Inter-individual variability in structural brain development from late childhood to young adulthood

A fundamental task in neuroscience is to characterize the brain's developmental course. While replicable group-level models of structural brain development from childhood to adulthood have recently been identified, we have yet to quantify and understand individual differences in structural brain development. The present study examined inter-individual variability and sex differences in changes in brain structure, as assessed by anatomical MRI, across ages 8.0-26.0 years in 269 participants (149 females) with three time points of data (807 scans), drawn from three longitudinal datasets collected in the Netherlands, Norway, and USA. We further investigated the relationship between overall brain size and developmental changes, as well as how females and males differed in change variability across development. There was considerable inter-individual variability in the magnitude of changes observed for all examined brain measures. The majority of individuals demonstrated decreases in total gray matter volume, cortex volume, mean cortical thickness, and white matter surface area in mid-adolescence, with more variability present during the transition into adolescence and the transition into early adulthood. While most individuals demonstrated increases in white matter volume in early adolescence, this shifted to a majority demonstrating stability starting in mid-to-late adolescence. We observed sex differences in these patterns, and also an association between the size of an individual's brain structure and the overall rate of change for the structure. The present study provides new insight as to the amount of individual variance in changes in structural morphometrics from late childhood to early adulthood in order to obtain a more nuanced picture of brain development. The observed individual-and sex-differences in brain changes also highlight the importance of further studying individual variation in developmental patterns in healthy, at-risk, and clinical populations.Pathways through Adolescenc

Structural brain development between childhood and adulthood: Convergence across four longitudinal samples

Pathways through Adolescenc

Group B Streptococcal β-Hemolysin/Cytolysin Directly Impairs Cardiomyocyte Viability and Function

BACKGROUND: Group B Streptococcus (GBS) is a leading cause of neonatal sepsis where myocardial dysfunction is an important contributor to poor outcome. Here we study the effects of the GBS pore-forming beta-hemolysin/cytolysin (Bh/c) exotoxin on cardiomyocyte viability, contractility, and calcium transients. METHODOLOGY/PRINCIPAL FINDINGS: HL-1 cardiomyocytes exposed to intact wild-type (WT) or isogenic Deltabeta h/c mutant GBS, or to cell-free extracts from either strain, were assessed for viability by trypan blue exclusion and for apoptosis by TUNEL staining. Functionality of exposed cardiomyocytes was analyzed by visual quantitation of the rate and extent of contractility. Mitochondrial membrane polarization was measured in TMRE-loaded cells exposed to GBS beta h/c. Effects of GBS beta h/c on calcium transients were studied in fura-2AM-loaded primary rat ventricular cardiomyocytes. Exposure of HL-1 cardiomyocytes to either WT GBS or beta h/c extracts significantly reduced both rate and extent of contractility and later induced necrotic and apoptotic cell death. No effects on cardiomyocyte viability or function were observed after treatment with Deltabeta h/c mutant bacteria or extracts. The beta h/c toxin was associated with complete and rapid loss of detectable calcium transients in primary neonatal rat ventricular cardiomyocytes and induced a loss of mitochondrial membrane polarization. These effects on viability and function were abrogated by the beta h/c inhibitor, dipalmitoyl phosphatidylcholine (DPPC). CONCLUSIONS/SIGNIFICANCE: Our data show a rapid loss of cardiomyocyte viability and function induced by GBS beta h/c, and these deleterious effects are inhibited by DPPC, a normal constituent of human pulmonary surfactant.. These findings have clinical implications for the cardiac dysfunction observed in neonatal GBS infections

Surfactant replacement and open lung concept – Comparison of two treatment strategies in an experimental model of neonatal ARDS

Background: Several concepts of treatment in neonatal ARDS have been proposed in the last years. The present study compared the effects of open lung concept positive pressure ventilation (PPVOLC) with a conventional ventilation strategy combined with administration of two different surfactant preparations on lung function and surfactant homoeostasis. Methods: After repeated whole-lung saline lavage, 16 newborn piglets were assigned to either PPVOLC(n = 5) or surfactant treatment under conventional PPV using a natural bovine (n = 5) or a monomeric protein B based surfactant (n = 6). Results: Comprehensive monitoring showed each treatment strategy to improve gas exchange and lung function, although the effect on PaO2and pulmonary compliance declined over the study period in the surfactant groups. The overall improvement of the ventilation efficiency index (VEI) was significantly greater in the PPVOLCgroup. Phospholipid and protein analyses of the bronchoalveolar lavage fluid showed significant alterations to surfactant homoeostasis in the PPVOLCgroup, whereas IL-10 and SP-C mRNA expression was tendentially increased in the surfactant groups. Conclusion: The different treatment strategies applied could be shown to improve gas exchange and lung function in neonatal ARDS. To which extent differences in maintenance of lung function and surfactant homeostasis may lead to long-term consequences needs to be studied further

Erythrocyte Inosine Triphosphatase Activity Is Decreased in HIV-Seropositive Individuals

Background: Inosine triphosphatase (ITPase) is encoded by the polymorphic gene ITPA and maintains low intracellular levels of the inosine nucleotides ITP and dITP. The most frequently reported polymorphisms are ITPA c.94C<A (rs 1127354) and ITPA c. 124+21 A<C (rs7270101). Some nucleoside-analogues used in the treatment of HIV-seropositive (HIV+) patients are potential substrates for ITPase. Therefore, the frequency of ITPA SNPs and ITPase activity were studied in a population of HIV+-patients. Methods: The study population consisted of 222 patients, predominantly Caucasian males, <95% using HAART. Erythrocyte ITPase activity was determined by measuring the formation of IMP from ITP. ITPA genotype was determined by sequencing genomic DNA. Distribution of ITPase activity, genotype-phenotype correlation and allele frequencies were compared to 198 control subjects. The effect of nucleoside analogues on ITPase activity was studied using lymphoblastic T-cell cultures and human recombinant ITPase. Enzyme kinetic experiments were performed on erythrocyte ITPase from HIV+ patients and controls. Results: No difference was observed in the allele frequencies between the HIV+-cohort (± HAART) and the control population. HIV+ carriers of the wild type and ITPA c.94C<A had significantly lower ITPase activities than control subjects with the same genotype (p<lt;0.005). This was not observed in ITPA c. 124+21 A<C carriers. Nucleoside analogues did not affect ITPase activity in cell culture and human recombinant ITPase. Conclusion: ITPA population genetics were identical in HIV+ and control populations. However, the majority of HIV+-patients had decreased erythrocyte ITPase activity compared to controls, probably due to decreased amounts of ITPase protein. It seems unlikely that ITPase activity is decreased due to nucleoside analogues (HAART). Long-term effects of HIV-infection altering ITPase protein expression or stability may explain the phenomenon observed

Morphological alterations of exogenous surfactant inhibited by meconium can be prevented by dextran

BACKGROUND: Surfactant dysfunction due to inhibition is involved in the pathophysiology of meconium aspiration syndrome. Dextran addition has been shown to reverse exogenous surfactant inactivation by meconium, but the precise mechanisms and the morphological correlate of this effect are yet unknown. Morphological surfactant analysis by transmission electron microscopy (TEM) and stereology allows the differentiation of active (large aggregates = LA) and inactive (small aggregates = SA) subtypes. METHODS: To determine the in vitro effects of meconium and dextran addition on the morphology of a modified porcine natural surfactant (Curosurf), Curosurf samples were either incubated alone or together with meconium or with meconium and dextran, fixed and processed for TEM. Volume fractions of surfactant subtypes [lamellar body-like forms (LBL), multilamellar vesicles (MV), unilamellar vesicles (UV)] were determined stereologically. RESULTS: All preparations contained LBL and MV (corresponding to LA) as well as UV (corresponding to SA). The volume fraction of UV increased with addition of meconium and decreased with further addition of dextran. Correspondingly, the UV/(LBL+MV) ratio (resembling the SA/LA ratio) increased when meconium was added and decreased when dextran was added to the surfactant-meconium mixture. CONCLUSION: Meconium causes alterations in the ultrastructural composition of Curosurf that can be visualized and analyzed by TEM and stereology. These alterations resemble an increase in the SA/LA ratio and are paralleled by an increase in minimum surface tension. Dextran prevents these effects and may therefore be a useful additive to exogenous surfactant preparations to preserve their structural and functional integrity, thereby improving their resistance to inactivation

Evidence-based nanoscopic and molecular framework for excipient functionality in compressed orally disintegrating tablets

The work investigates the adhesive/cohesive molecular and physical interactions together with nanoscopic features of commonly used orally disintegrating tablet (ODT) excipients microcrystalline cellulose (MCC) and D-mannitol. This helps to elucidate the underlying physico-chemical and mechanical mechanisms responsible for powder densification and optimum product functionality. Atomic force microscopy (AFM) contact mode analysis was performed to measure nano-adhesion forces and surface energies between excipient-drug particles (6-10 different particles per each pair). Moreover, surface topography images (100 nm2-10 μm2) and roughness data were acquired from AFM tapping mode. AFM data were related to ODT macro/microscopic properties obtained from SEM, FTIR, XRD, thermal analysis using DSC and TGA, disintegration testing, Heckel and tabletability profiles. The study results showed a good association between the adhesive molecular and physical forces of paired particles and the resultant densification mechanisms responsible for mechanical strength of tablets. MCC micro roughness was 3 times that of D-mannitol which explains the high hardness of MCC ODTs due to mechanical interlocking. Hydrogen bonding between MCC particles could not be established from both AFM and FTIR solid state investigation. On the contrary, D-mannitol produced fragile ODTs due to fragmentation of surface crystallites during compression attained from its weak crystal structure. Furthermore, AFM analysis has shown the presence of extensive micro fibril structures inhabiting nano pores which further supports the use of MCC as a disintegrant. Overall, excipients (and model drugs) showed mechanistic behaviour on the nano/micro scale that could be related to the functionality of materials on the macro scale. © 2014 Al-khattawi et al