Management of Patients with Acute Subdural Hemorrhage During Treatment with Direct Oral Anticoagulants.

BACKGROUND: Anticoagulation therapy is a major risk factor for unfavorable patient outcomes following (traumatic) intracranial hemorrhage. Direct oral anticoagulants (DOAC) are increasingly used for the prevention and treatment of thromboembolic diseases. Data on patients treated for acute subdural hemorrhage (SDH) during anticoagulation therapy with DOAC are limited. METHODS: We analyzed the medical records of consecutive patients treated at our institution for acute SDH during anticoagulation therapy with DOAC or vitamin K antagonists (VKA) during a period of 30 months. Patient characteristics such as results of imaging and laboratory studies, treatment modalities and short-term patient outcomes were included. RESULTS: A total of 128 patients with preadmission DOAC (n = 65) or VKA (n = 63) intake were compared. The overall 30-day mortality rate of this patient cohort was 27%, and it did not differ between patients with DOAC or VKA intake (26% vs. 27%; p = 1.000). Similarly, the rates of neurosurgical intervention (65%) and intracranial re-hemorrhage (18%) were comparable. Prothrombin complex concentrates were administered more frequently in patients with VKA intake than in patients with DOAC intake (90% vs. 58%; p < 0.0001). DOAC treatment in patients with acute SDH did not increase in-hospital and 30-day mortality rates compared to VKA treatment. CONCLUSIONS: These findings support the favorable safety profile of DOAC in patients, even in the setting of intracranial hemorrhage. However, the availability of specific antidotes to DOAC may further improve the management of these patients.

Unaltered Responses of Distal Motor Neurons to Non-Targeted Thoracic Spinal Cord Stimulation in Chronic Pain Patients.

INTRODUCTION: Spinal cord stimulation (SCS) represents an established interventional pain therapeutic; however, the SCS effects of SCS waveforms on motor neuron recruitment of the lower limbs of chronic pain patients remain largely unknown. METHODS: We investigated these effects by performing isometric ankle-dorsal flexions at varying force levels under four SCS conditions: SCS Off (1 week), burst SCS (40 Hz), SCS Off (acute), and tonic SCS (130 Hz). Muscle activity was recorded via high-density surface electromyography (64-electrode grid) on the tibialis anterior muscle. Motor unit action (MUs) potentials were analyzed for recruitment and de-recruitment thresholds, discharge rate, inter-spike interval, and common synaptic input. RESULTS: In this prospective study, we included nine patients (five females; four males; mean age 59 years) with chronic pain treated with thoracic (Th7-Th8) epidural spinal stimulation. A total of 97 MUs were found for 15% maximal voluntary torque (MVT) and 83 for 30%MVT, an average of 10.8 ± 3.7 for 15%MVT and 10.4 ± 3.5 for 30%MVT. While a few subject-specific variations were observed, our study suggests that the different SCS frequencies applied do not significantly influence motor unit discharge characteristics in the TA muscle among the participants (p values at 15%MVT were 0.586 (Chi2 = 1.933), 0.737 (Chi2 = 1.267), 0.706 (Chi2 = 1.4) and 0.586 (Chi2 = 1.933), respectively. The p values of the Friedman test at 30%MVT were 0.896 (Chi2 = 0.6), 0.583 (Chi2 = 1.95), 0.896 (Chi2 = 0.6) and 0.256 (Chi2 = 4.05). No significant difference was found for the different stimulation types for the delta (0-5 Hz), alpha (5-12 Hz), and beta (15-30 Hz) bands at both force levels. CONCLUSIONS: In summary, we did not observe any changes in motor unit oscillatory activity at any low and high bandwidths, indicating that SCS using different waveforms (tonic/burst) does not significantly influence motor neuron recruitment for non-motor individuals with chronic pain.

Progression Patterns in Non-Contrast-Enhancing Gliomas Support Brain Tumor Responsiveness to Surgical Lesions.

Purpose: The overall benefit of surgical treatments for patients with glioma is undisputed. We have shown preclinically that brain tumor cells form a network that is capable of detecting damage to the tumor, and repair itself. The aim of this study was to determine whether a similar mechanism might contribute to local recurrence in the clinical setting. Methods: We evaluated tumor progression patterns of 24 initially non-contrast-enhancing gliomas that were partially resected or biopsied. We measured the distance between the new contrast enhancement developing over time, and prior surgical lesioning, and evaluated tumor network changes in response to sequential resections by quantifying tumor cells and tumor networks with specific stainings against IDH1-R132H. Results: We found that new contrast enhancement appeared within the residual, non-enhancing tumor mass in 21/24 patients (87.5%). The location of new contrast enhancement within the residual tumor region was non-random; it occurred adjacent to the wall of the resection cavity in 12/21 patients (57.1%). Interestingly, the density of the glioma cell network increased in all patient tumors between initial resection or biopsy and recurrence. In line with the histological and radiological malignization, Ki67 expression increased from initial to final resections in 14/17 cases. Conclusion: The non-random distribution of glioma malignization in patients and unidirectional increase of anatomical tumor networks after surgical procedures provides evidence that surgical lesions, in the presence of residual tumor cells, can stimulate local tumor progression and tumor cell network formation. This argues for the development of intraoperative treatments increasing the benefits from surgical resection by specifically disrupting the mechanisms of local recurrence, particularly tumor cell network functionality.

Circulating monocytes and tumor-associated macrophages express recombined immunoglobulins in glioblastoma patients.

BACKGROUND: Glioblastoma is the most common and malignant brain tumor in adults. Glioblastoma is usually fatal 12-15 months after diagnosis and the current possibilities in therapy are mostly only palliative. Therefore, new forms of diagnosis and therapy are urgently needed. Since tumor-associated macrophages are key players in tumor progression and survival there is large potential in investigating their immunological characteristics in glioblastoma patients. Recent evidence shows the expression of variable immunoglobulins and TCRαß in subpopulations of monocytes, in vitro polarized macrophages and macrophages in the tumor microenvironment. We set out to investigate the immunoglobulin sequences of circulating monocytes and tumor-associated macrophages from glioblastoma patients to evaluate their potential as novel diagnostic or therapeutic targets. RESULTS: We routinely find consistent expression of immunoglobulins in tumor-associated macrophages (TAM) and circulating monocytes from all glioblastoma patients analyzed in this study. However, the immunoglobulin repertoires of circulating monocytes and TAM are generally more restricted compared to B cells. Furthermore, the immunoglobulin expression in the macrophage populations negatively correlates with the tumor volume. Interestingly, the comparison of somatic mutations, V-chain usage, CDR3-length and the distribution of used heavy chain genes on the locus of chromosome 14 of the immunoglobulins from myeloid to B cells revealed virtually no differences. CONCLUSIONS: The investigation of the immunoglobulin repertoires from TAM and circulating monocytes in glioblastoma-patients revealed a negative correlation to the tumor volume, which could not be detected in the immunoglobulin repertoires of the patients' B lymphocytes. Furthermore, the immunoglobulin repertoires of monocytes were more diverse than the repertoires of the macrophages in the tumor microenvironment from the same patients suggesting a tumor-specific immune response which could be advantageous for the use as diagnostic or therapeutic target.

Transcriptional regulation of the α-synuclein gene in human brain tissue.

The transcriptional regulation of the gene encoding α-synuclein (SNCA) is thought to play a critical role in the pathogenesis of Parkinson's disease (PD), as common genetic variability in this gene is associated with an elevated risk of developing PD. However, the relevant mechanisms are still poorly understood. So far, only few proteins have been identified as transcription factors (TFs) of SNCA in cellular models. Here we show that two of these TFs bind to the DNA in human brain tissue: the zinc finger protein ZSCAN21 occupies a region within SNCA intron 1, as described before, while GATA2 occupies a specific region within intron 2, where we have identified a new binding site within the complex structure of the 5'-promoter region of SNCA. Electrophoretic mobility shift assays confirmed these binding sites. Genetic investigations revealed no polymorphisms or mutations within these sites. A better understanding of TF-DNA interactions within SNCA may allow to develop novel therapies designed to reduce α-synuclein levels.