Thesis (Ph. D.)--University of Texas at Austin, 2005. / Vita. Includes bibliographical references.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterised by impaired socialisation. The current project examines the hypothesis that ASD represents a broad range of distinct disease processes typified by environmental insult(s) during a period crucial for the development of any of the systems responsible for social integration skills, sharing simply the fundamental disruption to social functioning with various, definable systemic pathologies related to the initial insult conferring the heterogeneity of the condition. ASD will therefore have both modifiable environmental factors relating to the aetio-pathogenesis of the condition and likely, remediable disease processes. Following an examination of the relevant literature this project presents the Variable Insult Model of Autism. As part of a wider research strategy, this project goes on to explore potential modifiable environmental factors in patients with ASD.Zinc deficiency was explored as a potential environmental modifiable factor involved in the pathophysiology of autism and co-morbid disease. 72 patients with ASD were compared with 234 non-ASD controls. Mean serum zinc levels in the ASD group vs. the control group were 10.01 umol/l (SD 1.52 umol/l) vs. 11.61 umol/l (SD 2.14 umol/l, with a statistically significant difference - p < 0.0001, CI 1.2 – 2.1). The findings withstood correction for age and sex, and zinc did not correlate with diet or supplement use in the ASD group. Total lymphocyte count increased as zinc increased in the ASD group with zinc levels of 10.5 umol/l or above, suggesting zinc status is poor in patients with autism and this is affecting immune function. Urinary metabolomics, quantitative PCR stool analysis and autonomic function were also explored in ASD, as biomarkers of systemic disease processes presenting potential modifiable factors. The urinary organic acids of 49 patients were analysed versus population norms. 90% of patients with ASD had at least one abnormality. A follow-up study of 122 patients revealed succinic acid and 2-hydroxyhippuric acid were significantly raised in the ASD group versus population means (p = < 0.0001 and < 0.0001 respectively). Quantitative PCR analysis was conducted on 29 patients with autism versus 7 age-matched controls. Firmicutes to Bacteriodetes ratio was significantly elevated in the autism group versus the controls 69:41 (SD 8) vs. 54:46 (SD 8) (p < 0.003). A follow-up study of 143 patients and 12 controls showed consistent abnormalities in the composition of firmicutes and bacteriodetes (p = 0.005) and this withstood correction for age and sex (p = 0.009), suggesting an on-going abnormality in gut flora composition in the ASD-cohort. Autonomic profiles were available in 45 patients with ASD. There was marked variability in vagal tone, however in 11 patients with ASD who had both autonomic profile and qPCR stool analysis there was suggestion of a positive correlation between vagal tone and microflora composition (represented by firmicutes to bacteriodetes ratio) (p < 0.003).In summary, evidence suggests there are modifiable environmental factors associated with the aetiology, pathophysiology and disease evolution in ASD, and this is worthy of further consideration and investigation. From the preliminary results presented here, zinc status is poor in ASD and may be affecting immune function; gut flora abnormalities appear common and may be affecting neurological function in ASD.

This project involved the study of mechanisms which modulate autonomic transmission within the sympathetic nervous system using the mouse vas deferens as a model tissue. Data was collected using contraction studies, electrophysiological techniques with sharp microelectrodes, and fluorescent calcium imaging of both smooth muscle cells and nerve terminal varicosities. An additional series of experiments was conducted using the PC12 cell line, derived from a phaeochromocytoma of the rat adrenal medulla, for flow cytometry experiments using fluorescence-activated cell sorting. During the course of this project a novel technique for studying the activity of the norepinephrine transporter within a whole organ preparation was developed using the neurotransmitter uptake assay. The uptake of this assay within the nerve terminals of the vas deferens was abolished by desipramine whilst its rate of washout was increased by amphetamine. However, some non-neuronal, peri-nuclear staining which could not be prevented by a range of pharmacological means was also observed. This new technique was then used in other work exploring putative NET regulation by cannabinoids. The modulatory effects of two pharmacological groups were assessed: testosterone and cannabinoids. Testosterone was found to have a rapid, non-genomic effect inhibiting neurotransmission within the vas deferens. This was a postjunctional effect which appeared to involve modulation of the opening of L-type calcium channels on the smooth muscle cells. For the studies of cannabinoids, two broad areas of research were conducted. First the effects of &Delta;⁹-tetrahydrocannabinol were investigated with regard to the pre-junctional release of neurotransmitters and the effect of THC on calcium dynamics within individual nerve terminal varicosities. Secondly, a surprising novel effect upon the norepinephrine transporter was identified and examined. This inhibitory effect was revealed initially by contraction experiments demonstrating a decrease in the rate of uptake of noradrenaline from the junction. This work demonstrates that there are still novel modes of regulation of sympathetic transmission to be uncovered. The ongoing challenge is to establish their role within physiology and pathophysiology.

xvi, 132 p. : ill. A print copy of this thesis is available through the UO Libraries. Search the library catalog for the location and call number. / The Differential Susceptibility Hypothesis and the related Biological Sensitivity to Context theory contend that individuals with "susceptible" traits reap the benefits of positive rearing environments and exhibit better outcomes compared to their less susceptible peers. Studies have largely focused on physiological reactivity as an index of this susceptibility in children and adults, and most have measured physiology by grand mean changes from baseline to a stressor. The goal of this dissertation was to examine baseline Respiratory Sinus Arrhythmia (RSA) and RSA stress reactivity by taking advantage of analytical techniques modeling growth over time, as well as individual differences in this growth-using latent Growth Modeling (LGM) and Growth Mixture Modeling (GMM), respectively. Maternal sensitivity at 5 months and the quality of the attachment environment at 17 months were used as indicators of environmental conditions that might interact with infant susceptibility. Problem behavior and social competence were assessed at 17 months as measures of child well-being. Consistent with the theory of differential susceptibility, there were no significant differences in problem behavior or social competence among infants with low baseline RSA, but infants with high baseline RSA exhibited the lowest levels of problem behavior if reared in an environment that fostered security and more competence if their mothers exhibited greater sensitivity. Contrary to hypotheses, LGM analyses revealed that withdrawal of infant RSA appeared to buffer the impact of being reared in an environment that fostered disorganization, as infants with disorganized attachment histories exhibited the lowest number of problem behaviors. Two distinct groups of children were identified by GMM analyses: a class of infants with low RSA that decreased across the still-face episode, and a class of infants with high RSA that increased across this episode. Class by maternal sensitivity interactions were significantly predictive of social competence, with the high increasing class emerging as the group most susceptible to environmental influences, consistent with the differential susceptibility hypothesis. This dissertation adds importantly to both the sharpening and extension of theories of differential susceptibility. / Committee in charge: Jennifer Ablow, Chairperson, Psychology; Philip Fisher, Member, Psychology; Jeffrey Measelle, Member, Psychology; Jane Squires, Outside Member, Special Education and Clinical Sciences

Made available in DSpace on 2014-06-11T19:22:49Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-12-13Bitstream added on 2014-06-13T18:49:43Z : No. of bitstreams: 1 gois_mo_me_prud.pdf: 334951 bytes, checksum: ea8f5682903159b02b38d10927a185dc (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Introdução: a contração concêntrica promove maior estresse cardiovascular em relação à contração excêntrica, sobretudo por apresentar maiores valores de frequência cardíaca (FC), pressão arterial sistólica (PAS), pressão arterial diastólica (PAD) e pressão arterial média (PAM) em estímulos agudos. Entretanto, no âmbito do treinamento, não se sabe sobre a relação custo benefício destes dois tipos de exercício. Objetivo: avaliar e comparar o efeito de um treinamento resistido, realizado com ênfase concêntrica vs excêntrica, sobre respostas cardiovasculares (PAS, PAD e FC) e autonômicas [variabilidade de frequência cardíaca (VFC)]. Casuística e métodos: o estudo foi composto por 80 homens, com idade entre 18 e 30 anos. Os sujeitos foram alocados em 4 grupos, sendo que os grupos G1 (concêntrico) e G2 (excêntrico) foram submetidos a apenas uma sessão de ER para o grupo extensor do joelho... / Introduction: the concentric contraction causes greater cardiovascular stress in relation to the eccentric contraction, mainly due to the higher values of heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and means arterial pressure (MAP) in acute exercise. However, in the training, it is unknown the cost benefit of these two types of exercise. Objective: to evaluate and compare the effect of a resistance training, performed eccentric versus concentric with emphasis on cardiovascular responses (SBP, DBP and HR) and autonomic [heart rate variability (HRV)]. Methods: the study consisted of 80 men, aged between 18 and 30 years. The subjects were divided into 4 groups, with G1 (concentric) and G2 (eccentric) underwent only one session of ER for the knee extensor group [3 sets of 1 rep at 100% of 1 repetition maximum (RM )] and G3 (concentric) and G4 (eccentric) performed 10 sessions of resistance training, in which the 10th session consisted of three sets of 1 rep at 100% of 1RM, also for the knee extensor group. The volunteers were monitored in two conditions: before and 24 hours after the training and before, during and after (45 minutes) the only session of the G1 and G2... (Complete abstract click electronic access below)

abstract: The objective of this study was to examine the potential effects of long term hormone replacement therapy on cardiovascular autonomic nervous system responses to laboratory social stressors. The participants were 38 postmenopausal women, 18 using estrogen and progesterone hormone replacement therapy for at least 2 years and 20 control participants without hormone replacement therapy. All women completed orthostasis (standing and sitting), then speech and math tasks (speech and math were counterbalanced). Cardiovascular measures of sympathetic nervous system (pre-ejection period, PEP) and parasympathetic nervous system (respiratory sinus arrhythmia, RSA) along with heart rate were collected throughout all periods (baseline, orthostasis, and stressors). For orthostasis, results of mixed analyses of variance (ANOVAs) showed expected period effects for heart rate, RSA and PEP, but no group or group by period interaction was significant. For the psychological stressors, period main effects were significant for all three variables, suggesting that the tasks were effective at inducing stress. Also, there was a significant interaction between group and period for RSA, demonstrated by greater decrease during the psychological stressor period in the group using HRT. The interactions between group and period for heart rate and PEP were non-significant. These findings support the notion that HRT may slow age-related decreases in parasympathetic responsiveness. Furthermore, changes in vagal reactivity in relation to use of HRT appear to occur within mechanisms involving response and coping with psychological stressors, rather than mechanisms that accommodate basic physiological task such as orthostasis. / Dissertation/Thesis / M.S. Psychology 2013

nÃo hà / A vincristina à um quimioterÃpico e seu uso à limitado devido a neuropatia perifÃrica, com acometimento autonÃmico, sensitivo e motor. Sulfato de vincristina ou salina foram injetados na veia da cauda, nas doses de 50 Âg/Kg (5 doses), 100 Âg/Kg (2-5 doses) ou 150 Âg/Kg (1, 2 ou 5 doses) a cada dois dias em 144 ratos Wistar machos (200-250 g). No dia seguinte, os animais receberam a refeiÃÃo-teste por gavagem e foram sacrificados 10 minutos apÃs. A recuperaÃÃo gÃstrica e intestinal de corante foi determinada por espectrofotometria. ConstipaÃÃo foi avaliada pelo peso colÃnico e neuropatia sensitiva pela latÃncia tÃrmica (51Â0,5ÂC). PressÃo arterial mÃdia (PAM) e freqÃÃncia cardÃaca (FC) basais e valores da PAM e FC apÃs a administraÃÃo de fenilefrina 5 Âg/Kg e atropina 0,5 mg/Kg foram usados para estudo dos baroreflexos. DiferenÃas foram avaliadas por One-Way ANOVA com P<0,05. Tratamentos crÃnicos com 5 doses de 50 Âg/Kg; 3, 4 e 5 doses de 100 Âg/Kg; 2 e 5 doses de 150 Âg/Kg causaram retardo do esvaziamento gÃstrico (EG) (P<0,05). Duas e 5 doses de 150 Âg/kg induziram constipaÃÃo e houve reduÃÃo da latÃncia tÃrmica apÃs 1 dose de 50 Âg/Kg, 100 Âg/Kg e 150 Âg/kg (P<0,05). O efeito da vincristina sobre o EG nÃo foi evidenciado uma e duas semanas apÃs o tratamento com 5 doses de 150 Âg/Kg (P>0,05). Houve reduÃÃo do tempo de latÃncia ao calor por atà duas semanas apÃs 5 doses de 150 Âg/Kg (P<0,05). Vincristina potencializou a reduÃÃo da FC induzida pela fenilefrina e aumentou a resposta cardÃaca à atropina (P<0,05). A neuropatia autonÃmica induzida pela vincristina cursa com retardo do EG, alteraÃÃes na resposta baroreflexa e aumento do peso colÃnico. A neuropatia sensitiva precede o surgimento das alteraÃÃes autonÃmicas e persiste apÃs a reversÃo destas. / Vincristine is a chemotherapy drug and its use is limited by peripheral neuropathy with autonomic, sensory and motor involvement. Vincristine sulphate or saline was injected into the tail vein at doses of 50 Âg/Kg (5 doses), 100 Âg/Kg (2-5 doses) or 150 Âg/Kg (1, 2 or 5 doses) QOD in 144 male Wistar rats (200-250g). Next day, they were gavage-fed with a test meal and sacrificed 10 minutes later. Gastric and intestinal dye recovery was determined by spectrophotometry. Basal mean arterial pressure (MAP) and heart rate (HR) and peak values of MAP and HR after i.v. phenylephrine 5 Âg/Kg and atropine 0.5 mg/Kg were used to evaluate the baroreflex responses. Differences were evaluated by One-Way ANOVA with P<0.05. Chronic treatment with 5 doses of 50 Âg/Kg; 3, 4 and 5 doses of 100 Âg/Kg; 2 and 5 doses of 150 Âg/Kg delayed gastric emptying (GE) (P<0.05). Two and 5 doses of 150 Âg/Kg induced constipation and reduction in withdrawal latencies occurred after 1 dose of 50 Âg/Kg, 100 Âg/Kg and 150 Âg/Kg (P<0.05). Vincristine (150 Âg/Kg) immediately decreased fecal output (P<0.05). The effect of vincristine on the GE was not present in rats treated with 5 doses of vincristine 150 Âg/kg one week and two weeks after the last dose (P>0.05). The withdrawal latency decrease lasted for at least 2 weeks after 5 doses of 150 Âg/Kg (P<0.05). Vincristine enhanced the HR reduction induced by phenylephrine and enhanced cardiac response to atropine (P<0.05). Vincristine-induced autonomic neuropathy courses with delayed GE, altered baroreflex responses and increased colonic weight. Sensory neuropathy preceded and outlasted these autonomic changes.

Abstract Autonomic nervous system (ANS) disturbances are common in Parkinson's disease (PD), but also in other Parkinsonian syndromes, especially in multiple system atrophy (MSA). The differentiation between various Parkinsonian syndromes may be difficult, but it is important for prognostic and therapeutic purposes. The aim of this study was to determine the ability of different analysis methods to reveal cardiovascular regulation disturbances in PD and to evaluate the diagnostic capacity of autonomic tests to differentiate between various Parkinsonian syndromes. Furthermore, this study aimed to evaluate the relationships between ANS disturbances and the clinical characteristics of PD. In addition, the cardiac autonomic function was evaluated during various sleep stages for the first time in untreated PD patients by using spectral heart rate variability (HRV) measures to determine possible sleep stage specific cardiovascular regulation disturbances. Cardiovascular autonomic reflexes were evaluated in 62 untreated and newly diagnosed PD patients, 34 PD patients under antiparkinsonian medication, 47 MSA patients and 15 patients with progressive supranuclear palsy (PSP). The usefulness of different analysis methods was evaluated in a subgroup of 32 untreated PD patients. A further 21 untreated PD patients underwent one-night polysomnography for nocturnal heart rate variability analysis. PD patients with hypokinesia/rigidity as their initial onset sign had a significantly lower max-min ratio in the deep breathing test than those patients with tremor as the initial sign. MSA patients showed significant reductions in both HRV and blood pressure responses during orthostatic provocation, whereas PSP patients had normal results. Absolute spectral measures yielded the clearest indicators separating the PD patients from the controls, while the cardiovascular reflexes proved more useful than the normalised spectral HRV measures in revealing the differences between the two groups. HRV was abnormally decreased during non-REM sleep in PD patients but not during REM sleep or the S1 sleep stage. The normalized high frequency power was significantly decreased in PD patients during sleep stages S2-4, while the standard deviation of the R-R intervals was increased during the same sleep stages, possibly corresponding to the increased motility of PD patients during these sleep stages. The clinical characteristics of PD deserve particular attention in connection with ANS disturbances, since autonomic failure seems to be more pronounced in PD patients with hypokinesia/rigidity as their initial sign. The evaluation of the autonomic function may also be helpful in the differential diagnosis of Parkinsonian syndromes. Spectral analysis methods should be implemented in the evaluation of ANS dysfunction to achieve the best possible efficacy in the differentiation of pathological responses from normal ones. Nocturnal analysis of cardiovascular regulation revealed new and interesting features of pathologic HRV in PD patients, thus when HRV is evaluated, the different sleep stages should be analysed separately.

Abstract Analysis of beat-to-beat heart rate variability (HRV) provides information of cardiac vagal outflow to the sinus node. Some methodological problems might, however, be involved in the analysis of cardiac vagal outflow from ambulatory Holter recordings, such as saturation, physical activity, and abrubt prolongations of R-R intervals unrelated to respiration. The purpose of this thesis was to assess the physiological basis of beat-to-beat HRV and to develop and assess new methods for the quantification of cardiac autonomic modulation from ambulatory Holter recordings. The study population consisted of 89 healthy volunteers (age 24 ± 4 years) and 590 patients with a recent acute myocardial infarction (AMI, age 61 ± 10 years). The relationship between R-R interval length and the high-frequency (HF) spectral power of the R-R intervals was assessed in 76 healthy subjects and 82 post-AMI patients. The effects of aerobic exercise training on the dynamics between R-R interval and HF power were evaluated by means of a controlled 8-week training intervention (n = 17). The effects of sympathetic activation and concomitant sympathetic and vagal outflow on beat-to-beat HR dynamics were studied in laboratory conditions (n = 13). A new method for quantifying beat-to-beat HRV from the R-R interval lengths where the relationship between HF power and R-R interval is most linear was developed to avoid the confounding effects of possible saturation, physical activity, and random R-R interval dynamics. The clinical significance of the new method was assessed in a series of 590 post-AMI patients. Saturated HF R-R interval dynamics, expressed as a lack of increase in HF power despite an increased R-R interval, was observed in 35 healthy subjects and 9 post-AMI patients. In the training study, 7 subjects out of a total of 17 had saturated HF power before the intervention. After the training period, 5 new cases of saturated HF power were observed. In laboratory conditions, co-activation of sympathetic and vagal outflow resulted in random R-R interval dynamics. In post-AMI patients, HF power analyzed exclusively from the R-R intervals where the relationship between the R-R interval and HF power was most linear (Vindex) predicted independently the occurrence of SCD among post-AMI patients, while traditionally analyzed HF power did not. In conclusion, the saturation of beat-to-beat HRV in ambulatory conditions is a common phenomenon. The prevalence of saturated HF power increases due to enhanced cardiac vagal outflow induced by aerobic training. Finally, the novel analysis of vagally mediated HRV (Vindex) provides unique information that cannot be obtained by traditional analysis of HF R-R interval dynamics.

Acute inhalation of airborne pollutants alters cardiovascular function and has been shown to have its greatest affects on individuals with pre-existing cardiovascular disease. Evidence suggests that pollutant-induced activation of airway sensory nerves via the gating of ion channels is critical to these systemic responses. Here, we have investigated the cardiovascular responses evoked by inhalation of AITC (TRPA1 agonist) and capsaicin (TRPV1 agonist) in healthy Sprague Dawley (SD) and Wistar Kyoto (WKY) rats, and cardiovascular diseased Spontaneously Hypertensive (SH) rats. Inhalation of the agonists by healthy SD and WKY rats caused significant bradycardia, atrio-ventricular (AV) block and prolonged PR-Intervals. Inhalation of TRP agonists caused differential cardiovascular responses in the cardiovascular diseased SH rats, such that the TRP agonists evoked brady-tachy with AV block and premature ventricular contractions (PVCs). Bradycardic responses to AITC were inhibited by the TRP channel blocker ruthenium red and the muscarinic antagonist atropine, but atropine did not prevent the tachycardic responses seen in the SH rats. Adrenergic inhibition with atenolol prevented the tachycardic responses, but did not prevent the bradycardic responses evoked by AITC in the SH rats. In healthy rats, AITC inhalation also caused a biphasic blood pressure response: a brief hypertensive phase followed by a hypotensive phase, while evoking hypertension in the SH rats. Atropine accentuated the hypertensive phase in all animals, while preventing the hypotension in the healthy animals. In all animals, AITC-evoked heart rate responses were not abolished by terazosin, the [U+F061]1 adrenoceptor inhibitor, which prevented the hypertensive responses. Anesthetics had profound effects on AITC-evoked bradycardia and AV block, which was abolished by urethane, ketamine and isoflurane. Nevertheless, AITC inhalation caused bradycardia and AV block in paralyzed and ventilated rats following pre-collicular decerebration. In conclusion, we provide evidence that activation of TRP channels expressed on nociceptive airway sensory nerves causes significant cardiovascular effects in healthy rats via reflex modulation of the autonomic nervous system (ANS), and that these effects are exacerbated in cardiovascular diseased rats.