Gastrointestinal symptoms in low-dose aspirin users: a comparison between plain and buffered aspirin.

BACKGROUND: Aspirin is associated with gastrointestinal side effects such as gastric ulcers, gastric bleeding and dyspepsia. High-dose effervescent calcium carbasalate (ECC), a buffered formulation of aspirin, is associated with reduced gastric toxicity compared with plain aspirin in healthy volunteers, but at lower cardiovascular doses no beneficial effects were observed. AIM: To compare the prevalence of self-reported gastrointestinal symptoms between low-dose plain aspirin and ECC. METHODS: A total of 51,869 questionnaires were sent to a representative sample of the Dutch adult general population in December 2008. Questions about demographics, gastrointestinal symptoms in general and specific symptoms, comorbidity, and medication use including bioequivalent doses of ECC (100 mg) and plain aspirin (80 mg) were stated. We investigated the prevalence of self-reported gastrointestinal symptoms on ECC compared with plain aspirin using univariate and multivariate logistic regression analyses. RESULTS: A total of 16,715 questionnaires (32 %) were returned and eligible for analysis. Of these, 911 (5 %) respondents reported the use of plain aspirin, 633 (4 %) ECC and 15,171 reported using neither form of aspirin (91 %). The prevalence of self-reported gastrointestinal symptoms in general was higher in respondents using ECC (27.5 %) compared with plain aspirin (26.3 %), but did not differ significantly with either univariate (OR 1.06, 95 %CI 0.84-1.33), or multivariate analysis (aOR 1.08, 95 %CI 0.83-1.41). Also, none of the specific types of symptoms differed between the two aspirin formulations. CONCLUSIONS: In this large cohort representative of the general Dutch population, low-dose ECC is not associated with a reduction in self-reported gastrointestinal symptoms compared with plain aspirin.

Gastrointestinal symptoms in NSAID users in an 'average risk population': results of a large population-based study in randomly selected Dutch inhabitants.

AIM: Non-steroidal anti-inflammatory drug (NSAID) use is widespread and associated with gastrointestinal symptoms and complications. The aims of this study were to assess (i) gastrointestinal symptoms in users of prescribed and over-the-counter (OTC) NSAIDs and (ii) proton pump inhibitor (PPI) co-prescription rates in NSAID users at increased risk for gastrointestinal complications. METHODS: Surveys were sent to a randomly selected sample of the adult Dutch general population in December 2008. Questions included demographics, gastrointestinal symptoms, medication use and comorbidity. Main outcome measure was presence of gastrointestinal symptoms. RESULTS: A total of 18,317 surveys were returned (response rate 35%), of which 16,758 surveys were eligible for analysis. Of these, 3233 participants (19%) reported NSAID use. NSAID users more frequently reported gastrointestinal symptoms than persons not using NSAIDs (33% vs. 24%, p < 0.01). Respondents who specified on prescription NSAID use (n = 683) were older, reported more comorbidity, and experienced more gastrointestinal symptoms (41%) compared with OTC users (n = 894, 33%, p < 0.01). This difference was not statistically significant after adjustment for confounders (0.99, 95% CI 0.71-1.37). In respondents with an increased gastrointestinal risk profile, PPI co-prescription rates were 51% for on prescription users and 25% for OTC users. CONCLUSIONS: Prevalence of gastrointestinal symptoms was high in both prescribed and OTC NSAID users, emphasising the side effects of both types of NSAIDs. PPI co-prescription rates in NSAID users at risk for gastrointestinal complication were low.

Management of Root Perforations Using MTA with or without Er:YAG Laser Irradiation: An In Vitro Study.

The aim of this in vitro study is to compare the microleakage of a root perforation sealed with MTA (mineral trioxide aggregate) (group M) to that sealed with MTA following Er:YAG laser irradiation (group ML). Forty-two recently extracted human monoroot teeth were used. Two cavities were prepared on each root surface. Randomly, on each root, the exposed dentine of one cavity was irradiated prior to MTA filling using an Er:YAG laser with the following settings: 200 mJ/pulses under an air water spray, 10 Hz, pulse duration of 50 µsec, and 0.7 mm beam diameter. All cavities were then sealed with MTA. submitted to thermocycling and immersed in 2% methylene blue dye solution for 12 h. The penetration of methylene blue in the microleakage of cavity was observed and recorded. The mean value dye penetration in cavities sealed with MTA following Er:YAG laser irradiation (23.91 ± 14.63%) was lower than that of unlased cavities sealed only with MTA (25.17 ± 17.53%). No significant difference was noted. The use of an Er:YAG laser beam for dentinal conditioning prior to MTA filling of perforated roots did not decrease significantly the microleakage of MTA sealing when compared to the conventional use of MTA filling.

Effect of low fluency dentin conditioning on tensile bond strength of composite bonded to Er:YAG laser-prepared dentin: a preliminary study.

Several studies in the literature have previously shown that the bond strength of a composite bonded to dentin is almost equivalent as when dentin is prepared by either bur or Er:YAG laser. The aim of this preliminary study is to assess the hypothesis that dentin conditioning at low fluency by means of Er:YAG laser can improve the value of adhesion of composites resin to dentin. Sixty surfaces of caries-free human third molars extracted for orthodontic purposes were randomly divided into five groups of 12 teeth. The bur group was the control, prepared using bur, group L was prepared using Er:YAG 200 mJ, SSP (50 µs), 20 Hz, 15 seconds of sweeping, for groups L80, L100, L120, they were prepared first, with the same parameters of the group L 200, and then they received a conditioning, which is, respectively, 15 s of irradiations at: 80 mJ (SSP, 10 Hz), 100 mJ (SSP, 10 Hz), and 120 mJ (SSP, 10 Hz). All samples were restored in a single-component adhesive system: Xenon (DENTSPLY), and ceramX (DENTSPLY) as the resin composite. The specimens were submitted to tensile bond strength test using a universal testing machine. Data were submitted to statistical analysis using ANOVA coupled to a Tukey-Kramer test at the 95% level. The mean values in MPa were 33.3 for group B, 36.73 for group L 200, 41.7 for group L80, 37.9 for group L100, and 39.1 for group L120. Our results showed that dentin conditioning at a low fluency of 12.58 J/cm(2) per pulse, with 80 mJ output energy and 50-µs pulse duration can significantly improve tensile bond strength of a composite bonded to Er:YAG laser-prepared dentine.

[Comparative study on dogs between CO2 laser and conventional technique in direct pulp capping]. / Etude comparative concernant l'apport du laser CO2 dans le coiffage pulpaire direct vs technique conventionnelle chez le chien.

UNLABELLED: Three dogs have been used in this experiment. Class V cavities were made in sixty teeth. A pulpal communication was provoked intentionally in these cavities. Teeth were randomly split in 2 groups (30 teeth for each). On first group, the pulp bleeding was stopped until appearance of coagulum on exposed pulp surfaces by means of CO2 laser irradiation (Output Power: 3 W, Pulse duration: 0.1 sec, frequency: 1 Hz, spot size diameter: 0.3 mm, Energy density: 425 J/cm2). Calcium Dihydroxide was deposited followed by a temporary filling (IRM, Dentsply, De Trey, Germany). In the second group, the calcium Dihydroxide was deposited directly on exposed bleed pulp (conventional technique) followed by the same temporary filling. Ten weeks later, all teeth were extracted and prepared for histological study. RESULTS: 93% of treated teeth preserved their pulp vitality in the group treated with CO2 laser for direct pulp capping versus 82% in the group treated by conventional technique. The average of the thickness of the dentinal bridge newly formed was 391.5 +/- 33 microm for teeth irradiated with laser and 294.1 +/- 28 microm for teeth treated by conventional technique. The thickness of the dentinal bridge newly formed in teeth treated by means of CO2 laser was 33% more important than in those treated by the conventional technique. Statistical analysis showed a significant difference between the averages of values in all groups (p < 0.05). To conclude, CO2 Laser use in the direct pulp capping increases significantly the percentage of pulp vitality preservation and the thickness of the dentinal bridge newly formed after pulp exposition.

Comparison of microleakages of photo-cured composites using three different light sources: halogen lamp, LED and argon laser: an in vitro study.

In this study, we compared the microleakage of composite fillings cured with halogen bulb, LED and argon ion laser (488 nm). Twenty-four extracted human molars were divided randomly in three groups. Six cavities were prepared on the coronal part of each tooth. Standard cavities (1.7 x 2 mm) were prepared. Cavities were acid etched, sealed with Scotch Bond 1 and filled by a hybrid composite. Cavities were exposed to one light source, thermocycled and immersed in a 2% methylene blue dye solution. Dye penetration in the leakage of cavities was recorded using a digital optical microscope. Mean values of percentage of dye penetrations in microleakages of cavities were 49.303 +/- 5.178% for cavities cured with LED, 44.486 +/- 6.075% with halogen bulb and 36.647 +/- 5.936% for those cured by argon laser. Statistically significant difference exists between cavities cured by halogen vs LED (P < 0.01), halogen vs laser (P < 0.001) and LED vs laser (P < 0.001). The lowest microleakage was observed in the cavities and composites cured with argon ion laser.

IL-4 abrogates the inhibitory effect of IL-10 on the development of experimental allergic encephalomyelitis in SJL mice.

IL-10 and IL-4 were studied with respect to their capacity to inhibit experimental allergic encephalomyelitis (EAE) induced in SJL/J mice by immunization with the proteolipid protein peptide PLP139-151. Treatment with 2 micrograms IL-10/day from day 0 until day 12 delayed onset of disease and inhibited the severity of EAE. By contrast, a daily dose of 0.5 microgram IL-4 was ineffective. Instead of acting in a synergistic fashion, IL-4 even abrogated the inhibitory effect of IL-10. The effects of IL-10 and IL-4 treatment were largely consistent with the (lack of) ability of these cytokines to down-regulate the inflammatory response in brain tissue. Although IL-4 was ineffective in the inhibition of EAE, lymph node cells from IL-4-treated mice displayed a strongly inhibited peptide-specific IFN-gamma production. By contrast, IL-10, which was effective in inhibiting EAE, showed no significant inhibition of IFN-gamma at this level. Neither cytokine treatment resulted in detectable levels of peptide-specific IL-4. Indirect evidence for the activity of Th2 cells in vivo came from the observation that IL-10 inhibited the primary PLP139-151-specific IgG2a and IgG3 response in favor of IgG1, whereas IL-4 inhibited the primary antibody response to the peptide, regardless of subclass. The combination of IL-4 and IL-10 did not affect the subclass composition. The observation that IL-10-treated mice remained sensitive to re-induction of EAE is not in support of an important role of Th2 cells in regulating disease activity in this model of actively induced EAE.

Alertness and memory after sleep deprivation and diazepam intake.

Benzodiazepines (BZDs) give rise to memory impairments. It has been questioned whether or not these impairments are related to the drug's sedative, alertness-reducing effects. Therefore, in this study, alertness was reduced in healthy subjects both pharmacologically (15 mg diazepam) and non-pharmacologically (24-h sleep deprivation, SD) in order to assess whether these manipulations both gave rise to memory impairments. Twelve subjects were tested using a repeated measures cross-over design. Drug administration was placebo-controlled and double-blind. A subjective alertness reduction was established after diazepam intake and even more after SD. Additionally, performance-disruptive effects were found on psychomotor tasks after both SD and liazepam intake. However, only diazepam, and not SD, impaired delayed recall of a word list and recall of paired associates. Thus a reduction in alertness, i.e. sedation, cannot fully account for BZD-induced memory impairments.

Enrichment for Th1 cells in the Mel-14+ CD4+ T cell fraction in aged mice.

CD4+ T cells from young and aged mice were sorted into Mel-14+ cells which are regarded as naive cells and Mel-14- cells which are regarded as memory cells. These subsets were stimulated in short-time cultures with anti-CD3 or anti-CD3/anti-CD28 in order to determine the presence of Th1 and/or Th2 cytokines. Based on the simultaneous production of IL-2, IL-4, IL-10, and IFN-gamma upon anti-CD3 stimulation by Mel-14- cells from young and aged mice, it is concluded that this cell population comprises Th1, Th2, and/or Th0 cells. Mel-14+ cells from young mice only secrete substantial amounts of IL-2 in the presence of anti-CD28 as a costimulatory signal and can therefore be regarded as Th precursor cells. By contrast, Mel-14+ cells from aged mice responded to anti-CD3 alone, not only by the production of IL-2 but also by the production of high amounts of IFN-gamma and minute amounts of IL-4 and IL-10, suggesting that these "naive" cells in aged mice are enriched for Th1 cells. This was not due to lack of CD28 triggering since anti-CD28 enhanced IFN-gamma as well as IL-4 and IL-10 to a similar extent. Our data therefore indicate that Mel-14 is not exclusively expressed on naive CD4+ T cells.

The in vivo effects of neutralizing antibodies against IFN-gamma, IL-4, or IL-10 on the humoral immune response in young and aged mice.

In the present study we investigated whether age-related changes in the composition and functional properties of murine CD4+ T cells are reflected in vivo by a changed humoral response to influenza vaccine in aged mice. After the primary immunization, the titers of influenza-specific IgM, IgG1, IgG2a, and IgG2b, but not of IgG3 and IgE, were significantly reduced in aged mice compared to young mice. Treatment of aged mice with anti-IFN-gamma, anti-IL-4, or anti-IL-10 resulted in levels of IgM and IgG1 comparable to those found in young mice, whereas IgG2a and IgG2b were further decreased. After the booster immunization IgE was significantly enhanced in aged mice, whereas no differences were observed with regard to the other isotypes. During the primary response in young mice, anti-IFN-gamma stimulated IgG1 and IgE, whereas an inhibition of IgG2a, IgG2b, and IgG3 was observed. Anti-IL-4 caused a decrease only in IgG3 while anti-IL-10 increased IgM and IgG1 and decreased IgG2b and IgG3. During the primary response in aged mice, all anti-cytokine antibodies enhanced IgM and IgG1 while IgE was only enhanced by anti-IL-10. By contrast, IgG3 was inhibited by anti-IFN-gamma and anti-IL-10. Anti-cytokine treatment of young mice increased all isotypes, except IgG3, in the secondary response, whereas the secondary response in aged mice was largely insensitive to anti-cytokine treatment. These data therefore support the idea that the in vivo effects of cytokines on isotype switching are dependent on the differentiation stage of B cells which may be different in young and aged mice.

Mel14+ CD4+ T cells from aged mice display functional and phenotypic characteristics of memory cells.

Aging is accompanied by an increased fraction of memory CD4+ T cells. Despite the fact that human memory cells have been reported to produce high levels of IL-2, studies in mice and man indicate an age-related decline in IL-2 production. In the present study, we examined whether these conflicting results depend on the activation pathway employed in a comparison of phenotypically distinct CD4+ T cells from young and aged mice. Our data indicate an age-related decline in IL-2 production by CD4+ T cells when the cells were stimulated with concanavalin A in the presence of accessory cells or the combination of immobilized anti-CD3 and soluble anti-CD28. However, when CD4+ T cells were only stimulated with immobilized anti-CD3, an age-related increase in IL-2 production was observed. This age-related increase in IL-2 could be attributed to the ability of CD4+ T cells from aged mice to produce IL-4 on this stimulation, since anti-IL-4 inhibited the IL-2 production in these cultures to levels found with cells from young mice. The addition of exogenous IL-4 greatly enhanced the IL-2 production of CD4+ T cells from young mice to levels far beyond that of the aged counterparts, emphasizing the dominant role of IL-4 in the induction of IL-2 stimulated with immobilized anti-CD3. No differences were observed in the activation requirements of Mel14- CD4+ T cells from young and aged mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative studies on graft-versus-leukemia after allogeneic bone marrow transplantation in rat models for acute myelocytic and lymphocytic leukemia.

The major shortcoming of present day treatment of leukemia by bone marrow transplantation (BMT) remains leukemia relapse. It has become clear that a graft-versus-host reaction (GVHR) is accompanied by a graft-versus-leukemia reaction (GVLR) which may prevent leukemia relapse. In two non-immunogenic rat leukemia models, the Brown Norway acute myelocytic leukemia (BNML) and the WAG/Rij acute lymphocytic leukemia L4415, total body irradiation (TBI) was given to induce 'minimal residual disease' (MRD). Subsequently, it was attempted to evoke a GVLR by using syngeneic or allogeneic BMT, with or without addition of graded numbers of lymphocytes. In both leukemia models the addition of high numbers of syngeneic lymphocytes to the syngeneic graft had no antileukemic effect. Allogeneic marrow grafts, which contain at the most 8% lymphocytes, only resulted in a GVLR when splenocytes were added. The therapeutic window was found to be narrow, i.e. in fully mismatched BMT the number of allogeneic splenocytes resulting in a significant GVLR (2-3 log leukemic cell kill) without inducing (lethal) acute GVHD was critical. Increasing the number of allogeneic spleen cells added to the allogeneic BM graft induced lethal acute GVHD. To date, our data indicate that the GVLR is an allogeneic effect, inseparable from GVHD.

The sensitivity of IL-4 production for cAMP inducers is lost in CD4+ T cells from aged mice.

CD4+ T cell clones have been demonstrated to display a differential sensitivity for the induction of cAMP. In the present study we investigated whether the differential sensitivity of CD4+ T cell clones for cAMP inducers is also applicable to freshly isolated phenotypically and functionally distinct CD4+ T cell subsets that develop naturally in aging mice. Our results show that the concanavalin A induced and anti-CD3 induced proliferative response of CD4+ T cells from young mice is more sensitive for prostaglandin E2 (PGE2) and forskolin than that of their aged counterparts, although the IL-2 production by these cells was equally sensitive. In contrast, only a slight or no inhibitory effect of these cAMP inducers was found when the cells were stimulated with the combination of phorbol myristate acetate and ionomycin. In contrast to the findings obtained with Th2 clones, IL-4 production by freshly isolated CD4+ T cells was inhibited by the cAMP inducers, whereas exogenous IL-2 had no restorative effect. However, the IL-4 production by CD4+ T cells from aged mice was less sensitive than the IL-4 production by CD4+ T cells from young mice, although CD4+ T cells from aged mice showed significantly higher levels of intracellular cAMP in response to PGE2. These higher levels of cAMP were related to the increased fraction of memory cells in aged mice: the Mel-14- Pgp-1++ CD4+ T cells responded with at least 2-fold higher levels of intracellular cAMP than the naive cells in young as well as in aged mice. Although memory CD4+ T cells from young as well as aged mice responded vigorously to PGE2 by an enhancement of intracellular cAMP, only the IL-4 production by cells from young mice was significantly inhibited. Therefore, it is not likely that the induction of cAMP is a major event in the skewing of a primary response towards a Th2 type of response.

Role of transforming growth factor-beta in the preferential induction of T helper cells of type 1 by staphylococcal enterotoxin B.

Stimulation of murine CD4+ T cells with staphylococcal enterotoxin B (SEB) results in the preferential development of T helper (Th) 1 cells [i.e. high interferon (IFN)-gamma and low interleukin (IL)-4, IL-5 and IL-10]; whereas in response to plate-bound anti-CD3 or anti-T cell receptor-alpha beta, Th1 as well as Th2 cells develop. In the present study, we examined the mechanism which is responsible for the selective Th1 development in the SEB system. The addition of IL-4 resulted in a strong development of Th2 cells showing that SEB stimulation can result in Th2 differentiation. Co-stimulation with anti-CD28 was insufficient in this regard. Lack of Th2 development in the SEB system was in part due to the inhibitory effect of endogenously produced transforming growth factor-beta (TGF-beta), because anti-TGF-beta allowed the development of Th2 cells. Similarly, TGF-beta inhibited Th2 development and stimulated Th1 development in the anti-CD3 system. This shift was only partially prevented by also including IL-4 in the cultures. The effects of TGF-beta could only partially be explained by stimulation of IFN-gamma or inhibition of IL-4 as intermediatory cytokines: (1) TGF-beta stimulated Th1 development even in the presence of anti-IL-4 and anti-IFN-gamma, and (2) a strong inhibitory effect of anti-TGF-beta on Th1 development was still observed when anti-IL-4 and IFN-gamma were simultaneously added to the cultures. It is concluded that SEB favors Th1 development by stimulation of TGF-beta production. Inhibition of Th2 development by TGF-beta is due, in part, to inhibition of IL-4 and stimulation of IFN-gamma, and, in part, to a direct effect of TGF-beta on the responding T cells.

L4415: further characterization of the rat model for human acute lymphocytic leukemia.

The biological properties of a transplantable lymphocytic leukemia, L4415 in the WAG/Rij rat, are described. The radiation-induced L4415 leukemia is characterized as a relatively slowly growing, non-immunogenic, immature T-cell leukemia which shows a reproducible growth pattern upon intravenous (i.v.) transfer. Survival time following i.v. inoculation is inversely related to the number of leukemic cells in the inoculum, which allows a quantitative estimate in terms of log leukemic cell kill of the effect of treatment. The first signs of leukemic growth are found in the bone marrow, the spleen, and the liver. Leukemic cells can be detected in the peripheral blood 13 days after inoculation. Due to replacement of normal hemopoietic tissue by leukemic cells and their number increasing exponentially thereafter, normal hemopoiesis is inhibited in the later stages of the disease as indicated by severe thrombocytopenia and anemia. Death is caused by a combination of splenic rupture, gastrointestinal and pulmonary hemorrhage, and impaired functions of heavily infiltrated organs. Hepatosplenomegaly and lymphadenopathy are prominent features at autopsy. Cyclophosphamide- and radiosensitivity of the clonogenic leukemic cells have been determined, a 2.9 log cell kill could be induced by single dose cyclophosphamide inoculation and a dosage giving a surviving fraction of 0.37 (D0) of 0.99 Gy with an extrapolation number (N) of 8.5 were calculated. Based on these data, the L4415 rat leukemia may be regarded as a relevant model for human acute lymphocytic leukemia and may thus serve to explore new treatment strategies.