Airway eosinophilia is a prominent feature of asthma that may be mediated in part through the expression of eotaxin, a potent eosinophil-active chemokine that is highly expressed by epithelial cells and inflammatory cells in asthmatic airways. / The major aim of this study was to determine whether human airway smooth muscle (ASM) cells may be a source of eotaxin in asthma. The evidence presented in this thesis shows constitutive eotaxin gene expression in ASM in vitro that is markedly increased following stimulation with the proinflammatory cytokines TNF-alpha and IL-1beta. Release of eotaxin was confirmed in ASM culture supernatants which contained significant chemoattractant activity for eosinophils that was partly inhibited with antibodies directed against eotaxin or RANTES, and maximally inhibited by a combined blockade of both chemokines. Strong signals for eotaxin immunoreactivity were also observed in vivo in smooth muscle in asthmatic airways. / In conclusion, the results of this study suggest that ASM may contribute to airway inflammation in asthma through the production and release of eotaxin.

Airway smooth muscle (ASM) shortening is the key event leading to broncho-constriction. The degree of airway narrowing which occurs with ASM shortening is a function both of the mechanical properties of the airway wall as well as the angle of orientation of ASM. If ASM is oriented very obliquely, ASM shortening would in part be transduced to a change in airway length rather than airway narrowing. Previous reports have suggested that the angle of ASM orientation may be as high as 30$ sp circ.$ To measure ASM orientation we have developed a technique based on en-face dissection. The lungs from 4 cats and one human were fixed with 10% buffered formalin at 25 cmH$ sb2$O for 48 hrs. The airway generations 4 to 17 were dissected out from the left lower lobes. Each airway generation was individually embedded in paraffin from which 5$ mu$m thick serial sections were cut parallel to the airway long axis ("en-face") and stained with haematoxylin-phloxine-saffron. Each block yielded 3-5 sections in which the orientation of ASM nuclei relative to the airway long axis ($ theta$) was measured as an index of ASM orientation. $ theta$ was measured clockwise and counterclockwise to the short axis by using a digitizing tablet and a light microscope (X250) equipped with a drawing tube attachment. Inspection of the sections revealed extensive ASM crisscrossing without a homogeneous orientation. Between 29 and 102 nuclei were measured per generation. Although there was considerable variation within airway generations, $ theta$ clustered between $-$20$ sp circ$ and 10$ sp circ$ in all generations and did not vary significantly between generations in any of the subjects. When $ theta$ was converted to an acute angle without regard to sign($ Theta$), the mean angle was 12-13$ sp circ$ both in cat and the human lung. (Abstract shortened by UMI.)

By techniques of immunohistochemical staining, flow cytometry, and image analysis, the present study demonstrated the following: (1) The ST3 antigen is expressed on the surface of thymocytes of young rats, and decreases in both percentage and intensity with increasing age (after 12 months). (2) The ST3 antigen also is expressed on the surface of thymic nurse cells. Although the majority of lymphoid cells within nurse cells also bear the ST3 antigen, a subpopulation contains lymphocytes that do not. These results suggest that the ST3 antigen may be a useful new marker for cortical lymphocytes, and imply that its expression may play a role in intra-thymic T-cell development, and in senescence of the organ.

Cell adhesion molecules are thought to have an important role in neoplastic progression as they are likely to be involved in the multiple steps of the metastatic cascade. We have focused on two adhesion molecules, E-cadherin and CD44, looking for changes in their expression in human colon cancer. The intercellular adhesion mediated by E-cadherin has been shown to be altered in cancer. We have investigated the expression of E-cadherin in normal and tumorigenic colorectal mucosa by immunohistochemistry. Tumor samples showed a down-regulation of expression correlating with the degree of tumor dedifferentiation. The second adhesion molecule, CD44, has been previously associated with metastasis in animal models. We have shown by Northern blotting that mRNA splice variants with domains IV + V are specifically over expressed in carcinomas. Immunohistochemistry showed redistribution of CD44 to the cellular basal membrane. Thus, the aberrant expression of E-cadherin and CD44 could be associated with malignant progression in colorectal cancer.

No description available.

This thesis investigated the speech-gesture relationship of chronic adult stutterers in comparison to fluent controls based on previous work by McNeill (1979, 1986). Significant differences were found in the speech and gesture characteristics of the narratives of stutterers as compared to fluent controls on a cartoon retelling task. Stutterers produced fewer cartoon details in their speech and fewer meanings per gesture. As well, stutterers were unable to begin a representational gesture at the same moment as a stuttered disfluency resulting in the freezing of gestures or maintaining the hand at rest. A second experiment showed that stutterers were able to maintain and initiate non-communicative hand movements at the same moment as stuttering. Gesture did not replace speech during moments of stuttering even though manual movement during stuttering was possible. The results demonstrate the strength of the speech-gesture relationship and show that stuttering affects both modalities of expression.

The objective of this study was to investigate predictors of language growth within the context of parent-child interaction among preschoolers with autism spectrum disorders (ASDs) and typically developing (TYP) toddlers. Children with ASDs are known to have delays in play and language development. Previous research has demonstrated concurrent and predictive associations between play skills and language ability in children with ASDs and in TYP children. Parent verbal responsiveness, or the extent to which parents' verbalizations are contingent on their children's focus of attention, has also been linked to language development in young children. The present study used a longitudinal correlational design with 30 participants, 15 ASD and 15 TYP. Child play skills and parent verbal responsiveness were analysed. The groups did not differ on play abilities or on the extent to which parents' verbalizations were responsive to their children's attention. Symbolic play was associated with language ability at study outset in both groups, but play ability and parent responsiveness were not associated with language gain over the 1-year study. Methodological factors are discussed in the interpretation of these findings. / L'objectif de cette étude était d'analyser des variables impliquées lors du développement du langage dans un contexte d'interaction parent-enfant chez des enfants atteints du trouble du spectre de l'autisme (TSA) et avec un développement typique (DT). Des retards dans le développement du langage et du jeu sont répandus chez des enfants ayant des TSA. Des études antérieures ont démontré que les capacités de jeu peuvent prédire les habilités du langage chez les enfants ayant des TSA ou avec DT. La sensibilité verbale des parents, ou la tendance du parent de parler d'un objet sur lequel l'enfant concentre déjà son attention, est aussi associée au développement du langage chez des jeunes enfants. La présente étude a utilisé une méthodologie longitudinale et corrélationnelle chez 30 participants, dont 15 avec TSA et 15 avec DT. Les variables étudiées lors de cette étude étaient les suivantes : les capacités de jeu de l'enfant et la sensibilité verbale du parent. Aucune différence n'a été observée entre les deux groupes, que ce soit au niveau des capacités de jeu des enfants ou au niveau de la sensibilité verbale des parents. Le jeu symbolique a été associé au niveau du langage des enfants des deux groupes au début de l'étude. Cependant, ni les capacités de jeu ni la sensibilité verbale des parents n'ont été associées au développement du langage lors de l'année de l'étude. La méthodologie est abordée dans l'interprétation des résultats.

Cells are constantly challenged by acute and chronic stresses that must be counteracted by upregulation of protective pathways. The premise of this thesis is that motor neurons have an impaired ability to trigger these protective mechanisms, which may contribute to their preferential vulnerability in the neurodegenerative disease, amyotrophic lateral sclerosis (ALS). The first objective was to study the involvement of metallochaperones in motor neuronal stress response, including their potential for rescuing motor neurons from toxicity conferred by a mutant Cu/Zn-superoxide dismutase (SOD1G93A ) that causes a form of familial ALS. Motor neurons in dissociated spinal cord cultures failed to induce the metallochaperone, metallothionein (MT), in response to classical MT inducers, although overexpression of MT in motor neurons failed to protect them from SOD1G93A. A second response system, involving protein chaperones called heat shock proteins (Hsp), was more therapeutically promising, but was also impaired in motor neurons due to an inability to activate the regulatory protein heat shock transcription factor 1 (Hsf1). The remaining objectives were to examine if activation of Hsf1 in motor neurons would protect against SOD1G93A and to understand the mechanisms responsible for its impaired activation. A constitutively active form of Hsf1 induced multiple Hsps in motor neurons and nearly eliminated SOD1G93A toxicity and aggregation. Experiments also demonstrated that failure of stressed motor neurons to activate endogenous Hsf1 is not a result of inappropriate or insufficient activity of kinases that phosphorylate key residues of Hsf1 in nonneuronal cell lines with a competent heat shock response. Disruption of inhibitory Hsp90/multichaperone complexes is another important step in Hsf1 activation. Four different pharmacological inhibitors of Hsp90 induced multiple Hsps in motor neurons, although failure to observe the same response by targeting inhibitory complexes with activator of Hsp90 ATPase 1 (Aha1) or Daxx suggested other mechanisms were involved. A constitutively active form of calcium/calmodulin-dependent kinase N induced Hsp70 in motor neurons, but not in fibroblasts and likely through an Hsf1-independent mechanism. These results provide further evidence for disparity between the stress response of motor neurons and other cells and suggest the possibility of a unique Hsp regulatory system in neurons.

The present study was conducted to examine semantic and phonologically mediated priming in normal and brain-damaged populations. Non-fluent and fluent aphasic patients and age-matched control subjects performed an auditory lexical decision task in three separate experimental subtests: semantic priming (e.g., manner-way), minimally-distinct mediated priming (e.g., nanner-way), and maximally-distinct mediated priming (e.g., zanner-way). Consistent with expectations, the findings revealed semantic priming effects in all groups. Interestingly, contrary to predictions based on previous studies, both non-fluent and fluent aphasic patient groups demonstrated mediated priming in both the minimally-distinct and the maximally-distinct subtests that was comparable to mediated priming effects shown by the normal control subjects. The results are discussed in light of current hypotheses concerning the nature of lexical access impairments in brain-damaged individuals. In addition, implications for models of normal word recognition are considered.

No description available.