The chromatin remodeling protein CHD-1 and the EFL-1/DPL-1 transcription factor cooperatively down regulate CDK-2 to control SAS-6 levels and centriole number.

Centrioles are submicron-scale, barrel-shaped organelles typically found in pairs, and play important roles in ciliogenesis and bipolar spindle assembly. In general, successful execution of centriole-dependent processes is highly reliant on the ability of the cell to stringently control centriole number. This in turn is mainly achieved through the precise duplication of centrioles during each S phase. Aberrations in centriole duplication disrupt spindle assembly and cilia-based signaling and have been linked to cancer, primary microcephaly and a variety of growth disorders. Studies aimed at understanding how centriole duplication is controlled have mainly focused on the post-translational regulation of two key components of this pathway: the master regulatory kinase ZYG-1/Plk4 and the scaffold component SAS-6. In contrast, how transcriptional control mechanisms might contribute to this process have not been well explored. Here we show that the chromatin remodeling protein CHD-1 contributes to the regulation of centriole duplication in the C. elegans embryo. Specifically, we find that loss of CHD-1 or inactivation of its ATPase activity can restore embryonic viability and centriole duplication to a strain expressing insufficient ZYG-1 activity. Interestingly, loss of CHD-1 is associated with increases in the levels of two ZYG-1-binding partners: SPD-2, the centriole receptor for ZYG-1 and SAS-6. Finally, we explore transcriptional regulatory networks governing centriole duplication and find that CHD-1 and a second transcription factor, EFL-1/DPL-1 cooperate to down regulate expression of CDK-2, which in turn promotes SAS-6 protein levels. Disruption of this regulatory network results in the overexpression of SAS-6 and the production of extra centrioles.

Allele-specific mitochondrial stress induced by Multiple Mitochondrial Dysfunctions Syndrome 1 pathogenic mutations modeled in Caenorhabditis elegans.

Multiple Mitochondrial Dysfunctions Syndrome 1 (MMDS1) is a rare, autosomal recessive disorder caused by mutations in the NFU1 gene. NFU1 is responsible for delivery of iron-sulfur clusters (ISCs) to recipient proteins which require these metallic cofactors for their function. Pathogenic variants of NFU1 lead to dysfunction of its target proteins within mitochondria. To date, 20 NFU1 variants have been reported and the unique contributions of each variant to MMDS1 pathogenesis is unknown. Given that over half of MMDS1 individuals are compound heterozygous for different NFU1 variants, it is valuable to investigate individual variants in an isogenic background. In order to understand the shared and unique phenotypes of NFU1 variants, we used CRISPR/Cas9 gene editing to recreate exact patient variants of NFU1 in the orthologous gene, nfu-1 (formerly lpd-8), in C. elegans. Five mutant C. elegans alleles focused on the presumptive iron-sulfur cluster interaction domain were generated and analyzed for mitochondrial phenotypes including respiratory dysfunction and oxidative stress. Phenotypes were variable between the mutant nfu-1 alleles and generally presented as an allelic series indicating that not all variants have lost complete function. Furthermore, reactive iron within mitochondria was evident in some, but not all, nfu-1 mutants indicating that iron dyshomeostasis may contribute to disease pathogenesis in some MMDS1 individuals.

[Interdisciplinary multimodal pain therapy in headache disorders]. / Interdisziplinäre multimodale Schmerztherapie bei Kopfschmerzerkrankungen.

Primary headaches are among the most common pain disorders. They include migraines (prevalence 15%), tension headaches (up to 80%), and others, including trigeminal autonomic headaches (about 0.2%). Migraine, in particular, leads to significant impairment of personal life and high societal costs. Therefore, the need for effective and sustainable therapeutic procedures is high. This article provides an overview of psychological procedures in headache therapy and critically summarizes the empirical evidence for the effectiveness of interdisciplinary multimodal pain therapy (IMST) consisting of psychotherapy and pharmacotherapy. It can be shown that psychoeducation, relaxation procedures, cognitive behavioral therapy, and biofeedback are psychological procedures from which headache patients can benefit. In the synopsis of multimodal approaches in the treatment of headache, consistently greater effects can be observed when both pharmacological treatment and psychotherapeutic procedures are used. This added value should be regularly taken into account in the treatment of headache disorders. This requires close cooperation between headache specialists and psychotherapists who specialize in the treatment of pain.

Household income is associated with attack frequency, but not with the prevalence of headache: an analysis of self-reported headache in the general population in Germany.

BACKGROUND: Headache disorders are among the most prevalent neurological disorders worldwide. However, whether groups differing in socioeconomic position (SEP) are disproportionately affected by headache disorders has not yet been adequately clarified. Our aim was to analyse (1) the headache prevalence by socioeconomic position (SEP) and (2) the attack frequency by SEP in a German population-based adult sample. METHODS: Cross-sectional data from a random general population were used. The sample included N = 2,189 participants aged ≥ 18 years. SEP was measured using net equivalised income (NEI) and education. A binary logistic regression model tested the effect of SEP in predicting the prevalence of headache in general. Ordinal logistic regressions were modeled to predict the effect of SEP on the likelihood of attack frequency. Attack frequency was categorized in low frequency episodic headache (LFEH: 0-3 days per month), moderate frequency episodic headache (MFEH: 4-14 days per month) and chronic headache (CH: ≥ 15 days per month). RESULTS: Of the 2,189 participants, 891 reported headache in the last six months. Neither income nor education was associated with headache prevalence. However, significant differences between income groups were found for attack frequency. Compared to participants with NEI > 150%, those with NEI < 60% were 5.21 times more likely (95%CI 2.03, 13.36) to experience higher headache frequency, and those with NEI between 60 and 150% were 2.29 times more likely (95%CI 1.02, 5.11), with adjustments made for a set of potential confounders, including depressive symptoms. CONCLUSIONS: To reduce headache attacks, it is essential to address both low- and middle-income groups affected by headaches. Universal public health prevention campaigns are particularly appropriate.

Immune checkpoint inhibition and targeted therapy for melanoma: A patient-oriented cross-sectional comparative multicentre study.

BACKGROUND: Choosing the adequate systemic treatment for melanoma is driven by clinical parameters and personal preferences. OBJECTIVE: Evaluation of the impact of disease and treatment on the daily life of patients receiving systemic therapy for melanoma. METHODS: A German-wide, cross-sectional comparative study was conducted at 13 specialized skin cancer centres from 08/2020 to 03/2021. A questionnaire was distributed to assess patients' perception of disease and symptoms, the impact of their current treatment on quality of life (QOL) and activities, adverse events (AEs), therapeutic visits, as well as believe in and satisfaction with their current systemic melanoma treatment. Patient-reported outcomes (PROs) were rated on a continuous numerical rating scale or selected from a given list. RESULTS: Four hundred and fourteen patients with systemic melanoma therapy were included. 359 (87%) received immune checkpoint inhibition (ICI) and 55 (13%) targeted therapy (TT). About 1/3 of patients were adjuvantly treated, the remaining because of unresectable/metastatic melanoma. In subgroup analyses, only in the adjuvant setting, TT patients reported a significant decrease in their treatment associated QOL compared to patients with ICI (p = 0.02). Patients with TT were 1.9 times more likely to report AEs than patients with ICI, a difference being significant just for the adjuvant setting (p = 0.01). ICI treatment intervals differed significantly between adjuvant and unresectable/metastatic setting (p = 0.04), though all patients, regardless of their specific ICI drug, evaluated their treatment frequency as adequate. TT patients with dabrafenib/trametinib (n = 37) or encorafenib/binimetinib (n = 15) did not differ regarding the strain of daily pill intake. Patients older than 63 years rated various PROs better than younger patients. CONCLUSIONS: Patients evaluated their treatment mainly positively. ICI might be preferred over TT regarding QOL and patient-reported AEs in the adjuvant setting. Older melanoma patients appeared to be less impacted by their disease and more satisfied with their treatment.

Headache impact and socioeconomic status: findings from a study of the German Migraine and Headache Society (DMKG).

BACKGOUND: Headache disorders are not only among the most prevalent, they are also among the most disabling disorders worldwide. This paper investigates the association between headache impact on daily life and the socioeconomic status (SES) of headache sufferers. METHODS: Data stem from a random general population sample in Germany. Respondents who reported having headache for at least a year and were aged ≥ 18 years were included in the study. A standardized questionnaire addressing headache and headache treatment was filled in during the face-to-face survey. The impact of headache on daily life was measured using the German version of the Headache Impact Test (HIT-6). RESULTS: Higher headache impact was found in low and medium SES compared to high SES. After adjustment for sociodemographics, headache-related factors (analgesic use, headache duration, headache frequency, migraine diagnosis), depressive symptoms, physical inactivity and obesity, an increased odds ratio of having higher headache impact in low SES compared to high SES was found: OR = 1.83, 95% CI [1.43, 2.23], p = .014. When the interactions "SES*obesity", "SES*depressive symptoms", and "SES*physical inactivity" were added, the results showed a significant interaction effect of "SES*obesity". Obese persons with low SES were 3.64 times more likely to have higher headache impact than non-obese persons with low SES. No significant differences between obese and non-obese persons were found in the medium and high SES groups. CONCLUSIONS: SES is an important factor that should not be neglected in headache awareness campaigns and headache treatment. Longitudinal studies are needed in the future to investigate whether lifestyle interventions, such as weight reduction, can help to reduce headache impact in people in lower SES.

Psychological factors associated with headache frequency, intensity, and headache-related disability in migraine patients.

BACKGROUND: Several psychological cofactors of migraine have been identified, but relationships to different headache parameters (e.g., headache frequency vs. headache-related disability) are only incompletely understood. METHODS: We cross-sectionally assessed 279 migraine patients at their first presentation at our tertiary headache center. We obtained headache and acute medication frequency, pain intensity, the Migraine Disability Assessment Scale (MIDAS), and the Pain Disability Index (PDI) as headache-related outcomes as well as scores of the Hospital Anxiety and Depression Scale (HADS), the Pain Catastrophizing Scale (PCS), Pain-Related Control Scale (PRCS), and Avoidance Endurance Questionnaire (AEQ) as psychological factors. RESULTS: Linear regression models revealed the highest associations of the psychological factors with the PDI (adjusted R2 = 0.296, p < 0.001, independent predictors: PCS, AEQ social avoidance, depression) followed by the MIDAS (adjusted R2 = 0.137, p < 0.001, predictors: depression, AEQ social avoidance) and headache frequency (adjusted R2 = 0.083, p < 0.001, predictors: depression, AEQ humor/distraction). Principal component analysis corroborated that psychological factors were preferentially associated with the PDI, while the MIDAS loaded together with headache frequency. CONCLUSION: Our results suggest that psychological factors are more strongly associated with the subjective degree of headache-related disability measured by the PDI than with the days with disability (MIDAS) or the more objective parameter of headache frequency. This once again highlights the need for comprehensive assessment of migraine patients with different headache parameters and the need for considering psychological treatment, especially in patients with high disability.

Optimizing telemedical care in neurological outpatients by characterizing the patients' needs in the physician-patient relationship-content analysis of guideline-based interviews.

BACKGROUND: The use of new concepts in patient care, such as video-consultations, reminder systems, and online evaluation portals, is becoming increasingly important in the physician-patient relationship and outpatient care. This study examines the acceptance of these approaches in a neurological setting and determines the patients' preferences. METHODS: We analyzed 16 guideline-based qualitative interviews with neurological patients using qualitative content analysis (inductive category formation). RESULTS: The patients commented on the benefits and challenges of integrating new concepts of medical care. They identified advantages of telemedical care, including time savings (7 of 16; 43,8%) for both the patient and the physician, the prospect of more intensive (4 of 16; 25%) care, and the possibility for a quick response in case of urgent needs (3 of 16; 18.8%). Several challenges were reported, such as the limitations for patients with psychiatric (2 of 16; 12.5%) or complex diseases (4 of 16; 25%) and limited options for diagnostic procedures (such as physical examination (4 of 16; 25%)). For individual neurological patients' needs, telemedical and telecommunication structures could be discussed, which support the patients' specific requirements, such as answering questions while having a recall (2 of 16; 12.5%) and avoiding the journey (8 of 16; 50%). Also, patients are rejecting evaluation portals and are skeptical of telecare in the treatment of neurological diseases. DISCUSSION: The perception of telemedical care and the successful integration of new medical care concepts depend on fulfilling the individual patient's needs. Regardless of the preferred nature of physician-patient interactions, there are specific instruments that can intensify the relationship. These individual needs of the patients must be inquired about and accommodated for. CONCLUSIONS: For the first time, we could characterize the properties of optimal telemedical care for neurological patients. Interviews like the ones we conducted should be repeated during and after the pandemic, referring to our results and compare.

Effectiveness of medication in cluster headache.

BACKGROUND: The aim of this work is to analyze the reports on cluster headache attacks collected online in the citizen science project CLUE with respect to the effectiveness of drugs taken during the attacks. The collection of data within the framework of citizen science projects opens up the possibility of investigating the effectiveness of acute medication on the basis of a large number of individual attacks instead of a simple survey of patients. METHODS: Data from 8369 cluster headache attacks, containing information about acute medication taken and the assessment of its effect, were collected from 133 participants using an online platform and a smartphone app. Chi-square tests were used to investigate whether the effect of the three recommended acute drugs differs when distinguishing between participants with chronic or episodic cluster headache. Furthermore, it was investigated whether there are differences between smokers and non-smokers in the assessment of the effect of the acute medication. RESULTS: Our participants rated the effectiveness of sumatriptan 6 mg s.c. as significantly better than oxygen and zolmitriptan nasal spray. Oxygen is considered to be significantly better in episodic versus chronic cluster headache, and sumatriptan is considered to be significantly better in chronic versus episodic cluster headache. Smokers rate the effect of oxygen as significantly better than non-smokers. CONCLUSIONS: Despite some methodological limitations, web-based data collection is able to support findings from clinical trials in a real world setting about effectiveness of acute cluster headache treatment in several situations.

Types of leisure time physical activities (LTPA) of community-dwelling persons who have been screened positive for dementia.

BACKGROUND: To (a) describe the pattern of leisure time physical activities (LTPA) in community-dwelling persons who have been screened positive for dementia and (b) determine the health-related and sociodemographic factors associated with LTPA. METHODS: Data of the general practitioner-based, randomized, controlled intervention trial, DelpHi-MV (Dementia: life- and person-centered help in Mecklenburg-Western Pomerania) were used. Patients aged 70 years or older, who lived at home and had a DemTect< 9 were informed about the study by their General practitioners and invited to participate. Data from 436 participants with complete baseline data were used. Standardized, computer-assisted assessments were made during face-to-face interviews at the participants' homes. RESULTS: Two hundred thirty-eight patients (54.6%) carried out LTPA (men 58.4%, women 51.8%). Physically active patients mentioned one to two different activities; diversity of LTPA was higher for men than for women. The most-frequently mentioned types of activity were gardening (35.3%), cycling (24.1%) and mobility training (12.4%); there was only a statistically significant difference between men and women in cycling, χ2(1) = 21.47, p < .001. The odds of LTPA increased with increasing quality of life (OR = 2.41), lower impairments in activities of daily living (OR = 0.85), and living in a rural environment (OR = 2.02). CONCLUSIONS: Our findings suggest that people who have been screened positive for dementia living in a rural area are more likely to be active than people living in an urban area. Following studies should investigate whether this difference has an effect on the progression of dementia. TRIAL REGISTRATION: ClinicalTrial.gov Identifier NCT01401582 .

[Migraine prophylaxis-all just antibodies? : Medical and nonmedical migraine preventive treatment in times of CGRP antibodies]. / Migräneprophylaxe ­ alles nur noch Antikörper? : Medikamentöse und nicht-medikamentöse Migräneprophylaxe in Zeiten der CGRP-Antikörper.

BACKGROUND: Migraine is a frequently underdiagnosed disease that is associated with a high burden on affected patients. There are a variety of prophylactic treatment options available, that have been expanded with the introduction of the CGRP-(receptor-)antibodies. OBJECTIVES: Status of pharmacologic and nonpharmacologic preventive treatment in migraine therapy. METHODS: Analysis and evaluation of internationally published articles concerning preventive treatment of episodic and chronic migraine. RESULTS: There are many approved medications for migraine prophylaxis with different evidence. The possibilities were further expanded with CGRP antibodies. Comparative studies of the new antibodies with previous prophylactic drugs have not yet been published, so it's unclear whether the antibodies are therapeutically superior. What should be emphasized is their rapid onset of action and their good tolerance. Basically, an individual choice of prophylaxis, which is based on affectedness, comorbidities and comedication, makes sense. In addition, a combination with nondrug measures is always mandatory. CONCLUSIONS: A variety of medicinal and non-medicinal measures are available for the treatment of migraine, which should be used multimodally.

[Medical Psychology and Medical Sociology in Transition - Review and Perspectives of the two Disciplines in Germany]. / Medizinische Psychologie und Medizinische Soziologie im Wandel ­ Bestandsaufnahme und Perspektiven der beiden Fächer in Deutschland.

AIM OF THE STUDY: Through the Master Plan for Medical Studies 2020 and the development of the National Competence-Based Learning Target Catalogue Medicine (NKLM), significant changes in university medicine were started. The aim of the study was a systematic analysis of the state and perspectives of the disciplines of medical psychology and sociology at the medical faculties in Germany. METHODOLOGY: An online survey was conducted on 5 topics (structure, teaching, research, care, perspectives). 46 departments and institutes of medical psychology and sociology were invited to the survey. RESULTS: 40 of the 46 contacted institutions have called up the online questionnaire, 35 have answered in full (return: 76.1%). 77% of the institutions are autonomous. In the median, the institutions have 15 employees (range: 1 to 149). 9 universities have established a model curriculum. More than half of the institutions use and train simulation patients. The main research priorities are clinical research, health care research, neuroscience and classical medical psychology or sociological research topics. The institutions receive primarily public funding and publish 19 publications (80% international, median) each year. Publication opportunities are considered "satisfactory" by 54% of institutions (2003: 44%), and by 29% as "very satisfactory" (2003: 21%). 9 out of 27 medical psychology institutes provide clinical services to patients and relatives with mental or chronic physical illness. Almost half of the institutions expect the Master Plan 2020 to further increase the relevance of the subjects. DISCUSSION: Since 2003 there has been a substantial increase in scientific staff, third-party funding and publications. The sites show a pronounced heterogeneity in terms of size and equipment, which leads to an imbalance in terms of teaching and research as well as clinical services. CONCLUSION: The subjects of medical psychology and medical sociology have developed very heterogeneously in terms of independence, size, equipment and possibilities at the various faculties in Germany. Therefore, it is very important in the future that the 2 disciplines intensify the dialogue with each other and also with other psychosocial disciplines in order to influence the current development regarding NKLM and Master Plan 2020 constructively. On the one hand, this calls for an expansion of disadvantaged institutions and a consolidation of the existing autonomous institutions.

[Headache in multiple sclerosis]. / Kopfschmerzen bei Multipler Sklerose.

The relationship between headache and multiple sclerosis (MS) has been a matter of controversy for over 60 years. Headaches are still rated as a "red flag", indicating alternative diagnoses to MS, although in the last few years numerous studies have shown a frequent association between headache and MS. In recent studies on MS patients, a link was found between lower age/shorter disease duration of MS and frequent headaches. A study of 50 patients manifesting MS for the first time showed the highest headache prevalence in MS of 78% reported so far.Headaches can also be a possible side effect of most disease-modifying MS drugs. In many cases, however, the headache appears to be a symptom of MS in terms of secondary headache. This is also supported by pathophysiological implications, for example, by detecting B cell follicles in the meninges of MS patients.Migraine is the most common type of headache in MS. In some cases, this is a comorbidity of two diseases with many similarities, but headaches caused by inflammatory MS lesions also appear to be phenomenologically very similar to classic migraines; thus, distinguishing between them is often only successful with the help of thorough differential diagnostics (cerebrospinal fluid, MRI etc.).The task of future studies must be to specify the phenomenology of headache in MS even more precisely, in order to, to gain knowledge in, among others, patients with radiologically isolated syndrome, who often suffer from headache, because in these patients a considerable differential diagnostic and therapeutic uncertainty exists.

Use of outpatient medical care by headache patients in Germany: a population-based cross-sectional study.

BACKGROUND: Headache sufferers in need of professional health care often do not utilize the care available, and factors influencing headache-specific physician consultation are not yet understood. Objectives of this study are (1) to assess self-reported headache-specific physician consultations and (2) to identify headache-related and sociodemographic predictors. METHODS: Data of a random sample of the general population in Germany aged ≥14 years were analyzed (N = 2461). A multivariate binary logistic regression was conducted to identify a parsimonious model to predict physician consultation. RESULTS: 50.7% of the participants with headache reported at least one headache-specific physician consultation during lifetime. Of these, 53.6% had seen one, 26.1% two, and 20.3% more than two physicians because of their headaches. The odds of physician consultation increased with the number of headache days per month (HDM) [(reference HDM < 1) HDM 1-3 (OR = 2.29), HDM 4-14 (OR = 2.41), and HDM ≥15 (OR = 4.83)] and increasing Headache Impact Test score (HIT-6) [(reference "no or little impact") moderate impact (OR = 1.74), substantial impact (OR = 3.01), and severe impact (OR = 5.08)]. Middle-aged participants were more likely to have consulted than younger and older ones [(reference 14-34 years) 35-54 years (OR = 1.90), 55-74 years (OR = 1.96), ≥75 years (OR = 1.02)]. The odds of physician consultation among self-employed subjects were lower than among employed manual workers (OR = 0.48). The living environment (rural versus urban) did not have an influence on the consultation frequency. CONCLUSION: The results indicate that apart from burden-related factors (headache frequency; headache impact), health care utilization patterns are also influenced by patients' occupational status and age. Further research is needed to analyze whether the lower consultation rate means that the self-employed have a higher risk of chronification or that they have more effective self-management strategies regarding headache.

Headache in the course of multiple sclerosis: a prospective study.

Multiple sclerosis (MS) is the most common immune-mediated inflammatory disease of the central nervous system (CNS). Early diagnosis and treatment is important to prevent progression of disability in the course of the chronic disease. Therefore, correct and fast identification of early symptoms is vital. Headache is generally not recognized as an early symptom of MS, although numerous studies could show a high prevalence of headache in MS patients. The most common misdiagnosis is migraine. The aim of this study is to investigate the prevalence as well as the phenomenology of headache in MS especially with regard to the progression of the disease. In a prospective, multicenter study, we unbiasedly recruited 150 patients with manifest MS based on the criteria of McDonald. 50 patients at the timepoint of initial diagnosis and 100 of them with a long-term course of the disease were included. Based on a semi-structured interview, we evaluated the occurrence of headache over the last 4 weeks as well as case history, clinical-neurological investigation and questionnaires about depression, fatigue, and quality of life. Prevalence of headache in all patients was 67%. Patients at the timepoint of symptom manifestation of MS showed the highest prevalence of headache that was ever been recorded of 78%. In general, patients with headache were younger, had a shorter duration of the disease, and were less physically affected. We noticed frequent occurrence of migraine and migraine-like headache. In the course of the disease, patients without disease-modifying drug (DMD) complained more frequently headaches than patients with any kind of therapy. Headache is an important early symptom of MS. This could be shown especially among 78% of patients with clinically isolated syndrome (CIS). Therefore, young people with frequent headache should undergo MRI of the head and in the case of abnormal findings a consecutive detailed differential diagnosis. This could reduce the latency until final diagnosis of MS, which is in general much too long. That way these patients could get the earliest possible treatment, which is important to stop the progression of the disease.

Distribution of migraine attacks over the days of the week: Preliminary results from a web-based questionnaire.

OBJECTIVES: The purpose of this work is the analysis of migraine attack reports collected online within the project Migraine Radar in respect to the distribution of the migraine attacks over the week on a single-participant level. MATERIALS & METHODS: Recording data using a web app as well as smartphone apps made it possible to collect data of 44 639 migraine attacks of 1085 participants who reported seven or more attacks over a participation period of at least 90 days. This allows the investigation of attack distributions on a single-participant level. Considering the day of the week with the highest attack frequency for each participant-the mode of the individual distribution-allows identifying participants suffering from weekend migraines. Namely, a weekend pattern is assumed if the mode falls on a Saturday or Sunday. RESULTS: For 15.9% of the participants, the attacks were not distributed equally (P < 0.05) over the days of the week. Instead, participants show different individual patterns for the distribution of their migraine attacks. Furthermore, the modes of the individual distributions are not distributed equally over the week. In fact, Saturday seems to be the predominant day for migraine attacks for a greater proportion of participants (195 of 1085). CONCLUSIONS: Concerning the individual attack distributions, we found that participants show individual attack patterns and weekend migraine can be determined for a subgroup of participants, while other participants show accumulations of their attacks on other days of the week.

Cooperative function of Pdx1 and Oc1 in multipotent pancreatic progenitors impacts postnatal islet maturation and adaptability.

The transcription factors pancreatic and duodenal homeobox 1 (Pdx1) and onecut1 (Oc1) are coexpressed in multipotent pancreatic progenitors (MPCs), but their expression patterns diverge in hormone-expressing cells, with Oc1 expression being extinguished in the endocrine lineage and Pdx1 being maintained at high levels in ß-cells. We previously demonstrated that cooperative function of these two factors in MPCs is necessary for proper specification and differentiation of pancreatic endocrine cells. In those studies, we observed a persistent decrease in expression of the ß-cell maturity factor MafA. We therefore hypothesized that Pdx1 and Oc1 cooperativity in MPCs impacts postnatal ß-cell maturation and function. Here our model of Pdx1-Oc1 double heterozygosity was used to investigate the impact of haploinsufficiency for both of these factors on postnatal ß-cell maturation, function, and adaptability. Examining mice at postnatal day (P) 14, we observed alterations in pancreatic insulin content in both Pdx1 heterozygotes and double heterozygotes. Gene expression analysis at this age revealed significantly decreased expression of many genes important for glucose-stimulated insulin secretion (e.g., Glut2, Pcsk1/2, Abcc8) exclusively in double heterozygotes. Analysis of P14 islets revealed an increase in the number of mixed islets in double heterozygotes. We predicted that double-heterozygous ß-cells would have an impaired ability to respond to stress. Indeed, we observed that ß-cell proliferation fails to increase in double heterozygotes in response to either high-fat diet or placental lactogen. We thus report here the importance of cooperation between regulatory factors early in development for postnatal islet maturation and adaptability.

High Achievement Motivation is Not Related to Increased Use of Acute Headache Medication in Migraine: A Cross-sectional Observational Cohort Study.

OBJECTIVE: To determine if migraine patients with high achievement motivation have an increased use of acute headache medication. BACKGROUND: It has been hypothesized that high achievement-motivated migraine patients have an increased use of acute headache medication to be able to perform at work and during daily life, putting them at risk for medication overuse headache (MOH). METHODS: The Achievement Motivation Inventory and use of acute headache medication were assessed in 117 migraine patients (60 episodic, 57 chronic) at their first appointment at our tertiary headache center. RESULTS: Patients with low vs high achievement motivation were not significantly different in acute headache medication days per month (10.8 ± 6.9 vs 10.9 ± 7.8, P = .98), in acute headache medication use in the absence of headache (to prevent occurrence of headache later that day: 51.8% vs 48.2%, P = .38), in having a diagnosis of MOH (37.9 vs 23.7%, P = .12), or in reduction of acute headache medication days at 3 and 6 months follow-up (both P > .20). CONCLUSIONS: High achievement motivation in migraine patients was not associated with increased acute headache medication use or more frequent diagnosis of MOH.

Headache at the Time of First Symptom Manifestation of Multiple Sclerosis: A Prospective, Longitudinal Study.

AIMS: Headaches have not been considered a typical symptom of multiple sclerosis (MS), although since 2000, almost every study showed high prevalence. We screened 50 MS patients at the time of first occurrence of neurological symptoms and found the highest prevalence of headache in MS that was ever recorded (78%). Postmortem histological analyses of MS patients' brains revealed lymphoid follicle-like structures in the cerebral meninges and a pathophysiological link between headache, and high inflammatory activity especially in the initial phase of MS could be suspected. The aim of this study was to get insights into the persistence of headache in the further progress of the disease. METHODS: In a prospective, multicenter study, 50 MS patients at the time of first symptom manifestation were screened for the presence of headache within the last 4 weeks and again 6 months later with help of the Rostock Headache Questionnaire (Rokoko) as well as using the evaluation of case history and clinical-neurological investigation. RESULTS: We found a decrease of headache prevalence after 6 months from 78 to 61% (p = 0.01). We could also show a decrease of headache frequency, measured by days with headache in the last 4 weeks (9.5 vs. 5.9, p = 0.001). Migraine or probable migraine was the most frequent headache. In both investigations, the most frequent headache was recurrent pain with pulsating and throbbing character that lasted between 4 and 72 h. CONCLUSION: Headaches should be taken seriously as an important symptom in early MS. The decrease of headache 6 months after first symptom manifestation of MS could be a result of the immunomodulatory therapy. Young patients in whom migraine-like headaches occur should obligatory undergo an MRI of the head, and in the case of abnormal findings differential diagnosis should be initiated. This could reduce latency until final diagnosis of MS and enable early treatment.

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.