Elevated levels of tripeptidyl peptidase 1 do not ameliorate pathogenesis in a mouse model of Alzheimer disease.

One potential therapeutic strategy for Alzheimer disease (AD) is to promote degradation of amyloid beta (Aß) and we previously demonstrated that the lysosomal protease tripeptidyl peptidase 1 (TPP1) can degrade Aß fibrils in vitro. In this study, we tested the hypothesis that increasing levels of TPP1 might promote degradation of Aß under physiological conditions, slowing or preventing its accumulation in the brain with subsequent therapeutic benefits. We used 2 approaches to increase TPP1 activity in the brain of J20 mice, an AD model that accumulates Aß and exhibits cognitive defects: transgenic overexpression of TPP1 in the brain and a pharmacological approach employing administration of recombinant TPP1. While we clearly observed the expected AD phenotype of the J20 mice based on pathology and measurement of behavioral and cognitive defects, we found that elevation of TPP1 activity by either experimental approach failed to have any measurable beneficial effect on disease phenotype.

Opioid Knowledge and Prescribing Preferences of Orthopaedic Surgery Residents Before and After an Educational Intervention.

Orthopaedic surgeons are among the highest prescribers of opioids. This study explores the effect of an educational intervention on orthopaedic surgery residents' opioid knowledge and prescribing practices. Orthopaedic residents were surveyed at three urban academic institutions. A pre-survey was administered to residents prior to an educational lecture and case-based session. This included background on the opioid epidemic, multimodal analgesia, opioid consumption in common orthopaedic procedures, and state laws regulating prescribing. Following this intervention, residents were given a post-survey to complete. There was a significant increase in resident confidence concerning their opioid prescribing training (p = 0.03) and their knowledge of alternative pain management therapies (p = 0.03). This was accompanied by an objective improvement in knowledge of state prescribing laws and of metrics regarding the opioid epidemic. Hypothetical opioid pills prescribed after common orthopaedic procedures decreased between the pre- and post-tests. The educational session significantly improved orthopaedic surgery residents' knowledge about opioids and prescribing habits. Formal resident education on opioid knowledge and evidence-based prescribing strategies is an area of potential improvement to combat the opioid crisis. (Journal of Surgical Orthopaedic Advances 31(1):030-033, 2022).

Inhibition of Histone Deacetylases 1, 2, and 3 Enhances Clearance of Cholesterol Accumulation in Niemann-Pick C1 Fibroblasts.

Niemann-Pick disease type C1 (NPC1) is a rare genetic cholesterol storage disorder caused by mutations in the NPC1 gene. Mutations in this transmembrane late endosome protein lead to loss of normal cholesterol efflux from late endosomes and lysosomes. It has been shown that broad spectrum histone deacetylase inhibitors (HDACi's) such as Vorinostat correct the cholesterol accumulation phenotype in the majority of NPC1 mutants tested in cultured cells. In order to determine the optimal specificity for HDACi correction of the mutant NPC1s, we screened 76 HDACi's of varying specificity. We tested the ability of these HDACi's to correct the excess accumulation of cholesterol in patient fibroblast cells that homozygously express NPC1 I1061T , the most common mutation. We determined that inhibition of HDACs 1, 2, and 3 is important for correcting the defect, and combined inhibition of all three is needed to achieve the greatest effect, suggesting a need for multiple effects of the HDACi treatments. Identifying the specific HDACs involved in the process of regulating cholesterol trafficking in NPC1 will help to focus the search for more specific druggable targets.

Validation of the recently developed Total Disability Index: a single measure of disability in neck and back pain patients.

OBJECTIVE: Neck and back pain are highly prevalent conditions that account for major disability. The Neck Disability Index (NDI) and Oswestry Disability Index (ODI) are the two most common functional status measures for neck and back pain. However, no single instrument exists to evaluate patients with concurrent neck and back pain. The recently developed Total Disability Index (TDI) combines overlapping elements from the ODI and NDI with the unique items from each. This study aimed to prospectively validate the TDI in patients with spinal deformity, back pain, and/or neck pain. METHODS: This study is a retrospective review of prospectively collected data from a single center. The 14-item TDI, derived from ODI and NDI domains, was administered to consecutive patients presenting to a spine practice. Patients were assessed using the ODI, NDI, and EQ-5D. Validation of internal consistency, test-retest reproducibility, and validity of reconstructed NDI and ODI scores derived from TDI were assessed. RESULTS: A total of 252 patients (mean age 55 years, 56% female) completed initial assessments (back pain, n = 115; neck pain, n = 52; back and neck pain, n = 55; spinal deformity, n = 55; and no pain/deformity, n = 29). Of these patients, 155 completed retests within 14 days. Patients represented a wide range of disability (mean ODI score: 36.3 ± 21.6; NDI score: 30.8 ± 21.8; and TDI score: 34.1 ± 20.0). TDI demonstrated excellent internal consistency (Cronbach's alpha = 0.922) and test-retest reliability (intraclass correlation coefficient = 0.96). Differences between actual and reconstructed scores were not clinically significant. Subanalyses demonstrated TDI's ability to quantify the degree of disability due to back or neck pain in patients complaining of pain in both regions. CONCLUSIONS: The TDI is a valid and reliable disability measure in patients with back and/or neck pain and can capture each spine region's contribution to total disability. The TDI could be a valuable method for total spine assessment in a clinical setting, and its completion is less time consuming than that for both the ODI and NDI.

2-Hydroxypropyl-ß-cyclodextrin is the active component in a triple combination formulation for treatment of Niemann-Pick C1 disease.

Niemann-Pick type C1 (NPC1) disease is a fatal neurovisceral disease for which there are no FDA approved treatments, though cyclodextrin (HPßCD) slows disease progression in preclinical models and in an early phase clinical trial. Our goal was to evaluate the mechanism of action of a previously described combination-therapy, Triple Combination Formulation (TCF) - comprised of the histone deacetylase inhibitor (HDACi) vorinostat/HPßCD/PEG - shown to prolong survival in Npc1 mice. In these studies, TCF's benefit was attributed to enhanced vorinostat pharmacokinetics (PK). Here, we show that TCF reduced lipid storage, extended lifespan, and preserved neurological function in Npc1 mice. Unexpectedly, substitution of an inactive analog for vorinostat in TCF revealed similar efficacy. We demonstrate that the efficacy of TCF was attributable to enhanced HPßCD PK and independent of NPC1 protein expression. We conclude that although HDACi effectively reduce cholesterol storage in NPC1-deficient cells, HDACi are ineffective in vivo in Npc1 mice.

Full-Body Radiographic Analysis of Postoperative Deviations From Age-Adjusted Alignment Goals in Adult Spinal Deformity Correction and Related Compensatory Recruitment.

BACKGROUND: Full-body stereographs for adult spinal deformity (ASD) have enhanced global deformity and lower-limb compensation associations. The advent of age-adjusted goals for classic ASD parameters (sagittal vertical axis, pelvic tilt, spino-pelvic mismatch [PI-LL]) has enabled individualized evaluation of successful versus failed realignment, though these remain to be radiographically assessed postoperatively. This study analyzes pre- and postoperative sagittal alignment to quantify patient-specific correction against age-adjusted goals, and presents differences in compensation in patients whose postoperative profile deviates from targets. METHODS: Single-center retrospective review of ASD patients ≥ 18 years with biplanar full-body stereographic x-rays. Inclusion: ≥ 4 levels fused, complete baseline and early (≤ 6-month) follow-up imaging. Correction groups generated at postoperative visit for actual alignment compared to age-adjusted ideal values for pelvic tilt, PI-LL, and sagittal vertical axis derived from clinically relevant formulas. Patients that matched exact ± 10-year threshold for age-adjusted targets were compared to unmatched cases (undercorrected or overcorrected). Comparison of spinal alignment and compensatory mechanisms (thoracic kyphosis, hip extension, knee flexion, ankle flexion, pelvic shift) across correction groups were performed with ANOVA and paired t tests. RESULTS: The sagittal vertical axis, pelvic tilt, and PI-LL of 122 patients improved at early postoperative visits (P < .001). Of lower-extremity parameters, knee flexion and pelvic shift improved (P < .001), but hip extension and ankle flexion were similar (P > .170); global sagittal angle decreased overall, reflecting global postoperative correction (8.3° versus 4.4°, P < .001). Rates of undercorrection to age-adjusted targets for each spino-pelvic parameter were 30.3% (sagittal vertical axis), 41.0% (pelvic tilt), and 43.6% (PI-LL). Compared to matched/overcorrections, undercorrections recruited increased posterior pelvic shift to compensate (P < .001); knee flexion was recruited in undercorrections for sagittal vertical axis and pelvic tilt; thoracic hypokyphosis was observed in PI-LL undercorrections. All undercorrected groups displayed consequentially larger global sagittal angle (P < .001). CONCLUSIONS: Global alignment cohort improvements were observed, and when comparing actual to age-adjusted alignment, undercorrections recruited pelvic and lower-limb flexion to compensate. LEVEL OF EVIDENCE: 3.

Realignment Planning in Adult Spinal Deformity: Formulas and Planning Tools.

Adult spinal deformity is a complex pathologic process that has many etiologies and several mechanisms of compensation. A complete understanding of spinopelvic alignment is required to differentiate the origin of spinal deformity from its compensation and, ultimately, optimize surgical correction. Surgeons should understand the spinopelvic parameters involved in the evaluation of a patient who has an adult spinal deformity and their implications for treatment.

Principal Radiographic Characteristics for Cervical Spinal Deformity: A Health-related Quality-of-life Analysis.

STUDY DESIGN: Retrospective study. OBJECTIVE: The aim of this study was to propose radiographic characteristics of patients with cervical disability and to investigate the relevant parameters when assessing cervical alignment. SUMMARY OF BACKGROUND DATA: Although cervical kyphosis is traditionally recognized as presentation of cervical deformity, an increasing number of studies demonstrated that cervical kyphosis may not equal cervical deformity. Therefore, several other differentiating criteria for cervical deformity should be investigated and supported with quality of life scores. METHODS: A database of full-body radiographs was retrospectively reviewed. Patients without previous cervical surgery, with a well-aligned thoracolumbar profile (defined as T1 pelvis angle <15°), and with an available Neck Disability Index (NDI) score were reviewed in this study. Subjects were stratified into an asymptomatic (64 subjects with NDI ≤15, Visual Analogue Scale [VAS] neck ≤3, and VAS arm ≤3) and a symptomatic group (107 subjects with NDI >15, VAS neck >3, or VAS arm >3). Independent t tests were performed to investigate differences between two groups. Logistic regressions and principal component analyses were then performed. RESULTS: NDI averaged 5.43 in asymptomatic group, significantly smaller than symptomatic group (5.43 vs. 41.25). t Test revealed that C2-C7 sagittal vertical axis (SVA), McGregor slope, and the slope of line of sight (SLS) were significantly different while C2-C7 angle (cervical curvature, CC) did not show statistical difference (P = 0.09). Logistic regressions were performed using the significantly different parameters as well as CC. Results identified C2-C7 SVA and SLS as independent risk factors for low health-related quality of life. The principal component analysis leads to a new factor (0.55 × C2C7SVA + 0.34 × COC2 + 0.77 × CC) with strong correlations with NDI, VAS, and EQ5D measurements. CONCLUSION: The traditional concept of cervical kyphosis should not be regarded as a standalone criterion of cervical deformity. The most clinically relevant components of cervical analysis are the C2-C7 SVA, C0C2 angle, and C2C7 angle. In addition, the three components should be assessed together in harmony and not individually. LEVEL OF EVIDENCE: 4.

Full-Body Analysis of Age-Adjusted Alignment in Adult Spinal Deformity Patients and Lower-Limb Compensation.

STUDY DESIGN: Single-center retrospective review. OBJECTIVE: The present study evaluates the effect of increasing spinal deformity deviation from age-adjusted alignment ideals on lower extremity compensation. SUMMARY OF BACKGROUND DATA: Although current understanding of compensatory mechanisms in adult spinal deformity (ASD) is progressing due to full-body stereographic assessment, the effect of age-adjusted deformity targets on lower-limb compensation remains unexamined. METHODS: ASD patients 18 years or older with biplanar full-body stereographic x-rays were included. Patients were stratified into age cohorts: younger than 40 years, 40-65 years, 65 years or older. Age-specific alignment goals (IDEAL) for pelvic tilt (PT), spinopelvic mismatch (PI-LL), sagittal vertical axis (SVA), and T1 pelvic angle (TPA) were calculated for each patient using published formulas and compared to patients' real (ACTUAL) radiographic parameters. The difference between ACTUAL and IDEAL alignment (OFFSET) was calculated. Analysis of variance compared ACTUAL, IDEAL, and OFFSET between age groups, and OFFSET was correlated with lower-limb compensation (sacrofemoral angle, pelvic shift, knee angle, ankle angle). RESULTS: Seven hundred seventy-eight patients with (74.1% female) were included. ACTUAL and IDEAL alignments matched for PT (P = 0.37) in patients younger than 40 years, SVA (P = 0.12) in patients 40 to 65 years and PT, SVA, and TPA (P > 0.05) in patients 65 years or older. SVA and TPA OFFSETs decreased significantly with increasing age (P < 0.001). Hip extension correlated with all OFFSETs in patients younger than 40 years (positively with PT, PI-LL, TPA; negatively with SVA). Knee flexion correlated with PI-LL, SVA, and TPA, across all age groups with strongest correlations (0.525 < r < 0.605) in patients 40 to 65 years. Ankle dorsiflexion only correlated positively with PT and PI-LL offsets in older (older than 40 years) age groups. Posterior pelvic displacement correlated positively with all OFFSET groups, and was highest (0.526 < r <0.712) in patients ages 40 to 65 years. CONCLUSION: Age-adjusted ideals for sagittal alignment provide targets for patients with ASD. Offsets from actual alignment (more severe sagittal deformity) revealed differential recruitment of lower-limb extension, which varied significantly with age. LEVEL OF EVIDENCE: 3.

The impact of obesity on compensatory mechanisms in response to progressive sagittal malalignment.

BACKGROUND CONTEXT: Obesity's impact on standing sagittal alignment remains poorly understood, especially with respect to the role of the lower limbs. Given energetic expenditure in standing, a complete understanding of compensation in obese patients with sagittal malalignment remains relevant. PURPOSE: This study compares obese and non-obese patients with progressive sagittal malalignment for differences in recruitment of pelvic and lower-limb mechanisms. STUDY DESIGN/SETTING: Single-center retrospective review. PATIENT SAMPLE: A total of 554 patients (277 obese, 277 non-obese) were identified for analysis. OUTCOME MEASURES: Upper body alignment parameters: sagittal vertical axis (SVA) and T1 spinopelvic inclination (T1SPi). Compensatory lower-limb mechanisms: pelvic translation (pelvic shift [PS]), knee (KA) and ankle (AA) flexion, hip extension (sacrofemoral angle [SFA]), and global sagittal angle (GSA). METHODS: Inclusion criteria were patients ≥18 years who underwent full-body stereographic x-rays. Included patients were categorized as non-obese (N-Ob: body mass index [BMI]<30 kg/m2) or obese (Ob: BMI≥30 kg/m2). To control for potential confounders, groups were propensity score matched by age, gender, and baseline pelvic incidence (PI), and subsequently categorized by increasing spinopelvic (pelvic incidence minus lumbar lordosis [PI-LL]) mismatch: <10°, 10°-20°, >20°. Independent t tests and linear regression models compared sagittal (SVA, T1SPi) and lower limb (PS, KA, AA, SFA, GSA) parameters between obesity cohorts. RESULTS: A total of 554 patients (277 Ob, 277 N-Ob) were included for analysis and were stratified to the following mismatch categories: <10°: n=367; 10°-20°: n=91; >20°: n=96. Obese patients had higher SVA, KA, PS, and GSA than N-Ob patients (p<.001 all). Low PI-LL mismatch Ob patients had greater SVA with lower SFA (142.22° vs. 156.66°, p=.032), higher KA (5.22° vs. 2.93°, p=.004), and higher PS (4.91 vs. -5.20 mm, p<.001) than N-Ob patients. With moderate PI-LL mismatch, Ob patients similarly demonstrated greater SVA, KA, and PS, combined with significantly lower PT (23.69° vs. 27.14°, p=.012). Obese patients of highest (>20°) PI-LL mismatch showed greatest forward malalignment (SVA, T1SPi) with significantly greater PS, and a concomitantly high GSA (12.86° vs. 9.67°, p=.005). Regression analysis for lower-limb compensation revealed that increasing BMI and PI-LL predicted KA (r2=0.234) and GSA (r2=0.563). CONCLUSIONS: With progressive sagittal malalignment, obese patients differentially recruit lower extremity compensatory mechanisms, whereas non-obese patients preferentially recruit pelvic mechanisms. The ability to compensate for progressive sagittal malalignment with the pelvic retroversion is limited by obesity.

The endocytic pathway in microglia during health, aging and Alzheimer's disease.

Microglia, the main phagocytes of the central nervous system (CNS), are involved in the surveillance and maintenance of nervous tissue. During normal tissue homeostasis, microglia migrates within the CNS, phagocytose dead cells and tissue debris, and modulate synapse pruning and spine formation via controlled phagocytosis. In the event of an invasion by a foreign body, microglia are able to phagocytose the invading pathogen and process it proteolytically for antigen presentation. Internalized substrates are incorporated and sorted within the endocytic pathway and thereafter transported via complex vesicular routes. When targeted for degradation, substrates are delivered to acidic late endosomes and lysosomes. In these, the enzymatic degradation relies on pH and enzyme content. Endocytosis, sorting, transport, compartment acidification and degradation are regulated by complex signaling mechanisms, and these may be altered during aging and pathology. In this review, we discuss the endocytic pathway in microglia, with insight into the mechanisms controlling lysosomal biogenesis and pH regulation. We also discuss microglial lysosome function associated with Alzheimer's disease (AD) and the mechanisms of amyloid-beta (Aß) internalization and degradation. Finally, we explore some therapies currently being investigated to treat AD and their effects on microglial response to Aß, with insight in those involving enhancement of lysosomal function.

Injury severity of pedestrians, bicyclists and motorcyclists resulting from crashes with reversing cars.

OBJECTIVE: Pedestrians, bicyclists and motorcyclists can suffer serious injury in road traffic crashes. To date, no studies examine the injury severity within this vulnerable cohort following collisions with reversing cars. MATERIAL AND METHODS: Our institution prospectively maintains a database including medical and technical information regarding traffic accidents in our area, including urban and suburban regions. In a retrospective review of this database, the authors describe the injury severity of pedestrians, bicyclists and motorcyclists following traffic crashes involving reversing cars. Injury severity was described using the abbreviated injury scale (AIS) as well as the maximum abbreviated injury scale (MAIS). RESULTS: This study included 234 crashes occurring between 1999 and 2012. The lower extremity was injured most often while also suffering more severe injuries with a median AIS of 1 compared to 0 in all other documented body regions. The upper extremity was injured second most often. AIS ranging from 4 to 6 were infrequent. AIS 3 however, was documented for the legs in 4.3% of patients. MAIS 0, 1, 2, 3, 5 and 9 were found in 1, 164, 46, 14, 1, and 8 patients in the study cohort, respectively. Pedestrians and motorcyclists were seriously injured in 9.1% and 9.6% of cases, respectively. In contrast, no bicyclists suffered serious injuries. As to the zone of impact, most collisions occurred at the rear center of the vehicle (35%) followed by rear left (26%), rear right (20%), side rear (11%), side center (4%) and side front (3%). 204 (87.2%) collisions occurred during the day, 19 (8.1%) at night and 11 (4.7%) at twilight. Speed was similar in crashes involving pedestrians, bicyclists and motorcyclists, being as high as 7.0±3.6, 7.0±4.0 and 7.9±4.2km/h respectively. CONCLUSIONS: This is the first study that analyzes injury severity among these vulnerable road users following collisions with reversing vehicles. The majority of collisions occur at low impact speed during the day. Most injuries resulting from these collisions are not serious, however pedestrians are at greatest risk of severe injury to any body region. The lower extremities suffer the most serious and frequent injuries within this cohort.

Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models.

Disability or death due to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron, and consequent oxidative stress. Iron chelators bind to free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms for this effect remain unclear. We show that the hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) family of iron-dependent, oxygen-sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in the mouse striatum improved functional recovery after ICH. A low-molecular-weight hydroxyquinoline inhibitor of the HIF-PHD enzymes, adaptaquin, reduced neuronal death and behavioral deficits after ICH in several rodent models without affecting total iron or zinc distribution in the brain. Unexpectedly, protection from oxidative death in vitro or from ICH in vivo by adaptaquin was associated with suppression of activity of the prodeath factor ATF4 rather than activation of an HIF-dependent prosurvival pathway. Together, these findings demonstrate that brain-specific inactivation of the HIF-PHD metalloenzymes with the blood-brain barrier-permeable inhibitor adaptaquin can improve functional outcomes after ICH in several rodent models.

A Comparison of Two Different Dosing Protocols for Tranexamic Acid in Posterior Spinal Fusion for Spinal Deformity: A Prospective, Randomized Trial.

BACKGROUND: Multilevel spinal fusions have typically been associated with significant blood loss. Previous studies have shown a reduction in blood loss with antifibrinolytics in both adolescent and adult spinal deformity patients. While this has been mirrored in other subspecialties as well, the dosing of TXA remains highly variable. To date, there remains a paucity of data guiding dosing for TXA in spine surgery and orthopedic surgery as a whole. METHODS/DESIGN: One hundred and fifty patients from 3 institutions (50 each site) will be consecutively enrolled and randomized to either a high dose of TXA (50mg/kg loading followed by 20mg/kg hourly) or a lose dose (10mg/kg, then 1mg/kg hourly). Both surgeons and patients will be blinded to the treatment group. Primary outcomes will be perioperative blood loss, drain output, and transfusion rate. Secondary outcomes will be length of stay, complications, and overall cost. DISCUSSION: The primary goal of this study is to provide level-1 comparative data for two TXA dosing regimens in adult spinal deformity surgery. Management of blood loss remains a critical factor in reducing complications during spinal deformity surgery. The null hypothesis is that there is no difference between high- and low-dose TXA with respect to any of the primary or secondary outcomes.

Degradation of Alzheimer's amyloid fibrils by microglia requires delivery of ClC-7 to lysosomes.

Incomplete lysosomal acidification in microglia inhibits the degradation of fibrillar forms of Alzheimer's amyloid ß peptide (fAß). Here we show that in primary microglia a chloride transporter, ClC-7, is not delivered efficiently to lysosomes, causing incomplete lysosomal acidification. ClC-7 protein is synthesized by microglia but it is mistargeted and appears to be degraded by an endoplasmic reticulum-associated degradation pathway. Activation of microglia with macrophage colony-stimulating factor induces trafficking of ClC-7 to lysosomes, leading to lysosomal acidification and increased fAß degradation. ClC-7 associates with another protein, Ostm1, which plays an important role in its correct lysosomal targeting. Expression of both ClC-7 and Ostm1 is increased in activated microglia, which can account for the increased delivery of ClC-7 to lysosomes. Our findings suggest a novel mechanism of lysosomal pH regulation in activated microglia that is required for fAß degradation.

Activation of microglia acidifies lysosomes and leads to degradation of Alzheimer amyloid fibrils.

Microglia are the main immune cells of the brain, and under some circumstances they can play an important role in removal of fibrillar Alzheimer amyloid beta peptide (fAbeta). Primary mouse microglia can internalize fAbeta, but they do not degrade it efficiently. We compared the level of lysosomal proteases in microglia and J774 macrophages, which can degrade fAbeta efficiently, and we found that microglia actually contain higher levels of many lysosomal proteases than macrophages. However, the microglial lysosomes are less acidic (average pH of approximately 6), reducing the activity of lysosomal enzymes in the cells. Proinflammatory treatments with macrophage colony-stimulating factor (MCSF) or interleukin-6 acidify the lysosomes of microglia and enable them to degrade fAbeta. After treatment with MCSF, the pH of microglial lysosomes is similar to J774 macrophages (pH of approximately 5), and the MCSF-induced acidification can be partially reversed upon treatment with an inhibitor of protein kinase A or with an anion transport inhibitor. Microglia also degrade fAbeta if lysosomes are acidified by an ammonia pulse-wash or by treatment with forskolin, which activates protein kinase A. Our results indicate that regulated lysosomal acidification can potentiate fAbeta degradation by microglia.