Analysis of changes in the action potential morphology of the mouse sinoatrial node true pacemaker cells during ontogenetic development in vitro and in silico.

BACKGROUND: Maturation of the mouse is accompanied by the increase in heart rate. However, the mechanisms underlying this process remain unclear. We performed an action potentials (APs) recordings in mouse sinoatrial node (SAN) true pacemaker cells and in silico analysis to clarify the mechanisms underlying pre-postnatal period heart rate changes. RESULTS: The APs of true pacemaker cells at different stages had similar configurations and dV/dtmax values. The cycle length, action potential duration (APD90 ), maximal diastolic potential (MDP), and AP amplitude decreased, meanwhile the velocity of diastolic depolarization (DDR) increased from E12.5 stage to adult. Using a pharmacological approach we found that in SAN true pacemaker cells ivabradine reduces the DDR and the cycle length significantly stronger in E12.5 than in newborn and adult mice, whereas the effects of Ni2+ and nifedipine were significantly stronger in adult mice. Computer simulations further suggested that the density of the hyperpolarization-activated pacemaker сurrent (If ) decreased during development, whereas transmembrane and intracellular Ca2+ flows increased. CONCLUSIONS: The ontogenetic decrease in IK1 density from E12.5 to adult leads to depolarization of MDP to the voltage range in which calcium currents are activated, thereby shifting the balance from the "membrane-clock" to the "calcium-clock."

Proposed general diagnostic criteria for secondary headaches.

BACKGROUND: The distinction between a pre-existing primary headache and a secondary headache at the onset of a disorder is important and has not been taken into account in the International Classification of Headache Disorders-3. This study aimed to improve the general diagnostic criteria for secondary headaches using results of our previous studies. MATERIALS AND METHODS: We analyzed characteristics of headaches including their changes in intensity, duration, frequency, localization and side, development of new accompanying symptoms, and therapeutic response at the onset of transient ischemic attacks (TIA) (n = 120, mean age 56.1, 55% females) and ischemic stroke (n = 550, mean age 63.1, 56% females) compared to the control group (n = 192, mean age 58.7, 64% females). RESULTS: Headache of a new type occurred in 8.4% of ischemic stroke patients and 5% of TIA patients on the day of admission but did not occur at all in the control group. Pre-existing headache with a change of at least one characteristic occurred significantly more often in stroke (5.4%) and TIA (7.5%) than in the control group (1%) (p = 0.01 and p = 0.003 respectively). CONCLUSION: The presence of a new type of headache and a pre-existing headache with altered characteristics in close temporal relation to a disorder indicates causality. Based on these data we propose revised general diagnostic criteria for secondary headaches.

Diagnosis of Migrainous Infarction: A Case Report and Analysis of Previously Published Cases.

Migrainous infarction (MI) is a rare disorder. The precise diagnostic criteria for this diagnosis have been available in the International Classification of Headache Disorders (ICHD) since 1988, but many cases do not fulfil these criteria. This paper describes a good example of MI and analyzes previously published case reports. We report a very special case of MI in an 18-year-old woman who had a recurrent episode of migraine with a similar aura with numbness of the right arm and speech disturbances which had an unusually long duration (>120 min). On admission to the headache centre "Europe-Asia", she complained of slowness of speech and problems with choice of words. An MRI showed acute lacunar infarcts in the left parietal subcortical area. Ischemic infarcts were localized in a relevant area on the left side and the aura symptoms were right-sided. The patient, therefore, fulfilled the ICHD-3 diagnostic criteria for "Migrainous infarction". An analysis of 35 previously published articles with case reports about MI showed that 22 did not meet the diagnostic criteria of the ICHD for migrainous infarction. Using all this, we developed diagnostic recommendations for migrainous infarction which can help to improve the quality of diagnosis when used together with the diagnostic criteria of the ICHD for migrainous infarction.

Sex steroid hormones and epilepsy: Effects of hormonal replacement therapy on seizure frequency of postmenopausal women with epilepsy-A systematic review.

BACKGROUND AND PURPOSE: Hormonal replacement therapy (HRT) is used for symptomatic treatment of menopause. Some evidence suggests a proconvulsant effect of estrogen and an anticonvulsant role of progesterone. Thus, the use of exogenous sex steroid hormones might influence the course of epilepsy in peri- and postmenopausal women with epilepsy (WWE). We conducted a systematic review on the impact of HRT on the frequency of seizures of WWE. METHODS: PubMed and Scopus were searched for articles published from inception until August 2022. Abstracts from the past 5 years from the European Academy of Neurology and European Epilepsy Congresses were also reviewed. Article reference lists were screened, and relevant articles were retrieved for consultation. Interventional and observational studies on WWE and animal models of estrogen deficiency were included. Critical appraisal was performed using the revised Cochrane risk-of-bias tool for randomized trials and ROBINS-E tool. RESULTS: Of 497 articles screened, 13 studies were included, including three human studies. One cross-sectional study showed a decrease in seizure frequency in WWE using combined HRT, a case-control study showed an increase in comparison with controls, and a randomized clinical trial found a dose-dependent increase in seizure frequency in women with focal epilepsy taking combined HRT. Ten studies addressing the impact of HRT in rat models were also included, which showed conflicting results. CONCLUSIONS: There is scarce evidence of the impact of HRT in WWE. Further studies should evaluate the harmful potential, and prospective registries are needed for monitoring this population.

Raman spectroscopy in chronic heart failure diagnosis based on human skin analysis.

This work aims at studying Raman spectroscopy in combination with chemometrics as an alternative fast noninvasive method to detect chronic heart failure (CHF) cases. Optical analysis is focused on the changes in the spectral features associated with the biochemical composition changes of skin tissues. A portable spectroscopy setup with the 785 nm excitation wavelength was used to record skin Raman features. In this in vivo study, 127 patients and 57 healthy volunteers were involved in measuring skin spectral features by Raman spectroscopy. The spectral data were analyzed with a projection on the latent structures and discriminant analysis. 202 skin spectra of patients with CHF and 90 skin spectra of healthy volunteers were classified with 0.888 ROC AUC for the 10-fold cross validated algorithm. To identify CHF cases, the performance of the proposed classifier was verified by means of a new test set that is equal to 0.917 ROC AUC.

Safety and tolerability of monoclonal antibodies targeting the CGRP pathway and gepants in migraine prevention: A systematic review and network meta-analysis.

BACKGROUND: Direct comparisons of the tolerability and safety of migraine preventive treatments targeting the calcitonin gene-related peptide pathway are lacking. This study aimed to compare the safety and tolerability of anti-calcitonin gene-related peptide monoclonal antibodies and gepants in migraine prevention. METHODS: A network meta-analysis of phase 3 randomized controlled trials assessing the safety and tolerability of anti-calcitonin gene-related peptide monoclonal antibodies (erenumab, eptinezumab, fremanezumab, or galcanezumab) and gepants (atogepant, rimegepant) in migraine prevention was performed. Primary outcomes were treatment-emergent adverse events and serious adverse events. Secondary outcomes included any adverse events, adverse events leading to treatment discontinuation and individual adverse events. RESULTS: We included 19 randomized controlled trials, comprising 14,584 patients. Atogepant 120 mg (OR 2.22, 95% CI [1.26, 3.91]) and galcanezumab 240 mg (OR 1.63, 95% CI [1.33, 2.00]) showed the largest odds of treatment-emergent adverse events compared to placebo. While eptinezumab 30 mg had greater odds of adverse events leading to treatment discontinuation (OR 2.62, 95% CI [1.03,6.66]). No significant differences in serious adverse events were found between active treatments and placebo. Eptinezumab was associated with the lowest odds of treatment-emergent adverse events and serious adverse events compared to placebo, whereas erenumab was associated with the lowest odds of any adverse events and quarterly fremanezumab with the lowest odds of treatment discontinuation due to adverse events. CONCLUSION: Monoclonal antibodies targeting the calcitonin gene-related peptide pathway and gepants are a safe and well tolerated option for migraine prevention.

Sex and age differences in migraine treatment and management strategies.

Migraine is one of the leading causes of disability worldwide, especially in women younger than 50 years old. Migraine has three times higher prevalence in women than in men and tends to decrease after the menopausal transition. Migraine has different clinical features in people of different ages. Clinical symptoms and factors associated with migraine can be various in women and men. Women have special types of migraine, such as pure menstrual migraine and menstrually related migraine. Besides, clinical symptoms of migraine can change during pregnancy, postpartum and lactation. Women are significantly more often than men consulting a doctor because of migraine. These features of migraine lead to different treatment and management strategies in females and males of different ages. Migraine therefore is a disorder that demonstrates the necessity of a personalization of healthcare-ensuring the proper treatment for the right patient, at the right time. Considering all the available literature and guidelines, in this chapter several strategies for management of acute and prophylactic treatments of migraine, according to sex and age differences, are discussed. The purpose of this chapter is to provide a useful piece of information improving the treatment and management of migraine.

Persistent headache after first-ever ischemic stroke: clinical characteristics and factors associated with its development.

BACKGROUND: It is poorly described how often headache attributed to stroke continues for more than 3 months, i.e. fulfils the criteria for persistent headache attributed to ischemic stroke. Our aims were: 1) to determine the incidence of persistent headache attributed to past first-ever ischemic stroke (International headache society categories 6.1.1.2); 2) to describe their characteristics and acute treatment; 3) to analyse the prevalence of medication overuse headache in patients with persistent headache after stroke; 4) to evaluate factors associated with the development of persistent headache after stroke. METHODS: The study population consisted of 550 patients (mean age 63.1, 54% males) with first-ever ischemic stroke, among them 529 patients were followed up at least three months after stroke. Standardized semi-structured interview forms were used to evaluate these headaches during professional face-to-face interviews at stroke onset and telephone interviews at 3 months. RESULTS: At three months, 61 patients (30 women and 31 men, the mean age 60.0) of 529 (11.5%) follow-up patients had a headache after stroke: 34 had a new type of headache, 21 had a headache with altered characteristics and 6 patients had a headache without any changes. Therefore 55 (10.4%) patients had a persistent headache attributed to ischemic stroke. Their clinical features included: less severity of accompanying symptoms, slowly decreasing frequency and development of medication overuse headache in one-third of the patients. The following factors were associated with these headaches: lack of sleep (29.1%, p = 0.009; OR 2.3; 95% CI 1.2-4.3), infarct in cerebellum (18.2%, p = 0.003; OR 3.0; 95% CI 1.4-6.6), stroke of undetermined etiology (50.9%, p = 0.003; OR 2.3; 95% CI 1.3-4.1), less than 8 points by NIHSS score (90.9%, p = 0.007; OR 3.4; 95% CI 1.4-8.6) and low prevalence of large-artery atherosclerosis (12.7%, p = 0.006; OR 0.3; 95% CI 0.2-0.80). CONCLUSION: Persistent headache attributed to ischemic stroke is not rare and frequently leads to medication overuse. The problem is often neglected because of other serious consequences of stroke but actually, it has a considerable impact on quality of life. It should be a focus of interest in the follow-up of stroke patients.

Mapping of European activities on the integration of sex and gender factors in neurology and neuroscience.

BACKGROUND: Neurological disorders pose a profound unmet medical need for which new solutions are urgently needed. The consideration of both biological (sex) and socio-cultural (gender) differences between men and women is necessary to identify more efficacious, safer and tailored treatments. Approaches for putting sex and gender medicine into practice have gathered momentum across Europe, but it is currently unclear to what extent they have been implemented in the field of neurology and neuroscience. METHODS: We mapped current activities in research, funding and education aimed at integrating sex and gender consideration in neuroscience and neurology in Europe. We examined and analyzed data gathered from (1) literature searches, (2) policy documents and reports by the European Commission and national funding agencies, (3) web-based searches, (4) "Web of Science", and (5) searches of project databases of funding agencies. An informative / non-systematic search was performed for sections on policies and funding, education, basic research, while a systematic literature and database review was conducted forquantitative analysis of research output and funded projects in terms of sex and gender analysis. RESULTS: Our mapping shows that there is a growing interest and attention towards sex and gender consideration in neurological fields, both from funding agencies and researchers. However, most activities, especially for education, are limited to the individual motivation of researchers and are not organically built within curricula and strategic research priorities. DISCUSSION: We recommend actions that might help increase the consideration of sex and gender specifically in the field of neuroscience and neurology.

Diagnostic criteria for acute headache attributed to ischemic stroke and for sentinel headache before ischemic stroke.

BACKGROUND: Defining the relationship between a headache and stroke is essential. The current diagnostic criteria of the ICHD-3 for acute headache attributed to ischemic stroke are based primarily on the opinion of experts rather than on published clinical evidence based on extensive case-control studies in patients with first-ever stroke. Diagnostic criteria for sentinel headache before ischemic stroke do not exist. The present study aimed to develop explicit diagnostic criteria for headache attributed to ischemic stroke and for sentinel headache. METHODS: This prospective case-control study included 550 patients (mean age 63.1, 54% males) with first-ever ischemic stroke and 192 control patients (mean age 58.7, 36% males) admitted to the emergency room without any acute neurological deficits or severe disorders. Standardized semi-structured interview forms were used to evaluate past and present headaches during face-to-face interviews by a neurologist on admission to the emergency room in both groups of patients. All headaches were diagnosed according to the ICHD-3. We tabulated the onset of different headaches before a first-ever ischemic stroke and at the time of onset of stroke. We divided them into three groups: a new type of headache, the previous headache with altered characteristics and previous unaltered headaches. The same was done for headaches in control patients within one week before admission to the hospital and at the time of entry. These data were used to create and test diagnostic criteria for acute headache attributed to stroke and sentinel headache. RESULTS: Our previous studies showed that headache at onset of ischemic stroke was present in 82 (14.9%) of 550 patients, and 81 (14.7%) patients had sentinel headache within the last week before a stroke. Only 60% of the headaches at stroke onset fulfilled the diagnostic criteria of ICHD-3. Therefore, we proposed alternative criteria with a sensitivity of 100% and specificity of 97%. Besides, we developed diagnostic criteria for sentinel headache for the first time with a specificity of 98% and a sensitivity of 100%. CONCLUSIONS: We suggest alternative diagnostic criteria for acute headache attributed to ischemic stroke and new diagnostic criteria for sentinel headache with high sensitivity and specificity.

FN14 mRNA Expression Correlates with an Increased Number of Veins during Angiogenesis in the Process of Liver Fibrosis.

In this study, we hypothesize that angiogenesis of special hepatic vessels such as sinusoid capillaries or veins is closely associated with increasing production of connective tissue in fibrogenesis. Thirty-six male Wistar rats were induced with hepatitis and cirrhosis of the liver using thioacetamide. The number of sinusoidal capillaries, veins, arteries and the area of connective tissue were counted and determined. Immunohistochemical study was performed on paraffin sections using monoclonal mouse anti-CD31. mRNA expression was determined using qPCR. We found a statistically significant reduction in the number of sinusoidal capillaries (p<0.0001) and an increase in the number of interlobular veins (p<0.0001) in the fibrosis and cirrhosis groups compared to the control group. There are no differences in the number of interlobular arteries (p=0.282) in the three groups. In our analysis, we found that the expression (mRNA) of Fn14 correlated with the number of veins in liver fibrosis (r=0.44, p=0.008). Our data shows that modulation of veins angiogenesis during fibrosis in chronic liver diseases may play an important role in increasing pathological changes of the liver.

Structured headache services as the solution to the ill-health burden of headache: 1. Rationale and description

In countries where headache services exist at all, their focus is usually on specialist (tertiary) care. This is clinically and economically inappropriate: most headache disorders can effectively and more efficiently (and at lower cost) be treated in educationally supported primary care. At the same time, compartmentalizing divisions between primary, secondary and tertiary care in many health-care systems create multiple inefficiencies, confronting patients attempting to navigate these levels (the "patient journey") with perplexing obstacles.High demand for headache care, estimated here in a needs-assessment exercise, is the biggest of the challenges to reform. It is also the principal reason why reform is necessary.The structured headache services model presented here by experts from all world regions on behalf of the Global Campaign against Headache is the suggested health-care solution to headache. It develops and refines previous proposals, responding to the challenge of high demand by basing headache services in primary care, with two supporting arguments. First, only primary care can deliver headache services equitably to the large numbers of people needing it. Second, with educational supports, they can do so effectively to most of these people. The model calls for vertical integration between care levels (primary, secondary and tertiary), and protection of the more advanced levels for the minority of patients who need them. At the same time, it is amenable to horizontal integration with other care services. It is adaptable according to the broader national or regional health services in which headache services should be embedded.It is, according to evidence and argument presented, an efficient and cost-effective model, but these are claims to be tested in formal economic analyses.

The place of millet in food globalization during Late Prehistory as evidenced by new bioarchaeological data from the Caucasus.

Two millets, Panicum miliaceum and Setaria italica, were domesticated in northern China, around 6000 BC. Although its oldest evidence is in Asia, possible independent domestication of these species in the Caucasus has often been proposed. To verify this hypothesis, a multiproxy research program (Orimil) was designed to detect the first evidence of millet in this region. It included a critical review of the occurrence of archaeological millet in the Caucasus, up to Antiquity; isotopic analyses of human and animal bones and charred grains; and radiocarbon dating of millet grains from archaeological contexts dated from the Early Bronze Age (3500-2500 BC) to the 1st Century BC. The results show that these two cereals were cultivated during the Middle Bronze Age (MBA), around 2000-1800 BC, especially Setaria italica which is the most ancient millet found in Georgia. Isotopic analyses also show a significant enrichment in 13C in human and animal tissues, indicating an increasing C4 plants consumption at the same period. More broadly, our results assert that millet was not present in the Caucasus in the Neolithic period. Its arrival in the region, based on existing data in Eurasia, was from the south, without excluding a possible local domestication of Setaria italica.

Migraine: epidemiology and systems of care.

Migraine is a neurovascular disorder that affects over 1 billion people worldwide. Its widespread prevalence, and associated disability, have a range of negative and substantial effects not only on those immediately affected but also on their families, colleagues, employers, and society. To reduce this global burden, concerted efforts are needed to implement and improve migraine care that is supported by informed health-care policies. In this Series paper, we summarise the data on migraine epidemiology, including estimates of its very considerable burden on the global economy. First, we present the challenges that continue to obstruct provision of adequate care worldwide. Second, we outline the advantages of integrated and coordinated systems of care, in which primary and specialist care complement and support each other; the use of comprehensive referral and linkage protocols should enable continuity of care between these systems levels. Finally, we describe challenges in low and middle-income countries, including countries with poor public health education, inadequate access to medication, and insufficient formal education and training of health-care professionals resulting in misdiagnosis, mismanagement, and wastage of resources.

Headache at onset of first-ever ischemic stroke: Clinical characteristics and predictors.

No studies have prospectively investigated headache at onset of first-ever ischemic stroke along with a large concurrent control group. Our aims were to answer two important questions: (i) Are headaches at stroke onset causally related to the stroke, and what are their typical clinical characteristics? (ii) What etiology of stroke is associated with these headaches? The study population consisted of 550 patients (mean age = 63.1, 54% males) with first-ever ischemic stroke and 192 control patients (mean age = 58.7, 36% males) admitted to the emergency room without any acute neurological deficits or serious disorders. All data were collected prospectively, using a standardized case-report form during face-to-face interviews by neurologists. Headache at onset of ischemic stroke was present in 82 (14.9%) of 550 patients. More than half (56%) had a new type of headache (mainly migraine-like) simultaneously with stroke onset, and 36% had headache with altered characteristics (mainly tension-type-like headache). Headaches were associated with cardioembolism (p = 0.002, odds ratio [OR] = 2.4, 95% confidence interval [CI] = 1.4-4.1), posterior circulation stroke (p = 0.01, OR = 2.0, 95% CI = 1.2-3.5), infarcts >15 mm (p = 0.03, 95% CI = 1.1-2.7), infarcts of the cerebellum (p = 0.02, OR = 2.3, 95% CI = 1.1-4.8), good neurological status (p = 0.01, OR = 2.5, 95% CI = 1.2-4.9), and low frequency of large-artery atherosclerosis (p = 0.004, OR = 0.4, 95% CI = 0.2-0.8). At stroke onset, headache of a new type and headache with altered characteristics were related to ischemic stroke. They were associated with certain etiologies of stroke.

Explicit Diagnostic Criteria for Transient Ischemic Attacks Used in the Emergency Department Are Highly Sensitive and Specific.

BACKGROUND: Making a correct diagnosis of a transient ischemic attack (TIA) is prone to errors because numerous TIA mimics exist and there is a shortage of evidence-based diagnostic criteria for TIAs. In this study, we applied for the first time the recently proposed explicit diagnostic criteria for transient ischemic attacks (EDCT) to a group of patients presenting to the emergency department of a large German tertiary care hospital with a suspected TIA. The aim was to determine the sensitivity and specificity of the EDCT in its clinical application. METHODS: A total of 128 patients consecutively presenting to the emergency department of the University Hospital of Lübeck, Germany, under the suspicion of a TIA were prospectively interviewed about their clinical symptoms at the time of presentation. The diagnosis resulting from applying the EDCT was compared to the diagnosis made independently by the senior physicians performing the usual diagnostic work-up ("gold standard"), allowing calculation of sensitivity and specificity of the EDCT. RESULTS: EDCT achieved a sensitivity of 96% and a specificity of 88%. When adding the additional criterion F ("the symptoms may not be better explained by another medical or mental disorder"), specificity significantly increased to 98%. CONCLUSIONS: The data show that the EDCT in its modified version as proposed by us are a highly useful tool for clinicians. They display a high sensitivity and specificity to accurately diagnose TIAs in patients referred to the emergency department with a suspected TIA.

Sentinel headache as a warning symptom of ischemic stroke.

BACKGROUND: There are no previous controlled studies of sentinel headache in ischemic stroke. The purpose of the present study was to evaluate the presence of such headache, its characteristics and possible risk factors as compared to a simultaneous control group. METHODS: Eligible patients (n = 550) had first-ever acute ischemic stroke with presence of new infarction on magnetic resonance imaging with diffusion-weighted imaging (n = 469) or on computed tomography (n = 81). As a control group we studied in parallel patients (n = 192) who were admitted to the emergency room without acute neurological deficits or serious neurological or somatic disorders. Consecutive patients with stroke and a simultaneous control group were extensively interviewed soon after admission using validated neurologist conducted semi-structured interview forms. Based on our previous study of sentinel headache in transient ischemic attacks we defined sentinel headache as a new type of headache or a previous kind of headache with altered characteristics (severe intensity, increased frequency, absence of effect of drugs) within seven days before stroke. RESULTS: Among 550 patients with stroke 94 patients (17.1%) had headache during seven days before stroke and 12 (6.2%) controls (p < 0.001; OR 3.9; 95% CI 1.7-5.8). Totally 81 patients (14.7%) had sentinel headache within the last week before stroke and one control. Attacks of arrythmia during seven days before stroke were significantly associated with sentinel headache (p = 0.04, OR 2.3; 95% CI 1.1-4.8). CONCLUSIONS: A new type of headache and a previous kind of headache with altered characteristics during one week before stroke are significantly more prevalent than in controls. These headaches represent sentinel headaches. Sudden onset of such headaches should alarm about stroke.

Dilatation Reserve of Pulmonary Arteries at Stages of the Chronic Obstructive Pulmonary Disease Model.

OBJECTIVES: To assess the state of pulmonary vascular mediator systems during the stepwise formation of the chronic obstructive pulmonary disease (COPD) model. MATERIALS AND METHODS: The COPD model was induced in rats by nitrogen dioxide (NO2) inhalation for 60 days. At different stages of COPD (15, 30, and 60 days), the effect of reagents-vasodilators (ß-adrenoceptor agonist isoproterenol, nitric oxide donor nitrosorbide, acetylcholine, activator of C-fibers capsaicin, corticosteroid beclometasone) on the isolated pulmonary arteries (diameter <0.5 mm) was studied. Vascular reactivity was assessed by determining isometric contraction (tension in milligrams) of arterial rings by using an electromechanical transducer. RESULTS: All vasodilators dose-dependently decreased the vascular tone of pulmonary arteries isolated from intact rats. After 15 days of NO2 exposure, dilatation effect of low doses of vasodilators did not differ from that of intact specimens. The functional state of the adrenergic system deteriorated faster than that of the nonadrenergic noncholinergic system as reflected by the weakening of the isoproterenol relaxation effect. On prolonged NO2 exposure, pulmonary arteries responded to the impact of all vasodilators with smaller relaxation. Dose dependence of the dilatation reaction disappeared for isoproterenol, capsaicin, beclometasone, and was less expressed for nitrosorbide and acetylcholine after 60 days of exposure. CONCLUSION: In the course of COPD model generation, the functioning of almost all neurotransmitter systems of pulmonary artery wall was negatively affected. This led to a decrease in the influence of vasodilators on pulmonary artery vascular tone and could facilitate the development of pulmonary hypertension, which is typical of COPD.