Showing papers by "University of Bern published in 1998"

Chemokines and leukocyte traffic

Abstract: Over the past ten years, numerous chemokines have been identified as attractants of different types of blood leukocytes to sites of infection and inflammation. They are produced locally in the tissues and act on leukocytes through selective receptors. Chemokines are now known to also function as regulatory molecules in leukocyte maturation, traffic and homing of lymphocytes, and the development of lymphoid tissues.

von Willebrand Factor–Cleaving Protease in Thrombotic Thrombocytopenic Purpura and the Hemolytic–Uremic Syndrome

Abstract: Background Thrombotic thrombocytopenic purpura and the hemolytic–uremic syndrome are severe microvascular disorders of platelet clumping with similar signs and symptoms. Unusually large multimers of von Willebrand factor, capable of agglutinating circulating platelets under high shear stress, occur in the two conditions. We investigated the prevalence of von Willebrand factor–cleaving protease deficiency in patients with familial and nonfamilial forms of these disorders. Methods Plasma samples were obtained from 53 patients with thrombotic thrombocytopenic purpura or hemolytic–uremic syndrome. Von Willebrand factor–cleaving protease was assayed in diluted plasma samples with purified normal von Willebrand factor as the substrate. The extent of the degradation of von Willebrand factor was assessed by electrophoresis in sodium dodecyl sulfate–agarose gels and immunoblotting. To determine whether an inhibitor of von Willebrand factor–cleaving protease was present, we measured the protease activity in normal ...

The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions.

Abstract: T cells infiltrating inflammatory sites are usually of the activated/memory type. The precise mechanism for the positioning of these cells within tissues is unclear. Adhesion molecules certainly play a role; however, the intricate control of cell migration appears to be mediated by numerous chemokines and their receptors. Particularly important chemokines for activated/memory T cells are the CXCR3 ligands IP-10 and Mig and the CCR5 ligands RANTES, macrophage inflammatory protein-1alpha, and macrophage inflammatory protein-1beta. We raised anti-CXCR3 mAbs and were able to detect high levels of CXCR3 expression on activated T cells. Surprisingly, a proportion of circulating blood T cells, B cells, and natural killer cells also expressed CXCR3. CCR5 showed a similar expression pattern as CXCR3, but was expressed on fewer circulating T cells. Blood T cells expressing CXCR3 (and CCR5) were mostly CD45RO+, and generally expressed high levels of beta1 integrins. This phenotype resembled that of T cells infiltrating inflammatory lesions. Immunostaining of T cells in rheumatoid arthritis synovial fluid confirmed that virtually all such T cells expressed CXCR3 and approximately 80% expressed CCR5, representing high enrichment over levels of CXCR3+ and CCR5+ T cells in blood, 35 and 15%, respectively. Analysis by immunohistochemistry of various inflamed tissues gave comparable findings in that virtually all T cells within the lesions expressed CXCR3, particularly in perivascular regions, whereas far fewer T cells within normal lymph nodes expressed CXCR3 or CCR5. These results demonstrate that the chemokine receptor CXCR3 and CCR5 are markers for T cells associated with certain inflammatory reactions, particularly TH-1 type reactions. Moreover, CXCR3 and CCR5 appear to identify subsets of T cells in blood with a predilection for homing to these sites.

Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation

Abstract: Dendritic cells (DC) migrate into inflamed peripheral tissues where they capture antigens and, following maturation, to lymph nodes where they stimulate T cells. To gain insight into this process we compared chemokine receptor expression in immature and mature DC. Immature DC expressed CCR1, CCR2, CCR5 and CXCR1 and responded to their respective ligands, which are chemokines produced at inflammatory sites. Following stimulation with LPS or TNF-alpha maturing DC expressed high levels of CCR7 mRNA and acquired responsiveness to the CCR7 ligand EBI1 ligand chemokine (ELC), a chemokine produced in lymphoid organs. Maturation also resulted in up-regulation of CXCR4 and down-regulation of CXCR1 mRNA, while CCR1 and CCR5 mRNA were only marginally affected for up to 40 h. However, CCR1 and CCR5 were lost from the cell surface within 3 h, due to receptor down-regulation mediated by chemokines produced by maturing DC. A complete down-regulation of CCR1 and CCR5 mRNA was observed only after stimulation with CD40 ligand of DC induced to mature by LPS treatment. These different patterns of chemokine receptors are consistent with "inflammatory" and "primary response" phases of DC function.

Bisphosphonates: Mechanisms of Action

Abstract: I. Introduction II. Chemistry III. Effects in Vivo A. Inhibition of calcification B. Inhibition of bone resorption C. Effects on bone formation D. Effects on noncalcified tissues IV. Mechanisms of Action A. Calcification B. Bone resorption C. Other effects V. Pharmacokinetics VI. Animal Toxicology and Human Adverse Events A. Animal toxicology B. Human adverse events VII. Conclusion

The Influence of Method of Administration and Covariates on the Pharmacokinetics of Propofol in Adult Volunteers

Abstract: Background: Unresolved issues with propofol include whether the pharmacokinetics are linear with dose, are influenced by method of administration (bolus vs. infusion), or are influenced by age. Recently, a new formulation of propofol emulsion, containing disodium edetate (EDTA), was introduced in the United States. Addition of EDTA was found by the manufacturer to significantly reduce bacterial growth. This study investigated the influences of method of administration, infusion rate, patient covariates, and EDTA on the pharmacokinetics of propofol.

CCR5 is characteristic of Th1 lymphocytes

Abstract: CD4+ lymphocytes can be assigned to two subsets1 Th1 lymphocytes secrete interferon gamma (IFNγ) and lymphotoxin, promoting cell-mediated immunity to intracellular pathogens; and Th2 lymphocytes secrete interleukins 4 and 5 (IL-4 and IL-5), which function in allergy and humoral immunity to parasites Th2 lymphocytes preferentially express the chemokine receptor CCR3 (23) We have studied the occurrence of two additional chemokine receptors, CCR5 and CXCR3, in human, antigen-specific CD4+ Th1 and Th2 cell clones4

B Cell–attracting Chemokine 1, a Human CXC Chemokine Expressed in Lymphoid Tissues, Selectively Attracts B Lymphocytes via BLR1/CXCR5

Abstract: Although most leukocytes, T lymphocytes in particular, respond to several different chemokines, there is virtually no information on chemokine activities and chemokine receptors in B lymphocytes. A putative chemokine receptor, BLR1, that is expressed in Burkitt's lymphoma cells and B lymphocytes was cloned a few years ago. Deletion of the gene for BLR1 yielded mice with abnormal primary follicles and germinal centers of the spleen and Peyer's patches, reflecting the inability of B lymphocytes to migrate into B cell areas. By screening expressed sequence tag DNA sequences, we have identified a CXC chemokine, termed B cell–attracting chemokine 1 (BCA-1), that is chemotactic for human B lymphocytes. BCA-1 cDNA encodes a protein of 109 amino acids with a leader sequence of 22 residues. The mature protein shares 23–34% identical amino acids with known CXC chemokines and is constitutively expressed in secondary lymphoid organs. BCA-1 was chemically synthesized and tested for activity on murine pre–B cells 300-19 transfected with BLR1 and on human blood B lymphocytes. In transfected cells, BCA-1 induced chemotaxis and Ca2+ mobilization demonstrating that it acts via BLR1. Under the same conditions, no activity was obtained with 10 CXC and 19 CC chemokines, lymphotactin, neurotactin/fractalkine and several other peptide ligands. BCA-1 was also a highly effective attractant for human blood B lymphocytes (which express BLR1), but was inactive on freshly isolated or IL-2–stimulated T lymphocytes, monocytes, and neutrophils. In agreement with the nomenclature rules for chemokine receptors, we propose the term CXCR5 for BLR1. Together with the observed disturbance of B cell colonization in BLR1/ CXCR5-deficient mice, the present results indicate that chemotactic recruitment by locally produced BCA-1 is important for the development of B cell areas of secondary lymphoid tissues.

Asynchrony of Antarctic and Greenland climate change during the last glacial period

Abstract: A central issue in climate dynamics is to understand how the Northern and Southern hemispheres are coupled during climate events. The strongest of the fast temperature changes observed in Greenland (so-called Dansgaard–Oeschger events) during the last glaciation have an analogue in the temperature record from Antarctica. A comparison of the global atmospheric concentration of methane as recorded in ice cores from Antarctica and Greenland permits a determination of the phase relationship (in leads or lags) of these temperature variations. Greenland warming events around 36 and 45 kyr before present lag their Antarctic counterpart by more than 1 kyr. On average, Antarctic climate change leads that of Greenland by 1–2.5 kyr over the period 47–23 kyr before present.

Bone response to unloaded and loaded titanium implants with a sandblasted and acid-etched surface : A histometric study in the canine mandible

Abstract: Many dental clinical implant studies have fo- cused on the success of endosseous implants with a variety of surface characteristics. Most of the surface alterations have been aimed at achieving greater bone-to-implant con- tact as determined histometrically at the light microscopic level. A previous investigation in non-oral bone under short- term healing periods (3 and 6 weeks) indicated that a sand- blasted and acid-etched titanium (SLA) implant had a greater bone-to-implant contact than did a comparably- shaped implant with a titanium plasma-sprayed (TPS) sur- face. In this canine mandible study, nonsubmerged implants with a SLA surface were compared to TPS-coated implants under loaded and nonloaded conditions for up to 15 months. Six foxhound dogs had 69 implants placed in an alternating pattern with six implants placed bilaterally in each dog. Gold crowns that mimicked the natural occlusion were fabricated for four dogs. Histometric analysis of bone contact with the implants was made for two dogs after 3 months of healing (unloaded group), 6 months of healing (3 months loaded), and after 15 months of healing (12 months loaded). The SLA implants had a significantly higher (p < 0.001) percentage of bone-to-implant contact than did the TPS implants after 3 months of healing (72.33 ± 7.16 versus 52.15 ± 9.19; mean ± SD). After 3 months of loading (6 months of healing) no significant difference was found be- tween the SLA and TPS surfaced implants (68.21 ± 10.44 and 78.18 ± 6.81, respectively). After 12 months of loading (15 months of healing) the SLA implants had a significantly greater percentage (p < 0.001) of bone-to-implant contact than did the TPS implants (71.68 ± 6.64 and 58.88 ± 4.62, respectively). No qualitative differences in bone tissue were observed between the two groups of implants nor was there any difference between the implants at the clinical level. These results are consistent with earlier studies on SLA im- plants and suggest that this surface promotes greater osse- ous contact at earlier time points compared to TPS-coated implants. © 1998 John Wiley & Sons, Inc. J Biomed Mater Res, 40, 1-11, 1998.

Doubling the critical temperature of La1.9Sr0.1CuO4 using epitaxial strain

Abstract: The discovery1 of high-temperature superconductivity in copper oxides raised the possibility that superconductivity could be achieved at room temperature. But since 1993, when a critical temperature (T c) of 133 K was observed in the HgBa2Ca2Cu3O8+δ (ref. 2), no further progress has been made in raising the critical temperature through material design. It has been shown, however, that the application of hydrostatic pressure can raise T c — up to ∼164 K in the case of HgBa2Ca2Cu3O8+δ (ref. 3). Here we show, by analysing the uniaxial strain and pressure derivatives of T c, that compressive epitaxial strain in thin films of copper oxide superconductors could in principle generate much larger increases in the critical temperature than obtained by comparable hydrostatic pressures. We demonstrate the experimental feasibility of this approach for the compound La1.9Sr0.1CuO4, where we obtain a critical temperature of 49 K in strained single-crystal thin films — roughly double the bulk value of 25 K. Furthermore, the resistive behaviour at low temperatures (but above T c) of the strained samples changes markedly, going from insulating to metallic.

Mutations in PROP1 cause familial combined pituitary hormone deficiency

Abstract: Combined pituitary hormone deficiency (CPHD) in man denotes impaired production of growth hormone (GH) and one or more of the other five anterior pituitary hormones. Mutations of the pituitary transcription factor gene POU1F1 (the human homologue of mouse Pit1) are responsible for deficiencies of GH, prolactin and thyroid stimulating hormone (TSH) in Snell and Jackson dwarf mice and in man, while the production of adrenocorticotrophic hormone (ACTH), luteiniz-ing hormone (LH) and follicle stimulating hormone (FSH) is preserved. The Ames dwarf (df) mouse displays a similar phenotype, and appears to be epistatic to Snell and Jackson dwarfism. We have recently positionally cloned the putative Ames dwarf gene Prop1 (ref. 1)f which encodes a paired-like homeodomain protein that is expressed specifically in embryonic pituitary and is necessary for Pit1 expression. In this report we have identified four CPHD families with homozy-gosity or compound heterozygosity for inactivating mutations of PROP1. These mutations in the human PROP1 gene result in a gene product with reduced DNA-binding and transcriptional activation ability in comparison to the product of the murine df mutation. In contrast to individuals with POU1F1 mutations, those with PROP1 mutations cannot produce LH and FSH at a sufficient level and do not enter puberty spontaneously. Our results identify a major cause of CPHD in humans and suggest a direct or indirect role for PROP1 in the ontogenesis of pituitary gonadotropes, as well as somatotropes, lactotropes and caudomedial thyrotropes.

Manufacturing Growth and Financial Development: Evidence from OECD Countries

Abstract: Recent theoretical models conjecture that the development of the financial sector is essential for economic growth. We investigate this hypothesis from a time-series perspective and find that financial sector GDP is cointegrated for many OECD countries not so much with manufacturing GDP but mostly with manufacturing total factor productivity. Moreover, this relation is in some instances characterized by long-run causality in the sense of Granger and Lin. However, even within this homogeneous group of countries, the variety of results suggests a more complex picture than is apparent from cross-sectional evidence.

The Seesaw Effect

Abstract: What are the origins of past, present, and future climate change? In his Perspective, Stocker discusses ways in which the climate system can act like a seesaw, as the high northern latitudes push and pull against the Southern Hemisphere to create abrupt shifts. Stocker briefly discusses a report in the same issue by Steig et al., showing that Northern and Southern Hemisphere climate shifts act in synchrony. A related Perspective by Cane looks at the role of the tropics in paleoclimate. Recent observations and model calculations indicate that effects of climate change in the tropical latitudes merit a closer look.

A new algorithm for error-tolerant subgraph isomorphism detection

Abstract: We propose a new algorithm for error-correcting subgraph isomorphism detection from a set of model graphs to an unknown input graph. The algorithm is based on a compact representation of the model graphs. This representation is derived from the set of model graphs in an off-line preprocessing step. The main advantage of the proposed representation is that common subgraphs of different model graphs are represented only once. Therefore, at run time, given an unknown input graph, the computational effort of matching the common subgraphs for each model graph onto the input graph is done only once. Consequently, the new algorithm is only sublinearly dependent on the number of model graphs. Furthermore, the new algorithm can be combined with a future cost estimation method that greatly improves its run-time performance.

Heterogeneous production of nitrous acid on soot in polluted air masses

Abstract: Polluted air masses are characterized by high concentrations of oxidized nitrogen compounds which are involved in photochemical smog and ozone formation. The OH radical is a key species in these oxidation processes. The photolysis of nitrous acid (HNO2), in the morning, leads to the direct formation of the OH radical and may therefore contribute significantly to the initiation of the daytime photochemistry in the polluted planetary boundary layer. But the formation of nitrous acid remains poorly understood: experimental studies imply that a suggested heterogeneous formation process involving NO2 is not efficient enough to explain the observed night-time build-up of HNO2 in polluted air masses1. Here we describe kinetic investigations which indicate that the heterogeneous production of HNO2 from NO2 on suspended soot particles proceeds 105 to 107 times faster than on previously studied surfaces. We therefore propose that the interaction between NO2 and soot particles may account for the high concentrations of HNO2 in air masses where combustion sources contribute to air pollution by soot and NOx emissions. We believe that the observed HNO2 formation results from the reduction of NO2 in the presence of water by C–O and C–H groups in the soot. Although prolonged exposure to oxidizing agents in the atmosphere is likely to affect the chemical activity of these groups, our observations nevertheless suggest that fresh soot may have a considerable effect on the chemical reactions occurring in polluted air.

The cell-surface heparan sulfate proteoglycan glypican-1 regulates growth factor action in pancreatic carcinoma cells and is overexpressed in human pancreatic cancer.

Abstract: Heparan sulfate proteoglycans (HSPGs) play diverse roles in cell recognition, growth, and adhesion. In vitro studies suggest that cell-surface HSPGs act as coreceptors for heparin-binding mitogenic growth factors. Here we show that the glycosylphosphatidylinositol- (GPI-) anchored HSPG glypican-1 is strongly expressed in human pancreatic cancer, both by the cancer cells and the adjacent fibroblasts, whereas expression of glypican-1 is low in the normal pancreas and in chronic pancreatitis. Treatment of two pancreatic cancer cell lines, which express glypican-1, with the enzyme phosphoinositide-specific phospholipase-C (PI-PLC) abrogated their mitogenic responses to two heparin-binding growth factors that are commonly overexpressed in pancreatic cancer: fibroblast growth factor 2 (FGF2) and heparin-binding EGF-like growth factor (HB-EGF). PI-PLC did not alter the response to the non-heparin-binding growth factors EGF and IGF-1. Stable expression of a form of glypican-1 engineered to possess a transmembrane domain instead of a GPI anchor conferred resistance to the inhibitory effects of PI-PLC on growth factor responsiveness. Furthermore, transfection of a glypican-1 antisense construct attenuated glypican-1 protein levels and the mitogenic response to FGF2 and HB-EGF. We propose that glypican-1 plays an essential role in the responses of pancreatic cancer cells to certain mitogenic stimuli, that it is relatively unique in relation to other HSPGs, and that its expression by pancreatic cancer cells may be of importance in the pathobiology of this disorder.

Moderately High Temperatures Inhibit Ribulose-1,5-Bisphosphate Carboxylase/Oxygenase (Rubisco) Activase-Mediated Activation of Rubisco

Abstract: We tested the hypothesis that light activation of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) is inhibited by moderately elevated temperature through an effect on Rubisco activase. When cotton (Gossypium hirsutum L.) or wheat (Triticum aestivum L.) leaf tissue was exposed to increasing temperatures in the light, activation of Rubisco was inhibited above 35 and 30°C, respectively, and the relative inhibition was greater for wheat than for cotton. The temperature-induced inhibition of Rubisco activation was fully reversible at temperatures below 40°C. In contrast to activation state, total Rubisco activity was not affected by temperatures as high as 45°C. Nonphotochemical fluorescence quenching increased at temperatures that inhibited Rubisco activation, consistent with inhibition of Calvin cycle activity. Initial and maximal chlorophyll fluorescence were not significantly altered until temperatures exceeded 40°C. Thus, electron transport, as measured by Chl fluorescence, appeared to be more stable to moderately elevated temperatures than Rubisco activation. Western-blot analysis revealed the formation of high-molecular-weight aggregates of activase at temperatures above 40°C for both wheat and cotton when inhibition of Rubisco activation was irreversible. Physical perturbation of other soluble stromal enzymes, including Rubisco, phosphoribulokinase, and glutamine synthetase, was not detected at the elevated temperatures. Our evidence indicates that moderately elevated temperatures inhibit light activation of Rubisco via a direct effect on Rubisco activase.

Lymphocyte‐specific chemokine receptor CXCR3: regulation, chemokine binding and gene localization

Abstract: Expression of CXCR3, the receptor for the CXC chemokines IFN-gamma-inducible 10-kDa protein (IP10) and monokine induced by IFN-gamma (Mig), in human T lymphocytes and their responses to IP10 and Mig were analyzed. About 40 % of resting T lymphocytes (and low numbers of B cells and natural killer cells) stained positive for CXCR3 but these cells did not express CXCR3 transcripts and did not respond to these chemokines. However, treatment with IL-2 with or without addition of phytohemagglutinin for 10 or more days resulted in cultures of fully responsive, CXCR3-positive T lymphocytes. Treatment with anti-CD3 antibodies in the presence or absence of soluble anti-CD28 antibodies was inhibitory. Addition of chondroitin sulfate C to CXCR3-expressing murine pre-B cells allowed the determination of high-affinity binding for Mig and IP10 with Kd of 0.9-1.2 nM and 0.2-0.3 nM, respectively, and 1.3 x 10(4) binding sites per cell. The gene for CXCR3 was localized on human chromosome Xq13 which is in clear contrast to all other chemokine receptor genes, suggesting unique function(s) for this receptor and its ligands that may lie beyond their established role in T cell-dependent immunity.

Synchronous Holocene climatic oscillations recorded on the Swiss Plateau and at timberline in the Alps

Abstract: Eight synchronous pre-Roman cold phases were found at 9600–9200, 8600–8150, 7550–6900, 6600– 6200, 5350–4900, 4600–4400, 3500–3200 and 2600–2350 radiocarbon years BP by reconstructing past climate at two sites on the Swiss Plateau and at timberline in the Alps. The cooling events during the early-and mid-Holocene represent temperature values similar to today, and apparently the onset of cooling events represents a deviation from today's mean annual temperature of about 1°C and is triggered at a 1000-year periodicity. At Wallisellen-Langachermoos (440 m), a former oligotrophic lake near Zurich, the correlation between sum mertime lake levels and the seed production of the amphi-Atlantic aquatic plantNajas flexilis was used to reconstruct lake levels over a 3000-year period during the first part of the Holocene. At Lake Seedorf on the western Swiss Plateau (609 m) the sedimentological, palynological and macrofossil record revealed fluctuations of lake levels for the complete Holocene. From Lago Basso in the...

The chemokine SLC is expressed in T cell areas of lymph nodes and mucosal lymphoid tissues and attracts activated T cells via CCR7

Abstract: Secondary lymphoid-tissue chemokine, SLC, also known as exodus-2 and 6Ckine, is a novel CC chemokine with selectivity for T lymphocytes and preferential expression in lymphoid tissues. We have studied its production, receptor usage and biological activities. High levels of SLC mRNA were detected in lymph nodes, the gastrointestinal tract and several gland tissues, but no expression was found by Northern blot analysis in freshly isolated or stimulated blood monocytes and lymphocytes, or neutrophils and eosinophils. In situ hybridization revealed constitutive expression of SLC in the T cell areas and the marginal zone of follicles in lymph nodes and the mucosa-associated lymphoid tissue, but not in B cell areas or sinuses. Comparison with immunocytochemical staining showed similarity between the in situ expression of SLC and the distribution of interdigitating dendritic cells but not with sinus-lining dendritic cells, macrophages or T lymphocytes. SLC induced chemotaxis of T lymphocytes and its activity increased considerably when the cells were conditioned with IL-2 or phytohemagglutinin (PHA). Under optimal conditions SLC had unusually high efficacy and induced the migration of up to 50 % of input T lymphocytes. SLC also induced Ca2+ mobilization in these cells. Similar responses were obtained with EBI1 ligand chemokine (ELC), and sequential stimulation with both chemokines led to cross-desensitization, suggesting that SLC acts via the ELC receptor, CCR7. This was confirmed using murine pre-B cells stably transfected with CCR7 which bound SLC with high affinity and showed chemotaxis and Ca2+ mobilization in response to both SLC and ELC. In T lymphocytes PHA and IL-2, which enhanced chemotactic responsiveness, also markedly enhanced CCR7 expression. In contrast to all known chemokine receptors, up-regulation of CCR7 by IL-2 was transient. A maximum was reached in 2-3 days and expression returned to initial levels within 8-10 days. The present study shows that SLC is constitutively produced within the T cell areas of secondary lymphoid organs and attracts T lymphocytes via CCR7.

Cigarette Smoking and Periodontal Diseases: Etiology and Management of Disease

Abstract: Cigarette smoking has long been suspected to be associated with a variety of oral conditions including periodontal diseases. Experimental evidence accumulated over the last 2 decades has indicated that cigarette smoking is probably a true risk factor for periodontitis. This environmental exposure has been associated with 2- to 3-fold increases in the odds of developing clinically detectable periodontitis. Smokers have both increased prevalence and more severe extent of periodontal disease, as well as higher prevalence of tooth loss and edentulism, compared to non-smokers. The greater severity of periodontal destruction may be partly accounted for by the reported increases in the rate of periodontal disease progression. The noxious effect of smoking has been shown to be dose dependent and to be particularly marked in younger individuals; in these subjects, up to 51% of the observed risk of periodontitis was associated with smoking. Much of the literature has also indicated that smokers affected with periodontitis respond less favorably to both non-surgical, surgical, and regenerative periodontal treatments. The success rate of dental implants has also been shown to be compromised in smokers. Furthermore, longterm studies have pointed out that smoking was associated with recurrence of periodontitis during periodontal maintenance; the effect appeared to be dose dependent, with heavy smokers (> 10 cigarettes/day) presenting with higher levels of disease progression. The indication that previous smokers have lower levels of risk for periodontitis compared to current smokers is considered to be the strongest available evidence that smoking cessation will result in improved periodontal health and that smoking cessation counseling should be an integral part of periodontal therapy and prevention. So far, however, no randomized controlled clinical trial establishing the effect of smoking cessation and/or reduction on the periodontal outcomes has been reported. Given the present state of uncertainty about the periodontal benefits, but in light of the established general health gains for the patient that could be derived from a smoking cessation program, practitioners are incorporating smoking cessation counseling as an integral part of periodontal therapy. Furthermore, smoking status represents a key parameter to assess the periodontal risk of an individual subject and therefore to make evidence-based clinical decisions.

Effects of inhibition of prostaglandin endoperoxide synthase-2 in chronic gastro-intestinal ulcer models in rats

Abstract: 1. In the stomach, prostaglandins protect the gastric mucosa against injuries. One rate-limiting step in prostaglandin synthesis is mediated by prostaglandin endoperoxide synthase (PGHS), the target enzyme of non-steroidal anti-inflammatory drugs (NSAIDs). Two isoforms of PGHS exist: a constitutive (PGHS-1) and an inducible (PGHS-2) enzyme. PGHS-1 is the major source of gastric prostaglandins under physiological conditions. Inhibition of prostaglandin synthesis by traditional NSAIDs such as indomethacin and diclofenac which non-selectively inhibit both PGHS-1 and PGHS-2, causes gastric and intestinal ulceration and delays gastric ulcer healing in chronic models. It has been shown that selective PGHS-2 inhibitors such as L-745,337 (5-methanesulphonamide-6-(2,4-difluorothio-phenyl)-1-inda none) are not ulcerogenic and do not inhibit gastro-intestinal prostaglandin synthesis. However, minimal information is available on the long-term effects of PGHS-2 inhibitors on the healing of previously established gastric injuries. We assessed the cellular localization and expression of PGHS-1 and PGHS-2 during gastric ulcer healing and assessed the effects of L-745,337 on previously established cryoulcers in the rat gastric stomach. 2. PGHS-1 and PGHS-2 were located and quantified by immunohistochemistry during experimental gastric ulcer healing. PGHS-2 immunoreactivity was only negligible in the normal gastric wall, but after gastric ulcerations, it was strongly detected in monocytes, macrophages, fibroblasts and endothelial cells below and between the regenerative glands. PGHS-1 immunoreactivity detected in normal gastric mucosa, disappeared after gastric ulceration in the mucosa adjacent to the ulcer crater. However, it reappeared in the regenerative glands from day 5 onwards. Thus, PGHS-1 and PGHS-2 were located at different sites and their maximal expression followed a different time-sequence. 3. We assessed the effects of L-745,337, indomethacin and diclofenac on gastric ulcer healing and histological healing parameters in rats. L-745,337, indomethacin and diclofenac dose-dependently decreased the healing of gastric ulcers. L-745,337, indomethacin and diclofenac decreased epithelial cell proliferation in the ulcer margin and microvessel density in the ulcer bed on day 8 and increased the thickness of the granulation tissue below the ulcer crater and the gap between both edges of the muscularis mucosae on day 15. Indomethacin and diclofenac, but not L-745,337, decreased synthesis of 6-keto-PGF1alpha and PGE2 in tissue fragments from the stomach and terminal ileum and decreased platelet thromboxane B2 synthesis in clotting whole blood. 4. Dose-response curves for the inhibition of chronic gastric ulcer healing by L-745,337 (administered twice daily intragastrically) showed an ID50 value of 1.7 mg (4.3 micromol) kg(-1). Dose-response curves for the inhibition of PGE2 synthesis in inflammatory exudates in the acute carrageenin sponge rat model, showed ID50 values of 1.1 mg (3.1 micromol) kg(-1) and 1.3 (3.3 micromol) mg kg(-1) for indomethacin and L-745,337, respectively. Thus, inhibition of chronic gastric ulcer healing by L-745,337 occurs within a potentially therapeutic dose-range. 5. In summary, PGHS-2 is markedly accumulated after gastric ulceration in monocytes, macrophages, fibroblasts and endothelial cells in regions of maximal repair activity. Selective inhibition of PGHS-2 by L-745,337 delayed gastric ulcer healing though interference with epithelial cell proliferation, angiogenesis and maturation of granulation tissue in a potentially therapeutic dose range. PGHS-2-derived prostaglandins seem to have an important role in gastric ulcer healing.

Establishing human prostate cancer cell xenografts in bone: Induction of osteoblastic reaction by prostate‐specific antigen‐producing tumors in athymic and SCID/bg mice using LNCaP and lineage‐derived metastatic sublines

Abstract: LNCaP lineage-derived human prostate cancer cell lines C4-2 and C4-2B4 acquire androgen independence and osseous metastatic potential in vivo. Using C4-2 and C4-2B4 the goals of the current investigation were 1) to establish an ideal bone xenograft model for prostate cancer cells in intact athymic or SCID/bg mice using an intraosseous route of tumor cell administration and 2) to compare prostate cancer metastasis by administering cells either through intravenous (i.v.) or intracardiac administration in athymic or SCID/bg mice. Subsequent to tumor cell administration, prostate cancer growth in the skeleton was assessed by radiographic bone density, serum prostate-specific antigen (PSA) levels, presence of hematogenous prostate cancer cells and histopathologic evaluation of tumor specimens in the lymph node and skeleton. Our results show that whereas LNCaP cells injected intracardially failed to develop metastasis, C4-2 cells injected similarly had the highest metastatic capability in SCID/bg mice. Retroperitoneal and mediastinal lymph node metastases were noted in 3/7 animals, whereas 2/7 animals developed osteoblastic spine metastases. Intracardiac injection of C4-2 in athymic hosts produced spinal metastases in 1/5 animals at 8-12 weeks post-injection; PC-3 injected intracardially also metastasized to the bone but yielded osteolytic responses. Intravenous injection of either LNCaP or C4-2 failed to establish tumor colonies. Intrailiac injection of C4-2 but not LNCaP nor C4-2B4 cells in athymic mice established rapidly growing tumors in 4/8 animals at 2-7 weeks after inoculation. Intrafemoral injection of C4-2 (9/16) and C4-2B4 (5/18) but not LNCaP (0/13) cells resulted in the development of osteoblastic bone lesions in athymic mice (mean: 6 weeks, range: 3-12 weeks). In SCID/bg mice, intrafemoral injection of LNCaP (6/8), C4-2 (8/8) and C4-2B4 (8/8) cells formed PSA-producing, osteoblastic tumors in the bone marrow space within 3-5 weeks after tumor cell inoculation. A stepwise increase of serum PSA was detected in all animals. Reverse transcription-polymerase chain reaction (RT-PCR) to detect hematogenously disseminated prostate cancer cells could not be correlated to either serum PSA level or histological evidence of tumor cells in the marrow space. We have thus established a PSA-producing and osteoblastic human prostate cancer xenograft model in mice.

The relationship between air and water temperatures in lakes of the Swiss Plateau: a case study with palæolimnological implications

Abstract: In palaeolimnological studies, inference models based on aquatic organisms are frequently used to estimate summer lake surface water temperatures. However, the calibration of such models is often unsatisfactory because of the sparseness of measured water temperature data. This study investigates the feasibility of using air temperature data, usually available at much higher resolution, to calibrate such models by comparing regional air temperatures with surface water temperatures in 17 lakes on the Swiss Plateau. Results show that altitude-corrected air temperatures are sufficiently uniform over the entire Swiss Plateau to allow local air temperatures at any particular lake site to be adequately estimated from standard composite air temperature series. In early summer, day-to-day variability in air temperature is reflected extremely well in the temperature of the uppermost metre of the water column, while monthly mean air temperatures correspond well, with respect to both absolute value and interannual variations, with water temperatures in most of the epilimnion. Standardised altitude-corrected air temperature series may therefore be a useful alternative to surface water temperatures for the purposes of calibrating lake temperature inference models. In Northern Hemisphere temperate regions, mean air and water temperatures are likely to correspond most closely in July, suggesting that calibration and reconstruction efforts be concentrated on this month.