Hintergrund: Die Schlafbezogene Atmungsstörung (SBAS) ist eine häufige Komorbidität der systolischen Herzinsuffizienz und mit einer kürzeren Lebenserwartung assoziiert. Es steht derzeit eine Vielzahl einfacher ambulanter SBAS-Screening-Geräte zur Verfügung. Keines davon wurde jedoch bisher für Patienten mit chronischer systolischer Herzinsuffizienz validiert. Fragestellung: Die vorliegende Untersuchung diente der Prüfung eines einfachen ambulanten SBAS-Screenings hinsichtlich diagnostischer Trennschärfe und prognostischer Relevanz für Patienten mit systolischer Herzinsuffizienz. Methoden: Bei Patienten mit symptomatischer systolischer Herzinsuffizienz (linksventrikuläre Ejektionsfraktion (LVEF) < 45%, NYHA ≥ II) wurden nächtlicher Atemfluss, Pulsfrequenz und Sauerstoffsättigung mit dem ApneaLinkTM (Fa. ResMed) ambulant aufgezeichnet. Hieraus werden der Apnoe-/Hypopnoe-Index (AHI) sowie der Entsättigungsindex (ODI) berechnet. Die Ergebnisse wurden der Diagnose des Schlafmediziners anhand einer PSG als gültigem Goldstandard der SBAS-Diagnostik gegenübergestellt. Der Überlebensstatus wurde bei allen Patienten durch ambulante bzw. telefonische Nachuntersuchungen erfasst. Mittels ROC-Analysen wurden diagnostische und durch Cox-Regressionen prognostische Schwellenwerte des SBAS-Screenings ermittelt. Ergebnisse: Insgesamt wurden 131 Patienten eingeschlossen: das mittlere Alter lag bei 68±13 Jahren, 110 Patienten (84%) waren männlich, 53 Patienten (41%) hatten ein NYHA-Stadium ≥3, die mittlere LVEF lag bei 34%. Bei 69 Patienten (53%) konnte eine PSG durchgeführt werden, welche bei 55 Patienten (80%) eine SBAS diagnostizierte. Bei 38 Patienten (55%) lag eine mind. mittelgradige, therapiepflichtige SBAS vor. In ROC-Analysen für ein mind. mittelgradige SBAS ergaben sich AUCs von 0.77; 0.82; 0.81; 0,79 und 0,82 für AHI; ODI; (AHI+ODI)/2; (2xAHI+ODI)/3 und (AHI+2xODI)/3. Die größtmögliche Spezifität (0,90) und Sensitivität (0,66) für die Diagnose einer Therapiepflichtigen SBAS lab bei einem cut-off von (AHI+2xODI)/3 ≥ 21/h. Die mediane Follow-up Zeit der Studie lag bei 23 (18; 27) Monaten; es starben 21 Patienten (16%). Es fand sich eine positive Korrelation zwischen (AHI+2xODI)/3 und Mortalitätsrate. Bereits für den (AHI+2xODI)/3 ≥9/h war die Mortalität signifikant erhöht (3,55 (95%CI: 1.04-12.13) p=0,04). Schlussfolgerung: Eine therapiepflichtige SBAS lässt durch ein ambulantes Screening zuverlässig diagnostizieren. Dabei ist der ODI dem AHI überlegen. Für die bestmögliche diagnostische Trennschärfe empfehlen wir einen (AHI+2xODI)/3 von 21/h heranzuziehen, wobei bereits ein Wert von 9/h prognostisch relevant ist, so dass bei Patienten mit einem (AHI+2xODI)/3 von 9-20/h zwar auf eine schlafmedizinische Untersuchung verzichtet werden kann, eine engmaschige kardiologische Kontrolle inklusive wiederholten Screenings jedoch unabdingbar bleibt. / Background: Sleep disordered breathing (SDB) is a frequent condition in chronic systolic heart failure (cSHF) and associated with an increased mortality risk. Several diagnostic screening modalities for SDB are available but none has been validated in cSHF. We aimed to evaluate the diagnostic utility and prognostic importance of a simple ambulatory screening algorithm for SDB in SHF. Methods: Using the ApneaLinkTM, in an ambulatory setting nocturnal nasal airflow, pulse and oxygen saturation were measured in outpatients suffering from cSHF (NYHA functional class ≥II, LVEF <45%). Apnea-/hypopnea index (AHI) and oxygen desaturation index (ODI) were calculated. Subsequent in-patient polysomnography (PSG) was performed. A sleep physician ascertained (established or excluded) the diagnosis of SDB and deduced therapeutic suggestions. Receiver operating characteristics (ROC) were constructed to illustrate the performance of AHI, ODI and also for three weighted indices in correctly identifying the need for nocturnal ventilatory support. Survival status was assessed after a median follow-up of 23 months. Results: We included 131 patients (mean age 68±13 years, 84% male, mean LVEF 34%). Subsequent PSG was performed in 69/131 patients of the total cohort (53%) revealed SDB in 55/69 subjects (80%); in 38/69 (55%) SDB required nocturnal ventilatory support according to the sleep physician’s estimation. The area under the ROC curve was 0.77, 0.82, 0.81, 0.79 and 0.82 for AHI, ODI, (AHI+ODI)/2, (2*AHI+ODI)/3 and (AHI+2*ODI)/3, respectively. From the coordinates of ROC curves, the value of (AHI+2*ODI)/3 ≥21/h was identified to predict the diagnosis of SBD with required nocturnal ventilatory support with highest sensitivity (0.66) and specificity (0.90). During follow-up, 21/131 patients (16%) had died. In Cox regression (AHI+2xODI)/3 !9/h was associated with an increased risk of mortality: HR 3.55, 95%CI 1.04-12.13) p=0.04). Conclusion: In cSHF, a simple ambulatory screening device identified patients with SDB requiring nocturnal ventilatory support. The weighted index of (AHI+2*ODI)/3, was the best predictor for this purpose. In patients with (AHI+2*ODI)/3 !21/h, SDB requiring specific treatment is most probable and PSG should be performed in order to initiate the appropriate therapy. In patients with (AHI+2*ODI)/3 ≥9/h, mortality risk is significantly increased, therefore intensified heart failure treatment and closer follow- up is advisable.

Ionisierende Strahlung (IR) ist in der medizinischen Diagnostik und in der Tumortherapie von zentraler Bedeutung, kann aber Genominstabilität und Krebs auslösen. Strahleninduzierte Genominstabilität (RIGI) ist in den klonalen Nachkommen bestrahlter Zellen zu beobachten, die zugrundeliegenden Mechanismen sind jedoch noch unverstanden. Zur Erforschung von verzögerten Strahleneffekten wurden primäre embryonale Fibroblastenkulturen mit 2 Gray bestrahlt und für 20 Populationsverdopplungen klonal expandiert. Zellen, die keiner Strahlung ausgesetzt waren, dienten als Kontrolle für normale Alterungsprozesse. Die Klone wurden durch klassische Chromosomenbänderungstechniken analysiert und in Abhängigkeit der Stabilität ihres Genoms in Gruppen eingeteilt. Ein Klon wurde als stabil gewertet, wenn die analysierten Metaphasen keinerlei Auffälligkeiten zeigten, während instabile Klone ein Mosaik aus normalen und abnormalen Metaphasen waren. Die Zellen von zwei Spendern wurden untersucht, um interindividuelle Strahleneffekte zu beurteilen. Nach Bestrahlung hatten mehr als die Hälfte der Klone Metaphasen mit strukturellen Aberrationen und wurden dementsprechend als instabil eingestuft. Drei Klone zeigten zudem numerische Aberrationen, die ausschließlich das Y Chromosom betrafen. Fluoreszenz in situ Hybridisierungen verifizierten diese Beobachtung in weiteren Klonen und deuteten an, dass der Verlust des Y Chromosoms mit RIGI assoziiert ist. Molekulare Karyotypisierungen mit SNP Arrays ergaben, dass IR in den Klonen Veränderungen der Kopienzahl auslöst. Ein Unterschied zwischen chromosomal stabilen und instabilen Klonen konnte jedoch nicht detektiert werden. Chromosomale Regionen, in denen sich bekanntermaßen fragile Stellen befinden, zeigten eine Anhäufung von CNVs. Ein RIGI Effekt konnte für die fragile Stelle 3B, in der sich das Gen FHIT befindet, identifiziert werden. Exom Sequenzierungen von Klonen und der entsprechenden Massenkultur zeigten eine alterungsassoziierte Entstehung von Varianten. Der Effekt wurde durch die Einwirkung von Strahlung erhöht. Auf Ebene von einzelnen Nukleotiden konnten ebenfalls Anhäufungen von Schäden in bestimmten genomischen Bereichen detektiert werden, dieser Effekt ging ohne die typischen RIGI Endpunkte einher. Die Ergebnisse der vorliegenden Arbeit zeigen, dass strahlenbedingte Veränderungen auf verschiedenen Ebenen (Chromosomen, Genkopienzahl und einzelnen Nukleotiden) beobachtet werden können, welche, unabhängig von RIGI, die Tumorentstehung begünstigen. Speziell Veränderungen im FRA3B Lokus und der Verlust des Y Chromosoms scheinen jedoch über die Destabilisierung des Genoms zur Krebsentstehung beizutragen. / Ionizing radiation is important in medical diagnosis and cancer treatment but can lead to genomic instability and secondary malignancies as a late effect. Radiation induced genomic instability (RIGI) can be observed in the progeny of irradiated cells but the underlying cellular processes remain to be elucidated. To study delayed genetic radiation effects, single cell fibroblast clones from two different male donors were established after a single X ray dose of 2 Gray. Non irradiated cells were used as controls to account for aging related effects. Clones were characterized using chromosome banding analysis. Stable clones were endowed with no karyotype abnormalities in all analysed metaphases after 20 Population doublings, whereas unstable clones showed both normal and abnormal metaphases. Two fibroblast strains were used to detect differences in radiation sensitivity. More than half of the irradiated clones were chromosomally abnormal and thus classified as unstable. Both banding analysis and fluorescence in situ hybridization revealed an increased rate of Y chromosome loss in irradiated clones which might be associated with RIGI. Using SNP Arrays, an increased rate of de novo copy number variations (CNVs) was detected in the progeny of irradiated cells when compared to non irradiated controls. However, a significant difference between chromosomally stable and unstable clones was not found. CNVs clustered in chromosomal regions that are associated with known fragile sites. The fragile site 3B, which encompasses the gene FHIT, was found to be affected by CNVs in unstable clones suggesting a RIGI related effect. Exome sequencing of clones and the respective primary cultures revealed an increased rate of variants during in vitro aging. This effect was further increased by radiation exposure. Analysis of single nucleotides showed a RIGI independent accumulation of damage in specific regions. The results of the present study show that radiation induced changes can manifest as chromosomal abnormalities, copy number variations and DNA sequence mutations promoting tumorigenesis independent from RIGI. However, changes in FRA3B and loss of Y chromosome might trigger cancer through destabilizing the genome.

In this thesis, molecular dynamics simulations, molecular docking, and homology modeling methods have been used in combination to design possible inhibitors as well as to study the structural changes and function of target proteins related to diseases that today are in the spotlight of drug discovery. The inwardly rectifying potassium (Kir) channels constitute the first target in this study; they are involved in cardiac problems. On the other hand, tensin, a promising target in cancer research, is the second target studied here. The first chapter includes a brief update on computational methods and the current proposal of the combination of MD simulations and docking techniques, a procedure that is applied for the engineering of a new blocker for Kir2.1 ion channels and for the design of possible inhibitors for Tensin. Chapter two focuses in Kir ion channels that belong to the family of potassium-selective ion channels which have a wide range of physiological activity. The resolved crystal structure of a eukaryotic Kir channel was used as a secondary structure template to build the Kir-channels whose crystallographic structures are unavailable. Tertiapin (TPN), a 21 a.a. peptide toxin found in honey bee venom that blocks a type of Kir channels with high affinity was also used to design new Kir channel blockers. The computational methods homology modeling and protein-protein docking were employed to yield Kir channel-TPN complexes that showed good binding affinity scores for TPN-sensitive Kir channels, and less favorable for Kir channels insensitive to TPN block. The binding pocket of the insensitive Kir-channels was studied to engineer novel TPN-based peptides that show favorable binding scores via thermodynamic mutant-cycle analysis. Chapter three is focused on the building of homology models for Tensin 1, 2 and 3 domains C2 and PTP using the PTEN X-ray crystallographic structure as a secondary structure template. Molecular docking was employed for the screening of druggable small molecules and molecular dynamics simulations were also used to study the tensin structure and function in order to give some new insights of structural data for experimental binding and enzymatic assays. Chapter four describes the conformational changes of FixL, a protein of bradyrhizobia japonicum. FixL is a dimer known as oxygen sensor that is involved in the nitrogen fixation process of root plants regulating the expression of genes. Ligand behavior has been investigated after the dissociation event, also the structural changes that are involved in the relaxation to the deoxy state. Molecular dynamics simulations of the CO-bound and CO-unbound bjFixL heme domain were performed during 10 ns in crystal and solution environments then analyzed using Principal Component Analysis (PCA). Our results show that the diffusion of the ligand is influenced by internal motions of the bound structure of the protein before CO dissociation, implying an important role for Arg220. In turn, the location of the ligand after dissociation affects the conformational changes within the protein. The study suggests the presence of a cavity close to the methine bridge C of the heme group in agreement with spectroscopic probes and that Arg220 acts as a gate of the heme cavity.

Background: Non-specific low back pain is a growing problem in society. No treatment have shown satisfying results to reduce pain or disability for patients with non-specific low back pain, and 1-18% of these patients develop chronic low back pain. STarT Back Screening Tool (SBST) is an instrument for sub grouping patients with non-specific low back pain into low, medium or high risk of developing chronic low back pain and then modifying the treatment after the different needs of every patient. The purpose of this study was to do a systematic review, investigating validation of the SBST to evaluate the justification of its use by clinicians. Method: Pubmed, Cinahl and Medline was searched in February 2017 for studies investigating criterion validity, construct validity and content validity of the SBST. The author (JG) assessed risk of bias and extracted relevant data following the procedures of PRISMA-statement. Result: 15 articles were identified for inclusion in the review. 8 articles investigated criterion validity, 11 articles investigated construct validity and 1 article investigated content validity. Predictive validity showed heterogeneous statistical analysis and varying results, a narrative result was presented that showed marginal benefits for the use of SBST for prediction of future outcome. Concurrent validity was measured with Spearman’s rank correlation coefficient in all investigated articles, showing results between 0.34-0.802. Discriminant validity was measured with Area under the curve analysis in all articles, scoring between 0.69-0.92. Convergent validity showed a Pearson’s correlation between 0.708-0.811 and a Spearman’s rank correlation between 0.35-0.74. Conclusion: Because of heterogeneity of the results it is not possible to draw conclusive conclusions. However, results tend to show limited evidence for the use of SBST as a predictive instrument for patients with non-specific low back pain.

The older woman's body is an example of the discontinuous nature of those beings who come under the rubric of woman and, as such, demontrates the impossibility of a unitary representation of woman. This thesis explores the social construction of the older woman's body both as abject and as 'docile/useful' and proposes how this abjectification can be re-inscribed as transgressive through a de-territorialization of the older woman's body.This thesis positions the older woman's body as (un)becoming because it lacks cultural intelligibility as representative of the feminine on the one hand and, on the other, because it disrupts normative ideals of femininity and eludes disciplinary practices. Sexuality is used as a resource to conjure, construct, reinforce and validate the 'ideal' woman, a model against which the older woman is redefined as asexual. I argue that the particular technologies employed in the production of the older woman's 'docile/useful' body are those of the health sciences. A 'docile/useful' body transforms the older woman into a knowable, treatable and profitable body through discourses of health. Mass mammographic screening is analysed in order to illustrate how the biomedical sciences are employed in the regulation of the older woman's body through the co-option of health promotion strategy as a disciplinary practice. / Doctor of Philosophy (PhD)

Depression is poorly recognised, under-assessed and under-treated in patients receiving palliative care for a life-limiting illness. There are barriers to assessment and diagnosis, and limited access to specialist clinicians who might assist in these complex assessments and who could provide options for treatment. The three studies presented, using different research methodologies, and using both qualitative and quantitative analysis, seek to clarify these issues and to provide some solutions. A questionnaire was sent to all Palliative Care Services (PCS) in Australia. Questions included what part specialist psychological clinicians played in multi-disciplinary team meetings and in the treatment or coordination of patient care. Very few PCS used a valid screening instrument for psychological distress and very few had regular support from a psychiatrist or psychologist. Many did not have access to social work support. There are two competing issues with regard to recognising and assessing depression in palliative populations. A rapid reliable screen that points to a likely problem would be useful, but also there is a need to understand something of the patient experience of depression. In the second study, the one- and two-item screening instruments widely used in palliative care are examined and limitations that have been found in other settings are confirmed. A new novel screening tool is developed from this data and tested empirically. This algorithm is short, has good psychometric properties and is validated for an Australian palliative care population. Depending on the response pattern it is possible to identify that a particular patient has significant symptoms of depression by asking between one and four questions. Professional carer and patient acceptability of the questions is high. The understanding of the experience and symptom profile of depression in Australian palliative care patients is addressed in the third study. Patients and family carers were recruited prospectively from palliative care and oncology ambulatory clinics of two teaching hospitals in an Australian capital city. The Geriatric Depression Scale (GDS) was administered to the patient and the Collateral Source version of this instrument was asked of the carer. A subset of this sample completed the measures twice. The results using this 30-item scale were then compared with all the known previously published short versions of this scale. Two short forms met as many psychometric criteria as the longer forms. None of the versions of the GDS showed sufficiently high correlations between carer-completed and patient-completed forms. The frequency of symptoms was also assessed. Patients more frequently reported fatigue and anhedonia than depressed affect. Despite many screening instruments being available for depression, their use is limited in Palliative Care Services. Although these studies have validated several options for Australian palliative care patients, the issues behind the low uptake rates for screening have not been resolved. The final chapter of this thesis constructs known and potential barriers into a logical structure and then offers some solutions to improve access to mental health professionals by considering service models and applying this theory to the problem of depression and its assessment in palliative care populations.

Thesis (Ph. D.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.

Diabetes is a psychologically demanding disease with a major impact on a patient’s quality and quantity of life. The outcome of diabetes is highly dependent on the self-care activities of the person with diabetes. Depression is common among people with diabetes, complicating this self-management and thereby increasing the risk of developing diabetes-related complications. Despite depression’s specific relevance to diabetes and the serious impact it has on the disease, it is estimated that only one third of people with both diabetes and major depression are recognized and appropriately treated for both disorders. The aim of this thesis therefore was to investigate the interrelationship between depression and diabetes and evaluate methods of improving recognition rates and access treatment within a health care setting. Routine screening for depression using standardised depression screening instruments has been recommended for all adults in primary care to improve the low recognition rates of depression in this population. The aim of Study 1 was therefore to compare the effectiveness of four commonly used depression screening instruments (CES-D, HADS, DMI, SCAD) in identifying depression in a diabetes sample. This research was important as little previous research had investigated the efficacy of these depression screening measures within this specialist group and an evaluation of their comparative performance had not yet been conducted. 150 patients with diabetes receiving care at the endocrinology outpatient clinics of two major public hospitals in Brisbane, Australia completed a battery of questionnaires and were also involved in a structured clinical interview (CIDI-SF) to establish a criterion standard. Results indicated that three of the screening measures (CES-D, HADS, DMI-10) could be considered reliable predictors of depression in this sample. There was however evidence that the CES-D could be considered the preferred measure as it had the best ability to discriminate between depression and non-depression, it showed reasonable sensitivity, high specificity, and it was able to stand alone as a predictor of major depression with its predictive ability not improved with the inclusion of diabetes symptoms. Study two of this thesis investigated the demographic, medical, and psychosocial correlates of depression in patients with diabetes. This research was important as information about risk profiles can help improve rates of diagnosis and treatment and may provide a method by which screening can be more focused and cost effective. 1069 hospital outpatient patients with diabetes were asked to complete a battery of questionnaires to accomplish this aim. The results found that co-morbid depression in patients with diabetes was associated with type-1 diabetes, younger age, poor glycaemic control, insulin treatment, co-morbid medical illness, increased diabetes symptoms, lack of a partner, lower income, stressful life events, low social support, and poor quality of life. Of particular interest was the finding that the inclusion of psychosocial predictors reduced the predictive ability of many demographic and medical factors. Study three of this thesis investigated the impact of a depression screening and feedback procedure on a patient’s level of depression, glucose control, and quality of life. While routine screening for depression has recently been recommended for all patients with diabetes, no previous research had been conducted to evaluate the efficacy of this approach on treatment and patients outcomes. 164 patients with diabetes who were found to be depressed in study 2 were involved in a randomised controlled trial which compared patients who received feedback regarding their depression status with those patients who did not receive any feedback. The results found high rates of depression in this sample and suggested that screening for depression and providing feedback to patients regarding the outcomes of screening had beneficial effects on depression at six months but not on glycaemic control or quality of life. The final study in this thesis attempted to investigate the help seeking behaviours of patients following feedback and to identify barriers to seeking care. 82 participants who received feedback regarding their depression status in study 3 were contacted for a structured telephone interview. Results indicated that only 52.44% of depressed diabetes patients followed the recommended advice and sought help for their depression. Of the patients that did not seek help, several barriers to seeking care were reported. Overall, the results indicated that attitudes relating to the severity of the disorder and the need for treatment were more salient barriers for participants in this study than logistical issues, stigma, or current levels of depression.

The SCQ is a popular screener for ASDs derived from the gold-standard diagnostic interview. This study examined the validity of the SCQ in a Hispanic sample. Additionally, the mother's expressed emotion toward her child with ASD was examined. Participants included 217 Hispanic and non-Hispanic white mothers of children with and without ASDs ages 4-10. The actual diagnostic status of all children was determined using a historical review of records. ROC curve analysis yielded much lower sensitivity and specificity than the original validation study, with very little difference found between the 15 and 22 cutoffs. A cutoff score of 12 performed the best with a sensitivity of .86 and specificity of .54 in distinguishing between ASD and Non-ASD. There were no significant findings in expressed emotion between Hispanics or Whites, nor did it predict SCQ score. Limitations included a small non-Hispanic White sample. Findings of this study corroborate recent validation results.

Adult mammalian central nervous system (CNS) neurons are unable to extend axons after injury, partially owing to the inhibitory myelin and chondroitin sulfate proteoglycans (CSPGs) present in the environment. A neuron's intrinsic state is also important for determining its regenerative potential. Peripheral nervous system (PNS) neurons, unlike their CNS counterparts, have increased ability to regrow their axons after injury, even in the presence of inhibitory molecules. With the goal of discovering novel regeneration associated genes, we have isolated the genes differentially expressed by PNS neurons. We then developed a high throughput neuronal transfection method to test whether these genes were sufficient to modify neurite growth in vitro. Using high content screening, we measured the ability of cerebellar neurons to initiate neurite outgrowth on inhibitory and permissive substrates. This combination of technologies (subtractive hybridization, microarray, high throughput electroporation and high content screening) allowed phenotypic examination of neurons after the overexpression of over a thousand genes. Additionally, kinases and phosphatases were assayed for their ability to modify neurite outgrowth in hippocampal neurons. Results from both of these large unbiased screens confirmed many of the existing candidates for neurite growth during development and regeneration. We also discovered many novel genes which promoted neurite outgrowth such as GPX3, EIF2B5, RBMX, CHKA, IRF6, and PKN2. To accurately interpret the large volume of data, new methods of analysis were performed. Finally, we developed novel techniques that took advantage of public databases to cluster genes and determine whether those clusters produced robust changes in neurite growth. In summary, we have provided a vast repository of functional data to study axon development and regeneration after injury as well as developing the tools needed to interpret that data.