bluuebunny/crossref_metadata_2025 huggingface dataset:
« Je ne suis pas donc je cogite » : un face à face Pascal‐Perec
Authors: Hillen Sabine
Published: March 2003

Pascal et Perec se rapprochent par leur écriture apparemment neutre qui réfute la vision substantialiste du sujet. Au premier abord, les deux auteurs arrivent à maîtriser le mot et à exercer un contrôle sur la naissance de la phrase : Pascal le fait par son ordre rhétorique, Perec par son souci de la contraiente oulipienne. En outre, l'écriture « objectiviste » qu'ils pratiquent, se particularise par « la crainte de livrer l'intime au grand public » (Van den Heuvel). Pascal, quand il accuse Montaigne du sot projet qu'il a de se peindre, préfère se cacher derrière le canevas rigide de ses pensées et restreindre sa présence dans le monde. En même temps, surtout dans les passages où le sujet de l'énonciation apparaît et où la maîtrise est relâchée dans le projet d'écriture, Pascal avoue son impuissance à se connaître : « Je ne sais qui m'a mis au monde, ni ce que c'est le monde, ni que moi‐même; je suis dans une ignorance terrible de toutes choses; je ne sais ce que c'est que mon corps, que mes sens, que mon âme et cette partie même de moi qui pense ce que je dis, qui fait réflexion sur tout et sur elle‐même, et ne se connaît non plus que tout le reste » (pensée 427).

Chez Perec, la maîtrise de l'écriture est moins causée par le refus du public que par un regard aveugle portéà soi‐même. Privé de sa possibilitéà dire « je », Perec le réduit à une litanie, dans Je me souviens, à un « tu » dans Un Homme qui dort, à une quasi‐absence dans La Vie mode d'emploi. Cependant, par son flirt avec le clinamen, détail faisant dériver la structure, l'intervention personnelle ressurgit comme un acte de résistance au silence imposé par la structure.

A la lumière des textes de Pascal et Perec, nous aimerions repenser la notion de sujet telle qu'elle se présente chez les deux auteurs. A cet effet, pour arriver à déterminer la naissance du moi dans la production artistique, il sera nécessaire de repérer les apparitions et dispartitions du sujet de l'énonciation à la première personne ainsi que d'interroger la marque stylistique du fragment.
Melanophore Lineage and Clonal Organization of the Epidermis in Xenopus Embryos as Revealed by Expression of a Biogenic Marker, GFP
Authors: FUKUZAWA TOSHIHIKO
Published: March 2003

Melanophore lineage during embryogenesis of Xenopus laevis was traced using the overexpression of a biogenic marker, green fluorescent protein (GFP). Two different approaches were applied after injection of GFP mRNA (hence a marker construct) into each blastomere at the 16‐cell stage. In in vivo experiments, the embryos injected with a marker construct were grown until stage 45, in which melanophores were distributed over the whole body and were good enough for checking GFP expression at their migratory destination. In in vitro experiments, neural tubes of the embryos injected with a marker construct were isolated and cultured at stage 21 to examine by virtue of GFP expression how neural crest cells differentiate into melanophores. The results obtained from both in vivo and in vitro experiments indicated the following: 1) selected animal blastomeres vastly contribute to the development of melanophores, whereas other animal blastomeres do so slightly at a limited pace; and 2) vegetal blastomeres never contribute to melanophores in normal development, whereas certain vegetal blastomeres have a potential to give rise to melanophores in vitro. The analyses using GFP also disclosed that the dorsal and ventral epidermis derive from the restricted animal blastomeres in the normal development. Since the dorso‐ventrality of the epidermis has been inseparably coupled with integumental pigmentation, the clonal organization of the epidermis observed in the present study is discussed in the light of pigment pattern formation attributed by melanophores.
Plasticity of Cadherin–Catenin Expression in the Melanocyte Lineage
Authors: JOUNEAU ALICE , YU YAN‐QIAN , PASDAR MANIJEH , LARUE LIONEL
Published: March 2003

Cadherins are calcium‐dependent cell adhesion receptors with strong morphoregulatory functions. To mediate functional adhesion, cadherins must interact with actin cytoskeleton. Catenins are cytoplasmic proteins that mediate the interactions between cadherins and the cytoskeleton. In addition to their role in cell–cell adhesion, catenins also participate in signaling pathways that regulate cell growth and differentiation. Cadherins and catenins appear to be involved in melanocyte development and transformation. Here, we investigated the function of cadherin–catenin complexes in the normal development and transformation of melanocytes by studying the patterns of expression of the cell–cell adhesion molecules, E‐, N‐ and P‐cadherin, and the expression of their cytoplasmic partners, α‐, β‐ and Γ‐catenin, during murine development. Similar analyses were performed in vitro using murine melanoblast, melanocyte, and melanoma cell lines in the presence and absence of keratinocytes, the cells with which melanocytes interact in vivo. Overall, the results suggest that the expression of cadherins and catenins is very plastic and depends on their environment as well as the transformation status of the cells. This plasticity is important in fundamental cellular mechanisms associated with normal and pathological ontogenesis, as well as with tumorigenesis.
The Tyrosinase Gene in Gorillas and the Albinism of ‘Snowflake’
Authors: MARTÍNEZ‐ARIAS ROSA , COMAS DAVID , ANDRÉS AIDA , ABELLÓ MARIA‐TERESA , DOMINGO‐ROURA XAVIER , BERTRANPETIT JAUME
Published: March 2003

The sequence of the tyrosinase (Tyr) gene coding tracts has been obtained for the gorilla (Gorilla gorilla gorilla). The five exons of the gene were sequenced in three gorillas and in a normally pigmented human. The tyrosinase gene has been found to be a very conserved locus with a very low substitution rate. Some nucleotide and amino acid differences were found between the gorilla and human tyrosinase coding sequences. One of the gorillas included in the study is the only known case of albinism in a gorilla (‘Snowflake’). Mutations of the TYR gene lead to Oculocutaneous Albinism type 1 (OCA1), the most common type of albinism in humans (OMIM accession number 203100). The TYR gene encodes the tyrosinase enzyme (E.C. 1.14.18.1), whose activity was found to be completely lacking in ‘Snowflake’, indicating that a mutation in the Tyr gene is the likely cause of his albinism. Nonetheless, no nucleotide changes were detected that could account for the lack of Tyr product or tyrosinase activity in Snowflake, and explanations of these findings are discussed.
Production of Melanocyte‐Specific Antibodies to Human Melanosomal Proteins: Expression Patterns in Normal Human Skin and in Cutaneous Pigmented Lesions
Authors: Virador Victoria , Matsunaga Naoko , Matsunaga Jun , Valencia Julio , Oldham Roger J. , Kameyama Koichiro , Peck Gary L. , Ferrans Victor J. , Vieira Wilfred D. , Abdel‐Malek Zalfa A. , Hearing Vincent J.
Published: March 2003

Multiple factors affect skin pigmentation, including those that regulate melanocyte and/or keratinocyte function. Such factors, particularly those that operate at the level of the melanosome, are relatively well characterized in mice, but the expression and function of structural and enzymatic proteins in melanocytes in human skin are not as well known. Some years ago, we generated peptide‐specific antibodies to murine melanosomal proteins that proved to be instrumental in elucidating melanocyte development and differentiation in mice, but cross‐reactivity of those antibodies with the corresponding human proteins often was weak or absent. In an effort to characterize the roles of melanosomal proteins in human skin pigmentation, and to understand the underlying mechanism(s) of abnormal skin pigmentation, we have now generated polyclonal antibodies against the human melanocyte‐specific markers, tyrosinase, tyrosinase‐related protein 1 (TYRP1), Dopachrome tautomerase (DCT) and Pmel17 (SILV, also known as GP100). We used these antibodies to determine the distribution and function of melanosomal proteins in normal human skin (adult and newborn) and in various cutaneous pigmented lesions, such as intradermal nevi, lentigo simplex, solar lentigines and malignant melanomas. We also examined cytokeratin expression in these same samples to assess keratinocyte distribution and function. Immunohistochemical staining reveals distinct patterns of melanocyte distribution and function in normal skin and in various types of cutaneous pigmented lesions. Those differences in the expression patterns of melanocyte markers provide important clues to the roles of melanocytes in normal and in disrupted skin pigmentation.
Genetic Association of the Catalase Gene (CAT) with Vitiligo Susceptibility
Authors: Casp Courtney B. , She Jin‐Xiong , Mccormack Wayne T.
Published: March 2003

Vitiligo susceptibility is a complex genetic trait that may involve genes important for melanin biosynthesis, response to oxidative stress, and/or regulation of autoimmunity, as well as environmental factors. We report here case–control and family‐based association studies for the catalase gene (CAT) in vitiligo patients. The CAT gene was selected as a candidate gene because of the reduction of catalase enzyme activity (EC 1.11.1.6) and concomitant accumulation of excess hydrogen peroxide observed in the entire epidermis of vitiligo patients. One of three CAT genetic markers studied was found to be informative for genotypic analysis of Caucasian vitiligo patients and control subjects. Both case/control and family‐based genetic association studies of the T/C single nucleotide polymorphism (SNP) in exon 9 of the CAT gene, which is detectable with the restriction endonuclease BstX I, suggest possible association between the CAT gene and vitiligo susceptibility. The observations that T/C heterozygotes are more frequent among vitiligo patients than controls and that the C allele is transmitted more frequently to patients than controls suggest that linked mutations in or near the CAT gene might contribute to a quantitative deficiency of catalase activity in the epidermis and the accumulation of excess hydrogen peroxide (H2O2). The CAT gene may, therefore, be a susceptibility gene in some vitiligo patients, further supporting the epidermal oxidative stress model for vitiligo pathogenesis.
The Etiology of Oculocutaneous Albinism (OCA) Type II: The Pink Protein Modulates the Processing and Transport of Tyrosinase
Authors: Toyofuku Kazutomo , Valencia Julio C. , Kushimoto Tsuneto , Costin Gertrude‐E. , Virador Victoria M. , Vieira Wilfred D. , Ferrans Victor J. , Hearing Vincent J.
Published: March 2003

Oculocutaneous albinism (OCA) is caused by reduced or deficient melanin pigmentation in the skin, hair, and eyes. OCA has different phenotypes resulting from mutations in distinct pigmentation genes involved in melanogenesis. OCA type 2 (OCA2), the most common form of OCA, is an autosomal recessive disorder caused by mutations in the P gene, the function(s) of which is controversial. In order to elucidate the mechanism(s) involved in OCA2, our group used several antibodies specific for various melanosomal proteins (tyrosinase, Tyrp1, Dct, Pmel17 and HMB45), including a specific set of polyclonal antibodies against the p protein. We used confocal immunohistochemistry to compare the processing and distribution of those melanosomal proteins in wild type (melan‐a) and in p mutant (melan‐p1) melanocytes. Our results indicate that the melanin content of melan‐p1 melanocytes was less than 50% that of wild type melan‐a melanocytes. In contrast, the tyrosinase activities were similar in extracts of wild type and p mutant melanocytes. Confocal microscopy studies and pulse‐chase analyses showed altered processing and sorting of tyrosinase, which is released from melan‐p1 cells to the medium. Processing and sorting of Tyrp1 was also altered to some extent. However, Dct and Pmel17 expression and subcellular localization were similar in melan‐a and in melan‐p1 melanocytes. In melan‐a cells, the p protein showed mainly a perinuclear pattern with some staining in the cytoplasm where some co‐localization with HMB45 antibody was observed. These findings suggest that the p protein plays a major role in modulating the intracellular transport of tyrosinase and a minor role for Tyrp1, but is not critically involved in the transport of Dct and Pmel17. This study provides a basis to understand the relationship of the p protein with tyrosinase function and melanin synthesis, and also provides a rational approach to unveil the consequences of P gene mutations in the pathogenesis of OCA2.
Molecular Regulation of Melanocyte Senescence
Authors: Bennett Dorothy C. , Medrano Estela E.
Published: March 2003

Cell senescence is the loss of ability to divide after a finite number of divisions, seen in normal mammalian somatic cells and often disrupted in cancer cells. The three genes so far associated with familial melanoma susceptibility –INK4A, CDK4 and ARF, are all implicated in the molecular pathways controlling cell senescence. Here we review those pathways, both as generally studied in fibroblasts and epithelial cells, and as specifically analysed in melanocytes. Key molecular effectors in melanocyte senescence appear to include some in common with other cell types – telomere attrition and the p16/RB pathway, and one that is not commonly mentioned in this connection, the cAMP signalling pathway that also regulates melanocyte differentiation. These findings are discussed in relation to the role of cell senescence in the development and molecular genetics of melanoma and its precursor lesions.
Regulatory Control of Both Microtubule‐ and Actin‐dependent Fish Melanosome Movement
Authors: Sköld Helén Nilsson , Norström Elisabeth , Wallin Margareta
Published: March 2003

In fish melanophores, melanosomes can either aggregate around the cell centre or disperse uniformly throughout the cell. This organelle transport involves microtubule‐ and actin‐dependent motors and is regulated by extracellular stimuli that modulate levels of intracellular cyclic adenosine 3‐phosphate (cAMP). We analysed melanosome dynamics in Atlantic cod melanophores under different experimental conditions in order to increase the understanding of the regulation and relative contribution of the transport systems involved. By inhibiting dynein function via injection of inhibitory antidynein IgGs, and modulating cAMP levels using forskolin, we present cellular evidence that dynein is inactivated by increased cAMP during dispersion and that the kinesin‐related motor is inactivated by low cAMP levels during aggregation. Inhibition of dynein further resulted in hyperdispersed melanosomes, which subsequently reversed movement towards a more normal dispersed state, pointing towards a peripheral feedback regulation in maintaining the evenly dispersed state. This reversal was blocked by noradrenaline. Analysis of actin‐mediated melanosome movements shows that actin suppresses aggregation and dispersion, and indicates the possibility of down‐regulating actin‐dependent melanosome movement by noradrenaline. Data from immuno‐electron microscopy indicate that myosinV is associated with fish melanosomes. Taken together, our study presents evidence that points towards a model where both microtubule‐ and actin‐mediated melanosome transport are synchronously regulated during aggregation and dispersion, and this provides a cell physiological explanation behind the exceptionally fast rate of background adaptation in fish.
Depigmenting Action of Phenylhydroquinone, an o‐Phenylphenol Metabolite, on the Skin of JY‐4 Black Guinea‐Pigs
Authors: Tayama Kuniaki , Takahama Motohide
Published: March 2003

The effects of o‐phenylphenol (OPP) and its metabolite, phenylhydroquinone (PHQ) on the skin of JY‐4 black guinea‐pigs were studied. Topical application of 1 or 5% PHQ on the black skin of the back caused marked depigmentation and hypopigmentation of the skin after 5 weeks, whereas OPP applied at the same concentrations had little effect. Depigmented skin had an increased L* (lightness) value in the CIE‐L*a*b* color system. This corresponded with a decreased number of melanocytes and melanosomes in the melanocytes and keratinocytes, the disruption of melanosomes in the melanocytes, and destruction of the membranous organelles of the melanocytes. These morphological and numerical changes in epidermal melanocytes indicate that selective melanocyte toxicity occurred. Furthermore, application of PHQ to the skin of white guinea‐pigs caused skin irritation, as shown by a colorimetric increase in a* value (redness) and by histological observation of inflammation. This study confirmed that OPP, which is a reported depigmenter, has little depigmenting action, while its metabolite, PHQ, is a potent depigmenter preferentially affecting melanocytes.
Ethnic Variation in Melanin Content and Composition in Photoexposed and Photoprotected Human Skin
Authors: Alaluf Simon , Atkins Derek , Barrett Karen , Blount Margaret , Carter Nik , Heath Alan
Published: March 2003

We have examined the quantity and composition of melanin in both photoprotected (volar upper arm) and chronically photoexposed (dorsal forearm) skin from a range of different ethnic skin types including African, Indian, Mexican, Chinese and European. The most lightly pigmented (European, Chinese and Mexican) skin types have approximately half as much epidermal melanin as the most darkly pigmented (African and Indian) skin types. However, the composition of melanin in these lighter skin types is comparatively more enriched with lightly coloured, alkali‐soluble melanin components (up to three‐fold). Regardless of ethnicity, epidermal melanin content is significantly greater in chronically photoexposed skin than it is in corresponding photoprotected skin (up to two‐fold). However, by comparison there is only a modest enrichment of lightly coloured, alkali soluble melanin components in photoprotected skin (up to 1.3‐fold). Analysis of melanosomes extracted from the epidermis in these subjects indicates that the proportion of spheroidal melanosomes is low in all skin types examined (<10%). This suggests that in human skin, pheomelanin is a very minor component of epidermal melanin, even in the lightest (European) skin types. Analysis of melanosome size revealed a significant and progressive variation in size with ethnicity: African skin having the largest melanosomes followed in turn by Indian, Mexican, Chinese and European. On the basis of these findings, we propose that variation in skin pigmentation is strongly influenced by both the amount and the composition (or colour) of the melanin in the epidermis. Variation in melanosome size may also play a significant role. However, the data also suggest that in human skin there are subtle differences in the mechanisms associated with the maintenance of constitutive pigmentation and facultative hyperpigmentation, respectively.
Humoral immune response in early‐onset periodontitis: influence of smoking
Authors: Mooney J. , Hodge P. J. , Kinane D. F.
Published: March 2003

Sixty‐five patients with generalised early‐onset periodontitis (G‐EOP)(age range 16–42 years, 32 smokers and 33 non‐smokers) were assessed for antibody titres and avidity to a panel of five suspected periodontal pathogens (Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, Prevotella intermedia, Treponema denticola and Bacteroides forsythus). Thirty‐four of these patients were untreated (17 smokers and 17 non‐smokers), and thirty‐one were in the maintenance phase of periodontal therapy (15 smokers and 16 non‐smokers). Previous studies have investigated the effect of smoking on IgG levels in periodontitis patients in the context of the more extensive periodontal destruction seen in smokers. Based on this literature our hypothesis was that smokers would have depressed serum IgG levels directed against recognised periodontal pathogens compared with non‐smokers. Antibody titres were measured by ELISA deploying fixed whole cells as coating. The IgG response was detected with biotin‐anti‐human IgG and avidin‐peroxidase; avidity was determined by elution with ammonium thiocyanate. Median titres to A. actinomycetemcomitans, P. intermedia and T. denticola were significantly lower in maintenance patient smokers (p=0.02, 0.02 and 0.002 respectively) but not in untreated patients. Avidity to P. gingivalis was also lower in smoking maintenance patients (p=0.003) but not in untreated patients. These findings may imply some interruption of immune maturation in smokers following periodontal treatment.
Binary regulation of interleukin(IL)‐6 production by EP1 and EP2/EP4 subtypes of PGE2 receptors in IL‐1β‐stimulated human gingival fibroblasts
Authors: Noguchi Kazuyuki , Shitashige Miki , Endo Hirahito , Kondo Hirobumi , Ishikawa Isao
Published: March 2003

Prostaglandin E2(PGE2) exerts its biological actions via EP receptors, which are divided into four subtypes of EP1, EP2, EP3 and EP4. In the present study, we investigated whether PGE2 regulated interleukin(IL)‐6 production in human gingival fibroblasts (HGF) stimulated with IL‐1β and if so, which subtype(s) of PGE2 receptors were involved. Indomethacin, a cyclooxygenase inhibitor, significantly enhanced IL‐1β‐induced IL‐6 production by HGF, although it completely inhibited IL‐1β‐induced PGE2 production. Exogenous PGE2 suppressed the IL‐1β‐induced IL‐6 production. Reverse transcription‐polymerase chain reaction analysis demonstrated that mRNA of EP1, EP2 and EP4, but not EP3 mRNA, was expressed in unstimulated and IL‐1β‐stimulated HGF. 11‐deoxy‐PGE1, a selective EP2/EP3/EP4 agonist, and butaprost, a selective EP2 agonist, inhibited IL‐1β‐induced IL‐6 production, although butaprost was less potent than 11‐deoxy‐PGE1. 17‐phenyl‐ω‐trinor PGE2, an EP1 agonist, enhanced IL‐1β‐induced IL‐6 production. Based on these data, we suggest that PGE2 can up‐ or downregulate IL‐1β‐induced IL‐6 production via EP1 receptors or via EP2/EP4 receptors in HGF, respectively. Expression and function of EP1, EP2 and EP4 receptors in HGF may play critical roles in controlling inflammatory jreiodontal conditions.
Compositional analysis of root cementum and dentin after Er:YAG laser irradiation compared with CO2 lased and intact roots using Fourier transformed infrared spectroscopy
Authors: Sasaki K. M. , Aoki A. , Masuno H. , Ichinose S. , Yamada S. , Ishikawa I.
Published: March 2003

The present study examines the dental root after Er:YAG laser irradiation, compared with CO2 lased and non‐treated surfaces, using Fourier Transformed Infrared (FTIR) spectroscopy. Freshly extracted human teeth were irradiated by Er:YAG laser at an energy output of 40 mJ/pulse, 10 Hz(0.4 watts), with or without water coolant, and by CO2 laser at an energy output of 0.5 watts in continuous wave mode without coolant. The surfaces were chalky and smooth after irradiation by Er:YAG laser with water coolant, were charred and irregular after irradiation by Er:YAG laser without water coolant, and were completely carbonized after CO2 laser irradiation. The FTIR profiles from samples of the surfaces that were irradiated by Er:YAG laser with water coolant were similar to those from non‐treated samples, except for a slight decrease on the OH and amide bands, which are mainly related to organic components. This decrease was observed to be extreme after CO2 laser irradiation and moderate after Er:YAG laser irradiation without coolant. The formation of new bands showing toxic substances was observed to a large extent after CO2 laser irradiation and to a smaller extent after Er:YAG laser irradiation without water coolant. In contrast, no such bands were detected after Er:YAG laser irradiation with water coolant. The present results show that these laser treatments selectively ablated more organic components than inorganic components and that Er:YAG laser irradiation with water coolant did not cause major compositional changes or chemically deleterious changes in either root cementum or dentin.
In Utero Exposure to Diethylstilboestrol or 4‐n‐Nonylphenol in Rats: Number of Sertoli Cells, Diameter and Length of Seminiferous Tubules Estimated by Stereological Methods
Authors: Dalgaard Majken , Pilegaard Kirsten , Ladefoged Ole
Published: March 2003

Abstract: The effects on testis weight and histopathology were studied in 11‐day‐old male Wistar rats after prenatal exposure to peanut oil (control), diethylstilboestrol 30 μg/kg b.wt./day, or 4‐n‐nonylphenol 75 mg/kg b.wt./day from gestational day 11 to 18. Additionally, the diameter and length of seminiferous tubules, and the number of Sertoli cells were investigated with stereological methods. Such unbiased methods have not previously been applied on testis diameter and length or on Sertoli cell number of 11‐day‐old rats. In the control group, the mean length of the seminiferous tubule was 3.0 m±0.6, the mean diameter of the seminiferous tubule was 83 μm±6, and the mean number of Sertoli cells was 26.1×106±4.6. No differences in testis weight, histopathology, or length or diameter of the seminiferous tubules were observed in the diethylstilboestrol and nonylphenol exposed groups when compared to the control group. In the diethylstilboestrol‐treated group, a statistically significant decrease in the number of Sertoli cells was observed (P<0.01) when compared to the control group, whereas nonylphenol had no effect. The result suggests that diethylstilboestrol decreases Sertoli cell proliferation in the foetal testis and furthermore indicate that oestrogens may pose a risk to the reproductive capacity in sensitive species, including man.
An Application of Population Kinetics Analysis to Estimate Pharmacokinetic Parameters of Sodium Tungstate after Multiple‐Dose during Preclinical Studies in Rats
Authors: Le Lamer Sophie , Cros Gérard , Piñol Carmen , Fernández‐Alvarez Josepha , Bressolle Françoise
Published: March 2003

Abstract: The purpose of this study was to use a population approach in the preclinical development program of sodium tungstate in the rat in order i) to compute individual pharmacokinetic parameters of this compound after repeated oral administrations, until the 4‐week toxicology study, using an empirical Bayes methodology; and ii) to study the influence of the administered dose, of the gender and of the duration of treatment on the pharmacokinetic parameters. Four studies were used representing a mixture of single intravenous administration and multiple oral administrations. The treatment duration ranged from 7 to 28 days. Intravenous dose was 9 mg/kg; three different oral doses were tested, 50, 100 and 200 mg/kg/day. Plasma concentration profiles versus time were compatible with a two‐compartment model. A significant gender effect was found on bioavailability. The duration of treatment and the administered dose did not significantly explain part of the interindividual variability of pharmacokinetic parameters. The absorption of tungsten was rapid (1–3 hr). Total plasma clearance and elimination half‐life averaged 2.8 ml/min./kg and 3.04 hr in males, and 3 ml/min./kg and 2.74 hr in females. The bioavailability was on an average 70%; being significantly higher in females than in males (0.78 versus 0.61). This compartmental approach should be considered as complementary to the usual non‐compartmental approach used for analysis of preclinical data and should be a valuable tool to characterise the pharmacokinetic/pharmacodynamic behaviour of a drug.
Suppression of Immunoreactive Macrophages in Atheromatous Lesions of Rabbits by Clodronate
Authors: Ylitalo Ritva , Syvälä Heimo , Tuohimaa Pentti , Ylitalo Pauli
Published: March 2003

Abstract: Bisphosphonates inhibit the development of experimental atherosclerosis and decrease the intima‐media thickness of human carotid artery. Since arterial macrophages have a key role in atherogenesis, we studied whether clodronate, an antiatherogenic bisphosphonate, will suppress the appearance of macrophages generated by atheromatous process in the rabbit aorta. The atherosclerosis was caused in rabbits by means of a high‐cholesterol (1%) diet, and the animals were treated simultaneously with saline (n=11) or 25 mg/kg of clodronate disodium (n=12) intravenously twice a week for 6 to 12 weeks. The cholesterol diet for 6 weeks caused no visible atheromatous plaques in the aorta, but feeding for 6 more weeks produced progressively atheromatous lesions. Immunohistochemistry with specific antimacrophage antibody showed an intensive accumulation of macrophages in the subendothelial layer of the aorta in cholesterol‐fed rabbits treated with saline or clodronate for 6 weeks. In the aorta of rabbits treated with cholesterol diet + saline for 12 weeks, the area of immunoreactive macrophages extended from the internal elastic lamina up to the luminal surface of the aorta. However, far less immunoreactive macrophages were present in the atheromatous regions of the aorta of rabbits medicated with clodronate for 12 weeks; in the clodronate‐treated animals the macrophages were located closer to the luminal surface of the aorta than in controls on saline. No atheromatous lesions and macrophages appeared in the aorta of rabbits on standard diet (n=7). The results suggest that clodronate suppresses the appearance of cholesterol‐phagocyting macrophages in arterial walls during atherogenesis.
Validation of Microdialysis Sampling for Oral Availability Studies by Means of a New Ganciclovir Prodrug
Authors: Lindén Karin , Zhou Xiao‐Xiong , Ståhle Lars
Published: March 2003

Abstract: Microdialysis sampling was validated for oral availability studies using ganciclovir (9‐(1, 3‐dihydroxy‐2‐propoxymethyl) guanine) and a ganciclovir prodrug (9‐(1‐L‐valyloxy‐3‐octadecanoyloxy‐prop‐2‐oxymethyl) guanine). Three different techniques were used in the study; microdialysis, blood and urinesampling. The oral uptake (11±2%) and the urinary recovery (106±5%) were determined. Animals given ganciclovir subcutaneously were subject either to microdialysis and blood sampling or to microdialysis alone. There was no significant difference between microdialysis and blood sampling in terms of blood concentration data, CL, Vd, half‐life or AUC by means of Student's t‐test. The oral bioavailability of the prodrug was 40±7% estimated from microdialysis sampling data and 48±4% estimated from urine sampling data. It is concluded that microdialysis is a valid method to use in pharmacokinetic studies of oral availability as well as for basic pharmacokinetic parameter estimation.
Affinities of Dihydrocodeine and its Metabolites to Opioid Receptors
Authors: Schmidt Helmut , Vormfelde Stefan V. , Klinder Klaus , Gundert‐Remy Ursula , Gleiter Christoph H. , Skopp Gisela , Aderjan Rolf , Fuhr Uwe
Published: March 2003

Abstract: Dihydrocodeine is metabolized to dihydromorphine, dihydrocodeine‐6‐O‐, dihydromorphine‐3‐O‐ and dihydromorphine‐6‐O‐glucuronide, and nordihydrocodeine. The current study was conducted to evaluate the affinities of dihydrocodeine and its metabolites to μ‐, δ‐ and κ‐opioid receptors. Codeine, morphine, d,l‐methadone and levomethadone were used as controls. Displacement binding experiments were carried out at the respective opioid receptor types using preparations of guinea pig cerebral cortex and the specific opioid agonists [3H]DAMGO (μ‐opioid receptor), [3H]DPDPE (δ‐opioid receptor) and [3H]U69,593 (κ‐opioid receptor) as radioactive ligands at concentrations of 0.5, 1.0 and 1.0 nmol/l, respectively. All substances had their greatest affinity to the μ‐opioid receptor. The affinities of dihydromorphine and dihydromorphine‐6‐O‐glucuronide were at least 70 times greater compared with dihydrocodeine (Ki 0.3 μmol/l), whereas the other metabolites yielded lower affinities. For the δ‐opioid receptor, the order of affinities was similar with the exception that dihydrocodeine‐6‐O‐glucuronide revealed a doubled affinity in relation to dihydrocodeine (Ki 5.9 μmol/l). In contrast, for the κ‐opioid receptor, dihydrocodeine‐6‐O‐ and dihydromorphine‐6‐O‐glucuronide had clearly lower affinities compared to the respective parent compounds. The affinity of nordihydrocodeine was almost identical to that of dihydrocodeine (Ki 14 μmol/l), whereas dihydromorphine had a 60 times higher affinity. These results suggest that dihydromorphine and its 6‐O‐glucuronide may provide a relevant contribution to the pharmacological effects of dihydrocodeine. The O‐demethylation of dihydrocodeine to dihydromorphine is mediated by the polymorphic cytochrome P‐450 enzyme CYP2D6, resulting in different metabolic profiles in extensive and poor metabolizers. About 7% of the caucasian population which are CYP2D6 poor metabolizers thus may experience therapeutic failure after standard doses.
Glutamate Uptake is Inhibited by Tamoxifen and Toremifene in Cultured Retinal Pigment Epithelial Cells
Authors: Mäenpää Hanna , Mannerström Marika , Toimela Tarja , Salminen Lotta , Saransaari Pirjo , Tähti Hanna
Published: March 2003

Abstract: The systemic drugs chloroquine and tamoxifen have caused retinal defects in human eye. The aim of our study was to investigate the effects of the amphiphilic drug tamoxifen, of its homologue toremifene, and of chloroquine on the glutamate uptake in retinal pigment epithelial (RPE) cells. Cultured human RPE cell line D407 and pig RPE cells were used in the study. Glutamate uptake was characterised and the glutamate transporters of pig RPE cells and the human RPE cell line D407 were compared to each other. The uptake of glutamate was studied using L‐[3H]glutamate as a tracer. The radioactivity in the solubilised RPE was measured with a liquid scintillation counter. In the uptake experiments, the cells were exposed to the test drugs, to the selected glutamate receptor antagonists, and to the glutamate transporter inhibitors. Both RPE cell types exhibited a high‐affinity transport system for glutamate. The glutamate transporter in RPE exhibited features characteristic of the uptake systems of neurotransmitters. The transport was Na+‐dependent, and L‐ and D‐aspartate were transported into the cell by the same transporter. Chloroquine had no effect on glutamate uptake, but tamoxifen and toremifene decreased the glutamate uptake of RPE cells dose‐dependently both in pig RPE cells and in human RPE cell line. The IC50 values of tamoxifen and toremifene were lower for pig RPE cells, compared to the human RPE cell line D407. The glutamate uptake was a sensitive target for the effects of tamoxifen and toremifene, and disturbances in this function could be considered as one of the possible mechanisms of retinal defects.
Amiodarone N‐Deethylation by CYP2C8 and its Variants, CYP2C8*3 and CYP2C8 P404A
Authors: Soyama Akiko , Hanioka Nobumitsu , Saito Yoshiro , Murayama Norie , Ando Masanori , Ozawa Shogo , Sawada Jun‐ichi
Published: March 2003

Abstract: Amiodarone is a potent Class III antiarrhythmic drug. The N‐deethylation of amiodarone to desethylamiodarone is known to be catalyzed by cytochrome P450 (CYP) 2C8. In the present study, amiodarone N‐deethylation by the CYP2C8s, CYP2C8*1 (wild‐type), CYP2C8*3, and CYP2C8 P404A (Pro404Ala substitution in exon 8), was investigated by their transient expression in Hep G2 cells. The expression levels of CYP2C8*1 and CYP2C8*3 were similar, whereas the level of CYP2C8 P404A was 55.6% of that of CYP2C8*1. The kinetic parameters of amiodarone N‐deethylation were obtained by means of Lineweaver‐Burk analysis. The intrinsic clearance (Vmax/Km, per mg of microsomal protein) of amiodarone by CYP2C8 P404A but not CYP2C8*3 was significantly (48.7%) less than that of CYP2C8*1. These results suggest that CYP2C8 P404A but not CYP2C8*3 is less effective in the N‐deethylation of amiodarone.
Subchronic Toxicity of Baltic Herring Oil and its Fractions in the Rat I: Fractionation and Levels of Organohalogen Pollutants
Authors: Öberg Mattias , Stern Natalia , Jensen ören , Wesén Clas , Haglund Peter , Casabona Helena , Johansson Niklas , Blomgren Kajsa , Håkansson Helen
Published: March 2003

Abstract: Baltic herring (Clupea harengus) oil was extracted and fractionated. To examine the contribution to toxicity and biological effects of different halogenated organic pollutants, the herring oil and the fractions were mixed into pelleted food and given to Sprague‐Dawley female rats at three levels, corresponding to a human intake of 1.6, 8.2 and 34.4 kg fish per week. Herring oil, its fractions, as well as liver tissues from exposed rats, were analyzed for: eight chlorinated biphenyls, all 2,3,7,8‐substituted chlorinated dibenzo‐p‐dioxins and dibenzofurans, hexachlorocyclohexanes, hexachlorobenzene, 1,1,1‐trichloro‐2,2‐bis(4‐chlorophenyl)ethane (DDT), DDT‐metabolites, three brominated diphenylethers as well as extractable organically bound chlorine and halogenated fatty acids. A bioassay (EROD) was used for measuring the dioxin‐like enzyme induction activity. Nordic Sea lodda (Mallotus villosus) oil was used as a nutritionally equivalent control, with much lower levels of halogenated organic pollutants. A full toxicological subchronic examination is reported in the following paper (Stern et al. 2002). In this study, we report that the fractionation procedure resulted in a substantial reduction of most of the pollutants in the triacylglycerol fraction, and a pronounced enrichment of most of the pollutants into the two other fractions. However, all contaminants were present at some levels in all of the fractions. The concentrations of organohalogens found in this study were representative for Baltic herring during the mid‐1990s. Rat liver tissue showed similar residue patterns as the diet, with the exception of chlorinated dibenzo‐p‐dioxin and dibenzofuran congeners that had a higher liver retention than pesticides, chlorinated biphenyls and brominated diphenylethers.
Solar urticaria: report of two cases with augmentation spectrum
Authors: Danno K. , Mori N.
Published: March 2003

Two adult Japanese patients with severe solar urticaria are reported. In both patients, an action spectrum existed in the visible light range, and an augmentation spectrum was demonstrated in the visible light range longer than the action spectrum. The augmentation phenomenon has rarely been documented, and in the previous reports, it was induced by preirradiation with the augmentation spectrum. In our cases, however, only postirradiation with the augmentation spectrum enhanced urticarial reactions.
Correlation between bathing time and photosensitivity in 8‐methoxypsoralen (8‐MOP) bath PUVA
Authors: Dolezal E. , Seeber A. , Hönigsmann H. , Tanew A.
Published: March 2003

Bath PUVA (psoralen plus ultraviolet A) using 8‐methoxypsoralen has become increasingly popular in recent years as an effective treatment option for a continuously expanding range of skin disorders. Among the various variables of bath PUVA treatment, the impact of bathing time on photosensitivity has never been investigated in detail. We therefore determined the threshold UVA dose for erythema induction after different bathing periods. A marked influence of bathing time on photosensitivity was found. Increasing the soaking period from 5 min to 30 min resulted in a greater than 60% reduction of the minimal phototoxic and minimal perceptible phototoxic dose. Our results demonstrate that the duration of the psoralen bath is a critical parameter in bath PUVA treatment and has a major influence on UVA dose requirements.
Time course of skin photosensitivity following trimethylpsoralen bath PUVA
Authors: Man I. , Wainwright N. J. , Gibbs N. K. , Ferguson J.
Published: March 2003

One aspect of bath photochemotherapy (PUVA) that requires clarification is the duration of psoralen‐induced cutaneous photosensitisation under conditions simulating clinical use. Using a half back comparison study technique, we investigated the persistence of trimethylpsoralen (TMP)‐induced photosensitivity in skin irradiated to simulate a first PUVA exposure compared with un‐irradiated skin. Baseline UVA minimal erythema dose and minimal phototoxic dose (MPD) were determined in 13 healthy volunteers. After readings at 72 h, subjects were bathed in TMP bath water for 15 min and one half of the back was immediately exposed to 40% of the MPD. Test sites (1.5 cm2) on both halves of the back were then irradiated with a UVA dose series at 15 min, 5, 10, 24, 34, 48 and 72 h after the bath. MPD readings were recorded visually at 72 h after each UVA exposure. The UVA MED was >25 J/cm2 in all the subjects. At each time point, a phototoxic index (PI) was calculated as UVA MED/MPD. In un‐irradiated skin, photosensitivity returned to normal (PI=1) within 24 h after the TMP bath. In contrast, skin pre‐irradiated to simulate the first PUVA treatment was still significantly photosensitive (PI=2.3; P=0.002) at 48 h. Contrary to previous recommendations, these data suggest that patients should be advised to avoid ambient or artificial sources of UVA throughout their course of TMP bath PUVA to reduce the risk of phototoxic erythema.
Successful treatment of lichen myxoedematosus with PUVA photochemotherapy
Authors: Adachi Y. , Iba S. , Horio T.
Published: March 2003

Lichen myxoedematosus is an unusual disorder of unknown etiology and pathogenesis. Although several treatments have reportedly been tried, therapeutic efficacies are variable and unsatisfactory. A patient with severe skin changes of this disease was successfully treated with PUVA photochemotherapy. PUVA therapy was carried out using 30 mg of 8‐methoxypsoralen orally, and subsequent exposure to UVA starting at 4 J/cm2. The eruption disappeared almost completely after 35 treatments at a cumulative dose of 202 J/cm2. Histologically, mucin deposition was greatly diminished after the therapy. The photochemotherapy may exert its effect directly by inhibiting proliferation of fibroblasts and synthesis of mucopolysaccharides, and also indirectly by immunomodulating action.
Reduction of minimal erythema dose by sweating
Authors: Moehrle Matthias , Koehle Welf , Dietz Klaus , Lischka Gerd
Published: March 2003

Background/Aims: Solar ultraviolet (UV) radiation is the most important environmental risk factor for melanoma and non‐melanoma skin cancer. It is known that tap water and saltwater baths have a photosensitizing capacity in subsequent UV irradiation of the skin. The aim of the present study was to determine the influence of sweating from heat or from physical activity on the photosensitivity of the skin.

Methods: Minimal erythema dose to ultraviolet B (MED/UVB) was determined on the inner forearms of 22 healthy volunteers with a Saalmann Multitester®. Sweating had been provoked by heat (sauna for 10 min) and, on another occasion, physical exercise (jogging for 15 min) followed by MED/UVB testing in a similar way.

Results: Compared to baseline MED/UVB there was a highly significant decrease in MED/UVB of up to 31.6% (median 15.8%, mean 15.9%±10.0) after 10 min in the sauna and up to 40.9% (median 16.3%, mean 17.2%±12.5) after 15 min jogging (P<0.0001).

Conclusion: Sweat influences the hydration of the horny layer of the skin, resulting in a decrease in reflection and dispersion of UV light. Moderate physical activities such as jogging and/or heat may facilitate erythema reaction. By sweating, outdoor workers and people practicing outdoor sports who are exposed to considerable amounts of solar UV radiation further increase their risk of sunburn.
Fixed solar urticaria to visible light successfully treated with fexofenadine
Authors: Schwarze H. P. , Marguery M. C. , Journé F. , Loche F. , Bazex J.
Published: March 2003

Fixed solar urticaria (FSU) represents an uncommon form of urticaria related mostly to radiation from the ultraviolet (UVB, UVA) and visible spectrum. The exact pathomechanism has so far remained unknown. A 52‐year‐old woman with a 3‐year history of urticated eruptions limited to certain skin areas is presented. Photobiological testing revealed positive reactions limited to the visible light range. The induced lesions appeared only in originally affected skin sites. The particular distribution of whealing supports the concept of specific alteration of mast cells in well defined areas. The clinical findings and the results of phototesting lead to the diagnosis of FSU to visible light. It is recommended to carry out phototesting in patients with FSU in the originally affected skin areas, usually covered and protected by the patient, to avoid false‐negative results. Fexofenadine given in the conventional dosage can prevent recurrences and represents a successful treatment measure when dealing with this peculiar form of solar urticaria.
The pathophysiology of photosensitivity in lupus erythematosus
Authors: Orteu Catherine H. , Sontheimer Richard D. , Dutz Jan P.
Published: March 2003

The strong association between photosensitivity and lupus erythematosus has led to the suggestion that abnormal photoreactivity participates in the pathogenesis of cutaneous lesions. In this review we discuss the evidence for abnormal cutaneous reactivity to sunlight in lupus and speculate on the cellular, molecular and genetic factors that may underlie this abnormality.
The effect of amniotic membrane extract on the expression of iNOS mRNA and generation of NO in HaCaT cell by ultraviolet B irradiation
Authors: Chang D. S. , Seo S. J. , Hong C. K.
Published: March 2003

Background/Purpose:
 Amniotic membrane (AM) is the innermost fetal membrane, which contains several proteinase inhibitors and expresses several growth factors. Nitric oxide (NO) has been implicated in the pathogenesis of various inflammatory diseases including sunburn and ultraviolet induced erythema. The expression of inducible nitric oxide synthase (iNOS) is up regulated by UVB irradiation and inhibited by TGF‐bβ and EGF‐bβ. We evaluated the effect of AM extract on the expression of iNOS mRNA by UV irradiation in HaCaT cell (immortalized human keratinocyte cell line).

Methods:
 HaCaT cells were irradiated UVB 30 mJ/cm2 and AM extract was added. The iNOS mRNA was isolated by RT‐PCR and NO production was assessed by spectrophotometric method based on Griess reaction.

Results:  The expression of iNOS mRNA was induced by UVB irradiation in HaCaT cell and the expression of iNOS mRNA was higher at 48 h than that at 24 h. AM extract down regulated the induction of iNOS mRNA in HaCaT cell by UVB irradiation. NO generation was increased by UVB irradiation, but down regulated by AM extract treatment in HaCaT cells.

Conclusion:  These results assured that the expression of iNOS mRNA and generation of NO are up regulated by UVB irradiation and showed that AM extract down regulated the induction of iNOS mRNA and decreased generation of NO by UVB irradiation.