Juvenile neuronal ceroid lipofuscinosis; psychiatric symptoms, GAD-autoantibodies, and response to medication

Juvenile neuronal ceroid lipofuscinosis (JNCL) is one of the most common neurodegenerative diseases in childhood. Its clinical onset, with visual failure as the first sign, is between the ages of 4 to 8 years. During the disease progress, epilepsy, motor symptoms, cognitive decline, and psychiatric symptoms become apparent. It leads to premature death between ages 15 and 30. Treatment consists of symptomatic drug administration and various forms of rehabilitation, but to date, no curative treatment exists. To gain a more comprehensive picture of psychiatric problems, symptoms were evaluated by the Child Behavior Checklist, the Teacher Report Form, and the Children s Depression Inventory. The JNCL patients had a great number of severe psychiatric symptoms, with wide inter-individual variability. The most common symptoms were social, thought, attention, and sleep problems, somatic complaints, and aggressive behaviour. Patients with psychotropic treatment had more problems than did those without psychotropic treatment, and female patients had more problems than did males. Between 10 and 20% of the patients reported depressive symptoms. In a 5-year follow-up, [123I]β-CIT SPECT and MRI revealed a tendency of decreasing serotonin transporter (SERT) availability and progressive brain atrophy. The correlation between changes in midbrain SERT and total brain volume was positive; no correlation appeared between SERT or brain atrophy and depressive symptoms. Thus, it seems likely that the low SERT availability is associated with progressive brain atrophy; it may also predispose towards depression, however. An open survey of psychotropic drugs and their efficacy was performed on JNCL patients in Finland. The most commonly used psychotropic drugs were the antidepressant citalopram and the antipsychotic risperidone. Their efficacy was good or satisfactory in the majority of cases and they seemed well tolerated. Quetiapine had a marked effect on one patient with a history of severe psychotic symptoms. Glutamate decarboxylase 65 autoantibodies (GAD65ab), found in JNCL patients, indicate that an immunomediated reaction against GAD or GABAergic neurons may play a part in the underlying pathogenetic mechanism. GAD65ab s also appeared in the serum of all eight JNCL patients included and intermittent corticosteroid therapy was initiated in all cases. After one year, the GAD65ab s had disappeared in the two oldest patients, who experienced an improvement in motor symptoms and alertness associated with their prednisolone therapy. Two younger patients experienced a significant IQ increase, but no change in GADab s. A randomized study with longer follow-up time is needed, however, to clarify the effect of prednisolone on disease progression.

From Polymorph Screening to Dissolution Testing - Solid Phase Analysis during Pharmaceutical Development and Manufacturing

Solid materials can exist in different physical structures without a change in chemical composition. This phenomenon, known as polymorphism, has several implications on pharmaceutical development and manufacturing. Various solid forms of a drug can possess different physical and chemical properties, which may affect processing characteristics and stability, as well as the performance of a drug in the human body. Therefore, knowledge and control of the solid forms is fundamental to maintain safety and high quality of pharmaceuticals. During manufacture, harsh conditions can give rise to unexpected solid phase transformations and therefore change the behavior of the drug. Traditionally, pharmaceutical production has relied on time-consuming off-line analysis of production batches and finished products. This has led to poor understanding of processes and drug products. Therefore, new powerful methods that enable real time monitoring of pharmaceuticals during manufacturing processes are greatly needed. The aim of this thesis was to apply spectroscopic techniques to solid phase analysis within different stages of drug development and manufacturing, and thus, provide a molecular level insight into the behavior of active pharmaceutical ingredients (APIs) during processing. Applications to polymorph screening and different unit operations were developed and studied. A new approach to dissolution testing, which involves simultaneous measurement of drug concentration in the dissolution medium and in-situ solid phase analysis of the dissolving sample, was introduced and studied. Solid phase analysis was successfully performed during different stages, enabling a molecular level insight into the occurring phenomena. Near-infrared (NIR) spectroscopy was utilized in screening of polymorphs and processing-induced transformations (PITs). Polymorph screening was also studied with NIR and Raman spectroscopy in tandem. Quantitative solid phase analysis during fluidized bed drying was performed with in-line NIR and Raman spectroscopy and partial least squares (PLS) regression, and different dehydration mechanisms were studied using in-situ spectroscopy and partial least squares discriminant analysis (PLS-DA). In-situ solid phase analysis with Raman spectroscopy during dissolution testing enabled analysis of dissolution as a whole, and provided a scientific explanation for changes in the dissolution rate. It was concluded that the methods applied and studied provide better process understanding and knowledge of the drug products, and therefore, a way to achieve better quality.

Immunodeficiencies, pathogens and sex in upper respiratory diseases

In the first part of this thesis the association of different forms of sinonasal diseases and plasma concentrations of C3, C4, immunoglobulins, immunoglobulin G subclasses, C4A and C4B gene numbers were studied in 287 adult patients and 150 sex-matched adult controls. Patients were well characterized and stratified into groups using strict clinical criteria and females and males were also studied as separate groups. Severe primary antibody antibody deficiencies were rare in patients coming to sinonasal operations. Female patients had more recurrent sinusitis and other mucosal infections and males had more nasal polyposis. Upregulation of complement activity was seen in acute rhinosinusitis patients (high levels of plasma C3, C4, and complement classical pathway activity CH50) and male patients coming to sinonasal operations (high levels of plasma C3 and C4). In females, total and partial C4B deficiencies and lower levels of IgG1 and IgG3 were associated with rhinosinusitis leading to sinonasal operations. C4A deficiencies were found to predispose to severe chronic rhinosinusitis in females and males. In female patients with chronic or recurrent rhinosinusitis with nasal polyposis C4B deficiencies seem to predispose to the disease, but in males with a similar disease C4B deficiencies seem to be protective. This suggests a different pathophysiology between sexes in this form of sinonasal disease. In the second part of this thesis work 213 children coming to elective tonsillectomy were studied and compared with 155 randomly selected school children. An association with recurrent upper respiratory tract infections and hypersensitivity disorders was seen especially in children under 7 years of age. However, this association was not seen in levels of specific IgE to respiratory allergens in the same age group. Both symptomatic respiratory allergy and specific IgE to respiratory allergens became more common in boys than girls over 7 years of age. We were able to show that although both rhinoviruses and bacterial pathogens were found in the tonsils, no association between their presence and clinical forms of tonsillar disease was seen. The ability of GAS to bind complement regulators FH and C4BP did not differ between strains causing tonsillar diseases or septicemia, suggesting that other virulence mechanisms of the bacteria are more important.

Aerosol size distribution and its connection to cloud droplet number concentration

In order to predict the current state and future development of Earth s climate, detailed information on atmospheric aerosols and aerosol-cloud-interactions is required. Furthermore, these interactions need to be expressed in such a way that they can be represented in large-scale climate models. The largest uncertainties in the estimate of radiative forcing on the present day climate are related to the direct and indirect effects of aerosol. In this work aerosol properties were studied at Pallas and Utö in Finland, and at Mount Waliguan in Western China. Approximately two years of data from each site were analyzed. In addition to this, data from two intensive measurement campaigns at Pallas were used. The measurements at Mount Waliguan were the first long term aerosol particle number concentration and size distribution measurements conducted in this region. They revealed that the number concentration of aerosol particles at Mount Waliguan were much higher than those measured at similar altitudes in other parts of the world. The particles were concentrated in the Aitken size range indicating that they were produced within a couple of days prior to reaching the site, rather than being transported over thousands of kilometers. Aerosol partitioning between cloud droplets and cloud interstitial particles was studied at Pallas during the two measurement campaigns, First Pallas Cloud Experiment (First PaCE) and Second Pallas Cloud Experiment (Second PaCE). The method of using two differential mobility particle sizers (DMPS) to calculate the number concentration of activated particles was found to agree well with direct measurements of cloud droplet. Several parameters important in cloud droplet activation were found to depend strongly on the air mass history. The effects of these parameters partially cancelled out each other. Aerosol number-to-volume concentration ratio was studied at all three sites using data sets with long time-series. The ratio was found to vary more than in earlier studies, but less than either aerosol particle number concentration or volume concentration alone. Both air mass dependency and seasonal pattern were found at Pallas and Utö, but only seasonal pattern at Mount Waliguan. The number-to-volume concentration ratio was found to follow the seasonal temperature pattern well at all three sites. A new parameterization for partitioning between cloud droplets and cloud interstitial particles was developed. The parameterization uses aerosol particle number-to-volume concentration ratio and aerosol particle volume concentration as the only information on the aerosol number and size distribution. The new parameterization is computationally more efficient than the more detailed parameterizations currently in use, but the accuracy of the new parameterization was slightly lower. The new parameterization was also compared to directly observed cloud droplet number concentration data, and a good agreement was found.

Leadership through the Gender Lens: Women and Men in Organisations

Leadership and management remain highly gendered. Recent decades have seen a major international growth of studies on gender relations in leadership, organisations and management, in both empirical research and theoretical analysis. The differential relations of women and men to leadership and management are a key question for both theory and practice. Recent research and discussion on the gendering of leadership have been influenced by and have addressed: feminism; recognition of women and women’s situations, experiences and voices in leadership; organisational culture; communication; divisions of labour, hierarchy, power and authority; imagery and symbolism; information technology; sexuality, harassment, bullying and violence in organisations; home-work relations; men and masculinities in leadership; globalisation, transnationalism, intersectionality and post¬¬colonialism – amongst other issues. Having said that, the vast majority of mainstream work on leadership retains little or no gender analysis. In most business schools and other universities the position of gender-explicit work on leadership is still not well established. Leadership through the Gender Lens brings together critical analyses and debates on gender, leadership and management with contributions from 13 countries and five continents. How leadership and management are gendered can mean more gender equal or more gender unequal conditions for women and men. This includes how education and training can contribute to gendered leadership and management. The volume is organised in three main sections, on: careers and leadership; management, hierarchy and leadership: and interventions in leadership.

Sociolinguistic Implications of Narratology: Focalization and ‘Double Deixis’ in Conversational Storytelling

Over the last few decades, literary narratology has branched out into a wide array of ‘post-classical’ narratologies that have borrowed concepts from cognitive psychology, sociology, anthropology, history, linguistics, and other disciplines. The question arises to what extent ‘classical’ narratological concepts can also be successfully exported to other disciplines which have an interest in narrative. In this article, I apply the concept of ‘focalization’ as well as David Herman’s insights into doubly-deictic ‘you’ in second-person narratives to an interview narrative and further materials from my empirical sociolinguistic study on general practitioners’ narrative discourse on intimate partner abuse. I consider how the narrative positioning of the GP as storyteller and ‘protagonist’ of his story corresponds with his social and professional positioning with regard to his patients in the context of intimate partner violence cases and vis-à-vis the interviewer during the research interview. Focalization and double deixis are shown to become part of a narrative strategy whereby the narrator distances himself from his own personal self in the narrative and at the same time tries to align the interviewer with his viewpoint.

Narratives of Travel and the Travelling Concept of Narrative: Genre Blending and the Art of Transformation

In this article I shall argue that understandings of what constitutes narrative, how it functions, and the contexts in which it applies have broadened in line with cultural, social and intellectual trends which have seen a blurring, if not the dissolution, of boundaries between ‘fact’ and ‘fiction’; ‘literary’ and ‘non-literary’ narrative spaces; history and story; concepts of time and space, text and image, teller and tale, representation and reality.To illustrate some of the ways in which the concept of narrative has travelled across disciplinary and generic boundaries, I shall look at The Art of Travel (de Botton 2003), with a view to demonstrating how the blending of genres works to produce a narrative that is at once personal and philosophical; visual and verbal; didactic and poetic. I shall show that such a text constitutes a site of interrogation of concepts of narrative, even as it depends on the reader’s ability to narrativize experience.

On the Epistemology of Narrative Theory: Narratology and Other Theories of Fictional Narrative

In this article, I propose to analyze narrative theory from an epistemological standpoint. To do so, I will draw upon both Genettian narratology and what I would call, following Shigeyuki Kuroda, “non-communicational” theories of fictional narrative. In spite of their very unequal popularity, I consider these theories as objective, or, in other words, as debatable and ripe for rational analyses; one can choose between them. The article is made up of three parts. The first part concerns the object of narrative theory, or the narrative as a constructed object, both in narratology (where narrative is likened to a narrative discourse) and in non-communicational narrative theories (where fictional narrative and discourse are mutually exclusive categories). The second part takes up the question of how the claims of these theories do or do not lend themselves to falsification. In particular, Gérard Genette’s claim that “every narrative is, explicitly or not, ‘in the first person’”, will be considered, through the lens of Ann Banfield’s theory of free indirect style. In the third part the reductionism of narrative theory will be dealt with. This leads to a reflection on the role of narrative theory in the analysis of fictional narratives.

Narrative, Memory and the Crisis of Mimesis: the Case of Adam Elsheimer and Giordano Bruno

The triangular space between memory, narrative and pictorial representation is the terrain on which this article is developed. Taking the art of memory developed by Giordano Bruno (1548 – 1600) and the art of painting subtly revolutionised by Adam Elsheimer (1578 – 1610) as test-cases, it is shown how both subvert the norms of mimesis and narration prevalent throughout the Renaissance, how disrupted memory creates “incoherent” narratives, and how perspective and the notion of “place” are questioned in a corollary way. Two paintings by Elsheimer are analysed and shown to include, in spite of their supposed “realism”, numerous incoherencies, aporias and strange elements – often overlooked. Thus, they do not conform to two of the basic rules governing both the classical art of memory and the humanist art of painting: well-defined places and the exhaustive translatability of words into images (and vice-versa). In the work of Bruno, both his philosophical claims and the literary devices he uses are analysed as hints for a similar (and contemporaneous) undermining of conventions about the transparency and immediacy of representation.