Organ failure and tight glycemic control in the SPRINT study

Introduction  

Intensive care unit mortality is strongly associated with organ failure rate and severity. The sequential organ failure assessment (SOFA) score is used to evaluate the impact of a successful tight glycemic control (TGC) intervention (SPRINT) on organ failure, morbidity, and thus mortality.     

Advances in Predicting and Manipulating the Immunogenicity of Biotherapeutics and Vaccines

Therapeutic proteins are vital to the future of human health provision and the survival and profitability of the global pharmaceutical industry. Returns from protein therapeutics are experiencing unprecedented growth: both their number and their economic dividend have increased by an order of magnitude in the last 10 years. The potential immunogenicity of protein therapeutics raises many clinical and safety concerns. Many poorly understood factors relating to both product and host affect immune responses. Available laboratory measurement of immunogenicity is of little utility for predicting the clinical properties of biotherapeutics. Coupled with assay variability and standardization issues, this precludes adequate prediction of the biological or clinical responses of therapeutic proteins, arguing for the utilization of informatic strategies in the analysis and prediction of protein immunogenicity. Currently, many unresolved issues must be addressed and thus circumvented before effective prediction can become routine.     

Glycoprotein Ib and glycoprotein IX are fully complexed in the intact platelet membrane

Two new murine monoclonal antibodies, AK 1 and SZ 1, reactive with the human platelet glycoprotein (GP) Ib-IX complex have been produced by the hybridoma technique. Both AK 1 and SZ 1 immunoprecipitated the GP Ib-IX complex from Triton X-100-solubilized, periodate-labeled platelets. With trypsinized, labeled platelets, AK 1, SZ 1, and FMC 25 (epitope on GP IX) immunoprecipitated a membrane-bound proteolytic fragment of the GP Ib-IX complex consisting of GP IX and an congruent to 25,000 mol wt remnant of the alpha-chain of GP lb disulfide-linked to the beta-subunit. Unexpectedly, although AK 1 and SZ 1 immunoprecipitated purified GP Ib-IX complex, neither antibody immunoprecipitated the individual components of this complex, GP Ib or GP IX. When GP Ib and GP IX were recombined, however, AK 1 and SZ 1 again immunoprecipitated the reformed complex, strongly suggesting that both antibodies were recognizing an epitope present only on the intact complex. Cross-blocking studies indicated that AK 1 and SZ 1 recognized a very similar or identical epitope that was proximal to the epitope for FMC 25. Both AK 1 and SZ 1 bound to a similar number of binding sites (congruent to 25,000) on intact platelets as monoclonal antibodies directed against either GP lb or GP IX. The combined data suggests that GP lb and GP IX are fully complexed in the intact platelet membrane.     

A randomized trial of a primary care-based disease management program to improve cardiovascular risk factors and glycated hemoglobin levels in patients with diabetes

PURPOSE: To assess the efficacy of a pharmacist-led, primary care-based, disease management program to improve cardiovascular risk factors and glycated hemoglobin (A(1C)) levels in vulnerable patients with poorly controlled diabetes. METHODS: A randomized controlled trial of 217 patients with type 2 diabetes and poor glycemic control (A(1C) level >or=8.0%) was conducted at an academic general medicine practice from February 2001 to April 2003. Intervention patients received intensive management from clinical pharmacists, as well as from a diabetes care coordinator who provided diabetes education, applied algorithms for managing glucose control and decreasing cardiovascular risk factors, and addressed barriers to care. Control patients received a one-time management session from a pharmacist followed by usual care from their primary care provider. Outcomes were recorded at baseline and at 6 and 12 months. Primary outcomes included blood pressure, A(1C) level, cholesterol level, and aspirin use. Secondary outcomes included diabetes knowledge, satisfaction, use of clinical services, and adverse events. RESULTS: For the 194 patients (89%) with 12-month data, the intervention group had significantly greater improvement than did the control group for systolic blood pressure (-9 mm Hg; 95% confidence interval [CI]: -16 to -3 mm Hg) and A(1C) level (-0.8%; 95% CI: -1.7% to 0%). Change in total cholesterol level was not significant. At 12 months, aspirin use was 91% in the intervention group versus 58% among controls (P <0.0001). Intervention patients had greater improvements in diabetes knowledge and satisfaction than did control patients. There were no significant differences in use of clinical services or adverse events. CONCLUSION: Our comprehensive disease management program reduced cardiovascular risk factors and A(1C) levels among vulnerable patients with type 2 diabetes and poor glycemic control.     

Myeloproliferative syndrome induced by MPSV in DBA/2 mice: presence of a mixed-colonies promoting activity (MPA) in the spleen

The myeloproliferative syndrome induced by the myeloproliferative sarcoma virus (MPSV) in DBA/2 mice stimulates the proliferation of pluripotent hemopoietic stem cells (HSC) and of progenitors committed toward granulomacrophagic and erythroid cell lines. This stimulation may result from a direct effect of the MPSV on HSC or from an indirect effect via locally secreted factors. Normal isogenic bone marrow cells were incubated in the mixed colony-forming unit system in semisolid medium supplemented with conditioned media obtained after incubating neoplastic spleen cells for 3 days at 37 degrees C. These spleen conditioned media contain an activity that is physically separable from MPSV by ultracentrifugation and which, in the presence of a very low quantity of erythropoietin, can induce in vitro the proliferation and differentiation of pluripotent HSC, detected by this Mix-CFU technique. We termed this activity mixed-colonies promoting activity (MPA). These results suggest that the hyperplasia of the nonlymphoid hematopoietic system in the neoplastic spleen results from an indirect effect of the MPSV on pluripotent HSC via locally secreted factors.     

The association of differing measures of overweight and obesity with prevalent atherosclerosis: the Dallas Heart Study.

OBJECTIVES: This study sought to evaluate the associations between different measures of obesity and prevalent atherosclerosis in a large population-based cohort. BACKGROUND: Although obesity is associated with cardiovascular mortality, it is unclear whether this relationship is mediated by increased atherosclerotic burden. METHODS: Using data from the Dallas Heart Study, we assessed the association between gender-specific obesity measures (i.e., body mass index [BMI]; waist circumference [WC]; waist-to-hip ratio [WHR]) and prevalent atherosclerosis defined as coronary artery calcium (CAC) score >10 Agatston units measured by electron-beam computed tomography and detectable aortic plaque measured by magnetic resonance imaging. RESULTS: In univariable analyses (n = 2,744), CAC prevalence was significantly greater only in the fifth versus first quintile of BMI, whereas it increased stepwise across quintiles of WC and WHR (p trend <0.001 for each). After multivariable adjustment for standard risk factors, prevalent CAC was more frequent in the fifth versus first quintile of WHR (odds ratio 1.91, 95% confidence interval 1.30 to 2.80), whereas no independent positive association was observed for BMI or WC. Similar results were observed for aortic plaque in both univariable and multivariable-adjusted analyses. The c-statistic for discrimination of prevalent CAC was greater for WHR compared with BMI and WC in women and men (p < 0.001 vs. BMI; p < 0.01 vs. WC). CONCLUSIONS: We discovered that WHR was independently associated with prevalent atherosclerosis and provided better discrimination than either BMI or WC. The associations between obesity measurements and atherosclerosis mirror those observed between obesity and cardiovascular mortality, suggesting that obesity contributes to cardiovascular mortality via increased atherosclerotic burden.     

Geometrical manipulation of complex supramolecular tessellations by hierarchical assembly of amphiphilic platinum(II) complexes

Here we report complex supramolecular tessellations achieved by the directed self-assembly of amphiphilic platinum(II) complexes. Despite the twofold symmetry, these geometrically simple molecules exhibit complicated structural hierarchy in a columnar manner. A possible key to such an order increase is the topological transition into circular trimers, which are noncovalently interlocked by metal···metal and π–π interactions, thereby allowing for cofacial stacking in a prismatic assembly. Another key to success is to use the immiscibility of the tailored hydrophobic and hydrophilic sidechains. Their phase separation leads to the formation of columnar crystalline nanostructures homogeneously oriented on the substrate, featuring an unusual geometry analogous to a rhombitrihexagonal Archimedean tiling. Furthermore, symmetry lowering of regular motifs by design results in an orthorhombic lattice obtained by the coassembly of two different platinum(II) amphiphiles. These findings illustrate the potentials of supramolecular engineering in creating complex self-assembled architectures of soft materials.

Tessellation in two dimensions (2D) is a very old topic in geometry on how one or more shapes can be periodically arranged to fill a Euclidean plane without any gaps. Tessellation principles have been extensively applied in decorative art since the early times. In natural sciences, there has been a growing attention on creating ordered structures with increasingly complex architectures inspired by semi-regular Archimedean tilings (ATs) and quasicrystalline textures on account of their intriguing physical properties (1–5) and biological functions (6). Recent advances in this regard have been achieved in various fields of supramolecular science, including the programmable self-assembly of DNA molecules (7), coordination-driven assembly (8–10), supramolecular interfacial engineering (11–13), crystallization of organic polygons (14, 15), colloidal particle superlattices (16), and other soft-matter systems (17–20). Moreover, tessellation in 2D can overcome the topological frustration to generate complex semi- or non-regular patterns by using geometrically simple motifs. As exemplified by the self-templating assembly of spherical soft microparticles (21), a vast array of 2D micropatterns encoding non-regular tilings, such as rectangular, rhomboidal, hexagonal, and herringbone superlattices were obtained by layer-by-layer strategy at a liquid–liquid interface. Tessellation principles have also been extended to the self-assembly of giant molecules in three dimensions (3D). Superlattices with high space-group symmetry (Im3¯m, Pm3¯n, and P4₂/mnm) were reported in dendrimers and dendritic polymers by Percec and coworkers (22–24). Recently, Cheng and coworkers identified the highly ordered Frank–Kasper phases obtained from giant amphiphiles containing molecular nanoparticles (25–28). Despite such advancements made in the field of soft matter, an understanding of how structural ordering in supramolecular materials is influenced by the geometric factors of its constituent molecules has so far remained elusive.In light of these developments and the desire to explore the supramolecular systems, square-planar platinum(II) (Pt^II) polypyridine complexes may serve as an ideal candidate for model studies not only because of their intriguing spectroscopic and luminescence properties (29, 30), but also because of their propensity to form supramolecular polymers or oligomers via noncovalent Pt···Pt and π–π interactions (31–39). Although rod-shaped and lamellar structures are the most commonly observed in the self-assembly of planar Pt^II complexes (34–39), 2D-ordered nanostructures, such as the hexagonally packed columns (31, 40) and honeycomb-like networks (41–43), were recently first demonstrated by us.Herein, we report a serendipitous discovery of a C_2h-symmetric Pt^II amphiphile (Fig. 1A) that can hierarchically self-assemble into a 3D-ordered nanostructure with hexagonal geometry. Interestingly, this structurally anisotropic molecule possibly undergoes topological transition and interlocks to form its circular trimer by noncovalent Pt···Pt and π–π interactions (Fig. 1B). The resultant triangular motif is architecturally stabilized and preorganized for one-dimensional (1D) prismatic assembly (Fig. 1C). Together with the phase separation of the tailored hydrophobic and hydrophilic sidechains, an unusual and unique 3D hexagonal lattice is formed (Fig. 1D), in which the Pt centers adopt a rare rhombitrihexagonal AT-like order. Finally, the nanoarchitecture develops in a hierarchical manner on the substrate due to the homogeneous nucleation (Fig. 1E).Open in a separate windowFig. 1.Hierarchical self-assembly of Pt^II amphiphile into hexagonal ordering. (A) Space-filling (CPK) model of a C_2h-symmetric Pt^II amphiphile (1). All of the hydrogen atoms and counterions are omitted for clarity. (B) CPK representations of possible models of regular triangular, tetragonal, pentagonal, and hexagonal motifs formed with Pt···Pt and π–π stacking. These motifs possess a hydrophilic core (red) with various diameters wrapped by a hydrophobic shell comprising long alkyl chains (gray). (C) CPK representation of a 1D prismatic structure consisting of circular trimers with long-range Pt···Pt and π–π stacking. (D) CPK representation of a 3D columnar lattice constructed by the prismatic assemblies adopting a rare rhombitrihexagonal AT-like order. With the assistance of the phase separation, the hydrophobic domain serves as a discrete column associated with six prismatic neighbors. (E) Schematic representation of the nanoarchitecture with homogeneous orientation.     

Induction of advanced glycation end products and alterations of the tensile properties of articular cartilage

OBJECTIVE: To determine whether increasing advanced glycation end products (AGEs) in bovine articular cartilage to levels present in aged human cartilage modulates the tensile biomechanical properties of the tissue. METHODS: Adult bovine articular cartilage samples were incubated in a buffer solution with ribose to induce the formation of AGEs or in a control solution. Portions of cartilage samples were assayed for biochemical indices of AGEs and tested to assess their tensile biomechanical properties, including stiffness, strength, and elongation at failure. RESULTS: Ribose treatment of cartilage induced increases in tissue fluorescence, absorbance, and pentosidine content (P < 0.001 for each comparison) by amounts similar to those that occur during aging in humans. Ribose treatment of cartilage also induced an increase in dynamic modulus (60% increase) and strength (35% increase), and a decrease (25% decrease) in strain (P < 0.001 for each comparison). CONCLUSION: The concomitant increase in AGEs and alteration of tensile properties of cartilage after ribose treatment suggest that aging-associated changes in AGEs have functional consequences for this tissue. The AGE-associated increases in strength and stiffness of cartilage may be beneficial by counteracting the decreases in these properties that are associated with degeneration. Conversely, the AGE-associated decrease in failure length, or increase in brittleness, together with increased stiffness may predispose cartilage to increased stress concentration, fracture, and aging-associated biomechanical dysfunction.