A psychological investigation into the relationship between hemispheric functioning and specific written language difficulties (dyslexia), using pharmaceutical intervention techniques

This thesis attempts a psychological investigation of hemispheric functioning in developmental dyslexia. Previous work using neuropsychological methods with developmental dyslexics is reviewed ,and original work is presented both of a conventional psychometric nature and also utilising a new means of intervention. At the inception of inquiry into dyslexia, comparisons were drawn between developmental dyslexia and acquired alexia, promoting a model of brain damage as the common cause. Subsequent investigators found developmental dyslexics to be neurologically intact, and so an alternative hypothesis was offered, namely that language is abnormally localized (not in the left hemisphere). Research in the last decade, using the advanced techniques of modern neuropsychology, has indicated that developmental dyslexics are probably left hemisphere dominant for language. The development of a new type of pharmaceutical prep~ration (that appears to have a left hemisphere effect) offers an oppertunity to test the experimental hypothesis. This hypothesis propounds that most dyslexics are left hemisphere language dominant, but some of these language related operations are dysfunctioning. The methods utilised are those of psychological assessment of cognitive function, both in a traditional psychometric situation, and with a new form of intervention (Piracetam). The information resulting from intervention will be judged on its therapeutic validity and contribution to the understanding of hemispheric functioning in dyslexics. The experimental studies using conventional psychometric evaluation revealed a dyslexic profile of poor sequencing and name coding ability, with adequate spatial and verbal reasoning skills. Neuropsychological information would tend to suggest that this profile was indicative of adequate right hemsiphere abilities and deficits in some left hemsiphere abilities. When an intervention agent (Piracetam) was used with young adult dyslexics there were improvements in both the rate of acquisition and conservation of verbal learning. An experimental study with dyslexic children revealed that Piracetam appeared to improve reading, writing and sequencing, but did not influence spatial abilities. This would seem to concord with other recent findings, that deve~mental dyslexics may have left hemisphere language localisation, although some of these language related abilities are dysfunctioning.

Species-specific differences in the expression of the HNF1A, HNF1B and HNF4A genes

Background: The HNF1A, HNF1B and HNF4A genes are part of an autoregulatory network in mammalian pancreas, liver, kidney and gut. The layout of this network appears to be similar in rodents and humans, but inactivation of HNF1A, HNF1B or HNF4A genes in animal models cause divergent phenotypes to those seen in man. We hypothesised that some differences may arise from variation in the expression profile of alternatively processed isoforms between species. Methodology/Principal Findings: We measured the expression of the major isoforms of the HNF1A, HNF1B and HNF4A genes in human and rodent pancreas, islet, liver and kidney by isoform-specific quantitative real-time PCR and compared their expression by the comparative Ct (??Ct) method. We found major changes in the expression profiles of the HNF genes between humans and rodents. The principal difference lies in the expression of the HNF1A gene, which exists as three isoforms in man, but as a single isoform only in rodents. More subtle changes were to the balance of HNF1B and HNF4A isoforms between species; the repressor isoform HNF1B(C) comprised only 6% in human islets compared with 24–26% in rodents (p = 0.006) whereas HNF4A9 comprised 22% of HNF4A expression in human pancreas but only 11% in rodents (p = 0.001). Conclusions/Significance: The differences we note in the isoform-specific expression of the human and rodent HNF1A, HNF1B and HNF4A genes may impact on the absolute activity of these genes, and therefore on the activity of the pancreatic transcription factor network as a whole. We conclude that alterations to expression of HNF isoforms may underlie some of the phenotypic variation caused by mutations in these genes.

Situation-specific cognitive behavioural self-therapy for erroneously suspected allergy or intolerance to a food:a short self-assessment tool

The recall of personal experiences relevant to a claim of food allergy or food intolerance is assessed by a psychologically validated tool for evidence that the suspected food could have caused the adverse symptom suffered. The tool looks at recall from memory of a particular episode or episodes when food was followed by symptoms resulting in self-diagnosis of food allergy or intolerance compared to merely theoretical knowledge that such symptoms could arise after eating the food. If there is detailed recall of events that point to the food as a potential cause of the symptom and the symptom is sufficiently serious, the tool user is recommended to seek testing at an allergy clinic or by the appropriate specialist for a non-allergic sensitivity. If what is recalled does not support the logical possibility of a causal connection between eating that food and occurrence of the symptom, then the user of the tool is pointed to other potential sources of the problem. The user is also recommended to investigate remedies other than avoidance of the food that had been blamed.

Antecedents, mechanisms and processes of deinstitutionalization and institutional change:a case study approach to understanding enterprise under duress

Adopting a grounded theory methodology, the study describes how an event and pressure impact upon a process of deinstitutionalization and institutional change. Three case studies were theoretically sampled in relation to each other. They yielded mainly qualitative data from methods that included interviews, observations, participant observations, and document reviews. Each case consisted of a boundaried cluster of small enterprises that were not industry specific and were geographically dispersed. Overall findings describe how an event, i.e. a stimulus, causes disruption, which in turn may cause pressure. Pressure is then translated as a tension within the institutional environment, which is characterized by opposing forces that encourage institutional breakdown and institutional maintenance. Several contributions are made: Deinstitutionalization as a process is inextricable from the formation of institutions – both are needed to make sense of institutional change on a conceptual level but are also inseparable experientially in the field; stimuli are conceptually different to pressures; the historical basis of a stimulus may impact on whether pressure and institutional change occurs; pressure exists in a more dynamic capacity rather than only as a catalyst; institutional breakdown is a non-linear irregular process; ethical and survival pressures as new types were identified; institutional current, as an underpinning mechanism, influences how the tension between institutional breakdown and maintenance plays out.

β-cell-specific glucocorticoid reactivation attenuates inflammatory β-cell destruction

Progression and severity of type 1 diabetes is dependent upon inflammatory induction of nitric oxide production and consequent pancreatic β-cell damage. Glucocorticoids (GCs) are highly effective anti-inflammatory agents but have been precluded in type 1 diabetes and in islet transplantation protocols because they exacerbated insulin resistance and suppressed β-cell insulin secretion at the high-doses employed clinically. In contrast, physiological-range elevation of GC action within β-cells ameliorated lipotoxic β-cell failure in transgenic mice overexpressing the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (MIP-HSD1^tg/+ mice). Here, we tested the hypothesis that elevated β-cell 11beta-HSD1 protects against the β-cell destruction elicited by streptozotocin (STZ), a toxin that dose-dependently mimics aspects of inflammatory and autoimmune β-cell destruction. MIP-HSD1^tg/+ mice exhibited an episodic protection from the severe hyperglycemia caused by a single high dose of STZ associated with higher and sustained β-cell survival, maintained β-cell replicative potential, higher plasma and islet insulin levels, reduced inflammatory macrophage infiltration and increased anti-inflammatory T regulatory cell content. MIP-HSD1^tg/+ mice also completely resisted mild hyperglycemia and insulitis induced by multiple low-dose STZ administration. In vitro, MIP-HSD1^tg/+ islets exhibited attenuated STZ-induced nitric oxide production, an effect reversed with a specific 11beta-HSD1 inhibitor. GC regeneration selectively within β-cells protects against inflammatory β-cell destruction, suggesting therapeutic targeting of 11beta-HSD1 may ameliorate processes that exacerbate type 1 diabetes and that hinder islet transplantation.

Cell-specific effects of Nox2 on the acute and chronic response to myocardial infarction

BACKGROUND: Increased reactive oxygen species (ROS) production is involved in the process of adverse cardiac remodeling and development of heart failure after myocardial infarction (MI). NADPH oxidase-2 (Nox2) is a major ROS source within the heart and its activity increases after MI. Furthermore, genetic deletion of Nox2 is protective against post-MI cardiac remodeling. Nox2 levels may increase both in cardiomyocytes and endothelial cells and recent studies indicate cell-specific effects of Nox2, but it is not known which of these cell types is important in post-MI remodeling. METHODS AND RESULTS: We have generated transgenic mouse models in which Nox2 expression is targeted either to cardiomyocytes (cardio-Nox2TG) or endothelial cells (endo-Nox2TG). We here studied the response of cardio-Nox2TG mice, endo-Nox2TG mice and matched wild-type littermates (WT) to MI induced by permanent left coronary artery ligation up to 4weeks. Initial infarct size assessed by magnetic resonance imaging (MRI) and cardiac dysfunction were similar among groups. Cardiomyocyte hypertrophy and interstitial fibrosis were augmented in cardio-Nox2TG compared to WT after MI and post-MI survival tended to be worse whereas endo-Nox2TG mice showed no significant difference compared to WT. CONCLUSIONS: These results indicate that cardiomyocyte rather than endothelial cell Nox2 may have the more important role in post-MI remodeling.