Togus VA Medical Center

The chemokine stromal-derived factor-1 (SDF-1, also known as CXCL12) and its receptor CXCR4 have been implicated in homing of stem cells to the bone marrow and the homing of bone marrow-derived cells to sites of injury. Bone marrow cells infiltrate brain and give rise to long-term resident cells following injury. Therefore, SDF-1 and CXCR4 expression patterns in 40 mice were examined relative to the homing of bone marrow-derived cells to sites of ischemic injury using a stroke model. Mice received bone marrow transplants from green fluorescent protein (GFP) transgenic donors and later underwent a temporary middle cerebral artery suture occlusion (MCAo). SDF-1 was associated with blood vessels and cellular profiles by 24 hours through at least 30 days post-MCAo. SDF-1 expression was principally localized to the ischemic penumbra. The majority of SDF-1 expression was associated with reactive astrocytes; much of this was perivascular. GFP+ cells were associated with SDF-1-positive vessels and were also found in the neuropil of regions with increased SDF-1 immunoreactivity. Most vessel-associated GFP+ cells resemble pericytes or perivascular microglia and the majority of the GFP+ cells in the parenchyma displayed characteristics of activated microglial cells. These findings suggest SDF-1 is important in the homing of bone marrow-derived cells, especially monocytes, to areas of ischemic injury.

Background and purpose - Fracture non-union remains a major clinical problem, yet there are no data available regarding the overall risk of fractures progressing to non-union in a large population. We investigated the rate of non-union per fracture in a large adult population. Methods - National data collected prospectively over a 5-year period and involving just under 5,000 non-unions were analyzed and compared to the incidence of fracture in the same period. Results and interpretation - The overall risk of non-union per fracture was 1.9%, which is considerably less than previously believed. However, for certain fractures in specific age groups the risk of non-union rose to 9%. As expected, these higher rates of non-union were observed with tibial and clavicular fractures, but-less expectedly-it was in the young and middle-aged adults rather than in the older and elderly population. This study is the first to examine fracture non-union rates in a large population according to age and site, and provides more robust (and lower) estimates of non-union risk than those that are frequently quoted.

Cells of the central nervous system were once thought to be incapable of regeneration. This dogma has been challenged in the last decade with studies showing new, migrating stem cells in the brain in many rodent injury models and findings of new neurones in the human hippocampus in adults. Moreover, there are reports of bone marrow-derived cells developing neuronal and vascular phenotypes and aiding in repair of injured brain. These findings have fuelled excitement and interest in regenerative medicine for neurological diseases, arguably the most difficult diseases to treat. There are numerous proposed regenerative approaches to neurological diseases. These include cell therapy approaches in which cells are delivered intracerebrally or are infused by an intravenous or intra-arterial route; stem cell mobilization approaches in which endogenous stem and progenitor cells are mobilized by cytokines such as granulocyte colony stimulatory factor (GCSF) or chemokines such as SDF-1; trophic and growth factor support, such as delivering brain-derived neurotrophic factor (BDNF) or glial-derived neurotrophic factor (GDNF) into the brain to support injured neurones; these approaches may be used together to maximize recovery. While initially, it was thought that cell therapy might work by a 'cell replacement' mechanism, a large body of evidence is emerging that cell therapy works by providing trophic or 'chaperone' support to the injured tissue and brain. Angiogenesis and neurogenesis are coupled in the brain. Increasing angiogenesis with adult stem cell approaches in rodent models of stroke leads to preservation of neurones and improved functional outcome. A number of stem and progenitor cell types has been proposed as therapy for neurological disease ranging from neural stem cells to bone marrow derived stem cells to embryonic stem cells. Any cell therapy approach to neurological disease will have to be scalable and easily commercialized if it will have the necessary impact on public health. Currently, bone marrow-derived cell populations such as the marrow stromal cell, multipotential progenitor cells, umbilical cord stem cells and neural stem cells meet these criteria the best. Of great clinical significance, initial evidence suggests these cell types may be delivered by an allogeneic approach, so strict tissue matching may not be necessary. The most immediate impact on patients will be achieved by making use of the trophic support capability of cell therapy and not by a cell replacement mechanism.

PURPOSE: In another study, it was demonstrated that NADPH oxidase-derived reactive oxygen species (ROS) are important for ischemia-induced increases in vascular endothelial growth factor (VEGF) and retinal neovascularization. Diabetes-induced increases in retinal ROS, VEGF expression, and vascular permeability are accompanied by increases in the NADPH oxidase catalytic subunit NOX2 within the retinal vessels. The goal of this study was to evaluate the potential role of NOX2 and NADPH oxidase activity in the development of retinal vascular inflammation. METHODS: Studies were performed in wild-type mice, mice lacking NOX2, and mice treated with the NADPH oxidase inhibitor apocynin in models of endotoxemia and streptozotocin-induced diabetes. Intracellular adhesion molecule (ICAM)-1 expression was determined by Western blot analysis. Leukocyte adhesion was assessed by labeling adherent leukocytes with concanavalin A. Vascular permeability was assessed by extravasation of FITC-conjugated albumin. ROS production was determined by dichlorofluorescein imaging. RESULTS: Both endotoxemia- and diabetes-induced increases in ICAM-1 expression and leukostasis were significantly inhibited by deletion of NOX2, indicating that this enzyme is critically involved in both conditions. Moreover, apocynin treatment and deletion of NOX2 were equally effective in preventing diabetes-induced increases in ICAM-1, leukostasis, and breakdown of the blood-retinal barrier, suggesting that NOX2 is primarily responsible for these early signs of diabetic retinopathy. CONCLUSIONS: These data suggest that NOX2 activity has a primary role in retinal vascular inflammation during acute and chronic conditions associated with retinal vascular inflammatory reactions. Targeting this enzyme could be a novel therapeutic strategy for treatment of the retinopathies associated with vascular inflammation.

OBJECTIVE: During diabetes, retinal microglial cells are activated to release inflammatory cytokines that initiate neuronal loss and blood-retinal barrier breakdown seen in diabetic retinopathy (DR). The mechanism by which diabetes activates microglia to release those inflammatory mediators is unclear and was therefore elucidated. RESEARCH DESIGN AND METHODS: Microglia activation was characterized in streptozocin-injected rats and in isolated microglial cells using immunofluorescence, enzyme-linked immunosorbent assay, RT-PCR, and Western blot analyses. RESULTS: In 8-week diabetic retina, phospho-extracellular signal-related kinase (ERK) and P38 mitogen-activated protein kinases were localized in microglia, but not in Mueller cells or astrocytes. At the same time, Amadori-glycated albumin (AGA)-like epitopes were featured in the regions of microglia distribution, implicating a pathogenic effect on microglial activation. To test this, diabetic rats were treated intravitreally with A717, a specific AGA-neutralizing antibody, or murine IgG. Relative to nondiabetic rats, diabetic rats (IgG-treated) manifested 3.9- and 7.9-fold increases in Iba-1 and tumor necrosis factor (TNF)-α mRNAs, respectively. Treatment of diabetic rats with A717 significantly attenuated overexpression of these mRNAs. Intravitreal injection of AGA per se in normal rats resulted in increases of Iba-1 expression and TNF-α release. Guided by these results, a cultured retinal microglia model was developed to study microglial response after AGA treatment and the mechanistic basis behind this response. The results showed that formation of reactive oxygen species and subsequent activation of ERK and P38, but not Jun NH2-terminal kinase, are molecular events underpinning retinal microglial TNF-α release during AGA treatment. CONCLUSIONS: These results provide new insights in understanding the pathogenesis of early DR, showing that the accumulated AGA within the diabetic retina elicits the microglial activation and secretion of TNF-α. Thus, intervention trials with agents that neutralize AGA effects may emerge as a new therapeutic approach to modulate early pathologic pathways long before the occurrence of vision loss among patients with diabetes.

BACKGROUND: Minocycline, a semi-synthetic tetracycline antibiotic, is an effective neuroprotective agent in animal models of cerebral ischemia when given in high doses intraperitoneally. The aim of this study was to determine if minocycline was effective at reducing infarct size in a Temporary Middle Cerebral Artery Occlusion model (TMCAO) when given at lower intravenous (IV) doses that correspond to human clinical exposure regimens. METHODS: Rats underwent 90 minutes of TMCAO. Minocycline or saline placebo was administered IV starting at 4, 5, or 6 hours post TMCAO. Infarct volume and neurofunctional tests were carried out at 24 hr after TMCAO using 2,3,5-triphenyltetrazolium chloride (TTC) brain staining and Neurological Score evaluation. Pharmacokinetic studies and hemodynamic monitoring were performed on minocycline-treated rats. RESULTS: Minocycline at doses of 3 mg/kg and 10 mg/kg IV was effective at reducing infarct size when administered at 4 hours post TMCAO. At doses of 3 mg/kg, minocycline reduced infarct size by 42% while 10 mg/kg reduced infarct size by 56%. Minocycline at a dose of 10 mg/kg significantly reduced infarct size at 5 hours by 40% and the 3 mg/kg dose significantly reduced infarct size by 34%. With a 6 hour time window there was a non-significant trend in infarct reduction. There was a significant difference in neurological scores favoring minocycline in both the 3 mg/kg and 10 mg/kg doses at 4 hours and at the 10 mg/kg dose at 5 hours. Minocycline did not significantly affect hemodynamic and physiological variables. A 3 mg/kg IV dose of minocycline resulted in serum levels similar to that achieved in humans after a standard 200 mg dose. CONCLUSIONS: The neuroprotective action of minocycline at clinically suitable dosing regimens and at a therapeutic time window of at least 4-5 hours merits consideration of phase I trials in humans in view of developing this drug for treatment of stroke.

OBJECTIVE: Recently we have shown that diabetes-induced retinal neurodegeneration positively correlates with oxidative stress and peroxynitrite. Studies also show that peroxynitrite impairs nerve growth factor (NGF) survival signaling in sensory neurons. However, the causal role of peroxynitrite and the impact of tyrosine nitration on diabetes-induced retinal neurodegeneration and NGF survival signaling have not been elucidated. RESEARCH DESIGN AND METHODS: Expression of NGF and its receptors was examined in retinas from human and streptozotocin-induced diabetic rats and retinal ganglion cells (RGCs). Diabetic animals were treated with FeTPPS (15 mg x kg(-1) x day(-1) ip), which catalytically decomposes peroxynitrite to nitrate. After 4 weeks of diabetes, retinal cell death was determined by TUNEL assay. Lipid peroxidation and nitrotyrosine were determined using MDA assay, immunofluorescence, and Slot-Blot analysis. Expression of NGF and its receptors was determined by enzyme-linked immunosorbent assay (ELISA), real-time PCR, immunoprecipitation, and Western blot analyses. RESULTS: Analyses of retinal neuronal death and NGF showed ninefold and twofold increases, respectively, in diabetic retinas compared with controls. Diabetes also induced increases in lipid peroxidation, nitrotyrosine, and the pro-apoptotic p75(NTR) receptor in human and rat retinas. These effects were associated with tyrosine nitration of the pro-survival TrkA receptor, resulting in diminished phosphorylation of TrkA and its downstream target, Akt. Furthermore, peroxynitrite induced neuronal death, TrkA nitration, and activation of p38 mitogen-activated protein kinase (MAPK) in RGCs, even in the presence of exogenous NGF. FeTPPS prevented tyrosine nitration, restored NGF survival signal, and prevented neuronal death in vitro and in vivo. CONCLUSIONS: Together, these data suggest that diabetes-induced peroxynitrite impairs NGF neuronal survival by nitrating TrkA receptor and enhancing p75(NTR) expression.

BACKGROUND: Modular polyethylene inserts have enabled surgeons to perform an isolated tibial insert exchange while retaining well fixed components. The purpose of this study was to review the results of insert revision and to clarify the role of this option compared with that of revision total knee arthroplasty. METHODS: Fifty-six patients (sixty-three knees) were managed with revision of a tibial polyethylene insert and retention of well aligned and stable femoral and tibial components. The implants had been in situ for an average of fifty-nine months (range, two to 108 months) at the time of the insert exchange. The inserts that were removed at the time of exchange were evaluated with regard to wear of the articular surface according to the classification system of Hood et al. and with regard to undersurface wear according to the method described by Wasielewski et al. Forty-eight knees were followed for an average of 7.4 years (range, 3.0 to 12.2 years) after the insert exchange. Knees that did not require an additional operation were considered to have had a successful exchange. RESULTS: Seven of the forty-eight exchanges failed, at an average of fifty-four months, because of accelerated wear of the new insert. All seven knees required complete revision of all components. Of the twenty-two exchanges that were performed because of severe wear of the primary insert, six (27 percent) failed at an average of less than five years; thus, knees in which the exchange was performed because of advanced wear were more likely to fail again (p < 0.05). In addition, primary inserts that were removed from knees in which the exchange procedure subsequently failed had higher delamination scores than those that were removed from knees in which the exchange was successful (p < 0.05). Most of the primary inserts had substantial undersurface wear at the time of the exchange procedure. Metallosis (thirty knees) and osteolysis (nineteen knees) were unrelated to failure of the exchange. CONCLUSIONS: An isolated revision of the tibial polyethylene insert should not be performed when there is accelerated wear of the insert with severe delamination and grade-3 or 4 undersurface wear within ten years after the primary procedure. Because a variety of patient-related, implant-related, and technical factors influence polyethylene wear, the orthopaedist must consider multiple variables whenever contemplating a limited revision.

AIMS: The mutual interactions between reactive oxygen species, airway inflammation, and alveolar cell death play crucial role in the pathogenesis of chronic obstructive pulmonary disease (COPD). In the present study, we investigated the possibility that hydrogen sulfide (H(2)S) donor sodium hydrosulfide (NaHS) might be a novel option for intervention in COPD. RESULTS: We used a mouse model of tobacco smoke (TS)-induced emphysema. Mice were injected with H(2)S donor NaHS (50 μmol/kg in 0.25 ml phosphate buffer saline, intraperitoneally) or vehicle daily before exposed to TS for 1 h/day, 5 days/week for 12 and 24 weeks. We found that NaHS ameliorated TS-induced increase in mean linear intercepts, the thickness of bronchial walls, and the numbers of total cell counts as well as neutrophils, monocytes, and tumor necrosis factor α in bronchial alveolar lavage. Moreover, NaHS reduced increases in right ventricular systolic pressure, the thickness of pulmonary vascular walls, and the ratio of RV/LV+S in TS-exposed mice. Further, TS exposure for 12 and 24 weeks reduced the protein contents of cystathionine γ-lyase (CGL), cystathionine β-synthetase (CBS), nuclear erythroid-related factor 2 (Nrf2), P(ser473)-Akt, as well as glutathione/oxidized glutathione ratio in the lungs. TS-exposed lungs exhibited large amounts of 8-hydroxyguanine-positive and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. Treatment with NaHS increased P(ser473)-Akt and attenuated TS-induced reduction of CGL, CBS, and Nrf2 as well as glutathione/oxidized glutathione ratio in the lungs. NaHS also reduced amounts of 8-hydroxyguanine-positive, terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and active caspase-3 in TS-exposed lungs. Additionally, knocking-down Akt protein abolished the protective effects of NaHS against TS-induced apoptosis and downregulation of Nrf2, CGL, and CBS in pulmonary artery endothelial cells. CONCLUSION: These results indicate that NaHS protects against TS-induced oxidative stress, airway inflammation, and remodeling and ameliorates the development of emphysema and pulmonary hypertension. H(2)S donors have therapeutic potential for the prevention and treatment of COPD caused by TS.

Powassan virus (POWV) disease is a rare human disease caused by a tick-borne encephalitis group flavivirus maintained in a transmission cycle between Ixodes cookei and other ixodid ticks and small and medium-sized mammals. During 1958-1998, only 27 POWV disease cases (mostly Powassan encephalitis) were reported from eastern Canada and the northeastern United States (average, 0.7 cases per year). During 1999-2005, nine cases (described herein) of serologically confirmed POWV disease were reported in the United States (average, 1.3 cases per year): four from Maine, two from New York, and one each from Michigan, Vermont, and Wisconsin. The Michigan and Wisconsin cases are the first ever reported from the north-central United States. Of these nine patients, 5 (56%) were men, the median age was 69 years (range: 25-91 years), and 6 (67%) had onset during May-July. All but one patient developed encephalitis with acute onset of profound muscle weakness, confusion, and other severe neurologic signs. In one case, no neurologic symptoms were present but the presence of pleocytosis, an elevated cerebrospinal fluid (CSF) protein concentration, and POWV-specific immunoglobulin M in CSF suggested neuroinvasion. All patients recovered from their acute disease, but most had long-term neurologic sequelae. Periresidential ecologic investigations were performed in three cases, including tests of local mammals and ticks for evidence of POWV infection. Woodchucks (Marmota monax), striped skunks (Mephitis mephitis), and a raccoon (Procyon lotor) collected at two of the Maine case-patients' residences had neutralizing antibody titers to POWV. I. cookei were found on woodchucks and skunks and questing in grassy areas of one of these residences; all were negative for POWV. Although POWV disease is rare, it is probably under-recognized, and it causes significant morbidity, and thus is an additional tick-borne emerging infectious disease entity. Because no vaccine or specific therapy is available, the basis of prevention is personal protection from ticks (or "tick hygiene") and reduced exposure to peridomestic wild mammals.

Diabetic retinopathy (DR) is one of the most common complications of diabetes. This devastating disease is a leading cause of blindness in people of working age in industrialized countries and affects the daily lives of millions of people. Despite tight glycemic control, blood pressure control and lipid-lowering therapy, the number of DR patients keeps growing and therapeutic approaches are limited. Moreover, there are significant limitations and side effects associated with the current therapies. Thus, there is a great need for development of new strategies for prevention and treatment of DR. Studies have shown that DR has prominent features of chronic, subclinical inflammation. This article focuses on the role of inflammation in DR and summarizes the progress of studies of anti-inflammatory strategies for DR.

OBJECTIVE: To explore the experience of early patient adopters who accessed their clinical notes online using the Blue Button feature of the My HealtheVet portal. METHODS: A web-based survey of VA patient portal users from June 22 to September 15, 2013. RESULTS: 33.5% of respondents knew that clinical notes could be viewed, and nearly one in four (23.5%) said that they had viewed their notes at least once. The majority of VA Notes users agreed that accessing their notes will help them to do a better job of taking medications as prescribed (80.1%) and be better prepared for clinic visits (88.6%). Nine out of 10 users agreed that use of visit notes will help them understand their conditions better (91.8%), and better remember the plan for their care (91.9%). In contrast, 87% disagreed that VA Notes will make them worry more, and 88.4% disagreed that access to VA Notes will be more confusing than helpful. Users who had either contacted their provider or healthcare team (11.9%) or planned to (13.5%) primarily wanted to learn more about a health issue, medication, or test results (53.7%). CONCLUSIONS: Initial assessment of the patient experience within the first 9 months of availability provides evidence that patients both value and benefit from online access to clinical notes. These findings are congruent with OpenNotes study findings on a broader scale. Additional outreach and education is needed to enhance patient awareness. Healthcare professionals should author notes keeping in mind the opportunity patient access presents for enhanced communication.

Frederick G. Novy, Sc.D., M.D., Ward J. McNeal, A.B.; On The Cultivation Of Trypanosoma Brucei, The Journal of Infectious Diseases, Volume 1, Issue 1, 1 Ja

PURPOSE: The production of proinflammatory cytokines has been shown to play a critical role in a variety of retinal vascular diseases. Angiotensin II and VEGF have been implicated in the initiation of vascular inflammation and retinal vascular disease. However, detailed mechanisms of this process and interactions between inflammatory agonists and angiotensin II in promoting retinopathy are poorly understood. The present study was an investigation of the role of interleukin (IL)-6 in angiotensin II-induced retinopathy. METHODS: Rats and IL-6-deficient and wild-type mice were treated with angiotensin II or IL-6, and their retinas were analyzed for leukocyte adhesion or for the expression and localization of VEGF or IL-6. Leukocyte adhesion was assayed by concanavalin A labeling. Vascular density was determined by morphometric analysis. NADPH oxidase activity was assayed by dihydroethidium imaging of superoxide. RESULTS: Intravitreal injection of angiotensin II caused increases in IL-6 mRNA and protein and in leukocyte adhesion to the retinal vessels. IL-6 protein was localized to CD11b-positive microglia and macrophage-like cells. Angiotensin II treatment stimulated increases in retinal levels of VEGF expression and NADPH oxidase activity, which were associated with increased surface area and remodeling of the retinal vessels. These effects were blocked by knocking out IL-6. Intravitreal IL-6 directly induced leukocyte adhesion in both wild-type and IL-6-deficient mice. CONCLUSIONS: The results indicate that IL-6 expression is essential for angiotensin II-induced increases in retinal VEGF expression, leukostasis, and vascular remodeling. The data suggest a critical role for IL-6 in mediating angiotensin II-induced retinal vascular inflammation and remodeling.

BACKGROUND: Given the paucity of information on dose intensity, the objective of this study is to describe the use of adjuvant chemotherapy for stage III colon cancer, focusing on relative dose intensity (RDI), overall survival (OS) and disease-free survival (DFS). METHODS: Retrospective cohort of 367 patients diagnosed with stage III colon cancer in 2003-2008 and treated at 19 VA medical centers. Kaplan-Meier curves summarize 5-year OS and 3-year DFS by chemotherapy regimen and RDI, and multivariable Cox proportional hazards regression was used to model these associations. RESULTS: 5-fluorouracil/leucovorin (FU/LV) was the most commonly initiated regimen in 2003 (94.4%) and 2004 (62.7%); in 2005-2008, a majority of patients (60%-74%) was started on an oxaliplatin-based regimen. Median RDI was 82.3%. Receipt of >70% RDI was associated with better 5-year OS (p < 0.001) and 3-year DFS (P = 0.009) than was receipt of ≤70% RDI, with 5-year OS rates of 66.3% and 50.5%, respectively and 3-year DFS rates of 66.1% and 52.7%, respectively. In the multivariable analysis of 5-year OS, oxaliplatin + 5-FU/LV (versus 5-FU/LV) (HR = 0.55; 95% CI = 0.34-0.91), >70% RDI at the first year (HR = 0.58; 95% CI = 0.37-0.89) and married status (HR = 0.66; 95% CI = 0.45-0.97) were associated with significantly decreased risk of death, while age ≥75 (versus 55-64) (HR = 2.06; 95% CI = 1.25-3.40), Charlson Comorbidity Index (HR = 1.17; 95% CI = 1.06-1.30), T4 tumor status (versus T1/T2) (HR = 5.88; 95% CI = 2.69-12.9), N2 node status (HR = 1.68; 95% CI = 1.12-2.50) and bowel obstruction (HR = 2.32, 95% CI = 1.36-3.95) were associated with significantly increased risk. Similar associations were observed for DFS. CONCLUSION: Patients with stage III colon cancer who received >70% RDI had improved 5-year OS. The association between RDI and survival needs to be examined in studies of adjuvant chemotherapy for colon cancer outside of the VA.

Abstract Vietnam combat veteran inpatients were evaluated after being treated in a PTSD special treatment unit. Selected pretreatment measures that included mental and physical problems, combat variables, PTSD symptoms, and the standard MMPI scales found no clinically meaningful differences between a group that was found to be “successes” and another group found to be “failures,” based on predetermined cutoff scores on the VETS scale, a reliable outcome measure for veteran patients. At 3 months post‐therapy, a significantly greater number of subjects treated with Direct Therapeutic Exposure (DTE) (flooding therapy) as compared to another group treated with a more conventional individual therapy, were identified as “successes” as opposed to “failures,” based on the VETs scale. Also, the number of “failures” was greater for those treated with the more conventional therapy and the number of “successess” was greater for those treated with DTE, when compared to all other subjects in the sample. These preliminary results were interpreted as indicating that DTE, when offered as part of an inpatient milieu, shows promise as an effective treatment for chronic/severe combat veteran PTSD sufferers.

BACKGROUND: To evaluate the practices and outcomes associated with a statewide, emergency medical services (EMS) protocol for trauma patient spine assessment and selective patient immobilization. METHODS: An EMS spine assessment protocol was instituted on July 1, 2002 for all EMS providers in the state of Maine. Spine immobilization decisions were prospectively collected with EMS encounter data. Prehospital patient data were linked to a statewide hospital database that included all patients treated for spine fracture during the 12-month period following the spine assessment protocol implementation. Incidence of spine fractures among EMS-assessed trauma patients and the correlation between EMS spine immobilization decisions and the presence of spine fractures-stable and unstable-were the primary investigational outcomes. RESULTS: There were 207,545 EMS encounters during the study period, including 31,885 transports to an emergency department for acute trauma-related illness. For this cohort, there were 12,988 (41%) patients transported with EMS spine immobilization. Linkage of EMS and hospital data revealed 154 acute spine fracture patients; 20 (13.0%) transported without EMS-reported spine immobilization interventions. This nonimmobilized group included 19 stable spine fractures and one unstable thoracic spine injury. The protocol sensitivity for immobilization of any acute spine fracture was 87.0% (95% confidence interval [CI], 81.7-92.3) with a negative predictive value of 99.9% (95% CI, 99.8-100). CONCLUSIONS: The use of this statewide EMS spine assessment protocol resulted in one nonimmobilized, unstable spine fracture patient in approximately 32,000 trauma encounters. Presence of the protocol affected a decision not to immobilize greater than half of all EMS-assessed trauma patients.

Asperger's disorder or syndrome is characterized by impaired social interaction, normal intelligence, and adequate language skills in the areas of grammar and vocabulary. The symptoms are pervasive in nature and usually manifested in childhood. Despite the gravity and chronicity of the condition, the medical literature remains sparse and offers no information about possible neuropathologic underpinnings. The present study is a case report on two patients with Asperger's syndrome. Neuropathologic examination revealed no degenerative changes or gliosis. A more detailed assessment with computerized image analysis indicated abnormalities in the minicolumnar organization of the three areas examined (9, 21, 22) (P = .032). Specifically, minicolumns were smaller, and their component cells were more dispersed than normal. A similar neuropathology has recently been reported for autism and disputes the uniqueness of these findings. The minicolumnar changes provide a possible link to receptive field abnormalities and a useful clinicopathologic correlate to Asperger's syndrome.

PURPOSE: The aim of this study was to determine whether NOX2, one of the homologs of NADPH oxidase, plays a role in neuronal cell death during retinal ischemia. METHODS: Ischemia reperfusion (I/R) injury was generated in C57/BL6 and NOX2(-/-) mice by increasing the intraocular pressure (IOP) to 110 mm Hg for 40 minutes followed by reperfusion. Quantitative PCR and Western blot analysis were performed to measure NOX2 expression. Reactive oxygen species (ROS) formation was assessed by dihydroethidium imaging of superoxide formation and Western blot analysis for tyrosine nitration. TUNEL assay was performed to determine cell death at 3 days after I/R. Survival of neurons within the ganglion cell layer (GCL) was assessed at 7 days after I/R by confocal morphometric imaging of retinal wholemounts immunostained with NeuN antibody. Activation of mitogen-activated protein kinases and nuclear factor κB (NF-κΒ) was measured by Western blot analysis. RESULTS: NOX2 mRNA and protein and ROS were significantly increased in wild-type I/R retinas. This effect was associated with a 60% decrease in the number of GCL neurons and a 10-fold increase in TUNEL-positive cells compared with the fellow sham control eyes. Phosphorylation of ERK and NF-κB was significantly increased in wild-type I/R retinas. Each of these effects was markedly attenuated in the NOX2(-/-) retina (P < 0.01). CONCLUSIONS: These data demonstrate that the deletion of NOX2 can reduce I/R-induced cell death and preserve retinal GCL neurons after I/R injury. The neuronal cell injury caused by I/R is associated with the activation of ERK and NF-κB signaling mechanisms.

In a cross-sectional investigation of the properties of DSM-III-R panic disorder (PD), panic disorder with agoraphobia (PDA), and agoraphobia without history of panic disorder (AWOPD), we analyzed demographic, descriptive, comorbidity, treatment, and course data for 562 subjects with PD, PDA, or AWOPD in a multicenter anxiety-disorders study. In general, AWOPD subjects had the worst functioning and PD subjects the best, as measured by length of intake episodes, education attained, likelihood of receiving financial assistance, depressive comorbidity, and likelihood of having experienced 8 weeks symptom-free. Panic disorder with agoraphobia was the most common disorder and emerged as a condition intermediate in severity between the other two. Treatments received varied little by diagnosis. Most subjects received medication, usually benzodiazepines. Psychodynamic psychotherapy was the most frequently received psychosocial treatment; cognitive and behavioral approaches were less common. Subjects classified with AWOPD were the most likely to have received exposure therapies.