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Although 80% of children with disabilities live in developing countries, there are few culturally appropriate developmental assessment tools available for these settings. Often tools from the West provide misleading findings in different cultural settings, where some items are unfamiliar and reference values are different from those of Western populations. Following preliminary and qualitative studies, we produced a draft developmental assessment tool with 162 items in four domains of development. After face and content validity testing and piloting, we expanded the draft tool to 185 items. We then assessed 1,426 normal rural children aged 0-6 y from rural Malawi and derived age-standardized norms for all items. We examined performance of items using logistic regression and reliability using kappa statistics. We then considered all items at a consensus meeting and removed those performing badly and those that were unnecessary or difficult to administer, leaving 136 items in the final Malawi Developmental Assessment Tool (MDAT). We validated the tool by comparing age-matched normal children with those with malnutrition (120) and neurodisabilities (80). Reliability was good for items remaining with 94%-100% of items scoring kappas >0.4 for interobserver immediate, delayed, and intra-observer testing. We demonstrated significant differences in overall mean scores (and individual domain scores) for children with neurodisabilities (35 versus 99 [p<0.001]) when compared to normal children. Using a pass/fail technique similar to the Denver II, 3% of children with neurodisabilities passed in comparison to 82% of normal children, demonstrating good sensitivity (97%) and specificity (82%). Overall mean scores of children with malnutrition (weight for height <80%) were also significantly different from scores of normal controls (62.5 versus 77.4 [p<0.001]); scores in the separate domains, excluding social development, also differed between malnourished children and controls. In terms of pass/fail, 28% of malnourished children versus 94% of controls passed the test overall. A culturally relevant developmental assessment tool, the MDAT, has been created for use in African settings and shows good reliability, validity, and sensitivity for identification of children with neurodisabilities.

Recent reports have indicated that microRNAs (miRNAs) play a critical role in malignancies, and regulations in the progress of adult leukemia. The role of miRNAs in pediatric leukemia still needs to be established. The purpose of this study was to investigate the aberrantly expressed miRNAs in pediatric acute leukemia and demonstrate miRNA patterns that are pediatric-specific and prognostic parameter-associated. A total of 111 pediatric bone marrow samples, including 99 patients and 12 normal donors, were enrolled in this study. Of those samples, 36 patients and 7 normal samples were used as a test cohort for the evaluation of miRNA profiling; 63 pediatric patients and 5 normal donors were used as a validation cohort to confirm the miRNA differential expression. Pediatric ALL- and AML-specific microRNA expression patterns were identified in this study. The most highly expressed miRNAs in pediatric ALL were miR-34a, miR-128a, miR-128b, and miR-146a, while the highly expressed miRNAs in pediatric AML were miR-100, miR-125b, miR-335, miR-146a, and miR-99a, which are significantly different from those reported for adult CLL and AML. miR-125b and miR-126 may serve as favorable prognosticators for M3 and M2 patients, respectively. Importantly, we identified a \"miRNA cascade\" associated with central nervous system (CNS) relapse in ALL. Additionally, miRNA patterns associated with prednisone response, specific risk group, and relapse of ALL were also identified. There are existing pediatric-associated and prognostic parameter-associated miRNAs that are independent of cell lineage and could provide therapeutic direction for individual risk-adapted therapy for pediatric leukemia patients.

The risk of indoor exposure to volatile organic compounds (VOCs) on allergic airway diseases in children remains unknown. We examined the residential concentrations of VOCs, emitted from building materials, paints, furniture, and other lifestyle practices and the risks of multiple allergic diseases as well as the IgE-sensitization in pre-school age children in Sweden. In a case-control investigation (198 case children with asthma and allergy and 202 healthy controls), air samples were collected in the room where the child slept. The air samples were analyzed for the levels of eight classes of VOCs. A natural-log unit of summed propylene glycol and glycol ethers (PGEs) in bedroom air (equal to interquartile range, or 3.43 - 15.65 µg/m(3)) was associated with 1.5-fold greater likelihood of being a case (95% CI, 1.1 - 2.1), 1.5-fold greater likelihood of asthma (95% CI, 1.0 - 2.3), 2.8-fold greater likelihood of rhinitis (95% CI, 1.6 - 4.7), and 1.6-fold greater likelihood of eczema (95% CI, 1.1 - 2.3), accounting for gender, secondhand smoke, allergies in both parents, wet cleaning with chemical agents, construction period of the building, limonene, cat and dog allergens, butyl benzyl phthalate (BBzP), and di(2-ethylhexyl)phthalate (DEHP). When the analysis was restricted to the cases, the same unit concentration was associated with 1.8-fold greater likelihood of IgE-sensitization (95% CI, 1.1 - 2.8) compared to the non-IgE sensitized cases. No similar associations were found for the other classes of VOCs. We propose a novel hypothesis that PGEs in indoor air exacerbate and/or induce the multiple allergic symptoms, asthma, rhinitis and eczema, as well as IgE sensitization respectively.

Lead is highly toxic to animals. Humans eating game killed using lead ammunition generally avoid swallowing shot or bullets and dietary lead exposure from this source has been considered low. Recent evidence illustrates that lead bullets fragment on impact, leaving small lead particles widely distributed in game tissues. Our paper asks whether lead gunshot pellets also fragment upon impact, and whether lead derived from spent gunshot and bullets in the tissues of game animals could pose a threat to human health. Wild-shot gamebirds (6 species) obtained in the UK were X-rayed to determine the number of shot and shot fragments present, and cooked using typical methods. Shot were then removed to simulate realistic practice before consumption, and lead concentrations determined. Data from the Veterinary Medicines Directorate Statutory Surveillance Programme documenting lead levels in raw tissues of wild gamebirds and deer, without shot being removed, are also presented. Gamebirds containing > or =5 shot had high tissue lead concentrations, but some with fewer or no shot also had high lead concentrations, confirming X-ray results indicating that small lead fragments remain in the flesh of birds even when the shot exits the body. A high proportion of samples from both surveys had lead concentrations exceeding the European Union Maximum Level of 100 ppb w.w. (0.1 mg kg(-1) w.w.) for meat from bovine animals, sheep, pigs and poultry (no level is set for game meat), some by several orders of magnitude. High, but feasible, levels of consumption of some species could result in the current FAO/WHO Provisional Weekly Tolerable Intake of lead being exceeded. The potential health hazard from lead ingested in the meat of game animals may be larger than previous risk assessments indicated, especially for vulnerable groups, such as children, and those consuming large amounts of game.

Postnatal glucocorticoid therapy in premature infants diminishes chronic lung disease, but it also increases the risk of hypertension in adulthood. Since glucocorticoid excess leads to overproduction of free radicals and endothelial dysfunction, this study tested the hypothesis that adverse effects on cardiovascular function of postnatal glucocorticoids are secondary to oxidative stress. Therefore, combined postnatal treatment of glucocorticoids with antioxidants may diminish unwanted effects. Male rat pups received a course of dexamethasone (Dex), or Dex with vitamins C and E (DexCE), on postnatal days 1-6 (P1-6). Controls received vehicle (Ctrl) or vehicle with vitamins (CtrlCE). At P21, femoral vascular reactivity was determined via wire myography. Dex, but not DexCE or CtrlCE, increased mortality relative to Ctrl (81.3 versus 96.9 versus 90.6 versus 100% survival, respectively; P<0.05). Constrictor responses to phenylephrine (PE) and thromboxane were enhanced in Dex relative to Ctrl (84.7+/-4.8 versus 67.5+/-5.7 and 132.7+/-4.9 versus 107.0+/-4.9% Kmax, respectively; P<0.05); effects that were diminished in DexCE (58.3+/-7.5 and 121.1+/-4.3% Kmax, respectively; P<0.05). Endothelium-dependent dilatation was depressed in Dex relative to Ctrl (115.3+/-11.9 versus 216.9+/-18.9, AUC; P<0.05); however, this effect was not restored in DexCE (68.3+/-8.3, AUC). Relative to Ctrl, CtrlCE alone diminished PE-induced constriction (43.4+/-3.7% Kmax) and the endothelium-dependent dilatation (74.7+/-8.7 AUC; P<0.05). Treatment of newborn rats with dexamethasone has detrimental effects on survival and peripheral vasoconstrictor function. Coadministration of dexamethasone with antioxidant vitamins improves survival and partially restores vascular dysfunction. Antioxidant vitamins alone affect peripheral vascular function.

Currently, a limited range of biochemical tests for hypoxia are in clinical use. Early diagnostic and functional biomarkers that mirror cellular metabolism and recovery during resuscitation are lacking. We hypothesized that the quantification of metabolites after hypoxia and resuscitation would enable the detection of markers of hypoxia as well as markers enabling the monitoring and evaluation of resuscitation strategies. Hypoxemia of different durations was induced in newborn piglets before randomization for resuscitation with 21% or 100% oxygen for 15 min or prolonged hyperoxia. Metabolites were measured in plasma taken before and after hypoxia as well as after resuscitation. Lactate, pH and base deficit did not correlate with the duration of hypoxia. In contrast to these, we detected the ratios of alanine to branched chained amino acids (Ala/BCAA; R(2).adj = 0.58, q-value<0.001) and of glycine to BCAA (Gly/BCAA; R(2).adj = 0.45, q-value<0.005), which were highly correlated with the duration of hypoxia. Combinations of metabolites and ratios increased the correlation to R(2)adjust = 0.92. Reoxygenation with 100% oxygen delayed cellular metabolic recovery. Reoxygenation with different concentrations of oxygen reduced lactate levels to a similar extent. In contrast, metabolites of the Krebs cycle (which is directly linked to mitochondrial function) including alpha keto-glutarate, succinate and fumarate were significantly reduced at different rates depending on the resuscitation, showing a delay in recovery in the 100% reoxygenation groups. Additional metabolites showing different responses to reoxygenation include oxysterols and acylcarnitines (n = 8-11, q<0.001). This study provides a novel strategy and set of biomarkers. It provides biochemical in vivo data that resuscitation with 100% oxygen delays cellular recovery. In addition, the oxysterol increase raises concerns about the safety of 100% O(2) resuscitation. Our biomarkers can be used in a broad clinical setting for evaluation or the prediction of damage in conditions associated with low tissue oxygenation in both infancy and adulthood. These findings have to be validated in human trials.

Birth asphyxia kills 0.7 to 1.6 million newborns a year globally with 99% of deaths in developing countries. Effective newborn resuscitation could reduce this burden of disease but the training of health-care providers in low income settings is often outdated. Our aim was to determine if a simple one day newborn resuscitation training (NRT) alters health worker resuscitation practices in a public hospital setting in Kenya. We conducted a randomised, controlled trial with health workers receiving early training with NRT (n = 28) or late training (the control group, n = 55). The training was adapted locally from the approach of the UK Resuscitation Council. The primary outcome was the proportion of appropriate initial resuscitation steps with the frequency of inappropriate practices as a secondary outcome. Data were collected on 97 and 115 resuscitation episodes over 7 weeks after early training in the intervention and control groups respectively. Trained providers demonstrated a higher proportion of adequate initial resuscitation steps compared to the control group (trained 66% vs control 27%; risk ratio 2.45, [95% CI 1.75-3.42], p<0.001, adjusted for clustering). In addition, there was a statistically significant reduction in the frequency of inappropriate and potentially harmful practices per resuscitation in the trained group (trained 0.53 vs control 0.92; mean difference 0.40, [95% CI 0.13-0.66], p = 0.004). Implementation of a simple, one day newborn resuscitation training can be followed immediately by significant improvement in health workers' practices. However, evidence of the effects on long term performance or clinical outcomes can only be established by larger cluster randomised trials. Controlled-Trials.com ISRCTN92218092.

Childhood anaemia is considered a severe public health problem in most countries of sub-Saharan Africa. We investigated the geographical distribution of prevalence of anaemia and mean haemoglobin concentration (Hb) in children aged 1-4 y (preschool children) in West Africa. The aim was to estimate the geographical risk profile of anaemia accounting for malnutrition, malaria, and helminth infections, the risk of anaemia attributable to these factors, and the number of anaemia cases in preschool children for 2011. National cross-sectional household-based demographic health surveys were conducted in 7,147 children aged 1-4 y in Burkina Faso, Ghana, and Mali in 2003-2006. Bayesian geostatistical models were developed to predict the geographical distribution of mean Hb and anaemia risk, adjusting for the nutritional status of preschool children, the location of their residence, predicted Plasmodium falciparum parasite rate in the 2- to 10-y age group (Pf PR(2-10)), and predicted prevalence of Schistosoma haematobium and hookworm infections. In the four countries, prevalence of mild, moderate, and severe anaemia was 21%, 66%, and 13% in Burkina Faso; 28%, 65%, and 7% in Ghana, and 26%, 62%, and 12% in Mali. The mean Hb was lowest in Burkina Faso (89 g/l), in males (93 g/l), and for children 1-2 y (88 g/l). In West Africa, severe malnutrition, Pf PR(2-10), and biological synergisms between S. haematobium and hookworm infections were significantly associated with anaemia risk; an estimated 36.8%, 14.9%, 3.7%, 4.2%, and 0.9% of anaemia cases could be averted by treating malnutrition, malaria, S. haematobium infections, hookworm infections, and S. haematobium/hookworm coinfections, respectively. A large spatial cluster of low mean Hb (<80 g/l) and maximal risk of anaemia (>95%) was predicted for an area shared by Burkina Faso and Mali. We estimate that in 2011, approximately 6.7 million children aged 1-4 y are anaemic in the three study countries. By mapping the distribution of anaemia risk in preschool children adjusted for malnutrition and parasitic infections, we provide a means to identify the geographical limits of anaemia burden and the contribution that malnutrition and parasites make to anaemia. Spatial targeting of ancillary micronutrient supplementation and control of other anaemia causes, such as malaria and helminth infection, can contribute to efficiently reducing the burden of anaemia in preschool children in Africa.

Zinc (Zn) is an essential trace element and it is abundant in connective tissues, however biological roles of Zn and its transporters in those tissues and cells remain unknown. Here we report that mice deficient in Zn transporter Slc39a13/Zip13 show changes in bone, teeth and connective tissue reminiscent of the clinical spectrum of human Ehlers-Danlos syndrome (EDS). The Slc39a13 knockout (Slc39a13-KO) mice show defects in the maturation of osteoblasts, chondrocytes, odontoblasts, and fibroblasts. In the corresponding tissues and cells, impairment in bone morphogenic protein (BMP) and TGF-beta signaling were observed. Homozygosity for a SLC39A13 loss of function mutation was detected in sibs affected by a unique variant of EDS that recapitulates the phenotype observed in Slc39a13-KO mice. Hence, our results reveal a crucial role of SLC39A13/ZIP13 in connective tissue development at least in part due to its involvement in the BMP/TGF-beta signaling pathways. The Slc39a13-KO mouse represents a novel animal model linking zinc metabolism, BMP/TGF-beta signaling and connective tissue dysfunction.

Most extremely preterm newborns exhibit cerebral atrophy/growth disturbances and white matter signal abnormalities on MRI at term-equivalent age. MRI brain volumes could serve as biomarkers for evaluating the effects of neonatal intensive care and predicting neurodevelopmental outcomes. This requires detailed, accurate, and reliable brain MRI segmentation methods. We describe our efforts to develop such methods in high risk newborns using a combination of manual and automated segmentation tools. After intensive efforts to accurately define structural boundaries, two trained raters independently performed manual segmentation of nine subcortical structures using axial T2-weighted MRI scans from 20 randomly selected extremely preterm infants. All scans were re-segmented by both raters to assess reliability. High intra-rater reliability was achieved, as assessed by repeatability and intra-class correlation coefficients (ICC range: 0.97 to 0.99) for all manually segmented regions. Inter-rater reliability was slightly lower (ICC range: 0.93 to 0.99). A semi-automated segmentation approach was developed that combined the parametric strengths of the Hidden Markov Random Field Expectation Maximization algorithm with non-parametric Parzen window classifier resulting in accurate white matter, gray matter, and CSF segmentation. Final manual correction of misclassification errors improved accuracy (similarity index range: 0.87 to 0.89) and facilitated objective quantification of white matter signal abnormalities. The semi-automated and manual methods were seamlessly integrated to generate full brain segmentation within two hours. This comprehensive approach can facilitate the evaluation of large cohorts to rigorously evaluate the utility of regional brain volumes as biomarkers of neonatal care and surrogate endpoints for neurodevelopmental outcomes.