La ciclosporine est un traitement immunosuppresseur très utilisé : elle inhibe l'activation des lymphocytes T via la calcineurine. Sa néphrotoxicité limite son utilisation : la ciclosporine induit une augmentation de la vasoconstriction ainsi qu'une augmentation de la réponse des cellules musculaires lisses vasculaires (CMLV) aux agents vasoactifs. Le récepteur minéralocorticoïde (RM), au-delà de ses effets sur la réabsorption sodée, agit sur le tonus vasculaire en modulant la réponse des cellules (endothéliales et musculaires lisses) vasculaires aux agents vasoactifs. Notre hypothèse était que le RM pouvait participer à l'action vasoconstrictrice de la ciclosporine ; son inactivation pourrait limiter la néphrotoxicité de la ciclosporine. Deux modèles de souris ont été invalidés génétiquement pour le RM : dans les cellules endothéliales et les CMLV (KO-RM CMLV). Seules les souris KO-RM CMLV étaient protégées contre la néphrotoxicité de la ciclosporine. Ces effets impliquent une action sur le tonus vasculaire rénal. L'antagonisme pharmacologique du RM (par le canrénoate) administré per os confère la même protection. En revanche, la néphrotoxicité induite par le tacrolimus (une autre anticalcineurine) n'est pas prévenue par l'antagonisme du RM. Utiliser un antagoniste sélectif du RM (l'éplérénone) pourrait prévenir la néphrotoxicité de la ciclosporine. Nous avons prouvé sa bonne tolérance en association à la ciclosporine chez les patients transplantés et insuffisants rénaux chroniques. Une kaliémie supérieure à 4,35mmol/L à l'initiation indique un sur-risque de développer une hyperkaliémie. L'efficacité reste à démontrer au cours d'un essai prospectif et randomisé. / Cyclosporine A (cyclo) is a widely used drug in kidney transplantation: its anticalcineurin actioninhibits T lymphocytes activation and prevents allograft rejection. Despite a huge benefit on graftsurvival, cyclo exerts a side effect that limits its use: nephrotoxicity. Vasculotoxicity appears to becentral: cyclo enhances renal vasoconstriction by altering vasoactive factors and vascular smoothmuscle cells (VSMC) response to vasoactive factors. Beyond its effects on sodium reabsorption,Mineralocorticoid Receptor (MR) acts on vascular tone by modulating both endothelial and VSMCresponses to vasoactive factors. Our working hypothesis was that MR could participate to cycloinducedvasoconstriction and that MR inactivating (pharmacologically or genetically) could alleviatecyclo-induced nephrotoxicity. Two genetically MR-knock out (MR-KO) were generated: inendothelial or VSMC. Only VSMC MR-KO mice were protected from cyclo-induced nephrotoxicity.We also show that such an effect was mediated by vascular tone modulation. This prevention was alsoconferred by the systemic pharmacological antagonism of MR (by canrenoate) in mice but not duringnephrotoxicity induced by tacrolimus (another anticalcineurine drug used in kidney transplantation).Then, we proposed to use MR pharmacological antagonism in humans (by eplerenone) during kidneytransplantation. We first had to prove its safety in such a population. Among 31 cyclo-treated patients,only 9 developed hyperkalemia (>5mmol/L) and none presented serious side effect. We propose akalemia higher than 4.35mmol/L at baseline to be the marker of a higher risk of developinghyperkalemia under treatment. The efficiency of eplerenone to prevent/alleviate cyclo-inducednephrotoxicity during kidney transplantation should be tested during a randomized controlled trial.

Diploma thesis Side Effects of UN Peacekeeping Missions deals with negative sid e ef f e cts of UN peacekeeping operations. The work aims at showing the relation between certain factors and the emergence of the side eff ect s. To do so, four interpretative case studies are used in this thesis. The missions analysed in the case studies share some common characteristics (type of mandate, time period etc.) but differ in the essence of the si de e ff e cts that has been detected during their deployment. For the sid e eff e ct s of human trafficking the UN mission UNMIBH in Bosnia and Hercegovina was analysed, for sexual abuse it was the MONUC in DRC, for diamonds smuggling the UNAMSIL mission in Sierra Leone and for the collaboration with warlords the UNPROFOR in Bosnia and Hercegovina. The applied factors are divided between external (presence of the s id e ef f e cts, the stage of conflict and the efficiency of the central government) and internal (national composition of the mission, level of corruption among the TCC's and the existence of SOFA) and are considered within the context of each case study. This work proofs the relevance of this factors in regard to the emergence of the s id e eff ec ts of peacekeeping.

Functional purity is a fundamental part of the functional programming paradigm. A function is functionally pure if it is side-effect free and deterministic. Pure functions provide many benefits compared to impure ones, including guaranteed thread-safety as well as easier testing, debugging and maintenance. But how can functional purity be measured? This thesis develops a method for statically measuring the level of functional purity in any given C# program. It also investigates problems with determining purity in object-oriented languages, with a focus on C#. Moreover, a prototype of the method is implemented in order to evaluate the method using a benchmark consisting of 11 open source repositories that use C#'s [Pure] attribute. The [Pure] attribute can be placed in front of a method declaration to indicate that it is side-effect free. Due to a number of limitations to the implementation as well as to [Pure]'s definition of functional purity, which excludes determinism, the results of the evaluation appear relatively poor. After normalizing the implementation's classification distribution for each repository, its classification of pure functions has a precision of 65% and recall 17%, and its classification of impure functions has 54% precision and 69% recall. Nevertheless, the prototype still shows the potential of the full analysis method. A complete implementation of the analysis method could potentially yield a fully working system for measuring any C# program's level of functional purity.

Thesis (MSc (Biomedical Technology))--Cape Peninsula University of Technology, 2019 / Introduction: The provision of access to safe and effective contraception is a critical element in the health of women that enables them to make choices about their fertility. This element of control empowers them and indirectly enables them to access better social and economic opportunities. Hormonal contraceptives are a convenient, effective and relatively safe method of fertility control. Extensive research has been done on the effects of hormonal contraceptives on undesirable metabolic and haemostatic changes, but data on the relationship between oxidative stress and oral contraceptives is scarce and remains subject to debate. Aging of the skin due to oestrogen loss at menopause is thought to include atrophy, decreased collagen content, water content, and sebaceous secretions, loss of elasticity, wrinkling, poor wound healing and manifestations of hyperandrogenism. A number of studies have shown that oestrogens serve many important beneficial and protective functions in skin physiology. Despite extensive clinical experience, many metabolic effects of oral contraceptive treatment remain to be explored. The effects of progesterone on body weight and composition are of interest from several standpoints. Since hormonal contraceptives are widely used, it is important to investigate the effect thereof on oxidative status, skin parameters and anthropometric indicators, to enable women make informed choices about the use of contraceptives, or to adapt their lifestyle if necessary. The aim of the present study was therefore, to assess certain effects of contraceptives in a student population at the Cape Peninsula University of Technology (CPUT). Objectives of the study: To determine the differences in skin health, anthropometric \parameters and oxidative stress status in female university students using various hormonal contraceptives versus non-contraceptive users. Research design: The study adopted a quantitative approach to examine a crosssectional research sample in order to provide a snapshot of the population at a particular time. Concenting participants were selected through the use of questionnaires aimed at ascertaining the type of contraceptive used as well as general health and lifestyle patterns. Blood samples were collected and the antioxidant status was determined. Body composition and skin analysis was conducted on each of the participants in the selected groups and the results were compared to determine the differences between contraceptive and non-contraceptive users. Results: With regards to oxidative stress status, the results indicated a significant increase in superoxide dismutase (SOD) activities within the triphasic contraceptive group compared to the monophasic contraceptive group, suggesting higher levels of oxidative stress in monophasic contraceptive groups. There was also an increase in lipid peroxidation (TBARS) for the triphasic contraceptive group when compared to the control, monophasic contraceptive and injectable contraceptive groups respectively, indicative of increased oxidative stress levels in the triphasic contraceptive group. In this study, skin parameters evaluation revealed that there was a general increase in the presence of erythema in the monophasic contraceptive group compared to the control; injectable contraceptive; implant contraceptive and triphasic contraceptive groups, symptomatic of higher vascular activity in the monophasic group. Melanocyte activity measured in the forehead, cheek and chin areas were also significantly increased when the monophasic contraceptive group was compared to the control and other contraceptive groups, characterised by the pigmentation pattern of chloasma/melasma known to be caused by hormones. The hydration measurements were significantly increased in the implant contraceptive group compared to the control and monophasic contraceptive groups. Furthermore, a significant increase in hydration was evident in the injectable contraceptive group when compared to the control and monophasic contraceptive groups. Injectable contraceptives and implant contraceptives mainly contain progesterone which has been proven to combat signs of aging and increase collagen and elastin in the skin. With respect to anthropometric measurements, there was a significant increase in the measurement of waist to hip ratio in the implant contraceptive group compared to the control group (non-contraceptive). Progesterone influence on adipose tissue distribution indicated a more significant increase of adipose tissue in the abdominal region. Conclusion: In this study there was some evidence that the type of hormonal contraceptive used does have significant effects on the variables tested in the population sample. These effects are dependent on the composition of the contraceptive and the levels of progesterone and/or oestrogen.

Thesis (M. Sc. (Biochemistry)) -- University of Limpopo, 2021 / Plant-derived products have been used for years in the treatment of various ailments with low or no side effects. Thus, screening of medicinal plants for potential anticancer activity, in vitro, could help identify plant extracts or compounds that can be developed for use as anticancer agents with less or no side effects. The aim of this study was to investigate the probable anticancer effects and induced mechanism of action of Momordica balsamina crude leaf acetone extract in lung A549 cancer cells. The effect of the extract on cell viability, proliferation and cell division cycle were determined using Muse count & viability, Ki67 proliferation and cell cycle assay kits, respectively. The presence of biochemical and morphological features associated with apoptosis were analysed by Muse annexin-V & dead cell assay kit and Acridine orange/Ethidium bromide dual staining. The effect of the extract on the mRNA expression levels of cell cycle regulatory genes was determined using RT PCR. Proteome profiler antibody array was used to determine the effect of the extract on the protein expression levels of apoptosis regulatory genes. The findings revealed that the crude leaf acetone extract of M. balsamina decreased the percentage viability of lung A549 cells with less effect on the percentage viability of normal cells (KMST-6). Furthermore, a significant anti-proliferative effect in extract treated A549 cells was observed. Characteristic nuclear and morphological features of apoptosis such as chromatin and nuclear condensation, externalisation of phosphatidylserine and loss of cell membrane function were observed in A549 cells treated with the extract. Although there was no relative upregulation of Bax and Bad protein expression, a downregulation of the Bcl-xl and Bcl-2 protein expression was observed in extract-treated cells. This led to the release of Cytochrome c and HTRA2/Omi leading to pro-caspase-3 cleavage. Furthermore, presence of HTRA2/Omi in the cytosol inhibited the functions of IAPs such as XIAP and cIAP1/2. Phosphorylation of p53 at different serine residues led to upregulated protein expression levels of p27/Kip1 protein which resulted in the cell division cycle arrest at G0/G1-phase. Reverse transcriptase polymerase chain reaction results showed that the extract modulated mRNA expression levels of p53, p21, cyclin B and cdc2 genes. In summary, M. balsamina extract induced cell division cycle arrest and apoptosis in A549 cells through intrinsic apoptosis pathway via p53-mediated mechanism. / South African Medical Research Council (SAMRC)

Bakgrund I majoriteten av länderna världen över klassas livmoderhalscancer som den näst vanligaste eller den vanligaste cancerdiagnosen hos kvinnor. Sjukdomen som till största del orsakas av ihållande infektioner med humant papillomvirus (HPV) kan bilda cellförändringar som senare utvecklar cancertumörer i livmoderhalsen. Aggressiva behandlingsformer i olika kombinationer sätts in och ger vanligen en rad olika biverkningar som påverkar kvinnorna på olika sätt. Ett sjukdomslidande är ett lidande som orsakas av sjukdomen i sig samt dess behandlingar. Kvinnor som får livmoderhalscancer har därav en ökad tendens till att uppleva ett lidande.  Syfte Syftet med studien var att belysa kvinnors erfarenheter och upplevelser av att leva med livmoderhalscancer.  Metod En icke-systematisk litteraturöversikt tillämpades och författarna baserade resultatet på 15 vetenskapliga artiklar med kvantitativ samt kvalitativ design. Via databaserna Public Medline (PubMed) samt Cumulative Index to Nursing & Allied Health literature (CINAHL) inhämtades artiklarna med hjälp av olika sökkombinationer. Artiklarna som inkluderades i studien kvalitetsgranskades utifrån bedömningsunderlaget framtaget av Sophiahemmet högskola. Därefter genomfördes en integrerad dataanalys där artiklarna till resultatdelen sorterades in i kategorier och underkategorier, genom detta utformades fyra huvudrubriker med tillhörande underrubriker.  Resultat I litteraturöversiktens resultat beskrivs hur kvinnor upplever livmoderhalscancer. I resultatet framkommer det att beskedet om diagnosen, genomförandet av behandling samt dess biverkningar påverkat majoriteten av kvinnornas fysiska, psykiska och sexuella förmåga. I resultatet framkommer det även att majoriteten av kvinnorna som lever med sjukdomen upplever en förändrad vardag med anledning av detta.  Slutsats Litteraturöversiktens resultat visar sammanfattningsvis att upplevelsen av livmoderhalscancer är varierande hos kvinnor, framför allt på grund av val av behandlingsmetod. Det framgår i resultatet att lidandet hos kvinnor är tydligt inom flertalet områden. Kvinnor upplever fysiska och psykiska hinder i livet både under och efter att ha diagnostiserats med livmoderhalscancer. / Background In the majority of countries around the world, cervical cancer is classified as the second most common or the most common cancer diagnosis in women. The disease, which is largely caused by persistent infections with human papillomavirus (HPV), can form cell changes that later develop cancerous tumors in the cervix. Aggressive forms of treatment in different combinations are used and usually cause a number of different side effects that affect women in different ways. The suffering of illness is a suffering caused by the disease itself and its treatments. Women who get cervical cancer therefore have an increased tendency to experience suffering.  Aim The purpose of this study was to illustrate women's experiences of living with cervical cancer.  Method A non-systematic literature overview was applied and the authors based their results from 15 scientific articles with quantitative and qualitative design. The articles are collected from the databases Public Medline (PubMed) and Cumulative Index to Nursing & Allies Health Literature (CINAHL), using different search combinations. The articles included in the study has been quality audited based on the assessment data produced by Sophiahemmet Högskola. Thereafter, an integrated data analysis was carried out where the articles were sorted into categories, and under categories, through this, four main headings with associated subheadings were designed.  Results In the result of the literature overview, it is described how women experience cervical cancer. The results show that the information about the diagnosis, the implementation of treatment and its side effects affected the majority of the women's physical, mental and sexual abilities. The results also show that the majority of women living with the disease experience a changed everyday life due to this.  Conclusions In summary, the result of the literature overview show that the experience of cervical cancer varies in women, mainly due to the choice of treatment method. The results show a clear suffering of women and in many areas. Women experience physical and mental barriers in life both during and after being diagnosed with cervical cancer.

No description available.

Post-marketing surveillance refers to any non-experimental or observational study, method, or monitoring strategy that is applied to obtain information on drug experience (primarily adverse) after a drug has been approved for clinical use. One of the major problems in post-marketing surveillance studies is the lack or under-reporting of drug experiences by health care professionals. This study was developed to describe the impact of three different prescription event monitoring programmes on the reporting of adverse drug reactions (ADR's) in the hospital situation. The intensive ADR monitoring programme and two voluntary ADR monitoring programmes which followed were conducted in the medical wards of an urban teaching and referral hospital. All patients admitted to the designated wards were monitored by a dedicated pharmacist in the intensive programme, ward pharmacists in the first voluntary programme and by medical and nursing staff in the second voluntary programme. The pharmacist monitored a cohort of patients prospectively in two medical wards for a period of three months. The patient's record was linked with any suspected ADR. All details, i.e. patient drug orders, characteristics and ADR description, were recorded and then reported. From 228 patients monitored, 25 cases have been reported. The impact of the intensive ADR monitoring programme was a reporting rate of 11 percent. Reports were received on ADR's of a particularly mild, common and pharmacologically predictable (type A) nature. The first voluntary ADR monitoring programme comprised the reporting of suspected AD R's and the recording of drug orders for the patients and the patient characteristics. The ward pharmacists monitored for suspected AD R's in all patients during their regular ward rounds. Six cases were reported in a population of 1506 patients monitored during the three months. The reports were mainly on moderate to severe suspected AD R's of pharmacologically unpredictable (type B) nature. The rate of reports received by the surveillance unit in this study was 4 reports per ward pharmacist per annum. The second voluntary ADR monitoring programme comprised the prospective monitoring of 1555 patients by medical and nursing staff during their stay at the designated medical wards during the three month period. Patients were monitored for any ADR and when an ADR was suspected, the patient characteristics and drug orders were recorded and reported to the surveillance unit. Ten cases were reported represented by six reports from doctors and four by sisters. The reporting rate was 2 reports per doctor in four years and 3 reports for each member of the nursing team in 5 years. Reports were mainly received on moderate to severe suspected ADR's of a pharmacologically unpredictable (type B) nature.

Contexte. Synonymes de progrès thérapeutique, les thérapies ciblées anticancéreuses ne sont pas sans effet secondaire, en particulier dermatologique. Très peu de données sont disponibles quant à leur impact sur la qualité de vie. Le service de dermatologie de Gustave Roussy a consacré une partie de son activité de recherche à cette thématique. Inscrite dans ces travaux, notre thèse avait pour objectif principal de décrire les changements observés du point de vue de l'état émotionnel, de l'image corporelle et des interactions sociales avec l'apparition des atteintes cutanées, en s'intéressant à la place des représentations associées au traitement dans le processus d'ajustement des patients.Méthode. L'étude prospective comprenait quatre temps d'évaluation (initiation du traitement, un, deux et trois mois après) et associait deux modes d'évaluation : quantitatif (questionnaires) et qualitatif (entretiens semi-directifs). L'inclusion était proposée par les oncologues aux patients allant débuter une thérapie ciblée. Les analyses statistiques ont été menées avec le logiciel SPSS 14.0 ; l'analyse des entretiens a combiné méthode thématique et méthode par questionnement analytique, en recourant au modèle théorique de Pedinielli. Résultats. Sur 82 patients inclus dans la recherche biomédicale, 62 ont accepté de participer à l'étude psychologique. La partie quantitative a été complétée par 33 patients, pour moitié hommes (âge moyen 56 ans) soignés pour un cancer métastatique ; 84% a développé au moins un des symptômes suivants: rash cutané, syndrome main-pied, alopécie ou photosensibilité. Les changements observés ont été un inconfort physique et une gêne à la réalisation des activités du quotidien. Aucun signe de perturbation de la sphère émotionnelle, de l'image du corps et des relations sociales n'a été mis en évidence. La représentation d'un médicament contrôlant la maladie a émergé comme un des facteurs significativement associés aux variations de l'impact des toxicités cutanées sur la qualité de vie. La partie qualitative a concerné 41 patients (caractéristiques médicales et sociodémographiques très similaires à celles de l'échantillon quantitatif). Pour une majorité les symptômes dermatologiques ont été « gênants », voire « perturbants » lorsqu'ils entraînaient douleurs, difficultés à la mobilité ou troubles du sommeil, mais sont restés « gérables, supportables ». Les représentations associées au traitement, très positives, sont apparues comme un élément soutenant dans l'ajustement des patients. Du discours des patients en souffrance psychologique sont ressorties une défiance vis-à-vis du regard d'autrui et une impossibilité d'amorcer le travail de renoncement nécessaire à l'intégration des transformations liées au cancer et à ses traitements. L'origine de cette souffrance serait un débordement des défenses psychiques par une angoisse de mort : la difficulté pour restaurer l'état d'équilibre psychique antérieur provenant de l'activation concurrentielle de deux dynamiques, l'une surnommée « substantielle », l'autre « identitaire ».Discussion. Ces résultats rejoignent les données de la littérature en concluant à un impact d'intensité faible à modérée des toxicités cutanées sur la qualité de vie pour une majorité de patients. Contrairement à ce qui était attendu, il n'a pas été observé de changement sur le plan de l'état émotionnel, de l'image corporelle et des interactions sociales. L'investissement positif du traitement, la réappréciation des valeurs, le très bon état général des patients et l'optimisme ont été évoqués l'absence de perturbation. L'importance de l'encadrement médico-soignant a aussi été soulignée.Conclusion. Le développement croissant des thérapies ciblées appelle à une consolidation des mesures de prévention et de prise en charge des symptômes dermatologiques, ce qui nécessite un renforcement des actions de formation et de sensibilisation des acteurs de soin à cette problématique. / Background. Considered as a significant therapeutic progress in cancer, targeted agents are not without side effects, particularly dermatological ones. Very little information is presently available about their consequences on patients' quality of life, that is why the dermatological team of Gustave Roussy has developed a prospective research. Integrated into this work, our thesis aimed to describe the psychosocial changes occurring with cutaneous toxicities and to explore the implication of treatment representations in the patient's adjustment process.Methods. The study included four phases of evaluation (treatment initiation, one, two and three months after) and used two methods: a quantitative one (questionnaires) and a qualitative one (semi-structured interviews). The inclusion was proposed by oncologists to patients who were about to start a targeted therapy. Statistical analyzes were conducted with SPSS 14.0 software; analyzes interviews combined thematic approach and analytical questioning methods and referred to the Pedinielli's theoretical model.Results. Eighty- two patients gave their consent for biomedical research, 62 of them agreed to participate to the psychological study. The quantitative part was completed by 33 patients (50% men, mean age 56 years) treated for a metastatic cancer; 84% developed at least one of the following symptoms: skin rash, hand-foot syndrome, alopecia or photosensitivity. The observed changes were characterized by a physical discomfort and difficulties in the activities of daily life. No sign of disturbance was noted in emotional domain, body image or social relations. The representation of a drug controlling the disease was significantly associated with a lower impact of skin problems on the quality of life. The qualitative part included 41 patients (medical and sociodemographic characteristics very similar to those of the quantitative sample). For most people, dermatological side effects were "boring", "uncomfortable", sometimes "impressive" or "disturbing" when they were associated with pain, mobility difficulties or sleeping troubles, but remained "manageable, bearable". The very positive treatment representations appeared as a supporting element in patients' adjustment. Psychological distress seemed appear when patients feared being stared by others and failed to engage themselves in the renouncement work which is needed to adjust oneself to the transformations related to cancer and its treatments. In such situation psychological distress was supposed to come from an overflow of the psychic defences by a fear of death; the difficulty to restore mental balance would be explained by the activation of two competitive dynamics, which struggle for the organism and the identity survival.Discussion. These results are consistent with the literature data. The skin toxicities impact on quality of life is mild to moderate for a majority of patients. Contrary to our expectations, there was no evidence of change in the domains of emotions, body image and social interactions. The positive investment of treatment, a reassessment of values, the very good physical state of patients and the influence of optimism in patients state of mind have been cited to explain not only the absence of disturbance, but also the very low levels of anxiety, sadness and fatigue generally reported. The importance of the caregiving provided by health professionals was also highlighted: anticipating difficulties, giving information about side effects and effectively managing problems secure patients.Conclusions. The growing development of targeted therapies implies strengthening prevention and management of dermatological side effects. Moreover, it requires to aware and to train more health professionals to this problem, recalling the singular dimension of each patient which can not being reduced to the medical observable.

The U.S. Food and Drug Administration (FDA) uses the FDA Adverse Event Reporting System (FAERS) to monitor adverse events resulting from pharmaceutical drug use. However, this system has limitations such as not allowing real-time data collection. To address these limitations, the FDA launched the Sentinel Initiative in 2008. This comparative case study was conducted to describe perceptions of investigating the efficacy of the Sentinel Initiative compared with the FAERS. The study was based on the theory of preemption as it emphasized the need for efficient means for providing unquestionable proof that consumers suffered adverse drug effects. The sample included interivews of 20 individuals, who worked closely with the FAERS program and were familiar with the Sentinel Initiative. In-depth key-informant interviews had been conducted to determine the perceptions of the participants regarding the challenges and benefits of the Sentinel Initiative compared with FAERS. To analyze data, content analysis was used. The study concluded that the FAERS and Sentinel Initiative provided a systematic database, which included health data, that could be used to improve public health. Due to the FAERS and Sentinel Initiative, adverse effects of drugs will be recognized and the safety of the patients and the public will be prioritized. The findings of this study have potential social impact for positive change at the societal level, organizational level, and individual level in terms of overall safety of the drugs. Sentinel initiative at its present state complements the existing FAERS and leverage its benefits by connecting at a grass roots level patients to an organization level as well as stakeholders to make an impact in providing safer drugs on the market.