Immunologic and Inflammatory Reactions to Exogenous Stem Cells Implications for Experimental Studies and Clinical Trials for Myocardial Repair

Intense research is under way to determine the optimal stem cell type and regimen for repairing diseased myocardium. Although initial studies in humans focused on the use of homologous stem cells, allogeneic or xenogeneic stem cells have been studied extensively in experimental work. Clinical trials with allogeneic stem cells are now under way, an approach based on the premise that stem cells and precursor cells are characterized as being immunotolerant. However, evidence indicates that stem cells may gain immune potency in vivo, especially when delivered to inflamed tissue, such as acutely infarcted myocardium. Histopathologic studies show the presence of a lymphohistiocytic inflammatory reaction at the sites of delivery of allogeneic stem cells, a response that is exaggerated with the use of xenogeneic stem cells. The immune-mediated inflammatory reaction to allogeneic and xenogeneic stem cells may elicit a spectrum of effects, ranging from beneficial (e.g., increased paracrine activity) to detrimental (e.g., accelerated damage and removal of stem cells). Although the issue of immune-mediated inflammatory responses to non-self stem cells requires further evaluation, non-self stem cells should not be considered as immunologically inert or exclusively immunosuppressive in vivo

Dynamic Remodeling of the Stressed Heart: Role of Protein Degradation Pathways

The heart is a remarkable organ. In order to maintain its function, it remodels in response to a variety of environmental stresses, including pressure overload, volume overload, mechanical or pharmacological unloading and hormonal or metabolic disturbances. All these responses are linked to the inherent capacity of the heart to rebuild itself. Particularly, cardiac pressure overload activates signaling pathways of both protein synthesis and degradation. While much is known about regulators of protein synthesis, little is known about regulators of protein degradation in hypertrophy. The ubiquitin-proteasome system (UPS) selectively degrades unused and abnormal intracellular proteins. I speculated that the UPS may play an important role in both qualitative and quantitative changes in the composition of heart muscle during hypertrophic remodeling. My study hypothesized that cardiac remodeling in response to hypertrophic stimuli is a dynamic process that requires activation of highly regulated mechanisms of protein degradation as much as it requires protein synthesis. My first aim was to adopt a model of left ventricular hypertrophy and determine its gene expression and structural changes. Male Sprague-Dawley rats were submitted to ascending aortic banding and sacrificed at 7 and 14 days after surgery. Sham operated animals served as controls. Effective aortic banding was confirmed by hemodynamic assessment by Doppler flow measurements in vivo. Banded rats showed a four-fold increase in peak stenotic jet velocities. Histomorphometric analysis revealed a significant increase in myocyte size as well as fibrosis in the banded animals. Transcript analysis showed that banded animals had reverted to the fetal gene program. My second aim was to assess if the UPS is increased and transcriptionally regulated in hypertrophic left ventricular remodeling. Protein extracts from the left ventricles of the banded and control animals were used to perform an in vitro peptidase assay to assess the overall catalytic activity of the UPS. The results showed no difference between hypertrophied and control animals. Transcript analysis revealed decreases in transcript levels of candidate UPS genes in the hypertrophied hearts at 7 days post-banding but not at 14 days. However, protein expression analysis showed no difference at either time point compared to controls. These findings indicate that elements of the UPS are downregulated in the early phase of hypertrophic remodeling and normalizes in a later phase. The results provide evidence in support of a dynamic transcriptional regulation of a major pathway of intracellular protein degradation in the heart. The discrepancy between transcript levels on the one hand and protein levels on the other hand supports post-transcriptional regulation of the UPS pathway in the hypertrophied heart. The exact mechanisms and the functional consequences remain to be elucidated

Full Information Product Pricing: An Information Strategy for Harnessing Consumer Choice to Create a More Sustainable World

Research and practice in the information systems (IS) field have been evolving over time, nourishing and promoting the development of applications that transform the relationships of individuals, corporations, and governments. Building on this evolution, we push forward a vision of the potential influence of the IS field into one of the most important problems of our times, an increasingly unsustainable world, which is traditionally considered the product of imperfect markets or market externalities. We describe our work in Full Information Product Pricing (FIPP) and our vision of a FIPP global socio-technical system, I-Choose, as a way to connect consumer choice and values with environmental, social, and economic effects of production and distribution practices. FIPP and I-Choose represent a vision about how information systems research can contribute to interdisciplinary research in supply chains, governance, and market economies to provide consumers with information packages that help them better understand how, where, and by whom the products they buy are produced. We believe that such a system will have important implications for international trade and agreements, for public policy, and for making a more sustainable world

Stabilizing Peri-Stent Restenosis Using a Novel Therapeutic Carrier

Late in-stent restenosis remains a significant problem. Bare-metal stents were implanted into peripheral arteries in miniature swine, followed by direct intra-arterial infusion of nitric oxide-loaded echogenic liposomes (ELIPs) and anti-intercellular adhesion molecule-1 conjugated ELIPs loaded with pioglitazone exposed to an endovascular catheter with an ultrasonic core. Ultrasound-facilitated delivery of ELIP formulations into stented peripheral arteries attenuated neointimal growth. Local atheroma-targeted, ultrasound-triggered delivery of nitric oxide and pioglitazone, an anti-inflammatory peroxisome proliferator-activated receptor-γ agonist, into stented arteries has the potential to stabilize stent-induced neointimal growth and obviate the need for long-term antiplatelet therapy

Safety and immunogenicity of pneumococcal conjugate vaccines in a high-risk population : A randomized controlled trial of 10-valent and 13-valent pneumococcal conjugate vaccine in Papua New Guinean infants

Background. There are little data on the immunogenicity of PCV10 and PCV13 in the same high-risk population. Methods. PCV10 and PCV13 were studied head-to-head in a randomized controlled trial in Papua New Guinea in which 262 infants received 3 doses of PCV10 or PCV13 at 1, 2, and 3 months of age. Serotype-specific immunoglobulin G (IgG) concentrations, and pneumococcal and nontypeable Haemophilus influenzae (NTHi) carriage were assessed prevaccination and at 4 and 9 months of age. Infants were followed up for safety until 9 months of age. Results. One month after the third dose of PCV10 or PCV13, 80% of infants had IgG concentrations ≥0.35µg/mL for vaccine serotypes, and 6 months postvaccination IgG concentrations ≥0.35 µg/mL were maintained for 8/10 shared PCV serotypes in > 75% of children vaccinated with either PCV10 or PCV13. Children carried a total of 65 different pneumococcal serotypes (plus nonserotypeable). At 4 months of age, 92% (95% confidence interval [CI] 85–96) of children vaccinated with PCV10 and 81% (95% CI 72–88) vaccinated with PCV13 were pneumococcal carriers (P = .023), whereas no differences were seen at 9 months of age, or for NTHi carriage. Both vaccines were well tolerated and not associated with serious adverse events. Conclusions. Infant vaccination with 3 doses of PCV10 or PCV13 is safe and immunogenic in a highly endemic setting; however, to significantly reduce pneumococcal disease in these settings, PCVs with broader serotype coverage and potency to reduce pneumococcal carriage are needed. Clinical Trials Registration. NCT01619462

1,8-Bis(silylamido)naphthalene complexes of magnesium and zinc synthesized through alkane elimination reactions

The reactions between magnesium or zinc alkyls and 1,8-bis(triorganosilyl)diaminonaphthalenes afford the 1,8-bis(triorganosilyl)diamidonaphthalene complexes with elimination of alkanes. The reaction between 1,8-C10H6(NSiMePh2H)2 and one or two equivalents of MgnBu2 affords two complexes with differing coordination environments for the magnesium; the reaction between 1,8-C10H6(NSiMePh2H)2 and MgnBu2 in a 1:1 ratio affords 1,8-C10H6(NSiMePh2)2{Mg(THF)2} (1), which features a single magnesium centre bridging both ligand nitrogen donors, whilst treatment of 1,8-C10H6(NSiR3H)2 (R3 = MePh2, iPr3) with two equivalents of MgnBu2 affords the bimetallic complexes 1,8-C10H6(NSiR3)2{nBuMg(THF)}2 (R3 = MePh2 2, R3 = iPr3 3), which feature four-membered Mg2N2 rings. Similarly, 1,8-C10H6(NSiiPr3)2{MeMg(THF)}2 (4) and 1,8-C10H6(NSiMePh2)2{ZnMe}2 (5) are formed through reactions with the proligands and two equivalents of MMe2 (M = Mg, Zn). The reaction between 1,8-C10H6(NSiMePh2H)2 and two equivalents of MeMgX affords the bimetallic complexes 1,8-C10H6(NSiMePh2)2(XMgOEt2)2 (X = Br 6; X = I 7). Very small amounts of [1,8-C10H6(NSiMePh2)2{IMg(OEt2)}]2 (8), formed through the coupling of two diamidonaphthalene ligands at the 4-position with concomitant dearomatisation of one of the naphthyl arene rings, were also isolated from a solution of 7

Low-coordinate first-row transition metal complexes in catalysis and small molecule activation

Enforcing unusually low coordination numbers on transition metals with sterically demanding ligands has long been an area of interest for chemists. Historically, the synthesis of these challenging molecules has helped to elucidate fundamental principles of bonding and reactivity. More recently, there has been a move towards exploiting these highly reactive complexes to achieve a range of transformations using cheap, earth-abundant metals. In this Perspective, we will highlight selected examples of transition metal complexes with low coordination numbers that have been used in catalysis and the activation of small molecules featuring strong bonds (N2, CO2, and CO)