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Chen Z.,Johns Hopkins University | Myers R.,Metals USA | Wei T.,Metals USA | Bind E.,Metals USA | And 11 more authors.
Journal of Exposure Science and Environmental Epidemiology | Year: 2014

There is an emerging hypothesis that exposure to cadmium (Cd), mercury (Hg), lead (Pb), and selenium (Se) in utero and early childhood could have long-term health consequences. However, there are sparse data on early life exposures to these elements in US populations, particularly in urban minority samples. This study measured levels of Cd, Hg, Pb, and Se in 50 paired maternal, umbilical cord, and postnatal blood samples from the Boston Birth Cohort (BBC). Maternal exposure to Cd, Hg, Pb, and Se was 100% detectable in red blood cells (RBCs), and there was a high degree of maternal-fetal transfer of Hg, Pb, and Se. In particular, we found that Hg levels in cord RBCs were 1.5 times higher than those found in the mothers. This study also investigated changes in concentrations of Cd, Hg, Pb, and Se during the first few years of life. We found decreased levels of Hg and Se but elevated Pb levels in early childhood. Finally, this study investigated the association between metal burden and preterm birth and low birthweight. We found significantly higher levels of Hg in maternal and cord plasma and RBCs in preterm or low birthweight births, compared with term or normal birthweight births. In conclusion, this study showed that maternal exposure to these elements was widespread in the BBC, and maternal-fetal transfer was a major source of early life exposure to Hg, Pb, and Se. Our results also suggest that RBCs are better than plasma at reflecting the trans-placental transfer of Hg, Pb, and Se from the mother to the fetus. Our study findings remain to be confirmed in larger studies, and the implications for early screening and interventions of preconception and pregnant mothers and newborns warrant further investigation. © 2014 Nature America, Inc. All rights reserved. Source

Guay J.,Universite de Sherbrooke | Suresh S.,Ann And Robert rie Childrens Hospital Of Chicago Research Center | Kopp S.,Rochester College
Cochrane Database of Systematic Reviews | Year: 2016

Background: The use of ultrasound guidance for regional anaesthesia has become popular over the past two decades. However, it is not recognized by all experts as an essential tool. The cost of an ultrasound machine is substantially higher than the cost of other tools such as a nerve stimulator. Objectives: To determine whether ultrasound guidance offers any clinical advantage when neuraxial and peripheral nerve blocks are performed in children in terms of increasing the success rate or decreasing the rate of complications. Search methods: We searched the following databases to March 2015: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OvidSP), EMBASE (OvidSP) and Scopus (from inception to 27 January 2015). Selection criteria: We included all parallel randomized controlled trials (RCTs) that evaluated the effects of ultrasound guidance used when a regional blockade technique was performed in children, and that included any of our selected outcomes. Data collection and analysis: We assessed selected studies for risk of bias by using the assessment tool of The Cochrane Collaboration. Two review authors independently extracted data. We graded the level of evidence for each outcome according to the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) Working Group scale. Main results: We included 20 studies (1241 participants) for which the source of funding was a government organization (two studies), a charitable organization (one study), an institutional department (four studies) or an unspecified source (11 studies); two studies declared that they received help from the industry (equipment loan). In 14 studies (939 participants), ultrasound guidance increased the success rate by decreasing the occurrence of a failed block: risk difference (RD) -0.11 (95% confidence interval (CI) -0.17 to -0.05); I2 = 64%; number needed for additional beneficial outcome for a peripheral nerve block (NNTB) 6 (95% CI 5 to 8). Blocks were performed under general anaesthesia (usual clinical practice in this population); therefore, haemodynamic changes to the surgical stimulus (rather than classic sensory/motor blockade evaluation) were used to define success. For peripheral nerve blocks, the younger the child, the greater was the benefit. In eight studies (414 participants), pain scores at one hour in the post-anaesthesia care unit were reduced when ultrasound guidance was used; however, the clinical relevance of the difference was unclear (equivalent to -0.2 on a scale from 0 to 10). In eight studies (358 participants), block duration was longer when ultrasound guidance was used: standardized mean difference (SMD) 1.21 (95% CI 0.76 to 1.65; I2 = 73%; equivalent to 62 minutes). Here again, younger children benefited most from ultrasound guidance. Time to perform the procedure was reduced when ultrasound guidance was used for pre-scanning before a neuraxial block (SMD -1.97, 95% CI -2.41 to -1.54; I2 = 0%; equivalent to 2.4 minutes; two studies with 122 participants) or as an out-of-plane technique (SMD -0.68, 95% CI -0.96 to -0.40; I2 = 0%; equivalent to 94 seconds; two studies with 204 participants). In two studies (122 participants), ultrasound guidance reduced the number of needle passes required to perform the block (SMD -0.90, 95% CI -1.27 to -0.52; I2 = 0%; equivalent to 0.6 needle pass per participant). For two studies (204 participants), we could not demonstrate a difference in the incidence of bloody puncture when ultrasound guidance was used for neuraxial blockade, but we found that the number of participants was well below the optimal information size (RD -0.07, 95% CI -0.19 to 0.04). No major complications were reported for any of the 1241 participants. We rated the quality of evidence as high for success, pain scores at one hour, block duration, time to perform the block and number of needle passes. We rated the quality of evidence as low for bloody punctures. Authors' conclusions: Ultrasound guidance seems advantageous, particularly in young children, for whom it improves the success rate and increases the block duration. Additional data are required before conclusions can be drawn on the effect of ultrasound guidance in reducing the rate of bloody puncture. © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Source

Martin A.,Oncology and Stem Cell Transplantation | Jones A.,Ann And Robert rie Childrens Hospital Of Chicago Research Center | Bryar P.J.,Northwestern University | Mets M.,Ann and Robert H. Lurie Childrens Hospital of Chicago | And 5 more authors.
Biochemical and Biophysical Research Communications | Year: 2013

Retinoblastoma is the most common pediatric cancer of the eye. Currently, the chemotherapeutic treatments for retinoblastoma are broad-based drugs such as vincristine, carboplatin, or etoposide. However, therapies targeted directly to aberrant signaling pathways may provide more effective therapy for this disease. The purpose of our study is to illustrate the relationship between the expressions of miRs-449a and -449b to retinoblastoma proliferation and apoptosis. We are the first to confirm an inhibitory effect of miR-449a and -449b in retinoblastoma by demonstrating significantly impaired proliferation and increased apoptosis of tumor cells when these miRNAs are overexpressed. This study suggests that these miRNAs could serve as viable therapeutic targets for retinoblastoma treatment. © 2013 Elsevier Inc. All rights reserved. Source

Rozen-Zvi B.,Northwestern University | Hayashida T.,Northwestern University | Hubchak S.C.,Northwestern University | Hanna C.,Northwestern University | And 5 more authors.
American Journal of Physiology - Renal Physiology | Year: 2013

Transforming growth factor (TGF)- β is a major mediator of kidney fibrosis. In the past decade it was recognized that, besides canonical Smad signaling, many other signaling pathways participate in the process of TGF- β - induced fibrogenesis. One such pathway involves mammalian target of rapamycin complex (mTORC)1. We recently reported that the hypoxia-inducible factor (HIF)-1 is essential for TGF- β -induced collagen expression regardless of ambient oxygen tension. A modulator of HIF expression other than oxygen tension is mTORC1. We therefore sought to evaluate a possible role for mTORC1 activity in TGF- β -induced fibrogenesis. mTORC1 activity was increased in human mesangial cells treated with TGF- β in a TGF- β receptordependent manner. Short hairpin (sh)RNA to Smad3 decreased, while overexpression of Smad3 increased, the mTORC1 activity, suggesting that TGF-β stimulation of mTORC1 also requires Smad3. Pretreatment with rapamycin or shRNA for a regulatory molecule of mTORC1, Raptor, reduced TGF- β -induced COL1A2-luc activity and collagen I protein expression. mTORC1 inhibition also prevented the TGF-β-stimulated increase in both hypoxia-responsive element (HRE) activity and HIF-1 protein expression, while activation of mTORC1 by active Rheb increased basal but not TGF--induced HRE activity. shRNA to Smad3 reduced HRE activity, while overexpression of Smad3 increased HIF-1 protein expression and activity in an mTORC1-dependent manner. Lastly, overexpression of HIF-1 bypassed the inhibitory effect of mTORC1 blockade on collagen expression. These results suggest that Smad3/mTORC1 interaction to promote HIF-1α expression is a key step in normoxic kidney fibrogenesis. Source

Heier C.R.,Center for Genetic Medicine Research | Heier C.R.,Northwestern University | Heier C.R.,Ann And Robert rie Childrens Hospital Of Chicago Research Center | DiDonato C.J.,Northwestern University | DiDonato C.J.,Ann And Robert rie Childrens Hospital Of Chicago Research Center
Frontiers in Bioscience - Elite | Year: 2015

Molecular technologies have produced diverse arrays of animal models for studying genetic diseases and potential therapeutics. Many have neonatal phenotypes. Spinal muscular atrophy (SMA) is a neuromuscular disorder primarily affecting children, and is of great interest in translational medicine. The most widely used SMA mouse models require all phenotyping to be performed in neonates since they do not survive much past weaning. Preclinical studies in neonate mice can be hindered by toxicity and a lack of quality phenotyping assays, since many assays are invalid in pups or require subjective scoring with poor inter-rater variability. We find, however, that passive electrocardiography (ECG) recording in conscious 11-day old SMA mice provides sensitive outcome measures, detecting large differences in heart rate, cardiac conduction, and autonomic control resulting from disease. We find significant drug benefits upon treatment with G418, an aminoglycoside targeting the underlying protein deficiency, even in the absence of overt effects on growth and survival. These findings provide several quantitative physiological biomarkers for SMA preclinical studies, and will be of utility to diverse disease models featuring neonatal cardiac arrhythmias. © 2014, Frontiers in Bioscience. All rights reserved. Source

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