The adaptor protein PID1 regulates receptor-dependent endocytosis of postprandial triglyceride-rich lipoproteins.

ObjectiveInsulin resistance is associated with impaired receptor dependent hepatic uptake of triglyceride-rich lipoproteins (TRL), promoting hypertriglyceridemia and atherosclerosis. Next to low-density lipoprotein (LDL) receptor (LDLR) and syndecan-1, the LDLR-related protein 1 (LRP1) stimulated by insulin action contributes to the rapid clearance of TRL in the postprandial state. Here, we investigated the hypothesis that the adaptor protein phosphotyrosine interacting domain-containing protein 1 (PID1) regulates LRP1 function, thereby controlling hepatic endocytosis of postprandial lipoproteins.MethodsLocalization and interaction of PID1 and LRP1 in cultured hepatocytes was studied by confocal microscopy of fluorescent tagged proteins, by indirect immunohistochemistry of endogenous proteins, by GST-based pull down and by immunoprecipitation experiments. The in vivo relevance of PID1 was assessed using whole body as well as liver-specific Pid1-deficient mice on a wild type or Ldlr-deficient (Ldlr-/-) background. Intravital microscopy was used to study LRP1 translocation in the liver. Lipoprotein metabolism was investigated by lipoprotein profiling, gene and protein expression as well as organ-specific uptake of radiolabelled TRL.ResultsPID1 co-localized in perinuclear endosomes and was found associated with LRP1 under fasting conditions. We identified the distal NPxY motif of the intracellular C-terminal domain (ICD) of LRP1 as the site critical for the interaction with PID1. Insulin-mediated NPxY-phosphorylation caused the dissociation of PID1 from the ICD, causing LRP1 translocation to the plasma membrane. PID1 deletion resulted in higher LRP1 abundance at the cell surface, higher LDLR protein levels and, paradoxically, reduced total LRP1. The latter can be explained by higher receptor shedding, which we observed in cultured Pid1-deficient hepatocytes. Consistently, PID1 deficiency alone led to increased LDLR-dependent endocytosis of postprandial lipoproteins and lower plasma triglycerides. In contrast, hepatic PID1 deletion on an Ldlr-/- background reduced lipoprotein uptake into liver and caused plasma TRL accumulation.ConclusionsBy acting as an insulin-dependent retention adaptor, PID1 serves as a regulator of LRP1 function controlling the disposal of postprandial lipoproteins. PID1 inhibition provides a novel approach to lower plasma levels of pro-atherogenic TRL remnants by stimulating endocytic function of both LRP1 and LDLR in the liver

High diagnostic stability of confirmed migraine and confirmed tension-type headache according to the ICHD-3 beta in adolescents

Background: Stable headache diagnosis classification is a prerequisite for identification of headache type specific risk factors. Does the stability of a headache diagnosis over time vary between migraine and tension-type headache (TTH)? Are there differences in diagnosis stability between a probable and a definite headache diagnosis? Findings: In a sample of 783 students (ages 12 to 18 years) participating in a headache intervention study in greater Munich, the stability of headache classification according to the International Classification of Headache Disorder - third edition (beta version) (ICHD-3 beta) after a follow-up of 7 months was examined. Differences in stability of probable or definite migraine and probable or definite TTH were assessed. The stability of the headache diagnosis was assessed as predictive value of headache diagnosis with regard to confirmation of the headache type using the same diagnostic instrument 7 months later. Predictive values with 95% confidence intervals (CI) are reported. Of students with initial migraine, a diagnosis of migraine was confirmed in 65.71% of students after 7 months (95%-CI {[}59.40-71.64]). A clear distinction between probable (44.71%, 95%-CI {[}33.91-53.89]) and confirmed diagnosis (76.88% 95%-CI {[}69.56-83.17]) of migraine was observed. For TTH the predictive value was 62.66% (95%-CI {[}57.07-68.01]) overall with a lower stability for probable (46.10%, 95%-CI {[}37.68-54.69]) compared to the confirmed diagnosis (69.71%, 95%-CI {[}23.58-37.67]). Conclusion: While confirmed migraine and confirmed TTH diagnoses seem stable over time, stability of a probable diagnosis for either headache type was lower

Period Prevalence of Dizziness and Vertigo in Adolescents

Objectives To assess the period prevalence and severity of dizziness and vertigo in adolescents. Methods In 1661 students in 8th-10th grade in twelve grammar schools in Munich, Germany information on vertigo/dizziness was assessed by a questionnaire in the class room setting. Three month prevalence of dizziness/vertigo was estimated;symptoms were categorized as orthostatic dizziness, spinning vertigo, swaying vertigo or unspecified dizziness. Duration of symptoms and impact on daily life activities were assessed. Results 72.0% (95%-CI = [69.8-74.2];N = 1196) of the students (mean age 14.5 +/- 1.1) reported to suffer fromat least one episode of dizziness or vertigo in the last three months. Most adolescents ticked to have symptoms of orthostatic dizziness (52.0%,95%-CI = [49.5-54.4],N = 863). The period prevalence for the other types of vertigo were spinning vertigo: 11.6%,95%-CI = [10.1-13.3],N = 193;swaying vertigo: 12.2%,95%-CI = [10.6-13.8],N = 202;and unspecified dizziness: 15.2%,95%-CI = [13.5-17.1],N = 253. About 50% of students with spinning vertigo and swaying vertigo also report to have orthostatic dizziness. Most vertigo/dizziness types were confined to less than one minute on average. The proportion of students with any dizziness/vertigo accounting for failure attending school, leisure activities or obliging them to stay in bed were more pronounced for spinning or swaying vertigo. Conclusion Dizziness and vertigo in grammar school students appear to be as common as in adults. In face of the high period prevalence and clinical relevance of dizziness/vertigo in adolescents there is a need for prevention strategies. Risk factors for dizziness/vertigo need to be assessed to allow for conception of an intervention programme

Self-reported neck and shoulder pain in adolescents is associated with episodic and chronic migraine

Aim: The aim of this study was to verify the association between self-reported neck/shoulder pain and migraine and to compare findings of chronic and episodic migraine in adolescents. Methods In this cross-sectional study, 601 secondary-school students filled in questionnaires about headache appearance, type and frequency, neck and shoulder pain and lifestyle factors. Results: The adjusted strength of the association between reported neck and shoulder pain and migraine (assessed in multinomial regression models) increased with the frequency of migraine: less than once a week (OR=1.40;95% CI=(0.85-2.30)), weekly (OR=2.14;95% CI=(1.42-3.24)), and at least 15 days/month (OR=7.27;95% CI=(3.42-15.44)). Conclusion: In adolescents the association between self-reported neck and shoulder pain and migraine is most pronounced in migraine with a high attack frequency

Migraine and tension type headache in adolescents at grammar school in Germany - burden of disease and health care utilization

Background Tension-type headache and migraine are among the most prevalent chronic disorders in children/adolescents. Data on health care utilization for headache in this age group, however, are sparse. Methods In 1399 grammar school students (aged 12–19 years) with headache in the last six months in Germany a) the burden of disease for headache (mean intensity, mean frequency in the last three months and PedMIDAS means), b) medical care utilization defined by proportion of students consulting a physician in the last 12 months and/or taking analgetic drugs in the last three months by headache types (migraine and tension-type headache) and by burden of disease were assessed. Results Primary headache substantially impaired daily living activities in adolescents which was mainly related to migraine. Medical care utilization and drug use, however, was low (consulting a physician: 12.0 %, 95 %-CI = [10.3-13.8]; taking analgetic drugs: 29.9 %, 95 %-CI = [27.5-32.4]) - even among students with severe headache (physician consultation: <35 %; taking analgetic drugs: <63 %). Two thirds of students with any headache and 40 % of those with migraine had neither seen a physician nor used analgetic drugs because of their headache in the preceding 12 months. Conclusions Adolescents with headache might too rarely seek professional help for treatment of headache. Health promotion in adolescents should increase awareness for evidence-based treatment options for headache

Alleviation of migraine symptoms by application of repetitive peripheral magnetic stimulation to myofascial trigger points of neck and shoulder muscles - A randomized trial

Migraine is a burdensome disease with an especially high prevalence in women between the age of 15 and 49 years. Non-pharmacological, non-invasive therapeutic methods to control symptoms are increasingly in demand to complement a multimodal intervention approach in migraine. Thirty-seven subjects (age: 25.0 +/- 4.1 years;36 females) diagnosed with high-frequency episodic migraine who presented at least one active myofascial trigger point (mTrP) in the trapezius muscles and at least one latent mTrP in the deltoid muscles bilaterally prospectively underwent six sessions of repetitive peripheral magnetic stimulation (rPMS) over two weeks. Patients were randomly assigned to receive rPMS applied to the mTrPs of the trapezius (n = 19) or deltoid muscles (n = 18). Whereas the trapezius muscle is supposed to be part of the trigemino-cervical complex (TCC) and, thus, involved in the pathophysiology of migraine, the deltoid muscle was not expected to interfere with the TCC and was therefore chosen as a control stimulation site. The headache calendar of the German Migraine and Headache Society (DMKG) as well as the Migraine Disability Assessment (MIDAS) questionnaire were used to evaluate stimulation-related effects. Frequency of headache days decreased significantly in both the trapezius and the deltoid group after six sessions of rPMS (trapezius group: p = 0.005;deltoid group: p = 0.003). The MIDAS score decreased significantly from 29 to 13 points (p = 0.0004) in the trapezius and from 31 to 15 points (p = 0.002) in the deltoid group. Thus, rPMS applied to mTrPs of neck and shoulder muscles offers a promising approach to alleviate headache frequency and symptom burden. Future clinical trials are needed to examine more profoundly these effects, preferably using a sham-controlled setting

Vertigo and dizziness in adolescents: Risk factors and their population attributable risk

Objectives: To assess potential risk factors for vertigo and dizziness in adolescents and to evaluate their variability by different vertigo types. The role of possible risk factors for vertigo and dizziness in adolescents and their population relevance needs to be addressed in order to design preventive strategies. Study design: The study population consisted of 1482 school-children between the age of 12 and 19 years, who were instructed to fill out a questionnaire on different vertigo types and related potential risk factors. The questionnaire specifically asked for any vertigo, spinning vertigo, swaying vertigo, orthostatic dizziness, and unspecified dizziness. Further a wide range of potential risk factors were addressed including gender, stress, muscular pain in the neck and shoulder region, sleep duration, migraine, coffee and alcohol consumption, physical activity and smoking. Results: Gender, stress, muscular pain in the neck and shoulder region, sleep duration and migraine were identified as independent risk factors following mutual adjustment: The relative risk was 1.17 [1.10 - 1.25] for female sex, 1.07 [1.02 - 1.13] for stress, 1.24 [1.17 - 1.32] for muscular pain, and 1.09 [1.03 - 1.14] for migraine. The population attributable risk explained by these risk factors was 26%, with muscular pain, stress, and migraine accounting for 11%, 4%, and 3% respectively. Conclusion: Several established risk factors in adults were also identified in adolescents. Risk factors amenable to prevention accounted for 17% of the total population risk. Therefore, interventions targeting these risk factors may be warranted

Functional Reorganization of Cortical Language Function in Glioma Patients—A Preliminary Study

Background: Functional reorganization (FR) was shown in glioma patients by direct electrical stimulation (DES) during awake craniotomy. This option for repeated mapping is available in cases of tumor recurrence and after decision for a second surgery. Navigated repetitive transcranial magnetic stimulation (nrTMS) has shown a high correlation with results of DES during awake craniotomy for language-negative sites (LNS) and allows for a non-invasive evaluation of language function. This preliminary study aims to examine FR in glioma patients by nrTMS.Methods: A cohort of eighteen patients with left-sided perisylvian gliomas underwent preoperative nrTMS language mapping twice. The mean time between mappings was 17 ± 12 months. The cortex was separated into anterior and posterior language-eloquent regions. We defined a tumor area and an area without tumor (WOT). Error rates (ER = number of errors per number of stimulations) and hemispheric dominance ratios (HDR) were calculated as the quotient of the left- and right-sided ER.Results: In cases in which most language function was located near the tumor during the first mapping, we found significantly more LNS in the tumor area during the second mapping as compared to cases in which function was not located near the tumor (p = 0.049). Patients with seizures showed fewer LNS during the second mapping. We found more changes of cortical language function in patients with a follow-up time of more than 13 months and lower WHO-graded tumors.Conclusion: Present results confirm that nrTMS can show FR of LNS in glioma patients. Its extent, clinical impact and correlation with DES requires further evaluation but could have a considerable impact in neuro-oncology

Migräne im Kindes- und Jugendalter — Ausblick auf innovative Behandlungsansätze im Rahmen multimodaler Therapiekonzepte

Although migraine is a~relevant health issue in children and adolescents, clinical care and research are still underrepresented and underfunded in this field. Quality of life can be significantly reduced when living with frequent episodes of pain. Due to the high level of vulnerability of the developing brain during adolescence, the risk of chronification and persistence into adulthood is high. In this narrative review, we describe the corner stones of a~patient-centered, multimodular treatment regimen. Further, an update on the pathophysiology of migraine is given considering the concept of a~periodically oscillating functional state of the brain in migraine patients (\textquotedblmigraine is a~brain state\textquotedbl). Besides central mechanisms, muscular structures with the symptoms of muscular pain, tenderness, or myofascial trigger points play an important role. Against this background, the currently available nonpharmacological and innovative neuromodulating approaches are presented focusing on the method of repetitive peripheral magnetic stimulation.Die Migräne ist auch im Kindes- und Jugendalter ein häufiges, aber in klinischer Versorgung und Wissenschaft oft unterrepräsentiertes Krankheitsbild. Gerade im Kindes- und Jugendalter bestehen relevante Einschränkungen der Lebensqualität durch das (häufige) Schmerzerfahren. Bedingt durch die entwicklungsspezifisch hohe Vulnerabilität des adoleszenten Gehirns besteht ein hohes Chronifizierungs- und Persistenzrisiko bis ins Erwachsenenalter hinein. In diesem Beitrag werden die Bestandteile eines patientenzentrierten, multimodalen Therapiekonzepts dargestellt. Darüber hinaus werden die aktuellsten Erkenntnisse zu den pathophysiologischen Grundlagen der Migräneerkrankung beleuchtet, nach denen Migräne durch einen sich phasenweise verändernden Funktionszustand des Gehirns entsteht (Stichwort: „migraine is a brain state“). Auch periphere Komponenten wie Muskelschmerzen, -verspannungen und -triggerpunkte spielen eine wichtige Rolle. Vor diesem Hintergrund werden nichtpharmakologische innovative Therapieansätze vorgestellt, die auf dem Prinzip der Neuromodulation beruhen, mit Fokus auf der repetitiven peripheren Magnetstimulation

Penumbral imaging and functional outcome in patients with anterior circulation ischaemic stroke treated with endovascular thrombectomy versus medical therapy: a meta-analysis of individual patient-level data

Background: CT perfusion (CTP) and diffusion or perfusion MRI might assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of irreversibly injured ischaemic core and potentially salvageable penumbra volumes were associated with functional outcome and whether they interacted with the treatment effect of endovascular thrombectomy on functional outcome. Methods: In this systematic review and meta-analysis, the HERMES collaboration pooled patient-level data from all randomised controlled trials that compared endovascular thrombectomy (predominantly using stent retrievers) with standard medical therapy in patients with anterior circulation ischaemic stroke, published in PubMed from Jan 1, 2010, to May 31, 2017. The primary endpoint was functional outcome, assessed by the modified Rankin Scale (mRS) at 90 days after stroke. Ischaemic core was estimated, before treatment with either endovascular thrombectomy or standard medical therapy, by CTP as relative cerebral blood flow less than 30% of normal brain blood flow or by MRI as an apparent diffusion coefficient less than 620 μm2/s. Critically hypoperfused tissue was estimated as the volume of tissue with a CTP time to maximum longer than 6 s. Mismatch volume (ie, the estimated penumbral volume) was calculated as critically hypoperfused tissue volume minus ischaemic core volume. The association of ischaemic core and penumbral volumes with 90-day mRS score was analysed with multivariable logistic regression (functional independence, defined as mRS score 0–2) and ordinal logistic regression (functional improvement by at least one mRS category) in all patients and in a subset of those with more than 50% endovascular reperfusion, adjusted for baseline prognostic variables. The meta-analysis was prospectively designed by the HERMES executive committee, but not registered. Findings: We identified seven studies with 1764 patients, all of which were included in the meta-analysis. CTP was available and assessable for 591 (34%) patients and diffusion MRI for 309 (18%) patients. Functional independence was worse in patients who had CTP versus those who had diffusion MRI, after adjustment for ischaemic core volume (odds ratio [OR] 0·47 [95% CI 0·30–0·72], p=0·0007), so the imaging modalities were not pooled. Increasing ischaemic core volume was associated with reduced likelihood of functional independence (CTP OR 0·77 [0·69–0·86] per 10 mL, pinteraction=0·29; diffusion MRI OR 0·87 [0·81–0·94] per 10 mL, pinteraction=0·94). Mismatch volume, examined only in the CTP group because of the small numbers of patients who had perfusion MRI, was not associated with either functional independence or functional improvement. In patients with CTP with more than 50% endovascular reperfusion (n=186), age, ischaemic core volume, and imaging-to-reperfusion time were independently associated with functional improvement. Risk of bias between studies was generally low. Interpretation: Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome. Combining ischaemic core volume with age and expected imaging-to-reperfusion time will improve assessment of prognosis and might inform endovascular thrombectomy treatment decisions. Funding: Medtronic