Cell Therapy for Cardiovascular Disease: A Comparison of Methods of Delivery

The field of myocardial regeneration utilizing novel cell-based therapies, gene transfer, and growth factors may prove to play an important role in the future management of ischemic heart disease and cardiomyopathy. Phases I and II clinical trials have been published for a variety of biologics utilizing four methods of delivery: systemic infusion, intracoronary infusion, transvenous coronary sinus, and intramyocardial. This review discusses the advantages and disadvantages of the delivery approaches above

Blood transfusion in preterm infants improves intestinal tissue oxygenation without alteration in blood flow

BACKGROUND AND OBJECTIVE: The objective of the study was to investigate the splanchnic blood flow velocity and oximetry response to blood transfusion in preterm infants according to postnatal age. MATERIALS AND METHODS: Preterm infants receiving blood transfusion were recruited to three groups: 1–7 (group 1; n = 20), 8–28 (group 2; n = 21) and ≥29 days of life (group 3; n = 18). Superior mesenteric artery (SMA) peak systolic (PSV) and diastolic velocities were measured 30–60 min pre- and post-transfusion using Doppler ultrasound scan. Splanchnic tissue haemoglobin index (sTHI), tissue oxygenation index (sTOI) and fractional tissue oxygen extraction (sFTOE) were measured from 15–20 min before to post-transfusion using near-infrared spectroscopy. RESULTS: The mean pretransfusion Hb in group 1, 2 and 3 was 11, 10 and 9 g/dl, respectively. The mean (SD) pretransfusion SMA PSV in group 1, 2 and 3 was 0·63 (0·32), 0·81 (0·33) and 0·97 (0·40) m/s, respectively, and this did not change significantly following transfusion. The mean (SD) pretransfusion sTOI in group 1, 2 and 3 was 36·7 (19·3), 44·6 (10·4) and 41·3 (10·4)%, respectively. The sTHI and sTOI increased (P < 0·01), and sFTOE decreased (P < 0·01) following transfusion in all groups. On multivariate analysis, changes in SMA PSV and sTOI following blood transfusion were not associated with PDA, feeding, pretransfusion Hb and mean blood pressure. CONCLUSION: Pretransfusion baseline splanchnic tissue oximetry and blood flow velocity varied with postnatal age. Blood transfusion improved intestinal tissue oxygenation without altering mesenteric blood flow velocity irrespective of postnatal ages

GMC formation by agglomeration and self gravity

We investigate the formation of GMCs in spiral galaxies through both agglomeration of clouds in the spiral arms, and self gravity. The simulations presented include two-fluid models, which contain both cold and warm gas, although there is no heating or cooling between them. We find agglomeration is predominant when both the warm and cold components of the ISM are effectively stable to gravitational instabilities. In this case, the spacing (and consequently mass) of clouds and spurs along the spiral arms is determined by the orbits of the gas particles and correlates with their epicyclic radii (or equivalently spiral shock strength). Notably GMCs formed primarily by agglomeration tend to be unbound associations of many smaller clouds, which disperse upon leaving the spiral arms. These GMCs are likely to be more massive in galaxies with stronger spiral shocks or higher surface densities. GMCs formed by agglomeration are also found to exhibit both prograde and retrograde rotation, a consequence of the clumpiness of the gas. At higher surface densities, self gravity becomes more important in arranging both the warm and cold gas into clouds and spurs, and determining the properties of the most massive GMCs. These massive GMCs can be distinguished by their higher angular momentum, exhibit prograde rotation and are more bound. For a 20 M$_{\odot}$ pc$^{-2}$ disc, the spacing between the GMCs fits both the agglomeration and self gravity scenarios, as the maximum unstable wavelength of gravitational perturbations in the warm gas is similar to the spacing found when GMCs form solely by agglomeration.Comment: 16 pages, 12 figures, accepted for publication in MNRAS. Version with higher resolution figures available at http://www.astro.ex.ac.uk/people/dobbs/Dobbsgr.pd

Investigation into the role of an extracellular loop in mediating proton-evoked inhibition of voltage-gated sodium channels

Proton-evoked activation of sensory neurons is counteracted by inhibition of voltage-gated Na+ channels, and the low acid-sensitivity of sensory neuron of the African naked mole-rat (ANMr) was reported to be due to a strong proton-evoked block of ANMrNav1.7. Here we aimed to reevaluate the role of the suggested negatively-charged motif in the ANMrNav1.7 domain IV P-loop for inhibition by protons. Patch clamp recordings were performed on the recombinant α-subunits Nav1.2–1.8. The insertion of the negatively charged motif (EKE) of ANMrNav1.7 into human Nav1.7 results in an increased proton-evoked tonic inhibition, but also in a reduced channel function. While the voltage-dependency of fast inactivation is changed in hNav1.7-EKE, pH 6.4 fails to induce a significant shift in both constructs. Proton-evoked inhibition of other channel α-subunits reveals a discrete differential inhibition among α-subunits with hNav1.7 displaying the lowest proton-sensitivity. The mutant hNav1.7-EKE displays a similar proton-sensitivity as Nav1.2, Nav1.3, Nav1.6 and Nav1.8. Overall, a correlation between proton-evoked inhibition and motif charge was not evident. Accordingly, a homology model of hNav1.7 shows that the EKE motif residues do not contribute to the pore lumen. Our data confirms that a negative charge of a postulated proton-motif encodes for a high proton-sensitivity when inserted into hNav1.7. However, a negatively charged motif is not a reliable predictor for a high proton-sensitivity in other α-subunits. Given the distance of the proton-motif from the pore mouth it seems unlikely that a blocking mechanism involving direct obstruction of the pore underlies the observed proton-evoked channel inhibition

The properties of the ISM in disc galaxies with stellar feedback

We perform calculations of isolated disc galaxies to investigate how the properties of the ISM, the nature of molecular clouds, and the global star formation rate depend on the level of stellar feedback. We adopt a simple physical model, which includes a galactic potential, a standard cooling and heating prescription of the ISM, and self gravity of the gas. Stellar feedback is implemented by injecting energy into dense, gravitationally collapsing gas, but is independent of the Schmidt-Kennicutt relation. We obtain fractions of gas, and filling factors for different phases of the ISM in reasonable ageement with observations. Supernovae are found to be vital to reproduce the scale heights of the different components of the ISM, and velocity dispersions. The GMCs formed in the simulations display mass spectra similar to the observations, their normalisation dependent on the level of feedback. We find ~40 per cent of the clouds exhibit retrograde rotation, induced by cloud-cloud collisions. The star formation rates we obtain are in good agreement with the observed Schmidt-Kennicutt relation, and are not strongly dependent on the star formation efficiency we assume, being largely self regulated by the feedback. We also investigate the effect of spiral structure by comparing calculations with and without the spiral component of the potential. The main difference with a spiral potential is that more massive GMCs are able to accumulate in the spiral arms. Thus we are able to reproduce massive GMCs, and the spurs seen in many grand design galaxies, even with stellar feedback. The presence of the spiral potential does not have an explicit effect on the star formation rate, but can increase the star formation rate indirectly by enabling the formation of long-lived, strongly bound clouds.Comment: 19 pages, 23 figures, accepted by MNRA

Placental 11-Beta Hydroxysteroid Dehydrogenase Methylation Is Associated with Newborn Growth and a Measure of Neurobehavioral Outcome

Background: There is growing evidence that the intrauterine environment can impact the neurodevelopment of the fetus through alterations in the functional epigenome of the placenta. In the placenta, the HSD11B2 gene encoding the 11-beta hydroxysteroid dehydrogenase enzyme, which is responsible for the inactivation of maternal cortisol, is regulated by DNA methylation, and has been shown to be susceptible to stressors from the maternal environment. Methodology/Principal Findings: We examined the association between DNA methylation of the HSD11B2 promoter region in the placenta of 185 healthy newborn infants and infant and maternal characteristics, as well as the association between this epigenetic variability and newborn neurobehavioral outcome assessed with the NICU Network Neurobehavioral Scales. Controlling for confounders, HSD11B2 methylation extent is greatest in infants with the lowest birthweights (P = 0.04), and this increasing methylation was associated with reduced scores of quality of movement (P = 0.04). Conclusions/Significance: These results suggest that factors in the intrauterine environment which contribute to birth outcome may be associated with placental methylation of the HSD11B2 gene and that this epigenetic alteration is in turn associated with a prospectively predictive early neurobehavioral outcome, suggesting in some part a mechanism for th

The stellar and sub-stellar IMF of simple and composite populations

The current knowledge on the stellar IMF is documented. It appears to become top-heavy when the star-formation rate density surpasses about 0.1Msun/(yr pc^3) on a pc scale and it may become increasingly bottom-heavy with increasing metallicity and in increasingly massive early-type galaxies. It declines quite steeply below about 0.07Msun with brown dwarfs (BDs) and very low mass stars having their own IMF. The most massive star of mass mmax formed in an embedded cluster with stellar mass Mecl correlates strongly with Mecl being a result of gravitation-driven but resource-limited growth and fragmentation induced starvation. There is no convincing evidence whatsoever that massive stars do form in isolation. Various methods of discretising a stellar population are introduced: optimal sampling leads to a mass distribution that perfectly represents the exact form of the desired IMF and the mmax-to-Mecl relation, while random sampling results in statistical variations of the shape of the IMF. The observed mmax-to-Mecl correlation and the small spread of IMF power-law indices together suggest that optimally sampling the IMF may be the more realistic description of star formation than random sampling from a universal IMF with a constant upper mass limit. Composite populations on galaxy scales, which are formed from many pc scale star formation events, need to be described by the integrated galactic IMF. This IGIMF varies systematically from top-light to top-heavy in dependence of galaxy type and star formation rate, with dramatic implications for theories of galaxy formation and evolution.Comment: 167 pages, 37 figures, 3 tables, published in Stellar Systems and Galactic Structure, Vol.5, Springer. This revised version is consistent with the published version and includes additional references and minor additions to the text as well as a recomputed Table 1. ISBN 978-90-481-8817-

Deletions at 14q in malignant mesothelioma detected by microsatellite marker analysis

Previous molecular cytogenetic studies by comparative genomic hybridization (CGH) on primary tumours of human malignant mesothelioma have revealed that loss of genetic material at chromosome 14q is one of the most frequently occurring aberrations. Here we further verify the frequency and pattern of deletions at 14q in mesothelioma. A high-resolution deletion mapping analysis of 23 microsatellite markers was performed on 18 primary mesothelioma tumours. Eight of these had previously been analysed by CGH. Loss of heterozygosity or allelic imbalance with at least one marker was detected in ten of 18 tumours (56%). Partial deletions of varying lengths were more common than loss of all informative markers, which occurred in only one tumour. The highest number of tumours with deletions at a specific marker was detected at 14q11.1–q12 with markers D14S283 (five tumours), D14S972 (seven tumours) and D14S64 (five tumours) and at 14q23–q24 with markers D14S258 (five tumours), D14S77 (five tumours) and D14S284 (six tumours). We conclude from these data that genomic deletions at 14q are more common than previously reported in mesothelioma. Furthermore, confirmation of previous CGH results was obtained in all tumours but one. This tumour showed deletions by allelotyping, but did not show any DNA copy number change at 14q by CGH. Although the number of tumours allelotyped was small and the deletion pattern was complex, 14q11.1–q12 and 14q23–q24 were found to be the most involved regions in deletions. These regions provide a good basis for further molecular analyses and may highlight chromosomal locations of tumour suppressor genes that could be important in the tumorigenesis of malignant mesothelioma. © 1999 Cancer Research Campaig

In Vivo Gene Knockdown in Rat Dorsal Root Ganglia Mediated by Self-Complementary Adeno-Associated Virus Serotype 5 Following Intrathecal Delivery

We report here in adult rat viral vector mediate-gene knockdown in the primary sensory neurons and the associated cellular and behavior consequences. Self-complementary adeno-associated virus serotype 5 (AAV5) was constructed to express green fluorescent protein (GFP) and a small interfering RNA (siRNA) targeting mammalian target of rapamycin (mTOR). The AAV vectors were injected via an intrathecal catheter. We observed profound GFP expression in lumbar DRG neurons beginning at 2-week post-injection. Of those neurons, over 85% were large to medium-diameter and co-labeled with NF200, a marker for myelinated fibers. Western blotting of mTOR revealed an 80% reduction in the lumbar DRGs (L4–L6) of rats treated with the active siRNA vectors compared to the control siRNA vector. Gene knockdown became apparent as early as 7-day post-injection and lasted for at least 5 weeks. Importantly, mTOR knockdown occurred in large (NF200) and small-diameter neurons (nociceptors). The viral administration induced an increase of Iba1 immunoreactivity in the DRGs, which was likely attributed to the expression of GFP but not siRNA. Rats with mTOR knockdown in DRG neurons showed normal general behavior and unaltered responses to noxious stimuli. In conclusion, intrathecal AAV5 is a highly efficient vehicle to deliver siRNA and generate gene knockdown in DRG neurons. This will be valuable for both basic research and clinic intervention of diseases involving primary sensory neurons