Growth and spectroscopic characterizations: properties of Nd:LiLaMosub(2)Osub(8) single crystal fibers

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Soft tissue sarcoma: biology and therapeutic correlates

Soft tissue sarcomas (STS) comprise a heterogenenous group of greater than 50 malignancies of putative mesenchymal cell origin and as such they may arise in diverse tissue types in various anatomical locations throughout the whole body. Collectively they account for approximately 1% of all human malignancies yet have a spectrum of aggressive behaviours amongst their subtypes. They thus pose a particular challenge to manage and remain an under investigated group of cancers with no generally applicable new therapies in the past 40 years and an overall 5-year survival rate that remains stagnant at around 50%. From September 2000 to July 2006 I undertook a full time post-doctoral level research fellowship at the MD Anderson Cancer Center, Houston, Texas, USA in the department of Surgical Oncology to investigate the biology of soft tissue sarcoma and test novel anti- sarcoma adenovirus-based therapy in the preclinical nude rat model of isolated limb perfusion against human sarcoma xenografts. This work, in collaboration with colleagues as indicated herein, led to a number of publications in the scientific literature furthering our understanding of the malignant phenotype of sarcoma and reported preclinical studies with wild-type p53, in a replication deficient adenovirus vector, and oncolytic adenoviruses administered by isolated limb perfusion. Additional collaborative and pioneering preclinical studies reported the molecular imaging of sarcoma response to systemically delivered therapeutic phage RGD-4c AAVP. Doxorubicin chemotherapy is the single most active broadly applicable anti-sarcoma chemotherapeutic yet only has an approximate 30% overall response rate with additional breakthrough tumour progression and recurrence after initial chemo-responsiveness further problematic features in STS management. Doxorubicin is a substrate for the multi- drug resistance (mdr) gene product p-glycoprotein drug efflux pump and exerts its main mode of action by induction of DNA double-strand breaks during the S-phase of the cell cycle. Two papers in my thesis characterise different aspects of chemoresistance in sarcoma. The first shows that wild-type p53 suppresses Protein Kinase Calpha (PKCα) phosphorylation (and activation) of p-glycoprotein by transcriptional repression of PKCα through a Sp-1 transcription factor binding site in its -244/-234 promoter region. The second paper demonstrates that Rad51 (a central mediator of homologous recombination repair of double strand breaks) has elevated levels in sarcoma and particularly in the S- G2 phase of the cell cycle. Suppression of Rad51 with small interfering RNA in sarcoma cell culture led to doxorubicin chemosensitisation. Reintroduction of wild-type p53 into STS cell lines resulted in decreased Rad51 protein and mRNA expression via transcriptional repression of the Rad51 promoter through increased AP-2 binding. In light of poor response rates to chemotherapy, escape from local control portends a poor prognosis for patients with sarcoma. Two papers in my thesis characterise aspects of sarcoma angiogenesis, invasion and metastasis. Human sarcoma samples were found to have high levels of matrix metalloproteinase-9 (MMP-9) with expression levels that correlated with p53 mutational status. MMP-9 is known to degrade extracellular collagen, contribute to the control of the angiogenic switch necessary in primary tumour progression and facilitate invasion and metastasis. Reconstitution of wild-type p53 function led to decreased levels of MMP-9 protein and mRNA as well as zymography-assessed MMP-9 proteolytic activity and decreased tumour cell invasiveness. Reintroduction of wild-type p53 into human sarcoma xenografts in-vivo decreased tumour growth and MMP-9 protein expression. Wild-type p53 was found to suppress mmp-9 transcription via decreased binding of NF-κB to its -607/-595 mmp-9 promoter element. Studies on the role of the VEGF165 in sarcoma found that sarcoma cells stably transfected with VEGF165 formed more aggressive xenografted tumours with increased vascularity, growth rate, metastasis, and resistance to chemotherapy. Use of the anti-VEGFR2 antibody DC101 enhanced doxorubicin sensitivity at sub-conventional dosing, inhibited tumour growth, decreased development of metastases, and reduced tumour micro-vessel density while increasing the vessel maturation index. These effects were explained primarily through effects on endothelial cells (e.c.s), rather than the tumour cells per se, where DC101 induced e.c. sensitivity to doxorubicin and suppressed e.c. production of MMPs. The p53 tumour suppressor pathway is the most frequently mutated pathway in sarcoma. Recapitulation of wild-type p53 function in sarcoma exerts a number of anti-cancer outcomes such as growth arrest, resensitisation to chemotherapy, suppression of invasion, and attenuation of angiogenesis. Using a modified nude rat-human sarcoma xenograft model for isolated limb perfusion (ILP) delivery of wild-type p53 in a replication deficient adenovirus vector I showed that functionally competent wild-type p53 could be delivered to and detected in human leiomyosarcoma xenografts confirming preclinical feasibility - although not efficacious due to low transgene expression. Viral fibre modification to express the RGD tripeptide motif led to greater viral uptake by sarcoma cells in vitro (transductional targeting) and changing the transgene promoter to a response element active in cells with active telomerase expression restricted the transgene expression to the tumour intracellular environment (transcriptional targeting). Delivery of the fibre-modified, selectively replication proficient oncolytic adenovirus Ad.hTC.GFP/ E1a.RGD by ILP demonstrated a more robust, and tumour-restricted, transgene expression with evidence of anti-sarcoma effect confirmed microscopically. Collaborative studies using the fibre modified phage RGD-4C AAVP confirmed that systemic delivery specifically, efficiently, and repeatedly targets human sarcoma xenografts, binds to αv integrins in tumours, and demonstrates a durable, though heterogeneous, transgene expression of 1-4 weeks. Incorporation of the Herpes Simplex Virus thymidine kinase (HSVtk) transgene into RGD-4C AAVP permitted CT-PET spatial and temporal molecular imaging in vivo of transgene expression and allowed quantification of tumour metabolic activity both before and after interval administration of a systemic cytotoxic with predictable and measurable response to treatment before becoming apparent clinically. These papers further the medical and scientific community’s understanding of the biology of soft tissue sarcoma and report preclinical studies with novel and promising anti- sarcoma therapeutics.

The Southeast Indian Ridge between 88°E and 118°E: Variations in crustal accretion at constant spreading rate

The temperature of the mantle and the rate of melt production are parameters which play important roles in controlling the style of crustal accretion along mid-ocean ridges. To investigate the variability in crustal accretion that develops in response to variations in mantle temperature, we have conducted a geophysical investigation of the Southeast Indian Ridge (SEIR) between the Amsterdam hotspot and the Australian-Antarctic Discordance (88 degrees E-118 degrees E). The spreading center deepens by 2100 m from west to east within the study area. Despite a uniform, intermediate spreading rate (69-75 mm yr-l), the SEIR exhibits the range in axial morphology displayed by the East Pacific Rise and the Mid-Atlantic Ridge (MAR) and usually associated with variations in spreading rate. The spreading center is characterized by an axial high west of 102 degrees 45'E, whereas an axial valley is prevalent east of this longitude. Both the deepening of the ridge axis and the general evolution of axial morphology from an axial high to a rift valley are not uniform. A region of intermediate morphology separates axial highs and MAR-like rift valleys. Local transitions in axial morphology occur in three areas along the ridge axis. The increase in axial depth toward the Australian-Antarctic Discordance may be explained by the thinning of the oceanic crust by similar to 4 km and the change in axial topography. The long-wavelength changes observed along the SEIR can be attributed to a gradient in mantle temperature between regions influenced by the Amsterdam and Kerguelen hot spots and the Australian-Antarctic Discordance. However, local processes, perhaps associated with an heterogeneous mantle or along-axis asthenospheric flow, may give rise to local transitions in axial topography and depth anomalies.

Análise da eficiência de indicadores da restauração ecológica em Mata Ripária no Cerrado, Planaltina - DF

Dissertação (mestrado)—Universidade de Brasília, Departamento de Engenharia Florestal, Programa de Pós-Graduação em Ciências Florestasi, 2015.

Does Epoetin Beta Still Have a Place in Peginterferon Alpha-2a Plus Ribavirin Treatment Strategies for Chronic Hepatitis C?

International audience

Influência do zinco suplementar na maturação biológica e no crescimento de jovens atletas de futebol do sexo masculino

Introdução O zinco é um importante elemento traço que auxilia na capacidade antioxidante, além de participar da maturação biológica. Em atletas, a suplementação de zinco tem efeito positivo nos parâmetros hematológicos e pode melhorar o rendimento esportivo. Sua deficiência é comumente observada nesses grupo e pode estar associada à diminuição da força física assim como da massa corporal, além de ter efeito significativo no crescimento. Assim os objetivos do presente estudo foram: comparar os métodos de avaliação da maturidade biológica e suas relações com variáveis antropométricas e de rendimento físico de acordo com o estado de zinco em jovens jogadores de futebol; comparar diferentes métodos de avaliação da composição corporal em jovens jogadores de futebol esratificados de acordo com os níveis plasmáticos de zinco e investigar o efeito do zinco suplementar na maturação biológica, no crescimento, na composição corporal e na força muscular de jogadores de futebol púberes do sexo masculino. Materiais e métodos Foram avaliados em dois momentos 48 jovens do sexo masculino (13±1 anos, massa corporal de 48±10kg, estatura de 160±10cm e zinco plasmático de 12,1±2,2 μmol/L). Todos eram jogadores de futebol de um tradicional clube do Rio de Janeiro e foram divididos aleatoriamente em dois grupos. Durante 12 semanas o grupo placebo (n=28) recebeu cápsulas de amido de milho e o grupo suplementado (n=20) recebeu cápsulas de gluconato de Zn (22mg/dia). O valor de 11,0 μmol/L foi considerado como ponto de corte para classificação dos jovens em normozincêmicos ou hipozincêmicos. No início da manhã, após jejum noturno, foram coletados sangue e urina para determinação da concentração de zinco. A massa corporal, alturas (do vértex, acromial, dactiloidal, iliocristal, trocantérica e sentado), composição corporal, força e maturidade esquelética (TW3) também foram determinadas por metodologias validadas. Resultados As comparações entre as categorias maturacionais definidas por cada método de avaliação mostraram que a idade óssea foi o único método que permitiu a identificação de diferenças entre as três categorias, em ao menos duas variáeis relacionadas ao rendimento (massa livre de gordura (MLG) e força na mão dominante (FMD) – p<0,0001). O método da pilosidade axilar foi capaz de discriminar apenas para a FMD (p<0,0001). Embora tenha fornecido quatro categorias maturacionais, o método por dosagem da testosterona não possibilitou a identificação de diferenças entre as categorias relativas a MLG, a FMD e as dobras cutâneas(DC). Quando observamos os métodos de avaliação da composição corporal não foram identificadas diferenças sigificativas entre os grupos hipozincêmico e normozincêmico no percentagem de gordura(PG) nem na MLG obtidas através dos métodos da absortometria de dupla energia (DXA) (p=0,06076 e p=0,5638 respectivamente), das DC (p=0,6840 and 0,5087) e através da bioimpedância elétrica (BIA) (p=0,3475 and p=0,3475). Entre os diferentes métodos também não foi encontrada diferenças significativas (PG: p=0,1272 e p=0,3231 - MLG: p=0,9229 and p=0,8933 para os grupos hipozincêmico e normozincêmico, respectivamente). As correlações entre os métodos foram significativas (PG: r= 0,3414 a 0,9765 e p<0,0001 a 0,0133 - MLG: r=0,9533 a 0,9998 e p<0,0001). Fortes coeficientes de determinação foram obtidos nas regressões múltiplas dos valores do DXA com a equação de Slaughter na estimativa da PG (r=0,86; r2=0,928 e SEE=2,37%) e ainda maiores para MLG (r=0,98; r2=0,990 e SEE=1,18kg). Valores menores foram encontrados para as outras equações com DC e para BIA. Ao analisar os efeitos da suplementação de zinco sobre o crescimento, a maturação, a composição corporal e a força, observou-se que somente as alterações ocorridas nos indicadores de crescimento foram significativas (p=0,0312), sendo que todas as demais não foram significativas - idade óssea (p=0,1391), massa livre de gordura (p=0,0593), percentual de massa gorda (p=0,2212) e força na mão dominante (p=0,6569). Conclusões Observando diferentes métodos de avaliação da maturidade biológica e as categorias por eles definidas, o método da idade óssea (IO) mostrou ser melhor, visto que ele permitiu identificar diferenças entre as três categorias possíveis, nas variáveis MLG e FMD, ao contrário dos outros métodos. Para a avaliação da composição corporal, os métodos baseados nas DC foram melhores que BIA, quando DXA não estiver disponível. A comparação entre os métodos baseados nas DC mostrou que a melhor associação foi obtida com a equação de Slaughter, seguida pela equação de Lohman com a utilização da IO ao invés da idade cronológica. Os níveis de zinco plasmático parecem não serem influenciados pela composição corporal, o que certamente justifica mais estudos. Os resultados da análise dos efeitos da suplementação de zinco no crescimento, na maturação, na composição corporal e na força, nos levam a concluir que o crescimento teve alteração positiva significativa e que os valores das demais variáveis estudadas (maturação, composição corporal e força muscular) não sofreram alterações significativas relacionadas à suplementação de zinco nos jovens jogadores de futebol do sexo masculino, na faixa etária dos 12 aos 14 anos.

Apps for IMproving FITness and increasing physical activity among young people: the AIMFIT pragmatic randomized controlled trial

BACKGROUND: Given the global prevalence of insufficient physical activity (PA), effective interventions that attenuate age-related decline in PA levels are needed. Mobile phone interventions that positively affect health (mHealth) show promise; however, their impact on PA levels and fitness in young people is unclear and little is known about what makes a good mHealth app. OBJECTIVE: The aim was to determine the effects of two commercially available smartphone apps (Zombies, Run and Get Running) on cardiorespiratory fitness and PA levels in insufficiently active healthy young people. A second aim was to identify the features of the app design that may contribute to improved fitness and PA levels. METHODS: Apps for IMproving FITness (AIMFIT) was a 3-arm, parallel, randomized controlled trial conducted in Auckland, New Zealand. Participants were recruited through advertisements in electronic mailing lists, local newspapers, flyers posted in community locations, and presentations at schools. Eligible young people aged 14-17 years were allocated at random to 1 of 3 conditions: (1) use of an immersive app (Zombies, Run), (2) use of a nonimmersive app (Get Running), or (3) usual behavior (control). Both smartphone apps consisted of a fully automated 8-week training program designed to improve fitness and ability to run 5 km; however, the immersive app featured a game-themed design and narrative. Intention-to-treat analysis was performed using data collected face-to-face at baseline and 8 weeks, and all regression models were adjusted for baseline outcome value and gender. The primary outcome was cardiorespiratory fitness, objectively assessed as time to complete the 1-mile run/walk test at 8 weeks. Secondary outcomes were PA levels (accelerometry and self-reported), enjoyment, psychological need satisfaction, self-efficacy, and acceptability and usability of the apps. RESULTS: A total of 51 participants were randomized to the immersive app intervention (n=17), nonimmersive app intervention (n=16), or the control group (n=18). The mean age of participants was 15.7 (SD 1.2) years; participants were mostly NZ Europeans (61%, 31/51) and 57% (29/51) were female. Overall retention rate was 96% (49/51). There was no significant intervention effect on the primary outcome using either of the apps. Compared to the control, time to complete the fitness test was -28.4 seconds shorter (95% CI -66.5 to 9.82, P=.20) for the immersive app group and -24.7 seconds (95% CI -63.5 to 14.2, P=.32) for the nonimmersive app group. No significant intervention effects were found for secondary outcomes. CONCLUSIONS: Although apps have the ability to increase reach at a low cost, our pragmatic approach using readily available commercial apps as a stand-alone instrument did not have a significant effect on fitness. However, interest in future use of PA apps is promising and highlights a potentially important role of these tools in a multifaceted approach to increase fitness, promote PA, and consequently reduce the adverse health outcomes associated with insufficient activity.

Challenging endoscopy reprocessing guidelines: a prospective study investigating the safe shelf life of flexible endoscopes in a tertiary gastroenterology unit.

Professional prac− tice guidelines for endoscope reprocessing re− commend reprocessing endoscopes between each case and proper storage following repro− cessing after the last case of the list. There is lim− ited empirical evidence to support the efficacy of endoscope reprocessing prior to use in the first case of the day; however, internationally, many guidelines continue to recommend this practice. The aim of this study is to estimate a safe shelf life for flexible endoscopes in a high−turnover gastroenterology unit. Materials and methods: In a prospective obser− vational study, all flexible endoscopes in active service during the 3−week study period were mi− crobiologically sampled prior to reprocessing be− fore the first case of the day (n = 200). The main outcome variables were culture status, organism cultured, and shelf life. Results: Among the total number of useable samples (n = 194), the overall contamination rate was 15.5 %, with a pathogenic contamination rate of 0.5 %. Mean time between last case one day and reprocessing before the first case on the next day (that is, shelf life) was 37.62 h (SD 36.47). Median shelf life was 18.8 h (range 5.27± 165.35 h). The most frequently identified organ− ism was coagulase−negative Staphylococcus, an environmental nonpathogenic organism. Conclusions: When processed according to es− tablished guidelines, flexible endoscopes remain free from pathogenic organisms between last case and next day first case use. Significant re− ductions in the expenditure of time and resources on reprocessing endoscopes have the potential to reduce the restraints experienced by high−turnover endoscopy units and improve ser− vice delivery.

A pilot randomised control trial of general practitioner and exercise physiologist interventions to reduce primary cardiovascular risk in overweight patients [Abstract]

Aims & Rationale/Objectives: With the knowledge that overweight is a major public health concern in Australia, that a multidisciplinary team approach to the management of lifestyle-related conditions is supported, and that the Australian Government recently recognised the role of the exercise physiologist (EP) in reducing the health burden of disease by their inclusion for reimbursement under the Medicare Plus scheme, this study sought to undertake a pilot RCT to compare GP and EP interventions to reduce primary cardiovascular risk in the overweight general practice population. Methods and Measures: Overweight patients recruited by a convenience sample of GPs were randomised into one of three arms: the control group, or the GP or EP intervention group (in which patients received either five GP or five EP consultations over 24 weeks). Patients had baseline, 12- and 24-week measures of body composition and cardio-respiratory fitness, and completed baseline and end-of-study surveys, fasting lipids and glucose. GPs and EPs completed an end-of-study survey. Results:Sixty-seven patients attended the baseline assessment. Overall retention rate was 67%. Patients were generally satisfied with the effectiveness of the interventions and their weight reduction. Favourable trends in BMI, weight, glucose and exercise levels for GP and EP intervention groups and in physical activity levels for all groups Conclusions: This study supports the feasibility of a RCT of GP and EP interventions for decreasing primary cardiovascular risk in the overweight general practice population.

The soft skills of project management : a view from diploma graduates

A research study was conducted in a key area of project management: stakeholder and relationship management through communication - ‘the soft skills’. It was conducted with Diploma of Project Management graduates from one Australian Registered Training Organisation (RTO), the Australian College of Project Management (ACPM). The study was designed to initially identify the qualifications and project management experience of the participants. Further, it identified the respondents’ understanding of and attitude to commonly held principles and literature within the project management field as it relates to the soft skills of projects. This is specifically connected to their project experience and knowledge, approach to project communications, and the stakeholder’s needs. Some of the literature showed that through the management and application of the project soft skills by project managers may actually be a recipe for project success. Hence, an important underpinning of this study was that the project manager can enhance project success (or reduce the impact of failure) by identifying and prioritising stakeholders, developing and implementing strategies for engaging and communicating with them. The use of a positivist approach to this research study allowed for the evaluation and understanding of respondents to the emergent theories of successful projects being delivered through the management of stakeholders, communications, and relationships. Consequently, a quantitative approach to this study was undertaken. The participants were drawn from graduates who completed (graduated) from the ACPM with the Diploma of Project Management between January 2004 and December 2007 only. A list of graduates was collated from this period indicating that a total of 656 graduates have completed and graduated with the qualification. The data collection for this study was done in one phase only. The questionnaire was emailed individually by the researcher directly to the selected potential respondents. Subsequently, a total of 44 responses were received, providing an overall response rate of 43%. Two key factors emerged from the survey questionnaire. Firstly, the need for the soft skills to be incorporated in project management curriculum and education programs, and secondly, that successful projects are delivered through the management and application of the project soft skills. It is expected that the findings of this study be provided across various forums (such as vocational education and training, and project management conferences) and via project management bodies such as the Australian Institute of Project Management (AIPM) to inform learning and provide greater insight into the soft skills of project management. It is the contention of the researcher that this quantitative study of Diploma of Project Management graduates’ views and attitudes highlights the importance of project soft skills and its importance in the delivery of successful projects as well as being part of the competencies of a successful project manager. This study also revealed the value of project experience and knowledge as it pertains to the management and application of the project soft skills.

Spectral coding methods for speech compression and speaker identification

This thesis investigates aspects of encoding the speech spectrum at low bit rates, with extensions to the effect of such coding on automatic speaker identification. Vector quantization (VQ) is a technique for jointly quantizing a block of samples at once, in order to reduce the bit rate of a coding system. The major drawback in using VQ is the complexity of the encoder. Recent research has indicated the potential applicability of the VQ method to speech when product code vector quantization (PCVQ) techniques are utilized. The focus of this research is the efficient representation, calculation and utilization of the speech model as stored in the PCVQ codebook. In this thesis, several VQ approaches are evaluated, and the efficacy of two training algorithms is compared experimentally. It is then shown that these productcode vector quantization algorithms may be augmented with lossless compression algorithms, thus yielding an improved overall compression rate. An approach using a statistical model for the vector codebook indices for subsequent lossless compression is introduced. This coupling of lossy compression and lossless compression enables further compression gain. It is demonstrated that this approach is able to reduce the bit rate requirement from the current 24 bits per 20 millisecond frame to below 20, using a standard spectral distortion metric for comparison. Several fast-search VQ methods for use in speech spectrum coding have been evaluated. The usefulness of fast-search algorithms is highly dependent upon the source characteristics and, although previous research has been undertaken for coding of images using VQ codebooks trained with the source samples directly, the product-code structured codebooks for speech spectrum quantization place new constraints on the search methodology. The second major focus of the research is an investigation of the effect of lowrate spectral compression methods on the task of automatic speaker identification. The motivation for this aspect of the research arose from a need to simultaneously preserve the speech quality and intelligibility and to provide for machine-based automatic speaker recognition using the compressed speech. This is important because there are several emerging applications of speaker identification where compressed speech is involved. Examples include mobile communications where the speech has been highly compressed, or where a database of speech material has been assembled and stored in compressed form. Although these two application areas have the same objective - that of maximizing the identification rate - the starting points are quite different. On the one hand, the speech material used for training the identification algorithm may or may not be available in compressed form. On the other hand, the new test material on which identification is to be based may only be available in compressed form. Using the spectral parameters which have been stored in compressed form, two main classes of speaker identification algorithm are examined. Some studies have been conducted in the past on bandwidth-limited speaker identification, but the use of short-term spectral compression deserves separate investigation. Combining the major aspects of the research, some important design guidelines for the construction of an identification model when based on the use of compressed speech are put forward.