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Aerobic exercise has been shown to impact brain structure and cognition in children and adults. Exercise-induced activation of a growth protein known as brain derived neurotrophic factor (BDNF) is thought to contribute to such relationships. To date, however, no study has examined how aerobic fitness relates to cortical brain structure during development and if BDNF genotype moderates these relationships. Using structural magnetic resonance imaging (MRI) and FreeSurfer, the current study examined how aerobic fitness relates to volume, thickness, and surface area in 34 male adolescents, 15 to 18 years old. Moreover, we examined if the val66met BDNF genotype moderated these relationships. We hypothesized that aerobic fitness would relate to greater thickness and volumes in frontal, parietal, and motor regions, and that these relationships would be less robust in individuals carrying a Met allele, since this genotype leads to lower BDNF expression. We found that aerobic fitness positively related to right rostral middle frontal cortical volume in all adolescents. However, results also showed BDNF genotype moderated the relationship between aerobic fitness and bilateral medial precuneus surface area, with a positive relationship seen in individuals with the Val/Val allele, but no relationship detected in those adolescents carrying a Met allele. Lastly, using self-reported levels of aerobic activity, we found that higher-fit adolescents showed larger right medial pericalcarine, right cuneus and left precuneus surface areas as compared to their low-fit peers. Our findings suggest that aerobic fitness is linked to cortical brain development in male adolescents, and that more research is warranted to determine how an individual’s genes may influence these relationships.

AbstractUnderstanding the expression of known and unknown gene products represents one of the key challenges in the post-genomic world. Here, we have developed a new class of reagents to examine protein expression in vivo that does not require transfection, radiolabeling, or the prior choice of a candidate gene. To do this, we constructed a series of puromycin conjugates bearing various fluorescent and biotin moieties. These compounds are readily incorporated into expressed protein products in cell lysates in vitro and efficiently cross cell membranes to function in protein synthesis in vivo as indicated by flow cytometry, selective enrichment studies, and Western analysis. Overall, this work demonstrates that fluorescent-puromycin conjugates offer a general means to examine protein expression in vivo.

Background Child survival initiatives historically prioritized efforts to reduce child morbidity and mortality from infectious diseases and maternal conditions. Little attention has been devoted to paediatric injuries in resource‐limited settings. This study aimed to evaluate the demographics and outcomes of paediatric injury in a sub‐Saharan African country in an effort to improve prevention and treatment. Methods A prospective trauma registry was established at the two university teaching campuses of the University of Rwanda to record systematically patient demographics, prehospital care, initial physiology and patient outcomes from May 2011 to July 2015. Univariable analysis was performed for demographic characteristics, injury mechanisms, geographical location and outcomes. Multivariable analysis was performed for mortality estimates. Results Of 11 036 patients in the registry, 3010 (27·3 per cent) were under 18 years of age. Paediatric patients were predominantly boys (69·9 per cent) and the median age was 8 years. The mortality rate was 4·8 per cent. Falls were the most common injury (45·3 per cent), followed by road traffic accidents (30·9 per cent), burns (10·7 per cent) and blunt force/assault (7·5 per cent). Patients treated in the capital city, Kigali, had a higher incidence of head injury (7·6 per cent versus 2·0 per cent in a rural town, P < 0·001; odds ratio (OR) 4·08, 95 per cent c.i. 2·61 to 6·38) and a higher overall injury‐related mortality rate (adjusted OR 3·00, 1·50 to 6·01; P = 0·019). Pedestrians had higher overall injury‐related mortality compared with other road users (adjusted OR 3·26, 1·37 to 7·73; P = 0·007). Conclusion Paediatric injury is a significant contributor to morbidity and mortality. Delineating trauma demographics is important when planning resource utilization and capacity‐building efforts to address paediatric injury in low‐resource settings and identify vulnerable populations. This study evaluated the demographics and outcomes of paediatric injury in Rwanda through a prospective trauma registry to inform capacity‐building for prevention and treatment. Patients treated in the capital city had a higher incidence of head injury and a higher overall injury‐related mortality than those in a rural town. Pedestrians had higher overall injury‐related mortality compared with other road‐users. Falls and road traffic accidents significant contributors to pediatric injury in Rwanda

The pore of the catfish olfactory cyclic nucleotide–gated (CNG) channel contains four conserved glutamate residues, one from each subunit, that form a high-affinity binding site for extracellular divalent cations. Previous work showed that these residues form two independent and equivalent high-pKa (∼7.6) proton binding sites, giving rise to three pH-dependent conductance states, and it was suggested that the sites were formed by pairing of the glutamates into two independent carboxyl-carboxylates. To test further this physical picture, wild-type CNG subunits were coexpressed in Xenopus oocytes with subunits lacking the critical glutamate residue, and single channel currents through hybrid CNG channels containing one to three wild-type (WT) subunits were recorded. One of these hybrid channels had two pH-dependent conductance states whose occupancy was controlled by a single high-pKa protonation site. Expression of dimers of concatenated CNG channel subunits confirmed that this hybrid contained two WT and two mutant subunits, supporting the idea that a single protonation site is made from two glutamates (dimer expression also implied the subunit makeup of the other hybrid channels). Thus, the proton binding sites in the WT channel occur as a result of the pairing of two glutamate residues. This conclusion places these residues in close proximity to one another in the pore and implies that at any instant in time detailed fourfold symmetry is disrupted.

Sickle cell disease (SCD) is an autosomal recessive disorder that arises from a single nucleotide mutation in the β–globin gene of hemoglobin. This change promotes hemoglobin S polymerization upon deoxygenation and results in the characteristic sickled-shape of red blood cells. Common characteristics of SCD include anemia, ongoing hemolysis, and a spectrum of complications impacting multiple organs. Anemia, caused by recurring hemolysis, contributes to more chronic consequences of SCD including functional renal damage and necrosis (1). Because the renal oxygen consumption rate is high, the kidney is especially sensitive to vaso-occlusion-induced hypoxia. Red blood cells exhibit a higher propensity to sickle in the renal medulla due to its hypoxic and acidotic ambient conditions (2). Further, recurrent episodes of hemoglobin S polymerization and red blood cell sickling alter the rheological properties of the erythrocyte and lead to increased adhesiveness of the sickled cells to the endothelium (3). Therefore, patients with SCD display many structural and functional renal abnormalities which are observed from the glomerulus to the papillary tip. The most common manifestation of glomerular injury in SCD is albuminuria, occurring in 26 to 68% of adults with SCD ≥21 years of age and 4.5 to 26% of younger patients (4). Patients may then go on to develop nephrotic syndrome, chronic renal failure, and end stage renal disease. Renal insufficiency occurs in 4–18% of patients with SCD and leads to significant morbidity and early mortality (2, 3). Valeshabad and colleagues sought to investigate an association between conjunctival hemodynamic properties and albuminuria in subjects with SCD and preserved glomerular filtration rate. Conjunctival microcirculation imaging techniques were used to obtain conjunctival diameter and axial velocity measurements in 35 subjects with SCD, and these were compared to 10 healthy control individuals. As described in previous studies, the authors used a high magnification optical imaging system (identified as EyeFlow™) to retrieve and derive frames of images that captured the movement of red blood cells within the conjunctival microcirculation (5, 6). A series of consecutive images were used to calibrate conjunctival velocity by measuring red blood cell movement along the centerline of the vessel (5). Analysis of these frames resulted in rows of diagonal bands, varying in intensity, as a function of time (5,6,7). The resulting data correlated with the flow of an aggregate of red blood cells (5). Finally, conjunctival velocity readings were obtained by determining the slope of the most prominent bands. Conjunctival microcirculation imaging results were then related to urinary albumin excretion ratio (AER). Conjunctival diameter and velocity measurements were observed in 179 and 432 conjunctival venules from the control and SCD subjects, respectively. The 35 subjects with SCD were assigned to one of three groups according to mean conjunctival axial blood velocity (V) readings that ranged from less than 0.40 mm/s to more than 0.60 mm/s. The authors report significantly elevated AER in the high conjunctival velocity group, in comparison to those of the low and normal conjunctival velocity groups. While they also found a significant positive correlation between conjunctival velocity and albuminuria (r=0.47, p=0.005), the authors note no statistically significant difference in AER between the normal and low conjunctival velocity groups and no significant correlation between conjunctival diameter and albuminuria. The AER in the high conjunctival velocity group falls within the macroalbuminuria range (defined as 300 mg/g creatinine) with a mean (+/− standard error) of 475 +/− 232 mg/g creatinine. These findings indicate for the first time that elevated conjunctival velocity levels are associated with macroalbuminuria in patients with SCD. While interesting, the findings are somewhat limited based on the cross-sectional design. More specifically, they could not assess whether conjunctival velocity predicted whether patients would develop macroalbuminuria and whether further increases in conjunctival flow are associated with progressive disease. Also, because all patients with SCD do not develop albuminuria, it would be ideal to predict who would develop even microalbuminuria based on slight increases in conjunctival velocity as compared to those who do not develop albuminuria so that preventive measures such as angiotensin converting enzyme inhibitors can be considered. Still, their findings that patients with macroalbuminuria display significantly increased conjunctival velocity are intriguing and suggest that further studies should be performed.

AbstractExosomes are critical mediators of intercellular crosstalk and regulator of cellular/tumor microenvironment. Exosomes have great prospects for clinical application as theranostic and prognostic probe. Nevertheless, the advancement of the exosomes research has been thwarted by limited knowledge elucidating the most efficient isolation method and theirin vivotrafficking. Here we have showed that combination of two size-based methods using 0.20 µm syringe filter and 100k centrifuge membrane filter followed by ultracentrifugation method yields a greater number of uniform exosomes. We also demonstrated the visual representation and quantification of differentialin vivodistribution of radioisotope131I-labelled exosomes from diverse cellular origins, e.g., tumor cells with or without treatments (HET0016 and GW2580), myeloid-derived suppressor cells and endothelial progenitor cells. We also determined that the distribution was dependent on the protein/cytokine contents of the exosomes. The appliedin vivoimaging modalities can be utilized to monitor disease progression, metastasis, and exosome-based targeted therapy.AbbreviationsbFGFbasic fibroblast growth factorCSF1Rcolony stimulating factor 1 receptorCTcomputed tomographyCTLA4cytotoxic T-lymphocyte-associated protein 4EGFepidermal growth factorEMTepithelial to mesenchymal transitionEVsextracellular vesiclesEPCsendothelial progenitor cellsFasLFas ligandG-CSFgranulocyte-colony stimulating factorGM-CSFgranulocyte-macrophage colony-stimulating factorHGFhepatocyte growth factorHSPheat shock proteinICAM-1intercellular adhesion molecule 1IFN-gammainterferon gammaIL – 1betainterleukin-1 betaIL – 1rainterleukin-1 receptor antagonistIL – 2interleukin-2IL – 4interleukin-4IL – 6interleukin-6IL – 7interleukin-7IL – 10interleukin-10IL – 12interleukin-12IL – 13interleukin-13IL – 17interleukin-17KCkeratinocyte-derived chemokineLIXlipopolysaccharide-induced CXC chemokineM-CSFmacrophage colony-stimulating factorMCP-1monocyte chemoattractant protein 1MDCmacrophage-derived chemokineMDSCsmyeloid derived suppressor cellsMFPmammary fat padMIP-1αmacrophage-inflammatory protein-1alphaMMP-2matrix metalloproteinase-2MRImagnetic resonance imagingNISsodium iodide symporterNTAnanoparticle tracking analysisPETpositron emission tomographyPF-4platelet factor 4RANTESregulated on activation, normal T cell expressed and secretedROIsregion of interestSDF-1αstromal cell-derived factor-1SEMstandard error of the meanSPECTsingle-photon emission computed tomographySCFstem cell factorTAMstumor-associated macrophagesTEMtransmission electron microscopyTIMP 2tissue inhibitors of metalloproteinases 2TLPCthin layer paper chromatographyTMEtumor microenvironmentTNF-αtumor necrosis factor-αTSLPthymic stromal lymphopoietinUCultracentrifugationVEGF-Avascular endothelial growth factor AVEGFR2vascular endothelial growth factor receptor 2.

ABSTRACT Objective To identify the effect of social capital on adolescent smoking. Method A stratified random sample of 1313 7th and 8th grade students from three counties in Transylvania, Romania, completed a self-administered questionnaire on smoking-related knowledge, attitudes and behaviours. The impact of social capital was measured (personal and community activities, school achievements and smoking-related knowledge). Multivariate multinomial logistic regression models were used to measure the association between social participation and smoking. Results Experimenting with smoking was mostly related to knowledge about smoking, academic performance and second-hand tobacco smoke exposure at home. The strongest risk factor of adolescent smoking was the smoking behaviour of classmates: those who reported a significant proportion of smokers among their classmates were nine times more likely to smoke themselves than in other cases (adjusted odds ratio [aOR]: 9.05). Those who considered smoking to be harmless were 4 times more likely to be smokers than those who considered this behaviour to be dangerous (aOR: 4.28). Poor academic results increased adolescents’ smoking (aOR: 3.22 and 2.66). The odds were significantly higher for smoking, if they had an active social life (aOR: 2.54). Regular church attendance proved to be a protective factor (aOR: 0.45). Conclusions Several social capital factors can play a role in adolescent smoking. The organization and the development of community activities aimed at prevention must strengthen the factors related to the community's social capital to reduce the likelihood of teenage smoking. RESUMEN Objetivo Evaluar el efecto del capital social sobre el consumo de tabaco en adolescentes. Método El estudio se realizó en un grupo aleatorizado y estratificado compuesto por 1313 estudiantes de séptimo y octavo grado de tres municipios en Transilvania (Rumanía). Los participantes contestaron un cuestionario autocumplimentado en relación con el consumo de tabaco y sobre actitudes y comportamientos respecto a este. El impacto del capital social, entendido como actividades personales y comunitarias, así como el desarrollo académico y la información sobre el consumo de tabaco, fueron algunas de las medidas. Resultados Experimentar con el hábito de fumar se relaciona principalmente con el conocimiento sobre dicha adicción, el rendimiento académico y la exposición al consumo de tabaco en el hogar. El mayor riesgo para el consumo se deriva de la interacción con compañeros de clase que incurren en el consumo de tabaco. En tal caso, la probabilidad de consumo aumenta nueve veces (odds ratio ajustada [ORa]: 9,05). Quienes consideraron que fumar es inofensivo tuvieron cuatro veces más probabilidades de ser fumadores que quienes consideraron este comportamiento como peligroso (ORa: 4,28). En cuanto a los/las estudiantes con bajo rendimiento académico se observa un mayor incremento del consumo (ORa: 3,22 y 2,66). Al mismo tiempo, dicho patrón también se observa entre aquellos/as con un entorno social activo (ORa: 2,54). La asistencia a la iglesia de manera regular es un factor protector (ORa: 0,45). Conclusiones Diferentes aspectos relacionados con el capital social se asocian al consumo de tabaco en adolescentes. La organización de actividades y el desarrollo comunitario deberán tener en cuenta estos aspectos para prevenir el consumo de tabaco. Hay que prestar especial atención a la clase social con el fin de reducir las probabilidades de consumo en adolescentes.

Limited data exist evaluating the effect of blood pressure (BP) on clinical outcomes among patients with acute ischemic stroke with large vessel occlusion treated with mechanical thrombectomy (MT). We sought to evaluate the association of BP levels on clinical outcomes among patients with acute ischemic stroke with large vessel occlusion treated with MT. Studies were identified that reported the association of systolic BP (SBP) or diastolic BP levels before, during, or after MT on the outcomes of patients with acute ischemic stroke treated with MT. Unadjusted and adjusted analyses of studies reporting odds ratios (OR adj ) per 10 mm Hg BP increment were performed. Our analysis included 25 studies comprising 6474 patients. Higher pre-MT mean SBP ( P =0.008) and post-MT maximum SBP ( P =0.009) levels were observed in patients who died within 3 months. Patients with 3-month functional independence were noted to have lower pre-MT ( P <0.001) and post-MT maximum SBP levels ( P <0.001). In adjusted analyses, increasing post-MT maximum SBP and diastolic BP levels were associated with 3-month mortality (OR adj , 1.19 [95% CI,1.00–1.43]; I 2 =78%, P value for Cochran Q test: 0.001) and symptomatic intracranial hemorrhage (OR adj , 1.65 [95% CI, 1.11–2.44]; I 2 =0%, P value for Cochran Q test: 0.80), respectively. Increasing pre- and post-MT mean SBP levels were associated with lower odds of 3-month functional independence (OR adj , 0.86 [95% CI, 0.77–0.96]; I 2 =18%, P value for Cochran Q test: 0.30) and (OR adj , 0.80 [95% CI, 0.72–0.89]; I 2 =0%, P value for Cochran Q test: 0.51), respectively. In conclusion, elevated BP levels before and after MT are associated with adverse outcomes among patients with acute ischemic stroke with large vessel occlusion.

Highly specific activity-dependent neuronal responses are necessary for modulating synapses to facilitate learning and memory. We present evidence linking a number of important processes involved in regulating synaptic plasticity, suggesting a mechanistic pathway whereby activity-dependent signaling, likely through protein kinase C (PKC)-mediated phosphorylation of HuD, can relieve basal repression of Bdnf mRNA translation in dendrites, allowing for increased TrkB signaling and synaptic remodeling. We demonstrate that the neuronal ELAV family of RNA binding proteins associates in vivo with several Bdnf mRNA isoforms present in the adult brain in an activity-dependent manner, and that one member, HuD, interacts directly with sequences in the long Bdnf 3' untranslated region (3'UTR) and co-localizes with Bdnf mRNA in dendrites of hippocampal neurons. Activation of PKC leads to increased dendritic translation of mRNAs containing the long Bdnf 3'UTR, a process that is dependent on the presence of HuD and its phosphorylation at threonine residues 149 and/or 165. Thus, we found a direct effect of HuD on regulating translation of dendritic Bdnf mRNAs to mediate local and activity-dependent increases in dendritic BDNF synthesis.