Background—Nebivolol is a β₁-selective adrenergic receptor antagonist with proposed nitric oxide (NO)–mediated vasodilating properties in humans. In this study, we explored whether nebivolol indeed induces NO production and, if so, by what mechanism. We hypothesized that not nebivolol itself but rather its metabolites augment NO production.Methods and Results—Mouse thoracic aorta segments were bathed in an organ chamber. Administration of nebivolol did not affect NO production. When nebivolol was allowed to metabolize in vivo in mice, addition of plasma of these mice caused a sustained 2-fold increase in NO release. Interestingly, coadministration of a selective β₂-adrenergic receptor antagonist (butoxamine) prevented the response. Immunohistochemistry and Western blot analysis demonstrated the presence of β₂- but not β₁-adrenergic receptors on endothelial cells. In the absence of calcium, metabolized nebivolol failed to increase NO production, suggesting a role for calcium-dependent NO synthase. With digital fluorescence imaging, a rapid and sustained rise in endothelial cytosolic free Ca²⁺concentration was observed after administration of metabolized nebivolol, which also was abrogated by butoxamine pretreatment.Conclusions—In vivo metabolized nebivolol increases vascular NO production. This phenomenon involves endothelial β₂-adrenergic receptor ligation, with a subsequent rise in endothelial free [Ca²⁺]_iand endothelial NO synthase–dependent NO production. This may be an important mechanism underlying the nebivolol-induced, NO-mediated arterial dilation in humans.

In patients with frequent migraine, prophylactic treatments are used. Patients often request non-pharmacological alternatives. One treatment option can be aerobic exercise. The value of aerobic exercise as prophylactic treatment however needs to be determined. A systematic review and meta-analysis was performed to investigate the result of aerobic exercise on the number of migraine days, duration and pain intensity in patients with migraine. After screening three online databases, PubMed, Cochrane library and Web of Science, using predefined in- and exclusion criteria, six studies were retained. Pooling of data was performed when possible. Significant reductions in the number of migraine days after aerobic exercise treatment were found with a mean reduction of 0.6 ± 0.3 migraine days/month. Other outcomes were too variable to pool due to heterogeneity of outcome measurements. Unpooled data revealed small to moderate reductions in attack duration (20–27%) and pain intensity (20–54%) after aerobic exercise intervention. Various exercise intensities are applied. There is moderate quality evidence that in patients with migraine aerobic exercise therapy can decrease the number of migraine days. No conclusion for pain intensity or duration of attacks can be drawn. Effect sizes are small due to a lack of uniformity. For future studies, we recommend standardized outcome measures and sufficiently intense training programs. CRD42018091178 .

The purpose of the study was to investigate whether severe fatigue, possibly leading to overreaching, could be diagnosed at an early stage by a combination of parameters. Seven well-trained male subjects (age [mean ± SD]: 25.3 ± 4.7 yr; body mass: 76 ± 6.6 kg; VO₂max: 61.1 ± 7 ml · kg^-1 · min^-1) increased their training load by doubling their training volume and increasing the intensity by 15 % over a period of two weeks. Before and after this intensified training period subjects underwent a series of tests including a maximal incremental cycle ergometer test (Wmax) with continuous ventilatory measurements and blood lactate values, time trial, basal blood parameter tests (red and white blood profile), hormones [growth hormone (GH), insulin-like growth factor 1(IGF-1), adreno-corticotropic hormone (ACTH), cortisol], neuro-endocrine stress test [short insulin tolerance test (SITT), combined anterior pituitary test (CAPT) and exercise], a shortened Profile of Mood State (POMS), the estimated rate of perceived exertion (RPE) and a cognitive reaction time test. The intensified training period resulted in a significant increase of the training load (p < 0.01), training monotony (p < 0.01) and training strain (p < 0.01). The RPE during training increased significantly (p < 0.01) during the intensified training period. Total mood score obtained from the POMS tended to increase (p = 0.06), reflecting an increase in worse mood state. A novel finding was that reaction times increased significantly, indicating that overreaching might adversely affect speed of information processing by the brain, especially for the most difficult conditions. After the intensified training period, neither changes in exercise-induced plasma hormone values, nor SITT values were observed. During the CAPT only cortisol showed a significant decrease after the intensified training period. Hemoglobin showed a significant decrease after the intensified training period whereas hematocrit, red blood cell count (RBC) and MCV tended to decrease. The intensified training had no effect on physical performance (Wmax or time trial), maximal blood lactate, maximal heart rate and white blood cell profile. The most sensitive parameters for detecting overreaching are reaction time performance (indicative for cognitive brain functioning), RPE and to a lesser extend the shortened POMS. This strongly suggests, that central fatigue precedes peripheral fatigue. All other systems,including the neuro-endocrine, are more robust and react most likely at a later stage in exhaustive training periods.

Background and Purpose —Body temperature is a strong predictor of outcome in acute stroke. However, it is unknown whether antipyretic treatment leads to early and clinically worthwhile reduction of body temperature in patients with acute stroke, especially when they have no fever. The main purpose of this trial was to study whether early treatment of acute ischemic stroke patients with acetaminophen (paracetamol) reduces body temperature. Methods —Seventy-five patients with acute ischemic stroke confined to the anterior circulation were randomized to treatment with either 500 mg (low dose) or 1000 mg (high dose) acetaminophen or with placebo, administered as suppositories 6 times daily during 5 days. Body temperatures were measured with a rectal electronic thermometer at the start of treatment and after 24 hours and with an infrared tympanic thermometer at 2-hour intervals during the first 24 hours and at 6-hour intervals thereafter. The primary outcome measure was rectal temperature at 24 hours after the start of treatment. Results —Treatment with high-dose acetaminophen resulted in 0.4°C lower body temperatures than placebo treatment at 24 hours (95% CI 0.1°C to 0.7°C). The mean reduction from baseline temperature with high-dose acetaminophen was 0.3°C (95% CI 0°C to 0.6°C) higher than that in placebo-treated patients. Treatment with low-dose acetaminophen did not result in lower body temperatures. After 5 days of treatment, no differences in temperature were found between the placebo and the high- or low-dose acetaminophen groups. Conclusions —Treatment with a daily dose of 6000 mg acetaminophen may result in a small, but potentially beneficial, decrease in body temperature shortly after ischemic stroke, even in normothermic and subfebrile patients. Further studies should determine whether this effect is reproducible and whether early reduction of body temperature leads to improved outcome.

Body temperature is a strong predictor of outcome in acute stroke. In a previous randomized trial we observed that treatment with high-dose acetaminophen (paracetamol) led to a reduction of body temperature in patients with acute ischemic stroke, even when they had no fever. The purpose of the present trial was to study whether this effect of acetaminophen could be reproduced, and whether ibuprofen would have a similar, or even stronger effect. Seventy-five patients with acute ischemic stroke confined to the anterior circulation were randomized to treatment with either 1000 mg acetaminophen, 400 mg ibuprofen, or placebo, given 6 times daily during 5 days. Treatment was started within 24 hours from the onset of symptoms. Body temperatures were measured at 2-hour intervals during the first 24 hours, and at 6-hour intervals thereafter. No difference in body temperature at 24 hours was observed between the three treatment groups. However, treatment with high-dose acetaminophen resulted in a 0.3°C larger reduction in body temperature from baseline than placebo treatment (95% CI: 0.0 to 0.6 °C). Acetaminophen had no significant effect on body temperature during the subsequent four days compared to placebo, and ibuprofen had no statistically significant effect on body temperature during the entire study period. Treatment with a daily dose of 6000 mg acetaminophen results in a small, but potentially worthwhile decrease in body temperature after acute ischemic stroke, even in normothermic and subfebrile patients. Further large randomized clinical trials are needed to study whether early reduction of body temperature leads to improved outcome.