Oxidative stress and its haemodynamic consequences in chronic kidney disease

Chronic kidney disease (CKD) is associated with increased cardiovascular risk in comparison with the general population. This can be observed even in the early stages of CKD, and rises in proportion to the degree of renal impairment. Not only is cardiovascular disease (CVD) more prevalent in CKD, but its nature differs too, with an excess of morbidity and mortality associated with congestive cardiac failure, arrhythmia and sudden death, as well as the accelerated atherosclerosis which is also observed. Conventional cardiovascular risk factors such as hypertension, dyslipidaemia, obesity, glycaemia and smoking, are highly prevalent amongst patients with CKD, although in many of these examples the interaction between risk factor and disease differs from that which exists in normal renal function. Nevertheless, the extent of CVD cannot be fully explained by these conventional risk factors, and non-conventional factors specific to CKD are now recognised to contribute to the burden of CVD. Oxidative stress is a state characterised by excessive production of reactive oxygen species (ROS) and other radical species, a reduction in the capacity of antioxidant systems, and disturbance in normal redox homeostasis with depletion of protective vascular signalling molecules such as nitric oxide (NO). This results in oxidative damage to macromolecules such as lipids, proteins and DNA which can alter their functionality. Moreover, many enzymes are sensitive to redox regulation such that oxidative modification to cysteine thiol groups results in activation of signalling cascades which result in adverse cardiovascular effects such as vascular and endothelial dysfunction. Endothelial dysfunction and oxidative stress are present in association with many conventional cardiovascular risk factors, and can be observed even prior to the development of overt, clinical, vascular pathology, suggesting that these phenomena represent the earliest stages of CVD. In the presence of CKD, there is increased ROS production due to upregulated NADPH oxidase (NOX), increase in a circulating asymmetric dimethylarginine (ADMA), uncoupling of endothelial nitric oxide synthase (eNOS) as well as other mechanisms. There is also depletion in exogenous antioxidants such as ascorbic acid and tocopherol, and a reduction in activity of endogenous antioxidant systems regulated by the master gene regulator Nrf-2. In previous studies, circulating markers of oxidative stress have been shown to be increased in CKD, together with a reduction in endothelial function in a stepwise fashion relating to the severity of renal impairment. Not only is CVD linked to oxidative stress, but the progression of CKD itself is also in part dependent on redox sensitive mechanisms. For example, administration of the ROS scavenger tempol attenuates renal injury and reduces renal fibrosis seen on biopsy in a mouse model of CKD, whilst conversely, supplementation with the NOS inhibitor L-NAME causes proteinuria and renal impairment. Previous human studies examining the effect of antioxidant administration on vascular and renal function have been conflicting however. The work contained in this thesis therefore examines the effect of antioxidant administration on vascular and endothelial function in CKD. Firstly, 30 patients with CKD stages 3 – 5, and 20 matched hypertensive controls were recruited. Participants with CKD had lower ascorbic acid, higher TAP and ADMA, together with higher augmentation index and pulse wave velocity. There was no difference in baseline flow mediated dilatation (FMD) between groups. Intravenous ascorbic acid increased TAP and O2-, and reduced central BP and augmentation index in both groups, and lowered ADMA in the CKD group only. No effect on FMD was observed. The effects of ascorbic acid on kidney function was then investigated, however this was hindered by the inherent drawbacks of existing methods of non-invasively measuring kidney function. Arterial spin labelling MRI is an emerging imaging technique which allows measurement of renal perfusion without administration of an exogenous contrast agent. The technique relies upon application of an inversion pulse to blood within the vasculature proximal to the kidneys, which magnetically labels protons allowing measurement upon transit to the kidney. At the outset of this project local experience using ASL MRI was limited and there ensued a prolonged pre-clinical phase of testing with the aim of optimising imaging strategy. A study was then designed to investigate the repeatability of ASL MRI in a group of 12 healthy volunteers with normal renal function. The measured T1 longitudinal relaxation times and ASL MRI perfusion values were in keeping with those found in the literature; T1 time was 1376 ms in the cortex and 1491 ms in the whole kidney ROI, whilst perfusion was 321 mL/min/100g in the cortex, and 228 mL/min/100g in the whole kidney ROI. There was good reproducibility demonstrated on Bland Altman analysis, with a CVws was 9.2% for cortical perfusion and 7.1% for whole kidney perfusion. Subsequently, in a study of 17 patients with CKD and 24 healthy volunteers, the effects of ascorbic acid on renal perfusion was investigated. Although no change in renal perfusion was found following ascorbic acid, it was found that ASL MRI demonstrated significant differences between those with normal renal function and participants with CKD stages 3 – 5, with increased cortical and whole kidney T1, and reduced cortical and whole kidney perfusion. Interestingly, absolute perfusion showed a weak but significant correlation with progression of kidney disease over the preceding year. Ascorbic acid was therefore shown to have a significant effect on vascular biology both in CKD and in those with normal renal function, and to reduce ADMA only in patients with CKD. ASL MRI has shown promise as a non-invasive investigation of renal function and as a biomarker to identify individuals at high risk of progressive renal impairment.

Molecular characterization of extended-spectrum cephalosporin-resistance in Escherichia coli in pigs on-farm and from clinical cases throughout Quebec, Canada during 16 years

Le développement de la multirésistance chez Escherichia coli est un problème important en médecine animale et humaine. En outre, l’émergence et la diffusion des déterminants de résistance aux céphalosporines à larges spectres de troisième génération (ESCs) parmi les isolats, incluant des céphalosporines essentielles en médecine humaine (ex. ceftriaxone et ceftiofur), est un problème majeur de santé publique. Cette thèse visait trois objectifs. D’abord étudier la dynamique de la résistance aux antimicrobiens (AMR) ainsi que la virulence et les profils génétiques de la AMR des E. coli isolées de porcs recevant une nourriture post-sevrage supplémentée avec de la chlortétracycline et de la pénicilline G, et, accessoirement, évaluer les effets d'additifs alimentaires sur cette dynamique en prenant pour exemple d'étude un minéral argileux, la clinoptilolite, étant donné son possible lien avec le gène blaCMY-2 qui confère la résistance au ceftiofur. L'objectif suivant était d'investiguer les mécanismes menant à une augmentation de la prévalence du gène blaCMY-2 chez les porcs qui reçoivent de la nourriture médicamentée et qui n'ont pas été exposés au ceftiofur Ici encore,nous avons examiné les effets d’un supplément alimentaire avec un minéral argileux sur ce phénomène. Enfin, notre dernier objectif était d’étudier, dans le temps, les génotypes des isolats cliniques d'E. coli résistant au ceftiofur, isolés de porcs malades au Québec à partir du moment où la résistance au ceftiofur a été rapportée, soit de 1997 jusqu'à 2012. Dans l'étude initiale, la prévalence de la résistance à 10 agents antimicrobiens, incluant le ceftiofur, s’accroît avec le temps chez les E.coli isolées de porcelets sevrés. Une augmentation tardive de la fréquence du gène blaCMY-2, encodant pour la résistance au ceftiofur, et la présence des gènes de virulence iucD et tsh a été observée chez les isolats. La nourriture supplémentée avec de la clinoptilolite a été associée à une augmentation rapide mais, par la suite, à une diminution de la fréquence des gènes blaCMY-2 dans les isolats. En parallèle, une augmentation tardive dans la fréquence des gènes blaCMY-2 et des gènes de virulence iucD et tsh a été observée dans les isolats des porcs contrôles, étant significativement plus élevé que dans les porcs ayant reçu l'additif au jour 28. La diversité, au sein des E. coli positives pour blaCMY-2 , a été observée au regard des profils AMR. Certaines lignées clonales d'E.coli sont devenues prédominantes avec le temps. La lignée clonale du phylotype A prédominait dans le groupe supplémenté, alors que les lignées clonales du phylotype B1, qui possèdent souvent le gène de virulence iucD associé aux ExPEC, prédominaient dans le groupe contrôle. Les plasmides d'incompatibilité (Inc) des groupes, I1, A/C, et ColE, porteurs de blaCMY-2, ont été observés dans les transformants. Parmi les souches cliniques d'E.coli ESC-résistantes, isolées de porcs malades au Québec de 1997 à 2012, blaCMY-2 était le gène codant pour une β-lactamase le plus fréquemment détecté; suivi par blaTEM et blaCTX-M,. De plus, les analyses clonales montrent une grande diversité génétique. Par contre, des isolats d'E. coli avec des profils PFGE identiques ont été retrouvés dans de multiples fermes la même année mais aussi dans des années différentes. La résistance à la gentamicine, kanamycine, chloramphenicol, et la fréquence de blaTEM et de IncA/C diminuent significativement au cour de la période étudiée, alors que la fréquence de IncI1 et de la multirésistance à sept catégories d'agents antimicrobiens augmente significativement avec le temps. L'émergence d'isolats d'E. coli positifs pour blaCTX-M, une β-lactamase à large spectre et produisant des ESBL, a été observée en 2011 et 2012 à partir de lignées clonales distinctes et chez de nombreuses fermes. Ces résultats, mis ensemble, apportent des précisions sur la dissémination de la résistance au ceftiofur dans les E. coli isolées de porcs. Au sein des échantillons prélevés chez les porcs sevrés recevant l'alimentation médicamentée sur une ferme, et pour laquelle une augmentation de la résistance au ceftiofur a été observée, les données révèlent que les souches d'E. coli positives pour blaCMY-2 et résistantes aux ESCs appartenaient à plusieurs lignées clonales différentes arborant divers profils AMR. Le gène blaCMY-2 se répand à la fois horizontalement et clonalement chez ces E. coli. L'ajout de clinoptilotite à la nourriture et le temps après le sevrage influencent la clonalité et la prévalence du gène blaCMY-2 dans les E. coli. Durant les 16 années d'étude, plusieurs lignées clonales différentes ont été observées parmi les souches d'E. coli résistantes au ceftiofur isolées de porc malades de fermes québécoises, bien qu’aucune lignée n'était persistante ou prédominante pendant l'étude. Les résultats suggèrent aussi que le gène blaCMY-2 s'est répandu à la fois horizontalement et clonalement au sein des fermes. De plus, blaCMY-2 est le gène majeur des β-lactamases chez ces isolats. À partir de 2011, nous rapportons l'émergence du gène blaCTX-M dans des lignées génétiques distinctes.

Pain, Disability, and Art: A Response to Verpaelst

Réponse à - travail créatif / Response to - Creative work

A SURVEY OF DISTANCE MAGIC GRAPHS

In this report, we survey results on distance magic graphs and some closely related graphs. A distance magic labeling of a graph G with magic constant k is a bijection l from the vertex set to {1, 2, . . . , n}, such that for every vertex x Σ l(y) = k,y∈NG(x) where NG(x) is the set of vertices of G adjacent to x. If the graph G has a distance magic labeling we say that G is a distance magic graph. In Chapter 1, we explore the background of distance magic graphs by introducing examples of magic squares, magic graphs, and distance magic graphs. In Chapter 2, we begin by examining some basic results on distance magic graphs. We next look at results on different graph structures including regular graphs, multipartite graphs, graph products, join graphs, and splitting graphs. We conclude with other perspectives on distance magic graphs including embedding theorems, the matrix representation of distance magic graphs, lifted magic rectangles, and distance magic constants. In Chapter 3, we study graph labelings that retain the same labels as distance magic labelings, but alter the definition in some other way. These labelings include balanced distance magic labelings, closed distance magic labelings, D-distance magic labelings, and distance antimagic labelings. In Chapter 4, we examine results on neighborhood magic labelings, group distance magic labelings, and group distance antimagic labelings. These graph labelings change the label set, but are otherwise similar to distance magic graphs. In Chapter 5, we examine some applications of distance magic and distance antimagic labeling to the fair scheduling of tournaments. In Chapter 6, we conclude with some open problems.

Iowa’s Title V Maternal and Child Health (MCH) Annual Report, 2012

Title V of the Social Security Act is the longest-standing public health legislation in American history. Enacted in 1935, Title V is a federal-state partnership that promotes and improves maternal and child health (MCH). According to each state’s unique needs, Title V supports a spectrum of services, from infrastructure building services like quality assurance and policy development, to gap-filling direct health care services. Title V resources are directed towards MCH priority populations: pregnant women, mothers, infants, women of reproductive years, children and adolescents and children and youth with special health care needs.

2009 Annual Report of the Iowa Board of Medicine, April 1, 2010

The Iowa State Board of Medical Examiners submits the following annual report pursuant to the provisions of section 258A.4(2)of the Code of Iowa. The report relates to Board activities during the calendar year.

2012 Annual Report of the Iowa Board of Medicine, May 29, 2013

The Board of Medicine, through efficient and effective organization, will license, monitor, discipline, educate, and when appropriate, rehabilitate physicians to assure their fitness and competence in the practice of medicine. The Board protects and enhances the public’s health, safety and welfare by establishing and maintaining standards of excellence used in regulating the practices of medicine, surgery, and acupuncture and ensuring quality health care for Iowans.

2013 Annual Report of the Iowa Board of Medicine, May 19, 2014

The Board of Medicine, through efficient and effective organization, will license, monitor, discipline, educate, and when appropriate, rehabilitate physicians to assure their fitness and competence in the practice of medicine. The Board protects and enhances the public’s health, safety and welfare by establishing and maintaining standards of excellence used in regulating the practices of medicine, surgery, and acupuncture and ensuring quality health care for Iowans.

2014 Annual Report of the Iowa Board of Medicine, March 30, 2015

The Board of Medicine, through efficient and effective organization, will license, monitor, discipline, educate, and when appropriate, rehabilitate physicians to assure their fitness and competence in the practice of medicine. The Board protects and enhances the public’s health, safety and welfare by establishing and maintaining standards of excellence used in regulating the practices of medicine, surgery, and acupuncture and ensuring quality health care for Iowans.

Molecular target therapy and immunotherapy of rare lung tumors

Lung cancer is an heterogeneous disease, with 1-2% of rare histology. New molecular profiling technologies, such as next generation sequencing (NGS), haverevolutionized the assessment of molecular alteration in clinical practice. We analyzed a cohort of 1408 NSCLC-A patients treated at the Sant'Orsola- Malpighi University Hospital from 2019 to 2021. This analysis was performed using the oncomine focus thermo fischer panel. Of them, 410 (29%) had rare alteration (RET 3%, NTRK 0,2%,FGFR1 2%, MET exon14 skipping 3%, BRAF V600 4%, ALK fusion EGFR exon 20 2%) and 36 (2%)had a uncommon mutation. We enrolled 7 RET- rearranged patients in CRETA and J2G-MC-JZJC clinical trials assessing respectively unselective and selective RET-inhibitors , another 7 patients tested positive for the BRAF V6006 mutation and have been enrolled in the Array clinical trial assessing a novel combination of anti-BRAF and anti-mek agents . Other molecular alterations found are KRAS (Gly12Cys), FGFR1-4 mutation, MET skipping ex14 mutations, respectively eligible for other ongoing open studies such as Amgen 20190009 comparing efficacy of sotorasib vs docetaxel, Fight-207 assessing activity of pemigatinib and CINC280J12201 assessing activity of the novel met inhibitor capmatinib. In 2018 we joined the CHANCE clinical trial,a multicenter study evaluating the efficacy and safety of atezolizumab in patients withrare lung cancer histologies where and 14 patients have been so far enrolled in the Bologna site. Our studies underline the need of tailored approach to NSCLC patients and our results showed that precision medicine is feasible and is an effective approach to cancer treatment.

Evaluation Of Different Treatment Methods Against Denture Stomatitis: A Randomized Clinical Study.

The aim of this clinical study was to determine the efficacy of Uncaria tomentosa (cat's claw) against denture stomatitis (DS). Fifty patients with DS were randomly assigned into 3 groups to receive 2% miconazole, placebo, or 2% U tomentosa gel. DS level was recorded immediately, after 1 week of treatment, and 1 week after treatment. The clinical effectiveness of each treatment was measured using Newton's criteria. Mycologic samples from palatal mucosa and prosthesis were obtained to determinate colony forming units per milliliter (CFU/mL) and fungal identification at each evaluation period. Candida species were identified with HiCrome Candida and API 20C AUX biochemical test. DS severity decreased in all groups (P < .05). A significant reduction in number of CFU/mL after 1 week (P < .05) was observed for all groups and remained after 14 days (P > .05). C albicans was the most prevalent microorganism before treatment, followed by C tropicalis, C glabrata, and C krusei, regardless of the group and time evaluated. U tomentosa gel had the same effect as 2% miconazole gel. U tomentosa gel is an effective topical adjuvant treatment for denture stomatitis.

Fine Needle Aspiration Cytology In The Diagnosis Of Perioral Adverse Reactions To Cosmetic Dermal Fillers.

Facial cosmetic procedures are increasingly requested, and dermal filler materials have been widely used as a nonsurgical option since the 1980s. However, injectable fillers have been implicated in local adverse reactions. Therefore, the aim of this article was to describe the use of fine needle aspiration cytology (FNAC) in the diagnosis of foreign-body reactions to the perioral injection of dermal fillers. A 69-year-old woman presented with a painful nodule on her right nasolabial fold. Intraoral FNAC was performed, and cytologic smears were examined under optical and polarized light microscopy, showing birefringent microspheres, confirming the diagnosis of an adverse reaction caused by polymethyl methacrylate filler. FNAC is a less invasive method to confirm the diagnosis of adverse reactions caused by perioral cosmetic dermal fillers.

Stromal Myofibroblasts In Squamous Cell Carcinoma Of The Tongue In Young Patients - A Multicenter Collaborative Study.

The purpose of this study was to evaluate the presence of myofibroblasts, frequently associated with a more aggressive neoplastic behavior, in oral tongue squamous cell carcinoma (TSCC) of young patients and to compare with the distribution observed in older patients. Tumor samples from 29 patients younger than 40 years old affected by TSCC were retrieved and investigated for the presence of stromal myofibroblasts by immunohistochemical reactions against α smooth muscle actin, and the results obtained were compared to TSCC cases affecting older patients. No positive reaction could be found in the stromal areas devoid of neoplastic tissue, whereas myofibroblasts were present in 58.6% of the lesions in young patients and in 75.9% of the older ones. No significant difference was found when comparing the invasive front and the overall stroma of both groups, and no correlation could be obtained with stromal α smooth muscle actin expression, higher tumor grades or clinical stage (P > .05). There was no significant difference between the presence of stromal myofibroblasts of TSCC affecting young and old individuals.

Tissue Microarray Is A Reliable Method For Immunohistochemical Analysis Of Pleomorphic Adenoma.

To determine the most adequate number and size of tissue microarray (TMA) cores for pleomorphic adenoma immunohistochemical studies. Eighty-two pleomorphic adenoma cases were distributed in 3 TMA blocks assembled in triplicate containing 1.0-, 2.0-, and 3.0-mm cores. Immunohistochemical analysis against cytokeratin 7, Ki67, p63, and CD34 were performed and subsequently evaluated with PixelCount, nuclear, and microvessel software applications. The 1.0-mm TMA presented lower results than 2.0- and 3.0-mm TMAs versus conventional whole section slides. Possibly because of an increased amount of stromal tissue, 3.0-mm cores presented a higher microvessel density. Comparing the results obtained with one, two, and three 2.0-mm cores, there was no difference between triplicate or duplicate TMAs and a single-core TMA. Considering the possible loss of cylinders during immunohistochemical reactions, 2.0-mm TMAs in duplicate are a more reliable approach for pleomorphic adenoma immunohistochemical study.

Nodular Swelling Of The Tongue.

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