Thesis (Ph. D.)--University of Chicago, Dept. of Neurobiology, Pharmacology and Physiology, August 2003. / Includes bibliographical references. Also available on the Internet.

Thesis (Ph. D.)--University of Chicago, Dept. of Neurobiology, Pharmacology and Physiology, August 2003. / Includes bibliographical references. Also available on the Internet.

The major objective of this project was to examine the potential for mediators of IgE-mediated allergic reactions to alter neural activity. The project was divided into three parts. In Part I, the ability of endogenously released chemical mediators to alter neural activity in vitro was assessed by measuring isometric contractile responses to electrical field stimulation (EFS) (2-128 Hz, 20 V, 0.5 msec. duration) of sensitized rabbit bronchi before and after exposure to the antigen horseradish peroxidase (HRP). Antigen enhanced bronchial responses to EFS with low frequencies: mean log (± S.E.) frequency which produced 20% of maximum response decreased from 1.04 (± 0.05) to 0.90 (± 0.07) Hz (p < 0.05). Responses of unsensitized bronchi were not enhanced by antigen. Chlorpheniramine, an H₁ antagonist, abolished the antigen effect. Antigen did not enhance the responses to exogenous acetylcholine. Hence, the antigen is apparently modulating neural activity and not smooth muscle per se. In Part II, the capacity for histamine to modulate vagally-induced bronchoconstriction in anesthetized, vagotomized, mechanically-ventilated rabbits was examined in vivo. Changes in pulmonary resistance induced by electrically stimulating the cut ends of the vagi (2-32 Hz, 20 V, 0.5 msec. duration) were assessed before and 10 minutes after histamine aerosolization (10 breaths of 10 mg/ml). Histamine inhalation potentiated vagally-induced bronchoconstriction at low frequencies: mean log (± S.E.) frequency producing a 20% change in pulmonary resistance decreased from 0.88 (± 0.09) to 0.56 (± 0.15) (p < 0.05). Chlorpheniramine abolished this effect. In Part III, the dependence on IgE antibodies of the in vitro modulation of neurally-induced contraction of sensitized bronchi was investigated. Rabbits were passively immunized with fractions enriched with HRP-specific IgE, IgG, or IgM antibodies. After 72 hours, rabbits were sacrificed and the responses of bronchi to EFS were assessed before and after antigen challenge. Antigen enhanced the responses to EFS only of bronchi passively sensitized with IgE. Therefore, antigen enhancement of neural activity was dependent on IgE. These studies demonstrate that the interaction between antigen and IgE antibodies can induce the release of chemical mediators which can alter neural activity.

Children with cerebral palsy and powerful whole body extensor spasms find sitting in a rigid seat uncomfortable and sometimes painful due to the large forces they apply to their constraints. They are usually unable to speak and communication is difficult. The spasms affect every aspect of their lives. This thesis describes the genesis of a new functional dynamic seat for children with severe whole body extensor spasms, and the novel method used to design it. This novel seat technology is known as ‘Whole Body Dynamic Seating’. The thesis describes the clinical need this seat addresses, and the design and technology context in which this research takes place. The user evaluation, observation, measurement, analysis and reasoning that led to a successful seat design are described in detail. Children with cerebral palsy sometimes have whole body spasms that mean they cannot be seated in conventional static seating that positions a child in a fixed posture. For this research the children were classified as functioning at Chailey Sitting Ability Level 1 and Gross Motor Functional Classification System Level V. Such children spend much of their time being held by a person, or lying on a mat, bed or pad. This results in difficulty with social engagement and physical functioning, particularly in school. This research created a seat that such children could sit in, providing a comfortable and functional seat for use in a home or school classroom environment. This seat was designed with the direct and essential involvement of disabled children, their parents, therapists, teachers and carers. The work is part of a larger programme of research into seating and support technology that will enhance a child’s ability to gain functional movement and communication skills that can be employed to enable the child’s free self expression and social participation. The research investigated means of supporting children with whole body extensor spasms through a progressive iterative method utilizing direct user evaluation of a series of prototypes incrementing in complexity and fidelity towards a fully functional physical seat. An iterative method was used to design, build and evaluate three dynamic seats. This method incorporated two new approaches to prototyping developed for the research programme in response to difficulties encountered in designing dynamic systems for children with highly complex neuromotor disability. Soft and Semi-soft prototyping and evaluation methods provided essential feedback on dynamic seating concepts that guided proposed solutions, without requiring costly and time-consuming manufacture. Video was used to create a record of the children’s movements and responses for subsequent analysis. Instrumentation was built into the seats to enable direct objective measurement of the reaction forces and seat movement caused by extensor spasms. This thesis presents several unique features created through this research programme: 1. Independent and virtually hinged anatomical dynamic thigh supports; 2. Independent anatomical dynamic foot supports; 3. A virtually hinged dynamic back support; 4. An anatomical dynamic head support concept. The final Whole Body Dynamic Seat was child-centred in its functionality and aesthetic design, and was favourably commented upon by parents, children and school staff. Use of the new dynamic seating by three children (including one from a previous work programme) showed that children with severe whole body extensor spasms can be seated comfortably. The children also demonstrated gains in physical and social function as a result of using the dynamic seats. The two fully independent dynamic seats made advances in comfort over static seating for children with whole body extensor spasms. One of the children especially liked the seat and resisted being put back into his usual seating. An adult with severe cerebral palsy and extensor spasms evaluated a dynamic foot support concept and reported very significant reductions in spasticity and pain, and gains in physical function. The Whole Body Dynamic Seats showed gains in postural symmetry and in hand and head function over the usual static seats when used by the children with spasms. These gains were reported by staff during long term evaluations and measured specifically during the final evaluation. Two children learned to control the movement of seats in which they were sat, and were able to control their posture and use that control to carry out functions such as switch pressing. Such learning through the use of dynamic seating by children with severe dystonic cerebral palsy and whole body extensor spasms has not previously been documented. The seats did not just affect the children - school staff were affected too. School staff working around the children in the dynamic seats were observed to be more inclusive towards the children, and to expect more interaction from them. The ability of the children to move altered staff expectations of their ability to participate and communicate. This new seating has improved the quality of life of the children that use it. Future implementation of this technology in commercially produced seating offers the possibility of similar gains to many more severely disabled children who are currently less comfortable and less functional than they need to be.

<strong>Aims:</strong> The purpose of the research presented in this thesis is to elucidate the mechanism of the stimulation of oxidative metabolism and contractile function that occurs in vascular smooth muscle during cerebral vasospasm (CV) after subarachnoid haemorrhage (SAH). The biochemical mechanisms leading to CV were investigated using an in vitro model of CV developed for this research. CSF (cerebrospinal fluid) from SAH patients at risk of vasospasm which stimulated oxygen consumption (CSF S ) was used to model vasospasm. The hypothesis is CSF_S contains a substance which stimulates tension generation over that of CSF_N ,(non-stimulatory cerebrospinal fluid) and also inhibits the myosin light chain phosphatase. <strong>Methods:</strong> The porcine carotid artery was used as a model for the human basilar artery. The rate of oxygen consumption (JO₂) was measured in response to CSF_S and tension generation was also examined. Various agents were used to treat or pretreat the tissue such as magnesium and andalpha;₁-adrenergic receptor agonists. Their effects on the CSF_S-induced stimulation were measured to study the mechanism of vasospasm. A myosin light chain phosphatase (MLCP) assay was developed to study the mechanisms leading to CV. <strong>Results and conclusion:</strong> Addition of CSF_S to the porcine carotid artery is a reliable and reproducible in vitro model of CV. Using this model, it was found that Mg⁺⁺ loading and andalpha;₁-adrenergic receptor agonists attenuated the vasospasm, but a non-specific endothelin antagonist had no effect. Acute addition of 12mM Mg⁺⁺ relaxed the tissue from a CSF_S induced contraction significantly and rendered the contraction rinsible. Okadaic acid (InM), a phosphatase inhibitor, had very similar effects to CSF_S because it stimulated JO₂ and slowed relaxation after a stretch. There was also significant inhibition of phosphatase caused by the CSF_S. Vasospasm appears to be caused by a combination of a contractile stimulus, and inhibition of MLCP activity.

Thesis (M.S.)--Indiana University, 2004. / Includes bibliographical references (leaves 67-88). Also available online (PDF file) by a subscription to the set or by purchasing the individual file.

Thesis (M.S.)--Indiana University, 2004. / Includes bibliographical references (leaves 67-88).

Thesis (doctoral)--Lund University, 1999. / Added t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (doctoral)--Lund University, 1999. / Added t.p. with thesis statement inserted. Includes bibliographical references.

INTRODUÇÃO: Pacientes com vias aéres hiperresponsivas têm uma resposta exarcebada das vias aéreas a vários estímulos. Nestes pacientes, a simples intubação é a causa mais freqüente do broncoespasmo, levando a complicações no peri-operatório. O óxido nítrico está envolvido na regulação da função fisiológica bem como em doenças das vias aéreas e nos últimos anos seu papel vem sendo constantemente estudado na modulação da broncoconstrição. OBJETIVO: Estudar a possibilidade da medida de óxido nítrico exalado (NOex) ser um marcador de episódios de broncoespasmo no intra-operatório. MÉTODOS: 146.358 fichas anestésicas foram analisadas no período de 1999/2004. Ocorreram registros de broncoespasmos em 863 pacientes neste período. Destas, nove sujeitos foram identificados como não asmáticos (grupo broncoespasmo), 12 sujeitos foram diagnosticados como asmáticos (grupo asma) e 10 indivíduos sem história prévia de doença foram selecionados aleatoriamente como grupo controle. Todos os sujeitos foram submetidos à medida de óxido nítrico exalado (partes/bilhão), espirometria e coleta de escarro induzido com salina hipertônica. Os dados foram comparados utilizando ANOVA seguido do teste de Tukey e Kruskal-Wallis seguido do teste de Dunn\'s. RESULTADOS: Os grupos broncoespasmo e controle apresentaram espirometria normal, com medidas estatísticamente diferentes do grupo asma (p <0,05). As porcentagens de eosinófilos (mediana) no escarro induzido foram maiores no grupo asma [2,5 (0,4-6,8)], menores no grupo broncoespasmo [0,5 (0-1,3), e grupo controle [0,0 (0)]. A medida de óxido nítrico exalado foi maior no grupo dos asmáticos [81,5 (57,6-86,8)] em relação aos controles [18,7 (16,0-24,7)] (p=0,001). Não houve diferença entre grupos broncoespasmo e asma, ambos significantemente diferentes do grupo controle (p <0,05). CONCLUSÃO: Pacientes não asmáticos que apresentaram broncoespasmo no intra-operatório durante a anestesia e manipulação da traquéia, possuem níveis de óxido nítrico no ar expirado exalado elevado. / INTRODUCTION: Airways of patients with bronchial hyperreactivity are characterized by exaggerated bronchoconstriction in response to a variety of stimuli. Henceforth, bronchospasm may occur during induction of anaesthesia. Nitric Oxide is part of either physiologic or pathophysiologic airway regulation and its role has been investigated as a bronchoconstrictior modulator. OBJECTIVE: to address the possibility of exhaled nitric oxide measurement (NOex) as a marker of intraoperative bronchospasm. METHODS: 146.358 anesthesia registered forms were revised (period: 1999/2004). Bronchospasm occurrence appeared registered in 863. From those, nine were identified as non-asthmatics patients (Bronchospasm group). Also, 12 asthmatics constituted one additional group (Asthma group) and 10 subjects with no previous airway disease or symptoms were randomly selected as control group. All subjects were submitted to exhaled nitric oxide measurements (parts/billion), spirometry and induced sputum. The data were compared by ANOVA followed by the Tukey test and Kruskal- Wallis followed by Dunn\'s test. RESULTS: Both bronchospasm and control groups had normal lung function test, different from asthma group (p <0.05). The percentage of eosinophils (median) in induced sputum was higher for asthma [2.5 (0.4-6.8)] lower for bronchospasm [0.5 (0-1.3)] and control group [0.0 (0)]. Exhaled Nitric Oxide was higher for asthmatic patients [81.5 (57.6-86.8)], compared to control group [18.7 (16.0-24.7)] (p=0.001). There was no difference between bronchospasm and asthma groups both different from control (p <0.05). CONCLUSION: non-asthmatics patients with intraoperative bronchospasm detected during anesthesia after airway manipulation showed higher nitric oxide expired levels.