<p>At the present time, here is no approved medical countermeasure (MCM) for mitigating or treating pneumonitis/fibrosis following acute radiation exposure. Since it is neither ethical nor feasible to evaluate potential MCMs against radiation injury in the clinical setting, the FDA permits MCM licensure under an alternative drug development pathway ("Animal Efficacy Rule") that relies on the predictive validity of animal models. The purpose of the current project was to design a research platform that addresses many of the critical knowledge gaps associated with successful adherence to the FDA Animal Rule. </p><p>In these studies, we evaluated the dose-response relationship for survival and function injury among CBA/J, C57L/J, and C57BL/6J mouse strains. These strains were previously identified to represent the full spectrum of pulmonary pathology associated with acute radiation exposure to the thorax. We next evaluated ultrastructural pathology to identify differences in tissue response among strains as early as twenty-four hours after radiation. Global differential gene expression analysis was utilized to identify the major signaling pathways and genes associated with development of radiation pneumonitis and/or fibrosis by exploiting the phenotypic differences in radiation-injury among strains. Genes with significant differences were validated by quantitative real-time PCR and their protein products validated by western blot. Finally, we performed longitudinal analysis of hypoxia-associated gene expression to elucidate the natural history of disease progression in "fibrosis prone" C57BL/6J mice. </p><p>In these studies, we identified significant differences in the dose-response, temporal onset, disease progression, and pathologic manifestations of radiation lung injury among murine strains. The severity of ultrastructural damage at twenty-four hours also differed among strains indicating the early tissue response to the radiation insult was dissimilar. A significant difference was found in gene expression among strains. The most interesting differences were associated with the acute-phase response, iron homeostasis, cell cycle/proliferation, and cell death. Lastly, hypoxia-associated gene expression, including HIF-1alpha; and HIF-2alpha; mRNA and protein stabilization, was dynamically altered during the temporal course of radiation pathogenesis in the "fibrosis-prone" C57BL/6J mice. As the C57BL/6J strain is more "resistant" to radiation-induced lung injury, a better understanding of the pathways involved in tissue response to radiation in this strain might elucidate the mechanisms that make the lungs of this strain significantly more radiotolerant than their counterparts. </p><p>The research platform developed in this project provides essential information to interpret and define the complex interrelationships in clinically relevant models of the human response to potentially lethal irradiation and treatment. The overall goal is to provide a rigorous scientific platform for MCM development under the Animal Efficacy Rule with reasonable expectation that MCMs acquired for the Strategic National Stockpile will effectively prevent, treat, or mitigate radiation-induced lung injury and improve survival among the exposed population.</p> / Dissertation

African trypanosomes are protozoan parasites that cause African trypanosomiasis, diseases that affect humans and their livestock. Not only has trypanosomiasis had an overwhelming effect on the development of tropical Africa in the past, but it also constitutes one of the most significant present economic problems of the continent. Trypanosomes alternate between a mammalian host and a tsetse vector using a complex life cycle. In the mammalian host the trypanosomes live as bloodstream forms (BSFs) that are so proficient at antigenic variation, and thus host immune system evasion, that no suitable vaccine candidates have yet been identified. In contrast, the lifecycle stages that exist in the tsetse vector do not undergo antigenic variation. This potentially makes the vector-occupying trypanosomes much better targets for control if strategies can be devised to disrupt their lifecycle in the vector or to interfere with their transmission to mammalian hosts. The primary impediment to developing strategies for disruption of trypanosome life cycles in tsetse is a lack of understanding of the molecular basis of trypanosome-tsetse interactions. Although several major surface molecules have been identified on insect form trypanosomes, these have not been well studied due to a lack of appropriate antibody probes and to the difficulty in obtaining sufficient quantities of the different parasite life cycle stages required for such molecular studies. My thesis research was focused on developing and using monoclonal antibody probes for analysis of expression of major surface molecules of Trypanosoma congolense, a serious pathogen of cattle in Africa. I used this species of trypanosome since in addition to being a socioeconomically important parasite, all four of its major life cycle stages can be grown in vitro in amounts sufficient for immunochemical analysis. I successfully derived and characterized monoclonal antibodies that were useful for detecting the three major surface proteins of T. congolense insect forms: glutamic acid/alanine rich protein (GARP), the T. congolense heptapeptide repeat protein (TcHRP) and congolense epimastogote specific protein (CESP). Selected monoclonal antibody probes were then employed for expression analysis of these molecules throughout the parasite life cycle using in vitro grown trypanosomes and parasites taken directly from infected tsetse. In addition, I determined the peptide epitopes for two of my GARP-specific monoclonal antibodies and in collaboration with Dr. Martin Boulanger and Jeremy Mason was able to localize the epitopes on a high resolution three-dimensional structure obtained by X-ray crystallography. This allowed us to derive a model that describes the orientation of GARP in the trypanosome surface membrane and explains the possible structure-function relationships involved in replacement of the bloodstream form variant surface glycoprotein (VSG) by GARP as trypanosomes differentiate in the tsetse vector after a bloodmeal.

The aim of this study was to investigate if the experiences of work environment of employees in the elder care in the municipality of Umeå can be linked to high or low sickness absence. The method used was semi-structural qualitative interviews. Six retirement homes participated in the study and were divided into two groups, based on whether they had high or low figures of sickness absence. 28 elder care workers of different educational levels were interviewed. The interview questions were divided into categories. For the key phrases; “Have great possibilities of influencing one´s schedule” (category influence), “Is offered education” (category development and challenge), “The work pace depends on the wellbeing of the residents” (category physical and psychological workload), “Reflect/Do not reflect on work at home” (category physical and psychological workload), “Difficult to resolve conflicts” (category working climate and wellbeing) and “Stressful work” (category working climate and wellbeing) statistically significant differences between the groups were detected. Risk factors in the work environment, such as, time pressure, conflicts and physical and psychological strain are described by employees at retirement homes with both higher and lower figures of sickness absence. Differences between the sexes could not be investigated, but that does not exclude possible differences. Based on the results the conclusion is drawn that aspects of influence, development and challenge, physical and psychological workload and working climate and wellbeing can be factors that impact on sickness absence in the elder care in the municipality of Umeå.

Objectives. Ascertain if there has been a secular trend in 3-months prevalence of casually reported back pain. Evaluate if such back pain predicts concurrent health as well as future sick leave, disability pension, hospitalization and survival. Study differences in diagnostic assessment and labelling between physicians. Evaluate if a comprehensive manual therapy programme reduces sickness absence. Materials and methods. Combined population samples from 1973 to 2003 with a total of 12,891 observations with self-reported back pain and covariates. 7,074 of these individuals were followed for an average of 8.5 years and outcomes were self-reported health as well as official register data on sick leave, disability pension, hospitalisation and mortality. The Gotland Low Back Pain Study, a randomised controlled trial with participation of two general practitioners and two orthopaedic surgeons treating 160 patients with acute/subacute low back pain, with 10 weeks diagnostic evaluation and treatment and a two-year follow up. Results. Back pain prevalence increased 16% per ten years (OR 1.16, 95%CI 1.11-1.22). Back pain was negatively associated with self-rated health (p&lt;0.0001), increased the risk of disability pension (p&lt;0.002), and hospital admissions (p&lt;0.0005), but not number of days in hospital, sick leave or mortality. General practitioners used terms from manual medicine and reported more pseudoradicular pain, while orthopaedic surgeons used non-specific pain labels, reported more true radicular pain and used more x-ray examinations. Among those on sick leave at baseline, manual therapy patients showed faster return to work (HR 1.62, 95%CI 1.006–2.60) and a lower point-prevalence of sick leave than reference patients at end of treatment period (ratio 0.35, 95% CI 0.13–0.97) but not after two years. Conclusions. There was a strong secular trend towards increase in self-reported back pain from 1973 to 2003. Such pain had a negative effect on some of the health outcomes and does not appear to be harmless. Physicians from different specialities labelled the condition differently. The manual therapy programme proved to be more effective than the established treatment regarding return to work.

Migraine, a neurovascular disorder, is associated with disturbances in brain stem activity during attacks. Interictal persistence of these disturbances might increase vulnerability to recurrent attacks of migraine. To explore this possibility, effects of motion sickness and pain on migrainous symptoms and extracranial vascular reponses were investigated in 27 migraine sufferers in the headache-free interval, and 23 healthy age/sex matched controls. Symptoms of migraine and motion sickness are remarkably similar. As both maladies involve reflexes that relay in the brain stem, they most probably share the same neural circuitry. Furthermore, migraineurs are usually susceptible to motion sickness and, conversely, motion sickness-prone individuals commonly experience migraine. Participants in the present study were exposed to optokinetic stimulation (OKS), a well-established way of inducing symptoms of motion sickness in susceptible individuals. Sensitivity to painful stimulation of the head and hand was also explored. Head pain is a hallmark of a migraine attack and cutaneous allodynia has been observed elsewhere in the body during attacks. The trigeminal nerve is associated with head pain in migraine, and trigeminal activity evokes reflexes that relay in the brain stem. To stimulate the trigeminal nerve, ice was applied to the temple. To stimulate nociceptors elsewhere in the body the participant immersed their fingers and palm in ice-water. Procedures used in this study were physically stressful and probably psychologically stressful. The impact of stress in relation to the development of symptomatic and vascular responses, particularly anticipatory stress-responses, was explored. This research involved one central experiment that consisted of six experimental conditions. On separate occasions participants were exposed to optokinetic stimulation and painful stimulation of the head or limb, individually and in combination. In migraine sufferers, symptomatic responses were enhanced during all procedures involving OKS and during temple pain after OKS, in the presence of residual motion sickness. During trigeminal stimulation independent of OKS, headache initially developed followed by nausea as the procedure progressed. In contrast, symptoms barely developed in controls during any of the six procedures except for slight dizziness, self-motion and visual-illusion during conditions involving OKS, and slight nausea when the temple was painfully stimulated during OKS and during OKS alone. Trigeminal stimulation during OKS intensified nausea and headache in migraine sufferers compared to during OKS alone or limb pain during OKS. However, the remaining symptomatic ratings were not affected by temple pain during OKS, suggesting a specific association between nausea and head pain. It may be that these cardinal symptoms compound one another during a migraine attack. Enhanced symptomatic responses in migraine sufferers during the headache interval may indicate activation of hypersensitive neural pathways that mediate symptoms of motion sickness or migraine. Migraineurs found procedures generally more unpleasant, and ice-induced pain ratings more intense and unpleasant, than controls, which may further indicate hyperexcitable nociception in this group, or a difference in their criterion of discomfort. Vascular responses, particularly during OKS alone, and during painful stimulation independent of OKS, were greater in migraine sufferers than in controls. The added stress of painful stimulation during OKS appeared to boost facial blood flow in controls to approach levels obtained in migraine sufferers. Enhanced vasodilatation was observed in migraineurs prior to painful stimulation, presumably due to anticipatory anxiety. For both groups ipsilateral vascular responses were greater than contralateral responses when the hand was painfully stimulated. During limb pain before OKS asymmetry was minimal in migraine sufferers but more apparent in controls. An enhanced stress response in migraineurs may have drawn ipsilateral and contralateral responses closer together. The development of symptoms during the procedures of this study provides an insight into how symptoms might develop sequentially in a migraine attack. Once the headache is in motion, nausea and headache may mutually exacerbate one another. In turn, trigemino-vascular responses and stress appear to be associated with the migraine crisis. Given the interactive nature of symptomatic, vascular, and stress responses, it may be more effective to target multiple, rather than individual, symptoms, in prophylactic or acute chemical and psychological interventions.

Doctor of Philosphy (PhD) / This thesis describes the work carried out during four treks, each over 10-11 days, from 1400m to 5000m in the Nepal Himalaya and further work performed during several two-night sojourns at the Barcroft Laboratory at 3800m on White Mountain in California, USA. Nineteen volunteers were studied during the treks in Nepal and seven volunteers were studied at White Mountain. All subjects were normal, healthy individuals who had not travelled to altitudes higher than 1000m in the previous twelve months. The aims of this research were to examine the effects on sleep, and the ventilatory patterns during sleep, of incremental increases in altitude by employing portable polysomnography to measure and record physiological signals. A further aim of this research was to examine the relationship between the ventilatory responses to hypoxia and hypercapnia, measured at sea level, and the development of periodic breathing during sleep at high altitude. In the final part of this thesis the possibility of preventing and treating Acute Mountain Sickness with non-invasive positive pressure ventilation while sleeping at high altitude was tested. Chapter 1 describes the background information on sleep, and breathing during sleep, at high altitudes. Most of these studies were performed in hypobaric chambers to simulate various high altitudes. One study measured sleep at high altitude after trekking, but there are no studies which systematically measure sleep and breathing throughout the whole trek. Breathing during sleep at high altitude and the physiological elements of the control of breathing (under normal/sea level conditions and under the hypobaric, hypoxic conditions present at high altitude) are described in this Chapter. The occurrence of Acute Mountain Sickness (AMS) in subjects who travel form near sea level to altitudes above 3000m is common but its pathophysiology not well understood. The background research into AMS and its treatment and prevention are also covered in Chapter 1. Chapter 2 describes the equipment and methods used in this research, including the polysomnographic equipment used to record sleep and breathing at sea level and the high altitude locations, the portable blood gas analyser used in Nepal and the equipment and methodology used to measure each individual’s ventilatory response to hypoxia and hypercapnia at sea level before ascent to the high altitude locations. Chapter 3 reports the findings on the changes to sleep at high altitude, with particular focus on changes in the amounts of total sleep, the duration of each sleep stage and its percentage of total sleep, and the number and causes of arousals from sleep that occurred during sleep at increasing altitudes. The lightest stage of sleep, Stage 1 non-rapid eye movement (NREM) sleep, was increased, as expected with increases in altitude, while the deeper stages of sleep (Stages 3 and 4 NREM sleep, also called slow wave sleep), were decreased. The increase in Stage 1 NREM in this research is in agreement with all previous findings. However, slow wave sleep, although decreased, was present in most of our subjects at all altitudes in Nepal; this finding is in contrast to most previous work, which has found a very marked reduction, even absence, of slow wave sleep at high altitude. Surprisingly, unlike experimental animal studies of chronic hypoxia, REM sleep was well maintained at all altitudes. Stage 2 NREM and REM sleep, total sleep time, sleep efficiency and spontaneous arousals were maintained at near sea level values. The total arousal index was increased with increasing altitude and this was due to the increasing severity of periodic breathing as altitude increased. An interesting finding of this research was that fewer than half the periodic breathing apneas and hypopneas resulted in arousal from sleep. There was a minor degree of upper airway obstruction in some subjects at sea level but this was almost resolved by 3500m. Chapter 4 reports the findings on the effects on breathing during sleep of the progressive increase of altitude, in particular the occurrence of periodic breathing. This Chapter also reports the results of changes to arterial blood gases as subjects ascended to higher altitudes. As expected, arterial blood gases were markedly altered at even the lowest altitude in Nepal (1400m) and this change became more pronounced at each new, higher altitude. Most subjects developed periodic breathing at high altitude but there was a wide variability between subjects as well as variability in the degree of periodic breathing that individual subjects developed at different altitudes. Some subjects developed periodic breathing at even the lowest altitude and this increased with increasing altitude; other subjects developed periodic breathing at one or two altitudes, while four subjects did not develop periodic breathing at any altitude. Ventilatory responses to hypoxia and hypercapnia, measured at sea level before departure to high altitude, was not significantly related to the development of periodic breathing when the group was analysed as a whole. However, when the subjects were grouped according to the steepness of their ventilatory response slopes, there was a pattern of higher amounts of periodic breathing in subjects with steeper ventilatory responses. Chapter 5 reports the findings of an experimental study carried out in the University of California, San Diego, Barcroft Laboratory on White Mountain in California. Seven subjects drove from sea level to 3800m in one day and stayed at this altitude for two nights. On one of the nights the subjects slept using a non-invasive positive pressure device via a face mask and this was found to significantly improve the sleeping oxyhemoglobin saturation. The use of the device was also found to eliminate the symptoms of Acute Mountain Sickness, as measured by the Lake Louise scoring system. This finding appears to confirm the hypothesis that lower oxygen saturation, particularly during sleep, is strongly correlated to the development of Acute Mountain Sickness and may represent a new treatment and prevention strategy for this very common high altitude disorder.

Diss. (sammanfattning) Linköping : Univ., 2003. / Härtill 6 uppsatser.

Diss. (sammanfattning) Umeå : Univ., 2007. / Härtill 4 uppsatser.

Thesis (M. Phil.)--Hong Kong University of Science and Technology, 2002. / Includes bibliographical references (leaves 139-146). Also available in electronic version. Access restricted to campus users.

The aim of this essay is to understand the social mechanisms for why people go to work when they are sick. To understand it, we investigated why upper secondary school teachers sickness presenteeism increased in the last twenty years. Data consists of interviews with eleven upper secondary school teachers and two principals, plus statistics. To find patterns in the data we examined the theory of professions and the theory of the new capitalist culture. School budgets are based on support from the government that provides money for each student. Since 1992 free schools are allowed in Sweden. This creates a competition between schools, which may lead to programs in schools with insufficient applicant students to be shut down. The results show that the market's growing influence in schools has given upper secondary school teachers an increased social function. The customer, in this case the students and parents, has become more at the center. This new task, the student caring role, forces the teacher to be more accessible and flexible which has made their profession weaker, giving them more stress and in a longer term, they are feeling sick more often. A combination between a striving to keep up their profession and to not losing students, teachers go to school even if they’re sick.