Experimental Induction of Paromomycin Resistance in Antimony-Resistant Strains of L. donovani: Outcome Dependent on In Vitro Selection Protocol

Paromomycin (PMM) has recently been introduced for treatment of visceral leishmaniasis in India. Although no clinical resistance has yet been reported, proactive vigilance should be warranted. The present in vitro study compared the outcome and stability of experimental PMM-resistance induction on promastigotes and intracellular amastigotes. Cloned antimony-resistant L. donovani field isolates from India and Nepal were exposed to stepwise increasing concentrations of PMM (up to 500 µM), either as promastigotes or intracellular amastigotes. One resulting resistant strain was cloned and checked for stability of resistance by drug-free in vitro passage as promastigotes for 20 weeks or a single in vivo passage in the golden hamster. Resistance selection in promastigotes took about 25 weeks to reach the maximal 97 µM inclusion level that did not affect normal growth. Comparison of the IC50 values between the parent and the selected strains revealed a 9 to 11-fold resistance for the Indian and 3 to 5-fold for the Nepalese strains whereby the resistant phenotype was also maintained at the level of the amastigote. Applying PMM pressure to intracellular amastigotes produced resistance after just two selection cycles (IC50 = 199 µM) compared to the parent strain (IC50 = 45 µM). In the amastigote-induced strains/clones, lower PMM susceptibilities were seen only in amastigotes and not at all in promastigotes. This resistance phenotype remained stable after serial in vitro passage as promastigote for 20 weeks and after a single in vivo passage in the hamster. This study clearly demonstrates that a different PMM-resistance phenotype is obtained whether drug selection is applied to promastigotes or intracellular amastigotes. These findings may have important relevance to resistance mechanism investigations and the likelihood of resistance development and detection in the field

Intention Seekers: Conspiracist Ideation and Biased Attributions of Intentionality

Conspiracist beliefs are widespread and potentially hazardous. A growing body of research suggests that cognitive biases may play a role in endorsement of conspiracy theories. The current research examines the novel hypothesis that individuals who are biased towards inferring intentional explanations for ambiguous actions are more likely to endorse conspiracy theories, which portray events as the exclusive product of intentional agency. Study 1 replicated a previously observed relationship between conspiracist ideation and individual differences in anthropomorphisation. Studies 2 and 3 report a relationship between conspiracism and inferences of intentionality for imagined ambiguous events. Additionally, Study 3 again found conspiracist ideation to be predicted by individual differences in anthropomorphism. Contrary to expectations, however, the relationship was not mediated by the intentionality bias. The findings are discussed in terms of a domain-general intentionality bias making conspiracy theories appear particularly plausible. Alternative explanations are suggested for the association between conspiracism and anthropomorphism

HPV.edu study protocol: a cluster randomised controlled evaluation of education, decisional support and logistical strategies in school-based human papillomavirus (HPV) vaccination of adolescents

Background The National Human Papillomavirus (HPV) Vaccination Program in Australia commenced in 2007 for females and in 2013 for males, using the quadrivalent HPV vaccine (HPV 6,11,16,18). Thus far, we have demonstrated very substantial reductions in genital warts and in the prevalence of HPV among young Australian women, providing early evidence for the success of this public health initiative. Australia has a long history of school-based vaccination programs for adolescents, with comparatively high coverage. However, it is not clear what factors promote success in a school vaccination program. The HPV.edu study aims to examine: 1) student knowledge about HPV vaccination; 2) psycho-social outcomes and 3) vaccination uptake. Methods/Design HPV.edu is a cluster randomised trial of a complex intervention in schools aiming to recruit 40 schools with year-8 enrolments above 100 students (approximately 4400 students). The schools will be stratified by Government, Catholic, and Independent sectors and geographical location, with up to 20 schools recruited in each of two states, Western Australia (WA) and South Australia (SA), and randomly allocated to intervention or control (usual practice). Intervention schools will receive the complex intervention which includes an adolescent intervention (education and distraction); a decisional support tool for parents and adolescents and logistical strategies (consent form returns strategies, in-school mop-up vaccination and vaccination-day guidelines). Careful process evaluation including an embedded qualitative evaluation will be undertaken to explore in depth possible mechanisms for any observed effect of the intervention on primary and secondary outcomes. Discussion This study is the first to evaluate the relative effectiveness of various strategies to promote best practice in school-based vaccination against HPV. The study aims to improve vaccination-related psychosocial outcomes, including adolescent knowledge and attitudes, decision-making involvement, self-efficacy, and to reduce fear and anxiety. The study also aims to improve school vaccination program logistics including reduction in time spent vaccinating adolescents and increased number of consent forms returned (regardless of decision). Less anxiety in adolescents will likely promote more efficient vaccination, which will be more acceptable to teachers, nurses and parents. Through these interventions, it is hoped that vaccination uptake will be increased. Trial registration Australian and New Zealand Clinical Trials Registry, ACTRN12614000404628, 14.04.2014. Electronic supplementary material The online version of this article (doi:10.1186/s12889-015-2168-5) contains supplementary material, which is available to authorized users

Targeting cell cycle and hormone receptor pathways in cancer

The cyclin/cyclin-dependent kinase (CDK)/retinoblastoma (RB)-axis is a critical modulator of cell cycle entry and is aberrant in many human cancers. New nodes of therapeutic intervention are needed that can delay or combat the onset of malignancies. The antitumor properties and mechanistic functions of PD-0332991 (PD; a potent and selective CDK4/6 inhibitor) were investigated using human prostate cancer (PCa) models and primary tumors. PD significantly impaired the capacity of PCa cells to proliferate by promoting a robust G1-arrest. Accordingly, key regulators of the G1-S cell cycle transition were modulated including G1 cyclins D, E and A. Subsequent investigation demonstrated the ability of PD to function in the presence of existing hormone-based regimens and to cooperate with ionizing radiation to further suppress cellular growth. Importantly, it was determined that PD is a critical mediator of PD action. The anti-proliferative impact of CDK4/6 inhibition was revealed through reduced proliferation and delayed growth using PCa cell xenografts. Finally, first-in-field effects of PD on proliferation were observed in primary human prostatectomy tumor tissue explants. This study shows that selective CDK4/6 inhibition, using PD either as a single-agent or in combination, hinders key proliferative pathways necessary for disease progression and that RB status is a critical prognostic determinant for therapeutic efficacy. Combined, these pre-clinical findings identify selective targeting of CDK4/6 as a bona fide therapeutic target in both early stage and advanced PCa and underscore the benefit of personalized medicine to enhance treatment response.C E S Comstock, M A Augello, J F Goodwin, R de Leeuw, M J Schiewer, W F Ostrander Jr, R A Burkhart, A K McClendon, P A McCue, E J Trabulsi, C D Lallas, L G Gomella, M M Centenera, J R Brody, L M Butler, W D Tilley and K E Knudse

Medical education in pediatrics: attitude assessment in health promotion and preventive care Educação médica na residência de pediatria: avaliação de atitudes em promoção e prevenção de saúde

OBJECTIVES: to evaluate attitudes in childcare and primary care in pediatrics, as well as aspects of training and medical education for residents in pediatrics consistent with the current medical paradigm. METHODS: the subjects were 133 residents of six pediatrics residency services in the city of Porto Alegre, RS. A cross-sectional, descriptive study was performed consisting of a questionnaire and an attitude measurement scale (Likert scale). Thirty propositions related to the issues of child care and primary care in pediatrics were simultaneously submitted to small groups of residents at their residency settings. RESULTS: women outnumbered men in a ratio of three to one in the residency programs. The majority aimed at a specialty in pediatrics, principally the ones involving high-tech procedures. Choices were influenced by prior training and by professors or tutors, although they stated they would like to work in prevention in the future. As for the scale, 87% had the right attitudes, both positive and negative, according to the Golden standard applied. CONCLUSIONS: the result obtained in this study related to attitude was very satisfactory but future professional choices are a concern to the medical educational system. The authors suggest that studies on attitude be further developed and improved to become a source of input for new strategies in the area of pediatrics education.<br>OBJETIVOS: avaliar atitudes sobre puericultura e cuidados primários em pediatria, bem como aspectos de treinamento e educação médica em residentes de pediatria, em consonância com o paradigma médico atual. MÉTODOS: os sujeitos foram 133 residentes de seis serviços de residência em pediatria da cidade de Porto Alegre. É um estudo transversal, descritivo, no qual os residentes responderam a um questionário e uma escala de mensuração de atitudes (escala de Likert) com 30 proposições acerca dos temas acima, aplicados simultaneamente, em pequenos grupos, nos locais de estágio. RESULTADOS: quanto ao sexo, nos estágios predominaram mulheres, na proporção de três para um. A maioria deles pretende especializar-se numa área da pediatria, principalmente aquelas que envolvem tecnologia avançada, sendo as escolhas influenciadas pelos estágios prévios e pelos professores ou tutores, embora informem desejar trabalhar em prevenção no futuro. Quanto à escala, 87% apresentaram atitudes adequadas, tanto positivas como negativas, conforme o padrão ouro utilizado. CONCLUSÕES: o resultado obtido neste estudo, quanto às atitudes, foi bastante satisfatório, porém, as escolhas profissionais futuras preocupam o sistema de educação médica. As autoras sugerem desenvolver e aprimorar estudos de atitudes, os quais poderão tornar-se fonte de subsídios para novas estratégias de educação pediátrica formativa