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Spinal canal narrowing with consecutive spinal cord compression is considered a key mechanism in degenerative cervical myelopathy (DCM). DCM is a common spine condition associated with progressive neurological disability, and timely decompressive surgery is recommended. However, the clinical and radiological diagnostic workup is often ambiguous, challenging confident proactive treatment recommendations. Cerebrospinal fluid pressure dynamics (CSFP) are altered by spinal canal narrowing. Therefore, we aim to explore the potential value of bedside CSFP assessments for qualitative and quantitative assessment of spinal canal narrowing in DCM. In this prospective case series, seven patients with DCM underwent bedside lumbar puncture with measurement of CSFP dynamics and routine CSF analysis (NCT02170155). The patients were enrolled when standard diagnostic algorithms did not permit a clear treatment decision. Measurements include baseline CSFP, cardiac-driven CSFP peak-to-trough amplitude (CSFPp), and the Queckenstedt's test (firm pressure on jugular veins) in neutral and reclined head position. From the Queckenstedt's test, proxies for craniospinal elastance (i.e., relative pulse pressure coefficient; RPPC-Q) were calculated analogously to infusion testing. CSFP metrics were deemed suspicious of canal narrowing when numbers were lower than the minimum value from a previously tested elderly spine-healthy cohort ( N = 14). Mean age was 56 ± 13 years (range, 38-75; 2F); symptom severity was mostly mild to moderate (mean mJOA, 13.5 ± 2.6; range, 9-17). All the patients showed some extent of cervical stenosis in the MRI of unclear significance (5/7 following decompressive cervical spine surgery with an adjacent level or residual stenosis). Baseline CSFP was normal except for one patient (range, 4.7-17.4 mmHg). Normal values were found for CSFPp (0.4-1.3 mmHg) and the Queckenstedt's test in normal head positioning (9.-25.3 mmHg). During reclination, the Queckenstedt's test significantly decreased in one, and CSFPp in another case (>50% compared to normal position). RPPC-Q (0.07-0.19) aligned with lower values from spine-healthy (0.10-0.44). Routine CSF examinations showed mild total protein elevation (mean, 522 ± 108 mg/ml) without further evidence for the disturbed blood brain barrier. Intrathecal CSFP measurements allow discerning disturbed from normal CSFP dynamics in this population. Prospective longitudinal studies should further evaluate the diagnostic utility of CSFP assessments in DCM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kheram, Pfender, Boraschi, Farshad, Kurtcuoglu, Curt, Schubert and Zipser.)

Background: To date, it remains difficult for clinicians to reliably assess the disease status of intracranial aneurysms. As an aneurysm's 3D shape is strongly dependent on the underlying formation processes, it is believed that the presence of certain shape features mirrors the disease status of the aneurysm wall. Currently, clinicians associate irregular shape with wall instability. However, no consensus exists about which shape features reliably predict instability. In this study, we present a benchmark to identify shape features providing the highest predictive power for aneurysm rupture status., Methods: 3D models of aneurysms were extracted from medical imaging data (3D rotational angiographies) using a standardized protocol. For these aneurysm models, we calculated a set of metrics characterizing the 3D shape: Geometry indices (such as undulation, ellipticity and non-sphericity); writhe- and curvature-based metrics; as well as indices based on Zernike moments. Using statistical learning methods, we investigated the association between shape features and aneurysm disease status. This processing was applied to a clinical dataset of 750 aneurysms (261 ruptured, 474 unruptured) registered in the AneuX morphology database. We report here statistical performance metrics [including the area under curve (AUC)] for morphometric models to discriminate between ruptured and unruptured aneurysms., Results: The non-sphericity index NSI ( AUC = 0.80), normalized Zernike energies Z N s u r f ( AUC = 0.80) and the modified writhe-index W ¯ m e a n L 1 ( AUC = 0.78) exhibited the strongest association with rupture status. The combination of predictors further improved the predictive performance (without location: AUC = 0.82, with location AUC = 0.87). The anatomical location was a good predictor for rupture status on its own ( AUC = 0.78). Different protocols to isolate the aneurysm dome did not affect the prediction performance. We identified problems regarding generalizability if trained models are applied to datasets with different selection biases., Conclusions: Morphology provided a clear indication of the aneurysm disease status, with parameters measuring shape (especially irregularity) being better predictors than size. Quantitative measurement of shape, alone or in conjunction with information about aneurysm location, has the potential to improve the clinical assessment of intracranial aneurysms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Juchler, Schilling, Bijlenga, Kurtcuoglu and Hirsch.)

Phenylketonuria (PKU) is an inherited metabolic disease characterized by abnormally high concentrations of the essential amino acid L-phenylalanine (Phe) in blood plasma caused by reduced activity of phenylalanine hydroxylase (PAH). While numerous studies have shown association between high plasma Phe concentration and intellectual impairment, it is not clear whether increased Phe fluctuations also observed in PKU affect the brain as well. To investigate this, time-resolved in vivo data on Phe and competing large neutral amino acid (LNAA) concentrations in neurons are needed, but cannot be acquired readily with current methods. We have used in silico modeling as an alternative approach to characterize the interactive dynamics of Phe and competing LNAAs (CL) in the neurovascular unit (NVU). Our results suggest that plasma Phe fluctuations can propagate into the NVU cells and change there the concentration of LNAAs, with the highest magnitude of this effect observed at low frequency and high amplitude-to-mean ratio of the plasma Phe concentration fluctuations. Our model further elucidates the effect of therapeutic LNAA supplementation in PKU, showing how abnormal concentrations of Phe and CL in the NVU move thereby toward normal physiologic levels.

The homeostatic regulation of large neutral amino acid (LNAA) concentration in the brain interstitial fluid (ISF) is essential for proper brain function. LNAA passage into the brain is primarily mediated by the complex and dynamic interactions between various solute carrier (SLC) transporters expressed in the neurovascular unit (NVU), among which SLC7A5/LAT1 is considered to be the major contributor in microvascular brain endothelial cells (MBEC). The LAT1-mediated trans-endothelial transport of LNAAs, however, could not be characterized precisely by available in vitro and in vivo standard methods so far. To circumvent these limitations, we have incorporated published in vivo data of rat brain into a robust computational model of NVU-LNAA homeostasis, allowing us to evaluate hypotheses concerning LAT1-mediated trans-endothelial transport of LNAAs across the blood brain barrier (BBB). We show that accounting for functional polarity of MBECs with either asymmetric LAT1 distribution between membranes and/or intrinsic LAT1 asymmetry with low intraendothelial binding affinity is required to reproduce the experimentally measured brain ISF response to intraperitoneal (IP) L-tyrosine and L-phenylalanine injection. On the basis of these findings, we have also investigated the effect of IP administrated L-tyrosine and L-phenylalanine on the dynamics of LNAAs in MBECs, astrocytes and neurons. Finally, the computational model was shown to explain the trans-stimulation of LNAA uptake across the BBB observed upon ISF perfusion with a competitive LAT1 inhibitor.

The ability to characterize the mechanical properties of erythrocytes is important in clinical and research contexts: to diagnose and monitor hematologic disorders, as well as to optimize the design of cardiovascular implants and blood circulating devices with respect to blood damage. However, investigation of red blood cell (RBC) properties generally involves preparatory and processing steps. Even though these impose mechanical stresses on cells, little is known about their impact on the final measurement results. In this study, we investigated the effect of centrifuging, vortexing, pipetting, and high pressures on several markers of mechanical blood damage and RBC membrane properties. Using human venous blood, we analyzed erythrocyte damage by measuring free hemoglobin, phosphatidylserine exposure by flow cytometry, RBC deformability by ektacytometry and the parameters of a complete blood count. We observed increased levels of free hemoglobin for all tested procedures. The release of hemoglobin into plasma depended significantly on the level of stress. Elevated pressures and centrifuging also altered mean cell volume (MCV) and mean corpuscular hemoglobin (MCH), suggesting changes in erythrocyte population, and membrane properties. Our results show that the effects of blood handling can significantly influence erythrocyte damage metrics. Careful quantification of this influence as well as other unwanted secondary effects should thus be included in experimental protocols and accounted for in clinical laboratories.

The aim of this study was to evaluate whether possible preglomerular arterial-to-venous oxygen shunting is affected by the interaction between renal preglomerular carbon dioxide and oxygen transport. We hypothesized that a reverse (venous-to-arterial) shunting of carbon dioxide will increase partial pressure of carbon dioxide and decrease pH in the arteries and thereby lead to increased oxygen offloading and consequent oxygen shunting. To test this hypothesis, we employed a segment-wise three-dimensional computational model of coupled renal oxygen and carbon dioxide transport, wherein coupling is achieved by shifting the oxygen-hemoglobin dissociation curve in dependence of local changes in partial pressure of carbon dioxide and pH. The model suggests that primarily due to the high buffering capacity of blood, there is only marginally increased acidity in the preglomerular vasculature compared to systemic arterial blood caused by carbon dioxide shunting. Furthermore, effects of carbon dioxide transport do not promote but rather impair preglomerular oxygen shunting, as the increase in acidity is higher in the veins compared to that in the arteries. We conclude that while substantial arterial-to-venous oxygen shunting might take place in the postglomerular vasculature, the net amount of oxygen shunted at the preglomerular vasculature appears to be marginal.