Prevalence of down syndrome among children and adolescents in metropolitan Atlanta

BACKGROUND: Down syndrome (DS) prevalence estimates beyond infancy are needed to assess health service needs among those with DS. METHODS: Children with DS born in metropolitan Atlanta from 1979 through 2003 were ascertained from a population-based birth defects registry. Vital status through 2003 was obtained using case records, vital records, and the National Death Index. Prevalence was calculated by dividing the children surviving with DS by the population derived from U.S. Census estimates. Variations in DS prevalence by race, heart defects, age, birth cohort, and time period were examined using Poisson regression. RESULTS: In metropolitan Atlanta in 2003, there were 67 livebirths with DS (13.0 per 10,000 livebirths) and 738 0- to 19-year-olds surviving with DS (8.3 per 10,000 population). Over time, births to mothers 35 years and older and DS birth prevalence increased. Birth prevalence was higher among Whites, did not vary by sex, and was higher for infants without heart defects. DS prevalence among 0- to 14-year-olds increased over time (p < .05). Within each 5 year birth cohort, prevalence decreased with age: this decrease was greater among Blacks than among Whites and among children with heart defects than among children without heart defects. CONCLUSIONS: DS prevalence increased among livebirths and among young children. Further studies are warranted to determine whether health services are meeting the needs of an increasing number of children with DS.     

The sporulation protein SirA inhibits the binding of DnaA to the origin of replication by contacting a patch of clustered amino acids

Bacteria regulate the frequency and timing of DNA replication initiation by controlling the activity of the replication initiator protein DnaA. SirA is a recently discovered regulator of DnaA in Bacillus subtilis whose synthesis is turned on at the start of sporulation. Here, we demonstrate that SirA contacts DnaA at a patch of 3 residues located on the surface of domain I of the replication initiator protein, corresponding to the binding site used by two unrelated regulators of DnaA found in other bacteria. We show that the interaction of SirA with domain I inhibits the ability of DnaA to bind to the origin of replication. DnaA mutants containing amino acid substitutions of the 3 residues are functional in replication initiation but are immune to inhibition by SirA.     

Immunosensitization with a Bcl-2 small molecule inhibitor

Several tumor immunotherapy approaches result in a low percentage of durable responses in selected cancers. We hypothesized that the insensitivity of cancer cells to immunotherapy may be related to an anti-apoptotic cancer cell milieu, which could be pharmacologically reverted through the inhibition of antiapoptotic Bcl-2 family proteins in cancer cells. ABT-737, a small molecule inhibitor of the antiapoptotic proteins Bcl-2, Bcl-w and Bcl-x_L, was tested for the ability to increase antitumor immune responses in two tumor immunotherapy animal models. The addition of systemic therapy with ABT-737 to the immunization of BALB/c mice with tumor antigen peptide-pulsed dendritic cells (DC) resulted in a significant delay in CT26 murine colon carcinoma tumor growth and improvement in survival. However, the addition of ABT-737 to either a vaccine strategy involving priming with TRP-2 melanoma antigen peptide-pulsed DC and boosting with recombinant Listeria monocytogenes expressing the same melanoma antigen, or the adoptive transfer of TCR transgenic cells, did not result in superior antitumor activity against B16 murine melanoma. In vitro studies failed to demonstrate increased cytotoxic lytic activity when testing the combination of ABT-737 with lymphokine activated killer (LAK) cells, or the death receptor agonists Fas, TRAIL-ligand or TNF-alpha against the CT26 and B16 cell lines. In conclusion, the Bcl-2 inhibitor ABT-737 sensitized cancer cells to the antitumor effect of antigen-specific immunotherapy in a vaccine model for the CT26 colon carcinoma in vivo but not in two immunotherapy strategies against B16 melanoma.     

Proteolysis and membrane capture of F-spondin generates combinatorial guidance cues from a single molecule

The formation of neuronal networks is governed by a limited number of guidance molecules, yet it is immensely complex. The complexity of guidance cues is augmented by posttranslational modification of guidance molecules and their receptors. We report here that cleavage of the floor plate guidance molecule F-spondin generates two functionally opposing fragments: a short-range repellent protein deposited in the membrane of floor plate cells and an adhesive protein that accumulates at the basement membrane. Their coordinated activity, acting respectively as a short-range repellant and a permissive short-range attractant, constricts commissural axons to the basement membrane beneath the floor plate cells. We further demonstrate that the repulsive activity of the inhibitory fragment of F-spondin requires its presentation by the lipoprotein receptor-related protein (LRP) receptors apolipoprotein E receptor 2, LRP2/megalin, and LRP4, which are expressed in the floor plate. Thus, proteolysis and membrane interaction coordinate combinatorial guidance signaling originating from a single guidance cue.     

Interpreting changes in the epidemiology of anencephaly and spina bifida following folic acid fortification of the U.S. grain supply in the setting of long-term trends, Atlanta, Georgia, 1968-2003

BACKGROUND: The prevalence of anencephaly (AN) and spina bifida (SB) was declining long before fortification of enriched grains in the U.S. with folic acid. We examined whether changes in these defects surrounding fortification could be distinguished from preexisting trends. METHODS: We used data from the Metropolitan Atlanta Congenital Defects Program to identify three ascertainment periods: Period 1 (1968-1981), prenatal diagnoses rarely made; Period 2 (1981-1993), prenatal diagnoses made but not ascertained; Period 3 (1994-2003), prenatal diagnoses ascertained. We compared the annual percent change (APC) in AN and SB for each period using Poisson regression, then compared prevalences during each period for categories of pregnancy outcome, sex, race, gravidity, and maternal age. RESULTS: The prevalence of AN (N = 434) and SB (N = 663) declined during 1968-2003. The APCs in Periods 1, 2, and 3, respectively, were -6.9%, -2.9%, and -6.8% for AN, and -7.1%, -7.0%, and -6.2% for SB; 95% confidence intervals around the APCs for Periods 2 and 3 overlapped for both defects. Prevalence ratios (PRs) for females relative to males decreased for AN (2.3 in Period 1; 1.2 in Period 3); PRs for whites relative to blacks or African Americans decreased for both AN (2.7 in Period 1; 1.2 in Period 3) and SB (2.5 in Period 1; 1.1 in Period 3). CONCLUSIONS: Our analysis suggests that changes in AN and SB surrounding folic acid fortification (Period 3) could be part of preexisting trends. This must be considered when evaluating prevention efforts.     

Anisotropy of Bullet-Shaped Magnetite Nanoparticles in the Magnetotactic Bacteria Desulfovibrio magneticus sp. Strain RS-1

Magnetotactic bacteria (MTB) build magnetic nanoparticles in chain configuration to generate a permanent dipole in their cells as a tool to sense the Earth’s magnetic field for navigation toward favorable habitats. The majority of known MTB align their nanoparticles along the magnetic easy axes so that the directions of the uniaxial symmetry and of the magnetocrystalline anisotropy coincide. Desulfovibrio magneticus sp. strain RS-1 forms bullet-shaped magnetite nanoparticles aligned along their (100) magnetocrystalline hard axis, a configuration energetically unfavorable for formation of strong dipoles. We used ferromagnetic resonance spectroscopy to quantitatively determine the magnetocrystalline and uniaxial anisotropy fields of the magnetic assemblies as indicators for a cellular dipole with stable direction in strain RS-1. Experimental and simulated ferromagnetic resonance spectral data indicate that the negative effect of the configuration is balanced by the bullet-shaped morphology of the nanoparticles, which generates a pronounced uniaxial anisotropy field in each magnetosome. The quantitative comparison with anisotropy fields of Magnetospirillum gryphiswaldense, a model MTB with equidimensional magnetite particles aligned along their (111) magnetic easy axes in well-organized chain assemblies, shows that the effectiveness of the dipole is similar to that in RS-1. From a physical perspective, this could be a reason for the persistency of bullet-shaped magnetosomes during the evolutionary development of magnetotaxis in MTB.     

A Genetic Strategy for Probing the Functional Diversity of Magnetosome Formation

Model genetic systems are invaluable, but limit us to understanding only a few organisms in detail, missing the variations in biological processes that are performed by related organisms. One such diverse process is the formation of magnetosome organelles by magnetotactic bacteria. Studies of model magnetotactic α-proteobacteria have demonstrated that magnetosomes are cubo-octahedral magnetite crystals that are synthesized within pre-existing membrane compartments derived from the inner membrane and orchestrated by a specific set of genes encoded within a genomic island. However, this model cannot explain all magnetosome formation, which is phenotypically and genetically diverse. For example, Desulfovibrio magneticus RS-1, a δ-proteobacterium for which we lack genetic tools, produces tooth-shaped magnetite crystals that may or may not be encased by a membrane with a magnetosome gene island that diverges significantly from those of the α-proteobacteria. To probe the functional diversity of magnetosome formation, we used modern sequencing technology to identify hits in RS-1 mutated with UV or chemical mutagens. We isolated and characterized mutant alleles of 10 magnetosome genes in RS-1, 7 of which are not found in the α-proteobacterial models. These findings have implications for our understanding of magnetosome formation in general and demonstrate the feasibility of applying a modern genetic approach to an organism for which classic genetic tools are not available.