Modeling Stroke in Mice - Middle Cerebral Artery Occlusion with the Filament Model

Stroke is among the most frequent causes of death and adult disability, especially in highly developed countries. However, treatment options to date are very limited. To meet the need for novel therapeutic approaches, experimental stroke research frequently employs rodent models of focal cerebral ischaemia. Most researchers use permanent or transient occlusion of the middle cerebral artery (MCA) in mice or rats

Clinical management and outcome of adult patients with extracorporeal life support device–associated intracerebral hemorrhage—a neurocritical perspective and grading

Intracerebral hemorrhage (ICH) is a devastating complication in patients treated with extracorporeal membrane oxygenation (ECMO) due to respiratory or cardiac issues. Neurosurgical evaluation and management of such cases has only insufficiently been studied. We conducted a retrospective, cohort study of adult patients treated with ECMO between January 2007 and January 2017 in a tertiary healthcare center. Demographics, clinical data, coagulation status, ICH characteristics, and treatment modalities were analyzed. The primary outcome parameter was defined as mortality caused by ICH during ECMO. 525 patients with ECMO therapy were eligible for analysis. An overall incidence for any type of intracranial bleeding of 12.3% was found. Small hemorrhages accounted for 6.4% and acute subdural and epidural hematoma for 1.2%. Twenty-four (4.6%) patients developed ICH, and 11 patients (46%) died due to the ICH. Mortality was significantly higher in patients with larger ICH volumes (86.8 +/- 34.8 ml vs 9.9 +/- 20.3 ml, p < 0.001), intraventricular hemorrhage (83% vs 8%, p = 0.01), and a fluid level inside the ICH (75% vs 31%, p = 0.04). All patients were classified according to the bleeding pattern on the initial CT scan into 3 types. Patients with type 1 bleeding were statistically more likely to die (p < 0.001). In 15 out of 24 patients (63%), correction of the coagulation status was possible within 12 h after ICH onset. Seven out of 9 patients (78%) without early coagulation correction died compared to 2 out of 15 patients (13%), in whom early coagulation correction was successful (p = 0.01). This is the first study evaluating the course and management of patients experiencing an ICH under ECMO therapy and establishing an ICH classification based on the bleeding patterns. Early correction of the coagulation is of paramount importance in the treatment of these patients

The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury

The migration of polymorphonuclear granulocytes (PMN) into the brain parenchyma and release of their abundant proteases are considered the main causes of neuronal cell death and reperfusion injury following ischemia. Yet, therapies targeting PMN egress have been largely ineffective. To address this discrepancy we investigated the temporo-spatial localization of PMNs early after transient ischemia in a murine transient middle cerebral artery occlusion (tMCAO) model and human stroke specimens. Using specific markers that distinguish PMN (Ly6G) from monocytes/macrophages (Ly6C) and that define the cellular and basement membrane boundaries of the neurovascular unit (NVU), histology and confocal microscopy revealed that virtually no PMNs entered the infarcted CNS parenchyma. Regardless of tMCAO duration, PMNs were mainly restricted to luminal surfaces or perivascular spaces of cerebral vessels. Vascular PMN accumulation showed no spatial correlation with increased vessel permeability, enhanced expression of endothelial cell adhesion molecules, platelet aggregation or release of neutrophil extracellular traps. Live cell imaging studies confirmed that oxygen and glucose deprivation followed by reoxygenation fail to induce PMN migration across a brain endothelial monolayer under flow conditions in vitro. The absence of PMN infiltration in infarcted brain tissues was corroborated in 25 human stroke specimens collected at early time points after infarction. Our observations identify the NVU rather than the brain parenchyma as the site of PMN action after CNS ischemia and suggest reappraisal of targets for therapies to reduce reperfusion injury after strok

Navigation accuracy and assessability of carbon fiber-reinforced PEEK instrumentation with multimodal intraoperative imaging in spinal oncology

Radiolucent carbon-fiber reinforced PEEK (CFRP) implants have helped improve oncological follow-up and radiation therapy. Here, we investigated the performance of 3D intraoperative imaging and navigation systems for instrumentation and precision assessment of CFRP pedicle screws across the thoraco-lumbar spine. Thirty-three patients with spinal tumors underwent navigated CFRP instrumentation with intraoperative CT (iCT), robotic cone-beam CT (rCBCT) or cone-beam CT (CBCT) imaging. Two different navigation systems were used for iCT-/rCBCT- and CBCT-based navigation. Demographic, clinical and outcome data was assessed. Four blinded observers rated image quality, assessability and accuracy of CFRP pedicle screws. Inter-observer reliability was determined with Fleiss` Kappa analysis. Between 2018 and 2021, 243 CFRP screws were implanted (iCT:93, rCBCT: 99, CBCT: 51), of which 13 were non-assessable (iCT: 1, rCBCT: 9, CBCT: 3; *p = 0.0475; iCT vs. rCBCT). Navigation accuracy was highest using iCT (74%), followed by rCBCT (69%) and CBCT (49%) (*p = 0.0064; iCT vs. CBCT and rCBCT vs. CBCT). All observers rated iCT image quality higher than rCBCT/CBCT image quality (*p < 0.01) but relevant pedicle breaches were reliably identified with substantial agreement between all observers regardless of the imaging modality. Navigation accuracy for CFRP pedicle screws was considerably lower than expected from reports on titanium implants and CT may be best for reliable assessment of CFRP materials

Vascular Endothelial Growth Factor Augments the Tolerance Towards Cerebral Stroke by Enhancing Neurovascular Repair Mechanism

The breakdown of the blood-brain barrier (BBB) is a critical event in the development of secondary brain injury after stroke. Among the cellular hallmarks in the acute phase after stroke are a downregulation of tight-junction molecules and the loss of microvascular pericyte coverage and endothelial sealing. Thus, a rapid repair of blood vessel integrity and re-stabilization of the BBB is considered an important strategy to reduce secondary brain damage. However, the mechanisms underlying BBB disruption remain poorly understood. Especially, the role of VEGF in this context remains inconclusive. With the conditional and reversible VEGF expression systems, we studied the time windows of deleterious and beneficial VEGF actions on blood vessel integrity in mice. Using genetic systems for gain of function and loss of function experiments, we activated and inhibited VEGF signaling prior and simultaneously to ischemic stroke onset. In both scenarios, VEGF seems to play a vital role in containing the stroke-induced damage after cerebral ischemia. We report that the transgenic overexpression of VEGF (GOF) prior to the stroke stabilizes the vasculature and prevents blood-brain barrier disruption in young and aged animals after stroke. Whereas inhibition of signals for endogenous VEGF (LOF) prior to stroke results in bigger infarction with massive brain swelling and enhanced BBB permeability, furthermore, activating or blocking VEGF signaling after ischemic stroke onset had comparable effects on BBB repair and cerebral edema. VEGF can function as an anti-permeability factor, and a VEGF-based therapy in the context of stroke prevention and recovery has an enormous potential

Clinical implementation of a 3D4K-exoscope (Orbeye) in microneurosurgery

Exoscopic surgery promises alleviation of physical strain, improved intraoperative visualization and facilitation of the clinical workflow. In this prospective observational study, we investigate the clinical usability of a novel 3D4K-exoscope in routine neurosurgical interventions. Questionnaires on the use of the exoscope were carried out. Exemplary cases were additionally video-documented. All participating neurosurgeons (n = 10) received initial device training. Changing to a conventional microscope was possible at all times. A linear mixed model was used to analyse the impact of time on the switchover rate. For further analysis, we dichotomized the surgeons in a frequent (n = 1) and an infrequent (n = 9) user group. A one-sample Wilcoxon signed rank test was used to evaluate, if the number of surgeries differed between the two groups. Thirty-nine operations were included. No intraoperative complications occurred. In 69.2% of the procedures, the surgeon switched to the conventional microscope. While during the first half of the study the conversion rate was 90%, it decreased to 52.6% in the second half (p = 0.003). The number of interventions between the frequent and the infrequent user group differed significantly (p = 0.007). Main reasons for switching to ocular-based surgery were impaired hand-eye coordination and poor depth perception. The exoscope investigated in this study can be easily integrated in established neurosurgical workflows. Surgical ergonomics improved compared to standard microsurgical setups. Excellent image quality and precise control of the camera added to overall user satisfaction. For experienced surgeons, the incentive to switch from ocular-based to exoscopic surgery greatly varies

Profiling peripheral nerve macrophages reveals two macrophage subsets with distinct localization, transcriptome and response to injury

The authors identify two subsets of peripheral nerve macrophages residing in the endoneurium and the epineurium and displaying a distinct transcriptome and response to injury. These cells lack the main microglia identity and have a distinct origin. While CNS microglia have been extensively studied, relatively little is known about macrophages populating the peripheral nervous system. Here we performed ontogenic, transcriptomic and spatial characterization of sciatic nerve macrophages (snMacs). Using multiple fate-mapping systems, we show that snMacs do not derive from the early embryonic precursors colonizing the CNS, but originate primarily from late embryonic precursors and become replaced by bone-marrow-derived macrophages over time. Using single-cell transcriptomics, we identified a tissue-specific core signature of snMacs and two spatially separated snMacs: Relm alpha(+)Mgl1(+) snMacs in the epineurium and Relm alpha(-)Mgl1(-) snMacs in the endoneurium. Globally, snMacs lack most of the core signature genes of microglia, with only the endoneurial subset expressing a restricted number of these genes. In response to nerve injury, the two resident snMac populations respond differently. Moreover, and unlike in the CNS, monocyte-derived macrophages that develop during injury can engraft efficiently in the pool of resident peripheral nervous system macrophages

PrImary decompressive Craniectomy in AneurySmal Subarachnoid hemOrrhage (PICASSO) trial: study protocol for a randomized controlled trial

BACKGROUND: Poor-grade aneurysmal subarachnoid hemorrhage (SAH) is associated with poor neurological outcome and high mortality. A major factor influencing morbidity and mortality is brain swelling in the acute phase. Decompressive craniectomy (DC) is currently used as an option in order to reduce intractably elevated intracranial pressure (ICP). However, execution and optimal timing of DC remain unclear. METHODS: PICASSO resembles a multicentric, prospective, 1:1 randomized standard treatment-controlled trial which analyzes whether primary DC (pDC) performed within 24 h combined with the best medical treatment in patients with poor-grade SAH reduces mortality and severe disability in comparison to best medical treatment alone and secondary craniectomy as ultima ratio therapy for elevated ICP. Consecutive patients presenting with poor-grade SAH, defined as grade 4–5 according to the World Federation of Neurosurgical Societies (WFNS), will be screened for eligibility. Two hundred sixteen patients will be randomized to receive either pDC additional to best medical treatment or best medical treatment alone. The primary outcome is the clinical outcome according to the modified Rankin Scale (mRS) at 12 months, which is dichotomized to favorable (mRS 0–4) and unfavorable (mRS 5–6). Secondary outcomes include morbidity and mortality, time to death, length of intensive care unit (ICU) stay and hospital stay, quality of life, rate of secondary DC due to intractably elevated ICP, effect of size of DC on outcome, use of duraplasty, and complications of DC. DISCUSSION: This multicenter trial aims to generate the first confirmatory data in a controlled randomized fashion that pDC improves the outcome in a clinically relevant endpoint in poor-grade SAH patients. TRIAL REGISTRATION: DRKS DRKS00017650. Registered on 09 June 2019. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13063-022-06969-4

Opportunities and Challenges of DLT (Blockchain) in Mobility and Logistics

This report presents the economic potential, legal framework, and technical foundations required to understand distributed ledger (DL) / blockchain technology and llustrates the opportunities and challenges they present, especially in the mobility and logistics sectors. It was compiled by the blockchain laboratory at Fraunhofer FIT on behalf of the German Federal Ministry of Transport and Digital Infrastructure (BMVI). Its intended audience comprises young companies seeking, for example, a legal assessment of data protection issues related to DL and blockchain technologies, decisionmakers in the private sector wishing concrete examples to help them understand how this technology can impact existing and emerging markets and which measures might be sensible from a business perspective, public policymakers and politicians wishing to familiarize themselves with this topic in order to take a position, particularly in the mobility and logistics sectors, and members of the general public interested in the technology and its potential. The report does not specifically address those with a purely academic or scientific interest in these topics, although parts of it definitely reflect the current state of academic discussion

Chancen und Herausforderungen von DLT (Blockchain) in Mobilität und Logistik

This basic report presents the economic potential e, the legal framework and the technical fundamentals of distributed ledger or blockchain technology necessary for understanding in order to exploit the opportunities and challenges of these technologies, especially in the mobility and logistics sector. clear. The basic report was prepared on behalf of the Federal Ministry of Transport and Digital Infrastructure (BMVI) by the blockchain laboratory of Fraunhofer FIT