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1
Warren, C. "Human serum glycosaminoglycans in health and disease." Thesis, University of Exeter, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.353990.
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McCarthy, Davis James. "Genomic variation in human health and disease." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:7675c27e-43fa-42e2-8932-bbca2e4e0b77.
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Understanding the structure and function of genomic variation within and be- tween individuals will be crucial for the translation of genomics into improved health and clinical outcomes. This thesis addresses current issues around the study of genomic variation in that context. Variant annotation is a vital step in the analysis of whole-genome and whole- exome sequence data. I compared variant annotations for 80 million variants from a clinically-focused whole-genome sequencing study, obtaining annotations with two different sets of transcripts and two different software tools. I found that choice of transcripts and choice of software both have a large effect on variant annotation. The extent of discrepancy in annotations has implications for all research that relies on variant annotation, especially as we try to use whole-genome sequencing in the clinic. Type 2 diabetes (T2D) is a common, complex genetic disease imposing a large global health burden. Although over 80 genomic loci have been associated with increased risk for T2D, many questions remain about the genomic architecture of the disease. I used 11 million rare, low-frequency and common single-nucleotide variants obtained from whole-genome sequence data from 2,657 individuals with and without T2D to assess the contributions of different classes of genomic variation to T2D susceptibility. Using linear mixed model methods and variance partitioning approaches I characterised contributions from variants in different allele frequency classes. Partitioning variance into different functional classes revealed significant four-fold enrichment (P < 0.01) for variants in enhancer regions identified in pancreatic islet cells and significant depletion for variants without any functional annotation (P < 0.01). Single-cell RNA-sequencing (scRNA-seq) technologies are rapidly gaining traction to interrogate transcriptomic heterogeneity across individual cells. How- ever, raw scRNA-seq data require a large amount of processing to obtain a clean, tidy dataset ready for statistical modeling. I have developed a new, self- contained R software package, SCATER, to fill the niche between raw scRNA-seq data and downstream analysis. The package streamlines the pre-processing, quality control and data normalisation procedures while enabling flexible ways to visualise data and integration with other scRNA-seq analysis tools.
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Lindberg, Mathilda. "The human gastric microbiota in health and disease." Stockholm, 2010. http://diss.kib.ki.se/2010/978-91-7409-859-4/.
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Bahubeshi, Mohamed-Amin. "Germline DICER1 mutations in human disease." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=104870.
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The DICER1 gene, which codes for a protein of the same name, is vital to the production of microRNA. As small ~20nt fragments of RNA, microRNAs alter gene expression post-transcriptionally by directly binding to mRNA and affecting translation. Current estimates suggest that expression of 30-70% of all protein-coding genes is modified by microRNA activity.Germline DICER1 mutations have recently been associated with cases of pleuropulmonary blastoma, a childhood lung tumor. We have discovered germline DICER1 mutations to be associated with other diseases by identifying mutations in nearly 60 individuals within 15 different families and across 7 different disease phenotypes. These include cases of pleuropulmonary blastoma, cystic nephroma - a benign kidney tumor, and Wilms tumor - the malignant version of cystic nephroma. Furthermore, we have identified DICER1 mutations in several families with Sertoli-Leydig cell tumor (SLCT) - a rare, androgen producing cancer of the ovaries, and multinodular goiter (MNG) - a relatively common thyroid hyperplasia. We have demonstrated that DICER1 is the genetic link between SLCT and MNG first hypothesized in 1974 by Fraumeni and colleagues. Also, we have identified DICER1 to be the gene of the MNG1 locus at 14q32, which was first pinpointed to this region in 1997 and identified in several MNG families. We further expanded the disease phenotype associated with DICER1 mutation to include cervical embryonal rhabdomyosarcoma.While DICER1 is a postulated to be a human tumor suppressor gene, we found no evidence of loss of heterozygosity in tumor DNA, a finding supported by recent evidence that DICER1 is a tumor suppressor with unique characteristics. Profiling of miRNA in affected cells showed significant differences in expression of miRNAs compared to controls. We demonstrate that DICER1 mutations are associated with diseases other than pleuropulmonary blastoma, an unsurprising revelation when the far-reaching implications of microRNA production are considered. These developments may be utilized in future therapeutic endeavors and for screening of families which present with a similar array of disease.<br>Le gène DICER1, qui code pour la protéine du même nom, est essentiel pour la production de microARNs. Ceux-ci étant aussi courts que 20 nucléotides, modifient l'expression des gènes ciblés en phase de posttranscription en se liant directement aux mARNs et en conséquences affectant leur translation. Présentement, on estime que l'expression de 30 à 70% de tous les gènes qui codent pour une protéine sont modifiés par des microARNs. Récemment, 60 à 70% de tous les cas de blastomes pleuropulmonaires, tumeurs pulmonaires infantiles, ont été associés à des mutations germinales de DICER1. Nous avons découvert que des mutations germinales de DICER1 sont impliquées dans un tableau de maladies en identifiant des mutations dans 60 personnes provenant de 15 familles différentes, ayant 7 phénotypes de maladies différents. Ceux-ci incluent des cas de blastomes pleuropulmonaires, de néphromes kystiques – des tumeurs rénales bénignes, et des tumeurs de Wilms – une forme maligne de la néphrome kystique. Par ailleurs, nous avons identifié des mutations de DICER1 dans plusieurs familles affectées par des tumeurs de cellules Sertoli-Leydig (TCSL) – un cancer rare de l'ovaire produisant de l'androgen, et la goitre multinodulaire (GMN) - une hyperplasie relativement fréquente de la thyroïde. Nous avons demontré que DICER1 est le lien entre TCSL et GMN ce qui a été suggéré en 1974 par Fraumeni et ses collegues. Nous avons également identifié que le gène MNG1 au locus 14q32 est DICER1. Cette région était découverte en 1997 dans plusieurs familles avec GMN. Nous avons élargi le phénotype des maladies associées avec DICER1, et ajouté le rhabdomyosarcome embryonnaire cervical à la liste. Quoique DICER1 est un gène suppresseur de tumeur, nous n'avons pas trouvé une preuve de la perte d'hétérozygotie dans l'ADN des tumeurs testées. Ceci est validé par des preuves récentes que DICER1 est un gène suppresseur de tumeur à caractère unique. L'expression des microARNs dans les cellules cancéreuses était significativement différente de celui observée dans les cellules normales. Nous avons démontré que les mutations de DICER1 sont associées à des maladies variées, une découverte pas très surprenante considérant son rôle de grande envergure dans la production de microARNs. Ces développements peuvent être utilisés dans de futurs efforts thérapeutiques et pour le dépistage des familles avec des maladies semblables.
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Dědová, Tereza [Verfasser]. "Human serum glycome in health and disease / Tereza Dědová." Berlin : Freie Universität Berlin, 2019. http://d-nb.info/1185486046/34.
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Griffiths, Natalie. "Neisseria meningitidis-human cell interactions in health and disease." Thesis, University of Bristol, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.690035.
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For human commensal Neisseria meningitidis (Nm) to initiate the pathology of which it is capable it must be able to cross cellular barriers, and once crossed, survive in the blood. It has been established by several studies that susceptibility to infection by Nm increases markedly following viral infection. A potential causative mechanism for this observed temporal effect may include the upregulation of bacterial receptors on host cells in response to virallyinduced cytokines. The initial part of the study presented aims to clarify the effect of inflammatory cytokines in upregulating epithelial receptors targeted by Nm. Results demonstrated that treatment of epithelial monolayers with IFN-V led to de novo synthesis of major Opa receptor, CEACAM1, which in turn, led to increased invasion of host cells by capsulate Opa-expressing bacteria. This is dependent on the activation of Nuclear factor-kappa B (NFKB) as demonstrated by the abrogation of infiltration in the presence of NFKB inhibitors. Once the bacterium has invaded the epithelial layer, the next step in pathogenesis is traversing the endothelial barrier of the host vasculature. Vitronectin (Vn) has been implicated previously in mediating adhesion to and invasion of human brain microvascular endothelial cells (HBMEC) by Opc-expressing Nm. The aim of the second part of the study was to investigate the nature of the Opc-Vn interaction. The data demonstrated that Opc-expressing Nm preferentially bind directly to the activated form of human Vn (aVn) in which sulphotyrosines YS6 and YS9 are exposed. Accordingly, cell association and invasion was abrogated in the presence of both sulphated Vn peptide spanning residues 43-68 and conformation-dependent antibody 8E6 binding at this site. Monomeric preparations of native Vn were also unable to support endothelial interactions with Nm. A second, lower affinity interaction was also observed in the presence of heparin with data indicating that the same region of Opc is responsible for both interactions.
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Malone, Paul. "Biomechanics of the human forearm in health and disease." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/biomechanics-of-the-humanforearm-in-health-and-disease(12bb39a6-3777-4ff0-899a-9a0baf2a8fcc).html.
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Introduction: The forearm is a complex biological unit, which has allowed man's evolution. This PhD commenced with an analysis of the normal biomechanical functioning of the key components of the forearm: notably the distal radioulnar joint (DRUJ), interosseous ligament (IOL) and proximal radioulnar joint (PRUJ). Understanding normal forearm physiology, a clinical study followed to delineate the pathophysiology of a new clinical entity, related to DRUJ dysfunction. Methods: Biomechanical Study: A biomechanical testing jig was developed to facilitate collection of data about normal functioning of the DRUJ, IOL and PRUJ in both unloaded and loaded states. This permitted testing throughout the range of forearm pronosupination. Thawed fresh frozen cadaveric upperlimbs were mounted into the jig. Using Microstrain® strain gauges and Tekscan™ pressure sensors, the functional anatomy of the key components of the forearm was delineated, both with the forearm flexed at 90° and maximally extended at the elbow. Clinical Study: A series of 3-Tesla MRI scans was undertaken on patients symptomatic of an intermittent ulnar neuropathy. The causative pathophysiology was determined using 3D qualitative and quantitative analyses. Results: Biomechanical Study: Reproducible patterns of force transmitted and joint contact area have been determined for the DRUJ, and for the first time, the PRUJ. With the exception of PMax and P60 for the PRUJ, application of load increases contact areas and transmitted forces across the joints (P<0.05). The converse is true for PMax and P60 in the PRUJ. The IOL is lax during pronation, strain gradually increasing as the arm moves to neutral. In neutral the middle-portion of the IOL (m-IOL) demonstrates most strain, this decreasing again in supination, whilst the distal and proximal portions (d- & p-IOL) exhibit more strain (P<0.05). Axial loading consistently increases strain in all ligaments (P<0.05). Observed behaviour patterns across the joints and in the ligaments alter with elbow extension (P<0.05). Clinical Study: Salient symptoms of the new syndrome were described. Displacement of the ulnar nerve from its normal course was seen with compression/distraction in the distal forearm and Guyon’s canal. This was considered causative of the syndrome. As a by-product of the research, a new clinical device was also developed, which improves the patient pathway when investigating DRUJ dysfunction. Conclusions and Outcomes: This research has analysed normal forearm biomechanics determining that the PRUJ is a load-bearing joint, interrelated with the DRUJ and IOL. Elbow extension has been shown to alter the normal biomechanics of the forearm. A clinical entity of a dysfunctional forearm has been defined, called subluxation-related ulnar neuropathy or SUN syndrome. Finally, a new clinical device has been developed, which it is anticipated will translate into visible improvements in patient care.
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Boxall, John David. "Migration of human tympanic epithelium in health and disease." Thesis, Open University, 1999. http://oro.open.ac.uk/54162/.
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Emery, Maurice George. "Aspects of human CYP 2E1 regulation in health and disease /." Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/7943.
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Adam, Elizabeth. "Morphological and functional glycobiological analysis of human airway cilia in health and disease." Thesis, University of Southampton, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246227.
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Senthilmohan, Tharmalingam. "The role of human alpha-2-macroglobulin in health and disease." Thesis, University of Sussex, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362274.
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Bacon, Caragh Rebecca. "The endothelin system in human contractile tissues in health and disease." Thesis, University of Cambridge, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.344041.
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Lin, Wey-Ran. "Tracing cell lineages in health and disease : experimental and human studies." Thesis, Queen Mary, University of London, 2010. http://qmro.qmul.ac.uk/xmlui/handle/123456789/556.
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This study aimed to investigate stem cell biology in the normal and diseased pancreas and liver employing robust methods for tracking stem cells and their progeny in both pre-clinical and human scenario. Bone marrow (BM) plasticity had been demonstrated in diseased organ remodelling. By detection of the Y chromosome in female mice receiving a sexmismatch BM transplantation, BM-derived cells were present in murine pancreas with cerulein-induced pancreatitis. BM-derived myofibroblasts functionally contributed to around 8% of the total population of myofibroblasts, the cells with a key fibrogenic role. Fibrocytes are circulating pro-fibrogenic cells; a decrease of BM-derived fibrocytes in blood and detection of these cells in areas of collagen deposition indicated they migrated to inflamed pancreas and played a role in extracellular matrix formation. IL-10 is an anti-inflammatory cytokine mainly secreted by BM; a lack of IL-10 increased the fibrosis, the inflammation and the numbers of BM-derived myofibroblasts suggesting a potential role of IL-10 in chronic pancreatitis. Mitochondrial DNA (mtDNA) mutations permit lineage tracing within human tissues. Cells having identical mtDNA mutations within a cytochrome c oxidase (CCO)- deficient area must be related having originated from a common founder cell, presumably a stem cell. I have demonstrated that regenerative nodules in cirrhotic liver are invariably clonal populations, and that these nodules often originate from progenitor cells from the abutting ductular reactions. An attempt to build a phylogenetic tree based on the accumulation of mutations in normal liver reinforced the belief that hepatic stem cells are located within the portal tract area and that their cell progeny migrate centrifugally from the portal tract region. The same techniques were applied to the pancreas, but many areas of CCO deficiency could be ascribed to autolysis, while the 3 discovery of identical mtDNA base changes within and outwith CCO-deficient patches suggested these were genetic polymorphisms, previously unreported.
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Kampoo, Kanokporn. "Bacteriological investigations of the human oral microbiota in health and disease." Thesis, University of Manchester, 2011. https://www.research.manchester.ac.uk/portal/en/theses/bacteriological-investigations-of-the-human-oral-microbiota-in-health-and-disease(d8e9433f-355d-472a-b821-40ef11b6a009).html.
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The human oral cavity harbours a diverse consortium of microoganisms which has a complex relationship with host health and disease. Dental caries for example, have mulitispecies aetiologies and analysis of the mechanisms which underlie the condition is complicated by the large portion of the oral microbiota which remain uncharacterised. In vivo studies can be problematical in terms of reproducibility, ethics and inter-individual variation; reproducible and representative in vitro models of the human oral cavity are therefore of considerable utility. This doctoral thesis presents a series of in vitro or ex vivo investigations of oral microbial ecology. In order to reproduce inter-individual variation within oral consortia, a gingival model was further validated for generating salivary microcosms. Plaques were analysed using differential viable counting, PCR-DGGE, combined with principal components analysis (PCA) and Confocal laser scanning microscopy (CLSM). Data indicated that inter-individual variation in human salivary composition could be replicated in modelled microcosms (Chapter 3). In Chapter 4, poloxamer hydrogel constructs were validated for the growth and analyses of oral biofilms. Biofilms were analysed using differential viable counting, PCR-DGGE combined with principal components analysis (PCA), Confocal laser scanning microscopy (CLSM) and pH was measured using a microelectrode. Data indicated that poloxamer can support oral bacterial growth in both single and multi species biofilms, maintain compositional stability and reproduce inter-individual variation and acidogenesis. In Chapter 5, the taxonomic composition of saliva, supragingival plaque and degraded dentine was investigated in 30 volunteers [10 healthy and 20 Type 2 diabetes mellitus (T2DM)], using culture, PCR-DGGE and cluster analysis combined with PCA. Unique PCR amplicons were sequenced for identity. Dental caries incidence was elevated in T2DM compared to healthy individuals but the oral bacterial composition in supragingival plaque between two groups was not significantly different. Salivary eubacterial profiles from T2DM patients with and without caries clustered separately. With respect to bacterial consortia associated with degraded dentine, Prevotella nigrescens, Neisseria mucosa and Streptococcus sanguinis were associated with diabetes. In order to investigate potential familial factors in oral disease aetiology, the oral microbiotas of members of 10 families [5 caries free (CF) and 5 severe early childhood caries (SECC) families] were characterised using differential viable counting, together with PCR-DGGE, cluster analysis and PCA (Chapter 6). There was a highly significant association between numbers of lactobacilli in saliva and plaque and caries experience in SECC patients. Additionally, the numbers of streptococci in dental plaque were significantly higher in SECC patients than in CF controls. Regression analysis showed that plaque index score correlated significantly with DMFT and with lactobacillus abundance in dental plaque in a highly predictive manner. However, eubacterial fingerprints did not cluster within or between CF and SECC groups and bacterial counts for the three sampling sites in SECC did not differ significantly. Numbers of anaerobes, facultative anaerobes and streptococci of parents and children were correlated. In terms of familial microbial similarities, DGGE concordance between children, their mothers and their siblings ranged between 43 percent to 73 percent, and 35 percent to 82 percent, respectively. Data indicated a possible aetiological role of lactobacilli and potentially provide novel means of prediction.
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CASTOLDI, ELISA. "ANALYSIS OF MARKERS OF DISEASE AND HEALTH STATUS ON HUMAN SKELETONS." Doctoral thesis, Università degli Studi di Milano, 2018. http://hdl.handle.net/2434/547155.
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One of the main aims of the forensic anthropological practice regards the proper identification of human remains. Years of studies and research provided many instruments for the reconstruction of the so-called “biological profile” (e.g. age at death, sex, stature, race); nevertheless, and despite the numerous information that it can provide, the pathological investigation of skeletons still displays many uncertainties. The identification of pathological signs from bones can in fact narrow the field of research in case of the recovery of unknown human remains, and can provide valuable data for the definition of a possible cause of death. However, the difficulties encountered when analyzing skeletal remains, due to taphonomic and environmental variables, non-specificity of the bone reaction and the monotony of bone tissue manifestation to stimuli, make pathological identification of diseases one of the most difficult fields of forensic anthropology. The aim of this research project is that of trying to narrow and clarify some aspects of skeletal pathology and forensic anthropology, by analyzing skeletons from three cemeteries of Milan, which are part of the Milano Cemetery Skeletal Collection. The main feature of this collection regards the availability, for many of its individuals, of ISTAT death certificates that make the observers aware of the main cause of death and related pathological conditions of such subjects. After collecting this information the attention then focused on the macroscopic investigation of specific pathologies, those that were more widespread in the available sample, to include: cancer metastases, diabetes, Cardiovascular Disease (CVD) and Human Immunodeficiency Virus (HIV) related to drug abuse. The skeletons of this research were selected and cleaned in a proper way; subsequently, the specific pathologic investigation was carried on after an accurate literature search, aimed at finding the most characteristic features that permit the correct identification of the pathology from bones. The analyses performed allowed the demonstration of the difficulties encountered in unequivocally describe and identify such diseases, despite the previous studies conducted, mainly due to the aspecific and often altered structures acquired by the stimulated areas on bones. The modifications caused by taphonomy, together with the subjectivity of the responses and the paucity of available reference data made the investigation quite difficult. However, the available causes of death permitted a baseline to better understand the observations in identifying and describing pathologic-related skeletal lesions, and to set the basis for a more detailed and comprehensive macroscopic pathologic investigation. Such macroscopic investigation, however, has it limits, as it can not go over a certain level of certainty; for this reason, additional investigation methods (such as x-rays, biochemistry, histology and so on) or additional antemortem data are necessary for increasing the amount of information we can gain from the examination of bare skeleton.
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Bonnin, Edith. "Elucidating the Functional Role of Human Nucleoporin Nup88 in Health and Disease." Doctoral thesis, Universite Libre de Bruxelles, 2018. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/268017.
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Movement is a prerequisite for normal fetal development and growth. Intrauterine movement restrictions cause a broad spectrum of disorders in which the unifying feature is a reduction or lack of fetal movement, giving rise to the term fetal akinesia deformations sequence (FADS [OMIM 208150]). FADS corresponds to a clinically and genetically heterogeneous constellation of properties and is characterized by multiple joint contractures, facial abnormalities, and lung hypoplasia as a result of the decreased in utero movement of the fetuses. Affected babies are often prematurely and stillborn, and those born alive typically die within minutes or hours after birth. The genetic causes for this fatal disorder are ill-defined as a genetic diagnosis is rarely executed, but mutations in three genes, namely RAPSN, DOK7, and MUSK, as well as in the subunits of the muscular nicotinic acetylcholine receptor (AChR) have been described. These mutations are thought to affect neuromuscular junctions, although this has not been proven experimentally.The nucleoporin NUP88 is a constituent of the nuclear pore complex (NPC), the gate for all trafficking between the nucleus and the cytoplasm. NUP88 resides on both the cytoplasmic and the nuclear side of NPCs, and it is found in two distinct subcomplexes. It associates with NUP214 and NUP62 on the cytoplasmic face, while on the nuclear side NUP88 binds NUP98 and the intermediate filament protein lamin A. The NUP88-NUP214-NUP62 complex plays an essential role in the nuclear export of a subset of proteins and pre-ribosomes, which is mediated by the nuclear export receptor CRM1. NUP88 in particular somewhat participates in the nuclear export of NF-κB proteins in a CRM1-dependent manner. Moreover, NUP88 is frequently overexpressed in a variety of human cancers, and its role in cancer appears linked to the deregulation of the anaphase-promoting complex. Here, we report the first Mendelian disorders caused by mutations in NUP88 and with that the first lethal developmental human disease due to mutations in a nuclear pore component. We demonstrate that biallelic mutations in NUP88 are likely to cause fetal akinesia of the Pena-Shokeir subtype. We confirm in zebrafish that loss of NUP88 impairs movement and the mutations identified in the affected individuals resemble a loss-of-function phenotype. We show that loss of NUP88 affects expression and localization of rapsyn, the protein encoded by RAPSN, in human and mouse cell lines, and patient samples. Consistent with altered rapsyn, AChR clustering and neuromuscular junction formation in zebrafish are abnormal. We therefore propose that defective NUP88 function cause FADS by affecting neuromuscular junction formation.Keywords: Nuclear pore complex, NUP88, Fetal Akinesia Deformation Sequence, rapsyn, acetylcholine receptor clustering, synaptic transmission, fetal development, inherited developmental disorder.<br>Doctorat en Sciences<br>info:eu-repo/semantics/nonPublished
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Bictash, Magna Nabil. "Chemometric and Spectroscopic Analysis of the Human Metabolome in Health and Disease." Thesis, Imperial College London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.503846.
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Marsden, Jonathan Frank. "Oscillatory activity in the human motor system in health and neurological disease." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393889.
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Warburton, Richard. "A microbiological assessment of the human biliary tract in health and disease." Thesis, University of East Anglia, 2017. https://ueaeprints.uea.ac.uk/67133/.
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The gastrointestinal tract in humans is home to 100 trillion bacteria, collectively referred to as the gut microbiota. This ‘bacterial organ’ has a vital role to play in both health and disease. Conventional wisdom dictates that bile in normal biliary systems is sterile. However, the liver is continually exposed to gut bacteria and their metabolites via the portal vein. Recent studies have identified bacterial populations within the biliary system of symptomatic patients undergoing cholecystectomy or biliary intervention. In this study we identified that there is a complex biliary microbiota within a normal biliary tract. Many bacterial species were isolated from the bile of patients undergoing hepatic resection or cholecystectomy and their identity established through sequencing their 16S ribosomal RNA gene. These included Staphylococcus, Micrococcus, Enterococcus and Bacillus sp. Isolated bacteria were examined for their resistance to bile salts and the results suggested that all the isolates were able to survive under physiologically relevant bile concentrations with some isolates expressing bile salt hydrolase activity. An in-depth analysis of the biliary microbiome using 16S-based metataxonomics was performed. Results suggested that human bile has a diverse and varied microbiota, a large proportion of which were unculturable. 34 different genera were identified with Pseudomonas being the most prevalent. Dysbiosis was noted between diseased (e.g. gallstone and biliary obstruction) and normal samples. The gut microbiota of the two most common chronic biliary conditions, Primary Sclerosing Cholangits and Primary Biliary Cholangitis, were also examined to see if dysbiosis was present. There is an emerging dysbiosis in patients with chronic cholestatic liver disease, although these results were possibly restricted through patient treatment with ursodeoxycholic acid. This study is the first to describe a complex biliary microbiota in normal human bile and in the future a detailed understanding of the function of this microbiota may provide a therapeutic target for biliary disease.
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Wilson, Heather Christine. "The biology and behaviour of human oligodendrocyte precursors in health and disease." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.615787.
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Sylvester, R. J. "The interaction between human vision and eye movements in health and disease." Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/19431/.
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Human motor behaviour depends on the successful integration of vision and eye movements. Many studies have investigated neural correlates of visual processing in humans, but typically with the eyes stationary and fixated centrally. Similarly, many studies have sought to characterise which brain areas are responsible for oculomotor control, but generally in the absence of visual stimulation. The few studies to explicitly study the interaction between visual perception and eye movements suggest strong influences of both static and dynamic eye position on visual processing and modulation of oculomotor structures by properties of visual stimuli. However, the neural mechanisms underlying these interactions are poorly understood. This thesis uses a range of fMRI methodologies such as retinotopic mapping, multivariate analsyis techniques, dynamic causal modelling and ultra high resolution imaging to examine the interactions between the oculomotor and visual systems in the normal human brain. The results of the experiments presented in this thesis demonstrate that oculomotor behaviour has complex effects on activity in visual areas, while spatial properites of visual stimuli modify activity in oculomotor areas. Specifically, responses in the lateral geniculate nucleus and early cortical visual areas are modulated by saccadic eye movements (a process potentially mediated by the frontal eye fields) and by changes in static eye position. Additionally, responses in oculomotor structures such as the superior colliculus are biased for visual stimuli presented in the temporal rather than nasal hemifield. These findings reveal that although the visual and oculomotor systems are spatially segregated in the brain, they show a high degree of integration at the neural level. This is consistent with our everyday experience of the visual world where frequent eye movements do not lead to disruption of visual continuity and visual information is seamlessly transformed into motor behaviour.
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Chung, Jae-Hoon. "Regulation of Human Cardiac Muscle Contraction and Relaxation in Health and Disease." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1522851185767187.
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Mukherjee, Chiranjit. "High Resolution Characterization of the Human Oral Microbiome in Health and Disease." The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1574678346902957.
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Bro, Viktor. "Volterra modeling of the human smooth pursuit system in health and disease." Licentiate thesis, Uppsala universitet, Avdelningen för systemteknik, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-385951.
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This thesis treats the identification of Volterra models of the human smooth pursuit system from eye-tracking data. Smooth pursuit movements are gaze movements used in tracking of moving targets and controlled by a complex biological network involving the eyes and brain. Because of the neural control of smooth pursuit, these movements are affected by a number of neurological and mental conditions, such as Parkinson's disease. Therefore, by constructing mathematical models of the smooth pursuit system from eye-tracking data of the patient, it may be possible to identify symptoms of the disease and quantify them. While the smooth pursuit dynamics are typically linear in healthy subjects, this is not necessarily true in disease or under influence of drugs. The Volterra model is a classical black-box model for dynamical systems with smooth nonlinearities that does not require much a priori information about the plant and thus suitable for modeling the smooth pursuit system. The contribution of this thesis is mainly covered by the four appended papers. Papers I–III treat the problem of reducing the number of parameters in Volterra models with the kernels parametrized in Laguerre functional basis (Volterra–Laguerre models), when utilizing them to capture the signal form of smooth pursuit movements. Specifically, a Volterra–Laguerre model is obtained by means of sparse estimation and principal component analysis in Paper I, and a Wiener model approach is used in Paper II. In Paper III, the same model as in Paper I is considered to examine the feasibility of smooth pursuit eye tracking for biometric purposes. Paper IV is concerned with a Volterra–Laguerre model that includes an explicit time delay. An approach to the joint estimation of the time delay and the finite-dimensional part of the Volterra model is proposed and applied to time-delay compensation in eye-tracking data.
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Mancini, Andrea. "Microbiota modulation in human health and disease: focus on the gut:liver:brain axis." Doctoral thesis, country:IT, 2017. http://hdl.handle.net/10449/38920.
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Intestinal microbiota dysbiosis and modification of intestinal permeability leading to bacterial translocation, have been implicated in the development of numerous liver diseases or worsening of hepatic disorders, such as cirrhosis, portal hypertension, hepatic encephalopathy (HE) and acute-on-chronic-liver failure. There is strong evidence that the pathogenesis of cirrhosis and HE is linked to a dysbiotic gut microbiota and accumulation of microbial by-products, such as ammonia, indoles, oxindoles and endotoxins, which the liver fails to detoxify. Indeed, current main line clinical treatments target microbiota dysbiosis by decreasing numbers of pathogenic bacteria and reducing blood endotoxemia and ammonia levels. Despite the large amount of existing data, there is still a need to study in more detail the composition and the metabolic output of the gut microbiota and its crosstalk with host physiological function in liver failure associated HE.
Aim of this thesis was to investigate the microbiota effects of the main current therapies used in clinical practice to treat HE. Impact of a prebiotic (lactulose), a probiotic (VLS#3) and an antibiotic (rifaximin) to modulate the gut microbiotia of cirrhotic patients both in terms of composition and metabolic output was investigated using pH controlled anaerobic batch cultures. Combining high-throughput Illumina sequencing of V3-V4 16S rRNA region, Fluorescent In Situ Hybridization coupled with flow cytometry and GC-MS, changes in faecal microbiota composition and metabolic output were measured. Significant metabolic rather than microbial changes were observed. Short chain fatty acids (acetate, propionate and acetate) production was promoted over time by lactulose and lactulose plus VSL#3 treatment and this increase was accompanied by a concomitant reduction of ammonia level and an increase in bifidobacteria. Rifaximin and its combination with lactulose was able to strongly reduce Streptococcaceae abundance, a known hallmark of cirrhotic dysbiosis, and concomitantly increase of Bifidobacteriales. Moreover I investigated how the use of VSL#3 impacted on the microbiota of paediatric patients and young adults affected by portal vein hypertension and minimal HE. VSL#3 supplementation resulted in a trend toward improved cognitive function and patients wellbeing. A trend towards an increased relative abundance in Actinobacteria and a 2 concomitant decrease in Bacteroidetes, known to be overabundant in HE dysbiosis, was observed . The results suggested also a slight increase in Ruminococcus and Faecalibacterium abundance. Indeed the data suggest an amelioration of dysbiotic condition by VSL#3 that could evolve in a decreased severity of cirrhosis progression. However, as the current pilot study was limited by sample size, these observation await confirmation in an adequately powered clinical trial. In an effort to design more efficacious microbiota modulatory tools, I also characterized a Lactobacillus brevis strain isolated from an alpine traditional cheese for its potential as a next-generation probiotics thanks to its ability to produce and secrete high amounts of the neurotransmitter γ-aminobutyric acid (GABA). Lb. brevis FEM 1874 was able to efficiently convert glutamate to GABA by the increased expression of the GAD operon genes resulting in high GABA accumulation in the culture medium. Moreover, FEM 1874 proved resistant to acidic pH, pancreatic fluids and bile acids, good indicators for probiotic survival in the gastro-intestinal tract. FEM 1874 was also able to ferment prebiotic fibres indicating the potential of using a synbiotic formulation targeting the gut:brain axis.
Overall, the research herein showed the potential of microbiota modulatory formulations to target the dysbiosis related to gut:liver:brain axis disruption in liver disease and inducing metabolic changes capable of ameliorating related clinical symptoms.
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Chávez-Ramos, Marcelo, César V. Munayco, and Gabriela Soto-Cabezas. "Characteristics of tuberculosis disease in health science students in Peru." Instituto Nacional de Salud, 2018. http://hdl.handle.net/10757/624645.
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Curtis, Maurice A. "Neural progenitor cells in the Huntington's Disease human brain." Thesis, University of Auckland, 2004. http://hdl.handle.net/2292/3114.
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The recent demonstration of endogenous progenitor cells in the adult mammalian brain raises the exciting possibility that these undifferentiated cells may be able to generate new neurons for cell replacement in diseases such as Huntington's disease (HD). Previous studies have shown that neural stem cells in the rodent brain subependymal layer (SEL), adjacent to the caudate nucleus, proliferate and differentiate into neurons and glial cells but no previous study has characterised the human SEL or shown neurogenesis in the diseased human brain. In this study, histochemical and immunohistochemical techniques were used to demonstrate the regional anatomy and staining characteristics of the normal and HD brain SEL using light and laser scanning confocal microscopy. The results demonstrated that the normal and HD SEL contained migrating neuroblasts, glial cells and precursor cells but there were more of each cell type present in the HD brain, and that the increase in cell numbers correlated with HD neuropathological grade. The normal and HD SEL was stained with a proliferative marker, proliferating cell nuclear antigen (PCNA), to label dividing cells. The results showed a significant increase in the number of dividing cells in the HD brain that correlated with HD grade and with CAG repeat length. Furthermore, the results showed that neurogenesis had occurred in the SEL as evidenced by co-localisation of PCNA and the neuronal marker βIII-tubulin. Also, gliogenesis had occurred in the SEL as evidenced by the co-localisation of PCNA with the glial marker GFAP. These studies also revealed a 2.6 fold increase in the number of new neurons in the HD SEL. PCNA positive cells were distributed throughout the SEL overlying the caudate nucleus but most notably the ventral and central regions of the SEL adjacent to the caudate nucleus contained the highest number of proliferating cells. I examined the SEL for mature cell markers and demonstrated many of the same cell types that are present in the normal striatum. With the exception of neuropeptide Y (NPY) neurons, there was a reduction in the number of mature neurons in the HD SEL. The NPY neurons were more abundant in the HD SEL suggesting they play a role in progenitor cell proliferation. The results in this thesis provide evidence of increased progenitor cell proliferation and neurogenesis in the diseased adult human brain and indicate the regenerative potential of the human brain. These findings may be of major relevance to the development of therapeutic approaches in the treatment of neurodegenerative diseases.
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Sunderman, Sarah Lyn. "Chronic wasting disease in New York State exposure and its implications for human health /." Online access via UMI:, 2008.
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Brewer, Sallieann Brown. "Genital human papillomavirus: Women's knowledge and attitudes of this sexually transmitted disease." FIU Digital Commons, 1996. http://digitalcommons.fiu.edu/etd/1806.
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The purpose of this study was to investigate women's knowledge and attitudes regarding genital human papillomavirus (n=100). Using a descriptive design, the Health Education Questionnaire was administered to 100 female patients (Mean Age = 33, SD = 7.17) at a physicians office in South Florida. The results indicated a lack of knowledge regarding genital human papillomavirus with 21 patients (21%) reported having knowledge and 79 (79%) having never heard of this disease. In addition, the group familiar with genital human papillomavirus also possessed a low level of knowledge with only 57% acknowledging an association of genital human papillomavirus and cervical cancer, 52% aware that a pap smear can detect the virus, 42% knowing that antibiotics can not treat the disease and 57% aware that it is not associated with a family history. An association was found between attitudes and health seeking behaviors. Subjects stating that they would take all measures to prevent genital human papillomavirus, were more likely to have a pap smear within the last year (Chi-square (1) = 4.33, p < .05). Higher levels of education and income were associated with increased knowledge regarding genital human papillomavirus when subjects were categorized according to sociodemographic characteristic (Chi-square (1) =9.45, p < .05; Chi-square (1) = 6.75, p < .05). There was no significant correlation between knowledge and ethnicity, marital status or age. Findings indicated the need for improved education and promotion of positive attitudes regarding human papillomaviurs in order to improve health seeking behaviors among women.
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Khalatbari, Afshin. "Significance of nitric oxide metabolites in the human circulation in health and disease." Thesis, Cardiff University, 2008. http://orca.cf.ac.uk/55785/.
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In this thesis I have investigated the profile and significance of nitric oxide metabolites in two human models: 1) Across healthy human coronary and pulmonary vascular beds 2) In the peripheral venous blood from patients with type 1 diabetes mellitus. Chapters 1-3 offer a comprehensive background detailing issues of relevance to the rest of this work. Chapter 4 outlines precise methodological protocols and materials used. The results of the above clinical and laboratory studies are presented and discussed in Chapters 5 and 6. Chapter 7 attempts to summarise the results obtained, drawing together conclusions and highlighting perspectives for future research. I found that nitric oxide was dynamically metabolised across the heart and that the compartmentalisation of its metabolites between plasma and erythrocytes was driven primarily by the oxygen saturation of the blood. Study of the changes in coronary arterial diameter and flow in response to exercise and inhibition of nitric oxide generation suggested the presence of an endothelium derived hyperpolarising factor-like activity in the epicardial coronary arteries. Among patients with type 1 diabetes, blood levels of nitric oxide metabolites were generally lower compared to controls and lower in those with microvascular complications comparing to those without. Vessel relaxation experiments suggested the existence of a red blood cell-related vasodilating factor (RRVF) which was present in both diabetics and controls but exerted stronger vasodilator activity when erythrocytes from the former group were added to aortic ring preparations in a hypoxic tissue bath system ex vivo. Another novel finding was a positive correlation between this RBC-related vasodilator activity and HbAic which was stronger in that group of patients who were generally younger with shorter duration of disease.
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Collison, Matthew Geoffrey. "Human-microbiota interactions in health and disease : bioinformatics analyses of gut microbiome datasets." Thesis, University of Newcastle upon Tyne, 2018. http://hdl.handle.net/10443/4154.
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The human gut harbours a vast diversity of microbial cells, collectively known as the gut microbiota, that are crucial for human health and dysfunctional in many of the most prevalent chronic diseases. Until recently culture dependent methods limited our ability to study the microbiota in depth including the collective genomes of the microbiota, the microbiome. Advances in culture independent metagenomic sequencing technologies have since provided new insights into the microbiome and lead to a rapid expansion of data rich resources for microbiome research. These high throughput sequencing methods and large datasets provide new opportunities for research with an emphasis on bioinformatics analyses and a novel field for drug discovery through data mining. In this thesis I explore a range of metagenomics analyses to extract insights from metagenomics data and inform drug discovery in the microbiota. Firstly I survey the existing technologies and data sources available for data mining therapeutic targets. Then I analyse 16S metagenomics data combined with metabolite data from mice to investigate the treatment model of a proposed antibiotic treatment targetting the microbiota. Then I investigate the occurence frequency and diversity of proteases in metagenomics data in order to inform understanding of host-microbiota-diet interactions through protein and peptide associated glycan degradation by the gut microbiota. Finally I develop a system to facilitate the process of integrating metagenomics data for gene annotations. One of the main challenges in leveraging the scale of data availability in microbiome research is managing the data resources from microbiome studies. Through a series of analytical studies I used metagenomics data to identify community trends, to demonstrate therapeutic interventions and to do a wide scale screen for proteases that are central to human-microbiota interactions. These studies articulated the requirement for a computational framework to integrate and access metagenomics data in a reproducible way using a scalable data store. The thesis concludes explaining how data integration in microbiome research is needed to provide the insights into metagenomics data that are required for drug discovery.
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MacRitchie, Laura. "Human campylobacteriosis : elucidating the exposure, disease burden, health cost and acceptability of interventions." Thesis, University of Aberdeen, 2012. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=195982.
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Campylobacter is the most commonly reported bacterial cause of gastrointestinal disease in developed countries. Campylobacteriosis is an infectious disease that causes severe diarrhoea, abdominal cramps, vomiting, blood in stools and fever, along with the inability to carry out normal activities for an estimated 3-5 days. Long term sequelae associated with Campylobacter infection includes Guillain Barré syndrome, irritable bowel syndrome and reactive arthritis. The incidence of human campylobacteriosis in the Grampian region was 138.8 per 100,000 people in 2011 which was one of the highest incidence rates within Scotland. Identified areas of limited knowledge in Campylobacter research include: population exposure to risk factors, financial burden and public acceptability of interventions to reduce Campylobacter in the poultry process. This thesis utilises questionnaire methods to gather data from the Grampian population to expand our knowledge in these research areas to assist in the reduction of human campylobacteriosis.
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Mackenzie, Scott. "Corticosterone versus cortisol : distinct roles for endogenous glucocorticoids in human health and disease." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/15849.
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Human plasma contains cortisol (F) and corticosterone (B) at a ratio of ~10:1. B is well studied in mice and rats, which do not produce F due to absent adrenal Cyp17, but is largely neglected in humans. Differential transmembrane export of F > B by ABCB1 may account for accumulation of B in the CNS. Conversely, ABCC1, expressed in human adipose tissue, preferentially exports B>F. Here we tested the hypotheses that: (i) negative feedback suppression of the hypothalamic-pituitary-adrenal (HPA) axis is disproportionately sensitive to B; (ii) adipose tissue is disproportionately sensitive to F; and (iii) low plasma B contributes to impaired HPA axis negative feedback and increased F action in metabolic syndrome. We validated a stable isotope tracer for B in vitro and demonstrated distinct kinetics of B and F in vivo. In a randomised crossover study, we undertook ramped steady state infusion of B or F in 10 patients with Addison’s disease. Although levels of B were marginally lower than F, ACTH was similarly suppressed, and yet glucocorticoid-responsive transcripts in adipose tissue were much higher following F than B (PER1 2.2-fold and LPL 1.3-fold; p < 0.05). We assessed associations of ACTH-stimulated plasma B and F with features of metabolic syndrome in a cross-sectional study (n=279). Glucose tolerance was impaired with higher F (β=0.146, p=0.01) but lower B (β = -0.056, p = 0.05). These data support the concept of differential tissue sensitivity to B and F, whereby B suppresses the HPA axis more effectively than it induces adverse effects in adipose tissue. Enhanced CYP17 activity, causing ‘relative B deficiency’, may contribute to HPA axis activation and enhanced F action in adipose tissue in obesity. B therapy might allow control of HPA axis activation without inducing adverse metabolic effects. The ‘neglected second glucocorticoid’, corticosterone, may optimise glucocorticoid action in the human CNS, and simultaneously limit adverse metabolic effects driven by cortisol excess.
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Saviola, Francesca. "Human brain functional dynamic connectivity: challenges and potentials in health and disease studies." Doctoral thesis, Università degli studi di Trento, 2022. https://hdl.handle.net/11572/360041.
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The continuous plastic and recurring networking of the human brain subtends an inherent dynamic property of the organ. Robust evidence has described the networking between distant but functionally interrelated regions in the brain (e.g. static functional connectivity) to be linked to a variety of cognitive processes and disrupted in neurodegenerative disorders. In recent years, the neuroscientific community has grown an interest in better understanding the spatiotemporal organization of functionally interacting brain regions. When derived from restingstate functional MRI (rs-fMRI), dynamic or time-varying connectivity (TVC) estimates result from temporal fluctuation correlations of BOLD fMRI time series between brain regions. However, given the novelty of this research line, there are still various challenges involved in TVC analysis and a standardized validated approach to quantify functional brain dynamics is lacking. These challenges represent fundamental limitations that affects experimental precision and reproducibility in neuroscience studies using TVC. This Ph.D. thesis focuses on the influence of several experimental variables in functional TVC estimates and their relationship with neuro-metabolism. It also investigates novel applications of TVC in populations of healthy controls and several brain disorders, including the consideration of different MRI scanner fields
and MR protocols (functional BOLD and edited MR spectroscopy). The main work of this thesis is described in five studies. The first three studies address several open issues about TVC and its relationship to experimental variables, cognitive functions and neuro-metabolism on healthy volunteers. Study #1 shows that TVC results are critically affected by fast fMRI protocols. Study #2 shows that TVC is very sensitive to head motion and differently affected by different commonly used motion denoising strategies. Study #3 shows that changes in working memory cognitive load produce correlated changes of TVC and neurometabolism (GABA and Glutamate) in the left medial prefrontal cortex. This study
also introduces a novel experimental design that interleaves fMRI with MR spectroscopy acquisitions. The last two studies evaluate novel clinical applications of TVC. Study #4 shows that in Parkinson’s disease volunteers there are associations between subcortical structures TVC and inhibitory neurotransmission. In Study #5 we completed a
longitudinal study that evaluates post-surgery reorganization of functional networks of glioma patients, considering tumor laterality and grade. Our main findings are that removal of left lateralized tumors shows slower recovery and that the default mode network may be important to consider in presurgical planning given its role in supporting longitudinal cognitive outcome. We also show preliminary promising results of TVC’s prediction of patient's cognitive outcome and improve pre-surgical planning. Overall, this dissertation contributes novel data about the sensitivity of TVC to various experimental variables, considerations that are important when comparing studies or planning new ones. The feasibility of novel interleaved fMRI and MR spectroscopy opens the path for its use in future studies investigating BOLD and neuro-metabolite activation, in health and disease. The findings of our glioma study
have been incorporated in a public tool that is routinely used by the Neurosurgery Unit of the Santa Chiara Hospital, Trento. Future work is also proposed that may contribute towards the use of TVC for basic neuroscience and clinical research.
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BASSET, Charbel. "MOLECULAR CHAPERONES IN HUMAN SALIVARY GLANDS: HSP90 A BIOMARKER IN HEALTH AND DISEASE." Doctoral thesis, Università degli Studi di Palermo, 2022. https://hdl.handle.net/10447/564096.
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Lake, April D. "Hepatic stress response mechanisms in progressive human nonalcoholic fatty liver disease." Thesis, The University of Arizona, 2013. http://pqdtopen.proquest.com/#viewpdf?dispub=3590010.
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<p> Nonalcoholic fatty liver disease (NAFLD) has become a worldwide, chronic liver disease of increasing clinical significance. It is closely associated with the rising epidemics of obesity and insulin resistance. Up to 17% of the United States population may progress from the disease stage characterized as simple, benign steatosis to the more severe, inflammatory stage of nonalcoholic steatohepatitis (NASH). This progression occurs through 2<sup>nd</sup> 'hits' of increased oxidative stress and inflammation to a liver that has been sensitized by lipotoxic stress. NASH is also characterized by increased collagen deposition resulting in fibrosis and architectural rearrangement of the liver. Progressive NAFLD is currently recognized as an important contributor to the development of cryptogenic cirrhosis and subsequent liver-related mortalities (estimated at 30-40% in these patients). </p><p> The pathological progression of NAFLD, as described by the 'two hit' hypothesis, characterizes the different stages of liver injury. However, the mechanism(s) responsible for the progression to NASH are unknown. Profiling global gene expression and metabolite patterns in human liver samples representing the full spectrum of progressive human NAFLD may reveal potential mechanisms of progressive disease. Human liver samples representing each stage of NAFLD progression were analyzed by methodologies such as high-throughput microarrays, high resolution mass spectrometry, and protein immunoblot techniques. Bioinformatics tools and gene expression/regulation database software were utilized in several studies to characterize the altered hepatic profiles of these patients. </p><p> Hepatic transcriptomic profiles of ADME (absorption, distribution, metabolism and elimination) and ER (endoplasmic reticulum) stress response genes exhibited initiated hepatoprotective responses in patients with NASH. The endogenous pathways of BA (bile acid) synthesis and BCAA (branched chain amino acid) metabolism also showed evidence of coordinately regulated alterations in response to disease-induced stress in NASH. The transcriptional regulation of the investigated pathways was confirmed by transcription factor binding sites enrichment analysis. The collective response to hepatic stress in human NAFLD, demonstrates a coordinated, hepatoprotective intent that may be utilized for future therapeutics in the battle against progressive liver disease.</p>
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Huang, Jing-Qi. "The immunoreactive expression of neuroendocrine cells or neuroendocrine bodies in human chronic lung disease /." Thesis, McGill University, 1989. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=61879.
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Pitcher, Richard D. "Radiological progression of lung disease in Human Immunodeficiency Virus (HIV)-infected children." Doctoral thesis, University of Cape Town, 2016. http://hdl.handle.net/11427/20351.
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Introduction: There are limited data on the chest X-ray (CXR) abnormalities in human immunodeficiency virus (HIV)-infected children in low- and middle-income countries (LMIC's). Aim: To investigate the evolution of CXR abnormalities in HIV-infected children in LMIC's, to correlate this with the severity of HIV-disease, and to assess the impact of anti-retroviral therapy (ART). Method: A prospective longitudinal study evaluating clinical, immunological and radiographic parameters at regular intervals over a minimum of 24 months. CXR abnormalities were stratified by severity and deemed persistent if present for 6 consecutive months or longer. Univariate and multiple logistic regression analyses assessed associations between radiological and clinical/immunological parameters at enrolment. An ordinal multiple logistic regression model assessed the association of enrolment and time-dependent variables with CXR findings over time.
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Chiari, M. "HEALTH MONITORING OF WILDLIFE FOR THE PROTECTION OF HUMAN, LIVESTOCK AND ENVIRONMENT HEALTH." Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/246391.
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The risk of spreading pathogens among wildlife, humans and livestock is increasing in recent years. This increased risk is being driven by multiple factors related to changes in human society (e.g., mobility, recreation), animal husbandry (e.g., intensification, range farming), natural habitat (e.g., forest cover, connectivity), and climate change (e.g., mean temperature, rainfall). Until these underlying factors are addressed, it is important to carry out effective surveillance activities for early warning of disease emergence. This requires disease surveillance of not only humans and livestock, but also of the reservoir for many of these diseases: wildlife. “Wildlife reservoir” is a deceptively simple term for a complex entity. For these reasons, a target surveilance was performed in Brescia Province aimed to idenentified the possible presence of diseases selected in base of the zoonotic risk, the possible impact on domestic animals and on wild animals(bovine tuberculosis, Aujeszky disease, EBHS).The application of the recommended approach (Boadella et al. 2011; Ryser-Degiorgis 2013) let to identify zoonotic disease as M. caprae in red deer, evaluate the natural prevalence of disease with high value for domestic as Aujeszky disease in wild boar, define through modelling the epidemiological trends of wildlife specific disease as EBHS in hare and standardize a new way of sampling and analyzing blood for EBHS. From the present experiences, it’s more evident that effective wildlife disease surveillance depends on knowledge of the biological characteristics of the target populations, as well as changes in population sizes and in geographical distribution over time. Such knowledge is required in order to design appropriate sampling protocols for disease surveys, to develop disease contingency plans, to assess the risk of disease transmission to other species, and to guide wildlife management strategies in general. For these reason, three actions can help to improve knowledge on wildlife diseases and capacity to deal with their consequences on animal and human health as well as conservation: (1) extend surveillance schemes to the not yet included regions and taxa, (2) improve coordination between surveillance schemes and other wildlife monitoring and (3) promote multidisciplinary research on the relevant wildlife diseases linked with local health situation.
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Mapelli, A. "TEMPOROMANDIBULAR JOINT IN HEALTH AND DISEASE: A 3D MORPHOFUNCTIONAL ANALYSIS." Doctoral thesis, Università degli Studi di Milano, 2012. http://hdl.handle.net/2434/168395.
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Quantitative, objective and accurate evaluation of masticatory muscle activity and jaw movement is mandatory for a better understanding of the normal function and dysfunction of the stomatognathic apparatus.
A non-invasive recording protocol, integrating an electromyographic system and an optoelectronic 3D-motion analyzer, has been developed and used to perform multifactorial estimations of TMJ functioning. The masticatory system has been objectively quantified, assessing bite stability, mandibular border movements and chewing performance, in both healthy and pathologic individuals. Three separate investigations have been made.
In the first study, functional symmetries of the craniofacial complex involving the patterns of jaw movements and the activities of masticatory muscles were assessed in a control group of clinically healthy subjects. Data were evaluated separately for men and women, and a gender-related effect was tested, together with the potential influence of mandibular dimensions.
In the second study, the same complete protocol was employed to analyze the masticatory function in patients with mild-moderate temporomandibular disorders, in order to provide new insight concerning a still controversial pathology.
The aim of the third study was to assess the recovery of mandibular range of motion in border movements, focusing on the potential changes in mandibular condylar motion, analyzed in untreated patients with skeletal Class III malocclusions, and patients who had received orthognathic surgery for the correction of this dentoskeletal deformity.
The outcomes suggest that the proposed method could be a useful tool to evaluate the neuromuscular coordination during the performance of static and dynamic masticatory activities, and to detect functionally altered stomatognathic conditions.
Diagnosis of alterations of the stomatognathic apparatus, and assessment of the effects of therapy, would both profit from this quantitative approach, thus reducing the discordance among several clinical examinations.
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Jafferali, Shelina. "Insulin-like growth factor-I and its receptor in normal human and Alzheimer's disease brains." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0030/MQ64376.pdf.
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Geyer, Philipp [Verfasser], and Matthias [Akademischer Betreuer] Mann. "Plasma proteome profiling to assess human health and disease / Philipp Geyer ; Betreuer: Matthias Mann." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2017. http://d-nb.info/1189066971/34.
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Monedero, Alonso David. "Characterization of cationic conductances of human erythrocytes and their involvement in health and disease." Electronic Thesis or Diss., Sorbonne université, 2019. http://www.theses.fr/2019SORUS554.
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La membrane des globules rouges est dotée de plusieurs canaux ioniques. Normalement silencieux, ils peuvent dissiper rapidement les gradients ioniques une fois activés. Lors de cette étude, l'utilisation du NS3623 à des concentrations supérieures à celles requises pour l'inhibition des voies de conductances anioniques montre que ce composé active les canaux cationiques non sélectifs permettant ainsi leur étude y compris en conditions hyperpolarisantes. Le suivi en temps réel du potentiel membranaire à l'aide de l'ionophore à protons CCCP permet d’observer directement l'activité des canaux ioniques lorsque leur ouverture modifie le potentiel membranaire. Cette méthode a été utilisée pour décrire l'homéostasie cationique dysfonctionnelle dans des cellules de patients affectés par différentes mutations sur les canaux Gárdos ou Piezo1. Elle pourrait constituer un outil de diagnostic alternatif. L'activité des canaux ioniques a été caractérisée tout au long de la période de stockage réglementaire des globules rouges stockés à 4 °C (42 jours), afin de mieux comprendre les lésions de stockage. Il a été démontré que l’activité du NSC augmentait avec le temps, devenant spectaculaire la dernière semaine de stockage. En conclusion, les canaux cationiques non sélectifs jouent un rôle dans l'homéostasie des globules rouges matures. Ils contribuent ou peuvent constituer l'origine de la fuite de cations. Ils sont à l'origine de maladies en cas de dysfonctionnement et la compréhension de leur fonctionnement dans ces conditions peut fournir des stratégies thérapeutiques. Enfin, ils sont impliqués dans les lésions de stockage compromettant par leur activité l'efficacité transfusionnelle<br>Red cell membranes are endowed with several ion channels. Normally silent, they will rapidly dissipate ionic gradients once activated. I present a pharmacological means (NS3623) for the enhancement of NSC channels in hyperpolarizing conditions with concomitant chloride conductance inhibition in freshly drawn healthy mature RBCs. Membrane potential estimation aided by proton ionophore CCCP allows the recording of membrane potential changes in real time, enabling the observation of ion channel activity as their opening alters the membrane potential. This method was used to describe dysfunctional cation homeostasis in hereditary anemia using patient cells affected by different mutations on Gárdos or Piezo1 channels. The technique is fast, reliable and inexpensive providing an alternative diagnostic tool with the added advantage of producing ion channel activity information. Ion channel activity was characterized throughout 42-day storage period of RBCs stored at 4 C in CPD-SAGM according to French regulations to address the issue of storage lesions, which reduce transfusion efficacy. NSC activity was shown to increase over time during storage and dramatic ion channel activity was observed during the last week. Consequently, NSC activity may jeopardize cell volume and morphology upon reinfusion. In conclusion, Non-Selective Cation channels play an important role in mature RBCs. They contribute or may constitute the origin of cation leak. They cause disease when malfunctioning and insight into their operation in these conditions may supply with therapeutic strategies. They are involved in the storage lesion, and may account for RBCs demise once back in the circulation
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Asad, Suzanne. "Expression of Trafficking Receptors by Regulatory T Cells in Human Health and Autoimmune Disease." Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/16442.
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Abnormalities in CD4+CD25+CD127loFoxP3+ regulatory T cells (Tregs) have been implicated in susceptibility to autoimmune disease. To define migratory Treg subsets that may be implicated in the pathogenesis of diseases manifested in different tissues, we designed 11 and 13 colour flow-cytometry panels to measure the expression of a range of chemokine receptors and integrins on Tregs in the peripheral blood (PB) of healthy individuals (n=44) and patients with rheumatoid arthritis (RA) (n=34) or psoriasis (n=44). We showed that CLA, CCR4, CCR5, CCR6, CCR10 and CD62L were expressed on a higher proportion of CD4+CD25+CD127lo Tregs than conventional CD4+ T cells (Tconvs) in healthy adults. A significantly lower proportion of Tregs expressed the gut homing α4 (CD49d) and β7 when compared to Tregs that expressed the skin homing CLA, CCR4 and CCR10. Furthermore, the skin homing receptors, CLA, CCR4 and CCR10, were expressed on a much higher proportion of Tregs than Tconvs. We used flow cytometry to analyse the levels of CXCR3+, CCR4+, CCR5+ and CCR6+ Tregs in the PB of RA patients. RA patients had significantly reduced levels of effector/memory Tregs in their PB. We also found a significantly reduced frequency of effector/memory Tregs expressing each of the chemokine receptors examined in the PB of RA patients. This could indicate a trafficking deficiency, resulting in less Tregs entering the joints and a consequent disruption of immune homeostasis at the site. We examined the levels of β7+, CD49d+, CLA+, CCR4+, CCR10+, CCR5+, CD62L+, CXCR3+ and CCR6+ Tregs in the PB of psoriasis patients. We found Treg frequency to be increased in the PB of untreated psoriasis patients. However, the frequency of effector/memory Tregs expressing CXCR3 and CCR6 was significantly reduced in the PB of these patients. CXCR3+ and CCR6+ Tregs are known to be crucial to regulating Th1 and Th17 type immune responses, which are both involved in the pathogenesis of psoriasis. Therefore a reduction in iv CXCR3 and CCR6 expression on Tregs could indicate a trafficking deficiency resulting in less Treg entry into psoriatic lesions. We used bioinformatic tools to analyse all flow cytometry data obtained from patients and controls. We hope these methods of analysis will facilitate the uptake of flow cytometry in detecting preclinical disease or selecting patients for optimal treatment.
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ORSENIGO, FEDERICA. "Characterisation of the myeloid CSF1R+ dendritic cell subsets and monocytes in health and disease." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2023. https://hdl.handle.net/10281/404675.
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Le cellule dendritiche (DC) e i monociti sono cellule immunitarie innate coinvolte nel riconoscimento di patogeni e molecole associate a danno, nello scatenare l’immunità adattativa e nel mantenimento dell’omeostasi. Queste cellule sono collettivamente chiamate cellule del sistema fagocitico mononucleare (MPS), e la loro origine ed il loro sviluppo nell’uomo richiedono ancora studio. I recettori delle citochine determinanti l’origine (LDCR) sono fattori di crescita con importante ruolo nel differenziamento e nella sopravvivenza delle cellule ematopoietiche. Questi recettori sono presenti anche su cellule mature, suggerendone un ruolo post-differenziamento.
Il legame tra DC e monociti è stato qui dimostrato usando CSF1R, un LDCR conosciuto in precedenza come espresso solo su macrofagi, ma ora caratterizzato anche su tutte le cellule del MPS. Il MPS c’è stato analizzato in diversi contesti patologici, per caratterizzarne lo stato di sviluppo e attivazione.
Le DC e i monociti sono stati studiati in due diversi vaccini antimalarici. Entrambi i vaccini contengono lo stesso antigene del Plasmodium falciparum, la proteina AMA1. Uno dei vaccini si basa su vettori virali, mentre l’altro contiene la proteina ricombinante somministrata con un adiuvante lipidico. Il MPS è risultato modulato, con percentuali di cellule diverse a seconda del vaccino somministrato. Inoltre, il vaccino a vettore virale ha causato una maggiore attivazione delle cellule rispetto al vaccino proteico. L’espressione di LDCR e proteine di superficie nelle cellule CSF1R+ è stata modificata in maniera dipendente dalla formulazione dei vaccini.
Le DC hanno un importante ruolo anche nelle malattie infettive. Nella pandemia globale di COVID-19, capire come il MPS è modulato dal virus SARS-CoV-2 era cruciale, specialmente per gli anziani e le persone con patologie pre-esistenti. Due gruppi di pazienti COVID del Sud Africa sono stati studiati, ed erano presenti coinfezioni da HIV e tubercolosi, trattamento con steroidi e altre comorbidità. Un impatto sulle cellule specifico della variante virale è stato individuato. Nei pazienti COVID+, c’è stata una diminuzione di cellule CSF1R+ circolanti esacerbata da condizioni come l’ipertensione e il diabete. Un’altra causa di mortalità oltre a patologie pre-esistenti è la “tempesta citochinica”, dove l’alto livello di citochine circolanti, rilasciate dalle cellule del MPS, interagendo con il complemento ed il sistema di coagulazione porta a coagulazione sanguigna, crisi respiratoria e insufficienza multiorgano. Per questo, la capacità di DC e monociti di attivare il proprio inflammasoma e quindi produrre citochine infiammatorie è stata testata. Il compartimento CD14+ dei monociti e le DC hanno risposto agli stimoli per l’attivazione dell’inflammosoma rilasciando interleuchina 1 β ed attivando un meccanismo specifico di morte cellulare, segnali di attivazione dell’inflammosoma.
Infine, il ruolo di DC e monociti è stato valutato nel contesto dei tumori, con un confronto, eseguito con dati di single-cell RNA sequencing pubblici, tra due tipi di cancro con due diversi infiltrati immunitari. Il primo, adenocarcinoma del polmone (LUAD), è solitamente definito come tumore “caldo” o infiltrato da cellule immunitarie, mentre il secondo, carcinoma del colon-retto (CRC), è solitamente definito come tumore “freddo”, senza importante infiltrato immunitario. CSF1R e CSF2R erano espressi in maniera diversa tra tumori, e un tipo di DC recentemente scoperto e ancora poco caratterizzato a livello funzionale ha avuto comportamento opposto tra i due tumori, accumulandosi in LUAD ma non in CRC. Per questo gruppo di DC, è stato proposto in questo lavoro un ruolo tollerogenico che necessita di validazione con studi funzionali.<br>Dendritic cells (DCs) and monocytes are innate immune cells involved in recognising pathogens or damage-associated molecules, triggering adaptive immune responses, and maintaining homeostatic conditions. DCs and monocytes are collectively referred to as Mononuclear Phagocyte System (MPS) cells, and their origin and development in humans still need elucidating. Lineage-determining cytokine receptors (LDCRs) are growth factors with a pivotal role in haematopoietic cell differentiation and survival. These receptors are retained on mature cell surface, suggesting an active role after differentiation.
Here, the link between DCs and monocytes at a developmental level was assessed at steady state using CSF1R, a LDCR previously known as expressed only on macrophages, but now proved to be on all cells of the MPS. The MPS was further studied across multiple diseases, to assess its development or effector state.
DCs and monocytes were assessed in two distinct anti-malarial vaccine challenges. Both vaccines targeted the same blood-stage Plasmodium falciparum antigen apical membrane protein 1 (AMA1), involved in erythrocyte invasion by malaria. One vaccine formulation was based on a prime-boost viral delivery of the antigen, while the other vaccine consisted of the recombinant protein administered with a liposome-based adjuvant system. The MPS was greatly affected and reshaped, with cell fluctuations in percentages depending on the vaccine formulation. The viral-vectored vaccine also seemed to activate cells more effectively compared to the protein vaccine. LDCR and surface marker expression in CSF1R+ cells was also affected by the different vaccine vector components.
DCs also play a role in infectious diseases. In the global pandemic of COVID-19, understanding how the MPS is modulated by the SARS-CoV-2 virus was crucial, especially for elderly people and individuals with underlying conditions. Two South African COVID patients’ cohorts were investigated, where HIV and Tb coinfections, steroid treatment, and other comorbidities where present. There was a direct variant-dependent impact of COVID-19 on the MPS. In COVID-19 patients, there was a decrease in circulating CSF1R+ MPS cells, enhanced by the presence of certain comorbidities such as hypertension and diabetes. Aside from underlying conditions, one of the causes of poor prognosis is a phenomenon called cytokine storm and it is linked to the MPS cells. The elevated levels of circulating cytokines released by the MPS cells interact with the complement and coagulation systems to induce coagulation, respiratory and multi-organ failure. Therefore, DCs and monocyte ability to activate their NLRP3 inflammasome and release pro-inflammatory cytokines was investigated. The CD14+ monocytic compartment and DCs were able to respond to NLRP3 activating stimuli by releasing interleukin 1 β and undergoing cell death, signs of activation of an inflammasome pathway.
Finally, the role of DCs and monocytes was investigated in the context of another pathological setting, with the comparison of two different types of tumours that usually display different immune infiltrated. The first tumour, lung adenocarcinoma (LUAD), is conventionally referred to as “hot” or immune infiltrated tumour, while the second, colorectal cancer (CRC), as “cold” or immune excluded. The comparison between these two tumours was pursuit using public single-cell RNA sequencing datasets. Different expression of CSF1R and CSF2R were noted across tumoral tissues, and a specific type of DCs recently discovered and poorly characterised at functional level displayed opposite behaviour, accumulating in LUAD but not in CRC. For this DC subset, a putative tolerogenic role was proposed that would need to be validated with functional studies.
This work underlined the importance of investigating the involvement of CSF1R+ MPS cells in health and diseases and provided a pan-MPS marker for human studies.
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Walczak, Katarzyna I. "Prototype decision support framework using geospatial technologies for analysing human health risk." Thesis, Queensland University of Technology, 2017. https://eprints.qut.edu.au/103630/1/Katarzyna%20Izabella_Walczak_Thesis.pdf.
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This thesis concentrates on the development of a prototype Decision Support Framework based on the landscape epidemiology concept and using GIS to determine human health risk in Semarang (Indonesia). This site was selected as representative of a rapidly urbanizing area in a developing country. The decision support framework examines climatic, landscape and socio-economic factors identified as having significant impacts on water quality and subsequent causation of waterborne and water-related diseases. The research outcomes potentially may be applied worldwide to identify and isolate areas most vulnerable to the effects of the mentioned diseases thus improving quality of life in developing countries.
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Vo, Thuy D. "Systems analysis of energy metabolism elucidates the roles of mitochondria in human health and disease." Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3238425.
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Thesis (Ph. D.)--University of California, San Diego, 2007.<br>Title from first page of PDF file (viewed January 4. 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 166-185).
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Gamble, Michelle. "Health and disease in Chalcolithic Cyprus : a problem-oriented palaeopathological study of the human remains." Thesis, University of Newcastle Upon Tyne, 2011. http://hdl.handle.net/10443/1303.
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Poor preservation of the human skeletal remains on Cyprus has, in the past, limited palaeopathological analyses conducted. The research presented here has two main aims: (1) to explore the possibility of deriving useful information from the poorly preserved human remains from Chalcolithic Cyprus and the methodological adjustments required to do so, and (2) to discuss the health status of the human Chalcolithic populations in Southwest Cyprus, determining patterns in the expression of pathologies related to age, sex or burial location which, if present, may further elucidate aspects of lifeways within and amongst the living populations. These aims are achieved through a macroscopic and microscopic analysis of the pathological lesions on the human skeletal remains from the Souskiou-Laona cemetery, the Lemba-Lakkous and Kissonerga-Mosphilia settlement sites which all date to the Middle Chalcolithic period. This research presents one of the first comprehensive palaeopathological studies for the Chalcolithic period in Cyprus with multi-site data. Lesions arising from osteoarthritic processes, non-specific diseases and disorders as well as trauma, dental pathologies and congenital defects are recorded, analysed and discussed within the archaeological context. The results presented in this thesis show that information regarding prehistoric peoples can be drawn from poorly preserved remains and it goes further to explore the limitations to the interpretations which can be postulated. The analyses of the research indicate that there are moderate to low prevalence of pathological lesions observed on the Chalcolithic skeletal remains. There is differential expression between males and females in the joints affected by osteoarthritic changes and the types of dental pathologies suffered by each sex. This research contributes to the overall historiography of health and disease in Cyprus, by filling a lacuna for the Chalcolithic period. Additionally, it provides an illustration of some methodological modifications, such as qualitative discussion, needed when dealing with poorly preserved and commingled material in a palaeopathological study.
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Bingham, Max. "The human gut microflora, the metabolism of dietary components and relevance to health and disease." Thesis, University of Reading, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408874.
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Emmett, Suzanne E. "Mineral elements in diet, health and disease : analysis of cow's milk and human tissue samples." Thesis, University of Surrey, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.328657.
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