We report the activation of outwardly rectifying anion currents by sphingosine-1-phosphate (S1P) in the murine macrophage cell line RAW 264.7. The S1P-induced current is mainly carried by anions, because the reversal potential of the current was shifted by replacement of extracellular Cl(-) by glutamate(-) but not when extracellular Na(+) was substituted by Tris(+). The inhibition of the current by hypertonic extracellular or hypotonic intracellular solution as well as the inhibitory effects of NPPB, tamoxifen, and glibenclamide indicates that the anion current is mediated by volume-regulated anion channels (VRAC). The S1P effect was blocked by intracellular GDPβS and W123, which points to signaling via the S1P receptor 1 (S1PR1) and G proteins. As cytochalasin D diminished the action of S1P, we conclude that the actin cytoskeleton is involved in the stimulation of VRAC. S1P and hypotonic extracellular solution induced secretion of ATP from the macrophages, which in both cases was blocked in a similar way by typical VRAC blockers. We suppose that the S1P-induced ATP secretion in macrophages via activation of VRAC constitutes a functional link between sphingolipid and purinergic signaling in essential processes such as inflammation and migration of leukocytes as well as phagocytosis and the killing of intracellular bacteria.

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Headache is frequent in patients with mitochondrial disorders. Previous studies point to a higher prevalence of headache in these patients than in the general population. As mitochondrial disorders often present a variety of other symptoms, the question arises how much the presence of headache really influences daily life. We performed a cross-sectional, questionnaire-based study investigation with 61 patients with a genetically proved mitochondrial disease mainly composed of CPEO phenotype. Headache was examined using a standardized questionnaire, and classified according to ICHD-2. Headache-related disability was evaluated by the Headache-Impact-Test-6 (HIT-6). Additionally, depression and anxiety were examined using the Hospital Anxiety and Depression Scale (HADS) and Short-Form-Health Survey (SF-12) was used to investigate the health-related quality of life. Headache was reported by 43/61 (70.5%) of the patients. 35/61 patients (57.4%) described a Tension-type headache (TTH) and 26 patients (42.6%) a migraine. Patients reporting headache had a significantly higher HIT-6 score than those without (mean: 54.47 vs. 38.47, p < 0.001). The HIT-6 score was significantly higher in patients reporting a migraine compared to those with a tension-type headache (mean: 62.13 vs. 46.18, p < 0.001). In the HADS score and in the SF-12 were not significantly influenced by the occurrence of headache. This study confirms the previously reported frequent occurrence of headache in a large cohort of patients with a confirmed mitochondrial disease. Migraine had the greatest impact on daily living, which appeared not to be confounded by depression and anxiety. Thus, we conclude that Migraine may be a substantial contributor for burden of disease in patients with mitochondrial diseases.

Background Headache attributed to ingestion or inhalation of a cold stimulus (HICS), colloquially called ice-cream headache, is a common form of a primary headache in adults and children. However, previous studies on adults are limited due to the small number of patients. Furthermore, most of the subjects in previous studies had a history of other primary headaches. Methods Biographic data, clinical criteria of HICS and prevalence of primary headache were collected by a standardized questionnaire. A total of 1213 questionnaires were distributed; the return rate was 51.9% (n = 629); 618 questionnaires could be analyzed. Results In a cohort of 618 people aged between 17–63 years (females: n = 426, 68.9%), the prevalence of HICS was 51.3% (317 out of 618). There was no difference between men and women (51.3% vs. 51.6%). The duration of HICS was shorter than 30 sec in 92.7%. In the HICS group, localization of the pain was occipital in 17%. Trigemino-autonomic symptoms occurred in 22%, and visual phenomena (e.g. flickering lights, spots or lines) were reported by 18% of the HICS group. The pain intensity, but not the prevalence of HICS, was higher when tension-type headache and migraine or both were present as co-morbid primary headaches (Numeric Rating Scale (NRS) 4.58 and 6.54, p = 0.006). There was no higher risk of participants with migraine getting HICS than for those who did not have migraine (odds ratio = 1.17, 95% confidence interval (CI) 0.75–1.83; p = 0.496). Conclusion The results of this study modified the current criteria for HICS in the ICHD-3 regarding duration and localization. In addition, accompanying symptoms in about one fifth of the participants are not mentioned in the ICHD-3. Neither migraine nor tension-type headache seems to be a risk factor for HICS. However, accompanying symptoms in HICS are more frequent in subjects with another primary headache than in those without such a headache.