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The time evolution of a coating layer of liquid on an inclined circular cylindrical substrate is studied experimentally and theoretically. For small-diameter cylinders, the motion of Newtonian liquids, driven by the combined influences of surface tension and gravity, is analyzed using the long-wave or "lubrication" approximation. Computed time-dependent solutions of the lubrication model are in general agreement with our experimental observations. Starting from a slightly-perturbed uniform coating, the full family of evolving flows is shown to depend only on three dimensionless parameters: the inclination angle of the cylinder from the vertical direction, the Bond number representing the ratio of gravity to surface tension effects, and a nondimensional measure of the initial coating thickness. Typically flow is initiated by the well-known Rayleigh-Plateau instability followed by drainage, and also wave propagation if the cylinder is not horizontal. Steady propagation of ring-like structures can occur as well as eventual overtaking, merging and reformation of the rings. We demonstrate that volumetric transport is maximized if the cylinder axis is inclined to, rather than aligned with, the direction of gravity. Results are relevant to the understanding, and potential optimization, of small-scale liquid transport. Such problems arise in the natural and industrial worlds., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: The purpose of this study is to determine if administration of total parenteral nutrition (TPN) immediately following radical cystectomy and urinary diversion provides significant recovery benefit when compared to patients who did not receive TPN., Methods: Retrospective chart review was performed on patients who underwent open radical cystectomy and urinary diversion from February 2002 to June 2010. Patients were divided into 2 cohorts-those who received immediate postoperative TPN and those who did not. Preoperative demographics, length of hospital stay, time until tolerating a regular diet and early postoperative complications of the 2 groups were extracted and compared., Results: One hundred seventy-four patients (104 receiving TPN, 70 without TPN) were available for analysis. No significant difference in preoperative characteristics, length of hospital stay, estimated blood loss, or time until tolerating a general diet between the 2 groups was noted. With regard to complications, the incidence of bacteremia was significantly higher in the TPN vs non-TPN cohort (9% vs 1%, P < 0.05)., Conclusion: Immediate administration of TPN following radical cystectomy and urinary diversion does not provide a significant postoperative benefit and may lead to an increased risk of bacteremia.

In rodents, p38 MAP kinase inhibitors (p38is) induce bone marrow hypocellularity and reduce reticulocyte and erythrocyte counts. To identify target cell populations affected, a differentiating primary liquid erythroid culture system using sca-1(+)cells from mouse bone marrow was developed and challenged with p38is SB-203580, SB-226882, and SB-267030. Drug-related alterations in genes involved at different stages of erythropoiesis, cell-surface antigen expression (CSAE), burst-forming unit erythroid (BFU-E) colony formation, and cellular morphology (CM), growth (CG), and viability were evaluated. CSAE, CM, and decreases in BFU-E formation indicated delayed maturation, while CG and viability were unaffected. Terminal differentiation was delayed until day 14 versus day 7 in controls. CSAE demonstrated higher percentages of sca-1(+)cells after day 2 and reduced percentages of ter119(+) cells after day 7 in all treated cultures. Real-time reverse transcriptase polymerase chain reaction revealed a transient delay in expression of genes involved at early, intermediate, and late stages of erythropoiesis, followed by rebound expression at later time points. Results demonstrate p38is do not irreversibly inhibit erythrogenesis but induce a potency-dependent, transient delay in erythropoietic activity. The delay in activity is suggestive of effects on sca-1(+)bone marrow cells caused by alterations in expression of genes related to erythroid commitment and differentiation resulting in delayed maturation.

This study was designed to evaluate effects of specific p38 MAP kinase inhibition on gene and protein expression of essential hematopoietic cytokines in primary human bone marrow stromal cells (HBMSC) and to identify downstream transcription factors (TF) regulated by the p38 MAP kinase signalling pathway. In vitro effects of p38 inhibitors (p38i) on cytokine regulation were compared to inhibitors of other major signalling pathways including PI3 kinase, JNK, MEK-1, NF-kappaB or protein kinase C (PKC). HBMSC were pre-treated with p38i (SB-203580) for 1 h and then stimulated with 200 ng/ml lipopolysaccharide (LPS). Supernatants and RNA were collected 6 h post LPS treatment for quantitative protein and mRNA analyses by ELISA and real-time RT-PCR, respectively, for interleukin-6 (IL-6), interleukin-11 (IL-11), granulocyte-monocyte colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) and Activin A. Effects of the inhibitors of PI3 kinase (LY294002), JNK (synthetic inhibitory peptide), MEK-1 (PD90859), NF-kappaB (pyrrolidinedithiocarbamate (PDTC)) and protein kinase C (calphostin C) on HBMSC expression hematopoietic cytokines were evaluated and compared. SB-203580 caused dose-dependent decreases in cytokine protein expression and decreased IL-6 and IL-11 mRNA expression. Of the pathway inhibitors examined, only NF-kappaB elicited similar effects on cytokine protein and mRNA expression. p38-regulated transcription factor activity was assessed using a DNA/Protein array. Several TFs linked to cytokine regulation were modulated by SB-203580, with 10 of 21 p38-regulated TFs identified have not been previously linked to downstream p38 signalling. These observations in cultured HBMSC have illustrated the involvement of cytokine proteins, mRNA and TF activities and may improve the current understanding of the in vivo p38i suppression of erythropoiesis. In addition, these results suggest that IL-6, IL-11, GM-CSF, G-CSF and Activin A are similarly regulated by p38 and NF-kappaB and that the MEK1, JNK and PKC pathways appear to play a more limited role in modulating cytokine expression in HBMSC.

Transcriptional profiling of specific elements of vasculature from animal models of vascular toxicity is an approach to gain insight into molecular mechanisms of vascular injury. Feasibility of using laser capture microdissection (LCM) to evaluate differential gene expression in selected elements of mesenteric arteries (MA) from untreated rats and rats given a single vasotoxic dose of 100 mg/kg Fenoldopam and euthanized 1 or 4 hours postdose was assessed. Regions of MA (endothelial cells [EC] and vascular smooth muscle cells [VSMC]) were selectively microdissected from optimal-cutting-temperature (O.C.T.)-embedded-frozen tissue sections. RNA was isolated, linearly amplified (LA), and hybridized to Affymetrix GeneChips. Enrichment for specific vascular elements was evident by unique gene-expression profiles. Statistical analysis indicated that Fenoldopam treatment resulted in differential expression of 333 versus 458 genes in EC and 371 versus 618 genes in VSMC at the 1-hour or 4-hour time point, respectively. Analysis of regulated EC and VSMC genes common to both time points identified several gene functions or pathways affected by treatment. Several genes were identified in EC and/or VSMC that have not been previously linked to vascular structure or function. These data indicate that tissue-element-enrichment by LCM in conjunction with LA and GeneChip analysis offers a refined approach for assessment of injury-mediated transcriptome changes in distinct elements of the vasculature.

SH-SY5Y human neuroblastoma cells were incubated with 6-hydroxydopamine (6-OHDA) for 4 and 24 h to examine the mechanism of cell death and to determine the time-dependent effects of 6-OHDA on cellular glutathione status. After 4 h, 6-OHDA significantly depleted cellular ATP and GSH concentrations with only slight increases in cell death. GSH:GSSG ratios and mitochondrial membrane potential (Deltapsim) were significantly decreased during 4 h incubations with 6-OHDA. High concentrations of 6-OHDA (100 microM) induced oxidative stress and mitochondrial dysfunction in SH-SY5Y cells within 4 h leading to cell death. In 24 h incubations, 25 and 50 microM 6-OHDA significantly decreased ATP concentrations; however, significant increases in cell death were only observed with 50 microM 6-OHDA. 6-OHDA induced a concentration-dependent increase in GSH and total glutathione concentrations after 24 h. After exposure to 50 microM 6-OHDA, GSH concentrations were increased up to 12-fold after 24 h with no change in the GSH:GSSG ratio. Gene analysis suggests that the increase in GSH concentration was due to increased expression of the GSH synthesis genes glutamate cysteine ligase modifier and catalytic subunits. Our results suggest that 6-OHDA induces oxidative stress in SH-SY5Y cells resulting in an adaptive increase in cellular GSH concentrations.

Objective: Erythropoiesis involves proliferation and differentiation of committed erythroid progenitors to mature red blood cells. The objective of this study was to characterize growth characteristics of human CD36+ erythroid progenitors and to profile temporal expression of lineage-specific transcription factors, structural proteins, and growth factor receptors involved in erythropoiesis., Materials and Methods: Erythropoietin-induced differentiation of human cord blood CD36+ erythroid progenitors was profiled for GATA-1, GATA-2, NFE2, EKLF, SCL, PU.1, Id1, Evi-1, c-myb, Hox2.2, c-kit, EpoR, glycophorin A (GPA), CD71, beta- and gamma-globin, and protein 4.2 gene and/or protein expression and DNA content analysis on days 4, 7, and 15 of culture., Results: Real-time RT-PCR analysis revealed upregulation of GATA-1, Id1, glycophorin A, and protein 4.2 mRNA expression on day 7 when compared to day 4 and decreased expression on day 15. EKLF, GATA-2, Hox2.2, c-myb, Evi-1, c-kit, and PU.1 mRNA expression decreased on days 7 and 15. NFE2, CD71, SCL, and EPO-R mRNA expression remained similar on days 4 and 7 but decreased on day 15. Expression of globin genes beta- and gamma-globin increased on both day 7 and day 15 compared to day 4. Values from flow cytometric quantitation of glycophorin A, transferrin receptor (CD71), and hemoglobin A proteins correlated with gene expression results. DNA analysis demonstrated that most cells lacked DNA content by day 15, a finding consistent with enucleation and terminal erythroid differentiation., Conclusion: These data indicate that in vitro liquid cultures of committed CD36+ erythroid progenitor cells retain, in part, many features of erythropoiesis at the cellular and molecular level and may provide a useful model for assessment of disease-related or drug-induced erythropoietic abnormalities.

A theoretical and numerical model is presented for the shape evolution of the thin liquid films separating the gas bubbles in a foam. The motion is due to capillary action, surface tension gradients, and the overall expansion of the foam. The expansion is the result of the increase in gas content with time. Process modeling is accomplished via the solution of three coupled partial differential equations. Two time scales are included in the model: a process time and a drying or curing time. It is demonstrated that the amount of surfactant is the dominant control mechanism for the final film thickness. If sufficient surfactant is present, the films will be shown to dilate uniformly in space. A number of known features of expanding foams are reproduced by the model.

Troglitazone (TRO), a member of the thiazolidinedione class of drugs, has been associated with hepatotoxicity in patients. The following in vitro study was conducted to investigate the effects of TRO on mitochondrial function and viability in a human hepatoma cell line, HepG2. TRO induced a concentration- and time-dependent increase in cell death, as measured by lactate dehydrogenase release. Exposure to 50 or 100 micro M TRO produced total loss of cell viability within 5 h. Preincubation of HepG2 cells with P450 inhibitors did not significantly protect against TRO-induced cell death suggesting that P450 metabolism was not required to induce cell death. Preincubation with the mitochondrial permeability transition inhibitor, cyclosporin A, provided complete protection against TRO-induced cell death. Our results also indicated that TRO produced concentration-dependent decreases in cellular ATP levels and mitochondrial membrane potential (MMP). Ultrastructural analysis demonstrated that TRO induced mitochondrial changes at concentrations of > or =10 micro M after 2 h. Decreased MMP and altered mitochondrial morphology occurred at time points that preceded cell death and at sublethal concentrations of TRO. These observations in HepG2 cells suggest that TRO disrupts mitochondrial function, leading to mitochondrial permeability transition and cell death.

Purpose: Report a case of acute angle closure glaucoma secondary to a choroidal melanoma., Methods: Case report of a 75-year-old woman who presented with acute angle closure glaucoma with bilateral narrow angles. After medical management with drops and peripheral laser iridotomies in both eyes, the pressure was controlled and the angles were noted to be open. This allowed safe dilation of the pupils to perform funduscopic examination. A large choroidal melanoma was noted in the eye with the acute angle closure attack., Results: Dilated fundus exam after peripheral laser iridotomies revealed a choroidal melanoma as the cause for the acute angle closure glaucoma., Conclusion: It is important to do a thorough eye examination to rule out secondary causes of angle closure, such as a potentially life-threatening tumor, when a patient presents with acute angle closure glaucoma.

Background: Allergic respiratory diseases are characterized by large numbers of eosinophils and their reactive products in airways and blood; these are believed to be involved in progressive airway damage and remodeling. IL-5 is the principal cytokine for eosinophil maturation, differentiation, and survival. Mepolizumab (SB-240563), a humanized monoclonal antibody (mAb) specific for human IL-5, is currently in clinical trials for treatment of asthma., Objective: The purpose of this study was to characterize the pharmacologic activity and long-term safety profile of an anti--human IL-5 mAb to support clinical trials in asthmatic patients., Methods: Naive and Ascaris suum -sensitive cynomolgus monkeys received various dose levels of mepolizumab and were monitored for acute and chronic pharmacologic and toxic responses., Results: To support preclinical safety assessment, cynomolgus monkey IL-5 was cloned, expressed, and characterized. Although monkey IL-5 differs from human IL-5 by 2 amino acids (Ala27Gly and Asn40His), mepolizumab has comparable inhibitory activity against both monkey IL-5 and human IL-5. In A suum--sensitive monkeys, single doses of mepolizumab significantly reduced blood eosinophilia, eosinophil migration into lung airways, and levels of RANTES and IL-6 in lungs for 6 weeks. However, mepolizumab did not affect acute bronchoconstrictive responses to inhaled A suum. In an IL-2--induced eosinophilia model (up to 50% blood eosinophilia), 0.5 mg/kg mepolizumab blocked eosinophilia by >80%. Single-dose and chronic (6 monthly doses) intravenous and subcutaneous toxicity studies in naive monkeys found no target organ toxicity or immunotoxicity up to 300 mg/kg. Monkeys did not generate anti-human IgG antibodies. Monthly mepolizumab doses greater than 5 mg/kg caused an 80% to 100% decrease in blood and bronchoalveolar lavage eosinophils lasting 2 months after dosing, and there was no effect on eosinophil precursors in bone marrow after 6 months of treatment. Eosinophil decreases correlated with mepolizumab plasma concentrations (half-life = 13 days)., Conclusion: These studies demonstrate that chronic antagonism of IL-5 by mepolizumab in monkeys is safe and has the potential, through long-term reductions in circulating and tissue-resident eosinophils, to be beneficial therapy for chronic inflammatory respiratory diseases.

Failure of a liquid coating to remain continuous on a substrate that exhibits a significant equilibrium contact angle is a common occurrence in industrial applications. The term "reticulation" is sometimes used to describe the resulting formation of a pattern of defects. The failure may take the form of coating perforations and dewetting, and it may ultimately lead to a set of isolated drops. We present mathematical and experimental results for reticulation. The theoretical and numerical results use a disjoining-conjoining pressure model to represent the substrate energetics. The theory uses the small-slope or "lubrication" approximation and also includes the effects of evaporation and drying of the coating. The model employs a two-component liquid where the viscosity depends on local values of the nonvolatile mixture fraction. A linear analysis for a slightly perturbed uniform layer predicts a most-unstable wavelength and an associated growth rate. These are in approximate agreement with the modeling results. Computations employing the full nonlinear model show the wide variety of patterns that can arise in the drying liquid. These patterns are both qualitatively and quantitatively similar to actual patterns that we observe experimentally. Small defects that are visible in the experiment are used to initiate reticulation in the numerical simulation. Copyright 2001 Academic Press.

Plasma von Willebrand factor (vWF) was evaluated as a potential biomarker of acute arterial damage in rats after a vasotoxic dose of the dopaminergic vasodilator, fenoldopam (FP). Male Sprague-Dawley rats were given FP or isotonic saline by subcutaneous injection, and plasma vWF was measured at 2, 6, and 24 hours after challenge. Mean plasma vWF values increased in FP-treated rats compared to controls at 2 hours (167 vs 122%; p < 0.05) and 6 hours postdose (172 vs 130%; p < 0.01) but were comparable to control values after 24 hours. Mesenteric arterial lesions were observed microscopically in all FP-treated rats 24 hours postdose but were not present in rats at 1, 2, 4, 6, or 8 hours after FP challenge. Further, plasma vWF concentrations increased in saline-treated rats after only the minimal perturbation of repeated venipuncture. These results indicate an early, minimal, and transient release of vWF that precedes the onset of morphologically evident vascular damage. The minimal increases in plasma vWF concentrations were of limited predictive value, may be more reflective of an acute-phase reactant response, and were not considered a reliable biomarker of acute FP-induced arterial damage in the rat.

Certain deep indentations observed in dry coatings are referred to as "craters". They are believed to arise from gradients in the coating surface tension. A mathematical model of surface-tension-gradient-driven flow, using the lubrication approximation for thin layers, is developed to study the formation of craters. The paint is modeled as consisting of an evaporating "solvent" part and a nonvolatile "resin" part. Surface tension gradients on the coating surface arise due to a nonuniform distribution of surfactant. Axisymmetric numerical simulations using the model are performed to explore two candidate crater production mechanisms: an initial release of concentrated surfactant and a steady surfactant source. The effects of changes in various properties, such as the paint drying rate, the surfactant diffusivity, and the viscosity increase during drying, are examined. The model produces craters with large diameters, pronounced rims, and central peaks, similar to those seen in practice. Drying rate has a large influence on crater diameter and depth, by limiting flow due to surface tension gradients within a given time. Reduction of the paint viscosity increase during drying causes increased flow rates, leading to larger craters. A preexisting layer of surfactant on the paint surface sharply reduces the extent of cratering. Surfactant diffusion also tends to reduce the severity of cratering by alleviating surface tension gradients. In some cases, a simplified form of the drying model may be used to quickly approximate the results of the full model. The model provides useful insights into the craters seen in industrial coating applications. Copyright 2000 Academic Press.

Several vasoactive drugs that lower blood pressure and increase heart rate induce regional cardiotoxicity in the dog, most frequently of right coronary arteries and right atrium. The basis for this selective damage is thought to result from local changes in vascular tone and blood flow. Administration of an endothelin receptor antagonist (ETRA, SB 209670) to dogs induced damage most frequent and severe in the right coronary artery and right atrium. Because site predisposition may correlate with distribution of vasoactive receptors, the objectives of this study were to map endothelin (ET) receptor distribution and density within regions of dog heart using both gene (mRNA) and protein expression endpoints for dog ET(A) and ET(B) receptors, and, additionally, correlate ET receptor subtype density with regional cardiac blood flow. A 10- to 15-mmHg reduction in mean arterial pressure with a concomitant increase in heart rate (10-20%), a six- and twofold increase in regional blood flow to the right and left atrium, respectively, and acute hemorrhage, medial necrosis, and inflammation were observed in the right coronary arteries and arteries of the right atrium after ETRA infusion for 5 days. Radioligand protein binding to quantify both ET receptors in normal dog heart indicated a twofold greater density of ET receptors in atrial regions versus ventricular regions. Importantly, ET receptor density in coronary arteries was markedly (about five- to sixfold) increased above that in atrial or ventricular tissues. ET receptor subtype characterization indicated ET(B) receptors were three times more prevalent in right coronary arteries compared to left coronary arteries and in situ hybridization confirmed localization of ET(B) in vascular smooth muscle. ET(A) receptor density was comparable in right and left coronary arteries. Quantitative real-time polymerase chain reaction for ET(A) and ET(B) receptor mRNA transcripts supported the site prevalence for message distribution. Consequently, the composite of protein and message expression profiles for ET(A) and ET(B) receptors indicated a disproportionate distribution of ET(B) receptors within right coronary artery of dog and this, along with functional measures of blood flow after ETRA infusion indicated a predisposition for exaggerated pharmacological responses and subsequent damage to right coronary arteries by ET and/or ETRAs.

Two-dimensional electrophoresis (2-DE) of liver proteins was applied to further characterize an unusual drug-induced increase in hepatocellular rough endoplasmic reticulum (RER) in Sprague-Dawley rats given a substituted pyrimidine derivative. Absolute liver weights of drug-treated rats (9.9 +/- 0.4 g) increased above vehicle-treated controls (7.2 +/- 0.2 g) by 37%. Light microscopy revealed diffuse granular basophilia of the hepatocellular cytoplasm, uncharacteristic of hepatocytes and suggested cells rich in ribosomes, which was confirmed by electron microscopy. Immunostaining for cell proliferation, viz., 5-bromo-2'-deoxyuridine (BrdU) and proliferating cell nuclear antigen (PCNA), indicated marked hepatocellular proliferative activity. 2-DE of solubilized liver using an ISO-DALT gel system indicated significant (p<0.001) quantitative changes in at least 17 liver proteins (12 increased, 5 decreased) compared to controls. The protein with the largest increase was homologous to acute-phase reactant, contrapsin-like protein inhibitor-6. Other markedly upregulated proteins were methionine adenosyltransferase, a catalyst in methionine/ATP metabolism and mitochondrial HMG-CoA synthase, involved in cholesterol synthesis. The complementary strategies of 2-DE coupled either with database spot mapping or protein isolation and amino acid sequencing successfully identified a subset of proteins from xenobiotic-damaged rodent livers, the expression of which differed from controls. However, the current bioinformatics platform for rodent hepatic proteins and limited knowledge of specific protein functionality restricted application of this proteomics profile to further define a mechanistic basis for this unusual hepatotoxicity.

A mathematical model is constructed to describe the two-dimensional flow in a vertical soap film that is draining under gravity. An asymptotic analysis is employed that uses the long-wave or "lubrication" approximation. The modeling results in three coupled partial differential equations that include a number of dimensionless input parameters. The equations are solved numerically. The three functions calculated, as they vary in space and time, are the film thickness, the surface concentration of an assumed insoluble surfactant, and the slip or surface velocity. The film is assumed to be supported by "wire frame" elements at both the top and the bottom; thus the liquid area and the total surfactant are conserved in the simulation. A two-term "disjoining" pressure is included in the model that allows the development of thin, stable, i.e., "black," films. While the model uses a simplified picture of the relevant physics, it appears to capture observed soap film shape evolution over a large range of surfactant concentrations. The model predicts that, depending on the amount of surfactant that is present, the film profile will pass through several distinct phases. These are (i) rapid initial draining with surfactant transport, (ii) slower draining with an almost immobile interface due to the surface tension gradient effect, and (iii) eventual formation of black spots at various locations on the film. This work is relevant to basic questions concerning surfactant efficacy, as well as to specific questions concerning film and foam draining due to gravity. Prospects for extension to three-dimensional soap film flows are also considered. Copyright 1999 Academic Press.

Immunohistochemical markers for proliferation (bromodeoxyuridine, BrdU) and apoptosis (in situ terminal deoxynucleotide transferase dUTP nick end-labeling, TUNEL) were localized within glutathione S-transferase (GSTP)-positive hepatic foci in rats. Using the TechMate Automated Staining System (BioTek Solutions: Santa Barbara, CA), formalin-fixed, paraffin-embedded sections were run through a double-label avidin-blotin-immunoperoxidase protocol in less than 10 hr. Steam heat-induced epitope retrieval and/or proteolytic digestion preceded each labeling procedure. Color development was achieved using diaminobenzidine (DAB) with nickel enhancement for BrdU and TUNEL and VIP for GSTP. Results illustrate clear staining, brown-black BrdU-positive nuclei or TUNEL-positive apoptotic bodies within purple GSTP-positive hepatocytes. This automated procedure provides a method to easily identify and quantitate proliferating or apoptotic cells within foci of altered hepatocytes in rat liver and may have general applications for studies of cell or tissue kinetics during development, differentiation, and various pathological conditions in animals and humans.

The lubrication form of the equations governing the flow of a thin liquid film on a horizontal right circular cylinder is derived. The equations are discretized and solved numerically using an alternating-direction implicit algorithm. Simulations demonstrate that the transition from a uniform coating to a final configuration of distinct drops follows a similar evolution for a wide range of cylinder radii. Initially gravity-driven drainage from the top and sides of the cylinder dampens the formation of any axial disturbances; only when this drainage slows do longitudinal waves begin to develop along the bottom of the cylinder. These waves grow rapidly and a series of alternating primary and satellite drops form during the transition from a linear to a nonlinear wave growth regime. This is followed by a slow drainage between adjacent drops as the drop pattern approaches an equilibrium state where surface tension forces exactly balance gravitational forces in each discrete drop. For large cylinder radii, these drops are localized on the bottom of the cylinder, while, for sufficiently small cylinder radii, these drops may wrap around the entire circumference of the cylinder. Integral measures of the evolving coating profile, such as the total energy and viscous dissipation rate, clearly show these growth phases. The equilibrium shape of large-amplitude pendant drops and the maximum sustainable drop volume for various cylinders are also considered.

Background and Objective: This study evaluated the efficacy of argon laser trabeculoplasty (ALT) in patients with aphakia or pseudophakia., Patients and Methods: The authors retrospectively analyzed 63 eyes of 63 patients with aphakia or pseudophakia who had uncontrolled open-angle glaucoma and were treated with 180 degrees or 360 degrees ALT., Results: The mean intraocular pressure (IOP) before ALT was 25.1 mm Hg (+/- 8.1 mm Hg). Two years after ALT, the mean IOP in the successfully treated group was 15.4 mm Hg. The mean survival time (50% success rate) for all treated eyes was 23 months, and treatment was successful in 34% of eyes at 36 months. Pseudophakic eyes had a better response than aphakic eyes (P = .06), and eyes that had extracapsular surgery did better than eyes with intracapsular surgery (P = .07)., Conclusion: ALT in aphakic or pseudophakic eyes with uncontrolled glaucoma is a safe, reasonably effective treatment that can delay the need for trabeculectomy.

Purpose: We compared the therapeutic efficacy and safety of timolol hemihydrate to timolol maleate in patients with ocular hypertension and chronic open-angle glaucoma., Methods: We conducted this three-month study as a multicentered, masked, parallel group comparison. Both the 0.25% and 0.5% concentrations were evaluated against similar concentrations of timolol maleate. Dosing was twice daily. An open-label, nine-month study followed the masked portion of the protocol, in which all patients received either 0.25% or 0.5% timolol hemihydrate. A total of 371 patients were included in both the 0.25% and 0.5% studies., Results: We found statistically similar intraocular pressures with both the 0.25% (18.3 and 18.6 mm Hg for the hemihydrate and maleate groups, respectively) and 0.5% (19.9 and 19.5 mm Hg for the hemihydrate and maleate groups, respectively) concentrations of timolol hemihydrate and timolol maleate after three months of masked treatment. Likewise, peak intraocular effect at two hours after taking the medication was statistically similar between medicines at both concentrations. Likewise, both ocular and systemic safety were similar between the maleate and hemihydrate preparations at both concentrations. In the nine-month open-label protocol, therapeutic efficacy (19.9 and 19.1 mm Hg for the 0.25% and 0.5% concentrations, respectively) and safety of timolol hemihydrate were similar to effect and safety of the three-month protocol., Conclusions: This study suggests that timolol hemihydrate had an ocular hypotensive efficacy and safety profile statistically equivalent to that of timolol maleate for up to three months of therapy. Timolol hemihydrate showed efficacy and safety similar to that observed within the first three months, for up to one year of therapy.

The effect of 5-ASA and 4-ASA, drugs used for the treatment of inflammatory bowel disease, on modulation of experimental colitis and on colonic generation of interleukin-1 was evaluated. Three weeks of treatment with 5-ASA or 4-ASA (50 micrograms/kg) and one week of treatment with 5-ASA significantly decreased colonic interleukin-1 generation and the extent and severity of inflammation in a rat model of colitis induced by trinitrobenzene sulphonic acid. Colonic biopsies were obtained from patients with active ulcerative colitis and organ cultured 24 hours in the absence or presence of the following drugs: sulphasalazine, sulphapyridine, 5-ASA and 4-ASA (25-100 micrograms/ml). Interleukin-1 content in tissue cultured in the presence of 5-ASA (100 micrograms/ml) was two-thirds of its content in tissue cultured in drug free medium and its release into the medium was decreased by 50%. Sulphasalazine 50 micrograms/ml significantly decreased by 33% the tissue content but did not affect interleukin-1 release and a higher dose was not more effective. Sulphapyridine and 4-ASA in doses up to 100 micrograms/ml did not affect either interleukin-1 colonic content or its release into the culture medium. We conclude that pharmacological suppression of colonic interleukin-1 generation may be one, although not the sole mechanism to explain the therapeutic efficacy of 5-ASA in the treatment of inflammatory bowel disease.

Current strategies for the treatment of ARDS have been unsuccessful in reducing mortality. In the present study, we have evaluated the role of cyclooxygenase (CO) products in a rat model of ARDS by testing naproxen, indomethacin, ibuprofen, and a thromboxane A2 (TXA2) receptor antagonist (SK&F 96148). Rats were treated 1 hr prior to endotoxin (LPS) exposure and 24 hr later, survival, body weight changes, wet/dry lung weight (W/D), total protein content (TP) of the bronchoalveolar lavage (BAL) fluid, and total erythrocyte and differential leukocyte counts of the BAL fluid were measured. In addition, the following hematologic measurements were taken: hemoglobin (Hb), hematocrit (Hct), circulating erythrocyte, differential leukocyte, and platelet counts. Treatment with the TXA2 receptor antagonist reduced mortality to zero after 24 hr after LPS administration. Other compounds had no significant effect on LPS-induced mortality. Pretreatment with CO inhibitors or the TXA2 receptor antagonist attenuated the LPS-induced increase in TP and W/D. Although all compounds tended to reduce the LPS-induced increase in BAL erythrocytes, only the TXA2 receptor antagonist did so significantly. The LPS-induced increase in BAL neutrophil counts was significantly reduced by 30 mg/kg ibuprofen, but not by the other compounds. In fact, the TXA2 receptor antagonist actually exacerbated BAL neutrophil counts, but diminished the peripheral neutrophilia and lymphopenia induced by LPS. None of the CO inhibitors tested significantly affected LPS-induced hematologic responses. We conclude that by virtue of its protection against LPS-induced mortality, the TXA2 receptor antagonist was the most effective compound in this model. However, it did cause certain negative side effects such as increased pulmonary inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study was designed to investigate the role of 5-lipoxygenase (5LO) metabolites in an endotoxin (LPS)-induced model of the adult respiratory distress syndrome (ARDS) in the rat. The therapeutic value of two 5LO inhibitors and a specific LTB4 and a LTD4 receptor antagonist were examined. Rats were treated 1 hr prior to administration of aerosolized LPS. Rats were either unexposed (n = 11), or pretreated with vehicle sham (n = 63), 50 mg/kg phenidone t.i.d. (n = 7, n = 10 for assessment of mortality), 30 mg/kg SK&F 103842 b.i.d. (n = 6), 50 mg/kg SK&F 106203 t.i.d. (n = 11), or 5 mg/kg SK&F 107324 b.i.d. (n = 6) 1 hr prior to the administration of aerosolized endotoxin (LPS, 7 mg/kg) or phosphate-buffered saline (PBS, n = 22). Twenty-four hours later, blood samples were collected for hematologic evaluation and after wet lung weight was determined, broncho-alveolar lavage (BAL) was performed to measure cells counts and total protein (TP). 5LO inhibition and LTD4 receptor antagonism reduced LPS-induced mortality to zero compared to 35% in rats pretreated with vehicle sham. Pretreatment with the LTD4 receptor antagonist attenuated the LPS-induced increased in wet/dry lung weight (W/D) whereas 5LO inhibition reduced TP increases. Both 5LO inhibition and LTD4 receptor antagonism attenuated the LPS-induced BAL erythrocyte increase. The LPS-induced thrombocytopenia was attenuated by phenidone, the 5LO receptor antagonist. We conclude that the increased microvascular permeability was associated with the formation of 5LO products since 5LO inhibition lessened the severity of the LPS-induced increase in W/D and TP.(ABSTRACT TRUNCATED AT 250 WORDS)

This study characterized the induction of the rat hepatic cytochrome P-450-dependent mixed function oxidase system by SK&F 86002 [6-(4'-fluorophenyl)-5-(4'-pyridyl)-2,3-dihydroimidazo-(2,1-b)thia zole], an inhibitor of both the cyclooxygenase and 5-lipoxygenase pathways of arachidonic acid metabolism. The induction characteristics of SK&F 86002 were compared to those of the classical inducer, phenobarbital, and morphological features of both SK&F 86002 and phenobarbital induced hepatocellular hypertrophy were quantitated. Rats were administered either SK&F 86002 (6, 18, or 60 mg/kg/day, po) or phenobarbital (8, 24, 80 mg/kg/day, ip) for 3 or 14 consecutive days. Liver to body weight ratio, total hepatic microsomal protein and cytochrome P-450 content, ethoxycoumarin-O-deethylase (ECOD) and leukotriene B4(LTB4) omega- and omega-1 hydroxylase were measured. Ultrastructural morphometry of the liver from control, and high dose SK&F 86002 (60 mg/kg/day) and phenobarbital (80 mg/kg/day) treated rats was completed. On day 3, phenobarbital increased liver to body weight ratio but only at the 80 mg/kg/day dosage; microsomal protein content was unchanged. ECOD activity increased in a dose-dependent fashion. LTB4 omega- and omega-1 hydroxylase activities were unaffected. Administration of SK&F 86002 for 3 days increased the liver to body weight ratio at both the 18 and 60 mg/kg/day dosage; microsomal protein content was unchanged. ECOD activity was significantly increased by the 60 mg/kg/day dosages of SK&F 86002. On day 14, phenobarbital increased the liver to body weight ratio and microsomal protein content but again only at the 80 mg/kg/day dosage. Cytochrome P-450 content was increased by all dosages.(ABSTRACT TRUNCATED AT 250 WORDS)

The protective effects of altered arachidonic acid metabolism, using either methylprednisolone or a dual cyclooxygenase and 5-lipoxygenase inhibitor (SK&F 86002), were compared in a rat model of adult respiratory distress syndrome (ARDS). Rats were either unexposed (n = 9) or pretreated with vehicle (n = 25), 100 mg/kg SK&F 86002 (n = 8) or 30 mg/kg methylprednisolone (MP, n = 7) 1 h prior to the intratracheal administration of 7 mg/kg aerosolized endotoxin (LPS) or phosphate buffered saline (PBS). Twenty-four hours later, blood samples were collected and the rats were anesthetized and exsanguinated. The lungs were surgically removed, weighed and bronchoalveolar lavage (BAL) was performed. LPS caused 30-35% mortality and induced significant differences in body weight, BAL erythrocyte and neutrophil counts, lung wet/dry weight ratio (W/D), total BAL protein (TP), hemoglobin (Hb), hematocrit (HCT), and circulating leukocyte and platelet counts as compared with controls. Pretreatment with MP reduced mortality to zero and also attenuated the LPS-induced alterations in body weight, W/D, TP, BAL erythrocyte count, and circulating platelet count. However, MP exacerbated LPS-induced increases in Hb, HCT and circulating neutrophil counts while enhancing lymphopenia. Pretreatment with SK&F 86002 also reduced mortality to zero and attenuated LPS-induced alterations in W/D, TP, HCT and circulating platelet count. Like MP, SK&F 86002 exacerbated the LPS-induced lymphopenia, and increased circulating neutrophils above baseline values. We conclude that both MP and SK&F 86002 provided protection against LPS-induced responses in this model of ARDS. Mechanistically, this indicates the critical role of eicosanoid mediators in this model. Therapeutically, SK&F 86002, or a similar compound, may be beneficial in preventing the acute phase responses so harmful to ARDS patients.

6-(4'-Fluorophenyl)-5-(4'-pyridyl)-2,3-dihydroimidazo-[2,1-b]-thia zole (SK&F 86002) is a dual inhibitor of arachidonic acid metabolism which has therapeutic potential for the treatment of inflammatory diseases. Previous studies in rats, in vivo, demonstrated that SK&F 86002 metabolism proceeds by sequential steps of sulfur and nitrogen oxidation. Therefore, these studies were designed to 1) identify the enzymes (flavin vs. cytochrome P-450-dependent monooxygenases) which were responsible for SK&F 86002 metabolism in vitro in hepatic microsomal suspensions from Sprague-Dawley rats, 2) characterize sex-dependent differences, and 3) quantitate the effect of pretreatment with SK&F 86002. All three steps in the sequential metabolism of SK&F 86002 to the N-oxide sulfone metabolite were quantitated individually. The three oxidation steps appeared to be catalyzed primarily by cytochrome P-450; heat inactivation (used to destroy flavin monooxygenase) had little effect on the metabolism of each compound. Further,N-octylamine failed to stimulate the metabolism of any compound and the cytochrome P-450 inhibitors (SK&F 525-A, metyrapone, and alpha-naphthoflavone) resulted in a marked inhibition of the metabolism of all three substrates. Maximal velocities for metabolism of all three substrates (SK&F 86002, sulfoxide, and sulfone) in microsomes isolated from male rats, were 3- to 5-fold greater than observed in female rats. Furthermore, pretreatment of male rats with SK&F 86002 (60 mg/kg/day for 3 days) resulted in a change in the in vitro metabolism of all three substrates generally characterized by an increase in Vmax and/or a fall in km.(ABSTRACT TRUNCATED AT 250 WORDS)

Patients with uncontrolled open-angle glaucoma were treated with argon laser to the trabecular meshwork. These patients were divided into six groups. Each group of eyes had a slightly different technique of argon laser therapy. Except for one group, there was an adequate pressure lowering effect at the longest follow-up (-18 to -28%). Since the worst complication of argon laser trabeculoplasty is the immediate elevation in intraocular pressure with subsequent worsening of the field and/or disc, the immediate rise in intraocular pressure was measured and compared for each of the various techniques. In addition comparison was made when treating 180 degrees in one eye and 360 degrees in the other eye of 30 individuals having similar glaucomatous disease bilaterally. Little difference was noted between the two eyes.

This paper describes the use of a pulsed argon laser to perform iridotomies in 87 patients. Diagnosis include: primary angle closure glaucoma, narrow angle in the fellow eye of patients with primary angle glaucoma, pupillary block, and after incomplete surgical iridectomies. Laser iridotomy was achieved in 79% of patients. Blue eyes were slightly more difficult to penetrate. Success was almost 100% in those with pupillary block. Penetration was most difficult in patients with primary angle closure glaucoma (64%), but more easily accomplished in the fellow eyes of such cases (87%). In 13 patients surgical peripheral iridectomy was performed on one eye while the other eye was treated with laser iridotomy. No apparent significant long term differences were noted between the two eyes of the same individual. Complications of laser iridotomy include corneal burns, pupil distortion, synechia formation, lenticular opacities, iritis, marked pigment dispersion, sudden rise in intraocular pressure, and retinal burns. At this time a longer follow-up is required before it can be stated that a laser PI is more advantageous than a surgical PI. However, the laser's simplicity and ease of administration appear to warrant its continued use at this time.

Tracheal explants from rats exposed to 0.8 ppm (1.9 mg per m3) of ozone 8 hours per day for 1 to 90 days were incubated in culture with glucosamine labeled with carbon-14 or hydrogen-3. Compared with tracheas from control rats exposed to filtered air, the explants demonstrated a decreased rate of glycoprotein secretion for exposure intervals of as long as one week, followed by a rebound to an increased rate of glycoprotein secretion for at least 12 weeks of continued exposure to ozone. Detailed study of the behavior of labeled glycoproteins from the culture medium on chromatography on columns of BioGel A-150m demonstrated that the ratio of the low to high molecular weight peaks increased when there was an increased rate of glycoprotein secretion. This is the first report of a direct biochemical effect induced by ozone on airway metabolism.

Bonnet monkeys (Macaca radiata) were exposed to 0.0, 0.5, or 0.8 ppm ozone for 7, 28, or 90 consecutive days, 8 hours per day. The pulmonary response was evaluated by means of pulmonary function testing, light microscopy, scanning electron microscopy, transmission microscopy, autoradiography, and morphometry. Pulmonary function values obtained before exposure did not statistically differ from values obtained after exposure. A general trend of increased quasistatic compliance of the lung was observed in both groups of exposed monkeys. Morphologic changes were principally characterized as low-grade chronic respiratory bronchiolitis. Major features were intraluminal accumulations of macrophages and hypertrophy and hyperplasia of cuboidal bronchiolar epithelial cells. The intensity of this inflammatory response was determined by counting the number of intraluminal inflammatory cells per millimeter of respiratory bronchiolar surface. The magnitude of inflammation was greatest at the 0.8 ppm ozone concentration at each exposure period; however, the number of inflammatory cells present at 90 days was less than one half that observed at 7 days, in spite of persistent ozone insult. Tritiated thymidine labeling and counts of respiratory bronchiolar epithelium demonstrated up to a 37-fold increase in labeling index at 7 days but only a sevenfold increase at 90 days. Differential cell counts demonstrated an increase in the proportion of cuboidal bronchiolar cells constituting the respiratory bronchiolar epithelium. In control monkeys, 60% of the epithelial cells were cuboidal bronchiolar cells. At 90 days of exposure, more than 90% of the respiratory bronchiolar cells were cuboidal in appearance. The cuboidal bronchiolar cell in control monkeys does not appear secretory, but membrane-bound electron-dense secretory granules are present in this cell type from exposed monkeys. Epithelial hyperplasia (increased number of cells per millimeter of airway length) persisted through 90 days of exposure at a level slightly above that present at 7 days.

Coccidioidomycosis was diagnosed after necropsy of a young adult male rhesus monkey obtained from El Paso, Tx. Clinical signs were confined to the respiratory tract and included tachypnea and dyspnea. Radiographic findings included multiple air-filled cavities and evidence of severe diffuse pulmonary disease. Pathologic changes were confined to the respiratory tract and were representative of the chronic progressive pulmonary form of coccidioidomycosis. Unique features of this case were the massive involvement of the pulmonary parenchyma, the formation of multiple miltiloculated cavities that arose from conducting airways, and the metaplastic epithelial changes within the cavities. Histologic examination revealed numerous spherules characteristic of Coccididioides immitis but an absence of mycelial forms.

Adenovirus SV-20 (ASV-20) was inoculated subcutaneously into adult rhesus macaques (Macaca mulatta), and various immunologic parameters were studied. Similar changes were observed in macaques that had anti-ASV-20 serum-neutralizing antibodies prior to inoculation and in those lacking detectable antibodies. There were absolute decreases in numbers of peripheral blood lymphocytes (PBL), erythrocyte-rosetting lymphocytes, complement-receptor lymphocytes, and Fc-receptor lymphocytes. These changes were most significant (P less than 0.05) on postinoculation days (PID) 3 and 7. Mitogenic responsiveness to concanavalin A, phytohemagglutinin, and pokeweed mitogen in cultured PBL from immune and nonimmune macaques was depressed on PID 3, 7, and 14. Ultraviolet-inactivated ASV-20 caused moderate suppression of phytohemagglutinin-induced mitogenesis when viral particles and lectin were added simultaneously to PBL cultures. Plasma cortisol (hydrocortisone) values were not significantly altered following inoculation of ASV-20. High titers of anti-ASV-20 antibody developed by PID 7 in nonimmune macaques, and previously immune macaques showed a booster effect in the same time period. Antibody titers were still increased 120 days after inoculation. There was no clinical evidence of an adverse effect of ASV-20 infection in these macaques.

The development of bleomycin-induced lung fibrosis was studied in hamsters drinking tap water or 2% alpha-difluoromethylornithine (DFMO) dissolved in tap water for 14 days. The fibrotic lesions in the lung were evaluated by biochemical measurements of total neutral salt soluble (NSS) and insoluble (NSI) collagens and by morphometric histopathologic techniques. Daily ingestion of DFMO failed to offer any protection against bleomycin-induced lung fibrosis; instead, it increased the deposition of total lung NSI collagen to 396% of control, as compared with 145% of control caused by bleomycin treatment alone. Daily intake of DFMO by itself increased the accumulation of total lung NSI collagen to 250% of control, as opposed to a 145% increase caused by bleomycin treatment alone. Histopathologically, the lung lesions in hamsters treated with bleomycin and DFMO were qualitatively similar to those of hamsters treated with bleomycin alone. However, morphometric estimates revealed that of lung lesions were more diffuse and severe in the former than in the latter group.

This study was undertaken to evaluate the effect of in vivo cigarette smoke exposure on glutathione peroxidase--related enzyme systems of the rat lung. These enzymes, acting in concert, are thought to be responsible for disposing of toxic lipid peroxides in pulmonary tissue. Thirty-day-old rats were exposed to thirteen cigarettes per day for 21 days with a Walton reverse-smoking exposure apparatus. After 21 days of smoke exposure, the activities of glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase were increased 34%, 24%, and 38%, respectively, over control values. This level of cigarette smoke exposure did not cause detectable histological lesions. We present the hypothesis that short-term, low-level cigarette smoke exposure is capable of initiating metabolic alterations in lung cells at exposures at which histological changes are not detectable by light microscopy.

This study was designed to determine the presence of cell-bound histamine and mast cells, if any, in the lung and skin of nonhuman primate fetuses and neonates. The results indicate that cell-bound histamine can be detected in both tissues of the rhesus monkey fetus by 60 days of gestation, the earliest age examined, at levels that are 2% to 3% of levels present in yearling animals. Levels increase markedly during the least 1 1/2 mo of gestation; however, at birth, levels are only 12% to 46% of those observed in the yearling and are lower than levels observed at 150 days of gestation. Most cell numbers in lung and skin of the fetus closely parallel histamine content.

Groups of Sprague-Dawley rats were exposed to 0.2, 0.5, or 0.8 p.p.m. of ozone 8 hours a day for 20, 50, or 90 consecutive days to evaluate the prolonged effect of oxidant exposure on the centriacinar area of the lung. Morphologic evaluation revealed that epithelial changes and accumulations of macrophages in centriacinar regions at 90 days were similar to but less severe than lesions seen at 7 days. Quantification of inflammatory cells in centriacinar regions using scanning electron microscopy revealed a 5-fold increase above controls after exposure to 0.8 p.p.m. of ozone for 20 days. Both the 0.5- and 0.8 p.p.m. exposure groups had significantly (p< 0.05) increased numbers of inflammatory cells within proximal alveoli at all time periods. Morphometric analysis applied to transmission electron microscope micrographs demonstrated that the arithmetic mean thickness of the air-blood barrier was 1.20 /+- 0.13 micrometer. (mean /+ standard deviation) in controls; 2.92 /+- 0.92 micrometer. and 2.17 /+ 0.18 micrometer. in rats exposed to 0.8 p.p.m. of ozone for 20 or 90 days, respectively. The increased thickness was accompanied by an increase in the relative volume of the interstitium. These results indicate that centriacinar lesions induced by ozone diminish with continued exposure, but that significant morphologic alterations do persist through 90 days of exposure at the 0.5 and 0.8 p.p.m. levels but not at the 0.2 p.p.m. ozone level.