Dissertations / Theses: 'Treatment of human diseases and conditions'

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Roodhouse, Amanda. "Modeling human leg arteries: a comparison of conditions and diseases." Thesis, Wichita State University, 2011. http://hdl.handle.net/10057/5029.

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Peripheral artery disease is a condition that is prevalent among the American population. It is caused by plaque buildup in arteries, known as atherosclerosis, other than those arteries in the heart and brain. While peripheral artery disease is not generally life threatening, complications from this disease can lead to intense pain, amputation and severe loss of quality of life. Most of the studies focusing on the lower limb arteries have been finite element studies looking at the bending effects on stents. These models are useful for stent design; however do not encompass the effects that curvatures, bifurcations and bends have on the fluid mechanics of blood flow. This thesis creates several computational fluid dynamics models of the Superficial Femoral, Deep Femoral and the Popliteal Arteries in an attempt to evaluate diseases and conditions that may contribute to peripheral artery disease. This includes the varying positions that the artery many take on during ordinary leg movement, the effects of pulsating flow, the effects of stenosis and stents, as well as the effects of increased and decreased viscosity caused by variable hemotocrit count. The results of these models were examined using various graphs of the mass flow rates, velocity profiles, wall shearing stress and static pressures. It was shown that stead state simulations will underestimate wall shearing stress and that diabetic blood will nearly double the wall shearing stress experienced in the arteries. The curvatures in the arteries will create areas of increased and decreased wall shear stress, as well as generate recirculation zones. Higher hemotocrit count decreases the recirculation zones and lower hemotocrit count increases these zones. These areas of low wall shear stress have a greater chance of forming plaque buildup; whereas the increased areas of stress can cause aneurisms in the arteries and put additional strain on the stent implants, possibly contributing failure.
Thesis (M.S.)--Wichita State University, College of Engineering, Dept. of Mechanical Engineering.

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Mondal, Utpal Kumar. "CARBONIC ANHYDRASE MODULATORS FOR DETECTION AND TREATMENT OF HUMAN DISEASES." Diss., Temple University Libraries, 2019. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/543241.

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Pharmaceutical Sciences
Ph.D.
Carbonic anhydrases (CAs, EC 4.2.1.1) are a class of metalloenzymes that catalyze the hydration of CO2 under physiologic conditions and are involved in many physiological and pathological processes. Modulation of CA activity, particularly CA inhibition is exploited pharmacologically for the treatment of many diseases such as cancer, glaucoma, edemas, mountain sickness. CA activation has been less frequently investigated till recently. Genetic deficiencies of several CA isozymes are reported in the literature and reflect the important role of carbonic anhydrases in human physiology and homeostasis. Activation of CA isozymes in brain have been correlated recently with spatial learning and memory. Based on these premises, activators of CA isozymes have the potential to alleviate mild dementias and to act as potential nootropic agents. In chapter 3, continuing our long-term interests towards the development of potent and selective CAAs, we carried out X-ray crystallographic studies with a small series of pyridinium histamine derivatives, previously developed as CAAs by our group. This study revealed important insights into the binding of this class of activators into the active site of CA II isozyme. A potent pyridinium histamine CAA 25i was successfully crystallized with CA II isozyme and was found to bind into the hydrophobic region of the active site, with two binding conformations being observed. This is one of the very few X-ray crystal structures of a CAA available. Based on the findings of this X-ray crystallographic study and building on our previously developed ethylene bis-imidazole CAAs, we advanced a novel series of lipophilic bis-imidazoles. Enzymatic assays carried out on purified human CA isozymes revealed several low nanomolar potent activators against various brain-relevant CA isozymes. Bis-imidazole 30e was found to be a nanomolar potent activator for CA IV, CA VA and CA IX. Due to their conjugated structure, these CAAs were also fluorescent and therefore were fully characterized in terms of photophysical properties, with several representatives proving to display very good fluorophores. The very good activation profile against several different CA isozymes, along with excellent fluorescence properties recommend these compounds as great molecular tools for elucidation of role of CA isozymes in brain physiology, as well as towards improvement of memory and learning. Focusing on inhibition of CA isozymes, it must be stressed that over the last decade a clear connection had been established between the expression of CA IX and CA XII and cancer. Since cancer is the second most common cause of death in the world, we explored the possibility to kill cancer cells via inhibition of different CA isozymes present in cancer cells. The membrane bound carbonic anhydrase IX (CA IX) isozyme represents a particularly interesting anticancer target as it is significantly overexpressed in many solid tumors as compared to normal tissues. In malign tissues this CA isozyme was found to play important role in pH homeostasis and promotes tumor cell survival, progression and metastasis. Thus, CA IX represents a potential biomarker and an appealing therapeutic target for the detection and treatment of cancer. CA IX can be targeted either through the development of small or large molecular weight, potent, and selective inhibitors or through the development of CA IX targeted drug delivery systems for selective delivery of potent chemotherapeutic agents. Building on these premises, in this dissertation, we also revealed our continuing efforts towards the development of potent and selective CA IX inhibitors along with their translation into the development of CA IX targeted drug delivery systems. In chapter 4, we designed a series of small molecular weight (MW) ureido 1,3,4-thiadiazole sulfonamide derivatives employing the “tail approach”, through the decoration of established sulfonamide CA inhibitor warheads with different tail moieties via ureido linker. The generated CAIs were tested against tumor associated CA IX and CA XII isozymes and off-target cytosolic isozymes CA I and CA II, and were revealed to be moderate to highly selective and nanomolar, even sub-nanomolar, potent CA IX inhibitors. Several potent pan-inhibitors were also identified in this section. We assessed these CAIs for their in vitro cell killing ability using MDA-MB 231 breast cancer cell line expressing CA IX and CA XII. The most efficient CAI proved to be ureido-1,3,4-thiadiazole-2-sulfonamide 69, which showed subnanomolar potency against purified human CA IX and CA XII isozymes, with good selectivity against CA I and CA II, and consistent, statistically significant cancer cell killing. In Chapter 5, continuing our efforts towards the development of potent and selective CA IX inhibitors, we designed, synthesized, characterized and evaluated a new series of PEGylated 1,3,4-thiadiazole-2-sulfonamide CAIs, bearing different PEG backbone length. We increased the PEG size from 1K to 20K, in order to better understand the impact of the PEG linker length on the in vitro cell killing ability against CA IX expressing cancer cell lines and also against a CA IX negative cell line. In vitro cell viability assays revealed the optimum PEG linker length for this type of bifunctional bis-sulfonamide CAIs in killing the tumor cells. The most efficient PEGylated CAI was found to bis-sulfonamide DTP1K 91, which showed consistent and significant cancer cell killing at concentrations of 10−100 μM across different CA IX and CA XII expressing cancer cell lines. DTP1K 91 did not affect the cell viability of CA IX negative NCI-H23 tumor cells, thus revealing a CA IX mediated cell killing for these inhibitors. In chapter 6, we decided to further explore the possibility of using CA IX as a targeting epitome for the development of a gold nanoparticle-based drug delivery system. We translated the oligoEG- and PEGylated CAI conjugates into efficient targeting ligands for gold nanoparticle decoration along with chemotherapeutic agent doxorubicin (Dox), in a novel multi-ligand gold nanoplatform designed to selectively release the drug intracellularly, in order to enhance the selective tumor drug uptake and tumor killing. We were successful in developing compatible CAI- and Dox- ligands for efficient dual functionalization of gold nanoparticles. Our optimized, CA IX targeted gold nanoplatform was found to be very efficient towards killing HT-29 tumor cells especially under hypoxic conditions, reducing the hypoxia-induced chemoresistance, thus confirmed the potentiating role of CA IX as a targeting epitome.
Temple University--Theses

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Masokwane, Patrick Maburu Dintle. "Prevalence of non-AIDS defining conditions and their associations with virologic treatment failure among adult patients on anti-retroviral treatment in Botswana." University of the Western Cape, 2016. http://hdl.handle.net/11394/5247.

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Magister Public Health - MPH
Background: The recognition of HIV/AIDS as a chronic life-long condition globally in recent years has demanded a different perception and an alignment to its association with other chronic diseases. Both HIV and other chronic non-communicable diseases are significant causes of morbidity and mortality. Their combined DALY contributions for Botswana would be significant if research and strategies in controlling these conditions are not put in place. Natural aging and specific HIV-related accelerated aging of patients who are on antiretroviral treatment means that age-related diseases will adversely affect this population. Princess Marina Hospital Infectious Diseases Care Clinic has been in operation since 2002. The clinic has initiated over 16 000 patients on anti-retroviral treatment (ART) since 2002. The current study estimated the prevalence of non-AIDS defining conditions (NADCs) in the attendees of the clinic in 2013. The majority of patients that attended the clinic had been on treatment for over three years with some patients more than ten years. These ART experienced patients were more likely to be susceptible to chronic non-communicable diseases, including non-AIDS defining conditions. The nomenclature used in classification of NADCs in the current study was appropriate for resource-limited settings; because the study setting offered HIV treatment under resources constraints. Aim: The current study characterised non-AIDS defining conditions, and determined their associations with virologic treatment failure in a cohort of patients that were enrolled at Princess Marina Hospital antiretroviral clinic in Gaborone, Botswana. Methods: A retrospective cross sectional study of records of patients who attended the Princess Marina Infectious Diseases Care Clinic in 2013. Stratified random sampling of a total of 228 patients’ records was achieved from a total population of 5,781 records. Data was transcribed into a Microsoft Excel Spreadsheet and then exported to Epi-Info statistical software for analysis. Results: Eighty (35%) cases of NADCs were reported/diagnosed in the study sample; with 27% (n=62) of the patients having at least one condition, 6.7% (n=17) two conditions, and 0.4% (n=1) three conditions. The top prevalent conditions were hypertension (n= 40), hyperlipidaemia (n=7) and lipodystrophy (n=7). The prevalence of NADCs on the various categories of patients compared with the total sample population was as follows: active patients (prevalence ratio= 0.70), transferred out patients (prevalence ratio = 1.24), patients who died (prevalence ratio=2.04) and patients who were lost to follow-up (prevalence ratio =2.86). The prevalence of NADCs was significantly associated with increasing age (p<0.001); having social problems (p=0.028); having been on treatment for over three years (p=0.007); an outcome of death (p = 0.03) and being lost to follow-up (p=0.007). The study showed that being controlled on second line or salvage regimen (p=0.014) and the presence of adherence problems in the past was associated with virologic failure (p=0.008). There was no association of presence of NADCs to virologic failure. Conclusions: There was significant morbidity of non-AIDS defining conditions in the Princess Marina Infectious Diseases Care Clinic shown by a prevalence of NADCs in the clinic of 35% in 2013.The significant associations of the presence of NADCs and virologic failure with outcomes of death and loss to follow-up illustrate the adverse effects that NADCs are having, and calls for strategies to address multi-morbidities in HIV patients on antiretroviral treatment.

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Langenhan, Jana [Verfasser]. "Development of specific immunoadsorbers for the treatment of human pemphigus diseases / Jana Langenhan." Lübeck : Zentrale Hochschulbibliothek Lübeck, 2012. http://d-nb.info/1026457408/34.

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Talegaonkar, Sonia S. "The Role of Human MSC Derived Exosomes in the Treatment of Periodontal Diseases." VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/4969.

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Periodontal disease affects 47% of Americans over 30. Characterized by microbial dysbiosis and unregulated inflammation, severe periodontitis causes degradation of bone and soft tissue around teeth. Current treatments have limited regenerative outcomes and frequent reinfection by harmful bacteria. Human mesenchymal stem cells (hMSCs) have been shown to promote wound healing and tissue regeneration. Many therapeutic benefits of hMSCs are due to their secretome products, like exosomes. Our long-term goal is to develop periodontal therapies with hMSC exosomes. The objectives of this study were to determine the effect of hMSC-derived exosomes on cellular activity of hMSCs and investigate whether hMSC exosome treatment reduces pro-inflammatory cytokine production in LPS-activated RAW264.7 cells. The specific aims of this study were: 1) Determine the characteristics of hMSC-derived exosomes, 2) Determine the biological effect of exosomes on cellular activity of hMSCs, 3) Determine whether exosomes treatment can inhibit cytokine production in activated RAW264.7 cells, and 4) Determine the role of exosomal miRNA in pro-inflammatory cytokine production of RAW264.7 cells. To investigate, exosomes were first harvested from hMSCs culture media through ultracentrifugation. Exosomes were then observed under a transmission electron microscope (TEM) and assessed for surface markers using Western Blot. A transwell migration assay was used to evaluate the chemotactic effect of exosomes. To study the effect of exosomes on stem cell proliferation, exosomes were administered to hMSCs. The immunogenicity of MSC exosome was also evaluated. After 72 hours, cells were lysed and DNA was measured. To study anti-inflammatory effects of exosomes, LPS stimulated RAW264.7 cells were treated with exosomes. Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα) levels of supernatant were measured by ELISA. To study exosomal miRNA, exosomal miRNAs were overexpressed in RAW264.7 cells and these cells were stimulated with LPS. IL-6 and TNFα were measured by ELISA. TEM images showed that exosomes are nano-sized vesicles (~100 nm). Western blot images showed that CD63 and CD81 are enriched in exosomes compared to total cell lysates. Exosome treatment increased cell proliferation and migration in hMSCs. At the doses that are chemotactic and mitogenic, MSC exosomes had minimal effect on the inflammatory cytokine IL-6 production. Treatment with exosomes significantly decreased IL-6 and TNFα production in RAW264.7 cells activated by LPS. Transfecting RAW264.7 cells with exosomal miR-760 significantly decreased IL-6 production, but had minimal effect on TNFα. Our results indicate that exosomes have a pleiotropic activity, which includes stimulating stem cell migration and proliferation, and mitigating the inflammatory response. Therefore, hMSC exosome delivery is promising for the treatment of periodontal diseases.

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Simon, Remil B. S., Darshan M. D. Shah, Peter B. S. Blosser, Demetrio M. D. Macariola, and Jeffrey M. D. Carlsen. "Treatment of CMV Vitritis in a Preterm Newborn." Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/asrf/2018/schedule/165.

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Title: Treatment of CMV Vitritis in a Preterm Newborn Author’s Section: Remil Simon1, Darshan Shah1, Peter Blosser1, Demetrio Macariola1, Jeffrey Carlsen2 1.Department of Pediatrics, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 2.Johnson City Eye Clinic, Johnson City, TN Body: Cytomegalovirus (CMV) infection in the neonate is an infrequent occurrence in the developing world, and observing the symptoms of ocular CMV infection such as vitritis is rare. Treating CMV infection promptly is necessary to prevent mortality and potential neurological deficits including blindness and hearing loss. We encountered a preterm infant presenting with CMV sepsis immediately after birth. Our question was: will the current standard of treatment for CMV sepsis prevent CMV ocular infection? With our method of treatment, we followed the current standard of treatment for CMV infection by administering intravenous Gancyclovir for 6 weeks and oral Valgancyclovir for 6 months. Despite using the standard treatment to prevent neurological sequelae, the patient developed CMV vitritis and retinitis bilaterally. Although the treatment did not prevent CMV ocular infection, the severity of CMV retinitis and vitritis improved with treatment, and full resolution of vitritis was noted by day of life 61.

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Lai, Wing-hon Kevin, and 黎永漢. "Generation of vasculogenic progenitor cells from human induced pluripotent stem cells for the treatment of cardiovascular diseases." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/197112.

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Pluripotent stem cells hold great promise in regenerative medicine. Theoretically, a variety of tissues can be generated from this progeny. The production of tailor-made stem cells for individualized patient treatment is the ultimate goal of stem cell based therapy. Human induced pluripotent stem cells (iPSCs) hold the precious key to success and promote the clinical application of stem cells. By reprogramming somatic cells, pluripotent stem cells can be generated in a patient-specific manner and subsequently differentiated into specific tissue for regeneration. Nonetheless exposure of hiPSCs to animal feeder cells and serum during generation and maintenance imposes a risk of transmitting animal pathogens to human subjects, thus hindering their potential therapeutic application. In addition, the efficacy of iPSC generation is < 1% of total somatic cells used. The first part of the study focused on the development of improved methods to produce a more efficient xenogen-free culture system to produce more clinically compatible iPSCs. Specific tissue or cells derived from stem cells may offer a solution and cell therapy using endothelial cells and their progenitors may be possible in treatment of severe cardiovascular diseases. In theory, endothelial cells can be generated from different sources of progenitor cells although no direct comparison of these various derived endothelial cells (ECs) has been reported. Thus in the second part of the study, the functional and physiological properties of BM, ESC and iPSC-ECs will be evaluated to determine their therapeutic potential in ischemic disease. A mouse hind limb ischemia model was used to assess and monitor neovascularization by the derived ECs. The results can provide further insight to evaluate the possibility of using iPSCEC as the cell source for patient-specific treatment. Use of pluripotent stem cells is a promising approach in therapeutic angiogenesis although numerous hurdles continue to hamper their widespread clinical use. Conditioned medium derived from progenitor cells may be another possible strategy in the treatment of ischemic diseases such that direct cell transplantation is avoided. Conditioned media produced from ex vivo culture of endothelial cells contain a combination of angiogenic factors that can be applied to promote neovascularization in ischemic tissue. Nonetheless the efficacy of this angiogenic application is unknown. The third part of the study focused on the potential application of EC-derived conditioned media in the treatment of ischemic disease using a mouse hind limb ischemia model. Some cardiovascular risk factors such as diabetes might affect endothelial cell function such that autologous application of ECs and their conditioned media is not feasible. A human embryonic stem cell line may offer and alternative means to obtain stable quality ECs and conditioned medium for therapeutic use. In summary, advances in stem cell technology hold great promise for the treatment of cardiovascular disease, further improved by the generation of patient-specific stem cells using iPSC technology. Vascular cells can be generated from different sources of stem cells with similar angiogenic properties and may be used in the treatment of ischemic diseases.
published_or_final_version
Medicine
Doctoral
Doctor of Philosophy

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Khalid, Mahwish Rani, and Mahwish Rani Khalid. "Line1: Implications in the Etiology of Human Diseases, Clinical Utilities, and Pharmacological Target for Disease Treatment." Thesis, The University of Arizona, 2017. http://hdl.handle.net/10150/626716.

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Long interspersed nuclear elements-1 (Line-1 or L1) accounts for approximately 17% of the human genome. The majority of L1s are inactive, but ~100 remain retrotransposon competent (RC-L1) and retrotranspose through RNA intermediates to different locations of the genome. It is well established that L1 is involved in both disease initiation and progression via retrotransposition dependent and independent mechanisms. Retrotransposed L1 sequences disrupt loci (e.g. gene structure) in ways that lead to human disease, and activities of L1 si/piRNA, ORF1 and ORF2 proteins are implicated in the etiology and progression of human diseases such as in breast and colon cancer (Miki et al., 1992; Ohms et al., 2014). Despite these implications, very little is known about pharmacological molecules that inhibit and reverse L1’s harmful effects. The clinical utility of L1 as a player in tumorigenesis and as a biomarker for disease initiation and progression is not thoroughly understood. In this review, we analyzed the life cycle of L1, its roles in disease initiation and progression, clinical utilities and potential as a pharmacological target and a biomarker for the diagnosis and treatment of human diseases, such as cancer.

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Li, Xiang, and 李想. "Effects of human mesenchymal stem cells on cigarette smoke-induced lung damage." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B49618209.

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Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease characterized by persistent airway obstruction that is only partially reversible. It is the fourth leading cause of death and is predicted to be the third by 2030. The progression of the disease involves chronic inflammation, oxidative stress, excess protease activity, increased lung cell apoptosis and accelerated lung aging, but the exact pathogenesis is still unclear. The major cause of COPD is cigarette smoking(CS). Although COPD is associated with increasing social and economical burden, there have been few advances in pharmacological therapy of COPD. Mesenchymal stem cells (MSCs) are fibroblast-like multipotent stem cells which can be isolated from a broad range of sources including bone marrow (BM) and adipose tissue. Administration of BM-derivedMSCs (BM-MSC) or adipose tissue-derived MSCs was reported to attenuate CS-induced emphysema in murine models. Induced pluripotent stem cell-derived MSC (IPSC-MSC) are MSCs differentiated from induced pluripotent stem cells(IPSCs), which are pluripotent cells generated by somatic cell reprogramming in vitro. IPSC-MSCs have several advantages over BM-MSC, including more abundant sources and high capacity of doubling without loss of differentiation potency. A general exploration and comparison on the effects of human IPSC-MSC and BM-MSC treatments were carried out in a 56-day CS-exposed rat model. Compared to BM-MSC, IPSC-MSC showed a higher capacity to reside in lung tissue. The two treatments shared similar efficacy to attenuate CS-induced lung cell apoptosis, to restore CS-induced reduction of lungIL-10and to alleviate CS-induced elevation of systemic TGF-β1. In addition, IPSC-MSC was found to cause reduction in CS-induced elevation of systemic oxidative stress and reversal of CS-induced reduction of lung adiponectin. Furthermore, in order to understand the possible paracrine mechanism involved, human airway epithelial cells were treated with IPSC-MSC or BM-MSC-conditioned medium in a cell culture system in the presence of cigarette smoke medium (CSM). Potentiation rather than attenuation of CSM-induced release of pro-inflammatory cytokine IL-8, MCP-1 and IL-6 was observed with IPSC-MSC or BM-MSC conditioned medium. It is currently unknown whether cultured IPSC-MSCs or BM-MSCs will release pro-inflammatory mediators into the conditioned medium or not. In order to study CS-induced oxidative stress and inflammation in a short time frame, anacute (5-day) CS-exposed rat model was established in juvenile and adult groups. An age-dependent alteration of CS-induced oxidative and inflammatory responses was demonstrated in this model. In summary, our in vivo rat model provides a platform for elucidating the effects of stem cell treatment in CS-induced oxidative stress and inflammation, leading to lung damage. Our findings suggest that treatment of IPSC-MSC or BM-MSC might be able to slow down CS-induced disease progression, possibly through anti-oxidant, anti-inflammatory and anti-apoptotic properties. However, caution should be taken as our in vitro data revealed that conditioned medium from MSCs may provoke pro-inflammatory responses. Further studies on the regulation of the activity of MSCs in vivo will be needed before developing IPSC-MSC into cell therapies for COPD to halt the progression over time.
published_or_final_version
Medicine
Master
Master of Philosophy

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Chacko, Anu. "Comparison of human and animal Chlamydia pneumoniae responses to interferon gamma and penicillin treatment." Thesis, Queensland University of Technology, 2015. https://eprints.qut.edu.au/85438/1/Anu_Chacko_Thesis.pdf.

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This thesis has made a significant contribution to future chlamydial research by uncovering the chlamydial pathogenic mechanisms which will potentially help in the development of targeted vaccine against the pathogen. This thesis has made important new contributions to our understanding of Chlamydia pneumoniae specific adaptations to stress responses and has provided new perspectives on the survival of this successful pathogen. This thesis has used two well established microbial stressors and has identified major differences in stress responses between human and animal Chlamydia pneumoniae isolates.

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Mahmood, Dler Faieeq Darweesh. "Thioredoxin-1 (Trx1) : a new target in the treatment of cardiovascular diseases." Phd thesis, Université Pierre et Marie Curie - Paris VI, 2014. http://tel.archives-ouvertes.fr/tel-01069096.

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The cardiovascular diseases (CVDs), resulting from complications of atherosclerosis, remain the leading cause of morbidity and death worldwide. Atherosclerosis as a chronic inflammatory disease, involves both innate and adaptive arms of immunity in which macrophages play the orchestral role in modulating lesion initiation, progression, and potentially devastating thrombotic complications. Available evidences support the notion of a central role of oxidative stress, due mainly to the imbalance between antioxidants and reactive oxygen species (ROS) in CVDs. Furthermore, the pathology is frequently associated with dynamic changes in macrophage activation, with classically activated M1 cells implicated in initiating and sustaining inflammation and M2 or M2-like cells associated with resolution or smoldering chronic inflammation. Among endogenous antioxidants, the thiordoxine-1 (Trx1) plays a central role in several diseases including CVD. Thus, the ubiquitous Trx1 has been reported to exert a myriad of beneficial roles. Indeed, it regulates not only cellular redox homeostasis and acts as a principal antioxidant defense system, but it also affects energy metabolism, modulates the immunological and inflammatory responses, and controls cell growth and survival. In contrast, its truncated form (Trx-80), exerts an opposite effects. However, several studies reported the beneficial role of Trx system in CVDs but the detailed molecular mechanism is not addressed yet. Therefore, the present study aims to investigate the role of both Trx1 and Trx80 in the biology of atherosclerosis through the modulation of macrophage polarization and the implicated signaling pathways as well. Our in vitro major findings, using human macrophages and murine peritoneal macrophages, revealed that Trx1 on one hand promoted the polarization of anti-inflammatory M2 macrophages through downregulation of p16INK4a and suppressing nuclear translocation of activator protein-1 (AP-1) and Ref-1 as evidenced by the expression of the CD206 and IL-10 markers. On the other hand Trx1 also reduced the lipopolysaccharide (LPS)-induced differentiation of inflammatory M1 macrophages, as indicated by the decreased expression of the M1 cytokines, tumor necrosis factor-α (TNF-) and monocyte chemoattractant protein-1 (MCP¨-1). By contrast, Trx80 treatment attenuated the polarization of anti-inflammatory M2 macrophages induced by IL-4 or IL-4/IL-13 even it potentiated LPS-induced M1 activation. To validate our obtained in vitro results, hyperlipoproteinemic C57Bl/6.ApoE2.ki mice and human atherosclerotic vessel specimens from patients undergoing vascular surgery were used. Consistently, Trx1 and Trx80 affected macrophage phenotype in thymus, liver and atherosclerotic lesions. As a consequence, Trx1 reduced whereas Trx80 increased the aortic lesion area in mice. Plasma levels of cholesterol and triglycerides did not changed by the treatment. To further explore our results, the implicated signaling pathways has been studied and it was found that both Trx1 and Trx80 activated Akt. Furthermore, Trx80 uses mTOR signaling pathway to exert its effect in polarizing macrophages toward M1 phenotype since it activated mTOR in a dose-dependent manner as demonstrated by the increased phosphorylation of P70S6K. Based on our results, Trx1 antagonizes whereas Trx80 potentiates atherosclerosis through changing M1/M2 phenotypes. Therefore, Trx1 represents a promising target for therapeutic interventions.

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Rocha, Mariana Frota Cúcio De Moraes. "A novel assay to measure mitochondrial dysfunction in human skeletal muscle : implications for the diagnosis and treatment of mitochondrial diseases." Thesis, University of Newcastle upon Tyne, 2016. http://hdl.handle.net/10443/3255.

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Mitochondrial dysfunction occurs in patients with mitochondrial disease, in neurodegenerative conditions and as part of the ageing process. It affects predominantly tissues with high metabolic requirements such as central nervous system and skeletal muscle. In patients with mitochondrial disease, both mitochondrial and nuclear genetic defects commonly cause a biochemical defect in muscle. However, due to the multi-copy nature of mitochondrial DNA, muscle displays a mosaic pattern of deficiency when the mitochondrial genome is affected. This particular pattern makes these defects challenging to quantify. Current standard methods to diagnose and investigate mitochondrial disease in affected tissues present several limitations. Biochemical studies are only suitable for cases with a high proportion of cells with mitochondrial respiratory chain deficiency. Moreover, histochemical assays only provide qualitative assessment of complex II and IV activities and are not capable of evaluating other complexes, such as complex I - the commonest affected respiratory complex in mitochondrial pathology. This project aimed therefore at developing a novel assay to accurately quantify mitochondrial dysfunction in human skeletal muscle. Once optimised, this assay was further used to explore: the mechanisms underlying mitochondrial pathology, its potential in helping the current diagnostic setting, as well as its potential to assess the effectiveness of therapeutic approaches aimed at treating mitochondrial dysfunction. This work described the development and validation of a novel quadruple immunofluorescent technique. This assay quantifies accurately key subunits of respiratory complexes I and IV together with mitochondrial mass, using a single 10μm section. The additional labelling of a cell membrane marker allows semi-automatic and computer-based sampling of large numbers of individual muscle fibres. Using this technique, this study characterised a variety of mitochondrial and nuclear genetic defects and demonstrated that specific genotypes exhibit distinct biochemical signatures in muscle. In patients with suspected mitochondrial disease, this assay provided clues on the possible genetic causes. Furthermore, this novel assay evaluated the effect of an endurance exercise program in patients with mitochondrial myopathy and was able to detect subtle changes in respiratory complexes levels.

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Sianangama, Pharaoh Collins. "Effects of human chorionic gonadotropin administration at various times following breeding on corpus luteum number, diameter, progesterone profiles and pregnancy rates in dairy cattle." Thesis, University of British Columbia, 1990. http://hdl.handle.net/2429/28745.

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Corpus luteum (CL) dysfunction has been implicated among various factors predisposing early embryonic mortality in cattle. Two experiments were conducted to evaluate the efficacy of using human chorionic gonadotropin (hCG) given either at the time of breeding (day 0) , day 7 or 14 post breeding, in reducing that component of early embryonic mortality caused by CL dysfunction. The aims of experiment 1 were to investigate the effectiveness of using hCG, in inducing the development of accessory CL, their formation and growth, and the effect of such treatments on the function of both the induced and spontaneous CL. Thirty-four lactating Holstein cows were randomly assigned to one of four treatments. A single intramuscular injection of 1000 IU of hCG was given either at the time of breeding (day 0, n=8), day 7 (n=9) or 14 (n=9) post breeding or no hCG given (control, n=8). A real-time ultrasound machine was used to study follicular dynamics and CL growth. The CL and antral follicle diameter was determined using a built-in system of calibrated callipers. Ultrasound scanning was carried out on days 7, 9, 11, 14, 16, 18, 21, 28, 35 and 42 post breeding. Blood and milk samples, for progesterone (P₄) determination using radioimmunoassay, were collected on days coincident with ultrasonography. Diameter of the CL is presented as the sum of the diameter of all luteal tissue in each animal. Differences in CL diameter, milk and plasma P₄ were analyzed using the General Linear Models Procedures while pregnancy data were analyzed using Chi-Square analysis in Statistical Analysis Systems (SAS, version 6.3). Based on the day 7 ultrasound scanning, the incidence of twin ovulations was higher among cows treated on day 0 (3/8) compared to control cows (1/8) and day 7 (1/9). Accessory CL were detected in 7/9 of the day 7-treated cows compared to 4/9 among the day-14 treated cows. Least squares means (LSMeans) for CL diameter were significantly higher (P<0.001) among cows treated with hCG compared to control cows starting at day 7 continually until day 42. Plasma P₄ profiles were significantly higher (P<0.05), at days 18, 35 and 42, in cows treated on day 7 or 14 compared to control cows. The first detectable differences (P<0.05) between hCG treated and control cows, in milk P₄ occurred at day 21 and persisted until day 42. Pregnancy rates were highest among cows treated with hCG on day 7 where 6 of the 9 cows were diagnosed pregnant. Corresponding pregnancy rates for day 0, 14 or control cows, were 4/8, 5/9 and 3/8, respectively. In the second experiment, two trials were conducted at two different farms to investigate the efficacy of using hCG to increase milk P₄ and pregnancy rates. In trial one, 79 lactating Holstein cows were exposed to the treatment protocol described in experiment 1. In addition to the milk sample collection schedule given in experiment 1, a sample was collected on day 0. Milk samples were stored at 4°C and later transported to the UBC laboratories for P₄ analysis. LSMeans for milk P₄ concentrations were different only at days 16 and 18 post breeding. Pregnancy rates were improved (P<0.01) by hCG treatments. The respective pregnancy rates for cows receiving hCG on day 0 (n=20), 7 (n=20), 14 (n=20) or control (n=19) were 25, 35, 35 and 21 %. In the second trial, 121 lactating Holstein cows were randomly assigned to treatments as described earlier. Weekly milk samples were collected from each animal and assayed for P₄ as described above. LSMeans for milk P₄ were significantly different (P<0.05) among groups starting at day 14 until day 42 post breeding. hCG increased pregnancy rates over control cows. The pregnancy rates for cows treated on day 0, 7, 14 and control were 31, 50, 41 and 26 %, respectively. In conclusion, this study revealed that treatment with hCG induced accessory CL development, increased P₄ production and improved pregnancy rates. It is evident, too, that treatment with hCG on day 7 post breeding may have greater potential for improving pregnancy rates not only in dairy and beef cattle but equally beneficial to the embryo transfer programmes. Increased pregnancy rates confirm the hypothesis that CL dysfunction does cost the livestock industry appreciable losses in embryos.
Land and Food Systems, Faculty of
Graduate

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Chan, Wan-yi, and 陳韻怡. "Influenza A virus infection of human respiratory epithelium: tissue tropism and innate immuneresponses." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B41633696.

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Stevenson, Cheryl. "Nutrient intake, gastrointestinal microbiota and the effect of Lactobacillus plantarum 299V in irritable bowel syndrome patients." Thesis, Stellenbosch : Stellenbosch University, 2014. http://hdl.handle.net/10019.1/96018.

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Thesis (PhD)--Stellenbosch University, 2014.
ENGLISH ABSTRACT: Background: Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) disorder. GI symptoms and impaired quality of life affect between 10-20% of all adults, corresponding to about 25-50% of all patients who visit a gastroenterologist’s clinic. In recent years, several novel mechanisms of IBS that likely relate to previously established theories have been identified. Inflammation, postinfectious low-grade inflammation, immunological and genetic predisposition along with altered microbiota are critical in IBS development, while several dietary factors may also play a role in this syndrome. However, none of these factors accounts for the full repertoire of IBS symptoms, and the pathophysiology of this condition is not fully understood. The overarching aim of this study was to investigate the nutrient intakes, GI microbiota and the effect of Lactobacillus plantarum (L.plantarum) 299v in IBS patients. Sub-aims: 1) Update healthcare professionals on current probiotic information and provide an overview of probiotic treatment approaches, with special emphasis on IBS, 2) conduct a well designed randomised, double blind, placebo-controlled trial (RCT) with L. plantarum 299v as part of an intervention and establish whether a course of probiotics may alleviate undesirable symptoms of IBS and improve quality of life, 3) assess nutrient intake in patients with irritable bowel syndrome (IBS) compared to dietary recommendations, 4) validate and assess the reproducibility of food records and 5) identify possible nutrient risk components for establishing GI microbiota involved in IBS and as part of an intervention, determine whether a course of probiotics may alter stool microbiota. Results: 1) A review article published by the author provides an overview of current probiotic treatment options to health care professionals and indicates certain probiotics are a promising therapeutic treatment option for management of IBS symtpoms, 2) the effects of the single strain probiotic, L. plantarum 299v, supplementation was evaluated in a RCT. Compared to placebo, the probiotic supplementation showed no significant reduction in GI symptom severity scores, particularly abdominal pain relief. Quality of life was also not improved in the treatment versus control group. Both the treatment and placebo groups improved significantly over the trial period, indicating a large placebo effect, 3) nutrient intakes of the IBS patients compared to current dietary reference recommendations indicates that this group of patients are at risk for nutrient inadequacies in key macro and micronutrients, 4) the validity and reliability of the dietary data showed good reliability but poor validity as measured by plasma fatty acids and 5) the GI microbiota composition in the phenotypically different diarrhoea-predominant IBS (D-IBS) vs. constipation-predominant IBS (C-IBS) showed that D-IBS patients had significantly lower counts of Lactobacillus plantarum compared to C-IBS patients. The probiotic had no significant effects on the GI microbiota as measured by quantitative polymerase chain reaction (qPCR). It was found that nutrient intakes had a significant impact on the microbiota. Lower fibre intakes were associated with higher Bacteroides spp., lower Bifidobacteria bifidum and Lactobacillus plantarum counts in both IBS groups. Conclusion: Taken together, L.plantarum 299v did not alleviate the GI symptoms of IBS, nor was it associated with significant changes in the GI microbiota. IBS patients may be at risk of key nutrient inadequacies. The influence of nutrient intakes on the GI microbiota provides an attractive explanation as a potential pathophysiological factor for IBS.
AFRIKAANSE OPSOMMING: Agtergrond: Prikkelbare derm-sindroom (PDS) is ‘n algemene gastro-intestinale (GI) stoornis. GI simptome affekteer die lewenskwaliteit van 10-20% van alle volwassenes. Dit stem ooreen met ongeveer 25-50% van alle pasiënte wat ‘n gastroënteroloog konsulteer. Verskeie oorspronklike meganismes vir die ontwikkeling van PDS is onlangs identifiseer. Inflammasie, post-infektiewe lae-graadse inflammasie, immunologiese en genetiese vatbaarheid tesame met veranderde mikrobiota is krities vir die ontwikkeling van PDS. Sekere dieetfaktore mag ook bydraend wees tot hierdie sindroom. Geen van hierdie faktore is egter verantwoordelik vir die volle spektrum van PDS simptome nie en die patofisiologie van die toestand word ook nog nie ten volle verstaan nie. Die oorkoepelende doel van hierdie studie is om nutriëntinname, GI mikrobiota en die uitwerking van L.plantarum 299v in PDS pasiënte bepaal. Sub-doelwitte: 1) Om gesondheidswerkers in te lig aangaande die nuutste inligting oor probiotika en om ‘n oorsig van probiotika behandelingsopsies te verskaf, met spesiale klem op PDS, 2) om ‘n goed beplande ewekansige, dubbel-blinde, plasebo-beheerde kliniese studie met L.plantarum 299v as deel van die intervensie uit te voer om sodoende te bepaal of ‘n kursus probiotika ongewensde simptome van PDS kan verbeter en lewenskwaliteit sodoende verhoog, 3) om nutriëntinname in pasiënte met PDS te bepaal vergeleke met dieet aanbevelings, 4) om die geldigheid en herhaalbaarheid van voedselrekords te bepaal en 5) om moontlike nutriënt risikokomponente vir die ontwikkeling van GI mikrobiota betrokke in PDS te identifiseer en om as deel van ‘n intervensie te bepaal of ‘n kursus probiotika stoelgang mikrobiota patrone verander. Resultate: 1) ‘n Oorsigartikel gepubliseer deur die kandidaat dui probiotika aan as ‘n belowende terapeutiese opsie in die behandeling van PDS simptome, 2) die effek van ‘n enkelstam probiotikum, L.plantarum 299v, is evalueer deur ‘n ewekansige, dubbel-blinde, plasebo-beheerde kliniese studie. Vergeleke met die plasebo, het probiotiese aanvulling geen betekenisvolle vermindering in die GI simptome in PDS pasiënte tot gevolg gehad nie. Lewenskwaliteit het ook nie verbeter in die behandelde versus die kontrole groep nie. Beide die behandelde en plasebo groepe het aansienlik verbeter oor die studietydperk, wat ‘n groot plasebo effek aandui, 3) nutriëntinname van die PDS groep vergeleke met huidige dieetaanbevelings, dui daarop dat hierdie groep pasiënte ‘n risiko het vir die ontwikkeling van kern nutriënttekorte (makro- en mikronutriënte), 4) die geldigheid en betroubaarheid van die dieetdata dui op goeie betroubaarheid, maar swak geldigheid soos bepaal deur plasma vetsure en 5) die dermkanaal mikrobiotiese samestelling in die verskillende fenotipes, diarree-oorheersende PDS (D-PDS) vs. konstipasie-oorheersende PDS (K-PDS) dui daarop dat D-PDS pasiënte aansienlike minder Lactobacillus plantarum gehad het vergeleke met K-PDS pasiënte. Die probiotikum het geen beduidende uitwerking op die oorheersende mikrobiota gehad nie, soos gemeet deur kwantitatiewe polimerase kettingreaksie (kPKR). Daar is gevind dat dieet ‘n beduidende impak op die mikrobiota gehad het. Daar is ‘n verband tussen laer vesel inname en hoёr Bacteroides spp. en laer Bifidobacteria bididum en Lactobacillus plantarum tellings gevind in beide PDS groepe. Gevolgtrekking: Die L.plantarum 299v enkelstam probiotikum het nie die gastrointestinale simptome van PDS pasiënte verlig nie en daar is ook geen beduidende veranderinge in die mikrobiota gevind nie. PDS pasiënte mag ‘n verhoogde risiko toon vir kern nutriënttekorte. Die invloed van nutriëntinname op GI mikrobiota verskaf ‘n belowende verduideliking as ‘n potensiële patofisiologiese faktor in PDS.

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Briggs, Virginia G. "Injection Treatment for Lower Back Pain in Older Adults with Lumbar Spinal Stenosis: A Dissertation." eScholarship@UMMS, 2009. https://escholarship.umassmed.edu/gsbs_diss/439.

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Background:Lower back pain is one of the most common health-related complaints in the adult population. Thirty percent of Americans 65 years and older reported symptoms of lower back pain in 2004. With an aging population, the proportion of people over the age of 65 is expected to reach 20% by the year 2030. Because of this increase in older adults, lumbar spinal stenosis (LSS) associated with arthritic changes will also likely increase. In older adults, lower back pain is most often caused by degenerative lumbar spinal stenosis. Stenosis is the narrowing ofthe spinal canal, causing pressure on the nerve roots and is frequently treated surgically. Lumbar spinal stenosis is one of the most common reasons for back surgery in patients 65 years and older 2. However, risks associated with surgery increase with age 3-5 and older patients may choose non-surgical treatment for their lower back pain, including injection treatment. Injection treatment, usually consisting of anti-inflammatory medications and analgesics, has improved since the mid-1990's when fluoroscopic guidance was developed. Information about injection treatment for lower back pain is limited, especially in the older population. An extensive review of published literature regarding injection treatment revealed a paucity of information about older adults diagnosed with lumbar spinal stenosis. In this study, three aims were designed to gain more information about the effectiveness of injection treatment in older patients with lumbar spinal stenosis. In the first (retrospective) study, information about receipt of second injections and time between injections was collected to examine injection usage. In the second and third (prospective) studies, information about pain relief and functional return following injection treatment was collected to examine the effectiveness of injection treatment in patients age 60 and older diagnosed with lumbar spinal stenosis. To our knowledge, such results have not been repolted for this population in the literature. Objective:Injection treatment is a commonly used non-surgical procedure to alleviate lower back pain in older adults. However, older patients do not have enough information about how long pain relief will last after treatment or the amount of pain relief and functional return they will experience. These studies focused on three topics: 1) usage of injection treatment; 2) effectiveness of injection treatment on pain relief; 3) effectiveness of injection treatment on functional return. In addition, the variations of the effectiveness were examined by selected patient attributes. Methods:In a retrospective study, medical records of patients aged 60 years or older from a high volume dedicated spine center at the University of Massachusetts Memorial Hospital were retrospectively reviewed. This study included those diagnosed with degenerative LSS, who had not received an injection for lower back pain within six months, and whom were treated between June I, 2006 and May 31, 2007. In two prospective studies, patients scheduled for lumbar injection treatment between January 1 and June 30, 2008 were selected from the University of Massachusetts Memorial Hospital Spine Center. Selection criteria included patients age 60 and over, diagnosed with degenerative lumbar spinal stenosis and no previous lumbar injection within 6 months or lumbar surgery within 2 years. The Pain sub-score of the SF-36 questionnaire was used to measure pain at baseline and at one and three months post injection. The Physical Component Score (PCS) of the SF-36 questionnaire and the Oswestry Disability Index (ODI) were used to measure function at baseline and at one and three months post injection. Variations in longitudinal changes in scores by patient characteristics were analyzed in both unadjusted (univariate) analyses using one-way analysis of variance (ANOVA), and adjusted (multiple regression) analyses using linear mixed effects models. Results: In the retrospective cohort, the mean age of the cohort was 68, 64% were female, 59% were married, with a mean Body Mass index of 32 kg/m2. Of 92 eligible patients, 57% returned for a second injection within six months of the first. The mean number of months between injections was 4.8 for all patients, ranging from 1 to 22 months. When patient characteristics were examined, the only variable that showed a statistically significant difference was age. Patients aged 70 years and older were found to be 67% less likely to return for a second injection when compared to patients age 60-69 (OR=0.33 (0.12 - 0.94)p In the prospective cohort, information was collected on 62 patients. Mean Pain scores improved significantly from baseline to one month (14.1 points), and from baseline to three months (8.3 points). Post injection changes in Pain scores varied by Body Mass Index (BMI) and baseline emotional health. Based on a linear mixed effects model analysis, higher baseline emotional health, as measured by the SF-36 Mental Component Score (MCS>50), was associated with greater reduction in pain over three months when compared to lower emotional health (MCS Conclusion: Patients over age 70 do not return for repeat injection as frequently as patients age 60-69. In addition, each year a patient ages over age 60, they are 10% less likely to return for a repeat injection. Lower back pain in older adults with LSS is clinically significantly alleviated after injection treatment. In addition, injection treatment for LSS is associated with return of lost function needed for daily living activities in older adults. Pain relief and functional return varies by patient personal and clinical characteristics. Higher emotional health was associated with more pain relief and more functional return experienced over three months following injection treatment. Additional information is needed about why older patients do not return for second injections at the same rate as younger patients and how emotional health affects response to injection treatment in older adults.

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Sharifi, Bella. "The Development of Novel Apurinic/Aprymidinic Endonuclease/Redox-factor 1 Inhibitors for the Treatment of Human Melanoma." Chapman University Digital Commons, 2019. https://digitalcommons.chapman.edu/pharmaceutical_sciences_theses/7.

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Apurinic/apyrimidinic DNA repair endonuclease-1 (APE1), first recognized as an important DNA excision repair enzyme, is also known as Redox Factor-1 (Ref-1) involved in the activation of many nuclear transcription factors in both redox-dependent and independent manner. It has been well-documented that the overexpression of APE/Ref-1 contributes to the development of chemo-resistance and is associated with tumor progression in many human malignancies [1]. Our previous study in melanoma demonstrated that the development of novel inhibitors targeting the redox regulation domain of APE/Ref-1 is a promising strategy for melanoma treatment. To date, limited successes have been reported in developing novel APE/Ref-1 inhibitors for cancer treatment. Utilizing a structure-based approach, our study identified and characterized small molecular inhibitors of APE/Ref-1. First, N-terminally truncated APE/Ref-1 protein lacking the first 40 amino acid residues (∆40APE-1wt) was cloned into the pGEX-6P1 vector to express the GST-∆40APE-1wtprotein. After cleavage of GST-tag, the concentrated ∆40APE-1wt protein was subjected to protein crystallization study. We have successfully diffracted ∆40APE-1wt crystals and collected data with a resolution of 1.57Å. The crystal structure was further determined by molecular replacement in Molrep using the already available human APE-1 structure (PDB: 5CFG). For the first time, we observed the dimerization of APE/Ref-1 protein formed under oxidative conditions, which may contribute to the redox regulation of APE/Ref-1. Such structural transformation of APE/Ref-1 protein under distinct redox conditions may pave the way for future drug development and optimization. The binding affinity of the candidate compounds with ∆40APE-1wt protein was also determined using Surface Plasmon Resonance (SPR), and the Ki values were analyzed. One of the potent inhibitors developed by our group by structure-based approach, exhibited promising anti-melanoma activities both in vitro and in vivo. Future studies on the structure-activity association are warranted.

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Lignell, Anders. "In vitro Pharmacodynamics of Antifungal Agents in the Treatment of Candida Infections." Doctoral thesis, Uppsala universitet, Infektionssjukdomar, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-133781.

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Pharmacodynamic studies are important for the optimal use of antimicrobial agents. Combination antifungal therapy may be one method to improve outcome in invasive Candida infections. An in vitro kinetic model to study the pharmacodynamic effects of a combination of two antifungal agents with different elimination rates was developed and the pharmacodynamics of amphotericin B (AMB), voriconazole (VRC) or the combination was evaluated. Exposure to VRC inhibited the fungicidal activity of sequential doses of AMB against VRC-susceptible strains of C. albicans. The interaction was VRC dose-dependent. AMB activity was regained once VRC was removed or it increased gradually when the concentration of VRC had fallen below the minimum inhibitory concentration (MIC). The VRC-AMB interaction, however, was also present against strains of C. albicans, C. glabrata and C. krusei despite reduced VRC susceptibility. Against these strains the interaction was not predicted by the MIC value, suggesting that mechanisms of resistance may be of importance. Until more data are available, a reasonable recommendation is probably to avoid the sequential use of VRC followed by AMB and to use the combination of VRC and AMB for the treatment of Candida infections with caution. Only the unbound fraction of a drug is generally accepted as pharmacologically active. The activity of posaconazole (POS) with a protein binding of 98-99% was tested in serum against Candida species and compared with the calculated unbound serum concentration in protein-free media. Significant differences emerged at clinically relevant POS serum concentrations of 1.0 and 0.10 mg/l compared with the serum control regimen against one strain of C. lusitaniae. In RPMI 1640 the corresponding calculated unbound concentrations resulted in no effect for the low dose regimen compared with the RPMI 1640 control regimen. Further, against seven additional Candida strains tested, the effect of POS was greater in serum than in RPMI 1640. A flux from serum protein bound to fungal lanosterol 14α-demethylase bound POS may be the explanatory mechanism.

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Burke, Arista. "Expression of the chimeric SAF gene from Human Papillomavirus in the methylotrophic yeasts Pichia pastoris and Hansenula polymorpha." Thesis, Stellenbosch : Stellenbosch University, 2011. http://hdl.handle.net/10019.1/6908.

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Thesis (MSc (Microbiology))--Stellenbosch University, 2011.
ENGLISH ABSTRACT: The link between infection with Human Papillomavirus (HPV) and the development of cervical cancer has been established by several epidemiology studies. Cervical cancer is the second most common cancer among women and it occurs at a rate of 22.8 cases per 100 000 women in South Africa. Approximately 86% of newly reported cases of cervical cancer occur in developing countries where limited access to medical facilities hampers efforts to prevent and screen for HPV infection. Two commercial virus-like particle (VLP) vaccines consisting of HPV major structural protein L1, which protect against the most common high-risk HPV-types, are currently available. The high cost and type specificity of these commercially available vaccines have necessitated the development of a low cost, broad-spectrum HPV vaccine. Inclusion of the minor structural protein L2 has been shown to induce broadly cross-neutralizing antibodies and therefore a chimera was constructed that contains an epitope of L2 inserted within the L1 sequence. This construct, renamed SAF, was shown to be highly immunogenic and thus has the potential to be used as a prophylactic cervical cancer vaccine. Methylotrophic yeasts are known to be excellent producers of recombinant proteins due to their strongly inducible promoters that allow culturing of these yeasts to very high cell densities. Pichia pastoris and Hansenula polymorpha have been employed in several studies for heterologous protein production and levels of protein higher than 1 g/L have been reported. These yeasts also have GRAS status and can therefore be used to manufacture products for use in humans. In this study, the potential of H. polymorpha and P. pastoris to produce SAF intracellularly was evaluated. The effect of increased gene dosage and peroxisomal targeting on SAF production was examined as possible strategies to increase the yield of SAF. Peroxisomal targeting was achieved by fusing the SAF gene at the C-terminal end with the Peroxisomal Targeting Sequence 1 (PTS1) which consists of a short tri-peptide: –SKL. The functionality of PTS1 was confirmed using green fluorescent protein (GFP), fluorescence microscopy and peroxisome isolation. Peroxisomal targeting was shown to have a negative effect on SAF production levels in both H. polymorpha and P. pastoris. An increase in gene dosage had no discernable effect on SAF yield in H. polymorpha which is in contrast to previous research. The highest production levels were achieved by P. pastoris KM71 (24.86 mg/L) which compares well to levels of L1 achieved by other research groups. The most significant insight emerging from this work was that all the strains that produced SAF at detectable levels were equally efficient at the production of SAF. Increased biomass was therefore the biggest contributor to high SAF levels (mg/L) in the P. pastoris strains as significantly higher cell densities were achieved during culturing of these strains. With the necessary optimisation, the methylotrophic yeasts have the potential to be used as hosts for the production of a broad-spectrum HPV vaccine.
AFRIKAANSE OPSOMMING: Die skakel tussen infeksie met Mens Papilloomvirus (HPV) en die ontwikkeling van servikale kanker is deur verskeie epidemiologiese studies bevestig. Servikale kanker is die tweede mees algemene kanker onder vroue en dit kom voor teen ‘n tempo van 22.8 gevalle per 100 000 vroue in Suid Afrika. Ongeveer 86% van alle nuwe gevalle kom voor in ontwikkelende lande waar beperkte toegang tot mediese fasiliteite pogings om HPV infeksie te voorkom en te behandel, belemmer. Twee pseudovirale-partikel (VLP) entstowwe teen HPV is tans op die mark beskikbaar en hierdie entstowwe verleen immuniteit teen die mees algemene hoë-risiko HPV tipes. Die hoë koste en nou spektrum van hierdie entstowwe het dit nodig gemaak om ‘n goedkoop, wye-spektrum HPV entstof te ontwikkel. Navorsing het bewys dat die insluiting van die strukturele L2 proteïen in die VLP entstof, lei tot die indusering van neutraliserende teenliggame, wat wye spektrum antigenisiteit tot gevolg het. ‘n Chimeriese proteïen wat ‘n epitoop van L2 binne die L1 volgorde bevat is gekonstrueer, en hierdie proteïen is benoem SAF. SAF het hoë immunogenisiteit en kan dus potensieel as ‘n voorkomende servikale kanker entstof gebruik word. Metielotrofiese giste is bekend vir hulle vermoë om hoë vlakke rekombinante proteïene te produseer as gevolg van hulle induseerbare promotors wat groei tot baie hoë sel digthede toelaat. Pichia pastoris en Hansenula polymorpha is in menigte studies gebruik om heteroloë proteïene te produseer tot vlakke bo 1 g/L. Hierdie giste en die proteïen produkte wat hulle vorm word algemeen aanvaar as veilig vir menslike gebruik. In hierdie studie het ons die potensiaal van H. polymorpha en P. pastoris om SAF intrasellulêr te produseer, geevalueer. Die effek op SAF produksie van verhoogde geen dosering asook die teiken van SAF na die peroksisoom was ondersoek as moontlike strategieë om die opbrengs van SAF te verhoog. Die teiken van SAF na die peroksisoom is behaal deur die Peroksisomale Teiken Volgorde 1 (PTS1) aan die C-terminaal van SAF te heg. Die funksionaliteit van PTS1 was bevestig deur gebruik te maak van groen fluoroserende proteïen (GFP), fluoressensie mikroskopie en isolering van peroksisome. Teiken van SAF na die peroksisoom het ‘n negatiewe uitwerking gehad op SAF uitdrukking in beide H. polymorpha en P. pastoris. ‘n Verhoging in geen dosering het geen onderskeibare effek gehad op SAF opbrengs in H. polymorpha nie wat in teenstelling is met vorige navorsing. Die hoogste produksie vlakke is opgelewer deur P. pastoris KM71 (24.86 mg/L) wat goed vergelyk met vlakke van L1 wat deur ander navorsings groepe behaal is. Die belangrikste gevolgtrekking wat gemaak kan word uit hierdie studie is dat al die rasse wat SAF geproduseer het in meetbare hoeveelhede ewe effektief was. Verhoogde biomassa was dus die grootste bydraende faktor tot hoë SAF vlakke (mg/L) in die P. pastoris rasse as gevolg van die hoë sel digthede wat hierdie rasse kan bereik. Dit is duidelik dat metielotrofiese giste, met die nodige optimisering, oor die potensiaal beskik om as gasheer sisteme te dien vir die produksie van ‘n wye spektrum HPV entstof.
The NRF and the Department of Microbiology for financial support

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Yeh, Hsin-Hsien. "Utility and validation of the histone deacetylase (HDAC) substrate, [18F]FAHA, as a positron emission tomography (PET) imaging biomarker in non-human primates and HD transgenic mice for evaluation of neurodegenerative diseases and HDAC inhibitor treatment." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/utility-and-validation-of-the-histone-deacetylase-hdac-substrate-18ffaha-as-a-positron-emission-tomography-pet-imaging-biomarker-in-nonhuman-primates-and-hd-transgenic-mice-for-evaluation-of-neurodegenerative-diseases-and-hdac-inhibitor-treatment(69cbe9a1-aa64-45d6-947f-9368eabb071c).html.

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Histone deacetylase (HDAC) inhibitors (HDACIs) have long been studied and shown promises in the treatment of various neurodegenerative disorders including Huntington’s disease (HD). Based on many demonstrated potentials of HDACIs in mitigating various diseases, we evaluated the utility of [18F]FAHA, a radiolabeled derivative of suberoylanilide hydroxamic acid (SAHA), as a PET imaging agent for characterizing HDAC activity in a non-human primate model and a R6/2 transgenic mouse model of HD. We were aiming at HD as a potential first application, and therefore also examined the expression of HDAC and acetyl histone (AH) in brains of HD patients. This thesis describes that [18F]FAHA was metabolized rapidly to [18F]FACE in both blood plasma and brain. Kinetic analysis indicated that peripherally generated [18F]FACE contributed to the total brain activity. We therefore used a dual-input function model to analyze the kinetics of tracer accumulation and inhibition by SAHA in rhesus monkeys. Parametric images demonstrated the inhibition of HDAC activity in the brain by SAHA in a dose-dependent manner. Huntington’s mice (R6/2) showed a gradual increase of [18F]FAHA accumulation in all organs including the brain with age. In human tissue we found significant losses of acetyl histons expression from cells in the caudate nucleus and Purkinje cells of the cerebellum in HD, while the level of HDAC 5 was increased in these cells. The data obtained in rhesus monkeys indicated that PET imaging with [18F]FAHA could be used as a pharmacodynamic biomarker of the inhibition of class IIa HDACs by HDACIs in the brain and facilitate the development and clinical translation of novel class-IIa HDACIs.

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French, Cynthia L. "Examining Change in Symptoms of Depression, Anxiety, and Stress in Adults after Treatment of Chronic Cough: A Dissertation." eScholarship@UMMS, 2014. https://escholarship.umassmed.edu/gsn_diss/31.

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Background: Chronic cough is a common health problem with variable success rates to standardized treatment. Psychologic symptoms of depression, anxiety, and stress have been reported in association with chronic cough. The purpose of this study was to examine changes in the psychologic symptoms of depression, anxiety, and stress in adults with chronic cough 3 months after management using the ACCP cough treatment guidelines. Methods: This study used a descriptive longitudinal observation design. The major tenets associated with the Theory of Unpleasant Symptoms were examined. Intervention fidelity to the study components was measured. Results: A sample of 80 consecutive patients with chronic cough of greater than 8 weeks duration was recruited from one cough specialty clinic. Mean age of subjects was 58.54 years; 68.7% were female; 98.7% were white, and 97.5% were non-smokers. Mean cough duration was 85.99 months and mean cough severity was 6.11 (possible 0 –10; higher scores equal greater cough severity). Cough severity improved post treatment (n=65, M=2.32, (SE =.291), t (64) =7.98, p=.000); cough-specific quality-of-life also improved (n=65, M=9.17, (SE=1.30), t (64) =7.02, p=.000). Physiologic (urge-to-cough r=.360, ability to speak r=.469) and psychologic factors (depression r=.512, anxiety r=.507, stress r=.484) were significantly related to cough-specific quality-of-life and to cough severity (urge-to-cough r=.643, ability to speak r=.674 and depression r=.356, anxiety r=.419, stress r=.323) (all r, p=.01); social support and number of diagnoses were not related to either variable. Those experiencing greater financial strain had worse cough severity. Women, those experiencing financial strain, and those taking self-prescribed therapy had worse cough-specific quality-of-life. Intervention fidelity to the study plan was rated as high according to observation, participant receipt, and patient/physician concordance. Qualitative review identified potential areas of variability with intervention fidelity. Conclusions: By measuring the factors related to the major tenets of the Theory of Unpleasant Symptoms, this theory has helped to explain why those with chronic cough may have symptoms of depression, anxiety, and stress and why these symptoms improve as cough severity and cough-specific quality-of-life improve. Moreover, by measuring intervention fidelity, it may be possible to determine why cough guidelines may not be yielding consistently favorable results.

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Fouche, Celeste. "Differential effects of TNfα on satellite cell differentiation." Thesis, Stellenbosch : Stellenbosch University, 2007. http://hdl.handle.net/10019.1/19596.

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Thesis (MSc)--University of Stellenbosch, 2007.
ENGLISH ABSTRACT: Tumour necrosis factor alpha (TNFα) is a pleiotropic cytokine and has a wide variety of dose dependent cellular effects ranging from cell growth and differentiation, to inducing apoptosis. It has long been implicated in muscle and non-muscle inflammatory disorders, such as muscle wasting in chronic disease states, and rheumatoid arthritis. However, a physiological role for TNFα in muscle regeneration has been proposed as elevated levels of the cytokine are present when muscle regeneration processes are initiated: TNFα is secreted by infiltrating inflammatory cells, and by injured muscle fibres. Adult skeletal muscle contains a population of resident stem cell-like cells called satellite cells, which become activated, proliferate and differentiate following muscle injury to bring about repair of damaged muscle. Much research on the effects of TNFα on satellite cell differentiation has been conducted in recent years. It is however difficult to get a complete characterisation of the cytokine’s action as all models used slightly differ. We aimed therefore at providing comprehensive assessment of the effects of increasing doses of chronically supplemented TNFα on differentiating C2C12 cells. Cells were allowed to differentiate with or without TNFα supplementation for 7 days. Differentiation was induced at day 0. The effect on differentiation was assessed at days 1, 3, 5, and 7 by western blot analysis, and supplementary immunohistochemical analysis at days 1, 4, and 7 of markers of differentiation - muscle regulatory factors: MyoD and myogenin, markers of the cell cycle p21, PCNA, and the integral signalling molecule, p38MAPK. TNFα supplementation at day 1 tended to positively regulate early markers of differentiation. With continued supplementation however, markers of differentiation decreased dose dependently in treated cultures as the initial effect appeared to be reversed: A trend towards a dose dependent decrease in MyoD, myogenin and p21 protein existed in treated cultures at days 3, 5, and 7. These findings were significant at day 5 (p21, p<0.05), and day 7 (myogenin, p<0.05). A significant dose dependent decrease in p38 phosphorylation was evident at day 3 (p<0.05), while phospho-p38 was dose dependently increased at day 7 (p<0.05). Taken together, these data show that TNFα supplementation for 24 hours following the induction of differentiation in vitro, tends to increase levels of early markers of differentiation, and with continued TNFα supplementation decrease markers of differentiation in a dose dependent fashion. This study provides a comprehensive characterisation of the dose and time dependent effects of TNFα on satellite cell differentiaton in vitro. The model system used in the current study, allows us to make conclusions on more chronic disease states.
AFRIKAANSE OPSOMMING: Tumor nekrose faktor alfa (TNFα) is ‘n pleiotropiese sitokien wat ‘n wye verskeidenheid, dosis afhanklike, sellulêre effekte te weeg bring. Hierdie sellulêre effekte sluit sel groei en differensiasie tot sel dood in. TNFα is by beide spier en niespier inflammatoriese stoornisse soos spier tering in kroniese siektetoestande, en rumatiese artritis betrek. ‘n Fisiologiese rol vir TNFα is egter voorgestel aangesien verhoogde vlakke van die sitokien tydens inisiasie van spier herstel meganismes teenwoordig is: TNFα word deur infiltrerende inflammatoriese selle, asook deur beseerde spier vesels afgeskei. Volwasse skeletspier bevat ‘n populasie stamselagtige selle, sogenoemde satelliet selle. Laasgenoemde word geaktiveer, prolifereer en differensieër volgende spierbesering, om sodoende herstel van beskadigde spier te weeg te bring. Baie navorsing op die effekte van TNFα op satelliet sel differensiasie is onlangs uitgevoer. Dit is egter aansienlik moeilik om volgens hierdie navorsing‘n algehele beeld van TNFα se aksies te vorm aangesien alle modelle wat gebruik word verskil. Ons doel was daarom om ‘n omvangryke assessering van toenemende konsentrasies kronies gesupplementeerde TNFα op differensieërende C2C12 selle op ‘n enkele model uit te voer. Selle was vir 7 dae met of sonder TNFα supplementasie gedifferentieër. Differensiasie was by Dag 0 geïnduseer. TNFα se effek op differensiasie is op dae 1, 3, 5, en 7 deur middel van western blot analise geassesseer. Aanvullende immunohistochemiese bepalings op dae 1, 4, en 7 is verder deurgevoer. Merkers vir differensiasie het die spier regulatoriese faktore MyoD en miogenien, sel siklus merkers p21 en PCNA, asook die integrale sein transduksie molekule p38MAPK ingesluit. TNFα supplementasie by dag 1 het geneig om vroeë merkers van differensiasie positief te reguleer. Met voortdurende supplementasie is die vroeë positiewe effekte (op ‘n dosis afhanklike manier) egter omgekeer: ‘n neiging teenoor (‘n dosis afhanklike) vermindering in MyoD, miogenien en p21 proteïen het in behandelde kulture op dae 3, 5, en 7 bestaan. Hierdie bevindinge was beduidend by dag 5 (p21, p<0.05), en dag 7 (miogenien, p<0.05). A beduidende dosis afhanklike afname in p38 fosforilasie was duidelik by dag 3 (p<0.05), terwyl fosfo-p38 by dag 7 verhoog het met verhoogde konsentrasie TNFα (p<0.05). Bogenoemde saamgevat, dui aan dat TNFα supplementasie 24h volgende die induksie van differensiasie in vitro, verhoogde vlakke van vroeë differnsiasie merkers te weeg bring. Met voortdurende TNFα supplementasie, word differensiasie merkers egter met toenemende dosis verminder. Hierdie studie voorsien ‘n omvattende karakterisering van die dosis- en tyd afhanklike effekte van TNFα op satelliet sel differesiasie in vitro. Die model sisteem in hierdie studie gebruik, maak afleidings oor meer kroniese siektetoestande moontlik.

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Leishman, Alison Jane. "Harnessing the immunomodulatory capacity of dendritic cells differentiated from human induced pluripotent stem cells and the therapeutic potential of dendritic cell-derived exosomes for the treatment of lysosomal storage diseases." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:97f6791f-ff69-4645-9a3d-2ff23ce69529.

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Lysosomal storage diseases (LSDs) are a collection of disorders that feature the pathological accumulation of substrate frequently due to an enzymatic defect within the lysosomes. The most effective treatment regime for LSDs is enzyme replacement therapy. However, this treatment has faced two main challenges which have limited its treatment efficacy and clinical impact. One challenge constitutes the potential immunogenicity of the replaced enzyme, which can lead to the induction of an antibody response that prevents its effective targeting. Therefore, this thesis investigated the potential to derive patient-specific autologous dendritic cells (ipDCs) from fibroblasts which were obtained from a healthy donor and from a patient diagnosed with infantile-onset Pompe disease and were reprogrammed into induced pluripotent stem cells (iPSCs). This study demonstrated the feasibility of differentiating these iPSCs into ipDCs and investigated the potential to modulate their immunogenicity using a variety of agents. Using IL-10, this work was able to show the feasibility of generating patient-specific ipDCs with pro-tolerogenic characteristics which may be exploited for the induction of tolerance towards therapeutic enzymes. Secondly, the delivery of therapeutic enzymes to the central nervous system (CNS), which is frequently involved in disease pathogenesis, is limited by the selective-permeability of the blood brain barrier. As specifically-labelled exosomes have been shown capable of targeting to the CNS for the delivery of therapeutic molecules, this study has shown the possibility of harvesting exosomes from ipDC cultures. The potential of exploiting the endocytic capacity of dendritic cells for the loading of enzyme into exosomes was explored. Furthermore, this study has found that the administration of syngeneic and allogeneic exosomes from mouse bone-marrow derived DCs and ipDCs elicited an antibody-mediated immune response which may limit the clinical application of exosomes further highlighting the need for tolerance induction. Altogether, this study constitutes a first step towards potential improvements in the treatment of LSDs.

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Leishman, Alison Jane. "Harnessing the immonomodulatory capacity of dendritic cells differentiated from human induced pluripotent stem cells and the therapeutic potential of dendritic cell-derived exosomes for the treatment of lysosomal storage diseases." Thesis, University of Oxford, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.711748.

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Odendaal, Louise. "The effect of dietary Red Palm Oil on the functional recovery and the PKB/Akt pathway in the ischaemic/reperfused isolated rat heart." Thesis, Stellenbosch : Stellenbosch University, 2007. http://hdl.handle.net/10019.1/21745.

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Thesis (MSc)--University of Stellenbosch, 2007.
ENGLISH ABSTRACT: Introduction Cardiovascular disease is one of the leading causes of death in the world. Formation of harmful reactive oxygen species (ROS) is associated with several pathological conditions, and contributes to ischaemia/reperfusion injury. Antioxidants can be added to the diet in an attempt to decrease the prevalence of cardiovascular disease by decreasing the harmful effects of ischaemia/reperfusion injury. Red Palm Oil (RPO) consists of saturated, monounsaturated and polyunsaturated fatty acids and is rich in antioxidants such as -carotene, tocopherols and tocotrienols. It has previously been shown that RPO-supplementation improved reperfusion mechanical function. In these studies it was found that RPO might exert its beneficial effects during reperfusion through increased PKB/Akt pathway activity, which may lead to inhibition of apoptosis and improved mechanical function. Aims The aims of this study were: 1) to determine whether RPO-supplementation protected against ischaemia/reperfusion injury in the isolated perfused rat heart, 2) to confirm RPO-supplementation’s effect on the PKB/Akt pathway activity and, 3) to elucidate the regulators in the PKB/Akt pathway that RPOsupplementation influenced. Methods Male Wistar rats were divided into 4 groups, 2 control groups and 2 experimental groups. The 2 control groups were fed a standard rat chow (SRC) for 4 weeks. The two experimental groups received SRC and RPOsupplementation for 4 weeks. Hearts were excised and transferred to a Langendorff perfusion apparatus and perfused with Krebs-Henseleit buffer. Mechanical functional recovery was measured after 25 min of total global noflow ischaemia. The following parameters were also measured during various time points in the protocol: left ventricular develop pressure, heart rate, coronary flow, rate pressure product. Hearts were also freeze-clamped for biochemical analysis at 10 min during reperfusion. The biochemical analysis was aimed at determining PKB/Akt involvement. In a second protocol, hearts were subjected to the same perfusion protocol, but wortmannin was also added to the perfusion fluid, in order to inhibit PI3- kinase. Results Hearts from the RPO-supplemented rats showed an improved RPP recovery (92.26 ± 5.89 % vs 63.86 ± 7.74 %) after 10 min of reperfusion. This finding corroborated the findings of previous studies. Hearts of the RPOsupplemented rats perfused with wortmannin, showed increased RPP recoveries at several time points. Biochemical results showed that wortmannin did indeed inhibit PI3-K phosphorylation in the RPO-supplemented group, as was expected. The RPO-supplemented group that was perfused with wortmannin had an increased PKB/Akt (Ser473) phosphoyrylation, when compared to the wortmannin control group. It was also found that the combination of RPO and wortmannin had prosurvival effects. Discussion This study showed that RPO-supplementation offered protection against ischaemia/reperfusion injury in the Langendorff-perfusion apparatus at 10 min into reperfusion. Thereafter the significance of the protection was lost. This protection has been confirmed in several previous studies and several mechanisms have been proposed for this protection. Since no conclusive evidence exists on the precise mechanism of protection, our investigation focused on the regulators of the pro-survival PKB/Akt pathway. An improved functional recovery was also seen in the RPO-supplemented group that was perfused with wortmannin. This was an unexpected finding, because Wortmannin is a known PI3-kinase inhibitor (as was confirmed by our biochemical data). PI3-kinase phosphorylation leads to PKB/Akt phosphorylation and therefore, activation of a pro-survival pathway. It would be expected that wortmannin would inhibit PKB/Akt and thus decrease the survival of the cells. The RPO-supplementation thus reversed wortmannin’s detrimental effect to such an extent that the functional recovery was far better than RPO-supplementation alone. In the RPO + wortmannin group, PKB/Akt (Ser473) phosphorylation was increased, contrary to previous findings. This is an indication that RPO may have the ability to override wortmannin’s inhibitory effect on PI3-kinase, or that PKB/Akt (Ser473) may be phosphorylated independently of PI3-kinase.
AFRIKAANSE OPSOMMING: Inleiding Kardiovaskulêre siektes is een van die hoof oorsake van sterftes in die wêreld. Die vorming van skadelike reaktiewe suurstof spesies word geassosieer met verskeie patologiese kondisies en dra ook by tot isgemie/reperfusie skade. ‘n Moontlike manier om die voorkoms van isgemie/herperfusie skade asook kardiovaskulêre siektes te voorkom, is om antioksidante by die dieet te voeg. Rooi Palm Olie (RPO) bevat versadigde, mono-onversadigde en polionversadigde vetsure. RPO bevat ook ‘n oorvloed van antioksidante soos β- karoteen en tokoferole en tokotriënole. Dit is bewys in vorige studies dat RPO-aanvulling verbeter funksionele herstel. Hierdie voordelige effekte mag dalk wees agv verhoogde PKB/Akt pad aktiwiteit. Die PKB/Akt pad word geassosieer met die inhibisie van apoptose en verhoogde meganiese funksie. Doelwitte Die doelwitte van hierdie studie was om te bepaal of 1) RPO-aanvulling beskermende effekte teen isgemie/herperfusie skade in die geisoleerde rotharte het, 2) Bevestig of RPO-aanvulling wel die PKB/Akt pad beïnvloed 3). om die effekte wat RPO-aanvulling het op die reguleerders van die PKB/Akt pad te onthul. Metodes Manlike Wistar rotte is in 4 groepe verdeel. 2 Groepe kontrole rotte is ‘n standaard rotkosmengsel gevoer vir 4 weke. Die 2 eksperimentele groepe het ook ‘n standaard rotkosmengsel gekry plus ‘n RPO-aanvulling vir 4 weke. Harte is uitgesny en op ‘n Langendorff perfusie sisteem gemonteer en met Krebs-Henseleit buffer geperfuseer. Meganiese funksie herstel is gemeet na 25 min totale globale geen-vloei isgemie. Linker ventrikulêre ontwikkelde druk, harttempo, koronêre vloei en tempo druk produk is gemeet by verskillende tydpunte. Sommige harte is na 10 min herperfusie vir biochemiese analiese gevriesklamp. Die biochemiese analisiese was beoog om die PKB/Akt pad betrokkenheid te bepaal. ‘n Tweede stel harte is aan dieselfde perfusie protokol blootgestel, maar wortmannin (PI3-kinase inhibitor) is ook bygevoeg by die perfusie vloeistof. Resultate Die groep wat met RPO aangevul is, het na 10 min herperfusie, ‘n verbeterde tempo druk produk herstel getoon (92.26 ± 5.89 % vs 63.86 ± 7.74. Hierdie bevinding is ook met ander studies bevestig. ‘n Interessante bevinding was dat die groep wat met RPO aangevul is en met wortmannin geperfuseer is, ‘n verbeterde meganiese funksionele herstel getoon het. Biochemiese resultate het getoon dat wortmannin wel PI3-K fosforilering geinhibeer het. Die harte van die rotte in die groep wat aangevul is met RPO en daarna met wortmannin geperfuseer is, het ‘n toename in PKB/Akt (Ser473) fosforilering getoon, relatief tot die wortmannin geperfuseerde harte van die rotte in die kontrole groep. Hierdie groep (RPO-aanvulling en wortmannin perfusie) het beskermende effekte getoon. Bespreking Hierdie studie het getoon dat RPO-aanvulling beskerming gebied het teen isgemie/herperfusie skade in die Langendorff geperfuseerde rothart na 10 min herperfusie. Daarna is die beduidenheid van die beskerming verloor. Hierdie bevindings ondersteun die resultate van vorige studies. Verskeie moontlike meganismes is voorgestel vir die beskerming, maar die presiese meganisme is nog nie duidelik nie. In hierdie studie is daar gekyk na die reguleerders van die PKB/Akt pad. Geen vorige studies het al gefokus op RPO-aanvulling en sy effek op die reguleerders van die PKB/Akt pad nie. ‘n Onverwagte bevinding is dat harte van die rotte in die RPO + wortmannin groep ‘n verbeterde funksionele herstel getoon het. Wortmannin is ‘n PI3- kinase inhibitor. PI3-K fosforilering lei tot PKB/Akt fosforilering, wat tot sel beskerming lei. Dus, aangesien wortmannin PI3-K inhibeer, sou dit verwag word dat wortmannin sel beskerming sal verminder. Die RPO het egter die wortmannin se nadelige effekte tot so ‘n mate oorskrei dat die funksionele herstel baie beter was as die RPO-aanvulling alleen. Die verhoogde PKB/Akt (Ser473) fosforilering, wat gesien is in die RPO + wortmannin groep kan toegeskryf word aan RPO se vermoë om wortmannin se nadelige effekte te oorskrei. ‘n Moontlike verduideliking vir hierdie bevinding mag wees dat rooi palm olie PKB/Akt (Ser473) op ‘n PI3-K onafhanklike manier fosforileer.

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Awad, Hamza H. "Use of Multinational Registries to Assess and Compare Outcomes of Patients with an Acute Coronary Syndrome: A Dissertation." eScholarship@UMMS, 2011. https://escholarship.umassmed.edu/gsbs_diss/546.

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Background Acute coronary syndromes (ACS) are a major cause of mortality and morbidity in the developed world. By 2020, ACS will be the leading cause of morbidity and mortality worldwide, largely due to substantial increases in ACS burden in developing countries. The developing world has been under-represented in international ACS registries. The Arabian Gulf area is a part of the developing world where little is known about the epidemiology of ACS. The first aim of the dissertation is to compare ACS patient characteristics, current practice patterns, and in-hospital outcomes in the Arabian Gulf area to a large multinational sample. Patients with an ACS suffer numerous clinical complications that worsen their prognosis. Cardiogenic shock (CS) is the most serious complication of ACS and the leading cause of in-hospital death. Despite advances in therapies; CS hospital mortality rates continue to exceed 50%. The second aim of the dissertation is to describe the characteristics of patients presenting with ACS complicated by cardiogenic shock, their management, and outcomes in a large multinational sample. In recent years, ACS has been increasingly affecting younger patients. While marked age-related differences have been observed in the risk of developing as well as the prognosis of ACS, few studies however examined time trends in the epidemiology of ACS in young adult patients. The third aim of the dissertation is to examine trends in frequency rates, patient characteristics, treatment practices, and outcomes in young adults hospitalized with an ACS. Methods Data from two large multinational registries of patients hospitalized with an ACS were used for this investigation. Nearly 65,000 patients were enrolled in the Global Registry of Acute Coronary Events (GRACE) between 2000 and 2007, while 6,700 patients participated in the Gulf Registry of Acute Coronary Events (Gulf RACE) in 2007. Results Aim1: Patients in Gulf RACE were significantly younger and were more likely to be male, diabetic, and smoke Compared to GRACE. Patients in Gulf RACE were less likely to receive evidence based therapies. Short-term mortality rates were comparable between the two patient cohorts. Aim2: Compared to patients with no CS, patients with CS were more likely to be older, female, have a history of diabetes, and heart failure. Patients with CS were less likely to receive effective cardiac catheterization and adjunctive cardiac medications. In-hospital case-fatality rate of patients with CS were 59.4%. While in-hospital mortality declines over the study period, incidence rates only showed minor declines. Aim2: Baseline characteristics of patients < 55 years of age did not significantly change, while the use of evidence based therapies increased significantly during the years under study. Rates of short-term adverse outcomes and mortality significantly declined over time. Conclusions We observed marked regional differences in the risk profile, clinical management, and outcomes of patients with an ACS internationally compared to the Arab Middle East. Despite the encouraging trends in the use of evidence based therapies which have likely contributed to the improving trends in the prognosis of ACS, rates of development of ACS, as well as mortality due to ACS complications, remain high.

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Djalali, Mahmoud. "Contribution à l'étude du métabolisme digestif des corrinoïdes chez l'homme dans les conditions physiologiques et pathologiques." Nancy 1, 1988. http://www.theses.fr/1988NAN10030.

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Mise au point de la purification des corrinoïdes et leur séparation par chromatographie liquide à haute performance. La détermination quantitative a été réalisée par dosage radioisotopique des corrinoïdes présents dans les fractions issues de la chromatographie. Les analogues représentent respectivement 18,5 %, 55 % et 95 % des corrinoïdes présents dans le plasma, la bile et les selles. L'étude de l'étape porto-hépatique du cycle entérohépatique des corrinoïdes a permis de mettre en évidence l'origine principalement digestive des analogues de la vitamine B12. Après avoir montré l'importance de la dégradation de l'haptocorrine au niveau duodénal, nous avons abordé 2 circonstances pathologiques (l'insuffisance pancréatique et la mucoviscidose) où il existe un défaut de dégradation de l'haptocorrine dû au déficit enzymatique. En cas de cirrhose hépatique d'origine alcoolique, les concentrations en corrinoïdes totaux et en cobalamine ainsi que les taux d'IgA augmentent avec le degré de sévérité de l'atteinte hépatique. Nous pouvons donc envisager une inhibition compétitive de la captation hépatique des complexes haptocorrine - corrinoïdes par élévation du taux circulant d'asialoglycoprotéines

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Harmon, Amanda L. "Preventing Mother-to-Child Transmission of Human Immunodeficiency Virus-1 (HIV-1): Effects of Intrapartum and Neonatal Single-Dose Nevirapine Prophylaxis and Subsequent HIV-1 Drug Resistance at Antiretroviral Treatment Initiation." Scholarship @ Claremont, 2011. http://scholarship.claremont.edu/cmc_theses/305.

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The prevention of mother-to-child transmission is one of the most powerful tools in human immunodeficiency virus type 1 (HIV-1) prevention and has huge potential to improve both maternal and child health. In the absence of any preventative measures, infants born to and breastfed by their HIV-positive mothers have roughly a one-in-three chance of acquiring the infection themselves. HIV can be passed on from mother-to-child during pregnancy, during labor and delivery, and even after during breastfeeding. Intrapartum and neonatal single-dose nevirapine (sd-NVP) is the foundation of preventing mother-to-child transmission in lower resource settings where it has been used alone or as part of combination regimens. Both its simplicity and its long plasma half-life contribute to the success of sd-NVP based therapy. However, sd-NVP frequently results in HIV-1 viral resistance in mothers and children who become HIV infected despite prophylaxis. Sd-NVP leads to the development of non-nucleoside reverse transcriptase inhibitors (NNRTI) drug resistance, compromising the success of treatment of mother and child with subsequent antiretroviral combinations. Resistance to NNRTIs is particularly worrisome in lower resource settings since many subsequent regimens for maternal and infant antiretroviral therapy include a NNRTI drug.

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Hurlimann, Thierry. "The duty to treat very defective neonates as "persons" : from the legal and moral personhood of very defective neonates to their best interests in medical treatment." Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=80929.

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The dramatic improvement of neonatal intensive care has produced vexing ethical and legal questions. One of the most striking issues is to determine whether the most defective neonates should be provided with intensive care and to what extent they should be treated. This thesis demonstrates that an attempt to answer this question and an analysis of the demands and limitations of a duty to treat defective neonates cannot properly occur without first considering the legal concerns and ethical issues surrounding the notion of "person". The author examines germane ethical theories and North-American jurisprudence to see what approaches and standards commentators and courts have adopted in this respect. This thesis demonstrates that in the context of the cessation or non-initiation of intensive care, the legal and moral status of very defective neonates remain ambiguous. In particular, the author suggests that a legal best interests analysis that includes quality of life considerations may actually involve the use of criteria similar to those supported by the authors of the controversial moral theories that negate the personhood of seriously handicapped newborns. The author ultimately concludes that a clear divide between the legal definition of the "person" and the moral and social perceptions of that term is misleading.

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Nguyen, Hoa L. "Age and Sex Differences in Duration of Pre-Hospital Delay, Hospital Treatment Practices, and Short-Term Outcomes in Patients Hospitalized with an Acute Coronary Syndrome/Acute Myocardial Infarction: A Dissertation." eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/471.

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BackgroundThe prompt seeking of medical care after the onset of symptoms suggestive of acute coronary syndromes (ACS)/acute myocardial infarction (AMI) is associated with the receipt of coronary reperfusion therapy, and effective cardiac medications in patients with an ACS/AMI and is crucial to reducing mortality and the risk of serious clinical complications in these patients. Despite declines in important hospital complications and short-term death rates in patients hospitalized with an ACS/AMI, several patient groups remain at increased risk for these adverse outcomes, including women and the elderly. However, recent trends in age and sex differences in extent of pre-hospital delay, hospital management practices, and short-term outcomes associated with ACS/AMI remain unexplored. The objectives of this study were to examine the overall magnitude, and changing trends therein, of age and sex differences in duration of pre-hospital delay (1986-2005), hospital management practices (1999-2007), and short-terms outcomes (1975-2005) in patients hospitalized with ACS/AMI. MethodsData from 13,663 residents of the Worcester, MA, metropolitan area hospitalized at all greater Worcester medical centers for AMI 15 biennial periods between 1975 and 2005 (Worcester Heart Attack Study), and from 50,096 patients hospitalized with an ACS in 106 medical centers in 14 countries participating in the Global Registry of Acute Coronary Events (GRACE) between 2000 and 2007 were used for this investigation. Results In comparison with men years, patients in other age-sex strata exhibited significantly longer pre-hospital delay, with the exception of women < 65 years; had a significantly lower odds of receiving aspirin, angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), beta blockers, statins, and undergoing coronary artery bypass graft surgery (CABG) surgery or percutaneous coronary intervention (PCI), and were significantly more likely to develop atrial fibrillation, cardiogenic shock, heart failure, and to die during hospitalization and in the first 30 days after admission. There was a significant interaction between age and sex in relation to the use of several medications and the development of several of these outcomes; in patients Conclusions Our results suggest that the elderly were more likely to experience longer prehospital delay, were less likely to be treated with evidence-based treatments during hospitalization for acute coronary syndrome, and were more likely to develop adverse outcomes compared to younger persons. Younger women were less likely to be treated with effective treatments and were more likely to develop adverse outcomes compared with younger men while there was no sex difference in these outcomes. Interventions targeted at older patients, in particular, are needed to encourage these high-risk patients to seek medical care promptly to maximize the benefits of currently available treatment modalities. More targeted treatment approaches during hospitalization for ACS/AMI for younger women and older patients are needed to improve their hospital prognosis.

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Nunes, Mérces da Silva. "A função social da empresa: a indústria farmacêutica, os medicamentos de alto custo e doenças raras." Pontifícia Universidade Católica de São Paulo, 2014. https://tede2.pucsp.br/handle/handle/6412.

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In a Democratic Constitutional State - which elected the human being as the ultimate end of everything and the greatest value of all forms of coexistence, human dignity is the mother principle that inspires, guides and radiates all the legal and social order, is the value that drives and directs the society and its members to commit actions aimed at effecting and promoting the welfare of the human person. Therefore, at the time the Constitution states the dignity of the human being as the founding principle of the Federative Republic of Brazil, it is actually explaining that Brazilian society as a whole has the duty to protect, support and respect the citizen in what the they have as the most sacred and essential to their existence, which is the equality of all human beings in their personal dignity. Recognizing the equality of the human being, in his personal dignity implies that this equality must be respected and observed in all its aspects, especially the political, economic, legal and social conditions regardless of the nature and differences of gender, race, belief, color, language, wealth, birth, national or social origin, as stated in Section II of the Universal Declaration of Human Rights, from 1948. Due to this, the human being must be protected by society and all its members, not only in the sense that this protection has to be a guarantee for them to remain alive, but mainly not to be attacked in their dignity of human people, because their right to live with dignity and the right to a dignified existence is ensured. Regarding the delimitation and scope of the present study, it is crucial to emphasize that when providing the Unified Health System SUS, free of charge, with expensive drugs for rare diseases and treatment of needy people, the pharmaceutical industry gives to the Property a social function - that in a Democratic Constitutional State goes far beyond the payment of taxes and the availability of vacancies, since the hiring of employees and the payment of taxes are prerequisites to the exercise of the economic activity itself without which even the existence of the company would not be considered. In fact, the business activity directed to the exploration of drugs, as in the pharmaceutical industry, should be developed seeking the social interest, to the recovery and improvement of human health . Thus, for the property to meet its social function, as determined by the article 170, III of the Federal Constitution, the pharmaceutical industry has the duty to participate and engage with the state, sharing the responsibility for ensuring the right to health - fundamental social right, and contributing to the achievement of the basic objectives stated in the article 3 of the Federal Constitution
o valor maior de todas as formas de convivência, a dignidade da pessoa humana é o princípio matriz que inspira, norteia e irradia todo o ordenamento jurídico e social, é o valor que move e direciona a sociedade e seus integrantes à prática de ações destinadas à efetivação e promoção do bem estar da pessoa humana. Bem por isso, no momento em que a Constituição Federal explicita a dignidade da pessoa humana como princípio fundante da República Federativa do Brasil, na verdade, está afirmando que a sociedade brasileira, como um todo, tem o dever de proteger, amparar e respeitar o cidadão naquilo que o Homem tem de mais sagrado e essencial à sua existência, que é a igualdade de todo ser humano em sua dignidade de pessoa. Reconhecer a igualdade do ser humano, em sua dignidade de pessoa, implica dizer que essa igualdade deve ser respeitada e observada em todos os seus aspectos, sobretudo, os de natureza política, econômica, jurídica e social independentemente das condições e diferenças de sexo, raça, credo, cor, língua, riqueza, nascimento, origem nacional ou social, tal como explicitado no Artigo II, da Declaração Universal dos Direitos Humanos, de 1948. Por essa razão, o ser humano deve ser protegido pela sociedade e por todos os seus integrantes, não apenas no sentido de essa proteção ser uma garantia de que o ser humano permaneça vivo, mas, principalmente, para que não seja atingido em sua dignidade de pessoa humana, porquanto lhe é assegurado o direito de viver de forma digna, o direito a uma existência digna. No que concerne à delimitação e ao alcance do presente estudo, imperioso destacar que ao destinar, gratuitamente, em favor do Sistema Único de Saúde - SUS- medicamentos de alto custo e doenças raras para tratamento de pessoas carentes, a indústria farmacêutica confere à propriedade uma função social que, num Estado Democrático de Direito, vai muito além do pagamento de tributos e da disposição em oferecer postos de trabalho, uma vez que a contratação de funcionários e/ou colaboradores e o pagamento de tributos são condições indispensáveis ao exercício da própria atividade econômica sem as quais sequer a existência da empresa haveria de ser considerada. Na verdade, a atividade empresarial voltada para a exploração de medicamentos, como é o caso da indústria farmacêutica, deve ser desenvolvida no interesse social, visando a recuperação e a melhoria da saúde humana. Assim, para que a propriedade atenda a sua função social, como determina o artigo 170, III da Constituição Federal, a indústria farmacêutica tem o dever de participar e de agir em conjunto com o Estado, compartilhando a responsabilidade pela efetivação do direito à saúde - direito fundamental social e contribuindo para a consecução dos objetivos fundamentais explicitados no art. 3º da Constituição Federal

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32

Borg, Karin. "Sickness Absence with Musculoskeletal Diagnoses : An Eleven-Year Follow-Up of Young Persons." Doctoral thesis, Linköping : Univ, 2003. http://www.ep.liu.se/diss/med/07/86/index.html.

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33

"Plant-Made Biologics: Human Butyrylcholinesterase Mutants for the Treatment of Cocaine Addiction-Related Diseases." Doctoral diss., 2015. http://hdl.handle.net/2286/R.I.29972.

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abstract: Cocaine abuse affects millions of people with disastrous medical and societal consequences. Despite this, there is still no FDA-approved treatment to decrease the likelihood of relapse in rehabilitated addicts, and acute cocaine toxicity (overdose) is only symptomatically treated. Studies have demonstrated a promising potential treatment option with the help of the human serum enzyme butyrylcholinesterase (BChE), an enzyme capable of breaking down cocaine into biologically inactive side products. This activity of wild-type BChE, however, is relatively low. This prompted the design of variants of BChE which exhibit significantly improved catalytic activity against cocaine. Plants were used as a sustainable, scalable, affordable platform system to produce large amounts of human biologics such as these cocaine hydrolase variants of BChE. Using a tobacco relative, Nicotiana benthamiana, recombinant enzymes can be produced at quantities relevant to clinical use with desired kinetic properties. Next, the ability of the most promising plant-produced cocaine super hydrolase, pCocSH, to counter the lethal effects of cocaine overdose in vivo was tested. These studies revealed that this plant-produced enzyme can protect mice from an otherwise lethal dose of cocaine. Most excitingly, it was found that pCocSH can rescue mice from overdose when given immediately after the onset of cocaine-induced seizures. These studies provide in vitro and in vivo proof-of-principle for a promising plant-derived biologic to be used as a pharmacokinetic-based treatment for cocaine addiction-related diseases such as overdose.
Dissertation/Thesis
Doctoral Dissertation Molecular and Cellular Biology 2015

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Mota, Catarina. "Towards the therapeutic use of regulatory T cells for the treatment of human autoimmune diseases." Doctoral thesis, 2015. http://hdl.handle.net/10451/23654.

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Tese de doutoramento, Medicina (Imunologia Clínica), Universidade de Lisboa, Faculdade de Medicina, 2016
Regulatory T Cells (Treg), constitutively expressing the transcription factor Foxp3/FOXP3, play a crucial role in maintaining self-tolerance, assuming particular relevance in the context of autoimmunity. Adoptive transfer of Treg has been shown to be highly efficient in the prevention and treatment of autoimmunity in rodents and clinical trials exploring Treg-based adoptive therapy in Type I Diabetes (T1D) are currently ongoing. These therapies require large numbers of Treg, stressing the importance of a better knowledge of the molecular and cellular requirements for human thymic and peripheral Treg development. Moreover, widespread application of Treg-based therapy dealt with several limitations regarding the stability and function of in vitro expanded populations for in vivo use. The creation of efficient protocols enabling stable FOXP3 acquisition by human non-regulatory cells could overcome the limited availability of thymus-derived (t)Treg and would facilitate the generation of antigen-specific Treg, an ideal candidate in autoimmune diseases (AID) setting. The overall objective of this work was to provide new insights into the principles dictating human thymic and peripheral Treg development and homeostasis, thus facilitating the progress of Treg-based immunotherapy. First, we proposed to investigate the capacity of human non-regulatory memory CD4+ T cells to differentiate in vitro into bona-fide FOXP3-expressing cells and to assess the role of the Notch signaling pathway in modulating this conversion. We showed that stable and functional bona-fide Treg can be generated from memory CD4+ T cells and that Delta like (DL)1-mediated Notch signaling activation enhanced this conversion. We additionally showed that DL1 increased Treg proliferation, reinforcing the possible role of Notch in the homeostasis of the human peripheral Treg compartment. Importantly, we also demonstrated that DL1 enhanced the expression of function-related molecules within these cells, contributing to the maintenance of their regulatory phenotype. In order to better clarify the principles governing Treg development in the human thymus, we investigated the role of common gamma-chain (c) cytokines in human tTreg differentiation. We identified interleukin (IL)-2 and IL-15 as key molecular determinants in this process and excluded a major function for IL-4, IL-7 and IL-21. Moreover, we revealed that IL-2 and IL-15 are expressed in a non-overlapping pattern in the human thymus, with the former produced mainly by mature αβ and γδ thymocytes and the latter by monocyte/macrophages and B lymphocytes. Overall, this work has provided a better understading of the core mechanisms governing human Treg differentiation and homeostasis that should facilitate the further establishment of Treg-based therapies.
As Células T Reguladoras (T Regs), expressando constitutivamente o factor de transcrição Foxp3/ FOXP3, desempenham um papel crucial na manutenção da auto-tolerância, assumindo particular relevância no contexto de auto-imunidade. A transferência adoptiva de T Regs demonstrou ser altamente eficaz na prevenção e no tratamento de autoimunidade em roedores e ensaios clínicos explorando terapêuticas baseadas em T Regs na Diabetes Tipo I estão actualmente em curso. Estas terapias exigem um grande número de células, pelo que é essencial um melhor conhecimento dos requisitos moleculares e celulares para o desenvolvimento no timo humano e na periferia de T Regs. Além disso, a aplicação generalizada desta terapêutica tem ainda várias limitações no que respeita à estabilidade e função das populações expandidas in vitro para utilização in vivo. A criação de protocolos eficientes que permitam a aquisição estável de FOXP3 por células não-reguladoras poderá ultrapassar a disponibilidade limitada de T Regs de origem tímica e facilitar a geração de T Regs com especificidade antigénica, potencialmente ideais no contexto de doenças auto-imunes. O objetivo global deste trabalho foi investigar os princípios que ditam o desenvolvimento tímico e periférico e a homeostasia das T Regs humanas, facilitando assim o progresso da imunoterapia utilizando T Regs. Em primeiro lugar, propusemo-nos investigar a capacidade das células T CD4+ de memória não-reguladoras para se diferenciarem in vitro em células que expressam FOXP3, avaliando o papel da via de sinalização Notch na modulação desta conversão. Revelámos que T Regs estáveis e funcionais podem ser geradas a partir de células T CD4+ de memória isoladas do sangue periférico de indivíduos saudáveis e que a activação de Notch mediada por DL1 aumenta esta conversão. Adicionalmente, demonstrámos que DL1 aumenta a proliferação de T Regs circulantes, reforçando o possível papel de Notch na homeostasia do compartimento periférico de T Regs. Mostrámos também que DL1 aumenta a expressão de moléculas relacionadas com a função de T Regs circulantes, contribuindo para a manutenção do fenótipo das T Regs. Com a finalidade de clarificar os princípios que regem o desenvolvimento de T Regs no timo humano, investigámos o papel das citocinas que utilizam um receptor com cadeia gama comum na diferenciação de T Regs humanas. Identificámos as interleucinas IL-2 e IL-15 como determinantes moleculares chave neste processo, tendo sido excluída uma função de relevo para IL-4, IL-7 e IL-21. Mais ainda, revelámos que IL-2 e IL-15 são expressas num padrão não sobreposto no timo humano, sendo a primeira produzida principalmente por timócitos maduros αβ e γδ e a última por monócitos/ macrófagos e linfócitos B. Em conclusão, este trabalho proporcionou um melhor conhecimento dos mecanismos fundamentais que regem o desenvolvimento, a homeostasia e manipulação in vitro das T Regs em humanos, contribuindo para o estabelecimento das terapêuticas baseadas em T Regs.

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Park, Joon-Hyuk. "Wearable Torso Exoskeletons for Human Load Carriage and Correction of Spinal Deformities." Thesis, 2016. https://doi.org/10.7916/D81V5F5G.

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The human spine is an integral part of the human body. Its functions include mobilizing the torso, controlling postural stability, and transferring loads from upper body to lower body, all of which are essential for the activities of daily living. However, the many complex tasks of the spine leave it vulnerable to damage from a variety of sources. Prolonged walking with a heavy backpack can cause spinal injuries. Spinal diseases, such as scoliosis, can make the spine abnormally deform. Neurological disorders, such as cerebral palsy, can lead to a loss of torso control. External torso support has been used in these cases to mitigate the risk of spinal injuries, to halt the progression of spinal deformities, and to support the torso. However, current torso support designs are limited by rigid, passive, and non-sensorized structures. These limitations were the motivations for this work in developing the science for design of torso exoskeletons that can improve the effectiveness of current external torso support solutions. Central features to the design of these exoskeletons were the abilities to sense and actively control the motion of or the forces applied to the torso. Two applications of external torso support are the main focus in this study, backpack load carriage and correction of spine deformities. The goal was to develop torso exoskeletons for these two applications, evaluate their effectiveness, and exploit novel assistive and/or treatment paradigms. With regard to backpack load carriage, current torso support solutions are limited and do not provide any means to measure and/or adjust the load distribution between the shoulders and the pelvis, or to reduce dynamic loads induced by walking. Because of these limitations, determining the effects of modulating these loads between the shoulders and the pelvis has not been possible. Hence, the first scientific question that this work aims to address is What are the biomechanical and physiological effects of distributing the load and reducing the dynamic load of a backpack on human body during backpack load carriage? Concerning the correction of spinal deformities, the most common treatment is the use of a spine brace. This method has been shown to effectively slow down the progression of spinal deformity. However , a limitation in the effectiveness of this treatment is the lack of knowledge of the stiffness characteristics of the human torso. Previously, there has been no means to measure the stiffness of human torso. An improved understanding of this subject would directly affect treatment outcomes by better informing the appropriate external forces (or displacements) to apply in order to achieve the desired correction of the spine. Hence, the second scientific question that this work aims to address is How can we characterize three dimensional stiffness of the human torso for quantifiable assessment and targeted treatment of spinal deformities? In this work, a torso exoskeleton called the Wearable upper Body Suit (WEBS) was developed to address the first question. The WEBS distributes the backpack load between the shoulders and the pelvis, senses the vertical motion of the pelvis, and provides gait synchronized compensatory forces to reduce dynamic loads of a backpack during walking. It was hypothesized that during typical backpack load carriage, load distribution and dynamic load compensation reduce gait and postural adaptations, the user’s overall effort and metabolic cost. This hypothesis was supported by biomechanical and physiological measurements taken from twelve healthy male subjects while they walked on a treadmill with a 25 percent body weight backpack. In terms of load distribution and dynamic load compensation, the results showed reductions in gait and postural adaptations, muscle activity, vertical and braking ground reaction forces, and metabolic cost. Based on these results, it was concluded that the wearable upper body suit can potentially reduce the risk of musculoskeletal injuries and muscle fatigue associated with carrying heavy backpack loads, as well as reducing the metabolic cost of loaded walking. To address the second question, the Robotic Spine Exoskeleton (ROSE) was developed. The ROSE consists of two parallel robot platforms connected in series that can adjust to fit snugly at different levels of the human torso and dynamically modulate either the posture of the torso or the forces exerted on the torso. An experimental evaluation of the ROSE was performed with ten healthy male subjects that validated its efficacy in controlling three dimensional corrective forces exerted on the torso while providing flexibility for a wide range of torso motions. The feasibility of characterizing the three dimensional stiffness of the human torso was also validated using the ROSE. Based on these results, it was concluded that the ROSE may alleviate some of the limitations in current brace technology and treatment methods for spine deformities, and offer a means to explore new treatment approaches to potentially improve the therapeutic outcomes of the brace treatment.

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36

"Apoptotic mechanism of anti-tumor treatment in human laryngeal squamous cell cancer infected with human papillomavirus type 16 (HPV16)." Thesis, 2006. http://library.cuhk.edu.hk/record=b6074228.

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In addition, we investigated the cytotoxic effect of a widely used chemotherapeutic agent 5Fu on laryngeal squamous cell cancer cell lines and evaluated the role of p53 in 5Fu treatment. We found that the apoptosis and G1/S cell arrest mediated by 5Fu in laryngeal cancers is p53-independent but p21 WAF1/CIP1-dependent. We further demonstrated the effect of 5Fu on HPV16-associated laryngeal cancer cells. Using cytotoxicity assay and Annexin V staining, we proved that 5Fu induces apoptosis in all of the transfected cells in a dose- and time-dependent manner, suggesting that the process was not prevented by HPV16 E6 or E7. 5Fu induced the accumulation of active pRb and cyclin dependent kinase inhibitor p21WAF1/CIP1 together with an increase in Bak and Bax expression and a decrease in Bcl-2 levels in all the transfected cells. In addition, G1/S phase cell cycle arrest was associated with the antiproliferation activity of 5Fu in all cell lines. Through RT-PCR, 5Fu also presented some effects on the E6 and E7 oncoproteins of HPV16 in transfected UMSCC 12 cells.
Our results suggest that HPV16 E6 and E7 oncoproteins do not prevent 5Fu medicated apoptosis and G1/S cell arrest in laryngeal cancers. The anti-cancer effect of 5Fu is probably decided by the level of p21 WAF1/CIP1 while the sensitivity of laryngeal cancer cells responded to 5Fu treatment is associated with the increase of Bak or/and the decrease in Bcl-2, not with the HPV16 viral proteins and p53 status. 5Fu also presented some effects on the E6 and E7 oncoproteins of HPV16 in laryngeal cancer. However, the anti-viral effect of 5Fu still needs further investigation.
Our study indicated that (1) the evasion of apoptosis mediated by HPV16 E6 and E7 plays a critical role in laryngeal carcinogenesis; (2) HPV16 E6 or E7 plays an important role in regulating the expression of Bak, Bax and Bcl-2; (3) The degradation of Bak by HPV16 E6 is not caused by interacting with the promoter of Bak; (4) The induction of Bcl-2 is mediated through HPV16 E7; (5) HPV16 transfection does not interfere with the apoptosis and cell cycle arrest mediated by 5Fu in human laryngeal squamous cancer cells.
There is a growing body of evidence that human papillomavirus type 16 (HPV16) is involved in the development of human laryngeal cancer, especially in Chinese population. The two oncoproteins, HPV16 E6 and E7 that target host cell tumor suppressor proteins p53 and Rb respectively, may generate antiapoptotic effects and induce cell immortalization. However, the effect of both oncoproteins on apoptosis in laryngeal cancers is not completely clear. In this study, we demonstrated the possible mechanism of high risk HPV16 in laryngeal carcinogenesis and evaluated the effect of 5Fu on HPV16-positive laryngeal cancer cells.
We employed two human laryngeal cancer cell lines---UMSCC12 (with truncated p53) and UMSCC11A (with mutant but functional p53) in this study. These two cell lines were stably transfected with HPV16 E6, E7 or empty vector, pcDNA3.1, which provided a good foundation for further study on the carcinogenic mechanism of HPV16 E6 or E7 in human laryngeal cancers. Through Annexin V staining and protein stability assay, we found that the transfection of HPV16 E6 and E7 induced fewer spontaneous apoptosis in both UMSCC11A and UMSCC12 cells accompanied with enhanced protein stability of Bcl-2 and increased protein degradation of Bak. Similar results were obtained when E6- and E7-transfected cells exposed to apoptosis stimuli---TNF-alpha/CHX. These results indicate that stable transfection of E6 and E7 in human laryngeal cancer cells on one hand shortened the half-life of Bak protein, and on the other hand, enhanced the steady-state levels of Bcl-2 protein. In order to gain insight into the role of Bak and Bcl-2 in regulating apoptosis in HPV-associated laryngeal cancer cells, we performed transient transfection of Bcl-2 into E6- and E7-transfected cells. It is found that HPV16 E7 statistically enhanced the expression of Bcl-2 in laryngeal cancer, indicating that the induction of Bcl-2 require the transfection of HPV16 E7. Furthermore, Luciferase assay was performed to investigate whether the viral proteins E6 and E7 altered the stability of Bak through interaction with the promoter of Bak. Negative results were obtained, suggesting that E6 or E7 do not alter the transcription activity of Bak, indicating the degradation of Bak by E6 or E7 may be mediated through other mechanisms.
Liu Han-ching.
"August 2006."
Advisers: C. A. van Hasselt; George G. Chen.
Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1569.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2006.
Includes bibliographical references (p. 245-274).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstracts in English and Chinese.
School code: 1307.

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37

Ratzeburg, Brenda. "A medical perspective of chiropractic, based on a survey conducted amongst medical professionals in the western region of Johannesburg and how they view chiropractic compared to physiotherapy in the treatment of neuromusculoskeletal conditions." Thesis, 2008. http://hdl.handle.net/10210/974.

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Worldwide there was a growing trend towards the recognition of Chiropractic, but little was known of this recognition in South Africa. However, with regards to the Western Region of Johannesburg, it was unclear how the medical profession viewed Chiropractic and how effective they viewed Chiropractic in the treatment of neuromusculoskeletal conditions. This study attempted to establish how medical doctors viewed Chiropractic and to determine how Chiropractors compared to physiotherapists in the opinion of the medical profession in the treatment of common neuromusculoskeletal conditions. A questionnaire was hand-delivered to the consulting rooms of each general practitioner, orthopedic surgeon and neurologist/neurosurgeon in the Western Region of Johannesburg. The researcher with the aid of a statistical consultant drew up the questionnaire. The data was analysed using the SPSS 13 (2005), SPSS Incorporated, Chicago using descriptives and frequencies. To compare Chiropractic treatment to physiotherapy, statistical significance was calculated using a Paired Samples Test (T-Test). The results of this study found that the doctors had a positive view of Chiropractic as a profession. When comparing Chiropractic to physiotherapy, statistical analysis revealed that physiotherapy was seen as more effective. Physiotherapists were also more likely to receive referrals from medical doctors than Chiropractors. The results of this study were in accordance with worldwide trends in that Chiropractic was growing in recognition and was viewed as beneficial in the health care system. However, more education of the medical profession with regards to Chiropractic and more research comparing Chiropractic effectiveness compared to physiotherapy were needed.
Dr. M. Moodley Dr. J. Mitchell

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Aina-Badejo, Danielle. "Elucidating the Unknown Role of Cyclin Dependent Kinase 5 in Cardiac Pathophysiological Conditions." Thesis, 2021. https://doi.org/10.7916/d8-j79v-jk33.

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Until now, the role of cyclin dependent kinase 5 (CDK5) in cardiac pathophysiology has not been explored. While CDK5 has been well studied in the neuroscience/Alzheimer’s field as a cyclin-independent kinase, there is currently no investigation into the cardiac-specific role of CDK5. Recently, it was established that inhibition of CDK5 in stem cell derived cardiomyocytes from individuals with Timothy Syndrome (TS) rescued the delayed inactivation phenotype; TS is a fatal genetic long QT syndrome (LQTS) caused by delayed inactivation of the L-type voltage gated Ca2+channel CaV1.2. While it is evident that CDK5 plays an important role in regulating CaV1.2 function, its role in cardiac tissue remains to be elucidated. To determine whether CDK5 is essential for cardiac function, two separate mouse models were established—a cardiac-deficient Cdk5 mouse model (Cdk5 flox x αMHC-MerCreMer+) and a Cdk5 activation mouse model via overexpression of Cdk5’s known activator, p35 (Cdk5r1/p35 OE x αMHC-MerCreMer+). Immediately after spatiotemporal induction of deficiency/activation of Cdk5 in adult mice, echocardiography, histology and proteomic analysis were performed to examine effects on cardiac structure and function. Analysis of cardiac function and morphology in Cdk5 deficient mice revealed severe systolic dysfunction and a dilated cardiomyopathy-like phenotype. These results were further validated by a pathway analysis of quantified global proteome changes. Conversely, mice with an activation of Cdk5 displayed only minor changes in cardiac function with a modest reduction in fractional shortening and ejection fraction. Notably, these mice did not have any significant changes in cardiac chamber morphology, nor any significant changes to their global proteome. Interestingly, however, phosphoproteomic analysis revealed over 3,000 differentially phosphorylated proteins. Pathway and gene ontology analysis of proteome changes revealed significant hits related to cell adhesion. Evidence for the extensively studied role of CDK5 in the brain has demonstrated a critical role for CDK5 kinase activity in the regulation of cell adhesion. Alterations in cell adhesion are observed in a number of cardiac pathologies including heart failure and dilated cardiomyopathy; it is therefore plausible that CDK5 potentially regulates cardiac function via cell adhesion mechanisms. A comparison of the phospho-proteome acutely after Cdk5 depletion vs the phospho-proteome acutely after Cdk5 activation, allowed for the identification of a novel cardiac-specific Cdk5 substrate, beta taxilin (Txlnb). Validation of this potential phospho-substrate with an in situ proximity ligation assay demonstrated the co-localization of Cdk5-Txlnb in wildtype mouse cardiac tissue sections. When looking at co-localization in Cdk5 deficient tissue sections, no signals were observed. Lastly, our lab obtained donor cardiac tissue samples from individuals who passed away due to either heart failure or non-cardiac causes (serving as control cardiac tissue). Analysis of cardiac tissue samples revealed a significant increase in both CDK5 and p35 expression in heart failure samples. Dysregulation of phosphorylation has been implicated in cardiac dysfunction, with known contribution to contractile failure and a number of cardiac pathologies including cardiomyopathies. These findings further support a role for CDK5 in cardiac function. In conclusion, it appears that CDK5 is imperative for the maintenance of healthy cardiac function. Cardiac-specific homozygous and heterozygous Cdk5 deficiency revealed severe systolic dysfunction along with a dilated cardiomyopathy-like phenotype. While the effects of Cdk5 activation in the heart need to be further investigated, initial findings report significant downstream effects on the phosphorylation of a number of proteins, including Txlnb. Moreover, Txlnb was identified as a potential novel cardiac-specific substrate of Cdk5. The importance of identifying a role for CDK5 in the heart extends beyond this study. CDK inhibitors have been at the forefront of drug development for cancer therapeutics and immunotherapy. While modulation of CDK5 activity may be beneficial in one physiological system, it may prove deleterious in another. It is therefore imperative that the full range of molecular and physiological roles of each CDK be fully elucidated prior to therapeutic application. Furthermore, outcomes from this study have the potential to be translational for drug discovery and the development of new therapeutic avenues for heart disease.

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Mignon, Charles, N. E. Uzunbajakava, B. Raafs, Natalia V. Botchkareva, and Desmond J. Tobin. "Photobiomodulation of human dermal fibroblasts in vitro: decisive role of cell culture conditions and treatment protocols on experimental outcome." 2017. http://hdl.handle.net/10454/15613.

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Yes
Photobiomodulation-based (LLLT) therapies show tantalizing promise for treatment of skin diseases. Confidence in this approach is blighted however by lamentable inconsistency in published experimental designs, and so complicates interpretation. Here we interrogate the appropriateness of a range of previously-reported treatment parameters, including light wavelength, irradiance and radiant exposure, as well as cell culture conditions (e.g., serum concentration, cell confluency, medium refreshment, direct/indirect treatment, oxygen concentration, etc.), in primary cultures of normal human dermal fibroblasts exposed to visible and near infra-red (NIR) light. Apart from irradiance, all study parameters impacted significantly on fibroblast metabolic activity. Moreover, when cells were grown at atmospheric O2 levels (i.e. 20%) short wavelength light inhibited cell metabolism, while negligible effects were seen with long visible and NIR wavelength. By contrast, NIR stimulated cells when exposed to dermal tissue oxygen levels (approx. 2%). The impact of culture conditions was further seen when inhibitory effects of short wavelength light were reduced with increasing serum concentration and cell confluency. We conclude that a significant source of problematic interpretations in photobiomodulation reports derives from poor optimization of study design. Further development of this field using in vitro/ex vivo models should embrace significant standardization of study design, ideally within a design-of-experiment setting.

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Pho, Anthony T. "Human Papillomavirus Vaccination, Online Health Information Seeking, and Health Literacy among Transgender and Gender Nonbinary People." Thesis, 2020. https://doi.org/10.7916/d8-e5am-9v36.

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BACKGROUND: Human Papillomavirus (HPV) is the most common sexually-transmitted infection in the U.S. and is associated with a number of cancers. A vaccine that can prevent 90% of HPV-associated cancers has been available since 2006, yet millions of young adults remain unvaccinated. Low vaccination uptake has been observed in cisgender sexual minority communities and less is known about HPV vaccination among transgender and gender nonbinary (TGNB) people. The aims of this dissertation were: (a) to identify facilitators for and barriers to HPV vaccination among gender minority people; (b) to compare HPV vaccination rates, HPV risk and situational factors like barriers to care, access to care, preventive care, HPV knowledge and Internet use in a sample of TGNB people and cisgender sexual minority people; and (c) to explore the association of online health information and HPV vaccination receipt among TGNB people compared to cisgender sexual minority people and determine if eHealth Literacy or general health literacy moderate this relationship. METHODS: The dissertation comprised three studies. First, an integrative review of the literature included searches of three electronic databases to identify and appraise studies that explore patient-, provider- and system-level HPV vaccination barriers among gender minority people. Second, guided by the Integrative Model of eHealth Use, a cross-sectional secondary analysis of The Population Research in Identities and Disparities for Equality (PRIDE) Study Annual Questionnaire 2018-19, compared the rate of HPV vaccination among TGNB and cisgender sexual minority people and described situation factors (e.g., barriers to care, access to care, preventive care), Internet use, HPV knowledge, HPV risk, and HPV vaccination among these communities. Third, a novel cross-sectional online survey of TGNB and cisgender sexual minority participants recruited from The PRIDE Study, also guided by the Integrative Model of eHealth Use, explored the association between online health information seeking and receipt of HPV vaccine, and whether eHealth literacy and/or general health literacy moderate this relationship. Statistical methods for the cross-sectional studies included prevalence ratios (PR) using robust Poisson statistics and multivariable logistic regression with post hoc Bonferroni-Holm correction. RESULTS: The integrative review identified six cross-sectional studies and one qualitative study that explored HPV vaccine barriers and facilitators among gender minority people. The majority of the studies included <10% gender minority participants. Key barriers to vaccination identified were misperceptions of risk at patient-level, bias towards vaccinating female assigned individuals at the provider-level and population effects of recommendations for girls-only at the policy-level. The cross-sectional secondary analysis of The PRIDE Study 2018-19 Annual Questionnaire and included N = 5,500 responses and found that: (a) the prevalence of ever receiving HPV vaccine was 1.2 times greater among TGNB participants than cisgender participants (PR 1.2; 95% CI, 1.1-1.3); (b) the prevalence of ever receiving HPV vaccine was 2.4 times greater among transgender men who were assigned female at birth compared to transgender women who were assigned male at birth (PR 2.4; 95% CI, 2.0-2.8); and (c) no differences in vaccination initiation and vaccination completion based on gender identity, sex assigned at birth, sex organs born with, or current sex organs. The cross-sectional novel online survey of PRIDE participants yielded N = 3,258 responses (response rate 19.6%). After controlling for covariates including age, race/ethnicity and educational attainment, we found that TGNB as compared to cisgender participants had increased odds (aOR=1.5=; 95% CI, 1.1-2.2) of reporting receipt of HPV vaccine ever and decreased odds (aOR=0.7; 95% CI, 0.5-0.9) of ever receiving of HPV vaccine when they looked for info on vaccines in the past year. Conversely, TGNB participants had over twice the odds (aOR=2.4; 95% CI, 1.1-5.6) of ever receiving HPV vaccine if they visited a social networking site like Facebook or Instagram in the past year. There were no moderating effects observed from eHealth or general health literacy. CONCLUSIONS: TGNB communities are understudied in terms of HPV vaccination and the existing literature shows misperceptions about the need of HPV vaccination among TGNB communities at both the patient and provider level. TGNB participants were more likely to have ever received HPV vaccine compared to cisgender sexual minority participants in the cross-sectional secondary analysis of The PRIDE Study 2018-19 Annual Questionnaire which may be attributed to high primary engagement in the cohort. Finally, online health information seeking about vaccines was associated with decreased receipt of HPV vaccine (ever) whereas social media use increased HPV vaccine receipt (ever) among TGNB participants compared to cisgender sexual minority participants. These conflicting findings suggest that the quality of online health information relating HPV vaccines, how, when and why TGNB people search for health information online may affect health behaviors like HPV vaccination. More research is warranted to explore how online health information seeking may influence personal health decision-making among TGNB communities.

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Yang, Yi Fang, and 楊宜芳. "Systemic exploration of redox proteome in human A431 cells under different Photofrin-mediated photodynamic treatment conditions by quantitative proteomics approach." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/52121421771566331555.

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碩士
長庚大學
生物醫學研究所
100
Photodynamic therapy (PDT) is a minimally invasive therapeutic clinical treatment for some cancer and non-tumor disorders. This process requires a photosensitizer which can absorb light and produce reactive oxygen species to damage biomolecules in target cells. Photofrin is the most widely used photosensitizer. Our previous studies showed that different distribution of Photofrin in cells results in distinct cell death after PDT and Photofrin can selectively interact with some proteins. Using human epidermoid carcinoma A431 cells as model, we herein applied SILAC-based quantitative proteome approach to systemically analyze the relationship between the subcellular location of Photofrin and the Photofrin-PDT-mediated protein oxidization (on Met residues). In addition, we try to identify Photofrin-interacting proteins in A431 cells. Our data showed that when Photofrin mainly localized to plasma membrane (condition I), intracellular organelles (condition II) and whole cell (condition III), there were 116, 84 and 199 proteins quantified greater than mean+2SD Met-oxidized proteins, respectively. Further analysis revealed that (i) the percentage of highly oxidized membrane proteins is significantly higher in condition I (13.33%) than in condition II (3.03%) and III (0.76%); (ii) the percentage of highly oxidized Golgi proteins is drastically higher in condition II (18.18%) than in condition I (3.33%) and III (9.09%); and (iii) the percentage of highly oxidized mitochondrial proteins is largely higher in condition III (30.3%) than in condition I (4.44%) and II (15.66%). The results indicate that PDT with Photofrin targeted to distinct subcellular localizations can affect the redox proteome in a site-specific manner in living cells. Regarding the Photofrin-interacting proteins, we have identified 66 such candidates via in vitro pull down assay (using Photofrin-coupled beads) combined with MS analysis. Among those highly oxidized proteins detected post Photofrin-PDT, we select protein A and B for further study. Mapping the observed oxidized Met residues into the 3D structure of the two proteins showed that these oxidized Met residues mainly distribute on the surface of the protein. We also provided evidence to show that Photofrin-PDT can directly inhibit the activity of protein A in vitro. Collectively, our data demonstrate for the first time that the relationship between protein Met oxidation and PDT with site-specific location of Photofrin in living cells. Our results also unravel many potential Photofrin-interacting proteins that deserve further investigation.

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Downs, Matthew. "Focused Ultrasound Mediated Blood-Brain Barrier Opening in Non-Human Primates: Safety, Efficacy and Drug Delivery." Thesis, 2015. https://doi.org/10.7916/D82B8XC7.

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The blood-brain barrier (BBB) is physiologically essential for brain homeostasis. While it protects the brain from noxious agents, it prevents almost all currently available drugs from crossing to the parenchyma. This greatly hinders drug delivery for the treatment of neurological diseases and disorders such as Parkinson’s, Alzheimer’s and Huntington’s, as well as the development of drugs for the treatment of such diseases. Current drug delivery techniques to the brain are either invasive and target specific, or non-invasive with low special specificity. Neither group of techniques are optimal for long term treatment of patients with neurological diseases or disorders. Focused ultrasound coupled with intravenous administration of microbubbles (FUS) has been proven as an effective technique to selectively and noninvasively open the BBB in multiple in vivo models including non-human primates (NHP). Although this technique has promising potential for clinical outpatient procedures, as well as a powerful tool in the lab, the safety and potential neurological effects of this technique need to be further investigated. This thesis focuses on validating the safety and efficacy of using the FUS technique to open the BBB in NHP as well as the ability of the technique to facility drug delivery. First, a longitudinal study of repeatedly applying the FUS technique targeting the basal ganglia region in four NHP was conducted to determine any potential long-term adverse side effects over a duration of 4-20 months. The safety of the technique was evaluated using both MRI as well as behavioral testing. Results demonstrated that repeated application of the FUS technique to the basal ganglia in NHP did not generate permanent side effects, nor did it induce a permanent opening of the BBB in the targeted region. The second study investigated the potential of the FUS technique as a method to deliver drugs, such as a low dose of haloperidol, to the basal ganglia in NHP and mice to elicit pharmacodynamical effects on responses to behavioral tasks. After opening the BBB in the basal ganglia of mice and NHP, a low dose of haloperidol was successfully delivered generating significant changes in their baseline motor responses to behavioral tasks. Domperidone was also successfully delivered to the caudate of NHP after opening the BBB and induced transient hemilateral neglect. In the final section of this thesis, the safety and efficacy of the FUS technique was evaluated in fully alert NHP. The FUS technique was successful in generating BBB opening volumes larger on average to that of the BBB opening volumes in anesthetized experiments. Safety results through MRI verification as well as behavioral testing during application of the technique demonstrated that the FUS technique did not generate adverse neurological effects. Conversely, the FUS technique was found to induce slight positive effects on the response of the NHP to the behavioral task. Collectively, the work presented in this thesis demonstrates the safety and effectiveness of the FUS technique to open the BBB and deliver neuroactive drugs in the NHP.

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Gupta, Manav. "Differentiation and characterization of cell types associated with retinal degenerative diseases using human induced pluripotent stem cells." Thesis, 2014. http://hdl.handle.net/1805/4839.

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Indiana University-Purdue University Indianapolis (IUPUI)
Human induced pluripotent stem (iPS) cells have the unique ability to differentiate into 200 or so somatic cell types that make up the adult human being. The use of human iPS cells to study development and disease is a highly exciting and interdependent field that holds great promise in understanding and elucidating mechanisms behind cellular differentiation with future applications in drug screening and cell replacement studies for complex and currently incurable cellular degenerative disorders. The recent advent of iPS cell technology allows for the generation of patient-specific cell lines that enable us to model the progression of a disease phenotype in a human in vitro model. Differentiation of iPS cells toward the affected cell type provides an unlimited source of diseased cells for examination, and to further study the developmental progression of the disease in vitro, also called the “disease-in-a-dish” model. In this study, efforts were undertaken to recapitulate the differentiation of distinct retinal cell affected in two highly prevalent retinal diseases, Usher syndrome and glaucoma. Using a line of Type III Usher Syndrome patient derived iPS cells efforts were undertaken to develop such an approach as an effective in vitro model for studies of Usher Syndrome, the most commonly inherited disorder affecting both vision and hearing. Using existing lines of iPS cells, studies were also aimed at differentiation and characterization of the more complex retinal cell types, retinal ganglion cells (RGCs) and astrocytes, the cell types affected in glaucoma, a severe neurodegenerative disease of the retina leading to eventual irreversible blindness. Using a previously described protocol, the iPS cells were directed to differentiate toward a retinal fate through a step-wise process that proceeds through all of the major stages of neuroretinal development. The differentiation process was monitored for a period of 70 days for the differentiation of retinal cell types and 150 days for astrocyte development. The different stages of differentiation and the individually derived somatic cell types were characterized by the expression of developmentally associated transcription factors specific to each cell type. Further approaches were undertaken to characterize the morphological differences between RGCs and other neuroretinal cell types derived in the process. The results of this study successfully demonstrated that Usher syndrome patient derived iPS cells differentiated to the affected photoreceptors of Usher syndrome along with other mature retinal cell types, chronologically analogous to the development of the cell types in a mature human retina. This study also established a robust method for the in vitro derivation of RGCs and astrocytes from human iPS cells and provided novel methodologies and evidence to characterize these individual somatic cell types. Overall, this study provides a unique insight into the application of human pluripotent stem cell biology by establishing a novel platform for future studies of in vitro disease modeling of the retinal degenerative diseases: Usher syndrome and glaucoma. In downstream applications of this study, the disease relevant cell types derived from human iPS cells can be used as tools to further study disease progression, drug screening and cell replacement strategies.

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Sun, Shu. "The Evaluation of Chinese therapeutic food for the treatment of dyslipidemia." Thesis, 2010. https://vuir.vu.edu.au/7689/.

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Cardiovascular disease which is mainly caused by atherosclerosis has the highest mortality rate in Australia. The Chinese therapeutic food, hawthorn fruit and Chinese kiwifruit, is recognized as both food and herbal medicine by the Chinese Ministry of Health. Previous studies have shown favorable effects of both on the treatment of dyslipidemia and atherosclerosis. This clinical study suggests that the intake of hawthorn fruit and Chinese kiwifruit supplement may increase the serum levels of HDL-c and decrease the ratios of TC/HDL-c and LDL-c/HDL-c, and therefore may reduce the risk of cardiovascular disease.

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Craven, Kelly E. "Angiogenic gene signature in human pancreatic cancer correlates with TGF-beta and inflammatory transcriptomes." Diss., 2016. http://hdl.handle.net/1805/10984.

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Indiana University-Purdue University Indianapolis (IUPUI)
Pancreatic ductal adenocarcinoma (PDAC), which comprises 85% of pancreatic cancers, is the 4th leading cause of cancer death in the United States with a 5-year survival rate of 8%. While human PDACs (hPDACs) are hypovascular, they also overexpress a number of angiogenic growth factors and receptors. Additionally, the use of anti-angiogenic agents in murine models of PDAC leads to reduced tumor volume, tumor spread, and microvessel density (MVD), and improved survival. Nonetheless, clinical trials using anti-angiogenic therapy have been overwhelmingly unsuccessful in hPDAC. On the other hand, pancreatic neuroendocrine tumors (PNETs) account for only 2% of pancreatic tumors, yet they are very vascular and classically angiogenic, respond to anti-angiogenic therapy, and confer a better prognosis than PDAC even in the metastatic setting. In an eﬀort to compare and contrast the angiogenic transcriptomes of these two tumor types, we analyzed RNA-Sequencing (RNA-Seq) data from The Cancer Genome Atlas (TCGA) and found that a pro-angiogenic gene signature is present in 35% of PDACs and that it is mostly distinct from the angiogenic signature present in PNETs. The pro-angiogenic PDAC subgroup also exhibits a transcriptome that reﬂects active TGF-β signaling, less frequent SMAD4 inactivation than PDACs without the signature, and up-regulation of several pro-inﬂammatory genes, including members of JAK signaling pathways. Consequently, targeting the TGF-β receptor type-1 kinase with SB505124 and JAK1/2 with ruxolitinib blocks proliferative crosstalk between human pancreatic cancer cells (PCCs) and human endothelial cells (ECs). Additionally, treatment of the KRC (oncogenic Kras, homozygous deletion of Rb1) and KPC (oncogenic Kras, mutated Trp53) genetically engineered PDAC mouse models with ruxolitinib suppresses murine PDAC (mPDAC) progression only in the KRC model, which shows superior enrichment and diﬀerential expression of the human pro-angiogenic gene signature as compared to KPC tumors. These ﬁndings suggest that targeting both TGF-β and JAK signaling in the 35% of PDAC patients whose cancers exhibit an pro-angiogenic gene signature should be explored in a clinical trial.

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46

"Innovative options for the treatment of non-melanoma skin cancer : Investigations on the activity of antimicrobial peptides against topical diseases and study of peptide penetration into human skin ex vivo." Berlin : Freie Universität Berlin, 2014. http://d-nb.info/1063934591/34.

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Baldwin, P. Clive. "Narrative, ethics and severe mental illness." 2005. http://hdl.handle.net/10454/3268.

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No
Starting from the premise that people are essentially narrative beings, I argue that the onset of severe mental illness compromises the narrative enterprise of being able to construct one's Self and one's relationships inmeaningful and coherent ways. This is due to both the curtailment of opportunities for narrative engagement and the dispossession of those whose narratives do not conform to the current conceptualization of narrative and narrativity. In these circumstances, supporting the narrative enterprise is an ethical endeavour that requires that we examine not only which narratives we construct, but also how we construct them. This requires a re-thinking of what might constitute narrative and how we might facilitate or enhance the narrativity of people with severe mental illness. Following this, I suggest four means to support the narrativity of people with severe mental illness: through maintaining narrative continuity, maintaining narrative agency, countering master narratives and attention to small stories.

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48

Marukutira, Tafireyi. "Factors influencing adherence to antiretroviral therapy in adolescents at Botswana-Baylor Children's Clinical Centre of Excellence : a qualitative study." Diss., 2012. http://hdl.handle.net/10500/6036.

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The aim of the study was to determine the factors that influence adherence to ART among adolescents who contracted HIV through vertical transmission. Qualitative research using descriptive phenomenology was conducted at Botswana-Baylor Children’s Clinical Centre of Excellence. Data was collected using in-depth individual semi-structured interviews. Eight (8) adolescents between 14 and 19 years who had been on ART for minimum of 4 years were interviewed. Thematic analysis of data was done and five (5) themes emerged from the participants' description of the experience of taking ART over a long period of time. The themes that emerged indicated the factors that influence adherence to ART, and they included knowledge and positive beliefs about ART, need for support, ART difficult treatment regimen, having a regular doctor and psychosocial emotional needs. The findings suggested that the adolescents who contracted HIV through vertical transmission require support while continuing on a simplified long-term ART regimen after an assessment of their psychological well beings and periodic checks.
Health Studies
M.A. (Public Health)

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49

"Dietary intake, diet-related knowledge and metabolic control of children with type 1 diabetes mellitus, aged 6-10 years attending the paediatric diabetic clinics at Grey's Hospital, Pietermaritzburg and Inkosi Albert Luthuli Central Hospital, Durban, KwaZulu-Natal." Thesis, 2007. http://hdl.handle.net/10413/3445.

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The aim of this study was to assess the dietary intake, diet-related knowledge and metabolic control in children with Type 1 Diabetes Mellitus between the ages of 6-10 years attending the Paediatric Diabetic Clinics at Grey’s Hospital, Pietermaritzburg and Inkosi Albert Luthuli Central Hospital, Durban, KwaZulu-Natal. This was a cross sectional observational study that was carried out in a total of 30 subjects out of a possible 35 subjects that qualified for inclusion in the study from both the Grey’s Hospital clinic (n=8) and IALCH clinic (n=22). The dietary intake was assessed in a total of 25 subjects using a three day dietary record (n=20) and a 24 hour recall of the third day of the record (n=16). Diet-related knowledge was assessed using a multiple choice questionnaire. Metabolic control was assessed using the most recent HbA1c and the mean HbA1c results over the previous 12 months from the date of data collection. Height and weight measurements were also carried out. Information on socioeconomic status and education status of the caregivers was obtained from 22 caregivers through follow-up phone calls. All measurements except for dietary intake were obtained from all subjects participating in the study. The mean percentage contribution of macronutrients to total energy was very similar to the International Society for Pediatric and Adolescent Diabetes (ISPAD) Consensus Guidelines (2002). The mean percentage contribution of macronutrients to total energy from the 3 day dietary records and the 24 hour recalls were as follows: carbohydrate (52% and 49%); sucrose (2% and 2%); protein (16% and 17%); fat (32% and 34%). Micronutrient intake was adequate for all micronutrients except for calcium and vitamin D which showed low intakes. The mean diet-related knowledge score for the sample was 67% with significantly higher scores in children older than 8 years of age. The latest HbA1c for the sample was 9.7% and the mean HbA1c over the previous 12 months from the date of data collection was 9.6%. There was a significant positive correlation between age of the participant and the latest HbA1c (r = 0.473; p=0.008) and a significant negative correlation between the education level of the caregivers and the latest HbA1c (r = - 0.578; p=0.005) and the mean HbA1c over 12 months (r = - 0.496; p=0.019). Significant differences were found between African and Indian children respectively for HbA1c, with higher values in African children. There was no correlation between BMI for age and latest HbA1c (r = 0.203, p=0.282) or mean HbA1c over 12 months (r = 0.101, p=0.594). Z score for BMI for age was also not correlated with latest HbA1c (r = 0.045, p=0.814) or mean HbA1c over 12 months (r = - 0.012, p=0.951). Children from the Grey’s Hospital Clinic were found to have higher HbA1c values (p=0.001) and lower diet-related knowledge scores as compared to the children from the IALCH Clinic (p=0.038). It should be noted that the ethnic and racial composition of the children attending these two clinics differed. In conclusion the macronutrient intake in this sample was found to be similar to the ISPAD Consensus Guidelines (2002) while calcium and vitamin D intakes were low. Overall this sample displayed good diet-related knowledge while metabolic control was found to be poor.
Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2007.

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50

Ribeiro, Isabel Patrícia Magalhães. "Implicações da COVID-19 no estado de saúde oral." Master's thesis, 2021. http://hdl.handle.net/10284/10572.

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No contexto da pandemia por SARS-CoV-2, em 2020 foram implementadas medidas para uma gestão controlada da propagação de contágio, minimizando ao máximo o risco de transmissão do vírus. A Direção Geral da Saúde legislou normas e recomendações que conduziram à interrupção da atividade nos consultórios e clínicas de medicina dentária em março daquele ano, e à retoma daquela atividade dois meses depois. Em que, para além das precauções universais, recomendou-se a adoção de medidas que assegurem a proteção pelo contágio através de gotículas e aerossóis contaminados. Esta doença é de fácil e rápido contágio, visto que a sua principal via de transmissão é por contacto direto com gotículas salivares portadoras do vírus. Os resultados desta revisão revelaram que as principais alterações orais associadas á COVID-19 são os distúrbios do paladar, xerostomia e ulcerações. Diversas manifestações orais foram observadas, contudo, não há evidências suficientes que comprovem uma relação de causalidade com a infeção por COVID-19. As implicações da COVID-19 no estado de saúde oral assentam na privação no acesso aos cuidados de saúde oral na fase de mitigação da COVID-19, o subdiagnóstico das manifestações orais na fase inicial da pandemia, e atualmente, desconhece-se uma associação cientificamente consistente entre a COVID-19 e as manifestações orais da doença.
In the context of the SARS-CoV-2 pandemic, in 2020 measures were implemented for a controlled management of the spread of contagion, minimizing the risk of virus transmission as much as possible. The General Directorate of Health legislated norms and recommendations that led to the interruption of activity in dental offices and clinics in March of that year, and the resumption of that activity two months later. In which, in addition to universal precautions, the adoption of measures to ensure protection from contagion through contaminated droplets and aerosols was recommended. This disease is easy and fast to spread, as its main transmission route is through direct contact with salivary droplets carrying the virus. The results of this review revealed that the main oral alterations associated with COVID-19 are taste disturbances, xerostomia and ulcerations. Several oral manifestations were observed, however, there is insufficient evidence to prove a causal relationship with COVID-19 infection. The implications of COVID-19 in the oral health status are based on the deprivation of access to oral health care in the mitigation phase of COVID-19, the underdiagnosis of oral manifestations in the initial phase of the pandemic, and currently, a scientific association is unknown. consistent between COVID-19 and the oral manifestations of the disease.

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Dissertations / Theses on the topic 'Treatment of human diseases and conditions'

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