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South Asians (SAs) have an increased prevalence of coronary artery disease (CAD) and myocardial infarction compared with age- and sex-adjusted White Caucasians (WCs). The mechanism for this increased risk is poorly understood. While classical CD14++CD16- monocytes act as independent predictors of cardiovascular disease, differences in the distribution of monocyte subsets between SA and WC have not been established. We aimed to determine if differences exist in monocyte subsets between SAs and WCs at risk for CAD.

If supercritical or near-critical carbon dioxide is mixed with an aqueous solution and the mixture is subsequently decompressed through a flow restrictor, a dense aerosol plume is formed¹ that can be rapidly dried at 25−95 °C. This temperature range is lower than that typically needed in conventional spray-drying aqueous solutions. At 1100 psi and ambient temperature, up to ≈2 mol % of carbon dioxide can dissolve in aqueous solutions, and when the aqueous solution is ejected from a 5-cm-long flow restrictor, 50−130 μm in inner diameter, it is hypothesized that fine droplets and microbubbles are formed. This aerosol plume can be diluted with dry nitrogen (or air if there is no explosion hazard) at temperatures usually between 25 and 80 °C. In a drying chamber <1-m long, the bubbles and droplets become rapidly dried and the powder is collected on a filter. The particles are usually spherical or nearly spherical and residual moisture is typically 1% or less. For some substances, such as sodium chloride, mannitol, or tobramycin sulfate, hollow particles can be formed. For others, such as lactose and albuterol sulfate, the spherical particles are solid, with diameters mostly between 0.5 and 5 μm. Depending on the solute and conditions of drying, the particles are crystalline in some cases and amorphous in others.

The reaction of KCpⁿⁱ (Cpⁿⁱ = (C3H7)nC5H5-n; n = 3, 4) with MnCl2 in THF produces the metallocenes (Cp³ⁱ)2Mn or (Cp⁴ⁱ)2Mn in good yield. Solid-state magnetic susceptibility measurements indicate that orange-red (Cp³ⁱ)2Mn is in high-spin/low-spin equilibrium at room temperature. In the solid-state, it has a centrosymmetric sandwich structure with an average Mn−C bond length (2.130(6) Å) typical of low-spin manganocenes. (Cp³ⁱ)2Mn reduces tetracyanoethylene (TCNE) to generate the TCNE radical anion. Despite the presence of additional electron-donating isopropyl groups, pale yellow (Cp⁴ⁱ)2Mn is entirely high-spin from room temperature to 10 K. The crystal structure of (Cp⁴ⁱ)2Mn reveals a bent metallocene structure, with a centroid−Mn−centroid angle of 167.4° and an average Mn−C distance of 2.42(2) Å. This structure is consistent with its high-spin electron configuration; the longer Mn−C bonds provide relief from the steric strain that would be present in a low-spin complex. The reaction of (Cp⁴ⁱ)2Mn with TCNE produces a tricyanovinylation product, C5(i-Pr)4HC(CN)&dbd;C(CN)2, which was characterized by X-ray diffraction.

To evaluate the possibility of administering therapeutic proteins via the respiratory route, we administered an aerosol of recombinant DNA-produced human alpha 1-antitrypsin (rAAT) to anesthetized sheep and measured levels of the protein in epithelial lining fluid (ELF), lung lymph, blood, and urine. Using a nebulizer that generated aerosol droplets with a mass median aerodynamic diameter of 2.7 micron (55% of droplets were less than 3 micron, a particle size optimal for deposition on the alveolar epithelium), in vitro studies demonstrated that the aerosolized rAAT remained intact and fully functional as an inhibitor of neutrophil elastase. When aerosolized to sheep, the 45-kDa rAAT molecule diffused across the alveolar epithelium, as evidenced by its presence in lung lymph and in blood. Comparison of ELF, lymph, blood, and urine rAAT levels demonstrated that the process was concentration dependent, with highest levels in ELF and in descending concentrations with approximately 10-fold concentration differences in each consecutive compartment, respectively. Importantly, evaluation with aerosolized 125I-labeled rAAT demonstrated that the rAAT molecules that reached the lung lymph and the systemic circulation remained intact as a 45-kDa protein. These results demonstrate the feasibility of using aerosolization to the pulmonary epithelial surface to administer sizeable proteins of therapeutic interest, thus circumventing the necessity of the traditional parenteral modes of administration of such molecules.

Successful gene transfer into stem cells would provide a potentially useful therapeutic modality for treatment of inherited and acquired disorders affecting hematopoietic tissues. Coculture of primate bone marrow cells with retroviral producer cells, autologous stroma, or an engineered stromal cell line expressing human stem cell factor has resulted in a low efficiency of gene transfer as reflected by the presence of 0.1-5% of genetically modified cells in the blood of reconstituted animals. Our experiments in a nonhuman primate model were designed to explore various transduction protocols that did not involve coculture in an effort to define clinically useful conditions and to enhance transduction efficiency of repopulating cells. We report the presence of genetically modified cells at levels ranging from 0.1% (granulocytes) to 14% (B lymphocytes) more than 1 year following reconstitution of myeloablated animals with CD34+ immunoselected cells transduced in suspension culture with cytokines for 4 days with a retrovirus containing the glucocerebrosidase gene. A period of prestimulation for 7 days in the presence of autologous stroma separated from the CD34+ cells by a porous membrane did not appear to enhance transduction efficiency. Infusion of transduced CD34+ cells into animals without myeloablation resulted in only transient appearance of genetically modified cells in peripheral blood. Our results document that retroviral transduction of primate repopulating cells can be achieved without coculture with stroma or producer cells and that the proportion of genetically modified cells may be highest in the B-lymphoid lineage under the given transduction conditions.

Effective gene therapy for the severe hemoglobin (Hb) disorders, sickle-cell anemia and thalassemia, will require an efficient method to transfer, integrate, and express a globin gene in primary erythroid cells. To evaluate recombinant adeno-associated virus (rAAV) for this purpose, we constructed a rAAV vector encoding a human gamma-globin gene (pJM24/vHS432A gamma). Its 4725-nucleotide genome consists of two 180-bp AAV inverted terminal repeats flanking the core elements of hypersensitive sites 2, 3, and 4 from the locus control region of the beta-globin gene cluster, linked to a mutationally marked A gamma-globin gene (A gamma) containing native promoter and RNA processing signals. CD34+ human hematopoietic cells were exposed to rAAV particles at a multiplicity of infection of 500-1000 and cultured in semisolid medium containing several cytokines. A reverse transcriptase polymerase chain reaction assay distinguished mRNA signals derived from transduced and endogenous human gamma-globin genes. Twenty to 40% of human erythroid burst-forming unit-derived colonies expressed the rAAV-transduced A gamma-globin gene at levels 4-71% that of the endogenous gamma-globin genes. The HbF content of pooled control colonies was 26%, whereas HbF was 40% of the total in pooled colonies derived from rAAV transduced progenitors. These data establish that rAAV containing elements from the locus control region linked to a gamma-globin gene are capable of transferring and expressing that gene in primary human hematopoietic cells resulting in a substantial increase in HbF content.

The hereditary disorder α1-antitrypsin (α1AT) deficiency results in the development of emphysema due to a diminished anti—neutrophil elastase screen of the lower respiratory tract. Specific therapy for this disorder is available in the form of weekly intravenous infusions of human plasma α1AT, which effectively reconstitute the anti-elastase screen of the lung in these individuals. In an attempt to reduce the frequency of therapy we evaluated the ability of monthly infusions of α1AT to provide equivalent lower respiratory tract protection against neutrophil elastase. Intravenous infusion of 250 mg/kg of α1AT at 28-day intervals to nine individuals with α1AT deficiency and emphysema was carried out for 12 months. Serum α1AT levels exceeded the protective threshold for an average of 25 days after each dose of α1AT was administered. Furthermore, the postinfusion level of α1AT in the nadir lung epithelial lining fluid was fivefold greater than the preinfusion level, and the anti—neutrophil elastase capacity of the nadir epithelial lining fluid also was elevated significantly, nearly threefold above the preinfusion level. These results indicate that monthly administration of human α1AT is fully capable of adequately augmenting serum and lung α1AT levels and anti-elastase capacity and is therefore a rational alternative to weekly therapy.(JAMA 1988;260:1259-1264)

AbstractThe signs of the Leslie viscosities α2and α3for rod-like and disc-like molecules in the uniaxial nematic phase are discussed using a dynamic molecular mean field theory based upon a Fokker-Planck equation. The viscosities are shown to depend on the particle geometry and alignment order parameters. In particular, for positive degree of alignment S2, the calculations tend to confirm Carlsson's conjecture relating the signs of the two viscosities to the particle geometry. Furthermore, a transition in the signs of α2for discotics and α3for nematics is predicted with increasing order parameter S2in accord with recent experiments. For small degree of alignment S2, the results reproduce previous calculations obtained by Hess in a truncation approximation. The qualitative flow behaviour depends upon the signs of these viscosities.

The monomeric bis(indenyl) complex [1,3-(C3H7)2C9H5)]2Cr is high spin from 20 K to room temperature. The isopropyl groups block the dimerization that occurs with the unsubstituted (C9H7)2Cr complex but do not affect its spin state.

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