Docetaxel maintains its cytotoxic activity under hypoxic conditions in prostate cancer cells

<p>OBJECTIVE: The efficacy of docetaxel has recently been shown to be increased under hypoxic conditions through the down-regulation of hypoxia-inducible-factor 1�� (HIF1A). Overexpression of the hypoxia-responsive gene class III ��-tubulin (TUBB3) has been associated with docetaxel resistance in a number of cancer models. We propose that administration of docetaxel to prostate patients has the potential to reduce the hypoxic response through HIF1A down-regulation and that TUBB3 down-regulation participates in sensitivity to docetaxel.</p><p>METHODS: The cytotoxic effect of docetaxel was determined in both 22Rv1 and DU145 prostate cancer cell lines and correlated with HIF1A expression levels under aerobic and hypoxic conditions. Hypoxia-induced chemoresistance was investigated in a pair of isogenic docetaxel-resistant PC3 cell lines. Basal and hypoxia-induced TUBB3 gene expression levels were determined and correlated with methylation status at the HIF1A binding site.</p><p>RESULTS: Prostate cancer cells were sensitive to docetaxel under both aerobic and hypoxic conditions. Hypoxic cytotoxicity of docetaxel was consistent with a reduction in detected HIF1A levels. Sensitivity correlated with reduced basal and hypoxia-induced HIF1A and TUBB3 expression levels. The TUBB3 HIF1A binding site was hypermethylated in prostate cell lines and tumor specimens, which may exclude transcription factor binding and induction of TUBB3 expression. However, acquired docetaxel resistance was not associated with TUBB3 overexpression.</p><p>CONCLUSION: These data suggest that the hypoxic nature of a tumor may have relevance as regard to their response to docetaxel. Further investigation into the nature of this relationship may allow identification of novel targets to improve tumor control in prostate cancer patients.</p>

Factors influencing the success of rural cataract surgery programs in China:The study of hospital administration and relative productivity (SHARP)

<p>PURPOSE. To explore factors potentially influencing the success or failure of rural Chinese hospitals in increasing cataract surgical output and quality. METHODS. Focus groups (FGs, n = 10) were conducted with hospital administrators, doctors, and nurses at 28 county hospitals in Guangdong Province. Discussions explored respondents' views on increasing surgical volume and quality and improving patient satisfaction. Respondents numerically ranked possible strategies to increase surgical volume and quality and patient satisfaction. FG transcripts were independently coded by two reviewers utilizing the constant comparative method following the grounded theory approach, and numerical responses were scored and ranked. RESULTS. Ten FGs and 77 ranking questionnaires were completed by 33 administrators, 23 doctors, and 21 nurses. Kappa values for the two coders were greater than 0.7 for all three groups. All groups identified a critical need for enhanced management training for hospital directors. Doctors and nurses suggested reducing surgical fees to enhance uptake, although administrators were resistant to this. Although doctors saw the need to improve equipment, administrators felt current material conditions were adequate. Respondents agreed that patient satisfaction was generally high, and did not view increasing patient satisfaction as a priority. CONCLUSIONS. Our findings highlight agreements and disagreements among the three stakeholder groups about improving surgical output and quality, which can inform strategies to improve cataract programs in rural China. Respondents' beliefs about high patient satisfaction are not in accord with other studies in the area, highlighting a potential area for intervention. �� 2013 The Association for Research in Vision and Ophthalmology, Inc.</p>

'"To have its cake and eat it too:" US policy toward South Africa during the Kennedy administration

The assumption that US policy toward Africa was characterized by continuity during the cold war has recently been challenged by scholars who argue that President John F. Kennedy embarked on an African policy that was distinct from his predecessors. This may be true for black Africa, but Kennedy���s support for African nationalism did not extend to South Africa. This article reveals that Kennedy���s cold war priorities ensured continuity in US policy toward the apartheid state and, in some cases, additional cooperation as cold war crises increased the perceived importance of South Africa as an ideological and strategic ally and bastion against communism on a rapidly changing continent. This article also explores the role South Africa���s apartheid government played in this cold war alliance. The ruling National Party recognized its importance to US foreign policy goals and used this to stave off serious American criticism of its racial policies, deflect attention in the United Nations, and ensure continued economic and military cooperation with the United States.

Novel methods of drug administration for the treatment and care of older patients

The number of older people globally is increasing, contributing to a growing burden of morbidity and mortality. With this shift in population demographic, comes a new challenge in terms of appropriate healthcare for the over 65 years age group. As medication is the principal therapeutic intervention, it is essential that it be fully optimised, to meet the needs of this heterogeneous population. The most common routes of drug administration are oral and injectable, which may display some limitations for older people, in cases of dysphagia or frailty for example. This review considers alternative methods of drug delivery to the norm, specifically discussing the nasal, pulmonary and transdermal routes, as well as novel orally disintegrating tablets. The changing physiology as ageing occurs must be considered in the development of novel drug delivery devices. This review considers the various aspects of ageing that will influence future drug formulation design and development.

Occurrence and fate of estrogens and antibiotics in the environment evaluated by low-cost analytical methodologies

Endocrine disruptors and pharmaceuticals are considered to be concerning environmental contaminants. During the last two decades, studies dealing with the occurrence and fate of these emerging contaminants in the aquatic environment have raised attention and its number is constantly increasing. The presence of these contaminants in the environment is particularly important since they are known to induce adverse effects in the ecosystems even at extremely low concentrations. Estrogens and antibiotics, in particular, are identified as capable of induce endocrine disruption and contribute for the appearance of multi-resistant bacteria, respectively. A better assessment and understanding of the real impact of these contaminants in the aquatic environment implies the evaluation of their occurrence and fate, which is the main aim of this Thesis. Two estrogens (17���-estradiol and 17���-ethinylestradiol) and an antibiotic (sulfamethoxazole) were the contaminants under study and their occurrence in surface and waste waters was assessed by the implementation of enzyme linked immunosorbent assays (ELISAs). The assays were optimized in order to accomplish two important aspects: to analyze complex water samples, giving special attention to matrix effects, and to increase the sensitivity. Since the levels of these contaminants in the environment are extremely low, a pre-concentration methodology was also object of study in this Thesis. Dispersive liquid-liquid microextraction (DLLME) was developed for the preconcentration of E2 and EE2, subsequently quantified by either highperformance liquid chromatography (HPLC) and the previously optimized ELISAs. Moreover, the use of anthropogenic markers, i.e. indicators of human presence or activity, has been discussed as a tool to track the origin and type of contamination. An ELISA for the quantification of caffeine, as an anthropogenic marker, was also developed in order to assess the occurrence of human domestic pollution in Portuguese surface waters. Finally, photodegradation is considered to be one of the most important pathways contributing for the mitigation of pollutants��� presence in the aquatic environment. Both direct and indirect photodegradation of E2 and EE2 were evaluated. Since the presence of humic substances (HS) is known to have a noticeable influence on the photodegradation of pollutants and in order to mimic the real aquatic environment, special attention was given to the influence of the presence and concentration of different fractions of HS on the photodegradation of both hormones.

Resistance to last-resort antibiotics in natural environments

Last-resort antibiotics are the final line of action for treating serious infections caused by multiresistant strains. Over the years the prevalence of resistant bacteria has been increasing. Natural environments are reservoirs of antibiotic resistance, highly influenced by human-driven activities. The importance of aquatic systems on the evolution of antibiotic resistance is highlighted from the assumption that clinically-relevant resistance genes have originated in strains ubiquitous in these environments. We hypothesize that: a) rivers are reservoirs and disseminators of antibiotic resistance; b) anthropogenic activities potentiate dissemination of resistance to last-resort antibiotics. Hence, the main goal of the work is to compare the last-resort antibiotics resistome, in polluted and unpolluted water. Rivers from the Vouga basin, exposed to different anthropogenic impacts, were sampled. Water quality parameters were determined to classify rivers as unpolluted or polluted. Two bacterial collections were established enclosing bacteria resistant to cefotaxime (3rd generation cephalosporin) and to imipenem (carbapenem). Each collection was characterized regarding: phylogenetic diversity, antibiotic susceptibility, resistance mechanisms and mobile genetic elements. The prevalence of cefotaxime- and imipenem-resistant bacteria was higher in polluted water. Results suggested an important role in the dissemination of antibiotic resistance for Enterobacteriaceae, Pseudomonas and Aeromonas. The occurrence of bacteria resistant to non-beta-lactams was higher among isolates from polluted water as also the number of multiresistant strains. Among strains resistant to cefotaxime, extended-spectrum beta-lactamase (ESBL) genes were detected (predominantly blaCTX-M-like) associated to mobile genetic elements previously described in clinical strains. ESBL-producers were often multiresistant as a result of co-selection mechanisms. Culture-independent methods showed clear differences between blaCTX-M-like sequences found in unpolluted water (similar to ancestral genes) and polluted water (sequences identical to those reported in clinical settings). Carbapenem resistance was mostly related to the presence of intrinsically resistant bacteria. Yet, relevant carbapenemase genes were detected as blaOXA-48-like in Shewanella spp. (the putative origin of these genes), and blaVIM-2 in Pseudomonas spp. isolated from polluted rivers. Culture-independent methods showed an higher than the previously reported diversity of blaOXA-48-like genes in rivers. Overall, clear differences between polluted and unpolluted systems were observed, regarding prevalence, phylogenetic diversity and susceptibility profiles of resistant bacteria and occurrence of clinically relevant antibiotic resistance genes, thus validating our hypotheses. In this way, rivers act as disseminators of resistance genes, and anthropogenic activities potentiate horizontal gene transfer and promote the constitution of genetic platforms that combine several resistance determinants, leading to multiresistance phenotypes that may persist even in the absence of antibiotics.

La publication en libre acc��s : ��tude sur les niveaux de connaissance et d'int��r��t de la communaut�� de recherche des Facult��s d'administration, de droit, d'��ducation, d'��ducation physique et sportive, de lettres et sciences humaines et de th��ologie et d'��tudes religieuses de l'Universit�� de Sherbrooke

Le pr��sent essai est l'aboutissement d'une r��flexion sur la place qu'occupe le libre acc��s dans la communaut�� scientifique. Bien que le libre acc��s ne constitue pas en soi une nouveaut��, il occupe une place relativement marginale. L'auteur s'est d'abord pench�� sur l'��volution du libre acc��s dans le monde avant d'entreprendre une recherche terrain a l'Universit�� de Sherbrooke pour mesurer l'int��r��t et les connaissances de la communaut�� de recherche. Au terme de cette recherche, l'auteur a produit une analyse �� partir des donn��es qu'il a r��colt��es. Des recommandations ont par la suite ��t�� produites �� l'intention de la direction du Service des biblioth��ques et archives (SBA) dans le but de promouvoir le libre acc��s, porteur selon l'auteur d'��conomies potentielles pour les universit��s et d'une plus grande accessibilit�� au savoir autant pour les chercheurs que pour le grand public. Voici un bref aper��u desdites recommandations: Recommandation 1: Mettre sur pied une s��ance d'information et une brochure pr��sentant le libre acc��s aux professeurs et aux ��tudiants de l'Universit�� de Sherbrooke. Recommandation 2: Encourager les facult��s �� faire en sorte que soient d��pos��s sur Savoirs UdeS les articles publi��s par les professeurs. Recommandation 3: Entamer un dialogue personnalise avec les repr��sentants de l'ensemble des facult��s de l'Universit�� de Sherbrooke pour ��tablir la voie verte au libre acc��s. Recommandation 4: Assurer la synergie des d��p��ts institutionnels des universit��s qu��b��coises. Recommandation 5: Assurer la d��fense des int��r��ts universitaires par un r��seautage aupr��s des organismes subventionnaires.

Locust bean gum-based microparticles for pulmonary delivery of antibiotics

Disserta����o de Mestrado, Ci��ncias Biom��dicas, Departamento de Ci��ncias Biom��dicas e Medicina, Universidade do Algarve, 2016