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.

Intravaginal and intracervical application of seminal plasma in in vitro fertilization or intracytoplasmic sperm injection treatment cycles--a double-blind, placebo-controlled, randomized pilot study

OBJECTIVE: To evaluate whether intravaginal application of seminal plasma at the time of follicle aspiration in IVF or intracytoplasmic sperm injection treatment cycles has the potential to increase pregnancy rate. To calculate the number of patients needed to achieve significance in a multicenter trial. DESIGN: Double-blind, placebo-controlled randomized pilot study. SETTING: University department of gynecological endocrinology and reproductive medicine. PATIENT(S): One hundred sixty-eight patients undergoing IVF or intracytoplasmic sperm injection treatment. INTERVENTION(S): Cryopreserved seminal plasma from the patient's partner or sodium chloride (placebo) was injected into the cervix and the posterior fornix of the vagina just after follicle aspiration. MAIN OUTCOME MEASURE(S): Clinical-pregnancy rate. RESULT(S): One hundred sixty-eight patients agreed to participate in the study. Participation was limited to one treatment cycle. Thirty-one patients (18%) were excluded from the study, mainly as a result of canceled embryo transfers. Seventy patients received placebo, and 67 received seminal plasma. The clinical-pregnancy rate was 25.7% (18/70) in the placebo group. The clinical-pregnancy rate in the seminal plasma group reached 37.3% (25/67), corresponding to a relative increase of 45%. CONCLUSION(S): Even though significance was not reached in this pilot study, the data suggest that seminal plasma has the potential to improve pregnancy rate. It is estimated that around 450 patients need to be recruited to reach significance in a multicenter study.

Growth hormone (GH) replacement therapy reduces serum sialic acid concentrations in adults with GH-deficiency: a double-blind placebo-controlled study

Patients with adult GH-deficiency are thought to have an increased risk of cardiovascular disease. Sialic acid (SA) concentrations have been proposed as a marker of atherosclerotic disease probably related to an inflammatory response of the arterial wall. SA as a marker of cardiovascular disease in adult GH-deficiency and its relation to changes in fasting lipid profile and hormone concentrations have not yet been investigated.

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.

Preemptive carprofen for peri-operative analgesia in dogs undergoing Tibial Plateau Leveling Osteotomy (TPLO): a prospective, randomized, blinded, placebo controlled clinical trial

Eighteen client-owned dogs undergoing Tibial Plateau Leveling Osteotomy (TPLO) were included in this blinded clinical study and randomly assigned to one of two treatment groups. Group C (carprofen) received intravenous (IV) carprofen, 4 mg/kg, prior to anesthesia, whereas group P (placebo) received IV saline. General anesthesia was maintained with isoflurane in oxygen and a constant rate infusion (CRI) of sufentanyl IV. Intra-operatively, assessment of nociception was based on changes in physiological parameters and on the analgesics requirement, whereas in the post-operative period evaluation of pain was performed by using a Hellyer and Gaynor pain score and by comparing the doses of rescue buprenorphine required by the two treatment groups. Although no statistically significant differences in intra-operative sufentanyl doses were found between treatment groups, group C had superior cardiovascular stability, and lower post-operative pain scores and rescue buprenorphine doses than group P. Our results indicate that administration of carprofen prior to surgery was effective in improving peri-operative analgesia in dogs undergoing TPLO.

Ultrasound-guided pudendal nerve block in cats undergoing perineal urethrostomy: a prospective, randomised, investigator-blind, placebo-controlled clinical trial

The objective of this study was to evaluate the clinical usefulness, in terms of analgesic efficacy and safety, of ultrasound-guided pudendal nerve block performed with bupivacaine in cats undergoing perineal urethrostomy. Eighteen client-owned male cats scheduled for perineal urethrostomy were enrolled in the study and assigned to one of two treatment groups. The pudendal nerve block was performed under general anaesthesia as described elsewhere, with 0.3 ml/kg of either saline (group C) or 0.5% bupivacaine (group B) - the total injection volume being split equally on the two sites of injection (left and right). Intra-operatively, assessment of nociception was based on the rescue analgesics requirement, as well as on the evaluation of changes in physiological parameters in comparison with the baseline values. Post-operative pain assessment was performed using three different pain scales at recovery and then 1, 2 and 3 h after recovery. Cats in group B showed lower heart rates and required fewer analgesics during surgery than group C. Post-operatively, group B had lower pain scores and needed less rescue buprenorphine than group C. Iatrogenic block-related complications were not observed. In conclusion, the ultrasound-guided pudendal nerve block can be considered clinically useful in feline medicine as it provides reliable analgesia in cats undergoing perineal urethrostomy.

The role of postoperative prophylactic antibiotics in the treatment of facial fractures: a randomized, double-blind, placebo-controlled pilot clinical study. Part 2: mandibular fractures in 59 patients

The aim of this study was to evaluate the difference between a 5-day and a 1-day postoperative course of antibiotic on the incidence of infection after mandibular fractures involving the alveolus. Sixty-two patients with fractures of the mandible involving the dentoalveolar region were randomly assigned to 2 groups, both of which were given amoxicillin/clavulanic acid 1.2 g intravenously every 8 h from admission until 24 h postoperatively. The 5-day group were then given amoxicillin/clavulanic acid 625 mg orally every 8 h for another 4 days. The 1-day group was given an oral placebo at the same intervals. Follow-up appointments were 1, 2, 4, 6, 12 weeks and 6 months postoperatively. Development of an infection was the primary end point. Fifty-nine of the 62 patients completed this study. Six of the 30 patients in the 5-day group (20%) and 6 out of the 29 in the 1-day group (21%) developed local wound infections. Three of the 6 in the 1-day group developed purulent discharge and swelling. One patient in the 5-day group developed a rash on the trunk. There were no significant differences in the incidence of infection or side effects between the groups. In fractures of the mandible involving the alveolus, a 1-day postoperative course of antibiotic is as effective in preventing infective complications as a 5-day regimen.

Cardiac Shock Wave Therapy for Chronic Refractory Angina Pectoris. A Prospective Placebo-Controlled Randomized Trial

Background: Cardiac shock wave therapy (CSWT) delivered to the myocardium increases capillary density and regional myocardial blood flow in animal experiments. In addition, nonenzymatic nitric oxide production and the upregulation of vascular growth factor's mRNA by CSWT have been described. The aim of the study was therefore to test its potential to relieve symptoms in patients with chronic stable angina pectoris. Methods: Twenty-one patients (mean age 68.2 ± 8.3 years, 19 males) with chronic refractory angina pectoris and evidence of inducible myocardial ischemia during MIBI-SPECT imaging, were randomized into a treatment (n = 11) and a placebo arm (n = 10). The region of exercise-induced ischemia was treated with echocardiographic guidance during nine sessions over a period of 3 months. One session of CSWT consisted of 200 shots/spot (9--12 spots/session) with an energy intensity of 0.09 mJ/mm2. In the control group acoustic simulation was performed without energy application. Medication was kept unchanged during the whole treatment period. Results: In the treatment group, symptoms improved in 9/11 patients, and the ischemic threshold, determined by cardiopulmonary exercise stress testing, increased from 80 ± 28 to 95 ± 28 W (P= 0.036). In the placebo arm, only 2/10 patients reported an improvement and the ischemic threshold remained unchanged (98 ± 23 to 107 ± 23 W; P= 0.141). The items “physical functioning” (P= 0.043), “general health perception” (P= 0.046), and “vitality” (P= 0.035) of the SF-36 questionnaire significantly improved in the treatment arm, whereas in the placebo arm, no significant change was noted. Neither arrhythmias, troponin rise nor complications were observed during treatment. Conclusions: This placebo controlled trial shows a significant improvement in symptoms, quality of life parameters and ischemic threshold during exercise in patients with chronic refractory angina pectoris treated with CSWT. Thus, CSWT represents a new option for the treatment of patients with refractory AP.

Dopaminergic modulation of the reward system in schizophrenia: A placebo-controlled dopamine depletion fMRI study

Background The brain reward circuitry innervated by dopamine is critically disturbed in schizophrenia. This study aims to investigate the role of dopamine-related brain activity during prediction of monetary reward and loss in first episode schizophrenia patients. Methods We measured blood–oxygen-level dependent (BOLD) activity in 10 patients with schizophrenia (SCH) and 12 healthy controls during dopamine depletion with α-methylparatyrosine (AMPT) and during a placebo condition (PLA). Results AMPT reduced the activation of striatal and cortical brain regions in SCH. In SCH vs. controls reduced activation was found in the AMPT condition in several regions during anticipation of reward and loss, including areas of the striatum and frontal cortex. In SCH vs. controls reduced activation of the superior temporal gyrus and posterior cingulate was observed in PLA during anticipation of rewarding stimuli. PLA patients had reduced activation in the ventral striatum, frontal and cingulate cortex in anticipation of loss. The findings of reduced dopamine-related brain activity during AMPT were verified by reduced levels of dopamine in urine, homovanillic-acid in plasma and increased prolactin levels. Conclusions Our results indicate that dopamine depletion affects functioning of the cortico-striatal reward circuitry in SCH. The findings also suggest that neuronal functions associated with dopamine neurotransmission and attribution of salience to reward predicting stimuli are altered in schizophrenia.

A randomized, double-blind, placebo-controlled pilot study of naltrexone in outpatients with bipolar disorder and alcohol dependence.

BACKGROUND: Alcohol dependence is extremely common in patients with bipolar disorder and is associated with unfavorable outcomes including treatment nonadherence, violence, increased hospitalization, and decreased quality of life. While naltrexone is a standard treatment for alcohol dependence, no controlled trials have examined its use in patients with co-morbid bipolar disorder and alcohol dependence. In this pilot study, the efficacy of naltrexone in reducing alcohol use and on mood symptoms was assessed in bipolar disorder and alcohol dependence. METHODS: Fifty adult outpatients with bipolar I or II disorders and current alcohol dependence with active alcohol use were randomized to 12 weeks of naltrexone (50 mg/d) add-on therapy or placebo. Both groups received manual-driven cognitive behavioral therapy designed for patients with bipolar disorder and substance-use disorders. Drinking days and heavy drinking days, alcohol craving, liver enzymes, and manic and depressed mood symptoms were assessed. RESULTS: The 2 groups were similar in baseline and demographic characteristics. Naltrexone showed trends (p < 0.10) toward a greater decrease in drinking days (binary outcome), alcohol craving, and some liver enzyme levels than placebo. Side effects were similar in the 2 groups. Response to naltrexone was significantly related to medication adherence. CONCLUSIONS: Results suggest the potential value and acceptable tolerability of naltrexone for alcohol dependence in bipolar disorder patients. A larger trial is needed to establish efficacy.

The role of postoperative prophylactic antibiotics in the treatment of facial fractures: a randomised, double-blind, placebo-controlled pilot clinical study. Part 3: Le Fort and zygomatic fractures in 94 patients

The aim of this study was to evaluate the difference between the effect of a 5-day and a 1-day postoperative course of antibiotics on the incidence of infection after midfacial fractures. A total of 98 patients with displaced Le Fort or zygomatic fractures that required operation were randomly assigned into 2 groups, both of which were given amoxicillin/clavulanic acid 1.2g intravenously every 8h from the time of admission until 24h postoperatively. The 5-day group was then given amoxicillin/clavulanic acid 625mg orally 8-hourly for another 4 days. The 1-day group was given placebo orally at the same time points. Patients were followed up 1, 2, 4, 6, and 12 weeks, and 6 months, postoperatively. The development of an infection of the wound was the primary end point. Ninety-four of the 98 patients completed the study. Two of the 45 patients in the 5-day group (4%) and 2/49 in the 1-day group (4%) developed postoperative wound infections. One in each group had a purulent infection, while the others had only wound breakdown. Two patients of the 5-day group and one in the 1-day group developed rashes on the trunk. There were no significant differences in the incidence of infection or side effects between the groups. In midfacial fractures a 1-day course of antibiotics postoperatively is as effective in preventing infective complications as a 5-day regimen.

Intrauterine instillation of diluted seminal plasma at oocyte pick-up does not increase the IVF pregnancy rate: a double-blind, placebo controlled, randomized study.

STUDY QUESTION Does intrauterine application of diluted seminal plasma (SP) at the time of ovum pick-up improve the pregnancy rate by ≥14% in IVF treatment? SUMMARY ANSWER Intrauterine instillation of diluted SP at the time of ovum pick-up is unlikely to increase the pregnancy rate by ≥14% in IVF. WHAT IS KNOWN ALREADY SP modulates endometrial function, and sexual intercourse around the time of embryo transfer has been suggested to increase the likelihood of pregnancy. A previous randomized double-blind pilot study demonstrated a strong trend towards increased pregnancy rates following the intracervical application of undiluted SP. As this study was not conclusive and as the finding could have been confounded by sexual intercourse, the intrauterine application of diluted SP was investigated in the present trial. STUDY DESIGN, SIZE, DURATION A single-centre, prospective, double-blind, placebo-controlled, randomized, superiority trial on women undergoing IVF was conducted from April 2007 until February 2012 at the University Department of Gynaecological Endocrinology and Reproductive Medicine, Heidelberg, Germany. PARTICIPANTS/MATERIALS, SETTING, METHODS The study was powered to detect an 14% increase in the clinical pregnancy rate and two sequential tests were planned using the Pocock spending function. At the first interim analysis, 279 women had been randomly assigned to intrauterine diluted SP (20% SP in saline from the patients' partner) (n = 138) or placebo (n = 141) at the time of ovum pick-up. MAIN RESULTS AND THE ROLE OF CHANCE The clinical pregnancy rate per randomized patient was 37/138 (26.8%) in the SP group and 41/141 (29.1%) in the placebo group (difference: -2.3%, 95% confidence interval of the difference: -12.7 to +8.2%; P = 0.69). The live birth rate per randomized patient was 28/138 (20.3%) in the SP group and 33/141 (23.4%) in the placebo group (difference: -3.1%, 95% confidence interval of the difference: -12.7 to +6.6%; P = 0.56). It was decided to terminate the trial due to futility at the first interim analysis, at a conditional power of 62%. LIMITATIONS, REASONS FOR CAUTION The confidence interval of the difference remains wide, thus clinically relevant differences cannot reliably be excluded based on this single study. WIDER IMPLICATIONS OF THE FINDINGS The results of this study cast doubt on the validity of the concept that SP increases endometrial receptivity and thus implantation in humans. STUDY FUNDING/COMPETING INTEREST(S) Funding was provided by the department's own research facilities. TRIAL REGISTRATION NUMBER DRKS00004615.

Sono-Electro-Magnetic Therapy for Treating Chronic Pelvic Pain Syndrome in Men: A Randomized, Placebo-Controlled, Double-Blind Trial.

OBJECTIVE To assess the efficacy and safety of sono-electro-magnetic therapy compared to placebo in men with refractory CPPS. PATIENTS AND METHODS In a randomized, placebo-controlled, double-blind single center trial, we assessed the effect of sono-electro-magnetic therapy in men with treatment refractory CPPS. Sixty male patients were randomly assigned to treatment with either sono-electro-magnetic (n = 30) or placebo therapy (n = 30) for 12 weeks. The primary outcome was a change in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) from baseline to 12 weeks. RESULTS The 12-week difference between sono-electro-magnetic and placebo therapy in changes of the NIH-CPSI total score was -3.1 points (95% CI -6.8 to 0.6, p = 0.11). In secondary comparisons of NIH-CPSI sub-scores, we found differences between groups most pronounced for the quality-of-life sub-score (difference at 12 weeks -1.6, 95% CI -2.8 to -0.4, p = 0.015). In stratified analyses, the benefit of sono-electro-magnetic therapy appeared more pronounced among patients who had a symptom duration of 12 months or less (difference in NIH-CPSI total score -8.3, 95% CI -14.5 to 2.6) than in patients with a longer symptom duration (-0.8, 95% CI -4.6 to 3.1; p for interaction = 0.023). CONCLUSIONS Sono-electro-magnetic therapy did not result in a significant improvement of symptoms in the overall cohort of treatment refractory CPPS patients compared to placebo treatment. Subgroup analysis indicates, however, that patients with a symptom-duration of 12 months or less may benefit from sono-electro-magnetic therapy, warranting larger randomized controlled trials in this subpopulation. TRIAL REGISTRATION ClinicalTrials.gov NCT00688506.