138 resultados para Hepatic Elimination


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Background Many countries are scaling up malaria interventions towards elimination. This transition changes demands on malaria diagnostics from diagnosing ill patients to detecting parasites in all carriers including asymptomatic infections and infections with low parasite densities. Detection methods suitable to local malaria epidemiology must be selected prior to transitioning a malaria control programme to elimination. A baseline malaria survey conducted in Temotu Province, Solomon Islands in late 2008, as the first step in a provincial malaria elimination programme, provided malaria epidemiology data and an opportunity to assess how well different diagnostic methods performed in this setting. Methods During the survey, 9,491 blood samples were collected and examined by microscopy for Plasmodium species and density, with a subset also examined by polymerase chain reaction (PCR) and rapid diagnostic tests (RDTs). The performances of these diagnostic methods were compared. Results A total of 256 samples were positive by microscopy, giving a point prevalence of 2.7%. The species distribution was 17.5% Plasmodium falciparum and 82.4% Plasmodium vivax. In this low transmission setting, only 17.8% of the P. falciparum and 2.9% of P. vivax infected subjects were febrile (≥38°C) at the time of the survey. A significant proportion of infections detected by microscopy, 40% and 65.6% for P. falciparum and P. vivax respectively, had parasite density below 100/μL. There was an age correlation for the proportion of parasite density below 100/μL for P. vivax infections, but not for P. falciparum infections. PCR detected substantially more infections than microscopy (point prevalence of 8.71%), indicating a large number of subjects had sub-microscopic parasitemia. The concordance between PCR and microscopy in detecting single species was greater for P. vivax (135/162) compared to P. falciparum (36/118). The malaria RDT detected the 12 microscopy and PCR positive P. falciparum, but failed to detect 12/13 microscopy and PCR positive P. vivax infections. Conclusion Asymptomatic malaria infections and infections with low and sub-microscopic parasite densities are highly prevalent in Temotu province where malaria transmission is low. This presents a challenge for elimination since the large proportion of the parasite reservoir will not be detected by standard active and passive case detection. Therefore effective mass screening and treatment campaigns will most likely need more sensitive assays such as a field deployable molecular based assay.

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S. japonicum infection is believed to be endemic in 28 of the 80 provinces of the Philippines and the most recent data on schistosomiasis prevalence have shown considerable variability between provinces. In order to increase the efficient allocation of parasitic disease control resources in the country, we aimed to describe the small scale spatial variation in S. japonicum prevalence across the Philippines, quantify the role of the physical environment in driving the spatial variation of S. japonicum, and develop a predictive risk map of S. japonicum infection. Data on S. japonicum infection from 35,754 individuals across the country were geo-located at the barangay level and included in the analysis. The analysis was then stratified geographically for Luzon, the Visayas and Mindanao. Zero-inflated binomial Bayesian geostatistical models of S. japonicum prevalence were developed and diagnostic uncertainty was incorporated. Results of the analysis show that in the three regions, males and individuals aged ≥ 20 years had significantly higher prevalence of S. japonicum compared with females and children <5 years. The role of the environmental variables differed between regions of the Philippines. S. japonicum infection was widespread in the Visayas whereas it was much more focal in Luzon and Mindanao. This analysis revealed significant spatial variation in prevalence of S. japonicum infection in the Philippines. This suggests that a spatially targeted approach to schistosomiasis interventions, including mass drug administration, is warranted. When financially possible, additional schistosomiasis surveys should be prioritized to areas identified to be at high risk, but which were underrepresented in our dataset.

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Background With dwindling malaria cases in Bhutan in recent years, the government of Bhutan has made plans for malaria elimination by 2016. This study aimed to determine coverage, use and ownership of LLINs, as well as the prevalence of asymptomatic malaria at a single time-point, in four sub-districts of Bhutan. Methods A cross-sectional study was carried out in August 2013. Structured questionnaires were administered to a single respondent in each household (HH) in four sub-districts. Four members from 25 HH, randomly selected from each sub-district, were tested using rapid diagnostic tests (RDT) for asymptomatic Plasmodium falciparum and Plasmodium vivax infection. Multivariable logistic regression models were used to identify factors associated with LLIN use and maintenance. Results All blood samples from 380 participants tested negative for Plasmodium infections. A total of 1,223 HH (92.5% of total HH) were surveyed for LLIN coverage and use. Coverage of LLINs was 99.0% (1,203/1,223 HH). Factors associated with decreased odds of sleeping under a LLIN included: washing LLINs nine months compared to washing LLINs every six months; HH in the least poor compared to the most poor socio-economic quintile; a HH income of Nu 5,001-10,000 (US$1 = Nu 59.55), and Nu >10,000, compared to HH with income of elimination.

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Chronic liver injury and inflammation lead to hepatic fibrosis, cirrhosis, and liver failure. Embryonic and mesenchymal stem cells have been shown to reduce experimental liver fibrosis but have potential limitations, including the formation of dysplastic precursors, tumors, and profibrogenic cells. Other stem-like cells may reduce hepatic inflammation and fibrosis without tumor and profibrogenic cell formation. To test this hypothesis we transplanted human amnion epithelial cells (hAEC), isolated from term delivered placenta, into immunocompetent C57/BL6 mice at week 2 of a 4-week regimen of carbon tetrachloride (CCl4) exposure to induce liver fibrosis. Two weeks following hAEC infusion, intact cells expressing the human-specific markers inner mitochondrial membrane protein and human leukocyte antigen-G were found in mouse liver without evidence of host rejection of the transplanted cells. Human albumin, known to be produced by hAEC, was detected in sera of hAEC-treated mice. Human DNA was detected in mouse liver and also spleen, lungs, and heart of some animals. Following hAEC transplantation, CCl4-treated animals showed decreased serum ALT levels and reduced hepatocyte apoptosis, compared to controls. hAEC-treated mouse liver had lower TNF-α and IL-6 protein levels and higher IL-10 compared to animals given CCl4 alone. Compared to CCl4 controls, hAEC-treated mice showed fewer activated collagen-producing hepatic stellate cells and less fibrosis area and collagen content. Reduced hepatic TGF-β levels in conjunction with a twofold increase in the active form of the collagen-degrading enzyme matrix metalloproteinase-2 in hAEC-treated mice compared to CCl4 controls may account for the reduction in fibrosis. hAEC transplantation into immunocompetent mice leads to cell engraftment, reduced hepatocyte apoptosis, and decreased hepatic inflammation and fibrosis.

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Quantifying the competing rates of intake and elimination of persistent organic pollutants (POPs) in the human body is necessary to understand the levels and trends of POPs at a population level. In this paper we reconstruct the historical intake and elimination of ten polychlorinated biphenyls (PCBs) and five organochlorine pesticides (OCPs) from Australian biomonitoring data by fitting a population-level pharmacokinetic (PK) model. Our analysis exploits two sets of cross-sectional biomonitoring data for PCBs and OCPs in pooled blood serum samples from the Australian population that were collected in 2003 and 2009. The modeled adult reference intakes in 1975 for PCB congeners ranged from 0.89 to 24.5 ng/kg bw/day, lower than the daily intakes of OCPs ranging from 73 to 970 ng/kg bw/day. Modeled intake rates are declining with half-times from 1.1 to 1.3 years for PCB congeners and 0.83 to 0.97 years for OCPs. The shortest modeled intrinsic human elimination half-life among the compounds studied here is 6.4 years for hexachlorobenzene, and the longest is 30 years for PCB-74. Our results indicate that it is feasible to reconstruct intakes and to estimate intrinsic human elimination half-lives using the population-level PK model and biomonitoring data only. Our modeled intrinsic human elimination half-lives are in good agreement with values from a similar study carried out for the population of the United Kingdom, and are generally longer than reported values from other industrialized countries in the Northern Hemisphere.

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Background In China, the national malaria elimination programme has been operating since 2010. This study aimed to explore the epidemiological changes in patterns of malaria in China from intensified control to elimination stages. Methods Data on nationwide malaria cases from 2004 to 2012 were extracted from the Chinese national malaria surveillance system. The secular trend, gender and age features, seasonality, and spatial distribution by Plasmodium species were analysed. Results In total, 238,443 malaria cases were reported, and the proportion of Plasmodium falciparum increased drastically from <10% before 2010 to 55.2% in 2012. From 2004 to 2006, malaria showed a significantly increasing trend and with the highest incidence peak in 2006 (4.6/100,000), while from 2007 onwards, malaria decreased sharply to only 0.18/100,000 in 2012. Males and young age groups became the predominantly affected population. The areas affected by Plasmodium vivax malaria shrunk, while areas affected by P. falciparum malaria expanded from 294 counties in 2004 to 600 counties in 2012. Conclusions This study demonstrated that malaria has decreased dramatically in the last five years, especially since the Chinese government launched a malaria elimination programme in 2010, and areas with reported falciparum malaria cases have expanded over recent years. These findings suggest that elimination efforts should be improved to meet these changes, so as to achieve the nationwide malaria elimination goal in China in 2020.

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Movement of malaria across international borders poses a major obstacle to achieving malaria elimination in the 34 countries that have committed to this goal. In border areas, malaria prevalence is often higher than in other areas due to lower access to health services, treatment-seeking behaviour of marginalised populations that typically inhabit border areas, difficulties in deploying prevention programs to hard-to-reach communities, often in difficult terrain, and constant movement of people across porous national boundaries. Malaria elimination in border areas will be challenging, and key to addressing the challenges is strengthening of surveillance activities for rapid identification of any importation or reintroduction of malaria. This could involve taking advantage of technological advances, such as spatial decision support systems, which can be deployed to assist program managers to carry out preventive and reactive measures, and mobile phone technology, which can be used to capture the movement of people in the border areas and likely sources of malaria importation. Additionally, joint collaboration in the prevention and control of cross-border malaria by neighbouring countries, and reinforcement of early diagnosis and prompt treatment are ways forward in addressing the problem of cross-border malaria.

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The accumulation of deficits with increasing age results in a decline in the functional capacity of multiple organs and systems. These changes can have a significant influence on the pharmacokinetics and pharmacodynamics of prescribed drugs. Although alterations in body composition and worsening renal clearance are important considerations, for most drugs the liver has the greatest effect on metabolism. Age-related change in hepatic function thereby causes much of the variability in older people’s responses to medication. In this review, we propose that a decline in the ability of the liver to inactivate toxins may contribute to a proinflammatory state in which frailty can develop. Since inflammation also downregulates drug metabolism, medication prescribed to frail older people in accordance with disease-specific guidelines may undergo reduced systemic clearance, leading to adverse drug reactions, further functional decline and increasing polypharmacy, exacerbating rather than ameliorating frailty status. We also describe how increasing chronological age and frailty status impact liver size, blood flow and protein binding and enzymes of drug metabolism. This is used to contextualise our discussion of appropriate prescribing practices. For example, while the general axiom of ‘start low, go slow’ should underpin the initiation of medication (titrating to a defined therapeutic goal), it is important to consider whether drug clearance is flow or capacity-limited. By summarising the effect of age-related changes in hepatic function on medications commonly used in older people, we aim to provide a guide that will have high clinical utility for practising geriatricians.

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Background Population pharmacokinetic models combined with multiple sets of age– concentration biomonitoring data facilitate back-calculation of chemical uptake rates from biomonitoring data. Objectives We back-calculated uptake rates of PBDEs for the Australian population from multiple biomonitoring surveys (top-down) and compared them with uptake rates calculated from dietary intake estimates of PBDEs and PBDE concentrations in dust (bottom-up). Methods Using three sets of PBDE elimination half-lives, we applied a population pharmacokinetic model to the PBDE biomonitoring data measured between 2002–2003 and 2010–2011 to derive the top-down uptake rates of four key PBDE congeners and six age groups. For the bottom-up approach, we used PBDE concentrations measured around 2005. Results Top-down uptake rates of Σ4BDE (the sum of BDEs 47, 99, 100, and 153) varied from 7.9 to 19 ng/kg/day for toddlers and from 1.2 to 3.0 ng/kg/day for adults; in most cases, they were—for all age groups—higher than the bottom-up uptake rates. The discrepancy was largest for toddlers with factors up to 7–15 depending on the congener. Despite different elimination half-lives of the four congeners, the age–concentration trends showed no increase in concentration with age and were similar for all congeners. Conclusions In the bottom-up approach, PBDE uptake is underestimated; currently known pathways are not sufficient to explain measured PBDE concentrations, especially in young children. Although PBDE exposure of toddlers has declined in the past years, pre- and postnatal exposure to PBDEs has remained almost constant because the mothers’ PBDE body burden has not yet decreased substantially.

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Background: Bhutan has reduced its malaria incidence significantly in the last 5 years, and is aiming for malaria elimination by 2016. To assist with the management of the Bhutanese malaria elimination programme a spatial decision support system (SDSS) was developed. The current study aims to describe SDSS development and evaluate SDSS utility and acceptability through informant interviews. Methods: The SDSS was developed based on the open-source Quantum geographical information system (QGIS) and piloted to support the distribution of long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) in the two sub-districts of Samdrup Jongkhar District. It was subsequently used to support reactive case detection (RACD) in the two sub-districts of Samdrup Jongkhar and two additional sub-districts in Sarpang District. Interviews were conducted to ascertain perceptions on utility and acceptability of 11 informants using the SDSS, including programme and district managers, and field workers. Results: A total of 1502 households with a population of 7165 were enumerated in the four sub-districts, and a total of 3491 LLINs were distributed with one LLIN per 1.7 persons. A total of 279 households representing 728 residents were involved with RACD. Informants considered that the SDSS was an improvement on previous methods for organizing LLIN distribution, IRS and RACD, and could be easily integrated into routine malaria and other vector-borne disease surveillance systems. Informants identified some challenges at the programme and field level, including the need for more skilled personnel to manage the SDSS, and more training to improve the effectiveness of SDSS implementation and use of hardware. Conclusions: The SDSS was well accepted and informants expected its use to be extended to other malaria reporting districts and other vector-borne diseases. Challenges associated with efficient SDSS use included adequate skills and knowledge, access to training and support, and availability of hardware including computers and global positioning system receivers.

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The PMBOK Guide is one of the most influential publications concerning the knowledge of the project manangement. Moreover, the pervasion of this guide seems to be set to increase as the basis of accreditation - in conjunction with the increasing global trend toward obtaining project management professional status. However, despite the influence and strengthening profile of this guide, reports continue to be published that detail numerous project failures in a wide range of different industries. The PMBOK Guide comprises mainly declarative (know-what) and procedural (know-how) information. In this sense, the guide is largely normative and provides a very good example of the limitations of this approach as highlighted by proponents of a move to the genuine application of positibe theory in project management.----- The aim of this paper is to determine the applicability of the guide in Australia and to determine the extent to which project success can be attributed to the guide. Project Managers from a variety of organisations were surveyed. This postal survey yielded 48 replies. Descriptive statistics was used to assess the incidence and effectivieness of all the processes in the guide. The results indicate that there were no processes that could be considered as peripheral or as a candidate for elimination from the guide. More specifically, all the processes were identified as either a key routine process or a key selective process and positively related to the level of project success. However, the results also indicated that other major factors pertaining to causal knowledge (know-why) are, at least, equally important determinants of project success. It is concluded that declarative, procedural and causal knowledge are all valuable, and given the preponderance of the first two types of knowledge, there seems to be an urgent need to now ensure an equal quest for causal knowledge. In terms of developing causal knowledge, a good starting point would appear to be both positive theory from production and economics.

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Design as seen from the designer's perspective is a series of amazing imaginative jumps or creative leaps. But design as seen by the design historian is a smooth progression or evolution of ideas that they seem self-evident and inevitable after the event. But the next step is anything but obvious for the artist/creator/inventor/designer stuck at that point just before the creative leap. They know where they have come from and have a general sense of where they are going, but often do not have a precise target or goal. This is why it is misleading to talk of design as a problem-solving activity - it is better defined as a problem-finding activity. This has been very frustrating for those trying to assist the design process with computer-based, problem-solving techniques. By the time the problem has been defined, it has been solved. Indeed the solution is often the very definition of the problem. Design must be creative-or it is mere imitation. But since this crucial creative leap seem inevitable after the event, the question must arise, can we find some way of searching the space ahead? Of course there are serious problems of knowing what we are looking for and the vastness of the search space. It may be better to discard altogether the term "searching" in the context of the design process: Conceptual analogies such as search, search spaces and fitness landscapes aim to elucidate the design process. However, the vastness of the multidimensional spaces involved make these analogies misguided and they thereby actually result in further confounding the issue. The term search becomes a misnomer since it has connotations that imply that it is possible to find what you are looking for. In such vast spaces the term search must be discarded. Thus, any attempt at searching for the highest peak in the fitness landscape as an optimal solution is also meaningless. Futhermore, even the very existence of a fitness landscape is fallacious. Although alternatives in the same region of the vast space can be compared to one another, distant alternatives will stem from radically different roots and will therefore not be comparable in any straightforward manner (Janssen 2000). Nevertheless we still have this tantalizing possibility that if a creative idea seems inevitable after the event, then somehow might the process be rserved? This may be as improbable as attempting to reverse time. A more helpful analogy is from nature, where it is generally assumed that the process of evolution is not long-term goal directed or teleological. Dennett points out a common minsunderstanding of Darwinism: the idea that evolution by natural selection is a procedure for producing human beings. Evolution can have produced humankind by an algorithmic process, without its being true that evolution is an algorithm for producing us. If we were to wind the tape of life back and run this algorithm again, the likelihood of "us" being created again is infinitesimally small (Gould 1989; Dennett 1995). But nevertheless Mother Nature has proved a remarkably successful, resourceful, and imaginative inventor generating a constant flow of incredible new design ideas to fire our imagination. Hence the current interest in the potential of the evolutionary paradigm in design. These evolutionary methods are frequently based on techniques such as the application of evolutionary algorithms that are usually thought of as search algorithms. It is necessary to abandon such connections with searching and see the evolutionary algorithm as a direct analogy with the evolutionary processes of nature. The process of natural selection can generate a wealth of alternative experiements, and the better ones survive. There is no one solution, there is no optimal solution, but there is continuous experiment. Nature is profligate with her prototyping and ruthless in her elimination of less successful experiments. Most importantly, nature has all the time in the world. As designers we cannot afford prototyping and ruthless experiment, nor can we operate on the time scale of the natural design process. Instead we can use the computer to compress space and time and to perform virtual prototyping and evaluation before committing ourselves to actual prototypes. This is the hypothesis underlying the evolutionary paradigm in design (1992, 1995).

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Non Alcoholic Fatty Liver Disease (NAFLD) is a condition that is frequently seen but seldom investigated. Until recently, NAFLD was considered benign, self-limiting and unworthy of further investigation. This opinion is based on retrospective studies with relatively small numbers and scant follow-up of histology data. (1) The prevalence for adults, in the USA is, 30%, and NAFLD is recognized as a common and increasing form of liver disease in the paediatric population (1). Australian data, from New South Wales, suggests the prevalence of NAFLD in “healthy” 15 year olds as being 10%.(2) Non-alcoholic fatty liver disease is a condition where fat progressively invades the liver parenchyma. The degree of infiltration ranges from simple steatosis (fat only) to steatohepatitis (fat and inflammation) steatohepatitis plus fibrosis (fat, inflammation and fibrosis) to cirrhosis (replacement of liver texture by scarred, fibrotic and non functioning tissue).Non-alcoholic fatty liver is diagnosed by exclusion rather than inclusion. None of the currently available diagnostic techniques -liver biopsy, liver function tests (LFT) or Imaging; ultrasound, Computerised tomography (CT) or Magnetic Resonance Imaging (MRI) are specific for non-alcoholic fatty liver. An association exists between NAFLD, Non Alcoholic Steatosis Hepatitis (NASH) and irreversible liver damage, cirrhosis and hepatoma. However, a more pervasive aspect of NAFLD is the association with Metabolic Syndrome. This Syndrome is categorised by increased insulin resistance (IR) and NAFLD is thought to be the hepatic representation. Those with NAFLD have an increased risk of death (3) and it is an independent predictor of atherosclerosis and cardiovascular disease (1). Liver biopsy is considered the gold standard for diagnosis, (4), and grading and staging, of non-alcoholic fatty liver disease. Fatty-liver is diagnosed when there is macrovesicular steatosis with displacement of the nucleus to the edge of the cell and at least 5% of the hepatocytes are seen to contain fat (4).Steatosis represents fat accumulation in liver tissue without inflammation. However, it is only called non-alcoholic fatty liver disease when alcohol - >20gms-30gms per day (5), has been excluded from the diet. Both non-alcoholic and alcoholic fatty liver are identical on histology. (4).LFT’s are indicative, not diagnostic. They indicate that a condition may be present but they are unable to diagnosis what the condition is. When a patient presents with raised fasting blood glucose, low HDL (high density lipoprotein), and elevated fasting triacylglycerols they are likely to have NAFLD. (6) Of the imaging techniques MRI is the least variable and the most reproducible. With CT scanning liver fat content can be semi quantitatively estimated. With increasing hepatic steatosis, liver attenuation values decrease by 1.6 Hounsfield units for every milligram of triglyceride deposited per gram of liver tissue (7). Ultrasound permits early detection of fatty liver, often in the preclinical stages before symptoms are present and serum alterations occur. Earlier, accurate reporting of this condition will allow appropriate intervention resulting in better patient health outcomes. References 1. Chalasami N. Does fat alone cause significant liver disease: It remains unclear whether simple steatosis is truly benign. American Gastroenterological Association Perspectives, February/March 2008 www.gastro.org/wmspage.cfm?parm1=5097 Viewed 20th October, 2008 2. Booth, M. George, J.Denney-Wilson, E: The population prevalence of adverse concentrations with adiposity of liver tests among Australian adolescents. Journal of Paediatrics and Child Health.2008 November 3. Catalano, D, Trovato, GM, Martines, GF, Randazzo, M, Tonzuso, A. Bright liver, body composition and insulin resistance changes with nutritional intervention: a follow-up study .Liver Int.2008; February 1280-9 4. Choudhury, J, Sanysl, A. Clinical aspects of Fatty Liver Disease. Semin in Liver Dis. 2004:24 (4):349-62 5. Dionysus Study Group. Drinking factors as cofactors of risk for alcohol induced liver change. Gut. 1997; 41 845-50 6. Preiss, D, Sattar, N. Non-alcoholic fatty liver disease: an overview of prevalence, diagnosis, pathogenesis and treatment considerations. Clin Sci.2008; 115 141-50 7. American Gastroenterological Association. Technical review on nonalcoholic fatty liver disease. Gastroenterology.2002; 123: 1705-25

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CRTA technology offers better resolution and a more detailed interpretation of the decomposition processes of a clay mineral such as sepiolite via approaching equilibrium conditions of decomposition through the elimination of the slow transfer of heat to the sample as a controlling parameter on the process of decomposition. Constant-rate decomposition processes of non-isothermal nature reveal changes in the sepiolite as the sepiolite is converted to an anhydride. In the dynamic experiment two dehydration steps are observed over the ~20-170 and 170-350°C temperature range. In the dynamic experiment three dehydroxylation steps are observed over the temperature ranges 201-337, 337-638 and 638-982°C. The CRTA technology enables the separation of the thermal decomposition steps.

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Controlled rate thermal analysis (CRTA) technology offers better resolution and a more detailed interpretation of the decomposition processes of a clay mineral such as sepiolite via approaching equilibrium conditions of decomposition through the elimination of the slow transfer of heat to the sample as a controlling parameter on the process of decomposition. Constant-rate decomposition processes of non-isothermal nature reveal changes in the sepiolite as the sepiolite is converted to an anhydride. In the dynamic experiment two dehydration steps are observed over the *20–170 and 170–350 �C temperature range. In the dynamic experiment three dehydroxylation steps are observed over the temperature ranges 201–337, 337–638 and 638–982 �C. The CRTA technology enables the separation of the thermal decomposition steps.