Revisiting Polymer-Particle Interaction in PEO Solutions.

We have measured the electrophoretic mobility and diffusion coefficient of carboxylate-modified and sulfate-modified polystyrene latex particles in poly(ethylene oxide) aqueous solutions. Carboxylate-modified polystyrene particles have shown a bound polymeric layer as the surface net charge vanishes even at very low poly(ethylene oxide) concentration. The polymeric layer causes a lower electrophoretic mobility and slower Brownian diffusion than that corresponding to the bare particles. We show that the diffusion is the result of a significantly increased effective particle size 2rheff = 30 nm. This bound layer is not present in sulfate-modified polystyrene latex particles. The interaction between the carboxylate-modified particle surface and the macromolecules has been confirmed by means of atomistic computer simulations. The grafted acrylate copolymers, which come from the preparation procedure of the latex particles, confer more hydrophobic surface ready to interact with the polymer. The simulations suggest that the interaction is modulated not only by the nature of the acrylic acid monomer but also by the length of the grafted copolymer. Our results have important implications for particle selection in microrheology experiments.

Reasons for not completing postvasectomy semen analysis.

OBJECTIVE: To identify noncompliance rates for 3-month postvasectomy semen analysis (PVSA) in men who have undergone vasectomy and to explore the self-reported reasons for not completing the 3-month PVSA. DESIGN: Retrospective chart review followed by semistructured telephone interviews. SETTING: Two family medicine clinics in Saskatoon, Sask. PARTICIPANTS: Men from the clinics who had undergone vasectomy since 2009. A total of 99 patients completed telephone interviews. METHODS: After a review of electronic medical records at 2 family medicine clinics, patients who had undergone vasectomy since 2009 were identified. Upon review of their charts, the number of patients who did not have PVSA results on file was determined. Some of these men were contacted with a predetermined telephone script to discuss reasons for noncompliance. MAIN FINDINGS: The combined noncompliance rate for the 2 clinics was high (60.5%). Three main reasons for not completing the PVSA were identified among the patient responses. These included patients feeling too busy to complete PVSA, patients feeling confident in the physician or procedure immediately after vasectomy, and patients feeling the PVSA process was too inconvenient. Our high noncompliance rates are consistent with other literature. However, the findings might also have been affected by the proportion of patients who had completed their PVSA who were not included in the telephone sample. Rates differed between the 2 clinics; the clinic with the higher compliance rate acts as an academic practice, with more time for appointments and fewer patients being referred from other physicians. CONCLUSION: Noncompliance rates for PVSA in this study were high. Three main reasons for noncompliance were identified that might help guide counseling opportunities in the future.

Cognitive Function in Parkinson's Disease Patients with and without Anxiety.

Research on the implications of anxiety in Parkinson's disease (PD) has been neglected despite its prevalence in nearly 50% of patients and its negative impact on quality of life. Previous reports have noted that neuropsychiatric symptoms impair cognitive performance in PD patients; however, to date, no study has directly compared PD patients with and without anxiety to examine the impact of anxiety on cognitive impairments in PD. This study compared cognitive performance across 50 PD participants with and without anxiety (17 PDA+; 33 PDA-), who underwent neurological and neuropsychological assessment. Group performance was compared across the following cognitive domains: simple attention/visuomotor processing speed, executive function (e.g., set-shifting), working memory, language, and memory/new verbal learning. Results showed that PDA+ performed significantly worse on the Digit Span forward and backward test and Part B of the Trail Making Task (TMT-B) compared to the PDA- group. There were no group differences in verbal fluency, logical memory, or TMT-A performance. In conclusion, anxiety in PD has a measurable impact on working memory and attentional set-shifting.

Indoleamine 2,3-dioxygenase as a modifier of pathogenic inflammation in cancer and other inflammation-associated diseases.

Chronic inflammation underlies the basis for development and progression of cancers and a variety of other disorders, but what specifically defines its pathogenic nature remains largely undefined. Recent genetic and pharmacological studies in the mouse suggest that the immune modulatory enzyme indoleamine 2,3-dioxygenase (IDO), identified as an important mediator of immune escape in cancer, can also contribute to the development of pathology in the context of chronic inflammatory models of arthritis and allergic airway disease. IDO-deficient mice do not display spontaneous disorders of classical inflammation and small molecule inhibitors of IDO do not elicit generalized inflammatory reactions. Rather, in the context of a classical model of skin cancer that is promoted by chronic inflammation, or in models of inflammation-associated arthritis and allergic airway disease, IDO impairment can alleviate disease severity. Here we offer a survey of preclinical literature suggesting that IDO functions as a modifier of inflammatory states rather than simply as a suppressor of immune function. We propose that IDO induction in a chronically inflamed tissue may shape the inflammatory state to support, or in some cases retard, pathogenesis and disease severity.

Synergistic effects in flows of mixtures of wormlike micelles and hydroxyethyl celluloses with or without hydrophobic modifications.

This work presents experimental results on simple shear and porous media flow of aqueous solutions of two hydroxyethyl celluloses (HEC) and two hydrophobically modified hydroxyethyl celluloses (HMHEC) with different molecular weights. Mixtures of these polymers with a cationic surfactant, cetyltrimethylammonium p-toluenesulfonate (CTAT) were also studied. Emphasis was given to the range of surfactant concentrations in which wormlike micelles are formed. The presence of hydrophobic groups, the effect of the molecular weight of the polymers, the surfactant and polymer concentrations, and the effect of the flow field type (simple shear versus porous media flow) were the most important variables studied. The results show that the shear viscosity of HEC/CTAT solutions is higher than the viscosities of surfactant and polymer solutions at the same concentrations, but surface tension measurements indicate that no complex formation occurs between CTAT and HEC. On the other hand, a complex driven by hydrophobic interactions was detected by surface tension measurements between CTAT and HMHEC. In this case, the viscosity of the mixture increases significantly more (up to four orders of magnitude at high CTAT concentrations) in comparison with HEC/CTAT aqueous solutions. Increments in the molecular weight of the polymers increase the interaction with CTAT and the shear viscosity of the solution, but make phase separation more feasible. In porous media flow, the polymer/CTAT mixtures exhibited higher apparent viscosities than in simple shear flows. This result suggests that the extensional component of the flow field in porous media flows leads to a stronger interaction between the polymer and the wormlike micelles, probably as a consequence of change of conformation and growth of the micelles.

A key in vivo antitumor mechanism of action of natural product-based brassinins is inhibition of indoleamine 2,3-dioxygenase.

Agents that interfere with tumoral immune tolerance may be useful to prevent or treat cancer. Brassinin is a phytoalexin, a class of natural products derived from plants that includes the widely known compound resveratrol. Brassinin has been demonstrated to have chemopreventive activity in preclinical models but the mechanisms underlying its anticancer properties are unknown. Here, we show that brassinin and a synthetic derivative 5-bromo-brassinin (5-Br-brassinin) are bioavailable inhibitors of indoleamine 2,3-dioxygenase (IDO), a pro-toleragenic enzyme that drives immune escape in cancer. Like other known IDO inhibitors, both of these compounds combined with chemotherapy to elicit regression of autochthonous mammary gland tumors in MMTV-Neu mice. Furthermore, growth of highly aggressive melanoma isograft tumors was suppressed by single agent treatment with 5-Br-brassinin. This response to treatment was lost in athymic mice, indicating a requirement for active host T-cell immunity, and in IDO-null knockout mice, providing direct genetic evidence that IDO inhibition is essential to the antitumor mechanism of action of 5-Br-brassinin. The natural product brassinin thus provides the structural basis for a new class of compounds with in vivo anticancer activity that is mediated through the inhibition of IDO.

Miscibility in poly(L-lactide)-b-poly(epsilon-caprolactone) double crystalline diblock copolymers.

Thermally stimulated depolarization currents, TSDC, wide-angle X-ray scattering, WAXS, differential scanning calorimetry, DSC, and polarized light optical microscopy, PLOM, have been used to examine poly(L-lactide)-b-poly(epsilon-caprolactone) diblock copolymers in a wide composition range. Both components are crystallizable and the miscibility in the amorphous phase has been determined from the behavior of the primary relaxations which are the dielectric manifestation of the glass transition, and also from the superstructural morphology revealed by PLOM and the compositional dependence of the melting points as determined by DSC. Distinct segmental mobilities in the amorphous phase which can be well resolved by TSDC are present; the alpha mode of the slower component shifts to lower temperatures as the PCL content increases while the glass transition of neat PCL is present for all compositions. A relaxation times bimodal distribution is apparent for PCL-rich copolymers. The composition dependence of the multiple glass transitions detected in these weakly segregated copolymers are predicted by the self-concentration model for a miscible blend made of components with a large T(g) contrast.

Effect of the flow field on the rheological behavior of aqueous cetyltrimethylammonium p-toluenesulfonate solutions.

It is well-known that solutions of cetyltrimethylammonium p-toluenesulfonate in water exhibit a pronounced shear-thickening phenomenon in a specific concentration range (0.1-0.8%) when they are subjected to simple-shear flows, as a consequence of flow-induced self-assembly of wormlike micelles. This work shows that a strong elongational flow field (opposed-jets flow), applied to the same solutions, does not lead to extension thickening because the extensional flow prevents or destroys micellar association. In flow through a porous medium, a substantial increase in apparent viscosity is observed beyond a critical apparent shear rate, which surpasses increases observed in simple-shear flows. This is explained as the result of a synergistic effect of shear and relatively weak elongation on the solution microstructure.

Local and segmental dynamics in homopolymer and triblock copolymers with one semicrystalline block.

Thermally stimulated depolarization currents, TSDC, experiments have been performed on a series of poly(styrene)-b-poly(butadiene)-b-poly(epsilon-caprolactone) triblock copolymers SBC with different proportions of the poly(epsilon-caprolactone) crystallizable block, PCL. The morphology of the segregated microphases varies with the PCL content and has been observed by transmission electron microscopy. The crystallinity of the PCL block is estimated by wide angle x-ray scattering, WAXS. The relaxation times distribution is extracted by a numerical decomposition of the TSDC spectra and it is shown that this distribution is not significantly changed on going from the homopolymer to the triblock copolymer with 16 wt % to 77 wt % of PCL in the original samples. Better segregation of the mesophase structure is reached when the samples are annealed at 413 K and important variations in the TSDC and WAXS spectra are observed as a result of the thermal treatment. For the S09B14C77 triblock copolymer the results obtained can be explained by postulating the existence of a rigid amorphous phase in the PCL block. Such rigid amorphous phase is located between the core-shell cylinders formed by the other blocks [with poly(styrene)(PS) as core and poly(butadiene)(PB) as shell] and is constrained by undulated lamellae of crystalline PCL material. In the case of S35B15C50 triblock copolymer, an important amount of diffuse PS-PCL interphase where the homopolymers are mixed must be present before annealing. The results for the material with the less abundant PCL block are explained as a result of the confinement in nanotubes of PCL surrounded by PB embedded in a vitreous PS matrix. Broadband dielectric experiments on these same materials confirm the results obtained by TSDC spectroscopy.

Elongational flow of solutions of poly(ethylene oxide) and sulfonated surfactants.

In this work, the elongational flow behavior of aqueous solutions of poly(ethylene oxide) (PEO) was studied in the presence of sulfonated surfactants. The technique of opposed-jets flow was used to generate an elongational flow field in which pressure drops were measured as a function of strain rates. The surfactants used were sodium dodecyl benzene sulfonate (SDBS) and an alpha-olefin sulfonate (AOS). Solutions of PEO and other flexible polymers exhibit extension thickening in opposed-jets flow due to the formation of transient networks of entangled molecules. This effect is present at concentrations below the static coil overlap concentration, due to the changes in molecular conformation induced by the flow. When SDBS or AOS are added to PEO solutions at low concentrations, the extension thickening weakens due to an increase in PEO intramolecular interactions that lead to coil contraction. This occurs until the surfactant concentration is close to the critical aggregation concentration reported in the literature. Further addition of surfactant induces the formation of intermolecular interactions as the PEO molecules are expanded by the electrostatic repulsion between attached micellar aggregates, with an associated strengthening of extension thickening. Intramolecular effects were not seen beyond a specific PEO concentration.

cis-dichlorobis(triethylarsine)platinum(II) and cis-dichlorobis(triethylphosphine)platinum(II).

The crystal structure of cis-[PtCl2(C6H15As)2], (I), is isostructural with a previously reported structure of cis-[PtCl2(C6H15P)2], (II). A new polymorph of (II) is also reported here. Selected geometrical parameters in the arsine complex are Pt-Cl 2.3412 (12) and 2.3498 (13), Pt-As 2.3563 (6) and 2.3630 (6) A, Cl-Pt-Cl 88.74 (5), As-Pt-As 97.85 (2), and Cl-Pt-As 171.37 (4) and 177.45 (4) degrees. Corresponding parameters in the phosphine complex are Pt-Cl 2.364 (2) and 2.374 (2), Pt-P 2.264 (2) and 2.262 (2) A, Cl-Pt-Cl 85.66 (9), P-Pt-P 98.39 (7), and Cl-Pt-P 170.26 (7) and 176.82 (8) degrees.

Interactions between Poly(ethylene Oxide) and Sodium Dodecyl Sulfate in Elongational Flows.

This work investigates the elongational flow of aqueous solutions of mixtures of a high-molecular-weight poly(ethylene oxide) (PEO) and sodium dodecyl sulfate (SDS). The formation of micellar aggregates of SDS along the PEO chain results in an increase in the strength of the extension thickening of the PEO solutions. This is especially pronounced under conditions in which the PEO molecules form transient entanglements in the flow field. The minimum PEO concentration required to form intermolecular entanglements is substantially reduced in the presence of micellar aggregates. This effect becomes quantitatively less important in solutions with NaCl, which suggests PEO coil contraction due to electrostatic screening of micellar aggregates. However, once extension thickening starts in the presence of NaCl, the growth of pressure drop is more abrupt than without salt, which suggests stronger interactions between PEO coils with attached aggregates. The critical aggregation concentrations of PEO/SDS and PEO/SDS/NaCl solutions agree with those reported in the literature, which were obtained by means of different experimental techniques. However, the saturation of the surfactant effect is attained at lower surfactant concentrations than the polymer saturation point previously reported. This might reflect a low sensitivity of the extension thickening effect to the amount of surfactant bound to the polymerchain as the saturation point is approached. Copyright 2001 Academic Press.

Prognostic value and quality of life in patients with normal rest thallium-201/stress technetium 99m-tetrofosmin dual-isotope myocardial SPECT.

BACKGROUND: The prognostic value of normal dual-isotope single photon emission computed tomography (SPECT), with technetium 99m-tetrofosmin for the stress images, is not well known. Furthermore, thallium-201 cross talk in the Tc-99m window may reduce the defect severity of the Tc-99m images. METHODS AND RESULTS: In a consecutive series of 610 patients, 246 patients with normal rest and stress SPECT images by means of visual semiquantitative analysis were included. The patients' pre-test likelihood of coronary artery disease was determined, based on age, sex, symptoms, and the results of stress electrocardiography. Quality of life was assessed by using a mailed self-administered general quality-of-life questionnaire. We compared the mean scores (8 dimensions) of our study population with the scores of 1063 control subjects, sampled randomly out of the inhabitant register of a Dutch city. The mean follow-up period was 25+/-3 months. Compared with the control group, patients in our study scored lower (less perceived health) for all dimensions of the SF-36 (P<.05), suggesting a selection of symptomatic or otherwise diseased patients. The primary cardiac event rate was 0.4% per year. The cardiac events occurred in patients with an intermediate-to-high pre-test likelihood of disease and negative or nondiagnostic exercise electrocardiographic results. In a subset of patients with a high pre-test likelihood of coronary artery disease (more than 85%), the primary cardiac event rate was 0.7% per year. CONCLUSIONS: Patients with normal results on dual-isotope myocardial perfusion scintigraphy, performed with Tc-99m-tetrofosmin for the stress images, have an excellent prognosis. Furthermore, our results suggest that Tl-201 cross talk in the Tc-99m window may be low and functionally and clinically unimportant.

A male germ cell tumor-susceptibility-determining locus, pgct1, identified on murine chromosome 13.

Inbred 129 strain mice are predisposed to developing male germ cell tumors (GCTs) of the testes. The inherent genetic defects that underlie male GCT susceptibility in the 129 mouse strain are unknown. GCT incidence is increased in 129 strain males that lack functional p53 protein, and we have used this finding to facilitate the generation of panels of GCT-bearing intercross and backcross mice for genetic mapping analysis. A 129 strain locus, designated pgct1, that segregates with the male GCT phenotype has been identified on chromosome 13 near D13Mit188. This region of murine chromosome 13 may be syntenic to a portion of human chromosome 5q that is implicated in male GCT susceptibility in humans.

Genetic mapping of the embryonal carcinoma transplantation resistance locus Gt(B6) to mouse Chromosome 8.

Cytotoxic T lymphocytes play a predominant role in allograft rejection. They mediate this process through recognition of foreign major histocompatibility complex (MHC) class I surface molecules encoded at the H2 locus. Embryonal carcinoma cells, the undifferentiated, neoplastic derivatives of primordial germ cells, typically lack detectable MHC class I gene expression. Despite this, embryonal carcinoma cells are subject to allograft rejection in several different mouse strains. In many instances, the H2 locus appears to be genetically linked to resistance. However, rejection of allografts of the F9 embryonal carcinoma cell line, a nullipotent cell line derived from the 129 mouse strain, does not appear to be H2-linked. Resistance to F9 tumor formation in the C57BL/6 mouse strain has been attributed to a single, unidentified locus termed Gt(B6). To genetically map the Gt(B6) locus, a total of 463 (C57BL/6x129)F2 mice were challenged with F9 cells, and 78 tumor-resistant mice were identified. Markers encompassing two candidate regions, the H2 locus on Chromosome (Chr) 17 and a second candidate locus on Chr 2, showed no indication of linkage to the resistance phenotype. Instead, results of a genome wide scan implicated mouse Chr 8, and evidence is presented demonstrating that the Gt(B6) locus maps to a region of less than 10 cM on the medial portion of Chr 8.

The FUSCA genes of Arabidopsis: negative regulators of light responses.

More than 200 fusca mutants of Arabidopsis have been isolated and characterised, defining 14 complementation groups. Mutations in at least nine FUSCA genes cause light-dependent phenotypic changes in the absence of light: high levels of anthocyanin accumulation in both the embryo and the seedling, inhibition of hypocotyl elongation, apical hook opening, and unfolding of cotyledons. In double mutants, the fusca phenotype is epistatic to the hy phytochrome-deficiency phenotype, indicating that the FUSCA genes act downstream of phytochrome. By contrast, the accumulation of anthocyanin is suppressed by mutations in TT and TTG genes, which affect the biosynthesis of anthocyanin, placing the FUSCA genes upstream of those genes. Regardless of the presence or absence of anthocyanin, fusca mutations limit cell expansion and cause seedling lethality. In somatic sectors, mutant fus1 cells are viable, expressing tissue-specific phenotypes: reduced cell expansion and accumulation of anthocyanin in subepidermal tissue, formation of ectopic trichomes but no reduced cell expansion in epidermal tissue. Our results suggest a model of FUSCA gene action in light-induced signal transduction.

En bloc substitution of the Src homology region 2 domain activates the transforming potential of the c-Abl protein tyrosine kinase.

Src homology region 2 (SH2) domains are present in many proteins involved in signal transduction. In nonreceptor protein tyrosine kinases the SH2 domain has been implicated in regulation of tyrosine kinase activity and in mediating interactions involved in downstream signaling. Different SH2 domains exhibit distinct binding specificities for both phosphotyrosine- and phosphoserine/phosphothreonine-containing proteins. We show that different SH2 domains are not functionally equivalent within the context of the c-ABL1b protooncogene. c-ABL1b, altered by replacement of its SH2 domain with the N-terminal SH2 domain of Ras GTPase-activating protein, exhibited activated transforming capability, caused intracellular tyrosine phosphorylation of p62, and was relocalized from nucleus to cytoplasm. This en bloc substitution apparently uncouples two distinct functions of the SH2 domain so that c-ABL escapes normal regulatory control while it retains the capability to elicit signals that promote transformation. The SH2 domain of the ARG protein tyrosine kinase, which shares high amino acid-sequence homology with the SH2 domain of ABL, was less effective in activating the oncogenic potential of c-ABL. The effects that the N-terminal SH2 domain of Ras GTPase-activating protein has in the context of c-ABL resemble the effects of deleting the SH3 domain. Thus, the SH2 and SH3 domains may have coordinate roles as regulatory control elements within the context of c-ABL.

A limited set of SH2 domains binds BCR through a high-affinity phosphotyrosine-independent interaction.

SH2 (src homology region 2) domains are implicated in protein-protein interactions involved in signal transduction pathways. Isolated SH2 domains bind proteins that are tyrosine phosphorylated. A novel, phosphotyrosine-independent binding interaction between BCR, the Philadelphia chromosome breakpoint cluster region gene product, and the SH2 domain of its translocation partner c-ABL has recently been reported. We have examined the ability of additional SH2 domains to bind phosphotyrosine-free BCR and compared this with their ability to bind tyrosine-phosphorylated c-ABL 1b. Of 11 individual SH2 domains examined, 8 exhibited relatively high affinity for c-ABL 1b, whereas only 4 exhibited relatively high affinity for BCR. Binding of tyrosine-phosphorylated c-ABL 1b by the relatively high-affinity ABL and ARG SH2 domains was quantitatively analyzed, and equilibrium dissociation constants for both interactions were estimated to be in the range of 5 x 10(-7) M. The ABL SH2 domain exhibited relatively high affinity for phosphotyrosine-free BCR as well; however, this interaction appears to be about two orders of magnitude weaker than binding of tyrosine-phosphorylated c-ABL 1b. The ARG SH2 domain exhibited relatively weak affinity for BCR and was determined to bind about 10-fold less strongly than the ABL SH2 domain. The ABL and ARG SH2 domains differ by only 10 of 91 amino acids, and the substitution of ABL-specific amino acids into either the amino- or carboxy-terminal half of the ARG SH2 domain was found to increase its affinity for BCR. We discuss these results in terms of a model which has been proposed for peptide binding by class I histocompatibility glycoproteins.

BCR sequences essential for transformation by the BCR-ABL oncogene bind to the ABL SH2 regulatory domain in a non-phosphotyrosine-dependent manner.

BCR-ABL is a chimeric oncogene implicated in the pathogenesis of Philadelphia chromosome-positive human leukemias. BCR first exon sequences specifically activate the tyrosine kinase and transforming potential of BCR-ABL. We have tested the hypothesis that activation of BCR-ABL may involve direct interaction between BCR sequences and the tyrosine kinase regulatory domains of ABL. Full-length c-BCR as well as BCR sequences retained in BCR-ABL bind specifically to the SH2 domain of ABL. The binding domain has been localized within the first exon of BCR and consists of at least two SH2-binding sites. This domain is essential for BCR-ABL-mediated transformation. Phosphoserine/phosphothreonine but not phosphotyrosine residues on BCR are required for interaction with the ABL SH2 domain. These findings extend the range of potential SH2-protein interactions in growth control pathways and suggest a function for SH2 domains in the activation of the BCR-ABL oncogene as well as a role for BCR in cellular signaling pathways.