Guidelines of the International Headache Society for controlled trials of pharmacological preventive treatment for persistent post-traumatic headache attributed to mild traumatic brain injury

Background: Persistent headache attributed to traumatic injury to the head is divided into two subtypes, one attributed to moderate or severe traumatic injury and another attributed to mild traumatic injury (i.e., concussion). The latter is much more prevalent, in part because more than 90% of cases with traumatic brain injury are classified as mild. The pathophysiology of persistent post-traumatic headache is poorly understood and the underlying mechanisms are likely multifactorial. There is currently no approved treatment specifically for persistent post-traumatic headache, and management strategies rely on medications used for migraine or tension-type headache. Therefore, high-quality trials are urgently needed to support clinical decision-making and optimize management strategies. International guidelines can facilitate appropriate trial design and ensure the acquisition of high-quality data evaluating the efficacy, tolerability, and safety of available and novel pharmacological therapies for the preventive treatment of persistent post-traumatic headache. Methods: The development of this guideline was based on a literature review of available studies in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, along with a review of previously published guidelines for controlled trials of preventive treatment for episodic and chronic migraine. The identified literature was critically appraised, and due to the scarcity of scientific evidence, recommendations were primarily based on the consensus of experts in the field. Objective: To provide guidelines for designing state-of-the-art controlled clinical trials aimed at evaluating the effectiveness of preventive treatments for persistent post-traumatic headache attributed to mild traumatic brain injury

Variability and connectivity of plaice populations from the Eastern North Sea to the Western Baltic Sea, and implications for assessment and management

An essential prerequisite of sustainable fisheries is the match between biologically relevant processes and management action. Various populations may however co-occur on fishing grounds, although they might not belong to the same stock, leading to poor performance of stock assessment and management. Plaice in Kattegat and Skagerrak have traditionally been considered as one stock unit. Current understanding indicates that several plaice components may exist in the transition area between the North Sea and the Baltic Sea. A comprehensive review of all available biological knowledge on plaice in this area is performed, including published and unpublished literature together with the analyses of commercial and survey data and historical tagging data. The results suggest that plaice in Skagerrak is closely associated with plaice in the North Sea, although local populations are present in the area. Plaice in Kattegat, the Belts Sea and the Sound can be considered a stock unit, as is plaice in the Baltic Sea. The analyses revealed great heterogeneity in the dynamics and productivity of the various local components, and suggested for specific action to maintain biodiversity

The Role of Reactive Oxygen Species in β-Adrenergic Signaling in Cardiomyocytes from Mice with the Metabolic Syndrome.

The metabolic syndrome is associated with prolonged stress and hyperactivity of the sympathetic nervous system and afflicted subjects are prone to develop cardiovascular disease. Under normal conditions, the cardiomyocyte response to acute β-adrenergic stimulation partly depends on increased production of reactive oxygen species (ROS). Here we investigated the interplay between beta-adrenergic signaling, ROS and cardiac contractility using freshly isolated cardiomyocytes and whole hearts from two mouse models with the metabolic syndrome (high-fat diet and ob/ob mice). We hypothesized that cardiomyocytes of mice with the metabolic syndrome would experience excessive ROS levels that trigger cellular dysfunctions. Fluorescent dyes and confocal microscopy were used to assess mitochondrial ROS production, cellular Ca2+ handling and contractile function in freshly isolated adult cardiomyocytes. Immunofluorescence, western blot and enzyme assay were used to study protein biochemistry. Unexpectedly, our results point towards decreased cardiac ROS signaling in a stable, chronic phase of the metabolic syndrome because: β-adrenergic-induced increases in the amplitude of intracellular Ca2+ signals were insensitive to antioxidant treatment; mitochondrial ROS production showed decreased basal rate and smaller response to β-adrenergic stimulation. Moreover, control hearts and hearts with the metabolic syndrome showed similar basal levels of ROS-mediated protein modification, but only control hearts showed increases after β-adrenergic stimulation. In conclusion, in contrast to the situation in control hearts, the cardiomyocyte response to acute β-adrenergic stimulation does not involve increased mitochondrial ROS production in a stable, chronic phase of the metabolic syndrome. This can be seen as a beneficial adaptation to prevent excessive ROS levels

The antioxidant NAC has no effect on the β-adrenergic stimulated SR Ca²⁺ release and contractility in cardiomyocytes from mice with the metabolic syndrome.

<p><b>(A)</b> Total body weight of mice after 8–10 weeks on control diet (Ctrl, n = 34) or high fat diet (HFD, n = 40). <b>(B)</b> Total body fat measured with DXA whole-body scan (n = 9–10). <b>(C)</b> Typical example of cross-sectional ORO staining showing fat accumulation (stained red) in left ventricles and mean data of ORO staining; eight sections per left ventricle from each group were analyzed (n = 3). Representative [Ca²⁺]_i transients from ctrl <b>(D)</b>, HFD <b>(E)</b> and <i>ob/ob</i> <b>(F)</b> cardiomyocytes obtained in the absence (full lines) and presence (dashed lines) of ISO (100 nM), and without (black lines) and with (red lines) NAC (5 mM). Average amplitude of Ca²⁺ transients <b>(G)</b>, fractional cell shortening (FS, <b><i>H</i></b>) and [Ca²⁺]_i transient decay time constant (tau) <b>(I)</b> with ISO and/or NAC as indicated from control (white bars), HFD (black bars) and <i>ob/ob</i> (grey bars) cardiomyocytes (n>16 cells from at least three mice). Representative Western blots <b>(J)</b> and mean data (n = 6) of ISO-induced PLB phosphorylation normalized to total PLB expression in left ventricles from control and HFD mice. Data are mean ± SEM; **<i>P</i> < 0.01, ***<i>P</i> < 0.001.</p

Cardiomyocytes from mice with the metabolic syndrome show normal β₁-AR, β₂-AR expression and distribution.

<p><b>(A)</b> Representative Western blots and mean data ± SEM (<b><i>B</i></b>; n = 6) of total expression of β₁- and β₂-ARs in left ventricles from control mice and HFD mice. Immunofluorescence staining of β₁-AR <b>(C)</b> and β₂-AR <b>(D)</b> co-stained with RyR2 in control and HFD cardiomyocytes. Merged (yellow) show the intensity overlap between β-ARs and RyR2 in the dyads. <b><i>E</i></b> and <b><i>F</i></b> show plotted intensity profiles of along the dashed lines in <i>C</i> and <i>D</i> with β-AR (red) and RyR2 (green).</p

The ISO-induced increases in L-type Ca²⁺ current density is ROS-independent in cardiomyocytes with the metabolic syndrome.

<p>Mean data (±SEM; n = 6–8 in each group) of <i>I-V</i> curves of peak current density in the absence and presence of ISO (100nM) and NAC (20 mM) as indicated from control <b>(A, D)</b>, HFD <b>(B, E)</b> and <i>ob/ob</i> <b>(C, F)</b> cardiomyocytes. The <i>I-V</i> relationships were obtained by giving test pulses varying from -80 mV to +50 mV from a holding potential of -80 mV. The mean basal current density (i.e. in the absence of NAC and ISO) was -6.1±0.5 pA/pF and for comparisons between groups each group were normalized its basal current to give a relative current density (relative pA/pF).</p

Diagnosis and management of migraine in ten steps.

Migraine is a disabling primary headache disorder that directly affects more than one billion people worldwide. Despite its widespread prevalence, migraine remains under-diagnosed and under-treated. To support clinical decision-making, we convened a European panel of experts to develop a ten-step approach to the diagnosis and management of migraine. Each step was established by expert consensus and supported by a review of current literature, and the Consensus Statement is endorsed by the European Headache Federation and the European Academy of Neurology. In this Consensus Statement, we introduce typical clinical features, diagnostic criteria and differential diagnoses of migraine. We then emphasize the value of patient centricity and patient education to ensure treatment adherence and satisfaction with care provision. Further, we outline best practices for acute and preventive treatment of migraine in various patient populations, including adults, children and adolescents, pregnant and breastfeeding women, and older people. In addition, we provide recommendations for evaluating treatment response and managing treatment failure. Lastly, we discuss the management of complications and comorbidities as well as the importance of planning long-term follow-up