Effects of a neurokinin-1 receptor antagonist in the acute phase after thoracic spinal cord injury in a rat model

Objective: Disruption of the blood-spinal cord barrier (BSCB) with subsequent edema formation and further neuroinflammation contributes to aggravation of spinal cord injury (SCI). We aimed to observe the effect of antagonizing the binding of the neuropeptide Substance-P (SP) to its neurokinin-1 (NK1) receptor in a rodent SCI model. Methods: Female Wistar rats were subjected to a T9 laminectomy with or without (Sham) a T9 clip-contusion/compression SCI, followed by the implantation of an osmotic pump for the continuous, seven-day-long infusion of a NK1 receptor antagonist (NRA) or saline (vehicle) into the intrathecal space. The animals were assessed via MRI, and behavioral tests were performed during the experiment. 7 days after SCI, wet & dry weight and immunohistological analyses were conducted. Results: Substance-P inhibition via NRA showed limited effects on reducing edema. However, the invasion of T-lymphocytes and the number of apoptotic cells were significantly reduced with the NRA treatment. Moreover, a trend of reduced fibrinogen leakage, endothelial and microglial activation, CS-GAG deposition, and astrogliosis was found. Nevertheless, only insignificant general locomotion recovery could be observed in the BBB open field score and the Gridwalk test. In contrast, the CatWalk gait analysis showed an early onset of recovery in several parameters. Conclusion: Intrathecal administration of NRA might reinforce the integrity of the BSCB in the acute phase after SCI, potentially attenuating aspects of neurogenic inflammation, reducing edema formation, and improving functional recovery

Gene therapy for aromatic L-amino acid decarboxylase deficiency: Requirements for safe application and knowledge-generating follow-up

The autosomal recessive defect of aromatic L-amino acid decarboxylase (AADC) leads to a severe neurological disorder with manifestation in infancy due to a pronounced, combined deficiency of dopamine, serotonin and catecholamines. The success of conventional drug treatment is very limited, especially in patients with a severe phenotype. The development of an intracerebral AAV2-based gene delivery targeting the putamen or substantia nigra started more than 10 years ago. Recently, the putaminally-delivered construct, Eladocagene exuparvovec has been approved by the European Medicines Agency and by the British Medicines and Healthcare products Regulatory Agency. This now available gene therapy provides for the first time also for AADC deficiency (AADCD) a causal therapy, leading this disorder into a new therapeutic era. By using a standardized Delphi approach members of the International Working Group on Neurotransmitter related Disorders (iNTD) developed structural requirements and recommendations for the preparation, management and follow-up of AADC deficiency patients who undergo gene therapy. This statement underlines the necessity of a framework for a quality-assured application of AADCD gene therapy including Eladocagene exuparvovec. Treatment requires prehospital, inpatient and posthospital care by a multidisciplinary team in a specialized and qualified therapy center. Due to lack of data on long-term outcomes and the comparative efficacy of alternative stereotactic procedures and brain target sites, a structured follow-up plan and systematic documentation of outcomes in a suitable, industry-independent registry study are necessary

Thermodynamic parameters of basic mineral compounds interaction of solid fuel

The calculation of the thermodynamic characteristics of the main substances mineral solid fuel using model approximating dependencies whose coefficients are functions of temperature. The analysis of approximations in a wide range of temperatures. The influence of the parameters of the model equations for the approximation error of the thermodynamic functions. Presents a graphic interpretation of the tabulated and calculated values of functions at given temperatures

The Brain Monitoring with Information Technology (BrainIT) collaborative network:: Past, Present and Future Direction

The BrainIT group works collaboratively on developing standards for collection and analyses of data from brain injured patients and to facilitate a more efficient infrastructure for assessing new health care technology with the primary objective of improving patient care. European Community funding supported meetings over a year to discuss and define a core dataset to be collected from patients with traumatic brain injury using IT based methods. In this paper, we give an overview of the aims and future directions of the group as well as present the results of an EC funded study with the aim of testing the feasibility of collecting this core dataset across a number of European sites and discuss the future direction of this research network. Over a three year period, data collection client and web-server based tools were developed and core data (grouped into 9 categories) were collected from 200 head-injured patients by local nursing staff in 22 European neuro-intensive care centres. Data were uploaded through the BrainIT web site and random samples of received data were selected automatically by computer for validation by data validation (DV) staff against primary sources held in each local centre. Validated data were compared with originally transmitted data and percentage error rates calculated by data category. Feasibility was assessed in terms of the proportion of missing data, accuracy of data collected andlimitations reported by users of the IT methods. Thirteen percent of data files required cleaning. Thirty “one-off” demographic and clinical data elements had significant amounts of missing data (> 15%). Validation staff conducted 19,461 comparisons between uploaded database data with local data sources and error rates were commonly less than or equal to 6%, the exception being the surgery data class where an unacceptably high error rate of 34% was found. Nearly 10,000therapies were successfully recorded with start-times but approximately a third had inaccurate or missing end times which limits the analysis of duration of therapy. Over 40,000 events and procedures were recorded but events with long durations (such as transfers) were more likely to have “end-times” missed. The BrainIT core dataset is a rich dataset for hypothesis generation and post-hoc analyses provided studies avoid known limitations in the dataset. Limitations in the current IT based data collection tools have been identified and have been addressed. In order for multi-centre data collection projects to be viable the resource intensive validation procedures will require a more automated process and this may include direct electronic access to hospital based clinical data sources for both validation purposes and for minimising the duplication of data entry. This type of infrastructure may foster and facilitate the remote monitoring of patient management and protocol adherence in future trials of patient management and monitoring.&nbsp

Die intrazerebrale Gentherapie des Aromatischen-L-Aminosäure-Decarboxylase-Mangels mit Eladocagene exuparvovec : Eine Stellungnahme der Gesellschaft für Neuropädiatrie (GNP), der Arbeitsgemeinschaft pädiatrischer Stoffwechselstörungen (APS), der Deutschen Gesellschaft für Neurochirurgie (DGNC) und der Deutschen Gesellschaft für Kinder- und Jugendmedizin (DGKJ)

Background The autosomal recessive defect of aromatic L‑amino acid decarboxylase (AADC) causes a severe combined deficiency of dopamine, serotonin and catecholamines. The clinical picture is characterized by truncal hypotonia, delayed or absent achievement of motor milestones, and oculogyric crises from infancy onwards. The response to conventional drug treatment is very limited, especially in severe cases. The intracerebral application of eladocagene exuparvovec, an AAV2-based gene therapy, which is expected to be approved in mid-2021, is the first available causal therapeutic approach. Aim In collaboration with the German Society of Neuropediatrics (GNP), the Working Group of Pediatric Metabolic Disorders (APS), the German Society of Neurosurgery (DGNC) and the German Society of Pediatrics and Adolescent Medicine (DGKJ), the structural requirements and practical aspects in the preparation, implementation and follow-up of the treatment with eladocagene exuparvovec were elaborated. Discussion The present statement compiles the necessary framework conditions for a quality-assured administration of eladocagene exuparvovec. The treatment requires prehospital, inpatient and posthospital care by a multiprofessional team in a specialized and qualified treatment center. Patient follow-up is intended to contribute to knowledge-generating care. Due to lack of data on the therapeutic (long-term) effect as well as on advantages and disadvantages of the different stereotactic approaches, a structured follow-up plan and documentation in an appropriate, industry-independent registry are necessary.Hintergrund Der autosomal-rezessiv vererbte Defekt der aromatischen L‑Aminosäure-Decarboxylase (AADC) führt zu einem ausgeprägten, kombinierten Mangel an Dopamin, Serotonin und Katecholaminen. Das klinische Bild ist charakterisiert durch eine rumpfbetonte, muskuläre Hypotonie, verzögertes oder fehlendes Erreichen der motorischen Meilensteine und okulogyre Krisen ab dem Säuglingsalter. Der Erfolg der konventionellen, medikamentösen Behandlung ist besonders bei schweren Verläufen sehr limitiert. Mit der intrazerebralen Applikation von Eladocagene exuparvovec (Upstaza®), einer AAV2-basierten Gentherapie, deren Zulassung für Mitte 2021 erwartet wird, steht erstmals ein kausaler Therapieansatz zur Verfügung. Ziel In Zusammenarbeit mit der Gesellschaft für Neuropädiatrie (GNP), der Arbeitsgemeinschaft pädiatrischer Stoffwechselstörungen (APS), der Gesellschaft für Neurochirurgie (DGNC) und der Deutschen Gesellschaft für Kinder- und Jugendmedizin (DGKJ) wurden die Strukturvoraussetzungen und die praktischen Aspekte in der Vorbereitung, Durchführung und Nachsorge der Therapie mit Eladocagene exuparvovec erarbeitet. Diskussion Die vorliegende Stellungnahme stellt die notwendigen Rahmenbedingungen für eine qualitätsgesicherte Anwendung von Eladocagene exuparvovec zusammen. Die Behandlung erfordert eine prästationäre, stationäre und poststationäre Betreuung durch ein multiprofessionelles Team in einem spezialisierten und qualifizierten Therapiezentrum. Die Nachsorge der Patienten soll zu einer wissensgenerierenden Versorgung beitragen. Aufgrund von fehlenden Daten zur therapeutischen (Langzeit‑)Wirkung sowie zu Vor- und Nachteilen der verschiedenen stereotaktischen Prozeduren sind ein strukturierter Nachsorgeplan und die Erfassung in einem geeigneten, industrieunabhängigen Register notwendig

Tumor infiltration in enhancing and non-enhancing parts of glioblastoma: A correlation with histopathology

To correlate histopathologic findings from biopsy specimens with their corresponding location within enhancing areas, non-enhancing areas and necrotic areas on contrast enhanced T1-weighted MRI scans (cT1).In 37 patients with newly diagnosed glioblastoma who underwent stereotactic biopsy, we obtained a correlation of 561 1mm3 biopsy specimens with their corresponding position on the intraoperative cT1 image at 1.5 Tesla. Biopsy points were categorized as enhancing (CE), non-enhancing (NE) or necrotic (NEC) on cT1 and tissue samples were categorized as "viable tumor cells", "blood" or "necrotic tissue (with or without cellular component)". Cell counting was done semi-automatically.NE had the highest content of tissue categorized as viable tumor cells (89% vs. 60% in CE and 30% NEC, respectively). Besides, the average cell density for NE (3764 ± 2893 cells/mm2) was comparable to CE (3506 ± 3116 cells/mm2), while NEC had a lower cell density with 2713 ± 3239 cells/mm2. If necrotic parts and bleeds were excluded, cell density in biopsies categorized as "viable tumor tissue" decreased from the center of the tumor (NEC, 5804 ± 3480 cells/mm2) to CE (4495 ± 3209 cells/mm2) and NE (4130 ± 2817 cells/mm2).The appearance of a glioblastoma on a cT1 image (circular enhancement, central necrosis, peritumoral edema) does not correspond to its diffuse histopathological composition. Cell density is elevated in both CE and NE parts. Hence, our study suggests that NE contains considerable amounts of infiltrative tumor with a high cellularity which might be considered in resection planning

Multimodales zerebrales Monitoring bei schweren Schädel-Hirn-Trauma

Die vorliegende Arbeit setzt sich mit der klinischen Anwendung von zwei neuen Monitoringparametern - Hirngewebe-PO2 in der weißen Substanz (PtiO2), und online intrakranielle Compliance (cICC) - im Rahmen des multimodalen zerebralen Monitorings bei Patienten mit schwerem Schädel-Hirn-Trauma auseinander. Bezüglich des PtiO2 konnte erstmalig eine Hypoxiegrenze von 8,5 mmHg durch vergleichende Messungen mit der jugular-venösen Oxymetrie ermittelt werden. Ferner konnte gezeigt werden, dass, bei intakter zerebraler Autoregulation, der PtiO2 bei einem zerebralen Perfusionsdruck (CPP) >60 mmHg über dem pathologischen Grenzwert liegt. Eine forcierte bzw. moderate Hyperventilation hingegen, induziert, trotz adäquatem CPP, eine Reduktion des PtiO2, die im individuellen Fall zur Unterschreitung des hypoxischen Grenzwerts führt. Das PtiO2-Verfahren ist somit v.a. dann indiziert, wenn eine Hyperventilationstherapie zur Kontrolle eines pathologisch erhöhten intrakraniellen Drucks (ICP) eingesetzt werden muss. PtiO2-Messwerte bedürfen aber einer kritischen Interpretation, sofern der PtiO2-Katheter in der Nähe einer Kontusion lokalisiert ist. Hier ist der PtiO2, als Ausdruck des perikontusionell reduzierten zerebralen Blutflusses, signifikant erniedrigt und somit nicht repräsentativ für die globale zerebrale Oxygenierung. Für die cICC konnte ebenfalls ein pathologischer Grenzwert angegeben werden (0,5 ml/mmHg). Die Dateninterpretation ist aber, durch die offensichtliche Abnahme der intrakraniellen Compliance mit zunehmendem Lebensalter, erschwert. Ferner bleibt die cICC bzgl. ihrer Datenqualität weit hinter etablierten Parametern zurück, so dass ihre routinemäßige Anwendung zum jetzigen Zeitpunkt nicht zu empfehlen ist. Basierend auf unseren Untersuchungen hat sich das PtiO2-Verfahren international als Langzeitmonitoring der zerebralen Oxygenierung etablieren können. Die cICC hingegen bedarf umfangreicher Systemänderungen, um eine frühe Risikoabschätzung bezüglich eines drohenden ICP-Anstiegs suffizient zu ermöglichen.The aim of our clinical and experimental studies was to evaluate two new monitoring parameters -brain tissue PO2 (PtiO2) of cerebral white matter, and online intracranial compliance (cICC) - in patients with severe traumatic brain injury by using a computerized multimodal cerebral monitoring system. By comparing PtiO2 with jugular vein oxygen saturation, we were able to establish the hypoxic PtiO2-threshold of 8.5 mmHg. Moreover, we demonstrated that in case of an intact cerebral autoregulation, PtiO2 was well above the hypoxic threshold as long as cerebral perfusion pressure (CPP) stayed above 60 mmHg. However, forced or moderate hyperventilation carried an individual risk of a PtiO2 reduction below the hypoxic threshold despite an adequate CPP. PtiO2 monitoring is therefore particularly indicated, if hyperventilation therapy is necessary for control of pathologically increased intracranial pressure (ICP). However, PtiO2-values needed critical interpretation, if catheters were placed close to contusions. In these situations, PtiO2 has been shown to be significantly reduced, presumably due to low peri-contusional blood flow. Thus, such PtiO2 measurements cannot be taken as representatives of global cerebral oxygenation. In cICC monitoring, a pathological threshold was accomplished (0.5 ml/mmHg). Due to a stepwise cICC reduction with increasing age, cICC data interpretation was aggravated, and cICC data quality was significantly reduced in comparison to other established monitoring parameters. Hence, a routine use of this device is currently not advisable. Based on ours results, the PtiO2-methode has been established internationally as an ideal tool for long-term monitoring of cerebral oxygenation. On the contrary, the cICC system needs extensive alterations in order to anticipate sufficiently pathological ICP rises

Cellular, molecular, and clinical mechanisms of action of deep brain stimulation—a systematic review on established indications and outlook on future developments

Abstract Deep brain stimulation (DBS) has been successfully used to treat movement disorders, such as Parkinson's disease, for more than 25 years and heralded the advent of electrical neuromodulation to treat diseases with dysregulated neuronal circuits. DBS is now superseding ablative techniques, such as stereotactic radiofrequency lesions. While serendipity has played a role in developing DBS as a therapy, research during the past two decades has shown that electrical neuromodulation is far more than a functional lesion that can be switched on and off. This understanding broadens the field to enable new types of stimulation, clinical indications, and research. This review highlights the complex effects of DBS from the single cell to the neuronal network. Specifically, we examine the electrical, cellular, molecular, and neurochemical mechanisms of DBS as applied to Parkinson's disease and other emerging applications

Surgical management of ventrally located cervical epidural abscess: A comparative analysis between patients aged 18–64 years and ≥65 years

Background: We aimed to compare the clinical course of patients aged 18–65 years and ≥65years who underwent anterior cervical discectomy and fusion (ACDF) or corpectomy for ventrally located CSEA. Methods: Clinical and imaging data were retrospectively collected from the institutional database between September 2005 and December 2021. Results: A total of 35 and 26 patients aged 18–64 and ≥ 65 years, respectively who were diagnosed with ventrally located CSEA were included. The overall mean age was 63.9 ± 3.2 years, with a predominance of the male sex (n = 43/61, 70.5%). Patients aged ≥65 years presented with significantly higher rates of comorbidities (10.3 ± 2.8), as indicated by the CCI, than their younger counterparts (18–64 years: 6.2 ± 2.6; p < 0.001). No differences in the surgical approach or characteristics were observed among the groups. Notably, patients aged ≥65 years had a significantly longer intensive care unit as well as overall hospital stay. In-hospital and 90-day mortality were similar across both groups. Following both types of surgery, a significant improvement was observed in the blood infection parameters and neurological status at discharge compared with the baseline measurements. Older age, higher rates of comorbidities, and higher grades of disability were significant predictors for mortality. Conclusions: Emergency surgical evacuation should be undertaken for CSEA in the presence of acute neurological deterioration regardless of the age. Factors, such as age, comorbidities, and neurological status on admission appear to be important predictors of disease outcomes. However, the risk profile of younger patients should not be underestimated