bluuebunny/crossref_metadata_2025 huggingface dataset:
Economics of biofortification
Authors: Qaim Matin , Stein Alexander J. , Meenakshi J. V.
Published: August 2010

Micronutrient malnutrition is a serious public health problem in many developing countries. Different interventions are currently used, but their overall coverage is relatively limited. Biofortification—that is, breeding staple food crops for higher micronutrient contents—is a new agriculture‐based approach, but relatively little is known about its ramifications. Here, the main factors influencing success are discussed and a methodology for economic impact assessment is presented. Ex ante studies from India and other countries suggest that biofortified crops can reduce the problem of micronutrient malnutrition in a cost‐effective way, when targeted to specific situations. Further research is needed to corroborate these findings and address certain issues still unresolved.
The Doha development round and Africa: partial and general equilibrium analyses of tariff preference erosion
Authors: Bchir Mohamed Hedi , Karingi Stephen N. , Mold Andrew , Osakwe Patrick N. , Sadni Jallab Mustapha
Published: August 2010

Erosion of trade preferences currently being enjoyed by the least developed countries (LDCs) and some developing countries remains an important area in the ongoing trade negotiations. The different positions regarding the preference erosion question besides being informed by political economy considerations are also founded on empirical results of this particular question. But does the methodology used for the empirical analysis matter? In this article, the importance of preference erosion due to MFN liberalization on agriculture is analyzed. Drawing from the potential complementary strengths in triangulation, the article uses both partial and general equilibrium analyses. The article shows that the ranking of preference erosion as an issue of policy concern is influenced by the empirical methodology adopted. However, irrespective of the rank, the article concludes that preference erosion is an important issue not only in terms of welfare, but also as it has impacts on incomes for preference‐receiving countries.
Auction markets for specialty food products with geographical indications
Authors: Schamel Günter
Published: August 2010

We present a first analysis of online auction markets for specialty food products. We identify auction prices, trade volume, and value for domestic and foreign‐origin specialty ham with geographical indications (GIs) that were sold in online auctions in Germany within a 1‐month period. Applying hedonic modeling, we examine potential factors that may influence online bidding behavior and final auction prices. We estimate positive auction price effects for weight, bidding activity, and auction length, that the domestic product is sold at a discount, that higher shipping costs have a negative impact on final prices, and that auctions ending on Fridays and Saturdays yield lower prices. The model may be used to estimate the value of GIs. In our example, we estimate relative price differences of 20–30% for the GIs of three specialty hams (Prosciutto di Parma, Jamón Serrano, and Schwarzwälder Schinken).
Shadow wages, allocative inefficiency, and labor supply in smallholder agriculture
Authors: Barrett Christopher B. , Sherlund Shane M. , Adesina Akinwumi A.
Published: August 2010

This article introduces a method for estimating structural labor supply models in the presence of unobservable wages and deviations of households' marginal revenue product of self‐employed labor from their shadow wage. This method is therefore robust to a wide range of assumptions about labor allocation decisions in the presence of uncertainty, market frictions, locational preferences, etc. We illustrate the method using data from rice producers in Côte d'Ivoire. These data, like previous studies, reveal significant systematic differences between shadow wages and the marginal revenue product of family farm labor. We demonstrate how one can exploit systematic deviations, in the present case related to household characteristics such as the land/labor endowment ratio, to control for both unobservable wages and prospective allocative inefficiency in labor allocation in structural household labor supply estimation.
Nitric oxide generation from hydroxylamine in the presence of neutrophils and in the cell‐free system
Authors: Klink Magdalena , Sawierzko Anna , SuLowska Zofia
Published: August 2010

Conversion of hydroxylamine (HA) to nitric oxide (NO) has been studied in the presence or absence of human neutrophils with or without myristate acetate phorbol (PMA), catalase (CAT), hydrogen peroxide (H2O2), and superoxide dismutase (SOD) and nitric oxide synthase (NOS) inhibitors. The generation of NO from HA in the presence of neutrophils was higher than in the cell‐free system. We found that catalase did not influence the nitrite generation from HA in the cell‐free system and in the presence of neutrophils. The H2O2 enhanced the NO generation from HA in the presence of neutrophils only. When catalase and H2O2 were added together, a high increase of NO generation from HA in both systems was observed. The addition of SOD decreased whereas addition of PMA enhanced the NO generation from HA in the presence of neutrophils. The presented data show the possible role of oxygen radicals in the decomposition of HA to NO. The addition of NOS inhibitors to the culture of neutrophils decreased the generation of nitrite from HA. Our results suggest that NO generation from HA, which is an intermediate in NO production from L‐arginine, may be supported by an enzymatic pathway in which cellular NO synthase is involved.
Monocytes, but not macrophages, produce the eosinophil cationic protein
Authors: Byström Jonas , Tenno Taavo , Håkansson Lena , Amin Kawa , Trulson Agneta , Högbom Erik , Venge Per
Published: August 2010

The eosinophil cationic protein (ECP) is a cytotoxic protein with ribonuclease activity, produced and stored in bone marrow eosinophil myelocytes. Mature circulating eosinophils contain about 10 pg ECP per cell. The aim of this study was to investigate the possibility that monocytes produce and store ECP. By results from flow cytometry and specific protein measurement it is shown that human monocytes contain ECP (monocytes about 10 fg ECP per cell). RT‐PCR analysis indicated the presence of mRNA coding for ECP in blood monocytes but not in alveolar macrophages. Furthermore, mRNA coding for ECP and low amounts of the protein were found in three myeloid cell lines representing different stages of monocytic differentiation. Differentiation of U‐937 cells to macrophages induced lowered transcription of the ECP gene and reduced protein production. Immunohistochemical staining of lung tissue indicated that lung macrophages do not contain ECP. It is concluded that ECP is produced to a low extent by human monocytes and that the production is shut down during macrophage differentiation. This might indicate an alternative transcriptional regulation of the ECP gene in the monocytic lineage compared to the eosinophil lineage.
Endocervical adenomyoma
Authors: Mikami Yoshiki , Maehata Kenichiro , Fujiwara Keiichi , Manabe Toshiaki
Published: August 2010

We report a case of adenomyoma of endocervical type arising in a 44‐year‐old female. Grossly, a well‐circumscribed tumor protruding from the right side of the uterine cervix was seen which was assumed to be an ovarian tumor by imaging studies carried out preoperatively. The tumor was composed of a mixture of proliferating glands of endocervical type and fascicles of smooth muscle cells. There was no distinct nuclear anaplasia in the proliferating glands, there were no architectural abnormalities, and there was no evidence of destructive stromal invasion such as desmoplasia. Minimal deviation adenocarcinoma, which shows a gastric phenotype with immunoreactivity for M‐GGMC‐1 and predominantly PAS‐positive neutral mucin, was a serious diagnostic possibility, but the lesion was well‐circumscribed, cytologic and architectural abnormalities were absent, and staining for M‐GGMC‐1 was negative, which suggested a diagnosis of endocervical adenomyoma. An increased Ki‐67 labeling index by up to 20%, the presence of predominantly PAS‐positive neutral mucin, and membranous immunoreactivity for CEA in limited areas were diagnostic pitfalls, which could lead to an erroneous diagnosis of minimal deviation adenocarcinoma of the uterine cervix. Therefore, the results of these ancillary techniques should be interpreted with caution and combined with gross and light microscopic features.
Molecular basis for the rhino Yurlovo (hrrhY) phenotype: severe skin abnormalities and female reproductive defects associated with an insertion in the hairless gene
Authors: Panteleyev A. A. , Ahmad W. , Malashenko A. M. , Ignatieva E. L. , Paus R. , Sundberg J. P. , Christiano A. M.
Published: August 2010

In 1989, mice bearing mutations at the hr (hairless) locus were first proposed as a model for the human hair growth disorder papular atrichia, since in both these mice and in corresponding patients, a complete hair loss develops due to disintegration of the normal follicle structure into dermal cysts and so‐called utriculi. Recently, the human hairless gene was characterized, and pathogenetic mutations were found to be associated with a recessively inherited form atrichia with papular lesions; however, the functions of hr gene remain unclear. Allelic mutations in the murine hairless gene represent a potentially powerful tool to elucidate the role of the hairless gene protein product in hair follicle physiology. In 1980, several naked animals were discovered in a breeding colony of B10.R109/Y mice maintained in the Laboratory of Experimental Biological Models (L.E.B.M., Yurlovo, Moscow District, Russia). By cross breeding with hairles HRS/J hr/hr mice, this mutation was shown to be allelic with hairless. Here, we describe the molecular basis of the hrrhY mutation in mice, which consists of a 13 bp insertion in exon 16 of the hr gene. Histological evaluation of Yurlovo mouse skin revealed some differences as compared to the hairless and rhino mutations, with the formation of dermal megacysts being the most specific peculiarity of the Yurlovo mutation. These results, together with previous studies of hrrhY/hrrhY mutant mice, suggest that the rhino Yurlovo (hrrhY) mutation represents a third and potentially more severe variation of the hairless phenotype.
Cutaneous barrier repair and pathophysiology following barrier disruption in IL‐1 and TNF type I receptor deficient mice
Authors: Man M.‐Q. , Wood L. , Elias P. M. , Feingold K. R.
Published: August 2010

Disruption of the permeability barrier elicits a homeostatic repair response which rapidly restores barrier function while repeated barrier perturbation results in cutaneous pathology. In response to barrier disruption there is a marked increase in epidermal TNF‐α and IL‐1 production. To determine the potential role of TNF and IL‐1 in mediating the cutaneous changes that occur following barrier disruption we compared the kinetics of barrier recovery and the degree of epidermal hyperplasia and cutaneous inflammation in TNF type I (p55) receptor and IL‐1 receptor type I (p80) deficient mice. No abnormalities in epidermal morphology were observed with light or electron microscopy in receptor deficient mice. Under baseline conditions epidermal barrier function was unchanged in receptor deficient mice. Following barrier disruption the kinetics of barrier recovery were similar in control vs TNF receptor deficient mice regardless if the barrier was disrupted by acetone treatment, SDS treatment, or tape stripping. In contrast, barrier recovery was slightly but significantly accelerated regardless of the method of barrier disruption in IL‐1 receptor deficient mice. The degree of epidermal hyperplasia and cutaneous inflammation following repeated barrier disruption was similar in control, TNF receptor, and IL‐1 receptor deficient mice. The present study demonstrates that barrier recovery is not delayed and the degree of epidermal hyperplasia and inflammation are not altered in either TNF receptor or IL‐1 receptor deficient mice, indicating that neither TNF nor IL‐1 alone are essential for either barrier repair or the cutaneous pathology induced by barrier perturbation. Whereas the increase in IL‐1 following barrier disruption may delay components of the repair response, whether either TNF‐α or IL‐1 regulate aspects of the homeostatic response remains unresolved.
Aluminium Toxicokinetics: An Updated MiniReview
Authors: Yokel Robert A. , McNamara Patrick J.
Published: August 2010

Abstract: This MiniReview updates and expands the MiniReview of aluminium toxicokinetics by Wilhelm et al. published by this journal in 1990. The use of 26Al, analyzed by accelerator mass spectrometry, now enables determination of Al toxicokinetics under physiological conditions. There is concern about aluminium in drinking water. The common sources of aluminium for man are reviewed. Oral Al bioavailability from water appears to be about 0.3%. Food is the primary common source. Al bioavailability from food has not been adequately determined. Industrial and medicinal exposure, and perhaps antiperspirant use, can significantly increase absorbed aluminium. Inhalation bioavailability of airborne soluble Al appears to be about 1.5% in the industrial environment. Al may distribute to the brain from the nasal cavity, but the significance of this exposure route is unknown. Systemic Al bioavailability after single underarm antiperspirant application may be up to 0.012%. All intramuscularly injected Al, e.g. from vaccines, may eventually be absorbed. Al distributes unequally to all tissues. Distribution and renal excretion appear to be enhanced by citrate. Brain uptake of Al may be mediated by Al transferrin and Al citrate complexes. There appears to be carrier‐mediated efflux of Al citrate from the brain. Elimination half‐lives of years have been reported in man, probably reflecting release from bone. Al elimination is primarily renal with ≤2% excreted in bile. The contribution of food to absorbed Al needs to be determined to advance our understanding of the major components of Al toxicokinetics.
Effects of Genetic Polymorphism of CYP1A2 Inducibility on the Steady‐State Plasma Concentrations of Trazodone and its Active Metabolite m‐Chlorophenylpiperazine in Depressed Japanese Patients
Authors: Mihara Kazuo , Kondo Tsuyoshi , Suzuki Akihito , Yasui‐Furukori Norio , Ono Shingo , Otani Koichi , Kaneko Sunao
Published: August 2010

Abstract: The effects of a genetic polymorphism of inducibility of cytochrome P450 (CYP) 1A2 on the steady‐state plasma concentrations of trazodone and its active metabolite, m‐chlorophenylpiperazine, were studied in order to clarify if these steady‐state plasma concentrations are dependent on the CYP1A2 polymorphism. Fifty‐eight Japanese depressed patients received trazodone 150 mg/day at bedtime. The steady‐state plasma concentrations of trazodone and m‐chlorophenylpiperazine were measured in duplicate using high performance liquid chromatographic method, and were corrected to the mean body weight for analyses. A point mutation from guanine (wild type) to adenine (mutated type) at position −2964 in the 5′‐flanking region of CYP1A2 gene was identified by polymerase chain reaction fragment length polymorphism method. The mean steady‐state plasma concentration of trazodone, but not m‐chlorophenylpiperazine was significantly (P<0.05) lower in smokers than in non‐smokers. Twenty‐two smokers had 16 homozygotes of the wild type allele, 5 heterozygotes of the wild type and mutated alleles, and one homozygote of the mutated allele. There was no significant difference in the mean steady‐state plasma concentration of trazodone or m‐chlorophenylpiperazine between smokers with no mutation and those with mutation, although one homozygote of the mutated allele had the highest steady‐state plasma concentration of trazodone in smokers. The present study thus suggests that CYP1A2 polymorphism does not necessarily have predictive value of the steady‐state plasma concentration of trazodone or m‐chlorophenylpiperazine in most of the smokers treated with trazodone.
Nimesulide Aggravates Kainic Acid‐Induced Seizures in the Rat
Authors: Kunz Tina , Oliw Ernst H.
Published: August 2010

Abstract: Treatment of rats with kainic acid (10 mg/kg, intraperitoneally) triggers limbic seizures. Cyclooxygenase‐2 mRNA is expressed in the hippocampus and cortex after 8 hr and marked cell loss occurs after 72 hr in the CA1‐CA3 areas of the hippocampus. We examined the effect of the cyclooxygenase‐2 inhibitor, nimesulide (N‐(4‐nitro‐2‐phenoxyphenyl)‐methanesulfonamide), on kainate‐induced seizures and delayed neurotoxicity. Nimesulide (10 mg/kg, intraperitoneally) was well tolerated given alone or 6–8 hr after kainate. However, pretreatment with nimesulide augmented seizures and increased the mortality rate from ∼10% to 69%. We examined the effect of nimesulide on delayed cell loss after 72 hr in the surviving animals with histological staining. Cell loss did not seem to be reduced in animals treated with nimesulide 6–8 hr after kainate, but in the surviving animals pretreated with nimesulide less cell loss occurred. We conclude that nimesulide should be used with caution as an antiinflammatory drug in patients with convulsive disorders.
β‐Lactam Antibiotic‐Mediated Changes in Platelet Reactivity and Vascular Endothelial Functions
Authors: Togna Giuseppina I. , Togna Anna Rita , Caprino Luciano
Published: August 2010

Abstract: To evaluate vascular and platelet compatibility of intravenous administration of β‐lactam antibiotics, we assessed the effects of therapeutic concentrations of ceftriaxone, aztreonam, and ceftazidime on platelet reactivity to different agonists (sodium arachidonate, collagen and adenosine diphosphate) and on selected vascular endothelial functions (adenosine diphosphatase activity, prostacyclin production and t‐PA release). Ceftriaxone and, to a lesser degree, aztreonam, enhanced platelet reactivity, evaluated as onset of platelet aggregating response, and increased thromboxane production to subthreshold concentrations of arachidonate. There was no modification in platelet reactivity after ceftazidime treatment. Ceftriaxone and ceftazidime, but not aztreonam, inhibited endothelial adenosine diphosphatase activity. Prostacyclin production and t‐PA release were inhibited only by ceftriaxone at high concentrations. While it is difficult to establish which marker (platelet or endothelial functions) has more clinical reference in human vascular compatibility, it seems feasible to consider aztreonam the most compatible of the β‐lactams studied.
2‐(Allylthio)pyrazine, a Cancer Chemopreventive Agent, Inhibits Liver Fibrosis Induced by Dimethylnitrosamine in Rats: Role of Inhibition of Transforming Growth Factor‐β1 Expression
Authors: Kang Keon Wook , Ha Jong Ryul , Kim Choon Won , Kim Nak Doo , Kim Sang Geon
Published: August 2010

Abstract: Exposure to nitrosamines may be the occupational risk factor for liver cirrhosis. 2‐(Allylthio)pyrazine, a chemopreventive agent, inhibits CYP2E1 and induces phase II enzymes. We examined the effects of 2‐(allylthio)pyrazine on hepatic fibrosis, a prepathologic state of cirrhosis, and on the expression of transforming growth factor‐β1 induced by dimethylnitrosamine. Treatment of rats with dimethylnitrosamine for 4 weeks increased plasma alanine/aspartate aminotransferase and γ‐glutamyl transpeptidase activities, and bilirubin content, whereas the total plasma protein and albumin levels were decreased. 2‐(Allylthio)pyrazine inhibited dimethylnitrosamine‐induced increases in the enzyme activities and bilirubin, and restored the plasma protein and albumin contents. Masson’s trichrome staining showed that dimethylnitrosamine induced liver fibrosis, the extent of which was reduced by 2‐(allylthio)pyrazine treatments. Reverse transcription‐polymerase chain reaction analysis revealed that 2‐(allylthio)pyrazine inhibited production of transforming growth factor‐β1 mRNA by dimethylnitrosamine. These results demonstrated that 2‐(allylthio)pyrazine might inhibit dimethylnitrosamine‐induced liver fibrosis due to suppression of CYP2E1 expression and transforming growth factor‐β1 production.
Pharmacological Coal Tar Induces G:C to T:A Transversion Mutations in the Skin of MutaTM Mouse
Authors: Vogel Ulla , Thein Nanna , Møller Peter , Wallin Håkan
Published: August 2010

Abstract: Coal tar is a by‐product of the distillation of coal. It consists of a complex chemical mixture of aromatic and aliphatic hydrocabons, with high concentrations of polycyclic aromatic hydrocarbons such as benzo[a]pyrene. We have previously shown that single painting on skin of mice increases the mutation frequency 16 times in murine epidermis cells (Thein et al. 2000). Here, we have determined the mutations by DNA sequencing. Coal tar was found to primarily induce G:C to T:A transversions and one‐base pair deletions of G:C base pairs. More than half of the mutations were at CpG sites. The mutational spectrum is in agreement with that of benzo[a]pyrene and other polycyclic aromatic hydrocarbon mixtures.
A Possible Mechanism of Naproxen‐Induced Lipid Peroxidation in Rat Liver Microsomes
Authors: Ji Bin , Masubuchi Yasuhiro , Horie Toshiharu
Published: August 2010

Abstract: Previous papers from our laboratory report that naproxen and salicylic acid induced lipid peroxidation in rat liver microsomes, however, the mechanism is still unclear. In the present paper, ferrous iron release, nicotinamide‐adenine dinucleotide phosphate reduced form (NADPH) oxidation and hydrogen peroxide (H2O2) formation have been measured to find out which mechanisms are involved in naproxen‐ and salicylic acid‐induced lipid peroxidation. While the increase of ferrous iron release was observed with high concentrations of naproxen, salicylic acid did not stimulate ferrous iron release. Neither of these drugs stimulated NADPH oxidation and H2O2 formation. However hexobarbital and perfluorohexane, known as uncouplers of cytochrome P450, stimulated microsomal NADPH oxidation, O2 consumption, H2O2 formation and water (H2O) formation involving four‐electron oxidase reaction. These results suggest that ferrous iron release contributes to naproxen‐induced microsomal lipid peroxidation and that naproxen and salicylic acid are not uncouplers of cytochrome P450. Apparently H2O2 does not play an important role in naproxen‐ and salicylic acid‐induced microsomal lipid peroxidation.
Aspects on the Pathophysiology of Migraine and Cluster Headache
Authors: Edvinsson Lars
Published: August 2010

Abstract: The specific cause of migraine headache remains unknown. Current theories suggest that the initiation of a migraine attack involves a primary CNS dysfunction with subsequent activation of the trigeminovascular system. Studies in patients have revealed a clear association between headache and the release of the neuropeptide calcitonin gene‐related peptide, probably from C fibres. In cluster headache and in a case of chronic paroxysmal headache there was in addition release of the parasympathetic neuropeptide vasoactive intestinal peptide, which was associated with headache, nasal congestion and rhinorrhea. Triptan administration, activating the 5‐HT1B/1D receptors, caused the headache to subside and the neuropeptide release to normalise. These data suggest the involvement of sensory and parasympathetic mechanisms in the pathophysiology of primary headaches.
GABA Mechanisms and Antinociception in Mice with Ligated Sciatic Nerve
Authors: Zarrindast Mohammad‐Reza , Mahmoudi M.
Published: August 2010

Abstract: In the present study, the effects of GABA (γ‐aminobutyric acid) receptor agonists and antagonists on hyperalgesia induced by sciatic nerve ligation was investigated in mice. The response to morphine or GABA receptor agonists was examined 14 days after unilateral nerve ligation by hot‐plate test. Intraperitoneal injection of different doses of morphine (3, 6 and 9 mg/kg), muscimol (0.5, 1 and 2 mg/kg) or baclofen (1, 2.5 and 5 mg/kg) induced a dose‐related antinociception in both intact and ligated mice. The response of morphine but not that of muscimol or baclofen, in nerve‐ligated mice was significantly less than that induced in the intact animals. The responses induced by muscimol or baclofen in nerve‐ligated animals, were reduced by bicuculline or CGP35348 [P‐(3‐aminopropyl)‐P‐diethoxymethyl‐phosphinic acid], respectively. However, morphine in combination with muscimol (2 mg/kg) tends to induce higher response; the combination of the GABA receptor agonists with morphine did not show potentiation, but additive effect. The opioid receptor antagonist naloxone reduced the response induced by muscimol in nerve‐ligated animals. It was concluded that although ligation of the sciatic nerve clearly reduced the analgesic effect of morphine and not that of the GABA agonists, the results nevertheless indicated that morphine and the GABAA agonist shared the same mechanism of action.
High‐Dose Stabilized Chlorite Matrix WF10 Prolongs Cardiac Xenograft Survival in the Hamster‐to‐Rat Model without Inducing Ultrastructural or Biochemical Signs of Cardiotoxicity
Authors: Hansen Alastair , Kemp Kåre , Kemp Ejvind , Bouchelouche Kirsten , Bouchelouche Pierre , Dieperink Hans , Horn Thomas , Larsen Svend
Published: August 2010

Abstract: WF10 is a stabilized chlorite matrix with immunosuppressive effects. In vitro studies have demonstrated its ability to suppress T cells and delay or abolish antigen presentation. Hence, WF10 may prove useful to prolong graft survival after transplantation. In this study, we evaluated the use of high dose WF10 as a single drug regimen in the hamster‐to‐rat xenotransplantation model and searched for possible cardiotoxic side effects. WF10 prolonged cardiac xenograft survival, but did not induce tolerence or inhibit pathological signs of acute rejection. Hamsters from the donor population, receiving high dose WF10 for 5 days, were compared with a matched control group. Ultrastructural examination of cardiac tissue as well as biochemical analysis of the cardiac enzymes troponin I, myoglobin and MB isoenzyme of creatine kinase showed no signs of damage. Thus, while prolonging graft survival, high dose WF10 seems to be non‐cardiotoxic and as such should not contribute to the differential diagnosis of acute graft failure.
Effects of 5‐HT4 Receptor Agonists, Cisapride and Mosapride Citrate on Electrocardiogram in Anaesthetized Rats and Guinea‐Pigs and Conscious Cats
Authors: Kii Yoshihide , Nakatsuji Katsuyoshi , Nose Isamu , Yabuuchi Masafumi , Mizuki Yasuyuki , Ito Tsugutaka
Published: August 2010

Abstract: The purpose of this study was to examine the arrhythmogenic potential of 5‐HT4 receptor agonists, cisapride and mosapride citrate (mosapride) in vivo. In anaesthetized rats, cisapride at intravenous infusion of 10 and 30 mg/kg/hr for 1 hr prolonged the electrocardiographic RR and QT intervals, whereas at 3 mg/kg/hr, it prolonged the RR interval without affecting the QT interval. Mosapride at 30 mg/kg/hr for 1 hr slightly, but not significantly, prolonged the QT interval. In anaesthetized guinea‐pigs, cisapride at intravenous infusion of 0.3, 1 and 3 mg/kg over 15 min. prolonged the RR interval (18–44%), QT interval (18–42%) and the corrected QT interval (QTc; 8–19%). Mosapride at 3, 10 and 30 mg/kg over 15 min. little affected the QTc although at 30 mg/kg, it slightly prolonged the RR and QT intervals. With repeated oral administrations of 30 mg/kg twice a day for 7 days, cisapride prolonged the QT interval (11–35%) and QTc (11–32%) at the 3rd and 7th days in conscious cats. In addition, cisapride depressed the ST segment in two out of five cats. Mosapride at 60 mg/kg twice a day for 7 days did not affect the QT interval or QTc in cats. The maximal plasma concentrations of mosapride and its main metabolite (a des‐4‐fluorobenzyl‐mosapride) at the 7th day in cats were 9.4±2.8 μM and 2.5±0.3 μM, respectively, being 100 and 30–60 times higher than those in man given therapeutic doses (Sakashita et al. 1993a&b). These results indicate that mosapride has little arrhythmogenic potential.
Effects of Mono‐n‐butyl Phthalate on the Development of Rat Embryos: In vivo and in vitro Observations
Authors: Saillenfait Anne Marie , Langonné Isabelle , Leheup Bruno
Published: August 2010

Abstract: The present study was conducted to further characterize the embryotoxic effects mono‐n‐butyl phthalate, a major metabolite of the plasticizer di‐n‐butyl phthalate, and evaluate its role in the developmental toxicity of di‐n‐butyl phthalate. The embryotoxic effects of mono‐n‐butyl phthalate were compared to those of the parent compound di‐n‐butyl phthalate after a single oral administration of 1.8, 3.6, 5.4, or 7.2 mmol/kg di‐n‐butyl phthalate or mono‐n‐butyl phthalate to Sprague‐Dawley rats on gestational day 10 (Day 10). Embryos were evaluated for growth and development on Day 12. Both chemicals induced concentration‐dependent developmental toxicity (i.e. decreased growth and malformations) which became apparent at 3.6 mmol/kg. Di‐n‐butyl phthalate and mono‐n‐butyl phthalate were approximately equally potent and produced qualitatively similar dysmorphogenic effects. Macroscopically, the most common malformations involved the prosencephalon, the optic system, and the mandibular and maxillary processes. In addition, the embryotoxic potential of mono‐n‐butyl phthalate was evaluated in vitro using the rat whole embryo culture system. Day 10 embryos were cultured for 48 hr in the presence of 0.5 to 5 mM mono‐n‐butyl phthalate and were then evaluated as the embryos grown in utero. Mono‐n‐butyl phthalate was a potent direct acting embryotoxicant, causing concentration‐related growth retardation and dysmorphogenesis. The spectrum of morphological defects observed in mono‐n‐butyl phthalate‐exposed embryos in vitro was comparable to those seen in vivo in the embryos at the same developmental stage after maternal administration of di‐n‐butyl phthalate or mono‐n‐butyl phthalate. These data provide additional evidence in support of the hypothesis that mono‐n‐butyl phthalate may be the active species for the developmental toxicity of ingested di‐n‐butyl phthalate in rats.
Cholestasis and Regulation of Genes Related to Drug Metabolism and Biliary Transport in Rat Liver Following Treatment with Cyclosporine A and Sirolimus (Rapamycin)
Authors: Bramow Stephan , Ott Peter , Thomsen Nielsen Finn , Bangert Kristian , Tygstrup Niels , Dalhoff Kim
Published: August 2010

Abstract: Cyclosporine A and sirolimus are used alone or in combination as immunosuppressants in organ transplantation. To elucidate hepatic side effects, we examined hepatic mRNA of proteins involved in biliary and hepatocellular transport of drugs, formation of glutathione (GSH) and drug metabolising cytochrome P‐450 enzymes (CYPs) in rats treated orally for 2 weeks with cyclosporine A (15 mg/kg/day), sirolimus (0.4 mg/kg/day), their combination (same doses), or vehicle. Liver function tests (alanine aminotransferase, alkaline phosphatase, γ‐glutamyl transferase and bilirubin) in blood were then analysed as were hepatic mRNA levels of canalicular transport proteins (Mrp2, Bsep, Mdr1b and Mdr2), sinusoidal transport proteins (Ntcp, Oatp1 and Oatp2), GSH related enzymes (γ‐glutamylcysteine synthetase light (GCSlc) and heavy (GCShc) chain subunits and glutathione‐S‐transferase) and CYPs (CYP3A9, CYP1A2, CYP2E1 and CYP2BI/II). Cyclosporine A caused moderate cholestatic changes in liver enzymes, which was synergistically exacerbated by sirolimus. The data suggest that the underlying mechanisms behind cholestasis were not totally identical in the different treatment regimens. Cholestasis secondary to cyclosporine A could be related to reduction in mRNA expression of GSH synthesising enzymes and Mrp2, leading to reduced protection against oxidative stress and reduced bile acid‐independent bile flow. After sirolimus treatment, Mrp2 mRNA was also reduced together with reduced levels of most CYPs and increased Oatp2, possibly leading to accumulation of toxic metabolites in the hepatocytes. The enhanced cholestatic effect of the combination treatment could be related to reduced GSH synthesising enzymes and even more pronounced reduction in Mrp2 mRNA and increase of Oatp2 mRNA.
Autoxidation and Toxicant‐Induced Oxidation of Lipid and DNA in Monkey Liver: Reduction of Molecular Damage by Melatonin
Authors: Cabrera Javier , Burkhardt Susanne , Tan Dun‐Xian , Manchester Lucien C. , Karbownik Malgorzata , Reiter Russel J.
Published: August 2010

Abstract: Melatonin, the main secretory product of the pineal gland, is a free radical scavenger and antioxidant which protects against oxidative damage due to a variety of toxicants. However, there is little information regarding melatonin's antioxidative capacity in tissues of primates. In this study we examined the protective effects of melatonin in monkey liver homogenates against lipid damage that occurred as a result of autoxidation or that induced by exogenous addition of H2O2 and ferrous iron (Fe2+). Additionally, we tested melatonin's protective effect against oxidative damage to DNA induced by chromium(III) (CrIII) plus H2O2. The levels of malondialdehyde and 4‐hydroxyalkenals were assayed as an index of lipid peroxidation, and the concentrations of 8‐hydroxydeoxyguanosine (8‐OHdG) as an endpoint of oxidative DNA damage. The increases in malondialdehyde+4‐hydroxyalkenals concentrations as a consequence of autoxidation or after the addition of H2O2 plus Fe2+ to the homogenates were time‐dependent. The accumulation of these damaged products due to either autoxidative processes or induced by H2O2 and Fe2+ were significantly reduced by melatonin in a concentration‐dependent‐manner. The levels of 8‐OHdG were elevated in purified monkey liver DNA incubated with a combination of CrCl3 plus H2O2. This rise in oxidatively damaged DNA was prevented by 10 μM concentration of melatonin. Also, melatonin reduced the damage to DNA that was caused by autoxidative processes. These findings in monkey liver tissue document the ability of melatonin to protect against oxidative damage to both lipid and DNA in primate tissue, as observed previously in rodent tissue. The findings provide support for the use of melatonin as suitable agent to reduce damage inflicted by free radical species in primates.
Neurochemical and Behavioural Effects of Chronic Aldicarb Administration in Rats
Authors: Palumbo Giancarlo , Bacchi Simona , Coppolino Maria Francesca , Pantaleoni Gian Carlo
Published: August 2010

Abstract: Changes in neurochemical parameters, behavioural and memory performances due to aldicarb (a carbamate pesticide) treatment was investigated after chronic oral administration in rats. Rats received water, or aldicarb 1 ppb (=0.12 g/kg/day), aldicarb 10 ppb (=1.2 g/kg/day) and aldicarb 100 ppb (=12 g/kg/day) for 4 months. The locomotor and explorative activities were reduced, and aldicarb significantly decreased brain AChE activity while an increase was found in the passive avoidance and water‐maze performance. In the striatum, aldicarb 10 ppb and 100 ppb, significantly reduced DOPA but not DOPAC concentrations, while the 10 ppb and 100 ppb doses significant increased DA levels. Aldicarb did not affect DA, DOPA and DOPAC levels in the accumbens. The neuropharmacologic effects of chronic dosing with aldicarb, AChE inhibition and dopaminergic modulation could be useful for treatment of memory deficits related to CNS disorders.)
Cyanoside Chloride and Chromocarbe Diethylamine are More Effective than Vitamin C against Exercise‐Induced Oxidative Stress
Authors: Márquez Rafael , Santángelo Gustavo , Sastre Juan , Goldschmidt Pablo , Luyckx Jacques , Pallardó Federico V. , Viña José
Published: August 2010

Abstract: Exercise generates free radicals only when it is exhaustive. Free radicals are involved in tissue damage caused by exercise. Antioxidant vitamins (vitamin C and E) and other antioxidants such as coenzyme Q, and N‐acetyl cysteine prevent muscle damage and decrease muscle fatigue. The main aim of this paper was to test the possible protective effect of two new antioxidants, cyanoside chloride and chromocarbe diethylamine, on the oxidative stress generated by exhaustive exercise. The antioxidants were given to rats daily (50 mg/kg) in drinking water for 30 days. Blood oxidized glutathione/ reduced glutathione ratio, and plasma malondialdehyde levels were determined as indexes of oxidative stress. Plasma creatine kinase, alanine‐aminotransferase and lactate dehydrogenase activities were used as markers of muscle damage. Both cyanoside chloride and chromocarbe diethylamine were more effective than vitamin C in the prevention of glutathione oxidation in blood. Furthermore, cyanoside chloride and chromocarbe diethylamine partially prevented muscle damage. Chromocarbe diethylamine was the most effective compound in the prevention of exercise‐induced lipid peroxidation (malondialdehyde) in plasma.
Diagnostic approach and treatment of cutaneous lupus erythematosus
Authors: Sticherling Michael , Bonsmann Gisela , Kuhn Annegret
Published: August 2010

Cutaneous lupus erythematosus (CLE) is a heterogeneous disorder with a wide range of skin manifestations. In the second part of this review, diagnostic procedures and treatment options in CLE are summarized.The diagnosis of the various subtypes of CLE is based on patients's history,clinical findings,laboratory features, and histological and immunofluorescent examinations of skin biopsies. In case of systemic organ involvement, further adequate technical investigations are necessary. The therapy has to be adjusted to the subtype of CLE and its inflammatory activity as well as the extent of skin involvement. The skin manifestations of CLE are primarily treated by topical therapy, such as glucocorticosteroids, in combination with antimalarials. The response of CLE to immunosuppressive drugs that control organ involvement in systemic lupus erythematosus is often disappointing. Recent advances in biotechnology resulted in the development of several novel systemic agents for the treatment of autoimmune diseases; however, controlled clinical trials are still necessary for the approval of new therapies in CLE.
RELIABILITY OF A QUANTITATIVE RATING SCALE FOR ASSESSMENT OF HORSES WITH DISTAL TARSAL OSTEOARTHRITIS
Authors: LABENS RAPHAEL , INNOCENT GILES T. , VOÛTE LANCE C.
Published: August 2010

Various radiographic rating scales have been described for use in horses with distal tarsal osteoarthritis but little information is available on their reliability. The aim of this study was to develop a radiographic rating scale based on the results of an expert consultation process (the Delphi process), and to test the reliability of the radiographic rating scale. Seven radiographic features were identified as important indicators of distal tarsal osteoarthritis and these were then incorporated in the radiographic rating scale, which used a 100‐mm‐long visual analog scale. On two occasions nine equine veterinarians applied the radiographic rating scale, and a verbal descriptive rating scale, to three sets of tarsal radiographs, each comprising four standard radiographic views. Reliability was assessed using Bland–Altman plots and by calculating the 95% agreement limits. Analysis of variance (ANOVA) was used to identify significant interactions between the ratings of different assessors made from different views and at each assessment. Rating of distal tarsal osteoarthritis was different for the nine assessors. The most precise second ratings were between 16 mm higher and 18 mm lower than the first. Significant variables were “joint,”“assessor,” and “assessment” (univariable ANOVA); and “joint and assessor” and “assessor and assessment” (multivariable ANOVA). The radiographic rating scale developed for interpretation of distal tarsal osteoarthritis was less reliable than a verbal descriptive rating scale.
IMAGING DIAGNOSIS—CANINE THORACIC MESOTHELIOMA
Authors: ECHANDI RITA L. , MORANDI FEDERICA , NEWMAN SHELLEY J. , HOLFORD AMY
Published: August 2010

A 12‐year‐old neutered female Pembroke Welsh Corgi had a 2‐month history of a progressive, productive cough nonresponsive to therapy. Mild pleural effusion, right middle lung lobe collapse, and multiple subpleural nodular lesions were detected in thoracic radiographs and computed tomography (CT) images. Histopathologic diagnosis of the pleural nodules was mesothelioma. Mesothelioma should be considered in patients where pleural masses are detected in radiographs or CT images.
IMAGING DIAGNOSIS — INTRACRANIAL EPIDERMOID CYST IN A DOBERMAN PINSCHER
Authors: STEINBERG T. , MATIASEK K. , BRÜHSCHWEIN A. , FISCHER A.
Published: August 2010

A 4‐year‐old Doberman Pinscher was evaluated for chronic progressive central vestibular disease and aggressiveness. A cyst‐like lesion was identified in the region of the left cerebellopontine angle. The lesion was hypointense on T1‐weighted and hyperintense on T2‐weighted images. Differentials included an epidermoid or dermoid cyst, cystic neoplasm, and brain abscess. Hyperintensity on subsequent fluid‐attenuated inversion recovery images excluded an arachnoid cyst. The histopathologic diagnosis was epidermoid cyst within the fourth ventricle.
IMAGING DIAGNOSIS: AZYGOUS CONTINUATION OF THE CAUDAL VENA CAVA WITH AND WITHOUT PORTOCAVAL SHUNTING
Authors: FISCHETTI ANTHONY J. , KOVAK JANET
Published: August 2010

The CT angiographic features of azygous continuation of an interrupted caudal vena cava in dogs with and without portocaval shunting are described. Azygous continuation of a discontinuous caudal vena cava is usually an incidental finding, not associated with portosystemic shunting. Identification of an associated portosystemic shunt will determine the need for surgical intervention. CT angiography provides a means for making this distinction and details the course and size of the anomalous vessels. Focal widening of the caudal vena cava on a VD thoracic radiograph should raise suspicion for azygous vein distension.
Expression and secretion of interleukin‐1β, tumour necrosis factor‐α and interleukin‐10 by hypoxia‐ and serum‐deprivation‐stimulated mesenchymal stem cells
Authors: Li Zongwei , Wei Hua , Deng Linzi , Cong Xiangfeng , Chen Xi
Published: August 2010

To understand the potential paracrine roles of interleukin‐1β (IL‐1β), tumour necrosis factor‐α (TNF‐α) and interleukin‐10 (IL‐10), the expression and secretion of these factors by rat bone marrow‐derived mesenchymal cells stimulated by hypoxia (4% oxygen) and serum deprivation (hypoxia/SD) were investigated. We found that hypoxia/SD induced nuclear factor kappa Bp65‐dependent IL‐1β and TNF‐α transcription. Furthermore, hypoxia/SD stimulated the translation of pro‐IL‐1β and its processing to mature IL‐1β, although the translation of TNF‐α was unchanged. Unexpectedly, the release of IL‐1β and TNF‐α from hypoxia/SD‐stimulated mesenchymal cells was undetectable unless ATP or lipopolysaccharide was present. This result suggests that IL‐1β and TNF‐α are not responsible for the paracrine effects of mesenchymal cells under ischaemic conditions. We also found that hypoxia/SD induced the transcription and secretion of IL‐10, which were significantly enhanced by lipopolysaccharide and the proteasomal inhibitor MG132. Moreover, both the conditioned medium from hypoxia/SD‐stimulated mesenchymal cells (MSC‐CM) and IL‐10 efficiently inhibited cardiac fibroblast proliferation and collagen expression in vitro, suggesting that mesenchymal cell‐secreted IL‐10 prevents cardiac fibrosis in a paracrine manner under ischaemic conditions. Taken together, these findings may improve understanding of the cellu‐lar and molecular basis of the anti‐inflammatory and paracrine effects of mesenchymal cells.
Atorvastatin Reduces Calcification in Rat Arteries and Vascular Smooth Muscle Cells
Authors: Li Huan , Tao Hui‐ren , Hu Tao , Fan Yan‐hong , Zhang Rong‐qing , Jia Guoliang , Wang Hai‐chang
Published: August 2010

Abstract:  To examine the in vivo effects of atorvastatin (AT) on arterial calcification in rats, arterial calcification was established by subcutaneous injection of vitamin D3 and Warfarin. Intragastric administration of AT began 4 days before establishment of arterial calcification in the AT group (n = 6). Blood samples were taken and abdominal aortas were collected and stained. After induction of calcification, plasma Ca2+ levels in the CA and AT groups were significantly higher than those before treatment and in the untreated controls. Plasma Ca2+ levels in the AT group were significantly lower than in the CA group. The relative calcification area in aortic specimens from the AT group was significantly smaller than in the CA group. Rat aortic vascular smooth muscle cells (VMSC) were isolated from abdominal aortic segments and pre‐treated with AT (1, 5, or 10 μM) for 24 hr. Cells in the calcification (CA) group and the AT group were cultured with β‐glycerophosphate, insulin and vitamin C for 14 days to induce cell calcification. Calcium deposition and alkaline phosphatase activity were significantly increased in the CA group compared to untreated controls (p < 0.01). This effect was ameliorated by AT (all p < 0.01). In vivo administration of AT reduced arterial calcification and plasma Ca2+ concentration. In vitro, AT reduced calcification markers in rat aortic vascular smooth muscle cells.
Grapefruit Juice Enhances the Exposure to Oral Oxycodone
Authors: Nieminen Tuija H. , Hagelberg Nora M. , Saari Teijo I. , Neuvonen Mikko , Neuvonen Pertti J. , Laine Kari , Olkkola Klaus T.
Published: August 2010

Abstract: Grapefruit juice alters the concentrations of many CYP3A substrates. The objective of this study was to examine the effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral oxycodone in a randomized cross‐over study with two phases at an interval of 4 weeks. Twelve healthy volunteers ingested 200 ml of grapefruit juice or water t.i.d. for 5 days. An oral dose of oxycodone hydrochloride 10 mg was administered on day 4. Oxycodone, noroxycodone, oxymorphone and noroxymorphone concentrations were analysed from the plasma samples for 48 hr and behavioural and analgesic effects were recorded for 12 hr. Grapefruit juice increased the mean area under the oxycodone concentration–time curve (AUC0–∞) by 1.7‐fold (p < 0.001), the peak plasma concentration by 1.5‐fold (p < 0.001) and the half‐life of oxycodone by 1.2‐fold (p < 0.001) as compared to the water. The metabolite‐to‐parent AUC0–∞ratios (AUCm/AUCp) of noroxycodone and noroxymorphone decreased by 44% (p < 0.001) and 45% (p < 0.001), respectively. Oxymorphone AUC0–∞increased by 1.6‐fold (p < 0.01) after grapefruit juice, but the AUCm/AUCpremained unchanged. Pharmacodynamic changes were modest and only self‐reported performance significantly impaired after grapefruit juice. Analgesic effects were not influenced. Grapefruit juice inhibited the CYP3A4‐mediated first‐pass metabolism of oxycodone, decreased the formation of noroxycodone and noroxymorphone and increased that of oxymorphone. We conclude that dietary consumption of grapefruit products may increase the concentrations and effects of oxycodone in clinical use.