ER Stress-Induced Secretion of Proteins and Their Extracellular Functions in the Heart.

Endoplasmic reticulum (ER) stress is a result of conditions that imbalance protein homeostasis or proteostasis at the ER, for example ischemia, and is a common event in various human pathologies, including the diseased heart. Cardiac integrity and function depend on the active secretion of mature proteins from a variety of cell types in the heart, a process that requires an intact ER environment for efficient protein folding and trafficking to the secretory pathway. As a consequence of ER stress, most protein secretion by the ER secretory pathway is decreased. Strikingly, there is a select group of proteins that are secreted in greater quantities during ER stress. ER stress resulting from the dysregulation of ER Ca2+ levels, for instance, stimulates the secretion of Ca2+-binding ER chaperones, especially GRP78, GRP94, calreticulin, and mesencephalic astrocyte-derived neurotrophic factor (MANF), which play a multitude of roles outside the cell, strongly depending on the cell type and tissue. Here we review current insights in ER stress-induced secretion of proteins, particularly from the heart, and highlight the extracellular functions of these proteins, ranging from the augmentation of cardiac cell viability to the modulation of pro- and anti-apoptotic, oncogenic, and immune-stimulatory cell signaling, cell invasion, extracellular proteostasis, and more. Many of the roles of ER stress-induced protein secretion remain to be explored in the heart. This article is part of a special issue entitled "The Role of Proteostasis Derailment in Cardiac Diseases."

An update on behavioral treatments in migraine - current knowledge and future options.

INTRODUCTION: Besides pharmacological and interventional treatments a variety of non-medical therapeutic options exist for migraine, which has largely been derived from behavioral therapy. Areas covered: For our update we collected available studies via PubMed searches. This review highlights that already consulting of the patient is able to reduce the frequency of migraine attacks. Relaxation techniques, especially progressive muscle relaxation, and various types of biofeedback are effective, as is the implementation of cognitive behavioral therapy. However, recent reviews also point to some existing inconsistencies and methodological limitations. The advent of modern information technology based approaches (e.g. online therapy, smartphone applications) further advanced the arsenal of behavioral treatment regimes. The combination of behavioral treatment options and the combination with pharmacotherapy lead to additive effects. In modern multidisciplinary treatment approaches, behavioral therapy is an indispensable component. Expert commentary: Behavioral treatment in prophylaxis of migraine is as effective as pharmacological treatment with additional effects when pharmacological and behavioral treatment is applied in combination. Novel treatment approaches using online technology and electronic devices offer interesting options that will spread more in the future.

Midbrain raphe hypoechogenicity in migraineurs: An indicator for the use of analgesics but not triptans.

Introduction The involvement of the serotonergic system of the brainstem raphe in the pathogenesis of migraine is discussed. Here we studied brainstem alterations in migraineurs using transcranial sonography and examined their relation to clinical features and self-medication. Methods We investigated 51 migraineurs (11 men, 40 women, mean age 29.7 ± 11.9 years) and 32 healthy individuals without history of headache or depressive disorder (eight men, 24 women, mean age 34.4 ± 13.0 years). Transcranial sonography was performed in an investigator-blinded fashion. Midbrain raphe echogenicity was quantified using digitized analysis. Migraine characteristics and the use of analgesics were evaluated by applying validated questionnaires. Eight migraineurs underwent neurophysiologic evaluation of contingent stimulus-related cortical potentials. Results Echo-reduced midbrain raphe was detected in 27 (53%) migraineurs, but only six (19%) control subjects (odds ratio = 4.87, p = 0.002). Lower raphe echogenicity correlated with both higher amplitude of terminal contingent negative variation (Spearman test, r = 0.76, p = 0.028) and higher use of analgesic drugs ( r = -0.45, p = 0.011), but not with use of triptans or with migraine frequency or severity (all p > 0.2). Compared to migraineurs without aura, migraineurs with aura had enlarged third ventricles (t-test, p = 0.014), while the lateral ventricle widths did not differ ( p = 0.62). Conclusions Midbrain raphe alteration is frequent in migraineurs and relates to self-medication behavior. This alteration may reflect the dysfunction of serotonergic raphe nuclei.

Progressive muscle relaxation reduces migraine frequency and normalizes amplitudes of contingent negative variation (CNV).

BACKGROUND: Central information processing, visible in evoked potentials like the contingent negative variation (CNV) is altered in migraine patients who exhibit higher CNV amplitudes and a reduced habituation. Both characteristics were shown to be normalized under different prophylactic migraine treatment options whereas Progressive Muscle Relaxation (PMR) has not yet been examined. We investigated the effect of PMR on clinical course and CNV in migraineurs in a quasi-randomized, controlled trial. METHODS: Thirty-five migraine patients and 46 healthy controls were examined. Sixteen migraineurs and 21 healthy participants conducted a 6-week PMR-training with CNV-measures before and after as well as three months after PMR-training completion. The remaining participants served as controls. The clinical course was analyzed with two-way analyses of variance (ANOVA) with repeated measures. Pre-treatment CNV differences between migraine patients and healthy controls were examined with t-tests for independent measures. The course of the CNV-parameters was examined with three-way ANOVAs with repeated measures. RESULTS: After PMR-training, migraine patients showed a significant reduction of migraine frequency. Preliminary to the PMR-training, migraine patients exhibited higher amplitudes in the early component of the CNV (iCNV) and the overall CNV (oCNV) than healthy controls, but no differences regarding habituation. After completion of the PMR-training, migraineurs showed a normalization of the iCNV amplitude, but neither of the oCNV nor of the habituation coefficient. CONCLUSIONS: The results confirm clinical efficacy of PMR for migraine prophylaxis. The pre-treatment measure confirms altered cortical information processing in migraine patients. Regarding the changes in the iCNV after PMR-training, central nervous mechanisms of the PMR-effect are supposed which may be mediated by the serotonin metabolism.

Migraine and Meditation: Characteristics of Cortical Activity and Stress Coping in Migraine Patients, Meditators and Healthy Controls-An Exploratory Cross-Sectional Study.

The aim of this exploratory cross-sectional study was to investigate the characteristics of cortical activity and stress coping in migraine patients, meditation experienced subjects, and healthy controls. 45 meditation experienced subjects, 46 migraine patients, and 46 healthy controls took part in the study. Cortical activity was measured with the contingent negative variation (CNV), a slow cortical event-related potential. Stress coping was examined with the standardized Stress Coping Questionnaire SVF-78. A one-way analysis of variance was used to investigate possible differences between the groups. CNV-amplitude was significantly higher in migraineurs than in controls. The meditators showed significantly lowest amplitudes. Migraine patients used negative stress-coping strategies significantly more often than meditators and healthy controls. Especially the application of the strategy "rumination" was most frequent in migraine patients and least frequent in meditators. Moreover, frequent rumination was significantly correlated with high CNV-amplitudes. Cortical and stress processing in people with meditation experience was improved compared to migraine patients and healthy controls.

Disease duration of episodic migraine correlates with modified amplitudes and habituation of contingent negative variation.

Cortical habituation in episodic migraine patients without medication overuse headache (MOH), recorded by contingent negative variation (CNV), is often reduced compared with healthy controls. There is evidence that with longer duration of migraine disease (DOD) amplitudes and habituation of CNV become progressively abnormal. The aim of the study was to examine habituation characteristics of contingent negative variation in episodic migraine patients suffering from short- and long-lasting migraine compared to matched healthy controls. 32 migraine patients without aura and without MOH diagnosed according to the revised ICHD-II criteria and 16 age- and sex-matched healthy controls were included. According to DOD, the total sample of migraine patients was divided into two groups (group a: DOD <121 months, n = 17 subjects, group b: DOD >120 months, n = 15 subjects). Both migraine groups did not differ in the number of days of migraine and the duration of attacks. Overall CNV and initial CNV differed significantly between migraine patients and controls, whereas the former produced more negative amplitudes. In the migraine group lack of or deficient habituation occurred, whilst controls showed habituation. There were middle range correlations between the DOD and overall CNV, initial CNV, and y-intercept. Patients suffering from long-lasting migraine produced higher CNV amplitudes with a higher y-intercept. The results are interpreted as "maladaptive plasticity" with a risen intercept in long-lasting migraine.

Clinical, genetic, and brain sonographic features related to Parkinson's disease in Gaucher disease.

Homozygous or compound heterozygous mutations in the glucocerebrosidase gene cause Gaucher disease. Moreover, heterozygous glucocerebrosidase gene mutations represent the most common genetic risk factor for Parkinson's disease (PD) known so far. Substantia nigra (SN) hyperechogenicity, a sonographic feature thought to reflect iron accumulation, has been described in both PD and Gaucher disease patients. Here we studied how clinical, genetic, and brain sonographic findings relate to the occurrence of PD in Gaucher disease. Sixteen Gaucher disease patients, 12 PD patients, and 32 control subjects were enrolled. The glucocerebrosidase genotypes were identified by DNA sequencing. All subjects underwent transcranial ultrasound, and eight Gaucher disease patients additionally MRI for comparison with SN ultrasound findings. SN hyperechogenicity and reduced echogenicity of brainstem raphe were more frequent in Gaucher disease patients (62, 37 %) than in controls (12, 12 %; p < 0.001, p < 0.05). SN hyperechogenicity in Gaucher disease patients was unrelated to type or severity of glucocerebrosidase gene mutation, but correlated with iron-sensitive MRI-T2 hypointensity of SN pars compacta, and with age at start of enzyme replacement therapy. While none of the five Gaucher disease patients with signs of PD (definite PD, n = 4; early PD, n = 1) had severe glucocerebrosidase gene mutations known to cause neuronopathic Gaucher disease, all carried a N370S allele, previously reported to predict non-neuronopathic Gaucher disease. Hyposmia, higher non-motor symptoms score (constipation, depression, executive dysfunction), and SN hyperechogenicity were characteristic features of Gaucher disease-related PD. We conclude that the combined clinical, genetic, and transcranial sonographic assessment may improve the PD risk evaluation in Gaucher disease.

Headache in children: update on biobehavioral treatments.

Biobehavioral pain treatment consists of relaxation techniques, biofeedback treatment, operant pain treatment, pain coping, cognitive-behavioral treatment, and multimodal treatment. Especially in the treatment of pediatric headache, biobehavioral procedures have been found to be highly efficient and are widely accepted. They present similar effects as pharmaceutical treatments. In general, when standardized treatment programs are applied, the sessions are highly effective.

Distribution of protein oxidation products in the proteome of thermally processed milk.

During thermal milk processing, severe oxidation can occur, which alters the technological and physiological properties of the milk proteins. Due to differences in composition and physicochemical properties, it can be expected that the particular milk proteins are differently affected by oxidative damage. Therefore, the protein-specific distribution of oxidation products in the heated milk proteome was investigated. Raw and heated milk samples were separated by one-dimensional gel electrophoresis. Protein oxidation was visualized by Western blot after derivatization of protein carbonyls with 2,4-dinitrophenylhydrazine. Thus, α-lactalbumin displayed enhanced oxidation compared to ß-lactoglobulin, despite its lower concentration in milk. Highly selective oxidation was detected for a previously unassigned minor milk protein. The protein was identified by its peptide mass fingerprint as a variant of α(S1)-casein (α(S1)-casein*). Similar oxidation patterns were observed in several commercial milk products.

Cortical habituation deficit in tinnitus sufferers: contingent negative variation as an indicator of duration of the disease.

Cortical attention and habituation parameters are altered in patients suffering from tinnitus. The aim of the study was to quantify cortical attention and habituation parameters in tinnitus patients by recording the contingent negative variation (CNV) response and to correlate amplitudes of different CNV parameters with duration of disease. Twenty patients suffering from tinnitus (median: 44 years) and twenty age- and sex-matched healthy controls (median: 41 years) were tested by a CNV paradigm. We recorded overall CNV, initial CNV, and terminal CNV and calculated habituation slopes. All CNV parameters were Spearman-correlated with individual duration of disease. Highly significant between groups differences emerged in total (tinnitus: -8.4 uV vs. controls: -3.8 uV), initial (-11.2 vs. -6.0 uV), and terminal CNV (-11.9 vs. -6.5 uV) demonstrating higher negative amplitudes in tinnitus patients. Habituation differed in total and terminal CNV, indicating missing habituation in tinnitus patients. Overall CNV (ϱ = -.365) and initial CNV (ϱ = -.529) showed a medium Spearman correlation with duration of disease. We conclude that the correlation between duration of tinnitus and the initial CNV amplitudes indicates an altered state of cortical excitability that can also be observed in more negative CNV-amplitudes in tinnitus patients. We assume that this state indicates a chronicity process in tinnitus disease.

Mapping the glycoxidation product Nε-carboxymethyllysine in the milk proteome.

Milk processing leads to severe protein damage caused by the formation of nonenzymatic posttranslational modifications (nePTMs), such as glycation and glycoxidation. As a result, the technological and nutritional function of milk proteins can be critically altered. The present study investigated the protein-specific distribution of the glycoxidation product N(ε) -carboxymethyllysine (CML) in the proteome of processed milk. For this purpose, raw milk and heated milk were separated by 1-D or 2-DE. The distribution of CML in the milk proteome was examined by immunoblotting. The changes in the protein composition that occurred during heating were monitored by Coomassie staining. Relative modification rates were measured for the major milk protein fractions after 30 and 60 min of heating at 120°C and normalized to the content of the respective protein fraction in the samples. The highest glycoxidation rates were detected in the high molecular weight aggregates that are generated during heating. The casein fraction and the whey protein ß-lactoglobulin were affected in a similar manner. The relevance of the results for industrial milk processing was confirmed by analyzing several commercial milk products accordingly. The presented approach allows nonenzymatic posttranslational modification mapping of the entire milk proteome.