Advanced breast cancer incidence following population-based mammographic screening

Background: Breast cancer mortality is declining in many Western countries. If mammography screening contributed to decreases in mortality, then decreases in advanced breast cancer incidence should also be noticeable.
Patients and methods: We assessed incidence trends of advanced breast cancer in areas where mammography screening is practiced for at least 7 years with 60% minimum participation and where population-based registration of advanced breast cancer existed. Through a systematic Medline search, we identified relevant published data for Australia, Italy, Norway, Switzerland, The Netherlands, UK and the USA. Data from cancer registries in Northern Ireland, Scotland, the USA (Surveillance, Epidemiology and End Results (SEER), and Connecticut), and Tasmania (Australia) were available for the study. Criterion for advanced cancer was the tumour size, and if not available, spread to regional/distant sites.
Results: Age-adjusted annual percent changes (APCs) were stable or increasing in ten areas (APCs of -0.5% to 1.7%). In four areas (Firenze, the Netherlands, SEER and Connecticut) there were transient downward trends followed by increases back to pre-screening rates.
Conclusions: In areas with widespread sustained mammographic screening, trends in advanced breast cancer incidence do not support a substantial role for screening in the decrease in mortality.

Use of bacterial whole-genome sequencing to investigate local persistence and spread in bovine tuberculosis

Mycobacterium bovis is the causal agent of bovine tuberculosis, one of the most important diseases currently facing the UK cattle industry. Here, we use high-density whole genome sequencing (WGS) in a defined sub-population of M. bovis in 145 cattle across 66 herd breakdowns to gain insights into local spread and persistence. We show that despite low divergence among isolates, WGS can in principle expose contributions of under-sampled host populations to M. bovis transmission. However, we demonstrate that in our data such a signal is due to molecular type switching, which had been previously undocumented for M. bovis. Isolates from farms with a known history of direct cattle movement between them did not show a statistical signal of higher genetic similarity. Despite an overall signal of genetic isolation by distance, genetic distances also showed no apparent relationship with spatial distance among affected farms over distances <5 km. Using simulations, we find that even over the brief evolutionary timescale covered by our data, Bayesian phylogeographic approaches are feasible. Applying such approaches showed that M. bovis dispersal in this system is heterogeneous but slow overall, averaging 2 km/year. These results confirm that widespread application of WGS to M. bovis will bring novel and important insights into the dynamics of M. bovis spread and persistence, but that the current questions most pertinent to control will be best addressed using approaches that more directly integrate WGS with additional epidemiological data.

HDAC1 and HDAC2 independently predict mortality in hepatocellular carcinoma by a competing risk regression model in a Southeast Asian population

Histone deacetylases (HDACs) are enzymes involved in transcriptional repression. We aimed to examine the significance of HDAC1 and HDAC2 gene expression in the prediction of recurrence and survival in 156 patients with hepatocellular carcinoma (HCC) among a South East Asian population who underwent curative surgical resection in Singapore. We found that HDAC1 and HDAC2 were upregulated in the majority of HCC tissues. The presence of HDAC1 in tumor tissues was correlated with poor tumor differentiation. Notably, HDAC1 expression in adjacent non-tumor hepatic tissues was correlated with the presence of satellite nodules and multiple lesions, suggesting that HDAC1 upregulation within the field of HCC may contribute to tumor spread. Using competing risk regression analysis, we found that increased cancer-specific mortality was significantly associated with HDAC2 expression. Mortality was also increased with high HDAC1 expression. In the liver cancer cell lines, HEP3B, HEPG2, PLC5, and a colorectal cancer cell line, HCT116, the combined knockdown of HDAC1 and HDAC2 increased cell death and reduced cell proliferation as well as colony formation. In contrast, knockdown of either HDAC1 or HDAC2 alone had minimal effects on cell death and proliferation. Taken together, our study suggests that both HDAC1 and HDAC2 exert pro-survival effects in HCC cells, and the combination of isoform-specific HDAC inhibitors against both HDACs may be effective in targeting HCC to reduce mortality.

Population genetics of C. Maenas : oceanography and larval dispersal

Decifrar a complexa interacção entre os ciclos de vida de espécies marinhas e a oceanografia revela-se fundamental para a compreensão do fluxo genético e da conectividade no meio marinho. Nas espécies marinhas com desenvolvimento indirecto o fluxo de genes entre populações depende da distância que separa as populações, bem como da interacção entre a duração do desenvolvimento larvar, do comportamento das larvas e dos padrões de circulação oceânica. A conectividade larvar influencia uma variedade de processos como a dinâmica de stocks e de populações, a distribuição e limites geográficos das espécies, a estrutura genética das populações e a dispersão de espécies invasivas e reveste-se consequentemente de uma importância fundamental na identificação das unidades populacionais evolucionariamente relevantes e para a gestão e conservação marinhas. Os marcadores genéticos e os Modelos Individuais Acoplados a Modelos Físico-Biológicos (“ICPBMs”) são actualmente ferramentas fundamentais para o estudo dos padrões de dispersão larvar e para avaliar o nível de conectividade populacional. A presente tese respeita à avaliação das escalas espaciais de conectividade de populações de uma espécie costeira, o caranguejo Carcinus maenas, e utiliza conjuntamente informação de marcadores genéticos, análise de séries temporais de fornecimento de larvas e um modelo numérico de circulação oceânica. O primeiro capítulo introduz a temática da conectividade em espécies marinhas e inclui algumas referências aos métodos moleculares, analíticos e de modelação seguidos ao longo da tese. Através da utilização de múltiplas ferramentas – avaliação da estrutura genética geográfica de C. maenas na sua distribuição nativa com recurso a marcadores de DNA (microssatélites) (Capítulo 2), avaliação da estrutura genética temporal das larvas que formam os eventos de fornecimento larvar à Ria de Aveiro, NW Portugal (Capítulo 3), descrição da variabilidade inter-anual do fornecimento larvar à Ria de Aveiro, NW Portugal (Capítulo 4) e validação de um modelo ICPBM que descreve os padrões observados de fornecimento (Capítulo 5) – esta tese espera poder contribuir para uma melhor compreensão dos mecanismos que regulam o fluxo de genes e a conectividade entre populações de organismos marinhos. No Capítulo 6 são apresentadas as principais conclusões da investigação. A análise genética com recurso a microssatélites indicou que as populações de C. maenas são geneticamente homogéneas ao longo de várias centenas de km, dentro da distribuição nativa da espécie. Paralelamente, não foram encontrados indícios da existência de reprodução por “sweepstakes” em C. maenas de populações da costa oeste da Península Ibérica, visto que não se obtiveram diferenças genéticas significativas entre os eventos larvares. Também não se encontrou qualquer estrutura familiar entre as larvas que formam cada episódio de fornecimento, e não houve nenhuma redução significativa da variabilidade genética das larvas quando comparada com a de caranguejos adultos. A análise de séries temporais de suprimento de larvas na Ria de Aveiro em cinco anos estudados indica que este é um fenómeno episódico e variável, sendo os maiores episódios de fornecimento coincidentes com as marés vivas e acentuados por fortes ventos de sul. O modelo ICPBM foi validado com sucesso e parece fornecer uma estimativa realística das escalas espaciais e temporais de dispersão larvar, de acordo com as observações da estrutura genética e da ausência de reprodução por “sweepstake” em C. maenas da costa oeste da Península Ibérica

Residual antimalarials in malaria patients from Tanzania--implications on drug efficacy assessment and spread of parasite resistance.

Repeated antimalarial treatment for febrile episodes and self-treatment are common in malaria-endemic areas. The intake of antimalarials prior to participating in an in vivo study may alter treatment outcome and affect the interpretation of both efficacy and safety outcomes. We report the findings from baseline plasma sampling of malaria patients prior to inclusion into an in vivo study in Tanzania and discuss the implications of residual concentrations of antimalarials in this setting. In an in vivo study conducted in a rural area of Tanzania in 2008, baseline plasma samples from patients reporting no antimalarial intake within the last 28 days were screened for the presence of 14 antimalarials (parent drugs or metabolites) using liquid chromatography-tandem mass spectrometry. Among the 148 patients enrolled, 110 (74.3%) had at least one antimalarial in their plasma: 80 (54.1%) had lumefantrine above the lower limit of calibration (LLC = 4 ng/mL), 7 (4.7%) desbutyl-lumefantrine (4 ng/mL), 77 (52.0%) sulfadoxine (0.5 ng/mL), 15 (10.1%) pyrimethamine (0.5 ng/mL), 16 (10.8%) quinine (2.5 ng/mL) and none chloroquine (2.5 ng/mL). The proportion of patients with detectable antimalarial drug levels prior to enrollment into the study is worrying. Indeed artemether-lumefantrine was supposed to be available only at government health facilities. Although sulfadoxine-pyrimethamine is only recommended for intermittent preventive treatment in pregnancy (IPTp), it was still widely used in public and private health facilities and sold in drug shops. Self-reporting of previous drug intake is unreliable and thus screening for the presence of antimalarial drug levels should be considered in future in vivo studies to allow for accurate assessment of treatment outcome. Furthermore, persisting sub-therapeutic drug levels of antimalarials in a population could promote the spread of drug resistance. The knowledge on drug pressure in a given population is important to monitor standard treatment policy implementation.

Front spreading in population dynamic models. Theory and application to the Neolithic transition

This thesis presents population dynamics models that can be applied to predict the rate of spread of the Neolithic transition (change from hunter-gathering to farming economics) across the European continent, which took place about 9000 to 5000 years ago. The first models in this thesis provide predictions at a continental scale. We develop population dynamics models with explicit kernels and apply realistic data. We also derive a new time-delayed reaction-diffusion equation which yields speeds about a 10% slower than previous models. We also deal with a regional variability: the slowdown of the Neolithic front when reaching the North of Europe. We develop simple reaction-diffusion models that can predict the measured speeds in terms of the non-homogeneous distribution of pre-Neolithic (Mesolithic) population in Europe, which were present in higher densities at the North of the continent. Such models can explain the observed speeds.

The impact of sarcoptic mange Sarcoptes scabiei on the British fox Vulpes vulpes population

1. Disease epizootics can significantly influence host population dynamics and the structure and functioning of ecological communities. Sarcoptic mange Sarcoptes scabiei has dramatically reduced red fox populations Vulpes vulpes in several countries, including Britain, although impacts on demographic processes are poorly understood. We review the literature on the impact of mange on red fox populations, assess its current distribution in Britain through a questionnaire survey and present new data on resultant demographic changes in foxes in Bristol, UK. 2. A mange epizootic in Sweden spread across the entire country in < 10 years resulting in a decline in fox density of up to 95%; density remained lowered for 15–20 years. In Spain, mange has been enzootic for > 75 years and is widely distributed; mange presence was negatively correlated with habitat quality. 3. Localized outbreaks have occurred sporadically in Britain during the last 100 years. The most recent large-scale outbreak arose in the 1990s, although mange has been present in south London and surrounding environs since the 1940s. The questionnaire survey indicated that mange was broadly distributed across Britain, but areas of perceived high prevalence (> 50% affected) were mainly in central and southern England. Habitat type did not significantly affect the presence/absence of mange or perceived prevalence rates. Subjective assessments suggested that populations take 15–20 years to recover. 4. Mange appeared in Bristol's foxes in 1994. During the epizootic phase (1994–95), mange spread through the city at a rate of 0.6–0.9 km/month, with a rise in infection in domestic dogs Canis familiaris c. 1–2 months later. Juvenile and adult fox mortality increased and the proportion of females that reproduced declined but litter size was unaffected. Population density declined by > 95%. 5. In the enzootic phase (1996–present), mange was the most significant mortality factor. Juvenile mortality was significantly higher than in the pre-mange period, and the number of juveniles classified as dispersers declined. Mange infection reduced the reproductive potential of males and females: females with advanced mange did not breed; severely infected males failed to undergo spermatogenesis. In 2004, Bristol fox population density was only 15% of that in 1994.

Spatial expansion and population structure of the neotropical malaria vector, Anopheles darlingi (Diptera: Culicidae)

Extensive population structuring is known to occur in Anopheles darlingi, the primary malaria vector of the Neotropics. We analysed the phylogeographic structure of the species using the mitochondrial cytochrome oxidase I marker. Diversity is divided into six main population groups in South America: Colombia, central Amazonia, southern Brazil, south-eastern Brazil, and two groups in north-east Brazil. The ancestral distribution of the taxon is hypothesized to be central Amazonia, and there is evidence of expansion from this region during the late Pleistocene. The expansion was not a homogeneous front, however, with at least four subgroups being formed due to geographic barriers. As the species spread, populations became isolated from each other by the Amazon River and the coastal mountain ranges of south-eastern Brazil and the Andes. Analyses incorporating distances around these barriers suggest that the entire South American range of An. darlingi is at mutation-dispersal-drift equilibrium. Because the species is distributed throughout such a broad area, the limited dispersal across some landscape types promotes differentiation between otherwise proximate populations. Moreover, samples from the An. darlingi holotype location in Rio de Janeiro State are substantially derived from all other populations, implying that there may be additional genetic differences of epidemiological relevance. The results obtained contribute to our understanding of gene flow in this species and allow the formulation of human mosquito health protocols in light of the potential population differences in vector capacity or tolerance to control strategies. (C) 2009 The Linnean Society of London, Biological Journal of the Linnean Society, 2009, 97, 854-866.

A mathematical model for the spread of Strepotococcus pneumoniae with transmission dependent on serotype

We examine a mathematical model for the transmission of Streptococcus Pneumoniae amongst young children when the carriage transmission coefficient depends on the serotype. Carriage means pneumococcal colonization. There are two sequence types (STs) spreading in a population each of which can be expressed as one of two serotypes. We derive the differential equation model for the carriage spread and perform an equilibrium and global stability analysis on it. A key parameter is the effective reproduction number R e. For R e ≤ 1,  there is only the carriage-free equilibrium (CFE) and the carriage will die out whatever be the starting values. For R e > 1, unless the effective reproduction numbers of the two STs are equal, in addition to the CFE there are two carriage equilibria, one for each ST. If the ST with the largest effective reproduction number is initially present, then in the long-term the carriage will tend to the corresponding equilibrium.

A mathematical model for the spread of streptococcus pneumoniae with transmission due to sequence type

This paper discusses a simple mathematical model to describe the spread of Streptococcus pneumoniae. We suppose that the transmission of the bacterium is determined by multi-locus sequence type. The model includes vaccination and is designed to examine what happens in a vaccinated population if MLSTs can exist as both vaccine and non vaccine serotypes with capsular switching possible from the former to the latter. We start off with a discussion of Streptococcus pneumoniae and a review of previous work. We propose a simple mathematical model with two sequence types and then perform an equilibrium and (global) stability analysis on the model. We show that in general there are only three equilibria, the carriage-free equilibrium and two carriage equilibria. If the effective reproduction number Re is less than or equal to one, then the carriage will die out. If Re > 1, then the carriage will tend to the carriage equilibrium corresponding to the multi-locus sequence type with the largest transmission parameter. In the case where both multi-locus sequence types have the same transmission parameter then there is a line of carriage equilibria. Provided that carriage is initially present then as time progresses the carriage will approach a point on this line. The results generalize to many competing sequence types. Simulations with realistic parameter values confirm the analytical results.

Genetic Diversity and Population Differentiation of the Causal Agent of Citrus Black Spot in Brazil

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

Spatial and Temporal Spread of Bovine Tuberculosis in Wild White-Tailed Deer in Michigan

In 1975, a wild white-tailed deer infected with bovine tuberculosis was shot in the northeastern Lower Peninsula, Michigan. The shooting of a second infected deer in the same area in 1994 triggered ongoing disease surveillance in the region. By 2002, bovine tuberculosis had been confirmed in 12 Michigan counties: from 449 deer; two elk; 41 non-cervid wildlife; one captive cervid facility and 28 cattle herds. We analyzed geographic spread of disease since the surveillance began and investigated factors influencing the prevalence of disease within the infected area. These analyses reveal that 78 percent of tuberculous deer came from within a 1560 km2 'core' area, within which the prevalence of apparent disease averaged 2.5 percent. Prevalence declined dramatically outside of the core and was an order of magnitude lower 30 km from its boundary. This prevalence gradient was highly significant (P<0.0001) and did not alter over the 6 year surveillance period (P= 0.98). Within the core, deer density and supplemental feeding by hunters were positively and independently correlated with tuberculosis prevalence in deer. Together, these two factors explained 55 percent of the variation in prevalence. We conclude that bovine tuberculosis was already well established in the deer population in 1994, that the infected area has not expanded significantly since that time, and that deer over-abundance and food supplementation have both contributed to ongoing transmission of disease. Managers are currently enforcing prohibitions on deer feeding in the core and are working to lower deer numbers there through increased hunting pressure.

Contributions of demography and dispersal parameters to the spatial spread of a stage-structured insect invasion

Stage-structured models that integrate demography and dispersal can be used to identify points in the life cycle with large effects on rates of population spatial spread, information that is vital in the development of containment strategies for invasive species. Current challenges in the application of these tools include: (1) accounting for large uncertainty in model parameters, which may violate assumptions of ‘‘local’’ perturbation metrics such as sensitivities and elasticities, and (2) forecasting not only asymptotic rates of spatial spread, as is usually done, but also transient spatial dynamics in the early stages of invasion. We developed an invasion model for the Diaprepes root weevil (DRW; Diaprepes abbreviatus [Coleoptera: Curculionidae]), a generalist herbivore that has invaded citrus-growing regions of the United States. We synthesized data on DRW demography and dispersal and generated predictions for asymptotic and transient peak invasion speeds, accounting for parameter uncertainty. We quantified the contributions of each parameter toward invasion speed using a ‘‘global’’ perturbation analysis, and we contrasted parameter contributions during the transient and asymptotic phases. We found that the asymptotic invasion speed was 0.02–0.028 km/week, although the transient peak invasion speed (0.03– 0.045 km/week) was significantly greater. Both asymptotic and transient invasions speeds were most responsive to weevil dispersal distances. However, demographic parameters that had large effects on asymptotic speed (e.g., survival of early-instar larvae) had little effect on transient speed. Comparison of the global analysis with lower-level elasticities indicated that local perturbation analysis would have generated unreliable predictions for the responsiveness of invasion speed to underlying parameters. Observed range expansion in southern Florida (1992–2006) was significantly lower than the invasion speed predicted by the model. Possible causes of this mismatch include overestimation of dispersal distances, demographic rates, and spatiotemporal variation in parameter values. This study demonstrates that, when parameter uncertainty is large, as is often the case, global perturbation analyses are needed to identify which points in the life cycle should be targets of management. Our results also suggest that effective strategies for reducing spread during the asymptotic phase may have little effect during the transient phase. Includes Appendix.

Phylodynamics and Dispersal of HRSV Entails Its Permanence in the General Population in between Yearly Outbreaks in Children

Background: Human respiratory syncytial virus (HRSV) is one of the major etiologic agents of respiratory tract infections among children worldwide. Methodology/Principal Findings: Here through a comprehensive analysis of the two major HRSV groups A and B (n = 1983) which comprise of several genotypes, we present a complex pattern of population dynamics of HRSV over a time period of 50 years (1956-2006). Circulation pattern of HRSV revealed a series of expansions and fluctuations of co-circulating lineages with a predominance of HRSVA. Positively selected amino acid substitutions of the G glycoprotein occurred upon population growth of GB3 with a 60-nucleotide insertion (GB3 Insert), while other genotypes acquired substitutions upon both population growth and decrease, thus possibly reflecting a role for immune selected epitopes in linkage to the traced substitution sites that may have important relevance for vaccine design. Analysis evidenced the co-circulation and predominance of distinct HRSV genotypes in Brazil and suggested a year-round presence of the virus. In Brazil, GA2 and GA5 were the main culprits of HRSV outbreaks until recently, when the GB3 Insert became highly prevalent. Using Bayesian methods, we determined the dispersal patterns of genotypes through several inferred migratory routes. Conclusions/Significance: Genotypes spread across continents and between neighboring areas. Crucially, genotypes also remained at any given region for extended periods, independent of seasonal outbreaks possibly maintained by re-infecting the general population.

Different levels of MT-I/II between patients with MTLE with or without seizure generalization: does hippocampal MT-I/II affects seizure spread, or does seizure spread promotes differential expression of MT-I/II?

In the central nervous system, zinc is released along with glutamate during neurotransmission and, in excess, can promote neuronal death. Experimental studies have shown that metallothioneins I/II (MT-I/II), which chelate free zinc, can affect seizures and reduce neuronal death after status epilepticus. Our aim was to evaluate the expression of MT-I/II in the hippocampus of patients with temporal lobe epilepsy (TLE). Hippocampi from patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) were evaluated for expression of MT-I/II and for neuronal, astroglial, and microglial populations. Compared to control cases, MTLE group displayed widespread increase in MT-I/II expression, astrogliosis and reduced neuronal population. MT-I/II levels did not correlate with any clinical variables, but patients with secondary generalized seizures (SGS) had less MT-I/II than patients without SGS. In conclusion, MT-I/II expression was increased in hippocampi from MTLE patients and our data suggest that it may be associated with different seizure spread patterns.