Obesity, white blood cell counts, and platelet counts among police officers

Objective: To determine the association between several obesity indices (BMI, waist circumference, waist‐to‐hip and waist‐to‐height ratios, and abdominal height) and hematologic parameters [white blood cell (WBC) and platelet counts] among police officers. Research Methods and Procedures: The authors conducted this cross‐sectional study among 104 randomly selected officers (41 women and 63 men) from the Buffalo, NY, Police Department. Anthropometric measures were performed by clinic staff, and fasting blood samples were drawn for complete blood counts. Pearson's correlation, Student's t tests, ANOVA, analysis of covariance, and linear regression were used to assess the associations. Results: Officers ranged in age from 26 to 61 years old and were predominantly white. Among women, current smokers had significantly higher WBC counts (7.4 × 10³ cells/µL ± 1.4) than former (5.2 × 10³ cells/µL ± 1.4) or never smokers (5.6 × 10³ cells/µL ± 1.5) (p = 0.002). Women had similar WBC counts but higher mean platelet counts than men (p = 0.005). Among women, abdominal height was positively associated with platelet count after adjustment for depression (p for trend = 0.039). Among women and men, a non‐significant step‐wise trend was observed between abdominal height and mean WBC counts before and after adjustment for smoking, race, and physical activity. No association was observed between obesity and platelet count among men. Discussion: Abdominal height was significantly associated with increased platelet counts among female officers. No significant associations were observed between obesity and WBC or platelet counts among male officers.     

Novel substituted pyrimidines as HCV replication (replicase) inhibitors

Compound 1 was identified as a HCV replication inhibitor from screening/early SAR triage. Potency improvement was achieved via modulation of substituent on the 5-azo linkage. Due to potential toxicological concern, the 5-azo linkage was replaced with 5-alkenyl or 5-alkynyl moiety. Analogs containing the 5-alkynyl linkage were found to be potent inhibitors of HCV replication. Further evaluation identified compounds 53 and 63 with good overall profile, in terms of replicon potency, selectivity and in vivo characteristics. Initial target engagement studies suggest that these novel carbanucleoside-like derivatives may inhibit the HCV replication complex (replicase).     

Synthesis and SAR of pyridothiazole substituted pyrimidine derived HCV replication inhibitors

Introduction of a nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzothiazole inhibitor 1, resulted in the discovery of the more potent pyridothiazole analogues 3. The potency and PK properties of the compounds were attenuated by the introductions of various functionalities at the R(1), R(2) or R(3) positions of the molecule (compound 3). Inhibitors 38 and 44 displayed excellent potency, selectivity (GAPDH/MTS CC(50)), PK parameters in all species studied, and cross genotype activity.     

Dendritic cell-mediated induction of mucosal cytotoxic responses following intravaginal immunization with the nontoxic B subunit of cholera toxin

The use of the nontoxic B subunit of cholera toxin (CTB) as mucosal adjuvant and carrier-delivery system for inducing secretory Ab responses has been documented previously with different soluble Ags. In this study, we have evaluated this approach for inducing CTL responses against a prototype Ag, OVA, in the female genital mucosa. We report here the ability of an immunogen comprised of CTB conjugated to OVA (CTB-OVA) given by intravaginal (ivag) route to induce genital OVA-specific CTLs in mice. Using adoptive transfer models, we demonstrate that ivag application of CTB-OVA activates OVA-specific IFN-gamma-producing CD4 and CD8 T cells in draining lymph nodes (DLN). Moreover, ivag CTB induces an expansion of IFN-gamma-secreting CD8+ T cells in DLN and genital mucosa and promotes Ab responses to OVA. In contrast, ivag administration of OVA alone or coadministered with CTB failed to induce such responses. Importantly, we demonstrate that ivag CTB-OVA generates OVA-specific CTLs in DLN and the genital mucosa. Furthermore, genital CD11b+ CD11c+ dendritic cells (DCs), but not CD8+ CD11c+ or CD11c- APCs, present MHC class I epitopes acquired after ivag CTB-OVA, suggesting a critical role of this DC subset in the priming of genital CTLs. Inhibition studies indicate that the presentation of OVA MHC class I epitopes by DCs conditioned with CTB-OVA involves a proteasome-dependent and chloroquine-sensitive mechanism. These results demonstrate that CTB is an efficient adjuvant-delivery system for DC-mediated induction of genital CTL responses and may have implications for the design of vaccines against sexually transmitted infections.     

The relation between the specific absorption rate and electromagnetic field intensity for heterogeneous exposure conditions at mobile communications frequencies

The relation between the incident electromagnetic field strength and both the whole‐body and the local specific absorption rate (SAR) was investigated for typical heterogeneous exposure scenarios for frequencies relevant for mobile communication. The results were compared to results from plane wave exposure. Heterogeneous exposure arises from multiple path propagation of the electromagnetic waves to the location of interest. It is shown that plane wave exposure does not represent worst‐case exposure conditions. When the electric field strength arising at plane wave exposure is compared to the electric field strength averaged over the volume of the human body occurring during multipath exposure, 12% of all heterogeneous cases examined represent worse exposure conditions than plane wave exposure for whole‐body exposure at 946 MHz, 15% at 1840 MHz, and 22% at 2140 MHz. The deviation between plane wave and heterogeneous whole‐body SAR ranges from ?54% to 54%. For partial‐body SAR averaged over 10 g of tissue, a range from ?93% to 209% was found when comparing multiple wave exposure to single incoming plane waves. The investigations performed using the Visible Human as phantom showed that the basic restrictions are met as long as the reference levels are not exceeded. However, this must not be necessarily the case when different phantoms are used to perform similar investigations because recent studies demonstrated that reference levels might not be conservative when phantoms of children are used. Therefore, the results of this work indicate the need to extend the investigations to numerical simulations with additional human phantoms representing parts of the human population having different anatomy and morphology compared to the phantom used within the frame of this project. This also applies to phantoms of children. Bioelectromagnetics 30:651–662, 2009. © 2009 Wiley‐Liss, Inc.     

Fine sediment affects on survival to emergence of robust redhorse

Robust redhorse (Moxostoma robustum) is a rare riverine sucker for which life history information is scarce. Spawning occurs over loose gravel substrate and eggs and larvae may be adversely affected by fine sediments among the gravel. A 2-year study was conducted to determine the threshold at which fine sediments are detrimental to successful egg incubation and larval emergence. Year 1 gravel treatments contained 0, 25, 50, and 75% fine sediments. Mean survival during Year 1 ranged from 63.5% in the 0% fine sediment treatment to 0% in the 75% fine sediment treatment. The results also indicated an adverse affect threshold between 0 and 25% fine sediment. Year 2 gravel treatments contained 0, 5, 10, 15, 20, and 25% fine sediments. Mean survival during Year 2 ranged from 69.8% in the 0% treatment to 9.1% in the 25% treatment. Year 2 results also identified the 15% fine sediment treatment as the threshold at which survival began to decline. Substrates at one known spawning area used by robust redhorse typically contain 25 to 50% fine sediment, but the spawning act cleans some fines from the egg pocket. Whether the “cleaning” that results from the spawning act reduces the fines sufficiently to avoid adverse effects is unknown. According to our results, survival rates of robust redhorse eggs and larvae are predicted to be about 8.0% or less when fine sediment is >25%.     

Quantitative in vivo magnetic resonance spectroscopy using synthetic signal injection

Accurate conversion of magnetic resonance spectra to quantitative units of concentration generally requires compensation for differences in coil loading conditions, the gains of the various receiver amplifiers, and rescaling that occurs during post-processing manipulations. This can be efficiently achieved by injecting a precalibrated, artificial reference signal, or pseudo-signal into the data. We have previously demonstrated, using in vitro measurements, that robust pseudo-signal injection can be accomplished using a second coil, called the injector coil, properly designed and oriented so that it couples inductively with the receive coil used to acquire the data. In this work, we acquired nonlocalized phosphorous magnetic resonance spectroscopy measurements from resting human tibialis anterior muscles and used pseudo-signal injection to calculate the Pi, PCr, and ATP concentrations. We compared these results to parallel estimates of concentrations obtained using the more established phantom replacement method. Our results demonstrate that pseudo-signal injection using inductive coupling provides a robust calibration factor that is immune to coil loading conditions and suitable for use in human measurements. Having benefits in terms of ease of use and quantitative accuracy, this method is feasible for clinical use. The protocol we describe could be readily translated for use in patients with mitochondrial disease, where sensitive assessment of metabolite content could improve diagnosis and treatment.     

GTP binding and hydrolysis kinetics of human septin 2

Septins are a family of conserved proteins that are essential for cytokinesis in a wide range of organisms including fungi, Drosophila and mammals. In budding yeast, where they were first discovered, they are thought to form a filamentous ring at the bridge between the mother and bud cells. What regulates the assembly and function of septins, however, has remained obscure. All septins share a highly conserved domain related to those found in small GTPases, and septins have been shown to bind and hydrolyze GTP, although the properties of this domain and the relationship between polymerization and GTP binding/hydrolysis is unclear. Here we show that human septin 2 is phosphorylated in vivo at Ser218 by casein kinase II. In addition, we show that recombinant septin 2 binds guanine nucleotides with a Kd of 0.28 microm for GTPgammaS and 1.75 microm for GDP. It has a slow exchange rate of 7 x 10(-5) s(-1) for GTPgammaS and 5 x 10(-4) s(-1) for GDP, and an apparent kcat value of 2.7 x 10(-4) s(-1), similar to those of the Ras superfamily of GTPases. Interestingly, the nucleotide binding affinity appears to be altered by phosphorylation at Ser218. Finally, we show that a single septin protein can form homotypic filaments in vitro, whether bound to GDP or GTP.