Characterizing the presentation, management, and clinical outcomes of patients with intradural spinal chordomas: a systematic review.

OBJECTIVE: Chordomas are locally aggressive neoplasms of the spine or skull base that arise from embryonic remnants of the notochord. Intradural chordomas represent a rare subset of these neoplasms, and few studies have described intradural chordomas in the spine. This review evaluates the presentation, management, and outcomes of intradural spinal chordomas. METHODS: A systematic review of PubMed/MEDLINE, EMBASE, Cochrane Library, Scopus, and Web of Science was performed. Studies describing at least 1 case of intradural chordomas anywhere in the spine were included. Extracted details included presenting symptoms, radiological findings, treatment course, follow-up, and disease progression. RESULTS: Thirty-one studies, with a total of 41 patients, were included in this review. Seventy-six percent (31/41) of patients had primary intradural tumors, whereas 24% (10/41) presented with metastasis. The most common signs and symptoms were pain (n = 27, 66%); motor deficits (n = 20, 49%); sensory deficits (n = 17, 42%); and gait disturbance (n = 10, 24%). The most common treatment for intradural chordoma was resection and postoperative radiotherapy. Sixty-six percent (19/29) of patients reported improvement or complete resolution of symptoms after surgery. The recurrence rate was 37% (10/27), and the complication rate was 25% (6/24). The median progression-free survival was 24 months (range 4-72 months). Four patient deaths were reported. The median follow-up time was 12 months (range 13 days-84 months). CONCLUSIONS: Treatment of intradural spinal chordomas primarily involves resection and radiotherapy. A significant challenge and complication in management is spinal tumor seeding after resection, with 9 studies proposing seeding as a mechanism of tumor metastasis in 11 cases. Factors such as tumor size, Ki-67 positivity, and distant metastasis may correlate with worse outcomes and demonstrate potential as prognostic indicators for intradural spinal chordomas. Further research is needed to improve understanding of this tumor and develop optimal treatment paradigms for these patients.

Predicting 30-day mortality after surgery for metastatic disease of the spine: the H2-FAILS score.

PURPOSE: Scoring systems for metastatic spine disease focus on predicting long- to medium-term mortality or a combination of perioperative morbidity and mortality. However, accurate prediction of perioperative mortality alone may be the most important factor when considering surgical intervention. We aimed to develop and evaluate a new tool, the H2-FAILS score, to predict 30-day mortality after surgery for metastatic spine disease. METHODS: Using the National Surgical Quality Improvement Program database, we identified 1195 adults who underwent surgery for metastatic spine disease from 2010 to 2018. Incidence of 30-day mortality was 8.7% (n = 104). Independent predictors of 30-day mortality were used to derive the H2-FAILS score. H2-FAILS is an acronym for: Heart failure (2 points), Functional dependence, Albumin deficiency, International normalized ratio elevation, Leukocytosis, and Smoking (1 point each). Discrimination was assessed using area under the receiver operating characteristic curve (AUC). The H2-FAILS score was compared with the American Society of Anesthesiologists Physical Status Classification (ASA Class), the 5-item modified Frailty Index (mFI-5), and the New England Spinal Metastasis Score (NESMS). Internal validation was performed using bootstrapping. Alpha = 0.05. RESULTS: Predicted 30-day mortality was 1.8% for an H2-FAILS score of 0 and 78% for a score of 6. AUC of the H2-FAILS was 0.77 (95% confidence interval: 0.72-0.81), which was higher than the mFI-5 (AUC 0.58, p < 0.001), ASA Class (AUC 0.63, p < 0.001), and NESMS (AUC 0.70, p = 0.004). Internal validation showed an optimism-corrected AUC of 0.76. CONCLUSIONS: The H2-FAILS score accurately predicts 30-day mortality after surgery for spinal metastasis. LEVEL OF EVIDENCE: Prognostic level III.

Poor sleep accelerates hippocampal and posterior cingulate volume loss in cognitively normal healthy older adults.

Poor sleep quality is a known risk factor for Alzheimer's disease. This longitudinal imaging study aimed to determine the acceleration in the rates of tissue loss in cognitively critical brain regions due to poor sleep in healthy elderly individuals. Cognitively-normal healthy individuals, aged ≥60 years, reported Pittsburgh Sleep Quality Index (PSQI) and underwent baseline and 2-year follow-up magnetic resonance imaging brain scans. The links between self-reported sleep quality, rates of tissue loss in cognitively-critical brain regions, and white matter hyperintensity load were assessed. A total of 48 subjects were classified into normal (n = 23; PSQI score <5) and poor sleepers (n = 25; PSQI score ≥5). The two groups were not significantly different in terms of age, gender, years of education, ethnicity, handedness, body mass index, and cognitive performance. Compared to normal sleepers, poor sleepers exhibited much faster rates of volume loss, over threefold in the right hippocampus and fivefold in the right posterior cingulate over 2 years. In contrast, there were no significant differences in the rates of volume loss in the cerebral and cerebellar grey and white matter between the two groups. Rates of volume loss in the right posterior cingulate were negatively associated with global PSQI scores. Poor sleep significantly accelerates volume loss in the right hippocampus and the right posterior cingulate cortex. These findings demonstrate that self-reported sleep quality explains inter-individual differences in the rates of volume loss in cognitively-critical brain regions in healthy older adults and provide a strong impetus to offer sleep interventions to cognitively normal older adults who are poor sleepers.

Structural Basal Ganglia Correlates of Subjective Fatigue in Middle-Aged and Older Adults.

OBJECTIVE: Fatigue is among the most common complaints in community-dwelling older adults, yet its etiology is poorly understood. Based on models implicating frontostriatal pathways in fatigue pathogenesis, we hypothesized that smaller basal ganglia volume would be associated with higher levels of subjective fatigue and reduced set-shifting in middle-aged and older adults without dementia or other neurologic conditions. METHODS: Forty-eight non-demented middle-aged and older adults (Mage = 68.1, SD = 9.4; MMMSE = 27.3, SD = 1.9) completed the Fatigue Symptom Inventory, set-shifting measures, and structural MRI as part of a clinical evaluation for subjective cognitive complaints. Associations were examined cross-sectionally. RESULTS: Linear regression analyses showed that smaller normalized basal ganglia volumes were associated with more severe fatigue (ß = -.29, P = .041) and poorer Trail Making Test B-A (TMT B-A) performance (ß = .30, P = .033) controlling for depression, sleep quality, vascular risk factors, and global cognitive status. Putamen emerged as a key structure linked with both fatigue (r = -.43, P = .003) and TMT B-A (ß = .35, P = .021). The link between total basal ganglia volume and reduced TMT B-A was particularly strong in clinically fatigued patients. CONCLUSION: This study is among the first to show that reduced basal ganglia volume is an important neurostructural correlate of subjective fatigue in physically able middle-aged and older adults without neurological conditions. Findings suggest that fatigue and rapid set-shifting deficits may share common neural underpinnings involving the basal ganglia, and provide a framework for studying the neuropathogenesis and treatment of subjective fatigue.

Innovative Biofouling Control for Membrane Bioreactors in Cold Regions by Inducing Environmental Adaptation in Quorum-Quenching Bacteria.

Bacterial quorum quenching (QQ), whose mechanism involves the degradation of quorum-sensing signal molecules, is an effective strategy for controlling biofouling in membrane bioreactors (MBRs). However, MBRs operated at low temperatures, either due to cold climates or seasonal variations, exhibit severe deterioration in QQ efficiency. In this study, a modified culture method for Rhodococcus sp. BH4, a QQ bacterium, was developed to induce environmental adaptation in cold regions. BH4-L, which was prepared by the modified culture method, showed enhancement in QQ efficiency at low temperatures. The higher QQ efficiency obtained by employing BH4-L at 10 °C (compared with that obtained by employing BH4 at 10 °C) was attributed to the higher live/dead cell ratio in the BH4-L-entrapping beads. When BH4-L-entrapping beads were applied to lab-scale MBRs operated at low temperatures, membrane biofouling in MBRs at low temperatures was successfully mitigated because BH4-L could substantially reduce the concentration of signal molecules (N-acyl homoserine lactones) in the biocake. Employing BH4-L in QQ-MBRs could offer a novel solution to the problem of severe membrane biofouling in MBRs in cold regions.

Role of the spinal canal compliance in regulating posture-related cerebrospinal fluid hydrodynamics in humans.

Mechanical compliance of a compartment is defined by the change in its volume with respect to a change in the inside pressure. The compliance of the spinal canal regulates the intracranial pressure (ICP) under postural changes. Understanding how gravity affects ICP is beneficial for poorly understood cerebrospinal fluid (CSF)-related disorders. The aim of this study was to evaluate postural effects on cranial hemo- and hydrodynamics. This was a prospective study, which included 10 healthy volunteers (three males, seven females, mean ± standard deviation age: 29 ± 7 years). Cine gradient-echo phase-contrast sequence acquired at 0.5 T, "GE double-doughnut" scanner was used. Spinal contribution to overall craniospinal compliance (CSC), craniospinal CSF stroke volume (SV), magnetic resonance (MR)-derived ICP (MR-ICP), and total cerebral blood flow (TCBF) were measured in supine and upright postures using automated blood and CSF flows quantification. Statistical tests performed were two-sided Student's t-test, Cohen's d, and Pearson correlation coefficient. MR-ICP and the craniospinal CSF SV were significantly correlated with the spinal contribution to the overall CSC (r = 0.83, p < 0.05) and (r = 0.62, p < 0.05), respectively. Cranial contribution to CSC increased from 44.5% ± 16% in supine to 74.9% ± 8.4% in upright posture. The average MR-ICP dropped from 9.9 ± 3.4 mmHg in supine to -3.5 ± 1.5 mmHg. The CSF SV was over 2.5 times higher in the supine position (0.55 ± 0.14 ml) than in the upright position (0.21 ± 0.13 ml). In contrast, TCBF was slightly higher in the supine posture (822 ± 152 ml/min) than in the upright posture (761 ± 139 ml/min), although not statistically significant (p = 0.16). The spinal-canal compliance contribution to CSC is larger than the cranial contribution in the supine posture and smaller in the upright posture. Thereby, the spinal canal plays a role in modulating ICP upon postural changes. The lower pressure craniospinal CSF system was more affected by postural changes than the higher-pressure cerebral vascular system. Craniospinal hydrodynamics is affected by gravity and is likely to be altered by its absence in space. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 2.

Poor sleep is associated with small hippocampal subfields in cognitively normal elderly individuals.

Recent studies demonstrated reduced hippocampal volumes in elderly healthy individuals who are cognitively normal but poor sleepers. The association between sleep quality and the pattern of volume loss across hippocampal subfields (HSs) is not well known. Thus, it is the focus of the present study. Sleep quality was self-assessed using the Pittsburgh Sleep Quality Index (PSQI). The HS volumes were measured using sub-millimetre in-plane resolution T2-weighted magnetic resonance imaging data. A total of 67 cognitively normal elderly individuals aged 60-83 years were classified into 30 normal sleepers with a PSQI <5 and 37 poor sleepers with a PSQI ≥5. The two groups were equivalent in age, gender distribution, ethnicity, education attainment, handedness and cognitive performance. Compared to normal sleepers, poor sleepers exhibited significantly lower normalised volumes in the left cornu ammonis field 1 (CA1), dentate gyrus (DG) and subiculum. In contrast, there were no significant differences in normalised grey and white matter volumes between the two groups. The global PSQI was negatively associated with the normalised volumes of the left CA1, DG and subiculum. Sleep duration was associated with the normalised volumes of the bilateral CA1, DG, left CA2 and subiculum. Verbal memory scores were associated with the left CA1 volume. In conclusion, poor sleep quality, especially insufficient sleep duration, was associated with volume loss in several HSs that are involved in specific learning and memory tasks. As the hippocampus does not regulate sleep, it is more likely that poor sleep leads to small hippocampi. Thus, based on this assumption, improving sleep quality of poor sleeper elderly individuals could benefit hippocampal health.

Targeted knockout of a chemokine-like gene increases anxiety and fear responses.

Emotional responses, such as fear and anxiety, are fundamentally important behavioral phenomena with strong fitness components in most animal species. Anxiety-related disorders continue to represent a major unmet medical need in our society, mostly because we still do not fully understand the mechanisms of these diseases. Animal models may speed up discovery of these mechanisms. The zebrafish is a highly promising model organism in this field. Here, we report the identification of a chemokine-like gene family, samdori (sam), and present functional characterization of one of its members, sam2 We show exclusive mRNA expression of sam2 in the CNS, predominantly in the dorsal habenula, telencephalon, and hypothalamus. We found knockout (KO) zebrafish to exhibit altered anxiety-related responses in the tank, scototaxis and shoaling assays, and increased crh mRNA expression in their hypothalamus compared with wild-type fish. To investigate generalizability of our findings to mammals, we developed a Sam2 KO mouse and compared it to wild-type littermates. Consistent with zebrafish findings, homozygous KO mice exhibited signs of elevated anxiety. We also found bath application of purified SAM2 protein to increase inhibitory postsynaptic transmission onto CRH neurons of the paraventricular nucleus. Finally, we identified a human homolog of SAM2, and were able to refine a candidate gene region encompassing SAM2, among 21 annotated genes, which is associated with intellectual disability and autism spectrum disorder in the 12q14.1 deletion syndrome. Taken together, these results suggest a crucial and evolutionarily conserved role of sam2 in regulating mechanisms associated with anxiety.

Diastolic Blood Pressure Is Associated With Regional White Matter Lesion Load: The Northern Manhattan Study.

Background and Purpose- Few studies have examined the separate contributions of systolic blood pressure and diastolic blood pressures (DBP) on subclinical cerebrovascular disease, especially using the 2017 American College of Cardiology/American Heart Association Blood Pressure Guidelines. Furthermore, associations with region-specific white matter hyperintensity volume (WMHV) are underexplored. Methods- Using data from the NOMAS (Northern Manhattan Study), a prospective cohort study of stroke risk and cognitive aging, we examined associations between systolic blood pressure and DBP, defined by the 2017 American College of Cardiology/American Heart Association guidelines, with regional WMHV. We used a linear mixed model approach to account for the correlated nature of regional brain measures. Results- The analytic sample (N=1205; mean age 64±8 years) consisted of 61% women and 66% Hispanics/Latinos. DBP levels were significantly related to WMHV differentially across regions (P for interaction<0.05). Relative to those with DBP 90+ mm Hg, participants with DBP <80 mm Hg had 13% lower WMHV in the frontal lobe (95% CI, -21% to -3%), 11% lower WMHV in the parietal lobe (95% CI, -19% to -1%), 22% lower WMHV in the anterior periventricular region (95% CI, -30% to -14%), and 16% lower WMHV in the posterior periventricular region (95% CI, -24% to -6%). Participants with DBP 80 to 89 mm Hg also exhibited about 12% (95% CI, -20% to -3%) lower WMHV in the anterior periventricular region and 9% (95% CI, -18% to -0.4%) lower WMHV in the posterior periventricular region, relative to participants with DBP 90≥ mm Hg. Post hoc pairwise t tests showed that estimates for periventricular WMHV were significantly different from estimates for temporal WMHV (Holms stepdown-adjusted P<0.05). Systolic blood pressure was not strongly related to regional WMHV. Conclusions- Lower DBP levels, defined by the 2017 American College of Cardiology/American Heart Association guidelines, were related to lower white matter lesion load, especially in the periventricular regions relative to the temporal region.

Three-Dimensional Vortex-Induced Reaction Hot Spots at Flow Intersections.

We show the emergence of reaction hot spots induced by three-dimensional (3D) vortices with a simple A+B→C reaction. We conduct microfluidics experiments to visualize the spatial map of the reaction rate with a chemiluminescence reaction and cross validate the results with direct numerical simulations. 3D vortices form at spiral-saddle-type stagnation points, and the 3D vortex flow topology is essential for initiating reaction hot spots. The effect of vortices on mixing and reaction becomes more vigorous for rough-walled channels, and our findings are valid over wide ranges of channel dimensions and Damköhler numbers.

Genome-wide association study identifies new susceptibility loci for diabetic nephropathy in Korean patients with type 2 diabetes mellitus.

Genetic factors are considered to be important in the pathogenesis of diabetic nephropathy (DN). Despite several genome-wide association studies (GWASs) demonstrating that specific polymorphisms of candidate genes were associated with DN, there were some limitations in previous studies. We conducted a GWAS using customized DNA chips to identify novel susceptibility loci for DN in Korean. We analyzed a total of 414 DN cases and 474 normoalbuminuric diabetic hyper-controls across two stages using customized DNA chips containing 98 667 single nucleotide polymorphisms (SNPs). We explored the associations between SNPs and DN in samples from 87 DN cases, mostly confirmed by renal biopsy, and 104 diabetic hyper-controls, and replicated these associations in independent cohort samples with 327 DN cases and 370 diabetic hyper-controls. The top significant SNPs from the discovery samples were selected for replication in the independent cohort. rs3765156 in PIK3C2B was significantly associated with DN in the replication cohort after multiple test. The SNPs identified in our study provide new insights into the pathogenesis of DN in the Korean population. Additional studies are needed to determine biological effects and clinical utility of our findings.

Comparing invasive with MRI-derived intracranial pressure measurements in healthy elderly and brain trauma cases: A pilot study.

BACKGROUND: Intracranial pressure (ICP) is an important physiological parameter in several neurological disorders. Considerable effort has been made to measure ICP noninvasively. MR-based ICP (MR-ICP) is a nonempirical method based on principles of cerebrospinal fluid (CSF) physiology, where ICP is obtained from measurements of blood and CSF flows to and from the cranium during the cardiac cycle. PURPOSE: To compare MR-ICP with invasive ICP measurements obtained using lumbar puncture (LP) or external ventricular drainage (EVD). STUDY TYPE: Prospective, cross-sectional, observational study. SUBJECTS: Ten cognitively healthy elderly subjects (age 69.6 ± 6.6 years; seven females) and six brain trauma patients (age 36.8 ± 19.7 years; two females). FIELD STRENGTH: Velocity encoding cine phase-contrast at 1.5 T and 3 T. ASSESSMENT: MR-ICP and craniospinal compliance distribution were estimated from arterial inflow and venous outflow to and from cranium, and craniospinal CSF flow at the upper cervical region, measured using cine phase contrast MRI. LP (done 177 ± 163 days after scan) and EVD measurements (at the time of scan) were performed in lateral recumbent and supine positions, respectively. STATISTICAL TESTS: Linear regression was used to assess the relationships of MR-ICP with invasive ICP, and the dependency of these measurements on age, weight, height, and BMI. A Shapiro-Wilks test and Bland-Altman plot were respectively used to evaluate the normality and agreement between these two pressure distributions. Student's t-test was used throughout the analysis to compare differences between the EVD and LP cohorts. RESULTS: In the combined cohort, MR-ICP and invasive ICP were positively correlated (r = 0.95, P < 0.001), with invasive ICP being higher than MR-ICP by 2.2 mmHg on average. In the healthy cohort, the cranial contribution to total craniospinal compliance was negatively correlated with MR-ICP (r = -0.90, P < 0.001). DATA CONCLUSION: MR-ICP provides a reliable estimate of ICP, with 14 out of 16 datapoints within the clinically acceptable error. Craniospinal compliance distribution plays a role in modulating ICP in supine position. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:975-981.

S-SCAM, a rare copy number variation gene, induces schizophrenia-related endophenotypes in transgenic mouse model.

Accumulating genetic evidence suggests that schizophrenia (SZ) is associated with individually rare copy number variations (CNVs) of diverse genes, often specific to single cases. However, the causality of these rare mutations remains unknown. One of the rare CNVs found in SZ cohorts is the duplication of Synaptic Scaffolding Molecule (S-SCAM, also called MAGI-2), which encodes a postsynaptic scaffolding protein controlling synaptic AMPA receptor levels, and thus the strength of excitatory synaptic transmission. Here we report that, in a transgenic mouse model simulating the duplication conditions, elevation of S-SCAM levels in excitatory neurons of the forebrain was sufficient to induce multiple SZ-related endophenotypes. S-SCAM transgenic mice showed an increased number of lateral ventricles and a reduced number of parvalbumin-stained neurons. In addition, the mice exhibited SZ-like behavioral abnormalities, including hyperlocomotor activity, deficits in prepulse inhibition, increased anxiety, impaired social interaction, and working memory deficit. Notably, the S-SCAM transgenic mice showed a unique sex difference in showing these behavioral symptoms, which is reminiscent of human conditions. These behavioral abnormalities were accompanied by hyperglutamatergic function associated with increased synaptic AMPA receptor levels and impaired long-term potentiation. Importantly, reducing glutamate release by the group 2 metabotropic glutamate receptor agonist LY379268 ameliorated the working memory deficits in the transgenic mice, suggesting that hyperglutamatergic function underlies the cognitive functional deficits. Together, these results contribute to validate a causal relationship of the rare S-SCAM CNV and provide supporting evidence for the rare CNV hypothesis in SZ pathogenesis. Furthermore, the S-SCAM transgenic mice provide a valuable new animal model for studying SZ pathogenesis.

Notch1 signaling contributes to stemness in head and neck squamous cell carcinoma.

Notch1 is associated with the initiation and progression of various solid tumors. However, the exact role of Notch1 expression in head and neck squamous cell carcinoma (HNSCC) remain unclear. We created cells ectopically expressing notch intracellular domain (NICD) from previously established HNSCC cells and examined self-renewal capacity and stem cell markers' expression compared with control cells. In addition, we knocked Notch1 down in primary spheres obtained from HNSCC tumor tissue and assessed the attenuation of stemness-associated traits in these cells in vitro and in vivo. Furthermore, we examined clinical relevance of Notch1 expression in HNSCC patients. Constitutive activation of NICD promoted the self-renewal capacity of HNSCC cells by activating sphere formation and increased the expression of stem cell markers such as Oct4, Sox2, and CD44. In contrast, Notch1 knockdown in primary HNSCC cancer stem cells (CSCs) attenuated CSC traits and augmented the chemosensitizing effects of cisplatin along with the decreased expression of almost all of ABC transporter genes. In addition, Notch1 knockdown in HNSCC CSCs inhibited tumor formation and increased survival of mice in a xenograft model. Also, Notch1 acted upstream of canonical Wnt signaling in HNSCC cells. Finally, elevated Notch1 expression is associated with poor prognosis in patients with HNSCC. In conclusion, Notch1 may be a critical regulator of stemness in HNSCC cells, and inactivation of this pathway could be a potential targeted approach for the treatment of HNSCC.

More Efficient Media Design for Enhanced Biofouling Control in a Membrane Bioreactor: Quorum Quenching Bacteria Entrapping Hollow Cylinder.

Recently, membrane bioreactors (MBRs) with quorum quenching (QQ) bacteria entrapping beads have been reported as a new paradigm in biofouling control because, unlike conventional post-biofilm control methods, bacterial QQ can inhibit biofilm formation through its combined effects of physical scouring of the membrane and inhibition of quorum sensing (QS). In this study, using a special reporter strain (Escherichia coli JB525), the interaction between QS signal molecules and quorum quenching bacteria entrapping beads (QQ-beads) was elucidated through visualization of the QS signal molecules within a QQ-bead using a fluorescence microscope. As a result, under the conditions considered in this study, the surface area of QQ-media was likely to be a dominant parameter in enhancing QQ activity over total mass of entrapped QQ bacteria because QQ bacteria located near the core of a QQ-bead were unable to display their QQ activities. On the basis of this information, a more efficient QQ-medium, a QQ hollow cylinder (QQ-HC), was designed and prepared. In batch experiments, QQ-HCs showed greater QQ activity than QQ-beads as a result of their higher surface area and enhanced physical washing effect because of their larger impact area against the membrane surface. Furthermore, it was shown that such advantages of QQ-HCs resulted in more effective mitigation of membrane fouling than from QQ-beads in lab-scale continuous MBRs.

Normobaric hypoxia and symptoms of acute mountain sickness: Elevated brain volume and intracranial hypertension.

OBJECTIVE: The study was undertaken to determine whether normobaric hypoxia causes elevated brain volume and intracranial pressure in individuals with symptoms consistent with acute mountain sickness (AMS). METHODS: Thirteen males age = (26 (sd 6)) years were exposed to normobaric hypoxia (12% O2 ) and normoxia (21% O2 ). After 2 and 10 hours, AMS symptoms were assessed alongside ventricular and venous vessel volumes, cerebral blood flow, regional brain volumes, and intracranial pressure, using high-resolution magnetic resonance imaging. RESULTS: In normoxia, neither lateral ventricular volume (R(2) = 0.07, p = 0.40) nor predominance of unilateral transverse venous sinus drainage (R(2) = 0.07, p = 0.45) was related to AMS symptoms. Furthermore, despite an increase in cerebral blood flow after 2 hours of hypoxia (hypoxia vs normoxia: Δ148ml/min(-1) , 95% confidence interval [CI] = 58 to 238), by 10 hours, when AMS symptoms had developed, cerebral blood flow was normal (Δ-51ml/min(-1) , 95% CI = -141 to 39). Conversely, at 10 hours brain volume was increased (Δ59ml, 95% CI = 8 to 110), predominantly due to an increase in gray matter volume (Δ73ml, 95% CI = 25 to 120). Therefore, cerebral spinal fluid volume was decreased (Δ-40ml, 95% CI = -67 to -14). The intracranial pressure response to hypoxia varied between individuals, and as hypothesized, the most AMS-symptomatic participants had the largest increases in intracranial pressure (AMS present, Δ7mmHg, 95% CI = -2.5 to 17.3; AMS not present, Δ-1mmHg, 95% CI = -3.3 to 0.5). Consequently, there was a significant relationship between the change in intracranial pressure and AMS symptom severity (R(2) = 0.71, p = 0.002). INTERPRETATION: The data provide the strongest evidence to date to support the hypothesis that the "random" nature of AMS symptomology is explained by a variable intracranial pressure response to hypoxia.

MRI measurements of intracranial pressure in the upright posture: The effect of the hydrostatic pressure gradient.

PURPOSE: To add the hydrostatic component of the cerebrospinal fluid (CSF) pressure to magnetic resonance imaging (MRI)-derived intracranial pressure (ICP) measurements in the upright posture for derivation of pressure value in a central cranial location often used in invasive ICP measurements. MATERIALS AND METHODS: Additional analyses were performed using data previously collected from 10 healthy subjects scanned in supine and sitting positions with a 0.5T vertical gap MRI scanner (GE Medical). Pulsatile blood and CSF flows to and from the brain were quantified using cine phase-contrast. Intracranial compliance and pressure were calculated using a previously described method. The vertical distance between the location of the CSF flow measurement and a central cranial location was measured manually in the mid-sagittal T1 -weighted image obtained in the upright posture. The hydrostatic pressure gradient of a CSF column with similar height was then added to the MR-ICP value. RESULTS: After adjustment for the hydrostatic component, the mean ICP value was reduced by 7.6 mmHg. Mean ICP referenced to the central cranial level was -3.4 ± 1.7 mmHg compared to the unadjusted value of +4.3 ± 1.8 mmHg. CONCLUSION: In the upright posture, the hydrostatic pressure component needs to be added to the MRI-derived ICP values for compatibility with invasive ICP at a central cranial location.

Oncologic and Functional Outcomes After Stereotactic Body Radiation Therapy for High-Grade Malignant Spinal Cord Compression.

Purpose: Although surgical decompression is the gold standard for metastatic epidural spinal cord compression (MESCC) from solid tumors, not all patients are candidates or undergo successful surgical Bilsky downgrading. We report oncologic and functional outcomes for patients treated with stereotactic body radiation therapy (SBRT) to high-grade MESCC. Methods and Materials: Patients with Bilsky grade 2 to 3 MESCC from solid tumor metastases treated with SBRT at a single institution from 2009 to 2020 were retrospectively reviewed. Patients who received upfront surgery before SBRT were included only if postsurgical Bilsky grade remained ≥2. Neurologic examinations, magnetic resonance imaging, pain assessments, and analgesic usage were assessed every 3 to 4 months post-SBRT. Cumulative incidence of local recurrence was calculated with death as a competing risk, and overall survival was estimated by Kaplan-Meier. Results: One hundred forty-three patients were included. The cumulative incidence of local recurrence was 5.1%, 7.5%, and 14.1% at 6, 12, and 24 months, respectively. At first post-SBRT imaging, 16.2% of patients with initial Bilsky grade 2 improved to grade 1, and 53.8% of patients were stable. Five of 13 patients (38.4%) with initial Bilsky grade 3 improved to grade 1 to 2. Pain response at 3 and 6 months post-SBRT was complete in 45.4% and 55.7%, partial in 26.9% and 13.1%, stable in 24.1% and 27.9%, and worse in 3.7% and 3.3% of patients, respectively. At 3 and 6 months after SBRT, 17.8% and 25.0% of patients had improved ambulatory status and 79.7% and 72.4% had stable status. Conclusions: We report the largest series to date of patients with high-grade MESCC treated with SBRT. The excellent local control and functional outcomes suggest SBRT is a reasonable approach in inoperable patients or cases unable to be successfully surgically downgraded.

S-SCAM/MAGI-2 is an essential synaptic scaffolding molecule for the GluA2-containing maintenance pool of AMPA receptors.

Synaptic plasticity, the cellular basis of learning and memory, involves the dynamic trafficking of AMPA receptors (AMPARs) into and out of synapses. One of the remaining key unanswered aspects of AMPAR trafficking is the mechanism by which synaptic strength is preserved despite protein turnover. In particular, the identity of AMPAR scaffolding molecule(s) involved in the maintenance of GluA2-containing AMPARs is completely unknown. Here we report that the synaptic scaffolding molecule (S-SCAM; also called membrane-associated guanylate kinase inverted-2 and atrophin interacting protein-1) plays the critical role of maintaining synaptic strength. Increasing S-SCAM levels in rat hippocampal neurons led to specific increases in the surface AMPAR levels, enhanced AMPAR-mediated synaptic transmission, and enlargement of dendritic spines, without significantly effecting GluN levels or NMDA receptor (NMDAR) EPSC. Conversely, decreasing S-SCAM levels by RNA interference-mediated knockdown caused the loss of synaptic AMPARs, which was followed by a severe reduction in the dendritic spine density. Importantly, S-SCAM regulated synaptic AMPAR levels in a manner, dependent on GluA2 not GluA1, sensitive to N-ethylmaleimide-sensitive fusion protein interaction, and independent of activity. Further, S-SCAM increased surface AMPAR levels in the absence of PSD-95, while PSD-95 was dependent on S-SCAM to increase surface AMPAR levels. Finally, S-SCAM overexpression hampered NMDA-induced internalization of AMPARs and prevented the induction of long term-depression, while S-SCAM knockdown did not. Together, these results suggest that S-SCAM is an essential AMPAR scaffolding molecule for the GluA2-containing pool of AMPARs, which are involved in the constitutive pathway of maintaining synaptic strength.

The SAUR19 subfamily of SMALL AUXIN UP RNA genes promote cell expansion.

The plant hormone auxin controls numerous aspects of plant growth and development by regulating the expression of hundreds of genes. SMALL AUXIN UP RNA (SAUR) genes comprise the largest family of auxin-responsive genes, but their function is unknown. Although prior studies have correlated the expression of some SAUR genes with auxin-mediated cell expansion, genetic evidence implicating SAURs in cell expansion has not been reported. The Arabidopsis SAUR19, SAUR20, SAUR21, SAUR22, SAUR23, and SAUR24 (SAUR19-24) genes encode a subgroup of closely related SAUR proteins. We demonstrate that these SAUR proteins are highly unstable in Arabidopsis. However, the addition of an N-terminal GFP or epitope tag dramatically increases the stability of SAUR proteins. Expression of these stabilized SAUR fusion proteins in Arabidopsis confers numerous auxin-related phenotypes indicative of increased and/or unregulated cell expansion, including increased hypocotyl and leaf size, defective apical hook maintenance, and altered tropic responses. Furthermore, seedlings expressing an artificial microRNA targeting multiple members of the SAUR19-24 subfamily exhibit short hypocotyls and reduced leaf size. Together, these findings demonstrate that SAUR19-24 function as positive effectors of cell expansion. This regulation may be achieved through the modulation of auxin transport, as SAUR gain-of-function and loss-of-function seedlings exhibit increased and reduced basipetal indole-3-acetic acid transport, respectively. Consistent with this possibility, SAUR19-24 proteins predominantly localize to the plasma membrane.