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Previous investigations of a single family aggregate with developmental language impairment have suggested that the impaired members are disabled in their ability to use anaphoric pronouns. The present thesis sought to investigate further the use of anaphoric reference in this family using detailed, discourse-oriented analyses. Oral narratives were elicited from eight mature-language users, four language-impaired and four unimpaired. Discourse analysis was accomplished using procedures taken from normal acquisitional studies in which both the form (pronominal or nominal) and the function served by each form (switching or maintaining reference) are considered. The analysis revealed some differences between the language-impaired and unimpaired subjects in their use of pronominals in their narratives. However, three of the four language-impaired subjects used the same nominal-pronominal reference tracking strategies as their unimpaired relatives. The implications of these findings for the general ability of the language-impaired subjects to use pronouns anaphorically as well as future research directions are discussed.

Mitochondrial myopathies are a group of diverse neuromuscular disorders. Defects in electron transport chain (ETC) subunits have been implicated in pediatric and adult onset cases. Skin fibroblasts from four patients were studied to elucidate the biochemical defects. / Cells from two patients with ETC complex I deficiency, showed reduced oxidation of alanine with normal oxidation of succinate. Analysis of complex I subunits indicated deficient synthesis of the 20 kDa subunit in the severely affected patient. In the milder patient, subunit abnormalities were not detected. / Fibroblasts from a patient with facioscapulohumeral disease (FSHD), showed reduced oxidation of alanine and succinate through the ETC. / A fourth patient, with decreased activity in several complexes in muscle and liver, was found to have a heteroplasmic mtDNA population in fibroblasts. / These studies exemplify the heterogeneity of mitochondrial myopathies and demonstrate the utility of fibroblasts in the investigation of these disorders.

Syntactic and semantic abilities were compared in 12 patients with mild to moderate dementia of the Alzheimer-Type (DAT) and matched controls. In Experiment 1A, performance on naming, word-picture matching, probe verification, and syntactic comprehension was assessed. Experiment 1B tested subjects' ability to use syntactic, semantic, and sentence contexts to choose the correct pronunciation of homographs and the correct spelling of homophones. Group data and individual patterns were reported. The main results revealed that: (1) all patients showed syntactic and semantic deficits; (2) patients were better able to use sentence contexts than syntactic or semantic contexts in isolation; syntax was not significantly different from semantics. The discussion addressed the concept of dissociation between language components, as well as the heterogeneous clinical presentation of DAT.

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Thymic stromal lymphopoietin (TSLP) is produced primarily but not exclusively by epithelial cells. It has been shown to induce the production of Th2 cytokines and inflammation in allergic disease. Since Th2 cytokines have been shown to be detrimental to the anti-tumor immune response, we hypothesized that TSLP promotes the development of a permissive microenvironment for breast cancer, which facilitates the growth and metastasis of primary tumors and that it does so, in part, by inducing the development of a Th2-mediated immune response. Using the 4T1 mouse breast cancer model, we used wild type (WT) and TSLP receptor deficient (TSLPR-/-) mice to compare primary tumor growth, metastasis to the lungs and brain, cytokine profiles and 4T1-directed lysis. Some of these parameters were also examined in mice treated with an anti-TSLP neutralizing antibody. We showed that in TSLPR-/- mice, primary tumor establishment, growth and metastasis to the lungs were reduced, compared to WT mice. Unexpectedly, we observed that metastasis to the brain was increased. When mice were treated with anti-TSLP neutralizing antibody, the only significant effect that we observed was a reduction in metastasis to the lung in WT mice. We also studied TSLP expression in a human invasive breast cancer microarray (TMA). Both the normal breast epithelial cells and breast cancer cells stained positively for TSLP, but it appears that it might be more highly expressed in the breast cancer tissue. Taken together, our data support the hypothesis that TSLP promotes the development of a permissive microenvironment for breast cancer. However, the role of TSLP appears to be complex since the absence of TSLP responsiveness resulted in a greater level of metastasis to the brain.

The long-term survival of heart transplants is limited by the development of allograft vasculopathy (AV), a vascular pathology that develops in spite of the use of modern immunosuppressive therapies. Although it is widely accepted that T cells play a major role in the development of AV, the contribution of B cells and antibody has been less well characterized. A fully MHC-mismatched cell transfer model was used to mimic the antigenic stimulus of a cardiac graft, we examined the production of antibody under conditions of clinically relevant immunosuppression in the form of the calcineurin inhibitor cyclosporine A (CyA). Anti-donor antibody with the capacity to mediate complement-dependent cytotoxicity of donor strain cells, but not third-party cells, developed in the presence of two different doses of CyA (30 mg/kg and 50 mg/kg). When this antibody was passively transferred into immunodeficient B6.RAG1-/- abdominal aortic graft recipients, the antibody alone had the capacity to mediate formation of a neointimal lesion and induce the loss of medial smooth muscle cells. These are two hallmark characteristics of AV in this animal model. A wild-type model, where BALB/c grafts were transplanted into B6 recipients and received daily CyA immunosuppression was used to test the de novo antibody response to the transplant itself. Again, anti-donor antibody was produced with the capacity to mediate complement-dependent cytotoxicity of donor cells. In addition, grafts showed evidence of C4d deposition in the medial area, indicating that area as a sit of antibody binding and activation of the classical complement cascade. The presence of anti-donor antibody has been demonstrated to correlate with poorer graft outcome and a higher risk of developing AV in patients. Examination of human epicardial coronary artery tissue from patients with cardiac transplants demonstrated the presence in the adventitia of ectopic lymphoid structures (ELS) containing CD20+ B cells, plasma cells, IgM, and IgG. These findings illustrate active, antibody-producing ELS in close proximity to the vessels developing AV. Of note was the finding of CD20+CD27+ memory B cells in these ectopic lymphoid structures. Memory B cells are rapidly re-activated following exposure to their cognate antigen and easily differentiate into plasma cells. Taken together, these data suggest that memory B cells and antibody may be contributing to long-term allograft rejection and therapeutic options should be considered to target these immune mechanisms.

The mechanisms of allergen induced airway narrowing, during allergen induced early (ER) and late (LR) responses, and airway hyperresponsiveness were investigated in vivo using the ovalbumin (OA) sensitized Brown Norway (BN) rat. ER and LR were induced by aerosolized OA. The lungs were fixed using a quick-freezing technique to maintain the pathological alterations as close as possible to their in vivo conditions. The results from both morphologic and morphometric studies showed that during the ER and LR, airway narrowing was mainly caused by airway smooth muscle contraction, but not by airway wall thickening or mucus. These findings were supported by intravenous administration of Evans blue which was used as a measure of vascular leakage. The degree of airway narrowing during the early response was greater in the large intrapulmonary airways than in the small intrapulmonary airways. Airway narrowing during the late response was limited to the large intrapulmonary airways. These findings were closely related to the mast cell distribution which progressively increased from small to large intrapulmonary airways in normal BN rats. These findings suggests that mast cells may play an important role in both early or late responses. / In order to study structural mechanisms of airway hyperresponsiveness, increased airway responses to inhaled methacholine were induced by repeated inhalational challenge of sensitized BN rats with OA. Quantitation of airway smooth muscle, airway wall area and epithelial area demonstrated that increased airway hyperresponsiveness was associated with the increased amount of airway smooth muscle but not with airway wall thickening. There was a correlation between the quantity of airway smooth muscle in large airways and the change in airway hyperresponsiveness. Hence, it is possible that an altered quantity of airway smooth muscle is an important mechanical contributor to airway narrowing in human allergic asthma.

Four areas of morphosyntax in Arabic-speaking children with Specific Language Impairment (SLI) were investigated: tense, subject-verb agreement, determiners, and prepositions. Spontaneous production data were analyzed for accuracy and error types in using these morphemes. Two groups of typically-developing Arabic-speaking children served as Mean Length Utterance (MLU)-matched and chronological age-matched controls. The results indicate that Arabic-speaking children with SLI were significantly different from the two control groups of children on percentage correct use of tense and subject-verb agreement. Furthermore, when an error in verbal inflection occurred, the substitute form was usually an underspecified/default form, namely the imperative. / The findings of the study are discussed in light of existing theoretical accounts of SLI. Three positions are examined: (a) tense marking constitutes the locus of SLI grammatical difficulties (Extended Optional Infinitive hypothesis, Rice & Wexler, 1996); (b) morphosyntactic problems stem from deficits in agreement relations (Grammatical Agreement Deficit account, Clahsen, 1989; Clahsen, Bartke, & Gollner, 1997); and (c) trouble with inflectional morphology is less pronounced in children with SLI acquiring richly inflected languages (Sparse Morphology account, Leonard, Bortolini, Caselli, McGregor, & Sabbadim, 1992). Special characteristics of Arabic such as its intricate morphological system and null subject properties make it particularly valuable in determining universal versus language-specific aspects of SLI. Clinical implications for SLI in Arabic and directions for future research are also explored.