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The Journal of Headache and Pain
Histamine and migraine revisited: mechanisms and possible drug targets
Jacob Worm1,
Katrine Falkenberg1 &
Jes Olesen ORCID: orcid.org/0000-0002-6712-27021
The Journal of Headache and Pain volume 20, Article number: 30 (2019) Cite this article
To review the existing literature on histamine and migraine with a focus on the molecule, its receptors, its use in inducing migraine, and antihistamines in the treatment of migraine.
Histamine has been known to cause a vascular type headache for almost a hundred years. Research has focused on antihistamines as a possible treatment and histamine as a migraine provoking agent but there has been little interest in this field for the last 25 years. In recent years two additional histamine (H3 and H4) receptors have been discovered and a series of non-sedating antihistamines have been developed. It is therefore timely to review the field again.
For this review the PubMed/MEDLINE database was searched for eligible studies. We searched carefully for all articles on histamine, antihistamines and histamine receptors in relation to migraine and the nervous system. The following search terms were used: histamine, migraine disorders, migraine, headache, antihistamines, histamine antagonists, clinical trials, induced headache, histamine H3 receptor, histamine H4 receptor and pharmacology. Four hundred thirty-six titles were read, 135 abstracts were read, 112 articles were read in full and 53 articles were used in this review. Review process resulted in 12 articles added to a total of 65.
Early studies of H1 and H2 antihistamines lack scientific strength and show conflicting results. Most of the antihistaminic drugs used in these trials bind also to other receptors which makes it difficult to conclude on the antihistaminic effect. Histamine is an efficient inducer of migraine attacks in migraine patients by an H1 mechanism most likely extracerebrally. These findings merit further investigation of antihistamines in clinical drug trials. The H3 and H4 receptors are found in primarily in CNS and immune tissues, respectively. H3 is likely to be involved in antinociception and has been linked with cognitive, neurodegenerative and sleep disorders. The only marketed H3 agent, pitolisant, is a brain penetrant H3 antagonist/inverse agonist which increases central histamine and causes headache. The experimental H3 agonist Nα-methylhistamine has shown promising results as a migraine preventative in studies of uncertain quality. With the current limited knowledge of the H4 receptor it is questionable whether or not the receptor is involved in migraine.
There is insufficient support for first generation antihistamines (both H1 and H2) as preventive migraine medications and sedation and weight gain are unacceptable side effects. Non-sedating H1 antihistamines need to be appropriately tested. Central H3 receptors seem to have a role in migraine that merit further investigation. The histaminergic system may be a goal for novel migraine drugs.
Histamine is a biogenic monoamine synthesized from the amino acid L-histidine by the L-histidine decarboxylase and metabolized by the enzyme histamine N-methyltransferase, using S-adenosylmethionine as a methyl donor. Histamine is located throughout the entire organism with high concentrations in lungs, skin and gastrointestinal tract. It is synthesized and stored in mast cells and basophils. It plays a role in multiple mechanisms both immunological and physiological, stimulating gastric secretion, inflammation, smooth muscle contraction, vasodilatation, permeability and much more. Histamine also functions as a neurotransmitter. It is synthesized in histaminergic neurons located in the posterior hypothalamus. These neurons have axons extending throughout the brain. Histamine carries out its effects via 4 subtypes of 7-transmembrane G-protein coupled receptors; H1, H2, H3 and H4 receptors [1,2,3].
The relation between histamine and headache has been on the agenda for almost a hundred years. A multitude of studies have been published focusing on the ability of histamine to induce headache and on the effect of antihistamines in the treatment of headache. During the last two decades the issue has, however, received almost no interest apart from two reviews [2, 4]. One reason that we now take this issue up is that there has been a massive development in the basic understanding of histamine biology, including the growing knowledge of histamine H3 and H4 receptors. Another is that a series of new generation antihistaminic drugs with or without the ability to penetrate the blood brain barrier have become available. It is therefore timely to review the issue.
Literature used in this review was primarily searched in the PubMed/MEDLINE database and we limited our search to publications in English. References were selected by reading titles and abstracts judging relevance to the topic. We began our search with a screening to identify existing reviews of histamine and migraine. The search histamine [MeSH Terms] OR histamine [All Fields]) AND migraine disorders [MeSH Terms] OR migraine [All Fields] AND disorders [All Fields] OR migraine disorders [All Fields] OR migraine [All Fields] with only articles from the last 5 years resulted in 41 articles of which 9 abstracts were read. We then searched for the very early literature of histamine and vascular headaches. This literature dates back almost a century and a systematic search is not possible. Therefore, bibliography from the PhD thesis by Lassen LH was examined to obtain references. Six articles were found eligible. To find articles regarding the studies of histamine antagonists in migraine prophylaxis we searched for the terms: antihistamine AND (migraine OR headache) AND clinical trial from 1945 to 1985. This resulted in 68 articles of which 41 abstracts were read. Articles concerning migraine provocation studies with histamine were searched for using the terms: histamine AND induced AND headache from 1980 to present. One hundred twenty-three articles were found of which 24 abstracts were read. Articles of histamine H3 and H4 receptor pharmacology was searched for by the MeSH terms: Pharmacology AND Receptors, histamine with review as publication type. The search lead to 44 articles of which 21 abstracts were read. Individual free text searches of histamine H3 receptor OR histamine H4 receptor AND pharmacology from 2000 until present was made and yielded 160 articles of which 40 abstracts were read. In addition to the search results we looked through the reference lists of the selected articles to find more relevant studies. The search combined resulted in 436 titles, of which 135 abstracts were read and 112 articles were read in full. Fifty-three were included in this review. Review process resulted in 12 articles added to a total of 65.
The research of histamine began over a century ago [5], with the first antihistamines being introduced to clinical use around 70 years ago (Fig. 1) [1]. In 1926 Harmer and Harris were the first to describe headache after infusion of histamine [6]. In the 1930s Pickering did a series of careful experimental studies. Although none of them were placebo controlled, histamine was intelligently investigated for its ability to induce a vascular headache. The headache after infusion of histamine was thoroughly described and it was shown that histamine induced headache in a dose-dependent manner but that there was great variability between subjects. Pickering proposed that the origin of the headache was intracranial. He suggested stretching of large intracranial arteries to be a possible explanation of the perceived pain because headache severity was reduced by lowering blood pressure or raising intracranial pressure (i.e. less expansion of the vasculature). He concluded that it is in the dura mater, via its trigeminal nerve supply, that the headache arises [7].
Historical timeline of histamine and its receptors. Reprinted from (11) Copyright© 2011 with permission from Elsevier, J Allergy Clin Immunol
In the following years several papers investigated the origin of histamine induced headache. Northfield injected histamine in the external and internal carotid artery and concluded that the pain arose from the internal carotid artery i.e. not from dura mater [8]. Another paper argued that the origin of pain in migraine headache is different from that of a histamine induced headache because of the absence of relief of migraine headache by increasing intracranial pressure while confirming a decrease of histamine induced headache [9]. Von Storch investigated the minimum dose of histamine required to induce headache. Migraineurs seemed to be more susceptible to histamine induced headache than control subjects [10]. Histamine was also tested as a treatment of migraine [11, 12]. The idea was to induce histamine tolerance in migraineurs based on a theory that these patients had lowered tolerance thus susceptible to external triggers of histamine (i.e. foods, antigens etc.). A method found successful but difficult to practice. The older literature had thus shown beyond doubt that histamine could induce a vascular type headache, the characteristics of which were carefully described. But how close was it to migraine? This could not be determined because there were no internationally accepted diagnostic criteria for migraine.
Experimental in vitro and animal studies have been performed adjacent to the clinical studies investigating histamines vasodilatory effect in the meningeal blood vessels as part of the underlying mechanism of migraine [13]. The research began decades ago with multiple studies published around the millennium [14] and researchers continue to investigate the endogenous mediators including histamine for their ability to generate migraine pain [15]. Histamine has been extensively studied alongside cytokines, chemokines and vasoactive peptides (i.e. the inflammatory soup) to gain knowledge of the underlying cellular mechanisms producing and maintaining the pain of migraine. At present a link between migraine and neurogenic inflammation comprising mast cell degranulation is widely accepted and this has been reviewed extensively most recently by Ramachandran [16].
Are H1 and H2 blockers effective in migraine treatment?
Because histamine induces a vascular headache with similarity to migraine, it was logical to test antihistamines in the treatment of migraine when the class of antihistamines became available. These old drugs were sedative and soon became classified as histamine receptor 1 and 2 antagonists as no other histamine receptors or antagonists were known at the time. The literature on clinical trials of the H1 and H2 receptor antagonists in the prevention of migraine is rather scarce. Few papers have been published. Even fewer are randomized controlled trials and mostly used drugs that did not bind exclusively to H1 or H2 receptors. The following section examines the existing literature on antihistamine trials performed in the years from around 1960 to 2014 (see Table 1 for overview). All the existing literature describes antihistamines as histamine receptor antagonists. Today most of these drugs are defined pharmacologically as inverse agonists i.e. inhibitors of the basal receptor activity instead of being neutral antagonists which solely block the agonist response [3, 17]. For ease, we will describe all antihistamines as compounds with a histamine antagonistic effect.
Table 1 Antihistamines in migraine prophylaxis
In a placebo controlled, but not double blinded or randomized study, Curran and Lance investigated cyproheptadine, an antiserotonin agent with H1 receptor antagonism, methysergide, a serotonin antagonist and bellergal (mixture of phenobarbitone 20 mg, ergotamine tartrate 0.3 mg and belladonna alkaloids 0.1 mg). Their ability to reduce attack frequency was compared and clinical improvement was defined as either headache free or substantially improved. Ninety-two patients received 12–24 mg/day of cyproheptadine, 137 patients received 6 mg/day of methysergide, 174 patients received the bellergal mixture and 50 were treated with placebo. Clinical improvement was 34% with bellergal, 64% with methysergide, 46% with cyproheptadine and 20% with placebo. No statistical analysis was made comparing cyproheptadine with placebo [18]. Thus, the result with cyproheptadine is only suggestive of a possible effect of antihistamines in migraine treatment.
Sicuteri et al. treated 32 outpatients suffering from migraine with the antihistaminic substance named BC-105, later known as pizotifen. BC-105 also possesses a strong antiserotonin effect. Patients were treated with a maintenance dose of 1.5–2 mg/day (up to 4–5 mg). No predetermined mandatory duration was mentioned and the study was not blinded or placebo controlled. Response to treatment was usually experienced after 10–20 days of treatment. A third of the patients reported absence or significant attenuation of attacks and 40% reported a lower frequency or increased response to acute therapy with ergotamine. Interestingly, BC-105 increased the resilience against migraine attacks induced with trinitroglycerin and reserpine. Side effects were well documented in this study, with 90% of the patients developing an increased appetite. Patients gained 2–5 kg during the first month of treatment. Fatigue and drowsiness was a side effect in 70%. The drug was administered with a starting dose of 0.5 mg twice a day (b.i.d.) increasing to 1 mg b.i.d. after 4–5 days. This was to minimize the initial drowsiness typically experienced during the first period of treatment [19].
Selby et al. studied BC-105 in 40 patients, 11 with migraine with aura, 27 with migraine without aura and 2 with cluster headache. Thirty-five were treated with a dose of 1.5 mg (3 tablets) daily. Two patients received 1 mg and three patients received 2–3 mg/day. The design was uncontrolled without placebo. 42.5% (17 patients) clinically improved with 2 becoming headache free and 15 with a reduction of attack frequency between 25 and 50%. This study reported fewer side effects which the author interpreted as a result of the lesser dose [20].
Another comparative trial investigated three drugs relevant to histamine. Cyproheptadine, BC-105 (pizotifen) and methdilazine, a drug with a four times greater antihistaminic action than promethazine. The patients recruited were not randomly allocated and furthermore had the possibility to shift to another group after 1 month if the current treatment failed. Because of the free movement between the groups, only data for the first month were statistically analyzed. The placebo group of patients was drawn from two other studies conducted simultaneously. Clinical improvement after 1 month was defined as headache free or a reduction in attack frequency of at least 50%. Sixty-one patients received cyproheptadine 4–8 mg three times a day (t.i.d.) of whom 40% improved. Fifty-three patients received 1.5–3 mg of BC-105 t.i.d. with 58% improving and 51 patients received methdilazine 8–16 mg b.i.d. of which 41% improved. All three resulted in a lesser improvement than methysergide, but the compound BC-105 was also significantly better than placebo. Cyproheptadine and methdilazine showed only a positive trend [21].
In a double-blind placebo controlled crossover study, Osterman investigated the effect of Sandomigran® (pizotifen or BC-105), and Divascan®, a serotonin antagonist in migraine prophylaxis. Four patients with migraine with aura and 26 patients with migraine without aura were included. All patients experienced at least 2–3 attacks per month and had a confirmed diagnosis based on then accepted criteria (Ad hoc committee on classification of headache 1962). Three patients discontinued due to adverse events, lack of compliance or unpleasant side effects. Twenty-seven patients were divided into three groups with different treatment sequences of divascan, pizotifen and placebo. Each treatment was given for 8 weeks in a total period of 24 weeks and all three compounds were given in gradually increasing doses using the same amount of capsules. The dose of pizotifen started at 0.5 mg (1 capsule) increasing to a daily maintenance dose of 3 mg (2 capsules, t.i.d.) at day 11. Divascan started at 2.5 mg (1 capsule) increasing to a daily maintenance dose of 15 mg (2 capsules t.i.d.) at day 11. Side effects caused some patients to discontinue the maintenance doses of both drugs. Four patients had only 1.5–2.5 mg/day and 2 patients 10–12.5 mg/day of pizotifen and divascan respectively. The patients kept a headache diary during the trial, with attack frequency, duration and severity as well as the use of attack medication. Severity was rated using an arbitrary 3 point scale and only data from the last 6 weeks of each treatment were analyzed as the first 2 weeks served as wash out period. Treatment with pizotifen gave a significantly lower attack frequency than both placebo and divascan. It also significantly reduced the mean headache index. No significant difference in the duration of attacks was observed. Consumption of ergotamines was significantly higher in the placebo group versus pizotifen and divascan respectively, but not when comparing pizotifen and divascan. In overall evaluation of the treatment divascan did significantly better than placebo but pizotifen had better effect than both placebo and divascan with 70% reporting a good or very good effect. However, when looking at the side effects the authors found that the treatment with pizotifen resulted in significantly more side effects. Most frequent were drowsiness and weight gain (> 1.5 kg) [22].
A multicenter double-blind placebo controlled study in 36 patients in general practice also investigated the effect of pizotifen. All patients had a history of migraine with at least 4 attacks per month. Twenty-four of the patients had failed previous prophylactic therapy. The dose of pizotifen was increased gradually to a daily dose of 1 mg three times a day at day 24 and onwards. The treatment period was 12 weeks and each patient kept a record of frequency and severity of migraine attacks. Twenty-eight patients completed the trial, 14 on pizotifen and 14 on placebo. No statistical analysis was made, but 6 patients reported complete resolution, 6 reported reduced frequency and severity and only 2 patients did not improve clinically. All fourteen patients given placebo failed to show any improvement [23].
Anthony and Lance performed a controlled double blind trial of the H2 receptor antagonist cimetidine alone or in combination with the H1 receptor antagonist chlorpheniramine as migraine prophylaxis. Twenty-four patients with migraine without aura, and 1 with basilar symptoms received 3 different treatments, each for 1 month during 3 consecutive months. The treatments consisted of 1 month of 200 mg (2 tablets four times a day (q.i.d.)) cimetidine and chlorpheniramine placebo (1 capsule q.i.d.), 1 month of 200 mg (two tablets q.i.d.) cimetidine and chlorpheniramine maleate 4 mg (1 capsule q.i.d) and 1 month of cimetidine placebo (2 tablets q.i.d.) and chlorpheniramine placebo (1 capsule q.i.d.). Patients were randomly allocated to the treatment sequence and kept a record of headache intensity and frequency as well as any side effects. Nineteen patients completed the trial and results were that neither cimetidine in combination with chlorpheniramine nor cimetidine alone proved better than placebo. The authors interpreted the outcome as a result of the intracellular histamine formation by decarboxylation of histidine in multiple tissues, generating headache via other pathways or mechanisms than H1 or H2 receptors [24]. Another explanation may be a short receptor residence time at the H1 receptor by chlorpheniramine (Ki 5–30 nM) [4]. Furthermore, by today's standards only 1 month of preventative medication is not sufficient to precisely estimate results in migraine prophylaxis. A minimum of 3 months for a phase II and up to 6 months for a phase III study is recommended [25]. Nanda et al. investigated the same drug-placebo combination for 3 months in each group over 9 months combined. Twenty-eight patients with migraine without aura and 6 patients with migraine with aura were included in the trial of which 22 patients began all three periods, but only 16 completed the full 9 months. These patients were allowed to move forward to another treatment group before the 3 months were completed if their headache frequency intensified. The authors failed to show a positive effect on migraine even with a 3 months treatment period. They found the same side effects with drowsiness related to chlorpheniramine and dizziness related to cimetidine [26]. These two studies were blind and placebo controlled and so provide the best evidence. However, using a H2 receptor antagonist alone or in combination with H1 receptor antagonist showed no significant relief of migraine when used prophylactically.
Cinnarizine, a calcium channel antagonist with H1 antihistaminic action and a drug used in Meniere's disease was tested in migraine prophylaxis. Two open label trials, one with 80 participants and another with 60 tried out cinnarizine in doses up to 75 mg daily in 12 and 14 weeks respectively. Safety and efficacy was measured and both studies generally consider cinnarizine well-tolerated in their participants. Although both groups report a significant reduction of headache frequency the open trial design limits the results to only a hypothetical positive prophylactic effect of cinnarizine [27, 28]. A double blind parallel group study investigated cinnarizine vs. sodium valproate. One hundred four participants were randomized to a daily treatment with either 50 mg cinnarizine (50 participants) or 400 mg valproate (54 participants) for 12 weeks. Dropout rate was ~ 20% for both arms and mainly because of side effects. Valproate proved more effective than cinnarizine but since there was no placebo control efficacy results may be overestimated [29].
A double blind placebo controlled parallel group study of cinnarizine in the prophylaxis of migraine in children was conducted by Ashrafi et al. [30]. Sixty-eight participants aged 5–17 years with migraine with and without aura according to the 2004 IHS criteria for migraine [31] were randomized into 2 groups after 4 weeks of washout. The groups consisted of a treatment group with 50 mg cinnarizine daily (1.5 mg/kg/day for children weighing less than 30 kg) and a placebo group. During a 12 week treatment period participants kept a headache diary and primary outcome measures were frequency, intensity and duration of migraine. Adverse events were too recorded with weight gain and extra pyramidal signs monitored during the trial. Dropout rate was ~ 12% and ~ 5% for the treatment and placebo group, respectively. Cinnarizine significantly reduced headache frequency to < 50% in 60% of the patients compared to only 31.3% in the placebo group.
In conclusion, low level of evidence and conflicting results make it difficult to determine whether or not H1 or H2 receptor antagonists are effective in migraine treatment. There is a reasonable indication that pizotifen, cinnarizine and also amitriptyline have effect but they have many other effects in addition to being antihistamines. More pure antihistamines such as chlorpheniramine have not shown convincing efficacy. It would be interesting to study the efficacy of pure antihistamines using modern principles of drug trials [25]. The antihistamines used in the trials have primarily an H1 antagonistic effect, but also exert antagonism on other receptors, mainly serotonin receptors. The serotonergic effects in migraine is well described elsewhere [32]. Although the complete sites of action remains to be fully described. Serotonin and histamine are both secreted from the mast cells in dura mater [13, 33] and it is likely that the antiserotonin and antihistamine effects potentiate each other, making the results difficult to interpret. Finally the old antihistamines could not be used in high doses because of sedation and weight gain. It might be worth to try high doses of non-sedating modern antihistamines.
Histamine induction of migraine
The advent of diagnostic criteria for migraine, first unofficial [34] and then internationally accepted ICHD-1 [35] made it possible to further study the relation between histamine induced headache and migraine. Although histamine induction of headache dates back to the 1920s [6] much remained to be elucidated when the modern provocation studies began. The initial hypothesis was that H1 and – to a lesser extend – H2 receptors on intracranial blood vessels was involved, but the clinical studies [36], experimental studies on cerebral blood flow in human [37] and isolated intra- and extracranial blood vessels [38] found that it was in fact the vasodilatation of the extracerebral vessels that caused the pain.
Krabbe and Olesen investigated a 30 min intravenous infusion of histamine with increasing doses (0.16–0.33-0.66 μg/kg/min.) in 48 participants, 13 healthy volunteers, 10 patients with chronic tension type headache then called chronic muscle contraction headache and 25 patients with migraine without aura, then called common migraine. The objective was to evaluate the sensitivity to histamine in normal subjects and in patients with these headaches and to develop an experimental model of vascular headache. All 48 participants received a continuous infusion of histamine chloride for 30 min. 24 of 25 migraineurs developed a throbbing headache, while participants from the two other groups only experienced, at worst, a moderate, pressing type of headache. Adverse events from the histamine infusion consisted mainly of a heating sensation in the face and palpitations. Objectively, all participants developed a flushing of the face, lowering of blood pressure and increased heart rate. No serious adverse events occurred during the study.
In 18 patients who developed headache during the histamine infusion, 0.5 mg/kg of the H1 receptor antagonist mepyramine was administered intravenously for the last 2 min of the histamine infusion. Mepyramine greatly reduced or abolished the headache in 15 of 18 migraineurs. In 10 of the patients suffering from migraine who developed a severe throbbing headache, another single blinded crossover study was performed with cimetidine, an H2 receptor antagonist. A pretreatment with cimetidine was administered intravenously with a bolus of 3.3 mg/kg, followed by a continuous infusion of 1.66 mg/kg/hour for 45 min finished by the infusion of histamine. The pretreatment with cimetidine slightly but significantly decreased the headache. The only side effect was a metallic taste in the mouth in the majority of the patients [36]. This study proved that histamine induces more or stronger headache in migraine patients than in normal individuals. H1 antagonism was effective in aborting the headache and pretreatment with an H2 antagonism had some effect.
In a double blind placebo-controlled cross-over study, Lassen et al. investigated whether pretreatment with the H1 receptor antagonist mepyramine had an effect on histamine induced headache. In 20 patients with migraine without aura histamine was administered intravenously as an infusion of 0.5 μg/kg/min for 20 min. Prior to this a pretreatment with 0.5 mg/kg mepyramine or placebo (0.9% NaCl) was infused intravenously for 10 min. Data from the first 3 h were documented at the study site and then data were recorded by the patients after discharge for 8 h. Histamine induced an immediate and a delayed headache. Immediate headache was defined as the headache occurring during the first 40 min after start of infusion and the delayed headache was defined as occurring from 40 min to 12 h after start of infusion.
The study was first of its kind describing that a histamine infusion can provoke a delayed genuine migraine attack in migraineurs, as 5 of 10 patients developed an attack fulfilling IHS criteria for migraine without aura. Pretreatment with mepyramine prevented development of both the immediate and the delayed headache [39]. Glyceryl trinitrate (GTN), a nitric oxide donor, is also a potent headache inducer [40] and similar to histamine capable of inducing an immediate headache followed hours later by a delayed migraine-like headache. The headache caused by both substances is biphasic in migraine patients suggesting a shared pathway. However, GTN induced migraine is resistant to H1 receptor blockade with mepyramine [41] and histamine could therefore not be the common mediator. The question of nitric oxide being a common mediator of histamine and GTN induced migraine was investigated in two double-blinded and placebo controlled studies, using L-NMMA, a non-selective nitric oxide synthase inhibitor to prevent histamine induced headache in 9 healthy male volunteers [42] and in 12 patients with migraine without aura [43]. Although nitric oxide synthase (NOS) inhibition is effective as a treatment of spontaneous attacks [44, 45], both studies showed no effect on the immediate or delayed headache induced by histamine after pre-treatment with L-NMMA. This underlines the need of further investigation of histamine's site of action. Because histamine is unable to cross the blood-brain barrier and H1 receptors are present in the endothelium of cerebral arteries, migraine attacks could have an origin in the walls of intracerebral arteries and not in the brain itself [41].
Histamine inhalation was investigated by Lassen et al. in 12 patients with migraine without aura, 2 patients with migraine with aura and 1 patient with migraine both with and without aura. They were matched with 15 healthy volunteers in a double blind study. All participants underwent 2 min inhalation periods with 2-fold increase in dose of histamine for every period. The objectives were to evaluate whether histamine inhalation could provoke a headache, whether it showed dose-dependency, whether induced attacks were genuine migraine attacks and whether attacks were induced with the same frequency in both groups. Immediate and delayed headache were reported in both groups with no significant difference, but only migraineurs (6 of 15) developed a headache fulfilling the IHS criteria for migraine without aura. Development of migraine after inhalation had a positive predictive value of 1.0, but the sensitivity was poor. The clinical signs and symptoms other than headache were flushing, heat sensation, palpitation, coughing, dizziness and dysphonia, none of which were severe [46].
Histamine plasma levels in migraine patients have been reported elevated compared with controls both ictally and interictally [47] while another study reported no change during attacks but significant difference between migraineurs and controls between attacks [48]. Latest unpublished results from a biomarker study in patients with migraine without aura using mass spectrometry found that histamine levels both during and outside of attacks were below detection limit and we will not review this further.
H3 and H4 receptor pharmacology and possible involvement in migraine
A third member of the histamine receptor family was discovered pharmacologically by Arrang in 1983 when he showed that histamine inhibited its own release from depolarized slices of rat cerebral cortex. The receptor responsible was identified as a presynaptic inhibitory receptor – an autoreceptor – independent of other neurotransmitter antagonists and with a different ligand profile. He concluded that a novel class of histamine receptors was discovered and proposed the name H3 [49]. The histamine H3 receptor cDNA was cloned by Lovenberg and colleagues in 1999 and they described an extensive expression in the rat CNS especially in the caudate nucleus, thalamus and cortex [50]. Apart from the receptor's full length polypeptide approximately 20 human isoforms have been described [3]. Studies of rat, guinea pig and human brains contribute to the knowledge of the H3 receptor's expression in mammalian CNS. The H3 receptor has been mapped by various methods such as autoradiography and later by in situ hybridization and reverse transcription polymerase chain reaction of H3 receptor mRNA. Countless studies report expression of the H3 receptor in the brain of rodents, guinea pigs, monkeys and humans. Thus there is good evidence that histamine H3 receptor is present in many important brain structures e.g. cortex, cerebellum, dorsal thalamus, hypothalamus, amygdala, hippocampus, striatum and basal ganglia. The receptor is primarily located as a presynaptic autoreceptor on histaminergic neurons (on dendrites, axons and somata), which are localized in the tuberomamillary nucleus in the posterior hypothalamus of rodents and humans, or as a heteroreceptor in non-histaminergic neurons. There is some evidence for a postsynaptic H3 receptor in the CNS as well as a location in the PNS (Fig. 2) [3, 51, 52].
Neuronal H3 receptors are located on both histaminergic (brown) and non-histaminergic neurons (arrows). On histaminergic neurons H3 acts as an autoreceptor inhibiting the release of histamine itself. The figure shows the complex distribution of H3 receptors that emphasizes the challenge of predicting the effects mediated by H3 receptors. Reprinted from (12) Copyright© 2015 with permission from ASPET, Pharmacol Rev.
The H3 receptor alone has been reviewed recently [52] and alongside the H1, H2 and H4 receptors [3]. The histamine H3 receptor has multiple signal transduction mechanisms. The receptor couples to Gi/o protein leading to inhibition of adenylate cyclase (AC) and a reduction of cytosolic cAMP (the opposite action of the H2 receptor which stimulates AC) is one of the main signaling mechanisms (Fig. 3). The H3 receptor also signals by activation of mitogen-activated protein kinase (MAPK), by the Akt/PKB signaling pathway and via activation of phospholipase C (PLC) leading to an increase in cytosolic calcium with the latter leading to an inhibition of histamine synthesis and release, hence the auto-receptor function [3].
Downstream signaling from the H3 receptor. Opposite to the H2 receptor, adenylate cyclase is inhibited by the H3 receptor. Reprinted from (13) Copyright© 2016 with permission from ASPET, Mol Pharmacol
The numerous functions of the histamine H3 receptor reflect its widespread localization in the central and peripheral nervous systems as well as interactions with - and influence by - other neurotransmitters and neuropeptides. Many functions are still hypothetical or controversial, particularly the effects in vivo. In general, the receptor mediates the function of histamine itself in the nervous system. The autoreceptor inhibits the release of histamine from histaminergic neurons and this receptor has a significant constitutive activity which refers to the ability of signaling independent of agonist action. The presynaptically located H3 receptor regulates the release of histamine and other neurotransmitters (serotonin, GABA, glutamate, noradrenaline and possibly acetylcholine and dopamine) and neuropeptides in the CNS and PNS (Fig. 4). This links the histamine H3 receptor to several neurological and psychiatric disorders with H3 agonists being potential treatments in Alzheimer's and Parkinson's disease, schizophrenia, sleep disorders and addiction [52]. H3 agonists might also perhaps be effective in migraine.
Structural formula of pitolisant
The role of histamine in neurogenic inflammation has been reviewed by Rosa and Fantozzi who described an interaction of mast cells and afferent nerve fibers. Mast cell degranulation is stimulated by release of neuropeptides (e.g. CGRP, substance P and VIP) from the nerve endings [16, 53] and is inhibited by histamine via the H3 receptor [54]. The degranulation of mast cells promotes an inflammatory response including neurogenic inflammation. This leads to a release of inflammatory mediators by afferent neurons which in turn stimulate other mast cells to degranulate and thereby sustain and prolong the inflammation. There is evidence that mast cell degranulation activates meningeal nociceptors and it is possible that mast cell degranulation has a role in migraine [13, 33, 53, 55]. A potential therapeutic target would be a receptor with a stabilizing function on mast cells preventing or minimizing the degranulation and secondly the neurogenic inflammation. Another possible target is a receptor located on the nerve terminals inhibiting the release of neuropeptides. The H3 receptor agonist Rα-methylhistamine inhibited plasma protein extravasation following capsaicin or electrical stimulation of the trigeminal nerve [56]. This suggests that neuropeptide release from sensory C fibers in the rat meninges is at least partially controlled by H3 receptors. Better knowledge of these mechanisms in neurogenic inflammation could create a possibility of intervening with receptor specific drugs.
Histamine reduces nociceptive transmission when injected into the cerebrospinal fluid or microinjected in brain structures. Central H1 and H2 receptors are thought to mediate this effect, but theoretically H3 receptors could also be involved. An antagonist effect on the H3 receptor leads to an increase of brain histamine and several basic studies of acute and chronic pain tests have investigated H3 antagonism as a modifier of nociceptive thresholds. Investigation of thioperamide, an H3 receptor inverse agonist, reduces nociception in rodents, but the effect is limited and shows a biphasic response with decreasing effects at highest doses [57].
A single research group investigated doses of 1–10 ng histamine injected subcutaneously twice a week as migraine treatment [58] and subsequently compared it with topiramate [59] in patients with refractory migraine with positive results. Their hypothesis was that histamine acts as an agonist on H3 receptors on mast cells thereby reducing the neurogenic inflammation. The group continued with an investigation of the H3 agonist Nα-methylhistamine in migraine prophylaxis. They published their results from phase I and II studies with 30 healthy volunteers and 17 patients with migraine without aura and 1 patient with migraine with aura. Doses of 1–3 ng subcutaneous twice a week proved effective in migraine patients with a reduction of frequency, intensity and duration of the attacks. Adverse effects were intense headache with doses above 10 ng and 4 ng in healthy volunteers and migraine patients respectively. The authors attributed this to an increased H1 agonistic effect [60]. A double blind placebo controlled phase III study was performed and results were published in 2006. Sixty patients with migraine (50 migraine without aura and 10 migraine with aura) were included. Two from the placebo group and 3 patients from the Nα group left the study and 55 patients completed the 12 week period. The study confirmed the results seen in the phase II trial along with lower intake of rescue analgesics in the Nα-group vs. the placebo group and without any adverse events. The hypothesis in the study was that low doses of a H3 agonist modulates the interaction between mast cells and C-fiber endings and by reducing histamine release lowering the neurogenic inflammation [61]. The doses used in these studies are unusually low making it difficult to understand the mechanism of action or to even accept the results of such minute doses. Furthermore, Nα-methylhistamine does not cross the blood brain barrier. Apparently, no filing for registration of Nα-methylhistamine has been done, so industry is not convinced of these results.
The only H3 receptor agent approved for medical use is pitolisant, an H3 inverse agonist. Pitolisant has recently been discovered to be an efficient treatment of narcolepsy and marketed by Bioprojet Pharma as Wakix. The mechanism behind is increased histamine in the brain leading to an increased wakefulness. One of the pivotal studies described headache as an adverse event in 35% of the participants [62]. In a review by Schwartz of the first clinical trials with pitolisant in narcolepsy and Parkinson's disease, he also describes headache as an adverse event of pitolisant. Overall in these studies 9.7% developed headache on pitolisant compared to 2.9% on placebo [63]. Pitolisant readily crosses the blood brain barrier [3] but histamine is known to lack this ability. It remains unclear if this headache observed in the pitolisant trials is due to central or peripheral mechanisms but it is interesting that a drug which promotes histamine release is linked to an increased susceptibility of headache.
The discovery of the histamine H4 receptor was reported by several independent research groups around the turn of the millennium. The H4 receptor has ~ 40% homology with the H3 receptor. Two additional inactive isoforms have been identified [3]. The H4 receptor is a coupled to Gi/Go protein and uses intracellular Ca2+ as the primary second messenger. In recombinant systems cAMP increase or decrease has been coupled to an agonist response and inverse agonist response, respectively, indicating mediation by adenylate cyclase. There are probably additional signaling mechanisms and supporting evidence is emerging. The localization of the H4 receptor is complicated by deficiency of validated H4 selective antibodies to identify the H4 receptor expression. Consensus is that H4 receptors are present in the bone marrow and hematopoietic cells. H4 receptor expression was also shown in sensory neurons innervating skin in mice but there is no evidence for its presence in human sensory neurons yet. Pharmacological methods have shown that the H4 receptor is expressed on mast cells [3] and there is some evidence that microglial cells express H4 receptors [64].
The literature describes an immune modulating function of the H4 receptor with an involvement in inflammatory responses. It mediates chemotaxis and is involved in cytokine release from various immune cells. Coruzzi et al. suggested anti-inflammatory and antinociceptive effects of H4 antagonists in a rat model [65], a characteristic shared with the H3 receptor [3]. The H4 receptor has not yet been associated with migraine and further description of its localization and function is needed.
Conclusions and future perspectives
Histamine receptors H1, H2, H3 and H4 are widespread throughout the body but there is limited knowledge about the H4 receptor. H3 is an autoreceptor, inhibiting release of histamine where H1 and H2 have pure agonistic effects and have effect on multiple sites. Modern provocation studies with histamine have increased the interest in the histaminergic system in relation to migraine because histamine proved to be an effective migraine provoking agent. Studies of the effect of antihistamines in migraine are limited and of poor quality. Thus, there is little support for H1 or H2 antihistamines as preventive migraine medication. In addition, there are undesirable adverse effects. Still, non-sedating H1 antihistamines need to be appropriately tested. This has not been done and it might provide valuable information of histamine's site of action and it's relation to migraine. There are positive reports about the H3 receptor agonist Nα-methylhistamine as migraine treatment, but the use of almost homeopathic doses makes the results less credible. Additional exploration of the histaminergic system, peripheral and central, could reveal further goals for migraine therapy.
B.i.d.:
Two times a day
CGRP:
Calcitonin gene-related peptide
Glyceryl trinitrate
MAPK:
Mitogen-activated protein kinase
NOS:
PLC:
Q.i.d.:
Four times a day
T.i.d.:
Three times a day
Vasoactive intestinal peptide
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Danish Headache Center and Department of Neurology N39, University of Copenhagen, Rigshospitalet Glostrup, DK-2600, Copenhagen, Denmark
Jacob Worm, Katrine Falkenberg & Jes Olesen
Jacob Worm
Katrine Falkenberg
Jes Olesen
JW and JO conceived and designed the review. JW conducted the literature search and drafted the manuscript. JO and KF contributed to the manuscript and all authors revised the manuscript for intellectual content. All authors read and approved the final manuscript.
Correspondence to Jes Olesen.
Worm, J., Falkenberg, K. & Olesen, J. Histamine and migraine revisited: mechanisms and possible drug targets. J Headache Pain 20, 30 (2019). https://doi.org/10.1186/s10194-019-0984-1
Accepted: 18 March 2019
Histamine receptors
Drug targets


text:
3975 Verdi este un asteroid din centura principală, descoperit pe 19 octombrie 1982 de Freimut Börngen.

Legături externe

 3975 Verdi în JPL Small-Body Database
 3975 Verdi în baza de date a Minor Planet Center
 Diagrama orbitei asteroidului 3975 Verdi (JPL)

Obiecte astronomice descoperite în 1982
Centura de asteroizi

redpajama_set_name: RedPajamaWikipedia


text:
Bridger Coal Company
932 9 mile road
Point of Rocks, WY 82942
Jim Bridger Plant is named for the renowned explorer and mountain man, John Jim Bridger.
His pioneering spirit is alive today in the way this power facility has responded to its role as a low-cost… read more
His pioneering spirit is alive today in the way this power facility has responded to its role as a low-cost energy producer, resource manager
and environmental steward. Energy, a natural resource. A massive amount of energy is held by nature beneath the rugged, beautiful face
of Wyoming: oil, gas, uranium, coal.
That geologic legacy is the foundation of what today is one
of the largest electric generating complexes in the Rocky
Mountain area: the coal-fueled Jim Bridger steam-electric plant.
Sub-bituminous coal stretches out for miles just beneath
the surface of southwestern Wyoming; the product of
forests and swamps changed by time into vast coal seams.
It is the energy locked in that coal that enables this facility
to produce up to 2,119,000 kilowatts of electricity per hour
from four generating units. That electricity serves people
throughout the West. To get the job done requires the talents
of nearly 350 skilled and dedicated Wyoming residents.
People, power and production
Converting coal into electric energy available at the flip
of a switch can be described in just a few words: coal is
burned to produce high-pressure steam that spins large
turbine-generators, which produce electricity. In practice,
this process requires a complex blending of systems.
Four operating units, each with a 2,800-degree furnace,
produce 1,000-degree steam, which turn turbines.

redpajama_set_name: RedPajamaCommonCrawl


Register to Vote in Tennessee - Now Online!
The primary election will be held on Thursday, August 2 with the general election set for Tuesday, November 6.
Registering to vote takes a few minutes and can be done with just a couple clicks. Register to vote now!


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text:
Q: C# generics issue that is not present in Java I'm having some difficulties understanding how csharp's generics work compared to Java ones.
I have written the following example in both c# and java
java
abstract class Gun { }

class Laser extends Gun { }

class Flamethrower extends Gun { }

abstract class GunConfig<T extends Gun> {
    public T gun;
}

class LaserConfig extends GunConfig<Laser> { }

class FlamethrowerConfig extends GunConfig<Flamethrower> { }

public class MyClass {
    public static void main(String args[]) {
      GunConfig[] configs = new GunConfig[2];

      configs[0] = new FlamethrowerConfig();
      configs[1] = new LaserConfig();

      System.out.println(configs[0]);
      System.out.println(configs[1]);
    }
}

csharp
abstract class Gun { }

class Laser : Gun { }

class Flamethrower : Gun { }

abstract class GunConfig<T> where T : Gun {
    public T gun;
}

class LaserConfig : GunConfig<Laser> { }

class FlamethrowerConfig : GunConfig<Flamethrower> { }

public class Program
{
    public static void Main()
    {
        GunConfig<Gun>[] configs = new GunConfig<Gun>[2];

        configs[0] = new FlamethrowerConfig();   // <--- Cannot implicitly convert 'FlamethrowerConfig' into 'GunConfig<Gun>'
        configs[1] = new LaserConfig();

        Console.WriteLine(configs[0]);
        Console.WriteLine(configs[1]);
    }
}

Before adding the generic type to the GunConfig class I had something like this
abstract class GunConfig {
    public Gun gun;
}

class LaserConfig : GunConfig {
    public void DoSomething() {
        var laser = (Laser)gun;
    }
}

I simply used to cast the base Gun instance to whatever my class was supposed to use, that make it so you can have a LaserConfig instance with another type of Gun based instance inside which would make the cast fail.

A: You can add another non-generic GunConfig class and derive GunConfig<T> from it - to circumvent that collection typeparameter issue. It's a little annoying with the extra class you don't really need outside the collection, but actually only one or two more lines of code.
abstract class Gun { }

class Laser : Gun { }

class Flamethrower : Gun { }

abstract class GunConfig { // this resolves the type mismatch issue
}

abstract class GunConfig<T> : GunConfig where T : Gun {
    public T gun;
}

class LaserConfig : GunConfig<Laser> { }

class FlamethrowerConfig : GunConfig<Flamethrower> { }

public class Program
{
    public static void Main()
    {
        GunConfig[] configs = new GunConfig[2];

        configs[0] = new FlamethrowerConfig();   // no error now
        configs[1] = new LaserConfig();

        Console.WriteLine(configs[0]);
        Console.WriteLine(configs[1]);
    }
}

redpajama_set_name: RedPajamaStackExchange


text:
Red Bull Considers F1 Return to Honda in Wake of Failed Deal with Porsche
Red Bull determined to be 'the only team besides Ferrari that builds the car and engine.'
Mark Thompson Getty Images The Red Bull racing marriage with Honda just might be getting another chance, as talks about re-firing a closer relationship are a"logical and interesting" step for Red Bull, team boss Christian Horner admits.Mark Thompson Getty Images The Red Bull racing marriage with Honda just might be getting another chance, as talks about re-firing a closer relationship are a"logical and interesting" step for Red Bull, team boss Christian Horner admits.Alex Albon was diagnosed with appendicitis —and the Dutchman arguably knocked it out of the park.ENGLEWOOD — The Broncos hired Nathaniel Hackett for his energy, innovation and offensive mind.
Logical and interesting in the wake of the collapse of Red Bull's talks with Porsche about a 50% works buy-in ended a potential deal.Red Bull team consultant Helmut Marko said he would instead be flying to Japan shortly for new talks with Honda.Red Bull team consultant Helmut Marko said he would instead be flying to Japan shortly for new talks with Honda.Honda took an official step away from Formula 1 at the end of last year, but the Red Bull Powertrains-branded power units in the 2022 care are still based on Honda infrastructure." According to ESPN , de Vries's name has in the running for a possible F1 seat next season as Williams has yet to confirm its 2023 driver lineup.Related Stories Horner: Red Bull Will Be Just Fine Without Porsche In the meantime, Red Bull has been ramping up its very own engine operations.Related Stories Horner: Red Bull Will Be Just Fine Without Porsche In the meantime, Red Bull has been ramping up its very own engine operations."When Honda announced their exit from Formula 1, we changed our attitude and decided to build engines ourselves," Horner told European outlet Speed Week.Clumsy moments were predictable for a first-time head coach and a first-time offensive coordinator (Justin Outten).
"That was associated with a clear risk, so a partnership with a fantastic company like Porsche was considered."That was associated with a clear risk, so a partnership with a fantastic company like Porsche was considered."I don't quite know if I am in such a luxury situation that I can choose," he said on the show, per motorsport.It would have made perfect sense.But at the same time we managed to attract highly qualified engineers who are among the best in Formula 1 for our engine project.But at the same time we managed to attract highly qualified engineers who are among the best in Formula 1 for our engine project.We set up the factory in 55 weeks and we already have our first V6 on the test bench.I have been in talks with Williams for a long time, and I was also able to make my debut there last weekend."We developed it entirely by ourselves," he insists."We developed it entirely by ourselves," he insists."It has to improve.
"We think we have the skills to go our own way." Red Bull is marching toward a F1 Constructors' Championship and Drivers' Championship with Max Verstappen." Red Bull is marching toward a F1 Constructors' Championship and Drivers' Championship with Max Verstappen.I will fly there on Monday.Dan Istitene - Formula 1 Getty Images Horner says full Ferrari-like independence is now in Red Bull's DNA, insisting that any collaboration with Porsche would have had to"respect these principles." "Porsche might have made sense," Horner said,"but it would have significantly changed the identity and integrity of our team." "Porsche might have made sense," Horner said,"but it would have significantly changed the identity and integrity of our team.In the future, we will be the only team besides Ferrari that builds the car and engine on the same site." Alpine reportedly isn't in a rush to fill the vacancy left by Fernando Alonso, who will compete for Aston Martin starting next season.5).
It's the next chapter in our F1 history.It's the next chapter in our F1 history." And Horner is not ruling out a scenario where Marko's forthcoming talks with Honda result in a deal."With the new rules for 2026, it's a completely new situation," he said."With the new rules for 2026, it's a completely new situation," he said.Within hours of the team's announcement about the 2023 driver lineup, the 21-year-old refuted the claim on Twitter, saying in part, that he had not "signed a contract with Alpine for 2023."Honda justified its exit by concentrating on the electrification of production cars, but with the new regulations and the 50-50 split between combustion and electric motors, there is an interesting new situation."It would be logical and interesting to discuss the new situation with Honda, but it's not an urgency."It would be logical and interesting to discuss the new situation with Honda, but it's not an urgency.Wilson is 8-for-17 for 49 yards in the red zone and 2-for-his-last-9.
" Advertisement - Continue Reading Below.24, news broke that McLaren and Ricciardo "mutually agreed".
Autoweek »
Red Bull Considers F1 Return to Honda in Wake of Failed Deal with Porsche Nyck de Vries Met With Red Bull Advisor About Possible F1 Future Broncos' red-faced, red zone offense needs boost Woman dies, 12-year-old grandson seriously injured after pit bull attack in Colorado
Red Bull Considers F1 Return to Honda in Wake of Failed Deal with PorscheRed Bull determined to be 'the only team besides Ferrari that builds the car and engine.'
Nyck de Vries Met With Red Bull Advisor About Possible F1 FutureNyck de Vries (nyckdevries) made his Formula One race debut at the Italian Grand Prix after Alex Albon was diagnosed with appendicitis—and the Dutchman arguably knocked it out of the park
Broncos' red-faced, red zone offense needs boostBroncos' red-faced, red zone offense needs boost. Finding balance at goal line critical to improvement after fumbles and battery of misfired passes.
Woman dies, 12-year-old grandson seriously injured after pit bull attack in ColoradoThe 89-year-old woman and her grandchild were attacked by two dogs they knew in the backyard of a home near Denver last week, according to police. Ban pitbull. i don't understand people keeping wild animals that can kill you as pets any breed which can be turned so easily into murder torpedoes with bite force measured in tonnage , with as many 'accidents' that simply continue to pile up in the tens of thousands, have no business being owned by anyone outside a zoo
89-year-old dies from injuries suffered in pit bull attackAn 89-year-old woman died four days after she and a 12-year-old boy were attacked by two pit bulls, according to authorities in Colorado.
22 September 2022, Thursday News
These Bay Area companies are announcing layoffs, but it's not all bad, researcher says
PolitiFact - Opponents of California's abortion rights measure mislead on expense to taxpayers


text:
La Nazionale olimpica della Germania di calcio è la rappresentativa calcistica della Germania che rappresenta l'omonimo stato ai Giochi olimpici. Ha ottenuto l'argento alle olimpiadi del 2016.

Storia

Statistiche dettagliate sui tornei internazionali

Giochi olimpici

Tutte le rose

Giochi olimpici

Germania Ovest (dal 1950 al 1990)

Germania riunificata (dal 1991)

NOTA: Per le informazioni sulle rose precedenti al 1952 visionare la pagina della Nazionale maggiore.

Note

Olimpica
Germania


An 11-year-old boy who stayed with and helped an injured homeless man who fell in the street has been honoured by Cambridgeshire's police commissioner.
Noah Fairweather, from St Neots, was given a private tour of police headquarters in Huntingdon on March 21 following a personal invite from Police and Crime Commissioner Jason Ablewhite.
He was invited to meet the commissioner with his parents and younger brother, Miles, after he helped a homeless man when he fell over.
After finding out that Noah wants to be a police officer one day, the commissioner decided a tour of police headquarters would be the best way to thank him. Noah was given a demonstration of police vehicles used by the roads policing officers David Tudman and Lee Rumsey and was also given a private tour of the armoury.
Commissioner Ablewhite said: "It's people like Noah who make me proud to come into work every day. His immediate concern and action for the man who fell shows great community spirit – something that will hold him in great stead as he grows up.


text:
Gold's Guide
Members Only ✦
4:22 is a densely ethereal album from Kanye West and Travis Scott producer Mike Dean
Mike Dean's second solo album has a familiar vibe that still feels brand new.
Tyler Gold — Jun 22, 2021
4:22 by Mike Dean is what's good.
This is the second solo album from hip-hop producer Mike Dean.
Last year, at the height of quarantine, Mike Dean released 4:20, an entrancing album of instrumental, spacey, electronic music.
4:20 was the precursor to this album, but it definitely wasn't the first project that you've heard from Mike Dean. He has production credits with artists including Beyonce, Frank Ocean, and even Madonna. He's worked on every single project album released by both Kanye West and Travis Scott.
Mike Dean is best known as a secret weapon. — Rolling Stone
Dean is also known as one of the most prolific stoners in hip-hop — hence the title of his previous album, which was also released on 4/20 (April 20th) of 4/20 (April 2020). To quote Travis Scott: "it's lit."
4:22 is a proper successor in every way. It's spacey and psychedelic but with more human elements to it. 4:20 leaned almost entirely on super heavy vocoder vocals, deep resonating synths, and electronic guitar instrumentals; 4:22 has some lighter vocoder and auto-tuned vocals, more airy guitars, and there are even some woodwinds thrown into the mix later on. 4:22 clocks in at 28 songs, lasting 1 hour and 50 minutes — about 20 minutes longer than its predecessor.
I didn't even realize this album was released back in April 2021; it was only this week that I opened up Apple Music and noticed it had been released (a delightful surprise).
Familiar, yet new
Some of the tracks on this song sound almost familiar; at times I think I'm listening to the Tenet soundtrack, other times I think it's a Travis Scott song. As soon as this happens, I'm immediately surprised by the ensuing switchup.
Compared to 4:20, which starts uplifting but progresses to an increasingly heavy conclusion, 4:22 feels more light, more uplifting, like the storm clouds moving on, the sunlight peeking out through dark skies.
4:22 is orchestral but modern, ethereal while still being earthly, in a way unlike any other music I've heard.
This is an album to get lost in.
Listen on Spotify or Apple Music, or YouTube Music.
Some additional thoughts
The last track on 4:22 is a reprise of "The Fifth Day", which makes up the earlier half of 4:20. And it's so freaking amazing.
There was an NFT drop to commemorate the album release, a collaboration between Mike Dean and Shepard Fairey, who created OBEY Clothing.
Obey 4:22 NFTs
Obey 4:22 NFTs - Buy, Sell and Trade Limited Edition Goods by Mike Dean x Shepard Fairey
Further reading, listening, and viewing
Zane Lowe does not disappoint here. I like how they mix music in with the interview so it feels like radio.
At Home With MIKE DEAN on Apple Music
Hear where the music takes you. Listen to At Home With MIKE DEAN, a streaming radio station on Apple Music.
"Took it to the moon."
The Needle Drop's interview with Mike Dean is a fascinating history of his career, starting all the way back with Dean's start back in the early 1980's, and moving to the current day. Some comments mentioned that Fantano gets a little weird after the 30 minute mark and I stopped watching around then.
I watched about halfway through the interview in one sitting before pausing to listen to some music and write this article.
Mike's Twitch streams from when he was building up to release are utterly epic.
422 DAY 10 FULL VOD - therealmikedean on Twitch
therealmikedean went live on Twitch. Catch up on their Music VOD now.
They're like full-fledged concerts, with lighting effects, epic music, and Mike smoking copious amounts of weed as he moves from keyboard to keyboard with an incredible dexterity.
Bonus: some memes which describe what it feels like to listen to this album
Travis Scott's "Highest in the Room" ends with an extended synth solo from Mike, which sparked a million memes that also adequately explain what this entire album feels like.
how i felt listening to the last 30 seconds of highest in the room for the first time pic.twitter.com/0BptHy6PoP
— ☻ jen⁷ #BLM (@babiejim1n) October 4, 2019
That Highest in the room outro was beautiful, it had me like:
#TravisScott pic.twitter.com/jDkWK8K3CZ
— Christopher Harris (@Cryptic_chri5) October 4, 2019
Me listening to the highest in the room outro pic.twitter.com/YKaLXrTtPg
— Rayymón (@RayymonBeatz) October 4, 2019
Subscribe to my monthly email about what's next for tech and content.
Great! Check your inbox and click the link to confirm your membership.
Read more about The Curve or view the archives.
capitalize on creativity
it turns out that writing in lowercase makes it more fun.
The new 'Dune' movie is the first chapter of the next mainstream sci-fi epic
I've read 'Dune' three times and Denis Villenueve's version of Frank Herbert's sci-fi classic surpassed my highest expectations. Here's how the movie compares to the book.
Oct 30, 2021 — 8 min read
About Gold's Guide
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Copyright © Tyler Gold 2021


A minor patch was released today. Patch notes are here. This patch finishes up systems that were rushed out with the last update. I am getting back to the farming and cooking systems this week and hope that the Test Server will be open to test both by the end of this week!


Welcome to Bentek Realty Inc.
Bentek Realty Inc. ...your St Lucia Real Estate Broker. We are committed to providing you with excellent service in the St Lucia Real Estate business. We believe that our customers are special and each has unique needs. We pride ourselves in helping each client through constant dialogue and follow through. Our dedication to quality is extremely important, and your best interest is our primary focus. We relish the opportunity to find "Your St. Lucia Property".


I was so glad to see your show at the TLA!!!!! Sorry when your set ended.
You guys are honestly amazing. Only God knows why you are not famous, and rich yet! Your songs bring emotion, and awesome sounds to our ears!
Hey Steve / Nick / Tyler ... This is Mark Allison ... Vocalist & Musician from Los Angeles.
I was checking out some bands and guitar players on Myspace when, literally by accident, lol ... I found your profile... So, I ended up listening to your samples and really liked what I heard... great tones... great tunes... everything sounds current and solid....congrats.
It's always better when we let the music do the talking... so, please feel free to check out my websites, including songs, bio, videos and pics.
Well, I'm more than aware how f*** far away from each other we are, but what the heck? At the end of the day... it's all about the music, isn't it?
If anything clicks... I'd welcome the chance to keep in touch and talk about future plans.
Anyways... thanks for your time.
I just happened upon your website - I am impressed, fellas; Nice work! I've been a musician for many years, and it is a breath of fresh air when you find real talent, good talent. You guys rock! I will be watching for you to come to Baltimore.
You guys rocked it at World Cafe Live!


Recent Arrival! Century Custom AUTOMATIC, contact our digital sales manager deanna.thompson@myfairwayford.com, 6-Way Power Driver Seat Adjuster, Body-Color Power Outside Rear-View Folding Mirrors, Custom Package, Dual Illuminated Visor Vanity Mirrors, Electronic Cruise Control w/Set & Resume Speed, Front & Rear Carpeted Floormats, Preferred Equipment Group 1SB, Trunk Cargo Convenience Net. CARFAX One-Owner. Clean CARFAX. Odometer is 19543 miles below market average! 20/29 City/Highway MPGWe PRIDE ourselves on making your vehicle purchase FUN and STRESS FREE!


text:
News & Events > NewsBreaks
Thomson Acquires Techstreet
by Barbara Quint
Thomson Scientific and Healthcare (http://www.thomson.com/scientific) has acquired a new operation in a move aimed at adding the standards and specifications literature to its document delivery services. Techstreet, Inc., founded in 1997, provides a digital full-text collection of over 500,000 technical information titles, including a master collection of some 150,000 industry standards and specifications. The Techstreet titles also include technical books, materials property data, and technical training material from over a thousand publishers, industry associations, and technical societies.
The Techstreet unit will form part of the Scientific business within the Thomson division and continue to be managed by its founders, Gregg Hammerman, president, and Andrew Bank, vice president of business development. With the Techstreet acquisition, Thomson Scientific adds industry standards to its already strong offerings in sci-tech journals and patents. Terms of the transaction were not disclosed.
In making the announcement, Mike Tansey, CEO of Thomson Scientific, stated: "This business provides Thomson a key source of foundational content that is required by our customers. Adding Techstreet makes Thomson a stronger one-stop resource for technical and intellectual property information for engineering research and development - delivering patents, journal literature, and standards information."
Hammerman added, "As part of Thomson, with its expertise and resources, we will continue to provide mission-critical information resources and information management tools for technical professionals."
Techstreet's collection draws on material from over 350 Standards Developing Organizations (SDOs) around the world, including the American Society for Testing and Materials (ASTM), the American Society of Mechanical Engineers (ASME), the British Standards Institution (BSI), the Institute of Electrical and Electronics Engineers (IEEE), and hundreds more. Most documents can be obtained in both print and electronic format, via subscription or single-document delivery.
The collection of books, technical documents, market research, conference proceedings, journal articles, and training and education products is searchable online and covers research, design, manufacturing, testing, and inspection information for industries such as electrical and electronics, petrochemical, architecture and construction, food safety and public health, wastewater engineering, information technology, and aerospace/aviation. Some 95,000 of its documents are immediately downloadable in Adobe PDF.
Bank stated that he and Hammerman were "excited about this event and the future of Techstreet. Since starting our business in a small Ann Arbor apartment in the pre-dot-com days, we have focused on expanding the company to the tune of double-digit growth. We are proud of our staff and our overall success in building a profitable business that serves 40,000 customers worldwide. We are all looking forward to future successes within the Thomson family."
Bank also indicated that the entire Techstreet staff would remain in place in Ann Arbor, Mich. He added: "Thomson's technology and tools for information delivery are among the best in the world. Long-term plans will incorporate these resources to provide unique product offerings and maximize standards subscription sales."
Chris Pooley, senior vice president for strategic marketing and planning at Thomson Scientific, stated that the acquisition represented a "third leg" in the document delivery services Thomson offers to the engineering community. Thomson plans to link standards and spec literature to other offerings in the future, for example, in the new Thomson Patent Store developed with Thomson's recent acquisition of Delphion.
Serving more than 20 million users, Thomson Corp. had 2002 revenues of $7.8 billion from its global business. The Thomson Scientific operation also includes Derwent, ISI, and Current Drugs among its units.
Barbara Quint was senior editor of Online Searcher, co-editor of The Information Advisor's Guide to Internet Research, and a columnist for Information Today.
5/2/2013 Thomson Reuters' Techstreet Launches Redesigned Website
1/2/2014 Thomson Reuters Updates Techstreet Subscriptions
5/11/2017 Techstreet Adds Licensed Content Through New Partnerships


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Hope Town to Marsh Harbour to collect Ding Ding III
After returning to Hope Town to sell Ding Ding II, we met Mary from London who was in the Bahamas with her employer. Mary works as the private teacher for an English girl while her family is in Miami every year for three months. She wasn't teaching the week she was in the Bahamas so she hitchhiked aboard Whisper to Marsh Harbour and caught the ferry back to Hope Town. As Hans says: "I didn't complain." Maybe we'll make the cover of the sailing magazine, "Latitudes and Attitudes."
Kit Kat's favorite game
Kit Kat's favorite game is "attack the bilge pump." She loves it when there is water in the bilge and she is continually trying to attack the water!
See you in the Exumas!
An update on our travel plans:
we're leaving Hope Town today to go to Marsh Harbour to pick up the new dinghy.
Friday: sail to Little Harbour which is at the southern end of the Abacos.
Saturday or Sunday: sail to Eleuthera
Sunday to April 13: make our way to Staniel Cay starting in the Northern Exumas and heading south.
We'll be out of communication for at least a week since we'll be stopping at small, uninhabited cays (islands) until we get to Staniel Cay. So in the meantime, don't worry about not hearing from us, we're okay and when we get to Staniel Cay we'll post some fantastic pictures of the Northern Exumas. How's that for optimism!
Hope Town's lighthouse
We realized this morning that we've never posted a good picture of the Hope Town lighthouse. We've really gotten to love Hope Town because it is a neat little town with a good bakery/grocery store, great beaches, easy day sails, of course the fun people, but none of that would be the same without the lighthouse. It adds a certain amount of character to the place.
Reaching the finish line
Today is Thursday, March 29, an ordinary day for a lot of people, but a very special day for the crew of Whisper. We're meeting a distinguished individual at the airport this afternoon to join our adventures. His name is Ding Ding III and he is a 10'4" inflatable dinghy all the way from Connecticut. We've already picked up his means of propulsion, an 8hp outboard, and we can't wait to meet him and zoom around the anchorages and to the reefs! Our dear friend Ding Ding II is leaving us today to join the crew of another sailboat, Goosebumps. We'll miss Ding Ding II, but hope that he will be happy and well looked after in his new home. Farewell Ding Ding II!
We've been working out the intricacies of customs in the Bahamas in order to import our new dinghy without paying the 40% duty the Bahamas requires on all imports. We spent some time at the efficient and friendly customs office in Marsh Harbour where we paid the duty on Ding Ding II which allowed us to legally sell him and import Ding Ding III duty free. We've been hankering after a longer dinghy for a long time, not only to take us out to the reefs where we can't get in Ding Ding II, but also to provide a more dry, stable and quick ride in the harbors. In Ding Ding II we've been getting soaked almost every time we go anywhere and have taken to wearing full length rain coats on hot sunny days! Well, as Kristen's dad would say: We're glad we're able to provide so much humour to the anchorage!
Sunday night was meant to be our last night in Hope Town, so our friend Dave treated us and the crew of Gray Fox to dinner at the Harbor Lodge. The food and wine were excellent. It was a real treat to go out to dinner and it was nice to spend some time with good friends that we've met here in Hope Town before leaving.
We sailed to Marsh Harbour on Monday to take care of the customs' paperwork and pick up a few supplies. On Tuesday morning we sailed over to the Southern end of Guana Cay and of course unsuccessfully looked for lobster. The season ends in a couple days so we're starting to get desperate! Pass me the dynamite honey!
Yesterday, in the spirit of harvesting dinner from the sea, we sailed Whisper north and out into the ocean to do some deep sea fishing. It was a bit of a roller coaster, however, and after an hour or so Kristen started to feel really quesy so we turned around and sailed to Hope Town on the Sea of Abaco (the protected, shallow waters of the Bahamas).
Dragging the lures behind Whisper whilst deep-sea fishing.
let's check the first lure....seaweed.
anything on the second lure? seaweed again.
As a wise Mexican once said: When there's no fish for dinner, make tortillas! Dinner in the cockpit anchored off of Guana Cay on Tuesday night: homemade tortillas, black beans, tomatoes, green peppers, scrambled eggs. Yum!
What, Hope Town? You thought we left? No, the lighthouse in Hope Town always pulls you back. Actually, it turns out the guy who bought Ding Ding II is anchored in Hope Town so we sailed back to make the sale. We met up with Toby from the catamaran Lickety Split and spent a rousing few hours at Cap'n Jacks with, gasp, people our own age! It was very exhilarating, but we didn't get back to Whisper until after 1AM and are feeling the effects this morning.
A schooner underway between Marsh Harbour and Man-o-War Cay.
Hope Town to Marsh Harbour to collect Ding Ding II...


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Q: MySQL Process Big Ok, so I don't know if this is a repeat question so I'm sorry if it is (I couldn't find anything like it after searching =/)
My server seems to be running what seems to me a larger than normal mysql process:
PID USER      PR  NI  VIRT  RES  SHR S %CPU %MEM    TIME+  COMMAND
31382 mysql     20   0  562m  97m 4244 S   73 19.7   2830:07 mysqld

But then when I do a SHOW PROCESSLIST in mysql, everything seems to be asleep:
mysql> SHOW PROCESSLIST;
+------+-------+-----------+------+---------+------+-------+------------------+
| Id   | User  | Host      | db   | Command | Time | State | Info             |
+------+-------+-----------+------+---------+------+-------+------------------+
| 3982 | dlp_w | localhost | dlp  | Sleep   |  767 |       | NULL             |
| 3983 | dlp_r | localhost | dlp  | Sleep   |    0 |       | NULL             |
| 3986 | dlp_w | localhost | dlp  | Sleep   |  788 |       | NULL             |
| 3987 | dlp_r | localhost | dlp  | Sleep   |    0 |       | NULL             |
| 3988 | dlp_w | localhost | dlp  | Sleep   |  727 |       | NULL             |
| 3989 | dlp_r | localhost | dlp  | Sleep   |    0 |       | NULL             |
| 4019 | root  | localhost | dlp  | Query   |    0 | NULL  | SHOW PROCESSLIST |
| 4020 | dlp_w | localhost | dlp  | Sleep   |  708 |       | NULL             |
| 4021 | dlp_r | localhost | dlp  | Sleep   |    0 |       | NULL             |
| 4022 | dlp_w | localhost | dlp  | Sleep   |   57 |       | NULL             |
| 4023 | dlp_r | localhost | dlp  | Sleep   |    0 |       | NULL             |
| 4024 | dlp_w | localhost | dlp  | Sleep   |  788 |       | NULL             |
| 4025 | dlp_r | localhost | dlp  | Sleep   |    0 |       | NULL             |
+------+-------+-----------+------+---------+------+-------+------------------+

Although, I am also confused as to why there are so many processes that are asleep. Shouldn't they all go away once a command is finished executing?
Thanks for any and all help =D

A: The process is only  using 100megs of memory. If you have any caching enabled in your config it will put the query+results in memory to make the next ones fast.
As for the sleeping connections. They are connections from your app that aren't closed yet. It would be a horrible assumption by mysql to close the connection after each query. It would mean your app would have to open a new connection for each query and slow down the render time for the page to load.


From the Albuquerque (NM) Journal, an article about Guardianship abuse – in Pennsylvania. We guess the rampant guardianship abuse cases all across New Mexico are simply too hot for the Albuquerque Journal to even report about, showing once again, the incredible power of the Judges in keeping all of their documented crimes and those of their court-appointees under total news black-out. We welcome the day when the Albuquerque Journal finds it within itself to show the same concern for New Mexico residents, as it does for those of Pennsylvania. Please scroll to the bottom of the linked version on the ABQJournal's website, and add your own comments, especially if you live in New Mexico and have suffered abuse under a court-appointed Guardian, Trustee, or Receiver.
For the ABQJournal version of this article, and to leave comments, please go to this webpage here.
New Mexico: What do rapists, pedophiles, thieves, and the court ordered for profit guardian-conservatorship industry have in common?
Debate: Are Florida's seniors endangered by guardianship?


text:
"We are quantum engineers, but on Sundays, we have principles..." J. S. Bell
US Naval Academy Quantum Photonics Laboratory
Magneto-optics
The lab continues to expand. This summer, we installed a room temperature magneto optical system capable of measure defects both in diamond as well as SiC. The image to the left shows the business end of the microscope, with approximately 100mW of 532nm excitation light illuminating a silicon oxide chip drop casted with 40nm diameter nanodiamonds. The GMW electromagnet can produce up to 0.5 T of transverse magnetic field in both directions.
© 2023 by Scientist Personal. Proudly created with Wix.com


How Venture Capital Works for Start-Ups and Small Businesses?
With almost unlimited opportunities the advancement in technology is creating over the past two decades, many startups and small businesses today tend to seek for capital that could bring their dream business to success says Carl Kruse. While there is a wide range of financial sources that they can tap on, most of these entrepreneurs are hesitant in borrowing money from banks and financial lenders because of the risks involve. But good thing is that they've found a good alternative and that is by raising venture capital from the venture capitalists or VCs.
Venture capital is that amount of money that VCs will invest in exchange of ownership in a company which includes a stake in equity and exclusive rights in running the business. Putting it in another way, venture capital is that funding offered by venture capital firms to companies with high potential for growth.
Venture capitalists are those investors who have the capacity and interest to finance certain types of business. Venture capital firms, on the other hand, are registered financial institutions with expertise in raising money from wealthy individuals, companies and private investors - the venture capitalists. VC firm, therefore, is the mediator between venture capitalists and capital seekers.
Because VCs are selective investors, venture capital is not for all businesses. Similar to the filing of bank loan or asking for a line of credit, you need to show proofs that your business has high potential for growth, particularly during the first three years of operation. VCs will ask for your business plan and they will scrutinize your financial projections. To qualify on the first round of funding (or seed round), you have to ensure that you have that business plan well-written and that your management team is fully ready for that business pitch.
Because VCs are the more experienced entrepreneurs, they want to ensure that they can get better Return on Investment (ROI) as well as a fair share in the company's equity. The mere fact that venture capitalism is a high-risk-high-return investment, intelligent investing has always been the standard model of trade. A formal negotiation between the fund seekers and the venture capital firm sets everything in their proper order. It starts with pre-money valuation of the company seeking for capital. After this, VC firm would then decide on how much venture capital are they going to put in. Both parties must also agree on the share of equity each is going to receive. In most cases, VCs get a percentage of equity ranging from 10% to 50%.
The funding lifecycle usually takes 3 to 7 years and could involve 3 to 4 rounds of funding. From startup and growth, to expansion and public listing, venture capitalists are there to assist the company. VCs can harvest the returns on their investments typically after 3 years and eventually earn higher returns when the company goes public in the 5th year onward.
The odds of failing are always there. But VC firms' strategy is to invest on 5 to 10 high-growth potential companies. Economists call this strategy of VCs the "law of averages" where investors believe that large profits of a few can even out the small loses of many.
Any company seeking for capital must ensure that their business is bankable. That is, before approaching a VC firm, they should be confident enough that their business idea is innovative, disruptive and profitable. Like any other investors, venture capitalists want to harvest the fruits of their investments in due time. They're expecting 20% to 40% ROI in a year. Aside from the venture capital, VCs also share their management and technical skills in shaping the direction of the business. Over the years, the venture capital market has become the driver of growth for thousands of startups and small businesses around the world.
There is absolutely no shortage of time-management practices and experts out there promising to increase your productivity levels. And, certainly, we all aspire to be more productive, feel more accomplished and ultimately achieve greater success than ever before.
Unfortunately, though, simply wanting these things or reading a time-management book by a favorite author is a small part of the equation and will get you only so far.
In order to truly become a more productive individual and accomplish more of what matters most, you must minimize distractions, instill new habits and have a great deal of self-discipline.
Carl Kruse believes that many of the problems we run into when it comes to maximizing our productivity stem from overcomplicating things -- and those complications usually end up decreasing our productivity. He wants to share with you three things that have worked exceptionally well when it comes to minimizing distractions and drastically elevating productivity levels.