15592441
Genomics knowledge and equity: a global public goods perspective of the patent system.
Genomics, the comprehensive examination of an organism's entire set of genes and their interactions, will have a major impact on the way disease is diagnosed, prevented and treated in the new millennium. Despite the tremendous potential it holds for improving global health, genomics challenges policy-makers to ensure that its benefits are harnessed equitably across populations and nations. The classification of genomics as a global public good and the inequity encountered in the development and application of genomics knowledge are outlined in this paper, We examine the effect of the current patent system on the distribution of costs and benefits relating to genomics knowledge between countries of different economic strength. The global public goods concept provides a normative economic rationale for the modification of certain aspects of the current patent system and for the creation of complementary mechanisms to respond to the health needs of low-income and middle-income countries.
7096884
Foreign direct investment and trade in health services: a review of the literature.
Globalization is a key challenge facing health policy-makers. A significant aspect of this is direct trade in health services, a result of the rise of transnational corporations, challenges in health care financing, porous borders and improved technology creating the scope for increased 'foreign direct investment' (FDI) in health care. This has gathered momentum with the General Agreement on Trade in Services (GATS), which aims to further liberalize trade in services, and within which FDI has been noted as perhaps the most critical area for trade negotiation. Given the rapid development of this area, there are little empirical data. This paper therefore seeks to provide the first comprehensive and systematic review of evidence concerning FDI and health services. This process included electronic bibliographic database searches, website searches and correspondence with experts in the area of trade in health services, from which 76 papers, books and reports were reviewed. Perhaps due to the rapid developments in this area, most of the literature is speculative, polarized between those arguing for the benefits of liberalization and those arguing against. However, there seem to be three issues which emerge as of most importance: (i) the extent to which a national health system is commercialized per se is of more significance than whether investment in it is foreign or domestic; (ii) the national regulatory environment and its 'strength' will significantly determine the economic and health impact of FDI, the effectiveness of safeguard measures, and the stability of GATS commitments; and (iii) any negotiations will depend upon parties having a common understanding of what is being negotiated, and the interpretation of key definitions is thus critical. Each of these issues is explored in some depth, with the overall conclusion that countries should take a step back and first think through the risks and benefits of commercialization of their health sector, rather than being sidetracked in to considering the level of foreign investment.
13856154
Macroeconomic impact of pandemic influenza and associated policies in Thailand, South Africa and Uganda
BACKGROUND
Research has shown the value of conducting a macroeconomic analysis of the impact of influenza pandemics. However, previous modelling applications focus on high-income countries, and there is a lack of evidence concerning the potential impact of an influenza pandemic on lower- and middle-income countries.


OBJECTIVES
To estimate the macroeconomic impact of pandemic influenza in Thailand, South Africa and Uganda with particular reference to pandemic (H1N1) 2009.


METHODS
A single-country whole-economy Computable General Equilibrium (CGE) model was set up for each of the three countries in question and used to estimate the economic impact of declines in labour attributable to morbidity, mortality and school closure.


RESULTS
Overall GDP impacts were less than 1% of GDP for all countries and scenarios. Uganda's losses were proportionally larger than those of Thailand and South Africa. Labour-intensive sectors suffer the largest losses.


CONCLUSION
The economic cost of unavoidable absence in the event of an influenza pandemic could be proportionally larger for low-income countries. The cost of mild pandemics, such as pandemic (H1N1) 2009, appears to be small, but could increase for more severe pandemics and/or pandemics with greater behavioural change and avoidable absence.
18066304
Macroeconomic impact of a mild influenza pandemic and associated policies in Thailand, South Africa and Uganda: a computable general equilibrium analysis
Background Previous research has demonstrated the value of macroeconomic analysis of the impact of influenza pandemics. However, previous modelling applications focus on high‐income countries and there is a lack of evidence concerning the potential impact of an influenza pandemic on lower‐ and middle‐income countries. Objectives To estimate the macroeconomic impact of pandemic influenza in Thailand, South Africa and Uganda with particular reference to pandemic (H1N1) 2009. Methods A single‐country whole‐economy computable general equilibrium (CGE) model was set up for each of the three countries in question and used to estimate the economic impact of declines in labour attributable to morbidity, mortality and school closure. Results Overall GDP impacts were less than 1% of GDP for all countries and scenarios. Uganda's losses were proportionally larger than those of Thailand and South Africa. Labour‐intensive sectors suffer the largest losses. Conclusions The economic cost of unavoidable absence in the event of an influenza pandemic could be proportionally larger for low‐income countries. The cost of mild pandemics, such as pandemic (H1N1) 2009, appears to be small, but could increase for more severe pandemics and/or pandemics with greater behavioural change and avoidable absence.
39397016
The relationship between reliability and size of willingness-to-pay values: a qualitative insight.
In a previous paper, the reliability of willingness-to-pay (WTP) values was found to be an increasing function of the size of WTP expressed. Here, the results of a qualitative exercise conducted alongside this quantitative study are presented. The results of this exercise suggest that higher WTP values may require more thought from the respondent which, in turn, gives them greater stability. At low levels of WTP, values appear to be taken from a 'discretionary account', where expenditure is more volatile. Caveats to this result, and suggestions for future research, are considered in the discussion.
26796548
Medical tourism: a review of the literature and analysis of a role for bi-lateral trade.
OBJECTIVES
With increasing globalization, many countries are considering opening their health systems to greater cross-border movement of patients. This is usually done from the viewpoint of a multi-lateral trade relationship. This paper considers the issues that arise from this debate from a bi-lateral perspective.


METHODS
A systematic literature review was carried out on 'Medical Tourism' from the perspective of a bi-lateral trade relationship, using the UK and India as a case study.


RESULTS
There is a dearth of data and discussion on such bi-lateral trade. This limited evidence offers some suggestions. Exporting countries may benefit from medical tourism by generating foreign exchange and reversing the brain drain, but run the risk of creating a dual system, where the local population is crowded out. Importing countries can benefit from alleviating waiting lists and lowering healthcare costs, but may risk quality of care and legal liability. However, evidence from a bi-lateral perspective suggests that the positive aspects can be capitalised, and the negative ones reduced.


CONCLUSIONS
The key recommendations from this paper are for more evidence to be collected at the country and international level, and for countries to consider trade in health services from a bi-lateral rather than multi-lateral perspective.
21083531
Intra- and extracellular regulation of activity and processing of legumain by cystatin E/M.
Legumain, an asparaginyl endopeptidase, is up-regulated in tumour and tumour-associated cells, and is linked to the processing of cathepsin B, L, and proMMP-2. Although legumain is mainly localized to the endosomal/lysosomal compartments, legumain has been reported to be localized extracellularly in the tumour microenvironment and associated with extracellular matrix and cell surfaces. The most potent endogenous inhibitor of legumain is cystatin E/M, which is a secreted protein synthesised with an export signal. Therefore, we investigated the cellular interplay between legumain and cystatin E/M. As a cell model, HEK293 cells were transfected with legumain cDNA, cystatin E/M cDNA, or both, and over-expressing monoclonal cell lines were selected (termed M38L, M4C, and M3CL, respectively). Secretion of prolegumain from M38L cells was inhibited by treatment with brefeldin A, whereas bafilomycin A1 enhanced the secretion. Cellular processing of prolegumain to the 46 and 36 kDa enzymatically active forms was reduced by treatment with either substance alone. M38L cells showed increased, but M4C cells decreased, cathepsin L processing suggesting a crucial involvement of legumain activity. Furthermore, we observed internalization of cystatin E/M and subsequently decreased intracellular legumain activity. Also, prolegumain was shown to internalize followed by increased intracellular legumain processing and activation. In addition, in M4C cells incomplete processing of the internalized prolegumain was observed, as well as nuclear localized cystatin E/M. Furthermore, auto-activation of secreted prolegumain was inhibited by cystatin E/M, which for the first time shows a regulatory role of cystatin E/M in controlling both intra- and extracellular legumain activity.
24512083
Effects of Perinatal HIV Infection and Associated Risk Factors on Cognitive Development Among Young Children
OBJECTIVE. We examined the effect of HIV, in combination with other important health and social factors, on the development of cognitive abilities of children perinatally exposed to HIV. METHODS. Serial cognitive assessments were performed for 117 children who were infected vertically and 422 children who were exposed to but not infected with HIV, in a multicenter, natural history, longitudinal study. Repeated-measures analyses were used to evaluate the neurocognitive development of children between the ages of 3 and 7 years, as measured by the McCarthy Scales of Children’s Abilities (MSCA). RESULTS. Children with HIV infection and class C status scored significantly lower in all domains of cognitive development, across all time points, than did those who were HIV infected without an AIDS-defining illness and those who were HIV exposed but not infected. There were no significant differences between the 2 latter groups in General Cognitive Index or specific domain scores. Rates of change in cognitive development were comparable (parallel) among all 3 groups over a period of 4 years. Factors that were associated consistently and significantly with lower mean scores were HIV status, number of times an examination had been completed previously, primary language, maternal education, and gender. No factors were related to rate of change of any mean domain score. CONCLUSIONS. An early AIDS-defining illness increased the risk of chronic static encephalopathy during the preschool and early school age years. Children with HIV infection but no class C event performed as well as noninfected children in measures of general cognitive ability. No significantly different profiles of strengths and weaknesses for verbal, perceptual-performance, quantitative, or memory functioning were observed among children with or without HIV infection. A number of factors were found to have significant effects on the mean scores of children in all 3 groups; however, they were not related to the rate at which learning occurred.
33674054
Timing of perinatal human immunodeficiency virus type 1 infection and rate of neurodevelopment. The Women and Infant Transmission Study Group.
BACKGROUND
Identifying HIV-1-infected children who are at greatest risk for disease-related morbidities is critical for optimal therapeutic as well as preventive care. Several factors have been implicated in HIV-1 disease onset and severity, including maternal and infant host characteristics, viral phenotype and timing of HIV-1 infection. Early HIV-1 culture positivity, i.e. intrauterine infection, has been associated with poor immunologic, virologic and clinical outcomes in children of HIV-infected women. However, a direct effect of timing of infection on neurodevelopmental outcome in infancy has not yet been identified.


METHODS
Serial neurodevelopmental assessments were performed with 114 infants vertically infected with HIV-1 in a multicenter natural history, longitudinal study. Median mental and motor scores were compared at three time points. Longitudinal regression analyses were used to evaluate the neurodevelopmental functioning of children with early positive cultures and those with late positive cultures.


RESULTS
Early infected infants scored significantly lower than late infected infants by 24 months of age and beyond on both mental (P = 0.05) and motor (P = 0.03) measures. Early HIV-1 infection was associated with a decline in estimated motor scores of 1 standard score point per month compared with 0.28 point in the late infected group (P < 0.02). Estimated mental scores of the early infected group declined 0.72 point/ month, whereas the average decline of the late infected group was 0.30 point/month (P < 0.13).


CONCLUSION
Early HIV-1 infection increases a child's risk for poor neurodevelopmental functioning within the first 30 months of life.
25322518
Corticotropin-releasing hormone in chimpanzee and gorilla pregnancies.
In humans, the length of gestation and the onset of parturition have been linked to the exponential production of placental CRH and a late gestational decline in maternal plasma CRH-binding protein (CRH-BP). CRH has been shown to have direct effects on the myometrium and on the fetal adrenal, where it stimulates production of the estrogen precursor dihydroepiandrosterone sulfate. In vitro placental CRH production is stimulated by cortisol and inhibited by progesterone. To determine whether this mechanism might operate in other apes, we sampled eight chimpanzees and two gorillas through their pregnancies for CRH, CRH-BP, cortisol, estradiol, progesterone, and alpha-fetoprotein. We show that both chimpanzee and gorilla maternal plasma CRH concentrations rise exponentially as observed in the human. The gorillas exhibited a human-like antepartum fall in CRH-BP, whereas CRH-BP in the chimpanzee remained stable. Pregnancy-associated changes in cortisol, estradiol, progesterone, and alpha-fetoprotein were qualitatively similar to those observed in humans. Maternal plasma cortisol correlated with plasma CRH in both gorillas (r = 0.60; P < 0.05) and chimpanzees (r = 0.36; P < 0.02). Further, there was a strong correlation between plasma estradiol and the log of plasma CRH in the gorilla (r = 0.93; P < 0.0001) and in the chimpanzee (r = 0.72; P < 0.001), which is consistent with the hypothesis that placental CRH determines the placental production of estradiol by stimulating the production of fetal adrenal dehydroepiandrosterone sulfate. Plasma CRH and progesterone were positively correlated providing no in vivo support for progesterone inhibition of CRH release.
7050862
The placenta, a transducer linking maternal nutrition to adult disease in the offspring?
This month’s Journal carries an article from Shanghai on the regulation of glucose transporters (GLUT) in humanplacenta(1).Thestudiesbringapossiblenewplayer into the ongoing drama of nutritional regulation of fetal growth and development. The in vitro studies by Gao et al. (1) examined the effects of CRH on mRNA and protein concentrations of GLUT1 and GLUT3. Using a variety of techniques, including small interfering RNA for the corticotrophin releasing hormone receptor type 1 (CRH-R1) receptor, antibodies to the receptor, and receptor blockers, the studies convincingly show that CRH stimulates trophoblast production of GLUT1 and inhibits the expression of GLUT3 via the CRH-R1 receptor. The area is of increasing interest as data accumulate that fetal growth is an important determinant of adult health. The Barker hypothesis posits that restricted intrauterine growth associated with the birth of a small infant leads to early onset diabetes, hypertension, and ischemic heart disease (2). This hypothesis is linked to the concept of phenotypic plasticity, a widespread phenomenon in nature whereby the environment interacts with the genome to determine an organism’s phenotype (3). In the setting of intrauterine growth restriction, it is proposed that impaired nutrient transfer to the fetus leads to the development of a metabolic phenotype that is adapted to an environment low in nutrients. The fetus adapted to low nutrients that is then born into a Western society with high-energy diets is maladapted, develops obesity, diabetes, hypertension, and early heart disease. There are strong animal data for this scenario; however, human data are more limited (4). Given the importance of optimizing fetal growth, the pathway to optimal fetal growth becomes of great interest. Unfortunately, this pathway is very poorly characterized. Worldwide, low birth weight is very common, leading to a recent Gates Foundation call for studies on the underlying mechanisms leading to impaired fetal growth (http://www. grandchallenges.org/GCGHDocs/Healthy_Growth_Rules_ and_Guidelines.pdf). Althoughconditions suchaspreeclampsia are well-known associates of impaired growth, there is little knowledge on the etiology of most cases. Major deficiencies in knowledge extend to even what might be the ideal diet for a pregnant woman to produce a healthy baby with an optimum metabolic phenotype for the 21st century. National guidelines for maternal intakes exist, but these are not founded on a sound evidence base of longitudinal studies of infant outcomes (5). Recent research on comparative nutritional intakes of protein, fat, and carbohydrate suggest that all animals have a genetically determined target intake of macronutrients (6). This work strongly suggests that an ideal target intake would exist for pregnant women, but this has not yet been defined. With an ideal maternal intake, the placenta is the port via which this nutrition is transported to the fetus. How exactly this occurs and how it is regulated again remains unclear. Nutrient sensing by the fetus may involve the IGF axis within the fetal liver (7). How is nutrient sensing performed by the placenta on behalf of the fetus? Syncytiotrophoblast expression of GLUT1 is stimulated by placental variant growth hormone, which increases across gestation as does GLUT1; so perhaps again the IGF axis is central (8). How does the placenta determine how much nutrient will be invested in placental growth and how much transferred to the fetus for fetal growth? How does the placenta regulate the nutrient mix it provides to the fetus and is the ideal nutrient mix for the mother the same for the fetus?