Comparison of edoxaban and enoxaparin in a rat model of AlCl3-induced thrombosis of the superior sagittal sinus.

Cerebral sinus venous thrombosis (CSVT) is an uncommon disease that is usually treated with anticoagulation (heparin, low-molecular heparin, or vitamin K-antagonists). We compared treatment with edoxaban, an oral factor Xa-antagonist, that has not been approved in patients with CSVT, with enoxaparin, a well-established therapy, in a rat model of CSVT. Fifty male Wistar rats were randomized into 5 groups (10 animals each) and subjected to aluminum chloride (AlCl3)-induced thrombosis of the superior sagittal sinus (SSS) or sham procedure. Animals with thrombosis of the SSS were treated with edoxaban, enoxaparin, or placebo. Diagnostic workup included neurological examination, MRI imaging, MR-flow measurements of the SSS, and immunohistochemical staining. Neurological examination revealed no differences between treatment groups. Seven days after initial thrombosis, flow in the SSS was lower in the active treatment group as compared to sham-operated animals (p < 0.05). Flow in the SSS in the active treatment groups (edoxaban 1 h prior to thrombosis: 0.16 cm/s ± 0.06 cm/s; edoxaban 6 h after thrombosis: 0.13 cm/s ± 0.05 cm/s; enoxaparin: 0.13 cm/s ± 0.04 cm/s; placebo: 0.07 cm/s ± 0.02 cm/s) was higher as compared to placebo (p < 0.05), but there were no differences between the active treatment groups (p > 0.05). Immunohistochemical staining showed no differences in the actively treated animals. Edoxaban proved to be similar to enoxaparin in a model of experimental AlCl3-induced CSVT.

[Model project on interdisciplinary university teaching-medical and psychology students learn together for the first time]. / Modellprojekt zur interdisziplinären universitären Lehre ­ Studierende der Medizin und der Psychologie lernen erstmals gemeinsam.

An interdisciplinary collaboration is required in the medical care of chronically ill patients with complex illnesses. Especially in the field of internistic rheumatology, interdisciplinary work is essential to consider the complex somatic and psychosocial aspects of a chronic illness. Nevertheless, the aspects of interprofessional work in the study of medicine and psychology are insufficiently addressed. For this reason, a model project for interdisciplinary university teaching was conceived, which combines both subjects. The course was held for the first time in semester 2019/2020 and was rated excellent by the participants. The main goal of the course is the implementation of interprofessional work in the training of medical personnel. In addition, the discipline of internistic rheumatology could be brought closer to the students.

Improvement of complex regional pain syndrome after plasmapheresis.

Complex regional pain syndrome is a severe complication following trauma that is associated with vasomotor, sudomotor and sensory disturbances in an affected limb or region of the body. The exact physiopathology is not fully understood yet. Recently, autoantibody findings suggested an immune-mediated physiopathology of the disease. We here describe two otherwise treatment-resistant patients with complex regional pain syndrome and high-titre beta2 adrenergic receptor autoantibodies, who did respond to plasmapheresis. Both patients showed strong improvement of pain and autonomic symptoms measured by impairment level sum score.

Anti-SOX1 antibodies in patients with paraneoplastic and non-paraneoplastic neuropathy.

Anti-SOX1 antibodies have been described to be positive in patients with paraneoplastic Lambert-Eaton myasthenic syndrome and, in a lower amount, in patients with anti-Hu positive paraneoplastic neurological syndromes, and with SCLC alone, respectively. We found 5/32 patients with paraneoplastic neuropathy and, surprisingly, 4/22 patients with neuropathy of unknown origin positive for anti-SOX1 antibodies, whereas no patient with inflammatory neuropathy and no healthy controls showed any reactivity (p=0.007). All patients with neuropathy of unknown origin where followed up for four years without diagnosis of a tumour so far. Anti-SOX1 antibodies are associated with paraneoplastic neuropathies and may define another group of non-paraneoplastic, immune-mediated neuropathies.

Elevated B-cell activating factor BAFF, but not APRIL, correlates with CSF cerebellar autoantibodies in pediatric opsoclonus-myoclonus syndrome.

Childhood opsoclonus-myoclonus syndrome (OMS) occurs idiopathic or, in association with a neuroblastoma, as a paraneoplastic syndrome. Since autoantibodies were identified in some patients, an autoimmune pathogenesis has been suspected. While the newly discovered B-cell activating factors BAFF and APRIL are involved in systemic autoimmune diseases, their association with neuroimmunological diseases is hardly understood. We here investigated the BAFF and APRIL levels in serum and cerebrospinal fluid (CSF) of OMS patients and their correlation with surface-binding autoantibodies. BAFF and APRIL were both determined by ELISA, and autoantibodies to cerebellar granular neurons (CGN) have been investigated by flow cytometry in 17 OMS patients, 16 neuroblastoma (NB) patients, 13 controls and 11 children with inflammatory neurological diseases (IND). BAFF, but no APRIL, was elevated in the CSF of OMS children and IND children. However, in contrast to IND patients, OMS patients did not have a blood-brain-barrier disturbance, indicating that BAFF was produced intrathecally in OMS patients, but not in IND patients. CSF BAFF levels showed a correlation with CSF CGN autoantibodies (r(2)=0.58, p<0.05). These data indicate that an activated B-cell system in the cerebrospinal fluid is involved in the pathogenesis of OMS, and BAFF may be a candidate parameter for the activation of B-cell immune system.

The disease relevance of human hepatocellular xenograft models: molecular characterization and review of the literature.

In recent years a number of new therapeutics has been developed that were not general toxins and inhibitors of cell division like classical chemotherapeutics, but were designed to target a specific pathway. A prerequisite for this development was the comprehensive characterization of molecular alterations occurring in human hepatocellular carcinoma (HCC). However, while much knowledge of the molecular pathogenesis of human HCC has been gained, the model systems used to test the functional relevance of these alterations and applied for preclinical evaluation of drug candidates are still poorly characterized. In this paper, we reviewed the literature about several commonly used HCC cell lines and xenotransplantation models and present our own data on the molecular characterization of these. Results obtained demonstrate that it is important to have a sound knowledge of the specific molecular constitution of the experimental model and to carefully evaluate the functional status of the pathway of interest. For this reason, we make the gene expression profiles publicly available to help researchers making an informed decision about which model to use.

Paraneoplastic neurological syndromes in patients with carcinoid.

BACKGROUND: Paraneoplastic neurological syndromes (PNS) are mainly associated with small-cell lung cancer, gynaecological tumours and lymphomas. Few studies report the association of neurological syndromes with a carcinoid, the majority being a serotonin-related myopathy. We report four patients with a PNS associated with carcinoid. PATIENTS AND RESULTS: The clinical syndromes were sensory neuropathy, limbic encephalitis, myelopathy and brain stem encephalitis. Two patients had antineuronal autoantibodies (one anti-Hu, one anti-Yo), one patient had antinuclear antibodies, and one patient had no autoantibodies. For two of the carcinoids, expression of HuD in the tumour could be demonstrated. CONCLUSION: This study demonstrates that carcinoids can also be associated with classical antineuronal antibody-associated PNS.

Synaptophysin is an autoantigen in paraneoplastic neuropathy.

Paraneoplastic neurological syndromes (PNS) are often associated with antineuronal autoantibodies and many of them could be identified in the recent years. However, there are still new antineuronal binding patterns with yet unidentified autoantigens. We here describe a new autoantibody associated with paraneoplastic sensorimotor and autonomic neuropathy in a patient with small cell lung cancer. In indirect immunofluorescence test, the patient's serum colocalised with the synaptic protein synaptophysin in the cerebellum and myenteric plexus of the gut. Immunoblotting showed a 38 kDa reactivity, which is also the molecular weight of synaptophysin. Therefore a Western Blot with recombinant synaptophysin has been used and revealed reactivity of the serum against synaptophysin. In patients with non-paraneoplastic neuropathies or healthy controls, anti-synaptophysin autoantibodies were not detectable. In 20 SCLC patients without neurological syndromes, two patients had low-titer anti-synaptophysin autoantibodies. The patient's serum and IgG fraction showed cytotoxicity to primary cultured myenteric plexus neurons. We conclude that synaptophysin is an autoantigen in paraneoplastic neurological syndromes.

Autoantibodies against glial antigens in paraneoplastic neurological diseases.

Paraneoplastic neurological syndromes are clinically heterogeneous manifestations of cancer, but are not caused by the tumor or its metastases. Because autoantibodies reacting with tumor and nervous system tissue have been described, an autoimmune pathogenesis is suspected. Most autoantibodies are directed against neuronal proteins. Here, we describe the impact of antiglial autoantibodies in paraneoplastic neurological syndromes. Anti-CRMP5 and antiglial nuclear antibody both can be associated with different paraneoplastic neurological syndromes and tumors.

Autoimmunity in complex-regional pain syndrome.

Complex regional pain syndrome (CRPS) is an etiologically unclear syndrome with the main symptoms being pain, trophic and autonomic disturbances, and functional impairment that develops after limb trauma or operation and is located at the distal site of the affected limb. Because autoantibodies against nervous system structures have been described in these patients, an autoimmune etiology of CRPS is discussed. These autoantibodies bind to the surface of peripheral autonomic neurons. Using a competitive binding assay, it can be shown that at least some of the CRPS sera bind to the same neuronal epitope. Autoimmune etiology of CRPS is a new pathophysiological concept and may have severe impact on the treatment of this often chronic disease.

IgG subclass distribution of autoantibodies in pediatric opsoclonus-myoclonus syndrome.

Opsoclonus-myoclonus syndrome (OMS) in children is a rare disorder including a severe eye movement disturbance, myoclonia, ataxia and often developmental retardation. Both OMS forms, idiopathic or neuroblastoma-associated (paraneoplastic), have been suspected to be autoimmune. Recently, autoantibodies have been found in OMS sera. We here show that autoantibodies in OMS, both intracellular and surface binding, belong mainly to the IgG3 subclass, although the total serum IgG3 level is normal. These results support the autoimmune hypothesis and point to a protein autoantigen as antigenic target.

Antinuclear antibodies define a subgroup of paraneoplastic neuropathies: clinical and immunological data.

OBJECTIVE: Paraneoplastic neuropathy is a clinical and immunological heterogeneous disorder and attempts have been made to classify subgroups of this disease. Only 30-50% of the clinical defined cases have antineuronal antibodies. METHODS: The clinical and immunological features of 36 patients with paraneoplastic neuropathy from the authors' database were analysed including the type and course of the neuropathy, associated tumours, and the presence of antineuronal and other autoantibodies. RESULTS: Antineuronal antibodies were detected in 17/36 patients (47%) and anti-Hu was the most frequent antineuronal antibody. Nine patients had high titre antinuclear antibodies (ANA, median titre 1/1000) without antineuronal antibodies. ANA reactivities were different in most patients. Comparison of the ANA positive and ANA negative patients revealed that ANA positive paraneoplastic neuropathy is more frequently associated with breast cancer but is not associated with lung cancer (p<0.05). The main clinical type in these patients was sensorimotor neuropathy. No ANA positive patient had central nervous system involvement. Although the Rankin score at the time of diagnosis was not different, the functional outcome in ANA positive patients was better than in ANA negative patients (p<0.05). CONCLUSIONS: Paraneoplastic neuropathy is a heterogeneous disorder. ANA may define a subgroup of paraneoplastic neuropathy with different clinical and immunological features and may be related to better prognosis of the neuropathic symptoms.

Autoimmune etiology of complex regional pain syndrome (M. Sudeck).

Sera of 12 patients with complex regional pain syndrome (CRPS) were tested for the occurrence of autoantibodies against nervous system structures. Immunohistochemistry revealed autoantibodies against autonomic nervous system structures in 5 of 12 (41.6%) of the patients. Western blot analysis showed neuronal reactivity in 11 of 12 (91.6%) patients. The authors hypothesize that CRPS can result from an autoimmune process against the sympathetic nervous system.