Stem cell therapy for the broken heart: mini-organ transplantation.

BACKGROUND: Myocardial infarction (MI) is characterized by irreversible loss of cardiomyocytes, resulting in impaired ventricular function. Stem cell therapy using autologous progenitor cells has emerged as a promising approach. Experimental studies have demonstrated that highly selected hematopoeitic stem cells, which are characterized by the presence of the surface markers CD34 and CD133, may contribute to repair of the acutely infarcted myocardium by inducing neovascularization, inhibiting apoptosis, and promoting cardiomyogenesis. We sought, to evaluate the intracoronary injection of CD133+ stem cells for cardiac repair in patients with dysfunctional myocardium after an acute MI. PATIENTS AND METHODS: In this Canadian randomized, double-blind, placebo-controlled, Phase I-II study ("COMPARE-AMI"), we are evaluating the feasibility, safety, and efficacy of intracoronary injection of selected CD133+ stem cells for cardiac repair in patients with impaired cardiac function after successfully stented acute MI. Since November 2007, we have enrolled 14 patients in the study. Their mean age was 50.5 +/- 9.1 years, including 93% men. The culprit lesion was always on the left anterior descending artery (LAD). Their maximum troponin and CKMB levels were 8.4 +/- 6.1 microg/L and 322 +/- 225 U/L, respectively. RESULTS: Compared with the baseline, we observed a significant 8.7% improvement in left ventricular ejection fraction at 4 months follow-up, namely, from 41.3 +/- 5.5% to 50.0 +/- 8.2% (n = 7; P = .008). There were no protocol-related complications. Our trial is designed to recruit 40 patients who are randomized 1:1 to receive CD133+ cells or placebo. PERSPECTIVE: There is a need to seek out new therapeutics for the treatment of ischemic heart disease addressing the early loss of viable myocytes. Stem cell transplantation has shown early promise; this appraisal needs well-designed, controlled studies.

Measurement of the Ec.m. = 184 keV resonance strength in the 26gAl (p, gamma)27 Si reaction.

The strength of the Ec.m. = 184 keV resonance in the 26gAl(p, gamma)27 reaction has been measured in inverse kinematics using the DRAGON recoil separator at TRIUMF's ISAC facility. We measure a value of omega gamma = 35 +/- 7 microeV and a resonance energy of Ec.m. = 184 +/- 1 keV, consistent with p-wave proton capture into the 7652(3) keV state in 27Si, and discuss the implications of these values for 26GAl nucleosynthesis in typical oxygen-neon white-dwarf novae.

Productivity of lexical categories in French-speaking children with cochlear implants.

The productivity of lexical categories was studied longitudinally in a sample of 17 young hearing-impaired French-speaking children with cochlear implants. Age of implantation ranged from 22 months to 76 months. Spontaneous speech samples were collected at six-month intervals over a period of 36 months, starting at the one-word stage. Four general measures of their linguistic production (number of utterances, verbal fluency, vocabulary, and grammatical production) as well as 36 specific lexical categories, according to the CHILDES codes, were computed in terms of tokens, i.e., total number of words. Cochlear-implanted children (CI) were compared to a French database of normally hearing children aged 2-4 compiled by the first author. Follow-up results indicate that, at the two-year post-implantation follow-up, noun, and verb morphology was significantly impaired. At the three-year follow-up, the cochlear-implanted group had recovered on adjectives, determiners and nouns, main verbs, and auxiliaries. The two groups differed significantly in processing locative adverbs, prepositions, pronouns, and verbs (infinitive verb, modal, and modal lexical), but individual variability within the cochlear-implanted group was substantial. Results are discussed in terms of recovery and developmental trends and variability in the acquisition of lexical categories by French children two years and three years post-implantation.

Language evolution in children with cochlear implants.

The capacity to incorporate significant words into the existing vocabulary and to use these words to form sentences with more mature syntactic structures emerges over a considerable time course in young deaf children who have undergone a cochlear implantation. The purpose of this follow-up study is to document the nature and time span of language production--in morphosyntactic and lexical skills--when a child's first experience with language sounds is provided artificially through electrical stimulation. To examine the development of these two aspects of linguistic processing, five deaf French children, all enrolled in similar postimplantation educational settings, were individually assessed at 6-month intervals over a period of 18 months. Computerized analyses were derived from their spontaneous speech in a 20-min standardized play session. Results for mean length of utterance and vocabulary revealed gradually improving performance for most children, in spite of the generally low starting point. Both measures of production nevertheless remained well below the norms established for normally hearing children. Although the achievement of higher production scores, which underlies more effective interpersonal exchanges, is evident after only 1 year of device use, it is clear that improvement does not always occur at the same pace, as shown by two of the children. This emphasizes the importance of longitudinal studies in documenting intersubject variability and intrasubject stability throughout the experience with an implant.

Novel mimics of sialyl Lewis X: design, synthesis and biological activity of a series of 2- and 3-malonate substituted galactoconjugates.

A series of potent inhibitors of P-selectin as potential anti-inflammatory agents is reported. These compounds are derivatives of galactocerebrosides bearing a malonate side chain in positions 2 and 3 of the galactose moiety. Based on the binding mode of sialyl Lewis X, the two acidic groups of the malonate are designed to form ionic interactions with two important lysines in the active site of P-selectin, Lys113 and Lys111. On the other hand, the 4- and 6-hydroxy groups on the galactose ring are arranged to chelate the calcium ion in the P-selectin active site. The synthesis and the biological activity of this series of compounds are described. Lead compounds having a greater potency than sialyl Lewis X are identified.

Asynchronous language acquisition in developmental dysphasia.

A longitudinal study was conducted to document and compare evolution of children with linguistic acquisition impairment. To determine whether development of the analytic mechanisms underlying linguistic processing occured in similar fashion, two children with mixed developmental dysphasia were assessed from 4 to 5:6 years of age with psycholinguistic tests at 6-months interval. Spontaneous speech and language production (consonant repertory in initial word position, MLU, and lexical diversity) were investigated in a standardized symbolic play context. The phonologic and lexico-morphologic evolution analyses revealed a marked improvement in motor control of phonology and in the application of morphosyntaxic rules in child 1, whereas child 2 was still impaired in phonology and morphosyntax. The singular developmental changes in spontaneous speech results indicate dynamic relationships between various language production facets and variability in the kind of deficit and lexical automation presented by these children. These contrasts in the evolution of language production profiles between child 1 and child 2 also underline the importance of longitudinal studies in the analysis of the atypical linguistic processing paths used by children with developmental dysphasia.

Amphotericin B toxicity as related to the formation of oxidatively modified low-density lipoproteins.

The effect of amphotericin B on the oxidation and degradation of low- and high-density lipoproteins was investigated by UV-vis spectroscopy, electron microscopy, electrophoresis, and size-exclusion chromatography. Two formulations of the drug were used: the commercial Fungizone and a new, less toxic, liposomal formulation, AmBisome. It was shown that Fungizone strongly enhanced the oxidative deformation of low-density lipoprotein structure while AmBisome did not bind to this lipoprotein fraction and did not affect its oxidation. It was shown that amphotericin B contained in Fungizone extracted cholesterol from low-density lipoproteins which sensitized them to oxidation. Both formulations of amphotericin B studied here did not bind to high-density lipoprotein and did not affect the process of its oxidation.

Molecular mechanism underlying the action of a novel fusion inhibitor of influenza A virus.

In the initial stages of influenza virus infection, the hemagglutinin (HA) protein of influenza virus mediates both adsorption and penetration of the virus into the host cell. Recently, we identified and characterized BMY-27709 as an inhibitor of the H1 and H2 subtypes of influenza A virus that specifically inhibits the HA function necessary for virus-cell membrane fusion (G.-X. Luo, R. Colonno, and M. Krystal, Virology 226:66-76, 1996). Studies presented herein show that the inhibition is mediated through specific interaction with the HA protein. This binding represses the low-pH-induced conformational change of the HA protein which is a prerequisite for membrane fusion. In an attempt to define the binding pocket within the HA molecule, a number of drug-resistant viruses have been isolated and characterized. Sequence analyses of the HA gene of these drug-resistant viruses mapped amino acid changes responsible for drug resistance to a region located near the amino terminus of HA2. In addition, we have identified inactive analogs of BMY-27709 which are able to compete out the inhibitory activity of BMY-27709. This finding suggests that inhibition of the HA-mediated membrane fusion by this class of compounds is not solely the result of binding within the HA molecule but requires specific interactions.

Spheroidal aggregate culture of rat liver cells: histotypic reorganization, biomatrix deposition, and maintenance of functional activities.

Liver cells isolated from newborn rats and seeded on a non-adherent plastic substratum were found to spontaneously re-aggregate and to form, within a few days, spheroidal aggregates that eventually reached a plateaued diameter of 150-175 micron. Analyses on frozen sections from these spheroids by immunofluorescence microscopy using antibodies to various cytoskeletal elements and extracellular matrix components revealed a sorting out and a histotypic reorganization of three major cell types. A first type consisted of cells that segregated out on the aggregate surface forming a monolayer cell lining; a second type was identified as hepatocytes that regrouped in small islands often defining a central lumen; and a third group of cells reorganized into bile duct-like structures. This intercellular organization in the aggregates was paralleled by the accumulation of extracellular matrix components (laminin, fibronectin, and collagen) and their deposition following a specific pattern around each cell population structure. Determinations of albumin secretion and tyrosine aminotransferase induction by dexamethasone and glucagon at various times after the initiation of the cultures revealed a maintenance of the hepatocyte-differentiated functions for at least up to 2 mo at the levels measured at 3-5 d. It is concluded that cells dispersed as single cells from newborn rat liver conserve in part the necessary information to reconstruct a proper three-dimensional cyto-architecture and that the microenvironment so generated most likely represents a basic requirement for the optimal functioning of these differentiated cells.

Secondary prevention of coronary events after myocardial infarction. Beta-blockers and/or anti-platelets: to whom, when and for how long. A review.

The institution of a "Cardioprophylactic" drug regimen after myocardial infarction should take into consideration the concept of high or low risk patients for secondary coronary events and the concept of a decremential mortality rate as time elapses after myocardial infarction. Thus, the efficacy of a particular drug in preventing secondary coronary events may vary with the time elapsed from infarction and thus with the underlying patho-physiologic mechanism. Furthermore, the administration of a possible effective or proven effective "Cardioprophylactic" drug or drug regimen at a specific time from infarction must take into account the balance between expected benefit and untoward side effects.