Stressed Astrocytes: Insights on the Pathology of Alexander Disease

Alexander disease (AxD) is a rare and fatal neurological disorder caused by mutations in the gene that encodes glial fibrillary acidic protein (GFAP), an intermediate filament protein found in astrocytes in the central nervous system. The clinical presentations of AxD are diverse, ranging from onset in infancy to onset in early adulthood, and include seizures, psychomotor retardation, ataxia, and a variety of neurological signs related to abnormal brain stem function. The defining neuropathological hallmark is the presence of cytoplasmic, proteinaceous inclusions called Rosenthal fibers in astrocytes. Although GFAP expression is astrocytic, AxD patients also show de/dysmyelination and variable amounts of neuronal loss, most severely in infantile-onset patients. Astrocytes undergo severe morphological changes, beyond that of typical reactive astrocytes, and develop several forms of cell stress. However, how stressed astrocytes cause the loss of myelin in this disease is unknown. In this work I have conducted a largely immunohistological investigation of AxD patient tissue, model mice, and primary astrocytes cultured from the AxD model mice, focusing on factors that might provide insight into the pathological manifestations of AxD and paying particular attention to those factors which might contribute to de/dysmyelination. To gain insight on the morphological transformation of astrocytes in AxD, I analyzed GFAP in the hippocampus of the most severely affected AxD mouse. Astrocytes in these mice lose their star-like shape, and become hypertrophic and often multinucleated. They accumulate large amounts of GFAP. Subsequent study of primary cultured astrocytes from AxD mice revealed that these cells have perinuclear inclusions of GFAP surrounded by displaced microtubules and displaced Golgi. I next investigated another mechanism of stress that may affect astrocyte function in AxD. Work in our lab and others' has demonstrated proteasomal inhibition in AxD astrocytes. Because the unfolded protein response in the endoplasmic reticulum (ER) can be enacted by proteasomal inhibition, I examined the immunohistochemical expression of two proteins commonly increased under conditions of ER stress. We found BIP/Grp78, an ER chaperone, increased in AxD patient astrocytes and model mice. Additionally, the CCAAT enhancer binding protein homologous protein (CHOP) was expressed by a small subset of astrocytes in the AxD mouse hippocampus, unveiling ER stress as a potential contributory factor in AxD pathology. Work in other labs has found iron in astrocytes in AxD model mice. To further elucidate mechanisms of cellular stress in AxD, I conducted an immunohistochemical analysis of iron and several regulatory proteins in AxD patients and found, by enhanced Perls' staining, Fe3+ in Rosenthal fibers and iron and ferritin accumulated in astrocytes. This finding is in marked contrast to what one sees in the normal CNS, with little staining of astrocytes, and easily detectable staining of oligodendrocytes. Finally, I examined the localization of the cell surface glycoprotein CD44, along with several related proteins, including its ligand hyaluronan. I found CD44 protein expression greatly increased in the white matter, cortex and hippocampus of AxD patients and in the hippocampus of AxD mice. Additionally, through use of a biotinylated hyaluronan binding protein, I found abnormally high levels of hyaluronan in the hippocampus of AxD mice in the same areas where increases in CD44 were found. Work elsewhere has found CD44 and hyaluronan in other disorders that affect myelination, and experiments have revealed an inhibitory effect of hyaluronan on oligodendrocyte development and myelination. The studies in this thesis contribute novel stressors to the list of those that impact astrocytes in AxD and, in particular, suggest the accumulation of iron in astrocytes as potentially important to the pathological manifestations of AxD. Additionally, my research has revealed dramatic increases in the expression of CD44 in AxD astrocytes which, in conjunction with widespread increases in hyaluronan, may be critical to understanding the mechanisms underlying the de/dysmyelination that occur in this disease

Boundaries Around Common Ground: Strategies In Supervision Of International Doctoral Candidates

Within critical fiscal and social gains of diversity in hosting International Doctoral (ID) Candidates, it is important to explore boundaries around the successful outcomes related to these cohorts. Interestingly, despite this significant field, little systematic research has been published on the teaching practices of supervisors in the ID context. Set with transition research, the paper identifies the central role of supervisory practices in bounding effective transition of ID candidates. Based on data from several sources including an extensive review of literature, qualitative interviews with International Doctorates (n= 26) and a series of supervisors‘ workshops; key strategies for establishing ‗common ground‘ between ID candidates and supervisors are recommended. The findings will be of direct interest within host institutions particularly for professional development of new or experienced supervisors and Doctoral Candidates‘ for perspective on the supervisor‘s role

A study of 300 drop-outs of the junior and senior high schools of Worcester.

Thesis (Ed.M.)--Boston Universit

Indigenous child care - leading the way

We believe that the Australian early childhood sector is not performing well. The incidence of poor outcomes for children is increasing, and we believe that current service delivery is not capable of addressing this. We argue that, as a sector, there is an abundance of evidence of the kinds of programs and initiatives that could address our national concerns, and review some of that evidence. We also point out that there is considerable knowledge in Australia, based on Australian programmes and experience, that can be used to build a different early childhood sector with the potential to significantly impact on growing disadvantage. We conclude with the principles or themes around which such initiatives should be developed and a call to advocate for the development of such services. Appropriate services supporting all of our young children, their families and their communities, have the potential to make a huge impact on our society, and we can no longer hide from our responsibilities and avoid providing such services

Volumetric growth rates of meningioma and its correlation with histological diagnosis and clinical outcome: a systematic review.

INTRODUCTION: Tumour growth has been used to successfully predict progression-free survival in low-grade glioma. This systematic review sought to establish the evidence base regarding the correlation of volumetric growth rates with histological diagnosis and potential to predict clinical outcome in patients with meningioma. METHODS: This systematic review was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Databases were searched for full text English articles analysing volumetric growth rates in patients with a meningioma. RESULTS: Four retrospective cohort studies were accepted, demonstrating limited evidence of significantly different tumour doubling rates and shapes of growth curves between benign and atypical meningiomas. Heterogeneity of patient characteristics and timing of volumetric assessment, both pre- and post-operatively, limited pooled analysis of the data. No studies performed statistical analysis to demonstrate the clinical utility of growth rates in predicting clinical outcome. CONCLUSION: This systematic review provides limited evidence in support of the use of volumetric growth rates in meningioma to predict histological diagnosis and clinical outcome to guide future monitoring and treatment

Glycemia Is Related to Impaired Cerebrovascular Autoregulation after Severe Pediatric Traumatic Brain Injury: A Retrospective Observational Study

Introduction: A strong association exists between hyperglycaemia and outcome in paediatric traumatic brain injury (TBI). Herein we describe observations of serum markers of glucose metabolism in a cohort of paediatric TBI patients and how these variables are related to parameters of intracranial pathophysiology. Methods: A retrospective analysis was performed on paediatric severe traumatic brain injury patients admitted to Addenbrookes Hospital Paediatric Intensive Care Unit (PICU) between January 2001 and December 2013. Demographic, outcome, systemic physiological, and cerebral autoregulatory data were extracted for patients who had received continuous invasive monitoring (ICM+, Cambridge Enterprise, Cambridge, UK). Data were analysed using a mixed linear model. Results: Forty-four patients with an average age of 12.2 years were admitted to the Paediatric Intensive Care Unit with a TBI requiring invasive neurosurgical monitoring. Thirty-two patients (73%) survived, with favourable outcomes in 62%. The mean (SD) intracranial pressure (ICP) was 17.6+9.0 mmHg, MAP was 89.7+9.0 mmHg and PRx was -0.01+0.23 a.u. The mean (SD) serum lactate was 2.2 (3.3) mmol/L. and the mean (SD) serum glucose was 6.1 (1.6) mmol/L. Early hyperglycaemia was strongly associated with both PRx (Pearson correlation 0.351, p <0.001) & ICP ((Pearson correlation 0.240, p = 0.002) death (p=0.021) and impaired cerebral autoregulation (p = 0.02). There was a strong association between ICP and serum lactate (p = 0.001). Conclusion: Increases in systemic glucose are associated with impaired cerebrovasular autoregulation after severe paediatric TBI. Moreover, deranged blood glucose is a marker of poor prognosis. Further studies are required to delineate putative mechanisms of hyperglycaemia induced cerebral harm.We gratefully acknowledge financial support as follows. Research support: the Medical Research Council (MRC, Grant Nos. G0600986 ID79068 and G1002277 ID98489) and the National Institute for Health Research Biomedical Research Centre (NIHR BRC) Cambridge (Neuroscience Theme; Brain Injury and Repair Theme). Authors’ support: PH—NIHR Research Professorship, Academy of Medical Sciences/Health Foundation Senior Surgical Scientist Fellowship and NIHR Cambridge BRC. AY is supported by an NIHR Academic Clinical Fellowship. JD is supported by a Woolf Fisher Scholarship

Demonstration of Niobium Tin in 218 MHz Low-beta Quarter Wave Accelerator Cavity

A 218 MHz quarter wave niobium cavity has been fabricated for the purpose of demonstrating Nb3Sn technology on a low-beta accelerator cavity. Niobiumtin has been established as a promising next generation SRF material, but development has focused primarily in high-beta elliptical cell cavities. This material has a significantly higher TC than niobium, allowing for design of higher frequency quarter wave cavities (that are subsequently smaller) as well as for significantly lowered cooling requirements (possibly leading to cryocooler based designs). The fabrication, initial cold testing, and Nb3Sn coating are discussed as well as test plans and details of future applications.Comment: 21st Intl Conf Radio Frequency Superconductivity (SRF 2023

Neutral perfect fluids of Majumdar-type in general relativity

We consider the extension of the Majumdar-type class of static solutions for the Einstein-Maxwell equations, proposed by Ida to include charged perfect fluid sources. We impose the equation of state $\rho+3p=0$ and discuss spherically symmetric solutions for the linear potential equation satisfied by the metric. In this particular case the fluid charge density vanishes and we locate the arising neutral perfect fluid in the intermediate region defined by two thin shells with respective charges $Q$ and $-Q$. With its innermost flat and external (Schwarzschild) asymptotically flat spacetime regions, the resultant condenser-like geometries resemble solutions discussed by Cohen and Cohen in a different context. We explore this relationship and point out an exotic gravitational property of our neutral perfect fluid. We mention possible continuations of this study to embrace non-spherically symmetric situations and higher dimensional spacetimes.Comment: 9 page

Dyspnea affective response: comparing COPD patients with healthy volunteers and laboratory model with activities of daily living

Background: Laboratory-induced dyspnea (breathing discomfort) in healthy subjects is widely used to study perceptual mechanisms, yet the relationship between laboratory-induced dyspnea in healthy volunteers and spontaneous dyspnea in patients with chronic lung disease is not well established. We compared affective responses to dyspnea 1) in COPD patients vs. healthy volunteers (HV) undergoing the same laboratory stimulus; 2) in COPD during laboratory dyspnea vs. during activities of daily living (ADL). Methods: We induced moderate and high dyspnea levels in 13 COPD patients and 12 HV by increasing end-tidal CO2 (PETCO2) during restricted ventilation, evoking air hunger. We used the multidimensional dyspnea profile (MDP) to measure intensity of sensory qualities (e.g., air hunger (AH) and work/effort (W/E)) as well as immediate discomfort (A1) and secondary emotions (A2). Ten of the COPD subjects also completed the MDP outside the laboratory following dyspnea evoked by ADL. Results: COPD patients and HV reported similar levels of immediate discomfort relative to sensory intensity. COPD patients and HV reported anxiety and frustration during laboratory-induced dyspnea; variation among individuals far outweighed the small differences between subject groups. COPD patients reported similar intensities of sensory qualities, discomfort, and emotions during ADL vs. during moderate laboratory dyspnea. Patients with COPD described limiting ADL to avoid greater dyspnea. Conclusions: In this pilot study, we found no evidence that a history of COPD alters the affective response to laboratory-induced dyspnea, and no difference in affective response between dyspnea evoked by this laboratory model and dyspnea evoked by ADL

Interior Weyl-type Solutions of the Einstein-Maxwell Field Equations

Static solutions of the electro-gravitational field equations exhibiting a functional relationship between the electric and gravitational potentials are studied. General results for these metrics are presented which extend previous work of Majumdar. In particular, it is shown that for any solution of the field equations exhibiting such a Weyl-type relationship, there exists a relationship between the matter density, the electric field density and the charge density. It is also found that the Majumdar condition can hold for a bounded perfect fluid only if the matter pressure vanishes (that is, charged dust). By restricting to spherically symmetric distributions of charged matter, a number of exact solutions are presented in closed form which generalise the Schwarzschild interior solution. Some of these solutions exhibit functional relations between the electric and gravitational potentials different to the quadratic one of Weyl. All the non-dust solutions are well-behaved and, by matching them to the Reissner-Nordstr\"{o}m solution, all of the constants of integration are identified in terms of the total mass, total charge and radius of the source. This is done in detail for a number of specific examples. These are also shown to satisfy the weak and strong energy conditions and many other regularity and energy conditions that may be required of any physically reasonable matter distribution.Comment: 21 pages, RevTex, to appear in General Relativity and Gravitatio