Predictors of dislocations after reverse shoulder arthroplasty: a study by the ASES complications of RSA multicenter research group.

BACKGROUND: Instability after reverse shoulder arthroplasty (RSA) is one of the most frequent complications and remains a clinical challenge. Current evidence is limited by small sample size, single-center, or single-implant methodologies that limit generalizability. We sought to determine the incidence and patient-related risk factors for dislocation after RSA, using a large, multicenter cohort with varying implants. METHODS: A retrospective, multicenter study was performed involving 15 institutions and 24 American Shoulder and Elbow Surgeons members across the United States. Inclusion criteria consisted of patients undergoing primary or revision RSA between January 2013 and June 2019 with minimum 3-month follow-up. All definitions, inclusion criteria, and collected variables were determined using the Delphi method, an iterative survey process involving all primary investigators requiring at least 75% consensus to be considered a final component of the methodology for each study element. Dislocations were defined as complete loss of articulation between the humeral component and the glenosphere and required radiographic confirmation. Binary logistic regression was performed to determine patient predictors of postoperative dislocation after RSA. RESULTS: We identified 6621 patients who met inclusion criteria with a mean follow-up of 19.4 months (range: 3-84 months). The study population was 40% male with an average age of 71.0 years (range: 23-101 years). The rate of dislocation was 2.1% (n = 138) for the whole cohort, 1.6% (n = 99) for primary RSAs, and 6.5% (n = 39) for revision RSAs (P < .001). Dislocations occurred at a median of 7.0 weeks (interquartile range: 3.0-36.0 weeks) after surgery with 23.0% (n = 32) after a trauma. Patients with a primary diagnosis of glenohumeral osteoarthritis with an intact rotator cuff had an overall lower rate of dislocation than patients with other diagnoses (0.8% vs. 2.5%; P < .001). Patient-related factors independently predictive of dislocation, in order of the magnitude of effect, were a history of postoperative subluxations before radiographically confirmed dislocation (odds ratio [OR]: 19.52, P < .001), primary diagnosis of fracture nonunion (OR: 6.53, P < .001), revision arthroplasty (OR: 5.61, P < .001), primary diagnosis of rotator cuff disease (OR: 2.64, P < .001), male sex (OR: 2.21, P < .001), and no subscapularis repair at surgery (OR: 1.95, P = .001). CONCLUSION: The strongest patient-related factors associated with dislocation were a history of postoperative subluxations and having a primary diagnosis of fracture nonunion. Notably, RSAs for osteoarthritis showed lower rates of dislocations than RSAs for rotator cuff disease. These data can be used to optimize patient counseling before RSA, particularly in male patients undergoing revision RSA.

Risk factors of acromial and scapular spine stress fractures differ by indication: a study by the ASES Complications of Reverse Shoulder Arthroplasty Multicenter Research Group.

BACKGROUND: Both patient and implant related variables have been implicated in the incidence of acromial (ASF) and scapular spine fractures (SSF) following reverse shoulder arthroplasty (RSA); however, previous studies have not characterized nor differentiated risk profiles for varying indications including primary glenohumeral arthritis with intact rotator cuff (GHOA), rotator cuff arthropathy (CTA), and massive irreparable rotator cuff tear (MCT). The purpose of this study was to determine patient factors predictive of cumulative ASF/SSF risk for varying preoperative diagnosis and rotator cuff status. METHODS: Patients consecutively receiving RSA between January 2013 and June 2019 from 15 institutions comprising 24 members of the American Shoulder and Elbow Surgeons (ASES) with primary, preoperative diagnoses of GHOA, CTA and MCT were included for study. Inclusion criteria, definitions, and inclusion of patient factors in a multivariate model to predict cumulative risk of ASF/SSF were determined through an iterative Delphi process. The CTA and MCT groups were combined for analysis. Consensus was defined as greater than 75% agreement amongst contributors. Only ASF/SSF confirmed by clinical and radiographic correlation were included for analysis. RESULTS: Our study cohort included 4764 patients with preoperative diagnoses of GHOA, CTA, or MCT with minimum follow-up of 3 months (range: 3-84). The incidence of cumulative stress fracture was 4.1% (n = 196). The incidence of stress fracture in the GHOA cohort was 2.1% (n = 34/1637) compared to 5.2% (n = 162/3127) (P < .001) in the CTA/MCT cohort. Presence of inflammatory arthritis (odds ratio [OR] 2.90, 95% confidence interval [CI] 1.08-7.78; P = .035) was the sole predictive factor of stress fractures in GHOA, compared with inflammatory arthritis (OR 1.86, 95% CI 1.19-2.89; P = .016), female sex (OR 1.81, 95% CI 1.20-2.72; P = .007), and osteoporosis (OR 1.56, 95% CI 1.02-2.37; P = .003) in the CTA/MCT cohort. CONCLUSION: Preoperative diagnosis of GHOA has a different risk profile for developing stress fractures after RSA than patients with CTA/MCT. Though rotator cuff integrity is likely protective against ASF/SSF, approximately 1/46 patients receiving RSA with primary GHOA will have this complication, primarily influenced by a history of inflammatory arthritis. Understanding risk profiles of patients undergoing RSA by varying diagnosis is important in counseling, expectation management, and treatment by surgeons.

Predictors of acromial and scapular stress fracture after reverse shoulder arthroplasty: a study by the ASES Complications of RSA Multicenter Research Group.

BACKGROUND: Acromial (ASF) and scapular spine (SSF) stress fractures are well-recognized complications of reverse shoulder arthroplasty (RSA), but much of the current data are derived from single-center or single-implant studies with limited generalizability. This study from the American Shoulder and Elbow Surgeons (ASES) Complications of Reverse Shoulder Arthroplasty Multicenter Research Group determined the incidence of ASF/SSF after RSA and identified preoperative patient characteristics associated with their occurrence. METHOD: Fifteen institutions including 21 ASES members across the United States participated in this study. Patients undergoing either primary or revision RSA between January 2013 and June 2019 with a minimum 3-month follow-up were included. All definitions and inclusion criteria were determined using the Delphi method, an iterative survey process involving all primary investigators. Consensus was achieved when at least 75% of investigators agreed on each aspect of the study protocol. Only symptomatic ASF/SSF diagnosed by radiograph or computed tomography were considered. Multivariable logistic regression was performed to identify factors associated with ASF/SSF development. RESULTS: We identified 6755 RSAs with an average follow-up of 19.8 months (range, 3-94). The total stress fracture incidence rate was 3.9% (n = 264), of which 3.0% (n = 200) were ASF and 0.9% (n = 64) were SSF. Fractures occurred at an average 8.2 months (0-64) following RSA with 21.2% (n = 56) following a trauma. Patient-related factors independently predictive of ASF were chronic dislocation (odds ratio [OR] 3.67, P = .04), massive rotator cuff tear without arthritis (OR 2.51, P < .01), rotator cuff arthropathy (OR 2.14, P < .01), self-reported osteoporosis (OR 2.21, P < .01), inflammatory arthritis (OR 2.18, P < .01), female sex (OR 1.51, P = .02), and older age (OR 1.02 per 1-year increase, P = .02). Factors independently associated with the development of SSF included osteoporosis (OR 2.63, P < .01), female sex (OR 2.34, P = .01), rotator cuff arthropathy (OR 2.12, P = .03), and inflammatory arthritis (OR 2.05, P = .03). CONCLUSION: About 1 in 26 patients undergoing RSA will develop a symptomatic ASF or SSF, more frequently within the first year of surgery. Our results indicate that severe rotator cuff disease may play an important role in the occurrence of stress fractures following RSA. This information can be used to counsel patients about potential setbacks in recovery, especially among older women with suboptimal bone health. Strategies for prevention of ASF and SSF in these at-risk patients warrant further study. A follow-up study evaluating the impact of prosthetic factors on the incidence rates of ASF and SSF may prove highly valuable in the decision-making process.

Profile of altered brain iron acquisition in restless legs syndrome.

Restless legs syndrome is a neurological disorder characterized by an urgency to move the legs during periods of rest. Data from a variety of sources provide a compelling argument that the amount of iron in the brain is lower in individuals with restless legs syndrome compared with neurologically normal individuals. Moreover, a significant percentage of patients with restless legs syndrome are responsive to intravenous iron therapy. The mechanism underlying the decreased iron concentrations in restless legs syndrome brains is unknown. We hypothesize that the source of the brain iron deficit is at the blood-brain interface. Thus we analysed the expression of iron management proteins in the epithelial cells of the choroid plexus and the brain microvasculature in post-mortem tissues. The choroid plexus, obtained at autopsy, from 18 neurologically normal controls and 14 individuals who had primary restless legs syndrome was subjected to histochemical staining for iron and immunostaining for iron management proteins. Iron and heavy chain ferritin staining was reduced in the epithelial cells of choroid plexus in restless legs syndrome. Divalent metal transporter, ferroportin, transferrin and its receptor were upregulated in the choroid plexus in restless legs syndrome. Microvessels were isolated from the motor cortex of 11 restless legs syndrome and 14 control brains obtained at autopsy and quantitative immunoblot analyses was performed. Expression of heavy chain ferritin, transferrin and its receptor in the microvessels from restless legs syndrome was significantly decreased compared with the controls but divalent metal protein 1, ferroportin, prohepcidin, mitochondrial ferritin and light-chain ferritin remained unchanged. The presence of an iron regulatory protein was demonstrated in the brain microvasculature and the activity of this protein is decreased in restless legs syndrome; a finding similar to our earlier report in neuromelanin cells from the substantia nigra of restless legs syndrome brains. This study reveals that there are alterations in the iron management protein profile in restless legs syndrome compared with controls at the site of blood-brain interface suggesting fundamental differences in brain iron acquisition in individuals with restless legs syndrome. Furthermore, the decrease in transferrin receptor expression in the microvasculature in the presence of relative brain iron deficiency reported in restless legs syndrome brains may underlie the problems associated with brain iron acquisition in restless legs syndrome. The consistent finding of loss of iron regulatory protein activity in restless legs syndrome brain tissue further implicates this protein as a factor in the underlying cause of the iron deficiency in the restless legs syndrome brain. The data herein provide evidence for regulation of iron uptake and storage within brain microvessels that challenge the existing paradigm that the blood-brain barrier is merely a transport system.

Pectoralis major tendon transfer for management of subscapularis failure after anatomic total shoulder arthroplasty: technique and results.

Background: Subscapularis tendon failure after anatomic total shoulder arthroplasty can lead to pain, dysfunction, and early component failure. The purpose of this study was to report on the results of pectoralis major tendon transfer for treatment of irreparable subscapularis tendon failure in the setting of prior shoulder arthroplasty. Methods: Patients who underwent pectoralis major muscle transfer for treatment of subscapularis failure in the setting of prior total shoulder arthroplasty or hemiarthroplasty were included in the study. The entirety of the pectoralis major tendon was transferred superficial to the conjoined tendon and placed lateral to the bicipital groove. Results: Eight patients were included in the study. All 7 patient who experienced pain in their shoulder had improvement in their pain postoperatively. Those patients with preserved active motion were able to regain that motion postoperatively. Radiographically, anterior translation was found to be temporarily improved; however, anterior instability would later recur in most cases, though this did not correlate with increased pain or decreased function. Discussion: Management options ranging from continued observation, revision repair, pectoralis muscle transfer, or revision to reverse total shoulder arthroplasty should be considered in a setting of subscapularis failure after shoulder arthroplasty. Decision-making should be based on physiological age of the patient as well as symptoms present as well as the position and stability of the arthroplasty components. Conclusion: Pectoralis muscle transfer can provide pain relief, improve subjective instability, and preserve function in physiological young patients with an irreparable subscapularis who have well-positioned and well-fixed anatomic shoulder arthroplasty components.

Operative Management of Failed Rotator Cuff Repair With Soft Tissue Release.

Background We hypothesize that revision surgery that includes soft tissue releases for patients with residual pain and reduced range of motion following rotator cuff repair can provide pain relief and improvement of motion and function. Methods Patients were identified via a retrospective chart over a 10-year period who had a history of previous rotator cuff repair and had revision surgery with or without a rotator cuff repair and soft tissue release. Changes in visual analog scores (VAS) pain score on a 10-point scale and shoulder motion including forward flexion and external rotation were evaluated from the preoperative visit to the postoperative visit. Results In total, 73 patients underwent procedures to address their symptoms following failed rotator cuff repair. Patients that underwent soft tissue release with revision rotator cuff repair and those who underwent isolated soft tissue release had decreased postoperative VAS pain scores (absolute reduction of 3 and 1.6 points, respectively) and improved postoperative forward flexion (15.3° and 13.6° respectively). Patients that have had one previous surgery had decreased pain (absolute reduction of 3.2 points), increased forward flexion and external rotation (16.2° and 4.9°). Patients that underwent two or more previous surgeries had decreased pain (absolute reduction of 1.8 points) and increased forward flexion (12.7°). Patients who were filing a Worker's compensation claim also had decreased pain (absolute reduction of 2.2 points) and increased forward flexion (14.9°). Overall, there was a VAS pain scores absolute reduction of 2.6 points or 49.5% when examining the entire patient population. Conclusion Operative management by performing soft tissue release with or without concurrent revision rotator cuff repair is successful for both decreasing pain as well as improving motion. This effect was noted both in patients with commercial insurance and worker's compensation claims. Improvements of pain and motion were more significant in patients who had undergone one prior surgery compared to those who have had multiple prior procedures.

Analysis of Long-Term Outcomes Following Surgical Contracture Release of the Elbow: A Case Series.

Background Elbow contracture is a debilitating condition with an incidence ranging from as low as almost 1% to as high as 20% and results in significant limiting consequences on a patient's activities of daily living (ADLs). Postoperative rehabilitation is important in maintaining the range of motion and sustaining an improved range of motion. The purpose of this study was to evaluate the long-term results of elbow contracture release surgery and the effect of an occupational therapy/physical therapy (OT/PT)-guided, self-directed rehabilitation program following surgery, without the use of continuous passive motion (CPM) devices. Methods We enrolled patients who had undergone elbow contracture release surgery from 2005 to 2016 at a single institution under the senior author. The evaluation included objective measurements of range-of-motion, strength, and neurological sensory testing. Provocative testing of the elbow and hand was performed. American Shoulder and Elbow Surgeons-elbow (ASES-e), Simple Shoulder Test-elbow (SST-e), Disabilities of the Arm and Shoulder (DASH), Mayo Elbow Performance Index (MEPI), Short Form-36 (SF-36), and an investigator questionnaire were completed. Results We enrolled 19 patients, six female and 13 male, with an average follow-up of 58.9 months (SD± 39.8, Range 22-117). We showed improvement and sustained motion between preoperative and postoperative research visit flexion (p<0.001) and flexion extension-arc (p<0.01). The mean increase in flexion was 98° to 131° and the flexion-extension arc was 36°. Patients were satisfied with the decision to undergo surgery and had sustained ability to complete ADLs. Discussion This patient cohort demonstrated a statistically significant increase, as well as long-term maintenance in the flexion and flexion-extension arc. A self-directed, OT/PT-guided, therapy program without CPM was effective. Patients showed good outcomes and were satisfied with their ability to perform ADLs, decreased pain, and the decision to undergo surgery.

Efficacy of local infiltration anesthesia versus interscalene nerve blockade for total shoulder arthroplasty.

BACKGROUND: Optimal modalities for pain control in shoulder arthroplasty are not yet established. Although regional nerve blockade has been a well-accepted modality, complications and rebound pain have led some surgeons to seek other pain control modalities. Local injection of anesthetics has recently gained popularity in joint arthroplasty. The purpose of this study was to evaluate the effectiveness and complication rate of a low-cost local anesthetic injection mixture for use in total shoulder arthroplasty (TSA) compared with interscalene brachial plexus blockade. METHODS: A total of 314 patients underwent TSA and were administered general anesthesia with either a local injection mixture (local infiltration anesthesia [LIA], n = 161) or peripheral nerve block (PNB, n = 144). Patient charts were retrospectively reviewed for postoperative pain scores, 24-hour opioid consumption, and 90-day postoperative complications. RESULTS: Immediate postoperative pain scores were not significantly different between groups (P = .94). The LIA group demonstrated a trend toward lower pain scores at 24 hours postoperatively (P = .10). Opioid consumption during the first 24 hours following surgery was significantly reduced in the LIA group compared with the PNB group (P < .0001). There was a trend toward fewer postoperative nerve and cardiopulmonary complications in the LIA group than the PNB group (P = .22 and P = .40, respectively). CONCLUSION: Periarticular local injection mixtures provide comparable pain control to regional nerve blocks while reducing opioid use and postoperative complications following TSA. Local injection of a multimodal anesthetic solution is a viable option for pain management in TSA.

Comparative study of the influence of Thy1 deficiency and dietary iron deficiency on dopaminergic profiles in the mouse striatum.

Thy-1, a glycosyl-phosphatidylinositol (GPI)-linked integral membrane protein, may play a role in stabilizing synapses. Thy1 was identified in a gene expression analysis as iron responsive, and subsequent cell culture and animal models of iron deficiency expanded this finding to the protein. The importance of Thy1 in influencing neurotransmitter feedback mechanisms led to this study to determine the relative effects of Thy1 deficiency and dietary iron deficiency on the dopaminergic system in the mouse striatum. The model for this analysis was the Thy1 null mutant mouse in the presence or absence of dietary iron deficiency. The results revealed significant differences in dopaminergic profiles associated with Thy1 and iron deficiency and also a sex effect. For example, both iron deficiency and the absence of Thy1 are associated with increased dopamine in both sexes, but the dopamine transporter is increased in these experimental groups only in female mice. In male mice, the increase in dopamine transporter is found only in the Thy1 null mutants. Increases in vesicular monoamine transporter and phosphorylated tyrosine hydroxlyase are found only in iron-deficient mice. In contrast decreased release of dopamine from synaptosomes is found only in the Thy1 null mutant animals. In general, these results indicate that a loss of Thy1 can influence the dopaminergic profile in the striatum. Furthermore, the results reveal consistent differences in the dopaminergic profile in Thy1 knockout mice compared with iron-deficient mice, indicating that the effects of iron deficiency are not due only to a change in Thy1 expression.

Altered iron metabolism in lymphocytes from subjects with restless legs syndrome.

OBJECTIVE: Studies using cerebrospinal fluid, magnetic resonance imaging, and autopsy tissue have implicated a primary role for brain iron insufficiency in restless legs syndrome (RLS). If the abnormalities of brain iron regulation reflect a basic disturbance of iron metabolism, then this might be expressed at least partially in some peripheral systems. Thus the study aim was to determine whether patients with RLS and control subjects show differences in lymphocyte iron regulator proteins. METHODS: Fasting morning blood samples were used to obtain common serum measures of iron status and to determine lymphocyte iron management proteins. Twenty-four women with early-onset RLS and 25 control women without RLS symptoms were studied. RESULTS: RLS and control subjects were matched for age, hemoglobin, and serum iron profile. However, transferrin receptor (TfR) and DMT1 (divalent metal transporter 1 protein) levels in lymphocytes were significantly higher for RLS patients than for controls. No significant differences in ferritin subtypes or transferrin levels were found. No significant correlations were found between lymphocyte and serum indices of iron status. INTERPRETATION: RLS lymphocytes showed an increase in ferroportin, implying increased cellular iron excretion, in the face of increased iron need (increased TfR and DMT1). In the absence of changes in H-ferritin, the findings indicate a balance between input and output with no net iron change but probable overall increase in iron turnover. The lack of any significant correlation between serum and lymphocyte iron indices indicates that iron management proteins from lymphocytes are at a minimum an alternative and independent marker of cellular iron metabolism.

A novel model for brain iron uptake: introducing the concept of regulation.

Neurologic disorders such as Alzheimer's, Parkinson's disease, and Restless Legs Syndrome involve a loss of brain iron homeostasis. Moreover, iron deficiency is the most prevalent nutritional concern worldwide with many associated cognitive and neural ramifications. Therefore, understanding the mechanisms by which iron enters the brain and how those processes are regulated addresses significant global health issues. The existing paradigm assumes that the endothelial cells (ECs) forming the blood-brain barrier (BBB) serve as a simple conduit for transport of transferrin-bound iron. This concept is a significant oversimplification, at minimum failing to account for the iron needs of the ECs. Using an in vivo model of brain iron deficiency, the Belgrade rat, we show the distribution of transferrin receptors in brain microvasculature is altered in luminal, intracellular, and abluminal membranes dependent on brain iron status. We used a cell culture model of the BBB to show the presence of factors that influence iron release in non-human primate cerebrospinal fluid and conditioned media from astrocytes; specifically apo-transferrin and hepcidin were found to increase and decrease iron release, respectively. These data have been integrated into an interactive model where BBB ECs are central in the regulation of cerebral iron metabolism.

Age-dependent retinal iron accumulation and degeneration in hepcidin knockout mice.

PURPOSE: Iron dysregulation can cause retinal disease, yet retinal iron regulatory mechanisms are incompletely understood. The peptide hormone hepcidin (Hepc) limits iron uptake from the intestine by triggering degradation of the iron transporter ferroportin (Fpn). Given that Hepc is expressed in the retina and Fpn is expressed in cells constituting the blood-retinal barrier, the authors tested whether the retina may produce Hepc to limit retinal iron import. METHODS: Retinas of Hepc(-/-) mice were analyzed by histology, autofluorescence spectral analysis, atomic absorption spectrophotometry, Perls' iron stain, and immunofluorescence to assess iron-handling proteins. Retinal Hepc mRNA was evaluated through qPCR after intravitreal iron injection. Mechanisms of retinal Hepc upregulation were tested by Western blot analysis. A retinal capillary endothelial cell culture system was used to assess the effect of exogenous Hepc on Fpn. RESULTS: Hepc(-/-) mice experienced age-dependent increases in retinal iron followed by retinal degeneration with autofluorescent RPE, photoreceptor death, and subretinal neovascularization. Hepc(-/-) mice had increased Fpn immunoreactivity in vascular endothelial cells. Conversely, in cultured retinal capillary endothelial cells, exogenous Hepc decreased both Fpn levels and iron transport. The retina can sense increased iron levels, upregulating Hepc after phosphorylation of extracellular signal regulated kinases. CONCLUSIONS: These findings indicate that Hepc is essential for retinal iron regulation. In the absence of Hepc, retinal degeneration occurs. Increases in Hepc mRNA levels after intravitreal iron injection combined with Hepc-mediated decreases in iron export from cultured retinal capillary endothelial cells suggest that the retina may use Hepc for its tissue-specific iron regulation.

Postmortem and imaging based analyses reveal CNS decreased myelination in restless legs syndrome.

BACKGROUND: Restless legs syndrome (RLS) is a neurological disorder characterized by a strong urge to move the legs and has been shown in many studies with abnormally low brain iron. Iron deficiency is associated with hypomyelination in brains of animals. Therefore we hypothesized that a myelin deficit should be present in the brains of patients with RLS. METHODS: We performed Western blot analysis on myelin isolated from RLS (n=11) and control (n=11) brain tissue obtained at autopsy for the expression of the integral myelin proteins, myelin basic protein (MBP), and proteolipid protein (PLP) and the oligodendrocyte specific enzyme 3'5'-cyclic nucleotide phosphohydrolase (CNPase). To expand the postmortem findings to in vivo, we analyzed the brains of RLS patients (n=23) and controls (n=23) using voxel-based morphometry (VBM). RESULTS: The expression of MBP, PLP and CNPase in the myelin from RLS was decreased by approximately 25% (p<0.05) compared to controls. The amounts of transferrin (Tf) and H-ferritin (H-Frt) in the myelin fraction were also significantly decreased in RLS compared to controls. The imaging analysis revealed significant small decreases in white matter volume in RLS patients compared to controls in the corpus callosum, anterior cingulum and precentral gyrus. CONCLUSION: A decrease in myelin similar to that reported in animal models of iron deficiency was found in the brains of individuals with RLS. The evidence for less myelin and loss of myelin integrity in RLS brains, coupled with decreased ferritin and transferrin in the myelin fractions, is a compelling argument for brain iron insufficiency in RLS. These data also indicate the need to look beyond the sensorimotor symptoms that typically define the syndrome and its assumed relation to the dopaminergic system. Understanding the full range of RLS pathology may help us better understand the complex, intermittent nature and diversity of the clinical features of RLS and expand our consideration of treatment options for RLS.

Gene-environment interactions: neurodegeneration in non-mammals and mammals.

The understanding of how environmental exposures interact with genetics in central nervous system dysfunction has gained great momentum in the last decade. Seminal findings have been uncovered in both mammalian and non-mammalian model in large result of the extraordinary conservation of both genetic elements and differentiation processes between mammals and non-mammalians. Emerging model organisms, such as the nematode and zebrafish have made it possible to assess the effects of small molecules rapidly, inexpensively, and on a miniaturized scale. By combining the scale and throughput of in vitro screens with the physiological complexity and traditional animal studies, these models are providing relevant information on molecular events in the etiology of neurodegenerative disorders. The utility of these models is largely driven by the functional conservation seen between them and higher organisms, including humans so that knowledge obtained using non-mammalian model systems can often provide a better understanding of equivalent processes, pathways, and mechanisms in man. Understanding the molecular events that trigger neurodegeneration has also greatly relied upon the use of tissue culture models. The purpose of this summary is to provide-state-of-the-art review of recent developments of non-mammalian experimental models and their utility in addressing issues pertinent to neurotoxicity (Caenorhabditis elegans and Danio rerio). The synopses by Aschner and Levin summarize how genetic mutants of these species can be used to complement the understanding of molecular and cellular mechanisms associated with neurobehavioral toxicity and neurodegeneration. Next, studies by Suñol and Olopade detail the predictive value of cultures in assessing neurotoxicity. Suñol and colleagues summarize present novel information strategies based on in vitro toxicity assays that are predictive of cellular effects that can be extrapolated to effects on individuals. Olopade and colleagues describe cellular changes caused by sodium metavanadate (SMV) and demonstrate how rat primary astrocyte cultures can be used as predicitive tools to assess the neuroprotective effects of antidotes on vanadium-induced astrogliosis and demyelination.

Role of surfactant protein-A (SP-A) in lung injury in response to acute ozone exposure of SP-A deficient mice.

Millions are exposed to ozone levels above recommended limits, impairing lung function, causing epithelial damage and inflammation, and predisposing some individuals to pneumonia, asthma, and other lung conditions. Surfactant protein-A (SP-A) plays a role in host defense, the regulation of inflammation, and repair of tissue damage. We tested the hypothesis that the lungs of SP-A(-/-) (KO) mice are more susceptible to ozone-induced damage. We compared the effects of ozone on KO and wild type (WT) mice on the C57BL/6 genetic background by exposing them to 2 parts/million of ozone for 3 or 6 h and sacrificing them 0, 4, and 24 h later. Lungs were subject to bronchoalveolar lavage (BAL) or used to measure endpoints of oxidative stress and inflammation. Despite more total protein in BAL of KO mice after a 3 h ozone exposure, WT mice had increased oxidation of protein and had oxidized SP-A dimers. In KO mice there was epithelial damage as assessed by increased LDH activity and there was increased phospholipid content. In WT mice there were more BAL PMNs and elevated macrophage inflammatory protein (MIP)-2 and monocyte chemoattractant protein (MCP)-1. Changes in MIP-2 and MCP-1 were observed in both KO and WT, however mRNA levels differed. In KO mice MIP-2 mRNA levels changed little with ozone, but in WT levels they were significantly increased. In summary, several aspects of the inflammatory response differ between WT and KO mice. These in vivo findings appear to implicate SP-A in regulating inflammation and limiting epithelial damage in response to ozone exposure.