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Elephant endotheliotropic herpesviruses (EEHVs) are the cause of acute hemorrhagic disease in endangered Asian and African elephants. In the present study, we report the incidence of EEHV infection and associated mortality in the captive elephant of Assam, India. Our result showed the gross morphology and histopathological changes of EEHV infection in the elephant. Moreover, the phylogenetic analysis of the polymerase, helicase, and GPCR genes from the infected tissue samples suggested the presence of EEHV1A virus.

There is a way to describe a family of plane curves different from that using Cartesian or polar co-ordinates. This is a trigonometric equation involving two angles. In this article, we highlight the fact that trigonometric equations are convenient to describe certain one-parameter families of plane curves. In some cases, the trigonometric form makes it easier to characterize the family than if one were to use the equivalent Cartesian or polar representations.

Retinoic acid (RA) is involved in the development of both the conducting airway and alveolar portions of the lung. RA plays a key role in the induction of the formation of alveolar septa. Retinoyl β-glucuronide (RAG), an endogenous retinoid, acts like RA, but is much less cytotoxic. We examined the effect of daily intraperitoneal doses of RA and RAG (1.66 μmol/kg) in dimethyl sulfoxide (DMSO) and cotton seed oil on the stores of retinol and retinyl ester (RE) in the lung of rats. In two separate experiments, one involving normal rats, and the other involving elastase-treated rats, there was up to a 9-fold increase in REs content in the lungs of rats that received RA or RAG for 12 days as compared to Control rats. The accumulation was most profound when RA was injected in DMSO and least when RAG was injected in cotton seed oil. The reason for the accumulation of REs in the lung is not clearly known.

Numerous reports have indicated that the biological activity of all-trans retinoyl beta-glucuronide (RAG) is similar to that of all-trans-retinoic acid (RA), but without the toxic side effects of RA. In the present series of studies, we report new findings that support the contention that RAG can function as a nontoxic substitute for RA in a variety of clinic settings. One study on the effects of s.c. injected graded doses of RA and RAG (20-480 micromol/kg BW) into pregnant Sprague-Dawley rats showed that any differences between RAG and RA could be observed only at the highest dose levels of 360 and 420 micromol/kg BW, with RAG being much less toxic than RA. Similarly, daily topical application of RAG (0.16-1.6%) and RA (0.1-0.5%) to shaved swine dorsal skin for six mo resulted in redness and scabbing in RA-treated patches, and to a lesser extent in 1.6% RAG-treated, but not in other RAG-treated patches. Histological scores were significantly higher in the dermis and epidermis of RA-treated pigs than in RAG-treated pigs. Studies to document the pharmacokinetics of chronically administered RAG in mice indicated that, unlike RA, sustained blood levels of parent retinoid (RAG) can be achieved during at least 2 mo of daily administration. Another investigation to study the effects of RAG on the development and growth in nude mice of tumors derived from the human neuroblastoma cell line LA-N-5 showed that s.c. injection of RAG (30 micromol/kg BW) reduced tumor formation when the retinoid was first administered 3 d before tumor injection and continued daily for 30 d thereafter. In established tumors, RAG was shown to inhibit progressive tumor growth, the antitumor effects of RAG being comparable with RA. However, with RAG, as opposed to RA, there were no significant adverse physical side effects. Based on the results of these series of studies along with ample published reports over the last 15 y, we conclude that RAG may be a safe and effective alternative to RA and some other retinoids that are presently being utilized in the clinic.

In order to prove the hypothesis that humans and animals with adequate vitamin A status do not absorb and metabolize orally administered all-trans retinoyl beta-glucuronide, unlabeled retinoyl glucuronide (0.1 mmol) was orally dosed to fasting well-nourished young men. Neither retinoyl glucuronide nor retinoic acid, a possible metabolite, appeared in the blood within 12 h after ingestion. Next, radiolabeled all-trans 15-[14C]-retinoyl beta-glucuronide was chemically synthesized by a new procedure, and fed orally to rats of different vitamin A status. Analysis of blood and other tissues 5 or 24 h after the dose, showed the presence of radioactivity ( approximately 0.5%) in the blood of vitamin A deficient rats, but not in sufficient rats. Livers of all rats contained small, but detectable amounts (0.3 to 1.1% of the dose) of radioactivity. The accumulation of radioactivity in the liver was highest in deficient rats. Analysis of the retinoids showed that the radioactivity in serum and liver was due to retinoic acid formed from retinoyl glucuronide. Within 24 h after the dose, 31 to 40% of the administered radioactivity was excreted in the feces, and 2 to 4.7% of the dose was excreted in the urine. Results of the present studies show that oral administration of retinoyl beta-glucuronide did not give rise to detectable changes in blood retinoyl glucuronide and/or retinoic acid concentrations in humans or rats with adequate vitamin A status.

The aim of this study was to determine the bioavailability and bioconversion to vitamin A of a single oral dose in oil or an aqueous dispersion of labeled beta-carotene in rats of different vitamin A status. Weanling Sprague-Dawley rats were fed a vitamin A-deficient diet and supplemented for 4 wk with 0, 7, 21 and 63 micro g/(rat. d) of retinyl acetate. The rats, of different vitamin A status, were then given a single oral dose of 11,12-(3)H-beta-carotene (0.15 micro mol) dissolved in corn oil or dispersed in aqueous Tween 80. The rats were killed 4 or 24 h after the dose, and serum, liver, the entire digestive tract, other tissues, urine and feces were analyzed for carotenoids, retinoids and associated radioactivity. At 4 h after the dose, 85 +/- 9% of the administered radioactivity was recovered. Almost 50% of the dose was present as intact beta-carotene in the large intestine where further absorption and conversion was ruled out. The absorption of beta-carotene was very low, and < 5% of the radioactive dose was converted to retinoids. The absorption and conversion to vitamin A did not differ among rats of different vitamin A status. The results suggest that a single oral dose of beta-carotene might not be an effective way of raising vitamin A stores in the body.

The efficacy of all-trans-retinoic acid (tRA) and all-trans-retinoyl β-glucuronide (RAG), a water-soluble metabolite of vitamin A, in the topical treatment of acne is comparable. However, whereas 3.3 mM tRA shows side effects, 3.3 mM RAG does not. To assess the relative toxic and histologic effects (dermal and epidermal changes) of long-term (24-week) daily applications of tRA and RAG on the skin, separate skin patches were measured and marked dorsally on the skin of six 21-day-old, castrated male pigs. Each skin patch area was treated daily with a cream formulation containing either 3.3 mM RAG, 16.5 mM RAG, 33 mM RAG, 3.3 mM tRA, 16.5 mM tRA or blank cream. To serve as controls, one patch received no treatment, one patch received blank cream only and for 5.3 weeks one ‘washed’ patch was given daily application of 33 mM RAG with routine cleansing using a mild soap typical of skin care. The amount of cream used per square centimeter remained the same during the course of the study. Biopsy tissue was collected at –1, 0, 2, 4, 8, 12 and 24 weeks from 7 test patches. The ‘washed’ patch was biopsied once at the 5.3-week mark. Topically applied RAG cream (3.3 mM) resulted in significantly lower histologic scores when compared with scores from tissue treated with an equimolar concentration of tRA. The highest concentration of RAG tested (33.3 mM) resulted in a response comparable to that observed in the lowest tRA (3.3 mM) treated patch area. Daily cleansing of the test area receiving 33.3 mM RAG completely eliminated any clinical signs or negative histologic changes. In conclusion, long-term topical tRA treatment in young pigs, as in humans, showed dose-dependent adverse effects on the skin, whereas RAG treatment had significantly lower histologic changes and less irritation and/or inflammation.

Increased intake of fruits and vegetables is associated with reduced risk of cancer and other chronic diseases. Epoxycarotenoids are widely distributed in nature and constitute major dietary carotenoids in a number of fruits and vegetables. Previous studies have shown that beta-carotene 5,6-epoxide was absorbed well by humans, and was much more active than beta-carotene in inducing the differentiation of NB4 cells. Xanthophyll epoxides such as neoxanthin, violaxanthin and lutein 5,6-epoxide, are more abundant than epoxy-hydrocarbon carotenes in a number of vegetables and fruits that humans consume. To determine whether xanthophyll epoxides are also absorbed by humans, lutein 5,6-epoxide (taraxanthin) and zeaxanthin 5,6,5'6'-diepoxide (violaxanthin) were chemically prepared, dissolved in corn oil and orally administered to three human subjects. Analysis of plasma for carotenoids within 9 h after a single oral dose of either violaxanthin or taraxanthin failed to show any violaxanthin, taraxanthin or any of their metabolites.

All-trans-retinoyl-beta-D-glucuronide (RAG) is an endogenous active metabolite of all-trans-retinoic acid (ATRA). In the present study, the pharmacokinetics of RAG was examined after the administration of a single intravenous does (5, 10, or 15 micromol/kg) and of multiple daily intravenous doses (5 micromol/kg) to rats for 8 days. The plasma concentrations of RAG and ATRA were measured by a reverse-phase HPLC method. A rapid distribution phase of approximately 1 h was observed in all of the rats after single or multiple doses. Thereafter, RAG was eliminated through a first-order process, in accord with a typical two-compartment first order pharmacokinetic profile. After single intravenous doses, the AUC of RAG increased proportionally with the dose and the clearance remained unchanged within the tested doses. There was no statistical significant difference in distribution rate constants from central compartment to peripheral compartment (K(12)) and from peripheral compartment to central compartment (K(21)) between different doses. However, as the dose increased from 5 micromol/kg to 10 micromol/kg, the volume of distribution at the steady state (V(ss)) and the volume of peripheral compartment (V(p)) decreased significantly (p0.05) from 1.290 +/- 0.269, 0.928 +/- 0.232. L/kg to 0.961 +/- 0.149, 0.647 +/- 0.107 L/kg, respectively. V(ss) and V(p) at a dose of 15 micromol/kg (0.924 +/- 0.187, 0.698 +/- 0.165 L/kg) were not significantly different from that at 10 micromol/kg. Thus, RAG might saturate the tissue-binding sites at higher doses. ATRA was detected as a metabolite of RAG at low levels (usually0.05 microM) only in the first 2 h after intravenous administration. RAG clearly was not extensively hydrolyzed to ATRA in our study. After multiple daily intravenous administration of RAG, the clearance (Cl) and the elimination rate constant (K(10)) remained unchanged (p0.05), indicating that long-term daily administration of RAG did not induce its accelerated metabolism. However, K(12), V(p), and V(ss) declined significantly (p0.05) from 1.67 +/- 0.54 h(-1), 0.928 +/- 0.232 L/kg, and 1.290 +/- 0.269 L/kg to 0.96 +/- 0.48 h(-1), 0.494 +/- 0.147 L/kg, and 0.818 +/- 0.187 L/kg, respectively. Therefore, long-term daily dosing of RAG seemed to decrease its distribution profile. Although the AUC of RAG did not change significantly after multiple dosing, the AUC of ATRA after RAG dosing significantly declined (p0.05) from 0.032 +/- 0.019 microM x h to 0.010 +/- 0.006 microM x h. The decline in the AUC of ATRA might reflect an increase in its uptake by tissue and/or in its metabolism. Because enhanced clearance is not associated with RAG after multiple administrations, RAG could be considered as an alternate to ATRA in appropriate clinical applications.

The work of Taguchi for determining the optimal settings of controllable factors through off-line experiments focuses on products with a single quality characteristic or response. However, most products have several quality characteristics or responses of interest. Taguchi's technique in itself optimizes a single response or performance characteristic yielding a set of process parameters. This particular setting may not give desired results for other characteristics of the product. In such cases, a need arises to obtain a single setting (optimal setting) of the process parameters, which can be used to produce the products with optimum or near optimum quality characteristics as a whole. Multi-characteristic response optimization may be the solution of the above problem. In the present paper a case study on V-processed castings of Al–7%Si alloy, utilizing a simplified multi-criterion methodology based on Taguchi's approach and utility concept, is discussed. Copyright © 2000 John Wiley & Sons, Ltd.

The global consciousness for quality has motivated designers and manufacturing engineers to be engaged constantly in product and process development. The approach, quality by design, developed by Taguchi has produced a unique and powerful quality improvement discipline that differs from traditional practices. In the present paper, Taguchi's technique has been applied to obtain an optimal setting of V-process parameters. The results indicate that the sand grain fineness number and amplitude of vibration are the control factors. These factors affect both the mean and the variation of the bulk density of the V-process mould. The signal factor, that is the factor that affects only the mean value, is time of vibration. The insignificant factor is the degree of vacuum imposed. The optimum value of bulk density (1.588 gm/cm 3 ) at the optimal setting of these parameters has been obtained and confirmed by further experiments.

The synthesis and characterization of the novel glucuronide conjugates of 9-cis and 13-cis retinoic acid and of all-trans, 9-cis and 13-cis 4-oxoretinoic acid are described.

The purpose of these studies was to compare directly the percutaneous absorption, excretion and metabolism of all-trans-retinoyl Β-glucuronide (RAG), a nontoxic retinoid, with all-trans-retinoic acid (RA) in the rat. Previously, it was demonstrated that topical treatment of human acne with either RAG or RA in cream resulted in a significant reduction of lesions. Whereas 0.1 % RA showed adverse effects, concentrations of RAG up to 2.4% did not cause any adverse reactions. In the present studies, radiolabeled RAG or RA, dispersed in a water-based cream, was applied to the shaved dorsal skin of vitamin A-sufficient rats. Both RAG and RA were absorbed from the skin in a similar way. In both cases, radioactivity peaked in the plasma within 2-4 h and within the liver at 4-12 h. During a 7-day period, the overall excretion of radioactivity derived from RA and RAG in the feces and urine were similar, e.g. 17 and 12%, respectively. It is concluded that: (1)the transport, metabolism and excretion of topically applied radioactive RA and RAG are similar, although not identical, in the rat and (2) the toxic skin manifestations induced by RA but not by RAG cannot be attributed to major differences in their overall absorption, metabolism and excretion.

The purpose of this study was to evaluate the efficacy towards acne and the skin surface toxicity of all-trans-retinoyl β-glucuronide (RBG), a naturally occurring retinoid possessing low cytotoxicity and teratogenicity in animal and cell culture studies. In a double-blind study, 15 acne patients treated with 1.2% RBG cream for 16 weeks showed median reductions of 56%, 25% and 67% in total, inflammatory, and noninflammatory lesions, respectively, whereas the placebo group (14 patients) showed median reductions of 31%, 4% and 62%, respectively. The median reduction in total lesions was highly significant in the RBG group (P = 0.002) but not in the placebo group (P = 0.06). In a second initially double-blind study, ten acne patients treated topically for 26 weeks with 0.16–0.32% RBG cream and five patients with 0.1% all-trans-retinoic acid (Retin-A) showed similar responses, i.e. median reductions in total facial lesions of 70% (P = 0.001) and 75% (P = 0.01), respectively. Whereas all subjects treated topica...

Retinoyl beta-glucuronide (RAG) and retinyl beta-glucuronide (ROG) inhibit prolactin-induced morphological developments in cultured mouse mammary gland, and are equally effective in depressing prolactin and steroid hormone-induced DNA synthesis in the same tissue. Retinol is essentially inactive by both assay methods. Although RAG and ROG show little or no toxicity in several cell and animal models, some possibly toxic manifestations were seen at higher concentrations in cultured mammary tissue. Nonetheless, because of the strong correlation between the actions of chemopreventive agents in culture mouse mammary glands and their effectiveness in vivo, the retinoid glucuronides may well prove to be useful cancer chemopreventive agents.

Retinoyl beta-glucuronide is a naturally occurring, biologically active metabolite of vitamin A. Although retinoyl beta-glucuronide is regarded as a detoxification product of retinoic acid, it plays several roles in the functions of vitamin A. It can serve as a source of retinoic acid, and it may be a vehicle for transport of retinoic acid to target tissues. Topically applied retinoyl beta-glucuronide is comparable in efficacy to retinoic acid in the treatment of acne in humans, without the same side effects. Retinoyl beta-glucuronide may or may not be teratogenic, depending on the mode of administration and the species in which it is used. It may be a valuable therapeutic compound for the treatment of skin disorders and certain types of cancers.