Interleukin-3 coordinates glial-peripheral immune crosstalk to incite multiple sclerosis.

Glial cells and central nervous system (CNS)-infiltrating leukocytes contribute to multiple sclerosis (MS). However, the networks that govern crosstalk among these ontologically distinct populations remain unclear. Here, we show that, in mice and humans, CNS-resident astrocytes and infiltrating CD44hiCD4+ T cells generated interleukin-3 (IL-3), while microglia and recruited myeloid cells expressed interleukin-3 receptor-ɑ (IL-3Rɑ). Astrocytic and T cell IL-3 elicited an immune migratory and chemotactic program by IL-3Rɑ+ myeloid cells that enhanced CNS immune cell infiltration, exacerbating MS and its preclinical model. Multiregional snRNA-seq of human CNS tissue revealed the appearance of IL3RA-expressing myeloid cells with chemotactic programming in MS plaques. IL3RA expression by plaque myeloid cells and IL-3 amount in the cerebrospinal fluid predicted myeloid and T cell abundance in the CNS and correlated with MS severity. Our findings establish IL-3:IL-3RA as a glial-peripheral immune network that prompts immune cell recruitment to the CNS and worsens MS.

DNA damage in oocytes induces a switch of the quality control factor TAp63α from dimer to tetramer.

TAp63α, a homolog of the p53 tumor suppressor, is a quality control factor in the female germline. Remarkably, already undamaged oocytes express high levels of the protein, suggesting that TAp63α's activity is under tight control of an inhibitory mechanism. Biochemical studies have proposed that inhibition requires the C-terminal transactivation inhibitory domain. However, the structural mechanism of TAp63α inhibition remains unknown. Here, we show that TAp63α is kept in an inactive dimeric state. We reveal that relief of inhibition leads to tetramer formation with ∼20-fold higher DNA affinity. In vivo, phosphorylation-triggered tetramerization of TAp63α is not reversible by dephosphorylation. Furthermore, we show that a helix in the oligomerization domain of p63 is crucial for tetramer stabilization and competes with the transactivation domain for the same binding site. Our results demonstrate how TAp63α is inhibited by complex domain-domain interactions that provide the basis for regulating quality control in oocytes.

Pathophysiology of Migraine: A Disorder of Sensory Processing.

Plaguing humans for more than two millennia, manifest on every continent studied, and with more than one billion patients having an attack in any year, migraine stands as the sixth most common cause of disability on the planet. The pathophysiology of migraine has emerged from a historical consideration of the "humors" through mid-20th century distraction of the now defunct Vascular Theory to a clear place as a neurological disorder. It could be said there are three questions: why, how, and when? Why: migraine is largely accepted to be an inherited tendency for the brain to lose control of its inputs. How: the now classical trigeminal durovascular afferent pathway has been explored in laboratory and clinic; interrogated with immunohistochemistry to functional brain imaging to offer a roadmap of the attack. When: migraine attacks emerge due to a disorder of brain sensory processing that itself likely cycles, influenced by genetics and the environment. In the first, premonitory, phase that precedes headache, brain stem and diencephalic systems modulating afferent signals, light-photophobia or sound-phonophobia, begin to dysfunction and eventually to evolve to the pain phase and with time the resolution or postdromal phase. Understanding the biology of migraine through careful bench-based research has led to major classes of therapeutics being identified: triptans, serotonin 5-HT1B/1D receptor agonists; gepants, calcitonin gene-related peptide (CGRP) receptor antagonists; ditans, 5-HT1F receptor agonists, CGRP mechanisms monoclonal antibodies; and glurants, mGlu5 modulators; with the promise of more to come. Investment in understanding migraine has been very successful and leaves us at a new dawn, able to transform its impact on a global scale, as well as understand fundamental aspects of human biology.

Management of cervical CSF-venous fistula causing acute cognitive impairment and coma.

CSF-venous fistulas (CVFs) are increasingly recognised as a cause of spontaneous intracranial hypotension. They may present atypically including with brain sagging pseudo-dementia. Cervical CVFs are rare and their management can be difficult due to associated eloquent nerve roots. We report the case of a 49-year-old woman who presented with cognitive decline progressing to coma. Brain imaging showed features of spontaneous intracranial hypotension and a right C7 CVF was identified at digital subtraction and CT myelography. Initial treatment with CT-guided injection of fibrin sealant produced temporary improvement in symptoms before surgical treatment resulted in total clinical remission and radiological resolution.

Neutralizing antibody responses 300 days after SARS-CoV-2 infection and induction of high antibody titers after vaccination.

Neutralizing antibodies against SARS-CoV-2 are important to protect against infection and/or disease. Using an assay to detect antibodies directed against the receptor binding domain (RBD) of SARS-CoV-2 Spike, we identified individuals with SARS-CoV-2 infection after an outbreak at a local health institution. All but one COVID-19 patient developed detectable anti-RBD antibodies and 77% had virus neutralizing antibody titers of >1:25. Antibody levels declined slightly over time. However, we still detected virus neutralizing antibody titers in 64% of the COVID-19 patients at >300 days after infection, demonstrating durability of neutralizing antibody levels after infection. Importantly, full COVID-19 vaccination of these individuals resulted in higher antibody titers compared to fully vaccinated individuals in the absence of prior infection. These data demonstrate long-lived antibody-mediated immunity after SARS-CoV-2 infection, and a clear benefit of two vaccine doses for recovered individuals.

Effectiveness and safety profile of greater occipital nerve blockade in cluster headache: a systematic review.

BACKGROUND: Greater occipital nerve (GON) blockade is a short-term preventive therapy for cluster headache (CH). We conducted a systematic review to evaluate the effectiveness and safety of GON blockade in patients with CH. METHODS: On 23 October 2020, we searched MEDLINE, Embase, Embase Classic, PsycINFO, CINAHL, CENTRAL and Web of Science databases from their inception date. Studies included participants with a CH diagnosis who received corticosteroid and local anaesthetic suboccipital region injections. Outcomes were change in the frequency/severity/duration of attacks; proportion of participants responding to treatment, time to attack freedom from an attack, change in attack bout length and/or the presence of adverse effects after GON blockade. Risk of bias was assessed with the Cochrane Risk of Bias V.2.0 (RoB2)/Risk of Bias in Non-randomized Studies - of Interventions (ROBINS- I) tools and a specific tool for case reports/series. RESULTS: Two RCTs, eight prospective and eight retrospective studies, and four case reports were included in the narrative synthesis. Every effectiveness study found a significant response in one or more of frequency/severity/duration of individual attacks or proportion of patients responding to treatment (47.8%-100.0%). There were five instances of potentially irreversible adverse effects. A higher injectate volume and use of concurrent prophylaxis may be associated with an increased likelihood of response. Methylprednisolone may have the best safety profile of available corticosteroids. DISCUSSION: GON blockade is safe and effective for CH prevention. Higher injectate volumes may improve likelihood of response, and the likelihood of serious adverse events may be reduced by using methylprednisolone. PROSPERO REGISTRATION NUMBER: CRD42020208435.

Orofacial pain for clinicians: A review of constant and attack-like facial pain syndromes.

BACKGROUND: Primary headache syndromes such as migraine are among the most common neurological syndromes. Chronic facial pain syndromes of non-odontogenic cause are less well known to neurologists despite being highly disabling. Given the pain localization, these patients often consult dentists first who may conduct unnecessary dental interventions even if a dental cause is not identified. Once it becomes clear that dental modalities have no effect on the pain, patients may be referred to another dentist or orofacial pain specialist, and later to a neurologist. Unfortunately, neurologists are also often not familiar with chronic orofacial pain syndromes although they share the neural system, i.e., trigeminal nerve and central processing areas for headache disorders. CONCLUSION: In essence, three broad groups of orofacial pain patients are important for clinicians: (i) Attack-like orofacial pain conditions, which encompass neuralgias of the cranial nerves and less well-known facial variants of primary headache syndromes; (ii) persistent orofacial pain disorders, including neuropathic pain and persistent idiopathic facial/dentoalveolar pain; and (iii) other differential diagnostically relevant orofacial pain conditions encountered by clinicians such as painful temporomandibular disorders, bruxism, sinus pain, dental pain, and others which may interfere (trigger) and overlap with headache. It is rewarding to know and recognize the clinical picture of these facial pain syndromes, given that, just like for headache, an internationally accepted classification system has been published and many of these syndromes can be treated with medications generally used by neurologists for other pain syndromes.

How does stress affect maternal and paternal perceptions of relationship strain after a preterm birth? Results of a retrospective survey study.

AIM: Strain on couple relationships is associated with a lower well-being. As premature birth is known to pose stress to parents, this study explores whether interparental relationship strain comes to pass within mothers and fathers during their infant's stay in a neonatal intensive care unit. METHODS: A retrospective cross-sectional survey was conducted with parents who experienced a preterm birth (September to December 2020). Linear regression was used to analyse associations between stress and relationship strain. RESULTS: The study included 437 mothers and 301 fathers. Fathers experienced lower relationship strain (M = 2.49, SD = 1.00) than mothers (M = 3.37, SD = 1.04). Overall, a significant association between relationship strain and stress due to the infant's behaviour and appearance was found for mothers (ß = 0.16, p = 0.02) and fathers, with a significantly higher association for fathers (ß = 0.27, p ≤ 0.002). With regard to parental role alterations, only mothers showed a significant association (ß = 0.21, p ≤ 0.001). CONCLUSION: Although mothers showed higher levels of stress and relationship strain, stress may also have an impact on fathers. Therefore, research should focus on stress prevention measures to meet both maternal and paternal needs.

Factors associated with the closure of obstetric units in German hospitals and its effects on accessibility.

BACKGROUND: An increase in regionalization of obstetric services is being observed worldwide. This study investigated factors associated with the closure of obstetric units in hospitals in Germany and aimed to examine the effect of obstetric unit closure on accessibility of obstetric care. METHODS: Secondary data of all German hospital sites with an obstetrics department were analyzed for 2014 and 2019. Backward stepwise regression was performed to identify factors associated with obstetrics department closure. Subsequently, the driving times to a hospital site with an obstetrics department were mapped, and different scenarios resulting from further regionalization were modelled. RESULTS: Of 747 hospital sites with an obstetrics department in 2014, 85 obstetrics departments closed down by 2019. The annual number of live births in a hospital site (OR = 0.995; 95% CI = 0.993-0.996), the minimal travel time between two hospital sites with an obstetrics department (OR = 0.95; 95% CI = 0.915-0.985), the availability of a pediatrics department (OR = 0.357; 95% CI = 0.126-0.863), and population density (low vs. medium OR = 0.24; 95% CI = 0.09-0.648, low vs. high OR = 0.251; 95% CI = 0.077-0.822) were observed to be factors significantly associated with the closure of obstetrics departments. Areas in which driving times to the next hospital site with an obstetrics department exceeded the 30 and 40 min threshold slightly increased from 2014 to 2019. Scenarios in which only hospital sites with a pediatrics department or hospital sites with an annual birth volume of ≥ 600 were considered resulted in large areas in which the driving times would exceed the 30 and 40 min threshold. CONCLUSION: Close distances between hospital sites and the absence of a pediatrics department at the hospital site associate with the closure of obstetrics departments. Despite the closures, good accessibility is maintained for most areas in Germany. Although regionalization may ensure high-quality care and efficiency, further regionalization in obstetrics will have an impact on accessibility.

Gynaecologists' perceptions of outpatient gynaecologic and obstetric care in Germany during the COVID-19 pandemic.

The measures taken to contain the COVID-19 pandemic had a major impact on society, affecting medical care as well as the utilization of medical services. We aimed to identify pandemic-related changes in gynaecologic/obstetric care through the personal experience of practitioners in the outpatient sector in Germany. Three consecutive anonymous online surveys of practising gynaecologists were conducted during the pandemic (07-09/2020, 11-12/2020 and 09-11/2021). Appointment management, medical supply and patients' demand as well as concomitant circumstances were queried. Data from 860 (393, 262 and 205 from the first, second and third surveys, respectively) respondents were analysed. At the peak of the first COVID-19 wave, more than 50% of the gynaecologists surveyed had cancelled cancer screening appointments. There was a significant association between fear of self-infection and cancellation of cancer screening appointments (p = 0.006). An increase in domestic violence was reported by 13%, an increase in obesity by 67% and more advanced tumours due to delayed screening by 24% of respondents. Primary gynaecological oncological prevention was reduced in supply and demand during the COVID-19 pandemic, and this shortfall should be addressed in future similar situations. Prenatal care has been offered continuously since the start of the pandemic in Germany.

Investigating the relationship between sleep and migraine in a global sample: a Bayesian cross-sectional approach.

BACKGROUND: There is a bidirectional link between sleep and migraine, however causality is difficult to determine. This study aimed to investigate this relationship using data collected from a smartphone application. METHODS: Self-reported data from 11,166 global users (aged 18-81 years, mean: 41.21, standard deviation: 11.49) were collected from the Migraine Buddy application (Healint Pte. Ltd.). Measures included: start and end times of sleep and migraine attacks, and pain intensity. Bayesian regression models were used to predict occurrence of a migraine attack the next day based on users' deviations from average sleep, number of sleep interruptions, and hours slept the night before in those reporting ≥ 8 and < 25 migraine attacks on average per month. Conversely, we modelled whether attack occurrence and pain intensity predicted hours slept that night. RESULTS: There were 724 users (129 males, 412 females, 183 unknown, mean age = 41.88 years, SD = 11.63), with a mean monthly attack frequency of 9.94. More sleep interruptions (95% Highest Density Interval (95%HDI [0.11 - 0.21]) and deviation from a user's mean sleep (95%HDI [0.04 - 0.08]) were significant predictors of a next day attack. Total hours slept was not a significant predictor (95%HDI [-0.04 - 0.04]). Pain intensity, but not attack occurrence was a positive predictor of hours slept. CONCLUSIONS: Sleep fragmentation and deviation from typical sleep are the main drivers of the relationship between sleep and migraine. Having a migraine attack does not predict sleep duration, yet the pain associated with it does. This study highlights sleep as crucial in migraine management.

Mode and site of action of therapies targeting CGRP signaling.

Targeting CGRP has proved to be efficacious, tolerable, and safe to treat migraine; however, many patients with migraine do not benefit from drugs that antagonize the CGRPergic system. Therefore, this review focuses on summarizing the general pharmacology of the different types of treatments currently available, which target directly or indirectly the CGRP receptor or its ligand. Moreover, the latest evidence regarding the selectivity and site of action of CGRP small molecule antagonists (gepants) and monoclonal antibodies is critically discussed. Finally, the reasons behind non-responders to anti-CGRP drugs and rationale for combining and/or switching between these therapies are addressed.

From basic mechanisms to therapeutic perspectives in cluster headache.

PURPOSE OF REVIEW: The pathophysiological understanding of cluster headache has evolved significantly over the past years. Although it is now well known that the trigeminovascular system, the parasympathetic system and the hypothalamus play important roles in its pathomechanism, we increasingly understand the functional role several neurotransmitters and hormones play in the communication between these structures. RECENT FINDINGS: This work will give an overview of the current understanding of the role of calcitonin gene-related peptide, vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide, melatonin and orexins in cluster headache. On the basis of recent evidence, this study will also review the relevance of the monoclonal calcitonin gene-related peptide antibody galcanezumab as well as the sleep-regulating hormone melatonin in the treatment of cluster headache. SUMMARY: Herein, we aim to review the basic mechanisms implicated in the pathophysiology of cluster headache and how the increased mechanistic understanding may lead to the discovery of novel therapeutic targets.

Membrane-Permeant, Bioactivatable Coumarin Derivatives for In-Cell Labelling.

The delivery of small molecule fluorophores with minimal compartmentalization is currently one of the most critical technical problems in intracellular labelling. Here we introduce sulfonated and phosphonated coumarin dyes, demonstrate rapid cell entry via a prodrug approach, and show a lack of interaction with membranes, organelles, or other compartments. The dyes show no specific localization and are evenly distributed in the cells. Our fluorogenic, clickable phosphonate derivatives successfully tagged model targets in intact cells and the increase in brightness upon click reaction was around 60-fold.

A systematic review of treatment for patients with burning mouth syndrome.

BACKGROUND: Burning mouth syndrome is a chronic idiopathic intractable intraoral dysaesthesia that remains a challenge to clinicians due to its poorly understood pathogenesis and inconsistent response to various treatments. AIM: This review aimed to study the short- (≤3 months) and long-term (>3 months) effectiveness and sustainable benefit of different burning mouth syndrome treatment strategies and the associated side effects. MATERIALS AND METHODS: Randomised controlled trials of burning mouth syndrome treatment compared with placebo or other interventions with a minimum follow up of 2 months were searched from the PubMed, Embase and Cochrane database (published to July 2020). RESULTS: Twenty-two studies were selected based on the inclusion and exclusion criteria and analysed. Nine categories of burning mouth syndrome treatment were identified: Anticonvulsant and antidepressant agents, phytomedicine and alpha lipoic acid supplements, low-level laser therapy, saliva substitute, transcranial magnetic stimulation, and cognitive behaviour therapy. Cognitive behaviour therapy, topical capsaicin and clonazepam, and laser therapy demonstrated favourable outcome in both short- and long-term assessment. Phytomedicines reported a short-term benefit in pain score reduction. The pooled effect of alpha lipoic acid (ALA) pain score improvement was low, but its positive effects increased in long term assessment. CONCLUSION: A more significant volume in terms of sample size, multi-centres, and multi-arm comparison of therapeutic agents with placebo and longitudinal follow-up studies is recommended to establish a standardised burning mouth syndrome treatment protocol. Further studies are required to assess the analgesic benefits of topical clonazepam and capsaicin, alternative medicines with neurodegenerative prevention capability and psychology support in treating burning mouth syndrome and reducing systemic adverse drug reactions.Registration International Prospective Register of Systematic Reviews (PROSPERO):Protocol ID - CRD42020160892.

KCl-induced repetitive cortical spreading depression inhibiting trigeminal neuronal firing is mediated by 5-HT1B/1D and opioid receptors.

BACKGROUND: We aimed to examine the effects of repetitive cortical spreading depression on the responses of nociceptive trigeminal neurons with dural afferents and characterize the role of 5-HT1B/1D and opioid receptors. METHODS: Trigeminocervical complex neurons (n = 53) responsive to nociceptive activation of the dura mater were studied in rats using electrophysiological techniques. RESULTS: A sub-population (n = 32) showed an average inhibition of dural-evoked responses of 65 ± 14% from baseline with cortical spreading depression. This response was reversed by the selective 5-HT1B/1D receptor antagonist, GR127935 (3 mg/kg; n = 6, iv), and a non-selective opioid receptor antagonist, naloxone (1.5 mg/kg; n = 6, iv), five minutes after injection. To determine the role of the nucleus raphe magnus in the trigeminocervical complex inhibitory effect, microinjection of lidocaine (2%, n = 6) or muscimol (100 mM, n = 5) into the nucleus raphe magnus was performed. There was no effect on cortical spreading depression-induced inhibition of neuronal firing in trigeminocervical complex by either. CONCLUSION: The data demonstrate that repetitive cortical spreading depression inhibits a subpopulation of dural nociceptive trigeminocervical neurons, an effect mediated by serotonin and opioid receptors. This inhibition does not involve modulation of nucleus raphe magnus neurons.

Erenumab in chronic migraine: Experience from a UK tertiary centre and comparison with other real-world evidence.

BACKGROUND AND PURPOSE: Chronic migraine is a highly disabling primary headache disorder that is the most common diagnosis of patients seen at tertiary headache centres. Typical oral preventive therapies are associated with many limitations that impact their therapeutic utility. Erenumab was the first available calcitonin gene-related peptide monoclonal antibody in the UK. It had proven efficacy in migraine prevention in clinical trials and limited real-world data in tertiary settings. METHODS: We audited our first 92 patients (n = 73 females) with severely disabling chronic migraine who were given monthly erenumab 70 mg sc for 6 months between December 2018 and December 2019. RESULTS: At 3 months, monthly migraine days were significantly reduced by a median of 4 days, and all other variables also showed significant improvement. The improvement was not affected by baseline analgesic use status. More than half of our patients experienced a clinically meaningful improvement in migraine days. No serious adverse events were reported. CONCLUSIONS: Our real-world data with erenumab demonstrate it is effective and well tolerated in managing patients with chronic migraine in a tertiary care setting.

Work climate in pandemic times: which burdens do German physicians in primary care report?

BACKGROUND: In Germany, general practitioners (GPs) provide basic and primary care in the ambulatory sector and refer patients to other specialists when necessary. Often, GPs present the first point of contact for patients in the German healthcare system. During the COVID-19 pandemic, GPs and other medical specialists in the ambulatory setting suddenly were confronted with unprecedented challenges. OBJECTIVE: To answer the following research questions: How did COVID-19-related challenges affect the work climate? Do physicians with deteriorated work climate simultaneously report a worsened provision of patient care? Which challenges were the most burdening? METHODS: In the course of the project COVID-GAMS more than 18 000 physicians of various specialties had been invited to a quantitative cross-sectional online survey (in Summer 2020). Analyses were conducted separately for the groups of GPs and other medical specialists. Group differences were analysed statistically and burdening factors were identified. RESULTS: 1703 participants were included in the analysis. 22.2% of GPs (other medical specialists: 19.9%) stated, their work climate had deteriorated. Physicians with a deteriorated work climate showed a tendency towards poorer personal provision of patient care (M = 3.75, SD = 0.98 versus M = 3.93, SD = 0.99) compared to unchanged or improved work climate. The lack of protective material in March/April 2020, changes in practice management and possible economic impacts on the practice were the most burdening factors reported by GPs. CONCLUSION: GPs who reported a negative impact on the work climate in the course of the first pandemic lockdown also tend to see own deficits in the provision of patient care.

Devices for Episodic Migraine: Past, Present, and Future.

PURPOSE OF REVIEW: Historically, therapies for migraine have generally involved pharmacological treatments using non-selective or selective analgesics and preventive treatments. However, for many patients these treatments are not effective, while others prefer to use non-pharmacological-based therapies. To fill this need, over the last 15 years, neuromodulatory devices have entered the market for migraine treatment. Here, we will review the most recent findings for the use of these devices in the treatment of migraine. RECENT FINDINGS: Non-invasive vagus nerve stimulation and spring-pulse transcranial magnetic stimulation are both cleared for the treatment of migraine, supported by preclinical studies that validate efficacy and mechanism of action, and complemented with clinical trial data. Other options also authorized for use include transcutaneous supraorbital nerve stimulation and remote electrical neuromodulation. Various options are available to treat migraine using authorized neuromodulatory devices. These data support their efficacy in the treatment of episodic migraine, although further studies are necessary to elucidate their mechanism of action and to provide rigor to clinical trial data.

Parental preference for webcams in neonatal intensive care units: an indicator of lacking trust?

BACKGROUND: Some neonatal intensive care units offer parents webcam systems for times when they cannot be in the ward. Leaving an infant in the ward can be challenging for parents, and trust in the neonatal healthcare professionals mitigates parents' worries of not knowing how their infant is doing while they are away. If parents lack trust in the neonatal healthcare professionals, they may attempt to compensate by using webcams. In this work, we examine whether an association exists between the parental preference to use a webcam and low trust in physicians and nursing staff. METHODS: In a nationwide, retrospective cross-sectional study, parents of infants with a birth weight below 1500 g were surveyed six to 18 months after their infant's birth. Parents who were not offered a webcam system in the ward were asked whether they would have opted for it. Trust was measured by the Trust in Physician and Trust in Nursing Staff scales. RESULTS: Of the parents who were not offered a webcam, 69% would have chosen to use a webcam if they had been granted the opportunity. The decision for or against a webcam was not significantly associated with either trust in physicians (OR = 0.654, 95% CI = 0.456, 0.937, p = .124) or trust in nursing staff (OR = 1.064, 95% CI = 0.783, 1.446, p = .932). CONCLUSIONS: While the majority of parents surveyed would opt for webcam usage, this preference should not be interpreted as an indicator of lacking trust in neonatal healthcare professionals.