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Background In recent years, argon has been shown to exert neuroprotective effects in an array of models. However, the mechanisms by which argon exerts its neuroprotective characteristics remain unclear. Accumulating evidence imply that argon may exert neuroprotective effects via modulating the activation and polarization of microglia/macrophages after ischemic stroke. In the present study, we analyzed the underlying neuroprotective effects of delayed argon application until 7 days after reperfusion and explored the potential mechanisms. Methods Twenty-one male Wistar rats underwent transient middle cerebral artery occlusion or sham surgery randomly for 2 h using the endoluminal thread model. Three hours after transient middle cerebral artery occlusion induction and 1 h after reperfusion, animals received either 50% vol Argon/50% vol O 2 or 50% vol N 2 /50% vol O 2 for 1 h. The primary outcome was the 6-point neuroscore from 24 h to d7 after reperfusion. Histological analyses including infarct volume, survival of neurons (NeuN) at the ischemic boundary zone, white matter integrity (Luxol Fast Blue), microglia/macrophage activation (Iba1), and polarization (Iba1/Arginase1 double staining) on d7 were conducted as well. Sample size calculation was performed using nQuery Advisor + nTerim 4.0. Independent t test, one-way ANOVA and repeated measures ANOVA were performed, respectively, for statistical analysis (SPSS 23.0). Results The 6-point neuroscore from 24 h to d7 after reperfusion showed that tMCAO Ar group displayed significantly improved neurological performance compared to tMCAO N 2 group ( p  = 0.026). The relative numbers of NeuN-positive cells in the ROIs of tMCAO Ar group significantly increased compared to tMCAO N 2 group ( p  = 0.010 for cortex and p  = 0.011 for subcortex). Argon significantly suppressed the microglia/macrophage activation as revealed by Iba1 staining ( p  = 0.0076) and promoted the M2 microglia/macrophage polarization as revealed by Iba1/Arginase 1 double staining ( p  = 0.000095). Conclusions Argon administration with a 3 h delay after stroke onset and 1 h after reperfusion significantly alleviated neurological deficit within the first week and preserved the neurons at the ischemic boundary zone 7 days after stroke. Moreover, argon reduced the excessive microglia/macrophage activation and promoted the switch of microglia/macrophage polarization towards the anti-inflammatory M2 phenotype. Studies making efforts to further elucidate the protective mechanisms and to benefit the translational application are of great value.

The assessment of treatment response in glioblastoma is difficult with MRI because reactive blood-brain barrier alterations with contrast enhancement can mimic tumor progression. In this study, we investigated the predictive value of PET using O-(2-(18)F-fluoroethyl)-l-tyrosine ((18)F-FET PET) during treatment. In a prospective study, 25 patients with glioblastoma were investigated by MRI and (18)F-FET PET after surgery (MRI-/FET-1), early (7-10 d) after completion of radiochemotherapy with temozolomide (RCX) (MRI-/FET-2), and 6-8 wk later (MRI-/FET-3). Maximum and mean tumor-to-brain ratios (TBR(max) and TBR(mean), respectively) were determined by region-of-interest analyses. Furthermore, gadolinium contrast-enhancement volumes on MRI (Gd-volume) and tumor volumes in (18)F-FET PET images with a tumor-to-brain ratio greater than 1.6 (T(vol 1.6)) were calculated using threshold-based volume-of-interest analyses. The patients were grouped into responders and nonresponders according to the changes of these parameters at different cutoffs, and the influence on progression-free survival and overall survival was tested using univariate and multivariate survival analyses and by receiver-operating-characteristic analyses. Early after completion of RCX, a decrease of both TBR(max) and TBR(mean) was a highly significant and independent statistical predictor for progression-free survival and overall survival. Receiver-operating-characteristic analysis showed that a decrease of the TBR(max) between FET-1 and FET-2 of more than 20% predicted favorable survival [corrected], with a sensitivity of 83% and a specificity of 67% (area under the curve, 0.75). Six to eight weeks later, the predictive value of TBR(max) and TBR(mean) was less significant, but an association between a decrease of T(vol 1.6) and PFS was noted. In contrast, Gd-volume changes had no significant predictive value for survival. In contrast to Gd-volumes on MRI, changes in (18)F-FET PET may be a valuable parameter to assess treatment response in glioblastoma and to predict survival time.

Minipigs are frequently used in (neuro-)interventional research. Longitudinal experiments may require repeated vessel access via the femoral artery. Anticoagulation and incompliance of the animals necessitates the use of a vascular closure device (VCD). The effects of the Angio-Seal VCD in minipigs were longitudinally assessed. Minipig (42±8.4 kg body weight) femoral arteries were sealed using the 8F (n = 6) or 6F (n = 7) Angio-Seal VCD. The pre-interventional femoral artery diameter was 5.1±0.4 mm (4.3-5.8 mm). Sealed puncture sites were analysed angiographically as well as by computed tomography angiography (CTA) for a mean period of 14.1±8.0 weeks (1-22 weeks). All animals were constantly treated with acetylsalicylic acid (ASS) (450 mg/d (n = 7) or 100 mg/d (n = 1)) and clopidogrel (75 mg/d (n = 8)). Non-instrumented (n = 2) and arteries sealed using the VCD (n = 2) were examined histologically. No postoperative hemorrhagic complications were observed. Three arteries were occluded after VCD placement (1 animal diagnosed after 4 weeks (8F), 2 animals after 1 week (6F)) and remained so until the end of the experiments after 22, 12 and 4 weeks, respectively. In one artery a 50% stenosis 8 weeks after application of a 6F Angio-Seal was detected. In 69.2% (n = 9) the VCD was applied without complications. Histopathological analysis of the sealed arterial segments showed subtotal obliteration of the vessel lumen, formation of collagenous tissue and partial damage of the internal elastic lamina. The Angio-Seal VCD prevents relevant hemorrhagic complications in minipigs treated with dual platelet inhibition, but is associated with increased vessel occlusion rates.

The liver-derived plasma protein fetuin-A is strongly expressed during fetal life, hence its name. Fetuin-A protein is normally present in most fetal organs and tissues, including brain tissue. Fetuin-A was neuroprotective in animal models of cerebral ischemia and lethal chronic inflammation, suggesting a role beyond the neonatal period. Little is known, however, on the presence of fetuin-A in mature human brain tissue under different physiological and pathological conditions. We studied by immunohistochemistry (IHC) the distribution of fetuin-A protein in mature human brain autopsy tissues from patients without neurological disease, patients with inflammatory brain disorders, and patients with ischemic brain lesions. To identify fetuin-A-positive cells in these tissues we co-localized fetuin-A with GFAP (astrocytes) and CD68 (macrophages, activated microglia). Unlike previous reports, we detected fetuin-A protein also in mature human brain as would be expected from an abundant plasma protein also present in cerebrospinal fluid. Fetuin-A immunoreactivity was increased in ischemic white matter and decreased in inflamed cerebellar tissue. Fetuin-A immunostaining was predominantly associated with neurons and astrocytes. Unlike the developing brain, the adult brain lacked fetuin-A immunostaining in CD68-positive microglia. Our findings suggest a role for fetuin-A in tissue remodeling of neonatal brain, which becomes obsolete in the adult brain, but is re-activated in damaged brain tissue. To further assess the role of fetuin-A in the mature brain, animal models involving ischemia and inflammation need to be studied.

In a previous study from our group, argon has shown to significantly attenuate brain injury, reduce brain inflammation and enhance M 2 microglia/macrophage polarization until 7 days after ischemic stroke. However, the long-term effects of argon have not been reported thus far. In the present study, we analyzed the underlying neuroprotective effects and potential mechanisms of argon, up to 30 days after ischemic stroke. Argon administration with a 3 h delay after stroke onset and 1 h after reperfusion demonstrated long-term neuroprotective effect by preserving the neurons at the ischemic boundary zone 30 days after stroke. Furthermore, the excessive microglia/macrophage activation in rat brain was reduced by argon treatment 30 days after ischemic insult. However, long-lasting neurological improvement was not detectable. More sensorimotor functional measures, age- and disease-related models, as well as further histological and molecular biological analyses will be needed to extend the understanding of argon’s neuroprotective effects and mechanism of action after ischemic stroke.

Recently aside from the \"classic\" endovascular monofilament perforation technique to induce experimental subarachnoid hemorrhage (SAH) a modification using a tungsten wire advanced through a guide tube has been described. We aim to assess both techniques for their success rate (induction of SAH without confounding pathologies) as primary endpoint. Further, the early tissue lesion pattern as evidence for early brain injury will be analyzed as secondary endpoint. Sprague Dawley rats (n=39) were randomly assigned to receive either Sham surgery (n=4), SAH using the \"classic\" technique (n=18) or using a modified technique (n=17). Course of intracranial pressure (ICP) and regional cerebral blood flow (rCBF) was analyzed; subsequent pathologies were documented either 6 or 24 h after SAH. Hippocampal tissue samples were analyzed via immunohistochemistry and western blotting. SAH-induction, regardless of confounding pathologies, was independent from type of technique (p=0.679). There was no significant difference concerning case fatality rate (classic: 40%; modified: 20%; p=0.213). Successful induction of SAH without collateral ICH or SDH was possible in 40% with the classic and in 86.7% with the modified technique (p=0.008). Peak ICP levels differed significantly between the two groups (classic: 94 +/- 23 mmHg; modified: 68 +/- 19 mmHg; p=0.003). Evidence of early cellular stress response and activation of apoptotic pathways 6 h after SAH was demonstrated. The extent of stress response is not dependent on type of technique. Both tested techniques successfully produce SAH including activation of an early stress response and apoptotic pathways in the hippocampal tissue. However, the induction of SAH with less confounding pathologies was more frequently achieved with the modified tungsten wire technique.

Purpose: Extensive lesions of the brachial plexus, or late cases, require free functional muscle grafts because the expected recovery time exceeds the critical threshold of 1.5 years, beyond which irreversible damage may be expected in the distal nerve stump and in the muscle. The reconstructive concept consists of a two-stage procedure where, in the first step, a nerve transfer is performed (from ipsi- or contralateral donor nerves). In the second step, after successful axonal regeneration within the graft has been confirmed, a free muscle transfer is performed. These grafts often exceed 40 cm in length, particularly for contralateral transfers. The purpose of this study was to assess whether robust motor recovery could be supported by such long nerve grafts. Methods: From April 2004 to April 2023, a total of 327 free functional muscle transfers were performed, the nerve graft length ranging from 0 cm (direct coaptation) to 90 cm (serial grafts). Motor recovery was evaluated 1.5 years after surgery according to the MRC scale. Results: A total of 208 patients were available for follow up. Direct coaptation yielded the best results, with 83% of patients reaching an M3 or M4 level of muscle strength. With the application of long (30–60 cm) grafts, 73% of the patients were classified as M3 or M4. The application of serial nerve grafts, however, only resulted in 18% of patients achieving a motor recovery rating of M3. Conclusions: These findings demonstrate that robust motor regeneration is supported by long (30–60 cm) nerve grafts, whereas serial nerve grafting results in a marked reduction in the quality of regeneration.

Background TCF4 acts as a transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5 motif. Dominant variants in TCF4 are associated with the manifestation of Pitt-Hopkins syndrome, a rare disease characterized by severe mental retardation, certain features of facial dysmorphism and, in many cases, with abnormalities in respiratory rhythm (episodes of paroxysmal tachypnea and hyperventilation, followed by apnea and cyanosis). Frequently, patients also develop epilepsy, microcephaly, and postnatal short stature. Although TCF4 is expressed in skeletal muscle and TCF4 seems to play a role in myogenesis as demonstrated in mice, potential myopathological findings taking place upon the presence of dominant TCF4 variants are thus far not described in human skeletal muscle. Method To address the pathological effect of a novel deletion affecting exons 15 and 16 of TCF4 on skeletal muscle, histological and immunofluorescence studies were carried out on a quadriceps biopsy in addition to targeted transcript studies and global proteomic profiling. Results We report on muscle biopsy findings from a Pitt-Hopkins patient with a novel heterozygous deletion spanning exon 15 and 16 presenting with neuromuscular symptoms. Microscopic characterization of the muscle biopsy revealed moderate fiber type I predominance, imbalance in the proportion of fibroblasts co-expressing Vimentin and CD90, and indicate activation of the complement cascade in TCF4 -mutant muscle. Protein dysregulations were unraveled by proteomic profiling. Transcript studies confirmed a mitochondrial vulnerability in muscle and confirmed reduced TCF4 expression. Conclusion Our combined findings, for the first time, unveil myopathological changes as phenotypical association of Pitt-Hopkins syndrome and thus expand the current clinical knowledge of the disease as well as support data obtained on skeletal muscle of a mouse model.

Awareness concerning iatrogenic cerebral amyloid angiopathy (iCAA) is increasing but its pathophysiology remains unclear. We discuss the implications of the clinical, imaging and neuropathological findings in two previously unpublished cases of probable iCAA: a 55-year-old female presenting with rapidly progressive cognitive impairment, showing imaging and histological evidence of CAA and having undergone neurosurgical treatment at the age of 6; and a 56-year-old male with a four-year history of recurring intracerebral hemorrhages (ICH) and neurosurgical intervention at the age of 5. In the first case, a brain biopsy was performed. Additionally, a systematic review of iCAA cases with neuropathological data suggests that most of the patients have concomitant amyloid parenchymal deposition and none or minimal tau pathology. The pathophysiological role of tau pathology in iCAA remains unclear. iCAA patients presenting with cognitive impairment without symptomatic ICH may be underdiagnosed.

Guidelines endorse targeted temperature management to reduce neurological sequelae and mortality after cardiac arrest (CA). Additional therapeutic approaches are lacking. Inhaled nitric oxide (iNO) given post systemic ischemia/reperfusion injury improves outcomes. Attenuated inflammation by iNO might be crucial in brain protection. iNO augmented mild therapeutic hypothermia (MTH) may improve outcome after CA exceeding the effect of MTH alone. Following ten minutes of CA and three minutes of cardiopulmonary resuscitation, 20 male Sprague-Dawley rats were randomized to receive MTH at 33 °C for 6hrs or MTH + 20ppm iNO for 5hrs; one group served as normothermic control. During the experiment blood was taken for biochemical evaluation. A neurological deficit score was calculated daily for seven days post CA. On day seven, brains and hearts were harvested for histological evaluation. Treatment groups showed a significant decrease in lactate levels six hours post resuscitation in comparison to controls. TNF-α release was significantly lower in MTH + iNO treated animals only at four hours post ROSC. While only the combination of MTH and iNO improved neurological function in a statistically significant manner in comparison to controls on days 4–7 after CA, there was no significant difference between groups treated with MTH and MTH + iNO.