AMPA Receptor Phosphorylation and Synaptic Colocalization on Motor Neurons Drive Maladaptive Plasticity below Complete Spinal Cord Injury.

Clinical spinal cord injury (SCI) is accompanied by comorbid peripheral injury in 47% of patients. Human and animal modeling data have shown that painful peripheral injuries undermine long-term recovery of locomotion through unknown mechanisms. Peripheral nociceptive stimuli induce maladaptive synaptic plasticity in dorsal horn sensory systems through AMPA receptor (AMPAR) phosphorylation and trafficking to synapses. Here we test whether ventral horn motor neurons in rats demonstrate similar experience-dependent maladaptive plasticity below a complete SCI in vivo. Quantitative biochemistry demonstrated that intermittent nociceptive stimulation (INS) rapidly and selectively increases AMPAR subunit GluA1 serine 831 phosphorylation and localization to synapses in the injured spinal cord, while reducing synaptic GluA2. These changes predict motor dysfunction in the absence of cell death signaling, suggesting an opportunity for therapeutic reversal. Automated confocal time-course analysis of lumbar ventral horn motor neurons confirmed a time-dependent increase in synaptic GluA1 with concurrent decrease in synaptic GluA2. Optical fractionation of neuronal plasma membranes revealed GluA2 removal from extrasynaptic sites on motor neurons early after INS followed by removal from synapses 2 h later. As GluA2-lacking AMPARs are canonical calcium-permeable AMPARs (CP-AMPARs), their stimulus- and time-dependent insertion provides a therapeutic target for limiting calcium-dependent dynamic maladaptive plasticity after SCI. Confirming this, a selective CP-AMPAR antagonist protected against INS-induced maladaptive spinal plasticity, restoring adaptive motor responses on a sensorimotor spinal training task. These findings highlight the critical involvement of AMPARs in experience-dependent spinal cord plasticity after injury and provide a pharmacologically targetable synaptic mechanism by which early postinjury experience shapes motor plasticity

The demographics of pain after spinal cord injury: a survey of our model system.

STUDY DESIGN: Survey OBJECTIVES: Better understand the demographics of pain after spinal cord injury (SCI). SETTING: Academic Level 1 trauma center and SCI Model System. METHODS: A survey including general demographic questions, questions of specific interest to the authors, the standardized SCI Pain Instrument (SCIPI), International SCI Pain Data Set, Basic form (ISCIPDS:B), Patient Reported Outcomes Measurement Information System (PROMIS) neuropathic 5a (PROMIS-Neur), and PROMIS nociceptive 5a (PROMIS-No). RESULTS: 81% of individuals with SCI experience chronic pain and 86% of individuals with pain have neuropathic pain. 55% of individuals had shoulder pain. Females and those who recall \u3e5/10 pain during initial hospital stay had significantly higher PROMIS-Neur scores. Completeness of injury correlates inversely with the degree of neuropathic pain. Those who recall \u3e5 pain during the initial hospital stay and those who reported the worst or second worst pain as being shoulder pain had significantly higher PROMIS-No scores. Lumbosacral injuries trended towards higher PROMIS-No scores and had the highest PROMIS-Neur scores. Those with tetraplegia were more likely to develop shoulder pain and those with shoulder pain had higher PROMIS-No scores. CONCLUSIONS: Chronic pain is almost universal in patients with SCI. Pain is more commonly reported as neuropathic in nature and females reported more neuropathic pain than males. Physicians should monitor for nociceptive shoulder pain, particularly in those with tetraplegia. Patients with incomplete injuries or lumbosacral injuries are more likely to report higher levels of neuropathic pain and pain levels should be monitored closely. Those with more neuropathic and nociceptive pain recall worse pain at initial hospitalization. Better understanding pain demographics in this population help screen, prevent and manage chronic pain in these patients

Human cytomegalovirus mediates APOBEC3B relocalization early during infection through a ribonucleotide reductase-independent mechanism

Human cytomegalovirus (HCMV) infections can range from asymptomatic to severe, particularly in neonates and immunocompromised patients. HCMV has evolved strategies to overcome host-encoded antiviral defenses to achieve lytic viral DNA replication and dissemination and, under some conditions, latency and long-term persistence. Here, we show that HCMV infection causes the antiviral factor, APOBEC3B, to relocalize from the nuclear compartment to the cytoplasm. This overall strategy resembles that used by related herpesviruses. However, the HCMV relocalization mechanism utilizes a different viral factor(s) and available evidence suggests the involvement of at least one protein expressed at the early stages of infection. This knowledge is important because a greater understanding of this mechanism could lead to novel antiviral strategies that enable APOBEC3B to naturally restrict HCMV infection.The APOBEC3 family of DNA cytosine deaminases comprises an important arm of the innate antiviral defense system. The gamma-herpesviruses Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus and the alpha-herpesviruses herpes simplex virus (HSV)-1 and HSV-2 have evolved an efficient mechanism to avoid APOBEC3 restriction by directly binding to APOBEC3B and facilitating its exclusion from the nuclear compartment. The only viral protein required for APOBEC3B relocalization is the large subunit of the ribonucleotide reductase (RNR). Here, we ask whether this APOBEC3B relocalization mechanism is conserved with the beta-herpesvirus human cytomegalovirus (HCMV). Although HCMV infection causes APOBEC3B relocalization from the nucleus to the cytoplasm in multiple cell types, the viral RNR (UL45) is not required. APOBEC3B relocalization occurs rapidly following infection suggesting the involvement of an immediate early or early (IE/E) viral protein. In support of this possibility, genetic (IE1 mutant) and pharmacologic (cycloheximide) strategies that prevent the expression of IE/E viral proteins also block APOBEC3B relocalization. In comparison, the treatment of infected cells with phosphonoacetic acid, which interferes with viral late protein expression, still permits A3B relocalization. These results combine to indicate that the beta-herpesvirus HCMV uses an RNR-independent, yet phenotypically similar, molecular mechanism to antagonize APOBEC3B. IMPORTANCEHuman cytomegalovirus (HCMV) infections can range from asymptomatic to severe, particularly in neonates and immunocompromised patients. HCMV has evolved strategies to overcome host-encoded antiviral defenses to achieve lytic viral DNA replication and dissemination and, under some conditions, latency and long-term persistence. Here, we show that HCMV infection causes the antiviral factor, APOBEC3B, to relocalize from the nuclear compartment to the cytoplasm. This overall strategy resembles that used by related herpesviruses. However, the HCMV relocalization mechanism utilizes a different viral factor(s) and available evidence suggests the involvement of at least one protein expressed at the early stages of infection. This knowledge is important because a greater understanding of this mechanism could lead to novel antiviral strategies that enable APOBEC3B to naturally restrict HCMV infection

The Copyright Term Extension Act of 1998: An Economic Analysis

This brief provides an economic analysis of the main feature of the Copyright Term Extension Act of 1998 ('CTEA'), a twenty-year extension of the copyright term for existing and future works. Taken as a whole, the authors believe that it is highly unlikely that the economic benefits from copyright extension under the CTEA outweigh the additional costs.Technology and Industry

Association of early imaging for back pain with clinical outcomes in older adults

IMPORTANCE: In contrast to the recommendations for younger adults, many guidelines allow for older adults with back pain to undergo imaging without waiting 4 to 6 weeks. However, early imaging may precipitate interventions that do not improve outcomes. OBJECTIVE: To compare function and pain at the 12-month follow-up visit among older adults who received early imaging with those who did not receive early imaging after a new primary care visit for back pain without radiculopathy. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort of 5239 patients 65 years or older with a new primary care visit for back pain (2011-2013) in 3 US health care systems. We matched controls 1:1 using propensity score matching of demographic and clinical characteristics, including diagnosis, pain severity, pain duration, functional status, and prior resource use. EXPOSURES: Diagnostic imaging (plain films, computed tomography [CT], magnetic resonance imaging [MRI]) of the lumbar or thoracic spine within 6 weeks of the index visit. PRIMARY OUTCOME: back or leg pain-related disability measured by the modified Roland-Morris Disability Questionnaire (score range, 0-24; higher scores indicate greater disability) 12 months after enrollment. RESULTS: Among the 5239 patients, 1174 had early radiographs and 349 had early MRI/CT. At 12 months, neither the early radiograph group nor the early MRI/CT group differed significantly from controls on the disability questionnaire. The mean score for patients who underwent early radiography was 8.54 vs 8.74 among the control group (difference, -0.10 [95% CI, -0.71 to 0.50]; mixed model, P = .36). The mean score for the early MRI/CT group was 9.81 vs 10.50 for the control group (difference,-0.51 [-1.62 to 0.60]; mixed model, P = .18). CONCLUSIONS AND RELEVANCE: Among older adults with a new primary care visit for back pain, early imaging was not associated with better 1-year outcomes. The value of early diagnostic imaging in older adults for back pain without radiculopathy is uncertain

Systematic Literature Review of Imaging Features of Spinal Degeneration in Asymptomatic Populations

ABSTRACT BACKGROUND AND PURPOSE: Degenerative changes are commonly found in spine imaging but often occur in pain-free individuals as well as those with back pain. We sought to estimate the prevalence, by age, of common degenerative spine conditions by performing a systematic review studying the prevalence of spine degeneration on imaging in asymptomatic individuals

Economic Growth and the Diffusion of Clean Technologies: Explaining Environmental Kuznets Curves

Production often causes pollution as a by-product. Once environmental degradation becomes too severe, regulation is introduced by which society forces the economy to make a transition to cleaner production processes. We model this transition as a change in general purpose technology" and investigate how it interferes with economic growth driven by quality-improvements. The model gives an explanation for the inverted U-shaped pollution-income relation found in empirical research for many pollutants (Environmental Kuznets Curve). We provide an analytical foundation for the claim that the rise and decline of pollution can be explained by policy-induced technology shifts and intrasectoral changes

Evaluating operational AVHRR sea surface temperature data at the coastline using surfers

Sea surface temperature (SST) is an essential climate variable that can be measured routinely from Earth Observation (EO) with high temporal and spatial coverage. To evaluate its suitability for an application, it is critical to know the accuracy and precision (performance) of the EO SST data. This requires comparisons with co-located and concomitant in situ data. Owing to a relatively large network of in situ platforms there is a good understanding of the performance of EO SST data in the open ocean. However, at the coastline this performance is not well known, impeded by a lack of in situ data. Here, we used in situ SST measurements collected by a group of surfers over a three year period in the coastal waters of the UK and Ireland, to improve our understanding of the performance of EO SST data at the coastline. At two beaches near the city of Plymouth, UK, the in situ SST measurements collected by the surfers were compared with in situ SST collected from two autonomous buoys located ∼7 km and ∼33 km from the coastline, and showed good agreement, with discrepancies consistent with the spatial separation of the sites. The in situ SST measurements collected by the surfers around the coastline, and those collected offshore by the two autonomous buoys, were used to evaluate the performance of operational Advanced Very High Resolution Radiometer (AVHRR) EO SST data. Results indicate: (i) a significant reduction in the performance of AVHRR at retrieving SST at the coastline, with root mean square errors in the range of 1.0 to 2.0 °C depending on the temporal difference between match-ups, significantly higher than those at the two offshore stations (0.4 to 0.6 °C); (ii) a systematic negative bias in the AVHRR retrievals of approximately 1 °C at the coastline, not observed at the two offshore stations; and (iii) an increase in the root mean square error at the coastline when the temporal difference between match-ups exceeded three hours. Harnessing new solutions to improve in situ sampling coverage at the coastline, such as tagging surfers with sensors, can improve our understanding of the performance of EO SST data in coastal regions, helping inform users interested in EO SST products for coastal applications. Yet, validating EO SST products using in situ SST data at the coastline is challenged by difficulties reconciling the two measurements, which are provided at different spatial scales in a dynamic and complex environment