Refractory migraine in a headache clinic population

<p>Abstract</p> <p>Background</p> <p>Many migraineurs who seek care in headache clinics are refractory to treatment, despite advances in headache therapies. Epidemiology is poorly characterized, because diagnostic criteria for refractory migraine were not available until recently. We aimed to determine the frequency of refractory migraine in patients attended in the Headache Unit in a tertiary care center, according to recently proposed criteria.</p> <p>Methods</p> <p>The study population consisted of a consecutive sample of 370 patients (60.8% females) with a mean age of 43 years (range 14-86) evaluated for the first time in our headache unit over a one-year period (between October 2008 and October 2009). We recorded information on clinical features, previous treatments, Migraine Disability Assessment Score (MIDAS), and final diagnosis.</p> <p>Results</p> <p>Overall migraine and tension-type headache were found in 46.4% and 20.5% of patients, respectively. Refractory migraine was found in 5.1% of patients. In refractory migraineurs, the mean MIDAS score was 96, and 36.8% were medication-overusers.</p> <p>Conclusions</p> <p>Refractory migraine is a relatively common and very disabling condition between the patients attended in a headache unit. The proposed operational criteria may be useful in identifying those patients who require care in headache units, the selection of candidates for combinations of prophylactic drugs or invasive treatments such as neurostimulation, but also to facilitate clinical studies in this patient group.</p

An Apo-14 Promoter-Driven Transgenic Zebrafish That Marks Liver Organogenesis

Several transgenic zebrafish lines for liver development studies had been obtained in the first decade of this century, but not any transgenic GFP zebrafish lines that mark the through liver development and organogenesis were reported. In this study, we analyzed expression pattern of endogenous Apo-14 in zebrafish embryogenesis by whole-mount in situ hybridization, and revealed its expression in liver primordium and in the following liver development. Subsequently, we isolated zebrafish Apo-14 promoter of 1763 bp 5′-flanking sequence, and developed an Apo-14 promoter-driven transgenic zebrafish Tg(Apo14: GFP). And, maternal expression and post-fertilization translocation of Apo-14 promoter-driven GFP were observed in the transgenic zebrafish line. Moreover, we traced onset expression of Apo-14 promoter-driven GFP and developmental behavior of the expressed cells in early heterozygous embryos by out-crossing the Tg(Apo14: GFP) male to the wild type female. Significantly, the Apo-14 promoter-driven GFP is initially expressed around YSL beneath the embryo body at 10 hpf when the embryos develop to tail bud prominence. In about 14-somite embryos at 16–17 hpf, a typical “salt-and-pepper” expression pattern is clearly observed in YSL around the yolk sac. Then, a green fluorescence dot begins to appear between the notochord and the yolk sac adjacent to otic vesicle at about 20 hpf, which is later demonstrated to be liver primordium that gives rise to liver. Furthermore, we investigated dynamic progression of liver organogenesis in the Tg(Apo14: GFP) zebrafish, because the Apo-14 promoter-driven GFP is sustainably expressed from hepatoblasts and liver progenitor cells in liver primordium to hepatocytes in the larval and adult liver. Additionally, we observed similar morphology between the liver progenitor cells and the GFP-positive nuclei on the YSL, suggesting that they might originate from the same progenitor cells in early embryos. Overall, the current study provides a transgenic zebrafish line that marks the through liver organogenesis

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Patients with migraine with aura have increased flow mediated dilation

<p>Abstract</p> <p>Background</p> <p>Endothelium-derived nitric oxide (NO) mediates the arterial dilation following a flow increase (i.e. flow-mediated dilation, FMD), easily assessed in the brachial artery. NO is also involved in cerebral hemodynamics and it is supposed to trigger vascular changes occurring during migraine. This study aimed at investigating whether migraine patients present an altered response to NO also in the peripheral artery system.</p> <p>Methods</p> <p>We enrolled 21 migraineurs (10 with aura [MwA], 11 without aura [MwoA]), and 13 controls. FMD was evaluated with ultrasound in all subjects by measuring the percentage increase of the brachial artery diameter induced by hyperaemia reactive to sustained cuff inflation around the arm above systolic pressure. FMD values were then normalized for shear stress.</p> <p>Results</p> <p>Normalized FMD values were higher in patients with MwA (28.5 10^-2%.s) than in controls (9.0 10^-2%.s) and patients with MwoA (13.7 10^-2%.s) (p < 0.001). FMD was over the median value (19%) in 23.1% of controls, in 45.5% of the MwoA patients, and in 90% of the MwA patients.</p> <p>Conclusions</p> <p>Migraineurs with aura present an excessive arterial response to hyperaemia, likely as an effect of an increased sensitivity to endothelium-derived nitric oxide. This phenomenon observed peripherally might reflect similar characteristics in the cerebral circulation.</p

The Metabolic Syndrome and the immediate antihypertensive effects of aerobic exercise: a randomized control design

<p>Abstract</p> <p>Background</p> <p>The metabolic syndrome (Msyn) affects about 40% of those with hypertension. The Msyn and hypertension have a common pathophysiology. Exercise is recommended for their treatment, prevention and control. The influence of the Msyn on the antihypertensive effects of aerobic exercise is not known. We examined the influence of the Msyn on the blood pressure (BP) response following low (LIGHT, 40% peak oxygen consumption, VO₂peak) and moderate (MODERATE, 60% VO₂peak) intensity, aerobic exercise.</p> <p>Methods</p> <p>Subjects were 46 men (44.3 ± 1.3 yr) with pre- to Stage 1 hypertension (145.5 ± 1.6/86.3 ± 1.2 mmHg) and borderline dyslipidemia. Men with Msyn (n = 18) had higher fasting insulin, triglycerides and homeostasis model assessment (HOMA) and lower high density lipoprotein than men without Msyn (n = 28) (p < 0.01). Subjects consumed a standard meal and 2 hr later completed one of three randomized experiments separated by 48 hr. The experiments were a non-exercise control session of seated rest and two cycle bouts (LIGHT and MODERATE). BP, insulin and glucose were measured before, during and after the 40 min experiments. Subjects left the laboratory wearing an ambulatory BP monitor for the remainder of the day. Repeated measure ANCOVA tested if BP, insulin and glucose differed over time among experiments in men without and with the Msyn with HOMA as a covariate. Multivariable regression analyses examined associations among BP, insulin, glucose and the Msyn.</p> <p>Results</p> <p>Systolic BP (SBP) was reduced 8 mmHg (p < 0.05) and diastolic BP (DBP) 5 mmHg (p = 0.052) after LIGHT compared to non-exercise control over 9 hr among men without versus with Msyn. BP was not different after MODERATE versus non-exercise control between Msyn groups (p ≥ 0.05). The factors accounting for 17% of the SBP response after LIGHT were baseline SBP (β = -0.351, r²= 0.123, p = 0.020), Msyn (β = 0.277, r²= 0.077, p = 0.069), and HOMA (β = -0.124, r²= 0.015, p = 0.424). Msyn (r²= 0.096, p = 0.036) was the only significant correlate of the DBP response after LIGHT.</p> <p>Conclusion</p> <p>Men without the Msyn respond more favorably to the antihypertensive effects of lower intensity, aerobic exercise than men with the Msyn. If future work confirms our findings, important new knowledge will be gained for the personalization of exercise prescriptions among those with hypertension and the Msyn.</p

The quality of preventive health care delivered to adults: results from a cross-sectional study in Southern Italy

<p>Abstract</p> <p>Background</p> <p>It is assumed that providing clinical preventive services to patients can identify or detect early important causes of adult mortality. The aim of this study was to quantify access to preventive services in Southern Italy and to assess whether and how the provision of preventive care was influenced by any specific characteristics of patients.</p> <p>Methods</p> <p>In a cross-sectional study adults aged 18 years and over attending primary care physician (PCP) offices located in Southern Italy were interviewed from June through December 2007. Quality indicators of preventive health care developed from RAND's Quality Assessment Tools and Behavioral Risk Factor Surveillance System (BRFSS) were used. Multivariate analysis was performed to identify and to assess the role of patients' characteristics on delivery of clinical preventive services.</p> <p>Results</p> <p>A total of 1467 subjects participated in the study. Excepting blood pressure preventive check (delivered to 64.4% of eligible subjects) and influenza vaccination (recommended to 90.2% of elderly), the rates of delivery of clinical preventive services were low across all measures, particularly for screening and counseling on health habits. Rates for providing cancer screening tests at recommended times were 21.3% for colonoscopy, 51.5% for mammography and 52.4% for Pap smear. Statistical analysis showed clear disparities in the provision of clinical preventive services associated with age, gender, education level, perceived health status, current health conditions and primary care access measures.</p> <p>Conclusions</p> <p>There is overwhelming need to develop and implement effective interventions to improve delivery of routine clinical preventive services.</p

Free Cysteine Modulates the Conformation of Human C/EBP Homologous Protein

The C/EBP Homologous Protein (CHOP) is a nuclear protein that is integral to the unfolded protein response culminating from endoplasmic reticulum stress. Previously, CHOP was shown to comprise extensive disordered regions and to self-associate in solution. In the current study, the intrinsically disordered nature of this protein was characterized further by comprehensive in silico analyses. Using circular dichroism, differential scanning calorimetry and nuclear magnetic resonance, we investigated the global conformation and secondary structure of CHOP and demonstrated, for the first time, that conformational changes in this protein can be induced by the free amino acid l-cysteine. Addition of l-cysteine caused a significant dose-dependent decrease in the protein helicity – dropping from 69.1% to 23.8% in the presence of 1 mM of l-cysteine – and a sequential transition to a more disordered state, unlike that caused by thermal denaturation. Furthermore, the presence of small amounts of free amino acid (80 µM, an 8∶1 cysteine∶CHOP ratio) during CHOP thermal denaturation altered the molecular mechanism of its melting process, leading to a complex, multi-step transition. On the other hand, high levels (4 mM) of free l-cysteine seemed to cause a complete loss of rigid cooperatively melting structure. These results suggested a potential regulatory function of l-cysteine which may lead to changes in global conformation of CHOP in response to the cellular redox state and/or endoplasmic reticulum stress

Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950-2019 : a comprehensive demographic analysis for the Global Burden of Disease Study 2019

Background Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10-14 and 50-54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings The global TFR decreased from 2.72 (95% uncertainty interval [UI] 2.66-2.79) in 2000 to 2.31 (2.17-2.46) in 2019. Global annual livebirths increased from 134.5 million (131.5-137.8) in 2000 to a peak of 139.6 million (133.0-146.9) in 2016. Global livebirths then declined to 135.3 million (127.2-144.1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2.1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27.1% (95% UI 26.4-27.8) of global livebirths. Global life expectancy at birth increased from 67.2 years (95% UI 66.8-67.6) in 2000 to 73.5 years (72.8-74.3) in 2019. The total number of deaths increased from 50.7 million (49.5-51.9) in 2000 to 56.5 million (53.7-59.2) in 2019. Under-5 deaths declined from 9.6 million (9.1-10.3) in 2000 to 5.0 million (4.3-6.0) in 2019. Global population increased by 25.7%, from 6.2 billion (6.0-6.3) in 2000 to 7.7 billion (7.5-8.0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58.6 years (56.1-60.8) in 2000 to 63.5 years (60.8-66.1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019. Interpretation Over the past 20 years, fertility rates have been dropping steadily and life expectancy has been increasing, with few exceptions. Much of this change follows historical patterns linking social and economic determinants, such as those captured by the GBD Socio-demographic Index, with demographic outcomes. More recently, several countries have experienced a combination of low fertility and stagnating improvement in mortality rates, pushing more populations into the late stages of the demographic transition. Tracking demographic change and the emergence of new patterns will be essential for global health monitoring. Copyright (C) 2020 The Author(s). Published by Elsevier Ltd.Peer reviewe

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: Regularly updated data on stroke and its pathological types, including data on their incidence, prevalence, mortality, disability, risk factors, and epidemiological trends, are important for evidence-based stroke care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) aims to provide a standardised and comprehensive measurement of these metrics at global, regional, and national levels. Methods: We applied GBD 2019 analytical tools to calculate stroke incidence, prevalence, mortality, disability-adjusted life-years (DALYs), and the population attributable fraction (PAF) of DALYs (with corresponding 95% uncertainty intervals [UIs]) associated with 19 risk factors, for 204 countries and territories from 1990 to 2019. These estimates were provided for ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and all strokes combined, and stratified by sex, age group, and World Bank country income level. Findings: In 2019, there were 12·2 million (95% UI 11·0–13·6) incident cases of stroke, 101 million (93·2–111) prevalent cases of stroke, 143 million (133–153) DALYs due to stroke, and 6·55 million (6·00–7·02) deaths from stroke. Globally, stroke remained the second-leading cause of death (11·6% [10·8–12·2] of total deaths) and the third-leading cause of death and disability combined (5·7% [5·1–6·2] of total DALYs) in 2019. From 1990 to 2019, the absolute number of incident strokes increased by 70·0% (67·0–73·0), prevalent strokes increased by 85·0% (83·0–88·0), deaths from stroke increased by 43·0% (31·0–55·0), and DALYs due to stroke increased by 32·0% (22·0–42·0). During the same period, age-standardised rates of stroke incidence decreased by 17·0% (15·0–18·0), mortality decreased by 36·0% (31·0–42·0), prevalence decreased by 6·0% (5·0–7·0), and DALYs decreased by 36·0% (31·0–42·0). However, among people younger than 70 years, prevalence rates increased by 22·0% (21·0–24·0) and incidence rates increased by 15·0% (12·0–18·0). In 2019, the age-standardised stroke-related mortality rate was 3·6 (3·5–3·8) times higher in the World Bank low-income group than in the World Bank high-income group, and the age-standardised stroke-related DALY rate was 3·7 (3·5–3·9) times higher in the low-income group than the high-income group. Ischaemic stroke constituted 62·4% of all incident strokes in 2019 (7·63 million [6·57–8·96]), while intracerebral haemorrhage constituted 27·9% (3·41 million [2·97–3·91]) and subarachnoid haemorrhage constituted 9·7% (1·18 million [1·01–1·39]). In 2019, the five leading risk factors for stroke were high systolic blood pressure (contributing to 79·6 million [67·7–90·8] DALYs or 55·5% [48·2–62·0] of total stroke DALYs), high body-mass index (34·9 million [22·3–48·6] DALYs or 24·3% [15·7–33·2]), high fasting plasma glucose (28·9 million [19·8–41·5] DALYs or 20·2% [13·8–29·1]), ambient particulate matter pollution (28·7 million [23·4–33·4] DALYs or 20·1% [16·6–23·0]), and smoking (25·3 million [22·6–28·2] DALYs or 17·6% [16·4–19·0]). Interpretation: The annual number of strokes and deaths due to stroke increased substantially from 1990 to 2019, despite substantial reductions in age-standardised rates, particularly among people older than 70 years. The highest age-standardised stroke-related mortality and DALY rates were in the World Bank low-income group. The fastest-growing risk factor for stroke between 1990 and 2019 was high body-mass index. Without urgent implementation of effective primary prevention strategies, the stroke burden will probably continue to grow across the world, particularly in low-income countries. Funding: Bill & Melinda Gates Foundation