GAD antibody-associated limbic encephalitis in a young woman with APECED

The autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) syndrome is a genetic disorder caused by a mutation in the autoimmune regulator (AIRE) gene. Immune deficiency, hypoparathyroidism and Addison’s disease due to autoimmune dysfunction are the major clinical signs of APECED. We report on a 21-year-old female APECED patient with two inactivating mutations in the AIRE gene. She presented with sudden onset of periodic nausea. Adrenal insufficiency was diagnosed by means of the ACTH stimulation test. Despite initiation of hormone replacement therapy with hydrocortisone and fludrocortisone, nausea persisted and the patient developed cognitive deficits and a loss of interest which led to the diagnosis of depression. She was admitted to the psychiatric department for further diagnostic assessment. An EEG showed a focal epileptic pattern. Glutamic acid decarboxylase (GAD) antibodies, which had been negative eight years earlier, were now elevated in serum and in the cerebrospinal fluid. Oligoclonal bands were positive indicating an inflammatory process with intrathecal antibody production in the central nervous system (CNS). The periodic nausea was identified as dialeptic seizures, which clinically presented as gastrointestinal aura followed by episodes of reduced consciousness that occurred about 3–4 times per day. GAD antibody-associated limbic encephalitis (LE) was diagnosed. Besides antiepileptic therapy, an immunosuppressive treatment with corticosteroids was initiated followed by azathioprine. The presence of nausea and vomiting in endocrine patients with autoimmune disorders is indicative of adrenal insufficiency. However, our case report shows that episodic nausea may be a symptom of epileptic seizures due to GAD antibodies-associated LE in patients with APECED

Factors associated with depressive mood at the onset of multiple sclerosis - an analysis of 781 patients of the German NationMS cohort

Background: Depression has a major impact on the disease burden of multiple sclerosis (MS). Analyses of overlapping MS and depression risk factors [smoking, vitamin D (25-OH-VD) and Epstein-Barr virus (EBV) infection] and sex, age, disease characteristics and neuroimaging features associated with depressive symptoms in early MS are scarce.Objectives: To assess an association of MS risk factors with depressive symptoms within the German NationMS cohort.Design: Cross-sectional analysis within a multicenter observational study.Methods: Baseline data of n = 781 adults with newly diagnosed clinically isolated syndrome or relapsing-remitting MS qualified for analysis. Global and region-specific magnetic resonance imaging (MRI)-volumetry parameters were available for n = 327 patients. Association of demographic factors, MS characteristics and risk factors [sex, age, smoking, disease course, presence of current relapse, expanded disability status scale (EDSS) score, fatigue (fatigue scale motor cognition), 25-OH-VD serum concentration, EBV nuclear antigen-1 IgG (EBNA1-IgG) serum levels] and depressive symptoms (Beck Depression Inventory-II, BDI-II) was tested as a primary outcome by multivariable linear regression. Non-parametric correlation and group comparison were performed for associations of MRI parameters and depressive symptoms.Results: Mean age was 34.3 years (95% confidence interval: 33.6-35.0). The female-to-male ratio was 2.3:1. At least minimal depressive symptoms (BDI-II > 8) were present in n = 256 (32.8%), 25-OH-VD deficiency (<20 ng/ml) in n = 398 (51.0%), n = 246 (31.5%) participants were smokers. Presence of current relapse [coefficient (c) = 1.48, p = 0.016], more severe fatigue (c = 0.26, p < 0.0001), lower 25-OH-VD (c = -0.03, p = 0.034) and smoking (c = 0.35, p = 0.008) were associated with higher BDI-II scores. Sex, age, disease course, EDSS, month of visit, EBNA1-IgG levels and brain volumes at baseline were not.Conclusion: Depressive symptoms need to be assessed in early MS. Patients during relapse seem especially vulnerable to depressive symptoms. Contributing factors such as fatigue, vitamin D deficiency and smoking, could specifically be targeted in future interventions and should be investigated in prospective studies

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis

Cascade Filtration With PCR Detection and Field-Flow-Fractionation Online With ICP-MS for the Characterization of DNA Interaction With Suspended Particulate Matter

The variety of applied antibiotics in animal and human medicine results in the release, development, and spread of relevant numbers of antibiotic resistance genes (ARGs) in the environment. The majority of ARGs are present in intracellular forms (in bacteria). Neglected aspects are extracellular variants of ARGs (eARGs) and their fragments, which have been detected in surface-water samples and sediments. The stability of eARGs is expected to be low; however, binding to particulate matter is likely to improve their stability and also affect their transport and dissemination behavior. Few studies have investigated DNA particle interactions, mostly via indirect characterization of adduct formation in model systems but not in real environmental matrices. Therefore, our study aims at a novel approach for direct characterization of desoxyribonucleic acid (DNA) particle interactions using both cascade filtration and field-flow fractionation. Cascade filtration with quantitative polymerase chain reaction (qPCR) detection indicated retention of ARGs on filters with much larger pore sizes supporting the hypothesis of ARG-particle interactions. However, artifacts from membrane clogging or DNA–membrane interaction cannot be excluded. Consequently, asymmetric flow field-flow fractionation was investigated as an alternative separation technique with the advantage of particle separation in a thin channel, reducing the risk of artifacts. The key method parameters, membrane composition, molecular weight cut off, and carrier composition, were systematically investigated using a calf-thymus DNA-spiked surface-water sample as a model. The results clearly showed a shift in the elution time of clay particles suggesting the presence of DNA–clay adducts. Multi-element detection by inductively coupled plasma mass spectrometry (ICP-MS) enabled monitoring of clay via the Al, Fe, and Si signals and DNA via the P signal. Matching peak profiles for the new fraction in the fractograms of the ARG and DNA-spiked water sample support adduct formation. Further evidence was provided by a novel post-channel filtration approach for the separation of free DNA from DNA–clay adducts

Chronic Serotonergic Overstimulation Mimicking Panic Attacks in a Patient with Parkinson’s Disease Receiving Additional Antidepressant Treatment with Moclobemide

Background. The pharmacological treatment options of Parkinson’s disease (PD) have considerably evolved during the last decades. However, therapeutic regimes are complicated due to individual differences in disease progression as well as the occurrence of complex nonmotor impairments such as mood and anxiety disorders. Antidepressants in particular are commonly prescribed for the treatment of depressive symptoms and anxiety in PD. Case Presentation. In this case report, we describe a case of a 62-year-old female patient with PD and history of depressive symptoms for which she had been treated with moclobemide concurrent with anti-Parkinson medications pramipexole, rasagiline, and L-DOPA+benserazide retard. An increase in the dosage of moclobemide 12 months prior to admission progressively led to serotonergic overstimulation and psychovegetative exacerbations mimicking the clinical picture of an anxiety spectrum disorder. After moclobemide and rasagiline were discontinued based on the hypothesis of serotonergic overstimulation, the patient’s psychovegetative symptoms subsided. Conclusions. The specific pharmacological regime in this case probably caused drug-drug interactions resulting in a plethora of psychovegetative symptoms. Likely due to the delayed onset of adverse effects, physicians had difficulties in determining the pharmacologically induced serotonin toxicity. This case report emphasizes the complexity of pharmacological treatments and the importance of drug-drug interaction awareness in the treatment of PD patients with complicating nonmotor dysfunctions such as depression

Adherence and Dietary Composition during Intermittent vs. Continuous Calorie Restriction: Follow-Up Data from a Randomized Controlled Trial in Adults with Overweight or Obesity

Although intermittent calorie restriction (ICR) has become popular as an alternative weight loss strategy to continuous calorie restriction (CCR), there is insufficient evidence on diet quality during ICR and on its feasibility over longer time periods. Thus, we compared dietary composition and adherence between ICR and CCR in a follow-up analysis of a randomized trial. A total of 98 participants with overweight or obesity [BMI (kg/m2) 25–39.9, 35–65 years, 49% females] were randomly assigned to ICR, operationalized as a “5:2 diet” (energy intake: ~100% on five non-restricted (NR) days, ~25% on two restricted (R) days), or CCR (daily energy intake: ~80%). The trial included a 12-week (wk) intervention phase, and follow-up assessments at wk24, wk50 and wk102. Apart from a higher proportion of energy intake from protein with ICR vs. CCR during the intervention (wk2: p &lt; 0.001; wk12: p = 0.002), there were no significant differences with respect to changes in dietary composition over time between the groups, while overall adherence to the interventions appeared to be good. No significant difference between ICR and CCR regarding weight change at wk102 was observed (p = 0.63). However, self-reported adherence was worse for ICR than CCR, with 71.1% vs. 32.5% of the participants reporting not to or only rarely have followed the regimen to which they were assigned between wk50 and wk102. These results indicate that within a weight management setting, ICR and CCR were equivalent in achieving modest weight loss over two years while affecting dietary composition in a comparable manner