More than 200 million people are at risk for schistosomiasis globally. Despite the availability of safe and effective therapeutics, the optimal approach for treating those at risk remains unclear. ...Presently, the WHO guidelines recommend mass drug administration (MDA) with praziquantel in endemic communities, with a focus on reducing the prevalence of high-intensity infections. With this approach, individuals aged 4 years and older are offered treatment either in their communities or at schools, with the frequency of MDA determined by community prevalence of infection. Many gaps remain, however, with respect to the optimal frequency of MDA and the target populations within endemic communities. Here, the report by collaborators from Kenya and Tanzania which provide combined results from key studies funded by the Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) is discussed.
Objective
Numerous studies have demonstrated increased load of de novo copy number variants or single nucleotide variants in individuals with neurodevelopmental disorders, including epileptic ...encephalopathies, intellectual disability, and autism.
Methods
We searched for de novo mutations in a family quartet with a sporadic case of epileptic encephalopathy with no known etiology to determine the underlying cause using high‐coverage whole exome sequencing (WES) and lower‐coverage whole genome sequencing. Mutations in additional patients were identified by WES. The effect of mutations on protein function was assessed in a heterologous expression system.
Results
We identified a de novo missense mutation in KCNB1 that encodes the KV2.1 voltage‐gated potassium channel. Functional studies demonstrated a deleterious effect of the mutation on KV2.1 function leading to a loss of ion selectivity and gain of a depolarizing inward cation conductance. Subsequently, we identified 2 additional patients with epileptic encephalopathy and de novo KCNB1 missense mutations that cause a similar pattern of KV2.1 dysfunction.
Interpretation
Our genetic and functional evidence demonstrate that KCNB1 mutation can result in early onset epileptic encephalopathy. This expands the locus heterogeneity associated with epileptic encephalopathies and suggests that clinical WES may be useful for diagnosis of epileptic encephalopathies of unknown etiology. Ann Neurol 2014;76:529–540
We performed this study to longitudinally compare rates of stunting, wasting and underweight among low birthweight (LBW), non-LBW, and/or small-for-gestational age (SGA) and non-SGA infants in Leyte, ...The Philippines and factors that predicted catch up. Birthweights of 357 infants born in Leyte, The Philippines were obtained within 48 hours of delivery and infants were evaluated at one, six and 12 months. Newborns were classified as LBW, SGA, or both. We derived length-for-age, weight-for-length and weight-for-age Z-scores using WHOAnthro. Generalized estimating equations models were used to compare the differences in prevalence and mean Z-scores for these growth and nutritional outcomes, with separate models made with LBW and SGA as distinct primary predictors. We compared the longitudinal risk of stunting, wasting and underweight during infancy among LBW versus non-LBW and SGA versus non-SGA infants, while also evaluating key potential confounding, explanatory and modifying covariates. Overall, 9.0% of infants were born prematurely, 14.0% of infants were LBW and 22.9% were SGA. LBW infants had significantly increased odds of stunting, wasting and underweight persisting to 12 months of age, and SGA infants had significantly increased odds of stunting and underweight. LBW and SGA infants had higher rates of weight-for-length gain in the first month of life. Maternal educational attainment and exclusive breastfeeding decreased the risk of stunting and undernutrition. In this setting, LBW and SGA infants have higher rates of growth stunting and undernutrition during the first year of life and do not exhibit catch-up growth by 12 months of age. Clinical Trial Registration NCT00486863
Periportal fibrosis is a late-stage manifestation of chronic infection with Schistosoma mansoni . Praziquantel (PZQ), the only drug available for the treatment of schistosomiasis, has limited effect ...in treating established morbidity. Preschool-age children (PSAC) are not considered to be an at-risk population for severe morbidity. However, the prevalence of periportal fibrosis in PSAC in S. mansoni endemic settings is unknown.
As part of a phase II clinical trial comparing different dosing regimens of PZQ in children age 12-47 months infected with S. mansoni in Uganda ("praziquantel in preschoolers" trial), we present baseline results assessing liver ultrasound (US) findings as per the WHO Niamey Protocol.
A total of 7/347 (2%) PSAC had Image Pattern C with pipe stems and echogenic rings suggestive of periportal fibrosis, 29/347 (8%) had Image Pattern B and 58 (17%) had evidence of periportal thickening There were higher adjusted odds of periportal thickening with older age odds ratio (OR): 1.04; 95% confidence interval (CI): 1.00-1.07, primary maternal education (OR: 1.04; 95% CI: 1.00-1.07) and being taken to the lake weekly (OR: 3.02; 95% CI: 1.19-7.63). A further 44/347 children (13%) had a rounded caudal liver edge which was associated with high S. mansoni infection intensity (adjusted OR: 3.31; 95% CI: 1.46-7.51).
Incipient schistosomiasis-related liver morbidity was detected in young children enrolled in the praziquantel in preschoolers trial. Adequate age-adjusted reference measurements for liver ultrasound findings in very small children are lacking but urgently needed. Schistosomiasis-related fibrosis may be delayed or averted with early and repeated PZQ treatment.
An update on anemia in less developed countries Tolentino, Karine; Friedman, Jennifer F
The American journal of tropical medicine and hygiene,
07/2007, Letnik:
77, Številka:
1
Journal Article
Recenzirano
The highest prevalence of anemia exists in the developing world where its causes are multi-factorial. Anemia is responsible for significant morbidity and mortality, particularly in less developed ...countries (LDCs). Understanding causes of anemia and potential mechanisms are crucial to our ability to intervene to reduce this burden. In the past decade, our understanding of the etiology and mechanisms of anemia in LDCs has advanced significantly. This review will focus on recent advances in our understanding of the burden of anemia in specific sub-groups, the causes and mechanisms of anemia, and consequences of anemia for the human host.
The IMCI is one of WHO/UNICEF's most successful strategies in reducing mortality in children under five years of age 7. Since it was first conceived in 1997, it has provided over 75 countries with ...easy-to-use tools for primary care health workers to promptly identify and treat life-threatening conditions such as pneumonia, diarrhea, malaria, measles, and malnutrition. ...the surplus from MDA programs could be given to health centers to allow year-round continuity of treatment.
•Placental cytokines are linked with neurocognitive development in offspring.•The effect of placental cytokines was partly mediated by DHEA-S in cord blood.•SES moderated the mediation effect of ...fetal DHEA-S on cognitive development.•Interventions to enhance LMIC’s children’s development should improve prenatal care.
Prenatal exposure to inflammation is related to the risk for cognitive impairment in offspring. However, mechanisms underlying the link between inflammatory cytokines at the maternal-fetal interface and human cognitive development are largely unknown. This study addressed this research gap by examining whether i) cytokines within the placenta are associated with different domains of neurocognitive development during infancy, and ii) if DHEA-S in cord blood mediates these associations. We also explored the role of early-life socioeconomic status (SES) in moderating the effect of fetal adrenal steroids on cognitive development in low- and middle-income country contexts. A cohort of 242 mother-infant dyads in Leyte, the Philippines participated in the study and all of them were followed from early pregnancy until 12-months. Concentrations of pro- and anti-inflammatory cytokines in the placenta, and DHEA-S in cord blood collected at delivery were evaluated. The multifactorial aspects of the infant’s cognitive functioning were assessed based on the Bayley Scales of Infant Development, third edition (BSID-III). We used Structural Equation Modelling (SEM) with an orthogonal rotation to examine associated paths among latent variables of pro- and anti-inflammatory cytokines in the placenta, fetal neuroendocrine factors, and cognitive development. Pathway analyses showed that both pro- and anti-inflammatory cytokines in the placenta were indirectly related to cognitive (p < 0.05) and language developmental outcomes (p < 0.1) via DHEA-S in cord blood among the low SES group. Yet, we found no statistically significant indirect effect of pro- or anti-inflammatory cytokines on neurocognitive development among the high SES sub-sample. This study extends our understanding of how early-life socioeconomic conditions modify biological pathways underlying the relationship between prenatal factors and postpartum cognitive development.
Schistosoma japonicum is endemic in the Philippines. The Kato-Katz (KK) method was used to diagnose S. japonicum. This is impractical, particularly when the sample size is limited. Knowledge on ...point-of-care circulating cathodic antigen (CCA) test performance for S. japonicum is limited. Determining the sensitivity and specificity of new diagnostics is difficult when the gold standard test is less effective or absent. Latent class analysis (LCA) can address some limitations. A total of 484 children and 572 adults from the Philippines were screened for S. japonicum. We performed Bayesian LCA to estimate the infection prevalence, sensitivity and specificity of each test by stratifying them into two age groups. Observed prevalence assessed by KK was 50.2% and 31.8%, and by CCA was 89.9% and 66.8%, respectively. Using Bayesian LCA, among children, the sensitivity and specificity of CCA were 94.8% (88.7-99.4) and 21.5% (10.5-36.1) while those of KK were 66.0% (54.2-83.3) and 78.1% (61.1-91.3). Among adults, the sensitivity and specificity of CCA were 86.4% (76.6-96.9) and 62.8% (49.1-81.1) while those of KK were 43.6% (35.1-53.9) and 85.5% (75.8-94.6). Overall, CCA was more sensitive than KK, regardless of the age group at diagnosis, as KK was more specific. KK and CCA have different diagnostic performance, which should inform their use in the planning and implementation of S. japonicum control programs.
Glutathione peroxidase 4 (GPX4), as the only enzyme in mammals capable of reducing esterified phospholipid hydroperoxides within a cellular context, protects cells from ferroptosis. We identified a ...homozygous point mutation in the GPX4 gene, resulting in an R152H coding mutation, in three patients with Sedaghatian-type spondylometaphyseal dysplasia. Using structure-based analyses and cell models, including patient fibroblasts, of this variant, we found that the missense variant destabilized a critical loop, which disrupted the active site and caused a substantial loss of enzymatic function. We also found that the R152H variant of GPX4 is less susceptible to degradation, revealing the degradation mechanism of the GPX4 protein. Proof-of-concept therapeutic treatments, which overcome the impaired R152H GPX4 activity, including selenium supplementation, selective antioxidants and a deuterated polyunsaturated fatty acid were identified. In addition to revealing a general approach to investigating rare genetic diseases, we demonstrate the biochemical foundations of therapeutic strategies targeting GPX4.
Abstract
Undernutrition is responsible for up to 45% of deaths in children under five, with low- and middle-income countries disproportionately affected. Adipokines are known modulators of metabolism ...and have been linked to growth rates and neurocognition during infancy. We examined the relationship(s) between cord blood adiponectin and leptin and both longitudinal growth and cognition during the first year of life using generalized estimating equations. Infants were classified as underweight (weight-for-age z-score WAZ), stunted (height-for-age z-score HAZ) or wasted (weight-for-height z-score WHZ) using WHOAnthro software. Cord blood adiponectin and leptin levels were highly correlated (r = 0.35, P < 0.0001) and positively associated with birth WAZ (r = 0.34 and r = 0.45, P < 0.0001, respectively). Adipokines were independently, inversely associated with weight gain. Infants in the highest quintile of adipokine production had a lower risk of being stunted, while neither was associated with lower WAZ or WHZ in final adjusted models. Cognition was not found to be independently related to cord blood leptin or adiponectin. The negative association with adipokines and rate of weight gain during infancy may reflect heightened nutritional status at birth rather than a direct hormonal influence. The relationship between leptin or adiponectin and longitudinal length gains suggests that both adipokines may promote linear growth during infancy.
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