Termination Kinetics of 1‐Vinylpyrrolidin‐2‐one Radical Polymerization in Aqueous Solution

Termination kinetics of 1‐vinylpyrrolidin‐2‐one radical polymerization in aqueous solution has been studied at 40 °C between 20 and 100 wt.‐% VP. The <k_t>/k_p values from laser single‐pulse experiments with microsecond time‐resolved NIR detection of monomer conversion, in conjunction with k_p from literature, yield chain‐length‐averaged termination rate coefficients, <k_t>. Because of better signal‐to‐noise quality, experiments were carried out at 2 000 bar, but also at 1 500, 1 000, and 500 bar, thus allowing for estimates of <k_t> at ambient pressure. The dependence of <k_t> on monomer conversion indicates initial control by segmental diffusion followed by translational diffusion and finally reaction diffusion control. To assist the kinetic studies, viscosities of VP–water mixtures at ambient pressure have been determined.

     

Epitope‐dependent synergism and antagonism between CD40 antibodies and soluble CD40 ligand for the regulation of CD23 expression and IgE synthesis in human B cells

BACKGROUND: The induction of IgE synthesis in naive B cells requires two T-cell-derived signals: one delivered through CD40 and the other via interleukin-4 (IL-4). The natural counterstructure to CD40 is the CD40 ligand (CD40L). We have asked about the interplay between CD40L and CD40 mAb that recognize distinct epitopes in delivering signals for regulating IL-4-dependent IgE synthesis and the expression of CD23, the low-affinity IgE receptor, in resting B cells. METHODS: After culture of purified human tonsillar B cells with CD40 agonists and IL-4, surface CD23 was determined by flow cytometric analysis. CD23 levels in cell lysates and supernatants were quantified by ELISA, as were those of secreted IgE. RESULTS: With regard to both induction of CD23 and IgE production, soluble CD40L trimer (sCD40LT) showed synergistic interaction with two mAb to CD40 which bind to epitopes located outside the ligand binding site (EA5 and 5C3), but not with a mAb (G28-5) which effectively competes for CD40L binding to CD40. Each of the two noncompeting mAb to CD40 was able to cooperate strongly with sCD40LT in promoting high-level induction of CD23 even in the absence of IL-4, an effect mirrored in the promotion of strong homotypic clustering and high-rate DNA synthesis. G28-5, uniquely, induced a down-regulation in IL-4-induced CD23 expression with time, a change that was accompanied by an increase in the amount of soluble CD23 detected. While the two noncompeting mAb consistently synergized with sCD40LT for the promotion of IL-4-dependent IgE synthesis, sCD40LT and G28-5 (which, by itself, was the most potent of the CD40 mAb at inducing IL-4-dependent IgE production) exhibited mutual antagonism in this regard, the level of which could be quite profound. CONCLUSIONS: This study demonstrates that appropriate targeting of CD40 can modulate IgE synthesis either positively or negatively.     

Etanercept (Enbrel) administration for idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation.

Acute pulmonary dysfunction remains a frequent and severe complication of hematopoietic stem cell transplantation (SCT). Almost half of the pulmonary insults that occur in this seating are noninfectious in origin and are referred to as idiopathic pneumonia syndrome (IPS). In this series of 3 patients, etanercept (Enbrel; Immunex, Seattle, WA), a soluble, dimeric tumor necrosis factor alpha-binding protein, was administered to 3 consecutive pediatric allogeneic BMT recipients with IPS. The administration of etanercept, in combination with standard immunosuppressive therapy, was well tolerated and associated with significant improvements in pulmonary dysfunction within the first week of therapy. These data suggest that etanercept may represent a safe, non-cross-reactive, therapeutic option for patients with IPS and that clinical trials studying etanercept for this indication are warranted.     

Increased sensitivity to IL-4 in cystic fibrosis patients with allergic bronchopulmonary aspergillosis

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is characterized by a heightened Th2 CD4+ T-cell response to Aspergillus fumigatus allergens and a hyper-immunoglobulin (Ig)E state compared with cystic fibrosis patients without ABPA. We hypothesize that one reason for this response is increased sensitivity to interleukin (IL)-4 in ABPA resulting in increased expression of CD23 and CD86 and leading to a positive amplification mechanism that increases Th2 CD4+ T cell responses. METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from seven ABPA CF and 19 non-ABPA CF patients and 16 nonatopic controls and stimulated with rIL-4 (range 0.1-10 ng/ml) and rIL-13 (range 1-10 ng/ml) for 48 h. The number of CD23 molecules and percentages of CD23+ B cells were quantified by flow cytometry. Both phorbol 12-myristate 13-acetate (PMA)/ionomycin (IO) and antigen stimulated, toxoid and Asp f2/f3/f4, PBMC were examined for cytoplasmic cytokine synthesis enumerated by cytokine staining using flow cytometry to measure Th2 and Th1 CD3+ T cells. RESULTS: The numbers of CD23 molecules on B-cells were significantly elevated at time 0 in ABPA CF patients compared with both non-ABPA CF patients and nonatopic controls. Following IL-4 stimulation in vitro, the numbers and percentages of CD23 expression on B cells were significantly up-regulated in ABPA CF patients compared with non-ABPA CF patients and controls. The IL-13 stimulation up-regulated CD23 expression; however, there was no significant difference in ABPA CF patients compared with non-ABPA CF patients and controls. The percentages of interferon (IFN)-gamma+ CD3+T cells following PMA/IO stimulation were significantly decreased in both ABPA and non-ABPA CF patients compared with controls. There were no significant differences of IL-4+ and IL-13+ CD3+ T cells between ABPA and non-ABPA CF patients. When tetanus toxoid stimulated T cells were examined, both ABPA and non-ABPA CF patients had significantly decreased IFN-gamma+ CD3+ T cells compared with controls. In Asp f2/f3/f4 stimulated T cells, ABPA CF patients had significantly increased IL-4+ CD3+ T cells compared with non-ABPA CF patients and controls. CONCLUSIONS: ABPA CF patients have increased sensitivity to IL-4 but not to IL-13 up-regulation of CD23 molecules compared with non-ABPA CF patients. There were decreased percentages of IFN-gamma+ and IL-2+ Th1 T cells in CF patients compared with nonatopic controls but similar percentages of IL-4+ Th2 T cells in all three groups. However, ABPA CF patients had increased frequency of Aspergillus-stimulated Th2 T cells. This indicated that there is skewing of Th2 T cells in ABPA CF patients. Thus, in CF ABPA patients there is increased Th2 T cells and increased sensitivity to IL-4.     

Anatomy,morphology and evolution of the patella in squamate lizards and tuatara (Sphenodon punctatus)

The patella (kneecap) is the largest and best‐known of the sesamoid bones, postulated to confer biomechanical advantages including increasing joint leverage and reinforcing the tendon against compression. It has evolved several times independently in amniotes, but despite apparently widespread occurrence in lizards, the patella remains poorly characterised in this group and is, as yet, completely undescribed in their nearest extant relative Sphenodon (Rhynchocephalia). Through radiography, osteological and fossil studies we examined patellar presence in diverse lizard and lepidosauromorph taxa, and using computed tomography, dissection and histology we investigated in greater depth the anatomy and morphology of the patella in 16 lizard species and 19 Sphenodon specimens. We have found the first unambiguous evidence of a mineralised patella in Sphenodon, which appears similar to the patella of lizards and shares several gross and microscopic anatomical features. Although there may be a common mature morphology, the squamate patella exhibits a great deal of variability in development (whether from a cartilage anlage or not, and in the number of mineralised centres) and composition (bone, mineralised cartilage or fibrotendinous tissue). Unlike in mammals and birds, the patella in certain lizards and Sphenodon appears to be a polymorphic trait. We have also explored the evolution of the patella through ancestral state reconstruction, finding that the patella is ancestral for lizards and possibly Lepidosauria as a whole. Clear evidence of the patella in rhynchocephalian or stem lepidosaurian fossil taxa would clarify the evolutionary origin(s) of the patella, but due to the small size of this bone and the opportunity for degradation or loss we could not definitively conclude presence or absence in the fossils examined. The pattern of evolution in lepidosaurs is unclear but our data suggest that the emergence of this sesamoid may be related to the evolution of secondary ossification centres and/or changes in knee joint conformation, where enhancement of extensor muscle leverage would be more beneficial.     

The scaling of postcranial muscles in cats (Felidae) I: forelimb,cervical, and thoracic muscles

The body masses of cats (Mammalia, Carnivora, Felidae) span a ~300‐fold range from the smallest to largest species. Despite this range, felid musculoskeletal anatomy remains remarkably conservative, including the maintenance of a crouched limb posture at unusually large sizes. The forelimbs in felids are important for body support and other aspects of locomotion, as well as climbing and prey capture, with the assistance of the vertebral (and hindlimb) muscles. Here, we examine the scaling of the anterior postcranial musculature across felids to assess scaling patterns between different species spanning the range of felid body sizes. The muscle architecture (lengths and masses of the muscle‐tendon unit components) for the forelimb, cervical and thoracic muscles was quantified to analyse how the muscles scale with body mass. Our results demonstrate that physiological cross‐sectional areas of the forelimb muscles scale positively with increasing body mass (i.e. becoming relatively larger). Many significantly allometric variables pertain to shoulder support, whereas the rest of the limb muscles become relatively weaker in larger felid species. However, when phylogenetic relationships were corrected for, most of these significant relationships disappeared, leaving no significantly allometric muscle metrics. The majority of cervical and thoracic muscle metrics are not significantly allometric, despite there being many allometric skeletal elements in these regions. When forelimb muscle data were considered in isolation or in combination with those of the vertebral muscles in principal components analyses and MANOVAs, there was no significant discrimination among species by either size or locomotory mode. Our results support the inference that larger felid species have relatively weaker anterior postcranial musculature compared with smaller species, due to an absence of significant positive allometry of forelimb or vertebral muscle architecture. This difference in strength is consistent with behavioural changes in larger felids, such as a reduction of maximal speed and other aspects of locomotor abilities.     

A Combined Computational and Experimental Study on the Free‐Radical Copolymerization of Styrene and Hydroxyethyl Acrylate

Bulk free‐radical copolymerization of styrene and 2‐hydroxyethyl acrylate (HEA) is investigated experimentally at 50 °C using pulsed‐laser polymerization and computationally using ab initio simulations. Arrhenius parameters for HEA chain‐end homopropagation are A = 1.72 × 10⁷ L mol^?1 s^?1 and E_a = 16.8 kJ mol^?1, based on experiments between 20 and 60 °C. Copolymer composition data are well fitted by the terminal model with reactivity ratios r_ST = 0.44 ± 0.03 and r_HEA = 0.18 ± 0.04, but the variation in the propagation rate coefficient with monomer composition is underpredicted. Results are compared with computational predictions assuming the terminal as well as the penultimate unit effect (PUE) model. Intramolecular H‐bonding is shown to have a significant influence on PUE calculations. Discrepancies between computational predictions and experiment are attributed to the influence of intermolecular H‐bonding.     

Enrollment of racial/ethnic minorities and women with HIV in clinical research studies of HIV medicines

PURPOSE: Inclusion of women and racial/ethnic minorities is a requirement for federally supported clinical research, but data on clinical research participation from women and racial/ethnic minorities with HIV are few. To describe participation in clinical research of HIV medicines among women and racial/ethnic minorities, and associated factors, we used data from a cross-sectional behavioral surveillance interview project conducted in 15 U.S. states. METHODS: Data were from 6,892 persons living with HIV infection, recruited in facilities in seven U.S. states and using population-based methods in eight other states, between 2000-2004. We calculated self-reported participation in a clinical research study of HIV medicines, factors associated with self-reported study participation among men and women, and reasons for not participating in a study among nonparticipants. MAIN FINDINGS: Overall, 17% of respondents had ever participated in a clinical research study. For men, the odds of participation were lower for black or Hispanic men (versus white men) and were higher for men whose risk for HIV infection was male-male sex (versus men with male-female sex risk) and for men with AIDS. For men who had not participated in a study, black men were more likely than white men to report not participating in a study because they were unaware of available studies or were not offered enrollment (75% vs. 69%), and because they did not want to be a "guinea pig" (11% vs. 8%). Among women, participation was not associated with race/ethnicity or risk for HIV infection but was associated with living in an area with an NIH- or CDC- supported clinical research network. HIV-infected women were more likely than HIV-infected men with comparable modes of HIV acquisition to have participated in a study. CONCLUSIONS: Among persons with HIV interviewed in these 15 states, self-reported participation in clinical research studies was higher among women than men, but racial/ethnic minority men were less likely to report study participation. Our data suggest that clinicians and researchers should make increased efforts to offer study participation to racial and ethnic minority men.     

Diagnostic inertia in obesity and the impact on cardiovascular risk in primary care: a cross-sectional study

BackgroundPrevalence of diagnostic inertia (DI), defined as a failure to diagnose disease, has not been analysed in patients with obesity.AimTo quantify DI for cardiovascular risk factors (CVRF) in patients with obesity, and determine its association with the cardiovascular risk score.MethodAll patients with obesity attending during the first 6 months of the preventive programme were analysed. Participants had to be free of CVD (myocardial ischaemia or stroke) and aged 40–65 years; the criteria used to measure SCORE (Systematic COronary Risk Evaluation). Three subgroups of patients with obesity with no personal history of CVRF but with poor control of risk factors were established. Outcome variable was DI, defined as poor control of risk factors and no action taken by the physician. Secondary variables were diabetes, fasting blood glucose (FBG), body mass index (BMI), and SCORE. Adjusted odds ratios (OR) was determined using multivariate logistic regression models.ResultsOf 8687 patients with obesity in the programme, 6230 fulfilled SCORE criteria. Prevalence of DI in the three subgroups was: hypertension, 1275/1816 (70.2%) patients affected (95% CI = 68.1 to 72.3%); diabetes, 335/359 (93.3%) patients affected (95% CI = 90.7 to 95.9%); dyslipidaemia subgroup, 1796/3341 (53.8%) patients affected (95% CI = 52.1 to 55.4%. Factors associated with DI for each subgroup were: for hypertension, absence of diabetes, higher BMI, and greater cardiovascular risk; for dyslipidaemia, diabetes, higher BMI, and greater cardiovascular risk (SCORE); and for diabetes, lower FBG levels, lower BMI, and greater cardiovascular risk.ConclusionThis study quantified DI in patients with obesity and determined that it was associated with a greater cardiovascular risk.     

Analysis of taste mixtures by adults and children

Children at mid-childhood (8-9 years), have limited perceptual-attentional skills to analyze complex stimuli (Shepp, Barrett, & Kolbet, 1987), and little is known of their skills to analyze chemosensory stimuli. Accordingly, this study investigated the ability of adults and 8-9 year old children to perceive tastes in binary mixtures. In Experiment 1, subjects used a selective attention procedure to indicate whether sweet, salty, and sour tastes were present in stimuli consisting of sucrose (sweet), sodium chloride (salty), citric acid (sour), and all possible binary mixtures of these tastants. Adults correctly recognized the two tastes in all mixtures, whilst children recognized only one in each mixture. Children were successful in recognizing sweet in both sweet-containing mixtures and salty in the sodium chloride-citric acid mixture. In Experiment 2, subjects used a similar selective attention paradigm to assess the perceived intensity of the three tastes in the above single and two-component stimuli. Suppression of one or both components was recorded with most mixtures by both age groups. However, with the mixture sodium chloride-citric acid, only the children recorded suppression of sourness, whilst for adults only saltiness was suppressed. In neither mixture containing sourness did children report suppression of sweetness or saltiness. It is concluded that at mid-childhood humans have difficulty analyzing taste mixtures into their components, due to attentional and possibly gustatory shortcomings.