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Autoantibodies targeting the intracellular 65-kDa isoform of glutamic acid decarboxylase (anti-GAD65) have been associated with a variety of autoimmune-related syndromes involving a spectrum of difficult-to-treat neurological disorders. However, the pathophysiological role of anti-GAD65 in neuroinflammation remains vague. Its understanding may be complicated by the possible pathogenic interaction between anti-GAD65 and potentially coexisting autoantibodies. We combined a broad spectrum of approaches ranging from antibody-antigen identification, immunoblotting, immunoprecipitation, mass-spectrometry, cell-based assays, subcellular binding pattern analysis in primary neuronal cultures, and immunohistochemistry to in vitro assays of neuronal uptake, viability, and multi-electrode arrays. In anti-GAD65-positive neurological patients, mass-spectrometric analysis revealed cytosolic 5'-nucleotidase 1 A (CN1A syn. NT5C1A) as the most abundant antigen. Subsequent screening of 118 anti-GAD65-positive patients revealed that 32 of them had additional autoantibodies targeting CN1A, which were also present in all available corresponding CSF samples. Limbic encephalitis was more often diagnosed in anti-CN1A/anti-GAD65-positive compared to the anti-GAD65-positive patients. Functionally, incubation of primary hippocampal neurons with anti-GAD65, but not with anti-CN1A, resulted in uptake into GABAergic neurons, neuronal cell death, and increased neuronal network activity. Moreover, simultaneous incubation with both antibodies (anti-CN1A/anti-GAD65) resulted in concomitant intraneuronal uptake in a concentration-dependent manner, which correlated with enhanced autophagy followed by massive neuronal death. GAD65 antibodies directly affect neuronal viability and network activity. Co-existing autoantibodies against CN1A, present in anti-GAD65-positive patients, enhance autophagy and subsequent neuronal death in vitro. Clinically, anti-GAD65-positive patients should be screened for anti-CN1A-associated diseases, and evaluation of anti-CN1A in anti-GAD65-related autoimmune conditions may clarify links between systemic autoimmunity and epilepsy.

Very rarely, adult NMDAR antibody-associated encephalitis (NMDAR-E) leads to persistent cerebellar atrophy and ataxia. Transient cerebellar ataxia is common in pediatric NMDAR-E. Immune-mediated cerebellar ataxia may be associated with myelin oligodendrocyte glycoprotein (MOG), aquaporin-4 (AQP-4), kelch-like family member 11 (KLHL11), and glutamate kainate receptor subunit 2 (GluK2) antibodies, all of which may co-occur in NMDAR-E. Here, we aimed to investigate the frequency, long-term outcome, and immunological concomitants of ataxia in NMDAR-E. In this observational study, patients with definite NMDAR-E with a follow-up of >12 months were recruited from the GENERATE registry. Cases with documented ataxia were analyzed in detail. In 12 of 62 patients (19%), ataxia was documented. Bilateral cerebellar ataxia without additional focal CNS findings was found in four (one child and three adults); one of these was previously reported as a case with persistent cerebellar atrophy and ataxia. Two patients with bilateral cerebellar ataxia had additional focal neurological symptoms, optic neuritis and facial palsy. Two patients developed hemiataxia: one with diplopia suggesting brainstem dysfunction and the other probably resulting from cerebellar diaschisis due to contralateral status epilepticus. In all but the one developing cerebellar atrophy, cerebellar ataxia was transient and not associated with a worse long-term outcome. In all five patients with cerebellar ataxia tested, MOG, AQP-4, GluK2, and KLHL11 antibodies were negative. In two additional patients negative for both MOG and AQP-4 antibodies, ataxia was sensory and explained by cervical myelitis as part of multiple sclerosis (MS) manifesting temporal relation to NMDAR-E. One of the patients with bilateral ataxia with focal neurological deficits was also diagnosed with MS upon follow-up. Finally, in two patients, ataxia was explained by cerebral hypoxic damage following circulatory failure during an ICU stay with severe NMDAR-E. Ataxia of different types is quite common in NMDAR-E. Cerebellar ataxia in NMDAR-E is mostly transient. NMDAR-E followed by persistent ataxia and cerebellar atrophy is very rare. Cerebellar ataxia in NMDAR-E may not be explained by concomitant KLHL11, MOG, AQP-4, or GluK2 autoimmunity. Of note, ataxia in NMDAR-E may result from treatment complications and, most interestingly, from MS manifesting in temporal association with NMDAR-E.

The BAFF-APRIL system is crucial for the pathogenesis of systemic lupus erythematosus (SLE) by promoting B cell survival, differentiation and the maintenance of humoral autoimmunity. Here, we investigated the relationship of BCMA expression on B cell subsets with its ligands BAFF and APRIL, together with soluble BCMA, and with clinical and serologic variables in a cohort of 100 SLE patients (86 under conventional and 14 under belimumab therapy) and 30 healthy controls (HCs) using multicolor flow cytometry and ELISA. We found that BCMA expression in SLE patients was significantly increased on all B cell subsets compared to HCs, with all examined components of the BAFF-APRIL system being upregulated. BCMA expression was significantly increased on switched and unswitched memory B cells compared to naïve B cells, both in HCs and SLE. BCMA expression on B cells correlated with plasmablast frequencies, serum anti-dsDNA antibodies and complement consumption, while soluble BCMA correlated with plasmablast frequency, highlighting its potential as a clinical biomarker. Belimumab treatment significantly reduced BCMA expression on most B cell subsets and soluble TACI and contributed to the inhibition of almost the entire BAFF-APRIL system and restoration of B cell homeostasis. These results provide insights into the complex dysregulation of the BAFF-APRIL system in SLE and highlight the therapeutic potential of targeting its components, particularly BCMA, in addition to its use as a biomarker for disease activity.

Background Autoantibodies targeting the intracellular 65-kDa isoform of glutamic acid decarboxylase (anti-GAD65) have been associated with a variety of autoimmune-related syndromes involving a spectrum of difficult-to-treat neurological disorders. However, the pathophysiological role of anti-GAD65 in neuroinflammation remains vague. Its understanding may be complicated by the possible pathogenic interaction between anti-GAD65 and potentially coexisting autoantibodies. Methods We combined a broad spectrum of approaches ranging from antibody-antigen identification, immunoblotting, immunoprecipitation, mass-spectrometry, cell-based assays, subcellular binding pattern analysis in primary neuronal cultures, and immunohistochemistry to in vitro assays of neuronal uptake, viability, and multi-electrode arrays. Results In anti-GAD65-positive neurological patients, mass-spectrometric analysis revealed cytosolic 5’-nucleotidase 1 A (CN1A syn. NT5C1A) as the most abundant antigen. Subsequent screening of 118 anti-GAD65-positive patients revealed that 32 of them had additional autoantibodies targeting CN1A, which were also present in all available corresponding CSF samples. Limbic encephalitis was more often diagnosed in anti-CN1A/anti-GAD65-positive compared to the anti-GAD65-positive patients. Functionally, incubation of primary hippocampal neurons with anti-GAD65, but not with anti-CN1A, resulted in uptake into GABAergic neurons, neuronal cell death, and increased neuronal network activity. Moreover, simultaneous incubation with both antibodies (anti-CN1A/anti-GAD65) resulted in concomitant intraneuronal uptake in a concentration-dependent manner, which correlated with enhanced autophagy followed by massive neuronal death. Conclusion GAD65 antibodies directly affect neuronal viability and network activity. Co-existing autoantibodies against CN1A, present in anti-GAD65-positive patients, enhance autophagy and subsequent neuronal death in vitro. Clinically, anti-GAD65-positive patients should be screened for anti-CN1A-associated diseases, and evaluation of anti-CN1A in anti-GAD65-related autoimmune conditions may clarify links between systemic autoimmunity and epilepsy. Significance What is already known on this topic – Even though autoantibodies against GAD65 protein have been identified in several autoimmune disorders their direct pathogenic effects are highly controversial and patients are often difficult to treat. What this study adds – Anti-GAD65-positive patients often have coexisting CN1A autoantibodies, leading to higher incidence of limbic encephalitis, increased neuronal activity, with combined autoantibody uptake enhancing neuronal death rate correlated with enhanced autophagy. How this study might affect research , practice or policy – Patients positive for anti-GAD65 should be screened for anti-CN1A-associated diseases, and broader evaluation of anti-CN1A in anti-GAD65-related autoimmune conditions (e.g., type 1 diabetes, vitiligo, Hashimoto’s thyroiditis) may clarify links between systemic autoimmunity and epilepsy. Bullet points Anti-GAD65-positive neurological patients show a high prevalence of coexisting autoantibodies against CN1A. CN1A/GAD65 autoantibody-positive patients are more often diagnosed with limbic encephalitis. Patient-derived GAD65 autoantibodies increase network activity in cultured neurons. Interneuronal dendritic uptake of anti-CN1A combined with anti-GAD65 leads to aggravated neurodegeneration associated with enhanced autophagy.

Background Reversible cerebral vasoconstriction syndrome (RCVS) and posterior reversible encephalopathy syndrome (PRES) are both rare disorders. The pathophysiology of both diseases is not yet fully understood. Methods We report the unique case of a 19-year-old comatose woman who was brought to the ER after a series of generalized tonic–clonic seizures 6 days post peridural anesthesia for cesarean section. Vital signs and initial laboratory testing including urine analysis and drug screening were unremarkable. Initial cranial CT scan showed an acute small subdural hematoma (17 mm length × 6 mm width × 30 mm height), cerebral edema with slit ventricles, and slight cerebellar tonsillar herniation as signs of intracranial hypotension. CT angiography depicted narrowing of the proximal intracranial vessels consistent with RCVS. MR imaging was also suggestive of both intracranial hypotension and RCVS and showed, in addition, vasogenic edema consistent with PRES. An extensive CSF leakage involving T1 to L2/L3 was confirmed by spinal MRI. Results The patient underwent conservative therapy for intracranial hypotension (e.g., head-down position) as well as epidural blood patch, which led to regression of the clinical symptoms within a few days. Follow-up MRI showed complete resolution of all radiological changes. Conclusions In summary, our patient developed clinical and neuroradiological signs of intracranial hypotension and a combination of PRES and RCVS associated with a CSF leakage caused by peridural anesthesia; by treating the intracranial hypotension, the other syndromes resolved. From a clinical point of view, it is important to look for CSF leakage as a treatable possible cause of PRES and/or RCVS triggered by intracranial hypotension as in our patient postpartum. Moreover, it is vital to obtain a good history as, in cases of suspected CSF leakage with classic postural headache, a recent spinal/cranial procedure is typically present.

Autoimmune disorders of the central nervous system (CNS) comprise a broad spectrum of clinical entities. The stratification of patients based on the recognized autoantigen is of great importance for therapy optimization and for concepts of pathogenicity, but for most of these patients, the actual target of their autoimmune response is unknown. Here we investigated oligodendrocyte myelin glycoprotein (OMGP) as autoimmune target, because OMGP is expressed specifically in the CNS and there on oligodendrocytes and neurons. Using a stringent cell-based assay, we detected autoantibodies to OMGP in serum of 8/352 patients with multiple sclerosis, 1/28 children with acute disseminated encephalomyelitis and unexpectedly, also in one patient with psychosis, but in none of 114 healthy controls. Since OMGP is GPI-anchored, we validated its recognition also in GPI-anchored form. The autoantibodies to OMGP were largely IgG1 with a contribution of IgG4, indicating cognate T cell help. We found high levels of soluble OMGP in human spinal fluid, presumably due to shedding of the GPI-linked OMGP. Analyzing the pathogenic relevance of autoimmunity to OMGP in an animal model, we found that OMGP-specific T cells induce a novel type of experimental autoimmune encephalomyelitis dominated by meningitis above the cortical convexities. This unusual localization may be directed by intrathecal uptake and presentation of OMGP by meningeal phagocytes. Together, OMGP-directed autoimmunity provides a new element of heterogeneity, helping to improve the stratification of patients for diagnostic and therapeutic purposes.

Purpose The design of participation processes influences their effectiveness. In light of processes which include both mandated and non-mandated direct participation and take place in collaboration with other actors, adequate leadership roles are an indispensable but challenging process element. The purpose of this paper is to analyze how mayors exercise leadership roles in such processes and how this relates to effective participation processes. Design/methodology/approach Applying a qualitative comparative case study design (n=7), this study investigates mayors’ leadership roles relative to other actors’ roles in the process of establishing a community-owned wind farm. Data collection relied on 21 semi-structured interviews, triangulated with documentary analyses and nine field-level expert interviews. Findings Findings reveal mayors’ exclusive roles of guarantor, formal convener, facilitator, and sponsor based on authority. Mayors’ various shared roles relate primarily to non-mandated participation. Mayors face tensions in their role exercise due to citizens’ expectations and their personal involvement. They experience a positive impact of shared leadership on the effectiveness of the participation process. Practical implications Mayors need to exercise specific leadership roles relative to other actors to effectively manage participation processes. Adequate role exercise relates to sensitization and mobilization for the issue, weakened opposition, and project adjustment to citizen demands. A strategic approach to process design can support mayors in their leadership efforts. Originality/value This paper adds to the knowledge on mayors’ leadership roles in participation processes and concretizes tensions and effectiveness of collaborative leadership. The paper reflects on the inference of findings for administrators as compared to mayors.

Background: One in fifty infants is conceived through assisted reproductive technologies (ART). To date, data on the cardiovascular morbidity of ART individuals is ambiguous. This study investigated the vascular function of young ART subjects using 24 hour ambulatory blood pressure monitoring (24 h ABPM). Methods: ART subjects and spontaneously conceived controls matched in age as well as sex were enrolled. A 24 h blood pressure profile including pulse wave analysis was executed in all study participants. Blood pressure readings were assessed every 15 min during daytime and every 30 min during nighttime. The 24 h systolic/diastolic blood pressure (SBP/DBP) as well as central blood pressure, nocturnal blood pressure decrease, and 24 h pulse wave velocity (PWV) were analyzed. Results: A total of 41 ART individuals and 46 spontaneously conceived peers were included in the final analysis (mean age: 15.37 ± 5.46 years vs. 16.48 ± 5.23 years, p = 0.338). The 24 h SBP (112.74 ± 9.24 mmHg vs. 112.73 ± 6.70 mmHg, p = 0.997), 24 h DBP (65.61 ± 7.98 mmHg vs. 66.57 ± 7.03 mmHg, p = 0.550), 24 h central blood pressure, nocturnal blood pressure decrease, and 24 h PWV did not demonstrate significant differences between the ART and control group. Conclusions: In contrast to previous studies, no significant differences in 24 h blood pressure were demonstrated between ART subjects and spontaneously conceived peers. Hence, the results of this study do not indicate an unfavorable blood pressure profile in ART offspring. Larger multi-centric studies are needed to validate these results in the future.

This article presents our recent experience studying public perceptions, discourses, and social values in Park Beverin, a Regional Nature Park in Switzerland. We applied four social research methods (news media analysis, survey with micro‐narratives, go‐along interviews, and focus groups), and delved into the subject of wolf Canis lupus adapting a triangulation protocol and systematic process from the health sciences. We observed the recurring perceptions of ‘wolf' throughout three of the four methods; however, depictions, values, prominence, and presence varied by method. Social values of the wolf were mostly silent when compared to other topics, and ‘wolf amplification' and ‘wolf fatigue' point to the need to rethink the social aspects in wolf management, conservation, and policy. The findings also show the need for diverse research methods for revealing social values and perceptions on sensitive topics that otherwise the use of one method may be masking or amplifying.