bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of transition metal ions (cobalt and nickel chlorides) on intestinal iron absorption
Authors: Latunde‐Dada G. O. , Shirali S. , McKie A. T. , Simpson R. J. , Peters T. J.
Published: September 2004

Background  Haem biosynthesis may regulate intestinal iron absorption through changes in cellular levels of δ‐aminolaevulinic acid (ALA), haem and perhaps other intermediates. CoCl2 and NiCl2 are activators of haem oxygenase, the rate‐limiting enzyme in haem catabolism. Co2+ and Ni2+ may also regulate and increase iron absorption through a mechanism that simulates hypoxic conditions in the tissues.

Design  We assayed intestinal iron absorption in mice dosed with CoCl2 or NiCl2. The effects of these metal ions on splenic and hepatic levels of ALA synthase and dehydratase as well as urinary levels of ALA and phosphobilinogen were also assayed.

Results  While Co2+ enhanced iron absorption when administered to mice at doses of 65, 125 and 250 µmoles kg−1 body weight, Ni2+ was effective only at the highest dose. Ni2+ but not Co2+ at the highest dose reduced urinary ALA in the treated mice. Both metals ions increased splenic expression of haem oxygenase 1 and iron regulated protein 1, proteins involved, respectively, in haem degradation and iron efflux. Co2+ induced erythropoietin expression.

Conclusions  The data suggest that while the effect of Ni2+ on iron absorption could be explained by effects on ALA, the effect of Co2+ may not be explained simply by changes in haem metabolism; therefore, effects mediated by alterations of specific haemoproteins by mechanisms that simulate tissue hypoxia could be important.
Effects of experimentally imposed climate scenarios on flowering phenology and flower production of subarctic bog species
Authors: Aerts R. , Cornelissen J. H. C. , Dorrepaal E. , Van Logtestijn R. S. P. , Callaghan T. V.
Published: September 2004

Climate scenarios for high‐latitude areas predict not only increased summer temperatures, but also larger variation in snowfall and winter temperatures. By using open‐top chambers, we experimentally manipulated both summer temperatures and winter and spring snow accumulations and temperatures independently in a blanket bog in subarctic Sweden, yielding six climate scenarios. We studied the effects of these scenarios on flowering phenology and flower production of Andromeda polifolia (woody evergreen) and Rubus chamaemorus (perennial herb) during 2 years. The second year of our study (2002) was characterized by unusually high spring and early summer temperatures.

Our winter manipulations led to consistent increases in winter snow cover. As a result, average and minimum air and soil temperatures in the high snow cover treatments were higher than in the winter ambient treatments, whereas temperature fluctuations were smaller. Spring warming resulted in higher average, minimum, and maximum soil temperatures. Summer warming led to higher air and soil temperatures in mid‐summer (June–July), but not in late summer (August–September).

The unusually high temperatures in 2002 advanced the median flowering date by 2 weeks for both species in all treatments. Superimposed on this effect, we found that for both Andromeda and Rubus, all our climate treatments (except summer warming for Rubus) advanced flowering by 1–4 days. The total flower production of both species showed a more or less similar response: flower production in the warm year 2002 exceeded that in 2001 by far. However, in both species flower production was only stimulated by the spring‐warming treatments.

Our results show that the reproductive ecology of both species is very responsive to climate change but this response is very dependent on specific climate events, especially those that occur in winter and spring. This suggests that high‐latitude climate change experiments should focus more on winter and spring events than has been the case so far.
The growth respiration component in eddy CO2 flux from a Quercus ilex mediterranean forest
Authors: Rambal S. , Joffre R. , Ourcival J. M. , Cavender‐Bares J. , Rocheteau A.
Published: September 2004

Ecosystem respiration, arising from soil decomposition as well as from plant maintenance and growth, has been shown to be the most important component of carbon exchange in most terrestrial ecosystems. The goal of this study was to estimate the growth component of whole‐ecosystem respiration in a Mediterranean evergreen oak (Quercus ilex) forest over the course of 3 years. Ecosystem respiration (Reco) was determined from night‐time carbon dioxide flux (Fc) using eddy correlation when friction velocity (u*) was greater than 0.35 m s−1

We postulated that growth respiration could be evaluated as a residual after removing modeled base Reco from whole‐ecosystem Reco during periods when growth was most likely occurring. We observed that the model deviated from the night‐time Fc‐based Reco during the period from early February to early July with the largest discrepancies occurring at the end of May, coinciding with budburst when active aboveground growth and radial growth increment are greatest. The highest growth respiration rates were observed in 2001 with daily fluxes reaching up to 4 g C m−2. The cumulative growth respiration for the entire growth period gave total carbon losses of 170, 208, and 142 g C m−2 for 1999, 2001, and 2002, respectively. Biochemical analysis of soluble carbohydrates, starch, cellulose, hemicellulose, proteins, lignin, and lipids for leaves and stems allowed calculation of the total construction costs of the different growth components, which yielded values of 154, 200, and 150 g C for 3 years, respectively, corresponding well to estimated growth respiration. Estimates of both leaf and stem growth showed very large interannual variation, although average growth respiration coefficients and average yield of growth processes were fairly constant over the 3 years and close to literature values. The time course of the growth respiration may be explained by the growth pattern of leaves and stems and by cambial activity. This approach has potential applications for interpreting the effects of climate variation, disturbances, and management practices on growth and ecosystem respiration.
Effect of elevated [CO2] on stem wood properties of mature Norway spruce grown at different soil nutrient availability
Authors: Kostiainen Katri , Kaakinen Seija , Saranpää Pekka , Sigurdsson Bjarni D. , Linder Sune , Vapaavuori Elina
Published: September 2004

The objective of the present study was to investigate the interactive effects of elevated [CO2] and soil nutrient availability on secondary xylem structure and chemical composition of 41‐year‐old Norway spruce (Picea abies (L.) Karst.) trees. The nonfertilized and irrigated‐fertilized trees were, for 3 years, continuously exposed to elevated [CO2] in whole‐tree chambers. Elevated [CO2] decreased concentrations of soluble sugars, acid‐soluble lignin and nitrogen in stem wood, but the effects were not consistent between sampling height and/or fertilization. The effect of 2*ambient [CO2] on wood structure depended on the exposure year and/or fertilization. Radial lumen diameter decreased and annual ring width increased in the second year of exposure (1999) in elevated [CO2]. In the latter, the CO2 effect was significant only in the nonfertilized trees. Stem wood chemistry and structure were significantly affected by fertilization. Fertilization increased the concentrations of nitrogen and gravimetric lignin, annual ring width, and radial lumen diameter. Fertilization decreased C/N ratio, mean ring density, earlywood density, latewood density, cell wall thickness, cell wall index, and latewood percentage. We conclude that elevated [CO2] had only minor effects on wood properties while fertilization had more marked effects and thus may affect ecosystem processes and suitability of wood for different end‐use purposes.
Disturbance and climate effects on carbon stocks and fluxes across Western Oregon USA
Authors: Law B. E. , Turner D. , Campbell J. , Sun O. J. , Van Tuyl S. , Ritts W. D. , Cohen W. B.
Published: September 2004

We used a spatially nested hierarchy of field and remote‐sensing observations and a process model, Biome‐BGC, to produce a carbon budget for the forested region of Oregon, and to determine the relative influence of differences in climate and disturbance among the ecoregions on carbon stocks and fluxes. The simulations suggest that annual net uptake (net ecosystem production (NEP)) for the whole forested region (8.2 million hectares) was 13.8 Tg C (168 g C m−2 yr−1), with the highest mean uptake in the Coast Range ecoregion (226 g C m−2 yr−1), and the lowest mean NEP in the East Cascades (EC) ecoregion (88 g C m−2 yr−1). Carbon stocks totaled 2765 Tg C (33 700 g C m−2), with wide variability among ecoregions in the mean stock and in the partitioning above‐ and belowground. The flux of carbon from the land to the atmosphere that is driven by wildfire was relatively low during the late 1990s (∼0.1 Tg C yr−1), however, wildfires in 2002 generated a much larger C source (∼4.1 Tg C). Annual harvest removals from the study area over the period 1995–2000 were ∼5.5 Tg C yr−1. The removals were disproportionately from the Coast Range, which is heavily managed for timber production (approximately 50% of all of Oregon's forest land has been managed for timber in the past 5 years). The estimate for the annual increase in C stored in long‐lived forest products and land fills was 1.4 Tg C yr−1. Net biome production (NBP) on the land, the net effect of NEP, harvest removals, and wildfire emissions indicates that the study area was a sink (8.2 Tg C yr−1). NBP of the study area, which is the more heavily forested half of the state, compensated for ∼52% of Oregon's fossil carbon dioxide emissions of 15.6 Tg C yr−1 in 2000. The Biscuit Fire in 2002 reduced NBP dramatically, exacerbating net emissions that year. The regional total reflects the strong east–west gradient in potential productivity associated with the climatic gradient, and a disturbance regime that has been dominated in recent decades by commercial forestry.
Would climate change drive species out of reserves? An assessment of existing reserve‐selection methods
Authors: Araújo Miguel B. , Cabeza Mar , Thuiller Wilfried , Hannah Lee , Williams Paul H.
Published: September 2004

Concern for climate change has not yet been integrated in protocols for reserve selection. However if climate changes as projected, there is a possibility that current reserve‐selection methods might provide solutions that are inadequate to ensure species' long‐term persistence within reserves. We assessed, for the first time, the ability of existing reserve‐selection methods to secure species in a climate‐change context. Six methods using a different combination of criteria (representation, suitability and reserve clustering) are compared. The assessment is carried out using European distributions of 1200 plant species and considering two extreme scenarios of response to climate change: no dispersal and universal dispersal. With our data, 6–11% of species modelled would be potentially lost from selected reserves in a 50‐year period. Measured uncertainties varied in 6% being 1–3% attributed to dispersal assumptions and 2–5% to the choice of reserve‐selection method. Suitability approaches to reserve selection performed best, while reserve clustering performed poorly. We also found that 5% of species modelled would lose their entire climatic envelope in the studied area; 2% of the species modelled would have nonoverlapping distributions; 93% of the species modelled would maintain varying levels of overlapping distributions. We conclude there are opportunities to minimize species' extinctions within reserves but new approaches are needed to account for impacts of climate change on species; especially for those projected to have temporally nonoverlapping distributions.
Airway hyper‐reactivity mediated by B‐1 cell immunoglobulin M antibody generating complement C5a at 1 day post‐immunization in a murine hapten model of non‐atopic asthma
Authors: Kawikova Ivana , Paliwal Vipin , Szczepanik Marian , Itakura Atsuko , Fukui Mieko , Campos Regis A. , Geba Gregory P. , Homer Robert J. , Iliopoulou Bettina P. , Pober Jordan S. , Tsuji Ryohei F. , Askenase Philip W.
Published: September 2004

Contact skin immunization of mice with reactive hapten antigen and subsequent airway challenge with the same hapten induces immediate airflow obstruction and subsequent airway hyper‐reactivity (AHR) to methacholine challenge, which is dependent on B cells but not on T cells. This responsiveness to airway challenge with antigen is elicited as early as 1 day postimmunization and can be adoptively transferred to naïve recipients via 1‐day immune cells. Responses are absent in 1‐day immune B‐cell‐deficient JH−/− mice and B‐1 B‐cell‐deficient xid male mice, as well as in recipients of 1‐day immune cells depleted of cells with the B‐1 cell phenotype (CD19+ B220+ CD5+). As B‐1 cells produce immunoglobulin M (IgM), we sought and found significantly increased numbers of anti‐hapten IgM‐producing cells in the spleen and lymph nodes of 1‐day immune wild‐type mice, but not in xid mice. Then, we passively immunized naive mice with anti‐hapten IgM monoclonal antibody and, following airway hapten challenge of the recipients, we showed both immediate airflow obstruction and AHR. In addition, AHR was absent in complement C5 and C5a receptor‐deficient mice. In summary, this study of the very early elicited phase of a hapten asthma model suggests, for the first time, a role of B‐1 cells in producing IgM to activate complement to rapidly mediate asthma airway reactivity only 1 day after immunization.
A novel adjuvant–allergen complex, CBP–rFel d 1, induces up‐regulation of CD86 expression and enhances cytokine release by human dendritic cells in vitro
Authors: Andersson Theresa N. , Ekman Gunilla J. , Grönlund Hans , Buentke Eva , Eriksson Tove L. J. , Scheynius Annika , Van Hage‐Hamsten Marianne , Gafvelin Guro
Published: September 2004

Allergen‐specific immunotherapy is commonly performed with allergen extracts adsorbed to aluminium hydroxide (alum). The undesirable effects associated with the use of alum, including granuloma formation at the site of injection and stimulation of T helper 2 (Th2) cytokine production, has generated interest in alternative allergen carriers, one being carbohydrate‐based particles (CBPs). Here, we have investigated the in vitro effects of the recombinant major cat allergen Fel d 1 (rFel d 1) coupled to CBPs (CBP–rFel d 1) on human monocyte‐derived dendritic cells (MDDCs) obtained from healthy blood donors. A majority of the CD1a+ MDDCs internalized fluorescein isothiocyanate‐labelled CBP–rFel d 1, as demonstrated by flow cytometry and confocal laser‐scanning microscopy. Furthermore, an up‐regulation of the expression of the costimulatory molecule, CD86, on the MDDCs was induced by CBP–rFel d 1, but not by rFel d 1 or CBPs alone. Finally, three‐ and fourfold increases in the release of interleukin‐8 and tumour necrosis factor‐α, respectively, were observed when MDDCs were cultured in the presence of CBP‐rFel d 1. Altogether, our results indicate that the use of CBPs as an allergen carrier and adjuvant is a promising candidate for the improvement of allergen‐specific immunotherapy.
Effects of a cysteinyl leukotriene receptor antagonist on eosinophil recruitment in experimental allergic rhinitis
Authors: Saito Hiroko , Morikawa Hiroshi , Howie Karen , Crawford Lynn , Baatjes Adrian J. , Denburg Elisha , Cyr Michael M. , Denburg Judah A.
Published: September 2004

The cysteinyl leukotrienes (cysLTs) are potent lipid mediators in allergic disease, acting through a receptor (cysLT1‐R) which can be targeted in rhinitis and asthma. We investigated the effects of cysLT1‐R antagonism in experimental allergic rhinitis, focusing on bone marrow eosinophil progenitor responses. BALB/c mice were sensitized, then given daily intranasal ovalbumin for 2 weeks, with montelukast sodium (5 mg/kg or 2·5 mg/kg) or placebo by gavage. Bone marrow eosinophil/basophil colonies were enumerated, and colony cells were morphologically assessed as indices of eosinophil differentiation and maturation. Montelukast treatment resulted in a significant decrease of eosinophils in the nasal mucosa, and in either bone marrow interleukin (IL)‐5‐, but not IL‐3‐, or granulocyte‐macrophage colony‐stimulating factor‐responsive eosinophil/basophil colony‐forming units, and IL‐5‐stimulated eosinophil maturation. These results indicate that cysLT1‐R antagonism in vivo limits both IL‐5‐responsive eosinophilopoiesis, acting at several stages of eosinophil differentiation and maturation. The anti‐allergic effects of cysLT1‐R antagonists are consistent with the concept that cysLTs and IL‐5 act together in the recruitment of eosinophils and eosinophil progenitors from the marrow during upper airway allergic inflammation.
Lycopene suppresses the lipopolysaccharide‐induced phenotypic and functional maturation of murine dendritic cells through inhibition of mitogen‐activated protein kinases and nuclear factor‐κB
Authors: Kim Gi‐Young , Kim Jong‐Hyun , Ahn Soon‐Cheol , Lee Hee‐Jeong , Moon Dong‐Oh , Lee Chang‐Min , Park Yeong‐Min
Published: September 2004

Dendritic cells (DC) are the most potent of antigen‐presenting cells. The most important function of DC is to initiate the immune response by presenting antigens to naïve T lymphocytes. Currently, little is known about the basic action of lycopene in murine bone marrow (BM)‐derived DC. In the present study, we have revealed that lycopene significantly attenuates the phenotypic and functional maturation of murine BM‐DC, especially in lipopolysaccharide‐induced DC maturation. We found that lycopene down‐regulates the expression of costimulatory molecules (CD80 and CD86) and major histocompatibility complex type II molecules. We also determined that lycopene‐treated DC were poor stimulators of naïve allogeneic T‐cell proliferation and induced lower levels of interleukin‐2 in responding T cells. They also exhibited impaired interleukin‐12 production. Additionally, lycopene was able to inhibit mitogen‐activated protein kinases, such as ERK1/2, p38 and JNK, and the transcription factor, nuclear factor‐κB. Assessment of the in vivo effects of lycopene may reveal an inability to induce a normal cell‐mediated immune response, despite the ability of the cells to migrate to the spleen. This data provides new insight into the immunopharmacology of lycopene and suggests a novel approach to the manipulation of DC for therapeutic application.
Histamine induces Toll‐like receptor 2 and 4 expression in endothelial cells and enhances sensitivity to Gram‐positive and Gram‐negative bacterial cell wall components
Authors: Talreja Jaya , Kabir Mohammad H. , B. Filla Michael , Stechschulte Daniel J. , Dileepan Kottarappat N.
Published: September 2004

Histamine is a major inflammatory molecule released from the mast cell, and is known to activate endothelial cells. However, its ability to modulate endothelial responses to bacterial products has not been evaluated. In this study we determined the ability of histamine to modulate inflammatory responses of endothelial cells to Gram‐negative and Gram‐positive bacterial cell wall components and assessed the role of Toll‐like receptors (TLR) 2 and 4 in the co‐operation between histamine and bacterial pathogens. Human umbilical vein endothelial cells (HUVEC) were incubated with lipopolysaccharide (LPS), lipoteichoic acid (LTA), or peptidoglycan (PGN) in the presence or absence of histamine, and the expression and release of interleukin‐6 (IL‐6), and NF‐κB translocation were determined. The effect of histamine on the expression of mRNA and proteins for TLR2 and TLR4 was also evaluated. Incubation of HUVEC with LPS, LTA and PGN resulted in marked enhancement of IL‐6 mRNA expression and IL‐6 secretion. Histamine alone markedly enhanced IL‐6 mRNA expression in HUVEC, but it did not stimulate proportional IL‐6 release. When HUVEC were incubated with LPS, LTA, or PGN in the presence of histamine marked amplification of both IL‐6 production and mRNA expression was noted. HUVEC constitutively expressed TLR2 and TLR4 mRNA and proteins, and these were further enhanced by histamine. The expression of mRNAs encoding MD‐2 and MyD88, the accessory molecules associated with TLR signalling, were unchanged by histamine treatment. These results demonstrate that histamine up‐regulates the expression of TLR2 and TLR4 and amplifies endothelial cell inflammatory responses to Gram‐negative and Gram‐positive bacterial components.
Resistance to re‐challenge in the Brown Norway rat model of vasculitis is not always complete and may reveal separate effector and regulatory populations
Authors: Vinen C. S. , Turner D. R. , Oliveira D. B. G.
Published: September 2004

Administration of mercuric chloride to Brown Norway rats results in T helper type 2 (Th2)‐ dominated autoimmunity characterized by high immunoglobulin E (IgE) concentrations, the production of multiple IgG autoantibodies, including those to glomerular basement membrane (GBM), arthritis and caecal vasculitis. After 14 days animals immunoregulate and auto‐immunity resolves even if mercuric chloride injections are continued. In a third phase, if animals are re‐challenged with mercuric chloride 6 weeks later, they show only attenuated autoimmunity with lower anti‐GBM antibody concentrations and arthritis scores. Resistance to the induction of anti‐GBM antibodies can also be achieved following an initial challenge with low‐dose (one‐tenth standard dose) mercuric chloride. We have now studied this resistant phase in more detail. We have shown, first, that following an initial full‐dose mercuric chloride challenge, resistance also affects susceptibility to caecal vasculitis. Second, following an initial full‐dose mercuric chloride challenge, the IgE response upon re‐challenge is initially accelerated but subsequently enters a resistant phase and third, following an initial challenge with low‐dose mercuric chloride, resistance is also seen to the induction of caecal vasculitis but is not seen in IgE serology (where results suggest competing effector and regulatory cell populations). Studying such regulatory phases in animal models of autoimmunity may be of benefit in the future in designing new therapies for human vasculitis.
CD4+ CCR5+ and CD4+ CCR3+ lymphocyte subset and monocyte apoptosis in patients with acute visceral leishmaniasis
Authors: Potestio Marcella , D'Agostino Pietro , Romano Giuseppina Colonna , Milano Salvatore , Ferlazzo Viviana , Aquino Alessandra , Di Bella Gloria , Caruso Rosalba , Gambino Giuseppe , Vitale Giustina , Mansueto Serafino , Cillari Enrico
Published: September 2004

The potential involvement of apoptosis in the pathogenesis of visceral leishmaniasis (VL) was examined by studying spontaneous and Leishmania antigen (LAg)‐induced apoptosis using cryopreserved peripheral blood mononuclear cells (PBMC) of Sicilian patients with VL. Results indicate that monocytes and T lymphocytes from acute VL patients show a significantly higher level of apoptosis compared with that observed in healed subjects. The percentage of apoptotic cells was higher in monocytes than in T lymphocytes. T cells involved in programmed cell death (PCD) were mainly of the CD4+ phenotype. In particular, the T helper 1‐type (Th1) subset, as evaluated by chemokine receptor‐5 (CCR5) expression, is involved in this process. Cell death in Th1‐type uses a CD95‐mediated mechanism. Furthermore, Th1‐type CCR5+ cells are prone to cell suicide in an autocrine or paracrine way, as attested by enhanced expression of CD95L in acute VL patients. The reduction in Th1‐type cells by apoptosis was confirmed by the decrease in interferon‐γ secretion. In conclusion, apoptosis of monocytes, CD4+ and CD4+ CCR5+ T cells could be involved in the failure of cell mediated immunity that is responsible for severe immune‐depression in VL.
Loss of CD154 impairs the Th2 extrafollicular plasma cell response but not early T cell proliferation and interleukin‐4 induction
Authors: Cunningham Adam F. , Serre Karine , Mohr Elodie , Khan Mahmood , Toellner Kai‐Michael
Published: September 2004

Ligation of CD40 by CD4 T cells through CD154 is key both to germinal centre induction and follicular T‐dependent Ig class switching, but its requirement for aspects of T cell priming and extrafollicular antibody responses is less clear. Here comparison of the T helper (Th) type 2 response in lymph nodes from wild‐type mice and CD154‐deficient mice after immunization with alum‐precipitated antigen reveals selective effects of this immunodeficiency. The timing and magnitude of the early interleukin (IL)‐4 induction and proliferation in T cells of the T zone were unaltered by CD154 deficiency. As expected, germinal centres were not induced. Additionally the T‐dependent extrafollicular antibody response, which initially requires T cell help but expands without further T cell involvement, was severely curtailed. The median number of extrafollicular antigen‐specific plasma cells was 370‐fold lower in CD154‐deficient mice. Of these plasma cells the median proportion that had switched to IgG1 was <5%, while in wild‐type mice the proportion was 89%. Surprisingly, some CD154‐deficient lymph nodes showed substantial switching to IgG1. Commensurately, increases in γ1 germline transcripts and Blimp‐1 mRNA were observed, albeit significantly lower than in controls, but activation‐induced cytidine deaminase mRNA was undetectable in CD154‐deficient mice. These experiments demonstrate that the acquisition of some T cell priming characteristics can be CD154‐independent; in contrast, T‐dependent extrafollicular responses require CD154. Thus functional CD154 ligation during the first encounter of T cells and B cells in the T zone is critical for follicular and extrafollicular antibody responses.
Haemophilus influenzae type b conjugate vaccines
Authors: Kelly Dominic F. , Moxon E. Richard , Pollard Andrew J.
Published: September 2004

Haemophilus influenzae type b (Hib) is one of the leading causes of invasive bacterial infection in young children worldwide. During childhood, acquisition of antibody directed against the polysaccharide capsule of the organism, presumably as a result of asymptomatic carriage, confers protection and disease is much less common after the age of 4 years. Like other polysaccharides, the polyribosyl ribitol phosphate (PRP) of the Hib capsule is a T‐independent antigen and not immunogenic when administered as a vaccine in infancy. Because the highest rates of disease occur in the first 2 years of life, efficacious Hib vaccines have been designed by covalently linking the PRP capsule to a carrier protein that recruits T‐cell help for the polysaccharide immune response and induces anti‐PRP antibody production even in the first 6 months of life. Introduction of Hib protein–polysaccharide conjugate vaccines into many industrialized countries over the past 15 years has resulted in the virtual elimination of invasive Hib disease. However, despite the success of the vaccine programme several factors may interfere with the effectiveness of the vaccine in the routine programme, as observed in the UK recently. Such factors may include interference with other concomitant vaccines, waning immunity in the absence of booster doses of vaccine, and reduced natural boosting as a result of decreased transmission of the organism. However, the burden of disease remains highest in resource‐poor countries and urgent efforts are needed to provide the benefits of this vaccine for children living in regions where it cannot be used for economic and logistical reasons.
Di‐(2‐ethylhexyl) phthalate induces severe aspermatogenesis in mice, however, subsequent antioxidant vitamins supplementation accelerates regeneration of the seminiferous epithelium
Authors: Ablake Maira , Itoh Masahiro , Terayama Hayato , Hayashi Shogo , Shoji Sunao , Naito Munekazu , Takahashi Kodo , Suna Shigeru , Jitsunari Fumihiko
Published: September 2004

Di‐(2‐ethylhexyl) phthalate (DEHP), now regarded as an endocrine disruptor, can experimentally induce spermatogenic disturbance in laboratory animals. Our previous study demonstrated that antioxidant vitamins (vitamins C and E) supplementation during DEHP‐treatment significantly protected the rat seminiferous epithelium from DEHP‐gonadotoxicity. In the present study, we gave these antioxidant vitamins to mice already having fully developed aspermatogenesis because of DEHP to determine whether or not the vitamins can cure the injured seminiferous epithelium. CD‐1 male mice were fed on a DEHP‐containing diet for 15 days and then fed on the DEHP‐free normal diet with or without supplementation of vitamins C and E in drinking water for another 50 days. The results showed that severe aspermatogenesis was induced by the DEHP‐treatment but that the damaged seminiferous epithelium spontaneously recovered whether the vitamins were provided or not. This indicates that the DEHP‐induced aspermatogenesis was reversible. However, the supplementation of antioxidant vitamins significantly accelerated regeneration of the injured seminiferous epithelium, suggesting that the vitamins have a therapeutic effect on DEHP‐induced aspermatogenesis.
Ontogenesis and cell specific localization of Fas ligand expression in the rat testis
Authors: D'Abrizio Piera , Baldini Enke , Russo Paola F. , Biordi Leda , Graziano Filomena M. , Rucci Nadia , Properzi Giuliana , Francavilla Sandro , Ulisse Salvatore
Published: September 2004

Over the past few years, a number of experimental evidences suggested the involvement of Fas Ligand (FasL) expressing Sertoli cells to induce apoptosis of Fas bearing germ cells. However, the FasL expression during testicular development and its cell specific localization within the testis is still a matter of debate. In the present study, we have monitored FasL expression during rat testis development by semiquantitative reverse transcriptase‐polymerase chain reaction (RT‐PCR) and evaluated cell specific localization of FasL expression, by in situ RT‐PCR and immunohistochemistry, on adult rat testis. RT‐PCR analysis, performed on total RNA from rat testes obtained from 1 day up to 1‐year‐old animals, demonstrated the presence of FasL transcripts at all developmental stages examined. In situ RT‐PCR analysis clearly indicated the presence of FasL mRNA in Sertoli cells of adult testis, while we could never detect FasL transcripts in germ cells. Immunohistochemistry experiments showed a strong immunostaining for FasL in Sertoli cells of adult testis and again, no immunopositivity was observed in germ cells. In conclusion, our data suggest that FasL expression in rat testis is present from the early postnatal days up to the adult, and the Sertoli cells is the main FasL expressing cell within the seminiferous tubule.
Effects of cigarette smoking on sperm plasma membrane integrity and DNA fragmentation
Authors: Belcheva Antoaneta , Ivanova‐Kicheva Maria , Tzvetkova Petia , Marinov Mihail
Published: September 2004

Cigarette smoking is a serious health problem of our society. It is known that cigarette smoke is a cell mutagen and carcinogen, and that it may affect adversely male fertility. The possible detrimental effects on sperm cells are of great interest but the data available to support this statement are somewhat elusive. To approach this problem we examined conventional semen parameters, plasma membrane translocation of phosphatidylserine (PS) (annexin V/6‐CFDA cell staining) and sperm DNA integrity (comet assay) in a group of healthy man smoking cigarettes on a regular basis. The results of the study were compared with the results of the same tests in healthy non‐smoking donors. Significant difference in standard sperm parameters between the two groups was not found. Intensive expression of PS on the sperm plasma membrane surface (assayed by annexin V positive staining) was detected in the smokers group. There is a significant increase of population of apoptotic spermatozoa in ejaculates of smokers. Albeit DNA damages (high frequencies of double‐ and single‐ stranded DNA breaks) in spermatozoa of smokers are increased compared with non‐smokers, but this difference is not statistically significant. Sperm DNA integrity of healthy smokers remains in the normal range, but a clear negative trend is observed, especially in respect of disturbance of plasma membrane phospholipid asymmetry.
Concentrations of polychlorinated biphenyls in blood and the risk for testicular cancer
Authors: Hardell Lennart , Van Bavel Bert , Lindström Gunilla , Carlberg Michael , Eriksson Mikael , Dreifaldt Ann Charlotte , Wijkström Hans , Starkhammar Hans , Hallquist Arne , Kolmert Torgny
Published: September 2004

An increasing incidence of testicular cancer has been reported from several western countries during the last decades. According to current hypothesis testicular cancer is initiated during the foetal period and exposure to endocrine disruptors such as some persistent organic pollutants has been of concern. We have previously reported the results for concentrations of polychlorinated biphenyls (PCBs), p,p′‐dichlorodiphenyl‐dichloroethylene (pp′‐DDE), hexachlorobenzene (HCB) and chlordanes in 58 cases with testicular cancer, 61 age‐matched controls and 44 case mothers and 45 control mothers. In that report, significant increase of odds ratio (OR) was found for sum of PCBs, HCB, trans‐ and cis‐nonachlordane in case mothers. These data have now been further analysed for 37 congeners of PCBs. No significant differences were found among cases and controls. However, case mothers had significantly increased concentrations of a number of PCB congeners. A priori decided grouping of PCBs yielded for oestrogenic PCBs OR = 2.4, 95% confidence interval (CI) = 0.95–6.0, enzyme‐inducing PCBsOR = 2.6, 95% CI = 1.03–6.5 and toxic equivalents (TEQ) yielded OR = 3.3, 95% CI = 1.3–8.4. These data further elucidate the role of foetal exposure to different PCB congeners in the aetiology of testicular cancer.
Micropapillary variant of transitional cell carcinoma of the bladder
Authors: SUGINO YOSHIO , NEGORO HIROMITSU , IWAMURA HIROSHI , MOROI SEIJI , OKA HIROYA , KAWAKITA MUTSUSHI , HANIOKA KEISUKE , TAKEUCHI HIDEO
Published: September 2004

Abstract A 77‐year‐old man visited the Kobe City General Hospital complaining of macroscopic hematuria. A computed tomography scan found a bladder tumor with left iliac and para‐aortic lymph node metastasis. Two courses of cisplatin, cyclophosphamide and doxorubicin chemotherapy resulted in a minimal response. Radical cystectomy and a retroperitoneal lymph node dissection with bilateral ureterocutaneostomy reconstruction were then performed. A pathological examination revealed a micropapillary variant of transitional cell carcinoma (Grade 3, pT1pN2M1). The patient died of pelvic recurrence 7 months after the initiation of chemotherapy. Peritonitis carcinomatosa and lung metastases were observed at autopsy.
Nephrogenic adenoma of the bladder in a girl with Turner's syndrome: An unusual association
Authors: KIBAR YUSUF , SÜMER FAHRI , YILDIRIM IBRAHIM , GAMSIZKAN MEHMET , AVCI ALI , DAYANÇ MURAT
Published: September 2004

Abstract We describe a nephrogenic adenoma of the bladder in a 14‐year‐old girl with Turner's syndrome. The patient also had a past history of urological surgery for vesicoureteral reflux. In this case, the multifocal lesions were successfully treated by transurethral resection.
A Double-Blind Study of SB-220453 (Tonerbasat) in the Glyceryltrinitrate (GTN) Model of Migraine
Authors: Tvedskov JF , Iversen HK , Olesen J
Published: September 2004

The need for experimental migraine models increases as therapeutic options widen. In the present study, we investigated SB-220453 for efficacy in the glyceryltrinitrate (GTN) human experimental migraine model. SB-220453 is a novel benzopyran compound, which in animal models inhibits neurogenic inflammation, blocks propagation of spreading depression and inhibits trigeminal nerve ganglion stimulation-induced carotid vasodilatation. We included 15 patients with migraine without aura in a randomized double-blind crossover study. SB-220453 40 mg or placebo was followed by a 20-min GTN infusion. Headache, scored 0-10, was registered for 12 h, and fulfillment of International Headache Society (IHS) criteria was recorded until 24 h. Four subjects had a hypotensive episode after SB-220453 plus GTN but none after GTN alone. The reaction was unexpected, since animal models and previous human studies had shown no vascular or sympaticolytic activity with SB-220453. The study was terminated prematurely due to this interaction. GTN was consistent in producing headache and migraine that resembled the patients' usual spontaneous migraine. Nine patients had GTN on both study days. Peak headache score showed a trend towards reduction after SB-220453 compared with placebo (median 4 vs. 7, P = 0.15). However, no reduction was seen in the number of subjects experiencing delayed headache (8 vs. 8), number of subjects reporting migraine (6 vs. 8), migraine attacks fulfilling IHS criteria 1.1 or 1.7 (6 vs. 7) or IHS 1.1 alone (4 vs. 5). SB-220453 had no significant pre-emptive anti-migraine activity compared with placebo in this human model of migraine. Interaction between SB-220453 and GTN was discovered. This is important for the future development of the compound and underlines the usefulness of experimental migraine models.
Paradoxical Postural Headaches in Cerebrospinal Fluid Leaks
Authors: Mokri B , Aksamit AJ , Atkinson JLD
Published: September 2004

Two patients with cerebrospinal fluid (CSF) leak, one at the level of fourth thoracic spine and another with undetermined level of leak, presented with paradoxical postural headaches in that the headaches were present when in a horizontal position and resolved if the patients were upright. One patient improved spontaneously and the other responded to a targeted epidural blood patch. Paradoxical postural headache is yet another headache type that can be associated with CSF leak and CSF volume depletion. Its mechanism is uncertain, but it could be related to congestion and dilatation of cerebral venous sinuses and large veins.
Efficacy of Phenazone in the Treatment of Acute Migraine Attacks: A Double-Blind, Placebo-Controlled, Randomized Study
Authors: Göbel H , Heinze A , Niederberger U , Witt T , Zumbroich V
Published: September 2004

In this study we compared the efficacy of 1000 mg phenazone with that of placebo in the treatment of acute migraine attacks in a randomized double-blind, placebo-controlled study of 208 patients. The main target criterion was the number of patients with a pain reduction from severe or moderate to slight or no pain 2 h after taking the pain medication. The percentage of patients satisfying the main target criterion was 48.6% for phenazone and 27.2% ( P < 0.05) for placebo. Freedom from pain after 2 h was reported by 27.6% with phenazone treatment and 13.6% ( P < 0.05) with placebo. Compared with placebo, the phenazone treatment also resulted in a significant improvement in the associated migraine symptoms of nausea, phonophobia and photophobia. Of patients treated with phenazone 11.4%, and 5.8% of those treated with placebo reported adverse events. There was no significant difference between the groups with regard to numbers of patients with adverse events. No serious adverse events occurred. The results show that phenazone at a dosage of 1000 mg is effective and well tolerated in the treatment of acute migraine attacks.
Radiofrequency Denervation of Facet Joints C2-C6 in Cervicogenic Headache: A Randomized, Double-Blind, Sham-Controlled Study
Authors: Stovner LJ , Kolstad F , Helde G
Published: September 2004

Cervicogenic headache is still a controversial disease entity, and good and reliable treatment is lacking. In the present randomized, sham-controlled, patient- and evaluator-blinded study, 12 patients with a disabling, long-standing and treatment-resistant strictly unilateral cervicogenic headache were included. The diagnosis was based on purely clinical criteria. Six were randomized to receive radiofrequency neurotomy of facet joints C2-C6 ipsilateral to the pain, and six were randomized to sham treatment. Patients were followed for 2 years with diary registration of pain for 14-days periods after 1, 3, 6, 12, 18 and 24 months, and also followed with algometry and neck mobility measurements at 3, 12 and 24 months. Side-effects were minor and short-lasting, and those patients who were treated with neurotomy were somewhat improved at 3 months, but later there were no marked differences between the groups. In conclusion, the procedure is probably not beneficial in cervicogenic headache.
Neuroprotective actions of eicosapentaenoic acid on lipopolysaccharide‐induced dysfunction in rat hippocampus
Authors: Lonergan Peter E. , Martin Darren S. D. , Horrobin David F. , Lynch Marina A.
Published: September 2004

Eicosapentaenoic acid (EPA) protects hippocampus from age‐related and irradiation‐induced changes that lead to impairment in synaptic function; the evidence suggests that this is due to its anti‐inflammatory effects, specifically preventing changes induced by the proinflammatory cytokine, interleukin‐1β (IL‐1β). In this study, we have investigated the possibility that EPA may prevent the effects of lipopolysaccharide (LPS) administration, which have been shown to lead to deterioration of synaptic function in rat hippocampus. The data indicate that treatment of hippocampal neurones with EPA abrogated the LPS‐induced increases in phosphorylation of the mitogen‐activated protein kinase, c‐Jun N‐terminal kinase (JNK), the transcription factor, c‐Jun and the mitochondrial protein, Bcl‐2. In parallel, we report that intraperitoneal administration of LPS to adult rats increases phosphorylation of JNK, c‐Jun and Bcl‐2 in hippocampal tissue and that these changes are coupled with increased IL‐1β concentration. Treatment of rats with EPA abrogates these effects and also blocks the LPS‐induced impairment in long‐term potentiation in perforant path‐granule cell synapses that accompanies these changes. We propose that the neuroprotective effect of EPA may be dependent on its ability to inhibit the downstream consequences of JNK activation.
P2Y2 receptors activate neuroprotective mechanisms in astrocytic cells
Authors: Chorna Nataliya E. , Santiago‐Pérez Laura I. , Erb Laurie , Seye Cheikh I. , Neary Joseph T. , Sun Grace Y. , Weisman Gary A. , González Fernando A.
Published: September 2004

Mechanical or ischemic trauma to the CNS causes the release of nucleotides and other neurotransmitters into the extracellular space. Nucleotides can activate nucleotide receptors that modulate the expression of genes implicated in cellular adaptive responses. In this investigation, we used human 1321N1 astrocytoma cells expressing a recombinant P2Y2 receptor to assess the role of this receptor in the regulation of anti‐apoptotic (bcl‐2 and bcl‐xl) and pro‐apoptotic (bax) gene expression. Acute treatment with the P2Y2 receptor agonist UTP up‐regulated bcl‐2 and bcl‐xl, and down‐regulated bax, gene expression. Activation of P2Y2 receptors was also coupled to the phosphorylation of cyclic AMP responsive element binding protein that positively regulates bcl‐2 and bcl‐xl gene expression. Cyclic AMP responsive element decoy oligonucleotides markedly attenuated the UTP‐induced increase in bcl‐2 and bcl‐xl mRNA levels. Activation of P2Y2 receptors induced the phosphorylation of the pro‐apoptotic factor Bad and caused a reduction in bax/bcl‐2 mRNA expression ratio. All these signaling pathways are known to be involved in cell survival mechanisms. Using cDNA microarray analysis and RT–PCR, P2Y2 receptors were found to up‐regulate the expression of genes for neurotrophins, neuropeptides and growth factors including nerve growth factor 2; neurotrophin 3; glia‐derived neurite‐promoting factor, as well as extracellular matrix proteins CD44 and fibronectin precursor – genes known to regulate neuroprotection. Consistent with this observation, conditioned media from UTP‐treated 1321N1 cells expressing P2Y2 receptors stimulated the outgrowth of neurites in PC‐12 cells. Taken together, our results suggest an important novel role for the P2Y2 receptor in survival and neuroprotective mechanisms under pathological conditions.
Chronometric readout from a memory trace: gamma‐frequency field stimulation recruits timed recurrent activity in the rat CA3 network
Authors: Fujisawa Shigeyoshi , Matsuki Norio , Ikegaya Yuji
Published: September 2004

Synchronous population activity is prevalent in neurones of the central nervous system and experimentally captured as oscillatory electric fields, the frequency of which can represent the state of the neural circuit, e.g. theta (∼5 Hz) and gamma (∼40 Hz). Such field oscillations, however, are not merely a result of coherent neuronal activity. They may also play active roles in information processing in the brain. In this study, we observed that, in cultured hippocampal slices, CA3 pyramidal cells responded to single‐pulse stimuli with monosynaptic and polysynaptic potentials and firing spikes which occurred after variable latencies. The variability of the spike latencies was greatly reduced in the presence of weak electric field oscillations, especially the oscillation in the gamma‐band frequency range, that per se induced only small fluctuations in the subthreshold membrane potential, and this effect was inhibited by blockade of NMDA receptor activity. Furthermore, the latency of the firing spikes changed if the stimulus was applied at a different phase of the imposed gamma oscillations. These results may suggest that the background field oscillations serve as an extracellular time reference and assure accurate and stable decoding of a memory trace present in cortical feedback networks.
Effect of exercise training on endothelium‐derived nitric oxide function in humans
Authors: Green Daniel J. , Maiorana Andrew , O'Driscoll Gerry , Taylor Roger
Published: September 2004

Vascular endothelial function is essential for maintenance of health of the vessel wall and for vasomotor control in both conduit and resistance vessels. These functions are due to the production of numerous autacoids, of which nitric oxide (NO) has been the most widely studied. Exercise training has been shown, in many animal and human studies, to augment endothelial, NO‐dependent vasodilatation in both large and small vessels. The extent of the improvement in humans depends upon the muscle mass subjected to training; with forearm exercise, changes are restricted to the forearm vessels while lower body training can induce generalized benefit. Increased NO bioactivity with exercise training has been readily and consistently demonstrated in subjects with cardiovascular disease and risk factors, in whom antecedent endothelial dysfunction exists. These conditions may all be associated with increased oxygen free radicals which impact on NO synthase activity and with which NO reacts; repeated exercise and shear stress stimulation of NO bioactivity redresses this radical imbalance, hence leading to greater potential for autacoid bioavailability. Recent human studies also indicate that exercise training may improve endothelial function by up‐regulating eNOS protein expression and phosphorylation. While improvement in NO vasodilator function has been less frequently found in healthy subjects, a higher level of training may lead to improvement. Regarding time course, studies indicate that short‐term training increases NO bioactivity, which acts to homeostatically regulate the shear stress associated with exercise. Whilst the increase in NO bioactivity dissipates within weeks of training cessation, studies also indicate that if exercise is maintained, the short‐term functional adaptation is succeeded by NO‐dependent structural changes, leading to arterial remodelling and structural normalization of shear. Given the strong prognostic links between vascular structure, function and cardiovascular events, the implications of these findings are obvious, yet many unanswered questions remain, not only concerning the mechanisms responsible for NO bioactivity, the nature of the cellular effect and relevance of other autacoids, but also such practical questions as the optimal intensity, modality and volume of exercise training required in different populations.