Does mass drug administration for the integrated treatment of neglected tropical diseases really work? Assessing evidence for the control of schistosomiasis and soil-transmitted helminths in Uganda

This paper was one of four papers commissioned to review the role of social sciences in NTD control by TDR, the Special Programme for Research and Training on Tropical Diseases, which is executed by WHO and co-sponsored by UNICEF, UNDP, the World Bank and WHO.This article has been made available through the Brunel Open Access Publishing Fund.Background: Less is known about mass drug administration [MDA] for neglected tropical diseases [NTDs] than is suggested by those so vigorously promoting expansion of the approach. This paper fills an important gap: it draws upon local level research to examine the roll out of treatment for two NTDs, schistosomiasis and soil-transmitted helminths, in Uganda. Methods: Ethnographic research was undertaken over a period of four years between 2005-2009 in north-west and south-east Uganda. In addition to participant observation, survey data recording self-reported take-up of drugs for schistosomiasis, soil-transmitted helminths and, where relevant, lymphatic filariasis and onchocerciasis was collected from a random sample of at least 10% of households at study locations. Data recording the take-up of drugs in Ministry of Health registers for NTDs were analysed in the light of these ethnographic and social survey data. Results: The comparative analysis of the take-up of drugs among adults revealed that although most long term residents have been offered treatment at least once since 2004, the actual take up of drugs for schistosomiasis and soil-transmitted helminths varies considerably from one district to another and often also within districts. The specific reasons why MDA succeeds in some locations and falters in others relates to local dynamics. Issues such as population movement across borders, changing food supply, relations between drug distributors and targeted groups, rumours and conspiracy theories about the 'real' purpose of treatment, subjective experiences of side effects from treatment, alternative understandings of affliction, responses to social control measures and historical experiences of public health control measures, can all make a huge difference. The paper highlights the need to adapt MDA to local circumstances. It also points to specific generalisable issues, notably with respect to health education, drug distribution and more effective use of existing public health legislation. Conclusion: While it has been an achievement to have offered free drugs to so many adults, current standard practices of monitoring, evaluation and delivery of MDA for NTDs are inconsistent and inadequate. Efforts to integrate programmes have exacerbated the difficulties. Improved assessment of what is really happening on the ground will be an essential step in achieving long-term overall reduction of the NTD burden for impoverished communities.This article is available through the Brunel Open Access Publishing Fund

Demographic Diversity and Sustainable Fisheries

Fish species are diverse. For example, some exhibit early maturation while others delay maturation, some adopt semelparous reproductive strategies while others are iteroparous, and some are long-lived and others short-lived. The diversity is likely to have profound effects on fish population dynamics, which in turn has implications for fisheries management. In this study, a simple density-dependent stage-structured population model was used to investigate the effect of life history traits on sustainable yield, population resilience, and the coefficient of variation (CV) of the adult abundance. The study showed that semelparous fish can produce very high sustainable yields, near or above 50% of the carrying capacity, whereas long-lived iteroparous fish can produce very low sustainable yields, which are often much less than 10% of the carrying capacity. The difference is not because of different levels of sustainable fishing mortality rate, but because of difference in the sensitivity of the equilibrium abundance to fishing mortality. On the other hand, the resilience of fish stocks increases from delayed maturation to early maturation strategies but remains almost unchanged from semelparous to long-lived iteroparous. The CV of the adult abundance increases with increased fishing mortality, not because more individuals are recruited into the adult stage (as previous speculated), but because the mean abundance is more sensitive to fishing mortality than its standard deviation. The magnitudes of these effects vary depending on the life history strategies of the fish species involved. It is evident that any past high yield of long-lived iteroparous fish is a transient yield level, and future commercial fisheries should focus more on fish that are short-lived (including semelparous species) with high compensatory capacity

Short-Term Environmental Enrichment Rescues Adult Neurogenesis and Memory Deficits in APPSw,Ind Transgenic Mice

Epidemiological studies indicate that intellectual activity prevents or delays the onset of Alzheimer's disease (AD). Similarly, cognitive stimulation using environmental enrichment (EE), which increases adult neurogenesis and functional integration of newborn neurons into neural circuits of the hippocampus, protects against memory decline in transgenic mouse models of AD, but the mechanisms involved are poorly understood. To study the therapeutic benefits of cognitive stimulation in AD we examined the effects of EE in hippocampal neurogenesis and memory in a transgenic mouse model of AD expressing the human mutant β-amyloid (Aβ) precursor protein (APPSw,Ind). By using molecular markers of new generated neurons (bromodeoxiuridine, NeuN and doublecortin), we found reduced neurogenesis and decreased dendritic length and projections of doublecortin-expressing cells of the dentate gyrus in young APPSw,Ind transgenic mice. Moreover, we detected a lower number of mature neurons (NeuN positive) in the granular cell layer and a reduced volume of the dentate gyrus that could be due to a sustained decrease in the incorporation of new generated neurons. We found that short-term EE for 7 weeks efficiently ameliorates early hippocampal-dependent spatial learning and memory deficits in APPSw,Ind transgenic mice. The cognitive benefits of enrichment in APPSw,Ind transgenic mice were associated with increased number, dendritic length and projections to the CA3 region of the most mature adult newborn neurons. By contrast, Aβ levels and the total number of neurons in the dentate gyrus were unchanged by EE in APPSw,Ind mice. These results suggest that promoting the survival and maturation of adult generated newborn neurons in the hippocampus may contribute to cognitive benefits in AD mouse models

When Are New Hippocampal Neurons, Born in the Adult Brain, Integrated into the Network That Processes Spatial Information?

Adult-born neurons in the dentate gyrus (DG) functionally integrate into the behaviorally relevant hippocampal networks, showing a specific Arc-expression response to spatial exploration when mature. However, it is not clear when, during the 4- to 6-week interval that is critical for survival and maturation of these neurons, this specific response develops. Therefore, we characterized Arc expression after spatial exploration or cage control conditions in adult-born neurons from rats that were injected with BrdU on one day and were sacrificed 1, 7, 15, 30, and 45 days post-BrdU injection (PBI). Triple immunostaining for NeuN, Arc, and BrdU was analyzed through the different DG layers. Arc protein expression in BrdU-positive cells was observed from day 1 to day 15 PBI but was not related to behavioral stimulation. The specific Arc-expression response to spatial exploration was observed from day 30 and 45 in about 5% of the BrdU-positive cell population. Most of the BrdU-positive neurons expressing Arc in response to spatial exploration (∼90%) were located in DG layer 1, and no Arc expression was observed in cells located in the subgranular zone (SGZ). Using the current data and that obtained previously, we propose a mathematical model suggesting that new neurons are unlikely to respond to exploration by expressing Arc after they are 301 days old, and also that in a 7-month-old rat the majority (60%) of the neurons that respond to exploration must have been born during adulthood; thus, suggesting that adult neurogenesis in the DG is highly relevant for spatial information processing

Effects of Enriched Physical and Social Environments on Motor Performance, Associative Learning, and Hippocampal Neurogenesis in Mice

We have studied the motor abilities and associative learning capabilities of adult mice placed in different enriched environments. Three-month-old animals were maintained for a month alone (AL), alone in a physically enriched environment (PHY), and, finally, in groups in the absence (SO) or presence (SOPHY) of an enriched environment. The animals' capabilities were subsequently checked in the rotarod test, and for classical and instrumental learning. The PHY and SOPHY groups presented better performances in the rotarod test and in the acquisition of the instrumental learning task. In contrast, no significant differences between groups were observed for classical eyeblink conditioning. The four groups presented similar increases in the strength of field EPSPs (fEPSPs) evoked at the hippocampal CA3-CA1 synapse across classical conditioning sessions, with no significant differences between groups. These trained animals were pulse-injected with bromodeoxyuridine (BrdU) to determine hippocampal neurogenesis. No significant differences were found in the number of NeuN/BrdU double-labeled neurons. We repeated the same BrdU study in one-month-old mice raised for an additional month in the above-mentioned four different environments. These animals were not submitted to rotarod or conditioned tests. Non-trained PHY and SOPHY groups presented more neurogenesis than the other two groups. Thus, neurogenesis seems to be related to physical enrichment at early ages, but not to learning acquisition in adult mice

An evaluation of gender equity in different models of primary care practices in Ontario

Background: The World Health Organization calls for more work evaluating the effect of health care reforms on gender equity in developed countries. We performed this evaluation in Ontario, Canada where primary care models resulting from reforms co-exist. // Methods: This cross sectional study of primary care practices uses data collected in 2005-2006. Healthcare service models included in the study consist of fee for service (FFS) based, salaried, and capitation based. We compared the quality of care delivered to women and men in practices of each model. We performed multi-level, multivariate regressions adjusting for patient socio-demographic and economic factors to evaluate vertical equity, and adjusting for these and health factors in evaluating horizontal equity. We measured seven dimensions of health service delivery (e.g. accessibility and continuity) and three dimensions of quality of care using patient surveys (n = 5,361) and chart abstractions (n = 4,108). // Results: Health service delivery measures were comparable in women and men, with differences ≤ 2.2% in all seven dimensions and in all models. Significant gender differences in the health promotion subjects addressed were observed. Female specific preventive manoeuvres were more likely to be performed than other preventive care. Men attending FFS practices were more likely to receive influenza immunization than women (Adjusted odds ratio: 1.75, 95% confidence intervals (CI) 1.05, 2.92). There was no difference in the other three prevention indicators. FFS practices were also more likely to provide recommended care for chronic diseases to men than women (Adjusted difference of -11.2%, CI -21.7, -0.8). A similar trend was observed in Community Health Centers (CHC). // Conclusions: The observed differences in the type of health promotion subjects discussed are likely an appropriate response to the differential healthcare needs between genders. Chronic disease care is non equitable in FFS but not in capitation based models. We recommend that efforts to monitor and address gender based differences in the delivery of chronic disease management in primary care be pursued.Funding for the original study on which this research is based was provided by the Ontario Ministry of Health and Long Term Care Primary Health Care Transition Fund. The views expressed in this report are the views of the authors and do not necessarily reflect those of the Ontario Ministry of Health and Long Term Care

Aggravation of Chronic Stress Effects on Hippocampal Neurogenesis and Spatial Memory in LPA1 Receptor Knockout Mice

The lysophosphatidic acid LPA₁ receptor regulates plasticity and neurogenesis in the adult hippocampus. Here, we studied whether absence of the LPA₁ receptor modulated the detrimental effects of chronic stress on hippocampal neurogenesis and spatial memory.Male LPA₁-null (NULL) and wild-type (WT) mice were assigned to control or chronic stress conditions (21 days of restraint, 3 h/day). Immunohistochemistry for bromodeoxyuridine and endogenous markers was performed to examine hippocampal cell proliferation, survival, number and maturation of young neurons, hippocampal structure and apoptosis in the hippocampus. Corticosterone levels were measured in another a separate cohort of mice. Finally, the hole-board test assessed spatial reference and working memory. Under control conditions, NULL mice showed reduced cell proliferation, a defective population of young neurons, reduced hippocampal volume and moderate spatial memory deficits. However, the primary result is that chronic stress impaired hippocampal neurogenesis in NULLs more severely than in WT mice in terms of cell proliferation; apoptosis; the number and maturation of young neurons; and both the volume and neuronal density in the granular zone. Only stressed NULLs presented hypocortisolemia. Moreover, a dramatic deficit in spatial reference memory consolidation was observed in chronically stressed NULL mice, which was in contrast to the minor effect observed in stressed WT mice.These results reveal that the absence of the LPA₁ receptor aggravates the chronic stress-induced impairment to hippocampal neurogenesis and its dependent functions. Thus, modulation of the LPA₁ receptor pathway may be of interest with respect to the treatment of stress-induced hippocampal pathology

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV

Perinatal asphyxia: current status and approaches towards neuroprotective strategies, with focus on sentinel proteins

Delivery is a stressful and risky event menacing the newborn. The mother-dependent respiration has to be replaced by autonomous pulmonary breathing immediately after delivery. If delayed, it may lead to deficient oxygen supply compromising survival and development of the central nervous system. Lack of oxygen availability gives rise to depletion of NAD+ tissue stores, decrease of ATP formation, weakening of the electron transport pump and anaerobic metabolism and acidosis, leading necessarily to death if oxygenation is not promptly re-established. Re-oxygenation triggers a cascade of compensatory biochemical events to restore function, which may be accompanied by improper homeostasis and oxidative stress. Consequences may be incomplete recovery, or excess reactions that worsen the biological outcome by disturbed metabolism and/or imbalance produced by over-expression of alternative metabolic pathways. Perinatal asphyxia has been associated with severe neurological and psychiatric sequelae with delayed clinical onset. No specific treatments have yet been established. In the clinical setting, after resuscitation of an infant with birth asphyxia, the emphasis is on supportive therapy. Several interventions have been proposed to attenuate secondary neuronal injuries elicited by asphyxia, including hypothermia. Although promising, the clinical efficacy of hypothermia has not been fully demonstrated. It is evident that new approaches are warranted. The purpose of this review is to discuss the concept of sentinel proteins as targets for neuroprotection. Several sentinel proteins have been described to protect the integrity of the genome (e.g. PARP-1; XRCC1; DNA ligase IIIα; DNA polymerase β, ERCC2, DNA-dependent protein kinases). They act by eliciting metabolic cascades leading to (i) activation of cell survival and neurotrophic pathways; (ii) early and delayed programmed cell death, and (iii) promotion of cell proliferation, differentiation, neuritogenesis and synaptogenesis. It is proposed that sentinel proteins can be used as markers for characterising long-term effects of perinatal asphyxia, and as targets for novel therapeutic development and innovative strategies for neonatal care