a sustained activation of hippocampal and forebrain areas characterized by high oxytocin receptor density. By contrast, intranasal administration of AVP produced a robust and sustained deactivation in cortico-parietal, thalamic and mesolimbic regions. Importantly, intravenous administration of OXT and AVP did not recapitulate the patterns of modulation produced by intranasal dosing, supporting a central origin of the observed functional changes. In keeping with this notion, hippocampal local field potential recordings revealed multi-band power increases upon intranasal OXT administration. We also show that the selective OXT-derivative TGOT reproduced the pattern of activation elicited by OXT and that the deletion of OXT receptors does not affect AVP-mediated deactivation. Collectively, our data document divergent modulation of brainwide neural systems by intranasal administration of OXT and AVP, an effect that involves key substrates of social and emotional behavior. The observed divergence calls for a deeper investigation of the systems-level mechanisms by which exogenous OXT and AVP modulate brain function and exert their putative therapeutic effects. PMID:27995932

Intranasal Oxytocin and Vasopressin Modulate Divergent Brainwide Functional Substrates.

PubMed

Galbusera, Alberto; De Felice, Alessia; Girardi, Stefano; Bassetto, Giacomo; Maschietto, Marta; Nishimori, Katsuhiko; Chini, Bice; Papaleo, Francesco; Vassanelli, Stefano; Gozzi, Alessandro

2017-06-01

The neuropeptides oxytocin (OXT) and vasopressin (AVP) have been identified as modulators of emotional social behaviors and associated with neuropsychiatric disorders characterized by social dysfunction. Experimental and therapeutic use of OXT and AVP via the intranasal route is the subject of extensive clinical research. However, the large-scale functional substrates directly engaged by these peptides and their functional dynamics remain elusive. By using cerebral blood volume (CBV) weighted fMRI in the mouse, we show that intranasal administration of OXT rapidly elicits the transient activation of cortical regions and a sustained activation of hippocampal and forebrain areas characterized by high oxytocin receptor density. By contrast, intranasal administration of AVP produced a robust and sustained deactivation in cortico-parietal, thalamic and mesolimbic regions. Importantly, intravenous administration of OXT and AVP did not recapitulate the patterns of modulation produced by intranasal dosing, supporting a central origin of the observed functional changes. In keeping with this notion, hippocampal local field potential recordings revealed multi-band power increases upon intranasal OXT administration. We also show that the selective OXT-derivative TGOT reproduced the pattern of activation elicited by OXT and that the deletion of OXT receptors does not affect AVP-mediated deactivation. Collectively, our data document divergent modulation of brainwide neural systems by intranasal administration of OXT and AVP, an effect that involves key substrates of social and emotional behavior. The observed divergence calls for a deeper investigation of the systems-level mechanisms by which exogenous OXT and AVP modulate brain function and exert their putative therapeutic effects.

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

PubMed

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

2014-01-01

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

Randomized Controlled Feasibility Trial of Intranasal Ketamine Compared to Intranasal Fentanyl for Analgesia in Children with Suspected Extremity Fractures.

PubMed

Reynolds, Stacy L; Bryant, Kathleen K; Studnek, Jonathan R; Hogg, Melanie; Dunn, Connell; Templin, Megan A; Moore, Charity G; Young, James R; Walker, Katherine Rivera; Runyon, Michael S

2017-12-01

We compared the tolerability and efficacy of intranasal subdissociative ketamine to intranasal fentanyl for analgesia of children with acute traumatic pain and investigated the feasibility of a larger noninferiority trial that could investigate the potential opioid-sparing effects of intranasal ketamine. This randomized controlled trial compared 1 mg/kg intranasal ketamine to 1.5 μg/kg intranasal fentanyl in children 4 to 17 years old with acute pain from suspected isolated extremity fractures presenting to an urban Level II pediatric trauma center from December 2015 to November 2016. Patients, parents, treating physicians, and outcome assessors were blinded to group allocation. The primary outcome, a tolerability measure, was the frequency of cumulative side effects and adverse events within 60 minutes of drug administration. The secondary outcomes included the difference in mean pain score reduction at 20 minutes, the proportion of patients achieving a clinically significant reduction in pain in 20 minutes, total dose of opioid pain medication in morphine equivalents/kg/hour (excluding study drug) required during the emergency department (ED) stay, and the feasibility of enrolling children presenting to the ED in acute pain into a randomized trial conducted under U.S. regulations. All patients were monitored until 6 hours after their last dose of study drug or until admission to the hospital ward or operating room. Of 629 patients screened, 87 received the study drug and 82 had complete data for the primary outcome (41 patients in each group). The median (interquartile range) age was 8 (6-11) years and 62% were male. Baseline pain scores were similar among patients randomized to receive ketamine (73 ± 26) and fentanyl (69 ± 26; mean difference [95% CI] = 4 [-7 to 15]). The cumulative number of side effects was 2.2 times higher in the ketamine group, but there were no serious adverse events and no patients in either group required intervention. The most

Implantable electrode for recording nerve signals in awake animals

NASA Technical Reports Server (NTRS)

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

1976-01-01

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

Long-term imaging in awake mice using removable cranial windows

PubMed Central

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

2015-01-01

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

Awake craniotomy: A qualitative review and future challenges

PubMed Central

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

2014-01-01

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

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

NASA Astrophysics Data System (ADS)

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

2010-07-01

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

Use of intranasal corticosteroids in adenotonsillar hypertrophy.

PubMed

Sakarya, E U; Bayar Muluk, N; Sakalar, E G; Senturk, M; Aricigil, M; Bafaqeeh, S A; Cingi, C

2017-05-01

This review examined the efficacy of intranasal corticosteroids for improving adenotonsillar hypertrophy. The related literature was searched using PubMed and Proquest Central databases. Adenotonsillar hypertrophy causes mouth breathing, nasal congestion, hyponasal speech, snoring, obstructive sleep apnoea, chronic sinusitis and recurrent otitis media. Adenoidal hypertrophy results in the obstruction of nasal passages and Eustachian tubes, and blocks the clearance of nasal mucus. Adenotonsillar hypertrophy and obstructive sleep apnoea are associated with increased expression of various mediators of inflammatory responses in the tonsils, and respond to anti-inflammatory agents such as corticosteroids. Topical nasal steroids most likely affect the anatomical component by decreasing inspiratory upper airway resistance at the nasal, adenoidal or tonsillar levels. Corticosteroids, by their lympholytic or anti-inflammatory effects, might reduce adenotonsillar hypertrophy. Intranasal corticosteroids reduce cellular proliferation and the production of pro-inflammatory cytokines in a tonsil and adenoid mixed-cell culture system. Intranasal corticosteroids have been used in adenoidal hypertrophy and adenotonsillar hypertrophy patients, decreasing rates of surgery for adenotonsillar hypertrophy.

Statistical and methodological considerations for the interpretation of intranasal oxytocin studies

PubMed Central

Walum, Hasse; Waldman, Irwin D.; Young, Larry J.

2015-01-01

Over the last decade, oxytocin (OT) has received focus in numerous studies associating intranasal administration of this peptide with various aspects of human social behavior. These studies in humans are inspired by animal research, especially in rodents, showing that central manipulations of the OT system affect behavioral phenotypes related to social cognition, including parental behavior, social bonding and individual recognition. Taken together, these studies in humans appear to provide compelling, but sometimes bewildering evidence for the role of OT in influencing a vast array of complex social cognitive processes in humans. In this paper we investigate to what extent the human intranasal OT literature lends support to the hypothesis that intranasal OT consistently influences a wide spectrum of social behavior in humans. We do this by considering statistical features of studies within this field, including factors like statistical power, pre-study odds and bias. Our conclusion is that intranasal OT studies are generally underpowered and that there is a high probability that most of the published intranasal OT findings do not represent true effects. Thus the remarkable reports that intranasal OT influences a large number of human social behaviors should be viewed with healthy skepticism, and we make recommendations to improve the reliability of human OT studies in the future. PMID:26210057

Wide Awake Hand Surgery.

PubMed

Lied, Line; Borchgrevink, Grethe E; Finsen, Vilhjalmur

2017-09-01

"Wide awake hand surgery", where surgery is performed in local anaesthesia with adrenaline, without sedation or a tourniquet, has become widespread in some countries. It has a number of potential advantages and we wished to evaluate it among our patients. All 122 patients treated by this method during one year were evaluated by the surgeons and the patients on a numerical scale from 0 (best/least) to 10 (worst/most). Theatre time was compared to that recorded for a year when regional or general anaesthesia had been used. The patients' mean score for the general care they had received was 0.1 (SD 0.6), for pain during lidocaine injection 2.4 (SD 2.2), for pain during surgery 0.9 (SD 1.5), and for other discomfort during surgery 0.5 (SD 1.4). Eight reported that they would want general anaesthesia if they were to be operated again. The surgeons' mean evaluation of bleeding during surgery was 1.6 (SD 1.8), oedema during surgery 0.4 (SD 1.1), general disadvantages with the method 1.0 (SD 1.6) and general advantages 6.5 (SD 4.3). The estimation of advantages was 9.9 (DS 0.5) for tendon suture. 28 patients needed intra-operative additional anaesthesia. The proportion was lower among trained hand surgeons and fell significantly during the study period. Non-surgical theatre time was 46 (SD 15) minutes during the study period and 55 (SD 22) minutes during the regional/general period (p < 0.001). This gain was cancelled out by a longer surgery time during the wide awake period. Wide awake surgery is fully acceptable to most patients. It has a number of advantages over general or regional anaesthesia, but we feel it is unlikely to improve the efficiency of the operating theatre.

[Pharmacokinetics of α-asarone after intranasal and intravenous administration with PLA-α-asarone nanoparticles].

PubMed

Lu, Jin; Guo, Li-Wei; Fu, Ting-Ming; Zhu, Guo-Long; Dai, Zhen-Nan; Zhan, Guan-Jun; Chen, Li-Li

2017-06-01

PLA-α-asarone nanoparticles were prepared by using organic solvent evaporation method, and their in vivo distribution and brain targeting after intranasal administration were studied as compared with intravenous administration. The results showed that brain targeting coefficient of PLA-α-asarone nanoparticles after intranasal and intravenous administration was 1.65 and 1.16 respectively. The absolute bioavailability, brain-targeting efficiency and the percentage of nasal-brain delivery of PLA-α-asarone nanoparticles were 74.2%, 142.24 and 29.83%, respectively after intranasal administration. The results of fluorescence labeling showed that the fluorescent intensity of coumarin-6 in the brain tissue was the highest after intranasal administration of PLA-α-asarone fluorescent nanoparticles, achieving the purpose of brain-targeted drug delivery. The fluorescent intensity of coumarin-6 in liver tissue after intravenous administration of PLA-α-asarone nanoparticles was much higher than that after intranasal administration, indicating that intranasal administration of PLA-α-asarone nanoparticles could decrease drug-induced hepatotoxicity. In addition, the fluorescent intensity of coumarin-6 in lung tissue was weaker after intranasal administration, which solved the shortcomings of intranasal administration of α-asarone dry powder prepared by airflow pulverization method. In vivo studies indicated that PLA-α-asarone nanoparticles after intranasal administration had a stronger brain targeting as compared with intravenous administration. Copyright© by the Chinese Pharmaceutical Association.

Anaesthetic Management of Supratentorial Tumor Craniotomy Using Awake-Throughout Approach.

PubMed

Shafiq, Faraz; Salim, Fahad; Enam, Ather; Parkash, Jai; Faheem, Mohammad

2017-12-01

The authors are reporting an anaesthetic management of patient presenting with left parietal lobe space occupying lesion and scheduled for Awake-craniotomy. Awake-throughout approach using scalp block was planned. Among techniques reported for keeping patient awake during the surgery, this one is really underutilized. The successful conduct requires thorough preoperative assessment and psychological preparation. We used powerpoint presentation as a preoperative teaching tool. The anatomical landmark technique was used to institute scalp block, where individual nerves were targeted bilaterally. Patient remained stable throughout and participated actively in intraoperative neurological monitoring. Postoperative period showed remarkable recovery, better pain control, and shorter length of stay in hospital.

Being with and Being There: Our Enactment of Wide-Awakeness

ERIC Educational Resources Information Center

Williams, Rebecca

2017-01-01

Maxine Greene championed that teachers and students can discover openings providing space for the development of wide-awakeness through art and aesthetic education. Wide-awakeness is a heightened sense of consciousness encouraging critical awareness and deep engagement with one's world. As individuals come alive in this way, their open-minded…

Patients' perceptions of awake and outpatient craniotomy for brain tumor: a qualitative study.

PubMed

Khu, Kathleen Joy; Doglietto, Francesco; Radovanovic, Ivan; Taleb, Faisal; Mendelsohn, Daniel; Zadeh, Gelareh; Bernstein, Mark

2010-05-01

Routine and nonselective use of awake and outpatient craniotomy for supratentorial tumors has been shown to be safe and effective from a medical standpoint. In this study the authors aim was to explore patients' perceptions about awake and outpatient craniotomy. Qualitative research methodology was used. Two semistructured, open-ended interviews were conducted with 27 participants, who were ambulatory adult patients who underwent craniotomy for brain tumor excision between October 2008 and April 2009. The participants were each assigned to one of the following categories: 1) awake outpatient; 2) awake inpatient; 3) outpatient under general anesthesia; and 4) inpatient under general anesthesia. Interviews were audiotaped and transcribed, and the data were subjected to thematic analysis. The following 6 overarching themes emerged from the data: 1) patients had a positive experience with awake craniotomy; 2) patient satisfaction with outpatient surgery was high; 3) patients understood the rationale behind awake surgery; 4) patients were surprised that brain surgery can be done on an outpatient basis; 5) trust in one's surgeon was important; and 6) patients were more concerned about the disease than the procedure. The results reflected positively on the patients' awake and outpatient surgery experience, but there were some areas that require improvement, specifically perioperative pain control and postoperative care. These insights on patients' perspectives can lead to better delivery of care, and ultimately, improved health outcomes.

Intranasal Delivery of Topically-Acting Levofloxacin to Rats: a Proof-of-Concept Pharmacokinetic Study.

PubMed

Sousa, Joana; Alves, Gilberto; Fortuna, Ana; Falcão, Amílcar

2017-11-01

To evaluate the potential of levofloxacin intranasal administration as a promising alternative approach to treat local infections such as chronic rhinosinusitis, by delivering drug concentrations directly to the site of infection. Drug concentrations were measured in plasma, olfactory bulb and nasal mucosa of anterior (ANM) and posterior regions after intranasal (0.24 mg/kg) and intravenous (10 mg/kg) administration to rats, and pharmacokinetic parameters were compared between routes. For intranasal administration a thermoreversible in-situ gel was used. Plasma and olfactory bulb exposure to levofloxacin was minimal following intranasal dose, preventing systemic and central nervous system adverse effects. Levofloxacin concentration-time profile in ANM revealed higher concentrations during the first 60 min of the study following intranasal administration than the corresponding ones obtained after intravenous administration. A rapid and continuous decay of levofloxacin concentration in this nasal region was observed after intranasal delivery, resulting in much lower values at the last sampling time-points. The higher dose-normalized concentrations and pharmacokinetic exposure parameters of levofloxacin in ANM after intranasal administration, demonstrates that intranasal delivery of the formulated gel is, by itself, advantageous for delivering levofloxacin to biophase and thus an attractive approach in management of chronic rhinosinusitis.

Awake craniotomy using electromagnetic navigation technology without rigid pin fixation.

PubMed

Morsy, Ahmed A; Ng, Wai Hoe

2015-11-01

We report our institutional experience using an electromagnetic navigation system, without rigid head fixation, for awake craniotomy patients. The StealthStation® S7 AxiEM™ navigation system (Medtronic, Inc.) was used for this technique. Detailed preoperative clinical and neuropsychological evaluations, patient education and contrast-enhanced MRI (thickness 1.5mm) were performed for each patient. The AxiEM Mobile Emitter was typically placed in a holder, which was mounted to the operating room table, and a non-invasive patient tracker was used as the patient reference device. A monitored conscious sedation technique was used in all awake craniotomy patients, and the AxiEM Navigation Pointer was used for navigation during the procedure. This offers the same accuracy as optical navigation, but without head pin fixation or interference with intraoperative neurophysiological techniques and surgical instruments. The application of the electromagnetic neuronavigation technology without rigid head fixation during an awake craniotomy is accurate, and offers superior patient comfort. It is recommended as an effective adjunctive technique for the conduct of awake surgery. Copyright © 2015 Elsevier Ltd. All rights reserved.

Anesthesia for awake craniotomy: case report.

PubMed

Bolzani, Nelson Davi; Junqueira, Daisy de Oliveira Pollon; Ferrari, Paulo André Pinheiro Fernandes; Ferrari, Antonio Fernandes; Gaia, Felipe; Tapajós, Caroline Moraes; Junior, José Francisco Cursino de Moura; Neto, Edmundo Pereira de Souza

2013-01-01

Some intracranial procedures are achievable with patients awake, however, there are challenges ranging from patient compliance to homeostasis. The aim of this study is to present a case of intracranial surgery for removal of a tumor in the left parietal lobe with the patient awake during the procedure. After patient selection and psychological preparation, the proposed excision of the left parietal lobe lesion in the waking state was clarified and accepted. Continuous infusion of propofol and remifentanil was administered to maintain a Ramsay score of 2-3. The bilateral scalp blockade was performed with ropivacaine. The Mayfield head fixation device was installed and drapes adjusted to maintain the airway and eyes accessible for mapping with electrical stimulation and tumor excision. For dura mater incision, a pad with 2% lidocaine was applied for 3 minutes. The surgery was uneventful. The patient was discharged on the seventh day of hospitalization without presenting complication. Although the maintenance of analgesia and hemodynamic stability was a challenge with the patient awake, the target-controlled infusion of propofol provided the desired level of consciousness, remifentanil titrated analgesia and sedation without drug accumulation, and the blockade with ropivacaine provided satisfactory analgesia. We conclude that the anesthetic technique was satisfactory for our patient. Copyright © 2013 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.

P10.05 Establishment of team work awake craniotomy: clinical experience in Taiwan

PubMed Central

Chen, P.; Chang, W.; Chao, Y.; Toh, C.; Wei, K.

2017-01-01

Abstract Introduction: Awake craniotomy provides the opportunity to maximize both extent of resection and preservation of neurological function. Serial preoperative and postoperative neurobehavial evaluation, magnetic resonance image examination and intraoperative task investigation need multidisciplinary experts to cooperate. Materials and Methods: From 2013, we gradually establish our team for awake craniotomy. Patient who had brain tumor with the symptom of aphasia or hemiparesis and are willing to cooperate would be entered the protocol of awake craniotomy. Patients would receive complete preoperative neurobehavial examination by psychologists and speech therapists and magnetic resonance image included diffuse tensor image. During operation, Patients went through asleep-awake-asleep anesthetic techniques. Direct electric stimulation was used for both cortical and subcortical mapping. Navigation included information of lesion and important fiber tract guided the direction of excision. Rehabilitation doctor performed the tasks and decided the positive response caused by stimulation or excisional procedure. After operation, post-operative image and neurobehavial examination would be performed within one week, 3 months, 6 months and one year later Results: We scheduled awake craniotomy on almost every Tuesday. In recent 89 patients who received awake craniotomy, Twenty-five participants with recurrent tumor underwent the operation. Seven patients received twice and one patient received three times of awake craniotomy. Two patients had controllable intraoperative seizure attack. Early termination of awake status was found in two patients due to general discomfort. Patients with modest preoperative performance status still benefit from the operation. Neurobehavioral functions improved over time and some specific feature correlate to certain aspect of quality of life. The grading of tumor and the extension of resection influence the recovery of neurobehavioral

Awake craniotomy, electrophysiologic mapping, and tumor resection with high-field intraoperative MRI.

PubMed

Parney, Ian F; Goerss, Stephan J; McGee, Kiaran; Huston, John; Perkins, William J; Meyer, Frederic B

2010-05-01

Awake craniotomy and electrophysiologic mapping (EPM) is an established technique to facilitate the resection of near eloquent cortex. Intraoperative magnetic resonance imaging (iMRI) is increasingly used to aid in the resection of intracranial lesions. Standard draping protocols in high-field iMRI units make awake craniotomies challenging, and only two groups have previously reported combined EPM and high-field iMRI. We present an illustrative case describing a simple technique for combining awake craniotomy and EPM with high-field iMRI. A movable platter is used to transfer the patient from the operating table to a transport trolley and into the adjacent MRI and still maintaining the patient's surgical position. This system allows excess drapes to be removed, facilitating awake craniotomy. A 57-year-old right-handed man presented with new onset seizures. Magnetic resonance imaging demonstrated a large left temporal mass. The patient underwent an awake, left frontotemporal craniotomy. The EPM demonstrated a single critical area for speech in his inferior frontal gyrus. After an initial tumor debulking, the scalp flap was loosely approximated, the wound was covered with additional drapes, and the excess surrounding drapes were trimmed. An iMRI was obtained. The image-guidance system was re-registered and the patient was redraped. Additional resection was performed, allowing extensive removal of what proved to be an anaplastic astrocytoma. The patient tolerated this well without any new neurological deficits. Standard protocols for positioning and draping in high-field iMRI units make awake craniotomies problematic. This straightforward technique for combined awake EPM and iMRI may facilitate safe removal of large lesions in eloquent cortex. Copyright © 2010 Elsevier Inc. All rights reserved.

Microdialysis pharmacokinetic study of scopolamine in plasma, olfactory bulb and vestibule after intranasal administration.

PubMed

Wei, Yan; Ying, Mingzhen; Xu, Shuai; Wang, Feng; Zou, Aifeng; Cao, Shilei; Jiang, Xinguo; Wang, Yajie

2016-01-01

The purpose of this study was to investigate the microdialysis pharmacokinetic of scopolamine in plasma, olfactory bulb and vestibule after intranasal administration. The pharmacokinetic study of subcutaneous and oral administration was also performed in rats. From the in vivo results, scopolamine intranasal administration can avoid hepatic first-pass effect. Tmax plasma samples after intranasal administration were significantly faster than oral administration and subcutaneous injection. The relative bioavailability of intranasal administrations was 51.8-70% when compared with subcutaneous injection. Moreover, one can see that in comparison with scopolamine subcutaneous administration, scopolamine intranasal gel and solutions can increased drug target index (DTI) with olfactory bulb 1.69 and 2.05, vestibule 1.80 and 2.15, respectively. The results indicated that scopolamine can be absorbed directly through the olfactory mucosa into the olfactory bulb, and then transported to various brain tissue after intranasal administration, with the characteristics of brain drug delivery.

Chronic and acute intranasal oxytocin produce divergent social effects in mice.

PubMed

Huang, Huiping; Michetti, Caterina; Busnelli, Marta; Managò, Francesca; Sannino, Sara; Scheggia, Diego; Giancardo, Luca; Sona, Diego; Murino, Vittorio; Chini, Bice; Scattoni, Maria Luisa; Papaleo, Francesco

2014-04-01

Intranasal administration of oxytocin (OXT) might be a promising new adjunctive therapy for mental disorders characterized by social behavioral alterations such as autism and schizophrenia. Despite promising initial studies in humans, it is not yet clear the specificity of the behavioral effects induced by chronic intranasal OXT and if chronic intranasal OXT could have different effects compared with single administration. This is critical for the aforementioned chronic mental disorders that might potentially involve life-long treatments. As a first step to address these issues, here we report that chronic intranasal OXT treatment in wild-type C57BL/6J adult mice produced a selective reduction of social behaviors concomitant to a reduction of the OXT receptors throughout the brain. Conversely, acute intranasal OXT treatment produced partial increases in social behaviors towards opposite-sex novel-stimulus female mice, while on the other hand, it decreased social exploration of same-sex novel stimulus male mice, without affecting social behavior towards familiar stimulus male mice. Finally, prolonged exposure to intranasal OXT treatments did not alter, in wild-type animals, parameters of general health such as body weight, locomotor activity, olfactory and auditory functions, nor parameters of memory and sensorimotor gating abilities. These results indicate that a prolonged over-stimulation of a 'healthy' oxytocinergic brain system, with no inherent deficits in social interaction and normal endogenous levels of OXT, results in specific detrimental effects in social behaviors.

Failed awake craniotomy: a retrospective analysis in 424 patients undergoing craniotomy for brain tumor.

PubMed

Nossek, Erez; Matot, Idit; Shahar, Tal; Barzilai, Ori; Rapoport, Yoni; Gonen, Tal; Sela, Gal; Korn, Akiva; Hayat, Daniel; Ram, Zvi

2013-02-01

Awake craniotomy for removal of intraaxial tumors within or adjacent to eloquent brain regions is a well-established procedure. However, awake craniotomy failures have not been well characterized. In the present study, the authors aimed to analyze and assess the incidence and causes for failed awake craniotomy. The database of awake craniotomies performed at Tel Aviv Medical Center between 2003 and 2010 was reviewed. Awake craniotomy was considered a failure if conversion to general anesthesia was required, or if adequate mapping or monitoring could not have been achieved. Of 488 patients undergoing awake craniotomy, 424 were identified as having complete medical, operative, and anesthesiology records. The awake craniotomies performed in 27 (6.4%) of these 424 patients were considered failures. The main causes of failure were lack of intraoperative communication with the patient (n = 18 [4.2%]) and/or intraoperative seizures (n = 9 [2.1%]). Preoperative mixed dysphasia (p < 0.001) and treatment with phenytoin (p = 0.0019) were related to failure due to lack of communication. History of seizures (p = 0.03) and treatment with multiple antiepileptic drugs (p = 0.0012) were found to be related to failure due to intraoperative seizures. Compared with the successful awake craniotomy group, a significantly lower rate of gross-total resection was achieved (83% vs 54%, p = 0.008), there was a higher incidence of short-term speech deterioration postoperatively (6.1% vs 23.5%, p = 0.0017) as well as at 3 months postoperatively (2.3% vs 15.4%, p = 0.0002), and the hospitalization period was longer (4.9 ± 6.2 days vs 8.0 ± 10.1 days, p < 0.001). Significantly more major complications occurred in the failure group (4 [14.8%] of 27) than in the successful group (16 [4%] of 397) (p = 0.037). Failures of awake craniotomy were associated with a lower incidence of gross-total resection and increased postoperative morbidity. The majority of awake craniotomy failures were preventable

Hippocampal replay in the awake state: a potential physiological substrate of memory consolidation and retrieval

PubMed Central

Carr, Margaret F.; Jadhav, Shantanu P.; Frank, Loren M.

2011-01-01

The hippocampus is required for the encoding, consolidation, and retrieval of event memories. While the neural mechanisms that underlie these processes are only partially understood, a series of recent papers point to awake memory replay as a potential contributor to both consolidation and retrieval. Replay is the sequential reactivation of hippocampal place cells that represent previously experienced behavioral trajectories and occurs frequently in the awake state, particularly during periods of relative immobility. Awake replay may reflect trajectories through either the current environment or previously visited environments that are spatially remote. The repetition of learned sequences on a compressed time scale is well suited to promote memory consolidation in distributed circuits beyond the hippocampus, suggesting that consolidation occurs in both the awake and sleeping animal. Moreover, sensory information can influence the content of awake replay, suggesting a role for awake replay in memory retrieval. PMID:21270783

Anaesthetic management for awake craniotomy in brain glioma resection: initial experience in Military Hospital Mohamed V of Rabat.

PubMed

Meziane, Mohammed; Elkoundi, Abdelghafour; Ahtil, Redouane; Guazaz, Miloudi; Mustapha, Bensghir; Haimeur, Charki

2017-01-01

The awake brain surgery is an innovative approach in the treatment of tumors in the functional areas of the brain. There are various anesthetic techniques for awake craniotomy (AC), including asleep-awake-asleep technique, monitored anesthesia care, and the recent introduced awake-awake-awake method. We describe our first experience with anesthetic management for awake craniotomy, which was a combination of these techniques with scalp nerve block, and propofol/rémifentanil target controlled infusion. A 28-year-oldmale underwent an awake craniotomy for brain glioma resection. The scalp nerve block was performed and a low sedative state was maintained until removal of bone flap. During brain glioma resection, the patient awake state was maintained without any complications. Once, the tumorectomy was completed, the level of anesthesia was deepened and a laryngeal mask airway was inserted. A well psychological preparation, a reasonable choice of anesthetic techniques and agents, and continuous team communication were some of the key challenges for successful outcome in our patient.

Anaesthetic management for awake craniotomy in brain glioma resection: initial experience in Military Hospital Mohamed V of Rabat

PubMed Central

Meziane, Mohammed; Elkoundi, Abdelghafour; Ahtil, Redouane; Guazaz, Miloudi; Mustapha, Bensghir; Haimeur, Charki

2017-01-01

The awake brain surgery is an innovative approach in the treatment of tumors in the functional areas of the brain. There are various anesthetic techniques for awake craniotomy (AC), including asleep-awake-asleep technique, monitored anesthesia care, and the recent introduced awake-awake-awake method. We describe our first experience with anesthetic management for awake craniotomy, which was a combination of these techniques with scalp nerve block, and propofol/rémifentanil target controlled infusion. A 28-year-oldmale underwent an awake craniotomy for brain glioma resection. The scalp nerve block was performed and a low sedative state was maintained until removal of bone flap. During brain glioma resection, the patient awake state was maintained without any complications. Once, the tumorectomy was completed, the level of anesthesia was deepened and a laryngeal mask airway was inserted. A well psychological preparation, a reasonable choice of anesthetic techniques and agents, and continuous team communication were some of the key challenges for successful outcome in our patient. PMID:28904684

Intraoperative seizures and seizures outcome in patients underwent awake craniotomy.

PubMed

Yuan, Yang; Peizhi, Zhou; Xiang, Wang; Yanhui, Liu; Ruofei, Liang; Shu, Jiang; Qing, Mao

2016-11-25

Awake craniotomies (AC) could reduce neurological deficits compared with patients under general anesthesia, however, intraoperative seizure is a major reason causing awake surgery failure. The purpose of the study was to give a comprehensive overview the published articles focused on seizure incidence in awake craniotomy. Bibliographic searches of the EMBASE, MEDLINE,were performed to identify articles and conference abstracts that investigated the intraoperative seizure frequency of patients underwent AC. Twenty-five studies were included in this meta-analysis. Among the 25 included studies, one was randomized controlled trials and 5 of them were comparable studies. The pooled data suggested the general intraoperative seizure(IOS) rate for patients with AC was 8%(fixed effect model), sub-group analysis identified IOS rate for glioma patients was 8% and low grade patients was 10%. The pooled data showed early seizure rates of AC patients was 11% and late seizure rates was 35%. This systematic review and meta-analysis shows that awake craniotomy is a safe technique with relatively low intraoperative seizure occurrence. However, few RCTs were available, and the acquisition of further evidence through high-quality RCTs is highly recommended.

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

PubMed

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. © 2014 British Small Animal Veterinary Association.

Development of a safe and pragmatic awake craniotomy program at Maine Medical Center.

PubMed

Rughani, Anand I; Rintel, Theodor; Desai, Rajiv; Cushing, Deborah A; Florman, Jeffrey E

2011-01-01

Awake craniotomy offers an excellent means of performing intraoperative mapping and optimizing surgical resection of brain tumors. Awake craniotomy relies on a strong collaboration between anesthesiologists, neurosurgeons, and operating room staff. The authors recently introduced awake craniotomy for tumor resection at the Maine Medical Center and propose that it can be performed safely, effectively, and efficiently in a high-volume community hospital. We describe a practical approach to performing awake craniotomy involving streamlined anesthetic protocols and simplified intraoperative testing parameters in a carefully selected group of patients. Our first 25 patients are retrospectively reviewed with particular attention to the anesthetic protocol, the extent of resection, the operative time, post-operative complications, the length of hospitalization, and their functional status at follow-up. The authors established an anesthetic protocol based primarily on midazolam, fentanyl, propofol, and local anesthetic. The authors note that all but one patient was able to tolerate the awake procedure. Gross total resection was achieved in nearly 80% of patients with a glial tumor. Operative time was short, averaging 159 minutes of entire anesthesia care. Length of stay averaged 3.7 days. Persistent new post-operative deficits were noted in 2 of 25 patients. There was no substantial difference in total hospital charges for patients undergoing awake craniotomy when compared to a matched historical control. With attention focused on patient selection and a streamlined anesthetic protocol, the authors were able to successfully implement an awake craniotomy protocol in a community setting with satisfying results, including low operative morbidity, short operative times, low anesthetic complications, and excellent patient tolerance.

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

PubMed

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

2015-02-01

Circadian rhythm is crucial for preventing hepatic insulin resistance, although the mechanism remains uncovered. Here we report that the wake-active hypothalamic orexin system plays a key role in this regulation. Wild-type mice showed that a daily rhythm in blood glucose levels peaked at the awake period; however, the glucose rhythm disappeared in orexin knockout mice despite normal feeding rhythm. Central administration of orexin A during nighttime awake period acutely elevated blood glucose levels but subsequently lowered daytime glucose levels in normal and diabetic db/db mice. The glucose-elevating and -lowering effects of orexin A were suppressed by adrenergic antagonists and hepatic parasympathectomy, respectively. Moreover, the expression levels of hepatic gluconeogenic genes, including Pepck, were increased and decreased by orexin A at nanomolar and femtomolar doses, respectively. These results indicate that orexin can bidirectionally regulate hepatic gluconeogenesis via control of autonomic balance, leading to generation of the daily blood glucose oscillation. Furthermore, during aging, orexin deficiency enhanced endoplasmic reticulum (ER) stress in the liver and caused impairment of hepatic insulin signaling and abnormal gluconeogenic activity in pyruvate tolerance test. Collectively, the daily glucose rhythm under control of orexin appears to be important for maintaining ER homeostasis, thereby preventing insulin resistance in the liver. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Awake, Offline Processing during Associative Learning.

PubMed

Bursley, James K; Nestor, Adrian; Tarr, Michael J; Creswell, J David

2016-01-01

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

Awake, Offline Processing during Associative Learning

PubMed Central

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

2016-01-01

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

Intranasal gene delivery for treating Parkinson's disease: overcoming the blood-brain barrier.

PubMed

Aly, Amirah E-E; Waszczak, Barbara L

2015-01-01

Developing a disease-modifying gene therapy for Parkinson's disease (PD) has been a high priority for over a decade. However, due to the inability of large biomolecules to cross the blood-brain barrier (BBB), the only means of delivery to the brain has been intracerebral infusion. Intranasal administration offers a non-surgical means of bypassing the BBB to deliver neurotrophic factors, and the genes encoding them, directly to the brain. This review summarizes: i) evidence demonstrating intranasal delivery to the brain of a number of biomolecules having therapeutic potential for various CNS disorders; and ii) evidence demonstrating neuroprotective efficacy of a subset of biomolecules specifically for PD. The intersection of these two spheres represents the area of opportunity for development of new intranasal gene therapies for PD. To that end, our laboratory showed that intranasal administration of glial cell line-derived neurotrophic factor (GDNF), or plasmid DNA nanoparticles encoding GDNF, provides neuroprotection in a rat model of PD, and that the cells transfected by the nanoparticle vector are likely to be pericytes. A number of genes encoding neurotrophic factors have therapeutic potential for PD, but few have been tested by the intranasal route and shown to be neuroprotective in a model of PD. Intranasal delivery provides a largely unexplored, promising approach for development of a non-invasive gene therapy for PD.

Intranasal mucoadhesive microemulsions of clonazepam: preliminary studies on brain targeting.

PubMed

Vyas, Tushar K; Babbar, A K; Sharma, R K; Singh, Shashi; Misra, Ambikanandan

2006-03-01

The aim of this investigation was to prepare clonazepam microemulsions (CME) for rapid drug delivery to the brain to treat acute status epileptic patients and to characterize and evaluate the performance of CME in vitro and in vivo in rats. The CME were prepared by the titration method and were characterized for globule size and size distribution, zeta potential, and drug content. CME was radiolabeled with (99m)Tc (technetium) and biodistribution of drug in the brain was studied in Swiss albino rats after intranasal and intravenous administrations. Brain scintigraphy imaging in rabbits was also performed to ascertain the uptake of the drug into the brain. Pre and postCME formulation treated human nasal mucosa was subjected to transmission electron microscopy to investigate the mechanism of drug uptake across the nasal mucosa. CME were transparent and stable with mean globule size of 15 +/- 10 nm and zeta potential of -30 mV to -40 mV. (99m)Tc-labeled clonazepam solution ((99m)Tc CS)/ clonazepam microemulsion (CME)/clonazepam mucoadhesive microemulsion (CMME) were found to be stable and suitable for in vivo studies. Brain/blood uptake ratios at 0.50 hour (h) following intranasal CMME, CME, clonazepam solution (CS), and intravenous CME administrations were found to be 0.67, 0.50, 0.48, and 0.13, respectively indicating more effective targeting with intranasal administration and best targeting of the brain with intranasal CMME. Brain/blood ratio at all sampling points up to 8 h following intranasal administration of CMME compared to intravenous was found to be twofold higher indicating larger extent of distribution of the drug in brain. Rabbit brain scintigraphy also showed higher intranasal uptake of the drug into the brain. Transmission electron microscopy revealed significant accretion of CMME within interstitial spaces and paracellular mode of transport due to stretching of the tight junctions present in the nasal mucosa. This investigation demonstrates a more

Central nervous insulin resistance: a promising target in the treatment of metabolic and cognitive disorders?

PubMed

Hallschmid, M; Schultes, B

2009-11-01

Research on functions and signalling pathways of insulin has traditionally focused on peripheral tissues such as muscle, fat and liver, while the brain was commonly believed to be insensitive to the effects of this hormone secreted by pancreatic beta cells. However, since the discovery some 30 years ago that insulin receptors are ubiquitously found in the central nervous system, an ever-growing research effort has conclusively shown that circulating insulin accesses the brain, which itself does not synthesise insulin, and exerts pivotal functions in central nervous networks. As an adiposity signal reflecting the amount of body fat, insulin provides direct negative feedback to hypothalamic nuclei that control whole-body energy and glucose homeostasis. Moreover, insulin affects distinct cognitive processes, e.g. by triggering the formation of psychological memory contents. Accordingly, metabolic and cognitive disorders such as obesity, type 2 diabetes mellitus and Alzheimer's disease are associated with resistance of central nervous structures to the effects of insulin, which may derive from genetic polymorphisms as well as from long-term exposure to excess amounts of circulating insulin due to peripheral insulin resistance. Thus, overcoming central nervous insulin resistance, e.g. by pharmacological interventions, appears to be an attractive strategy in the treatment and prevention of these disorders. Enhancement of central nervous insulin signalling by administration of intranasal insulin, insulin analogues and insulin sensitisers in basic research approaches has yielded encouraging results that bode well for the successful translation of these effects into future clinical practice.

Oxytocin Intranasal Administration Affects Neural Networks Upstream of GNRH Neurons.

PubMed

Salehi, Mohammad Saied; Khazali, Homayoun; Mahmoudi, Fariba; Janahmadi, Mahyar

2017-08-01

The last decade has witnessed a surge in studies on the clinical applications of intranasal oxytocin as a method of enhancing social interaction. However, the molecular and cellular mechanisms underlying its function are not completely understood. Since oxytocin is involved in the regulation of hypothalamic-pituitary-gonadal axis by affecting the gonadotropin-releasing hormone (GNRH) system, the present study addressed whether intranasal application of oxytocin has a role in affecting GNRH expression in the male rat hypothalamus. In addition, we assessed expression of two excitatory (kisspeptin and neurokinin B) and two inhibitory (dynorphin and RFamide-related peptide-3) neuropeptides upstream of GNRH neurons as a possible route to relay oxytocin information. Here, adult male rats received 20, 40, or 80 μg oxytocin intranasally once a day for 10 consecutive days, and then, the posterior (PH) and anterior hypothalamus (AH) dissected for evaluation of target genes. Using qRT-PCR, we found that oxytocin treatment increased Gnrh mRNA levels in both the PH and AH. In addition, oxytocin at its highest dose increased kisspeptin expression in the AH by around 400%, whereas treatments, dose dependently decreased kisspeptin mRNA in the PH. The expression of neurokinin B was increased from the basal levels following the intervention. Furthermore, although intranasal-applied oxytocin decreased hypothalamic RFamide-related peptide-3 mRNA level, the dynorphin mRNA was not affected. These observations are consistent with the hypothesis that applications of intranasal oxytocin can affect the GNRH system.

Awake craniotomy anesthetic management using dexmedetomidine, propofol, and remifentanil

PubMed Central

Prontera, Andrea; Baroni, Stefano; Marudi, Andrea; Valzania, Franco; Feletti, Alberto; Benuzzi, Francesca; Bertellini, Elisabetta; Pavesi, Giacomo

2017-01-01

Introduction Awake craniotomy allows continuous monitoring of patients’ neurological functions during open surgery. Anesthesiologists have to sedate patients in a way so that they are compliant throughout the whole surgical procedure, nevertheless maintaining adequate analgesia and anxiolysis. Currently, the use of α2-receptor agonist dexmedetomidine as the primary hypnotic–sedative medication is increasing. Methods Nine patients undergoing awake craniotomy were treated with refined monitored anesthesia care (MAC) protocol consisting of a combination of local anesthesia without scalp block, low-dose infusion of dexmedetomidine, propofol, and remifentanil, without the need of airways management. Results The anesthetic protocol applied in our study has the advantage of decreasing the dose of each drug and thus reducing the occurrence of side effects. All patients had smooth and rapid awakenings. The brain remained relaxed during the entire procedure. Conclusion In our experience, this protocol is safe and effective during awake brain surgery. Nevertheless, prospective randomized trials are necessary to confirm the optimal anesthetic technique to be used. PMID:28424537

Awake craniotomy anesthetic management using dexmedetomidine, propofol, and remifentanil.

PubMed

Prontera, Andrea; Baroni, Stefano; Marudi, Andrea; Valzania, Franco; Feletti, Alberto; Benuzzi, Francesca; Bertellini, Elisabetta; Pavesi, Giacomo

2017-01-01

Awake craniotomy allows continuous monitoring of patients' neurological functions during open surgery. Anesthesiologists have to sedate patients in a way so that they are compliant throughout the whole surgical procedure, nevertheless maintaining adequate analgesia and anxiolysis. Currently, the use of α2-receptor agonist dexmedetomidine as the primary hypnotic-sedative medication is increasing. Nine patients undergoing awake craniotomy were treated with refined monitored anesthesia care (MAC) protocol consisting of a combination of local anesthesia without scalp block, low-dose infusion of dexmedetomidine, propofol, and remifentanil, without the need of airways management. The anesthetic protocol applied in our study has the advantage of decreasing the dose of each drug and thus reducing the occurrence of side effects. All patients had smooth and rapid awakenings. The brain remained relaxed during the entire procedure. In our experience, this protocol is safe and effective during awake brain surgery. Nevertheless, prospective randomized trials are necessary to confirm the optimal anesthetic technique to be used.

Humidification of inspired oxygen is increased with pre-nasal cannula, compared to intranasal cannula.

PubMed

Dellweg, Dominic; Wenze, Markus; Hoehn, Ekkehard; Bourgund, Olaf; Haidl, Peter

2013-08-01

Oxygen therapy is usually combined with a humidification device, to prevent mucosal dryness. Depending on the cannula design, oxygen can be administered pre- or intra-nasally (administration of oxygen in front of the nasal ostia vs cannula system inside the nasal vestibulum). The impact of cannula design on intra-nasal humidity, however, has not been investigated to date. First, to develop a system, that samples air from the nasal cavity and analyzes the humidity of these samples. Second, to investigate nasal humidity during pre-nasal and intra-nasal oxygen application, with and without humidification. We first developed and validated a sampling and analysis system to measure humidity from air samples. By means of this system we measured inspiratory air samples from 12 subjects who received nasal oxygen with an intra-nasal and pre-nasal cannula at different flows, with and without humidification. The sampling and analysis system showed good correlation to a standard hygrometer within the tested humidity range (r = 0.99, P < .001). In our subjects intranasal humidity dropped significantly, from 40.3 ± 8.7% to 35.3 ± 5.8%, 32 ± 5.6%, and 29.0 ± 6.8% at flows of 1, 2, and 3 L, respectively, when oxygen was given intra-nasally without humidification (P = .001, P < .001, and P < .001, respectively). We observed no significant change in airway humidity when oxygen was given pre-nasally without humidification. With the addition of humidification we observed no significant change in humidity at any flow, and independent of pre- or intranasal oxygen administration. Pre-nasal administration of dry oxygen achieves levels of intranasal humidity similar to those achieved by intranasal administration in combination with a bubble through humidifier. Pre-nasal oxygen simplifies application and may reduce therapy cost.

Iatrogenic Cushing's syndrome caused by intranasal steroid use.

PubMed

Dursun, Fatma; Kirmizibekmez, Heves

2017-01-01

Cushing's syndrome (CS) is common after oral steroid use and has also been reported following topical or inhaled use, but it is extremely uncommon after intranasal administration. This is the case of a 6-year-old child who developed Cushing's syndrome after intranasal application of dexamethasone sodium phosphate for a period of 6 months. Pediatricians and other clinical practitioners should be aware that high-dose and long-term nasal steroid administration may cause iatrogenic Cushing's syndrome characterized by complications of glucocorticoid excess as well as serious and even life-threatening complications of adrenal insufficiency.

Experimental transmission of enzootic intranasal tumors of goats.

PubMed

De las Heras, M; García de Jalón, J A; Minguijón, E; Gray, E W; Dewar, P; Sharp, J M

1995-01-01

The successful experimental transmission of enzootic intranasal tumor (EIT) from goat to goat is described. Ten kids, less than 48 hours old, from a flock free of the disease and seronegative for ruminant lentiviruses were inoculated intranasally or intrasinusally with either nasal fluid from goats with naturally occurring EIT or EIT retrovirus concentrated from such fluids. EIT was induced in three kids after 12-24 months. The EIT retrovirus was demonstrated in tumor material from each of the three kids by western blotting and electron microscopy. All kids were seronegative for ruminant lentiviruses.

The Potential Benefits of Awake Craniotomy for Brain Tumor Resection: An Anesthesiologist's Perspective.

PubMed

Meng, Lingzhong; Berger, Mitchel S; Gelb, Adrian W

2015-10-01

Awake craniotomy for brain tumor resection is becoming a standard of care for lesions residing within or in close proximity to regions presumed to have language or sensorimotor function. Evidence shows an improved outcome including greater extent of resection, fewer late neurological deficits, shorter hospital stay, and longer survival after awake brain tumor resection compared with surgery under general anesthesia. The surgeon's ability to maximize tumor resection within the constraint of preserving neurological function by intraoperative stimulation mapping in an awake patient is credited for this advantageous result. It is possible that the care provided by anesthesiologists, especially the avoidance of certain components of general endotracheal anesthesia, may also be important in the outcome of awake brain tumor resection. We present our interpretation of the evidence that we believe substantiates this proposition. However, due to the lack of direct evidence based on randomized-controlled trials and the heterogeneity of anesthetic techniques used for awake craniotomy, our perspective is largely speculative and hypothesis generating that needs to be validated or refuted by future quality research.

Patients' perspective on awake craniotomy for brain tumors-single center experience in Brazil.

PubMed

Leal, Rafael Teixeira Magalhaes; da Fonseca, Clovis Orlando; Landeiro, Jose Alberto

2017-04-01

Awake craniotomy with brain mapping is the gold standard for eloquent tissue localization. Patients' tolerability and satisfaction have been shown to be high; however, it is a matter of debate whether these findings could be generalized, since patients across the globe have their own cultural backgrounds and may perceive and accept this procedure differently. We conducted a prospective qualitative study about the perception and tolerability of awake craniotomy in a population of consecutive brain tumor patients in Brazil between January 2013 and April 2015. Seventeen patients were interviewed using a semi-structured model with open-ended questions. Patients' thoughts were grouped into five categories: (1) overall perception: no patient considered awake craniotomy a bad experience, and most understood the rationale behind it. They were positively surprised with the surgery; (2) memory: varied from nothing to the entire surgery; (3) negative sensations: in general, it was painless and comfortable. Remarks concerning discomfort on the operating table were made; (4) postoperative recovery: perception of the postoperative period was positive; (5) previous surgical experiences versus awake craniotomy: patients often preferred awake surgery over other surgery under general anesthesia, including craniotomies. Awake craniotomy for brain tumors was well tolerated and yielded high levels of satisfaction in a population of patients in Brazil. This technique should not be avoided under the pretext of compromising patients' well-being.

Path to AWAKE: Evolution of the concept

DOE PAGES

Caldwell, A.; Adli, E.; Amorim, L.; ...

2016-01-02

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

Outcome of elderly patients undergoing awake-craniotomy for tumor resection.

PubMed

Grossman, Rachel; Nossek, Erez; Sitt, Razi; Hayat, Daniel; Shahar, Tal; Barzilai, Ori; Gonen, Tal; Korn, Akiva; Sela, Gal; Ram, Zvi

2013-05-01

Awake-craniotomy allows maximal tumor resection, which has been associated with extended survival. The feasibility and safety of awake-craniotomy and the effect of extent of resection on survival in the elderly population has not been established. The aim of this study was to compare surgical outcome of elderly patients undergoing awake-craniotomy to that of younger patients. Outcomes of consecutive patients younger and older than 65 years who underwent awake-craniotomy at a single institution between 2003 and 2010 were retrospectively reviewed. The groups were compared for clinical variables and surgical outcome parameters, as well as overall survival. A total of 334 young (45.4 ± 13.2 years, mean ± SD) and 90 elderly (71.7 ± 5.1 years) patients were studied. Distribution of gender, mannitol treatment, hemodynamic stability, and extent of tumor resection were similar. Significantly more younger patients had a better preoperative Karnofsky Performance Scale score (>70) than elderly patients (P = 0.0012). Older patients harbored significantly more high-grade gliomas (HGG) and brain metastases, and fewer low-grade gliomas (P < 0.0001). No significantly higher rate of mortality, or complications were observed in the elderly group. Age was associated with increased length of stay (4.9 ± 6.3 vs. 6.6 ± 7.5 days, P = 0.01). Maximal extent of tumor resection in patients with HGG was associated with prolonged survival in the elderly patients. Awake-craniotomy is a well-tolerated and safe procedure, even in elderly patients. Gross total tumor resection in elderly patients with HGG was associated with prolonged survival. The data suggest that favorable prognostic factors for patients with malignant brain tumors are also valid in elderly patients.

Large-scale brain networks in the awake, truly resting marmoset monkey.

PubMed

Belcher, Annabelle M; Yen, Cecil C; Stepp, Haley; Gu, Hong; Lu, Hanbing; Yang, Yihong; Silva, Afonso C; Stein, Elliot A

2013-10-16

Resting-state functional MRI is a powerful tool that is increasingly used as a noninvasive method for investigating whole-brain circuitry and holds great potential as a possible diagnostic for disease. Despite this potential, few resting-state studies have used animal models (of which nonhuman primates represent our best opportunity of understanding complex human neuropsychiatric disease), and no work has characterized networks in awake, truly resting animals. Here we present results from a small New World monkey that allows for the characterization of resting-state networks in the awake state. Six adult common marmosets (Callithrix jacchus) were acclimated to light, comfortable restraint using individualized helmets. Following behavioral training, resting BOLD data were acquired during eight consecutive 10 min scans for each conscious subject. Group independent component analysis revealed 12 brain networks that overlap substantially with known anatomically constrained circuits seen in the awake human. Specifically, we found eight sensory and "lower-order" networks (four visual, two somatomotor, one cerebellar, and one caudate-putamen network), and four "higher-order" association networks (one default mode-like network, one orbitofrontal, one frontopolar, and one network resembling the human salience network). In addition to their functional relevance, these network patterns bear great correspondence to those previously described in awake humans. This first-of-its-kind report in an awake New World nonhuman primate provides a platform for mechanistic neurobiological examination for existing disease models established in the marmoset.

Association of temporomandibular disorder pain with awake and sleep bruxism in adults.

PubMed

Sierwald, Ira; John, Mike T; Schierz, Oliver; Hirsch, Christian; Sagheri, Darius; Jost-Brinkmann, Paul-Georg; Reissmann, Daniel R

2015-07-01

Parafunctional habits such as clenching or grinding (bruxism) during daytime and at night are considered to have a great impact on the etiopathogenesis of temporomandibular disorders (TMD). However, the size of the effect and how daytime activities interact with nocturnal activities is not yet clear. The aim of this study was to assess the association of TMD pain with both awake and sleep bruxism in adults. In this case-control study, data of a consecutive sample of 733 TMD patients (cases; mean age ± SD: 41.4 ± 16.3 years; 82% women) with at least one pain-related TMD diagnosis according to the German version of the Research Diagnostic Criteria for TMD (RDC/TMD) and of a community-based probability sample of 890 subjects (controls; mean age ± SD: 40.4 ± 11.8 years; 57% female) without TMD were evaluated. Clenching or grinding while awake and/or asleep was assessed with self-reports. Association of TMD pain with awake and sleep bruxism was analyzed using multiple logistic regression analyses and controlled for potential confounders. Odds ratios (OR) with corresponding 95% confidence intervals (CI) were calculated. While 11.2% of the controls reported clenching or grinding while awake, this proportion was significantly higher in TMD patients (33.9%; p < 0.001). Nocturnal clenching or grinding was reported by 23.5% of the controls and 49.4% of the TMD patients (p < 0.001). Risk for TMD pain did not differ substantially for the separate reports of awake (OR 1.7; CI 1.0-2.7) or sleep bruxism (OR 1.8; CI 1.4-2.4). However, risk for TMD pain substantially increased in cases of simultaneous presence of awake and sleep bruxism (OR 7.7; CI 5.4-11.1). When occurring separately, awake and sleep bruxism are significant risk factors for TMD pain. In case of simultaneous presence, the risk for TMD pain is even higher.

A Randomized Controlled Trial Comparing Intranasal Midazolam and Chloral Hydrate for Procedural Sedation in Children.

PubMed

Stephen, Marie Christy Sharafine; Mathew, John; Varghese, Ajoy Mathew; Kurien, Mary; Mathew, George Ani

2015-12-01

To evaluate the efficacy and safety of intranasal midazolam and chloral hydrate syrup for procedural sedation in children. Prospective randomized placebo-controlled trial (double blind, double dummy). Tertiary care hospital over 18 months. Eighty-two children, 1 to 6 years old, undergoing auditory brainstem response testing were randomized to receive either intranasal midazolam with oral placebo or chloral hydrate syrup with placebo nasal spray. Intranasal midazolam was delivered at 0.5 mg/kg (100 mcg per spray) and oral syrup at 50 mg/kg. Children not sedated at 30 minutes had a second dose at half the initial dose. The primary outcomes measured were safety and efficacy. Secondary outcomes were time to onset of sedation, parental separation, nature of parental separation, parental satisfaction, audiologist's satisfaction, time to recovery, and number of attempts. Forty-one children were in each group, and no major adverse events were noted. The chloral hydrate group showed earlier onset of sedation (66%) compared with the intranasal midazolam group (33%). Significant difference in time to recovery was noted in the chloral hydrate group (78 minutes) versus the intranasal midazolam group (108 minutes). The parents' and audiologist's satisfaction was higher for chloral hydrate (95% and 75%) than for intranasal midazolam (49% and 29%, respectively). Overall, sedation was 95% with chloral hydrate versus 51% with intranasal midazolam. Both drugs maintained sedation. Intranasal midazolam and chloral hydrate are both safe and efficacious for pediatric procedural sedation. Chloral hydrate was superior to intranasal midazolam, with an earlier time to onset of sedation, a faster recovery, better satisfaction among parents and the audiologist, and successful sedation. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.

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

PubMed

Costello, T G

2014-08-01

An awake craniotomy for epilepsy surgery is presented where a bilingual patient post-operatively reported temporary aphasia of his first language (Spanish). This case report discusses the potential causes for this clinical presentation and methods to prevent the occurrence of this in future patients undergoing this form of surgery. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

PubMed

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

2015-01-01

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

Awake craniotomy and electrophysiological mapping for eloquent area tumours.

PubMed

Chacko, Ari George; Thomas, Santhosh George; Babu, K Srinivasa; Daniel, Roy Thomas; Chacko, Geeta; Prabhu, Krishna; Cherian, Varghese; Korula, Grace

2013-03-01

An awake craniotomy facilitates radical excision of eloquent area gliomas and ensures neural integrity during the excision. The study describes our experience with 67 consecutive awake craniotomies for the excision of such tumours. Sixty-seven patients with gliomas in or adjacent to eloquent areas were included in this study. The patient was awake during the procedure and intraoperative cortical and white matter stimulation was performed to safely maximize the extent of surgical resection. Of the 883 patients who underwent craniotomies for supratentorial intraaxial tumours during the study period, 84 were chosen for an awake craniotomy. Sixty-seven with a histological diagnosis of glioma were included in this study. There were 55 men and 12 women with a median age of 34.6 years. Forty-two (62.6%) patients had positive localization on cortical stimulation. In 6 (8.9%) patients white matter stimulation was positive, five of whom had responses at the end of a radical excision. In 3 patients who developed a neurological deficit during tumour removal, white matter stimulation was negative and cessation of the surgery did not result in neurological improvement. Sixteen patients (24.6%) had intraoperative neurological deficits at the time of wound closure, 9 (13.4%) of whom had persistent mild neurological deficits at discharge, while the remaining 7 improved to normal. At a mean follow-up of 40.8 months, only 4 (5.9%) of these 9 patients had persistent neurological deficits. Awake craniotomy for excision of eloquent area gliomas enable accurate mapping of motor and language areas as well as continuous neurological monitoring during tumour removal. Furthermore, positive responses on white matter stimulation indicate close proximity of eloquent cortex and projection fibres. This should alert the surgeon to the possibility of postoperative deficits to change the surgical strategy. Thus the surgeon can resect tumour safely, with the knowledge that he has not damaged

Pain during awake craniotomy for brain tumor resection. Incidence, causes, consequences and management.

PubMed

Fontaine, D; Almairac, F

2017-06-01

Awake craniotomy for brain tumor resection is usually well-tolerated and most of the patients are satisfied. However, in studies reporting the patients' postoperative perception of the awake craniotomy procedure, about half of them have experienced some degree of intraoperative pain. Pain was mild (intensity between 1 and 2 on the visual analogical score) short lasting in most cases, and did not challenge the procedure. Pain was reported as moderate in about 25% and exceptionally severe. We conducted a preliminary survey among French centers (n=9) routinely performing awake craniotomy. Neurosurgeons' opinions were concordant with patient's reports. Intraoperative pain exceptionally challenged the awake craniotomy procedure or led to changes in the resection strategy. For neurosurgeons, the most challenging causes of intraoperative pain were the patient's inadequate installation, the contact of surgical tools with pain-sensitive intracranial structures, especially the dura mater of the skull base, falx cerebri, and the leptomeninges of the lateral fissure and neighboring sulci. Strategies to deal with these causes included focusing the patient on the intraoperative functional tests to distract their attention away from the pain, and avoiding contacts with the pain-sensitive intracranial structures during the awake phase. Adequate preoperative patient information and preparation, trained anesthesiologists and application of recommendations for awake craniotomy procedures as well as adaptation of surgical technique to avoid contact with pain-sensitive intracranial structures are key factors to prevent intraoperative pain and ensure patient's postoperative satisfaction. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Awake craniotomy for assisting placement of auditory brainstem implant in NF2 patients.

PubMed

Zhou, Qiangyi; Yang, Zhijun; Wang, Zhenmin; Wang, Bo; Wang, Xingchao; Zhao, Chi; Zhang, Shun; Wu, Tao; Li, Peng; Li, Shiwei; Zhao, Fu; Liu, Pinan

2018-06-01

Auditory brainstem implants (ABIs) may be the only opportunity for patients with NF2 to regain some sense of hearing sensation. However, only a very small number of individuals achieved open-set speech understanding and high sentence scores. Suboptimal placement of the ABI electrode array over the cochlear nucleus may be one of main factors for poor auditory performance. In the current study, we present a method of awake craniotomy to assist with ABI placement. Awake surgery and hearing test via the retrosigmoid approach were performed for vestibular schwannoma resections and auditory brainstem implantations in four patients with NF2. Auditory outcomes and complications were assessed postoperatively. Three of 4 patients who underwent awake craniotomy during ABI surgery received reproducible auditory sensations intraoperatively. Satisfactory numbers of effective electrodes, threshold levels and distinct pitches were achieved in the wake-up hearing test. In addition, relatively few electrodes produced non-auditory percepts. There was no serious complication attributable to the ABI or awake craniotomy. It is safe and well tolerated for neurofibromatosis type 2 (NF2) patients using awake craniotomy during auditory brainstem implantation. This method can potentially improve the localization accuracy of the cochlear nucleus during surgery.

Awake craniotomy for excision of arteriovenous malformations? A qualitative comparison study with stereotactic radiosurgery.

PubMed

Chan, David Yuen Chung; Chan, Danny Tat Ming; Zhu, Cannon Xian Lun; Kan, Patricia Kwok Yee; Ng, Amelia Yikjin; Hsieh, Yi-Pin Sonia; Abrigo, Jill; Poon, Wai Sang; Wong, George Kwok Chu

2018-05-01

Treatment of arteriovenous malformations (AVM) located at the eloquent area has been a challenge. Awake brain mapping allows identification of a non-eloquent gyrus for intervention and can potentially facilitate resection with preservation of functions. An alternative treatment option is stereotactic radiosurgery (SRS). The objective of this study was to perform a qualitative comparison of the treatment outcome of awake AVM excision versus SRS. We conducted a 13-year retrospective review of AVM excision under awake craniotomy performed at Prince of Wales Hospital, Hong Kong, from 2003 to 2016. Patients' presentation, Spetzler-Martin (SM) grading, rate of obliteration and complication were reviewed and analyzed with the modified radiosurgery-based AVM score (RS score). Six patients had excision of AVM under awake mapping during this period of time. Two were SM Grade II and four were SM Grade III. Five located at the peri-rolandic region while one at the temporal language area. None had failed mapping. Five out of six achieved complete obliteration (83.3%). Qualitative comparative analysis had revealed better treatment outcome with awake AVM excision as compared to SRS with the obliteration rate of 100% versus 96% for RS score ≤1.00, 100% versus 78% for RS score 1.01-1.50, and 66% versus 50% for RS score >2.00 respectively. In conclusion, awake mapping and excision of AVMs at the eloquent area is feasible. Qualitative comparative analysis had revealed higher obliteration rate with awake AVM excision as compared to SRS. Copyright © 2018 Elsevier Ltd. All rights reserved.

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

PubMed

Sheshadri, Veena; Chandramouli, B A

2016-08-01

Resection of lesions near the eloquent cortex of brain necessitates awake craniotomy to reduce the risk of permanent neurologic deficits during surgery. There are limited reports of anesthetic management of awake craniotomy in pediatric patients. This report is on use of dexmedetomidine sedation for awake craniotomy in a 11-year-old child, without any airway adjuncts throughout the procedure. Dexmedetomidine infusion administered at a dosage of 0.2 to 0.7μg kg(-1) h(-1) provided adequate sedation for the entire procedure. There were no untoward incidents or any interference with electrocorticography, intraoperative stimulation, and functional mapping. Adequate preoperative visits and counseling of patient and parents regarding course and nature of events along with well-planned intraoperative management are of utmost importance in a pediatric age group for successful intraoperative awake craniotomy. Copyright © 2016 Elsevier Inc. All rights reserved.

Engineering intranasal mRNA vaccines to enhance lymph node trafficking and immune responses.

PubMed

Li, Man; Li, You; Peng, Ke; Wang, Ying; Gong, Tao; Zhang, Zhirong; He, Qin; Sun, Xun

2017-12-01

Intranasal mRNA vaccination provides immediate immune protection against pandemic diseases. Recent studies have shown that diverse forms of polyethyleneimine (PEI) have potent mucosal adjuvant activity, which could significantly facilitate the delivery of intranasal mRNA vaccines. Nevertheless, optimizing the chemical structure of PEI to maximize its adjuvanticity and decrease its toxicity remains a challenge. Here we show that the chemical structure of PEI strongly influences how well nanocomplexes of PEI and mRNA migrate to the lymph nodes and elicit immune responses. Conjugating cyclodextrin (CD) with PEI600 or PEI2k yielded CP (CD-PEI) polymers with different CD/PEI ratios. We analyzed the delivery efficacy of CP600, CP2k, and PEI25k as intranasal mRNA vaccine carriers by evaluating the lymph nodes migration and immune responses. Among these polymers, CP2k/mRNA showed significantly higher in vitro transfection efficiency, stronger abilities to migrate to lymph nodes and stimulate dendritic cells maturation in vivo, which further led to potent humoral and cellular immune responses, and showed lower local and systemic toxicity than PEI25k/mRNA. These results demonstrate the potential of CD-PEI2k/mRNA nanocomplex as a self-adjuvanting vaccine delivery vehicle that traffics to lymph nodes with high efficiency. As we face outbreaks of pandemic diseases such as Zika virus, intranasal mRNA vaccination provides instant massive protection against highly variant viruses. Various polymer-based delivery systems have been successfully applied in intranasal vaccine delivery. However, the influence of molecular structure of the polymeric carriers on the lymph node trafficking and dendritic cell maturation is seldom studied for intranasal vaccination. Therefore, engineering polymer-based vaccine delivery system and elucidating the relationship between molecular structure and the intranasal delivery efficiency are essential for maximizing the immune responses. We hereby

Deposition of intranasal glucocorticoids--preliminary study.

PubMed

Rapiejko, Piotr; Sosnowski, Tomasz R; Sova, Jarosław; Jurkiewicz, Dariusz

2015-01-01

Intranasal glucocorticoids are the treatment of choice in the therapy of rhinitis. The differences in efficiency of particular medications proven by therapeutic index may result from differences in composition of particular formulations as well as from diverse deposition in nasal cavities. Intranasal formulations of glucocorticoids differ in volume of a single dose in addition to variety in density, viscosity and dispenser nozzle structure. The aim of this report was to analyze the deposition of most often used intranasal glucocorticoids in the nasal cavity and assessment of the usefulness of a nose model from a 3D printer reflecting anatomical features of a concrete patient. Three newest and most often used in Poland intranasal glucocorticoids were chosen to analysis; mometasone furoate (MF), fluticasone propionate (FP) and fluticasone furoate (FF). Droplet size distribution obtained from the tested formulations was determined by use of a laser aerosol spectrometer Spraytec (Malvern Instruments, UK). The model of the nasal cavity was obtained using a 3D printer. The printout was based upon a tridimensional reconstruction of nasal cavity created on the basis of digital processing of computed tomography of paranasal sinuses. The deposition of examined medications was established by a method of visualization combined with image analysis using commercial substance which colored itself intensively under the influence of water being the dominant ingredient of all tested preparations. On the basis of obtained results regions of dominating deposition of droplets of intranasal medication on the wall and septum of the nasal cavity were compared. Droplet size of aerosol of tested intranasal medications typically lies within the range of 25-150 µm. All tested medications deposited mainly on the anterior part of inferior turbinate. FP preparation deposited also on the anterior part of the middle nasal turbinate, marginally embracing a fragment of the central part of this

Pediatric awake craniotomy and intra-operative stimulation mapping.

PubMed

Balogun, James A; Khan, Osaama H; Taylor, Michael; Dirks, Peter; Der, Tara; Carter Snead Iii, O; Weiss, Shelly; Ochi, Ayako; Drake, James; Rutka, James T

2014-11-01

The indications for operating on lesions in or near areas of cortical eloquence balance the benefit of resection with the risk of permanent neurological deficit. In adults, awake craniotomy has become a versatile tool in tumor, epilepsy and functional neurosurgery, permitting intra-operative stimulation mapping particularly for language, sensory and motor cortical pathways. This allows for maximal tumor resection with considerable reduction in the risk of post-operative speech and motor deficits. We report our experience of awake craniotomy and cortical stimulation for epilepsy and supratentorial tumors located in and around eloquent areas in a pediatric population (n=10, five females). The presenting symptom was mainly seizures and all children had normal neurological examinations. Neuroimaging showed lesions in the left opercular (n=4) and precentral or peri-sylvian regions (n=6). Three right-sided and seven left-sided awake craniotomies were performed. Two patients had a history of prior craniotomy. All patients had intra-operative mapping for either speech or motor or both using cortical stimulation. The surgical goal for tumor patients was gross total resection, while for all epilepsy procedures, focal cortical resections were completed without any difficulty. None of the patients had permanent post-operative neurologic deficits. The patient with an epileptic focus over the speech area in the left frontal lobe had a mild word finding difficulty post-operatively but this improved progressively. Follow-up ranged from 6 to 27 months. Pediatric awake craniotomy with intra-operative mapping is a precise, safe and reliable method allowing for resection of lesions in eloquent areas. Further validations on larger number of patients will be needed to verify the utility of this technique in the pediatric population. Copyright © 2014 Elsevier Ltd. All rights reserved.

[A Case of Psychogenic Tremor during Awake Craniotomy].

PubMed

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

2016-01-01

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

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

PubMed

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

2014-01-01

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

Development of a brain monitoring system for multimodality investigation in awake rats.

PubMed

Limnuson, Kanokwan; Narayan, Raj K; Chiluwal, Amrit; Bouton, Chad; Ping Wang; Chunyan Li

2016-08-01

Multimodal brain monitoring is an important approach to gain insight into brain function, modulation, and pathology. We have developed a unique micromachined neural probe capable of real-time continuous monitoring of multiple physiological, biochemical and electrophysiological variables. However, to date, it has only been used in anesthetized animals due to a lack of an appropriate interface for awake animals. We have developed a versatile headstage for recording the small neural signal and bridging the sensors to the remote sensing units for multimodal brain monitoring in awake rats. The developed system has been successfully validated in awake rats by simultaneously measuring four cerebral variables: electrocorticography, oxygen tension, temperature and cerebral blood flow. Reliable signal recordings were obtained with minimal artifacts from movement and environmental noise. For the first time, multiple variables of cerebral function and metabolism were simultaneously recorded from awake rats using a single neural probe. The system is envisioned for studying the effects of pharmacologic treatments, mapping the development of central nervous system diseases, and better understanding normal cerebral physiology.

[Efficacy of intranasal antihistamine in the treatment of allergic rhinitis: a meta-analysis].

PubMed

Feng, Shaoyan; Deng, Chuntao; Li, Lei; Liao, Wei; Fan, Yunping; Xu, Geng; Li, Huabin

2014-10-01

To systematically evaluate the efficacy of intranasal antihistamine in the treatment of allergic rhinitis. The randomized controlled trials (RCT) about intranasal antihistamines for the treatment of allergic rhinitis between January 1985 and January 2014 were searched in OVID, PubMed, EMBASE, CNKI, WanFang Data and Cochrane Library. Two reviewers independently screened the literatures, extracted the data, and evaluated the methodological quality, then meta-analysis was performed by using RevMan 5.1 software. A total of thirteen RCTs were included. The results of meta-analysis showed that the efficacy of intranasal antihistamine group was superior to the placebo group in total nasal symptom scores (TNSS), the difference was significant[WMD = -1.96, 95%CI (-2.06;-1.85), P < 0.01], and individual nasal symptom scores (blocked nose, rhinorrhea, and sneezing) [WMD = -0.18, 95%CI (-0.28;-0.08); WMD = -0.45, 95%CI (-0.52;-0.38); WMD = -0.41, 95%CI (-0.58;-0.24), all P < 0.01], with significant differences. There was no significant difference between the intranasal antihistamine group and the corticosteroid group in TNSS [WMD = -1.51, 95%CI (-3.51;0.49), P = 0.14], but the intranasal antihistamines group was superior to the corticosteroid group in individual nasal symptom scores (blocked nose, rhinorrhea, and sneezing) [WMD = -0.23, 95%CI (-0.40;-0.06); WMD = -0.35, 95%CI (-0.65;-0.05); WMD = -0.25, 95%CI (-0.42;-0.08), all P < 0.05], with significant differences. The intranasal antihistamine group was superior to the oral antihistamines group in TNSS [WMD = -0.88, 95%CI (-1.51;-0.25), P < 0.01]. Intranasal antihistamine is effective in the control of nasal symptoms in AR patients.

"Imagine your neighbor mows the lawn": a pilot study of psychological sequelae due to awake craniotomy: clinical article.

PubMed

Milian, Monika; Luerding, Ralf; Ploppa, Annette; Decker, Karlheinz; Psaras, Tsambika; Tatagiba, Marcos; Gharabaghi, Alireza; Feigl, Guenther C

2013-06-01

Although it has been reported that awake neurosurgical procedures are well tolerated, the long-term occurrence of general psychological sequelae has not yet been investigated. This study assessed the frequency and effects of psychological symptoms after an awake craniotomy on health-related quality of life (HRQOL). Sixteen patients undergoing an awake surgery were surveyed with a self-developed questionnaire, the Posttraumatic Stress Disorder Inventory For Awake Surgery Patients, which adopts the core components of the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) posttraumatic stress disorder (PTSD) criteria. The mean time between surgery and data collection was 97.3 ± 93.2 weeks. Health-related quality of life was assessed with the 36-Item Short Form Health Survey. Forty-four percent of the patients stated that they had experienced either repetitive distressing recollections or dreams related to the awake surgery, 18.8% stated persistent avoidance of stimuli associated with the awake surgery, and symptoms of increased arousal occurred in 62.5%. Two patients presented with postoperative psychological sequelae resembling PTSD symptoms. Younger age at surgery and female sex were risk factors for symptoms of increased arousal. The experience of intense anxiety during awake surgery appears to favor the development of postsurgical PTSD symptoms, while recurrent distressing recollections particularly affect HRQOL negatively. In many cases awake craniotomy is necessary to preserve language and motor function. However, in some cases awake craniotomy can lead to postoperative psychological sequelae resembling PTSD symptoms. Therefore, possible long-term effects of an awake surgery should be considered and discussed with the patient when planning this type of surgery.

Out-of-Body Experience During Awake Craniotomy.

PubMed

Bos, Eelke M; Spoor, Jochem K H; Smits, Marion; Schouten, Joost W; Vincent, Arnaud J P E

2016-08-01

The out-of-body experience (OBE), during which a person feels as if he or she is spatially removed from the physical body, is a mystical phenomenon because of its association with near-death experiences. Literature implicates the cortex at the temporoparietal junction (TPJ) as the possible anatomic substrate for OBE. We present a patient who had an out-of-body experience during an awake craniotomy for resection of low-grade glioma. During surgery, stimulation of subcortical white matter in the left TPJ repetitively induced OBEs, in which the patient felt as if she was floating above the operating table looking down on herself. We repetitively induced OBE by subcortical stimulation near the left TPJ during awake craniotomy. Diffusion tensor imaging tractography implicated the posterior thalamic radiation as a possible substrate for autoscopic phenomena. Copyright © 2016 Elsevier Inc. All rights reserved.

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

PubMed

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

2016-06-08

Intranasal vaccination with inactivated influenza viral antigens is an attractive and valid alternative to currently available influenza (flu) vaccines; many of which seem to need efficient and safe adjuvant, however. In this study, we examined whether hydroxypropyl-β-cyclodextrin (HP-β-CD), a widely used pharmaceutical excipient to improve solubility and drug delivery, can act as a mucosal adjuvant for intranasal flu vaccines. We found that intranasal immunization of mice with hemagglutinin split- as well as inactivated whole-virion influenza vaccine with HP-β-CD resulted in secretion of antigen-specific IgA and IgGs in the airway mucosa and the serum as well. As a result, both HP-β-CD adjuvanted-flu intranasal vaccine protected mice against lethal challenge with influenza virus, equivalent to those induced by experimental cholera toxin-adjuvanted ones. Of note, intranasal use of HP-β-CD as an adjuvant induced significantly lower antigen-specific IgE responses than that induced by aluminum salt adjuvant. These results suggest that HP-β-CD may be a potent mucosal adjuvant for seasonal and pandemic influenza vaccine. Copyright © 2016 Elsevier Ltd. All rights reserved.

Evaluation of Mice Undergoing Serial Oral Gavage While Awake or Anesthetized.

PubMed

Jones, Carissa P; Boyd, Kelli L; Wallace, Jeanne M

2016-11-01

Although oral gavage is the most straightforward approach to achieve precise enteric administration in rodents, it is associated with potential adverse consequences. Here we compare the effects of serial oral gavage in awake compared with anesthetized mice. Female C57BL/6J mice (n = 20 per group) were assigned to 1 of 3 treatment groups (control, awake gavage, or anesthetized gavage) and gavaged daily with 0.2 mL of saline (with no manipulation on weekends) for a total of 18 treatment days. Body weight and clinical appearance were monitored throughout the treatment period, after which mice were euthanized and necropsied. Endpoints evaluated included adrenal gland weight, plasma corticosterone, lymphocyte:neutrophil ratio, and esophageal histopathology. Mean body weight did not differ between groups. Compared with other groups, the awake gavage group had more mice removed (3 of 20) prior to study completion due to body weight loss greater than 10%, with corresponding gross and histopathologic lesions attributed to the gavage procedure. Mice gavaged when awake had an over 20-fold higher incidence of incomplete retention of the administered saline than did anesthetized mice. Of the mice that completed the study, esophageal inflammation was not apparent at necropsy regardless of treatment, with the exception of a single mouse in the awake gavage group. Although WBC and lymphocyte counts were lower in mice in the anesthetized gavage group compared with other groups, none of the endpoints measured to evaluate stress (adrenal gland weight, neutrophil:lymphocyte ratio, plasma corticosterone) differed. These findings support the use of brief isoflurane anesthesia when performing serial oral gavage in mice.

Awake craniotomy in a developmentally delayed blind man with cognitive deficits.

PubMed

Burbridge, Mark; Raazi, Mateen

2013-04-01

To describe the complex perioperative considerations and anesthetic management of a cognitively delayed blind adult male who underwent awake craniotomy to remove a left anterior temporal lobe epileptic focus. A 28-yr-old left-handed blind cognitively delayed man was scheduled for awake craniotomy to resect a left anterior temporal lobe epileptic focus due to intractable epilepsy despite multiple medications. His medical history was also significant for retinopathy of prematurity that rendered him legally blind in both eyes and an intracerebral hemorrhage shortly after birth that resulted in a chronic brain injury and developmental delay. His cognitive capacity was comparable with that of an eight year old. Since patient cooperation was the primary concern during the awake electrocorticography phase of surgery, careful assessment of the patient's ability to tolerate the procedure was undertaken. There was extensive planning between surgeons and anesthesiologists, and a patient-specific pharmacological strategy was devised to facilitate surgery. The operation proceeded without complication, the patient has remained seizure-free since the procedure, and his quality of life has improved dramatically. This case shows that careful patient assessment, effective interdisciplinary communication, and a carefully tailored anesthetic strategy can facilitate an awake craniotomy in a potentially uncooperative adult patient with diminished mental capacity and sensory deficits.

Comparison of computed tomography and magnetic resonance imaging for the evaluation of canine intranasal neoplasia.

PubMed

Drees, R; Forrest, L J; Chappell, R

2009-07-01

Canine intranasal neoplasia is commonly evaluated using computed tomography to indicate the diagnosis, to determine disease extent, to guide histological sampling location and to plan treatment. With the expanding use of magnetic resonance imaging in veterinary medicine, this modality has been recently applied for the same purpose. The aim of this study was to compare the features of canine intranasal neoplasia using computed tomography and magnetic resonance imaging. Twenty-one dogs with confirmed intranasal neoplasia underwent both computed tomography and magnetic resonance imaging. The images were reviewed retrospectively for the bony and soft tissue features of intranasal neoplasia. Overall computed tomography and magnetic resonance imaging performed very similarly. However, lysis of bones bordering the nasal cavity and mucosal thickening was found on computed tomography images more often than on magnetic resonance images. Small amounts of fluid in the nasal cavity were more often seen on magnetic resonance images. However, fluid in the frontal sinuses was seen equally well with both modalities. We conclude that computed tomography is satisfactory for evaluation of canine intranasal neoplasia, and no clinically relevant benefit is gained using magnetic resonance imaging for intranasal neoplasia without extent into the cranial cavity.

Anesthetic approach to high-risk patients and prolonged awake craniotomy using dexmedetomidine and scalp block.

PubMed

Garavaglia, Marco M; Das, Sunit; Cusimano, Michael D; Crescini, Charmagne; Mazer, C David; Hare, Gregory M T; Rigamonti, Andrea

2014-07-01

Awake craniotomy with intraoperative speech or motor testing is relatively contraindicated in cases requiring prolonged operative times and in patients with severe medical comorbidities including anxiety, anticipated difficult airway, obesity, large tumors, and intracranial hypertension. The anesthetic management of neurosurgical patients who possess these contraindications but would be optimally treated by an awake procedure remains unclear. We describe a new anesthetic approach for awake craniotomy that did not require any airway manipulation, utilizing a bupivacaine-based scalp nerve block, and dexmedetomidine as the primary hypnotic-sedative agent. Using this technique, we provided optimal operative conditions to perform awake craniotomy facilitating safe tumor resection, while utilizing intraoperative electrocorticography for motor and speech mapping in a cohort of 10 patients at a high risk for airway compromise and complications associated with patient comorbidities. All patients underwent successful awake craniotomy, intraoperative mapping, and tumor resection with adequate sedation for up to 9 hours (median 3.5 h, range 3 to 9 h) without any loss of neurological function, airway competency, or the need to provide any active rescue airway management. We report 4 of these cases that highlight our experience: 1 case required prolonged surgery because of the complexity of tumor resection and 3 patients had important medical comorbidities and/or relative contraindication for an awake procedure. Dexmedetomidine, with concurrent scalp block, is an effective and safe anesthetic approach for awake craniotomy. Dexmedetomidine facilitates the extension procedure complexity and duration in patients who might traditionally not be considered to be candidates for this procedure.

Ameliorating Impact of Prophylactic Intranasal Oxytocin on Signs of Fear in a Rat Model of Traumatic Stress

PubMed Central

Renicker, Micah D.; Cysewski, Nicholas; Palmer, Samuel; Nakonechnyy, Dmytro; Keef, Andrew; Thomas, Morgan; Magori, Krisztian; Daberkow, David P.

2018-01-01

Oxytocin treatment reduces signs of long-term emotional stress after exposure to trauma; however, little is known about the potential protective effects of oxytocin treatment on behavioral and physiological changes associated with extreme stress exposure. The objective of this study was to investigate oxytocin treatment as a prophylactic measure against rat signs of fear. Two separate experiments were conducted in which the time of intranasal oxytocin administration differed. Intranasal oxytocin (1.0 μg/kg) was administered 5 min after daily exposure to foot shock in Experiment #1 and 1 h before foot shock in Experiment #2. In Experiment #1, possible massage-evoked oxytocin release (5 min after foot shock) was also investigated. In both experiments, a contextual fear conditioning procedure was employed in which stress was induced via inescapable foot shock (3 days, 40 shocks/day, 8 mA/shock) in a fear conditioning chamber. Male Sprague-Dawley rats (n = 24) were divided into four groups (n = 6, per group) for each experiment. Experiment #1 groups: Control Exp#1 (intranasal saline and no foot shock); Stress Exp#1 (intranasal saline 5 min after foot shock); Massage+Stress Exp#1 (massage-like stroking and intranasal saline 5 min after foot shock); Oxytocin+Stress Exp#1 (intranasal oxytocin 5 min after foot shock). Experiment #2 groups: Control Exp#2 (intranasal saline and no foot shock); Stress Exp#2 (intranasal saline 1 h before foot shock); Oxytocin Exp#2 (intranasal oxytocin and no foot shock); Oxytocin+Stress Exp#2 (intranasal oxytocin 1 h before foot shock). One week after fear conditioning (and other treatments), rats were independently evaluated for behavioral signs of fear. Two weeks after conditioning, physiological signs of fear were also assessed (Experiment #1). Relative to controls, rats treated with intranasal oxytocin 5 min after daily foot shock sessions exhibited significantly less immobility upon re-exposure to the shock chamber and attenuated

Intranasal delivery of ciprofloxacin to rats: A topical approach using a thermoreversible in situ gel.

PubMed

Sousa, Joana; Alves, Gilberto; Oliveira, Paula; Fortuna, Ana; Falcão, Amílcar

2017-01-15

Intranasal administration of antibiotics is an alternative and attractive delivery approach in the treatment of local infections such as chronic rhinosinusitis. This topical route has the advantage of delivering high drug concentrations directly to the site of infection when trying to eradicate the highly resistant bacterial biofilms. The purpose of this study was to assess and compare the pharmacokinetic parameters of ciprofloxacin following intranasal and intravenous administrations to rats in plasma, olfactory bulb and nasal mucosa of two different nasal regions. For intranasal administration a thermoreversible in situ gel was used to increase drug residence time in nasal cavity. Ciprofloxacin concentration time-profile in nasal mucosa of the studied anterior region (at naso- and maxilloturbinates level) was markedly higher after intranasal administration (0.24mg/kg) than that following intravenous administration (10mg/kg), while in nasal mucosa of the more posterior region (at ethmoidal turbinates level) ciprofloxacin concentrations were found to be higher after intranasal administration when the different dose administered by both routes is taken into account. A plateau in ciprofloxacin concentration was observed in nasal mucosa of both studied regions after intranasal administration, suggesting a slow delivery of the drug over a period of time using the nasal gel formulation. In plasma and olfactory bulb, concentration of ciprofloxacin was residual after intranasal administration, which demonstrates this is a safe administration route by preventing systemic and particularly central nervous system adverse effects. Dose-normalized pharmacokinetic parameters of ciprofloxacin exposure to nasal mucosa revealed higher values after intranasal delivery not only in the anterior region but also in the posterior nasal region. In conclusion, topical intranasal administration appears to be advantageous for delivering ciprofloxacin to the biophase, with negligible systemic

Design and Efficacy of Nanogels Formulations for Intranasal Administration.

PubMed

Aderibigbe, Blessing A; Naki, Tobeka

2018-05-23

Nanogels are drug delivery systems that can bypass the blood-brain barrier and deliver drugs to the desired site when administered intranasally. They have been used as a drug delivery platform for the management of brain diseases such as Alzheimer disease, migraine, schizophrenia and depression. nanogels have also been developed as vaccine carriers for the protection of bacterial infections such as influenza, meningitis, pneumonia and as veterinary vaccine carriers for the protection of animals from encephalomyelitis and mouth to foot disease. It has been developed as vaccine carriers for the prevention of lifestyle disease such as obesity. Intranasal administration of therapeutics using nanogels for the management of brain diseases revealed that the drug transportation was via the olfactory nerve pathway resulting in rapid drug delivery to the brain with excellent neuroprotective effect. The application of nanogels as vaccine carriers also induced significant responses associated with protective immunity against selected bacterial and viral infections. This review provides a detailed information on the enhanced therapeutic effects, mechanisms and biological efficacy of nanogels for intranasal administration.

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

PubMed

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

2014-07-01

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

A Novel Approach to Brachycephalic Syndrome. 1. Evaluation of Anatomical Intranasal Airway Obstruction.

PubMed

Oechtering, Gerhard U; Pohl, Sabine; Schlueter, Claudia; Lippert, Johanna P; Alef, Michaele; Kiefer, Ingmar; Ludewig, Eberhard; Schuenemann, Riccarda

2016-02-01

To evaluate airway obstruction due to abnormal intranasal anatomy in 3 brachycephalic dog breeds using computed tomography and rhinoscopy. Prospective clinical study. A total of 132 brachycephalic dogs (66 Pugs, 55 French Bulldogs, and 11 English Bulldogs) with severe respiratory distress due to brachycephalic syndrome. Computed tomography and anterior and posterior rhinoscopy were performed to evaluate endonasal obstruction. All dogs had abnormal conchal growth that obstructed the intranasal airways. Rostral aberrant turbinates (RAT) were common in Pugs (90.9%) but less frequent in French (56.4%) and English (36.4%) Bulldogs. Caudal aberrant turbinates (CAT) obstructing the nasopharyngeal meatus were commonly found in all breeds (66.7%). Deviation of the nasal septum was an almost consistent finding in Pugs (98.5%) but was less common in bulldogs. Obstructing turbinates had multiple points of mucosal contact responsible for obstruction of the intranasal airway. Interconchal and intraconchal mucosal contacts were evident in 91.7% of dogs. Selective breeding for short head conformation reduces the size of the nasal cavities to such an extent that intranasal structures grow aberrantly and malformed, leading to obstructed air conducting spaces. Intranasal airway obstruction of brachycephalic dogs may contribute to their exercise and heat intolerance because of impaired pulmonary ventilation and compromised thermoregulatory functions of the canine nose. Failure to address intranasal obstruction might be an explanation for lack of therapeutic success after conventional surgery for brachycephalic syndrome. Future consideration should be given to the diagnosis, management, and treatment of this newly described aspect of airway obstruction. © Copyright 2016 by The American College of Veterinary Surgeons.

[Awake craniotomy. Considerations in special situations].

PubMed

Solera Ruiz, I; Uña Orejón, R; Valero, I; Laroche, F

2013-01-01

Awake craniotomy was the earliest surgical procedure known, and it has become fashionable again. In the past it was used for the surgical management of intractable epilepsy, but nowadays, its indications are increasing, and it is a widely recognized technique for the resection of mass lesions involving the eloquent cortex, and for deep brain stimulation. The procedure is safe, provides excellent results, and saves money and resources. The anesthesiologist should know the principles underlying neuroanesthesia, the technique of scalp blockade, and the sedation protocols, as well as feeling comfortable with advanced airway management. The main anesthetic aim is to keep patients cooperating when required (analgesia-based anesthesia). This review attempts to summarize the most recent evidence from the clinical literature, a long as the number of patients undergoing craniotomies in the awake state are increasing, specifically in the pediatric population. Copyright © 2011 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Published by Elsevier España. All rights reserved.

Hippocampal awake replay in fear memory retrieval

PubMed Central

Wu, Chun-Ting; Haggerty, Daniel; Kemere, Caleb; Ji, Daoyun

2017-01-01

Hippocampal place cells are key to episodic memories. How these cells participate in memory retrieval remains unclear. Here, after rats acquired a fear memory by receiving mild foot-shocks at a shock zone of a track, we analyzed place cells when the animals were placed back to the track and displayed an apparent memory retrieval behavior: avoidance of the shock zone. We found that place cells representing the shock zone were reactivated, despite the fact that the animals did not enter the shock zone. This reactivation occurred in ripple-associated awake replay of place cell sequences encoding the paths from the animal’s current positions to the shock zone, but not in place cell sequences within individual cycles of theta oscillation. The result reveals a specific place cell pattern underlying the inhibitory avoidance behavior and provides strong evidence for the involvement of awake replay in fear memory retrieval. PMID:28218916

Intranasal mast cell tumor in the dog: A case series

PubMed Central

Khoo, Alison; Lane, Amy; Wyatt, Ken

2017-01-01

The medical records of 4 dogs with histologically confirmed intranasal mast cell tumors (MCTs) were retrospectively evaluated to determine their biological behavior. Information on signalment, presenting clinical signs, tumor grade, treatment administered, and survival times was obtained from the medical record. All 4 patients had high grade tumors and received chemotherapy. Survival times ranged from 27 to 134 days. All 4 dogs showed signs of local or distant disease progression, suggestive of an aggressive behavior of intranasal MCTs. PMID:28761193

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

PubMed

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

2009-08-01

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. Male Wistar rats received one intranasal cannula, an intra-cerebral microdialysis probe, and two blood cannulas for drug administration and serial blood sampling respectively. To evaluate this novel model, the following experiments were conducted. 1) Evans Blue was administered to verify the selectivity of intranasal exposure. 2) During a 1 min infusion 10, 20, or 40 microl saline was administered intranasally or 250 microl intravenously. Corticosterone plasma concentrations over time were compared as biomarkers for stress. 3) 200 microg of the model drug acetaminophen was given in identical setup and plasma, and brain pharmacokinetics were determined. In 96% of the rats, only the targeted nasal cavity was deeply colored. Corticosterone plasma concentrations were not influenced, neither by route nor volume of administration. Pharmacokinetics of acetaminophen were identical after intravenous and intranasal administration, although the Cmax in microdialysates was reached a little earlier following intravenous administration. A new minimal-stress model for intranasal administration in freely moving rats has been successfully developed and allows direct comparison with intravenous administration.

Relative Bioavailability, Intranasal Abuse Potential, and Safety of Benzhydrocodone/Acetaminophen Compared with Hydrocodone Bitartrate/Acetaminophen in Recreational Drug Abusers.

PubMed

Guenther, Sven M; Mickle, Travis C; Barrett, Andrew C; Roupe, Kathryn Ann; Zhou, Jing; Lam, Vincent

2018-05-01

Benzhydrocodone is a hydrocodone prodrug that has been combined with acetaminophen (APAP) in a novel immediate-release analgesic. This study evaluated the relative bioavailability, intranasal abuse potential, and safety of benzhydrocodone/APAP compared with commercially available hydrocodone bitartrate (HB)/APAP. Single-center, randomized, double-blind, double-dummy, two-part study comprising a Dose Selection (Part A) phase and a Main Study (Part B) phase. Clinical research site. Healthy adult, nondependent, recreational opioid users with a history of intranasal abuse. Subjects (N = 42) in Part B received five in-clinic treatments consisting of intranasal and oral benzhydrocodone/APAP (13.34/650 mg), intranasal and oral hydrocodone/APAP (15/650 mg), and placebo, with four or more days of washout between treatments. Pharmacodynamic assessments included subjective effects of Drug Liking, Overall Drug Liking, and Take Drug Again (assessed on visual analog scale [VAS]), as well as nasal irritation. Pharmacokinetics and safety were also assessed. Hydrocodone Cmax was 11% lower for intranasal benzhydrocodone/APAP vs intranasal HB/APAP (P = 0.0027). Early cumulative hydrocodone exposures for intranasal benzhydrocodone/APAP through 0.5, 1, and 2 hours were reduced by approximately 50%, 29%, and 15%, respectively (P ≤ 0.0024). Correspondingly, Drug Liking VAS values up to two hours postdose were significantly lower for intranasal benzhydrocodone/APAP vs intranasal HB/APAP (P ≤ 0.0079), although peak Drug Liking VAS (Emax) scores were not different (P = 0.2814). Adverse nasal effects were more frequent for intranasal benzhydrocodone/APAP vs intranasal HB/APAP. Reduced hydrocodone exposure and drug liking at early time intervals, coupled with adverse nasal effects, can be expected to provide a level of deterrence to the intranasal route of abuse for benzhydrocodone/APAP.

Intranasal vaccine trial for canine infectious tracheobronchitis (kennel cough).

PubMed

Glickman, L T; Appel, M J

1981-08-01

Two field trials were conducted during periods of endemic (summer) and epizootic (winter) canine infectious tracheobronchitis activity to evaluate the efficacy of three intranasal vaccines in a closed commercial beagle breeding kennel. A trivalent vaccine containing Bordetella bronchiseptica, canine parainfluenza, and canine adenovirus-2 was administered at 3 weeks of age. The vaccine was 71.2% and 81.8% effective in decreasing the incidence of coughing during the winter and summer trials, respectively. The number of deaths was lower in each of the vaccine groups than in the placebo groups. No adverse reactions were observed with any of the intranasal vaccines.

Comparison of computed tomography and magnetic resonance imaging for the evaluation of canine intranasal neoplasia

PubMed Central

Drees, R.; Forrest, L. J.; Chappell, R.

2009-01-01

Objectives Canine intranasal neoplasia is commonly evaluated using computed tomography to indicate the diagnosis, to determine disease extent, to guide histological sampling location and to plan treatment. With the expanding use of magnetic resonance imaging in veterinary medicine, this modality has been recently applied for the same purpose. The aim of this study was to compare the features of canine intranasal neoplasia using computed tomography and magnetic resonance imaging. Methods Twenty-one dogs with confirmed intranasal neoplasia underwent both computed tomography and magnetic resonance imaging. The images were reviewed retrospectively for the bony and soft tissue features of intranasal neoplasia. Results Overall computed tomography and magnetic resonance imaging performed very similarly. However, lysis of bones bordering the nasal cavity and mucosal thickening was found on computed tomography images more often than on magnetic resonance images. Small amounts of fluid in the nasal cavity were more often seen on magnetic resonance images. However, fluid in the frontal sinuses was seen equally well with both modalities. Clinical Significance We conclude that computed tomography is satisfactory for evaluation of canine intranasal neoplasia, and no clinically relevant benefit is gained using magnetic resonance imaging for intranasal neoplasia without extent into the cranial cavity. PMID:19508490

Police officer attitudes towards intranasal naloxone training.

PubMed

Ray, Bradley; O'Donnell, Daniel; Kahre, Kailyn

2015-01-01

One approach to reduce fatal opioid overdose is by distributing naloxone to law enforcement officers. While several cities have implemented these naloxone programs, little research has investigated officer attitudes about their training. The present research attempts to fill this gap by analyzing survey data from police officers following intranasal naloxone training. All of the police officers within the same district in Indianapolis, Indiana, underwent training to recognize opioid overdose and to administer intranasal naloxone (N=117). Following training, officers completed a survey that measured prior experience with opioid overdose, perceived importance of training, and items from the Opioid Overdose Attitudes Scale (OOAS) to measure attitudes following training. The officers had overwhelmingly positive feelings about the training, that it was not difficult, and that other officers should be trained to use naloxone. The OOAS items suggest that officers know the appropriate actions to take in the event of an overdose and feel that administering intranasal naloxone will not be difficult. Finally, we found that officers who had more experience with opioid overdose had more positive attitudes about the training. Distributing naloxone to police officers is likely a trend that will continue so it is important to understand how police officers respond to training to assure that future trainings are as effective as possible. Further research is needed to investigate the impact that these programs have on the community. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

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

PubMed

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

2014-01-01

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

The Association of Industry Payments to Physicians with Prescription of Brand-Name Intranasal Corticosteroids.

PubMed

Morse, Elliot; Fujiwara, Rance J T; Mehra, Saral

2018-06-01

Objectives To examine the association of industry payments for brand-name intranasal corticosteroids with prescribing patterns. Study Design Cross-sectional retrospective analysis. Setting Nationwide. Subjects and Methods We identified physicians prescribing intranasal corticosteroids to Medicare beneficiaries 2014-2015 and physicians receiving payment for the brand-name intranasal corticosteroids Dymista and Nasonex. Prescription and payment data were linked by physician, and we compared the proportion of prescriptions written for brand-name intranasal corticosteroids in industry-compensated vs non-industry-compensated physicians. We associated the number and dollar amount of industry payments with the relative frequency of brand-name prescriptions. Results In total, 164,587 physicians prescribing intranasal corticosteroids were identified, including 7937 (5%) otolaryngologists; 10,800 and 3886 physicians received industry compensation for Dymista and Nasonex, respectively. Physicians receiving industry payment for Dymista prescribed more Dymista as a proportion of total intranasal corticosteroid prescriptions than noncompensated physicians (3.1% [SD = 9.6%] vs 0.2% [SD = 2.5%], respectively, P < .001). Similar trends were seen for Nasonex (12.0% [SD = 16.8%] vs 4.8% [SD = 13.6%], P < .001). The number and dollar amount of payment were significantly correlated to the relative frequency of Dymista (ρ = 0.26, P < .001 and ρ = 0.20, P < .001, respectively) and Nasonex prescriptions (ρ = 0.09, P < .001 and ρ = 0.15, P < .001, respectively). For Dymista, this association was stronger in otolaryngologists than general practitioners ( P < .001). There was a stronger correlation between the percentage of prescriptions and the number and dollar amount of payments for Dymista than for Nasonex ( P = .014 and P < .001). Conclusions Industry compensation for brand-name intranasal corticosteroids is significantly associated with prescribing patterns. The magnitude of

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

PubMed Central

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

2016-01-01

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

Music is Beneficial for Awake Craniotomy Patients: A Qualitative Study.

PubMed

Jadavji-Mithani, Radhika; Venkatraghavan, Lashmi; Bernstein, Mark

2015-01-01

Patients undergoing awake craniotomy may experience high levels of stress. Minimizing anxiety benefits patients and surgeons. Music has many therapeutic effects in altering human mood and emotion. Tonality of music as conveyed by composition in major or minor keys can have an impact on patients' emotions and thoughts. Assessing the effects of listening to major and minor key musical pieces on patients undergoing awake craniotiomy could help in the design of interventions to alleviate anxiety, stress and tension. Twenty-nine patients who were undergoing awake craniotomy were recruited and randomly assigned into two groups: Group 1 subjects listened to major key music and Group 2 listened to minor key compositions. Subjects completed a demographics questionnaire, a pre- and post-operative Beck Anxiety Inventory (BAI) and a semi-structured open-ended interview. RESULTS were analyzed using modified thematic analysis through open and axial coding. Overall, patients enjoyed the music regardless of the key distinctions and stated they benefitted from listening to the music. No adverse reactions to the music were found. Subjects remarked that the music made them feel more at ease and less anxious before, during and after their procedure. Patients preferred either major key or minor key music but not a combination of both. Those who preferred major key pieces said it was on the basis of tonality while the individuals who selected minor key pieces stated that tempo of the music was the primary factor. Overall, listening to music selections was beneficial for the patients. Future work should further investigate the effects of audio interventions in awake surgery through narrative means.

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

PubMed

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

2015-10-01

Although intranasal vaccination has been shown to be effective for the protection against inhalational anthrax, establishment of long-term immunity has yet to be achieved. Here, we investigated whether intranasal immunization with recombinant protective antigen (rPA) of Bacillus anthracis induces immunological memory responses in the mucosal and systemic compartments. Intranasal immunization with rPA plus cholera toxin (CT) sustained PA-specific antibody responses for 6 months in lung, nasal washes, and vaginal washes as well as serum. A significant induction of PA-specific memory B cells was observed in spleen, cervical lymph nodes (CLNs) and lung after booster immunization. Furthermore, intranasal immunization with rPA plus CT remarkably generated effector memory CD4(+) T cells in the lung. PA-specific CD4(+) T cells preferentially increased the expression of Th1- and Th17-type cytokines in lung, but not in spleen or CLNs. Collectively, the intranasal immunization with rPA plus CT promoted immunologic memory responses in the mucosal and systemic compartments, providing long-term immunity. Copyright © 2015 Elsevier Ltd. All rights reserved.

The effect of single low-dose dexamethasone on vomiting during awake craniotomy.

PubMed

Kamata, Kotoe; Morioka, Nobutada; Maruyama, Takashi; Komayama, Noriaki; Nitta, Masayuki; Muragaki, Yoshihiro; Kawamata, Takakazu; Ozaki, Makoto

2016-12-01

Intraoperative vomiting leads to serious respiratory complications that could influence the surgical decision-making process for awake craniotomy. However, the use of antiemetics is still limited in Japan. The aim of this study was to investigate the effect of prophylactically administered single low-dose dexamethasone on the incidence of vomiting during awake craniotomy. The frequency of hyperglycemia was also examined. We conducted a retrospective case review of awake craniotomy for glioma resection between 2012 and 2015. Of the 124 patients, 91 were included in the analysis. Dexamethasone was not used in 43 patients and the 48 remaining patients received an intravenous bolus of 4.95 mg dexamethasone at anesthetic induction. Because of stable operating conditions, no one required conscious sedation throughout functional mapping and tumor resection. Although dexamethasone pretreatment reduced the incidence of intraoperative vomiting (P = 0.027), the number of patients who complained of nausea was comparable (P = 0.969). No adverse events related to vomiting occurred intraoperatively. Baseline blood glucose concentration did not differ between each group (P = 0.143), but the samples withdrawn before emergence (P = 0.018), during the awake period (P < 0.0001) and at the end of surgery (P < 0.0001) showed significantly higher glucose levels in the dexamethasone group. Impaired wound healing was not observed in either group. A single low-dose of dexamethasone prevents intraoperative vomiting for awake craniotomy cases. However, as even a small dose of dexamethasone increases the risk for hyperglycemia, antiemetic prophylaxis with dexamethasone should be administered after careful consideration. Monitoring of perioperative blood glucose concentration is also necessary.

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

PubMed Central

Klimek, Markus; Hol, Jaap W.; Wens, Stephan; Heijmans-Antonissen, Claudia; Niehof, Sjoerd; Vincent, Arnaud J.; Klein, Jan; Zijlstra, Freek J.

2009-01-01

Background. Surgical stress triggers an inflammatory response and releases mediators into human plasma such as interleukins (ILs). Awake craniotomy and craniotomy performed under general anesthesia may be associated with different levels of stress. Our aim was to investigate whether those procedures cause different inflammatory responses. Methods. Twenty patients undergoing craniotomy under general anesthesia and 20 patients undergoing awake function-controlled craniotomy were included in this prospective, observational, two-armed study. Circulating levels of IL-6, IL-8, and IL-10 were determined pre-, peri-, and postoperatively in both patient groups. VAS scores for pain, anxiety, and stress were taken at four moments pre- and postoperatively to evaluate physical pain and mental duress. 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. PMID:19536349

Intranasal nerve growth factor attenuating the seizure onset via p75R/Caspase pathway in the experimental epilepsy.

PubMed

Lei, Jing'an; Feng, Fang; Duan, Yuanyuan; Xu, Feng; Liu, Zhiguang; Lian, Lifei; Liang, Qiming; Zhang, Na; Wang, Furong

2017-09-01

Nerve growth factor (NGF) shows neuroprotection while it is hard to cross the blood-brain barrier due to its large molecular weight. Our study used intranasal delivery of NGF to treat the experimental epilepsy. The seizure was induced by injection of pentylenetetrazol (40mg/kg) into the rat. Based on the behavior performance, the successful models were randomized into control and NGF groups, given medium or NGF intranasally, respectively. The onset and duration of seizure were recorded. The neuron loss was assessed by immunohistochemistry and TUNEL staining. The expressions of Caspase-3, p75R and TrkA were measured by western blotting. Intranasal NGF significantly reduced the seizure onset and shortened the seizure duration. Intranasal NGF alleviated the neuron loss in the epileptic brain. The number of TUNEL-positive cells in the NGF group was less than that in the control group (P<0.05). Overexpression of Caspase-3 and activation of p75R induced by seizure were inhibited by intranasal NGF. Intranasal NGF protected neurons in the epileptic brain by inactivation of p75R/Caspase pathway. Intranasal NGF may be a novel therapeutic strategy for epilepsy. Copyright © 2017 Elsevier Inc. All rights reserved.

Intranasal bacille Calmette–Guérin (BCG) vaccine dosage needs balancing between protection and lung pathology

PubMed Central

TREE, J A; WILLIAMS, A; CLARK, S; HALL, G; MARSH, P D; IVANYI, J

2004-01-01

Intranasal vaccination may offer practical benefits and better protection against respiratory infections, including tuberculosis. In this paper, we investigated the persistence of the Mycobacterium bovis-strain bacille Calmette–Guérin (BCG) Pasteur, lung granuloma formation and protection against pathogenic tuberculous challenge in mice. A pronounced BCG dose-dependent granulomatous infiltration of the lungs was observed following intranasal, but not after subcutaneous, vaccination. Corresponding doses of BCG, over a 100-fold range, imparted similar protection against H37Rv challenge when comparing the intranasal and subcutaneous vaccination routes. Interestingly, a BCG dose-dependent reduction of the H37Rv challenge infection was observed in the lungs, but not in the spleens, following both intranasal and subcutaneous vaccination. In the light of the observed concurrence between the extent of granuloma formation and the level of protection of the lungs, we conclude that intranasal vaccination leading to best protective efficacy needs to be balanced with an acceptable safety margin avoiding undue pathology in the lungs. PMID:15544615

Enclosure for small animals during awake animal imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goddard, Jr., James S

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 mademore » 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.« less

Use of intranasal fentanyl in children undergoing myringotomy and tube placement during halothane and sevoflurane anesthesia.

PubMed

Galinkin, J L; Fazi, L M; Cuy, R M; Chiavacci, R M; Kurth, C D; Shah, U K; Jacobs, I N; Watcha, M F

2000-12-01

Many children are restless, disoriented, and inconsolable immediately after bilateral myringotomy and tympanosotomy tube placement (BMT). Rapid emergence from sevoflurane anesthesia and postoperative pain may increase emergence agitation. The authors first determined serum fentanyl concentrations in a two-phase study of intranasal fentanyl. The second phase was a prospective, placebo-controlled, double-blind study to determine the efficacy of intranasal fentanyl in reducing emergence agitation after sevoflurane or halothane anesthesia. In phase 1, 26 children with American Society of Anesthesiologists (ASA) physical status I or II who were scheduled for BMT received intranasal fentanyl, 2 microg/kg, during a standardized anesthetic. Serum fentanyl concentrations in blood samples drawn at emergence and at postanesthesia care unit (PACU) discharge were determined by radioimmunoassay. In phase 2, 265 children with ASA physical status I or II were randomized to receive sevoflurane or halothane anesthesia along with either intranasal fentanyl (2 microg/kg) or saline. Postoperative agitation, Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) scores, and satisfaction of PACU nurses and parents with the anesthetic technique were evaluated. In phase 1, the mean fentanyl concentrations at 10 +/- 4 min (mean +/- SD) and 34 +/- 9 min after administering intranasal fentanyl were 0.80 +/- 0.28 and 0.64 +/- 0.25 ng/ml, respectively. In phase 2, the incidence of severe agitation, highest CHEOPS scores, and heart rate in the PACU were decreased with intranasal fentanyl. There were no differences between sevoflurane and halothane in these measures and in times to hospital discharge. The incidence of postoperative vomiting, hypoxemia, and slow respiratory rates were not increased with fentanyl. Serum fentanyl concentrations after intranasal administration exceed the minimum effective steady state concentration for analgesia in adults. The use of intranasal fentanyl during

The effects of adjunctive intranasal oxytocin in patients with schizophrenia.

PubMed

Ota, Miho; Yoshida, Sumiko; Nakata, Masanori; Yada, Toshihiko; Kunugi, Hiroshi

2018-01-01

Both human and animal studies have suggested that oxytocin may have therapeutic potential in the treatment of schizophrenia. We evaluated the effects of intranasal oxytocin on cognition and its predictive factors in Japanese patients with schizophrenia. Subjects were 16 chronic schizophrenia patients who underwent intranasal oxytocin treatment for 3 months and were assessed for changes in severity of clinical symptoms and cognitions. Fifteen of the 16 subjects underwent 3-Tesla magnetic resonance imaging. Oxytocin significantly reduced scores on the positive and negative syndrome scale, especially on the negative symptoms. As for cognition, there was an improvement of the verbal fluency. Furthermore, the change of the negative score in positive and negative syndrome scale showed a negative correlation with the gray matter volumes of the right insula and left cingulate cortex. Our results indicate that daily administration of intranasal oxytocin may be effective for ameliorating clinical symptoms and cognitive functions in chronic schizophrenia patients, and this improvement may be related to the gray matter volume of the right insula and left cingulate cortex.

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

PubMed Central

Rossaint, Rolf; Veldeman, Michael

2016-01-01

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

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

PubMed

Stevanovic, Ana; Rossaint, Rolf; Veldeman, Michael; Bilotta, Federico; Coburn, Mark

2016-01-01

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

Rapid transport within cerebral perivascular spaces underlies widespread tracer distribution in the brain after intranasal administration.

PubMed

Lochhead, Jeffrey J; Wolak, Daniel J; Pizzo, Michelle E; Thorne, Robert G

2015-03-01

The intranasal administration route is increasingly being used as a noninvasive method to bypass the blood-brain barrier because evidence suggests small fractions of nasally applied macromolecules may reach the brain directly via olfactory and trigeminal nerve components present in the nasal mucosa. Upon reaching the olfactory bulb (olfactory pathway) or brainstem (trigeminal pathway), intranasally delivered macromolecules appear to rapidly distribute within the brains of rodents and primates. The mechanisms responsible for this distribution have yet to be fully characterized. Here, we have used ex vivo fluorescence imaging to show that bulk flow within the perivascular space (PVS) of cerebral blood vessels contributes to the rapid central distribution of fluorescently labeled 3 and 10 kDa dextran tracers after intranasal administration in anesthetized adult rats. Comparison of tracer plasma levels and fluorescent signal distribution associated with the PVS of surface arteries and internal cerebral vessels showed that the intranasal route results in unique central access to the PVS not observed after matched intravascular dosing in separate animals. Intranasal targeting to the PVS was tracer size dependent and could be regulated by modifying nasal epithelial permeability. These results suggest cerebral perivascular convection likely has a key role in intranasal drug delivery to the brain.

Surgery-Independent Language Function Decline in Patients Undergoing Awake Craniotomy.

PubMed

Gonen, Tal; Sela, Gal; Yanakee, Ranin; Ram, Zvi; Grossman, Rachel

2017-03-01

Despite selection process before awake-craniotomy, some patients experience an unexpected decline in language functions in the operating room (OR), compared with their baseline evaluation, which may impair their functional monitoring. To investigate this phenomenon we prospectively compared language function the day before surgery and on entrance to the OR. Data were collected prospectively from consecutive patients undergoing awake-craniotomy with intraoperative cortical mapping for resection of gliomas affecting language areas. Language functions of 79 patients were evaluated and compared 1-2 days before surgery and after entering the OR. Changes in functional linguistic performance were analyzed with respect to demographic, clinical, and pathologic characteristics. There was a significant decline in language function, beyond sedation effect, after entering the OR, (from median/interquartile range: 0.94/0.72-0.98 to median/interquartile range: 0.86/0.51-0.94; Z = -7.19, P < 0.001). Univariate analyses revealed that this decline was related to age, preoperative Karnofsky Performance Scale, tumor location, tumor pathology, and preexisting language deficits. Multivariate stepwise regression identified tumor pathology and the presence of preoperative language deficit as significant independent predictors for this functional decline. Patients undergoing awake-craniotomy may experience a substantial decline in language functioning after entering the OR. Tumor grade and the presence of preoperative language deficits were significant risk factors for this phenomenon, suggesting a possible relation between cognitive reserve, psychobehavioral coping abilities and histologic features of a tumor involving language areas. Capturing and identifying this unique population of patients who are prone to experience such language decline may improve our ability in the future to select patients eligible for awake-craniotomy. Copyright © 2016 Elsevier Inc. All rights reserved.

Intranasal and sublingual delivery of inactivated polio vaccine.

PubMed

Kraan, Heleen; Soema, Peter; Amorij, Jean-Pierre; Kersten, Gideon

2017-05-09

Polio is on the brink of eradication. Improved inactivated polio vaccines (IPV) are needed towards complete eradication and for the use in the period thereafter. Vaccination via mucosal surfaces has important potential advantages over intramuscular injection using conventional needle and syringe, the currently used delivery method for IPV. One of them is the ability to induce both serum and mucosal immune responses: the latter may provide protection at the port of virus entry. The current study evaluated the possibilities of polio vaccination via mucosal surfaces using IPV based on attenuated Sabin strains. Mice received three immunizations with trivalent sIPV via intramuscular injection, or via the intranasal or sublingual route. The need of an adjuvant for the mucosal routes was investigated as well, by testing sIPV in combination with the mucosal adjuvant cholera toxin. Both intranasal and sublingual sIPV immunization induced systemic polio-specific serum IgG in mice that were functional as measured by poliovirus neutralization. Intranasal administration of sIPV plus adjuvant induced significant higher systemic poliovirus type 3 neutralizing antibody titers than sIPV delivered via the intramuscular route. Moreover, mucosal sIPV delivery elicited polio-specific IgA titers at different mucosal sites (IgA in saliva, fecal extracts and intestinal tissue) and IgA-producing B-cells in the spleen, where conventional intramuscular vaccination was unable to do so. However, it is likely that a mucosal adjuvant is required for sublingual vaccination. Further research on polio vaccination via sublingual mucosal route should include the search for safe and effective adjuvants, and the development of novel oral dosage forms that improve antigen uptake by oral mucosa, thereby increasing vaccine immunogenicity. This study indicates that both the intranasal and sublingual routes might be valuable approaches for use in routine vaccination or outbreak control in the period after

Awake craniotomy induces fewer changes in the plasma amino acid profile than craniotomy under general anesthesia.

PubMed

Hol, Jaap W; Klimek, Markus; van der Heide-Mulder, Marieke; Stronks, Dirk; Vincent, Arnoud J; Klein, Jan; Zijlstra, Freek J; Fekkes, Durk

2009-04-01

In this prospective, observational, 2-armed study, we compared the plasma amino acid profiles of patients undergoing awake craniotomy to those undergoing craniotomy under general anesthesia. Both experimental groups were also compared with a healthy, age-matched and sex-matched reference group not undergoing surgery. It is our intention to investigate whether plasma amino acid levels provide information about physical and emotional stress, as well as pain during awake craniotomy versus craniotomy under general anesthesia. Both experimental groups received preoperative, perioperative, and postoperative dexamethasone. The plasma levels of 20 amino acids were determined preoperative, perioperative, and postoperatively in all groups and were correlated with subjective markers for pain, stress, and anxiety. In both craniotomy groups, preoperative levels of tryptophan and valine were significantly decreased whereas glutamate, alanine, and arginine were significantly increased relative to the reference group. Throughout time, tryptophan levels were significantly lower in the general anesthesia group versus the awake craniotomy group. The general anesthesia group had a significantly higher phenylalanine/tyrosine ratio, which may suggest higher oxidative stress, than the awake group throughout time. Between experimental groups, a significant increase in large neutral amino acids was found postoperatively in awake craniotomy patients, pain was also less and recovery was faster. A significant difference in mean hospitalization time was also found, with awake craniotomy patients leaving after 4.53+/-2.12 days and general anesthesia patients after 6.17+/-1.62 days; P=0.012. This study demonstrates that awake craniotomy is likely to be physically and emotionally less stressful than general anesthesia and that amino acid profiling holds promise for monitoring postoperative pain and recovery.

Clinical outcomes of asleep vs awake deep brain stimulation for Parkinson disease.

PubMed

Brodsky, Matthew A; Anderson, Shannon; Murchison, Charles; Seier, Mara; Wilhelm, Jennifer; Vederman, Aaron; Burchiel, Kim J

2017-11-07

To compare motor and nonmotor outcomes at 6 months of asleep deep brain stimulation (DBS) for Parkinson disease (PD) using intraoperative imaging guidance to confirm electrode placement vs awake DBS using microelectrode recording to confirm electrode placement. DBS candidates with PD referred to Oregon Health & Science University underwent asleep DBS with imaging guidance. Six-month outcomes were compared to those of patients who previously underwent awake DBS by the same surgeon and center. Assessments included an "off"-levodopa Unified Parkinson's Disease Rating Scale (UPDRS) II and III, the 39-item Parkinson's Disease Questionnaire, motor diaries, and speech fluency. Thirty participants underwent asleep DBS and 39 underwent awake DBS. No difference was observed in improvement of UPDRS III (+14.8 ± 8.9 vs +17.6 ± 12.3 points, p = 0.19) or UPDRS II (+9.3 ± 2.7 vs +7.4 ± 5.8 points, p = 0.16). Improvement in "on" time without dyskinesia was superior in asleep DBS (+6.4 ± 3.0 h/d vs +1.7 ± 1.2 h/d, p = 0.002). Quality of life scores improved in both groups (+18.8 ± 9.4 in awake, +8.9 ± 11.5 in asleep). Improvement in summary index ( p = 0.004) and subscores for cognition ( p = 0.011) and communication ( p < 0.001) were superior in asleep DBS. Speech outcomes were superior in asleep DBS, both in category (+2.77 ± 4.3 points vs -6.31 ± 9.7 points ( p = 0.0012) and phonemic fluency (+1.0 ± 8.2 points vs -5.5 ± 9.6 points, p = 0.038). Asleep DBS for PD improved motor outcomes over 6 months on par with or better than awake DBS, was superior with regard to speech fluency and quality of life, and should be an option considered for all patients who are candidates for this treatment. NCT01703598. This study provides Class III evidence that for patients with PD undergoing DBS, asleep intraoperative CT imaging-guided implantation is not significantly different from awake microelectrode recording-guided implantation in improving motor outcomes at 6 months. © 2017

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

NASA Technical Reports Server (NTRS)

Putcha, Lakshmi; Crady, Camille; Putcha, Lakshmi

2012-01-01

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

Technical Aspects of Awake Craniotomy with Mapping for Brain Tumors in a Limited Resource Setting.

PubMed

Leal, Rafael Teixeira Magalhaes; Barcellos, Bruno Mendonça; Landeiro, Jose Alberto

2018-05-01

Brain tumor surgery near or within eloquent regions is increasingly common and is associated with a high risk of neurologic injury. Awake craniotomy with mapping has been shown to be a valid method to preserve neurologic function and increase the extent of resection. However, the technique used varies greatly among centers. Most count on professionals such as neuropsychologists, speech therapists, neurophysiologists, or neurologists to help in intraoperative patient evaluation. We describe our technique with the sole participation of neurosurgeons and anesthesiologists. A retrospective review of 19 patients who underwent awake craniotomies for brain tumors between January 2013 and February 2017 at a tertiary university hospital was performed. We sought to identify and describe the most critical stages involved in this surgery as well as show the complications associated with our technique. Preoperative preparation, positioning, anesthesia, brain mapping, resection, and management of seizures and pain were stages deemed relevant to the accomplishment of an awake craniotomy. Sixteen percent of the patients developed new postoperative deficit. Seizures occurred in 24%. None led to awake craniotomy failure. We provide a thorough description of the technique used in awake craniotomies with mapping used in our institution, where the intraoperative patient evaluation is carried out solely by neurosurgeons and anesthesiologists. The absence of other specialized personnel and equipment does not necessarily preclude successful mapping during awake craniotomy. We hope to provide helpful information for those who wish to offer function-guided tumor resection in their own centers. Copyright © 2018 Elsevier Inc. All rights reserved.

Efficacy and safety of dexmedetomidine infusion for patients undergoing awake craniotomy: An observational study.

PubMed

Mahajan, Charu; Rath, Girija Prasad; Singh, Gyaninder Pal; Mishra, Nitasha; Sokhal, Suman; Bithal, Parmod Kumar

2018-01-01

The goal of awake craniotomy is to maintain adequate sedation, analgesia, respiratory, and hemodynamic stability and also to provide a cooperative patient for neurologic testing. An observational study carried out to evaluate the efficacy of dexmedetomidine sedation for awake craniotomy. Adult patients with age >18 year who underwent awake craniotomy for intracranial tumor surgery were enrolled. Those who were uncooperative and had difficult airway were excluded from the study. In the operating room, the patients received a bolus dose of dexmedetomidine 1 μg/kg followed by an infusion of 0.2-0.7 μg/kg/h (bispectral index target 60-80). Once the patients were sedated, scalp block was given with bupivacaine 0.25%. The data on hemodynamics at various stages of the procedure, intraoperative complications, total amount of fentanyl used, intravenous fluids required, blood loss and transfusion, duration of surgery, Intensive Care Unit (ICU), and hospital stay were collected. The patients were assessed for Glasgow outcome scale (GOS) score and patient satisfaction score (PSS). A total of 27 patients underwent awake craniotomy during a period of 2 years. Most common intraoperative complication was seizures; observed in five patients (18.5%). None of these patients experienced any episode of desaturation. Two patients had tight brain for which propofol boluses were administered. The average fentanyl consumption was 161.5 ± 85.0 μg. The duration of surgery, ICU, and hospital stays were 231.5 ± 90.5 min, 14.5 ± 3.5 h, and 4.7 ± 1.5 days, respectively. The overall PSS was 8 and GOS was good in all the patients. The use of dexmedetomidine infusion with regional scalp block in patients undergoing awake craniotomy is safe and efficacious. The absence of major complications and higher PSS makes it close to an ideal agent for craniotomy in awake state.

Development of brain-wide connectivity architecture in awake rats.

PubMed

Ma, Zilu; Ma, Yuncong; Zhang, Nanyin

2018-08-01

Childhood and adolescence are both critical developmental periods, evidenced by complex neurophysiological changes the brain undergoes and high occurrence rates of neuropsychiatric disorders during these periods. Despite substantial progress in elucidating the developmental trajectories of individual neural circuits, our knowledge of developmental changes of whole-brain connectivity architecture in animals is sparse. To fill this gap, here we longitudinally acquired rsfMRI data in awake rats during five developmental stages from juvenile to adulthood. We found that the maturation timelines of brain circuits were heterogeneous and system specific. Functional connectivity (FC) tended to decrease in subcortical circuits, but increase in cortical circuits during development. In addition, the developing brain exhibited hemispheric functional specialization, evidenced by reduced inter-hemispheric FC between homotopic regions, and lower similarity of region-to-region FC patterns between the two hemispheres. Finally, we showed that whole-brain network development was characterized by reduced clustering (i.e. local communication) but increased integration (distant communication). Taken together, the present study has systematically characterized the development of brain-wide connectivity architecture from juvenile to adulthood in awake rats. It also serves as a critical reference point for understanding circuit- and network-level changes in animal models of brain development-related disorders. Furthermore, FC data during brain development in awake rodents contain high translational value and can shed light onto comparative neuroanatomy. Copyright © 2018 Elsevier Inc. All rights reserved.

Awake replay of remote experiences in the hippocampus

PubMed Central

Karlsson, Mattias P.; Frank, Loren M.

2009-01-01

Hippocampal replay is thought to be essential for the consolidation of event memories in hippocampal–neocortical networks. Replay is present during both sleep and waking behavior, but while sleep replay involves the reactivation of stored representations in the absence of specific sensory inputs, awake replay is thought to depend on sensory input from the current environment. Here we show that stored representations are reactivated during both waking and sleep replay. We found frequent awake replay of sequences of rat hippocampal place cells from a previous experience. This spatially remote replay was as common as local replay of the current environment and was most robust when the animal had recently been in motion as compared to during extended periods of quiescence. These results indicate that the hippocampus consistently replays past experiences during brief pauses in waking behavior, suggesting a role for waking replay in memory consolidation and retrieval. PMID:19525943

Restricted sedation and absence of cognitive impairments after administration of intranasal scopolamine.

PubMed

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

2015-12-01

Space motion sickness in astronauts during spaceflight causes significant discomfort, which might impede their functionality. Pharmacological treatment has been mainly restricted to promethazine. Transdermal and oral scopolamine have also been used in space; however, their use was reduced due to unpredictable effectiveness and side effects. Recently, intranasal scopolamine administration has gained much interest, since this route ensures fast and reliable absorption with a decreased incidence of undesirable side effects. The aim of this study was to evaluate the effect of intranasal scopolamine on cognitive performance and to determine its side effects. This double-blind, placebo controlled, repeated measures study evaluated vigilant attention, short-term memory, implicit memory and working memory. Side effects were reported on a 22-item questionnaire and sleepiness was assessed by the Karolinska, Stanford and Epworth Sleepiness Scales. Scopolamine had no effect on cognitive function. Only the Karolinska score was significantly increased for scopolamine compared to placebo. Participants reported a dry mouth and dizziness after receiving scopolamine. Results show that intranasal scopolamine did not impair cognitive performance. Intranasal scopolamine might be a good alternative to promethazine for the alleviation of space motion sickness, since the agent has minimal sedative effects and does not hamper cognitive performance. © The Author(s) 2015.

Intranasal pirodavir (R77,975) treatment of rhinovirus colds.

PubMed Central

Hayden, F G; Hipskind, G J; Woerner, D H; Eisen, G F; Janssens, M; Janssen, P A; Andries, K

1995-01-01

A randomized, double-blind, placebo-controlled trial assessed the therapeutic efficacy of intranasal pirodavir in naturally occurring rhinovirus colds. Adults with symptoms of < or = 2 days' duration were randomly assigned to intranasal sprays of pirodavir (2 mg per treatment) or placebo six times daily for 5 days. In people with laboratory-documented rhinovirus colds (53 in the pirodavir group, 55 in the placebo group), no significant differences in the resolution of respiratory symptoms were apparent between the groups. The median duration of illness was 7 days in each group. Similarly, scores for individual symptoms found no differences in favor of pirodavir during or after treatment. In contrast, reduced frequencies of rhinovirus shedding were observed in the pirodavir group on day 3 (70 versus 23%; P < 0.001) and day 5 (38 versus 12%; P = 0.002) but not after the cessation of treatment, on day 7 (19 versus 21%). No pirodavir-resistant viruses were recovered from treated individuals. The pirodavir group had higher rates of nasal dryness, blood in mucus, or unpleasant taste on several study days. In summary, intranasal sprays of pirodavir were associated with significant antiviral effects but no clinical benefit in treating naturally occurring rhinovirus colds. PMID:7726484

Fibre-optic awake intubation for caesarean section in a parturient with predicted difficult airway.

PubMed

Trevisan, P

2002-10-01

Anaesthetic management of a parturient with predicted difficult airway presenting for caesarean section (CS) is not a straightforward decision: general anaesthesia should be avoided because intubation can be impossible and a "cannot intubate, cannot ventilate" scenario might ensue, on the other hand regional techniques can be unsuccessful or, though rarely, have complications that require emergency intubation. The case is presented of a primigravida admitted to hospital at 37 weeks' gestation with hypertension, intrauterine growth retardation and oligohydramnios. After a few days' observation, it was decided to proceed with an elective CS. The preoperative airway examination revealed a poor mouth opening with an interdental distance of 20 mm and a Mallampati class IV. The patient was classified as a case of difficult intubation and the following anaesthetic options were considered: epidural anaesthesia, spinal anaesthesia and awake fibreoptic intubation followed by general anaesthesia. The pros and the cons of these techniques were explained to the patient and it was suggested that awake fibreoptic intubation was the safest option. The patient gave her consent, so an uneventful nasal awake fibreoptic intubation was carried out under local anaesthesia. This case report offers the opportunity to underline the risk to perform a central blockade in a parturient with predicted difficult intubation, arguing that the safest course of action is an awake fibrescopic intubation, besides some controversial points to safely perform awake fibreoptic intubation in obstetric patients are discussed.

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

NASA Astrophysics Data System (ADS)

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

2016-09-01

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

Dose escalation pharmacokinetics of intranasal scopolamine gel formulation.

PubMed

Wu, Lei; Boyd, Jason L; Daniels, Vernie; Wang, Zuwei; Chow, Diana S-L; Putcha, Lakshmi

2015-02-01

Astronauts experience Space Motion Sickness requiring treatment with an anti-motion sickness medication, scopolamine during space missions. Bioavailability after oral administration of scopolamine is low and variable, and absorption form transdermal patch is slow and prolonged. Intranasal administration achieves faster absorption and higher bioavailability of drugs that are subject to extrahepatic, first pass metabolism after oral dosing. We examined pharmacokinetics of 0.1, 0.2, and 0.4 mg doses of the Investigational New Drug formulation of intranasal scopolamine gel (INSCOP) in 12 healthy subjects using a randomized, double-blind cross-over study design. Subjects received one squirt of 0.1 g of gel containing either 0.1 mg or 0.2 mg/0.1 mL scopolamine or placebo in each nostril. Serial blood samples and total urine voids were collected after dosing and drug concentrations were determined using a modified LC-MS-MS method. Results indicate dose-linear pharmacokinetics of scopolamine with linear increases in Cmax and AUC within the dose range tested. Plasma drug concentrations were significantly lower in females than in males after administration of 0.4 dose. All three doses were well tolerated with no unexpected or serious adverse side effects reported. These results suggest that intranasal scopolamine gel formulation (INSCOP) offers a fast, reliable, and safe alternative for the treatment of motion sickness. © 2014, The American College of Clinical Pharmacology.

Reading Wide Awake: Politics, Pedagogies, and Possibilities

ERIC Educational Resources Information Center

Shannon, Patrick

2011-01-01

In his new book, popular author Patrick Shannon examines reading as agency--why reading critically is essential to civic engagement and a healthy democracy. We follow the author on a journey of self discovery as he practices "wide-awake reading" with a variety of everyday texts, from radio programs to legal documents to more traditional books and…

Nose-to-Brain Delivery of Peptide Drugs Enhanced by Coadministration of Cell-penetrating Peptides: Therapeutic Potential for Dementia.

PubMed

Kamei, Noriyasu

2017-01-01

Recent reports suggest that peptide drugs such as insulin have the potential to serve as therapeutics in neurodegenerative diseases such as Alzheimer's disease. However, the transport of these drugs to the therapeutic target, the brain, is significantly hindered by the blood-brain barrier (BBB). Intranasal administration appears to be an ideal solution for drug delivery to the brain, bypassing the BBB, however the entry of peptide drugs into neuronal and epithelial cells in the olfactory mucosa remains low. In this study, we therefore examined whether intranasal coadministration of cell-penetrating peptides (CPPs) could improve nose-to-brain drug transport. In both mice and rats, we found that direct transport of insulin into the brain was significantly facilitated when coadministered with amphipathic CPP penetratin, and eventually insulin reached the deeper regions of the brain such as the hippocampus. In the mouse line senescence-accelerated mouse prone-8 (SAMP8), spatial learning tests demonstrated that long-term intranasal coadministration of insulin with penetratin improved mild memory loss in the early stages of dementia. In contrast, the severe cognitive dysfunction in the aged SAMP8 mice was preserved despite intranasal coadministration of insulin with penetratin. The immunohistological examination of the hippocampus suggested that enhanced nose-to-brain delivery of insulin had a partial neuroprotective effect but unexpectedly increased amyloid β plaque deposition. In conclusion, intranasal coadministration of insulin with CPPs has the potential to serve as a therapeutic for mild cognitive dysfunction. To identify suitable pharmacotherapy for dementia with severe pathology, further studies of nose-to-brain delivery of molecularly appropriate biopharmaceuticals are necessary.

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

PubMed

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

2016-02-01

The intranasal route of drug administration has gained increased popularity as it is thought to allow large molecules, such as peptide hormones, more direct access to the brain, while limiting systemic exposure. Several studies have investigated the effects of intranasal oxytocin administration in humans as this peptide is associated with prosocial behavior. There are, however, few preclinical studies investigating the effects of intranasal oxytocin administration in rodents. Oxytocin modulates hypothalamic-pituitary-adrenal (HPA) axis functioning and it has been suggested that oxytocin's ability to increase sociability may occur through a reduction in stress reactivity. Another peptide that appears to influence both social behavior and HPA axis activity is gastrin-releasing peptide (GRP), but it is not known if these GRP-induced effects are related. With this in mind, in the present study, we assessed the effects of intranasal and intraperitoneal oxytocin and GRP administration on social interaction and release of corticosterone in rats. Intranasal and intraperitoneal administration of 20, but not 5 μg, of oxytocin significantly increased social interaction, whereas intranasal and peripheral administration of GRP (20 but not 5 μg) significantly decreased levels of social interaction. In addition, while intranasal oxytocin (20 μg) had no effect on blood corticosterone levels, a marked increase in blood corticosterone levels was observed following intraperitoneal oxytocin administration. With GRP, intranasal (20 μg) but not peripheral administration increased corticosterone levels. These findings provide further evidence that intranasal peptide delivery can induce behavioral alterations in rodents which is consistent with findings from human studies. In addition, the peptide-induced changes in social interaction were not linked to fluctuations in corticosterone levels. Copyright © 2015 Elsevier Ltd. All rights reserved.

A case of loss of consciousness with contralateral acute subdural haematoma during awake craniotomy

PubMed Central

Kamata, Kotoe; Maruyama, Takashi; Nitta, Masayuki; Ozaki, Makoto; Muragaki, Yoshihiro; Okada, Yoshikazu

2014-01-01

We are reporting the case of a 56-year-old woman who developed loss of consciousness during awake craniotomy. A thin subdural haematoma in the contralateral side of the craniotomy was identified with intraoperative magnetic resonance imaging and subsequently removed. Our case indicates that contralateral acute subdural haematoma could be a cause of deterioration of the conscious level during awake craniotomy. PMID:25301378

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

PubMed

Sun, Bao-Liang; He, Mei-Qing; Han, Xiang-Yu; Sun, Jing-Yi; Yang, Ming-Feng; Yuan, Hui; Fan, Cun-Dong; Zhang, Shuai; Mao, Lei-Lei; Li, Da-Wei; Zhang, Zong-Yong; Zheng, Cheng-Bi; Yang, Xiao-Yi; Li, Yang V; Stetler, R Anne; Chen, Jun; Zhang, Feng

2016-01-01

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

Voluntary running enhances glymphatic influx in awake behaving, young mice.

PubMed

von Holstein-Rathlou, Stephanie; Petersen, Nicolas Caesar; Nedergaard, Maiken

2018-01-01

Vascular pathology and protein accumulation contribute to cognitive decline, whereas exercise can slow vascular degeneration and improve cognitive function. Recent investigations suggest that glymphatic clearance measured in aged mice while anesthetized is enhanced following exercise. We predicted that exercise would also stimulate glymphatic activity in awake, young mice with higher baseline glymphatic function. Therefore, we assessed glymphatic function in young female C57BL/6J mice following five weeks voluntary wheel running and in sedentary mice. The active mice ran a mean distance of 6km daily. We injected fluorescent tracers in cisterna magna of awake behaving mice and in ketamine/xylazine anesthetized mice, and later assessed tracer distribution in coronal brain sections. Voluntary exercise consistently increased CSF influx during wakefulness, primarily in the hypothalamus and ventral parts of the cortex, but also in the middle cerebral artery territory. While glymphatic activity was higher under ketamine/xylazine anesthesia, we saw a decrease in glymphatic function during running in awake mice after five weeks of wheel running. In summary, daily running increases CSF flux in widespread areas of the mouse brain, which may contribute to the pro-cognitive effects of exercise. Copyright © 2017 Elsevier B.V. All rights reserved.

Intranasal delivery of cyclobenzaprine hydrochloride-loaded thiolated chitosan nanoparticles for pain relief.

PubMed

Patel, Deepa; Naik, Sachin; Chuttani, Krishna; Mathur, Rashi; Mishra, Anil K; Misra, Ambikanandan

2013-09-01

The purpose of present investigation was to formulate and characterize the cyclobenzaprine HCl (CBZ)-loaded thiolated chitosan nanoparticles and assessment of in-vitro cell viability, trans-mucosal permeability on RPMI2650 cell monolayer, in-vivo pharmacokinetic and pharmacodynamic study of thiolated chitosan nanoparticles on Swiss albino mice after intranasal administration. A significant high permeation of drug was observed from thiolated chitosan nanoparticles with less toxicity on nasal epithelial cells. Brain uptake of the drug after (99m)Tc labeling was significantly enhanced after thiolation of chitosan. CBZ-loaded thiolated chitosan NPs significantly reverse the N-Methyl-.-Aspartate (NMDA)-induced hyperalgesia by intranasal administration than the CBZ solution. The studies of present investigation revealed that thiolation of chitosan significantly reduce trans-mucosal toxicity with enhanced trans-mucosal permeability via paracellular pathway and brain uptake of a hydrophilic drug (normally impermeable across blood brain barrier) and pain alleviation activity via intranasal route.

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

PubMed Central

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

2014-01-01

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

Mapping oxygen concentration in the awake mouse brain.

PubMed

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

2016-02-02

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

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

PubMed Central

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

2016-01-01

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

Comparison of propofol pharmacokinetic and pharmacodynamic models for awake craniotomy: A prospective observational study.

PubMed

Soehle, Martin; Wolf, Christina F; Priston, Melanie J; Neuloh, Georg; Bien, Christian G; Hoeft, Andreas; Ellerkmann, Richard K

2015-08-01

Anaesthesia for awake craniotomy aims for an unconscious patient at the beginning and end of surgery but a rapidly awakening and responsive patient during the awake period. Therefore, an accurate pharmacokinetic/pharmacodynamic (PK/PD) model for propofol is required to tailor depth of anaesthesia. To compare the predictive performances of the Marsh and the Schnider PK/PD models during awake craniotomy. A prospective observational study. Single university hospital from February 2009 to May 2010. Twelve patients undergoing elective awake craniotomy for resection of brain tumour or epileptogenic areas. Arterial blood samples were drawn at intervals and the propofol plasma concentration was determined. The prediction error, bias [median prediction error (MDPE)] and inaccuracy [median absolute prediction error (MDAPE)] of the Marsh and the Schnider models were calculated. The secondary endpoint was the prediction probability PK, by which changes in the propofol effect-site concentration (as derived from simultaneous PK/PD modelling) predicted changes in anaesthetic depth (measured by the bispectral index). The Marsh model was associated with a significantly (P = 0.05) higher inaccuracy (MDAPE 28.9 ± 12.0%) than the Schnider model (MDAPE 21.5 ± 7.7%) and tended to reach a higher bias (MDPE Marsh -11.7 ± 14.3%, MDPE Schnider -5.4 ± 20.7%, P = 0.09). MDAPE was outside of accepted limits in six (Marsh model) and two (Schnider model) of 12 patients. The prediction probability was comparable between the Marsh (PK 0.798 ± 0.056) and the Schnider model (PK 0.787 ± 0.055), but after adjusting the models to each individual patient, the Schnider model achieved significantly higher prediction probabilities (PK 0.807 ± 0.056, P = 0.05). When using the 'asleep-awake-asleep' anaesthetic technique during awake craniotomy, we advocate using the PK/PD model proposed by Schnider. Due to considerable interindividual variation, additional monitoring of anaesthetic depth is

Efficacy and safety of dexmedetomidine infusion for patients undergoing awake craniotomy: An observational study

PubMed Central

Mahajan, Charu; Rath, Girija Prasad; Singh, Gyaninder Pal; Mishra, Nitasha; Sokhal, Suman; Bithal, Parmod Kumar

2018-01-01

Background: The goal of awake craniotomy is to maintain adequate sedation, analgesia, respiratory, and hemodynamic stability and also to provide a cooperative patient for neurologic testing. An observational study carried out to evaluate the efficacy of dexmedetomidine sedation for awake craniotomy. Materials and Methods: Adult patients with age >18 year who underwent awake craniotomy for intracranial tumor surgery were enrolled. Those who were uncooperative and had difficult airway were excluded from the study. In the operating room, the patients received a bolus dose of dexmedetomidine 1 μg/kg followed by an infusion of 0.2–0.7 μg/kg/h (bispectral index target 60–80). Once the patients were sedated, scalp block was given with bupivacaine 0.25%. The data on hemodynamics at various stages of the procedure, intraoperative complications, total amount of fentanyl used, intravenous fluids required, blood loss and transfusion, duration of surgery, Intensive Care Unit (ICU), and hospital stay were collected. The patients were assessed for Glasgow outcome scale (GOS) score and patient satisfaction score (PSS). Results: A total of 27 patients underwent awake craniotomy during a period of 2 years. Most common intraoperative complication was seizures; observed in five patients (18.5%). None of these patients experienced any episode of desaturation. Two patients had tight brain for which propofol boluses were administered. The average fentanyl consumption was 161.5 ± 85.0 μg. The duration of surgery, ICU, and hospital stays were 231.5 ± 90.5 min, 14.5 ± 3.5 h, and 4.7 ± 1.5 days, respectively. The overall PSS was 8 and GOS was good in all the patients. Conclusion: The use of dexmedetomidine infusion with regional scalp block in patients undergoing awake craniotomy is safe and efficacious. The absence of major complications and higher PSS makes it close to an ideal agent for craniotomy in awake state. PMID:29628833

Awake craniotomy for microsurgical obliteration of mycotic aneurysms: technical report of three cases.

PubMed

Lüders, Jürgen C; Steinmetz, Michael P; Mayberg, Marc R

2005-01-01

Infectious (mycotic) aneurysms that do not resolve with medical treatment require surgical obliteration, usually requiring sacrifice of the parent artery. In addition, patients with mycotic aneurysms frequently need subsequent cardiac valve repair, which often necessitates anticoagulation. Three cases of awake craniotomy for microsurgical clipping of mycotic aneurysms are presented. Awake minimally invasive craniotomy using frameless stereotactic guidance on the basis of computed tomographic angiography enables temporary occlusion of the parent artery with neurological assessment before obliteration of the aneurysm. A 56-year-old woman presented with progressively worsening mitral valve disease and a history of subacute bacterial endocarditis and subarachnoid hemorrhage 30 years previously. A cerebral angiogram revealed a 4-mm left middle cerebral artery (MCA) angular branch aneurysm, which required obliteration before mitral valve replacement. The second patient, a 64-year-old woman with a history of rheumatic fever, had an 8-mm right distal MCA aneurysm diagnosed in the setting of pulmonary abscess and worsening cardiac function as a result of mitral valve disease. The third patient, a 57-year-old man with a history of fevers, night sweats, and progressive mitral valve disease, had an enlarging left MCA angular branch aneurysm despite the administration of antibiotics. Because of their location on distal MCA branches, none of the aneurysms were amenable to preoperative test balloon occlusion. After undergoing stereotactic computed tomographic angiography with fiducial markers, the patients underwent a minimally invasive awake craniotomy with frameless stereotactic navigation. In all cases, the results of the neurological examination were unchanged during temporary parent artery occlusion and the aneurysms were successfully obliterated. Awake minimally invasive craniotomy for an infectious aneurysm located in eloquent brain enables awake testing before permanent

Intranasal Mesenchymal Stem Cell Treatment for Neonatal Brain Damage: Long-Term Cognitive and Sensorimotor Improvement

PubMed Central

Donega, Vanessa; 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 window and dose response relationships. Furthermore, the appearance of MSCs at the lesion site in relation to the therapeutic window was examined. Nine-day-old mice were subjected to unilateral carotid artery occlusion and hypoxia. MSCs were administered intranasally at 3, 10 or 17 days after hypoxia-ischemia (HI). Motor, cognitive and histological outcome was investigated. PKH-26 labeled cells were used to localize MSCs in the brain. We identified 0.5×106 MSCs as the minimal effective dose with a therapeutic window of at least 10 days but less than 17 days post-HI. A single dose was sufficient for a marked beneficial effect. MSCs reach the lesion site within 24 h when given 3 or 10 days after injury. However, no MSCs were detected in the lesion when administered 17 days following HI. We also show for the first time that intranasal MSC treatment after HI improves cognitive function. Improvement of sensorimotor function and histological outcome was maintained until at least 9 weeks post-HI. The capacity of MSCs to reach the lesion site within 24 h after intranasal administration at 10 days but not at 17 days post-HI indicates a therapeutic window of at least 10 days. Our data strongly indicate that intranasal MSC treatment may become a promising non-invasive therapeutic tool to effectively reduce neonatal encephalopathy. PMID:23300948

A randomized controlled trial of intranasal ketamine in migraine with prolonged aura.

PubMed

Afridi, Shazia K; Giffin, Nicola J; Kaube, Holger; Goadsby, Peter J

2013-02-12

The aim of our study was to test the hypothesis that ketamine would affect aura in a randomized controlled double-blind trial, and thus to provide direct evidence for the role of glutamatergic transmission in human aura. We performed a double-blinded, randomized parallel-group controlled study investigating the effect of 25 mg intranasal ketamine on migraine with prolonged aura in 30 migraineurs using 2 mg intranasal midazolam as an active control. Each subject recorded data from 3 episodes of migraine. Eighteen subjects completed the study. Ketamine reduced the severity (p = 0.032) but not duration of aura in this group, whereas midazolam had no effect. These data provide translational evidence for the potential importance of glutamatergic mechanisms in migraine aura and offer a pharmacologic parallel between animal experimental work on cortical spreading depression and the clinical problem. This study provides class III evidence that intranasal ketamine is effective in reducing aura severity in patients with migraine with prolonged aura.

Scalp Block for Awake Craniotomy in a Patient With a Frontal Bone Mass: A Case Report

PubMed Central

Amiri, Hamid Reza; Kouhnavard, Marjan; Safari, Saeid

2012-01-01

“Anesthesia” for awake craniotomy is a unique clinical condition that requires the anesthesiologist to provide changing states of sedation and analgesia, to ensure optimal patient comfort without interfering with electrophysiologic monitoring and patient cooperation, and also to manipulate cerebral and systemic hemodynamics while guaranteeing adequate ventilation and patency of airways. Awake craniotomy is not as popular in developing countries as in European countries. This might be due to the lack of information regarding awake craniotomy and its benefits among the neurosurgeons and anesthetists in developing countries. From the economic perspective, this procedure may decrease resource utilization by reducing the use of invasive monitoring, the duration of the operation, and the length of postoperative hospital stay. All these reasons also favor its use in the developing world, where the availability of resources still remains a challenge. In this case report we presented a successful awake craniotomy in patient with a frontal bone mass. PMID:24904791

Comparative efficacy of intranasal and injectable vaccines in stimulating Bordetella bronchiseptica-reactive anamnestic antibody responses in household dogs

PubMed Central

Ellis, John A.; Gow, Sheryl P.; Lee, Lindsey B.; Lacoste, Stacey; Ball, Eileen C.

2017-01-01

In order to determine the comparative efficacy of injectable and intranasal vaccines to stimulate Bordetella bronchiseptica (Bb)-reactive anamnestic antibodies, a trial was conducted using 144 adult household dogs of various breeds and ages, which had been previously administered intranasal Bb vaccine approximately 12 months before enrollment. Dogs were randomized into 2 groups and blood, nasal swabs, and pharyngeal swabs were collected prior to the administration of single component Bb vaccines intranasally or parenterally. Ten to 14 days later all dogs were resampled to measure changes in systemic and local antibody to Bb. There were no differences in the changes in Bb-reactive serum IgG and nasal IgA between the groups, whereas intranasally vaccinated dogs had significantly higher Bb-reactive serum IgA. These data indicate that both of the current generation of intranasal (modified-live) and injectable (acellular) Bb vaccines can stimulate anamnestic local and systemic antibody responses in previously vaccinated, Bb-seropositive adult household dogs. PMID:28761185

Saliva oxytocin measures do not reflect peripheral plasma concentrations after intranasal oxytocin administration in men.

PubMed

Quintana, Daniel S; Westlye, Lars T; Smerud, Knut T; Mahmoud, Ramy A; Andreassen, Ole A; Djupesland, Per G

2018-05-16

Oxytocin plays an important role in social behavior. Thus, there has been significant research interest for the role of the oxytocin system in several psychiatric disorders, and the potential of intranasal oxytocin administration to treat social dysfunction. Measurement of oxytocin concentrations in saliva are sometimes used to approximate peripheral levels of oxytocin; however, the validity of this approach is unclear. In this study, saliva and plasma oxytocin was assessed after two doses of Exhalation Delivery System delivered intranasal oxytocin (8 IU and 24 IU), intravenous oxytocin (1 IU) and placebo in a double-dummy, within-subjects design with men. We found that intranasal oxytocin (8 IU and 24 IU) administration increased saliva oxytocin concentrations in comparison to saliva oxytocin concentration levels after intravenous and placebo administration. Additionally, we found that saliva oxytocin concentrations were not significantly associated with plasma oxytocin concentrations after either intranasal or intravenous oxytocin administration. Altogether, we suggest that saliva oxytocin concentrations do not accurately index peripheral oxytocin after intranasal or intravenous oxytocin administration, at least in men. The data indicates that elevated oxytocin saliva levels after nasal delivery primarily reflect exogenous administered oxytocin that is cleared from the nasal cavity to the oropharynx, and is therefore a weak surrogate for peripheral blood measurements. Copyright © 2018 Elsevier Inc. All rights reserved.

Chronic Intranasal Oxytocin Causes Long-term Impairments in Partner Preference Formation in Male Prairie Voles

PubMed Central

Bales, Karen L.; Perkeybile, Allison M.; Conley, Olivia G.; Lee, Meredith H.; Guoynes, Caleigh D.; Downing, Griffin M.; Yun, Catherine R.; Solomon, Marjorie; Jacob, Suma; Mendoza, Sally P.

2012-01-01

Background Oxytocin (OT) is a hormone shown to be involved in social bonding in animal models. Intranasal OT is currently in clinical trials for use in disorders such as autism and schizophrenia. We examined long-term effects of intranasal OT given developmentally in the prairie vole (Microtus ochrogaster), a socially monogamous rodent, often used as an animal model to screen drugs that have therapeutic potential for social disorders. Methods We treated voles with one of three dosages of intranasal OT, or saline, from day 21 (weaning) through day 42 (sexual maturity). We examined both social behavior immediately following administration, as well as long-term changes in social and anxiety behavior after treatment ceased. Group sizes varied from 8 to 15 voles (n = 89 voles total). Results Treatment with OT resulted in acute increases in social behavior in males with familiar partners, as seen in humans. However, long-term developmental treatment with low doses of intranasal OT resulted in a deficit in partner preference behavior (a reduction of contact with a familiar opposite-sex partner, used to index pair-bond formation) by males. Conclusions Long-term developmental treatment with OT may show results different to those predicted by short-term studies, as well as significant sex differences and dosage effects. Further animal study is crucial to determining safe and effective strategies for use of chronic intranasal OT, especially during development. PMID:23079235

Intranasal immunization with chitosan/pCETP nanoparticles inhibits atherosclerosis in a rabbit model of atherosclerosis.

PubMed

Yuan, Xiying; Yang, Xiaorong; Cai, Danning; Mao, Dan; Wu, Jie; Zong, Li; Liu, Jingjing

2008-07-04

In search of a convenient and pain-free route of administration of DNA vaccine against atherosclerosis, the plasmid pCR-X8-HBc-CETP (pCETP) encoding B-cell epitope of cholesteryl ester transfer protein C-terminal fragment displayed by Hepatitis B virus core particle was condensed with chitosan to form chitosan/pCETP nanoparticles. Cholesterol-fed rabbits were then intranasally immunized with the chitosan/pCETP nanoparticles to evaluate antiatherogenic effects. The results showed that significant serum antibodies against CETP were detected by enzyme-linked immunosorbent analysis and verified by Western blot analysis. The significant anti-CETP IgG lasted for 21 weeks in the rabbits immunized intranasally. Moreover, the atherogenic index was significantly lower compared with the saline control (5.95 versus 2.39, p<0.05). In addition, the average percentage of aortic lesions in the entire aorta area in the rabbits intranasally vaccinated with nanoparticles was 59.2% less than those treated with saline (29.0+/-10.9% versus 71.0+/-14.4%, p<0.01) and was similar to those intramuscularly injected with pCETP solution (29.0+/-10.9% versus 21.2+/-14.2%, p>0.05). Thus, chitosan/pCETP nanoparticles could significantly attenuate the progression of atherosclerosis by intranasal immunization. The results suggested that intranasal administration could be potentially developed as a vaccination route against atherosclerosis.

A Method for Generating Natural and User-Defined Sniffing Patterns in Anesthetized or Reduced Preparations

PubMed Central

Carey, Ryan M.; Wachowiak, Matt

2009-01-01

Sniffing has long been thought to play a critical role in shaping neural responses to odorants at multiple levels of the nervous system. However, it has been difficult to systematically examine how particular parameters of sniffing behavior shape odorant-evoked activity, in large part because of the complexity of sniffing behavior and the difficulty in reproducing this behavior in an anesthetized or reduced preparation. Here we present a method for generating naturalistic sniffing patterns in such preparations. The method involves a nasal ventilator whose movement is controlled by an analog command voltage. The command signal may consist of intranasal pressure transients recorded from awake rats and mice or user-defined waveforms. This “sniff playback” device generates intranasal pressure and airflow transients in anesthetized animals that approximate those recorded from the awake animal and are reproducible across trials and across preparations. The device accurately reproduces command waveforms over an amplitude range of approximately 1 log unit and up to frequencies of approximately 12 Hz. Further, odorant-evoked neural activity imaged during sniff playback appears similar to that seen in awake animals. This method should prove useful in investigating how the parameters of odorant sampling shape neural responses in a variety of experimental settings. PMID:18791186

Intranasal Delivery of pGDNF Nanoparticles for Parkinson's Disease

NASA Astrophysics Data System (ADS)

Harmon, Brendan Trevor

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

Prospective study of awake craniotomy used routinely and nonselectively for supratentorial tumors.

PubMed

Serletis, Demitre; Bernstein, Mark

2007-07-01

The authors prospectively assessed the value of awake craniotomy used nonselectively in patients undergoing resection of supratentorial tumors. The demographic features, presenting symptoms, tumor location, histological diagnosis, outcomes, and complications were documented for 610 patients who underwent awake craniotomy for supratentorial tumor resection. Intraoperative brain mapping was used in 511 cases (83.8%). Mapping identified eloquent cortex in 115 patients (22.5%) and no eloquent cortex in 396 patients (77.5%). Neurological deficits occurred in 89 patients (14.6%). In the subset of 511 patients in whom brain mapping was performed, 78 (15.3%) experienced postoperative neurological worsening. This phenomenon was more common in patients with preoperative neurological deficits or in those individuals in whom mapping successfully identified eloquent tissue. Twenty-five (4.9%) of the 511 patients suffered intraoperative seizures, and two of these individuals required intubation and induction of general anesthesia after generalized seizures occurred. Four (0.7%) of the 610 patients developed wound complications. Postoperative hematomas developed in seven patients (1.1%), four of whom urgently required a repeated craniotomy to allow evacuation of the clot. Two patients (0.3%) required readmission to the hospital soon after being discharged. There were three deaths (0.5%). Awake craniotomy is safe, practical, and effective during resection of supratentorial lesions of diverse pathological range and location. It allows for intraoperative brain mapping that helps identify and protect functional cortex. It also avoids the complications inherent in the induction of general anesthesia. Awake craniotomy provides an excellent alternative to surgery of supratentorial brain lesions in patients in whom general anesthesia has been induced.

The effects of oral d-amphetamine on impulsivity in smoked and intranasal cocaine users.

PubMed

Reed, Stephanie Collins; Evans, Suzette M

2016-06-01

Effective treatments for cocaine use disorders remain elusive. Two factors that may be related to treatment failures are route of cocaine used and impulsivity. Smoked cocaine users are more likely to have poorer treatment outcomes compared to intranasal cocaine users. Further, cocaine users are impulsive and impulsivity is associated with poor treatment outcomes. While stimulants are used to treat Attention Deficit Hyperactivity Disorder (ADHD) and attenuate certain cocaine-related behaviors, few studies have comprehensively examined whether stimulants can reduce behavioral impulsivity in cocaine users, and none examined route of cocaine use as a factor. The effects of immediate release oral d-amphetamine (AMPH) were examined in 34 cocaine users (13 intranasal, 21 smoked). Participants had three separate sessions where they were administered AMPH (0, 10, or 20mg) and completed behavioral measures of impulsivity and risk-taking and subjective measures of abuse liability. Smoked cocaine users were more impulsive on the Delayed Memory Task, the GoStop task and the Delay Discounting Task than intranasal cocaine users. Smoked cocaine users also reported more cocaine craving and negative mood than intranasal cocaine users. AMPH produced minimal increases on measures of abuse liability (e.g., Drug Liking). Smoked cocaine users were more impulsive than intranasal cocaine users on measures of impulsivity that had a delay component. Additionally, although AMPH failed to attenuate impulsive responding, there was minimal evidence of abuse liability in cocaine users. These preliminary findings need to be confirmed in larger samples that control for route and duration of cocaine use. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The Effects of Oral d-Amphetamine on Impulsivity in Smoked and Intranasal Cocaine Users

PubMed Central

Reed, Stephanie Collins; Evans, Suzette M.

2016-01-01

BACKGROUND Effective treatments for cocaine use disorders remain elusive. Two factors that may be related to treatment failures are route of cocaine used and impulsivity. Smoked cocaine users are more likely to have poorer treatment outcomes compared to intranasal cocaine users. Further, cocaine users are impulsive and impulsivity is associated with poor treatment outcomes. While stimulants are used to treat Attention Deficit Hyperactivity Disorder (ADHD) and attenuate certain cocaine-related behaviors, few studies have comprehensively examined whether stimulants can reduce behavioral impulsivity in cocaine users, and none examined route of cocaine use as a factor. METHODS The effects of immediate release oral d-amphetamine (AMPH) were examined in 34 cocaine users (13 intranasal, 21 smoked). Participants had three separate sessions where they were administered AMPH (0, 10, or 20 mg) and completed behavioral measures of impulsivity and risk-taking and subjective measures of abuse liability. RESULTS Smoked cocaine users were more impulsive on the Delayed Memory Task, the GoStop task and the Delay Discounting Task than intranasal cocaine users. Smoked cocaine users also reported more cocaine craving and negative mood than intranasal cocaine users. AMPH produced minimal increases on measures of abuse liability (e.g., Drug Liking). CONCLUSIONS Smoked cocaine users were more impulsive than intranasal cocaine users on measures of impulsivity that had a delay component. Additionally, although AMPH failed to attenuate impulsive responding, there was minimal evidence of abuse liability in cocaine users. These preliminary findings need to be confirmed in larger samples that control for route and duration of cocaine use. PMID:27114203

Survival times for canine intranasal sarcomas treated with radiation therapy: 86 cases (1996-2011).

PubMed

Sones, Evan; Smith, Annette; Schleis, Stephanie; Brawner, William; Almond, Gregory; Taylor, Kathryn; Haney, Siobhan; Wypij, Jackie; Keyerleber, Michele; Arthur, Jennifer; Hamilton, Terrance; Lawrence, Jessica; Gieger, Tracy; Sellon, Rance; Wright, Zack

2013-01-01

Sarcomas comprise approximately one-third of canine intranasal tumors, however few veterinary studies have described survival times of dogs with histologic subtypes of sarcomas separately from other intranasal tumors. One objective of this study was to describe median survival times for dogs treated with radiation therapy for intranasal sarcomas. A second objective was to compare survival times for dogs treated with three radiation therapy protocols: daily-fractionated radiation therapy; Monday, Wednesday, and Friday fractionated radiation therapy; and palliative radiation therapy. Medical records were retrospectively reviewed for dogs that had been treated with radiation therapy for confirmed intranasal sarcoma. A total of 86 dogs met inclusion criteria. Overall median survival time for included dogs was 444 days. Median survival time for dogs with chondrosarcoma (n = 42) was 463 days, fibrosarcoma (n = 12) 379 days, osteosarcoma (n = 6) 624 days, and undifferentiated sarcoma (n = 22) 344 days. Dogs treated with daily-fractionated radiation therapy protocols; Monday, Wednesday and Friday fractionated radiation therapy protocols; and palliative radiation therapy protocols had median survival times of 641, 347, and 305 days, respectively. A significant difference in survival time was found for dogs receiving curative intent radiation therapy vs. palliative radiation therapy (P = 0.032). A significant difference in survival time was also found for dogs receiving daily-fractionated radiation therapy vs. Monday, Wednesday and Friday fractionated radiation therapy (P = 0.0134). Findings from this study support the use of curative intent radiation therapy for dogs with intranasal sarcoma. Future prospective, randomized trials are needed for confirmation of treatment benefits. © 2012 Veterinary Radiology & Ultrasound.

Effect of administration method, animal weight and age on the intranasal delivery of drugs to the brain.

PubMed

Krishnan, Jishnu K S; Arun, Peethambaran; Chembukave, Bhadra; Appu, Abhilash P; Vijayakumar, Nivetha; Moffett, John R; Puthillathu, Narayanan; Namboodiri, Aryan M A

2017-07-15

The intranasal route of administration has proven to be an effective method for bypassing the blood brain barrier and avoiding first pass hepatic metabolism when targeting drugs to the brain. Most small molecules gain rapid access to CNS parenchyma when administered intranasally. However, bioavailability is affected by various factors ranging from the molecular weight of the drug to the mode of intranasal delivery. We examined the effects of animal posture, intranasal application method and animal weight and age on the delivery of radiolabeled pralidoxime ( 3 H-2-PAM) to the brain of rats. We found that using upright vs. supine posture did not significantly affect 3 H-2-PAM concentrations in different brain regions. Older animals with higher weights required increased doses to achieve the same drug concentration throughout the brain when compared to young animals with lower body weights. The use of an intranasal aerosol propelled delivery device mainly increased bioavailability in the olfactory bulbs, but did not reliably increase delivery of the drug to various other brain regions, and in some regions of the brain delivered less of the drug than simple pipette administration. In view of the emerging interest in the use of intranasal delivery of drugs to combat cognitive decline in old age, we tested effectiveness in very old rats and found the method to be as effective in the older rats. Copyright © 2017 Elsevier B.V. All rights reserved.

Mapping oxygen concentration in the awake mouse brain

PubMed Central

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

2016-01-01

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

A Randomized Controlled Trial of Intranasal Ketamine in Major Depressive Disorder

PubMed Central

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

2014-01-01

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

Awake Craniotomy for Tumor Resection: Further Optimizing Therapy of Brain Tumors.

PubMed

Mehdorn, H Maximilian; Schwartz, Felix; Becker, Juliane

2017-01-01

In recent years more and more data have emerged linking the most radical resection to prolonged survival in patients harboring brain tumors. Since total tumor resection could increase postoperative morbidity, many methods have been suggested to reduce the risk of postoperative neurological deficits: awake craniotomy with the possibility of continuous patient-surgeon communication is one of the possibilities of finding out how radical a tumor resection can possibly be without causing permanent harm to the patient.In 1994 we started to perform awake craniotomy for glioma resection. In 2005 the use of intraoperative high-field magnetic resonance imaging (MRI) was included in the standard tumor therapy protocol. Here we review our experience in performing awake surgery for gliomas, gained in 219 patients.Patient selection by the operating surgeon and a neuropsychologist is of primary importance: the patient should feel as if they are part of the surgical team fighting against the tumor. The patient will undergo extensive neuropsychological testing, functional MRI, and fiber tractography in order to define the relationship between the tumor and the functionally relevant brain areas. Attention needs to be given at which particular time during surgery the intraoperative MRI is performed. Results from part of our series (without and with ioMRI scan) are presented.

Assessment of the pharmacodynamics of intranasal, intravenous and oral scopolamine

NASA Technical Reports Server (NTRS)

Tietze, Karen J.

1990-01-01

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

Comparison of intranasal midazolam with intravenous diazepam for treating febrile seizures in children: prospective randomised study

PubMed Central

Lahat, Eli; Goldman, Michael; Barr, Joseph; Bistritzer, Tzvi; Berkovitch, Matithyahu

2000-01-01

Objective To compare the safety and efficacy of midazolam given intranasally with diazepam given intravenously in the treatment of children with prolonged febrile seizures. Design Prospective randomised study. Setting Paediatric emergency department in a general hospital. Subjects 47 children aged six months to five years with prolonged febrile seizure (at least 10 minutes) during a 12 month period. Interventions Intranasal midazolam (0.2 mg/kg) and intravenous diazepam (0.3 mg/kg). Main outcome measures Time from arrival at hospital to starting treatment and cessation of seizures. Results Intranasal midazolam and intravenous diazepam were equally effective. Overall, 23 of 26 seizures were controlled with midazolam and 24 out of 26 with diazepam. The mean time from arrival at hospital to starting treatment was significantly shorter in the midazolam group (3.5 (SD 1.8) minutes, 95% confidence interval 3.3 to 3.7) than the diazepam group (5.5 (2.0), 5.3 to 5.7). The mean time to control of seizures was significantly sooner (6.1 (3.6), 6.3 to 6.7) in the midazolam group than the diazepam group (8.0 (0.5), 7.9 to 8.3). No significant side effects were observed in either group. Conclusion Seizures were controlled more quickly with intravenous diazepam than with intranasal midazolam, although midazolam was as safe and effective as diazepam. The overall time to cessation of seizures after arrival at hospital was faster with intranasal midazolam than with intravenous diazepam. The intranasal route can possibly be used not only in medical centres but in general practice and, with appropriate instructions, by families of children with recurrent febrile seizures at home. PMID:10884257

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

PubMed

Charlton, Bruce G; Andras, Peter

2009-07-01

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

RGC Neuroprotection Following Optic Nerve Trauma Mediated By Intranasal Delivery of Amnion Cell Secretome

PubMed Central

Grinblat, Gabriela A.; Khan, Reas S.; Dine, Kimberly; Wessel, Howard; Brown, Larry; Shindler, Kenneth S.

2018-01-01

Purpose Intranasally delivered ST266, the biological, proteinaceous secretome of amnion-derived multipotent progenitor cells, reduces retinal ganglion cell (RGC) loss, optic nerve inflammation, and demyelination in experimental optic neuritis. This unique therapy and novel administration route delivers numerous cytokines and growth factors to the eye and optic nerve, suggesting a potential to also treat other optic neuropathies. Thus, ST266-mediated neuroprotection was examined following traumatic optic nerve injury. Methods Optic nerve crush injury was surgically induced in C57BL/6J mice. Mice were treated daily with intranasal PBS or ST266. RGC function was assessed by optokinetic responses (OKRs), RGCs were counted, and optic nerve sections were stained with luxol fast blue and anti-neurofilament antibodies to assess myelin and RGC axon damage. Results Intranasal ST266 administered daily for 5 days, beginning at the time that a 1-second optic nerve crush was performed, significantly attenuated OKR decreases. Furthermore, ST266 treatment reduced damage to RGC axons and myelin within optic nerves, and blocked RGC loss. Following a 4-second optic nerve crush, intranasal ST266 increased RGC survival and showed a trend toward reduced RGC axon and myelin damage. Ten days following optic nerve crush, ST266 prevented myelin damage, while also inducing a trend toward increased RGC survival and visual function. Conclusions ST266 significantly attenuates traumatic optic neuropathy. Neuroprotective effects of this unique combination of biologic molecules observed here and previously in optic neuritis suggest potential broad application for preventing neuronal damage in multiple optic nerve disorders. Furthermore, results support intranasal delivery as a novel, noninvasive therapeutic modality for eyes and optic nerves. PMID:29847652

Intranasal Dexmedetomidine for Procedural Sedation in Children, a Suitable Alternative to Chloral Hydrate.

PubMed

Cozzi, Giorgio; Norbedo, Stefania; Barbi, Egidio

2017-04-01

Sedation is often required for children undergoing diagnostic procedures. Chloral hydrate has been one of the sedative drugs most used in children over the last 3 decades, with supporting evidence for its efficacy and safety. Recently, chloral hydrate was banned in Italy and France, in consideration of evidence of its carcinogenicity and genotoxicity. Dexmedetomidine is a sedative with unique properties that has been increasingly used for procedural sedation in children. Several studies demonstrated its efficacy and safety for sedation in non-painful diagnostic procedures. Dexmedetomidine's impact on respiratory drive and airway patency and tone is much less when compared to the majority of other sedative agents. Administration via the intranasal route allows satisfactory procedural success rates. Studies that specifically compared intranasal dexmedetomidine and chloral hydrate for children undergoing non-painful procedures showed that dexmedetomidine was as effective as and safer than chloral hydrate. For these reasons, we suggest that intranasal dexmedetomidine could be a suitable alternative to chloral hydrate.

Intranasal tissue necrosis associated with opioid abuse: Case report and systematic review.

PubMed

Morrison, Danielle A; Wise, Sarah K; DelGaudio, John M; Chowdhury, Naweed I; Levy, Joshua M

2017-12-27

Opioid abuse is a common disorder affecting over 2 million Americans. Intranasal tissue necrosis is a previously described sequela of nasal opioid inhalation, with a similar presentation to invasive fungal rhinosinusitis (IFRS). The goal of this case report and systematic review is to evaluate the evidence supporting this uncommon disease, with qualitative analysis of the presentation, management and treatment outcomes. MEDLINE, EMBASE, Google Scholar, Scopus, and Web of Science. Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were utilized to identify English-language studies reporting intranasal mucosal injury associated with prescription opioid abuse. Primary outcomes included clinical presentation, treatment strategies, and outcomes. Systematic review identified 61 patients for qualitative analysis. Common clinical features include facial pain without a history of chronic sinusitis or known immunodeficiency. Diagnostic nasal endoscopy revealed superficial debris with underlying tissue necrosis, consistent with a preliminary diagnosis of IFRS. Characteristic pathologic findings include mucosal ulceration with an overlying acellular substrate, often with polarizable material. Fungal colonization is often reported, with several accounts of angiocentric invasion in immunocompetent patients. Complete symptom resolution is expected following surgical debridement with cessation of intranasal opioid inhalation, with 89% of identified patients experiencing a complete resolution of disease. Intranasal opioid abuse is a prevalent condition associated with chronic pain and tissue necrosis that is clinically concerning for invasive fungal disease. Whereas IFRS must be excluded, even in patients without known immunodeficiency, complete resolution of symptoms can be expected following surgical debridement with cessation of opioid abuse. Laryngoscope, 2017. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

Guanidinylated Neomycin Conjugation Enhances Intranasal Enzyme Replacement in the Brain.

PubMed

Tong, Wenyong; Dwyer, Chrissa A; Thacker, Bryan E; Glass, Charles A; Brown, Jillian R; Hamill, Kristina; Moremen, Kelley W; Sarrazin, Stéphane; Gordts, Philip L S M; Dozier, Lara E; Patrick, Gentry N; Tor, Yitzhak; Esko, Jeffrey D

2017-12-06

Iduronidase (IDUA)-deficient mice accumulate glycosaminoglycans in cells and tissues and exhibit many of the same neuropathological symptoms of patients suffering from Mucopolysaccharidosis I. Intravenous enzyme-replacement therapy for Mucopolysaccharidosis I ameliorates glycosaminoglycan storage and many of the somatic aspects of the disease but fails to treat neurological symptoms due to poor transport across the blood-brain barrier. In this study, we examined the delivery of IDUA conjugated to guanidinoneomycin (GNeo), a molecular transporter. GNeo-IDUA and IDUA injected intravenously resulted in reduced hepatic glycosaminoglycan accumulation but had no effect in the brain due to fast clearance from the circulation. In contrast, intranasally administered GNeo-IDUA entered the brain rapidly. Repetitive intranasal treatment with GNeo-IDUA reduced glycosaminoglycan storage, lysosome size and number, and neurodegenerative astrogliosis in the olfactory bulb and primary somatosensory cortex, whereas IDUA was less effective. The enhanced efficacy of GNeo-IDUA was not the result of increased nose-to-brain delivery or enzyme stability, but rather due to more efficient uptake into neurons and astrocytes. GNeo conjugation also enhanced glycosaminoglycan clearance by intranasally delivered sulfamidase to the brain of sulfamidase-deficient mice, a model of Mucopolysaccharidosis IIIA. These findings suggest the general utility of the guanidinoglycoside-based delivery system for restoring missing lysosomal enzymes in the brain. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

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

PubMed

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.

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

PubMed

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.

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

PubMed

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.

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

PubMed Central

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

2015-01-01

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

CXCR6 is a marker for protective antigen-specific cells in the lungs after intranasal immunization against Mycobacterium tuberculosis.

PubMed

Lee, Lian Ni; Ronan, Edward O; de Lara, Catherine; Franken, Kees L M C; Ottenhoff, Tom H M; Tchilian, Elma Z; Beverley, Peter C L

2011-08-01

Convincing correlates of protective immunity against tuberculosis have been elusive. In BALB/c mice, intranasal immunization with a replication-deficient recombinant adenovirus expressing Mycobacterium tuberculosis antigen 85A (adenovirus-85A) induces protective lower respiratory tract immunity against pulmonary challenge with Mycobacterium tuberculosis, while intradermal immunization with adenovirus-85A does not. Here we report that intranasal immunization with adenovirus-85A induces expression of the chemokine receptor CXCR6 on lung CD8 T lymphocytes, which is maintained for at least 3 months. CXCR6-positive antigen-specific T cell numbers are increased among bronchoalveolar lavage-recoverable cells. Similarly, intranasal immunization with recombinant antigen 85A with adjuvant induces CXCR6 expression on lung CD4 cells in BALB/c and C57BL/6 mice, while a synthetic ESAT6(1-20) peptide with adjuvant induces CXCR6 expression in C57BL/6 mice. Parenteral immunization fails to do so. Upregulation of CXCR6 is accompanied by a transient elevation of serum CXCL16 after intranasal immunization, and lung cells cultured ex vivo from mice immunized intranasally show increased production of CXCL16. Administration of CXCL16 and cognate antigen intranasally to mice previously immunized parenterally increases the number of antigen-specific T lymphocytes in the bronchoalveolar lavage-recoverable population, which mediates inhibition of the early growth of Mycobacterium tuberculosis after challenge. We conclude that expression of CXCR6 on lung T lymphocytes is a correlate of local protective immunity against Mycobacterium tuberculosis after intranasal immunization and that CXCR6 and CXCL16 play an important role in the localization of T cells within lung tissue and the bronchoalveolar lavage-recoverable compartment.

CXCR6 Is a Marker for Protective Antigen-Specific Cells in the Lungs after Intranasal Immunization against Mycobacterium tuberculosis▿

PubMed Central

Lee, Lian Ni; Ronan, Edward O.; de Lara, Catherine; Franken, Kees L. M. C.; Ottenhoff, Tom H. M.; Tchilian, Elma Z.; Beverley, Peter C. L.

2011-01-01

Convincing correlates of protective immunity against tuberculosis have been elusive. In BALB/c mice, intranasal immunization with a replication-deficient recombinant adenovirus expressing Mycobacterium tuberculosis antigen 85A (adenovirus-85A) induces protective lower respiratory tract immunity against pulmonary challenge with Mycobacterium tuberculosis, while intradermal immunization with adenovirus-85A does not. Here we report that intranasal immunization with adenovirus-85A induces expression of the chemokine receptor CXCR6 on lung CD8 T lymphocytes, which is maintained for at least 3 months. CXCR6-positive antigen-specific T cell numbers are increased among bronchoalveolar lavage-recoverable cells. Similarly, intranasal immunization with recombinant antigen 85A with adjuvant induces CXCR6 expression on lung CD4 cells in BALB/c and C57BL/6 mice, while a synthetic ESAT61–20 peptide with adjuvant induces CXCR6 expression in C57BL/6 mice. Parenteral immunization fails to do so. Upregulation of CXCR6 is accompanied by a transient elevation of serum CXCL16 after intranasal immunization, and lung cells cultured ex vivo from mice immunized intranasally show increased production of CXCL16. Administration of CXCL16 and cognate antigen intranasally to mice previously immunized parenterally increases the number of antigen-specific T lymphocytes in the bronchoalveolar lavage-recoverable population, which mediates inhibition of the early growth of Mycobacterium tuberculosis after challenge. We conclude that expression of CXCR6 on lung T lymphocytes is a correlate of local protective immunity against Mycobacterium tuberculosis after intranasal immunization and that CXCR6 and CXCL16 play an important role in the localization of T cells within lung tissue and the bronchoalveolar lavage-recoverable compartment. PMID:21628524

Conscious sedation for awake craniotomy in intraoperative magnetic resonance imaging operating theater

PubMed Central

Takrouri, Mohamad Said Maani; Shubbak, Firas A.; Al Hajjaj, Aisha; Maestro, Rolando F. Del; Soualmi, Lahbib; Alkhodair, Mashael H.; Alduraiby, Abrar M.; Ghanem, Najeeb

2010-01-01

This case report describes the first case in intraoperative magnetic resonance imaging operating theater (iMRI OT) (BrainSuite®) of awake craniotomy for frontal lobe glioma excision in a 24-year-old man undergoing eloquent cortex language mapping intraoperatively. As he was very motivated to take pictures of him while being operated upon, the authors adapted conscious sedation technique with variable depth according to Ramsey's scale, in order to revert to awake state to perform the intended neurosurgical procedure. The patient tolerated the situation satisfactorily and was cooperative till the finish, without any event. We elicit in this report the special environment of iMRI OT for lengthy operation in pinned fixed patient having craniotomy. PMID:25885085

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

PubMed

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.

A novel paraplegia model in awake behaving macaques.

PubMed

Krucoff, Max O; Zhuang, Katie; MacLeod, David; Yin, Allen; Byun, Yoon Woo; Manson, Roberto Jose; Turner, Dennis A; Oliveira, Laura; Lebedev, Mikhail A

2017-09-01

Lower limb paralysis from spinal cord injury (SCI) or neurological disease carries a poor prognosis for recovery and remains a large societal burden. Neurophysiological and neuroprosthetic research have the potential to improve quality of life for these patients; however, the lack of an ethical and sustainable nonhuman primate model for paraplegia hinders their advancement. Therefore, our multidisciplinary team developed a way to induce temporary paralysis in awake behaving macaques by creating a fully implantable lumbar epidural catheter-subcutaneous port system that enables easy and reliable targeted drug delivery for sensorimotor blockade. During treadmill walking, aliquots of 1.5% lidocaine with 1:200,000 epinephrine were percutaneously injected into the ports of three rhesus macaques while surface electromyography (EMG) recorded muscle activity from their quadriceps and gastrocnemii. Diminution of EMG amplitude, loss of voluntary leg movement, and inability to bear weight were achieved for 60-90 min in each animal, followed by a complete recovery of function. The monkeys remained alert and cooperative during the paralysis trials and continued to take food rewards, and the ports remained functional after several months. This technique will enable recording from the cortex and/or spinal cord in awake behaving nonhuman primates during the onset, maintenance, and resolution of paraplegia for the first time, thus opening the door to answering basic neurophysiological questions about the acute neurological response to spinal cord injury and recovery. It will also negate the need to permanently injure otherwise high-value research animals for certain experimental paradigms aimed at developing and testing neural interface decoding algorithms for patients with lower extremity dysfunction. NEW & NOTEWORTHY A novel implantable lumbar epidural catheter-subcutaneous port system enables targeted drug delivery and induction of temporary paraplegia in awake, behaving nonhuman

Comparison of dexmedetomidine and propofol for conscious sedation in awake craniotomy: a prospective, double-blind, randomized, and controlled clinical trial.

PubMed

Shen, She-liang; Zheng, Jia-yin; Zhang, Jun; Wang, Wen-yuan; Jin, Tao; Zhu, Jing; Zhang, Qi

2013-11-01

It has been reported that dexmedetomidine (DEX) can be used for conscious sedation in awake craniotomy, but few data exist to compare DEX versus propofol (PRO). To compare the efficacy and safety of DEX versus PRO for conscious sedation in awake craniotomy. Thirty patients of American Society of Anesthesiologists grade I-II scheduled for awake craniotomy, were randomized into 2 groups each containing 15 subjects. Group D received DEX and group P received PRO. Two minutes after tracheal intubation (T1), PRO (target plasma concentration) was titrated down to 1 to 4 µg/mL in group P. In group D, PRO was discontinued and DEX was administered 1.0 µg/kg followed by a maintenance dose of 0.2 to 0.7 µg/kg/h. The surgeon preset the anticipated awake point-in-time (T0) preoperatively. Ten minutes before T0 (T3), DEX was titrated down to 0.2 µg/kg/h in group D, PRO was discontinued and normal saline (placebo) 5 mL/h was infused in group P. Arousal time, quality of revival and adverse events during the awake period, degree of satisfaction from surgeons and patients were recorded. Arousal time was significantly shorter in group D than in group P (P < .001). The quality of revival during the awake period in group D was similar to that of group P (P = .68). The degree of satisfaction of surgeons was significantly higher in group D than in group P (P < .001), but no difference was found between the 2 groups with respect to patient satisfaction (P = .80). There was no difference between the 2 groups in the incidence of adverse events during the awake period (P > .05). Either DEX or PRO can be effectively and safely used for conscious sedation in awake craniotomy. Comparing the two, DEX produced a shorter arousal time and a higher degree of surgeon satisfaction.

Awake surgery for hemispheric low-grade gliomas: oncological, functional and methodological differences between pediatric and adult populations.

PubMed

Trevisi, Gianluca; Roujeau, Thomas; Duffau, Hugues

2016-10-01

Brain mapping through a direct cortical and subcortical electrical stimulation during an awake craniotomy has gained an increasing popularity as a powerful tool to prevent neurological deficit while increasing extent of resection of hemispheric diffuse low-grade gliomas in adults. However, few case reports or very limited series of awake surgery in children are currently available in the literature. In this paper, we review the oncological and functional differences between pediatric and adult populations, and the methodological specificities that may limit the use of awake mapping in pediatric low-grade glioma surgery. This could be explained by the fact that pediatric low-grade gliomas have a different epidemiology and biologic behavior in comparison to adults, with pilocytic astrocytomas (WHO grade I glioma) as the most frequent histotype, and with WHO grade II gliomas less prone to anaplastic transformation than their adult counterparts. In addition, aside from the issue of poor collaboration of younger children under 10 years of age, some anatomical and functional peculiarities of children developing brain (cortical and subcortical myelination, maturation of neural networks and of specialized cortical areas) can influence direct electrical stimulation methodology and sensitivity, limiting its use in children. Therefore, even though awake procedure with cortical and axonal stimulation mapping can be adapted in a specific subgroup of children with a diffuse glioma from the age of 10 years, only few pediatric patients are nonetheless candidates for awake brain surgery.

OUTCOME OF DOGS WITH INTRANASAL LYMPHOMA TREATED WITH VARIOUS RADIATION AND CHEMOTHERAPY PROTOCOLS: 24 CASES.

PubMed

George, Rebecca; Smith, Annette; Schleis, Stephanie; Brawner, William; Almond, Gregory; Kent, Michael; Wypij, Jackie; Borrego, Juan; Moore, Antony; Keyerleber, Michele; Kraiza, Sarah

2016-05-01

Tumors of the nasal cavity comprise approximately 1% of all neoplasms in dogs. Canine intranasal lymphoma is rare and reports evaluating the outcome of treatment are lacking. The goal of this observational, descriptive, multi-institutional study was to evaluate the overall median survival times (MSTs) in a group of dogs with intranasal lymphoma that were treated with irradiation and/or chemotherapy. Dogs meeting these inclusion criteria were retrospectively recruited from medical archives at multiple institutions. Eighteen cases of intermediate to high grade intranasal lymphoma and six cases of low-grade intranasal lymphoma were identified. The date of diagnosis, method of diagnosis, treatment received (radiation and/or chemotherapy protocols), and date of death were recorded. Kaplan-Meier survival analysis was performed on the intermediate to high grade group to calculate overall MST. Log-rank tests were performed to compare effects of treatment with radiation therapy ± chemotherapy and chemotherapy alone. Kaplan-Meier survival analysis was performed separately on the low-grade group. The overall MST was 375 days for the intermediate to high grade group. Cases treated with radiation ± chemotherapy had an MST of 455 days (n = 12) and those treated with chemotherapy alone (n = 6) had an MST of 157 days in the intermediate to high grade group. The MST was 823 days for the low-grade group. Results support the use of radiation therapy for treatment of canine intranasal lymphoma, however a randomized, controlled, clinical trial would be needed for more definitive recommendations. The role of adjunctive chemotherapy also may require further investigation. © 2016 American College of Veterinary Radiology.

Intranasal Pharmacokinetics of Morphine ARER, a Novel Abuse-Deterrent Formulation: Results from a Randomized, Double-Blind, Four-Way Crossover Study in Nondependent, Opioid-Experienced Subjects

PubMed Central

Pantaleon, Carmela; Iverson, Matthew; Smith, Michael D.; Kinzler, Eric R.; Aigner, Stefan

2018-01-01

Objective To investigate the pharmacokinetics (PK) of Morphine ARER, an extended-release (ER), abuse-deterrent formulation of morphine sulfate after oral and intranasal administration. Methods This randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study assessed the PK of morphine and its active metabolite, M6G, from crushed intranasal Morphine ARER and intact oral Morphine ARER compared with crushed intranasal ER morphine following administration to nondependent, recreational opioid users. The correlation between morphine PK and the pharmacodynamic parameter of drug liking, a measure of abuse potential, was also evaluated. Results Mean maximum observed plasma concentration (Cmax) for morphine was lower with crushed intranasal Morphine ARER (26.2 ng/mL) and intact oral Morphine ARER (18.6 ng/mL), compared with crushed intranasal ER morphine (49.5 ng/mL). The time to Cmax (Tmax) was the same for intact oral and crushed intranasal Morphine ARER (1.6 hours) and longer for crushed intranasal morphine ER (1.1 hours). Higher mean maximum morphine Cmax, Tmax, and abuse quotient (Cmax/Tmax) were positively correlated with maximum effect for drug liking (R2 ≥ 0.9795). Conclusion These data suggest that Morphine ARER maintains its ER profile despite physical manipulation and intranasal administration, which may be predictive of a lower intranasal abuse potential compared with ER morphine.

Assessment of insulin resistance in fructose-fed rats with 125I-6-deoxy-6-iodo-D-glucose, a new tracer of glucose transport.

PubMed

Perret, Pascale; Slimani, Lotfi; Briat, Arnaud; Villemain, Danièle; Halimi, Serge; Demongeot, Jacques; Fagret, Daniel; Ghezzi, Catherine

2007-05-01

Insulin resistance, characterised by an insulin-stimulated glucose transport defect, is an important feature of the pre-diabetic state that has been observed in numerous pathological disorders. The purpose of this study was to assess variations in glucose transport in rats using (125)I-6-deoxy-6-iodo-D-glucose (6DIG), a new tracer of glucose transport proposed as an imaging tool to assess insulin resistance in vivo. Two protocols were performed, a hyperinsulinaemic-euglycaemic clamp and a normoinsulinaemic-normoglycaemic protocol, in awake control and insulin-resistant fructose-fed rats. The tracer was injected at steady state, and activity in 11 tissues and the blood was assessed ex vivo at several time points. A multicompartmental mathematical model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the organs. Insulin sensitivity of fructose-fed rats, estimated by the glucose infusion rate, was reduced by 40% compared with control rats. At steady state, 6DIG uptake was significantly stimulated by insulin in insulin-sensitive tissues of control rats (basal versus insulin: diaphragm, p < 0.01; muscle, p<0.05; heart, p<0.001), whereas insulin did not stimulate 6DIG uptake in insulin-resistant fructose-fed rats. Moreover, in these tissues, the fractional transfer coefficients of entrance were significantly increased with insulin in control rats (basal vs insulin: diaphragm, p<0.001; muscle, p<0.001; heart, p<0.01) whereas no significant changes were observed in fructose-fed rats. This study sets the stage for the future use of 6DIG as a non-invasive means for the evaluation of insulin resistance by nuclear imaging.

Assessment of insulin resistance in fructose-fed rats with 125I-6-deoxy-6-iodo-D-glucose, a new tracer of glucose transport

PubMed Central

Perret, Pascale; Slimani, Lotfi; Briat, Arnaud; Villemain, Danièle; Halimi, Serge; Demongeot, Jacques; Fagret, Daniel; Ghezzi, Catherine

2007-01-01

Purpose Insulin resistance, characterised by an insulin-stimulated glucose transport defect, is an important feature of the pre-diabetic state and it has been observed in numerous pathological disorders. The purpose of this study was to assess variations in glucose transport in rats with 125I-6-Deoxy-6-Iodo-D-glucose (6DIG), a new tracer of glucose transport proposed as an imaging tool to assess insulin resistance in vivo. Methods Two protocols were performed, a hyperinsulinaemic-euglycaemic clamp and a normoinsulinaemic normoglycaemic protocol, in awake control and insulin-resistant fructose-fed rats. The tracer was injected at steady state, and activity in 11 tissues and the blood were assessed ex vivo at several time points. A multicompartmental mathematical model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the organs. Results Insulin sensitivity of fructose-fed rats, estimated by the glucose infusion rate, was reduced by 40% compared with control rats. At steady-state, 6DIG uptake was significantly stimulated by insulin in insulin-sensitive tissues of control rats (basal versus insulin: diaphragm, p<0.01; muscle, p<0.05; heart, p<0.001), whereas insulin did not stimulate 6DIG uptake in insulin-resistant fructose-fed rats. Moreover, in these tissues, the fractional transfer coefficients of entrance were significantly increased with insulin in control rats (basal vs insulin: diaphragm, p<0.001; muscle, p<0.001; heart, p<0.01) and whereas no significant changes were observed in fructose-fed rats. Conclusion This study sets the stage for the future use of 6DIG as a non-invasive means for the evaluation of insulin resistance by nuclear imaging. PMID:17171359

Physiological and subjective effects of acute intranasal methamphetamine during extended-release alprazolam maintenance

PubMed Central

Lile, Joshua A.; Stoops, William W.; Glaser, Paul E.A.; Hays, Lon R.; Rush, Craig R.

2015-01-01

Background Medications development for methamphetamine dependence is ongoing, but no widely accepted, effective pharmacotherapy has been identified. Previous studies have demonstrated neurobiological perturbations to central GABAA activity following chronic stimulant use, and that positive modulation of GABAA receptors attenuates the neurochemical and behavioral response to stimulant drugs such as methamphetamine. Therefore, GABAA modulators could be useful as pharmacotherapies for stimulant-use disorders. Methods This study tested the hypothesis that intranasal methamphetamine would be safe and well tolerated during maintenance on extended-release alprazolam (XR), and that the effects of methamphetamine would be attenuated. Eight non-treatment-seeking, stimulant-dependent individuals completed an inpatient experiment in which ascending doses of intranasal methamphetamine (0, 5, 10, 20 and 30 mg) were administered after four days of alprazolam XR maintenance (0 and 1 mg/day). Results Intranasal methamphetamine produced prototypical effects (e.g., increased positive subjective ratings and elevated cardiovascular signs). The combination of intranasal methamphetamine and alprazolam XR was safe and well tolerated. Alprazolam XR produced small, but orderly, reductions in some of the subjective effects of methamphetamine, and performance impairment. Conclusions The present results demonstrate that methamphetamine use during alprazolam XR treatment would not pose a significant safety risk. Given the potential of GABAA positive modulators to manage certain aspects of stimulant abuse and dependence (i.e., drug-induced seizures, anxiety and stress), but the relatively small impact on the acute abuse-related effects of methamphetamine observed here, additional research with GABAA positive modulators is warranted, but should consider their use as an adjunct component of combination behavioral and/or drug treatment. PMID:21737214

The Reinforcing and Subjective Effects of Intravenous and Intranasal Buprenorphine in Heroin Users

PubMed Central

Jones, Jermaine D.; Madera, Gabriela; Comer, Sandra D.

2014-01-01

Abuse of buprenorphine (BUP) by the intravenous (IV) route has been documented in several studies, and reports of intranasal (IN) abuse are increasing. However, no studies have directly compared the effects of BUP when it is administered intranasally and intravenously. The present secondary analysis used data from two separate studies to compare the reinforcing and subjective effects of IV and IN buprenorphine. One study evaluated IV buprenorphine (N=13) and the other evaluated IN buprenorphine (N=12). Participants were maintained on 2 mg sublingual (SL) BUP and tested with each intranasal or intravenous buprenorphine test dose (0 mg, 2 mg, 4 mg, 8 mg, and 16 mg). During morning laboratory sessions, participants received money (US $20) and sample doses of IN or IV BUP, and then completed subjective effects questionnaires. Later that day, they completed a self-administration task to receive 10% portions of the drug and/or money they previously sampled. In general, positive subjective ratings for both IV and IN BUP were significantly greater than placebo, with IV BUP having a greater effect than IN BUP. All active BUP doses (IV and IN) maintained significantly higher progressive ratio breakpoint values than placebo, but breakpoint values for IV BUP were greater than for IN BUP. Buprenorphine is an effective maintenance treatment for opioid dependence, valued for its ability to reduce the positive subjective effects of other opioids. Nevertheless, the present data demonstrate that in participants maintained on a low dose of SL BUP, the medication itself has abuse liability when used intravenously or intranasally. PMID:24793093

Brain insulin signalling, glucose metabolism and females' reproductive aging: A dangerous triad in Alzheimer's disease.

PubMed

Duarte, A I; Santos, M S; Oliveira, C R; Moreira, P I

2018-02-20

Alzheimer's disease (AD) constitutes a major socioeconomic challenge due to its disabling features and the rise in prevalence (especially among (peri)menopausal women and type 2 diabetes patients). The precise etiopathogenesis of AD remains poorly understood. Importantly, its neurodegenerative perspective has been challenged towards a more "systemic" view. Amyloid-β (Aβ) and hyperphosphorylated Tau protein (P-Tau) (the main AD neuropathological features) affect and are affected by peripheral and brain insulin signalling dysfunction, leading to glucose dysmetabolism, synaptic loss and AD-related cognitive deficits. This may be anticipated and exacerbated by the progressive loss of estrogen (and interactions, e.g., with insulin) during females' aging, increasing their risk for AD, especially during menopause. Under this perspective, we aimed to discuss the recent findings (and controversies) behind the peripheral view of AD, and the role for insulin deficits and brain glucose dysmetabolism in such diseased brain. We also focused on the metabolic shift and the putative effects of gender (especially during midlife/perimenopause) herein. We finally discussed AD as the potential "type 3 diabetes", and the therapeutic potential of restoring brain insulin levels or glucose energy metabolism via administration of intranasal insulin and use of ketogenic diets. In sum, AD appears to lie on an intricate crosstalk between age-related metabolic, hormonal and specific genetic changes that challenge its traditional view. Hence, clarification of AD risk factors (besides aging and gender) and pathophysiological mechanisms will allow to establish accurate preventive strategies, biomarkers and more efficient drugs - all urgent medical needs in our increasingly aged societies. Copyright © 2018 Elsevier Ltd. All rights reserved.

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

PubMed

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. Copyright © 2015 John Wiley & Sons, Inc.

Abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered crushed oxycodone HCl abuse-deterrent controlled-release tablets in recreational opioid users

PubMed Central

Harris, Stephen C; Perrino, Peter J; Smith, Ira; Shram, Megan J; Colucci, Salvatore V; Bartlett, Cynthia; Sellers, Edward M

2014-01-01

The objective of this study was to evaluate abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered, crushed reformulated OxyContin® (oxycodone HCl controlled-release) tablets (ORF), relative to crushed original OxyContin® (OC), oxycodone powder (Oxy API), and OC placebo. This randomized, double-blind, positive- and placebo-controlled crossover study enrolled healthy, adult, nonphysically dependent recreational opioid users with recent history of intranasal drug abuse (N = 27). Active treatments contained oxycodone (30 mg). Pharmacokinetics, pharmacodynamics (e.g., Overall Drug Liking [ODL], Take Drug Again [TDA], and High Visual Analog Scales [VAS]; Subjective Drug Value [SDV]; pupillometry; intranasal irritation), and safety (e.g., adverse events, vital signs, laboratory tests) were assessed to 24 hours postdose. Crushed ORF administration yielded reduced oxycodone Cmax and increased Tmax versus crushed OC and Oxy API. Peak effects for pharmacodynamic measures were delayed with ORF (1–2 hours) versus OC and Oxy API (0.5–1 hour). ODL, TDA, High VAS, and SDV Emax values were significantly lower (P ≤ .05) and some intranasal irritation ratings were greater for ORF versus OC and Oxy API. No significant or unexpected safety findings were observed. Compared with OC and Oxy API, intranasally administered ORF was associated with lower and delayed peak plasma concentrations, decreased drug-liking, and decreased intranasal tolerability. This suggests that ORF has a decreased potential for intranasal oxycodone abuse. There were no significant or unexpected safety findings. As is true for all abuse potential studies, epidemiological or other appropriate post-marketing studies are required to assess the impact of the reduction in intranasal oxycodone abuse potential observed in the present study on real-world patterns of ORF misuse, abuse, and diversion. PMID:24243216

Intranasal hemangiosarcoma in a dog.

PubMed

Fujita, Michio; Takaishi, Yumi; Yasuda, Daiji; Hasegawa, Daisuke; Taniguchi, Akiko; Takahashi, Kimimasa; Orima, Hiromitsu

2008-05-01

Magnetic resonance (MR) was conducted for an 8-year-old, intact male Spitz with sneezing, serous discharge and epistaxis from the left nasal cavity. MR imaging showed a nasal cavity-occupied mass of iso-intensity on T1WI , high-intensity on T2WI and markedly enhanced on contrast-enhanced T1WI at parts of rostal to medial ocular angle in the left cavity. After Surgery and intraoperative radiation, the mass was diagnosed intranasal hemangiosarcoma by histopathology. Although the dog showed the finding, which suggested recurrence after the treatment ending, about 30 months later, it maintained good conditions without evidence of metastasis.

Early Experience with Combining Awake Craniotomy and Intraoperative Navigable Ultrasound for Resection of Eloquent Region Gliomas.

PubMed

Moiyadi, Aliasgar; Shetty, Prakash

2017-03-01

Introduction  Optimal resection of tumors in eloquent locations requires a combination of intraoperative imaging and functional monitoring during surgery. Combining awake surgery with intraoperative magnetic resonanceis logistically challenging. Navigable ultrasound (US) is a useful alternative in such cases. Methods  A total of 22 subjects with eloquent tumors were operated on (1 intended biopsy and 21 intended radical resections) using combined modality three-dimensional (3D) US and awake craniotomy with intraoperative clinical monitoring. We describe the technical details for these cases specifically addressing the feasibility of combining the two modalities. Results  US was used for resection control in 18 cases. There were technical limitations in three cases. Transient intraoperative worsening was encountered in eight, necessitating premature termination of the procedure. All patients tolerated the awake procedure well. Mean duration of the surgery was 3.2 hours. Radical resections were obtained in 14 of 18 where this was intended and in 12 of the 13 where there was no adverse intraoperative monitoring event prompting premature termination of the resection. Conclusions  Combining awake surgery with 3DUS is feasible and beneficial. It does not entail any additional surgical workflow modification or patient discomfort. This combined modality intraoperative monitoring can be beneficial for eloquent region tumors. Georg Thieme Verlag KG Stuttgart · New York.

Intraoperative Subcortical Electrical Mapping of the Optic Tract in Awake Surgery Using a Virtual Reality Headset.

PubMed

Mazerand, Edouard; Le Renard, Marc; Hue, Sophie; Lemée, Jean-Michel; Klinger, Evelyne; Menei, Philippe

2017-01-01

Brain mapping during awake craniotomy is a well-known technique to preserve neurological functions, especially the language. It is still challenging to map the optic radiations due to the difficulty to test the visual field intraoperatively. To assess the visual field during awake craniotomy, we developed the Functions' Explorer based on a virtual reality headset (FEX-VRH). The impaired visual field of 10 patients was tested with automated perimetry (the gold standard examination) and the FEX-VRH. The proof-of-concept test was done during the surgery performed on a patient who was blind in his right eye and presenting with a left parietotemporal glioblastoma. The FEX-VRH was used intraoperatively, simultaneously with direct subcortical electrostimulation, allowing identification and preservation of the optic radiations. The FEX-VRH detected 9 of the 10 visual field defects found by automated perimetry. The patient who underwent an awake craniotomy with intraoperative mapping of the optic tract using the FEX-VRH had no permanent postoperative visual field defect. Intraoperative visual field assessment with the FEX-VRH during direct subcortical electrostimulation is a promising approach to mapping the optical radiations and preventing a permanent visual field defect during awake surgery for epilepsy or tumor. Copyright © 2016 Elsevier Inc. All rights reserved.

Is a wake-up call in order? Review of the evidence for awake craniotomy.

PubMed

Paldor, Iddo; Drummond, Katharine J; Awad, Mohammed; Sufaro, Yuval Z; Kaye, Andrew H

2016-01-01

Awake craniotomy (AC) has been used in increasing frequency in the past few decades. It has mainly been used for resection of intrinsic tumors, but also, rarely, for other pathologies. The vast majority of reports specific to one pathology, however, have focused on resection of low grade glioma in the awake setting. Tumors in eloquent areas have mainly been resected when the patient is awake for the purpose of preservation of function. Motor function is the most documented, and most successfully preserved function. Other functions are harder to localize with direct electrical stimulation (DES), and thus more difficult to preserve. The success rate of DES localization correlates to the rate of function preservation. The effect of AC on extent of resection is inconsistent in the literature. Other functions, such as sensory and visuospatial recognition, have been protected during AC, but this is best performed in large, referral centers that have experience with the procedure. Other benefits to AC, such as cost-effectiveness and reduction in patient pain and anxiety, have also been reported. Copyright © 2015 Elsevier Ltd. All rights reserved.

Intranasally administered mesenchymal stem cells promote a regenerative niche for repair of neonatal ischemic brain injury.

PubMed

Donega, Vanessa; Nijboer, Cora H; van Tilborg, Geralda; Dijkhuizen, Rick M; Kavelaars, Annemieke; Heijnen, Cobi J

2014-11-01

Previous work from our group has shown that intranasal MSC-treatment decreases lesion volume and improves motor and cognitive behavior after hypoxic-ischemic (HI) brain damage in neonatal mice. Our aim was to determine the kinetics of MSC migration after intranasal administration, and the early effects of MSCs on neurogenic processes and gliosis at the lesion site. HI brain injury was induced in 9-day-old mice and MSCs were administered intranasally at 10days post-HI. The kinetics of MSC migration were investigated by immunofluorescence and MRI analysis. BDNF and NGF gene expression was determined by qPCR analysis following MSC co-culture with HI brain extract. Nestin, Doublecortin, NeuN, GFAP, Iba-1 and M1/M2 phenotypic expression was assessed over time. MRI and immunohistochemistry analyses showed that MSCs reach the lesion site already within 2h after intranasal administration. At 12h after administration the number of MSCs at the lesion site peaks and decreases significantly at 72h. The number of DCX(+) cells increased 1 to 3days after MSC administration in the SVZ. At the lesion, GFAP(+)/nestin(+) and DCX(+) expression increased 3 to 5days after MSC-treatment. The number of NeuN(+) cells increased within 5days, leading to a dramatic regeneration of the somatosensory cortex and hippocampus at 18days after intranasal MSC administration. Interestingly, MSCs expressed significantly more BDNF gene when exposed to HI brain extract in vitro. Furthermore, MSC-treatment resulted in the resolution of the glial scar surrounding the lesion, represented by a decrease in reactive astrocytes and microglia and polarization of microglia towards the M2 phenotype. In view of the current lack of therapeutic strategies, we propose that intranasal MSC administration is a powerful therapeutic option through its functional repair of the lesion represented by regeneration of the cortical and hippocampal structure and decrease of gliosis. Copyright © 2014. Published by Elsevier Inc.

Anesthetic management with scalp nerve block and propofol/remifentanil infusion during awake craniotomy in an adolescent patient -A case report-

PubMed Central

Sung, Bohyun; Park, Jin-Woo; Byon, Hyo-Jin; Kim, Jin-Tae; Kim, Chong Sung

2010-01-01

Despite of various neurophysiologic monitoring methods under general anesthesia, functional mapping at awake state during brain surgery is helpful for conservation of speech and motor function. But, awake craniotomy in children or adolescents is worrisome considering their emotional friabilities. We present our experience on anesthetic management for awake craniotomy in an adolescent patient. The patient was 16 years old male who would undergo awake craniotomy for removal of brain tumor. Scalp nerve block was done with local anesthetics and we infused propofol and remifentanil with target controlled infusion. The patient endured well and was cooperative before scalp suture, but when surgeon sutured scalp, he complained of pain and was suddenly agitated. We decided change to general anesthesia. Neurosurgeon did full neurologic examinations and there was no neurologic deficit except facial palsy of right side. Facial palsy had improved with time. PMID:21286435

Awake craniotomy may further improve neurological outcome of intraoperative MRI-guided brain tumor surgery.

PubMed

Tuominen, Juho; Yrjänä, Sanna; Ukkonen, Anssi; Koivukangas, John

2013-10-01

Results of awake craniotomy are compared to results of resections done under general anesthesia in patients operated with IMRI control. We hypothesized that stimulation of the cortex and white matter during awake surgery supplements IMRI control allowing for safer resection of eloquent brain area tumors. The study group consisted of 20 consecutive patients undergoing awake craniotomy with IMRI control. Resection outcome of these patients was compared to a control group of 20 patients operated in the same IMRI suite but under general anesthesia without cortical stimulation. The control group was composed of those patients whose age, sex, tumor location, recurrence and histology best matched to patients in study group. Cortical stimulation identified functional cortex in eight patients (40 %). Postoperatively the neurological condition in 16 patients (80 %) in the study group was unchanged or improved compared with 13 patients (65 %) in the control group. In both groups, three patients (15 %) had transient impairment symptoms. There was one patient (5 %) with permanent neurological impairment in the study group compared to four patients (20 %) in the control group. These differences between groups were not statistically significant. There was no surgical mortality in either group and the overall infection rate was 5 %. Mean operation time was 4 h 45 min in the study group and 3 h 15 min in the control group. The study consisted of a limited patient series, but it implies that awake craniotomy with bipolar cortical stimulation may help to reduce the risk of postoperative impairment following resection of tumors located in or near speech and motor areas also under IMRI control.

Reliability and sensitivity of the TonoLab rebound tonometer in awake Brown Norway rats.

PubMed

Morrison, John C; Jia, Lijun; Cepurna, William; Guo, Ying; Johnson, Elaine

2009-06-01

To compare the sensitivity of the TonoLab rebound tonometer with the Tono-Pen in awake Brown Norway rats and to compare their ability to predict optic nerve damage induced by experimental IOP elevation. TonoLab and Tono-Pen tonometers were calibrated in cannulated rat eyes connected to a pressure transducer. The TonoLab was used in awake animals housed in standard lighting to measure IOP during light and dark phases. Both instruments were used to monitor chronically elevated IOP produced by episcleral vein injection of hypertonic saline. Measured IOPs were correlated with quantified optic nerve damage in injected eyes. Although they were lower than transducer and Tono-Pen measurements at all levels, TonoLab readings showed an excellent linear fit with transducer readings from 20 to 80 mm Hg (R(2) = 0.99) in cannulated eyes. In awake animals housed in standard lighting, the TonoLab documented significantly higher pressures during the dark phase (27.9 +/- 1.7 mm Hg) than during the light phase (16.7 +/- 2.3 mm Hg). With elevated IOP, correlation between TonoLab and Tono-Pen readings (R(2) = 0.86, P < 0.0001) was similar to that in cannulated eyes. Although both instruments provided measurements that correlated well with optic nerve injury grade, only the Tono-Pen documented significant IOP elevation in eyes with the least amount of injury (P < 0.05). The TonoLab is sensitive enough to be used in awake Brown Norway rats, though instrument fluctuation may limit its ability to identify significant pressure elevations in eyes with minimal optic nerve damage.

Short-term weight loss attenuates local tissue inflammation and improves insulin sensitivity without affecting adipose inflammation in obese mice.

PubMed

Jung, Dae Young; Ko, Hwi Jin; Lichtman, Eben I; Lee, Eunjung; Lawton, Elizabeth; Ong, Helena; Yu, Kristine; Azuma, Yoshihiro; Friedline, Randall H; Lee, Ki Won; Kim, Jason K

2013-05-01

Obesity is a major cause of insulin resistance, and weight loss is shown to improve glucose homeostasis. But the underlying mechanism and the role of inflammation remain unclear. Male C57BL/6 mice were fed a high-fat diet (HFD) for 12 wk. After HFD, weight loss was induced by changing to a low-fat diet (LFD) or exercise with continuous HFD. The weight loss effects on energy balance and insulin sensitivity were determined using metabolic cages and hyperinsulinemic euglycemic clamps in awake mice. Diet and exercise intervention for 3 wk caused a modest weight loss and improved glucose homeostasis. Weight loss dramatically reduced local inflammation in skeletal muscle, liver, and heart but not in adipose tissue. Exercise-mediated weight loss increased muscle glucose metabolism without affecting Akt phosphorylation or lipid levels. LFD-mediated weight loss reduced lipid levels and improved insulin sensitivity selectively in liver. Both weight loss interventions improved cardiac glucose metabolism. These results demonstrate that a short-term weight loss with exercise or diet intervention attenuates obesity-induced local inflammation and selectively improves insulin sensitivity in skeletal muscle and liver. Our findings suggest that local factors, not adipose tissue inflammation, are involved in the beneficial effects of weight loss on glucose homeostasis.

Taking the alternative route: Women's experience of intranasal fentanyl, subcutaneous fentanyl or intramuscular pethidine for labour analgesia.

PubMed

Fleet, Julie-Anne; Jones, Meril; Belan, Ingrid

2017-10-01

To compare women's experience of receiving either intranasal fentanyl, subcutaneous fentanyl or intramuscular pethidine for labour analgesia. A content analysis was undertaken as part of the third phase of a larger randomised controlled trial, using the per-protocol dataset to examine women's experiences of treatment received. Healthy women birthing at term, who received intranasal fentanyl (n=41), subcutaneous fentanyl (n=37) and/or intramuscular pethidine (n=38) for labour analgesia, were contacted at 6 weeks postpartum to complete a phone questionnaire. A tertiary and regional maternity unit in South Australia. Over 80% of women who received intranasal or subcutaneous fentanyl reported that they would use the treatment again compared to 44.8% of women who had received pethidine (self-administered intranasal fentanyl provided more expressive responses emphasising the route provided a strong sense of control and enablement. Route of administration influenced the women's experience, more women who self-administered intranasal fentanyl reported positive emotional responses, with women reporting increased autonomy and satisfaction. Whereas, women who relied on the midwife to administer subcutaneous fentanyl or intramuscular pethidine, were more often focused on the physical effect of the drug. Pethidine was the least preferred option due to adverse effects. For women requesting parenteral analgesia, fentanyl administered by less invasive routes offers women additional options that may better meet their emotional, cognitive and physical needs than the current practice of administering intramuscular pethidine. Copyright © 2017 Elsevier Ltd. All rights reserved.

Formulation and In-vivo Pharmacokinetic Consideration of Intranasal Microemulsion and Mucoadhesive Microemulsion of Rivastigmine for Brain Targeting.

PubMed

Shah, Brijesh; Khunt, Dignesh; Misra, Manju; Padh, Harish

2018-01-02

Presence of tight junctions in blood brain barrier (BBB) pose a major hurdle for delivery of drug and severely affects adequate therapeutic concentration to reach the brain. In present work, we have selected Rivastigmine hydrogen tartrate (RHT), a reversible cholinesterase inhibitor, which exhibits extensive first-pass metabolism, resulting in limited absolute bioavailability (36%). RHT shows extremely low aqueous solubility and poor penetration, resulting in inadequate concentration reaching the brain, thus necessitating frequent oral dosing. To overcome these problems of RHT, microemulsion (ME) and mucoadhesive microemulsion (MME) of RHT were formulated for brain targeting via intranasal delivery route and compared on the basis of in vivo pharmacokinetics. ME and MME formulations containing RHT were developed by water titration method. Characterization of ME and MME was done for various physicochemical parameters, nasal spray pattern, and in vivo pharmacokinetics quantitatively and qualitatively (gamma scintigraphy studies). The developed ME and MME were transparent having globule size approximately in the range of 53-55 nm. Pharmacokinetic studies showed higher values for C max and DTP for intranasal RHT: CH-ME over RHT-ME, thus indicating the effect of chitosan in modulating tight junctions, thereby enhanced paracellular transport of RHT. Gamma scintigraphy and in vivo pharmacokinetic study suggested enhanced RHT concentration, upon intranasal administration of RHT:CH-ME, compare with other groups administered formulations intranasally. These findings suggested the potential of non-invasive intranasal route for brain delivery, especially for therapeutics, facing challenges in oral administration.

Pulmonary permeability assessed by fluorescent-labeled dextran instilled intranasally into mice with LPS-induced acute lung injury.

PubMed

Chen, Honglei; Wu, Shaoping; Lu, Rong; Zhang, Yong-guo; Zheng, Yuanyuan; Sun, Jun

2014-01-01

Several different methods have been used to assess pulmonary permeability in response to acute lung injury (ALI). However, these methods often involve complicated procedures and algorithms that are difficult to precisely control. The purpose of the current study is to establish a feasible method to evaluate alterations in lung permeability by instilling fluorescently labeled dextran (FITC-Dextran) intranasally. For the mouse model of direct ALI, lipopolysaccharide (LPS) was administered intranasally. FITC-Dextran was instilled intranasally one hour before the mice were euthanized. Plasma fluorescence intensities from the LPS group were significantly higher than in the control group. To determine the reliability and reproducibility of the procedure, we also measured the lung wet-to-dry weight ratio, the protein concentration of the bronchoalveolar lavage fluid, tight and adherens junction markers and pathological changes. Consistent results were observed when the LPS group was compared with the control group. Simultaneously, we found that the concentration of plasma FITC-Dextran was LPS dose-dependent. The concentration of plasma FITC-Dextran also increased with initial intranasal FITC-Dextran doses. Furthermore, increased fluorescence intensity of plasma FITC-Dextran was found in the intraperitoneally LPS-induced ALI model. In conclusion, the measurement of FITC-Dextran in plasma after intranasal instillation is a simple, reliable, and reproducible method to evaluate lung permeability alterations in vivo. The concentration of FITC-Dextran in the plasma may be useful as a potential peripheral biomarker of ALI in experimental clinical studies.

Intranasal haloperidol-loaded miniemulsions for brain targeting: Evaluation of locomotor suppression and in-vivo biodistribution.

PubMed

El-Setouhy, Doaa Ahmed; Ibrahim, A B; Amin, Maha M; Khowessah, Omneya M; Elzanfaly, Eman S

2016-09-20

Haloperidol is a commonly prescribed antipsychotic drug currently administered as oral and injectable preparations. This study aimed to prepare haloperidol intranasal miniemulsion helpful for psychiatric emergencies and exhibiting lower systemic exposure and side effects associated with non-target site delivery. Haloperidol miniemulsions were successfully prepared by spontaneous emulsification adopting 2(3) factorial design. The effect of three independent variables at two levels each namely; oil type (Capmul®-Capryol™90), lipophilic emulsifier type (Span 20-Span 80) and HLB value (12-14) on globule size, PDI and percent locomotor activity inhibition in mice was evaluated. The optimized formula (F4, Capmul®, Tween 80/Span 20, HLB 14) showed globule size of 209.5±0.98nm, PDI of 0.402±0.03 and locomotor inhibition of 83.89±9.15% with desirability of 0.907. Biodistribution study following intranasal and intravenous administration of the radiolabeled (99m)Tc mucoadhesive F4 revealed that intranasal administration achieved 1.72-fold higher and 6 times faster peak brain levels compared with intravenous administration. Drug targeting efficiency percent and brain/blood exposure ratios remained above 100% and 1 respectively after intranasal instillation compared to a maximum brain/blood exposure ratio of 0.8 post intravenous route. Results suggested the CNS delivery of major fraction of haloperidol via direct transnasal to brain pathway that can be a promising alternative to oral and parenteral routes in chronic and acute situations. Haloperidol concentration of 275.6ng/g brain 8h post intranasal instillation, higher than therapeutic concentration range of haloperidol (0.8 to 5.15ng/ml), suggests possible sustained delivery of the drug through nasal route. Copyright © 2016 Elsevier B.V. All rights reserved.

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

PubMed Central

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

2015-01-01

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

Sumatriptan (intranasal route of administration) for acute migraine attacks in adults

PubMed Central

Derry, Christopher J; Derry, Sheena; Moore, R Andrew

2014-01-01

Background Migraine is a highly disabling condition for the individual and also has wide-reaching implications for society, healthcare services, and the economy. Sumatriptan is an abortive medication for migraine attacks, belonging to the triptan family. Intranasal administration may be preferable to oral for individuals experiencing nausea and/or vomiting, although it is primarily absorbed in the gut, not the nasal mucosa. Objectives To determine the efficacy and tolerability of intranasal sumatriptan compared to placebo and other active interventions in the treatment of acute migraine attacks in adults. Search methods We searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, online databases, and reference lists for studies through 13 October 2011. Selection criteria We included randomised, double-blind, placebo- and/or active-controlled studies using intranasal sumatriptan to treat a migraine headache episode, with at least 10 participants per treatment arm. Data collection and analysis Two review authors independently assessed trial quality and extracted data. We used numbers of participants achieving each outcome to calculate relative risk (or ‘risk ratio’) and numbers needed to treat to benefit (NNT) or harm (NNH) compared to placebo or a different active treatment. Main results Twelve studies (4755 participants) compared intranasal sumatriptan with placebo or an active comparator. Most of the data were for the 10 mg and 20 mg doses. Sumatriptan surpassed placebo for all efficacy outcomes. For sumatriptan 10 mg versus placebo the NNTs were 7.3, 7.4, and 5.5 for pain-free at two hours, and headache relief at one and two hours, respectively. For sumatriptan 20 mg versus placebo the NNTs were 4.7, 4.9, and 3.5, respectively, for the same outcomes. The 20 mg dose was significantly better than the 10 mg dose for each of these three primary efficacy outcomes. Relief of headache-associated symptoms, including nausea, photophobia, and

Pitfalls of Intranasal Naloxone

PubMed Central

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

2016-01-01

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

Surgical benefits of combined awake craniotomy and intraoperative magnetic resonance imaging for gliomas associated with eloquent areas.

PubMed

Motomura, Kazuya; Natsume, Atsushi; Iijima, Kentaro; Kuramitsu, Shunichiro; Fujii, Masazumi; Yamamoto, Takashi; Maesawa, Satoshi; Sugiura, Junko; Wakabayashi, Toshihiko

2017-10-01

OBJECTIVE Maximum extent of resection (EOR) for lower-grade and high-grade gliomas can increase survival rates of patients. However, these infiltrative gliomas are often observed near or within eloquent regions of the brain. Awake surgery is of known benefit for the treatment of gliomas associated with eloquent regions in that brain function can be preserved. On the other hand, intraoperative MRI (iMRI) has been successfully used to maximize the resection of tumors, which can detect small amounts of residual tumors. Therefore, the authors assessed the value of combining awake craniotomy and iMRI for the resection of brain tumors in eloquent areas of the brain. METHODS The authors retrospectively reviewed the records of 33 consecutive patients with glial tumors in the eloquent brain areas who underwent awake surgery using iMRI. Volumetric analysis of MRI studies was performed. The pre-, intra-, and postoperative tumor volumes were measured in all cases using MRI studies obtained before, during, and after tumor resection. RESULTS Intraoperative MRI was performed to check for the presence of residual tumor during awake surgery in a total of 25 patients. Initial iMRI confirmed no further tumor resection in 9 patients (36%) because all observable tumors had already been removed. In contrast, intraoperative confirmation of residual tumor during awake surgery led to further tumor resection in 16 cases (64%) and eventually an EOR of more than 90% in 8 of 16 cases (50%). Furthermore, EOR benefiting from iMRI by more than 15% was found in 7 of 16 cases (43.8%). Interestingly, the increase in EOR as a result of iMRI for tumors associated mainly with the insular lobe was significantly greater, at 15.1%, than it was for the other tumors, which was 8.0% (p = 0.001). CONCLUSIONS This study revealed that combining awake surgery with iMRI was associated with a favorable surgical outcome for intrinsic brain tumors associated with eloquent areas. In particular, these benefits were

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

NASA Astrophysics Data System (ADS)

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

2011-12-01

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

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

PubMed

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

2014-02-01

Evidence suggests that intranasal oxytocin enhances the perception of emotion in facial expressions during standard emotion identification tasks. However, it is not clear whether this effect is desirable in people who do not show deficits in emotion perception. That is, a heightened perception of emotion in faces could lead to "oversensitivity" to the emotions of others in nonclinical participants. The goal of this study was to assess the effects of intranasal oxytocin on emotion perception using ecologically valid social and nonsocial visual tasks. Eighty-two participants (42 women) self-administered a 24 IU dose of intranasal oxytocin or a placebo in a double-blind, randomized experiment and then completed the perceiving and understanding emotion components of the Mayer-Salovey-Caruso Emotional Intelligence Test. In this test, emotion identification accuracy is based on agreement with a normative sample. As expected, participants administered intranasal oxytocin rated emotion in facial stimuli as expressing greater emotional intensity than those given a placebo. Consequently, accurate identification of emotion in faces, based on agreement with a normative sample, was impaired in the oxytocin group relative to placebo. No such effect was observed for tests using nonsocial stimuli. The results are consistent with the hypothesis that intranasal oxytocin enhances the salience of social stimuli in the environment, but not nonsocial stimuli. The present findings support a growing literature showing that the effects of intranasal oxytocin on social cognition can be negative under certain circumstances, in this case promoting "oversensitivity" to emotion in faces in healthy people. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Awake intubation creates feelings of being in a vulnerable situation but cared for in safe hands: a qualitative study.

PubMed

Knudsen, Kati; Nilsson, Ulrica; Högman, Marieann; Pöder, Ulrika

2016-08-30

Awake fiberoptic intubation is an alternative procedure for securing the airway and is a recommended option when a difficult airway is expected. The aim of the present study was to describe patient experiences with this procedure. A qualitative, descriptive design was used and patients were recruited from three county hospitals and one university hospital in Sweden. Data was collected by semi-structured interviews with 13 patients who underwent awake fiberoptic intubation. A qualitative content analysis extracted theme, categories, and subcategories. From the patient statements, one main theme emerged, feelings of being in a vulnerable situation but cared for in safe hands, which were described in five categories with 15 subcategories. The categories were: a need for tailored information, distress and fear of the intubation, acceptance and trust of the staff's competence, professional caring and support, and no hesitation about new awake intubation. The patients felt they lacked information about what to expect and relied on the professionals' expertise. Some patients felt overwhelmed by the information they were given and wanted less specific information about the equipment used but more information about how they would be cared for in the operating room. Undergoing awake intubation was an acceptable experience for most patients, whereas others experienced it as being painful and terrifying because they felt they could not breathe or communicate during the procedure itself. Tailored information about what to expect, ensuring eye contact and breathing instruction during the procedure seems to reduce patient distress when undergoing awake fiberoptic intubation. Most of the patients would not hesitate to undergo awake intubation again in the future if needed.

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

PubMed

Mans, Christoph; Guzman, David Sanchez-Migallon; Lahner, Lesanna L; Paul-Murphy, Joanne; Sladky, Kurt K

2012-09-01

Administration of intranasal midazolam (2 mg/kg) was evaluated for sedation and effects on cloacal temperature, respiratory rate, and heart rate in manually restrained Hispaniolan Amazon parrots (Amazona ventralis). Adult parrots (n=9) were administered either midazolam (2 mg/kg) or an equal volume of saline solution intranasally before a 15-minute manual restraint in a complete crossover study. Respiratory rate and sedation scores were recorded before and during capture and during and after 15 minutes of manual restraint. Heart rate and cloacal temperature were recorded during manual restraint. After restraint, the parrots received intranasal flumazenil (0.05 mg/kg) or an equal volume of saline solution, and the recovery time was recorded. In those birds that received midazolam, sedation was observed within 3 minutes of administration, and vocalization, flight, and defense responses were significantly reduced during capture. During manual restraint, the mean rate of cloacal temperature increase was significantly slower and remained significantly lower in birds that received midazolam compared with controls. Mean respiratory rates were significantly lower for up to 12 minutes in parrots that received midazolam compared with those receiving saline solution. Flumazenil antagonized the effects of midazolam within 10 minutes. No overt clinical adverse effects to intranasal midazolam and flumazenil administration were observed. Further studies on the safety of intranasal midazolam and flumazenil in this species are warranted.

Effects of Intranasal Oxytocin on the Interpretation and Expression of Emotions in Anorexia Nervosa.

PubMed

Leppanen, J; Cardi, V; Ng, K W; Paloyelis, Y; Stein, D; Tchanturia, K; Treasure, J

2017-03-01

Altered social-emotional functioning is considered to play an important role in the development and maintenance of anorexia nervosa (AN). Recently, there has been increasing interest in investigating the role of intranasal oxytocin in social-emotional processing. The present study aimed to investigate the effects of intranasal oxytocin on the interpretation and expression of emotions among people with AN. Thirty women with AN and 29 age-matched healthy women took part in the present study, which used a double-blind, placebo-controlled, cross-over design. The participants received a single dose of 40 IU of intranasal oxytocin in one session and a placebo spray in the other. Fifteen minutes after administration, the participants completed the Reading the Mind in the Eyes Test to assess the interpretation of complex emotions and mental states followed by a video task, which assessed expressions of facial affect when they were viewing humorous and sad film clips. The intranasal oxytocin did not significantly influence the expression or interpretation of emotions in the AN or healthy comparison groups. The AN group expressed significantly less positive emotion, spent more time looking away and reported experiencing a significantly more negative affect in response to the film clips. The finding that intranasal oxytocin had little to no effect on the interpretation or expression of emotions in either group supports the notion that the effects of oxytocin on social-emotional processing are not straightforward and may depend on individual and environmental differences, as well as the emotion being processed. Replication of these findings is necessary to explore the effect of timing on the effects of oxytocin before firm conclusions can be drawn. Nonetheless, these findings add to the steady accumulation of evidence that people with AN have reduced emotional expression and avoidance of emotionally provoking stimuli. © 2017 The Authors. Journal of Neuroendocrinology

Effect of terfenadine on nasal, eustachian tube, and pulmonary function after provocative intranasal histamine challenge.

PubMed

Skoner, D P; Doyle, W J; Boehm, S; Fireman, P

1991-12-01

Previous studies have documented that intranasal histamine challenge results in nasal and eustachian tube obstruction (ETO) in human volunteers. The purpose of the present study was to assess the effect of pretreatment with terfenadine, a nonsedating antihistamine on the pathophysiologic consequences of intranasal histamine challenge. Fifteen subjects with allergic rhinitis were challenged intranasally with saline and increasing histamine doses (0.01, 0.1, 0.5, 1.0, 5.0, and 10.0 mg) before pretreatment (baseline) and after 1 week of pretreatment with terfenadine, 60 mg b.i.d., terfenadine, 120 mg b.i.d., and placebo. Nasal conductance as measured by posterior rhinomanometry showed a dose-dependent, monotonic decrease following sequential administration of the histamine solutions, but there were no apparent differences in the average responses among the four challenge sessions. The frequency of ETO after histamine challenge was decreased by pretreatment with both doses of terfenadine, although this was not significant. Histamine-induced sneezing and rhinorrhea, but not congestion, were significantly reduced by terfenadine pretreatment. There was no evidence of extension of the histamine effects to the lower airway. The results of the present study suggest that terfenadine, a nonsedating antihistamine, had a favorable effect on sneezing and rhinorrhea after provocative intranasal histamine challenge, but did not significantly attenuate the subjective or objective nasal and ET obstructive responses.

Cross-sectional study of anxiety symptoms and self-report of awake and sleep bruxism in female TMD patients.

PubMed

Tavares, Luisa Maria Faria; da Silva Parente Macedo, Leonora Cristina; Duarte, Cristina Maria Rabelais; de Goffredo Filho, Gilberto Senechal; de Souza Tesch, Ricardo

2016-11-01

The aim of this study was to assess the relationship between levels of anxiety symptoms and prevalence of self-report of awake and sleep bruxism in patients with temporomandibular disorders (TMD). One hundred and eighty-one female patients, aged 19-77 years, were consecutively evaluated. The patients were selected from among those who sought treatment at the TMD and Orofacial Pain Outpatient Clinic of the Petrópolis School of Medicine. All patients completed the questionnaire and underwent clinical examination, both components of the RDC/TMD, in addition to answering questions pertaining to the assessment of levels of anxiety symptoms, taken from the Symptom Check List 90 self-report instrument. The subjects were classified according to the presence of self-reported only awake bruxism, only sleep bruxism, both, or none. A logistic regression procedure was performed to evaluate the possible association through odds ratio between anxiety symptoms and self-reported awake or sleep bruxism. The cofactors for each outcome were age, self-reported bruxism during the circadian period other than the one being evaluated, and the use of selective serotonin reuptake inhibitors. It was possible to demonstrate the presence of a positive and statistically significant relationship between anxiety levels and self-reported awake bruxism. This finding was not observed in those subjects who reported sleep bruxism. A positive relationship was found between self-reported awake bruxism and levels of anxiety symptoms, but not between sleep bruxism and anxiety.

A Randomized, Controlled Trial of Intranasal Oxytocin as an Adjunct to Behavioral Therapy for Autism Spectrum Disorder

DTIC Science & Technology

2013-10-01

Intranasal Oxytocin as an Adjunct to Behavioral Therapy for Autism Spectrum Disorder PRINCIPAL INVESTIGATOR: John Gabrieli...SUBTITLE A Randomized, Controlled Trial of Intranasal Oxytocin as an Adjunct to Behavioral Therapy for Autism Spectrum Disorder 5a. CONTRACT NUMBER...dysfunctions and (2) oxytocin (OT) administration prior to CBT sessions will each enhance social function in young adults with autism spectrum disorders

Physiological and subjective effects of acute intranasal methamphetamine during extended-release alprazolam maintenance.

PubMed

Lile, Joshua A; Stoops, William W; Glaser, Paul E A; Hays, Lon R; Rush, Craig R

2011-12-15

Medications development for methamphetamine dependence is ongoing, but no widely accepted, effective pharmacotherapy has been identified. Previous studies have demonstrated neurobiological perturbations to central GABA(A) activity following chronic stimulant use, and that positive modulation of GABA(A) receptors attenuates the neurochemical and behavioral response to stimulant drugs such as methamphetamine. Therefore, GABA(A) modulators could be useful as pharmacotherapies for stimulant-use disorders. This study tested the hypothesis that intranasal methamphetamine would be safe and well tolerated during maintenance on extended-release alprazolam (XR), and that the effects of methamphetamine would be attenuated. Eight non-treatment-seeking, stimulant-dependent individuals completed an inpatient experiment in which ascending doses of intranasal methamphetamine (0, 5, 10, 20 and 30 mg) were administered after four days of alprazolam XR maintenance (0 and 1mg/day). Intranasal methamphetamine produced prototypical effects (e.g., increased positive subjective ratings and elevated cardiovascular signs). The combination of intranasal methamphetamine and alprazolam XR was safe and well tolerated. Alprazolam XR produced small, but orderly, reductions in some of the subjective effects of methamphetamine, and performance impairment. The present results demonstrate that methamphetamine use during alprazolam XR treatment would not pose a significant safety risk. Given the potential of GABA(A) positive modulators to manage certain aspects of stimulant abuse and dependence (i.e., drug-induced seizures, anxiety and stress), but the relatively small impact on the acute abuse-related effects of methamphetamine observed here, additional research with GABA(A) positive modulators is warranted, but should consider their use as an adjunct component of combination behavioral and/or drug treatment. Copyright © 2011. Published by Elsevier Ireland Ltd.

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

PubMed

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

2015-01-01

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

Meta-analysis of the effects of intranasal oxytocin on interpretation and expression of emotions.

PubMed

Leppanen, Jenni; Ng, Kah Wee; Tchanturia, Kate; Treasure, Janet

2017-07-01

Accurate interpretation and appropriate expression of emotions are key aspects of social-cognition. Several mental disorders are characterised by transdiagnostic difficulties in these areas and, recently, there has been increasing interest in exploring the effects of oxytocin on social-emotional functioning. This review consists of 33 studies. Fifteen of the studies included people with autism spectrum disorder, schizophrenia, borderline personality disorder, frontotemporal dementia, anorexia nervosa, bulimia nervosa, post-traumatic stress disorder, depression, and opioid and alcohol dependence. We conducted ten meta-analyses examining the effects of intranasal oxytocin on expression of emotions, emotional theory of mind, sensitivity to recognise basic emotions, and recognition of basic emotions. A single dose of intranasal oxytocin significantly improved the recognition of basic emotions, particularly fear, and increased the expression of positive emotions among the healthy individuals. Oxytocin did not significantly influence theory of mind or the expression of negative emotions among the healthy individuals. Finally, intranasal oxytocin did not significantly influence interpretation or expression of emotions among the clinical populations. Copyright © 2017. Published by Elsevier Ltd.

Effect of Intranasal Oxytocin Administration on Psychiatric Symptoms: A Meta-Analysis of Placebo-Controlled Studies

PubMed Central

Hofmann, Stefan G.; Fang, Angela; Brager, Daniel N.

2015-01-01

Clinical trials of intranasal administration of oxytocin for treating psychiatric problems have yielded mixed results. To conduct a quantitative review of placebo-controlled clinical trials of intranasally-administered oxytocin (OT) for psychiatric symptoms, manual and electronic searches using PubMed and PsycINFO were conducted. Of 1,828 entries, 16 placebo-controlled studies totaling 330 participants were included in the analysis. The overall placebo-controlled effect size was moderately strong (Hedges’ g = 0.67) and robust as suggested by the fail-safe N and funnel plot analysis. OT reduced symptoms of depression, anxiety, autism/repetitive behaviors, psychotic symptoms, and general psychopathology. In the combined sample, symptom reduction was moderated by frequency of administration. Publication year and diagnostic category did not moderate the effect of OT on the clinical outcome measures. We conclude that intranasal administration of OT is a potentially useful intervention for reducing psychiatric symptoms. However, more studies are needed to determine the best treatment target and to identify the mechanism of treatment change. PMID:26094200

Intraoperative linguistic performance during awake brain surgery predicts postoperative linguistic deficits.

PubMed

Chang, Wei-Han; Pei, Yu-Cheng; Wei, Kuo-Chen; Chao, Yi-Ping; Chen, Mei-Hui; Yeh, Heng-An; Jaw, Fu-Shan; Chen, Pin-Yuan

2018-04-10

Awake craniotomy pursues a balance between extensive tumor resection and preservation of postoperative language function. A dilemma exists in patients whose tumor resection is restricted due to signs of language impairment observed during awake craniotomy. In order to determine the degree to which recovery of language function caused by tumor resection can be achieved by spontaneous neuroplasticity, the change in postoperative language function was compared to quantified intraoperative linguistic performance. The modified, short-form Boston Diagnostic Aphasia Examination (sfBDAE) was used to assess pre- and postoperative language functions; visual object naming (DO 80) and semantic-association (Pyramid and Palm Tree Test, PPTT) tests assessed intraoperative linguistic performance. DO 80 and PPTT were performed alternatively during subcortical functional monitoring while performing tumor resection and sfBDAE was assessed 1-week postoperatively. Most patients with observed language impairment during awake surgery showed improved language function postoperatively. Both intraoperative DO 80 and PPTT showed significant correlation to postoperative sfBDAE domain scores (p < 0.05), with a higher correlation observed with PPTT. A linear regression model showed that only PPTT predicted the postoperative sfBDAE domain scores with the adjusted R 2 ranging from 0.51 to 0.89 (all p < 0.01). Receiver operating characteristic analysis showed a cutoff value of PPTT that yielded a sensitivity of 80% and specificity of 100%. PPTT may be a feasible tool for intraoperative linguistic evaluation that can predict postoperative language outcomes. Further studies are needed to determine the extent of tumor resection that optimizes the postoperative language following neuroplasticity.

Intranasal immunization with a non-adjuvanted adhesive protein descended from Pasteurella pneumotropica and its preventive efficacy against opportunistic infection in mice.

PubMed

Sasaki, Hiraku; Ishikawa, Hiroki; Kojima, Ken; Itoh, Masahiro; Matsumoto, Tetsuya; Itoh, Takumi; Hosomi, Osamu; Kawamoto, Eiichi

2013-11-19

Intranasal vaccination is one of the most effective means of protecting against invading and colonizing pathogens because the vaccine elicits a mucosal immune response. The exploitation of vaccine adjuvants and delivery systems for intranasal vaccines is an important way to evoke antigen immunogenicity and elicit a better immune response at the mucosal sites. In the present study, we assessed the potential of intranasal immunization using a non-adjuvanted bacterial adhesive protein toward the host organs. We evaluated intranasal immunization with modified recombinant PnxIIIA (MP3) from Pasteurella pneumotropica and its preventive efficacy against opportunistic infection caused by P. pneumotropica, without using any adjuvants or delivery systems. The 100-kDa MP3 was confirmed to retain its immunogenicity and binding activity to collagen type I similar to the parent PnxIIIA. When MP3 was fused to green-fluorescent protein and inoculated into C57BL/6J mice intranasally, fluorescence intensity in the intranasal airway could be observed until 3 h after inoculation. Mice were intranasally immunized with MP3 at a maximum of 4 doses, with 7-day intervals. The antibody titer of serum IgG and IgA specific for MP3, as well as that of bronchoalveolar lavage fluid IgA, showed more than 9 (log₂) after 3 or 4 rounds of immunization. Experimentally infecting immunized mice with P. pneumotropica resulted in the inability to isolate the bacterium from the nasal cavity, trachea, conjunctiva, or cecum with more than 3 doses in the immunized mice. Although the detection in each organ seldom changed with less than 2 rounds of immunization, unlike that observed in the non-immunized mice, the detection remarkably decreased with 3 or more rounds of immunization. These results suggest that intranasal immunization with a non-adjuvanted adhesive protein could have preventive effects against opportunistic infection by P. pneumotropica. Copyright © 2013 Elsevier Ltd. All rights reserved.

Increased brain radioactivity by intranasal 32P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels

PubMed Central

Perez, Ana Paula; Mundiña-Weilenmann, Cecilia; Romero, Eder Lilia; Morilla, Maria Jose

2012-01-01

Background Molecules taken up by olfactory and trigeminal nerve neurons directly access the brain by the nose-to-brain pathway. In situ-forming mucoadhesive gels would increase the residence time of intranasal material, favoring the nose-to-brain delivery. In this first approach, brain radioactivity after intranasal administration of 32P-small interference RNA (siRNA) complexed with poly(amidoamine) G7 dendrimers (siRNA dendriplexes) within in situ-forming mucoadhesive gels, was determined. Materials 32P-siRNA dendriplexes were incorporated into in situ-forming mucoadhesive gels prepared by blending thermosensitive poloxamer (23% w/w) with mucoadhesive chitosan (1% w/w, PxChi) or carbopol (0.25% w/w, PxBCP). Rheological properties, radiolabel release profile, and local toxicity in rat nasal mucosa were determined. The best-suited formulation was intranasally administered to rats, and blood absorption and brain distribution of radioactivity were measured. Results The gelation temperature of both formulations was 23°C. The PxChi liquid showed non-Newtonian pseudoplastic behavior of high consistency and difficult manipulation, and the gel retained 100% of radiolabel after 150 minutes. The PxCBP liquid showed a Newtonian behavior of low viscosity and easy manipulation, while in the gel phase showed apparent viscosity similar to that of the mucus but higher than that of aqueous solution. The gel released 35% of radiolabel and the released material showed silencing activity in vitro. Three intranasal doses of dendriplexes in PxCBP gel did not damage the rat nasal mucosa. A combination of 32P-siRNA complexation with dendrimers, incorporation of the dendriplexes into PxCBP gel, and administration of two intranasal doses was necessary to achieve higher brain radioactivity than that achieved by intravenous dendriplexes or intranasal naked siRNA. Conclusion The increased radioactivity within the olfactory bulb suggested that the combination above mentioned favored the

Comparison of Two Different Intranasal Doses of Dexmedetomidine in Children for Magnetic Resonance Imaging Sedation.

PubMed

Tug, Aslihan; Hanci, Ayse; Turk, Hacer Sebnem; Aybey, Ferda; Isil, Canan Tulay; Sayin, Pinar; Oba, Sibel

2015-12-01

Anaesthetic agents used for magnetic resonance imaging (MRI) in paediatric patients should cause few adverse effects and allow fast anaesthetic induction and recovery. The administration route is also important and should be minimally invasive. In this study, we aimed to compare two different doses of intranasal dexmedetomidine applied to children for MRI sedation. Sixty patients between 1 and 10 years of age with American Society of Anesthesiologists Physical Status classification I or II who were scheduled for MRI were recruited into this prospective, randomized, double-blind study. Intranasal dexmedetomidine was administered at doses of 3 µg kg(-1) (Group 1) and 4 µg kg(-1) (Group 2) before imaging. Heart rate (HR), peripheral oxygen saturation, respiratory rate and Ramsay Sedation Scale (RSS) scores were recorded before the anaesthetic induction of sedation and every 10 min until discharge. If intranasal sedation failed, an intravenous cannula was placed and propofol was applied as a rescue anaesthetic. Bispectral Index (BIS) scores were also recorded before and after MRI. We recorded onset time of sedation, mood at separation from parents (defined as parental separation score), imaging quality, MRI duration, rescue anaesthetic requirement, total duration of sedation, recovery duration, parents' satisfaction and adverse effects. The results related to age, weight and adverse effects were not statistically different between the groups. The parental separation score was significantly higher in Group 2 (P = 0.003). Rescue anaesthetic requirement was significantly higher in Group 1 (P = 0.002). The results related to recovery duration, MRI duration, parents' satisfaction, onset time of sedation and total duration of sedation were not statistically different. HR was significantly lower in all time intervals compared with basal values in both groups. In Group 2, RSS scores were significantly higher in the 30th, 40th and 50th min. The BIS scores in Group 2 were

Computed Intranasal Spray Penetration: Comparisons Before and After Nasal Surgery

PubMed Central

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

2012-01-01

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

Visually Evoked 3-5 Hz Membrane Potential Oscillations Reduce the Responsiveness of Visual Cortex Neurons in Awake Behaving Mice.

PubMed

Einstein, Michael C; Polack, Pierre-Olivier; Tran, Duy T; Golshani, Peyman

2017-05-17

Low-frequency membrane potential ( V m ) oscillations were once thought to only occur in sleeping and anesthetized states. Recently, low-frequency V m oscillations have been described in inactive awake animals, but it is unclear whether they shape sensory processing in neurons and whether they occur during active awake behavioral states. To answer these questions, we performed two-photon guided whole-cell V m recordings from primary visual cortex layer 2/3 excitatory and inhibitory neurons in awake mice during passive visual stimulation and performance of visual and auditory discrimination tasks. We recorded stereotyped 3-5 Hz V m oscillations where the V m baseline hyperpolarized as the V m underwent high amplitude rhythmic fluctuations lasting 1-2 s in duration. When 3-5 Hz V m oscillations coincided with visual cues, excitatory neuron responses to preferred cues were significantly reduced. Despite this disruption to sensory processing, visual cues were critical for evoking 3-5 Hz V m oscillations when animals performed discrimination tasks and passively viewed drifting grating stimuli. Using pupillometry and animal locomotive speed as indicators of arousal, we found that 3-5 Hz oscillations were not restricted to unaroused states and that they occurred equally in aroused and unaroused states. Therefore, low-frequency V m oscillations play a role in shaping sensory processing in visual cortical neurons, even during active wakefulness and decision making. SIGNIFICANCE STATEMENT A neuron's membrane potential ( V m ) strongly shapes how information is processed in sensory cortices of awake animals. Yet, very little is known about how low-frequency V m oscillations influence sensory processing and whether they occur in aroused awake animals. By performing two-photon guided whole-cell recordings from layer 2/3 excitatory and inhibitory neurons in the visual cortex of awake behaving animals, we found visually evoked stereotyped 3-5 Hz V m oscillations that disrupt

Therapeutic effect of intranasal evaporative cooling in patients with migraine: a pilot study.

PubMed

Vanderpol, Jitka; Bishop, Barbara; Matharu, Manjit; Glencorse, Mark

2015-01-26

Cryotherapy is the most common non-pharmacological pain-relieving method. The aim of this pilot study was to ascertain whether intranasal evaporative cooling may be an effective intervention in an acute migraine attack. Studies have previously demonstrated effectiveness of a variety of cryotherapy approaches. Intranasal evaporative cooling due to vascular anatomy, allows the transfer of venous blood from nasal and paranasal mucous membranes to the dura mater, thereby providing an excellent anatomical basis for the cooling processes. We conducted a prospective, open-label, observational, pilot study. Twenty-eight patients who satisfied the International Classification of Headache Disorders (ICHD 2) diagnostic criteria for migraine were recruited. A total of 20 treatments were administered in 15 patients. All patients provided pain severity scores and migraine-associated symptoms severity scores (based on a 0-10 visual analogue scale, [VAS]). Out of the 20 treatments, intranasal evaporative cooling rendered patients' pain and symptoms free immediately after treatment, in 8 of the treatments (40%), a further 10 treatments (50%) resulted in partial pain relief (headache reduced from severe or moderate to mild) and partial symptoms relief. At 2 hours, 9 treatments (45%) provided full pain and symptoms relief, with a further 9 treatments (45%) resulting in partial pain and symptoms relief. At 24 hours, 10 treatments (50%) resulted in patients reporting pain and symptom freedom and 3 (15%) provided partial pain relief. In summary 13 patients (87%) had benefit from the treatment within 2 hours that was sustained at 24 hours. Intranasal evaporative cooling gave considerable benefit to patients with migraine, improving headache severity and migraine-associated symptoms. A further randomised, placebo controlled, double blinded, parallel clinical trial is required to further investigate the potential of this application. Clinicaltrials.gov registered trial, Clinical

Intranasal oxytocin, but not vasopressin, augments neural responses to toddlers in human fathers.

PubMed

Li, Ting; Chen, Xu; Mascaro, Jennifer; Haroon, Ebrahim; Rilling, James K

2017-07-01

This study investigates paternal brain function with the hope of better understanding the neural basis for variation in caregiving involvement among men. The neuropeptides oxytocin (OT) and vasopressin (AVP) are implicated in paternal caregiving in humans and other species. In a double-blind, placebo-controlled, within-subject pharmaco-functional MRI experiment, we randomized 30 fathers of 1-2year old children to receive either 24IU intranasal OT before one scan and placebo before the other scan (n=15) or 20IU intranasal AVP before one scan and placebo before the other scan (n=15). Brain function was measured with fMRI as the fathers viewed pictures of their children, unknown children and unknown adults, and as they listened to unknown infant cry stimuli. Intranasal OT, but not AVP, significantly increased the BOLD fMRI response to viewing pictures of own children within the caudate nucleus, a target of midbrain dopamine projections, as well as the dorsal anterior cingulate (dACC) and visual cortex, suggesting that intranasal oxytocin augments activation in brain regions involved in reward, empathy and attention in human fathers. OT effects also varied as a function of order of administration such that when OT was given before placebo, it increased activation within several reward-related structures (substantia nigra, ventral tegmental area, putamen) more than when it was given after placebo. Neither OT nor AVP had significant main effects on the neural response to cries. Our findings suggest that the hormonal changes associated with the transition to fatherhood are likely to facilitate increased approach motivation and empathy for children, and call for future research that evaluates the potential of OT to normalize deficits in paternal motivation, as might be found among men suffering from post-partum depression. Copyright © 2017 Elsevier Inc. All rights reserved.

Brain State Effects on Layer 4 of the Awake Visual Cortex

PubMed Central

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

2014-01-01

Awake mammals can switch between alert and nonalert brain states hundreds of times per day. Here, we study the effects of alertness on two cell classes in layer 4 of primary visual cortex of awake rabbits: presumptive excitatory “simple” cells and presumptive fast-spike inhibitory neurons (suspected inhibitory interneurons). We show that in both cell classes, alertness increases the strength and greatly enhances the reliability of visual responses. In simple cells, alertness also increases the temporal frequency bandwidth, but preserves contrast sensitivity, orientation tuning, and selectivity for direction and spatial frequency. Finally, alertness selectively suppresses the simple cell responses to high-contrast stimuli and stimuli moving orthogonal to the preferred direction, effectively enhancing mid-contrast borders. Using a population coding model, we show that these effects of alertness in simple cells—enhanced reliability, higher gain, and increased suppression in orthogonal orientation—could play a major role at increasing the speed of cortical feature detection. PMID:24623767

Intranasal administration of testosterone increased immobile-sniffing, exploratory behavior, motor behavior and grooming behavior in rats.

PubMed

Zhang, Guoliang; Shi, Geming; Tan, Huibing; Kang, Yunxiao; Cui, Huixian

2011-04-01

Currently, testosterone (T) replacement therapy is typically provided by oral medication, injectable T esters, surgically implanted T pellets, transdermal patches and gels. However, most of these methods of administration are still not ideal for targeting the central nervous system. Recently, therapeutic intranasal T administration (InT) has been considered as another option for delivering T to the brain. In the present study, the effects of 21-day InT treatment were assessed on open field behavior in gonadectomized (GDX) rats and intact rats. Subcutaneous injections of T at same dose were also tested in GDX rats. A total of 12 behavioral events were examined in GDX groups with or without T and in intact groups with or without InT. Significant decreases in open field activity were observed in rats after GDX without InT compared to sham-operated rats. The open field activity scores for most tests significantly increased with InT treatment in GDX rats and in intact rats compared with the corresponding GDX rats and intact rats. Intranasal administration of T improved the reduced behaviors resulted from T deficiency better than subcutaneous injection of T, demonstrating that T can be delivered to the brain by intranasal administration. Our results suggest that intranasal T delivery is an effective option for targeting the central nervous system. Copyright © 2011 Elsevier Inc. All rights reserved.

Intranasal post-cardiac arrest treatment with orexin-A facilitates arousal from coma and ameliorates neuroinflammation.

PubMed

Modi, Hiren R; Wang, Qihong; Gd, Sahithi; Sherman, David; Greenwald, Elliot; Savonenko, Alena V; Geocadin, Romergryko G; Thakor, Nitish V

2017-01-01

Cardiac arrest (CA) entails significant risks of coma resulting in poor neurological and behavioral outcomes after resuscitation. Significant subsequent morbidity and mortality in post-CA patients are largely due to the cerebral and cardiac dysfunction that accompanies prolonged whole-body ischemia post-CA syndrome (PCAS). PCAS results in strong inflammatory responses including neuroinflammation response leading to poor outcome. Currently, there are no proven neuroprotective therapies to improve post-CA outcomes apart from therapeutic hypothermia. Furthermore, there are no acceptable approaches to promote cortical or cognitive arousal following successful return of spontaneous circulation (ROSC). Hypothalamic orexinergic pathway is responsible for arousal and it is negatively affected by neuroinflammation. However, whether activation of the orexinergic pathway can curtail neuroinflammation is unknown. We hypothesize that targeting the orexinergic pathway via intranasal orexin-A (ORXA) treatment will enhance arousal from coma and decrease the production of proinflammatory cytokines resulting in improved functional outcome after resuscitation. We used a highly validated CA rat model to determine the effects of intranasal ORXA treatment 30-minute post resuscitation. At 4hrs post-CA, the mRNA levels of proinflammatory markers (IL1β, iNOS, TNF-α, GFAP, CD11b) and orexin receptors (ORX1R and ORX2R) were examined in different brain regions. CA dramatically increased proinflammatory markers in all brain regions particularly in the prefrontal cortex, hippocampus and hypothalamus. Post-CA intranasal ORXA treatment significantly ameliorated the CA-induced neuroinflammatory markers in the hypothalamus. ORXA administration increased production of orexin receptors (ORX1R and ORX2R) particularly in hypothalamus. In addition, ORXA also resulted in early arousal as measured by quantitative electroencephalogram (EEG) markers, and recovery of the associated behavioral neurologic

Intranasal oxytocin increases neural responses to social reward in post-traumatic stress disorder

PubMed Central

van Zuiden, Mirjam; Koch, Saskia B.J.; Frijling, Jessie L.; Veltman, Dick J.; Olff, Miranda

2017-01-01

Abstract Therapeutic alliance and perceived social support are important predictors of treatment response for post-traumatic stress disorder (PTSD). Intranasal oxytocin administration may enhance treatment response by increasing sensitivity for social reward and thereby therapeutic alliance and perceived social support. As a first step to investigate this therapeutical potential, we investigated whether intranasal oxytocin enhances neural sensitivity to social reward in PTSD patients. Male and female police officers with (n = 35) and without PTSD (n = 37) were included in a double-blind, randomized, placebo-controlled cross-over fMRI study. After intranasal oxytocin (40 IU) and placebo administration, a social incentive delay task was conducted to investigate neural responses during social reward and punishment anticipation and feedback. Under placebo, PTSD patients showed reduced left anterior insula (AI) responses to social rewards (i.e. happy faces) compared with controls. Oxytocin administration increased left AI responses during social reward in PTSD patients, such that PTSD patients no longer differed from controls under placebo. Furthermore, in PTSD patients, oxytocin increased responses to social reward in the right putamen. By normalizing abberant insula responses and increasing putamen responses to social reward, oxytocin administration may enhance sensitivity for social support and therapeutic alliance in PTSD patients. Future studies are needed to investigate clinical effects of oxytocin. PMID:27614769

Awake craniotomy for gliomas in a high-field intraoperative magnetic resonance imaging suite: analysis of 42 cases.

PubMed

Maldaun, Marcos V C; Khawja, Shumaila N; Levine, Nicholas B; Rao, Ganesh; Lang, Frederick F; Weinberg, Jeffrey S; Tummala, Sudhakar; Cowles, Charles E; Ferson, David; Nguyen, Anh-Thuy; Sawaya, Raymond; Suki, Dima; Prabhu, Sujit S

2014-10-01

The object of this study was to describe the experience of combining awake craniotomy techniques with high-field (1.5 T) intraoperative MRI (iMRI) for tumors adjacent to eloquent cortex. From a prospective database the authors obtained and evaluated the records of all patients who had undergone awake craniotomy procedures with cortical and subcortical mapping in the iMRI suite. The integration of these two modalities was assessed with respect to safety, operative times, workflow, extent of resection (EOR), and neurological outcome. Between February 2010 and December 2011, 42 awake craniotomy procedures using iMRI were performed in 41 patients for the removal of intraaxial tumors. There were 31 left-sided and 11 right-sided tumors. In half of the cases (21 [50%] of 42), the patient was kept awake for both motor and speech mapping. The mean duration of surgery overall was 7.3 hours (range 4.0-13.9 hours). The median EOR overall was 90%, and gross-total resection (EOR ≥ 95%) was achieved in 17 cases (40.5%). After viewing the first MR images after initial resection, further resection was performed in 17 cases (40.5%); the mean EOR in these cases increased from 56% to 67% after further resection. No deficits were observed preoperatively in 33 cases (78.5%), and worsening neurological deficits were noted immediately after surgery in 11 cases (26.2%). At 1 month after surgery, however, worsened neurological function was observed in only 1 case (2.3%). There was a learning curve with regard to patient positioning and setup times, although it did not adversely affect patient outcomes. Awake craniotomy can be safely performed in a high-field (1.5 T) iMRI suite to maximize tumor resection in eloquent brain areas with an acceptable morbidity profile at 1 month.

Awake Fibreoptic Intubation for Forearm Injury in a Patient with Occipito-Cervical Fixator

PubMed Central

Akkaya, Akcan; Yıldız, İsa; Demirhan, Abdullah; Tekelioğlu, Ümit Yaşar; Koçoğlu, Hasan

2013-01-01

A 23-year-old male patient with occipitocervical fixator was scheduled for surgery due to injury to the right forearm. The patient’s thyromental distance was 5 cm, mouth opening grade II, sternomental distance 10 cm and Mallampati score 4. Loss of extension and rotation movements of the head was assessed as difficult intubation criteria. Anaesthetic procedures are almost always difficult in patients with occipitocervical fixation; the limited cervical extension complicated both intubation and ventilation. In this report, application of general anaesthesia using awake fibreoptic bronchoscopic intubation (FOB) is described. After routine monitoring of vital signs and premedication, hypopharyngeal topical anaesthesia was accomplished by instilling 10% lidocaine spray twice via the appropriate nostril. Superior laryngeal nerve block was performed with local anaesthetic infiltration of tissues 1 cm below the greater horns of the hyoid bone. Lingual and pharyngeal branches of the glossopharyngeal nerve were blocked. Transtracheal block was performed. Following completion of local anaesthesia, the patient was intubated using the awake FOB technique, on 5 L min−1 of 100% O2. After muscle relaxation, the patient underwent a microsurgical operation to repair eight tendons, one artery, and one nerve. Surgery lasted for 5 hours. When the extubation criteria were met, the patient was extubated. In cases of occipitocervical fixation, which causes severe limitation of neck movements, the use of awake fibreoptic intubation should be considered. PMID:27366367

Is non-awake surgery for supratentorial adult low-grade glioma treatment still feasible?

PubMed

Duffau, Hugues

2018-01-01

In this short review, the author performs a database search, summarizes, and discusses studies that provide information on the need to perform awake surgery to preserve quality of life/return to work of adult patients who undergo resection for a supratentorial low-grade glioma (LGG). Based upon the currently available data, the author concludes that in LGG, patients with no or only mild deficits at diagnosis, non-awake surgery can no longer be achieved. Indeed, awake craniotomy with intrasurgical electrical mapping has resulted in an increase of the extent of resection and overall survival in LGG. Furthermore, in order to resume a normal familial, social, and professional life, LGG patients with a prolonged survival expectancy have to benefit not only from language mapping when the tumor involves the left "dominant" hemisphere, but also from intraoperative mapping of sensorimotor, visuospatial, higher cognitive, and emotional functions under local anesthesia, even for gliomas situated within presumed "non-language" areas such as the right "non-dominant" hemisphere. In other words, the ultimate goal is to map the functional connectome for each patient in order to perform the resection up to the eloquent networks and then to optimize the onco-functional balance of LGG surgery. To this end, an objective neuropsychological assessment has to be achieved in a more systematic manner before and after resection. Early postoperative cognitive rehabilitation is also recommended, whenever needed.

Intranasal budesonide treatment for children with mild obstructive sleep apnea syndrome.

PubMed

Kheirandish-Gozal, Leila; Gozal, David

2008-07-01

Intranasal corticosteroids have been advanced as a nonsurgical therapeutic alternative for pediatric obstructive sleep apnea syndrome, particularly for patients with mild disease, and aims at reducing the size of hypertrophic adenotonsillar tissue. Of 71 possible candidates, 62 children with polysomnographically diagnosed mild obstructive sleep apnea syndrome were recruited onto a double-blind, randomized, crossover trial of intranasal budesonide (32 microg per nostril at bedtime) or placebo for 6 weeks followed by an additional 6-week treatment in the alternative treatment arm after allowing for a 2-week washout period. Polysomnographic assessment and radiographs for assessment of adenoid size were performed after completion of each phase. There were significant improvements in both polysomnographic measures (sleep latency, slow-wave sleep, and rapid-eye-movement sleep), in the magnitude of respiratory disturbance (apnea/hypopnea index, nadir pulse oxygen saturation), and in adenoid size among the 48 children who completed the treatment phase compared with 32 children who received placebo in their initial arm, with normalization of sleep measures in 54.1% of the treated children. Furthermore, discontinuation of treatment for 8 weeks for 25 children revealed a sustained duration of the initial treatment effect. A 6-week treatment with intranasal budesonide effectively reduced the severity of mild obstructive sleep apnea syndrome and the magnitude of the underlying adenoidal hypertrophy, and this effect persisted for at least 8 weeks after cessation of therapy. These findings justify the use of topical steroids as the initial therapeutic option in otherwise healthy children with mild obstructive sleep apnea.

Impact of preoperative functional magnetic resonance imaging during awake craniotomy procedures for intraoperative guidance and complication avoidance.

PubMed

Trinh, Victoria T; Fahim, Daniel K; Maldaun, Marcos V C; Shah, Komal; McCutcheon, Ian E; Rao, Ganesh; Lang, Frederick; Weinberg, Jeffrey; Sawaya, Raymond; Suki, Dima; Prabhu, Sujit S

2014-01-01

We wanted to study the role of functional MRI (fMRI) in preventing neurological injury in awake craniotomy patients as this has not been previously studied. To examine the role of fMRI as an intraoperative adjunct during awake craniotomy procedures. Preoperative fMRI was carried out routinely in 214 patients undergoing awake craniotomy with direct cortical stimulation (DCS). In 40% of our cases (n = 85) fMRI was utilized for the intraoperative localization of the eloquent cortex. In the other 129 cases significant noise distortion, poor task performance and nonspecific BOLD activation precluded the surgeon from using the fMRI data. Compared with DCS, fMRI had a sensitivity and specificity, respectively, of 91 and 64% in Broca's area, 93 and 18% in Wernicke's area and 100 and 100% in motor areas. A new intraoperative neurological deficit during subcortical dissection was predictive of a worsened deficit following surgery (p < 0.001). The use of fMRI for intraoperative localization was, however, not significant in preventing worsened neurological deficits, both in the immediate postoperative period (p = 1.00) and at the 3-month follow-up (p = 0.42). The routine use of fMRI was not useful in identifying language sites as performed and, more importantly, practiced tasks failed to prevent neurological deficits following awake craniotomy procedures. © 2014 S. Karger AG, Basel.

Oral-Fluid Thiol-Detection Test Identifies Underlying Active Periodontal Disease Not Detected by the Visual Awake Examination.

PubMed

Queck, Katherine E; Chapman, Angela; Herzog, Leslie J; Shell-Martin, Tamara; Burgess-Cassler, Anthony; McClure, George David

Periodontal disease in dogs is highly prevalent but can only be accurately diagnosed by performing an anesthetized oral examination with periodontal probing and dental radiography. In this study, 114 dogs had a visual awake examination of the oral cavity and were administered an oral-fluid thiol-detection test prior to undergoing a a full-mouth anesthetized oral examination and digital dental radiographs. The results show the visual awake examination underestimated the presence and severity of active periodontal disease. The thiol-detection test was superior to the visual awake examination at detecting the presence and severity of active periodontal disease and was an indicator of progression toward alveolar bone loss. The thiol-detection test detected active periodontal disease at early stages of development, before any visual cues were present, indicating the need for intervention to prevent periodontal bone loss. Early detection is important because without intervention, dogs with gingivitis (active periodontal disease) progress to irreversible periodontal bone loss (stage 2+). As suggested in the current AAHA guidelines, a thiol-detection test administered in conjunction with the visual awake examination during routine wellness examinations facilitates veterinarian-client communication and mitigates under-diagnosis of periodontal disease and underutilization of dental services. The thiol-detection test can be used to monitor the periodontal health status of the conscious patient during follow-up examinations based on disease severity.

Intranasal naltrexone and atipamezole for reversal of white-tailed deer immobilized with carfentanil and medetomidine

PubMed Central

Shury, Todd K.; Caulkett, Nigel A.; Woodbury, Murray R.

2010-01-01

Carfentanil and medetomidine were used to immobilize 8 captive female white-tailed deer (Odocoileus virginianus) using mean dosages [± standard deviation (s)] of 14.2 ± 1.11 μg/kg carfentanil and 17.8 ± 2.03 μg/kg of medetomidine. Deer were reversed by intranasally or intramuscularly administered naltrexone and atipamezole. Dosages of carfentanil and medetomidine proved reliable for immobilization of most, but not all deer, with a mean induction time of 13.3 ± 3.13 min. Effective and reliable immobilization will require higher dosages of carfentanil and possibly medetomidine than were used in this study. No significant differences in recovery times were observed for deer given reversal agents intranasally (9.45 ± 5.37 min) versus intramuscularly (7.60 ± 4.42 min). Naltrexone and atipamezole can be administered intranasally at 1.5 mg/kg and 0.1 mg/kg, respectively to safely and quickly reverse the effects of carfentanil and medetomidine in immobilized white-tailed deer. This route could potentially be useful for other reversal agents. PMID:20676292

Right Hemisphere Cognitive Functions: From Clinical and Anatomic Bases to Brain Mapping During Awake Craniotomy Part I: Clinical and Functional Anatomy.

PubMed

Bernard, Florian; Lemée, Jean-Michel; Ter Minassian, Aram; Menei, Philippe

2018-05-12

The nondominant hemisphere (usually the right) is responsible for primary cognitive functions such as visuospatial and social cognition. Awake surgery using direct electric stimulation for right cerebral tumor removal remains challenging because of the complexity of the functional anatomy and difficulties in adapting standard bedside tasks to awake surgery conditions. An understanding of semiology and anatomic bases, along with an analysis of the available cognitive tasks for visuospatial and social cognition per operative mapping allow neurosurgeons to better appreciate the functional anatomy of the right hemisphere and its relevance to tumor surgery. In this article, the first of a 2-part review, we discuss the anatomic and functional basis of right hemisphere function. Whereas part II of the review focuses primarily on semiology and surgical management of right-sided tumors under awake conditions, this article provides a comprehensive review of knowledge underpinning awake surgery on the right hemisphere. Copyright © 2018 Elsevier Inc. All rights reserved.

Sedative effects of midazolam and xylazine with or without ketamine and detomidine alone following intranasal administration in Ring-necked Parakeets.

PubMed

Vesal, Nasser; Eskandari, Mohammad H

2006-02-01

To evaluate the effects of intranasal administration of midazolam and xylazine (with or without ketamine) and detomidine and their specific antagonists in parakeets. Prospective study. 17 healthy adult Ring-necked Parakeets (Psittacula krameri) of both sexes (mean weight, 128.83+/-10.46 g [0.28+/-0.02 lb]). The dose of each drug or ketamine-drug combination administered intranasally that resulted in adequate sedation (ie, unrestrained dorsal recumbency maintained for >or=5 minutes) was determined; the onset of action, duration of dorsal recumbency, and duration of sedation associated with these treatments were evaluated. The efficacy of the reversal agents flumazenil, yohimbine, and atipamezole was also evaluated. In parakeets, intranasal administration of midazolam (7.3 mg/kg [3.32 mg/lb]) or detomidine (12 mg/kg [5.45 mg/lb]) caused adequate sedation within 2.7 and 3.5 minutes, respectively. Combinations of midazolam (3.65 mg/kg [1.66 mg/lb]) and xylazine (10 mg/kg [4.55 mg/lb]) with ketamine (40 to 50 mg/kg [18.2 to 22.7 mg/lb]) also achieved adequate sedation. Compared with detomidine, duration of dorsal recumbency was significantly longer with midazolam. Intranasal administration of flumazenil (0.13 mg/kg [0.06 mg/lb]) significantly decreased midazolam-associated recumbency time. Compared with the xylazineketamine combination, duration of dorsal recumbency was longer after midazolam-ketamine administration. Intranasal administration of flumazenil, yohimbine, or atipamezole significantly decreased the duration of sedation induced by midazolam, xylazine, or detomidine, respectively. Intranasal administration of sedative drugs appears to be an acceptable method of drug delivery in Ring-necked Parakeets. Reversal agents are also effective when administered via this route.

Classifying multiple types of hand motions using electrocorticography during intraoperative awake craniotomy and seizure monitoring processes—case studies

PubMed Central

Xie, Tao; Zhang, Dingguo; Wu, Zehan; Chen, Liang; Zhu, Xiangyang

2015-01-01

In this work, some case studies were conducted to classify 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) participated in the experiments. Subjects performed three types of hand motions (Grasp, Thumb-finger motion and Index-finger motion) contralateral 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 to extract features, and additional waveform length (WL) feature has been considered, finally the linear discriminative analysis (LDA) was used as the classifier. Method II: stationary subspace analysis (SSA) was applied for data preprocessing, and the common spatial pattern (CSP) was used for feature extraction before LDA decoding process. Applying method I, the three-class accuracy of P1~P4 were 90.17, 96.00, 91.77, and 92.95% respectively. For method II, the three-class accuracy of P1~P4 were 72.00, 93.17, 95.22, and 90.36% respectively. This study verified the possibility of decoding multiple hand motion types during an awake craniotomy, which is the first step toward dexterous neuroprosthetic control during surgical implantation, in order to verify the optimal placement of electrodes. The accuracy during awake craniotomy was comparable to results during seizure monitoring. This study also indicated that ECoG was a promising approach for precise identification of eloquent cortex during awake craniotomy, and might form a promising BCI system that could benefit both patients and neurosurgeons. PMID:26483627

Tumor location and IDH1 mutation may predict intraoperative seizures during awake craniotomy.

PubMed

Gonen, Tal; Grossman, Rachel; Sitt, Razi; Nossek, Erez; Yanaki, Raneen; Cagnano, Emanuela; Korn, Akiva; Hayat, Daniel; Ram, Zvi

2014-11-01

Intraoperative seizures during awake craniotomy may interfere with patients' ability to cooperate throughout the procedure, and it may affect their outcome. The authors have assessed the occurrence of intraoperative seizures during awake craniotomy in regard to tumor location and the isocitrate dehydrogenase 1 (IDH1) status of the tumor. Data were collected in 137 consecutive patients who underwent awake craniotomy for removal of a brain tumor. The authors performed a retrospective analysis of the incidence of seizures based on the tumor location and its IDH1 mutation status, and then compared the groups for clinical variables and surgical outcome parameters. Tumor location was strongly associated with the occurrence of intraoperative seizures. Eleven patients (73%) with tumor located in the supplementary motor area (SMA) experienced intraoperative seizures, compared with 17 (13.9%) with tumors in the other three non-SMA brain regions (p < 0.0001). Interestingly, there was no significant association between history of seizures and tumor location (p = 0.44). Most of the patients (63.6%) with tumor in the SMA region harbored an IDH1 mutation compared with those who had tumors in non-SMA regions. Thirty-one of 52 patients (60%) with a preoperative history of seizures had an IDH1 mutation (p = 0.02), and 15 of 22 patients (68.2%) who experienced intraoperative seizures had an IDH1 mutation (p = 0.03). In a multivariate analysis, tumor location was found as a significant predictor of intraoperative seizures (p = 0.002), and a trend toward IDH1 mutation as such a predictor was found as well (p = 0.06). Intraoperative seizures were not associated with worse outcome. Patients with tumors located in the SMA are more prone to develop intraoperative seizures during awake craniotomy compared with patients who have a tumor in non-SMA frontal areas and other brain regions. The IDH1 mutation was more common in SMA region tumors compared with other brain regions, and may be an

Surgical and anesthesiological considerations of awake craniotomy: Cerrahpasa experience.

PubMed

Sanus, Galip Zihni; Yuksel, Odhan; Tunali, Yusuf; Ozkara, Cigdem; Yeni, Naz; Ozlen, Fatma; Tanriverdi, Taner; Ozyurt, Emin; Uzan, Mustafa

2015-01-01

Awake craniotomy (AC) with electrical cortical stimulation has become popular during the last ten years although the basic principles were introduced almost 50 years ago. The aim of this paper is to share with the readers our experience in 25 patients who underwent AC with electrical stimulation. Twenty-five patients who underwent AC between 2010 and 2013 are the subjects of this paper. All patients were diagnosed with intraaxial lesions involving the functional area itself or very close to it by preoperative imaging. During surgery, the functional area was demonstrated by cortical electrical stimulation and resection aimed to preserve it in order to avoid an irreversible functional deficit. Total resection was possible in 80% while in 20% subtotal resection had to be performed because of involvement of the functional area itself. The neurological complication rate was found to be 16% (4 patients) and all were transient. No complication regarding anesthesia was noted. Awake craniotomy in selected patients is very effective, safe and practical for supratentorial lesions close to the eloquent area. Complications related to the surgery itself are uncommon and general anesthesia is avoided. The hospital stay including the intensive care unit is short which makes it very economical surgical procedure.

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

PubMed Central

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

2016-01-01

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

Intranasal dexmedetomidine for sedation for pediatric computed tomography imaging.

PubMed

Mekitarian Filho, Eduardo; Robinson, Fay; de Carvalho, Werther Brunow; Gilio, Alfredo Elias; Mason, Keira P

2015-05-01

This prospective observational pilot study evaluated the aerosolized intranasal route for dexmedetomidine as a safe, effective, and efficient option for infant and pediatric sedation for computed tomography imaging. The mean time to sedation was 13.4 minutes, with excellent image quality, no failed sedations, or significant adverse events. Registered with ClinicalTrials.gov: NCT01900405. Copyright © 2015 Elsevier Inc. All rights reserved.

The effects of intranasal oxytocin on smoothie intake, cortisol and attentional bias in anorexia nervosa.

PubMed

Leppanen, Jenni; Cardi, Valentina; Ng, Kah Wee; Paloyelis, Yannis; Stein, Daniel; Tchanturia, Kate; Treasure, Janet

2017-05-01

Anorexia nervosa (AN) is characterised by severe malnutrition as well as intense fear and anxiety around food and eating with associated anomalies in information processing. Previous studies have found that the neuropeptide, oxytocin, can influence eating behaviour, lower the neurobiological stress response and anxiety among clinical populations, and alter attentional processing of food and eating related images in AN. Thirty adult women with AN and twenty-nine healthy comparison (HC) women took part in the current study. The study used double blind, placebo controlled, crossover design to investigate the effects of a single dose of intranasal oxytocin (40 IU) on a standard laboratory smoothie challenge, and on salivary cortisol, anxiety, and attentional bias towards food images before and after the smoothie challenge in AN and HC participants. Attentional bias was assessed using a visual probe task. Relative to placebo intranasal oxytocin reduced salivary cortisol and altered anomalies in attentional bias towards food images in the AN group only. The oxytocin-induced reduction in attentional avoidance of food images correlated with oxytocin induced reduction in salivary cortisol in the AN group before the smoothie challenge. Intranasal oxytocin did not significantly alter subjective feelings of anxiety or intake during the smoothie challenge in the AN or HC groups. Intranasal oxytocin may moderate the automated information processing biases in AN and reduce neurobiological stress. Further investigation of the effects of repeated administration of oxytocin on these processes as well as on eating behaviour and subjective anxiety would be of interest. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Behavioral Effects of Acclimatization To Restraint Protocol Used for Awake Animal Imaging

PubMed Central

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

2013-01-01

Functional MRI of awake rats involves acclimatization to restraint to minimize motion. We designed a study to examine the effects of an acclimatization protocol (5 days of restraint, 60 minutes per day) on the emission of 22-kHz ultrasonic vocalizations and performance on a forced swim test (FST). Our results show that USV calls are reduced significantly by day 3, 4 and 5 of acclimatization. Although rats show less climbing activity (and more immobility) in FST on day 5 compared to the 1st day of restraint acclimatization, the difference is gone once animals are given a 2 week hiatus. Overall, we show that animals adapt to the restraint over the five day period, however, restraint may introduce confounding behavioral outcomes that may hinder the interpretation of results derived from awake rat imaging. The present data warrant further testing of the effects of MRI restraint on behavior. PMID:23562621

Wide-awake Anesthesia No Tourniquet Trapeziometacarpal Joint Prosthesis Implantation.

PubMed

Müller, Camillo Theo; Christen, Thierry; Heidekruger, Paul I; Lamouille, Jessie; Raffoul, Wassim; McKee, Daniel; Lalonde, Donald H; Durand, Sébastien

2018-04-01

Wide awake local anesthesia no tourniquet (WALANT) hand surgery is a rapidly growing in popularity. WALANT has been used by hand surgeons when operating on bones, tendons, ligaments, nerve entrapments. We offer a case report of the first case in the literature describing WALANT technique when performing trapeziometacarpal joint arthroplasty with prosthesis implantation. We offer technical points on how to perform this procedure and the advantages that are associated with using WALANT for prosthesis arthroplasty.

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

ERIC Educational Resources Information Center

Naber, Fabienne B. A.; Poslawsky, Irina E.; van Ijzendoorn, Marinus H.; van Engeland, Herman; Bakermans-Kranenburg, Marian J.

2013-01-01

Oxytocin seems associated with parenting style, and experimental work showed positive effects of intranasally administered oxytocin on parenting style of fathers. Here, the first double-blind, placebo-controlled, within-subject experiment with intranasal oxytocin administration to fathers of children with autism spectrum disorder (ASD) is…

Effects of intraperitoneal and intranasal application of Lentinan on cellular response in rats.

PubMed

Markova, Nadya; Kussovski, Vesselin; Radoucheva, Tatyana; Dilova, Krasimira; Georgieva, Neli

2002-11-01

Lentinan (Ajinomoto, Japan) was administrated intraperitoneally (i.p.) and intranasally (i.n.) at different doses (1, 5 and 10 mg/kg) to rats. Effectiveness of Lentinan treatment was evaluated by comparative testing of cell activation (establishing the number, glycolytic and acid phosphatase activity, H2O2 production and killing ability against Salmonella enteritidis and Staphylococcus aureus) at two different compartments--peritoneal and broncho-alveolar cavities. The results indicated that Lentinan induced high-grade activation of peritoneal cells (PCs) and especially of broncho-alveolar cells (BACs) with markedly enhanced effector function (killing ability against S. aureus). Generally, Lentinan, known usually with its parenteral routes of application, can be successful to stimulate the host cell response in the respiratory tract by intranasal route of administration.

Comparative analysis of monotherapy versus duotherapy antiseizure drug management for postoperative seizure control in patients undergoing an awake craniotomy.

PubMed

Eseonu, Chikezie I; Eguia, Francisco; Garcia, Oscar; Kaplan, Peter W; Quiñones-Hinojosa, Alfredo

2018-06-01

OBJECTIVE Postoperative seizures are a common complication in patients undergoing an awake craniotomy, given the cortical manipulation during tumor resection and the electrical cortical stimulation for brain mapping. However, little evidence exists about the efficacy of postoperative seizure prophylaxis. This study aims to determine the most appropriate antiseizure drug (ASD) management regimen following an awake craniotomy. METHODS The authors performed a retrospective analysis of data pertaining to patients who underwent an awake craniotomy for brain tumor from 2007 to 2015 performed by a single surgeon. Patients were divided into 2 groups, those who received a single ASD (the monotherapy group) and those who received 2 types of ASDs (the duotherapy group). Patient demographics, symptoms, tumor characteristics, hospitalization details, and seizure outcome were evaluated. Multivariable logistic regression was used to evaluate numerous clinical variables associated with postoperative seizures. RESULTS A total of 81 patients underwent an awake craniotomy for tumor resection of an eloquent brain lesion. Preoperative baseline characteristics were comparable between the 2 groups. The postoperative seizure rate was 21.7% in the monotherapy group and 5.7% in the duotherapy group (p = 0.044). Seizure outcome at 6 months' follow-up was assessed with the Engel classification scale. The duotherapy group had a significantly higher proportion of seizure-free (Engel Class I) patients than the monotherapy group (90% vs 60%, p = 0.027). The length of stay was similar, 4.02 days in the monotherapy group and 4.51 days in the duotherapy group (p = 0.193). The 90-day readmission rate was higher for the monotherapy group (26.1% vs 8.5% in the duotherapy group, p = 0.044). Multivariate logistic regression showed that preoperative seizure history was a significant predictor for postoperative seizures following an awake craniotomy (OR 2.08, 95% CI 0.56-0.90, p < 0.001). CONCLUSIONS

Influence of acute bupropion pre-treatment on the effects of intranasal cocaine.

PubMed

Stoops, William W; Lile, Joshua A; Glaser, Paul E A; Hays, Lon R; Rush, Craig R

2012-06-01

The aim of this experiment was to determine the influence of acute bupropion pre-treatment on subject-rated effects and choice of intranasal cocaine versus money. A randomized, within-subject, placebo-controlled, double-blind experiment. An out-patient research unit. Eight cocaine-using adults. Subjects completed nine experimental sessions in which they were pre-treated with 0, 100 or 200 mg oral immediate release bupropion. Ninety minutes later they sampled an intranasal cocaine dose [4 (placebo), 15 or 45 mg] and made six choices between that dose and an alternative reinforcer (US$0.25), available on independent, concurrent progressive ratio schedules. Subjects also completed a battery of subject-rated, performance and physiological measures following the sample doses of cocaine. After 0 mg bupropion, the high dose of cocaine (45 mg) was chosen five of six times on average compared to 2.25 of six choices for placebo cocaine (4 mg) (P < 0.05). Active bupropion reduced choice of 45 mg cocaine to 3.13 (100 mg) or 4.00 (200 mg) out of six drug choices on average. Bupropion also consistently enhanced positive subject-rated effects of cocaine (e.g. good effects; willing to take again) while having no effects of its own. The atypical antidepressant, bupropion, acutely appears to reduce preference for intranasal cocaine versus a small amount of money but to increase reported positive experiences of the drug. © 2011 The Authors, Addiction © 2011 Society for the Study of Addiction.

Treating respiratory viral diseases with chemically modified, second generation intranasal siRNAs.

PubMed

Barik, Sailen

2009-01-01

Chemically synthesized short interfering RNA (siRNA) of pre-determined sequence has ushered a new era in the application of RNA interference (RNAi) against viral genes. We have paid particular attention to respiratory viruses that wreak heavy morbidity and mortality worldwide. The clinically significant ones include respiratory syncytial virus (RSV), parainfluenza virus (PIV) and influenza virus. As the infection by these viruses is clinically restricted to the respiratory tissues, mainly the lungs, the logical route for the application of the siRNA was also the same, i.e., via the nasal route. Following the initial success of intranasal siRNA against RSV, second-generation siRNAs were made against the viral polymerase large subunit (L) that were chemically modified and screened for improved stability, activity and pharmacokinetics. 2'-O-methyl (2'-O-Me) and 2'-deoxy-2'-fluoro (2'-F) substitutions in the ribose ring were incorporated in different positions of the sense and antisense strands and the resultant siRNAs were tested with various transfection reagents intranasally against RSV. Based on these results, we propose the following consensus for designing intranasal antiviral siRNAs: (i) modified 19-27 nt long double-stranded siRNAs are functional in the lung, (ii) excessive 2'-OMe and 2'-F modifications in either or both strands of these siRNAs reduce efficacy, and (iii) limited modifications in the sense strand are beneficial, although their precise efficacy may be position-dependent.

Cellular Immune Responses to Nine Mycobacterium tuberculosis Vaccine Candidates following Intranasal Vaccination

PubMed Central

Sable, Suraj B.; Cheruvu, Mani; Nandakumar, Subhadra; Sharma, Sunita; Bandyopadhyay, Kakali; Kellar, Kathryn L.; Posey, James E.; Plikaytis, Bonnie B.; Amara, Rama Rao; Shinnick, Thomas M.

2011-01-01

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. PMID:21799939

General anesthesia selectively disrupts astrocyte calcium signaling in the awake mouse cortex

PubMed Central

Thrane, Alexander Stanley; Zeppenfeld, Douglas; Lou, Nanhong; Xu, Qiwu; Nagelhus, Erlend Arnulf; Nedergaard, Maiken

2012-01-01

Calcium signaling represents the principle pathway by which astrocytes respond to neuronal activity. General anesthetics are routinely used in clinical practice to induce a sleep-like state, allowing otherwise painful procedures to be performed. Anesthetic drugs are thought to mainly target neurons in the brain and act by suppressing synaptic activity. However, the direct effect of general anesthesia on astrocyte signaling in awake animals has not previously been addressed. This is a critical issue, because calcium signaling may represent an essential mechanism through which astrocytes can modulate synaptic activity. In our study, we performed calcium imaging in awake head-restrained mice and found that three commonly used anesthetic combinations (ketamine/xylazine, isoflurane, and urethane) markedly suppressed calcium transients in neocortical astrocytes. Additionally, all three anesthetics masked potentially important features of the astrocyte calcium signals, such as synchronized widespread transients that appeared to be associated with arousal in awake animals. Notably, anesthesia affected calcium transients in both processes and soma and depressed spontaneous signals, as well as calcium responses, evoked by whisker stimulation or agonist application. We show that these calcium transients are inositol 1,4,5-triphosphate type 2 receptor (IP3R2)-dependent but resistant to a local blockade of glutamatergic or purinergic signaling. Finally, we found that doses of anesthesia insufficient to affect neuronal responses to whisker stimulation selectively suppressed astrocyte calcium signals. Taken together, these data suggest that general anesthesia may suppress astrocyte calcium signals independently of neuronal activity. We propose that these glial effects may constitute a nonneuronal mechanism for sedative action of anesthetic drugs. PMID:23112168

Intranasal oxytocin increases neural responses to social reward in post-traumatic stress disorder.

PubMed

Nawijn, Laura; van Zuiden, Mirjam; Koch, Saskia B J; Frijling, Jessie L; Veltman, Dick J; Olff, Miranda

2017-02-01

Therapeutic alliance and perceived social support are important predictors of treatment response for post-traumatic stress disorder (PTSD). Intranasal oxytocin administration may enhance treatment response by increasing sensitivity for social reward and thereby therapeutic alliance and perceived social support. As a first step to investigate this therapeutical potential, we investigated whether intranasal oxytocin enhances neural sensitivity to social reward in PTSD patients. Male and female police officers with (n = 35) and without PTSD (n = 37) were included in a double-blind, randomized, placebo-controlled cross-over fMRI study. After intranasal oxytocin (40 IU) and placebo administration, a social incentive delay task was conducted to investigate neural responses during social reward and punishment anticipation and feedback. Under placebo, PTSD patients showed reduced left anterior insula (AI) responses to social rewards (i.e. happy faces) compared with controls. Oxytocin administration increased left AI responses during social reward in PTSD patients, such that PTSD patients no longer differed from controls under placebo. Furthermore, in PTSD patients, oxytocin increased responses to social reward in the right putamen. By normalizing abberant insula responses and increasing putamen responses to social reward, oxytocin administration may enhance sensitivity for social support and therapeutic alliance in PTSD patients. Future studies are needed to investigate clinical effects of oxytocin. © The Author (2016). Published by Oxford University Press.

The neuronal correlates of intranasal trigeminal function – An ALE meta-analysis of human functional brain imaging data

PubMed Central

Albrecht, Jessica; Kopietz, Rainer; Frasnelli, Johannes; Wiesmann, Martin; Hummel, Thomas; Lundström, Johan N.

2009-01-01

Almost every odor we encounter in daily life has the capacity to produce a trigeminal sensation. Surprisingly, few functional imaging studies exploring human neuronal correlates of intranasal trigeminal function exist, and results are to some degree inconsistent. We utilized activation likelihood estimation (ALE), a quantitative voxel-based meta-analysis tool, to analyze functional imaging data (fMRI/PET) following intranasal trigeminal stimulation with carbon dioxide (CO2), a stimulus known to exclusively activate the trigeminal system. Meta-analysis tools are able to identify activations common across studies, thereby enabling activation mapping with higher certainty. Activation foci of nine studies utilizing trigeminal stimulation were included in the meta-analysis. We found significant ALE scores, thus indicating consistent activation across studies, in the brainstem, ventrolateral posterior thalamic nucleus, anterior cingulate cortex, insula, precentral gyrus, as well as in primary and secondary somatosensory cortices – a network known for the processing of intranasal nociceptive stimuli. Significant ALE values were also observed in the piriform cortex, insula, and the orbitofrontal cortex, areas known to process chemosensory stimuli, and in association cortices. Additionally, the trigeminal ALE statistics were directly compared with ALE statistics originating from olfactory stimulation, demonstrating considerable overlap in activation. In conclusion, the results of this meta-analysis map the human neuronal correlates of intranasal trigeminal stimulation with high statistical certainty and demonstrate that the cortical areas recruited during the processing of intranasal CO2 stimuli include those outside traditional trigeminal areas. Moreover, through illustrations of the considerable overlap between brain areas that process trigeminal and olfactory information; these results demonstrate the interconnectivity of flavor processing. PMID:19913573

Ameliorating treatment-refractory depression with intranasal ketamine: potential NMDA receptor actions in the pain circuitry representing mental anguish.

PubMed

Opler, Lewis A; Opler, Mark G A; Arnsten, Amy F T

2016-02-01

This article reviews the antidepressant actions of ketamine, an N-methyl-D-aspartame glutamate receptor (NMDAR) antagonist, and offers a potential neural mechanism for intranasal ketamine's ultra-rapid actions based on the key role of NMDAR in the nonhuman primate prefrontal cortex (PFC). Although intravenous ketamine infusions can lift mood within hours, the current review describes how intranasal ketamine administration can have ultra-rapid antidepressant effects, beginning within minutes (5-40 minutes) and lasting hours, but with repeated treatments needed for sustained antidepressant actions. Research in rodents suggests that increased synaptogenesis in PFC may contribute to the prolonged benefit of ketamine administration, beginning hours after administration. However, these data cannot explain the relief that occurs within minutes of intranasal ketamine delivery. We hypothesize that the ultra-rapid effects of intranasal administration in humans may be due to ketamine blocking the NMDAR circuits that generate the emotional representations of pain (eg, Brodmann Areas 24 and 25, insular cortex), cortical areas that can be overactive in depression and which sit above the nasal epithelium. In contrast, NMDAR blockade in the dorsolateral PFC following systemic administration of ketamine may contribute to cognitive deficits. This novel view may help to explain how intravenous ketamine can treat the symptoms of depression yet worsen the symptoms of schizophrenia.

Intranasal boosting with an adenovirus-vectored vaccine markedly enhances protection by parenteral Mycobacterium bovis BCG immunization against pulmonary tuberculosis.

PubMed

Santosuosso, Michael; McCormick, Sarah; Zhang, Xizhong; Zganiacz, Anna; Xing, Zhou

2006-08-01

Parenterally administered Mycobacterium bovis BCG vaccine confers only limited immune protection from pulmonary tuberculosis in humans. There is a need for developing effective boosting vaccination strategies. We examined a heterologous prime-boost regimen utilizing BCG as a prime vaccine and our recently described adenoviral vector expressing Ag85A (AdAg85A) as a boost vaccine. Since we recently demonstrated that a single intranasal but not intramuscular immunization with AdAg85A was able to induce potent protection from pulmonary Mycobacterium tuberculosis challenge in a mouse model, we compared the protective effects of parenteral and mucosal booster immunizations following subcutaneous BCG priming. Protection by BCG prime immunization was not effectively boosted by subcutaneous BCG or intramuscular AdAg85A. In contrast, protection by BCG priming was remarkably boosted by intranasal AdAg85A. Such enhanced protection by intranasal AdAg85A was correlated to the numbers of gamma interferon-positive CD4 and CD8 T cells residing in the airway lumen of the lung. Our study demonstrates that intranasal administration of AdAg85A represents an effective way to boost immune protection by parenteral BCG vaccination.

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

PubMed

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. Copyright © 2016 Elsevier Inc. All rights reserved.

Fenofibrate Decreases Insulin Clearance and Insulin Secretion to Maintain Insulin Sensitivity*

PubMed Central

Ramakrishnan, Sadeesh K.; Russo, Lucia; Ghanem, Simona S.; Patel, Payal R.; Oyarce, Ana Maria; Heinrich, Garrett; Najjar, Sonia M.

2016-01-01

High fat diet reduces the expression of CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1), a transmembrane glycoprotein that promotes insulin clearance and down-regulates fatty acid synthase activity in the liver upon its phosphorylation by the insulin receptor. Because peroxisome proliferator-activated receptor α (PPARα) transcriptionally suppresses CEACAM1 expression, we herein examined whether high fat down-regulates CEACAM1 expression in a PPARα-dependent mechanism. By activating PPARα, the lipid-lowering drug fenofibrate reverses dyslipidemia and improves insulin sensitivity in type 2 diabetes in part by promoting fatty acid oxidation. Despite reducing glucose-stimulated insulin secretion, fenofibrate treatment does not result in insulin insufficiency. To examine whether this is mediated by a parallel decrease in CEACAM1-dependent hepatic insulin clearance pathways, we fed wild-type and Pparα−/− null mice a high fat diet supplemented with either fenofibrate or Wy14643, a selective PPARα agonist, and examined their effect on insulin metabolism and action. We demonstrated that the decrease in insulin secretion by fenofibrate and Wy14643 is accompanied by reduction in insulin clearance in wild-type but not Pparα−/− mice, thereby maintaining normoinsulinemia and insulin sensitivity despite continuous high fat intake. Intact insulin secretion in L-CC1 mice with protected hepatic insulin clearance and CEACAM1 levels provides in vivo evidence that insulin secretion responds to changes in insulin clearance to maintain physiologic insulin and glucose homeostasis. These results also emphasize the relevant role of hepatic insulin extraction in regulating insulin sensitivity. PMID:27662905

Effects of analgesics on olfactory function and the perception of intranasal trigeminal stimuli.

PubMed

Mizera, L; Gossrau, G; Hummel, T; Haehner, A

2017-01-01

There is some evidence suggesting that analgesics have an impact on human chemosensory function, especially opioids and cannabinoids are known to interfere with olfactory function. However, largely unknown is the effect of a long-term use of analgesics on the intranasal trigeminal system so far. Here, we investigated olfactory function and the perception of intranasal trigeminal stimuli in pain patients with long-term use of analgesics compared to age-matched healthy controls. For this purpose, a psychophysical approach was chosen to measure these sensory functions in 100 chronic pain patients and 95 controls. Olfactory testing was performed using the 'Sniffin' Sticks' test kit, which involves tests for odour threshold, odour discrimination and odour identification. Further, participants were asked to rate the intensity of trigeminal stimuli by using a visual analogue scale. We observed that the chronic use of pain medication was associated with significantly reduced perception of intranasal trigeminal stimuli and olfactory function compared to age-matched controls without intake of analgesics. Results indicate that non-opioid and opioid drugs, or a combination of both did not differ in their effects on chemosensory function. Further, after eliminating the effect of a co-existing depression and the use of co-analgesics, the negative influence of analgesics on olfactory function and trigeminal perception was still evident. The observed effect might be mediated due to interaction with opioid receptors in trigeminal ganglia and nuclei or due to trigeminal/olfactory interaction. As a practical consequence, patients should be made aware of a possible impairment of their olfactory and trigeminal function under long-term analgesic treatment. WHAT DOES THIS STUDY ADD?: We observed that the chronic use of pain medication was associated with significantly reduced olfactory function and perception of intranasal trigeminal stimuli compared to age-matched controls without

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

PubMed

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

2013-07-15

Functional MRI in awake rats involves acclimatization to restraint to minimize motion. We designed a study to examine the effects of an acclimatization protocol (5 days of restraint, 60 min per day) on the emission of 22-kHz ultrasonic vocalizations and performance in a forced swim test (FST). Our results showed that USV calls are reduced significantly by days 3, 4 and 5 of acclimatization. Although the rats showed less climbing activity (and more immobility) in FST on day 5 compared to the 1st day of restraint acclimatization, the difference was not detected once the animals were given a 2-week hiatus. Overall, we showed that animals adapt to the restraint over a five-day period; however, restraint may introduce confounding behavioral outcomes that may hinder the interpretation of results derived from awake rat imaging. The present data warrants further testing of the effects of MRI restraint on behavior. Copyright © 2013 Elsevier B.V. All rights reserved.

Effects of Intranasal Oxytocin Administration on Sexual Functions in Healthy Women: A Laboratory Paradigm.

PubMed

Kruger, Tillmann H C; Deiter, Frank; Zhang, Yuanyuan; Jung, Stefanie; Schippert, Cordula; Kahl, Kai G; Heinrichs, Markus; Schedlowski, Manfred; Hartmann, Uwe

2018-06-01

The neuropeptide oxytocin (OXT) has a variety of physiological functions in maternal behavior and attachment including sexual behavior. Based on animal research and our previous human studies, we set out to investigate intranasal administration of OXT and hypothesized that OXT should be able to modulate sexual function in women. In a double-blind, placebo-controlled, crossover laboratory setting, the acute effects of intranasal administered OXT (24 international units) on sexual drive, arousal, orgasm, and refractory aspects of sexual behavior were analyzed in 27 healthy females (mean age ± SD, 27.52 ± 8.04) together with physiological parameters using vaginal photoplethysmography. Oxytocin administration showed no effect on subjective sexual parameters (eg, postorgasmic tension; P = 0.051). Physiological parameters (vaginal photoplethysmography amplitude and vaginal blood volume) showed a response pattern towards sexual arousal but were not affected by OXT. Using a well-established laboratory paradigm, we did not find that intranasal OXT influences female sexual parameters. Also, sexual drive and other functions were not affected by OXT. These findings indicate that OXT is not able to significantly increase subjective and objective parameters of sexual function in a setting with high internal validity; however, this might be different in a more naturalistic setting.

Pharmacokinetics and -dynamics of intramuscular and intranasal naloxone: an explorative study in healthy volunteers.

PubMed

Skulberg, Arne Kristian; Tylleskar, Ida; Nilsen, Turid; Skarra, Sissel; Salvesen, Øyvind; Sand, Trond; Loftsson, Thorsteinn; Dale, Ola

2018-03-22

This study aimed to develop a model for pharmacodynamic and pharmacokinetic studies of naloxone antagonism under steady-state opioid agonism and to compare a high-concentration/low-volume intranasal naloxone formulation 8 mg/ml to intramuscular 0.8 mg. Two-way crossover in 12 healthy volunteers receiving naloxone while receiving remifentanil by a target-controlled infusion for 102 min. The group were subdivided into three different doses of remifentanil. Blood samples for serum naloxone concentrations, pupillometry and heat pain threshold were measured. The relative bioavailability of intranasal to intramuscular naloxone was 0.75. Pupillometry showed difference in antagonism; the effect was significant in the data set as a whole (p < 0.001) and in all three subgroups (p < 0.02-p < 0.001). Heat pain threshold showed no statistical difference. A target-controlled infusion of remifentanil provides good conditions for studying the pharmacodynamics of naloxone, and pupillometry was a better modality than heat pain threshold. Intranasal naloxone 0.8 mg is inferior for a similar dose intramuscular. Our design may help to bridge the gap between studies in healthy volunteers and the patient population in need of naloxone for opioid overdose. clinicaltrials.gov : NCT02307721.

Insulin degludec and insulin aspart: novel insulins for the management of diabetes mellitus

PubMed Central

Atkin, Stephen; Javed, Zeeshan; Fulcher, Gregory

2015-01-01

Patients with type 2 diabetes mellitus require insulin as disease progresses to attain or maintain glycaemic targets. Basal insulin is commonly prescribed initially, alone or with one or more rapid-acting prandial insulin doses, to limit mealtime glucose excursions (a basal–bolus regimen). Both patients and physicians must balance the advantages of improved glycaemic control with the risk of hypoglycaemia and increasing regimen complexity. The rapid-acting insulin analogues (insulin aspart, insulin lispro and insulin glulisine) all have similar pharmacokinetic and pharmacodynamic characteristics and clinical efficacy/safety profiles. However, there are important differences in the pharmacokinetic and pharmacodynamic profiles of basal insulins (insulin glargine, insulin detemir and insulin degludec). Insulin degludec is an ultra-long-acting insulin analogue with a flat and stable glucose-lowering profile, a duration of action exceeding 30 h and less inter-patient variation in glucose-lowering effect than insulin glargine. In particular, the chemical properties of insulin degludec have allowed the development of a soluble co-formulation with prandial insulin aspart (insulin degludec/insulin aspart) that provides basal insulin coverage for at least 24 h with additional mealtime insulin for one or two meals depending on dose frequency. Pharmacokinetic and pharmacodynamic studies have shown that the distinct, long basal glucose-lowering action of insulin degludec and the prandial glucose-lowering effect of insulin aspart are maintained in the co-formulation. Evidence from pivotal phase III clinical trials indicates that insulin degludec/insulin aspart translate into sustained glycaemic control with less hypoglycaemia and the potential for a simpler insulin regimen with fewer daily injections. PMID:26568812

Successful Insular Glioma Removal in a Deaf Signer Patient During an Awake Craniotomy Procedure.

PubMed

Metellus, Philippe; Boussen, Salah; Guye, Maxime; Trebuchon, Agnes

2017-02-01

Resection of tumors located within the insula of the dominant hemisphere represents a technical challenge because of the complex anatomy, including the surrounding vasculature, and the relationship to functional (motor and language) structures. We report here the case of a successful resection of a left insular glioma in a native deaf signer during an awake craniotomy. The patient, a congenitally deaf right-handed patient who is a native user of sign language, presented with a seizure 1 week before he was referred to our department. Magnetic resonance imaging revealed a left heterogeneous insular tumor enhanced after intravenous gadolinium infusion. Because of its deep and dominant hemisphere location, an awake craniotomy was decided. The patient was evaluated intraoperatively using object naming, text reading, and sign repetition tasks. An isolated inferior frontal gyrus site evoked repeated object naming errors. A transopercular parietal approach was performed and allowed the successful removal of the tumor under direct electric stimulation and electrocorticography. To our knowledge, this is the first report of successful removal of a left insular tumor without any functional sequelae in a native deaf signer using intraoperative direct cerebral stimulation during an awake craniotomy. The methodology used also provides the first evidence of the actual anatomo-functional organization of language in deaf signers. Copyright © 2016 Elsevier Inc. All rights reserved.

Simple platform for chronic imaging of hippocampal activity during spontaneous behaviour in an awake mouse

PubMed Central

Villette, Vincent; Levesque, Mathieu; Miled, Amine; Gosselin, Benoit; Topolnik, Lisa

2017-01-01

Chronic electrophysiological recordings of neuronal activity combined with two-photon Ca2+ imaging give access to high resolution and cellular specificity. In addition, awake drug-free experimentation is required for investigating the physiological mechanisms that operate in the brain. Here, we developed a simple head fixation platform, which allows simultaneous chronic imaging and electrophysiological recordings to be obtained from the hippocampus of awake mice. We performed quantitative analyses of spontaneous animal behaviour, the associated network states and the cellular activities in the dorsal hippocampus as well as estimated the brain stability limits to image dendritic processes and individual axonal boutons. Ca2+ imaging recordings revealed a relatively stereotyped hippocampal activity despite a high inter-animal and inter-day variability in the mouse behavior. In addition to quiet state and locomotion behavioural patterns, the platform allowed the reliable detection of walking steps and fine speed variations. The brain motion during locomotion was limited to ~1.8 μm, thus allowing for imaging of small sub-cellular structures to be performed in parallel with recordings of network and behavioural states. This simple device extends the drug-free experimentation in vivo, enabling high-stability optophysiological experiments with single-bouton resolution in the mouse awake brain. PMID:28240275

Intranasal oxytocin reduces social perception in women: Neural activation and individual variation.

PubMed

Hecht, Erin E; Robins, Diana L; Gautam, Pritam; King, Tricia Z

2017-02-15

Most intranasal oxytocin research to date has been carried out in men, but recent studies indicate that females' responses can differ substantially from males'. This randomized, double-blind, placebo-controlled study involved an all-female sample of 28 women not using hormonal contraception. Participants viewed animations of geometric shapes depicting either random movement or social interactions such as playing, chasing, or fighting. Probe questions asked whether any shapes were "friends" or "not friends." Social videos were preceded by cues to attend to either social relationships or physical size changes. All subjects received intranasal placebo spray at scan 1. While the experimenter was not blinded to nasal spray contents at Scan 1, the participants were. Scan 2 followed a randomized, double-blind design. At scan 2, half received a second placebo dose while the other half received 24 IU of intranasal oxytocin. We measured neural responses to these animations at baseline, as well as the change in neural activity induced by oxytocin. Oxytocin reduced activation in early visual cortex and dorsal-stream motion processing regions for the social > size contrast, indicating reduced activity related to social attention. Oxytocin also reduced endorsements that shapes were "friends" or "not friends," and this significantly correlated with reduction in neural activation. Furthermore, participants who perceived fewer social relationships at baseline were more likely to show oxytocin-induced increases in a broad network of regions involved in social perception and social cognition, suggesting that lower social processing at baseline may predict more positive neural responses to oxytocin. Copyright © 2016 Elsevier Inc. All rights reserved.

[Studies on formulations of Panax notoginsenosides for intranasal administration].

PubMed

Xu, Qing-fang; Fang, Xiao-ling; Chen, Dao-feng; Li, Jun-chan

2003-11-01

To develop high bioavailability preparations without irritation for Panax notoginsenosides. The effects of some additives such as microcrystalline cellulose, beta-cyclodextrin and hydroxypropyl cellulose on drug in the preparations were examined. Saponins of Panax notoginseng (PNS) was absorbed in rabbits more when administered intranasally than through other routines, and the formulations including MCC both gave high bioavailability and low irritation. Bioavailability of Panax notoginsenosides can be increased through changing routine of administration and formulations.

Efficacy of intranasal LaAg vaccine against Leishmania amazonensis infection in partially resistant C57Bl/6 mice.

PubMed

Pratti, Juliana Elena Silveira; Ramos, Tadeu Diniz; Pereira, Joyce Carvalho; da Fonseca-Martins, Alessandra Marcia; Maciel-Oliveira, Diogo; Oliveira-Silva, Gabriel; de Mello, Mirian França; Chaves, Suzana Passos; Gomes, Daniel Claudio Oliveira; Diaz, Bruno Lourenço; Rossi-Bergmann, Bartira; de Matos Guedes, Herbert Leonel

2016-10-06

We have previously demonstrated that intranasal vaccination of highly susceptible BALB/c mice with whole Leishmania amazonensis antigens (LaAg) leads to protection against murine cutaneous leishmaniasis. Here, we evaluate the response of partially resistant C57BL/6 mice to vaccination as a more representative experimental model of human cutaneous leishmaniasis. C57BL/6 mice from different animal facilities were infected with L. amazonensis (Josefa strain) to establish the profile of infection. Intranasal vaccination was performed before the infection challenge with two doses of 10 μg of LaAg alone or associated with the adjuvant ADDAVAX® by instillation in the nostrils. The lesion progression was measured with a dial caliper and the parasite load by limited dilution assay in the acute and chronic phases of infection. Cytokines were quantified by ELISA in the homogenates of infected footpads. C57BL/6 mice from different animal facilities presented the same L. amazonensis infection profile, displaying a progressive acute phase followed by a controlled chronic phase. Parasites cultured in M199 and Schneider's media were equally infective. Intranasal vaccination with LaAg led to milder acute and chronic phases of the disease. The mechanism of protection was associated with increased production of IFN-gamma in the infected tissue as measured in the acute phase. Association with the ADDAVAX® adjuvant did not improve the efficacy of intranasal LaAg vaccination. Rather, ADDAVAX® reduced vaccination efficacy. This study demonstrates that the efficacy of adjuvant-free intranasal vaccination with LaAg is extendable to the more resistant C57Bl/6 mouse model of infection with L. amazonensis, and is thus not exclusive to the susceptible BALB/c model. These results imply that mucosal immunomodulation by LaAg leads to peripheral protection irrespective of the genetic background of the host.

High-Flow Nasal Oxygen in Patient With Obstructive Sleep Apnea Undergoing Awake Craniotomy: A Case Report.

PubMed

Wong, Jaclyn W M; Kong, Amy H S; Lam, Sau Yee; Woo, Peter Y M

2017-12-15

Patients with obstructive sleep apnea are frequently considered unsuitable candidates for awake craniotomy due to anticipated problems with oxygenation, ventilation, and a potentially difficult airway. At present, only a handful of such accounts exist in the literature. Our report describes the novel use of high-flow nasal oxygen therapy for a patient with moderate obstructive sleep apnea who underwent an awake craniotomy under deep sedation. The intraoperative application of high-flow nasal oxygen therapy achieved satisfactory oxygenation, maintained the partial carbon dioxide pressure within a reasonable range even during periods of deep sedation, permitted responsive patient monitoring during mapping, and provided excellent patient and surgeon satisfaction.

Default-Mode-Like Network Activation in Awake Rodents

PubMed Central

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

2011-01-01

During wakefulness and in absence of performing tasks or sensory processing, the default-mode network (DMN), an intrinsic central nervous system (CNS) network, is in an active state. Non-human primate and human CNS imaging studies have identified the DMN in these two species. Clinical imaging studies have shown that the pattern of activity within the DMN is often modulated in various disease states (e.g., Alzheimer's, schizophrenia or chronic pain). However, whether the DMN exists in awake rodents has not been characterized. The current data provides evidence that awake rodents also possess ‘DMN-like’ functional connectivity, but only subsequent to habituation to what is initially a novel magnetic resonance imaging (MRI) environment as well as physical restraint. Specifically, the habituation process spanned across four separate scanning sessions (Day 2, 4, 6 and 8). At Day 8, significant (p<0.05) functional connectivity was observed amongst structures such as the anterior cingulate (seed region), retrosplenial, parietal, and hippocampal cortices. Prior to habituation (Day 2), functional connectivity was only detected (p<0.05) amongst CNS structures known to mediate anxiety (i.e., anterior cingulate (seed region), posterior hypothalamic area, amygdala and parabracial nucleus). In relating functional connectivity between cingulate-default-mode and cingulate-anxiety structures across Days 2-8, a significant inverse relationship (r = −0.65, p = 0.0004) was observed between these two functional interactions such that increased cingulate-DMN connectivity corresponded to decreased cingulate anxiety network connectivity. This investigation demonstrates that the cingulate is an important component of both the rodent DMN-like and anxiety networks. PMID:22125628

Intranasal administration of Lactobacillus rhamnosus GG protects mice from H1N1 influenza virus infection by regulating respiratory immune responses.

PubMed

Harata, G; He, F; Hiruta, N; Kawase, M; Kubota, A; Hiramatsu, M; Yausi, H

2010-06-01

To investigate whether intranasal Lactobacillus administration protects host animals from influenza virus (IFV) infection by enhancing respiratory immune responses in a mouse model. After 3 days of intranasal exposure to Lactobacillus rhamnosus GG (LGG), BALB/c mice were infected with IFV A/PR/8/34 (H1N1). Mice treated with LGG showed a lower frequency of accumulated symptoms and a higher survival rate than control mice (P < 0.05). The YAC-1 cell-killing activity of lung cells isolated from mice treated with LGG was significantly greater than those isolated from control mice (P < 0.01). Intranasal administration of LGG significantly increased mRNA expression of interleukin (IL)-1 beta, tumour necrosis factor (TNF) and monocyte chemotactic protein (MCP)-1 (P < 0.01). These results suggest that intranasal administration of LGG protects the host animal from IFV infection by enhancing respiratory cell-mediated immune responses following up-regulation of lung natural killer (NK) cell activation. We have demonstrated that probiotics might protect host animals from viral infection by stimulating immune responses in the respiratory tract.

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

PubMed

Takahashi, Susumu

2015-10-20

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

Intranasal approach for manipulating the depressor septi nasi.

PubMed

Oh, Sang-Ha; Choi, Sangmun; Kim, Dong Woon; Jeong, Jae Yong

2012-03-01

A hyperactivated depressor septi nasi is an important factor contributing to nasal tip drooping. Although many studies have examined this, its treatment remains controversial. This study presents a surgical intervention based on an anatomic study.Ten fresh cadavers with large noses were used for the anatomic study. Between April 2008 and September 2010, 20 patients underwent surgical intervention for hyperactivated depressor septi nasi.In all of the cadaver dissections, the depressor septi nasi was present, although it was difficult to identify the muscle clearly in 6 of the cadavers. We found that the depressor septi nasi in the other 4 cadavers consisted of 3 fascicles. The medial fascicles were divided into superficial and deep fibers. Both the deep and superficial fibers were inserted into the dermocartilaginous ligament in the nearby nasal tip. After the superficial fibers were interdigitated with the orbicularis oris, they originated from the alveolar bone. The deep fibers originated at the anterior nasal spine. The intermediate fascicles inserted to the footplates of the medial crus and caudal septum. After interdigitating with the medial fascicles and orbicularis oris, they also originated from the alveolar bone. The drooping nasal tips were improved in all cases using an intranasal approach to manipulate the depressor septi nasi. No specific complication was seen. Surgical intervention of a hyperactivated depressor septi nasi using an intranasal approach was a useful method for correcting a drooping nasal tip.

Antiviral Activity of Intranasally Applied Human Leukocyte Interferon

PubMed Central

Greenberg, Stephen B.; Harmon, Maurice W.; Johnson, Paul E.; Couch, Robert B.

1978-01-01

Previous studies in our laboratory have demonstrated that the development of antiviral activity of human leukocyte interferon (IF) in nasal epithelial cells is time and concentration dependent and that the loss of intranasally applied human leukocyte IF is rapid. The present studies compared the activity of IF applied intranasally either by nasal drops or by a saturated cotton pledget. Adult volunteers had IF applied to an area of nasal mucosa (2 by 2 cm2) either by repeated nose drops or by a saturated cotton pledget that was applied to the nasal mucosa and left in place for 1 h. Nasal epithelial cells scraped from the area of application, as well as the control, untreated side of the same volunteers, were challenged with vesicular stomatitis virus. No significant reduction in mean virus yield was found in volunteers who received 80,000 U by nose drops. Significant reduction (P < 0.025) in mean virus yield was found in cells obtained 4 h after 80,000, 50,000, or 20,000 U was applied by cotton pledget or in volunteers pretreated with oral antihistamines prior to receiving 80,000 U by nose drops. These experiments indicate that nasal epithelial cells can be made antiviral in vivo by application of human leukocyte IF. However, practical usefulness of human leukocyte IF for prophylaxis against respiratory viral infections may depend on the method of local application. PMID:214028

Bioavailability of intranasal promethazine dosage forms in dogs

NASA Technical Reports Server (NTRS)

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

1998-01-01

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

AMELIORATING TREATMENT-REFRACTORY DEPRESSION WITH INTRANASAL KETAMINE: POTENTIAL NMDA RECEPTOR ACTIONS IN THE PAIN CIRCUITRY REPRESENTING MENTAL ANGUISH

PubMed Central

Opler, Lewis A.; Opler, Mark G.; Arnsten, Amy F.T.

2014-01-01

This paper reviews the anti-depressant actions of the N-methyl-D-aspartame glutamate receptor (NMDAR) antagonist, ketamine, and offers a potential neural mechanism for intranasal ketamine’s ultra-rapid actions based on the key role of NMDAR in the nonhuman primate prefrontal cortex (PFC). Although intravenous ketamine infusions can lift mood within hours, the current review describes how intranasal ketamine administration can have ultra-rapid antidepressant effects, beginning within minutes (5–40 minutes) and lasting hours, but with repeated treatments needed for sustained antidepressant actions. Research in rodents suggests that increased synaptogenesis in PFC may contribute to the prolonged benefit of ketamine administration, beginning hours after administration. However, these data cannot explain the relief that occurs within minutes of intranasal ketamine delivery. We hypothesize that the ultra-rapid effects of intranasal administration in humans may be due to ketamine blocking the NMDAR circuits that generate the emotional representations of pain (e.g. Brodmann Areas 24 and 25, insular cortex), cortical areas that can be overactive in depression and which sit above the nasal epithelium. In contrast, NMDAR blockade in the dorsolateral PFC following systemic administration of ketamine may contribute to cognitive deficits. This novel view may help to explain how intravenous ketamine can treat the symptoms of depression yet worsen the symptoms of schizophrenia. PMID:25619798

Wireless modification of the intraoperative examination monitor for awake surgery.

PubMed

Yoshimitsu, Kitaro; Maruyama, Takashi; Muragaki, Yoshihiro; Suzuki, Takashi; Saito, Taiichi; Nitta, Masayuki; Tanaka, Masahiko; Chernov, Mikhail; Tamura, Manabu; Ikuta, Soko; Okamoto, Jun; Okada, Yoshikazu; Iseki, Hiroshi

2011-01-01

The dedicated intraoperative examination monitor for awake surgery (IEMAS) was originally developed by us to facilitate the process of brain mapping during awake craniotomy and successfully used in 186 neurosurgical procedures. This information-sharing device provides the opportunity for all members of the surgical team to visualize a wide spectrum of the integrated intraoperative information related to the condition of the patient, nuances of the surgical procedure, and details of the cortical mapping, practically without interruption of the surgical manipulations. The wide set of both anatomical and functional parameters, such as view of the patient's mimic and face movements while answering the specific questions, type of the examination test, position of the surgical instruments, parameters of the bispectral index monitor, and general view of the surgical field through the operating microscope, is presented compactly in one screen with several displays. However, the initially designed IEMAS system was occasionally affected by interruption or detachment of the connecting cables, which sometimes interfered with its effective clinical use. Therefore, a new modification of the device was developed. The specific feature is installation of wireless information transmitting technology using audio-visual transmitters and receivers for transfer of images and verbal information. The modified IEMAS system is very convenient to use in the narrow space of the operating room.

Chronic orbital inflammatory disease and optic neuropathy associated with long-term intranasal cocaine abuse: 2 cases and literature review.

PubMed

Siemerink, Martin J; Freling, Nicole J M; Saeed, Peerooz

2017-10-01

Orbital inflammatory disease and secondary optic neuropathy is a rare but devastating complication of long-term intranasal cocaine abuse. We describe 2 patients with a history of intranasal cocaine consumption who presented with subacute onset of unilateral vision loss from optic neuropathy and limitation of abduction in the affected eye. Magnetic resonance imaging findings included an orbital mass in combination with absent nasal septum and partial destruction of the paranasal sinuses. Biopsies and histopathologic examination of the nasal cavity and the orbital mass revealed chronic inflammation. Both patients were treated with oral corticosteroids, ocular movements completely normalized but no improvement of visual acuity was noted. Intranasal cocaine abuse can cause orbital complications from chronic sinonasal inflammatory disease and these patients are at risk to develop optic neuropathy. Optic neuropathy may be caused by compression, infiltration, or ischaemia.

Quetiapine Nanoemulsion for Intranasal Drug Delivery: Evaluation of Brain-Targeting Efficiency.

PubMed

Boche, Mithila; Pokharkar, Varsha

2017-04-01

To evaluate the possibility of improved drug delivery of quetiapine fumarate (QTP), a nanoemulsion system was developed for intranasal delivery. Effects of different HLBs of Emalex LWIS 10, PEG 400 and Transcutol P, as co-surfactants, were studied on isotropic region of pseudoternary-phase diagrams of nanoemulsion system composed of capmul MCM (CPM) as oil phase, Tween 80 as surfactant and water. Phase behaviour, globule size, transmission electron microscope (TEM) photographs and brain-targeting efficiency of quetiapine nanoemulsion were investigated. In vitro dissolution study of optimised nanoemulsion formulation, with mean diameter 144 ± 0.5 nm, showed more than twofold increase in drug release as compared with pure drug. According to results of in vivo tissue distribution study in Wistar rats, intranasal administration of QTP-loaded nanoemulsion had shorter T max compared with that of intravenous administration. Higher drug transport efficiency (DTE%) and direct nose-to-brain drug transport (DTP%) was achieved by nanoemulsion. The nanoemulsion system may be a promising strategy for brain-targeted delivery of QTP.

Specificities of Awake Craniotomy and Brain Mapping in Children for Resection of Supratentorial Tumors in the Language Area.

PubMed

Delion, Matthieu; Terminassian, Aram; Lehousse, Thierry; Aubin, Ghislaine; Malka, Jean; N'Guyen, Sylvie; Mercier, Philippe; Menei, Philippe

2015-12-01

In the pediatric population, awake craniotomy began to be used for the resection of brain tumor located close to eloquent areas. Some specificities must be taken into account to adapt this method to children. The aim of this clinical study is to not only confirm the feasibility of awake craniotomy and language brain mapping in the pediatric population but also identify the specificities and necessary adaptations of the procedure. Six children aged 11 to 16 were operated on while awake under local anesthesia with language brain mapping for supratentorial brain lesions (tumor and cavernoma). The preoperative planning comprised functional magnetic resonance imaging (MRI) and neuropsychologic and psychologic assessment. The specific preoperative preparation is clearly explained including hypnosis conditioning and psychiatric evaluation. The success of the procedure was based on the ability to perform the language brain mapping and the tumor removal without putting the patient to sleep. We investigated the pediatric specificities, psychological experience, and neuropsychologic follow-up. The children experienced little anxiety, probably in large part due to the use of hypnosis. We succeeded in doing the cortical-subcortical mapping and removing the tumor without putting the patient to sleep in all cases. The psychological experience was good, and the neuropsychologic follow-up showed a favorable evolution. Preoperative preparation and hypnosis in children seemed important for performing awake craniotomy and contributing language brain mapping with the best possible psychological experience. The pediatrics specificities are discussed. Copyright © 2015 Elsevier Inc. All rights reserved.

Use of Intranasal Naloxone by Basic Life Support Providers.

PubMed

Weiner, Scott G; Mitchell, Patricia M; Temin, Elizabeth S; Langlois, Breanne K; Dyer, K Sophia

2017-01-01

Intranasal delivery of naloxone to reverse the effects of opioid overdose by Advanced Life Support (ALS) providers has been studied in several prehospital settings. In 2006, in response to the increase in opioid-related overdoses, a special waiver from the state allowed administration of intranasal naloxone by Basic Life Support (BLS) providers in our city. This study aimed to determine: 1) if patients who received a 2-mg dose of nasal naloxone administered by BLS required repeat dosing while in the emergency department (ED), and 2) the disposition of these patients. This was a retrospective review of patients transported by an inner-city municipal ambulance service to one of three academic medical centers. We included patients aged 18 and older that were transported by ambulance between 1/1/2006 and 12/12/2012 and who received intranasal naloxone by BLS providers as per a state approved protocol. Site investigators matched EMS run data to patients from each hospital's EMR and performed a chart review to confirm that the patient was correctly identified and to record the outcomes of interest. Descriptive statistics were then generated. A total of 793 patients received nasal naloxone by BLS and were transported to three hospitals. ALS intervened and transported 116 (14.6%) patients, and 11 (1.4%) were intubated in the field. There were 724 (91.3%) patients successfully matched to an ED chart. Hospital A received 336 (46.4%) patients, Hospital B received 210 (29.0%) patients, and Hospital C received 178 (24.6%) patients. Mean age was 36.2 (SD 10.5) years and 522 (72.1%) were male; 702 (97.1%) were reported to have abused heroin while 21 (2.9%) used other opioids. Nasal naloxone had an effect per the prehospital record in 689 (95.2%) patients. An additional naloxone dose was given in the ED to 64 (8.8%) patients. ED dispositions were: 507 (70.0%) discharged, 105 (14.5%) admitted, and 112 (15.5%) other (e.g., left against medical advice, left without being seen, or

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

PubMed Central

Xu, Yingying; Yuen, Pak-Wai; Lam, Jenny Ka-Wing

2014-01-01

Intranasal delivery of DNA vaccines has become a popular research area recently. It offers some distinguished advantages over parenteral and other routes of vaccine administration. Nasal mucosa as site of vaccine administration can stimulate respiratory mucosal immunity by interacting with the nasopharyngeal-associated lymphoid tissues (NALT). Different kinds of DNA vaccines are investigated to provide protection against respiratory infectious diseases including tuberculosis, coronavirus, influenza and respiratory syncytial virus (RSV) etc. DNA vaccines have several attractive development potential, such as producing cross-protection towards different virus subtypes, enabling the possibility of mass manufacture in a relatively short time and a better safety profile. The biggest obstacle to DNA vaccines is low immunogenicity. One of the approaches to enhance the efficacy of DNA vaccine is to improve DNA delivery efficiency. This review provides insight on the development of intranasal DNA vaccine for respiratory infections, with special attention paid to the strategies to improve the delivery of DNA vaccines using non-viral delivery agents. PMID:25014738

Intranasal Location and Immunohistochemical Characterization of the Equine Olfactory Epithelium.

PubMed

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

Intranasal Location and Immunohistochemical Characterization of the Equine Olfactory Epithelium

PubMed Central

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

2016-01-01

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

Intranasal immunization with novel EspA-Tir-M fusion protein induces protective immunity against enterohemorrhagic Escherichia coli O157:H7 challenge in mice.

PubMed

Lin, Ruqin; Zhu, Bo; Zhang, Yiduo; Bai, Yang; Zhi, Fachao; Long, Beiguo; Li, Yawen; Wu, Yuhua; Wu, Xianbo; Fan, Hongying

2017-04-01

Enterohemorrhagic Escherichia coli (EHEC) O157:H7 causes hemorrhagic colitis and hemolytic uremic syndrome in humans. Due to the risks associated with antibiotic treatment against EHEC O157:H7 infection, vaccines represent a promising method for prevention of EHEC O157:H7 infection. Therefore, we constructed the novel bivalent antigen EspA-Tir-M as a candidate EHEC O157:H7 subunit vaccine. We then evaluated the immunogenicity of this novel EHEC O157:H7 subunit vaccine. Immune responses to the fusion protein administered by intranasal and subcutaneous routes were compared in mice. Results showed higher levels of specific mucosal and systemic antibody responses induced by intranasal as compared to subcutaneous immunization. Intranasal immunization enhanced the concentration of interleukin-4, interleukin-10, and interferon-γ, while subcutaneous immunization enhanced only the latter two. In addition, intranasal immunization protected against EHEC O157:H7 colonization and infection in mice at a rate of 90%.Histopathological analysis revealed that vaccination reduced colon damage, especially when administered intranasally. In contrast, subcutaneous immunization elicited a weak immune response and exhibited a low protection rate. These findings demonstrate that intranasal immunization with the fusion protein induces both humoral and cellular immune (Th1/Th2) responses in mice. The novel EspA-Tir-M novel fusion protein therefore represents a promising subunit vaccine against EHEC O157:H7 infection. Copyright © 2017 Elsevier Ltd. All rights reserved.

Intranasal exposure to monoclonal antibody Fab fragments to Japanese cedar pollen Cry j1 suppresses Japanese cedar pollen‐induced allergic rhinitis

PubMed Central

Mizutani, N

2016-01-01

Background and Purpose Fab fragments (Fabs) of antibodies have the ability to bind to specific allergens but lack the Fc portion that exerts effector functions via binding to receptors including FcεR1 on mast cells. In the present study, we investigated whether intranasal administration of the effector function‐lacking Fabs of a monoclonal antibody IgG1 (mAb, P1‐8) to the major allergen Cry j1 of Japanese cedar pollen (JCP) suppressed JCP‐induced allergic rhinitis in mice. Experimental Approach Balb/c mice sensitized with JCP on days 0 and 14 were challenged intranasally with the pollen on days 28, 29, 30 and 35. Fabs prepared by the digestion of P1‐8 with papain were also administered intranasally 15 min before each JCP challenge. Key Results Intranasal administration of P1‐8 Fabs was followed by marked suppression of sneezing and nasal rubbing in mice with JCP‐induced allergic rhinitis. The suppression of these allergic symptoms by P1‐8 Fabs was associated with decreases in mast cells and eosinophils and decreased hyperplasia of goblet cells in the nasal mucosa. Conclusions and Implications These results demonstrated that intranasal exposure to P1‐8 Fabs was effective in suppressing JCP‐induced allergic rhinitis in mice, suggesting that allergen‐specific mAb Fabs might be used as a tool to regulate allergic pollinosis. PMID:26895546

Causality Assessment of Olfactory and Gustatory Dysfunction Associated with Intranasal Fluticasone Propionate: Application of the Bradford Hill Criteria.

PubMed

Muganurmath, Chandrashekhar S; Curry, Amy L; Schindzielorz, Andrew H

2018-02-01

Causality assessment is crucial to post-marketing pharmacovigilance and helps optimize safe and appropriate use of medicines by patients in the real world. Self-reported olfactory and gustatory dysfunction are common in the general population as well as in patients with allergic rhinitis and nasal polyposis. Intranasal corticosteroids, including intranasal fluticasone propionate (INFP), are amongst the most effective drugs indicated in the treatment of allergic rhinitis and nasal polyposis. While intranasal corticosteroids are associated with olfactory and gustatory dysfunction and are currently labeled for these adverse events, causality assessment has not been performed to date. Although there is no single widely accepted method to assess causality in pharmacovigilance, the Bradford Hill criteria offer a robust and comprehensive approach because nine distinct aspects of an observed potential drug-event association are assessed. In this literature-based narrative review, Hill's criteria were applied to determine causal inference between INFP and olfactory and gustatory dysfunction.

Asleep-awake-asleep craniotomy: a comparison with general anesthesia for resection of supratentorial tumors.

PubMed

Rajan, Shobana; Cata, Juan P; Nada, Eman; Weil, Robert; Pal, Rakhi; Avitsian, Rafi

2013-08-01

The anesthetic plan for patients undergoing awake craniotomy, when compared to craniotomy under general anesthesia, is different, in that it requires changes in states of consciousness during the procedure. This retrospective review compares patients undergoing an asleep-awake-asleep technique for craniotomy (group AW: n = 101) to patients undergoing craniotomy under general anesthesia (group AS: n = 77). Episodes of desaturation (AW = 31% versus AS = 1%, p < 0.0001), although temporary, and hypercarbia (AW = 43.75 mmHg versus AS = 32.75 mmHg, p < 0.001) were more common in the AW group. The mean arterial pressure during application of head clamp pins and emergence was significantly lower in AW patients compared to AS patients (pinning 91.47 mmHg versus 102.9 mmHg, p < 0.05 and emergence 84.85 mmHg versus 105 mmHg, p < 0.05). Patients in the AW group required less vasopressors intraoperatively (AW = 43% versus AS = 69%, p < 0.01). Intraoperative fluids were comparable between the two groups. The post anesthesia care unit (PACU) administered significantly fewer intravenous opioids in the AW group. The length of stay in the PACU and hospital was comparable in both groups. Thus, asleep-awake-asleep craniotomies with propofol-dexmedetomidine infusion had less hemodynamic response to pinning and emergence, and less overall narcotic use compared to general anesthesia. Despite a higher incidence of temporary episodes of desaturation and hypoventilation, no adverse clinical consequences were seen. Copyright © 2013 Elsevier Ltd. All rights reserved.

Serotonin Decreases the Gain of Visual Responses in Awake Macaque V1.

PubMed

Seillier, Lenka; Lorenz, Corinna; Kawaguchi, Katsuhisa; Ott, Torben; Nieder, Andreas; Pourriahi, Paria; Nienborg, Hendrikje

2017-11-22

Serotonin, an important neuromodulator in the brain, is implicated in affective and cognitive functions. However, its role even for basic cortical processes is controversial. For example, in the mammalian primary visual cortex (V1), heterogenous serotonergic modulation has been observed in anesthetized animals. Here, we combined extracellular single-unit recordings with iontophoresis in awake animals. We examined the role of serotonin on well-defined tuning properties (orientation, spatial frequency, contrast, and size) in V1 of two male macaque monkeys. We find that in the awake macaque the modulatory effect of serotonin is surprisingly uniform: it causes a mainly multiplicative decrease of the visual responses and a slight increase in the stimulus-selective response latency. Moreover, serotonin neither systematically changes the selectivity or variability of the response, nor the interneuronal correlation unexplained by the stimulus ("noise-correlation"). The modulation by serotonin has qualitative similarities with that for a decrease in stimulus contrast, but differs quantitatively from decreasing contrast. It can be captured by a simple additive change to a threshold-linear spiking nonlinearity. Together, our results show that serotonin is well suited to control the response gain of neurons in V1 depending on the animal's behavioral or motivational context, complementing other known state-dependent gain-control mechanisms. SIGNIFICANCE STATEMENT Serotonin is an important neuromodulator in the brain and a major target for drugs used to treat psychiatric disorders. Nonetheless, surprisingly little is known about how it shapes information processing in sensory areas. Here we examined the serotonergic modulation of visual processing in the primary visual cortex of awake behaving macaque monkeys. We found that serotonin mainly decreased the gain of the visual responses, without systematically changing their selectivity, variability, or covariability. This

Serotonin Decreases the Gain of Visual Responses in Awake Macaque V1

PubMed Central

Seillier, Lenka; Lorenz, Corinna; Kawaguchi, Katsuhisa; Ott, Torben; Pourriahi, Paria

2017-01-01

Serotonin, an important neuromodulator in the brain, is implicated in affective and cognitive functions. However, its role even for basic cortical processes is controversial. For example, in the mammalian primary visual cortex (V1), heterogenous serotonergic modulation has been observed in anesthetized animals. Here, we combined extracellular single-unit recordings with iontophoresis in awake animals. We examined the role of serotonin on well-defined tuning properties (orientation, spatial frequency, contrast, and size) in V1 of two male macaque monkeys. We find that in the awake macaque the modulatory effect of serotonin is surprisingly uniform: it causes a mainly multiplicative decrease of the visual responses and a slight increase in the stimulus-selective response latency. Moreover, serotonin neither systematically changes the selectivity or variability of the response, nor the interneuronal correlation unexplained by the stimulus (“noise-correlation”). The modulation by serotonin has qualitative similarities with that for a decrease in stimulus contrast, but differs quantitatively from decreasing contrast. It can be captured by a simple additive change to a threshold-linear spiking nonlinearity. Together, our results show that serotonin is well suited to control the response gain of neurons in V1 depending on the animal's behavioral or motivational context, complementing other known state-dependent gain-control mechanisms. SIGNIFICANCE STATEMENT Serotonin is an important neuromodulator in the brain and a major target for drugs used to treat psychiatric disorders. Nonetheless, surprisingly little is known about how it shapes information processing in sensory areas. Here we examined the serotonergic modulation of visual processing in the primary visual cortex of awake behaving macaque monkeys. We found that serotonin mainly decreased the gain of the visual responses, without systematically changing their selectivity, variability, or covariability. This

Benefits of awake uniportal pulmonary resection in a patient with a previous contralateral lobectomy

PubMed Central

Navarro-Martinez, Jose; Bolufer, Sergio; Lirio, Francisco; Mafe, Juan Jose; Rivera, Maria Jesus; Roca, Joaquin; Baschwitz, Benno

2014-01-01

Surgical resection of a contralateral recurrence of non-small cell lung cancer (NSCLC) is indicated in patients without evidence of disseminated disease and considered functionally operable. General anesthesia and double-lumen intubation involves one lobe ventilation in a patient treated with a previous lobectomy, thus increasing the risks of ventilator-induced injuries and the morbidity. Awake procedures facilitate the surgery decreasing the anesthetic and surgical times, keeping the diaphragm motion and diminishing the ventilator-induced injuries into the remaining contralateral lobe. We present a 43-year-old woman with a previous left-lower lobectomy for a 3.1-cm mucinous adenocarcinoma 15 months before without nodal involvement, who presents a right-lower lobe 8-mm cavitated nodule, with evident radiological growth and fine-needle aspiration concordant with mucinous adenocarcinoma. We suggest an awake procedure with locoregional epidural anesthesia. PMID:25405168

Benefits of awake uniportal pulmonary resection in a patient with a previous contralateral lobectomy.

PubMed

Galvez, Carlos; Navarro-Martinez, Jose; Bolufer, Sergio; Lirio, Francisco; Mafe, Juan Jose; Rivera, Maria Jesus; Roca, Joaquin; Baschwitz, Benno

2014-09-01

Surgical resection of a contralateral recurrence of non-small cell lung cancer (NSCLC) is indicated in patients without evidence of disseminated disease and considered functionally operable. General anesthesia and double-lumen intubation involves one lobe ventilation in a patient treated with a previous lobectomy, thus increasing the risks of ventilator-induced injuries and the morbidity. Awake procedures facilitate the surgery decreasing the anesthetic and surgical times, keeping the diaphragm motion and diminishing the ventilator-induced injuries into the remaining contralateral lobe. We present a 43-year-old woman with a previous left-lower lobectomy for a 3.1-cm mucinous adenocarcinoma 15 months before without nodal involvement, who presents a right-lower lobe 8-mm cavitated nodule, with evident radiological growth and fine-needle aspiration concordant with mucinous adenocarcinoma. We suggest an awake procedure with locoregional epidural anesthesia.

A high power, high density helicon discharge for the plasma wakefield accelerator experiment AWAKE

NASA Astrophysics Data System (ADS)

Buttenschön, B.; Fahrenkamp, N.; Grulke, O.

2018-07-01

A plasma cell prototype for the plasma wakefield accelerator experiment AWAKE based on a helicon discharge is presented. In the 1 m long prototype module a multiple antenna helicon discharge with an rf power density of 100 MW m‑3 is established. Based on the helicon dispersion relation, a linear scaling of plasma density with magnetic field is observed for rf frequencies above the lower hybrid frequency, ω LH ≤ 0.8ω rf. Density profiles are highest on the device axis and show shallow radial gradients, thus providing a relatively constant plasma density in the center over a radial range of Δr ≈ 10 mm with less than 10% variation. Peak plasma densities up to 7 × 1020 m‑3 are transiently achieved with a reproducibility that is sufficient for AWAKE. The results are in good agreement with power balance calculations.

A randomised controlled trial of oral chloral hydrate vs. intranasal dexmedetomidine before computerised tomography in children.

PubMed

Yuen, V M; Li, B L; Cheuk, D K; Leung, M K M; Hui, T W C; Wong, I C; Lam, W W; Choi, S W; Irwin, M G

2017-10-01

Chloral hydrate is commonly used to sedate children for painless procedures. Children may recover more quickly after sedation with dexmedetomidine, which has a shorter half-life. We randomly allocated 196 children to chloral hydrate syrup 50 mg.kg -1 and intranasal saline spray, or placebo syrup and intranasal dexmedetomidine spray 3 μg.kg -1 , 30 min before computerised tomography studies. More children resisted or cried after drinking chloral hydrate syrup than placebo syrup, 72 of 107 (67%) vs. 42 of 87 (48%), p = 0.009, but there was no difference after intranasal saline vs. dexmedetomidine, 49 of 107 (46%) vs. 40 of 87 (46%), p = 0.98. Sedation was satisfactory in 81 of 107 (76%) children after chloral hydrate and 64 of 87 (74%) children after dexmedetomidine, p = 0.74. Of the 173 children followed up for at least 4 h after discharge, 38 of 97 (39%) had recovered normal function after chloral hydrate and 32 of 76 (42%) after dexmedetomidine, p = 0.76. Six children vomited after chloral hydrate syrup and placebo spray vs. none after placebo syrup and dexmedetomidine spray, p = 0.03. © 2017 The Association of Anaesthetists of Great Britain and Ireland.

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

PubMed Central

Takahashi, Susumu

2015-01-01

Episodic memory retrieval of events at a specific place and time is effective for future planning. Sequential reactivation of the hippocampal place cells along familiar paths while the animal pauses is well suited to such a memory retrieval process. It is, however, unknown whether this awake replay represents events occurring along the path. Using a subtask switching protocol in which the animal experienced three subtasks as ‘what’ information in a maze, I here show that the replay represents a trial type, consisting of path and subtask, in terms of neuronal firing timings and rates. The actual trial type to be rewarded could only be reliably predicted from replays that occurred at the decision point. This trial-type representation implies that not only ‘where and when’ but also ‘what’ information is contained in the replay. This result supports the view that awake replay is an episodic-like memory retrieval process. DOI: http://dx.doi.org/10.7554/eLife.08105.001 PMID:26481131

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

PubMed

Sasportas, Laura Sarah; Gambhir, Sanjiv Sam

2014-01-01

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

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

PubMed Central

Sasportas, Laura Sarah; Gambhir, Sanjiv Sam

2014-01-01

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

Comparison of the Efficacy, Side Effects, and Cost of Modafinil and Intranasal Mometasone Furoate in Obstructive Sleep Apnea-Hypopnea Syndrome: A Preliminary Clinical Study

PubMed Central

Zhang, Shujia; Duan, Zhongnin

2018-01-01

Background Obstructive sleep apnea-hypopnea syndrome (OSAHS) is characterized by repeated episodes of reduction in airflow due to the collapse of the upper airway during sleep. The aim of this study was to compare clinical outcome, side effects, and cost of treatment between modafinil and intranasal mometasone furoate in patients with OSAHS. Material/Methods Patients with OSAHS (N=250) were divided into two groups: the modafinil group (MG) (N=125) were treated with 100 mg modafinil twice a day; the intranasal mometasone furoate group (IMFG) (N=125) were treated with 100 μg of intranasal mometasone furoate in the evening. Quality of life, grading of OSAHS, plain-film radiography, the adenoidal-nasopharyngeal ratio (AN ratio), side effects, cost of treatment, and beneficial effects after discontinuation of treatment were evaluated for all patients. Results Duration of sleep apnea was significantly reduced in the IMFG compared with the MG (p=0.0145, q=9.262). Modafinil and intranasal mometasone furoate both had moderate effects on improvement of the OSAHS score. The IMFG showed a significantly greater beneficial effect on the AN ratio when compared with the MG (p=0.0001, q=6.584). No adverse events of treatment with modafinil and intranasal mometasone furoate were reported. Cost of treatment and beneficial effect after discontinuation were both significantly greater for the IMFG compared with the MG. Conclusions The findings of this preliminary clinical study were that for patients diagnosed with OSAHS, night-time treatment with intranasal mometasone furoate was more effective than modafinil. PMID:29749371

Awake craniotomy to maximize glioma resection: methods and technical nuances over a 27-year period.

PubMed

Hervey-Jumper, Shawn L; Li, Jing; Lau, Darryl; Molinaro, Annette M; Perry, David W; Meng, Lingzhong; Berger, Mitchel S

2015-08-01

Awake craniotomy is currently a useful surgical approach to help identify and preserve functional areas during cortical and subcortical tumor resections. Methodologies have evolved over time to maximize patient safety and minimize morbidity using this technique. The goal of this study is to analyze a single surgeon's experience and the evolving methodology of awake language and sensorimotor mapping for glioma surgery. The authors retrospectively studied patients undergoing awake brain tumor surgery between 1986 and 2014. Operations for the initial 248 patients (1986-1997) were completed at the University of Washington, and the subsequent surgeries in 611 patients (1997-2014) were completed at the University of California, San Francisco. Perioperative risk factors and complications were assessed using the latter 611 cases. The median patient age was 42 years (range 13-84 years). Sixty percent of patients had Karnofsky Performance Status (KPS) scores of 90-100, and 40% had KPS scores less than 80. Fifty-five percent of patients underwent surgery for high-grade gliomas, 42% for low-grade gliomas, 1% for metastatic lesions, and 2% for other lesions (cortical dysplasia, encephalitis, necrosis, abscess, and hemangioma). The majority of patients were in American Society of Anesthesiologists (ASA) Class 1 or 2 (mild systemic disease); however, patients with severe systemic disease were not excluded from awake brain tumor surgery and represented 15% of study participants. Laryngeal mask airway was used in 8 patients (1%) and was most commonly used for large vascular tumors with more than 2 cm of mass effect. The most common sedation regimen was propofol plus remifentanil (54%); however, 42% of patients required an adjustment to the initial sedation regimen before skin incision due to patient intolerance. Mannitol was used in 54% of cases. Twelve percent of patients were active smokers at the time of surgery, which did not impact completion of the intraoperative mapping

The Cost of Brain Surgery: Awake vs Asleep Craniotomy for Perirolandic Region Tumors.

PubMed

Eseonu, Chikezie I; Rincon-Torroella, Jordina; ReFaey, Karim; Quiñones-Hinojosa, Alfredo

2017-08-01

Cost effectiveness has become an important factor in the health care system, requiring surgeons to improve efficacy of procedures while reducing costs. An awake craniotomy (AC) with direct cortical stimulation (DCS) presents one method to resect eloquent region tumors; however, some authors assert that this procedure is an expensive alternative to surgery under general anesthesia (GA) with neuromonitoring. To evaluate the cost effectiveness and clinical outcomes between AC and GA patients. Retrospective analysis of a cohort of 17 patients with perirolandic gliomas who underwent an AC with DCS were case-control matched with 23 patients with perirolandic gliomas who underwent surgery under GA with neuromonitoring (ie, motor-evoked potentials, somatosensory-evoked potentials, phase reversal). Inpatient costs, quality-adjusted life years (QALY), extent of resection, and neurological outcome were compared between the groups. Total inpatient expense per patient was $34 804 in the AC group and $46 798 in the GA group ( P = .046). QALY score for the AC group was 0.97 and 0.47 for the GA group ( P = .041). The incremental cost per QALY for the AC group was $82 720 less than the GA group. Postoperative Karnofsky performance status was 91.8 in the AC group and 81.3 in the GA group (P = .047). Length of hospitalization was 4.12 days in the AC group and 7.61 days in the GA group ( P = .049). The total inpatient costs for awake craniotomies were lower than surgery under GA. This study suggests better cost effectiveness and neurological outcome with awake craniotomies for perirolandic gliomas. Copyright © 2017 by the Congress of Neurological Surgeons

Intranasal Oxytocin Failed to Affect Chimpanzee (Pan troglodytes) Social Behavior

PubMed Central

Calcutt, Sarah E.; Burke, Kimberly; de Waal, Frans B. M.

2017-01-01

Oxytocin has been suggested as a treatment to promote positive social interactions in people with Autism Spectrum Disorders (ASD). However, it is difficult to test this effect outside of the laboratory in realistic social situations. One way to resolve this issue is to study behavioral changes in closely related species with complex social relationships, such as chimpanzees. Here, we use captive, socially housed chimpanzees to evaluate the effects of oxytocin in a socially complex environment. After administering intranasal oxytocin or a placebo to an individual chimpanzee (total n = 8), she was returned to her social group. An experimenter blind to the condition measured the subject's social behavior. We failed to find a behavioral difference between conditions. As one of the goals for oxytocin administration as a treatment for ASD is increasing prosocial behaviors during ‘real world’ encounters, it is problematic that we failed to detect behavioral changes in our closest living relatives. However, our null findings may be related to methodological challenges such as determining an effective dose of oxytocin for chimpanzees and how long oxytocin takes to cross the blood-brain barrier. Thus, more research on intranasal oxytocin dosing and uptake are needed to continue exploring whether oxytocin changes social behavior in naturalistic settings and as a treatment for ASD. PMID:28845444

[Intranasal epitalon infusion modulates neuronal activity in the rat neocortex].

PubMed

Sibarov, D A; Vol'nova, A B; Frolov, D S; Nosdrachev, A D

2006-08-01

Properties of tetrapeptide epitalon (Ala-Glu-Asp-Gly) constructed on the basis of pineal peptide extract, have been studied. The intranasal infusions: a noninvasive way to deliver this peptide to CNS hypassing the blood-brain barrier, was used. The aim of the study is to estimate epitalon action on rat motor cortex spontaneous activity. Wistar male rats were anesthetized with urethane (1 g/kg). Extracellular unit recording was made using glass microelectrodes (1-2 MOhm). After recording of spontaneous activity (10-15 min), epitalon intranasal infusion (2 ng) was followed by 30-minute recording. Within a few minutes after the infusion, significant activation of neural activity was observed (2-2.5-fold higher frequency of neuronal spikes). Complex response consisting of several phases was identified in some recordings. The spikes frequency growth during 5 to 7 min (first phase) after the infusion was followed by the second (11-12 min) and the third (17-18 min) phases. An increase of neuronal spontaneous activity was conditioned by the higher frequency of already active units and by the involvement of previously silent cells. At least the first phase of epitalon action can be explained by direct action of the peptide on the cells of the motor cortex.

Intranasal Opioid Administration in Rhesus Monkeys: PET Imaging and Antinociception.

PubMed

Saccone, Phillip A; Lindsey, Angela M; Koeppe, Robert A; Zelenock, Kathy A; Shao, Xia; Sherman, Phillip; Quesada, Carole A; Woods, James H; Scott, Peter J H

2016-11-01

The goal of this study was to evaluate the effects of intranasally administered opioids in rhesus monkeys using the tail-withdrawal assay, and to correlate these effects with measures of receptor occupancy using positron emission tomography (PET) imaging. Initial experiments characterized the antinociceptive effects of intranasal (IN) fentanyl and buprenorphine relative to intramuscular (IM) injection. Fentanyl (0.010-0.032 mg/kg) and buprenorphine (0.1-1.0 mg/kg) produced dose-dependent increases in tail-withdrawal latency that did not differ between routes of delivery. The second experiment compared the ability of IN and intravenous (IV) naloxone (NLX) to block the antinociceptive effects IV fentanyl, and to measure receptor occupancy at equipotent doses of NLX using PET imaging. IN and IV NLX (0.0032-0.032 mg/kg) produced dose-dependent decreases in fentanyl-induced antinociception. Again, there was no difference observed in overall potency between routes. PET imaging showed that IV and IN NLX produced similar decreases in receptor occupancy as measured by [ 11 C]carfentanil blocking, although there was a trend for IV NLX to produce marginally greater occupancy changes. This study validated the first procedures to evaluate the IN effects of opioids in rhesus monkeys. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

A Case Report of Onyx Pulmonary Arterial Embolism Contributing to Hypoxemia During Awake Craniotomy for Arteriovenous Malformation Resection.

PubMed

Tolly, Brian T; Kosky, Jenna L; Koht, Antoun; Hemmer, Laura B

2017-02-15

A healthy 26-year-old man with cerebral arteriovenous malformation underwent staged endovascular embolization with Onyx followed by awake craniotomy for resection. The perioperative course was complicated by tachycardia and severe intraoperative hypoxemia requiring significant oxygen supplementation. Postoperative chest computed tomography (CT) revealed hyperattenuating Onyx embolization material within the pulmonary vasculature, and an electrocardiogram indicated possible right heart strain, supporting clinically significant embolism. With awake arteriovenous malformation resection following adjunctive Onyx embolization becoming increasingly employed for lesions involving the eloquent cortex, anesthesiologists need to be aware of pulmonary migration of Onyx material as a potential contributor to significant perioperative hypoxemia.

Operative Strategies during Awake Surgery Affect Deterioration of Paresis a Month after Surgery for Brain Lesions in the Primary Motor Area.

PubMed

Shinoura, Nobusada; Midorikawa, Akira; Yamada, Ryoji; Hiromitsu, Kentaro; Itoi, Chihiro; Saito, Shoko; Yagi, Kazuo

2017-07-01

Introduction  We analyzed factors associated with worsened paresis at 1-month follow-up in patients with brain tumors located in the primary motor area (M1) to establish protocols for safe awake craniotomy for M1 lesions. Methods  Patients with M1 brain tumors who underwent awake surgery in our hospital ( n  = 61) were evaluated before, during, and immediately and 1 month after surgery for severity of paresis, tumor location, extent of resection, complications, preoperative motor strength, histology, and operative strategies (surgery stopped or continued after deterioration of motor function). Results  Worsened paresis at 1-month follow-up was significantly associated with worsened paresis immediately after surgery and also with operative strategy. Specifically, when motor function deteriorated during awake surgery and did not recover within 5 to 10 minutes, no deterioration was observed at 1-month follow-up in cases where we stopped surgery, whereas 6 of 13 cases showed deteriorated motor function at 1-month follow-up in cases where we continued surgery. Conclusion  Stopping tumor resection on deterioration of motor function during awake surgery may help prevent worsened paresis at 1-month follow-up. Georg Thieme Verlag KG Stuttgart · New York.

Coordinated Excitation and Inhibition of Prefrontal Ensembles During Awake Hippocampal Sharp-Wave Ripple Events

PubMed Central

Jadhav, Shantanu P.; Rothschild, Gideon; Roumis, Demetris K.; Frank, Loren M.

2016-01-01

SUMMARY Interactions between the hippocampus and prefrontal cortex (PFC) are critical for learning and memory. Hippocampal activity during awake sharp wave ripple (SWR) events is important for spatial learning, and hippocampal SWR activity often represents past or potential future experiences. Whether or how this reactivation engages the PFC, and how reactivation might interact with ongoing patterns of PFC activity remains unclear. We recorded hippocampal CA1 and PFC activity in animals learning spatial tasks and found that many PFC cells showed spiking modulation during SWRs. Unlike in CA1, SWR-related activity in PFC comprised both excitation and inhibition of distinct populations. Within individual SWRs, excitation activated PFC cells with representations related to the concurrently reactivated hippocampal representation, while inhibition suppressed PFC cells with unrelated representations. Thus, awake SWRs mark times of strong coordination between hippocampus and PFC that reflects structured reactivation of representations related to ongoing experience. PMID:26971950

Radiographic findings in cats with intranasal neoplasia or chronic rhinitis: 29 cases (1982-1988).

PubMed

O'Brien, R T; Evans, S M; Wortman, J A; Hendrick, M J

1996-02-01

To compare radiographic findings and determine useful criteria to differentiate between intranasal neoplasia and chronic rhinitis in cats. Retrospective study. Cats with chronic nasal disease caused by neoplasia (n = 18) or by chronic rhinitis (n = 11). Radiographs were reviewed by 3 radiologists, followed by group review. Diagnosis was determined by intranasal biopsy or necropsy, and specimens were reviewed by a pathologist to confirm cause and histologic diagnosis. Lymphosarcoma was the most common (n = 5) of the 6 histopathologic types in the neoplasia group. Cats in the neoplasia and chronic rhinitis groups had a high prevalence of aggressive radiographic lesions. Prevalence of a facial mass in cats with neoplasia (8/18) versus in those with chronic rhinitis (4/11) and of deviation (9/18 vs 6/11, respectively) or lysis (12/18 vs 7/11) of the nasal septum was similar. However, significantly (P = 0.02) more cats with neoplasia than with chronic rhinitis (13/16 vs 3/7, respectively) had unilateral turbinate destruction/lysis. Additionally, unilateral lateral bone erosion and loss of teeth associated with adjacent intranasal disease were more prevalent in cats with neoplasia (7/8 and 5/18, respectively) than in cats with chronic rhinitis (1/3 and 0/11, respectively). Features that may assist in radiographic diagnosis of neoplasia include the appearance of unilateral aggressive lesions, such as lysis of lateral bones, nasal turbinate destruction, and loss of teeth. Bilaterally symmetric lesions are more suggestive of chronic rhinitis than of neoplasia.

Comparison of sedation by intranasal dexmedetomidine and oral chloral hydrate for pediatric ophthalmic examination.

PubMed

Cao, Qianzhong; Lin, Yiquan; Xie, Zhubin; Shen, Weihua; Chen, Ying; Gan, Xiaoliang; Liu, Yizhi

2017-06-01

Pediatric ophthalmic examinations can be conducted under sedation either by chloral hydrate or by dexmedetomidine. The objective was to compare the success rates and quality of ophthalmic examination of children sedated by intranasal dexmedetomidine vs oral chloral hydrate. One hundred and forty-one children aged from 3 to 36 months (5-15 kg) scheduled to ophthalmic examinations were randomly sedated by either intranasal dexmedetomidine (2 μg·kg -1 , n = 71) or oral chloral hydrate (80 mg·kg -1 , n = 70). The primary endpoint was successful sedation to complete the examinations including slit-lamp photography, tonometry, anterior segment analysis, and refractive error inspection. The secondary endpoints included quality of eye position, intraocular pressure, onset time, duration of examination, recovery time, discharge time, any side effects during examination, and within 48 h after discharge. Sixty-one children were sedated by dexmedetomidine with a success rate of 85.9%, which is significantly higher than that by chloral hydrate (64.3%) [OR 3.39, 95% CI: 1.48-7.76, P = 0.003]. Furthermore, children in the dexmedetomidine group displayed better eye position in anterior segment analysis than in chloral hydrate group median difference. All children displayed stable hemodynamics and none suffered hypoxemia in both groups. Oral chloral hydrate induced higher percentages of vomiting and altered bowel habit after discharge than dexmedetomidine. Intranasal dexmedetomidine provides more successful sedation and better quality of ophthalmic examinations than oral chloral hydrate for small children. © 2017 John Wiley & Sons Ltd.

Oral steroids alone or followed by intranasal steroids versus watchful waiting in the management of otitis media with effusion.

PubMed

Hussein, A; Fathy, H; Amin, S M; Elsisy, N

2017-10-01

To evaluate the effects of oral steroids alone or followed by intranasal steroids versus watchful waiting on the resolution of otitis media with effusion in children aged 2-11 years. A total of 290 children with bilateral otitis media with effusion were assigned to 3 groups: group A was treated with oral steroids followed by intranasal steroids, group B was treated with oral steroids alone and group C was managed with watchful waiting. Patients were evaluated with audiometry and tympanometry. The complete resolution rates of otitis media with effusion were higher in groups A and B than in group C at six weeks. There were no significant differences in otitis media with effusion resolution rates between the groups at three, six and nine months. Oral steroids lead only to a quick resolution of otitis media with effusion, with no long-term benefits. There was no benefit of using intranasal steroids in the management of otitis media with effusion.

Pharmacokinetic Modeling of Intranasal Scopolamine in Plasma Saliva and Urine

NASA Technical Reports Server (NTRS)

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

2014-01-01

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

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Blecharz-Klin, Kamilla; Piechal, Agnieszka; Joniec-Maciejak, Ilona

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 spatialmore » 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.« less

Buccal sulcus versus intranasal approach for postoperative periorbital oedema and ecchymosis in lateral nasal osteotomy.

PubMed

Ghazipour, Ali; Alani, Nadereh; Ghavami Lahiji, Shervin; Akbari Dilmaghani, Nader

2014-10-01

Lateral osteotomies are used in rhinoplasty to narrow the nasal bones, close the open roof deformity after hump removal, and achieve symmetry of an asymmetrical framework. But this procedure causes periorbital oedema & ecchymosis. Different techniques have been described for lateral osteotomy. To compare the postoperative ecchymosis and oedema after buccal sulcus lateral osteotomy versus intranasal lateral osteotomy. In a prospective experimental study, buccal sulcus approach was performed on the right side and an intranasal approach performed on the left side of patients randomly. Then blind analysis of postoperative photographs was performed to determine the incidence of oedema and ecchymosis on each side. Fifty patients were enrolled in the study after exclusion of unfit patients. On the right side (buccal approach osteotomies), a significantly lower incidence of upper and lower eyelid oedema and upper eyelid ecchymosis was seen on both the 2nd day and after 7th day (P < 0.05). The odds ratio of progression of ecchymosis was 2.66 (OR = 2.66, 95% CI: 1.09-5.52, p = 0.048) in intranasal group compare to buccal sulcus group. No significant complication observed. The buccal sulcus approach is a safe method for lateral osteotomy with a lower rate of postoperative oedema and ecchymosis and no significant complications. Copyright © 2014 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

Intranasal delivery of recombinant parvovirus-like particles elicits cytotoxic T-cell and neutralizing antibody responses.

PubMed

Sedlik, C; Dridi, A; Deriaud, E; Saron, M F; Rueda, P; Sarraseca, J; Casal, J I; Leclerc, C

1999-04-01

We previously demonstrated that chimeric porcine parvovirus-like particles (PPV:VLP) carrying heterologous epitopes, when injected intraperitoneally into mice without adjuvant, activate strong CD4(+) and CD8(+) T-cell responses specific for the foreign epitopes. In the present study, we investigated the immunogenicity of PPV:VLP carrying a CD8(+) T-cell epitope from the lymphocytic choriomeningitis virus (LCMV) administered by mucosal routes. Mice immunized intranasally with recombinant PPV:VLP, in the absence of adjuvant, developed high levels of PPV-specific immunoglobulin G (IgG) and/or IgA in their serum, as well as in mucosal sites such as the bronchoalveolar and intestinal fluids. Antibodies in sera from mice immunized parenterally or intranasally with PPV:VLP were strongly neutralizing in vitro. Intranasal immunization with PPV:VLP carrying the LCMV CD8(+) T-cell epitope also elicited a strong peptide-specific cytotoxic-T-cell (CTL) response. In contrast, mice orally immunized with recombinant PPV:VLP did not develop any antibody or CTL responses. We also showed that mice primed with PPV:VLP are still able to develop strong CTL responses after subsequent immunization with chimeric PPV:VLP carrying a foreign CD8(+) T-cell epitope. These results highlight the attractive potential of PPV:VLP as a safe, nonreplicating antigen carrier to stimulate systemic and mucosal immunity after nasal administration.

Intranasal Delivery of Recombinant Parvovirus-Like Particles Elicits Cytotoxic T-Cell and Neutralizing Antibody Responses

PubMed Central

Sedlik, C.; Dridi, A.; Deriaud, E.; Saron, M. F.; Rueda, P.; Sarraseca, J.; Casal, J. I.; Leclerc, C.

1999-01-01

We previously demonstrated that chimeric porcine parvovirus-like particles (PPV:VLP) carrying heterologous epitopes, when injected intraperitoneally into mice without adjuvant, activate strong CD4+ and CD8+ T-cell responses specific for the foreign epitopes. In the present study, we investigated the immunogenicity of PPV:VLP carrying a CD8+ T-cell epitope from the lymphocytic choriomeningitis virus (LCMV) administered by mucosal routes. Mice immunized intranasally with recombinant PPV:VLP, in the absence of adjuvant, developed high levels of PPV-specific immunoglobulin G (IgG) and/or IgA in their serum, as well as in mucosal sites such as the bronchoalveolar and intestinal fluids. Antibodies in sera from mice immunized parenterally or intranasally with PPV:VLP were strongly neutralizing in vitro. Intranasal immunization with PPV:VLP carrying the LCMV CD8+ T-cell epitope also elicited a strong peptide-specific cytotoxic-T-cell (CTL) response. In contrast, mice orally immunized with recombinant PPV:VLP did not develop any antibody or CTL responses. We also showed that mice primed with PPV:VLP are still able to develop strong CTL responses after subsequent immunization with chimeric PPV:VLP carrying a foreign CD8+ T-cell epitope. These results highlight the attractive potential of PPV:VLP as a safe, nonreplicating antigen carrier to stimulate systemic and mucosal immunity after nasal administration. PMID:10074120

Clinical utility of insulin and insulin analogs

PubMed Central

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

2013-01-01

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

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

NASA Astrophysics Data System (ADS)

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.

Intranasal delivery of hypoxia-preconditioned bone marrow-derived mesenchymal stem cells enhanced regenerative effects after intracerebral hemorrhagic stroke in mice.

PubMed

Sun, Jinmei; Wei, Zheng Zachory; Gu, Xiaohuan; Zhang, James Ya; Zhang, Yongbo; Li, Jimei; Wei, Ling

2015-10-01

Intracerebral hemorrhagic stroke (ICH) causes high mortality and morbidity with very limited treatment options. Cell-based therapy has emerged as a novel approach to replace damaged brain tissues and promote regenerative processes. In this study we tested the hypothesis that intranasally delivered hypoxia-preconditioned BMSCs could reach the brain, promote tissue repair and improve functional recovery after ICH. Hemorrhagic stroke was induced in adult C57/B6 mice by injection of collagenase IV into the striatum. Animals were randomly divided into three groups: sham group, intranasal BMSC treatment group, and vehicle treatment group. BMSCs were pre-treated with hypoxic preconditioning (HP) and pre-labeled with Hoechst before transplantation. Behavior tests, including the mNSS score, rotarod test, adhesive removal test, and locomotor function evaluation were performed at varying days, up to 21days, after ICH to evaluate the therapeutic effects of BMSC transplantation. Western blots and immunohistochemistry were performed to analyze the neurotrophic effects. Intranasally delivered HP-BMSCs were identified in peri-injury regions. NeuN+/BrdU+ co-labeled cells were markedly increased around the hematoma region, and growth factors, including BDNF, GDNF, and VEGF were significantly upregulated in the ICH brain after BMSC treatment. The BMSC treatment group showed significant improvement in behavioral performance compared with the vehicle group. Our data also showed that intranasally delivered HP-BMSCs migrated to peri-injury regions and provided growth factors to increase neurogenesis after ICH. We conclude that intranasal administration of BMSC is an effective treatment for ICH, and that it enhanced neuroregenerative effects and promoted neurological functional recovery after ICH. Overall, the investigation supports the potential therapeutic strategy for BMSC transplantation therapy against hemorrhagic stroke. Copyright © 2015 Elsevier Inc. All rights reserved.

Prolonged protection against Intranasal challenge with influenza virus following systemic immunization or combinations of mucosal and systemic immunizations with a heat-labile toxin mutant.

PubMed

Zhou, Fengmin; Goodsell, Amanda; Uematsu, Yasushi; Vajdy, Michael

2009-04-01

Seasonal influenza virus infections cause considerable morbidity and mortality in the world, and there is a serious threat of a pandemic influenza with the potential to cause millions of deaths. Therefore, practical influenza vaccines and vaccination strategies that can confer protection against intranasal infection with influenza viruses are needed. In this study, we demonstrate that using LTK63, a nontoxic mutant of the heat-labile toxin from Escherichia coli, as an adjuvant for both mucosal and systemic immunizations, systemic (intramuscular) immunization or combinations of mucosal (intranasal) and intramuscular immunizations protected mice against intranasal challenge with a lethal dose of live influenza virus at 3.5 months after the second immunization.

Curdlan sulfate-O-linked quaternized chitosan nanoparticles: potential adjuvants to improve the immunogenicity of exogenous antigens via intranasal vaccination.

PubMed

Zhang, Shu; Huang, Shengshi; Lu, Lu; Song, Xinlei; Li, Pingli; Wang, Fengshan

2018-01-01

The development of ideal vaccine adjuvants for intranasal vaccination can provide convenience for many vaccinations. As an ideal intranasal vaccine adjuvant, it should have the properties of assisting soluble antigens to pass the mucosal barrier and potentiating both systemic and mucosal immunity via nasal administration. By using the advantages of polysaccharides, which can promote both T-helper 1 and 2 responses, curdlan sulfate (CS)- O -(2-hydroxyl)propyl-3-trimethyl ammonium chitosan chloride ( O -HTCC) nanoparticles were prepared by interacting CS with O -HTCC, and the adjuvancy of the nanoparticles was investigated. The results showed that the polysaccharide-based nanoparticles induced the proliferation and activation of antigen-presenting cells. High protein-loading efficiency was obtained by testing with the model antigen ovalbumin (Ova), and the Ova adsorbed onto the cationic CS/ O -HTCC complexes was taken up easily by the epithelium. To evaluate the capacity of the Ova/CS/ O -HTCC nanoparticles for immune enhancement in vivo, we collected and analyzed immunocytes, serum, and mucosal lavage fluid from intranasally vaccinated mice. The results showed that Ova/CS/ O -HTCC nanoparticles induced activation and maturation of antigen-presenting cells and provoked the proliferation and differentiation of lymphocytes more significantly compared to the immunization of Ova mixed with aluminum hydroxide gel. Furthermore, CS/ O -HTCC evoked a significantly higher level of Ova-specific antibodies. Therefore, these results suggest that CS/ O -HTCC nanoparticles are ideal vaccine adjuvants for soluble antigens used in intranasal or mucosal vaccination.

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

PubMed Central

Silasi, Gergely; Xiao, Dongsheng; Vanni, Matthieu P.; Chen, Andrew C. N.; Murphy, Timothy H.

2016-01-01

Background Craniotomy-based window implants are commonly used for microscopic imaging, in head-fixed rodents, however their field of view is typically small and incompatible with mesoscopic functional mapping of cortex. New Method We describe a reproducible and simple procedure for chronic through-bone wide-field imaging in awake head-fixed mice providing stable optical access for chronic imaging over large areas of the cortex for months. Results The preparation is produced by applying clear-drying dental cement to the intact mouse skull, followed by a glass coverslip to create a partially transparent imaging surface. Surgery time takes about 30 minutes. A single set-screw provides a stable means of attachment for mesoscale assessment without obscuring the cortical field of view. Comparison with Existing Methods We demonstrate the utility of this method by showing seed-pixel functional connectivity maps generated from spontaneous cortical activity of GCAMP6 signals in both awake and anesthetized mice. Conclusions We propose that the intact skull preparation described here may be used for most longitudinal studies that do not require micron scale resolution and where cortical neural or vascular signals are recorded with intrinsic sensors. PMID:27102043

Anesthesia for awake craniotomy: a how-to guide for the occasional practitioner.

PubMed

Meng, Lingzhong; McDonagh, David L; Berger, Mitchel S; Gelb, Adrian W

2017-05-01

Awake craniotomy (AC), defined as the performance of at least part of an open cranial procedure with the patient awake, has been tied to beneficial outcomes compared with similar surgery under general anesthesia. Improved anesthetic techniques have made a major contribution to the increasing popularity of AC. However, the heterogeneity of practice among institutions doing large numbers of ACs raises questions (often among those who only occasionally perform AC - i.e., practitioners in low-volume AC institutions) as to the ideal anesthetic technique for AC. The procedure presents a variety of decision-making dilemmas, the origins of which are the varying institutional preferences, lack of quality evidence, and several practice controversies. Evidence-based data that support a single anesthetic algorithm for AC are sparse. In this narrative review, the technical nuances of 13 aspects of anesthetic care for AC are discussed based on institutional preferences and available evidence, and the various controversies and research priorities are discussed. The skills, experience, and commitment of both the surgeon and the anesthesiologist are large variables that are likely more important than what the literature suggests about "best" techniques for AC. Optimizing patient outcome is the fundamental goal of the anesthesiologist.

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

ERIC Educational Resources Information Center

Anderson, Ross W.; Strowbridge, Ben W.

2014-01-01

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

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

PubMed

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. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Electrocorticographic Frequency Alteration Mapping of Speech Cortex during an Awake Craniotomy: Case Report

PubMed Central

Breshears, J.; Sharma, M.; Anderson, N.R.; Rashid, S.; Leuthardt, E.C.

2010-01-01

Objective Traditional electrocortical stimulation (ECS) mapping is limited by the lengthy serial investigation (one location at a time) and the risk of afterdischarges in localizing eloquent cortex. Electrocorticographic frequency alteration mapping (EFAM) allows the parallel investigation of many cortical sites in much less time and with no risk of afterdischarges because of its passive nature. We examined its use with ECS in the context of language mapping during an awake craniotomy for a tumor resection. Clinical Presentation The patient was a 61-year-old right-handed Caucasian male who presented with headache and mild aphasia. Imaging demonstrated a 3-cm cystic mass in the posterior temporal-parietal lobe. The patient underwent an awake craniotomy for the mapping of his speech cortex and resection of the mass. Intervention Using a 32-contact electrode array, electrocorticographic signals were recorded from the exposed cortex as the patient participated in a 3-min screening task involving active (patient naming visually presented words) and rest (patient silent) conditions. A spectral comparison of the 2 conditions revealed specific cortical locations associated with activation during speech. The patient was then widely mapped using ECS. Three of 4 sites identified by ECS were also identified passively and in parallel by EFAM, 2 with statistical significance and the third by qualitative inspection. Conclusion EFAM was technically achieved in an awake craniotomy patient and had good concordance with ECS mapping. Because it poses no risk of afterdischarges and offers substantial time savings, EFAM holds promise for future development as an adjunct intraoperative mapping tool. Additionally, the cortical signals obtained by this modality can be utilized for localization in the presence of a tumor adjacent to the eloquent regions. PMID:19940544

A Method to Administer Agents to the Larynx in an Awake Large Animal

ERIC Educational Resources Information Center

Durkes, Abigail; Sivasankar, M. Preeti

2017-01-01

Purpose: This research note describes an adapted experimental methodology to administer an exogenous agent to the larynx and upper airway of awake animals. The exogenous agent could be a perturbation. In the current study, the agent was isotonic saline. Isotonic saline was selected because it is safe, of similar composition to extracellular fluid,…

[Incidence and causes of early end in awake surgery for language mapping not directly related to eloquence].

PubMed

Villalba, Gloria; Pacreu, Susana; Fernández-Candil, Juan Luis; León, Alba; Serrano, Laura; Conesa, Gerardo

2016-01-01

The incidence and causes that may lead to an early end (unfinished cortical/subcortical mapping) of awake surgery for language mapping are little known. A study was conducted on 41 patients with brain glioma located in the language area that had awake surgery under conscious sedation. Surgery was ended early in 6 patients. The causes were: tonic-clonic seizure (1), lack of cooperation due to fatigue/sleep (4), whether or not word articulation was involved, a decreased level of consciousness for ammonia encephalopathy that required endotracheal intubation (1). There are causes that could be expected and in some cases avoided. Tumour size, preoperative aphasia, valproate treatment, and type of anaesthesia used are variables to consider to avoid failure in awake surgery for language mapping. With these results, the following measures are proposed: l) If the tumour is large, perform surgery in two times to avoid fatigue, 2) if patient has a preoperative aphasia, do not use sedation during surgery to ensure that sleepiness does not cause worse word articulation, 3) if the patient is on valproate treatment, it is necessary to rule out the pre-operative symptoms that are not due to ammonia encephalopathy. Copyright © 2015 Sociedad Española de Neurocirugía. Published by Elsevier España. All rights reserved.

Differential effects of intranasal oxytocin on sexual experiences and partner interactions in couples.

PubMed

Behnia, Behnoush; Heinrichs, Markus; Bergmann, Wiebke; Jung, Stefanie; Germann, Janine; Schedlowski, Manfred; Hartmann, Uwe; Kruger, Tillmann H C

2014-03-01

Knowledge about the effects of the neuropeptide oxytocin (OXT) on human sexual behaviors and partner interactions remains limited. Based on our previous studies, we hypothesize that OXT should be able to positively influence parameters of sexual function and couple interactions. Employing a naturalistic setting involving 29 healthy heterosexual couples (n=58 participants), we analyzed the acute effects of intranasally administered OXT (24IU) on sexual drive, arousal, orgasm and refractory aspects of sexual behavior together with partner interactions. Data were assessed by psychometric instruments (Acute Sexual Experiences Scale, Arizona Sexual Experience Scale) as well as biomarkers, such as cortisol, α-amylase and heart rate. Intranasal OXT administration did not alter "classical" parameters of sexual function, such as sexual drive, arousal or penile erection and lubrication. However, analysis of variance and a hierarchical linear model (HLM) revealed specific effects related to the orgasmic/post-orgasmic interval as well as parameters of partner interactions. According to HLM analysis, OXT increased the intensity of orgasm, contentment after sexual intercourse and the effect of study participation. According to ANOVA analysis, these effects were more pronounced in men. Men additionally indicated higher levels of sexual satiety after sexual intercourse with OXT administration. Women felt more relaxed and subgroups indicated better abilities to share sexual desires or to empathize with their partners. The effect sizes were small to moderate. Biomarkers indicated moderate psychophysiological activation but were not affected by OXT, gender or method of contraception. Using a naturalistic setting, intranasal OXT administration in couples exerted differential effects on parameters of sexual function and partner interactions. These results warrant further investigations, including subjects with sexual and relationship problems. Copyright © 2014 Elsevier Inc. All

Pediatric emergency department triage-based pain guideline utilizing intranasal fentanyl: Effect of implementation.

PubMed

Schoolman-Anderson, Kristin; Lane, Roni D; Schunk, Jeff E; Mecham, Nancy; Thomas, Richard; Adelgais, Kathleen

2018-01-16

Pain management guidelines in the emergency department (ED) may reduce time to analgesia administration (TTA). Intranasal fentanyl (INF) is a safe and effective alternative to intravenous opiates. The effect of an ED pain management guideline providing standing orders for nurse-initiated administration of intranasal fentanyl (INF) is not known. The objective of this study was to determine the impact of a pediatric ED triage-based pain protocol utilizing intranasal fentanyl (INF) on time to analgesia administration (TTA) and patient and parent satisfaction. This was a prospective study of patients 3-17 years with an isolated orthopedic injury presenting to a pediatric ED before and after instituting a triage-based pain guideline allowing for administration of INF by triage nurses. Our primary outcome was median TTA and secondary outcomes included the proportion of patients who received INF for pain, had unnecessary IV placement, and patient and parent satisfaction. We enrolled 132 patients; 72 pre-guideline, 60 post-guideline. Demographics were similar between groups. Median TTA was not different between groups (34.5 min vs. 33 min, p = .7). Utilization of INF increased from 41% pre-guideline to 60% post-guideline (p = .01) and unnecessary IV placement decreased from 24% to 0% (p = .002). Patients and parents preferred the IN route for analgesia administration. A triage-based pain protocol utilizing INF did not reduce TTA, but did result in increased INF use, decreased unnecessary IV placement, and was preferred by patients and parents to IV medication. INF is a viable analgesia alternative for children with isolated extremity injuries. Copyright © 2018. Published by Elsevier Inc.

Intranasal delivery: physicochemical and therapeutic aspects.

PubMed

Costantino, Henry R; Illum, Lisbeth; Brandt, Gordon; Johnson, Paul H; Quay, Steven C

2007-06-07

Interest in intranasal (IN) administration as a non-invasive route for drug delivery continues to grow rapidly. The nasal mucosa offers numerous benefits as a target issue for drug delivery, such as a large surface area for delivery, rapid drug onset, potential for central nervous system delivery, and no first-pass metabolism. A wide variety of therapeutic compounds can be delivered IN, including relatively large molecules such as peptides and proteins, particularly in the presence of permeation enhancers. The current review provides an in-depth discussion of therapeutic aspects of IN delivery including consideration of the intended indication, regimen, and patient population, as well as physicochemical properties of the drug itself. Case examples are provided to illustrate the utility of IN dosing. It is anticipated that the present review will prove useful for formulation scientists considering IN delivery as a delivery route.

Insulin and insulin signaling play a critical role in fat induction of insulin resistance in mouse

PubMed Central

Ning, Jie; Hong, Tao; Yang, Xuefeng; Mei, Shuang; Liu, Zhenqi; Liu, Hui-Yu

2011-01-01

The primary player that induces insulin resistance has not been established. Here, we studied whether or not fat can cause insulin resistance in the presence of insulin deficiency. Our results showed that high-fat diet (HFD) induced insulin resistance in C57BL/6 (B6) mice. The HFD-induced insulin resistance was prevented largely by the streptozotocin (STZ)-induced moderate insulin deficiency. The STZ-induced insulin deficiency prevented the HFD-induced ectopic fat accumulation and oxidative stress in liver and gastrocnemius. The STZ-induced insulin deficiency prevented the HFD- or insulin-induced increase in hepatic expression of long-chain acyl-CoA synthetases (ACSL), which are necessary for fatty acid activation. HFD increased mitochondrial contents of long-chain acyl-CoAs, whereas it decreased mitochondrial ADP/ATP ratio, and these HFD-induced changes were prevented by the STZ-induced insulin deficiency. In cultured hepatocytes, we observed that expressions of ACSL1 and -5 were stimulated by insulin signaling. Results in cultured cells also showed that blunting insulin signaling by the PI3K inhibitor LY-294002 prevented fat accumulation, oxidative stress, and insulin resistance induced by the prolonged exposure to either insulin or oleate plus sera that normally contain insulin. Finally, knockdown of the insulin receptor prevented the oxidative stress and insulin resistance induced by the prolonged exposure to insulin or oleate plus sera. Together, our results show that insulin and insulin signaling are required for fat induction of insulin resistance in mice and cultured mouse hepatocytes. PMID:21586696

Sedation with intranasal midazolam of Angolan children undergoing invasive procedures.

PubMed

Kawanda, Lumana; Capobianco, Ivan; Starc, Meta; Felipe, Daniel; Zanon, Davide; Barbi, Egidio; Munkela, Nadine; Rodrigues, Verónica; Malundo, Lúis; Not, Tarcisio

2012-07-01

Ambulatory surgery is a daily requirement in poor countries, and limited means and insufficient trained staff lead to the lack of attention to the patient's pain. Midazolam is a rapid-onset, short-acting benzodiazepine which is used safely to reduce pain in children. We evaluated the practicability of intranasal midazolam sedation in a suburban hospital in Luanda (Angola), during the surgical procedures. Intranasal midazolam solution was administered at a dose of 0.5 mg/kg. Using the Ramsay's reactivity score, we gave a score to four different types of children's behaviour: moaning, shouting, crying and struggling, and the surgeon evaluated the ease of completing the surgical procedure using scores from 0 (very easy) to 3 (managing with difficulty). Eighty children (median age, 3 years) were recruited, and 140 surgical procedures were performed. Fifty-two children were treated with midazolam during 85 procedures, and 28 children were not treated during 55 procedures. We found a significant difference between the two groups on the shouting, crying and struggling parameters (p < 0.001). The mean score of the ease of completing the procedures was significantly different among the two groups (p < 0.0001). These results provide a model of procedural sedation in ambulatory surgical procedures in poor countries, thus abolishing pain and making the surgeon's job easier. © 2012 The Author(s)/Acta Paediatrica © 2012 Foundation Acta Paediatrica.

Autophagy Differentially Regulates Insulin Production and Insulin Sensitivity.

PubMed

Yamamoto, Soh; Kuramoto, Kenta; Wang, Nan; Situ, Xiaolei; Priyadarshini, Medha; Zhang, Weiran; Cordoba-Chacon, Jose; Layden, Brian T; He, Congcong

2018-06-12

Autophagy, a stress-induced lysosomal degradative pathway, has been assumed to exert similar metabolic effects in different organs. Here, we establish a model where autophagy plays different roles in insulin-producing β cells versus insulin-responsive cells, utilizing knockin (Becn1 F121A ) mice manifesting constitutively active autophagy. With a high-fat-diet challenge, the autophagy-hyperactive mice unexpectedly show impaired glucose tolerance, but improved insulin sensitivity, compared to mice with normal autophagy. Autophagy hyperactivation enhances insulin signaling, via suppressing ER stress in insulin-responsive cells, but decreases insulin secretion by selectively sequestrating and degrading insulin granule vesicles in β cells, a process we term "vesicophagy." The reduction in insulin storage, insulin secretion, and glucose tolerance is reversed by transient treatment of autophagy inhibitors. Thus, β cells and insulin-responsive tissues require different autophagy levels for optimal function. To improve insulin sensitivity without hampering secretion, acute or intermittent, rather than chronic, activation of autophagy should be considered in diabetic therapy development. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Suicide and sleep: Is it a bad thing to be awake when reason sleeps?

PubMed

Perlis, Michael L; Grandner, Michael A; Chakravorty, Subhajit; Bernert, Rebecca A; Brown, Gregory K; Thase, Michael E

2016-10-01

Suicide is the second leading cause of death, worldwide, for those between the ages of 24 and 44 y old. In 2013, more than 41,000 suicides occurred in the United States. These statistics underscore the need to 1) understand why people die by suicide and 2) identify risk factors that are potentially modifiable. While it has been posited that sleep disturbance may represent one such factor, systematic research in this arena did not begin until the 2000s. Since that time, sleep disturbance has been reliably identified as a risk factor for suicidal ideation, suicide attempts, and suicide. While insomnia, nightmares, and other sleep disorders have each been found to contribute to the risk for suicidal ideation and behavior, it is also possible that these factors share some common variance. One possibility is that sleep disturbance results in being awake at night, and being awake at night also confers risk. The hypothesis proffered here is that being awake when one is not biologically prepared to be so results in "hypofrontality" and diminished executive function, and that this represents a common pathway to suicidal ideation and behavior. Such a proposition is highly testable under a variety of possible protocols. The current review summarizes the extant literature on suicide rates by time-of-day, and discusses circadian, psychosocial, and neurocognitive explanations of risk. Such a focus promises to enhance our understanding of how sleep disturbance may confer risk, allows for the identification of future lines of research, and further justifies the need for interventions that promote good sleep continuity among at-risk individuals. Copyright © 2015 Elsevier Ltd. All rights reserved.

Awake craniotomy for glioma resection: Technical aspects and initial results in a single institution.

PubMed

Trimble, Gillian; McStravick, Clodagh; Farling, Peter; Megaw, Katie; McKinstry, Steven; Smyth, Graham; Law, Gillian; Courtney, Heather; Quigley, Gavin; Flannery, Thomas

2015-01-01

Although variations in the technique of awake craniotomy (AC) have been widely reported, a key member of this interdisciplinary procedure is the healthcare professional performing assessments of neurological function during resection. The expertise of the latter will depend on the neurological function to be tested and on available resources of the institution. This report details our initial experience of an AC service utilizing the expertise of a speech and language therapist (SLT) and an experienced neuro-physiotherapist (NP) to monitor patient function during glioma resection. Forty-five patients underwent 50 AC procedures for eloquently located gliomas over a 3-year period. Patients with a glioma involving speech or sensorimotor areas were assessed preoperatively by the SLT/NP respectively. The same therapist monitored the patient's neurological function intraoperatively and executed a rehabilitation program tailored to the needs of the patient in the postoperative period. Three patients underwent biopsy only, due to intraoperative seizures precluding intraoperative mapping (2 cases) or speech arrest on stimulation of a small recurrent tumor. The remaining 47 cases were suitable for repetitive neurological assessment "awake" during tumor debulking. One patient with a large sensorimotor tumor developed intraoperative hemiparesis due to outward brain herniation (which recovered postoperatively). Ten patients developed a new or worsened neurological deficit in the initial postoperative period (6 were detected intraoperatively), of which 5 eventually had resolution and returned to baseline function within 2 weeks. In our initial experience based anecdotally on a previous similar "non-awake" caseload, we have found AC with the input of the SLT/NP to be a key component in ensuring optimal functional outcomes for patients with gliomas in eloquently located areas.

Suicide and sleep: Is it a bad thing to be awake when reason sleeps?

PubMed Central

Perlis, Michael L.; Grandner, Michael A.; Chakravorty, Subhajit; Bernert, Rebecca A.; Brown, Gregory K.; Thase, Michael E.

2016-01-01

Suicide is the second leading cause of death, worldwide, for those between the ages of 24 and 44 y old. In 2013, more than 41,000 suicides occurred in the United States. These statistics underscore the need to 1) understand why people die by suicide and 2) identify risk factors that are potentially modifiable. While it has been posited that sleep disturbance may represent one such factor, systematic research in this arena did not begin until the 2000s. Since that time, sleep disturbance has been reliably identified as a risk factor for suicidal ideation, suicide attempts, and suicide. While insomnia, nightmares, and other sleep disorders have each been found to contribute to the risk for suicidal ideation and behavior, it is also possible that these factors share some common variance. One possibility is that sleep disturbance results in being awake at night, and being awake at night also confers risk. The hypothesis proffered here is that being awake when one is not biologically prepared to be so results in “hypofrontality” and diminished executive function, and that this represents a common pathway to suicidal ideation and behavior. Such a proposition is highly testable under a variety of possible protocols. The current review summarizes the extant literature on suicide rates by time-of-day, and discusses circadian, psychosocial, and neuro-cognitive explanations of risk. Such a focus promises to enhance our understanding of how sleep disturbance may confer risk, allows for the identification of future lines of research, and further justifies the need for interventions that promote good sleep continuity among at-risk individuals. PMID:26706755

Intranasal desmopressin versus blood transfusion in cirrhotic patients with coagulopathy undergoing dental extraction: a randomized controlled trial.

PubMed

Stanca, Carmen M; Montazem, Andre H; Lawal, Adeyemi; Zhang, Jin X; Schiano, Thomas D

2010-01-01

Cirrhotic patients waiting for liver transplantation who need dental extractions are given fresh frozen plasma and/or platelets to correct coagulopathy. This is costly and may be associated with transfusion reactions and fluid overload. We evaluated the efficacy of intranasal desmopressin as an alternative to transfusion to correct the coagulopathy of cirrhotic patients undergoing dental extraction. Cirrhotic patients with platelet counts of 30,000 to 50,000/microL and/or international normalized ratio (INR) 2.0 to 3.0 were enrolled in a prospective, controlled, randomized clinical trial. Blood transfusion (fresh frozen plasma 10 mL/kg and/or 1 unit of single donor platelets, respectively) or intranasal desmopressin (300 microg) were given before dental extraction. A standard oral and maxillofacial surgical treatment protocol was performed by the same surgeon. Patients were followed for postextraction bleeding and side-effects over the next 24 to 48 hours. No significant differences were noted between the 2 groups in gender, age, INR, platelet count, creatinine, total bilirubin, ALT, albumin, MELD score, or number of teeth removed (median 3 vs 4). The number of teeth removed ranged between 1 and 31 in the desmopressin group and 1 and 22 in the transfusion group. No patients in desmopressin group required rescue blood transfusion after extraction. One patient in the transfusion group had bleeding after the procedure and required an additional transfusion. Another patient experienced an allergic reaction at the end of transfusion, which was effectively treated with diphenhydramine. Treatment associated average costs were lower for desmopressin ($700/patient) compared with transfusion ($1,173/patient). Intranasal desmopressin was as effective as blood transfusion in achieving hemostasis in cirrhotic patients with moderate coagulopathy undergoing dental extraction. Intranasal desmopressin was much more convenient, less expensive, and well tolerated.

Non-invasive intranasal delivery of quetiapine fumarate loaded microemulsion for brain targeting: Formulation, physicochemical and pharmacokinetic consideration.

PubMed

Shah, Brijesh; Khunt, Dignesh; Misra, Manju; Padh, Harish

2016-08-25

Systemic drug delivery in schizophrenia is a major challenge due to presence of obstacles like, blood-brain barrier and P-glycoprotein, which prohibit entry of drugs into the brain. Quetiapine fumarate (QF), a substrate to P-glycoprotein under goes extensive first pass metabolism leading to limited absorption thus necessitating frequent oral administration. The aim of this study was to develop QF based microemulsion (ME) with and without chitosan (CH) to investigate its potential use in improving the bioavailability and brain targeting efficiency following non-invasive intranasal administration. QF loaded ME and mucoadhesive ME (MME) showed globule size, pH and viscosity in the range of 29-47nm, 5.5-6.5 and 17-40cP respectively. CH-ME with spherical globules having mean size of 35.31±1.71nm, pH value of 5.61±0.16 showed highest ex-vivo nasal diffusion (78.26±3.29%) in 8h with no sign of structural damage upon histopathological examination. Circular plume with an ovality ratio closer to 1.3 for CH-ME depicted ideal spray pattern. Significantly higher brain/blood ratio of CH-ME in comparison to QF-ME and drug solution following intranasal administration revealed prolonged retention of QF at site of action suggesting superiority of CH as permeability enhancer. Following intranasal administration, 2.7 and 3.8 folds higher nasal bioavailability in brain with CH-ME compared to QF-ME and drug solution respectively is indicative of preferential nose to brain transport (80.51±6.46%) bypassing blood-brain barrier. Overall, the above finding shows promising results in the area of developing non-invasive intranasal route as an alternative to oral route for brain delivery. Copyright © 2016 Elsevier B.V. All rights reserved.

Rescue Sedation With Intranasal Dexmedetomidine for Pediatric Ophthalmic Examination After Chloral Hydrate Failure: A Randomized, Controlled Trial.

PubMed

Gan, Xiaoliang; Lin, Haotian; Chen, Jingjing; Lin, Zhuoling; Lin, Yiquan; Chen, Weirong

2016-06-01

It is a challenge to rescue ophthalmology examinations performed in children in the sedation room after initial chloral hydrate failure. Intranasal dexmedetomidine can be used in rescue sedation in children undergoing computed tomography. The present study aimed to assess the efficacy and tolerability of intranasal dexmedetomidine use in children undergoing ophthalmic examination after chloral hydrate failure. Sixty uncooperative pediatric patients with cataract (aged 5-36 months; weight, 7-15 kg) presented for follow-up ophthalmic examination. Patients who experienced chloral hydrate failure were randomized to 1 of 2 groups to receive intranasal dexmedetomidine 1 or 2 μg/kg for rescue sedation. Each group contained 30 patients. The primary outcome was the rate of a successful ophthalmic examination. Secondary outcomes included sedation onset time, recovery time, duration of examination, discharge time, and adverse events, including percentage of heart rate reduction, respiratory depression, vomiting, and postsedative agitation. A successful ophthalmic examination was achieved in 93.3% (28/30) of patients in the 2-μg/kg dose group and in 66.7% (20/30) of patients in the 1-μg/kg dose group (P = 0.021). The onset time, recovery time, and discharge time did not significantly differ between the 2 groups. None of the patients required clinical intervention due to heart rate reduction, and none of the patients in either group experienced vomiting, respiratory depression, or agitation after the administration of dexmedetomidine. In children undergoing ophthalmic examination, intranasal dexmedetomidine can be administered in the sedation room for rescue sedation after chloral hydrate failure, with the 2-μg/kg dose being more efficacious than the 1-μg/kg dose, as measured by success rate. ClinicalTrials.gov identifier: NCT02077712. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Efficacy of Intranasal Scopolamine Gel for Motion Sickness Treatment in Aviation Candidates

DTIC Science & Technology

2009-04-13

Baseline 15 25 80 115 145 190 M ea n B lo o d P re ss u re (m m H g ) 0 20 40 60 80 100 120 140 Systolic BP P Systolic BPIN Diastolic BPP Diastolic...scopolamine when compared to placebo, p < .05. BPP = Blood Pressure, Placebo, BPIN = Blood Pressure, Intranasal Scopolamine 31 Time (min) Baseline 15 25 80

Comparative pathogenesis of H3N2 canine influenza virus in beagle dogs challenged by intranasal and intratracheal inoculation.

PubMed

Luo, Jie; Lu, Gang; Ye, Shaotang; Ou, Jiajun; Fu, Cheng; Zhang, Xin; Wang, Xiangbin; Huang, Ji; Wu, Peixin; Xu, Haibin; Wu, Liyan; Li, Shoujun

2018-05-31

As important companion animals, dogs may serve as intermediate hosts for transmitting influenza virus to humans. However, knowledge regarding H3N2 canine influenza virus (CIV) pathogenicity is not comprehensive, which directly affects the animal models of pathogenicity in H3N2 CIV vaccine research. Here, to assess H3N2 CIV pathogenicity, we utilized 30 ten-week-old purpose-bred beagles intratracheally or intranasally inoculated with 10 6 50 % egg-infectious dose. Intratracheal inoculation was more virulent to dogs than intranasal inoculation as shown by lung pathology score, histopathological changes, clinical symptoms, and body temperature. More intense virus replication was observed in the upper and lower respiratory tracts by intratracheal than intranasal inoculation according to nasal swabs, various organ virus titers, and antigen expression. These results may enhance the H3N2 CIV infection model, providing a more complete experimental basis for studying intrinsic H3N2 CIV pathogenic mechanism, and also serving a reference role for CIV prevention and treatment. Copyright © 2018. Published by Elsevier B.V.

Insulin Secretagogues

MedlinePlus

... the Spikes Is mealtime insulin right for you? Insulin Secretagogues September 2017 Download PDFs English Espanol Editors ... Additional Resources Affordable Insulin Project FDA What are insulin secretagogues? Insulin secretagogues are one type of medicine ...

Clinical outcomes from maximum-safe resection of primary and metastatic brain tumors using awake craniotomy.

PubMed

Groshev, Anastasia; Padalia, Devang; Patel, Sephalie; Garcia-Getting, Rosemarie; Sahebjam, Solmaz; Forsyth, Peter A; Vrionis, Frank D; Etame, Arnold B

2017-06-01

To retrospectively analyze outcomes in patients undergoing awake craniotomies for tumor resection at our institution in terms of extent of resection, functional preservation and length of hospital stay. All cases of adults undergoing awake-craniotomy from September 2012-February 2015 were retrospectively reviewed based on an IRB approved protocol. Information regarding patient age, sex, cancer type, procedure type, location, hospital stay, extent of resection, and postoperative complications was extracted. 76 patient charts were analyzed. Resected cancer types included metastasis to the brain (41%), glioblastoma (34%), WHO grade III anaplastic astrocytoma (18%), WHO grade II glioma (4%), WHO grade I glioma (1%), and meningioma (1%). Over a half of procedures were performed in the frontal lobes, followed by temporal, and occipital locations. The most common indication was for motor cortex and primary somatosensory area lesions followed by speech. Extent of resection was gross total for 59% patients, near-gross total for 34%, and subtotal for 7%. Average hospital stay for the cohort was 1.7days with 75% of patients staying at the hospital for only 24h or less post surgery. In the postoperative period, 67% of patients experienced improvement in neurological status, 21% of patients experienced no change, 7% experienced transient neurological deficits, which resolved within two months post op, 1% experienced transient speech deficit, and 3% experienced permanent weakness. In a consecutive series of 76 patients undergoing maximum-safe resection for primary and metastatic brain tumors, awake-craniotomy was associated with a short hospital stay and low postoperative complications rate. Copyright © 2017 Elsevier B.V. All rights reserved.

Using a Virtual Reality Social Network During Awake Craniotomy to Map Social Cognition: Prospective Trial.

PubMed

Bernard, Florian; Lemée, Jean-Michel; Aubin, Ghislaine; Ter Minassian, Aram; Menei, Philippe

2018-06-26

In awake craniotomy, it is possible to temporarily inactivate regions of the brain using direct electrical stimulation, while the patient performs neuropsychological tasks. If the patient shows decreased performance in a given task, the neurosurgeon will not remove these regions, so as to maintain all brain functions. The objective of our study was to describe our experience of using a virtual reality (VR) social network during awake craniotomy and discuss its future applications for perioperative mapping of nonverbal language, empathy, and theory of mind. This was a single-center, prospective, unblinded trial. During wound closure, different VR experiences with a VR headset were proposed to the patient. This project sought to explore interactions with the neuropsychologist's avatar in virtual locations using a VR social network as an available experience. Three patients experienced VR. Despite some limitations due to patient positioning during the operation and the limitation of nonverbal cues inherent to the app, the neuropsychologist, as an avatar, could communicate with the patient and explore gesture communication while wearing a VR headset. With some improvements, VR social networks can be used in the near future to map social cognition during awake craniotomy. ClinicalTrials.gov NCT03010943; https://clinicaltrials.gov/ct2/show/NCT03010943 (Archived at WebCite at http://www.webcitation.org/70CYDil0P). ©Florian Bernard, Jean-Michel Lemée, Ghislaine Aubin, Aram Ter Minassian, Philippe Menei. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 26.06.2018.

Rapid intranasal delivery of chloramphenicol acetyltransferase in the active form to different brain regions as a model for enzyme therapy in the CNS.

PubMed

Appu, Abhilash P; Arun, Peethambaran; Krishnan, Jishnu K S; Moffett, John R; Namboodiri, Aryan M A

2016-02-01

The blood brain barrier (BBB) is critical for maintaining central nervous system (CNS) homeostasis by restricting entry of potentially toxic substances. However, the BBB is a major obstacle in the treatment of neurotoxicity and neurological disorders due to the restrictive nature of the barrier to many medications. Intranasal delivery of active enzymes to the brain has therapeutic potential for the treatment of numerous CNS enzyme deficiency disorders and CNS toxicity caused by chemical threat agents. The aim of this work is to provide a sensitive model system for analyzing the rapid delivery of active enzymes into various regions of the brain with therapeutic bioavailability. We tested intranasal delivery of chloramphenicol acetyltransferase (CAT), a relatively large (75kD) enzyme, in its active form into different regions of the brain. CAT was delivered intranasally to anaesthetized rats and enzyme activity was measured in different regions using a highly specific High Performance Thin Layer Chromatography (HP-TLC)-radiometry coupled assay. Active enzyme reached all examined areas of the brain within 15min (the earliest time point tested). In addition, the yield of enzyme activity in the brain was almost doubled in the brains of rats pre-treated with matrix metalloproteinase-9 (MMP-9). Intranasal administration of active enzymes in conjunction with MMP-9 to the CNS is both rapid and effective. The present results suggest that intranasal enzyme therapy is a promising method for counteracting CNS chemical threat poisoning, as well as for treating CNS enzyme deficiency disorders. Published by Elsevier B.V.

Insulin secretion and insulin action in non-insulin-dependent diabetes mellitus: which defect is primary?

PubMed

Reaven, G M

1984-01-01

Defects in both insulin secretion and insulin action exist in patients with non-insulin-dependent diabetes mellitus (NIDDM). The loss of the acute plasma insulin response to intravenous glucose is seen in patients with relatively mild degrees of fasting hyperglycemia, but patients with severe fasting hyperglycemia also demonstrate absolute hypoinsulinemia in response to an oral glucose challenge. In contrast, day-long circulating insulin levels are within normal limits even in severely hyperglycemic patients with NIDDM. The relationship between NIDDM and insulin action in NIDDM is less complex, and is a characteristic feature of the syndrome. This metabolic defect is independent of obesity, and the severity of the resistance to insulin-stimulated glucose uptake increases with magnitude of hyperglycemia. Control of hyperglycemia with exogenous insulin ameliorates the degree of insulin resistance, and reduction of insulin resistance with weight loss in obese patients with NIDDM leads to an enhanced insulin response. Since neither therapeutic intervention is capable of restoring all metabolic abnormalities to normal, these observations do not tell us which of these two defects is primarily responsible for the development of NIDDM. Similarly, the observation that most patients with impaired glucose tolerance are hyperinsulinemic and insulin resistant does not prove that insulin resistance is the primary defect in NIDDM. In conclusion, reduction in both insulin secretion and action is seen in patients with NIDDM, and the relationship between these two metabolic abnormalities is very complex.(ABSTRACT TRUNCATED AT 250 WORDS)

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

NASA Astrophysics Data System (ADS)

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

2016-09-01

AWAKE, the Advanced Proton-Driven Plasma Wakefield Acceleration Experiment, is a proof-of-principle R&D experiment at CERN using a 400 GeV / c proton beam from the CERN SPS (longitudinal beam size σz = 12 cm) which will be sent into a 10 m long plasma section with a nominal density of ≈ 7 ×1014 atoms /cm3 (plasma wavelength λp = 1.2 mm). In this paper we show that by measuring the time integrated transverse profile of the proton bunch at two locations downstream of the AWAKE plasma, information about the occurrence of the self-modulation instability (SMI) can be inferred. In particular we show that measuring defocused protons with an angle of 1 mrad corresponds to having electric fields in the order of GV/m and fully developed self-modulation of the proton bunch. Additionally, by measuring the defocused beam edge of the self-modulated bunch, information about the growth rate of the instability can be extracted. If hosing instability occurs, it could be detected by measuring a non-uniform defocused beam shape with changing radius. Using a 1 mm thick Chromox scintillation screen for imaging of the self-modulated proton bunch, an edge resolution of 0.6 mm and hence an SMI saturation point resolution of 1.2 m can be achieved.

Intranasal scopolamine affects the semicircular canals centrally and peripherally.

PubMed

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

2015-08-01

Space motion sickness (SMS), a condition caused by an intravestibular conflict, remains an important obstacle that astronauts encounter during the first days in space. Promethazine is currently the standard treatment of SMS, but scopolamine is used by some astronauts to prevent SMS. However, the oral and transdermal routes of administration of scopolamine are known to have substantial drawbacks. Intranasal administration of scopolamine ensures a fast absorption and rapid onset of therapeutic effect, which might prove to be suitable for use during spaceflights. The aim of this study was to evaluate the effects of intranasally administered scopolamine (0.4 mg) on the semicircular canals (SCCs) and the otoliths. This double-blind, placebo-controlled study was performed on 19 healthy male subjects. The function of the horizontal SCC and the vestibulo-ocular reflex, as well as the saccular function and utricular function, were evaluated. Scopolamine turned out to affect mainly the SCCs centrally and peripherally but also the utricles to a lesser extent. Centrally, the most probable site of action is the medial vestibular nucleus, where the highest density of muscarinic receptors has been demonstrated and afferent fibers from the SCCs and utricles synapse. Furthermore, our results suggest the presence of muscarinic receptors in the peripheral vestibular system on which scopolamine has a suppressive effect. Given the depressant actions on the SCCs, it is suggested that the pharmacodynamic effect of scopolamine may be attributed to the obliteration of intravestibular conflict that arises during (S)MS. Copyright © 2015 the American Physiological Society.

Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction.

PubMed

Rilling, James K; Demarco, Ashley C; Hackett, Patrick D; Chen, Xu; Gautam, Pritam; Stair, Sabrina; Haroon, Ebrahim; Thompson, Richmond; Ditzen, Beate; Patel, Rajan; Pagnoni, Giuseppe

2014-01-01

Both oxytocin (OT) and vasopressin (AVP) are known to modulate social behavior, and dysfunction in both systems has been postulated as a potential cause of certain psychiatric disorders that involve social behavioral deficits. In particular, there is growing interest in intranasal OT as a potential treatment for certain psychiatric disorders, and preliminary pre-clinical and clinical studies suggest efficacy in alleviating some of the associated symptoms. However, the vast majority of research participants in these studies have been male, and there is evidence for sexually differentiated effects of nonapeptides in both humans and non-human animals. To date, no study has investigated the effect of intranasal OT on brain function in human males and females within the same paradigm. Previously, in a randomized, placebo-controlled, double-blind fMRI study, we reported effects of intranasal OT and AVP on behavior and brain activity of human males as they played an interactive social game known as the Prisoner's Dilemma Game. Here, we present findings from an identical study in human females, and compare these with our findings from males. Overall, we find that both behavioral and neural responses to intranasal OT and AVP are highly sexually differentiated. In women, AVP increased conciliatory behavior, and both OT and AVP caused women to treat computer partners more like humans. In men, AVP increased reciprocation of cooperation from both human and computer partners. However, no specific drug effects on behavior were shared between men and women. During cooperative interactions, both OT and AVP increased brain activity in men within areas rich in OT and AVP receptors and in areas playing a key role in reward, social bonding, arousal and memory (e.g., the striatum, basal forebrain, insula, amygdala and hippocampus), whereas OT and AVP either had no effect or in some cases actually decreased brain activity in these regions in women. OT treatment rendered neural responses

A field trial, of preshipment vaccination, with intranasal infectious bovine rhinotracheitis-parainfluenza-3 vaccines.

PubMed Central

Martin, W; Willson, P; Curtis, R; Allen, B; Acres, S

1983-01-01

A total of 849 calves, 278 controls, 335 vaccinated intranasally with IBR-PI3/TS and 236 vaccinated intranasally with IBR-PI3/PTC were studied in a field trial of preimmunization. All calves were vaccinated in Saskatchewan at least three weeks prior to shipment to feedlots. Four hundred and twenty six calves were not sold within eight weeks of vaccination; however, seven of these died within four weeks of vaccination. Treatment rates varied from 1.0% to 5.2%. There was no significant effect of vaccination on treatment rates. Similarly, there was no significant effect of vaccination in the 74 calves sold to feedlots in Saskatchewan. Three hundred and forty nine calves were sold to feedlots in Ontario. Two of these died from fibrinous pneumonia. Treatment rates varied from 1.7% to 33.3% in different feedlots, but there was no significant effect of vaccination on treatment rates. Therefore, preimmunization is unlikely to significantly reduce the overall treatment rate in calves entering feedlots. PMID:6315194

Awake craniotomy for brain lesions within and near the primary motor area: A retrospective analysis of factors associated with worsened paresis in 102 consecutive patients

PubMed Central

Shinoura, Nobusada; Midorikawa, Akira; Yamada, Ryoji; Hana, Taijun; Saito, Akira; Hiromitsu, Kentaro; Itoi, Chisato; Saito, Syoko; Yagi, Kazuo

2013-01-01

Background: We analyzed factors associated with worsened paresis in a large series of patients with brain lesions located within or near the primary motor area (M1) to establish protocols for safe, awake craniotomy of eloquent lesions. Methods: We studied patients with brain lesions involving M1, the premotor area (PMA) and the primary sensory area (S1), who underwent awake craniotomy (n = 102). In addition to evaluating paresis before, during, and one month after surgery, the following parameters were analyzed: Intraoperative complications; success or failure of awake surgery; tumor type (A or B), tumor location, tumor histology, tumor size, and completeness of resection. Results: Worsened paresis at one month of follow-up was significantly associated with failure of awake surgery, intraoperative complications and worsened paresis immediately after surgery, which in turn was significantly associated with intraoperative worsening of paresis. Intraoperative worsening of paresis was significantly related to preoperative paresis, type A tumor (motor tract running in close proximity to and compressed by the tumor), tumor location within or including M1 and partial removal (PR) of the tumor. Conclusions: Successful awake surgery and prevention of deterioration of paresis immediately after surgery without intraoperative complications may help prevent worsening of paresis at one month. Factors associated with intraoperative worsening of paresis were preoperative motor deficit, type A and tumor location in M1, possibly leading to PR of the tumor. PMID:24381792

Restraint training for awake functional brain scanning of rodents can cause long-lasting changes in pain and stress responses.

PubMed

Low, Lucie A; Bauer, Lucy C; Pitcher, Mark H; Bushnell, M Catherine

2016-08-01

With the increased interest in longitudinal brain imaging of awake rodents, it is important to understand both the short-term and long-term effects of restraint on sensory and emotional processing in the brain. To understand the effects of repeated restraint on pain behaviors and stress responses, we modeled a restraint protocol similar to those used to habituate rodents for magnetic resonance imaging scanning, and studied sensory sensitivity and stress hormone responses over 5 days. To uncover lasting effects of training, we also looked at responses to the formalin pain test 2 weeks later. We found that while restraint causes acute increases in the stress hormone corticosterone, it can also cause lasting reductions in nociceptive behavior in the formalin test, coupled with heightened corticosterone levels and increased activation of the "nociceptive" central nucleus of the amygdala, as seen by Fos protein expression. These results suggest that short-term repeated restraint, similar to that used to habituate rats for awake functional brain scanning, could potentially cause long-lasting changes in physiological and brain responses to pain stimuli that are stress-related, and therefore could potentially confound the functional activation patterns seen in awake rodents in response to pain stimuli.

Analgesic and sedative effects of intranasal dexmedetomidine in third molar surgery under local anaesthesia.

PubMed

Cheung, C W; Ng, K F J; Liu, J; Yuen, M Y V; Ho, M H A; Irwin, M G

2011-09-01

Dexmedetomidine (DEX) is an alpha 2-adrenoreceptor agonist, which induces sedation and analgesia. This study aimed to determine whether intranasal DEX offered perioperative sedation and better postoperative analgesia. Patients having unilateral third molar surgery under local anaesthesia were recruited and allocated to receive either intranasal DEX 1 µg kg(-1) (Group D) or same volume of saline (Group P) 45 min before surgery. Patient-controlled sedation with propofol was offered as a rescue sedative. Perioperative sedation, postoperative pain relief and analgesic consumption, vital signs, adverse events, postoperative recovery, and satisfaction in sedation and analgesia were assessed. Thirty patients from each group were studied. Areas under curve (AUC) of postoperative numerical rating scale (NRS) pain scores 1-12 h at rest and during mouth opening were significantly lower in Group D (P=0.003 and 0.009, respectively). AUC BIS values and OAA/S sedation scores were significantly lower before surgery and at the recovery area (all P<0.01) with significantly less intra-operative propofol used in group D (P<0.01). In group D, heart rate was significantly lower at recovery period (P=0.005) while systolic blood pressure in different periods of the study (all P<0.01), but the decreases did not require treatment. More patients from placebo group experienced dizziness (P=0.026) but no serious adverse event was found. No difference was found in postoperative psychomotor recovery and satisfaction in pain relief and sedation. Patients receiving intranasal DEX for unilateral third molar surgery with local anaesthesia were more sedated perioperatively with better postoperative pain relief. No delay in psychomotor recovery was seen.

Effectiveness of mouthpiece nebulization and nasal swab stick packing for topical anesthesia in awake fiberoptic nasotracheal intubation.

PubMed

Techanivate, Anchalee; Leelanukrom, Ruenreong; Prapongsena, Prut; Terachinda, Danuchit

2007-10-01

To evaluate the effectiveness of using mouthpiece nebulization and nasal swab stick packing for topical anesthesia in awake fiberoptic nasotracheal intubation. This was a prospective descriptive study of 30 patients with ASA I-II who underwent elective surgery and suspected of difficult intubation between March 2004 and June 2006. After 2% lidocaine 5 ml was nebulizated in a micronebulizer using oxygen 10 L/min as a driving gas through a standard mouthpiece and 10% cocaine 1 ml on cotton swab-stick was applied to the selected nostril for 15 min, fiberoptic nasotracheal intubation was done while the patient was awake. If the patient had severe gag or cough reflex, 1% lidocaine 5 ml per each time could be injected through the working channel of the fiberoptic bronchoscope. The descriptive statistics were calculated by using SPSS version 11.0. The success rate of awake fiberoptic nasotracheal was 100%. The mean duration of awake fiberoptic nasotracheal intubation was 119.0 +/- 76.8 sec. The responses of the patient to instrumentation during 4 periods, i.e.: passing the endotracheal tube into the nose, passing the bronchoscope into the pharynx-larynx, passing the bronchoscope into the trachea-carina and passing the endotracheal tube into the trachea were, as follows: no response in about 53.3%, 63.3%, 23.3%,and 13.3%; mild pain or reflex in about 46.7%, 10%, 70%, and 86.7%; moderate pain or reflex in about 0%, 3.3%, 6.7%, and 0%; and severe pain or reflex requiring more local anesthetic in about 0%, 23.3%, 0%, and 0%, respectively. Despite complete topical anesthesia in the majority of the patients, two patients required 5 ml more 1% lidocaine and five patients required 10 mL more of the drug through the fiberoptic bronchoscope. There was no serious complication such as hypoxemia, arrhythmia. Twenty-four patients (80%) were satisfied with mouthpiece nebulization and nasal swab packing because they felt safe, did not have pain, and were comfortable; only three patients

No short-term effects of digital mobile radio telephone on the awake human electroencephalogram

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roeschke, J.; Mann, K.

1997-05-01

A recent study reported the results of an exploratory study of alterations of the quantitative sleep profile due to the effects of a digital mobile radio telephone. Rapid eye movement (REM) was suppressed, and the spectral power density in the 8--13 Hz frequency range during REM sleep was altered. The aim of the present study was to illuminate the influence of digital mobile radio telephone on the awake electroencephalogram (EEG) of healthy subjects. For this purpose, the authors investigated 34 male subjects in a single-blind cross-over design experiment by measuring spontaneous EEGs under closed-eyes condition from scalp positions C{sub 3}more » and C{sub 4} and comparing the effects of an active and an inactive digital mobile radio telephone (GSM) system. During exposure of nearly 3.5 min to the 900 MHz electromagnetic field pulsed at a frequency of 217 Hz and with a pulse width of 580 {micro}s, the authors could not detect any difference in the awake EEGs in terms of spectral power density measures.« less

Invasive aspergillosis in severely neutropenic patients over 18 years: impact of intranasal amphotericin B and HEPA filtration.

PubMed

Withington, S; Chambers, S T; Beard, M E; Inder, A; Allen, J R; Ikram, R B; Schousboe, M I; Heaton, D C; Spearing, R I; Hart, D N

1998-01-01

The impact of intranasal amphotericin B and high-efficiency particulate air (HEPA) filtration on the incidence of invasive aspergillosis was reviewed in patients from 1977 to 1994 undergoing intensive chemotherapy. Overall, the incidence of proven invasive aspergillosis was reduced from 24.4% (1977-1984) to 7.1% (1985-1991) (P < 0.001) following the introduction of intranasal prophylaxis, but when probable cases of aspergillosis were included and lymphoma cases excluded, there was no change in incidence. Following the introduction of HEPA filtration, patient exposure to aspergillus spores as measured by air sampling was markedly reduced and there were no new cases of invasive aspergillosis. HEPA filtration proved effective in reducing invasive aspergillosis and has allowed increasingly aggressive treatment regimens to be introduced.

Critical evaluation of colon submucosal microdialysis in awake, mobile rats.

PubMed

Cibicek, Norbert; Ehrmann, Jiri; Proskova, Jitka; Vecera, Rostislav

2018-01-01

Sensors able to record large bowel physiology and biochemistry in situ in awake rodents are lacking. Microdialysis is a mini-invasive technique that may be utilized to continuously deliver or recover low-molecular substances from various tissues. In this experiment we evaluated the feasibility of in vivo microdialysis to monitor extracellular fluid chemistry in the descending colon submucosa of conscious, freely moving rodents. Following surgical implantation of a microdialysis probe, male Wistar rats were housed in metabolic cages where they were analgized and clinically followed for four days with free access to standard diet and water. To assess local microcirculation and probe function, glucose, lactate, glucose-to-lactate ratio and urea clearance were determined in the dialysates from the three postoperative days with focus on the final 24-h period. In an attempt to mitigate the expected tissue inflammatory response, one group of animals had the catheters perfused with 5-aminosalicylic acid-enriched medium with final concentration 1 μmol/L. For verification of probe position and the assessment of the surrounding foreign body reaction, standard histological and immunohistochemical methods were employed. Microdialysis of rat gut is associated with considerable technical challenges that may lead to the loss of probe function and high drop-out rate. In this setting, limited data did not allow to draw any firm conclusion regarding local anti-inflammatory effectiveness of 5-aminosalicylic acid perfusion. Although intestinal microdialysis may be suitable for larger anesthetized animals, low reproducibility of the presented method compromises its routine experimental use in awake and freely moving small-sized rodents.

Pharmacokinetics and Abuse Potential of Benzhydrocodone, a Novel Prodrug of Hydrocodone, After Intranasal Administration in Recreational Drug Users.

PubMed

Mickle, Travis C; Guenther, Sven M; Barrett, Andrew C; Roupe, Kathryn Ann; Zhou, Jing; Dickerson, Daniel; Webster, Lynn R

2017-10-28

Developing an acetaminophen-free, immediate-release hydrocodone product remains an unmet medical need; however, new opioid analgesics should not introduce new abuse risks. Benzhydrocodone is a prodrug of hydrocodone that must be metabolized into hydrocodone by enzymes in the intestinal tract to optimally deliver its pharmacologic effects. This study evaluated the intranasal pharmacokinetics and abuse potential of benzhydrocodone active pharmaceutical ingredient (API) compared with hydrocodone bitartrate (HB) API. Single-center, randomized, double-blind, crossover study. Clinical research site. Healthy adult, nondependent, recreational opioid users. Subjects (N = 51 Completers) were randomized to receive 13.34 mg of intranasal benzhydrocodone API and 15.0 mg of intranasal HB API (molar-equivalent doses of hydrocodone). Blood samples were taken, and Drug Liking scores (assessed on a bipolar visual analog scale) were obtained throughout each dosing interval. Nasal irritation and safety were assessed. Peak hydrocodone plasma concentration (Cmax) was 36.0% lower, and total hydrocodone exposures (AUClast and AUCinf) were 20.3% and 19.5% lower, respectively, for benzhydrocodone API compared with HB API (P < 0.0001). All partial AUC values were lower for benzhydrocodone API, with a ≥ 75% reduction in hydrocodone exposure at all time intervals up to one hour postdose (P < 0.0001). Median Tmax of hydrocodone following benzhydrocodone API was delayed by more than one hour compared with HB. Drug Liking score, as assessed by maximal liking (Emax), was significantly lower for benzhydrocodone API vs HB API (P = 0.004), with 45% of subjects showing a ≥ 30% reduction in Drug Liking Emax. Reductions in hydrocodone exposure and associated decreases in Drug Liking relative to HB suggest that the prodrug benzhydrocodone may deter intranasal abuse. © 2017 American Academy of Pain Medicine.

Immunogenicity and protective efficacy of an elastase-dependent live attenuated swine influenza virus vaccine administered intranasally in pigs.

PubMed

Masic, Aleksandar; Lu, Xinya; Li, Junwei; Mutwiri, George K; Babiuk, Lorne A; Brown, Earl G; Zhou, Yan

2010-10-08

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. Copyright © 2010 Elsevier Ltd. All rights reserved.

Effect of a Combination of Intranasal Ketorolac and Nitrous Oxide on the Success of the Inferior Alveolar Nerve Block in Patients with Symptomatic Irreversible Pulpitis: A Prospective, Randomized, Double-blind Study.

PubMed

Stentz, Daniel; Drum, Melissa; Reader, Al; Nusstein, John; Fowler, Sara; Beck, Mike

2018-01-01

Previous studies in patients with irreversible pulpitis have reported increased success of the inferior alveolar nerve block (IANB) using premedication with ketorolac. Preemptive nitrous oxide administration has also shown an increase in the success of the IANB. Recently, ketorolac has been made available for intranasal delivery. Perhaps combining ketorolac and nitrous oxide would increase success. Therefore, the purpose of this prospective, randomized, double-blind study was to determine the effect of a combination of intranasal ketorolac and nitrous oxide/oxygen on the anesthetic success of the IANB in patients presenting with symptomatic irreversible pulpitis. One hundred two patients experiencing spontaneous moderate to severe pain with symptomatic irreversible pulpitis in a mandibular posterior tooth participated. Patients were randomly divided into 2 groups and received either 31.5 mg intranasal ketorolac or intranasal saline placebo 20 minutes before the administration of nitrous oxide/oxygen. Ten minutes after the administration of nitrous oxide/oxygen, the IANB was given. After profound lip numbness, endodontic treatment was performed. Success was defined as the ability to perform endodontic access and instrumentation with no pain or mild pain. The odds of success for the IANB was 1.631 in the intranasal saline/nitrous oxide group versus the intranasal ketorolac/nitrous oxide group with no significant difference between the groups (P = .2523). Premedication with intranasal ketorolac did not significantly increase the odds of success for the IANB over the use of nitrous oxide/oxygen alone. Supplemental anesthesia will still be needed to achieve adequate anesthesia. Copyright © 2017 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Nanoemulsions for Intranasal Delivery of Riluzole to Improve Brain Bioavailability: Formulation Development and Pharmacokinetic Studies.

PubMed

Parikh, Rajesh H; Patel, Ravish J

2016-01-01

Amyotrophic Lateral Sclerosis (ALS), a motor neuron disease (MND), is a progressive neurodegenerative disorder characterized by the deterioration of both upper and lower motor neurons. Only one drug (riluzole) has been approved for the treatment of ALS. Riluzole is a BCS class II drug having 60% absolute bioavailability. It is a substrate of P-glycoprotein and BBB restricts its entry in brain. This investigation was aimed to develop O/W nanoemulsion system of riluzole to improve its brain bioavailability. Riluzole loaded nanoemulsion was prepared by phase titration method. It was consisting of 3% w/w Sefsol 218, 28.3% w/w Tween 80:Carbitol (1:1) and 68.7% w/w water. It was characterized for drop size, drop size distribution, transmittance, viscosity, pH, zeta potential, conductivity and nasal ciliotoxicity study. Thermodynamic stability and room temperature stability of prepared nanoemulsion formulation were evaluated. Pharmacokinetic and brain uptake study was carried out using albino rats (wistar) post intranasal and oral administration. Riluzole loaded nanoemulsion was having a drop size of 23.92±0.52 nm. It was free from nasal ciliotoxicity and stable for three months. Brain uptake of riluzole post intranasal administration of riluzole loaded nanoemulsion was significantly (P <4.10 × 10-6) higher when it was compared with oral administration of riluzole loaded nanoemulsion. This study indicates that nanoemulsion of riluzole for intranasal administration could be a promising approach for the treatment of ALS to minimize the dose of riluzole in order to avoid dose related adverse events.

Continuous physical examination during subcortical resection in awake craniotomy patients: Its usefulness and surgical outcome.

PubMed

Bunyaratavej, Krishnapundha; Sangtongjaraskul, Sunisa; Lerdsirisopon, Surunchana; Tuchinda, Lawan

2016-08-01

To evaluate the value of physical examination as a monitoring tool during subcortical resection in awake craniotomy patients and surgical outcomes. Authors reviewed medical records of patients underwent awake craniotomy with continuous physical examination for pathology adjacent to the eloquent area. Between January 2006 and August 2015, there were 37 patients underwent awake craniotomy with continuous physical examination. Pathology was located in the left cerebral hemisphere in 28 patients (75.7%). Thirty patients (81.1%) had neuroepithelial tumors. Degree of resections were defined as total, subtotal, and partial in 16 (43.2%), 11 (29.7%) and 10 (27.0%) patients, respectively. Median follow up duration was 14 months. The reasons for termination of subcortical resection were divided into 3 groups as follows: 1) by anatomical landmark with the aid of neuronavigation in 20 patients (54%), 2) by reaching subcortical stimulation threshold in 8 patients (21.6%), and 3) by abnormal physical examination in 9 patients (24.3%). Among these 3 groups, there were statistically significant differences in the intraoperative (p=0.002) and early postoperative neurological deficit (p=0.005) with the lowest deficit in neuronavigation group. However, there were no differences in neurological outcome at later follow up (3-months p=0.103; 6-months p=0.285). There were no differences in the degree of resection among the groups. Continuous physical examination has shown to be of value as an additional layer of monitoring of subcortical white matter during resection and combining several methods may help increase the efficacy of mapping and monitoring of subcortical functions. Copyright © 2016 Elsevier B.V. All rights reserved.

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

NASA Astrophysics Data System (ADS)

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

2015-02-01

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

Bioluminescent Study of the Distribution of High-Molecular-Weight Protein Fraction of Cellex Daily Preparation in the Brain after Intranasal Administation.

PubMed

Baklaushev, V P; Yusubalieva, G M; Burenkov, M S; Mel'nikov, P A; Bozhko, E A; Mentyukov, G A; Lavrent'eva, L S; Sokolov, M A; Chekhonin, V P

2017-12-01

Permeability of the blood-brain barrier for protein fractions 50-100 kDa (PF 50-100 ) of Cellex Daily preparation labeled with fluorescent tracer FITC and non-conjugated FITC were compared after intranasal administration of the preparations to healthy rats. Fluorimetrical analysis of the serum and cerebrospinal fluid samples showed that Cellex Daily PF 50-100 -FITC administered intranasally penetrated into the blood and cerebrospinal fluid with maximum accumulation in 2 h after administration and persists in the circulation for 24 h probably due to binding with plasma proteins. The differences in the kinetic profile of PF 50-100 -FITC and free FITC indirectly suggest that the major part of the preparation is not degraded within 24 h and FITC is probably not cleaved from the protein components of the preparation. In vivo fluorescence analysis showed significant fluorescent signal in the olfactory bulbs in 6 h after intranasal administration; hence, the preparation administered via this route can bypass the blood-brain barrier. Scanning laser confocal microscopy of rat brain sections confirmed penetration of the high-molecular weight protein fraction PF 50-100 -FITC into CNS structures. The most pronounced accumulation of the labeled drug was observed in the olfactory bulb in 6 and 12 h after administration. In contrast to free FITC administered in the control group, significant accumulation of PF 50-100 -FITC in the olfactory cortex and frontal cortex neurons with functionally active nuclei was observed in 6, 12 and 24 h after intranasal administration.

Central insulin signaling is attenuated by long-term insulin exposure via insulin receptor substrate-1 serine phosphorylation, proteasomal degradation, and lysosomal insulin receptor degradation.

PubMed

Mayer, Christopher M; Belsham, Denise D

2010-01-01

Central insulin signaling is critical for the prevention of insulin resistance. Hyperinsulinemia contributes to insulin resistance, but it is not yet clear whether neurons are subject to cellular insulin resistance. We used an immortalized, hypothalamic, clonal cell line, mHypoE-46, which exemplifies neuronal function and expresses the components of the insulin signaling pathway, to determine how hyperinsulinemia modifies neuronal function. Western blot analysis indicated that prolonged insulin treatment of mHypoE-46 cells attenuated insulin signaling through phospho-Akt. To understand the mechanisms involved, time-course analysis was performed. Insulin exposure for 4 and 8 h phosphorylated Akt and p70-S6 kinase (S6K1), whereas 8 and 24 h treatment decreased insulin receptor (IR) and IR substrate 1 (IRS-1) protein levels. Insulin phosphorylation of S6K1 correlated with IRS-1 ser1101 phosphorylation and the mTOR-S6K1 pathway inhibitor rapamycin prevented IRS-1 serine phosphorylation. The proteasomal inhibitor epoxomicin and the lysosomal pathway inhibitor 3-methyladenine prevented the degradation of IRS-1 and IR by insulin, respectively, and pretreatment with rapamycin, epoxomicin, or 3-methyladenine prevented attenuation of insulin signaling by long-term insulin exposure. Thus, a sustained elevation of insulin levels diminishes neuronal insulin signaling through mTOR-S6K1-mediated IRS-1 serine phosphorylation, proteasomal degradation of IRS-1 and lysosomal degradation of the IR.

The Pharmacokinetics and Efficacy of a Low-dose, Aqueous, Intranasal Scopolamine Spray

DTIC Science & Technology

2017-09-27

In this study , we found no correlation between plasma levels at any time point and the number of head tilts tolerated. However, there was a positive... study protocol was approved by the Naval Medical Research Unit Dayton Institutional Review Board in compliance with all applicable Federal...The study examined both the pharmacokinetic properties and efficacy of a low-dose, aqueous, intranasal scopolamine spray (INSCOP) as an anti-motion

Effect of long-term intranasal oxytocin on sexual dysfunction in premenopausal and postmenopausal women: a randomized trial.

PubMed

Muin, Dana A; Wolzt, Michael; Marculescu, Rodrig; Sheikh Rezaei, Safoura; Salama, Mohamed; Fuchs, Carola; Luger, Anton; Bragagna, Elia; Litschauer, Brigitte; Bayerle-Eder, Michaela

2015-09-01

To assess the effect of on-demand intranasal oxytocin administration on female sexual function and activity. Randomized, prospective, double-blind, placebo-controlled, crossover trial with duration of 22 weeks. Academic medical center. Thirty pre-and postmenopausal women with sexual dysfunction. Over 8 weeks, intranasal oxytocin (32 IU) or placebo self-administered by women within 50 minutes before sexual intercourse; after a washout period of 2 weeks, crossover with patients switched to the alternate group for another 8 weeks. Primary outcome parameter: Female Sexual Function Index (FSFI); secondary outcome parameters: Female Sexual Distress Scale (FSDS), Sexual Quality of Life-Female (SQOL-F), Sexual Interest and Desire Inventory-Female (SIDI-F), and Hamilton depression scale (HDS). After oxytocin and placebo, the FSFI score increased by 26% and 31%, SQOL-F score by 144% and 125%, and SIDI-F score by 29% and 23%, respectively (repeated measures analysis of variance between groups). After oxytocin and placebo, the FSDS score decreased by 36% and 45%, respectively (repeated measures analysis of variance between groups). There was no statistically significant treatment, sequence (placebo first/second), or interaction effect. Long-term intranasal oxytocin and placebo administration both improved sexual function and symptoms of depression in women over time with no treatment, sequence (placebo first/second), or interaction effect. NCT02229721. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Using Gelatin Nanoparticle Mediated Intranasal Delivery of Neuropeptide Substance P to Enhance Neuro-Recovery in Hemiparkinsonian Rats.

PubMed

Zhao, Ying-Zheng; Jin, Rong-Rong; Yang, Wei; Xiang, Qi; Yu, Wen-Ze; Lin, Qian; Tian, Fu-Rong; Mao, Kai-Li; Lv, Chuan-Zhu; Wáng, Yi-Xiáng J; Lu, Cui-Tao

2016-01-01

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.

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

PubMed

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

“Awake” intraoperative functional MRI (ai-fMRI) for mapping the eloquent cortex: Is it possible in awake craniotomy?☆

PubMed Central

Lu, Jun-Feng; Zhang, Han; Wu, Jin-Song; Yao, Cheng-Jun; Zhuang, Dong-Xiao; Qiu, Tian-Ming; Jia, Wen-Bin; Mao, Ying; Zhou, Liang-Fu

2012-01-01

As a promising noninvasive imaging technique, functional MRI (fMRI) has been extensively adopted as a functional localization procedure for surgical planning. However, the information provided by preoperative fMRI (pre-fMRI) is hampered by the brain deformation that is secondary to surgical procedures. Therefore, intraoperative fMRI (i-fMRI) becomes a potential alternative that can compensate for brain shifts by updating the functional localization information during craniotomy. However, previous i-fMRI studies required that patients be under general anesthesia, preventing the wider application of such a technique as the patients cannot perform tasks unless they are awake. In this study, we propose a new technique that combines awake surgery and i-fMRI, named “awake” i-fMRI (ai-fMRI). We introduced ai-fMRI to the real-time localization of sensorimotor areas during awake craniotomy in seven patients. The results showed that ai-fMRI could successfully detect activations in the bilateral primary sensorimotor areas and supplementary motor areas for all patients, indicating the feasibility of this technique in eloquent area localization. The reliability of ai-fMRI was further validated using intraoperative stimulation mapping (ISM) in two of the seven patients. Comparisons between the pre-fMRI-derived localization result and the ai-fMRI derived result showed that the former was subject to a heavy brain shift and led to incorrect localization, while the latter solved that problem. Additionally, the approaches for the acquisition and processing of the ai-fMRI data were fully illustrated and described. Some practical issues on employing ai-fMRI in awake craniotomy were systemically discussed, and guidelines were provided. PMID:24179766

Language mapping with verbs and sentences in awake surgery: a review.

PubMed

Rofes, Adrià; Miceli, Gabriele

2014-06-01

Intraoperative language mapping in awake surgery is typically conducted by asking the patient to produce automatic speech and to name objects. These tasks might not map language with sufficient accuracy, as some linguistic processes can only be triggered by tasks that use verbs and sentences. Verb and sentence processing tasks are currently used during surgery, albeit sparsely. Medline, PubMed, and Web of Science records were searched to retrieve studies focused on language mapping with verbs/sentences in awake surgery. We review the tasks reported in the published literature, spell out the language processes assessed by each task, list the cortical and subcortical regions whose stimulation inhibited language processing, and consider the types of errors elicited by stimulation in each region. We argue that using verb tasks allows a more thorough evaluation of language functions. We also argue that verb tasks are preferable to object naming tasks in the case of frontal lesions, as lesion and neuroimaging data demonstrate that these regions play a critical role in verb and sentence processing. We discuss the clinical value of these tasks and the current limitations of the procedure, and provide some guidelines for their development. Future research should aim toward a differentiated approach to language mapping - one that includes the administration of standardized and customizable tests and the use of longitudinal neurocognitive follow-up studies. Further work will allow researchers and clinicians to understand brain and language correlates and to improve the current surgical practice.

Protection against tuberculosis by a single intranasal administration of DNA-hsp65 vaccine complexed with cationic liposomes

PubMed Central

Rosada, Rogério S; Torre, Lucimara Gaziola de la; Frantz, Fabiani G; Trombone, Ana PF; Zárate-Bladés, Carlos R; Fonseca, Denise M; Souza, Patrícia RM; Brandão, Izaíra T; Masson, Ana P; Soares, Édson G; Ramos, Simone G; Faccioli, Lúcia H; Silva, Célio L; Santana, Maria HA; Coelho-Castelo, Arlete AM

2008-01-01

Background The greatest challenges in vaccine development include optimization of DNA vaccines for use in humans, creation of effective single-dose vaccines, development of delivery systems that do not involve live viruses, and the identification of effective new adjuvants. Herein, we describe a novel, simple technique for efficiently vaccinating mice against tuberculosis (TB). Our technique consists of a single-dose, genetic vaccine formulation of DNA-hsp65 complexed with cationic liposomes and administered intranasally. Results We developed a novel and non-toxic formulation of cationic liposomes, in which the DNA-hsp65 vaccine was entrapped (ENTR-hsp65) or complexed (COMP-hsp65), and used to immunize mice by intramuscular or intranasal routes. Although both liposome formulations induced a typical Th1 pattern of immune response, the intramuscular route of delivery did not reduce the number of bacilli. However, a single intranasal immunization with COMP-hsp65, carrying as few as 25 μg of plasmid DNA, leads to a remarkable reduction of the amount of bacilli in lungs. These effects were accompanied by increasing levels of IFN-γ and lung parenchyma preservation, results similar to those found in mice vaccinated intramuscularly four times with naked DNA-hsp65 (total of 400 μg). Conclusion Our objective was to overcome the significant obstacles currently facing DNA vaccine development. Our results in the mouse TB model showed that a single intranasal dose of COMP-hsp65 elicited a cellular immune response that was as strong as that induced by four intramuscular doses of naked-DNA. This formulation allowed a 16-fold reduction in the amount of DNA administered. Moreover, we demonstrated that this vaccine is safe, biocompatible, stable, and easily manufactured at a low cost. We believe that this strategy can be applied to human vaccines to TB in a single dose or in prime-boost protocols, leading to a tremendous impact on the control of this infectious disease. PMID

Training anesthesiology residents in providing anesthesia for awake craniotomy: learning curves and estimate of needed case load.

PubMed

Bilotta, Federico; Titi, Luca; Lanni, Fabiana; Stazi, Elisabetta; Rosa, Giovanni

2013-08-01

To measure the learning curves of residents in anesthesiology in providing anesthesia for awake craniotomy, and to estimate the case load needed to achieve a "good-excellent" level of competence. Prospective study. Operating room of a university hospital. 7 volunteer residents in anesthesiology. Residents underwent a dedicated training program of clinical characteristics of anesthesia for awake craniotomy. The program was divided into three tasks: local anesthesia, sedation-analgesia, and intraoperative hemodynamic management. The learning curve for each resident for each task was recorded over 10 procedures. Quantitative assessment of the individual's ability was based on the resident's self-assessment score and the attending anesthesiologist's judgment, and rated by modified 12 mm Likert scale, reported ability score visual analog scale (VAS). This ability VAS score ranged from 1 to 12 (ie, very poor, mild, moderate, sufficient, good, excellent). The number of requests for advice also was recorded (ie, resident requests for practical help and theoretical notions to accomplish the procedures). Each task had a specific learning rate; the number of procedures necessary to achieve "good-excellent" ability with confidence, as determined by the recorded results, were 10 procedures for local anesthesia, 15 to 25 procedures for sedation-analgesia, and 20 to 30 procedures for intraoperative hemodynamic management. Awake craniotomy is an approach used increasingly in neuroanesthesia. A dedicated training program based on learning specific tasks and building confidence with essential features provides "good-excellent" ability. © 2013 Elsevier Inc. All rights reserved.

Diagnostic work up for language testing in patients undergoing awake craniotomy for brain lesions in language areas.

PubMed

Bilotta, Federico; Stazi, Elisabetta; Titi, Luca; Lalli, Diana; Delfini, Roberto; Santoro, Antonio; Rosa, Giovanni

2014-06-01

Awake craniotomy is the technique of choice in patients with brain tumours adjacent to primary and accessory language areas (Broca's and Wernicke's areas). Language testing should be aimed to detect preoperative deficits, to promptly identify the occurrence of new intraoperative impairments and to establish the course of postoperative language status. Aim of this case series is to describe our experience with a dedicated language testing work up to evaluate patients with or at risk for language disturbances undergoing awake craniotomy for brain tumour resection. Pre- and intra operative testing was accomplished with 8 tests. Intraoperative evaluation was accomplished when patients were fully cooperative (Ramsey < 3). Postoperative evaluation was scheduled at early (within 21 days) and long-term follow-up (3-6 months). Twenty consecutive patients were prospectively recruited. Preoperative language testings were normal in 9 patients (45%), showed mild to moderate language deficit in 8 (40%) and severe language deficit or aphasic disorders in 3 (15%). Broca's area was identified in 15 patients, in all cases by counting arrest during stimulation and in 12 cases by naming arrest. In this article we describe our experience using a language testing work up to evaluate - pre, intra and postoperatively - patients undergoing awake craniotomy for brain tumour resection with preoperative language disturbances or at risk for postoperative language deficits. This approach allows a systematic evaluation and recording of language function status and can be accomplished even when a neuropsychologist or speech therapist are not involved in the operation crew.

Restraint training for awake functional brain scanning of rodents can cause long-lasting changes in pain and stress responses

PubMed Central

Low, Lucie A.; Bauer, Lucy C.; Pitcher, Mark H.; Bushnell, M. Catherine

2016-01-01

Abstract With the increased interest in longitudinal brain imaging of awake rodents, it is important to understand both the short-term and long-term effects of restraint on sensory and emotional processing in the brain. To understand the effects of repeated restraint on pain behaviors and stress responses, we modeled a restraint protocol similar to those used to habituate rodents for magnetic resonance imaging scanning, and studied sensory sensitivity and stress hormone responses over 5 days. To uncover lasting effects of training, we also looked at responses to the formalin pain test 2 weeks later. We found that while restraint causes acute increases in the stress hormone corticosterone, it can also cause lasting reductions in nociceptive behavior in the formalin test, coupled with heightened corticosterone levels and increased activation of the “nociceptive” central nucleus of the amygdala, as seen by Fos protein expression. These results suggest that short-term repeated restraint, similar to that used to habituate rats for awake functional brain scanning, could potentially cause long-lasting changes in physiological and brain responses to pain stimuli that are stress-related, and therefore could potentially confound the functional activation patterns seen in awake rodents in response to pain stimuli. PMID:27058679

A novel intranasal breath-powered delivery system for sumatriptan: a review of technology and clinical application of the investigational product AVP-825 in the treatment of migraine.

PubMed

Cady, Roger

2015-01-01

AVP-825, formerly 'OptiNose Sumatriptan,' is an investigational Breath-Powered(TM) Bi-Directional(TM) intranasal delivery system containing low-dose sumatriptan (22 mg intranasal powder) that avoids limitations of other types of intranasal administration by taking advantage of unique features of nasal anatomy and physiology. This review summarizes intranasal drug delivery for migraine, how the breath-powered technology works, and AVP-825 pharmacokinetic, efficacy and safety/tolerability findings. To identify AVP-825 clinical studies, a PubMed/MEDLINE database search was conducted with the terms AVP-825, OptiNose, OptiNose Sumatriptan, Breath-Powered Nasal Delivery or sumatriptan powder. Of 20 articles, 5 clinical studies were identified, including the head-to-head comparative COMPASS trial (AVP-825 vs oral sumatriptan) and two placebo-controlled studies. AVP-825 has faster sumatriptan absorption versus oral tablets or traditional liquid nasal spray. In Phase II/III randomized, double-blind, placebo-controlled trials, AVP-825 produced early and sustained efficacy with minimal triptan-related adverse effects. In COMPASS, AVP-825 produced earlier reduction of migraine pain intensity and migraine-associated symptoms than 100 mg oral sumatriptan, and higher early rates of pain relief and pain freedom, similar sustained efficacy, and fewer atypical sensations. AVP-825 has the potential to provide migraine patients with improved intranasal administration of sumatriptan that may enhance efficacy and tolerability.

Gene Silencing of SOCS3 by siRNA Intranasal Delivery Inhibits Asthma Phenotype in Mice

PubMed Central

Mazzeo, Carla; Gámez, Cristina; Rodriguez Marco, Ainara; de Zulueta, Ana; Sanz, Veronica; Bilbao, Izaskun; Ruiz-Cabello, Jesús; Zubeldia, Jose M.; del Pozo, Victoria

2014-01-01

Suppresors of cytokine signaling (SOCS) proteins regulate cytokine responses and control immune balance. Several studies have confirmed that SOCS3 is increased in asthmatic patients, and SOCS3 expression is correlated with disease severity. The objective of this study was to evaluate if delivering of SOCS3 short interfering RNA (siRNA) intranasally in lungs could be a good therapeutic approach in an asthma chronic mouse model. Our results showed that intranasal treatment with SOCS3-siRNA led to an improvement in the eosinophil count and the normalization of hyperresponsiveness to methacholine. Concomitantly, this treatment resulted in an improvement in mucus secretion, a reduction in lung collagen, which are prominent features of airway remodeling. The mechanism implies JAK/STAT and RhoA/Rho-kinase signaling pathway, because we found a decreasing in STAT3 phosphorylation status and down regulation of RhoA/Rho-kinase protein expression. These results might lead to a new therapy for the treatment of chronic asthma. PMID:24637581

Oculomotor Behavior Metrics Change According to Circadian Phase and Time Awake

NASA Technical Reports Server (NTRS)

Flynn-Evans, Erin E.; Tyson, Terence L.; Cravalho, Patrick; Feick, Nathan; Stone, Leland S.

2017-01-01

There is a need for non-invasive, objective measures to forecast performance impairment arising from sleep loss and circadian misalignment, particularly in safety-sensitive occupations. Eye-tracking devices have been used in some operational scenarios, but such devices typically focus on eyelid closures and slow rolling eye movements and are susceptible to the intrusion of head movement artifacts. We hypothesized that an expanded suite of oculomotor behavior metrics, collected during a visual tracking task, would change according to circadian phase and time awake, and could be used as a marker of performance impairment.

In Vivo Biomarker Analysis of the Effects of Intranasally Dosed PC945, a Novel Antifungal Triazole, on Aspergillus fumigatus Infection in Immunocompromised Mice

PubMed Central

Kimura, Genki; Nakaoki, Takahiro; Colley, Thomas; Rapeport, Garth; Strong, Pete; Kizawa, Yasuo

2017-01-01

ABSTRACT PC945 is a novel triazole optimized for lung delivery, and the objective of this study is to determine the effects of intranasally dosed PC945 on Aspergillus fumigatus infection and associated biomarkers in immunocompromised mice. PC945, posaconazole, or voriconazole was administered intranasally once daily on days 0 to 3 (early intervention) or days 1 to 3 (late intervention) postinfection in temporarily neutropenic A/J mice infected intranasally with A. fumigatus, and bronchoalveolar lavage fluid (BALF) and serum were collected on day 3. The effects of extended prophylaxis treatment (daily from days −7 to +3 or days −7 to 0) were also compared with those of the shorter treatment regimens (days −1 to +3 or days −1 and 0). Early and late interventions with PC945 (2.8 to 350 μg/mouse; approximately 0.11 to ∼14 mg/kg of body weight) were found to inhibit lung fungal loads and to decrease the concentrations of galactomannan (GM) in both BALF and serum as well as several biomarkers in BALF (interferon gamma [IFN-γ], interleukin-17 [IL-17], and malondialdehyde) and serum (tumor necrosis factor alpha [TNF-α] and IL-6) in a dose-dependent manner and were >3- and >47-fold more potent than intranasally dosed posaconazole and voriconazole, respectively. Furthermore, extended prophylaxis with low-dose PC945 (0.56 μg/mouse; 0.022 mg/kg) was found to inhibit fungal loads and to decrease the concentrations biomarkers more potently than did the shorter treatment regimens. Thus, PC945 dosed intranasally once daily showed potent antifungal effects, and the effects of PC945 accumulated upon repeat dosing and were persistent. Therefore, PC945 has the potential to be a novel inhaled therapy for the treatment of A. fumigatus infection in humans. PMID:28630185

One should avoid retro-orbital pharmacokinetic sample collections for intranasal dosing in rats: Illustration of spurious pharmacokinetics generated for anti-migraine drugs zolmitriptan and eletriptan.

PubMed

Patel, Harilal; Patel, Prakash; Modi, Nirav; Shah, Shaival; Ghoghari, Ashok; Variya, Bhavesh; Laddha, Ritu; Baradia, Dipesh; Dobaria, Nitin; Mehta, Pavak; Srinivas, Nuggehally R

2017-08-30

Because of the avoidance of first pass metabolic effects due to direct and rapid absorption with improved permeability, intranasal route represents a good alternative for extravascular drug administration. The aim of the study was to investigate the intranasal pharmacokinetics of two anti-migraine drugs (zolmitriptan and eletriptan), using retro-orbital sinus and jugular vein sites sampling. In a parallel study design, healthy male Sprague-Dawley (SD) rats aged between 8 and 12weeks were divided into groups (n=4 or 5/group). The animals of individual groups were dosed intranasal (~1.0mg/kg) and oral doses of 2.1mg/kg of either zolmitriptan or eletriptan. Serial blood sampling was performed from jugular vein or retro-orbital site and plasma samples were analyzed for drug concentrations using LC-MS/MS assay. Standard pharmacokinetics parameters such as T max , C max , AUC last , AUC 0-inf and T 1/2 were calculated and statistics of derived parameters was performed using unpaired t-test. After intranasal dosing, the mean pharmacokinetic parameters C max and AUC inf of zolmitriptan/eletriptan showed about 17-fold and 3-5-fold higher values for retro-orbital sampling as compared to the jugular vein sampling site. Whereas after oral administration such parameters derived for both drugs were largely comparable between the two sampling sites and statistically non-significant. In conclusion, the assessment of plasma levels after intranasal administration with retro-orbital sampling would result in spurious and misleading pharmacokinetics. Copyright © 2017 Elsevier B.V. All rights reserved.

Biosimilar insulins.