Pathophysiologic consequences following inhibition of a CFTR-dependent developmental cascade in the lung

BACKGROUND: Examination of late gestation developmental genes in vivo may be limited by early embryonic lethality and compensatory mechanisms. This problem is particularly apparent in evaluating the developmental role of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in the cystic fibrosis (CF) phenotype. A previously described transient in utero knockout (TIUKO) technology was used to address the developmental role of CFTR in the rat lung. RESULTS: Rat fetuses transiently treated with antisense cftr in utero developed pathology that replicated aspects of the human CF phenotype. The TIUKO CF rat developed lung fibrosis, chronic inflammation, reactive airway disease, and the CF Antigen (MRP8/14), a marker for CF in human patients, was expressed. CONCLUSIONS: The transient in utero antisense technology can be used to evaluate genes that exhibit either early lethality or compensating gene phenotypes. In the lung CFTR is part of a developmental cascade for normal secretory cell differentiation. Absence of CFTR results in a constitutive inflammatory process that is involved in some aspects of CF pathophysiology

Noncovariant gauge fixing in the quantum Dirac field theory of atoms and molecules

Starting from the Weyl gauge formulation of quantum electrodynamics (QED), the formalism of quantum-mechanical gauge fixing is extended using techniques from nonrelativistic QED. This involves expressing the redundant gauge degrees of freedom through an arbitrary functional of the gauge-invariant transverse degrees of freedom. Particular choices of functional can be made to yield the Coulomb gauge and Poincar\'{e} gauge representations. The Hamiltonian we derive therefore serves as a good starting point for the description of atoms and molecules by means of a relativistic Dirac field. We discuss important implications for the ontology of noncovariant canonical QED due to the gauge freedom that remains present in our formulation.Comment: 8 pages, 0 figure

Nonradiative interaction and entanglement between distant atoms

We show that nonradiative interactions between atomic dipoles placed in a waveguide can give rise to deterministic entanglement at ranges much larger than their resonant wavelength. The range increases as the dipole-resonance approaches the waveguide's cutoff frequency, caused by the giant density of photon modes near cutoff, a regime where the standard (perturbative) Markov approximation fails. We provide analytical theories for both the Markovian and non-Markovian regimes, supported by numerical simulations, and discuss possible experimental realizations.Comment: 9 pages, 2 figure

Long term physiologic modification using rAAV in utero gene-therapy

BACKGROUND: Transfer of genes in utero via the amniotic fluid was shown previously with recombinant adeno-associated viruses (rAAV) to be highly efficient. Expression for over one year was demonstrated using reporter genes. In addition, it was shown previously that transgenes delivered by this method release protein into the general circulation. Given these results experiments were designed to test the hypothesis that in utero rAAV gene therapy could result in long term physiologic modification. METHODS: A rAAV recombinant expressing ciliary neurotrophic factor (cntf) and green fluorescent (gfp) in a polycistronic messenger was used to treat rat fetuses in utero. CNTF causes weight loss and decreased water consumption as a measurable physiologic effect. GFP was used as a marker of gene expression. RESULTS: In utero gene transfer with rAAV carrying human cntf and gfp resulted in long-term gene expression in rat. CNTF-specific physiologic effects of a decrease in weight and water intake were obtained. Expression of the GFP was documented in the treated animals at one year of age. CONCLUSION: Given this data, in utero gene therapy with rAAV into multipotential stem cells resulted in long term systemic physiologic modification of the treated animals by the transgene product. In utero rAAV gene therapy potentially could be used for gene replacement therapy in metabolic disorders

Placental Structure in Preterm Birth Among HIV-Positive Versus HIV-Negative Women in Kenya.

BackgroundPreterm birth (PTB) is a major cause of infant morbidity and mortality in developing countries. Recent data suggest that in addition to Human Immunodeficiency Virus (HIV) infection, use of antiretroviral therapy (ART) increases the risk of PTB. As the mechanisms remain unexplored, we conducted this study to determine whether HIV and ART were associated with placental changes that could contribute to PTB.SettingWe collected and evaluated placentas from 38 HIV-positive women on ART and 43 HIV-negative women who had preterm deliveries in Nairobi, Kenya.MethodsAnatomical features of the placentas were examined at gross and microscopic levels. Cases were matched for gestational age and compared by the investigators who were blinded to maternal HIV serostatus.ResultsAmong preterm placentas, HIV infection was significantly associated with thrombosis (P = 0.001), infarction (P = 0.032), anomalies in cord insertion (P = 0.02), gross evidence of membrane infection (P = 0.043), and reduced placental thickness (P = 0.010). Overall, preterm placentas in both groups were associated with immature villi, syncytial knotting, villitis, and deciduitis. Features of HIV-positive versus HIV-negative placentas included significant fibrinoid deposition with villus degeneration, syncytiotrophoblast delamination, red blood cell adhesion, hypervascularity, and reduction in both surface area and perimeter of the terminal villi.ConclusionsThese results imply that HIV infection and/or ART are associated with morphological changes in preterm placentas that contribute to delivery before 37 weeks. Hypervascularity suggests that the observed pathologies may be attributable, in part, to hypoxia. Further research to explore potential mechanisms will help elucidate the pathways that are involved perhaps pointing to interventions for decreasing the risk of prematurity among HIV-positive women

In utero recombinant adeno-associated virus gene transfer in mice, rats, and primates

BACKGROUND: Gene transfer into the amniotic fluid using recombinant adenovirus vectors was shown previously to result in high efficiency transfer of transgenes into the lungs and intestines. Adenovirus mediated in utero gene therapy, however, resulted in expression of the transgene for less than 30 days. Recombinant adenovirus associated viruses (rAAV) have the advantage of maintaining the viral genome in daughter cells thus providing for long-term expression of transgenes. METHODS: Recombinant AAV2 carrying green fluorescent protein (GFP) was introduced into the amniotic sac of fetal rodents and nonhuman primates. Transgene maintenance and expression was monitor. RESULTS: Gene transfer resulted in rapid uptake and long-term gene expression in mice, rats, and non-human primates. Expression and secretion of the reporter gene, GFP, was readily demonstrated within 72 hours post-therapy. In long-term studies in rats and nonhuman primates, maintenance of GFP DNA, protein expression, and reporter gene secretion was documented for over one year. CONCLUSIONS: Because only multipotential stem cells are present at the time of therapy, these data demonstrated that in utero gene transfer with AAV2 into stem cells resulted in long-term systemic expression of active transgene roducts. Thus, in utero gene transfer via the amniotic fluid may be useful in treatment of gene disorders

Atomic multipole relaxation rates near surfaces

The spontaneous relaxation rates for an atom in free space and close to an absorbing surface are calculated to various orders of the electromagnetic multipole expansion. The spontaneous decay rates for dipole, quadrupole and octupole transitions are calculated in terms of their respective primitive electric multipole moments and the magnetic relaxation rate is calculated for the dipole and quadrupole transitions in terms of their respective primitive magnetic multipole moments. The theory of electromagnetic field quantization in magnetoelectric materials is used to derive general expressions for the decay rates in terms of the dyadic Green function. We focus on the decay rates in free space and near an infinite half space. For the decay of atoms near to an absorbing dielectric surface we find a hierarchy of scaling laws depending on the atom-surface distance z.Comment: Updated to journal version. 16 page