Hippocampal bone morphogenetic protein signaling mediates behavioral effects of antidepressant treatment.

Many antidepressants stimulate adult hippocampal neurogenesis, but the mechanisms by which they increase neurogenesis and modulate behavior are incompletely understood. Here we show that hippocampal bone morphogenetic protein (BMP) signaling is modulated by antidepressant treatment, and that the changes in BMP signaling mediate effects of antidepressant treatment on neural progenitor cell proliferation and behavior. Treatment with the selective serotonin reuptake inhibitor fluoxetine suppressed BMP signaling in the adult mouse hippocampus both by decreasing levels of BMP4 ligand and increasing production of the BMP inhibitor noggin. Increasing BMP signaling in the hippocampus via viral overexpression of BMP4 blocked the effects of fluoxetine on proliferation in the dentate gyrus and on depressive behavior. Conversely, inhibiting BMP signaling via viral overexpression of noggin in the hippocampus or infusion of noggin into the ventricles exerted antidepressant and anxiolytic activity along with an increase in hippocampal neurogenesis. Similarly, conditional genetic deletion of the type II BMP receptor in Ascl1-expressing cells promoted neurogenesis and reduced anxiety- and depression-like behaviors, suggesting that neural progenitor cells contribute to the effects of BMP signaling on affective behavior. These observations indicate that BMP signaling in the hippocampus regulates depressive behavior, and that decreasing BMP signaling may be required for the effects of some antidepressants. Thus BMP signaling is a new and powerful potential target for the treatment of depression.

Element specific determination of the magnetic properties of two macrocyclic tetranuclear 3d-4f complexes with a Cu3Tb core by means of X-ray magnetic circular dichroism (XMCD).

We apply X-ray magnetic circular dichroism to study the internal magnetic structure of two very promising star shaped macrocyclic complexes with a CuII3TbIII core. These complexes are rare examples prepared with a macrocyclic ligand that show indications of SMM (Single Molecule Magnet) behavior, and they differ only in ring size: one has a propylene linked macrocycle, [CuII3TbIII(LPr)(NO3)2(MeOH)(H2O)2](NO3)·3H2O (nickname: Cu3Tb(LPr)), and the other has the butylene linked analogue, [CuII3TbIII(LBu)(NO3)2(MeOH)(H2O)](NO3)·3H2O (nickname: Cu3Tb(LBu)). We analyze the orbital and spin contributions to the Cu and Tb ions quantitatively by applying the spin and orbital sum rules concerning the L2 (M4)/L3 (M5) edges. In combination with appropriate ligand field simulations, we demonstrate that the Tb(iii) ions contribute with high orbital magnetic moments to the magnetic anisotropy, whereas the ligand field determines the easy axis of magnetization. Furthermore, we confirm that the Cu(ii) ions in both molecules are in a divalent valence state, the magnetic moments of the three Cu ions appear to be canted due to 3d-3d intramolecular magnetic interactions. For Cu3Tb(LPr), the corresponding element specific magnetization loops reflect that the Cu(ii) contribution to the overall magnetic picture becomes more important as the temperature is lowered. This implies a low value for the 3d-4f coupling.

Rapid mapping of schistosomiasis and other neglected tropical diseases in the context of integrated control programmes in Africa.

There is growing interest and commitment to the control of schistosomiasis and other so-called neglected tropical diseases (NTDs). Resources for control are inevitably limited, necessitating assessment methods that can rapidly and accurately identify and map high-risk communities so that interventions can be targeted in a spatially-explicit and cost-effective manner. Here, we review progress made with (1) mapping schistosomiasis across Africa using available epidemiological data and, more recently, climate-based risk prediction; (2) the development and use of morbidity questionnaires for rapid identification of high-risk communities of urinary schistosomiasis; and (3) innovative sampling-based approaches for intestinal schistosomiasis, using the lot quality assurance sampling technique. Experiences are also presented for the rapid mapping of other NTDs, including onchocerciasis, loiasis and lymphatic filariasis. Future directions for an integrated rapid mapping approach targeting multiple NTDs simultaneously are outlined, including potential challenges in developing an integrated survey tool. The lessons from the mapping of human helminth infections may also be relevant for the rapid mapping of malaria as its control efforts are intensified.

Schistosomiasis and neglected tropical diseases: towards integrated and sustainable control and a word of caution.

In May 2001, the World Health Assembly (WHA) passed a resolution which urged member states to attain, by 2010, a minimum target of regularly administering anthelminthic drugs to at least 75% and up to 100% of all school-aged children at risk of morbidity. The refined global strategy for the prevention and control of schistosomiasis and soil-transmitted helminthiasis was issued in the following year and large-scale administration of anthelminthic drugs endorsed as the central feature. This strategy has subsequently been termed 'preventive chemotherapy'. Clearly, the 2001 WHA resolution led the way for concurrently controlling multiple neglected tropical diseases. In this paper, we recall the schistosomiasis situation in Africa in mid-2003. Adhering to strategic guidelines issued by the World Health Organization, we estimate the projected annual treatment needs with praziquantel among the school-aged population and critically discuss these estimates. The important role of geospatial tools for disease risk mapping, surveillance and predictions for resource allocation is emphasised. We clarify that schistosomiasis is only one of many neglected tropical diseases and that considerable uncertainties remain regarding global burden estimates. We examine new control initiatives targeting schistosomiasis and other tropical diseases that are often neglected. The prospect and challenges of integrated control are discussed and the need for combining biomedical, educational and engineering strategies and geospatial tools for sustainable disease control are highlighted. We conclude that, for achieving integrated and sustainable control of neglected tropical diseases, a set of interventions must be tailored to a given endemic setting and fine-tuned over time in response to the changing nature and impact of control. Consequently, besides the environment, the prevailing demographic, health and social systems contexts need to be considered.

Remote sensing, geographical information system and spatial analysis for schistosomiasis epidemiology and ecology in Africa.

Beginning in 1970, the potential of remote sensing (RS) techniques, coupled with geographical information systems (GIS), to improve our understanding of the epidemiology and control of schistosomiasis in Africa, has steadily grown. In our current review, working definitions of RS, GIS and spatial analysis are given, and applications made to date with RS and GIS for the epidemiology and ecology of schistosomiasis in Africa are summarised. Progress has been made in mapping the prevalence of infection in humans and the distribution of intermediate host snails. More recently, Bayesian geostatistical modelling approaches have been utilized for predicting the prevalence and intensity of infection at different scales. However, a number of challenges remain; hence new research is needed to overcome these limitations. First, greater spatial and temporal resolution seems important to improve risk mapping and understanding of transmission dynamics at the local scale. Second, more realistic risk profiling can be achieved by taking into account information on people's socio-economic status; furthermore, future efforts should incorporate data on domestic access to clean water and adequate sanitation, as well as behavioural and educational issues. Third, high-quality data on intermediate host snail distribution should facilitate validation of infection risk maps and modelling transmission dynamics. Finally, more emphasis should be placed on risk mapping and prediction of multiple species parasitic infections in an effort to integrate disease risk mapping and to enhance the cost-effectiveness of their control.

Bayesian spatial analysis of a national urinary schistosomiasis questionnaire to assist geographic targeting of schistosomiasis control in Tanzania, East Africa.

Spatial modelling was applied to self-reported schistosomiasis data from over 2.5 million school students from 12,399 schools in all regions of mainland Tanzania. The aims were to derive statistically robust prevalence estimates in small geographical units (wards), to identify spatial clusters of high and low prevalence and to quantify uncertainty surrounding prevalence estimates. The objective was to permit informed decision-making for targeting of resources by the Tanzanian national schistosomiasis control programme. Bayesian logistic regression models were constructed to investigate the risk of schistosomiasis in each ward, based on the prevalence of self-reported schistosomiasis and blood in urine. Models contained covariates representing climatic and demographic effects and random effects for spatial clustering. Degree of urbanisation, median elevation of the ward and median normalised difference vegetation index (NDVI) were significantly and negatively associated with schistosomiasis prevalence. Most regions contained wards that had >95% certainty of schistosomiasis prevalence being >10%, the selected threshold for bi-annual mass chemotherapy of school-age children. Wards with >95% certainty of schistosomiasis prevalence being >30%, the selected threshold for annual mass chemotherapy of school-age children, were clustered in north-western, south-western and south-eastern regions. Large sample sizes in most wards meant raw prevalence estimates were robust. However, when uncertainties were investigated, intervention status was equivocal in 6.7-13.0% of wards depending on the criterion used. The resulting maps are being used to plan the distribution of praziquantel to participating districts; they will be applied to prioritising control in those wards where prevalence was unequivocally above thresholds for intervention and might direct decision-makers to obtain more information in wards where intervention status was uncertain.

The health impact of polyparasitism in humans: are we under-estimating the burden of parasitic diseases?

Parasitic infections are widespread throughout the tropics and sub-tropics, and infection with multiple parasite species is the norm rather than the exception. Despite the ubiquity of polyparasitism, its public health significance has been inadequately studied. Here we review available studies investigating the nutritional and pathological consequences of multiple infections with Plasmodium and helminth infection and, in doing so, encourage a reassessment of the disease burden caused by polyparasitism. The available evidence is conspicuously sparse but is suggestive that multiple human parasite species may have an additive and/or multiplicative impact on nutrition and organ pathology. Existing studies suffer from a number of methodological limitations and adequately designed studies are clearly necessary. Current methods of estimating the potential global morbidity due to parasitic diseases underestimate the health impact of polyparasitism, and possible reasons for this are presented. As international strategies to control multiple parasite species are rolled-out, there is a number of options to investigate the complexity of polyparasitism, and it is hoped that that the parasitological research community will grasp the opportunity to understand better the health of polyparasitism in humans.

Modelling heterogeneity and the impact of chemotherapy and vaccination against human hookworm.

There is a growing emphasis on the development of vaccines against helminths (worms), and mathematical models provide a useful tool to assess the impact of new vaccines under a range of scenarios. The present study describes a stochastic individual-based model to assess the relative impact of chemotherapy and vaccination against human hookworm infection and investigates the implications of potential correlations between risk of infection and vaccine efficacy. Vaccination is simulated as a reduction in susceptibility to infection and the model includes population heterogeneities and dynamical waning of protection. To help identify appropriate measures of vaccine impact, we present a novel framework to quantify the vaccine impact on the infection-associated morbidity and introduce a measure of symmetry to study the correspondence between reduction in intensity and reduction in morbidity. Our modelling shows that, in high-transmission settings, the greatest impact of vaccination will be attained when vaccine efficacy is the greatest among individuals harbouring the heaviest worm burdens, and that the decline of morbidity primarily depends on the level of protection attained in the most at risk 8-12% of the population. We also demonstrate that if risk of infection and vaccine protection are correlated, there is not always a direct correspondence between the reduction in worm burden and in morbidity, with the precise relationship varying according to transmission setting.

Estimates of disease burden due to land-snake bite in Sri Lankan hospitals.

Snake bite is a common cause of hospital admission in Sri Lanka. Despite this, there have been no countrywide studies or national estimates of disease burden due to snake bites in Sri Lankan hospitals. We assessed the disease burden due to snake bite in our hospitals and estimated the frequency of admissions due to bites by different snake species. Sri Lanka was divided into four zones based on climate and topography. Hospital morbidity and mortality data, which are available on an administrative district basis, were collated for the four zones. A survey of opinion among specialist physicians (the Delphi technique) was used to estimate the proportion of bites by different species, and requirements for anti-venom (AV) and intensive care facilities for management of snake bites in hospitals in each of the four zones. A study of hospital admissions due to snake bites in seven selected hospitals was also performed to validate the opinion survey. There was a clear difference in the incidence of hospital admissions due to snake bites in the different zones. Estimates of hospital admissions due to bites by different species also varied considerably between zones. These trends corresponded to estimates of requirements of AV and other supportive health care. Health care planning using data based on environmental information, rather than merely on political boundaries, could lead to targeted distribution of AV and intensive care requirements to manage snake bites.

Associations between school- and household-level water, sanitation and hygiene conditions and soil-transmitted helminth infection among Kenyan school children.

BACKGROUND: Soil-transmitted helminths, a class of parasitic intestinal worms, are pervasive in many low-income settings. Infection among children can lead to poor nutritional outcomes, anaemia, and reduced cognition. Mass treatment, typically administered through schools, with yearly or biannual drugs is inexpensive and can reduce worm burden, but reinfection can occur rapidly. Access to and use of sanitation facilities and proper hygiene can reduce infection, but rigorous data are scarce. Among school-age children, infection can occur at home or at school, but little is known about the relative importance of WASH in transmission in these two settings. METHODS: We explored the relationships between school and household water, sanitation, and hygiene conditions and behaviours during the baseline of a large-scale mass drug administration programme in Kenya. We assessed several WASH measures to quantify the exposure of school children, and developed theory and empirically-based parsimonious models. RESULTS: Results suggest mixed impacts of household and school WASH on prevalence and intensity of infection. WASH risk factors differed across individual worm species, which is expected given the different mechanisms of infection. CONCLUSIONS: No trend of the relative importance of school versus household-level WASH emerged, though some factors, like water supply were more strongly related to lower infection, which suggests it is important in supporting other school practices, such as hand-washing and keeping school toilets clean.

The potential of geographical information systems and remote sensing in the epidemiology and control of human helminth infections.

Geographic information systems (GIS) and remote sensing (RS) technologies are being used increasingly to study the spatial and temporal patterns of infectious diseases. For helminth infections, however, such applications have only recently begun despite the recognition that infection distribution patterns in endemic areas may have profound effects on parasite population dynamics and therefore the design and implementation of successful control programmes. Here, we review the early applications of these technologies to the major human helminths (geohelminths, schistosomes and the major lymphatic filarial worms), which demonstrate the potential of these tools to serve as: (1) an effective data capture, mapping and analysis tool for the development of helminth atlases; (2) an environment for modeling the spatial distribution of infection in relation to RS and environmental variables, hence furthering the understanding of the impact of density-independent factors in underlying observed parasite spatial distributions and their effective prediction; and (3) a focal tool in parasite control programming given their abilities to (i) better define endemic areas, (ii) provide more precise estimates of populations-at-risk, (iii) map their distribution in relation to health facilities and (iv) by facilitating the stratification of areas by infection risk probabilities, to aid in the design of optimal drug or health measure delivery systems. These applications suggest a successful role for GIS/RS applications in investigating the spatial epidemiology of the major human helminths. It is evident that further work addressing a range of critical issues include problems of data quality, the need for a better understanding of the population biological impact of environmental factors on critical stages of the parasite life-cycle, the impacts and consequences of spatial scale on these relationships, and the development and use of appropriate spatially-explicit statistical and modeling techniques in data analysis, is required if the true potential of this tool to helminthology is to be fully realized.

Snake bites in Kenya: a preliminary survey of four areas.

Primary data were collected on the incidence, severity and species responsible for snake bites in 4 areas of Kenya: (i) Kakamega and western Kenya, (ii) Lake Baringo and Laikipia, (iii) Kilifi and Malindi, and (iv) northern Kenya. The overall average frequency of snake bite was 13.8 per 100,000 population per year (range 1.9-67.9). The minimum rate of snake bite mortality was 0.45/100,000/year. Thirty-four of the 50 units visited reported no knowledge of death from snake bite in the last 5 years. Possible reasons for the low estimates are discussed. Traditional treatments were common, especially the use of herbal remedies and incisions at the wound site.

Patterns of concurrent hookworm infection and schistosomiasis in schoolchildren in Tanzania.

A cross-sectional study of 6897 schoolchildren in 59 out of the 155 primary schools in Magu District on the shores of Lake Victoria, Tanzania, was undertaken in 1997 to determine the prevalence of single- and multiple-species helminth infection. Schistosoma haematobium, hookworm (primarily Necator americanus) and S. mansoni were the most common helminth species infecting schoolchildren in the district. The prevalences of Ascaris lumbricoides and Trichuris trichiura were negligible (< 1%). Anaemia and stunting were highly prevalent and widespread. Hookworm and S. mansoni occurred more frequently in multiple infections with other helminths than as single-species infections, but triple-species infection was rare. Analysis of the frequency distribution of infection amongst schools showed that prevalences of S. haematobium and hookworm tended to be normally distributed, with medians 75% and 45%, respectively, while the distribution of S. mansoni was markedly skewed such that only 17% schools had a prevalence greater than 20%. An inverse association between S. mansoni and S. haematobium was observed. Geographical information system (GIS) analysis indicated that S. mansoni infection was highly prevalent only along the shore of Lake Victoria, whilst S. haematobium was homogeneously prevalent everywhere except the lakeshore. This pattern appears to reflect the distribution of schistosome species-specific snail intermediate hosts. The results imply that joint treatment for hookworm infection and schistosomiasis would be beneficial throughout the district.

Development and validation of a 'tablet pole' for the administration of praziquantel in sub-Saharan Africa.

A pole estimating, for each individual, the number of praziquantel tablets needed for treatment according to height was tested in 20 data sets (n = 25,688). In more than 98% of the cases the indicated dose was within the range that has proven efficacious and safe (30 and 60 mg/kg).

The epidemiology of hookworm infection and its contribution to anaemia among pre-school children on the Kenyan coast.

Intestinal nematode infections are recognized as a major public health problem, and helminth control is currently being directed towards school-aged children who are known to harbour the heaviest infections and are most likely to suffer from associated morbidity. However, few data are available for the epidemiology of intestinal nematodes in pre-school children in Africa, and the contribution of hookworm infection to the aetiology and severity of anaemia among pre-school children remains poorly understood. This paper investigates the epidemiology of parasitic infections in 460 pre-school children who were part of a larger case-control study of severe malaria in Kilifi on the Kenyan coast. Almost one-third (28.7%) were infected with hookworm, 20.2% with Ascaris lumbricoides and 15.0% with Trichuris trichiura. Infection prevalence of each species rose with age, and the prevalence of heavy infection with hookworm and mean intensity of hookworm were markedly age-dependent. One-third (34.3%) of children had malaria. Overall, 76.3% of children were anaemic (haemoglobin < 110 g/L), with the prevalence decreasing with age. Anaemia was significantly worst in children with heavy hookworm infection (> 200 eggs per gram). This relationship held for all ages, both sexes, and was independent of socioeconomic factors. The application of attributable morbidity methods confirmed the contribution of hookworm infection to anaemia.

Schistosomes, snails and satellites.

This paper gives an overview of the recent progress made in the use and application of geographical information systems (GIS) and remotely sensed (RS) satellite sensor data for the epidemiology and control of schistosomiasis in sub-Saharan Africa. Details are given of the use of GIS to collate, map and analyse available parasitological data. The use of RS data to understand better the broad scale environmental factors influencing schistosome distribution is defined and examples detailed for the prediction of schistosomiasis in unsampled areas. Finally, the current practical application of GIS and remote sensing are reviewed in the context of national control programmes.

Spatial and intensity-dependent variations in associations between multiple species helminth infections.

Estimated associations between infections with different helminth species can be used to predict the proportion of a population infected with multiple species infections. This is an important measure of disease burden, as those with multiple infections are often at an increased risk of morbidity. In this paper, we investigate variation amongst the estimated associations between Ascaris lumbricoides, Trichuris trichiura and hookworm, over a number of different spatial levels among schoolchildren in Cameroon. Associations between species were largely homogeneous within districts, provinces and ecological zones, although variation between these regions was identified, implying that a single measure of association may not be appropriate in different epidemiological settings. Further data collected amongst school children in Kenya and Uganda were analysed, to assess the dependence of the associations on the intensity of infection. It was found that the strength of the association between A. lumbricoides and T. trichiura increased with intensity, such that those with more intense infections with one species are increasingly likely to harbour concurrent intense infections with the other species. The implications of these results are discussed in relation to the estimation of the disease burden due to multiple helminth species.

Age patterns in stunting and anaemia in African schoolchildren: a cross-sectional study in Tanzania.

OBJECTIVE: To describe the nutritional status of schoolchildren from a rural area of Tanzania, with a particular emphasis on older adolescents to determine the timing of the growth spurt and differences by sex. DESIGN: A cross-sectional survey using a randomly selected sample. SUBJECTS: Six thousand eight hundred and one children aged 7-18 y randomly selected from those enrolled in standards 2-5 in 59 primary schools in Magu District, Tanzania. RESULTS: Overall, 52.5% of children were stunted and 43.0% were underweight, with significantly more boys stunted and underweight than girls. Z-scores of height-for-age for both boys and girls decreased progressively between 7 and 12 y. After 12 y the height-for-age z-scores of girls show a marked upturn, whilst z-scores for boys continue to decrease throughout the school-aged years until 16 y when a slight upturn is observed. Anaemia (Hb<120 g/L) was present in 62.6% of children, with the prevalence decreasing with age. Anaemia improved throughout the school years for boys, but did not for girls. Age, sex and hookworm infection were significant predictors of anaemia. CONCLUSION: Stunting and anaemia are exceptionally common conditions in African schoolchildren. The findings highlight important differences between boys and girls, which are suggestive of compensatory growth at 12 y for girls and at 16 y for boys, although it remains unclear whether boys will catch up in height at older ages. SPONSORSHIP: Funding was provided by the Wellcome Trust. European Journal of Clinical Nutrition (2000) 54, 36-40

What is the prevalence of symptomatic or asymptomatic femoral head osteonecrosis in patients previously treated with chemoradiation? A magnetic resonance study of anal cancer patients.

It is generally assumed that femoral head osteonecrosis (FHO) is a serious but rare complication of pelvic radiotherapy. A review of the literature carried out by the authors indicates a prevalence of 4/763 (95% confidence interval 0.1%-1.3%). A recent publication has suggested that the prevalence of symptomatic FHO may be much greater than previously assumed as a result of sensitization of bone to radiation by concomitant treatment with chemotherapy. Magnetic resonance imaging (MRI) is currently the most sensitive modality for detecting and confirming symptomatic or asymptomatic FHO of any aetiology. The aim of this study therefore was to assess the prevalence of symptomatic and asymptomatic FHO in patients previously treated for anal cancer by chemoradiation (CRT). The hips of 34 currently disease-free individuals (11 men and 23 women; median age 67 years, range 32-86) were scanned using a coronal T1-weighted sequence. The images were assessed for evidence of FHO. The median time of scanning after the end of CRT was 35 months (range 6-107). No cases (0/34) of symptomatic or asymptomatic FHO were detected in these patients. Given the established sensitivity of MRI in the detection of FHO, it is concluded that changes indicative of osteonecrosis were uncommon after CRT in the current cohort of patients. Recent evidence from the literature suggests, however, that elderly females are at greatest risk of developing FHO after CRT.

Mapping soil-transmitted helminths in Southeast Asia and implications for parasite control.

Establishing the current status and distribution of soil-transmitted helminths is essential for developing and implementing parasite control. Although Southeast Asia is known to have a high prevalence of infection, a precise estimate of the total disease burden has not been fully described. Here, we use Geographical Information Systems (GIS) to collate and map recent published surveys on soil-transmitted helminth epidemiology and distribution for this region. Distinct geographical variation was observed, which is suggested to reflect climatic variation, as well as behavioral differences. However, for much of the region few data are available, and therefore it proved necessary to generate predictions of the distribution of soil-transmitted helminths using remotely sensed (RS) satellite sensor environmental variables. A significant finding was the importance of land surface temperature in influencing the distribution of Ascaris lumbricoides and Trichuris trichiura. Spatial analyses using RS satellite sensor data were then used to generate predictive maps of infection risk. This information provided the basis for an estimate of the population at risk of infection and the numbers requiring treatment. These applications of GIS and remote sensing provide a good basis for developing control of soil-transmitted helminths in the region.