Innate Immunity in Type 2 Diabetes Pathogenesis: Role of the Lipopolysaccharide Signaling Cascade: A Dissertation

Once seen as a disease of wealthy nations, type 2 diabetes mellitus is now showing unprecedented growth throughout the world, fueling increases in microvascular and macrovascular complications. A compelling and growing body of evidence suggests that glucose intolerance and insulin resistance, hallmarks of the diabetic patient, may be driven by chronic inflammation. In particular, a predominance of visceral fat has been associated with enhanced inflammatory cytokine secretion that may contribute to enhanced risk of diabetes and comorbid cardiovascular disease in these individuals. As a function of its potency and wide environmental and biological distribution, we hypothesized that bacterial lipopolysaccharide (LPS, also known as endotoxin) may promote adipose inflammation and concomitant metabolic dysfunction. Indeed, expression of the LPS receptor CD14 is enhanced on visceral adipocytes of ob/ob mice, paralleling enhanced IL-6 secretion ex vivo. Furthermore, rosiglitazonefed ob/obmice demonstrated a reduction in CD14 that coordinated with diminished IL-6 secretion, suggesting a basis for the touted anti-inflammatory effects of this commonly employed type 2 diabetes medication. Mice deficient in components of the LPS signaling cascade, namely CD14, TLR4, and MyD88, yielded adipocytes with markedly attenuated IL-6 secretion, corroborating the central importance of LPS in adipocyte inflammation and supporting the role of this signaling pathway in depot-specific inflammation. Despite the prominent role of LPS signaling in adipocyte inflammation, CD14-, TLR4-, and MyD88-deficient mice failed to show resistance to diet induced obesity. Surprisingly, cd14-/- and tlr4-/- mice had marked glucose intolerance without alteration in total weight or adipose accumulation. In contrast, myd88-/- mice revealed minor glucose intolerance only with high fat diet challenge at an advanced age despite being overtly obese. In cd14-/- and tlr4-/-, but not myd88-/-, mice, an exaggerated rebound to hypoglycemia was associated with enhanced norepinephrine secretion, which could be abrogated by the adrenergic β-blocker propranolol. The overlay of these mouse models reveals a divergence of phenotypes that demonstrate LPS signaling disruption may lead to glucose intolerance and insulin resistance in part due to enhanced sympathoadrenal tone, uncovering an essential role of innate immunity in physiological stress and its impact upon glucose homeostasis

In-Vitro Effects of Cytokines on Normal and Myeloid Leukaemic Haemopoiesis

The growth of chronic myeloid leukaemic (CML) and acute myeloid leukaemic (AML) cells in vitro and their response to various cytokines were studied and compared to normal peripheral blood and bone marrow cells. In normal mononuclear cells (MNC) the three cytokines [granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-3 (IL-3)] had no appreciable difference at stimulating (colony-forming unit granulocyte-macrophage) CFU-GM-formation. By contrast, G-CSF was a more potent stimulator of CFU-CML, than GM-CSF or IL-3. Interleukin-4 (IL-4) augmented G-CSF-induced colony formation of CML chronic phase cells. Transforming growth factor beta1 (TGFbeta1) reduced G-CSF-induced CFU-CML from CML chronic phase (p< 0.005) and blast transformation MNC, but had no effect on normal CFU-GM stimulated by G- CSF. The growth of CML mononuclear cells in vitro could not be correlated to the white cell count or percentage of CD34+ cells present. The mechanisms for the inhibitory effects of TGFbeta1 on CML cells were studied using in-situ hybridisation techniques to demonstrate the expression of the G-CSF and IL-4 receptors. The results suggest that this response is more likely to be due to a difference in signal transduction or protein synthesis rather in transcription

Effet de la topologie de l'ADN du promoteur sur la transcription par l'ARN polymérase II

La transcription des gènes est un processus relativement simple chez les organismes procaryotes. Une seule enzyme en est responsable, l'ADN polymérase (ARN pol) qui est composée de quatre sous-unités [alpha][indice inférieur 2], [bêta]' et [bêta]. Afin de pouvoir transcrire, l'ADN polymérase procaryote a recours au facteur [sigma]. Ensemble, ces cinq sous-unités forment l'holoenzyme procaryote fonctionel en transcription. En présence d'ATP, le complexe prétranscriptionnel est en mesure d'ouvrir le promoteur au site d'initiation de la transcription. La formation du complexe prétranscriptionnel et l'ouverture du promoteur nécessitent l'enroulement de l'ADN du promoteur autour de l'ADN pol II. Puisque l'enroulement de l'ADN joue un rôle important dans l'assemblage du complexe d'initiation, notre hypothèse est que la courbure naturelle de l'ADN du promoteur peut influencer la force transcriptionnelle basale du promoteur. Afin de vérifier cette idée, nous avons introduit une série de cinq adénines (A[indice inférieur 5]), reconnue pour induire une courbure d'un angle de 18[degré] dans l'ADN, à différentes positions le long du promoteur majeur tardif de l'Adénovirus."--Résumé abrégé par UMI

The recruitment and role of effector and regulatory T cells in renal cell carcinoma

Immunotherapy for renal cell carcinoma (RCC) has yielded some clinical responses. However this approach frequently fails, possibly due to inefficient migration of T-cells to tumour tissue or immunosuppressive mechanisms within the tumour environment. To aid development of T-cell therapy for RCC I investigated how T-cells are recruited to this tumour, which T-cell subsets infiltrate, and how they function. Analysis of the expression of all 19 chemokine receptors on matched TIL and PBMC demonstrated that CCR5, CXCR3 and CXCR6 were expressed at significantly higher levels on tumour-infiltrating T-cells than memory T-cells in PBMC, suggesting a role for these receptors in recruitment to RCC. Immunohistochemistry showed the corresponding ligands were present in RCC, and transwell assays confirmed the ligands induce migration of TIL. I demonstrated Foxp3$^+$CD25$^{hi}$CD127$^{low}$ Tregs were enriched within the tumour, and also expressed high levels of CCR5, CXCR3 and CXCR6, as well as CCR6. They lacked expression of IL-2 and IFN-$\gamma$ post-stimulation, consistent with a regulatory phenotype. Functional characterisation of Foxp3$^-$ TIL demonstrated they can function ex vivo, however their high expression of the inhibitory molecule PD-1 may indicate exhaustion in vivo. Double positive CD4$^+$CD8$^+$ T-cells were also enriched in TIL and had a similar functional profile to CD8 T-cells

Novel Research in Sexuality and Mental Health

Sexuality is considered as a great human value related to happiness and satisfaction, but unfortunately, when affecting mental disorders, they tend to be associated with second level human functions. Nevertheless, sexual dysfunction often accompanies psychiatric disorder, intensely influencing compliance, quality of life and human relationships. Sexuality could be influenced either by a mental disorder itself, difficulties to get and maintain couple relationships or by the use of psychotropic treatments. Treatment-related adverse events are unfortunately under-recognized by clinicians, scarcely spontaneously communicated by patients, and rarely investigated in clinical trials. The most frequent psychotropic compounds that could deteriorate sexuality and quality of life include antidepressants, antipsychotics and mood regulators. There are important differences between them related to some variations in mechanisms of action including serotonin, dopamine and prolactin levels. Little is known about the relevance of sexuality and its dysfunctions in chronic and frequent mental and neurological disorders, such as psychosis, mood disorders, anxiety, phobias, eating disorders, alcohol or drug dependencies, epilepsy and childhood pathology. Poor sexual life, low satisfaction and more frequent risky sex behavior than in the general population are associated with severe mental diseases. There is a need for increasing research in this field, including epidemiological, psychological, neurophysiological, neuroanatomical and genetic variables related to sexual life to get a better understanding of the implicated mechanisms. To increase the sensibility of clinicians, the identification and management of sexual disturbances after the onset of any mental disorder should be highlighted. This would avoid unnecessary suffering and deterioration of quality of life

Cancer Biomarker Research and Personalized Medicine

Biomarkers are measures of a biological state. The treatment of individual patients based on particular factors, such as biomarkers, distinguishes standard, generalized treatment plans from personalized medicine. Even though personalized medicine is applicable to most branches of medicine, the field of oncology is perhaps where it is most easily employed. Cancer is a heterogeneous disease; although patients may be diagnosed histologically with the same cancer type, their tumors can comprise varying tumor microenvironments and molecular characteristics that can impact treatment response and prognosis. There has been a major drive over the past decade to try and realize personalized cancer medicine through the discovery and use of disease-specific biomarkers. This book, entitled “Cancer Biomarker Research and Personalized Medicine”, encompasses 22 publications from colleagues working on a diverse range of cancers, including prostate, breast, ovarian, head and neck, liver, gastric, bladder, colorectal, and kidney. The biomarkers assessed in these studies include genes, intracellular or secreted proteins, exosomes, DNA, RNA, miRNA, circulating tumor cells, circulating immune cells, in addition to radiomic features

A Personalized Medicine Approach to the Diagnosis and Management of Autism Spectrum Disorder

This collection of articles provides an overview of the current and future methods for applying a personalized medicine approach to the diagnosis, management, and treatment of autism spectrum disorder

Official Register of the United States, containing a list of the officers and employes in the Civil, Military, and Naval Service on the first of July, 1893; together with a list of vessels belonging to the United States. Volume II, Pt. 2 of 2.

Official Register of the U.S. 1 July. HMD 29 (pts. 1 and 2), 53-2. v2-3. 2779p. [3230-3231] Lists all employees of the Indian service