Elasticity, fracture and thermoreversible gelation of highly filled physical gels.

We describe a physically associating triblock copolymer-based gel that exhibits a reversible transition between solid and liquid states at a temperature of approximately 55 degrees C. The thermal transition of the gel enables us to compare the properties of liquid suspensions and elastic composites with identical particle loadings, with particle volume fractions as large as 0.55. The suspension viscosity and the composite elasticity scale in a similar manner with the overall particle volume fraction, a result that is rationalized in terms of an effective strain amplification factor that depends only on the particle loading. Measured values of the strain amplification factor are in good agreement with the expected form for well-dispersed spheres. We also find that the elastic composites are exceptionally strong, with fracture strengths that exceed the modulus of the base gel by a factor of 100 or more. Deviations from purely elastic behavior became important for high particle volume fractions, and were probed by stress relaxation experiments.

Influence of surface ordering on the wetting of structured liquids.

The substrate is shown to induce substantial ordering in diblock copolymer thin films above the bulk order-disorder transition (ODT) where, thermodynamically, a phase mixed state is favored. Initially, uniform films reorganize to form a hierarchy of transient surface patterns and stable film thicknesses that depend on the initial film thickness and on the substrate. Self-consistent field calculations of the free energy of the system for different situations, depending on the relative tendency for the different block components to be attracted to the substrate and/or free surface, provide an explanation of the formation of the stable film thicknesses. A continuum picture proposed earlier by Brochard et al. provides an explanation of the wetting characteristics of this system. In some cases the ordering destabilizes the film so that dewetting occurs (wetting autophobicity), whereas in other cases the surface ordering results in a kinetic stabilization of a film that would otherwise dewet.

Preclinical evaluation of anti-inflammatory activities of the novel pyrrolopyrimidine PNU-142731A, a potential treatment for asthma.

The anti-inflammatory properties of a novel pyrrolopyrimidine, PNU-142731A, in a murine model of antigen-induced eosinophilic lung inflammation are described. PNU-142731A, when given orally, demonstrated a dose-related inhibition of eosinophil- and lymphocyte-rich accumulation in the airways of ovalbumin (OA)-sensitized and challenged (OA/OA) C57BL/6 mice. The magnitude of the suppression of lung inflammation was also dependent on length of treatment. Reductions in the levels of interleukin (IL)-5, IL-6, and IgA in the bronchoalveolar lavage fluid of treated OA/OA mice, when compared with vehicle-sensitized control mice (V/OA), were observed. Plasma concentrations of IL-5, total IgE, and OA-specific IgG1 were also lowered in OA/OA mice by treatment. Histological assessment of formalin-fixed lung tissue sections confirmed that the compound blocked the accumulation of eosinophils in the airway tissue. Furthermore, significantly less mucus glycoproteins were seen in the lungs of PNU-142731A-treated OA/OA mice. Reverse transcription-polymerase chain reaction of lung tissue from PNU-142731A-dosed OA/OA mice demonstrated that mRNA for Th2 cytokines was less than that in vehicle-treated OA/OA controls. OA-elicited production of IL-4 by disaggregated lung tissue cells from PNU-142371A-treated OA/OA mice was also less than that of controls. In contrast, the release of Th1 cytokines (IL-2 and interferon-gamma) were elevated. Similarly, the OA-stimulated release of Th2 cytokines (IL-5 and IL-10) by splenocytes from PNU-142731A-treated OA/OA mice were inhibited. Combined therapy of OA/OA mice with PNU-142731A and suboptimal doses of dexamethasone revealed that PNU-142731A had steroid-sparing effects. These characteristics of PNU-142731A in a murine model of allergic tissue inflammation support its clinical development as a potential treatment for asthma.

Involvement of intercellular adhesion molecule-1 in the antigen-induced infiltration of eosinophils and lymphocytes into the airways in a murine model of pulmonary inflammation.

We investigated the effects of in vivo intraperitoneal treatment with the rat monoclonal antibody (mAb), YN1.7.4 (YN1) against intercellular adhesion molecule-1 (ICAM-1) on the ovalbumin (OA)-inhalation-induced infiltration of leukocytes into the airways of OA-sensitized mice. YN1 (100 to 400 microg) given over a period of 72 h dose-dependently reduced the influx of lymphocytes and eosinophils into the bronchial lumen by > 60% and > or = 70%, respectively, when compared with saline or purified rat IgG-treated controls. Alveolar macrophages (AM) in the bronchoalveolar lavage fluid (BALF) were also decreased by > 50%. Lung tissue inflammation as determined by histopathologic examination was reduced. The number of neutrophils in the blood of OA-sensitized mice 3 days after challenge was significantly increased by treatment with YN1. However, at 24 h and 72 h after OA-challenge, the numbers of eosinophils and mononuclear cells in the bone marrow were reduced by YN1 treatment. Additionally, at 72 h after OA-challenge, the numbers of bone-marrow neutrophils were depressed. BALF levels of interleukin-5 (IL-5) and of IgA were lower for YN1-treated mice than for controls. With increasing doses of YN1, the levels of anti-ICAM-1 mAb in the plasma were proportionally increased. To correlate these results with YN1 treatment, blood and BALF T cells and BALF eosinophils were examined with flow cytometry. Blood T cells from YN1-treated mice were unable to bind phycoerythrin (PE)-labeled anti-ICAM- mAb ex vivo. These results implied that ICAM-1 on these cells was bound (occupied) by YN1 administered in vivo. Dose-related decreases were observed in the percentage and mean channel fluorescence (MCF) values of ICAM-1+ BALF T cells and eosinophils. The percentages of CD11a+ or CD49d+ eosinophils were also suppressed. Our data suggest that ICAM-1 is an important molecule involved in the recruitment of leukocytes into the airways of sensitized mice after pulmonary challenge.

Intercellular adhesion molecule-1-deficient mice have antibody responses but impaired leukocyte recruitment.

The role of intercellular adhesion molecule-1 (ICAM-1) in murine lung inflammation was examined in vivo. Ovalbumin (Ova)-sensitized and -challenged ICAM-1-deficient (KO) mice had decreased accumulation of leukocytes in the bronchoalveolar lavage fluid compared with wild-type (WT) mice. Lung tissue inflammation was also attenuated. Ova immunization and challenge produced equivalent plasma levels of Ova-specific immunoglobulin (Ig) G1 and higher concentrations of IgE in KO versus WT mice. Ova-dependent induction of cytokines in vitro, as measured by enzyme-linked immunosorbent assay, was impaired in splenocytes from KO mice compared with the comparable release of interleukin (IL)-5 and IL-10 from anti-CD3-stimulated WT and KO splenocytes. Methacholine-induced increases in trapped gas in lungs of Ova-sensitized and -challenged WT mice were greater than those of KO mice. The activation of lung tissue nuclear factor-kappa B was diminished in KO mice after Ova provocation. This suggests that ICAM-1 was important for activation of the inflammatory cascade leading to the recruitment of leukocytes but was not critical for the generation of antibody responses in vivo.

Identification of cytokine and adhesion molecule mRNA in murine lung tissue and isolated T cells and eosinophils by semi-quantitative reverse transcriptase-polymerase chain reaction.

We have used a semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay to detect the expression of mRNA for inflammatory cytokines, integrins and selectins in murine lung tissue, and T cells and eosinophils isolated from lung and bronchoalveolar lavage (BAL) fluid in an in vivo model of ovalbumin (OA)-induced airway inflammation. RNA was isolated from whole lung tissue at 1, 6, 24, 48, 72 h, and 7 days after OA inhalation. mRNA for the Th2 cytokines, IL-4, -5, -6, -10 and -13 in OA-sensitized mice were significantly elevated compared with non-sensitized mice. IL-2, TNF-beta, and eotaxin mRNA were also increased, but IFN-gamma mRNA was not. P- and E-selectin mRNA levels were also enhanced in lung tissue between 6 and 72 h after challenge. Lung T cells were isolated by cell sorting with a flow cytometer at 3, 12, 24, 48 and 72 h after challenge. mRNA levels for IL-5 and -10 were greater in T cells from OA-sensitized and -challenged mice than controls at 24 h. BAL fluid from OA-sensitized and -challenged mice also had significantly higher IL-5 levels than controls. BAL fluid T cells and eosinophils were obtained at 48 and 72 h after aerosol challenge and were purified by cell sorting. Messenger RNA for IL-1 alpha, -2, -4, -5, -10, IFN-gamma, and beta 1 were detected in T cells at both time points. Transcripts for IL-1 alpha, -4, -5, -13, TNF-alpha and beta, and alpha 4, beta 1 and beta 7 were also identified in BAL eosinophils. These data show that in addition to murine lung T cells, airway eosinophils may also contribute to the inflammatory response by their ability to express mRNA for cytokines and integrins.

The penetration enhancer SEPA augments stimulation of scalp hair growth by topical minoxidil in the balding stumptail macaque.

The purpose of this study was to determine if the penetration enhancer SEPA (2-n-nonyl-1,3-dioxolane) would augment the scalp hair growth effects of topical minoxidil in the balding stumptail macaque. A 1-in2 area on the balding scalp of 40 adult female monkeys (four drug-treated and four vehicle-treated groups of 5 monkeys each) was topically treated 5 days/week, q.d. or b.i.d., with approximately 250 microliters of minoxidil-SEPA (2.5% minoxidil, weight/volume in 10% SEPA, 25% propylene glycol and 65% isopropyl alcohol), Rogaine topical solution (TS, 2% minoxidil, weight/volume in 20% propylene glycol, 60% ethanol and 20% water) or respective vehicles (without drug) for 16 weeks via paintbrush application. Scalp hair was collected by shaving and vacuuming the dosed area at baseline and at 4-week intervals. The shaved hair was filtered, weighed and recorded as the change from baseline. The q.d. and b.i.d. minoxidil-SEPA groups displayed a significant increase in hair weight compared to their respective vehicles at week 4 whereas q.d. and b.i.d. Rogaine TS groups were not active until week 8 and 12, respectively. Both minoxidil-SEPA treatments produced significantly greater cumulative hair weight over the entire 16-week study compared to either of the Rogaine TS treatments. Comparable increases in cumulative hair weight were evident between q.d. and b.i.d. minoxidil-SEPA groups and between q.d. and b.i.d. Rogaine TS groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Low-vision elders living arrangements, loneliness, and social support.

1. Loneliness was not found to be a significant problem in a study of low-vision older clients with various living arrangements. Different types of support networks did serve different functions depending on whether clients lived alone or with others. 2. Clients living alone were more satisfied with supporters who helped them when they were feeling down, whereas clients living with others were more satisfied with supporters who cared about them. 3. Clients living alone relied on friends and children as the most important sources of support; clients living with others relied most on children for the majority of their needs. 4. Supportive expectations should be shared with supporters in the network to prevent burnout of the support person and lack of support for the client in crises if the supportive person is not available.

Marital status, social support, and loneliness in visually impaired elderly people.

The purpose of this study was to investigate relationships between marital status, social support, and loneliness in visually impaired elderly people. The sample was derived from a larger study designed to examine loneliness in low-vision adults (Foxall et al. 1992). Subjects were 87 visually impaired elderly people who were at least 65 years of age, had a visual acuity of 20/70 or less in the better eye, had been visually impaired for at least 1 year, and were not totally blind. Data were collected by interview using the Revised UCLA Loneliness Scale, the Social Support Questionnaire, and a demographic and health information form. Results indicate marital status was not directly related to loneliness but may be indirectly related through social support. Loneliness was associated with greater network dissatisfaction related to caring and relaxation. Findings provide direction for nursing assessment of and intervention into loneliness with visually impaired elderly people.

Living arrangements, loneliness, and social support of low-vision older clients.

1. Loneliness has been linked to both psychological and medical problems. The study of loneliness and social support should interest nurses because nursing interventions may assist in preventing or alleviating potential health problems. 2. Study results indicate that low-vision older clients who lived alone were no lonelier than those who lived with others. Clients who lived alone were as satisfied with their social networks as those who lived with others. The actual number of supporters in the social network had no effect on loneliness for either group. 3. Neither group was particularly lonely. The nurse cannot assume that the combination of low-vision and living alone results in loneliness. Because different categories of supporters were linked to different areas of need, nurses need to help clients determine their emotional needs and identify who in the clients' network can best meet these needs.

Loneliness in low-vision older women.

The purpose of this analysis was to identify predictors of loneliness in women 75 years of age and older with low vision. The sample of 56 women was derived from a larger study of low-vision adults. Women's loneliness, optimism, social support, living arrangement, vision, and perceived health were examined using the revised University of California, Los Angeles, Loneliness Scale, the Life Orientation Test, the Social Support Questionnaire, and a demographic questionnaire. Data were analyzed using descriptive statistics, Pearson correlations, multiple regressions, and t-tests. Optimism and social support satisfaction were found to predict degree of loneliness in the sample. Women who were less optimistic and less satisfied with their social support system experienced higher levels of loneliness. Duration of visual impairment was associated with duration of loneliness. The findings provide nurses with information for identifying low-vision older women who are at risk for loneliness.

Potassium channel conductance: a mechanism affecting hair growth both in vitro and in vivo.

The opening of intracellular potassium channels has been suggested as a mechanism regulating hair growth. Enhancing the flux of potassium ions is a mechanism shared by several structurally diverse antihypertensive agents including minoxidil sulfate (the active metabolite of minoxidil), pinacidil, P-1075 (a potent pinacidil analog), RP-49,356, diazoxide, cromakalim, and nicorandil. Of these drugs, minoxidil, pinacidil, and diazoxide have been reported to elicit hypertrichosis in humans. This potassium channel hypothesis was examined by testing these drugs for effects on hair growth both in vitro and in vivo. For the in vitro studies, mouse vibrissae follicles were cultured for 3 d with drug and the effects on hair growth were measured by metabolic labeling. All drugs, except diazoxide, enhanced cysteine incorporation into the hair shafts of the cultured vibrissae. Diazoxide was poorly soluble and thus was tested only at low doses. Minoxidil, P-1075, cromakalim, and RP-49,356 were also evaluated in vivo by measuring hair growth effects in balding stumptail macaque monkeys. The drugs were administered topically to defined sites on balding scalps once per day for 4-5 months and the amount of hair grown was determined by monthly measurements of shaved hair weight. Three of the drugs produced significant increases in hair weight whereas, the RP-49,356 had no effect. These studies provide correlative evidence that the opening of potassium channels is an important regulatory mechanism for hair growth. This provides the impetus for further studies on this potentially important mechanism affecting hair biology.

Hair growth effects of oral administration of finasteride, a steroid 5 alpha-reductase inhibitor, alone and in combination with topical minoxidil in the balding stumptail macaque.

A 5 alpha-reductase inhibitor, finasteride, was administered orally at 0.5 mg/day, alone or in combination with topical 2% minoxidil, for 20 weeks to determine the effects on scalp hair growth in balding adult male stumptail macaque monkeys. A 7-day dose-finding study showed that both 0.5- and 2.0-mg doses of the drug produced a similar diminution in serum dihydrotestosterone (DHT) in male stumptails. Hair growth was evaluated by shaving and weighing scalp hair at baseline and at 4-week intervals during treatment to obtain cumulative delta hair weight (sum of the 4-week changes in hair weight from baseline) for the 20-week study. The activity of the 5 alpha-reductase enzyme was assessed by RIA of serum testosterone (T) and DHT at 4-week intervals. The combination of finasteride and minoxidil generated significant augmentation of hair weight (additive effect) compared to either drug alone. Finasteride increased hair weight in four of five monkeys. When the data of the one nonresponsive monkey were excluded, finasteride elicited a significant elevation in hair weight compared to topical vehicle alone. Minoxidil also evoked a significant increase in hair weight compared to vehicle alone. Serum T was unchanged, whereas serum DHT was significantly depressed in monkeys that received either finasteride or the combination of finasteride and minoxidil. These data suggest that inhibition of the conversion of T to DHT by this 5 alpha-reductase inhibitor reverses the balding process and enhances hair regrowth by topical minoxidil in the male balding stumptail macaque.

The role of primary varicose veins in venous ulceration.

"Venous" ulceration is usually ascribed to deep venous insufficiency. We record the cases of 20 patients with 23 ulcers without a history suggestive of deep vein disease who were found to have a normal deep venous system when evaluated by Doppler ultrasound, ambulatory venous pressures, and photoplethysmography. All had gross varicose veins present for many years (mean 24 years; range 10 to 35 years), and only 14 limbs had incompetent calf perforating veins. Effective treatment is facilitated by recognition of the relationship of varicose ulcer to superficial venous disease, usually incompetence of the saphenofemoral junction, with or without the presence of incompetent calf perforating veins.