Identification of a novel inositol phosphate recognition site: specific [3H]inositol hexakisphosphate binding to brain regions and cerebellar membranes

[3H]Inositol hexakisphosphate (InsP6) binds with a heterogeneous distribution to frozen sections of unfixed rat brain and is displaced by unlabelled InsP6. The pattern of binding correlates with binding to neuronal cell bodies. [3H]InsP6 binding to cerebellar membranes has been further characterised, is reversible, and saturable, and exhibits high specificity for inositol polyphosphates. The IC50 for competition by unlabelled InsP6 is approximately 100nM, whereas inositol 1,3,4,5,6 pentakisphosphate (Ins(13456)P5), inositol 1,3,4,5 tetrakisphosphate (Ins(1345)P4), and inositol 1,4,5 trisphosphate (Ins(145)P3) bind with an affinity at least one order of magnitude lower. [3H]InsP6 binding is clearly distinct from previously characterised Ins(145)P3 (ref. 1, 2) and Ins(1345)P4 (ref. 3) binding, both in terms of pharmacology and brain distribution.

Foundations of an intervention package to improve communication in residential care settings:a mixed methods study

Background: The prevalence of hearing loss is considerably higher in individuals in residential care than in people within the community-dwelling population, and yet hearing aids and hearing services are relatively underused. Care staff have a key role in supporting access to services. Objectives: This study identifies staff perspectives on hearing loss and their views about potential hearing service improvements. Study design: A four-stage mixed methods study was used, made up of qualitative interviews, observation, a survey and a stakeholder involvement meeting. Results: The qualitative stages indicated that staff were concerned about their levels of interaction with residents. Staff considered maximizing communication as part of their professional role. The quantitative survey indicated that these views were widely held by staff, and the stakeholder stage identified the need for social support and dedicated staff training opportunities. Conclusion: Care home staff regard communication as a shared issue. Future interventions could enhance access to hearing services and provide care home staff with training in hearing loss and hearing aid management. © 2013 Informa Healthcare.

Improving brain drug targeting through exploitation of the nose-to-brain route:a physiological and pharmacokinetic perspective

With an ageing population and increasing prevalence of central-nervous system (CNS) disorders new approaches are required to sustain the development and successful delivery of therapeutics into the brain and CNS. CNS drug delivery is challenging due to the impermeable nature of the brain microvascular endothelial cells that form the blood-brain barrier (BBB) and which prevent the entry of a wide range of therapeutics into the brain. This review examines the role intranasal delivery may play in achieving direct brain delivery, for small molecular weight drugs, macromolecular therapeutics and cell-based therapeutics, by exploitation of the olfactory and trigeminal nerve pathways. This approach is thought to deliver drugs into the brain and CNS through bypassing the BBB. Details of the mechanism of transfer of administrated therapeutics, the pathways that lead to brain deposition, with a specific focus on therapeutic pharmacokinetics, and examples of successful CNS delivery will be explored. © 2014 Bentham Science Publishers.

Developing a tool to support communication of parental concerns when a child is in hospital

The involvement of parents in their child’s hospital care has been strongly advocated in paediatric healthcare policy and practice. However, incorporating parental worries about their child’s condition into clinical care can be difficult for both parents and healthcare professionals. Through our “Listening To You” quality improvement project we developed and piloted an innovative approach to listening, incorporating and responding to parental concerns regarding their child’s condition when in hospital. Here we describe the phases of work undertaken to develop our “Listening To You” communications bundle, including a survey, literature review and consultation with parents and staff, before findings from the project evaluation are presented and discussed.

Phytochemical-loaded mesoporous silica nanoparticles for nose-to-brain olfactory drug delivery

Central nervous system (CNS) drug delivery is often hampered due to the insidious nature of the blood-brain barrier (BBB). Nose-to-brain delivery via olfactory pathways have become a target of attention for drug delivery due to bypassing of the BBB. The antioxidant properties of phytochemicals make them promising as CNS active agents but possess poor water solubility and limited BBB penetration. The primary aim of this study was the development of mesoporous silica nanoparticles (MSNs) loaded with the poorly water-soluble phytochemicals curcumin and chrysin which could be utilised for nose-to-brain delivery. We formulated spherical MSNP using a templating approach resulting in ∼220nm particles with a high surface porosity. Curcumin and chrysin were successfully loaded into MSNP and confirmed through Fourier transformation infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and HPLC approaches with a loading of 11-14% for curcumin and chrysin. Release was pH dependant with curcumin demonstrating increased chemical stability at a lower pH (5.5) with a release of 53.2%±2.2% over 24h and 9.4±0.6% for chrysin. MSNP were demonstrated to be non-toxic to olfactory neuroblastoma cells OBGF400, with chrysin (100μM) demonstrating a decrease in cell viability to 58.2±8.5% and curcumin an IC50 of 33±0.18μM. Furthermore confocal microscopy demonstrated nanoparticles of <500nm were able to accumulate within cells with FITC-loaded MSNP showing membrane localised and cytoplasmic accumulation following a 2h incubation. MSNP are useful carriers for poorly soluble phytochemicals and provide a novel vehicle to target and deliver drugs into the CNS and bypass the BBB through olfactory drug delivery.

Role for cell-to-cell communication in stem cell specification toward pancreatic progenitors: relevance to the design of novel therapies for diabetes.

Thesis (Ph.D.)--University of Washington, 2016-08

Nanostructured lipid carriers for nose-to-brain delivery in neurodegenerative diseases therapy

191 p.

MEASURING HEAD IMPACT CONTACT PRESSURE IN COLLEGIATE FOOTBALL GAMES TO CORRELATE HEAD KINEMATICS TO BRAIN KINETICS ELUCIDATING BRAIN INJURY DYNAMICS

Does a brain store thoughts and memories the way a computer saves its files? How can a single hit or a fall erase all those memories? Brain Mapping and traumatic brain injuries (TBIs) have become widely researched fields today. Many researchers have been studying TBIs caused to adult American football players however youth athletes have been rarely considered for these studies, contradicting to the fact that American football enrolls highest number of collegiate and high-school children than adults. This research is an attempt to contribute to the field of youth TBIs. Earlier studies have related head kinematics (linear and angular accelerations) to TBIs. However, fewer studies have dealt with brain kinetics (impact pressures and stresses) occurring during head-on collisions. The National Operating Committee on Standards for Athletic Equipment (NOCSAE) drop tests were conducted for linear impact accelerations and the Head Impact Contact Pressures (HICP) calculated from them were applied to a validated FE model. The results showed lateral region of the head as the most vulnerable region to damage from any drop height or impact distance followed by posterior region. The TBI tolerance levels in terms of Von-Mises and Maximum Principal Stresses deduced for lateral impact were 30 MPa and 18 MPa respectively. These levels were corresponding to 2.625 feet drop height. The drop heights beyond this value will result in TBI causing stress concentrations in human head without any detectable structural damage to the brain tissue. This data can be utilized for designing helmets that provide cushioning to brain along with providing a resistance to shear.

Pedagogical interventions to overcome communication apprehension in employment interviews among career students.

Career programs in the Cegep system base their training on various learning activities, which are followed by a practicum. The objective is to achieve a certain number of competencies, deemed necessary by the Ministry of Education, for entry-level occupations in to the workforce. The Graphic Communications program offered at Champlain College Saint-Lambert is a three-year career program that leads to employment in the field of graphics. Many students have part-time jobs during their schooling period but most of those jobs do not relate to their field of study. Several graduates stated they were unable to persuade employers to hire them for an externship or stage at the end of their program. While jobs are important for their general skills, since they are not directly related to the field, these jobs may not have given the students a suitable model for the conduct of an employment interview. Practice interviews may be one of many successful training methods to lower communication apprehension (CA) levels. CA is defined as "an individual's level of fear or anxiety associated with either real or anticipated communication with another person or persons." This paper examines the literature on CA and employment interviews and evaluates whether pedagogical interventions, including monitored phone calls to employers and practice-videotaped interviews, allow students to feel more confident about interviewing for a future job. A qualitative tool was used to gather scientific measurements of the participants' levels of CA both at the beginning and at the end of the Career Planning course. Open-ended reflective journals gathered quantitative data on the impact specific instructional strategies had on the participants. The pedagogical interventions that were examined and tested were as follows: preparation of scripts, monitored phone calls, videotaped practice interviews, and inclass access to professional assistance. Results indicate that all interventions had a positive impact on lowering levels of CA. It is clear that positive conclusions were drawn by the students as to usefulness of these activities. Overall, participants who responded to the reflective journal questions felt positive about the contribution of this preparatory career course to their CA levels. The results of the quantitative tool were consistent with previous research and the analysis of the reflective journals gave additional support to the usefulness of the interventions on students' confidence levels. Recommandations for improvements to the curriculum include the need for students to be taugh formally about metacognition and how to monitor it. Students need to be exposed to videotaped interviews more often. They should be better prepared for unexpected interview questions, and they should experience formal rehearsals with one of their instructors before the actual practice interview. Some of these recommendations have already been successfully implemented in the program's curriculum.||Résumé:Le but de ce travail était de vérifier si certaines activités pédagogiques sont efficaces pour faire baisser le niveau d'anxiété lié à la communication orale lors de leurs entrevues d'embauche. L'objectif des programmes techniques au Québec est de fournir aux étudiants un certain nombre de compétences définies par le ministèe de l'Éducation, des Loisirs et du Sport afin que ces derniers puissent fournir des services de techniciens spécialisés aux entreprises. Le programme nommé Office Systems Technology (412) du collège Champlain de Saint-Lambert, a choisi la voie de la spécialisation en microédition et hypermédia en 1999 et a changé son nom pour Graphic Communications en 2005. Les programmes techniques au Cégep incluent un stage en milieu de travail à la fin d'un programme de trois ans et par le fait même, une entrevue pour obtenir un stage en entreprise. La compétence visée par cette étude est l'intégration au marché du travail et le cheminement professionnel des étudiants. Lors d'enquêtes informelles, plusieurs étudiants du programme ont fait part de leurs difficultés à trouver un stage en fin d'études. Certains auteurs suggèrent que ces étudiants n'ont pas de modèles appropriés lors de la tenue d'une entrevue d'emploi. Ils proposent de diminuer le niveau d'anxiété lié à la communication orale lors d'entrevues d'embauche en offrant des pratiques d'entrevue aux étudiants. Cette recherche a examiné la littérature au sujet de l'anxiété de communication, plus précisément lors d'entrevues. Elle avait pour mandat d'évaluer si les activités pédagogiques d'un cours de préparation à la carrière ont été efficaces pour faire baisser les taux d'anxiété en communication orale lors d'entrevues. En plus, une conseillère à l'emploi fut invitée à plusieurs reprises afin de fournir un support professionnel en classe, étant donné que les étudiants ne prennent pas nécessairement le temps de consulter des professionnels en raison de leurs activités personnelles trop nombreuses. Le type d'enseignement évalué est considéré comme stratégique, étant donné qu'il agit au niveau cognitif et métacognitif de l'étudiant. Le cours de préparation à l'emploi débute par la vérification des acquis antérieurs des étudiants et il tient compte de leur motivation scolaire et professionnelle. De plus, il est axé sur la construction du savoir en proposant des activités de plus en plus complexes, débutant par la rédaction de textes à utiliser lors d'appels aux employeurs, en passant par la préparation et la pratique d'appels et se terminant par des entrevues d'emploi qui serviront de modèle à perfectionner par chaque étudiant. Ces entrevues se font avec des employeurs qui ont déjà embauché des étudiants du programme de Graphic Communications au collège Champlain de Saint-Lambert et sont enregistrées sur bande vidéo afin de permettre une visualisation ultérieure et cohérente avec les objectifs visés. La méthodologie de cette recherche inclut deux outils, un quantitatif et un qualitatif. L'outil quantitatif permet de mesurer scientifiquement les taux d'appréhension en communication des étudiants au début et à la fin du cours de préparation à l'emploi. Cet outil est la fusion de deux outils, le Personal Report of Communication Apprehension ou PRCA-24, qui fut développé par McCroskey (1984), en tandem avec celui de Wongprasert & Ayres (2000), qui lui met l'accent sur les entrevues d'emploi. Les réponses à cet outil combiné sont évaluées sur une échelle Likert de cinq points. L'outil qualitatif est une série de questions auxquelles les étudiants ont répondu quatre fois lors de la session. Les réponses à ces questions ont été analysées et les commentaires des étudiants évalués. Il découle de cette analyse que les niveaux d'anxiété des étudiants qui ont participé (14) étaient définitivement à la baisse en fin de cours. La pratique téléphonique structurée, dans un laboratoire avec les téléphones, a été très révélatrice pour les étudiants. Ils ont appris comment utiliser un script comme piste de départ pour un appel et qu'il était possible de contourner certains obstacles de façon professionnelle. Ensuite, lors d'une visite d'une compagnie de graphisme, ils ont pu observer divers modèles d'emploi. Ils ont eu la possibilité de poser des questions sur le fonctionnement et les besoins de l'entreprise. Ceci facilita la rédaction de leur curriculum vitae en leur permettant de mieux décrire leurs acquis en fonction d'emplois recherchés. Par la suite, ils se sont préparés pour une pratique d'entrevue, filmée. Les interviewers avaient déjà travaillé avec le collège et avaient déjà embauché certains étudiants de ce programme, donc ils connaissaient leur potentiel. Une liste de questions possibles fut suggérée mais il n'en restait pas moins que les interviewers pouvaient les modifier, ceci étant représentatif du marché de l'emploi. Même si le collège fournit un enseignement en anglais, un des intervieweurs donna ses entrevues en français. Trois étudiants se sont portés volontaires, mais deux ont constaté qu'ils auraient dû pratiquer leur script en français avant l'entrevue pour mieux diminuer leur niveau d'anxiété. Finalement, les étudiants durent visionner leur segment d'entrevue : ceci leur a permis de voir si leur attitude non-verbale concordait avec ce qu'ils ressentaient en entrevue et d'emmener les correctifs appropriés. Les taux d'anxiété furent vérifiés une deuxième fois en fin de session et les résultats ont démontré une baisse des taux d'appréhension. Les résultats de cette étude concordent donc avec ceux trouvés dans la littérature et donnent de bonnes pistes pour l'amélioration de ce cours de préparation à la carrière. L'auteur recommande d'enseigner la métacognition de façon formelle et ainsi de faciliter la prise de conscience des apprentissages que les étudiants effectuent. De plus, les étudiants devraient être filmés en studio au moins une fois par année pour diminuer le facteur de stress causé par les caméras et finalement ils pourraient certainement bénéficier de pratiques formelles d'entrevue avec un instructeur avant l'entrevue filmée. L'augmentation des pratiques a déjà été mise en oeuvre dans le programme et des résultats positifs se sont ensuivis.

A crucial role for IL-6 in the CNS of rats during fever induced by the injection of live E. coli

Interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha, and IL-6 have been established as important mediators of fever induced by lipopolysaccharide (LPS) from Gram-negative bacteria. Whether these pro-inflammatory cytokines are also important in mediating fever induced by live bacteria remains less certain. We therefore investigated the following: (1) the synthesis of TNF-alpha, IL-1 beta, and IL-6 during E. coli-induced fever and (2) the effect of blocking the action of cytokines within the brain on E. coli-induced fever. Body or tail skin temperature (bT or Tsk, respectively) was measured by biotelemetry or telethermometry, every 30 min, during 6 or 24 h. Depending on the number of colony-forming units (CFU) injected i.p., administration of E. coli induced a long-lasting increase in bT of male Wistar rats. The duration of fever did not correlate with the number of CFU found in peritoneal cavity or blood. Because 2.5 x 10(8) CFU induced a sustained fever without inducing a state of sepsis/severe infection, this dose was used in subsequent experiments. The E. coli-induced increase in bT was preceded by a decrease in Tsk, reflecting a thermoregulatory response. TNF-alpha, IL-1 beta, and IL-6 were detected at 3 h in serum of animals injected i.p. with E. coli. In the peritoneal exudates, TNF-alpha, IL-1 beta, and IL-6 were detected at 0.5 and 3 h after E. coli administration. Moreover, both IL-1 beta and IL-6, but not TNF-alpha, were found in the cerebrospinal fluid (CSF) and hypothalamus of animals injected with E. coli. Although pre-treatment (i.c.v., 2 mu l, 15 min before) with anti-IL-6 antibody (anti-IL-6, 5 mu g) reduced E. coli-induced fever, pre-treatment with either IL-1 receptor antagonist (IL-1ra, 200 mu g) or soluble TNF receptor I (sTNFRI, 500 ng) had no effect on the fever response. In conclusion, replicating E. coli promotes an integrated thermoregulatory response in which the central action of IL-6, but not IL-1 and TNF, appears to be important.

The role of reactive astrocytes in the resistance of melanoma brain metastasis to chemotherapy

Brain metastasis is resistant to chemotherapy while the leaky blood-brain-barrier in brain metastasis can not be the underlying reason. Metastatic tumor cells (“seed”) exploit the host microenvironment (“soil”) for survival advantages. Astrocytes which maintain the homeostasis of the brain microenvironment become reactive subsequent to brain damages and protect neurons from various injuries. We observed reactive astrocytes surrounding and infiltrating into brain metastasis in both clinical specimen and experimental animal model, thus raising a possibility that reactive astrocytes may protect tumor cells from cytotoxic chemotherapeutic drugs. ^ To test this hypothesis, we first generated an immortalized astrocyte cell line from H-2Kb-tsA58 mice. The immortal mouse astrocytes expressed specific markers including GFAP. Scanning electron microscopy demonstrated that astrocytes formed direct physical contact with tumor cells. Moreover, the expression of GFAP by astrocytes was up-regulated subsequent to co-culture with tumor cells, indicating that the co-culture of astrocytes and tumor cells may serve as a model to recapitulate the pathophysiological situation of brain metastasis. ^ In co-culture, astrocytes dramatically reduced apoptosis of tumor cells produced by various chemotherapeutic drugs. This protection effect was not because of culturing cells from different species since mouse fibroblasts did not protect tumor cells from chemotherapy. Furthermore, the protection by astrocytes was completely dependent on a physical contact. ^ Gap junctional communication (GJC) served as this physical contact. Tumor cells and astrocytes both expressed the major component of gap junctional channel—connexin 43 and formed functional GJC as evidenced by the “dye transfer” assay. The blockage of GJC between tumor cells and astrocytes by either specific chemical blocker carbenoxolone (CBX) or by genetically knocking down connexin 43 on astrocytes reversed the chemo-protection. ^ Calcium was the signal molecule transmitted through GJC that rescued tumor cells from chemotherapy. Accumulation of cytoplasmic calcium preceded the progress of apoptosis in tumor cells treated with chemotherapeutic drugs. Furthermore, chelation of accumulated cytoplasmic calcium inhibited the apoptosis of tumor cells treated with chemotherapeutic drugs. Most importantly, astrocytes could “shunt” the accumulated cytoplasmic calcium from tumor cells (treated with chemotherapeutic drug) through GJC. We also used gene expression micro-array to investigate global molecular consequence of tumor cells forming GJC with astrocytes. The data demonstrated that astrocytes (but not fibroblasts), through GJC, up-regulated the expressions of several well known survival genes in tumor cells. ^ In summary, this dissertation provides a novel mechanism underlying the resistance of brain metastasis to chemotherapy, which is due to protection by astrocytes through GJC. Interference with the GJC between astrocytes and tumor cells holds great promise in sensitizing brain metastasis to chemotherapy and improving the prognosis for patients with brain metastasis. ^

Adaptive Brain-Computer Interface Systems For Communication in People with Severe Neuromuscular Disabilities

Brain-computer interfaces (BCI) have the potential to restore communication or control abilities in individuals with severe neuromuscular limitations, such as those with amyotrophic lateral sclerosis (ALS). The role of a BCI is to extract and decode relevant information that conveys a user's intent directly from brain electro-physiological signals and translate this information into executable commands to control external devices. However, the BCI decision-making process is error-prone due to noisy electro-physiological data, representing the classic problem of efficiently transmitting and receiving information via a noisy communication channel.

This research focuses on P300-based BCIs which rely predominantly on event-related potentials (ERP) that are elicited as a function of a user's uncertainty regarding stimulus events, in either an acoustic or a visual oddball recognition task. The P300-based BCI system enables users to communicate messages from a set of choices by selecting a target character or icon that conveys a desired intent or action. P300-based BCIs have been widely researched as a communication alternative, especially in individuals with ALS who represent a target BCI user population. For the P300-based BCI, repeated data measurements are required to enhance the low signal-to-noise ratio of the elicited ERPs embedded in electroencephalography (EEG) data, in order to improve the accuracy of the target character estimation process. As a result, BCIs have relatively slower speeds when compared to other commercial assistive communication devices, and this limits BCI adoption by their target user population. The goal of this research is to develop algorithms that take into account the physical limitations of the target BCI population to improve the efficiency of ERP-based spellers for real-world communication.

In this work, it is hypothesised that building adaptive capabilities into the BCI framework can potentially give the BCI system the flexibility to improve performance by adjusting system parameters in response to changing user inputs. The research in this work addresses three potential areas for improvement within the P300 speller framework: information optimisation, target character estimation and error correction. The visual interface and its operation control the method by which the ERPs are elicited through the presentation of stimulus events. The parameters of the stimulus presentation paradigm can be modified to modulate and enhance the elicited ERPs. A new stimulus presentation paradigm is developed in order to maximise the information content that is presented to the user by tuning stimulus paradigm parameters to positively affect performance. Internally, the BCI system determines the amount of data to collect and the method by which these data are processed to estimate the user's target character. Algorithms that exploit language information are developed to enhance the target character estimation process and to correct erroneous BCI selections. In addition, a new model-based method to predict BCI performance is developed, an approach which is independent of stimulus presentation paradigm and accounts for dynamic data collection. The studies presented in this work provide evidence that the proposed methods for incorporating adaptive strategies in the three areas have the potential to significantly improve BCI communication rates, and the proposed method for predicting BCI performance provides a reliable means to pre-assess BCI performance without extensive online testing.

Group-to-group bidirectional Wi-Fi direct communication with two relay nodes

The current capabilities of mobile phones in terms of communication, processing and storage, enables its use to form autonomous networks of devices that can be used in case of collapse or inexistent support from a communication infrastructure. In this paper, we propose a network configuration of nodes that provides high-speed bidirectional device-to-device communication, with symmetrical data transfer rates, in Wi-Fi Direct multi-group scenarios, without using performance hindering broadcasts. Copyright © 2015 ICST.

Brain abscess secondary to frontal osteomyelitis

Frontal osteomyelitis is a rare complication of sinusitis. Common intracranial complications of the frontal osteomyelitis are meningitis, epidural empyema, subdural empyema and brain abscess. We described a case of frontal osteomyelitis with brain abscess caused by Staphylococcus aureus with improve after needle aspiration and antibiotics to brain abscess for eight weeks and for chronic osteomyelitis for four months.