Oral administration of rapamycin and cyclosporine differentially alter intestinal function in rabbits

The immunosuppressive drugs rapamycin (Rap) and cyclosporine A (CsA) are used clinically to modify or abolish immune-mediated functions. This study examined the effect of orally administered regimens of Rap, CsA, and a combination of Rap/CsA on intestinal function in male New Zealand white rabbits. Animals received oral doses of CsA (15 mg/kg/body weight/day), low-dose (LD) and high-dose (HD) Rap (0.25 or 1 mg/kg/body wt/day, respectively), or Rap/CsA (0.25 and 5 mg/kg/body wt/day, or 0.5 and 5 mg/kg/body wt/day, respectively) for 20 days. We measured in vitro uptake of nutrients and permeability, and morphometric measurements in the jejunum and ileum were made. Animals receiving HD-Rap or HD-Rap/CsA had decreased food intake, body weight, and intestinal weight, when compared with LD-Rap, LD-Rap/CsA, CsA, or controls. The maximal transport rate (Vmax) for the active jejunal uptake of D-glucose was increased in HD-Rap and CsA, but not in the HD-Rap/CsA-treated animals. The jejunal Vmax of D-glucose in the LD-Rap- or -Rap/CsA-treated animals was no different from controls. In the HD-Rap- and HD-Rap/ CsA-treated animals, jejunal rates of uptake of stearic, linoleic, and linolenic acids were reduced when compared with controls. Jejunal and ileal permeability (as assessed by the passive uptake of L-glucose, tissue conductance, and mucosal-to-serosal flux of [3H]inulin) was increased in animals treated with HD-Rap or HD-Rap/CsA, when compared with CsA or controls. These parameters of permeability were no different at lower doses of Rap or Rap/CsA. The jejunal and ileal villous surface area was increased in CsA, but decreased in HD-Rap or HD-Rap/CsA animals. Thus, HD-Rap given alone or in combination with CsA reduced body weight gain, in part due to reduced food intake and malabsorption of lipids, which was due at least in part to reduced intestinal surface area. The relevance of these findings to patients undergoing chronic immunosuppressive drug therapy needs to be established.     

Spontaneous remission in patients with essential blepharospasm and Meige syndrome

PURPOSE: To determine the frequency of remission in patients with essential blepharospasm and Meige syndrome. METHOD: Retrospective analysis of patients by means of questionnaire in an institutional setting. RESULTS: Among 238 patients diagnosed in a single institution as having essential blepharospasm or Meige syndrome, 27 (11.3%) claimed to be symptom free without curative surgery. The average time between onset and resolution in the patients who claimed remission was 4.85 years (range, 3 months to 22 years). Among these patients, the duration of remission averaged 6.33 years (range, 1 year to 14 years). CONCLUSION: Patients with essential blepharospasm or Meige syndrome have a small but definite potential for spontaneous remission of symptoms, particularly within the first 5 years after onset of symptoms.     

Characterization of Apo-Form Selective Inhibition of Indoleamine 2,3-Dioxygenase**

Indoleamine-2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the rate-limiting step in the kynurenine pathway of tryptophan (TRP) metabolism. As it is an inflammation-induced immunoregulatory enzyme, pharmacological inhibition of IDO1 activity is currently being pursued as a potential therapeutic tool for the treatment of cancer and other disease states. As such, a detailed understanding of the mechanism of action of IDO1 inhibitors with various mechanisms of inhibition is of great interest. Comparison of an apo-form-binding IDO1 inhibitor (GSK5628) to the heme-coordinating compound, epacadostat (Incyte), allows us to explore the details of the apo-binding inhibition of IDO1. Herein, we demonstrate that GSK5628 inhibits IDO1 by competing with heme for binding to a heme-free conformation of the enzyme (apo-IDO1), whereas epacadostat coordinates its binding with the iron atom of the IDO1 heme cofactor. Comparison of these two compounds in cellular systems reveals a long-lasting inhibitory effect of GSK5628, previously undescribed for other known IDO1 inhibitors. Detailed characterization of this apo-binding mechanism for IDO1 inhibition might help design superior inhibitors or could confer a unique competitive advantage over other IDO1 inhibitors vis-à-vis specificity and pharmacokinetic parameters.     

Comparative reactivities of coal asphaltenes during hydropyrolysis

Comparisons have been drawn in the relative reactivities of three coal asphaltenes during hydropyrolysis. All were derived from hydrogen donor-solvent extracts of bituminous coal, but had different hydrotreatment histories and different carbon contents (87.1, 91.9 and 90.8 wt% for asphaltenes 1, 2 and 3, respectively). The hydropyrolyses were carried out in the presence of CoO–MoO₃ catalyst and gaseous hydrogen at 8.7 MPa. For two of the asphaltenes (1 and 2) systematic comparisons were made for different reaction times at 425°C; for all three asphaltenes comparisons were made for l h of hydropyrolysis at 425°C. The general pattern of asphaltenes conversion indicated that more pentane-soluble product was produced from asphaltene isolated from straight coal extract (asphaltene 1). For the asphaltenes isolated from hydrotreated extracts, the extent of conversion to liquids was limited when the carbon content was high (asphaltene 2) although the pattern of conversion was similar in the other hydrotreated asphaltene (asphaltene 3). The aliphatic content of the liquid products formed was low, and the distribution of hydrogenated species in the highly aromatic liquid products indicated that complete hydrogenation of the polyaromatics produced in pyrolysis is difficult. Altogether the aliphatics made up ≈ 10 wt% of the asphaltene 1 hydropyrolysate. Aromatic hydrocarbons made up 90% of the liquid product. Phenanthrene, pyrene and anthracene were prominent, and the largest component in the mixture was phenanthrene which, together with other polyaromatics such as fluoroanthene, dominated the liquid product.     

Fish oil prevents change in arachidonic acid and cholesterol content in rat caused by dietary cholesterol

Rats were fed diets high in either saturated fat (beef tallow) or α-linolenic acid (linseed oil) or eicosapentaenoic and docosahexaenoic acids (fish oil) with or without 2% cholesterol supplementation. Consumption of linseed oil and fish oil diets for 28 days lowered arachidonic acid content of plasma, liver and heart phospholipids. Addition of 2% cholesterol to diets containing beef tallow or linseed oil lowered 20∶4ω6 levels but failed to reduce 20∶4ω6 levels when fed in combination with fish oil. Feeding ω3 fatty acids lowered plasma cholesterol levels. Addition of 2% cholesterol to the beef tallow or linseed oil diet increased plasma cholesterol concentrations but not when fish oil was fed. Feeding the fish oil diet reduced the cholesterol content of liver, whereas feeding the linseed oil diet did not. Dietary cholesterol supplementation elevated the cholesterol concentration in liver in the order: linseed oil > beef tallow > fish oil (8.6-, 5.5-, 2.6-fold, respectively). Feeding fish oil and cholesterol apparently reduced 20∶4ω6 levels in plasma and tissue lipids. Fish oil accentuates the 20∶4ω6 lowering effect of dietary cholesterol and appears to prevent accumulation of cholesterol in plasma and tissue lipids under a high dietary load of cholesterol.     

Lipid composition and peroxide levels of mucosal cells in the rat large intestine in relation to dietary fat

To examine whether dietary fat alters membrane lipid composition and peroxidation of polyunsaturated fatty acids in “non-proliferative” and “proliferative” cells in the large intestine, Sprague-Dawley rats were fed diets providing a polyunsaturated-to-saturated fatty acid ratio of 1.2 or 0.3 at a high or low level of fat intake for a 25-day period. Cell populations were isolated and the effect of dietary fat on membrane polyunsaturated fatty acid content and peroxide levels was determined. Neither fat level nor fatty acid composition of diet influenced total cholesterol, total phospholipids, and percentage of phospholipid classes in membrane phospholipids. Feeding the high fat and/or high polyunsaturated-to-saturated fatty acid ratio diet increased polyunsaturated fatty acid content of mucosal cell phospholipids. Increase in polyunsaturated fatty acid content was paralleled by a decrease in the monounsaturated fatty acid content of mucosal cell phospholipids. Membrane content of total saturated fatty acids was not significantly affected by diet. Variation in phospholipid fatty acid composition between “non-proliferative” and ”proliferative” cells was observed. Lipid peroxide levels in mucosal cell lipid fractions were altered by dietary fat treatment. Animals fed high fat diets, compared to groups fed low fat diets, exhibited higher membrane peroxide levels when results are expressed as nmol/mg protein. Higher peroxide levels were observed in mucosal cells for rats fed high polyunsaturated-to-saturated fatty acid ratio diets when results were expressed per nmol of phospholipid. It is concluded that changes in fat level and fatty acid composition of the diet alters the mucosal cell membrane lipid composition in the rat large intestine and influences susceptibility of mucosal cell lipid to peroxidation. Further research is required to delineate which dietary factors—fat level, polyunsaturated-to-saturated fatty acid ratio, or both—have a primary influence on the degree of lipid peroxidation.     

Complete relaxation and conformational exchange matrix (CORCEMA) analysis of NOESY spectra of interacting systems; two-dimensional transferred NOESY

A very general procedure entitled complete relaxation and conformational exchange matrix (CORCEMA) analysis has been developed to analyze the 2D-NOESY spectra of interacting systems undergoing multistate conformational exchange. This is an extension of earlier work from this laboratory on the methodological treatment of multistate conformational exchange [Krishna et al., Biopolymers 19, 2003 (1980)] and the theory of transferred NOESY for finite exchange off-rates [Lee and Krishna, J. Magn. Reson. 98, 36 (1992)]. The current theory is based on generalized rate matrices for relaxation and conformational exchange. The CORCEMA algorithm explicitly incorporates intermolecular dipolar cross relaxation between the molecules when they are complexed. It permits an analysis of NOESY intensities for the intra- as well as intermolecular contacts between the interacting molecules under a variety of binding conditions. Its application is illustrated on two examples of transferred NOESY simulations: (1) a two-state system involving a ligand and an enzyme forming a ligand-enzyme complex, and (2) a three-state system in which the ligand-enzyme complex can undergo a conformational transition from an "open state" to a "closed state," and can include conformational changes in both the complexed ligand and the complexed enzyme, such as hinge-bending motions. Simplifying expressions for generalized matrix analyses are derived for three limiting cases of the three-state system. This three-state example is illustrated using a hypothetical model of the hinge-bending motion in a thermolysin-inhibitor complex. It is shown that: (1) The neglect of cross relaxation between the interacting species in their complexed forms can lead to misleading conclusions on the "bound" conformation of the ligand. (2) If protein-mediated spin diffusion is dominant, caution is needed in analyses based on initial slopes alone due to one's inability to identify the exact range of the initial growth curve under poor signal/noise situations. (3) The neglect of conformational changes upon complexation, e.g., hinge-bending motions of the ligand-enzyme complex, can lead to erroneous results on the nature of "bound" conformations of the ligand. In this case, attempts to analyze the transferred NOESY data with a two-state model will result in a "virtual" conformation for the bound ligand. (4) When the hinge-bending rate is slower than the cross relaxation and enzyme off-rates, the bound conformation of a ligand deduced from the transferred NOESY experiment is more likely to represent nonspecific or weak binding in an open state of the enzyme.(ABSTRACT TRUNCATED AT 400 WORDS)     

Low temperature preparation of fluoroalkanes from a mixture of carbon tetrachloride,dichloromethane and anhydrous hydrogen fluoride using a fluorinated γ-alumina supported iron(II,III)/cobalt(II,III) oxide catalyst

1,1,1,2-tetrafluoroethane has been prepared at 473 K under static conditions, from a feedstock of carbon tetrachloride, dichloromethane and anhydrous hydrogen fluoride using a-alumina supported fluorinated Co(II, III)₈₅Fe(II, III)₁₅O_x catalyst. Conversion to hydrofluoroalkanes was ca. 58% efficiency as quantified by liquid phase¹⁹F NMR analysis.     

The DIPPR® databases

The Design Institute for Physical Property Data® (DIPPR), one of the Sponsored Research groups of the American Institute of Chemical Engineers (AIChE), has been in existence for 15 years and has supported a total of 14 projects, some completed, some ongoing. Four of these projects are database projects for which the primary product is a database of carefully evaluated property data. These projects are Data Compilation; Evaluated Data on Mixtures; Environmental, Safety, and Health Data Compilation; and Difusivities and Thermal Properties of Polymer Solutions. This paper lists the existing DIPPR projects; discusses DIPPR's structure and modes of dissemination of results; describes DIPPR's supporters and its unique characteristics; and finally, discusses the origin, nature, and content of the four database projects.Paper presented at the Twelfth Symposium on Thermophysical Properties, June 19–24, 1994, Boulder, Colorado, U.S.A.