Differential gene expression patterns in cyclooxygenase-1 and cyclooxygenase-2 deficient mouse brain

BACKGROUND: Cyclooxygenase (COX)-1 and COX-2 produce prostanoids from arachidonic acid and are thought to have important yet distinct roles in normal brain function. Deletion of COX-1 or COX-2 results in profound differences both in brain levels of prostaglandin E(2 )and in activation of the transcription factor nuclear factor-κB, suggesting that COX-1 and COX-2 play distinct roles in brain arachidonic acid metabolism and regulation of gene expression. To further elucidate the role of COX isoforms in the regulation of the brain transcriptome, microarray analysis of gene expression in the cerebral cortex and hippocampus of mice deficient in COX-1 (COX-1(-/-)) or COX-2 (COX-2(-/-)) was performed. RESULTS: A majority (>93%) of the differentially expressed genes in both the cortex and hippocampus were altered in one COX isoform knockout mouse but not the other. The major gene function affected in all genotype comparisons was 'transcriptional regulation'. Distinct biologic and metabolic pathways that were altered in COX(-/- )mice included β oxidation, methionine metabolism, janus kinase signaling, and GABAergic neurotransmission. CONCLUSION: Our findings suggest that COX-1 and COX-2 differentially modulate brain gene expression. Because certain anti-inflammatory and analgesic treatments are based on inhibition of COX activity, the specific alterations observed in this study further our understanding of the relationship of COX-1 and COX-2 with signaling pathways in brain and of the therapeutic and toxicologic consequences of COX inhibition

Aero-Heating of Shallow Cavities in Hypersonic Freestream Flow

The purpose of these experiments and analysis was to augment the heating database and tools used for assessment of impact-induced shallow-cavity damage to the thermal protection system of the Space Shuttle Orbiter. The effect of length and depth on the local heating disturbance of rectangular cavities tested at hypersonic freestream conditions has been globally assessed using the two-color phosphor thermography method. These rapid-response experiments were conducted in the Langley 31-Inch Mach 10 Tunnel and were initiated immediately prior to the launch of STS-114, the initial flight in the Space Shuttle Return-To-Flight Program, and continued during the first week of the mission. Previously-designed and numerically-characterized blunted-nose baseline flat plates were used as the test surfaces. Three-dimensional computational predictions of the entire model geometry were used as a check on the design process and the two-dimensional flow assumptions used for the data analysis. The experimental boundary layer state conditions were inferred using the measured heating distributions on a no-cavity test article. Two test plates were developed, each containing 4 equally-spaced spanwise-distributed cavities. The first test plate contained cavities with a constant length-to-depth ratio of 8 with design point depth-to-boundary-layer-thickness ratios of 0.1, 0.2, 0.35, and 0.5. The second test plate contained cavities with a constant design point depth-to-boundary-layer-thickness ratio of 0.35 with length-to-depth ratios of 8, 12, 16, and 20. Cavity design parameters and the test condition matrix were established using the computational predictions. Preliminary results indicate that the floor-averaged Bump Factor (local heating rate nondimensionalized by upstream reference) at the tested conditions is approximately 0.3 with a standard deviation of 0.04 for laminar-in/laminar-out conditions when the cavity length-to-boundary-layer thickness is between 2.5 and 10 and for cavities in the depth-to-boundary-layer-thickness range of 0.3 to 0.8. Over this same range of conditions and parameters, preliminary results also indicate that the maximum Bump Factor on the cavity centerline falls between 2.0 and 2.75, as long as the cavity-exit conditions remain laminar. Cavities with length-to-boundary-layer-thickness ratio less than 2.5 can not be easily classified with this approach and require further analysis

In Vivo Magnetic Resonance Spectroscopy of Hyperpolarized [1-

BACKGROUND: Alterations in glycolysis are central to the increasing incidence of non-alcoholic fatty liver disease (NAFLD), highlighting a need for in vivo, non-invasive technologies to understand the development of hepatic metabolic aberrations. PURPOSE: To use hyperpolarized magnetic resonance spectroscopy (MRS) and proton density fat fraction (PDFF) magnetic resonance imaging (MRI) techniques to investigate the effects of a chronic, life-long exposure to the Western diet (WD) in an animal model resulting in NAFLD; to investigate the hypothesis that exposure to the WD will result in NAFLD in association with altered pyruvate metabolism. STUDY TYPE: Prospective. ANIMAL MODEL: Twenty-eight male guinea pigs weaned onto a control diet (N = 14) or WD (N = 14). FIELD STRENGTH/SEQUENCE: 3 T; T1-weighted gradient echo, T2-weighted spin-echo, three-dimensional gradient multi-echo fat-water separation (IDEAL-IQ), and broadband point-resolved spectroscopy (PRESS) chemical-shift sequences. ASSESSMENT: Median PDFF was calculated in the liver and hind limbs. [1- STATISTICAL TESTS: Unpaired Student\u27s t-tests were used to determine differences in measurements between the two diet groups. The Pearson correlation coefficient was calculated to determine correlations between measurements. RESULTS: Life-long WD consumption resulted in significantly higher liver PDFF and elevated triglyceride content in the liver. The WD group exhibited a decreased TTP for lactate production, and ex vivo analysis highlighted increased liver lactate dehydrogenase (LDH) activity. DATA CONCLUSION: PDFF MRI results suggest differential fat deposition patterns occurring in animals fed a life-long WD characteristic of lean, or lacking excessive subcutaneous fat, NAFLD. The decreased liver lactate TTP and increased ex vivo LDH activity suggest lipid accumulation occurs in association with a shift from oxidative metabolism to anaerobic glycolytic metabolism in WD-exposed livers. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1

In Vivo Magnetic Resonance Spectroscopy of Hyperpolarized [1-\u3csup\u3e13\u3c/sup\u3eC]Pyruvate and Proton Density Fat Fraction in a Guinea Pig Model of Non-Alcoholic Fatty Liver Disease Development After Life-Long Western Diet Consumption

Background: Alterations in glycolysis are central to the increasing incidence of non-alcoholic fatty liver disease (NAFLD), highlighting a need for in vivo, non-invasive technologies to understand the development of hepatic metabolic aberrations. Purpose: To use hyperpolarized magnetic resonance spectroscopy (MRS) and proton density fat fraction (PDFF) magnetic resonance imaging (MRI) techniques to investigate the effects of a chronic, life-long exposure to the Western diet (WD) in an animal model resulting in NAFLD; to investigate the hypothesis that exposure to the WD will result in NAFLD in association with altered pyruvate metabolism. Study Type: Prospective. Animal Model: Twenty-eight male guinea pigs weaned onto a control diet (N = 14) or WD (N = 14). Field Strength/Sequence: 3 T; T1-weighted gradient echo, T2-weighted spin-echo, three-dimensional gradient multi-echo fat-water separation (IDEAL-IQ), and broadband point-resolved spectroscopy (PRESS) chemical-shift sequences. Assessment: Median PDFF was calculated in the liver and hind limbs. [1-13C]pyruvate dynamic MRS in the liver was quantified by the time-to-peak (TTP) for each metabolite. Animals were euthanized and tissue was analyzed for lipid and cholesterol concentration and enzyme level and activity. Statistical Tests: Unpaired Student\u27s t-tests were used to determine differences in measurements between the two diet groups. The Pearson correlation coefficient was calculated to determine correlations between measurements. Results: Life-long WD consumption resulted in significantly higher liver PDFF and elevated triglyceride content in the liver. The WD group exhibited a decreased TTP for lactate production, and ex vivo analysis highlighted increased liver lactate dehydrogenase (LDH) activity. Data Conclusion: PDFF MRI results suggest differential fat deposition patterns occurring in animals fed a life-long WD characteristic of lean, or lacking excessive subcutaneous fat, NAFLD. The decreased liver lactate TTP and increased ex vivo LDH activity suggest lipid accumulation occurs in association with a shift from oxidative metabolism to anaerobic glycolytic metabolism in WD-exposed livers. Level of Evidence: 2. Technical Efficacy Stage: 1

History and Evolution of the Minimally Invasive Transforaminal Lumbar Interbody Fusion

The minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) is a popular surgical technique for lumbar arthrodesis, widely considered to hold great efficacy while conferring an impressive safety profile through the minimization of soft tissue damage. This elegant approach to lumbar stabilization is the byproduct of several innovations throughout the past century. In 1934, Mixter and Barr’s paper in the New England Journal of Medicine elucidated the role of disc herniation in spinal instability and radiculopathy, prompting surgeons to explore new approaches and instruments to access the disc space. In 1944, Briggs and Milligan published their novel technique, the posterior lumbar interbody fusion (PLIF), involving continuous removal of vertebral bone chips and replacement of the disc with a round bone peg. The following decades witnessed several PLIF modifications, including the addition of long pedicle screws. In 1982, Harms and Rolinger sought to redefine the posterior corridor by approaching the disc space through the intervertebral foramen, establishing the transforaminal lumbar interbody fusion (TLIF). In the 1990s, lumbar spine surgery experienced a paradigm shift, with surgeons placing increased emphasis on tissue-sparing minimally invasive techniques. Spurred by this revolution, Foley and Lefkowitz published the novel MIS-TLIF technique in 2002. The MIS-TLIF has demonstrated comparable surgical outcomes to the TLIF, with an improved safety profile. Here, we present a view into the history of the posterior-approach treatment of the discogenic radiculopathy, culminating in the MIS-TLIF. Additionally, we evaluate the hallmark characteristics, technical variability, and reported outcomes of the modern MIS-TLIF and take a brief look at technologies that may define the future MIS-TLIF

Conserved and Differential Effects of Dietary Energy Intake on the Hippocampal Transcriptomes of Females and Males

The level of dietary energy intake influences metabolism, reproductive function, the development of age-related diseases, and even cognitive behavior. Because males and females typically play different roles in the acquisition and allocation of energy resources, we reasoned that dietary energy intake might differentially affect the brains of males and females at the molecular level. To test this hypothesis, we performed a gene array analysis of the hippocampus in male and female rats that had been maintained for 6 months on either ad libitum (control), 20% caloric restriction (CR), 40% CR, intermittent fasting (IF) or high fat/high glucose (HFG) diets. These diets resulted in expected changes in body weight, and circulating levels of glucose, insulin and leptin. However, the CR diets significantly increased the size of the hippocampus of females, but not males. Multiple genes were regulated coherently in response to energy restriction diets in females, but not in males. Functional physiological pathway analyses showed that the 20% CR diet down-regulated genes involved in glycolysis and mitochondrial ATP production in males, whereas these metabolic pathways were up-regulated in females. The 40% CR diet up-regulated genes involved in glycolysis, protein deacetylation, PGC-1α and mTor pathways in both sexes. IF down-regulated many genes in males including those involved in protein degradation and apoptosis, but up-regulated many genes in females including those involved in cellular energy metabolism, cell cycle regulation and protein deacetylation. Genes involved in energy metabolism, oxidative stress responses and cell death were affected by the HFG diet in both males and females. The gender-specific molecular genetic responses of hippocampal cells to variations in dietary energy intake identified in this study may mediate differential behavioral responses of males and females to differences in energy availability

Gene expression atlas of the mouse central nervous system: impact and interactions of age, energy intake and gender

The transcriptional profiles of five regions of the central nervous system (CNS) of mice varying in age, gender and dietary intake were measured by microarray. The resulting data provide insights into the mechanisms of age-, diet- and gender-related CNS plasticity and vulnerability in mammals

The Distance to NGC 1316 (Fornax A) From Observations of Four Type Ia Supernovae

The giant elliptical galaxy NGC 1316 (Fornax A) is a well-studied member of the Fornax Cluster and a prolific producer of Type Ia supernovae, having hosted four observed events since 1980. Here we present detailed optical and near-infrared light curves of the spectroscopically normal SN 2006dd. These data are used, along with previously published photometry of the normal SN 1980N and SN 1981D, and the fast-declining, low-luminosity SN 2006mr, to compute independent estimates of the host reddening for each supernova, and the distance to NGC 1316. From the three normal supernovae, we find a distance of 17.8 +/- 0.3 (random) +/- 0.3 (systematic) Mpc for Ho = 72. Distance moduli derived from the "EBV" and Tripp methods give values that are mutually consistent to 4 -- 8%. Moreover, the weighted means of the distance moduli for these three SNe for three methods agree to within 3%. This consistency is encouraging and supports the premise that Type Ia supernovae are reliable distance indicators at the 5% precision level or better. On the other hand, the two methods used to estimate the distance of the fast-declining SN 2006mr both yield a distance to NGC 1316 which is 25-30% larger. This disparity casts doubt on the suitability of fast-declining events for estimating extragalactic distances. Modest-to-negligible host galaxy reddening values are derived for all four supernovae. Nevertheless, two of them (SN 2006dd and SN 2006mr) show strong NaID interstellar lines in the host galaxy system. The strength of this absorption is completely inconsistent with the small reddening values derived from the supernova light curves if the gas in NGC 1316 is typical of that found in the interstellar medium of the Milky Way. In addition, the equivalent width of the NaID lines in SN 2006dd appear to have weakened significantly some 100-150 days after explosion.Comment: 50 pages, 13 figures, 10 tables; constructive comments welcome. Accepted for publication in A

Does Baseline Severity of Arm Pain Influence Outcomes Following Single-Level Anterior Cervical Discectomy and Fusion?

Study Design Retrospective cohort. Purpose To assess preoperative arm pain severity influence on postoperative patient-reported outcomes measures (PROMs) and minimal clinically important difference (MCID) achievement following single-level anterior cervical discectomy and fusion (ACDF). Overview of Literature There is evidence that preoperative symptom severity can affect postoperative outcomes. Few have evaluated this association between preoperative arm pain severity and postoperative PROMs and MCID achievement following ACDF. Methods Individuals undergoing single-level ACDF were identified. Patients were grouped by preoperative Visual Analog Scale (VAS) arm ≤8 vs. >8. PROMs collected preoperatively and postoperatively included VAS-arm/VAS-neck/Neck Disability Index (NDI)/12-item Short Form (SF-12) Physical Composite Score (PCS)/SF-12 mental composite score (MCS)/Patient-Reported Outcomes Measurement Information System physical function (PROMIS-PF). Demographics, PROMs, and MCID rates were compared between cohorts. Results A total of 128 patients were included. The VAS arm ≤8 cohort significantly improved for all PROMs excepting VAS arm at 1-year/2-years, SF-12 MCS at 12-weeks/1-year/2-years, and SF-12 PCS/PROMIS-PF at 6-weeks, only (p≤0.021, all). The VAS arm >8 cohort significantly improved for VAS neck at all timepoints, VAS arm from 6-weeks to 1-year, NDI from 6-weeks to 6-months, and SF-12 MCS/PROMIS-PF at 6-months (p≤0.038, all). Postoperatively, the VAS arm >8 cohort had higher VAS-neck (6 weeks/6 months), VAS-arm (12 weeks/6 months), NDI (6 weeks/6 months), lower SF-12 MCS (6 weeks/6 months), SF-12 PCS (6 months), and PROMIS-PF (12 weeks/6 months) (p≤0.038, all). MCID achievement rates were higher among the VAS arm >8 cohort for the VAS-arm at 6-weeks/12-weeks/1-year/overall and NDI at 2 years (p≤0.038, all). Conclusions Significance in PROM score differences between VAS arm ≤8 vs. >8 generally dissipated at the 1-year and 2-year time-point, although higher preoperative arm pain patients suffered from worse pain, disability, and mental/physical function scores. Furthermore, clinically meaningful rates of improvement were similar throughout the vast majority of timepoints for all PROMs studied

Do Patient Expectations Represent a More Important Clinical Difference? A Study of Surgical Outcomes in the Cervical Spine

Objective This study aims to compare the impact of achieving an MCID or meeting preoperative expectations on patient satisfaction following cervical spine procedures. Methods A surgical database was retrospectively reviewed for cervical spine surgery patients from 2016 to 2020. Inclusion criteria were primary or revision, single- or multilevel cervical disc arthroplasty or anterior cervical discectomy and fusions (ACDF). Visual analogue scale (VAS) neck and arm pain was assessed preoperatively and postoperatively (6-week, 12-weeks, 6-months, 1-year). Preoperative patient expectation and postoperative satisfaction were recorded. MCID achievement was determined using previously established values. Expectations met and MCID achievement were compared as possible predictors of satisfaction. Results One hundred and six cervical spine patients were included. Both meeting expectations and achieving MCID were significant predictors of satisfaction for arm pain at 6-weeks and 12-weeks (all p≤0.007). Achieving MCID significantly predicted satisfaction for neck pain at all timepoints (all p≤0.007) and meeting expectations predicted satisfaction for neck pain at 6-weeks, 12-weeks, and 1-year (all p≤0.003). Comparison of coefficients revealed no significant difference in effect size between meeting expectations and achievement of MCID as predictors of patient satisfaction (all p>0.050). Conclusion MCID achievement and meeting expectations were significant predictors of satisfaction for neck pain and short-term arm pain. Both measures may be similarly useful for interpretation of patient outcomes and the optimal choice of metric may depend on practice-specific factors