Aspirin, but not propranolol, attenuates the acute stress-induced increase in circulating levels of interleukin-6: a randomized, double-blind, placebo-controlled study

Psychosocial stress might increase the risk of atherothrombotic events by setting off an elevation in circulating levels of the proinflammatory cytokine interleukin (IL)-6. We investigated the effect of aspirin and propranolol on the responsiveness of plasma IL-6 levels to acute psychosocial stress. For 5 days, 64 healthy subjects were randomized, double-blind, to daily oral aspirin 100mg plus long-acting propranolol 80 mg, aspirin 100mg plus placebo, long-acting propranolol 80 mg plus placebo, or placebo plus placebo. Thereafter, all subjects underwent the 13-min Trier Social Stress Test, which combines a preparation phase, a job interview, and a mental arithmetic task. Plasma IL-6 levels were measured in blood samples collected immediately pre- and post-stress, and 45 min and 105 min thereafter. The change in IL-6 from pre-stress to 105 min post-stress differed between subjects with aspirin medication and those without (p =0.033; eta p2=0.059). IL-6 levels increased less from pre-stress to 105 min post-stress (p <0.027) and were lower (p =0.010) at 105 min post-stress in subjects with aspirin than in subjects without aspirin. The significance of these results was maintained when controlling for gender, age, waist-to-hip ratio, mean arterial blood pressure, and smoking status. Medication with propranolol was not significantly associated with the stress-induced change in IL-6 levels. Also, aspirin and propranolol did not significantly interact in determining the IL-6 stress response. Aspirin but not propranolol attenuated the stress-induced increase in plasma IL-6 levels. This suggests one mechanism by which aspirin treatment might reduce the risk of atherothrombotic events triggered by acute mental stress.

Is perioperative point-of-care prothrombin time testing accurate compared to the standard laboratory test?

There is no accepted way of measuring prothrombin time without time loss for patients undergoing major surgery who are at risk of intraoperative dilution and consumption coagulopathy due to bleeding and volume replacement with crystalloids or colloids. Decisions to transfuse fresh frozen plasma and procoagulatory drugs have to rely on clinical judgment in these situations. Point-of-care devices are considerably faster than the standard laboratory methods. In this study we assessed the accuracy of a Point-of-care (PoC) device measuring prothrombin time compared to the standard laboratory method. Patients undergoing major surgery and intensive care unit patients were included. PoC prothrombin time was measured by CoaguChek XS Plus (Roche Diagnostics, Switzerland). PoC and reference tests were performed independently and interpreted under blinded conditions. Using a cut-off prothrombin time of 50%, we calculated diagnostic accuracy measures, plotted a receiver operating characteristic (ROC) curve and tested for equivalence between the two methods. PoC sensitivity and specificity were 95% (95% CI 77%, 100%) and 95% (95% CI 91%, 98%) respectively. The negative likelihood ratio was 0.05 (95% CI 0.01, 0.32). The positive likelihood ratio was 19.57 (95% CI 10.62, 36.06). The area under the ROC curve was 0.988. Equivalence between the two methods was confirmed. CoaguChek XS Plus is a rapid and highly accurate test compared with the reference test. These findings suggest that PoC testing will be useful for monitoring intraoperative prothrombin time when coagulopathy is suspected. It could lead to a more rational use of expensive and limited blood bank resources.

Dermatophagoides farinae-specific immunotherapy in atopic dogs with hypersensitivity to multiple allergens: a randomised, double blind, placebo-controlled study

A randomised, placebo-controlled, double blind study was conducted on 25 dogs that had atopic dermatitis, together with skin test reactivity and elevated serum IgE to Dermatophagoides farinae (Df) and at least one additional allergen. Dogs were treated with either a Df-restricted immunotherapy solution (n=14) or a placebo (n=11) and evaluated 6 weeks and 3, 5, 7 and 9 months after the initiation of treatment using a clinical scoring system (SASSAD) and pruritus analogue scale scores. The Df-restricted solution and the placebo had an equal effect on both pruritus and the skin manifestations (P>0.05). The results of this study indicate that in dogs with atopic dermatitis based on hypersensitivity to environmental allergens in addition to D. farinae, Df-restricted immunotherapy is insufficient to control the disease. Consequently, a solution for allergen-specific immunotherapy should remain customised.

Effectiveness of a calcium sodium phosphosilicate-containing prophylaxis paste in reducing dentine hypersensitivity immediately and 4 weeks after a single application: a double-blind randomized controlled trial

AIMS The aim of this single-site, randomized, controlled, double-blind, 3-arm parallel study was to determine the effectiveness of a prophylaxis paste containing 15% calcium sodium phosphosilicate (CSPS; NovaMin(®) ) with and without fluoride in reducing dentine hypersensitivity immediately after a single application and 28 days following dental scaling and root planing. MATERIALS & METHODS Overall, 151 subjects were enrolled in this study. All subjects received a scaling and root planing procedure followed by a final prophylaxis step using one of three different prophylaxis pastes: Test-A (15% NovaMin(®) and NaF), Test-B (15% NovaMin(®) ) and a control. Dentine hypersensitivity was assessed by tactile stimulus (Yeaple Probe(®) ) and by air blast (Schiff scale) at baseline, immediately after and 28 days after a prophylaxis procedure. One hundred and forty-nine subjects completed the study. RESULTS Subjects having received the test prophylaxis pastes showed statistically lower (anova, p < 0.05) dentine hypersensitivity compared with the control group immediately after the prophylaxis procedure (Yeaple Probe(®) : Test-A = 20.9 ± 12.6, Test-B = 22.7 ± 12.9, Control=11.2 ± 3.1; Schiff score: Test-A = 1.1 ± 0.6, Test-B = 1.1 ± 0.6, Control = 2.0 ± 0.7) and after 28 days (Yeaple probe: Test-A = 21.5 ± 11.9, Test-B = 20.6 ± 11.3, Control = 11.8 ± 6.0; Schiff score: Test-A = 1.0 ± 0.6, Test-B = 1.0 ± 0.6, Control = 2.0 ± 0.7). CONCLUSIONS In conclusion, the single application of both fluoridated and non-fluoridated prophylaxis pastes containing 15% CSPS (NovaMin(®) ) provided a significant reduction of dentine hypersensitivity up to at least 28 days.

Comparison of globules prepared from high dilutions of various starting materials by ultraviolet light spectroscopy

Background: High and ultra-high dilutions of various starting materials, e.g. copper sulfate, Hypericum perforatum and sulfur, showed significant differences in ultraviolet light (UV) transmission from controls and amongst different dilution levels [1,2]. Verum and placebo globules of Aconitum napellus 30c or calcium carbonate/quercus e cortice 6x from the same packs as used in previous clinical trials and dissolved in water could be distinguished by UV spectroscopy [3]. However, it was unclear whether the differences in UV absorbance originated from specific characteristics of the starting materials, from differences in the production of verum and placebo globules, and/or other unknown interference factors. Aims: The aim of this study was to investigate whether globules produced with high and ultra-high dilutions (6x, 12x, 30c, 200c, 200CF (centesimal discontinuous fluxion), 10,000CF) of various starting materials (Aconitum napellus, Atropa belladonna, phosphorus, sulfur, Apis mellifica, quartz) could be distinguished by UV spectroscopy. Methodology: The globules were specially produced for this study by Spagyros AG (Gümligen, Switzerland) and differed only in the starting materials of the dilutions (but not in the batch of globules or ethanol used). Globules were dissolved in water at 10 mg/ml, in quadruplicates, approximately 22 h prior to the measurements. Absorbance of the samples in the UV range (from 190 to 340 nm) was measured in a randomized order with a Shimadzu double beam UV-1800 spectrophotometer equipped with an auto sampler. Samples of each starting material were prepared and measured on 5 independent days. The daily variations of the spectrophotometer as well as the drift during the measurements were corrected for. The average absorbance from 200 to 340 nm was compared among various starting materials within equal dilution levels using a Kruskal-Wallis test. Results: Statistically significant differences were found among 30c (Figure 1), 200c and 200CF dilutions of the various starting materials. No differences were found among 6x, 12x and 10,000CF dilutions. Conclusions: Globules prepared from high dilutions of various starting materials may show significantly different UV absorbance when dissolved in water. References [1] Wolf U, Wolf M, Heusser P, Thurneysen A, Baumgartner S. Homeopathic preparations of quartz, sulfur and copper sulfate assessed by UV-spectroscopy. Evid Based Complement Alternat Med. 2011;2011:692798. [2] Klein SD, Sandig A, Baumgartner S, Wolf U. Differences in median ultraviolet light transmissions of serial homeopathic dilutions of copper sulfate, Hypericum perforatum, and sulfur. Evid Based Complement Alternat Med. 2013;2013:370609. [3] Klein SD, Wolf U. Investigating homeopathic verum and placebo globules with ultraviolet spectroscopy. Forsch Komplementmed. 2013, accepted.

A randomised double-blind, cross-over trial of 4-aminopyridine for downbeat nystagmus--effects on slowphase eye velocity, postural stability, locomotion and symptoms

Objective The effects of 4-aminopyridine (4-AP) on downbeat nystagmus (DBN) were analysed in terms of slow-phase velocity (SPV), stance, locomotion, visual acuity (VA), patient satisfaction and side effects using standardised questionnaires. Methods Twenty-seven patients with DBN received 5 mg 4-AP four times a day or placebo for 3 days and 10 mg 4-AP four times a day or placebo for 4 days. Recordings were done before the first, 60 min after the first and 60 min after the last drug administration. Results SPV decreased from 2.42 deg/s at baseline to 1.38 deg/s with 5 mg 4-AP and to 2.03 deg/s with 10 mg 4-AP (p<0.05; post hoc: 5 mg 4-AP: p=0.04). The rate of responders was 57%. Increasing age correlated with a 4-AP-related decrease in SPV (p<0.05). Patients improved in the ‘get-up-and-go test’ with 4-AP (p<0.001; post hoc: 5 mg: p=0.025; 10 mg: p<0.001). Tandem-walk time (both p<0.01) and tandem-walk error (4-AP: p=0.054; placebo: p=0.059) improved under 4-AP and placebo. Posturography showed that some patients improved with the 5 mg 4-AP dose, particularly older patients. Near VA increased from 0.59 at baseline to 0.66 with 5 mg 4-AP (p<0.05). Patients with idiopathic DBN had the greatest benefit from 4-AP. There were no differences between 4-AP and placebo regarding patient satisfaction and side effects. Conclusions 4-AP reduced SPV of DBN, improved near VA and some locomotor parameters. 4-AP is a useful medication for DBN syndrome, older patients in particular benefit from the effects of 5 mg 4-AP on nystagmus and postural stability.

Caries-preventive effectiveness of fluoride varnish as adjunct to oral health promotion and supervised tooth brushing in preschool children: a double-blind randomized controlled trial.

OBJECTIVES To evaluate the effect of biannual fluoride varnish applications in preschool children as an adjunct to school-based oral health promotion and supervised tooth brushing with 1000ppm fluoride toothpaste. METHODS 424 preschool children, 2-5 year of age, from 10 different pre schools in Athens were invited to this double-blind randomized controlled trial and 328 children completed the 2-year programme. All children received oral health education with hygiene instructions twice yearly and attended supervised tooth brushing once daily. The test group was treated with fluoride varnish (0.9% diflurosilane) biannually while the control group had placebo applications. The primary endpoints were caries prevalence and increment; secondary outcomes were gingival health, mutans streptococci growth and salivary buffer capacity. RESULTS The groups were balanced at baseline and no significant differences in caries prevalence or increment were displayed between the groups after 1 and 2 years, respectively. There was a reduced number of new pre-cavitated enamel lesions during the second year of the study (p=0.05) but the decrease was not statistically significant. The secondary endpoints were unaffected by the varnish treatments. CONCLUSIONS Under the present conditions, biannual fluoride varnish applications in preschool children did not show significant caries-preventive benefits when provided as an adjunct to school-based supervised tooth brushing with 1000ppm fluoride toothpaste. CLINICAL SIGNIFICANCE In community based, caries prevention programmes, for high caries risk preschool children, a fluoride varnish may add little to caries prevention, when 1000ppm fluoride toothpaste is used daily.

Double seronegative myasthenia gravis with antiphospholipid syndrome: a case report

INTRODUCTION Myasthenia gravis is an autoimmune disease characterized by fluctuating muscle weakness. It is often associated with other autoimmune disorders, such as thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, and antiphospholipid syndrome. Many aspects of autoimmune diseases are not completely understood, particularly when they occur in association, which suggests a common pathogenetic mechanism. CASE PRESENTATION We report a case of a 42-year-old Caucasian woman with antiphospholipid syndrome, in whom myasthenia gravis developed years later. She tested negative for both antibodies against the acetylcholine receptor and against muscle-specific receptor tyrosine-kinase, but had typical decremental responses at the repetitive nerve stimulation testing, so that a generalized myasthenia gravis was diagnosed. Her thromboplastin time and activated partial thromboplastin time were high, anticardiolipin and anti-β2 glycoprotein-I antibodies were slightly elevated, as a manifestation of the antiphospholipid syndrome. She had a good clinical response when treated with a combination of pyridostigmine, prednisone and azathioprine. CONCLUSIONS Many patients with myasthenia gravis test positive for a large variety of auto-antibodies, testifying of an immune dysregulation, and some display mild T-cell lymphopenia associated with hypergammaglobulinemia and B-cell hyper-reactivity. Both of these mechanisms could explain the occurrence of another autoimmune condition, such as antiphospholipid syndrome, but further studies are necessary to shed light on this matter.Clinicians should be aware that patients with an autoimmune diagnosis such as antiphospholipid syndrome who develop signs and neurological symptoms suggestive of myasthenia gravis are at risk and should prompt an emergent evaluation by a specialist.

Small-diameter titanium grade IV and titanium-zirconium implants in edentulous mandibles: five-year results from a double-blind, randomized controlled trial.

BACKGROUND The aim of this study was to compare the 5-year survival and success rates of 3.3 mm dental implants either made from titanium-zirconium (TiZr) alloy or from Grade IV titanium (Ti Grade IV) in mandibular implant-based removable overdentures. METHODS The core study had a follow-up period of 36 months and was designed as a randomized, controlled, double-blind, split-mouth multicenter clinical trial. Patients with edentulous mandibles received two Straumann Bone Level implants (diameter 3.3 mm, SLActive®), one of TiZr (test) and one of Ti Grade IV (control), in the interforaminal region. This follow-up study recruited patients from the core study and evaluated the plaque and sulcus bleeding indices, radiographic crestal bone level, as well as implant survival and success 60 months after implant placement. RESULTS Of the 91 patients who initially received implants, 75 completed the 36 month follow-up and 49 were available for the 60 month examination. Two patients were excluded so that a total of 47 patients with an average age of 72 ± 8 years were analysed. The characteristics and 36-month performance of the present study cohort did not differ from the non-included initial participants (p > 0.05). In the period since the 36-month follow-up examination, no implant was lost. The cumulative implant survival rate was 98.9 % for the TiZr group and 97.8 % for the Ti Grade IV group. Crestal bone level changes at 60 months were not different in the test and control group (TiZr -0.60 ± 0.69 mm and Ti Grade IV -0.61 ± 0.83 mm; p = 0.96). The cumulative implant success rate after 60 months was 95.8 and 92.6 % for TiZr and Ti Grade IV, respectively. CONCLUSIONS After 60 months, the positive outcomes of the 36 month results for TiZr and Ti Grade IV implants were confirmed, with no significant differences with regard to crestal bone level change, clinical parameters and survival or success rates. TiZr implants performed equally well compared to conventional Ti Grade IV 3.3 mm diameter-reduced implants for mandibular removable overdentures. TRIAL REGISTRATION Registered on www.clinicaltrials.gov: NCT01878331.

Small-diameter titanium Grade IV and titanium-zirconium implants in edentulous mandibles: three-year results from a double-blind, randomized controlled trial

OBJECTIVE The aim of this study was to compare crestal bone-level changes, soft tissue parameters and implant success and survival between small-diameter implants made of titanium/zirconium (TiZr) alloy or of Grade IV titanium (Ti) in edentulous mandibles restored with removable overdentures. MATERIALS AND METHODS This was a randomized, controlled, double-blind, split-mouth multicenter clinical trial. Patients with edentulous mandibles received two Straumann bone-level implants (diameter 3.3 mm), one of Ti Grade IV (control) and one of TiZr (test), in the interforaminal region. Implants were loaded after 6-8 weeks and removable Locator-retained overdentures were placed within 2 weeks of loading. Modified plaque and sulcus bleeding indices, radiographic bone level, and implant survival and success were evaluated up to 36 months. RESULTS Of 91 treated patients, 75 completed the three-year follow-up. Three implants were lost (two control and one test implant). The survival rates were 98.7% and 97.3%, and the mean marginal bone level change was -0.78 ± 0.75 and -0.60 ± 0.71 mm for TiZr and Ti Grade IV implants. Most patients had a plaque score of 0 or 1 (54% for test and 51.7% for control), and a sulcus bleeding score of 0 (46.1% for test and 44.9% for control). No significant differences were found between the two implant types for bone-level change, soft tissue parameters, survival and success. CONCLUSIONS After 36 months, similar outcomes were found between Ti Grade IV and TiZr implants. The results confirm that the results seen at 12 months continue over time.

An evaluation of sleep hypnotic and stimulant effect on human performance using a computerized psychological test battery

This study evaluated the administration-time-dependent effects of a stimulant (Dexedrine 5-mg), a sleep-inducer (Halcion 0.25-mg) and placebo (control) on human performance. The investigation was conducted on 12 diurnally active (0700-2300) male adults (23-38 yrs) using a double-blind, randomized sixway-crossover three-treatment, two-timepoint (0830 vs 2030) design. Performance tests were conducted hourly during sleepless 13-hour studies using a computer generated, controlled and scored multi-task cognitive performance assessment battery (PAB) developed at the Walter Reed Army Institute of Research. Specific tests were Simple and Choice Reaction Time, Serial Addition/Subtraction, Spatial Orientation, Logical Reasoning, Time Estimation, Response Timing and the Stanford Sleepiness Scale. The major index of performance was "Throughput", a combined measure of speed and accuracy.^ For the Placebo condition, Single and Group Cosinor Analysis documented circadian rhythms in cognitive performance for the majority of tests, both for individuals and for the group. Performance was best around 1830-2030 and most variable around 0530-0700 when sleepiness was greatest (0300).^ Morning Dexedrine dosing marginally enhanced performance an average of 3% with reference to the corresponding in time control level. Dexedrine AM also increased alertness by 10% over the AM control. Dexedrine PM failed to improve performance with reference to the corresponding PM control baseline. With regard to AM and PM Dexedrine administrations, AM performance was 6% better with subjects 25% more alert.^ Morning Halcion administration caused a 7% performance decrement and 16% increase in sleepiness and a 13% decrement and 10% increase in sleepiness when administered in the evening compared to corresponding in time control data. Performance was 9% worse and sleepiness 24% greater after evening versus morning Halcion administration.^ These results suggest that for evening Halcion dosing, the overnight sleep deprivation occurring in coincidence with the nadir in performance due to circadian rhythmicity together with the CNS depressant effects combine to produce performance degradation. For Dexedrine, morning administration resulted in only marginal performance enhancement; Dexedrine in the evening was less effective, suggesting the 5-mg dose level may be too low to counteract the partial sleep deprivation and nocturnal nadir in performance. ^

Turbidity measurements in 96-wells microplates to determine the densities of copiotrophic and oligotrophic bacteria with the Most-Probable-Number-method during POLARSTERN cruise ANT-XI/2

A new microtiter-plate dilution method was applied during the expedition ANTARKTIS-XI/2 with RV Polarstern to determine the distribution of copiotrophic and oligotrophic bacteria in the water columns at polar fronts. Twofold serial dilutions were performed with an eight-channel Electrapette in 96-wells plates by mixing 150 µl of seawater with 150 µl of copiotrophic or olitrophic Trypticase-Broth, three times per well. After incubation of about 6 month at 2 °C, turbidities were measured with an eight-channel photometer at 405 nm and combinations of positive test results for three consecutive dilutions chosen and compared with a Most Probable Number table, calculated for 8 replicates and twofold serial dilutions. Densities of 12 to 661 cells/ml for copiotrophs, and 1 to 39 cells/ml for oligotrophs were found. Colony Forming Units on copiotrophic Trypticase-Agar were between 6 and 847 cells/ml, which is in the same range as determined with the MPN method.

DNA topoisomerase targets of the fluoroquinolones: A strategy for avoiding bacterial resistance

Fluoroquinolones are antibacterial agents that attack DNA gyrase and topoisomerase IV on chromosomal DNA. The existence of two fluoroquinolone targets and stepwise accumulation of resistance suggested that new quinolones could be found that would require cells to obtain two topoisomerase mutations to display resistance. For wild-type cells to become resistant, the two mutations must be acquired concomitantly. That is expected to occur infrequently. To identify such compounds, fluoroquinolones were tested for the ability to kill a moderately resistant gyrase mutant. Compounds containing a C8-methoxyl group were particularly lethal, and incubation of wild-type cultures on agar containing C8-methoxyl fluoroquinolones produced no resistant mutant, whereas thousands arose during comparable treatment with control compounds lacking the C8 substituent. When the test strain contained a preexisting topoisomerase IV mutation, which by itself conferred no resistance, equally high numbers of resistant mutants were obtained for C8-methoxyl and control compounds. Thus C8-methoxyl fluoroquinolones required two mutations for expression of resistance. Although highly lethal, C8-methoxyl fluoroquinolones were not more effective than C8-H controls at blocking bacterial growth. Consequently, quinolone action involves two events, which we envision as formation of drug–enzyme–DNA complexes followed by release of lethal double-strand DNA breaks. Release of DNA breaks, which must occur less frequently than complex formation, is probably the process stimulated by the C8-methoxyl group. Understanding this stimulation should provide insight into intracellular quinolone action and contribute to development of fluoroquinolones that prevent selection of resistant bacteria.

Numerical test of the Cardy-Jacobsen conjecture in the site-diluted Potts model in three dimensions

We present a microcanonical Monte Carlo simulation of the site-diluted Potts model in three dimensions with eight internal states, partly carried out on the citizen supercomputer Ibercivis. Upon dilution, the pure model’s first-order transition becomes of the second order at a tricritical point. We compute accurately the critical exponents at the tricritical point. As expected from the Cardy-Jacobsen conjecture, they are compatible with their random field Ising model counterpart. The conclusion is further reinforced by comparison with older data for the Potts model with four states.

Nord Stream II – Another test for EU unity. EPC Commentary, 9 October 2015

In September 2015, Gazprom and major European energy companies (Germany's E.ON and BASF/Wintershall, Austria's OMV, France’s ENGIE and Royal Dutch Shell) signed an agreement to double the Nord Stream gas pipeline’s capacity by 2019. The plan is to transport up to 55 billion additional cubic meters of gas a year to Germany through the Baltic Sea, bypassing Ukraine and other Central-Eastern European countries.