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Introduction Relative impacts of coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) on mortality and end-stage kidney disease (ESKD) in chronic kidney disease (CKD) are uncertain. Methods Data from Massachusetts residents with CKD undergoing CABG or PCI from 2003 to 2012 were linked to the United States Renal Data System. Associations with death, ESKD, and combined death and ESKD were analyzed in propensity score−matched multivariable survival models. Results We identified 6805 CABG and 17,494 PCI patients. Among 3775 matched-pairs, multi-vessel disease was present in 97%, and stage 4 CKD was present in 11.9% of CABG and 12.2% of PCI patients. One-year mortality (CABG 7.7%, PCI 11.0%) was more frequent than ESKD (CABG 1.4%, PCI 1.7%). Overall survival was improved and ESKD risk decreased with CABG compared to PCI, but effects differed in the presence of left main disease and prior myocardial infarction (MI). Survival was worse following PCI than following CABG among patients with left main disease and without MI (hazard ratio = 3.7, 95% confidence interval = 1.3−10.5). ESKD risk was higher with PCI for individuals with left main disease and prior infarction (hazard ratio = 8.1, 95% confidence interval = 1.7−39.2). Conclusion Risks following CABG and PCI were modified by left main disease and prior MI. In individuals with CKD, survival was greater after CABG than after PCI in patients with left main disease but without MI, whereas ESKD risk was lower with CABG in those with left main and MI. Absolute risks of ESKD were markedly lower than for mortality, suggesting prioritizing mortality over ESKD in clinical decision making., Graphical abstract

In addition to acute injury requiring interventional radiologic treatments, patients with traumatic injuries can develop delayed or chronic complications. These injuries can involve nearly all solid organs in the abdomen. Coupled with significant improvements in visualizing these injuries with advanced imaging techniques such as minimally invasive procedures, nonoperative management of both acute traumatic injuries and their longer term sequelae has become the norm. This article reviews frequently seen complications of traumatic injury and their management by interventional radiologists.

Background The Centers for Medicare and Medicaid Services (CMS) use colon surgical site infection (SSI) rates to rank hospitals and apply financial penalties. The CMS’ risk-adjustment model omits potentially impactful variables that might disadvantage hospitals with complex surgical populations. Methods We analyzed adult patients who underwent colon surgery within facilities associated with HCA Healthcare from 2014 to 2016. SSIs were identified from National Health Safety Network (NHSN) reporting. We trained and validated 3 SSI prediction models, using (1) current CMS model variables, including hospital-specific random effects (HCA-adapted CMS model); (2) demographics and claims-based comorbidities (expanded-claims model); and (3) demographics, claims-based comorbidities, and NHSN variables (claims-plus–electronic health record [EHR] model). Discrimination, calibration, and resulting rankings were compared among all models and the current CMS model with published coefficient values. Results We identified 39 468 colon surgeries in 149 hospitals, resulting in 1216 (3.1%) SSIs. Compared to the HCA-adapted CMS model, the expanded-claims model had similar performance (c-statistic, 0.65 vs 0.67, respectively), while the claims-plus-EHR model was more accurate (c-statistic, 0.70; 95% confidence interval, .67–.73; P = .004). The sampling variation, due to the low surgical volume and small number of infections, contributed 74% of the total variation in observed SSI rates between hospitals. When CMS model rankings were compared to those from the expanded-claims and claims-plus-EHR models, 18 (15%) and 26 (22%) hospitals changed quartiles, respectively, and 10 (8.3%) and 12 (10%) hospitals changed into or out of the lowest-performing quartile, respectively. Conclusions An expanded set of variables improved colon SSI risk predictions and quartile assignments, but low procedure volumes and SSI events remain a barrier to effectively comparing hospitals., Using additional variables can improve risk adjustments of hospital-level colon surgical site infection rates, but have limited impact on financial penalties. Low procedure and infection rates contribute to much of the between-hospital variation.

Background— Although risk adjustment remains a cornerstone for comparing outcomes across hospitals, optimal strategies continue to evolve in the presence of many confounders. We compared conventional regression-based model to approaches particularly suited to leveraging big data. Methods and Results— We assessed hospital all-cause 30-day excess mortality risk among 8952 adults undergoing percutaneous coronary intervention between October 1, 2011, and September 30, 2012, in 24 Massachusetts hospitals using clinical registry data linked with billing data. We compared conventional logistic regression models with augmented inverse probability weighted estimators and targeted maximum likelihood estimators to generate more efficient and unbiased estimates of hospital effects. We also compared a clinically informed and a machine-learning approach to confounder selection, using elastic net penalized regression in the latter case. Hospital excess risk estimates range from −1.4% to 2.0% across methods and confounder sets. Some hospitals were consistently classified as low or as high excess mortality outliers; others changed classification depending on the method and confounder set used. Switching from the clinically selected list of 11 confounders to a full set of 225 confounders increased the estimation uncertainty by an average of 62% across methods as measured by confidence interval length. Agreement among methods ranged from fair, with a κ statistic of 0.39 (SE: 0.16), to perfect, with a κ of 1 (SE: 0.0). Conclusions— Modern causal inference techniques should be more frequently adopted to leverage big data while minimizing bias in hospital performance assessments.

Purpose To examine the extent of visual function abnormality outside the dark lesion on short-wavelength fundus autofluorescence (SW-AF), and its correlation with background SW-AF features and optical coherence tomography (OCT) in recessive Stargardt disease (STGD1). Methods Forty-nine eyes of 25 participants in the ProgStar (the Natural History of the Progression of Atrophy Secondary to Stargardt Disease) study at our center were included. Patients underwent microperimetry (both threshold and dense scotoma mapping), OCT, SW-AF, and visual acuity testing. The Fisher's exact test, the χ2 test, and unpaired t-tests were used to analyze the data. Results Of 40 eyes without central fixation, 33 (82%) placed fixation remote (most ≥5°) from the dense scotoma edge, despite good intervening retinal sensitivity. OCT findings accounted for the remote fixation in 75%. Eighteen (37%) of all 49 eyes had dense scotoma extending past the dark lesion border. OCT was not adequate to define the edge of the scotoma. Of the 49 eyes, 28 (57%) had the mottled background pattern, 10 (20%) had the uniform pattern, and 11 (22%) had the other pattern, with >75% of eyes in each pattern having remote fixation. The dense scotoma exceeded the dark lesion primarily in the mottled pattern. The two eyes of each patient were concordant in all features. Conclusions Functional abnormalities in STGD1 extend past the SW-AF dark lesion. The disruption of the ellipsoid zone shows that photoreceptor abnormality extends peripheral to the dark lesion, and it explains in part the remote fixation pattern and the dense scotoma exceeding the dark lesion. This has implications for clinical trials for STGD1.

Background and Objective: Women of color (WOC) (African American, Hispanic, Native American/Alaskan Native, and Asian American) faculty remain disproportionately underrepresented among medical school faculty and especially at senior ranks compared with White female faculty. The barriers or facilitators to the career advancement of WOC are poorly understood. The Women and Inclusion in Academic Medicine (WIAM) study was developed to characterize individual, institutional and sociocultural factors that influence the entry, progression and persistence, and advancement of women faculty in academic medical careers with a focus on WOC.Methods: Using a purposive sample of 13 academic medical institutions, we collected qualitative interview data from 21 WOC junior faculty and quantitative data from 3,127 (38.9% of 8,053 eligible women) respondents via an online survey. To gather institutional data, we used an online survey and conducted 23 key administrative informant interviews from the 13 institutions. Grounded theory methodology will be used to analyze qualitative data. Multivariable analysis including hierarchical linear modeling will be used to investigate outcomes, such as the inclusiveness of organizational gender climate and women faculty’s intent to stay.Conclusion: We describe the design, methods, rationale and limitations of one of the largest and most comprehensive studies of women faculty in academic medicine with a focus on WOC. This study will enhance our understanding of challenges that face women, and, especially WOC, faculty in academic medicine and will provide solutions at both the individual and institutional levels. Ethn Dis. 2016;26(2): 245-254; doi:10.18865/ed.26.2.245

Objective To evaluate the clinical outcomes after aortic valve replacement or aortic valve replacement and coronary artery bypass grafting in a large contemporary population, and to determine if outcomes are associated with patient ethnicity and gender status. Methods Using the Massachusetts Cardiac Surgery Database, we identified 6809 adults aged 18 years or older who had undergone isolated aortic valve replacement or aortic valve replacement and coronary artery bypass grafting in all non-federal acute-care Massachusetts hospitals from 2002 to 2008. Univariate and multivariate logistic regression analyses were used to identify differences in patient characteristics, major morbidity, and 30-day and 1-year mortality between men (n = 4043) and women (n = 2766) and between whites (n = 6481) and nonwhites (n = 328). Results The unadjusted 30-day mortality rate was 2.6% for the men and 3.1% for the women ( P = .296) and 2.8% for whites and 3.7% for nonwhites ( P = .342). In adjusted logistic regression models, the 30-day mortality was not different between the female and male patients (odds ratio, 0.88; 95% confidence interval, 0.26–3.02, P = .84) nor between the nonwhites and whites (odds ratio, 1.57; 95% confidence interval, 0.45–5.44; P = .48). The incidence of postoperative stroke was greater in women (3.0% women and 2.2% men, P = .031), and the incidence of postoperative myocardial infarction (10.9% women and 13.6% men; P = .001) and septicemia (1.2% women and 2.0% men; P = .009) was greater in men. Conclusions Ethnicity and gender were not associated with greater 30-day and 1-year mortality after aortic valve replacement or aortic valve replacement and coronary artery bypass grafting. Differences in postoperative outcomes were not observed between ethnic groups.

A spray track was designed and built to conduct replicated laboratory and field studies to compare different nozzle configurations on the ability of each to achieve lower canopy spray coverage. The purpose was to determine which nozzles might be more affective in preventing or controlling Asian Soybean Rust. Twenty nozzle types were compared in the lab and twelve nozzle types were compared in the field trials. All comparisons were at 187 L ha-1 and at a spraying speed of 16 KPH. Orifice size and operating spray pressure for each nozzle was adjusted to maintain the desired spray droplet size (200-300 microns VMD) at the calibrated flow rate of 2.5 LPM (187 L/Ha at 16 KPH). A tank mix solution of water and non-ionic surfactant was used for each comparison to simulate a field spraying scenario. For the field trials a fungicide was added to the solution to further simulate a field spraying scenario. Water Sensitive Paper and DropletScan™ was used to measure and compare VMD, percent area coverage (PAC), and number of droplets per square centimeter (DPS). In the laboratory trial, significant differences were found with PAC comparisons ranging from 5.1 to 1.6 percent. The TT11006 sprayed at 344 kPa had the most coverage. Significant differences were also found with number of D/SC with the TT11004 at 655 kPa the highest (145.5). In the field trials, significant differences were found with percent area coverage comparisons ranging from 10 to 6 percent. The TT11005 sprayed at 517 kPa had the most coverage. Significant differences were also found with number of D/SC with the TT11004 at 655 kPa the highest (43). In both experiments the single nozzle designs on average provided more coverage than the double nozzle designs. Actual measured VMD’s for all the nozzle treatments in both experiments were higher than expected. The twin or double nozzle treatments had the smaller VMD’s.

Increased soybean foliar disease potential has heightened grower interest in fungicide application techniques. Application field trials comparing application rate [187 vs. 112 L/ha (20 vs. 12 gal/acre)], nozzle style (twin-orifice; single-orifice) and spray quality (fine vs. medium and coarse spray quality), and application technique (with and without air-assist) along with an unsprayed check were done at two locations over two years. Fungicide deposition (coverage and droplet size) and disease severity in the bottom, middle, and top parts of the plant canopy, and soybean yield were measured.

A field study was conducted in 2007 and 2008 to determine the influence of nozzle type and water volume on the control of dollar spot of greens-height creeping bentgrass, caused by Sclerotinia homoeocarpa F. T. Bennett. The nozzles utilized were XR, TurfJet, Air Induction, Turbo TwinJet, and Turbo Drop Twin Fan, all producing flat spray patterns. For each nozzle type, three flow rates were used to produce water carrier volumes equivalent to 0.5, 1.0, or 2.0 gal/1000 ft². Chlorothalonil (1.8 oz/1000 ft²) was applied on a 14-day interval. Disease was assessed by counting the number of dollar spot infection centers in plot centers where spray coverage was complete. Overall, all nozzles except for TurfJet provided similar dollar spot suppression, and water volume was rarely a factor. On one rating date in 2007, all nozzle-volume combinations reduced dollar spot compared to untreated turf except for the TurfJet nozzles at the lower water volumes. On one date in 2008, all nozzle and volume combinations reduced dollar spot compared to untreated turf, with the exception of plots receiving fungicide through XR and TurfJet nozzles at 0.5 gal/1000 ft² or Air Induction nozzles at 1.0 gal/1000 ft². Therefore, the use of a reduced water volume and an air induction drift reducing nozzle may be a practical option for managing dollar spot with a contact fungicide in creeping bentgrass.

Background: The amount of time devoted to musculoskeletal medicine in the typical undergraduate curriculum is disproportionately low compared with the frequency of musculoskeletal complaints that occur in a general practice. Consequently, whether because of the quantity or quality of the education, the competence level of graduating physicians regarding musculoskeletal problems is inadequate. Our purposes were to design a self-contained, system-based course in musculoskeletal medicine for medical students in the preclinical years and to measure the level of competence achieved by a class of first-year medical students who took the course. Methods: The course was formulated by faculty from the departments of orthopaedic surgery, anatomy, and rheumatology and included elements of both objectives-based and problem-centered curricular models. The clinical lectures were preceded by pertinent anatomy lectures and dissections to provide a context for the clinical information. The lectures on basic science were designed to rationalize and explicate clinical practices. Small-group activities were incorporated to permit engagement of the students in critical thinking and problem-solving. A general musculoskeletal physical examination was taught in two two-hour-long small-group sessions with the orthopaedic residents serving as instructors. Cognitive competency was evaluated with use of comprehensive anatomy laboratory and written examinations, the latter of which included a validated basic competency examination in musculoskeletal medicine. Process-based skills were evaluated in the small-group meetings and in a timed, mock patient encounter in which each student's ability to perform the general musculoskeletal physical examination was assessed. Results: The course lasted six weeks and consisted of forty-four lecture hours, seventeen hours of small-group meetings, and twenty-eight hours of anatomy laboratory. The average student score on the basic competency examination was 77.8%, compared with 59.6% for a historical comparison group (p < 0.05). Each student demonstrated the ability to adequately perform a general musculoskeletal physical examination in twenty minutes. The survey of student opinion after the course indicated a high level of student satisfaction. Conclusions: The main features of the course were: (1) an emphasis on both cognitive and process-based knowledge; (2) more contact hours and broader content than in previously described courses in musculoskeletal medicine; (3) the use of small groups to focus on problem-solving and physical examination competencies; (4) basic-science content directly related to clinical goals. These features might be used at other institutions that employ a system-based curriculum for the preclinical years to help improve competence in musculoskeletal medicine.

Objective . Budgetary pressures have led some states to limit Medicaid eligibil- ity. We evaluated access to care for all low-income adults by the extent of state Medicaid coverage. Methods . Current Population Survey data compiled by the Kaiser Commission on Medicaid and the Uninsured were used to rank the 48 continental states by the extent of Medicaid coverage for low-income non-elderly adults during 2000-2003. Data from the Behavioral Risk Factor Surveillance System for 2000-2003 were used to assess indicators of access to care, including being unable to see a physician due to cost, not obtaining routine checkups, and four preventive services for appropriate age groups by state. Access gaps were calculated between low-income (under $25,000/year) and high-income ($50,000 or more/year) adults within each state to control for unmeasured economic and health system differences between states. Results . Access gaps between high and low-income people who could not see physicians due to cost were significantly smaller in states with the broadest Medicaid coverage compared with states with the narrowest coverage (19.2% vs. 23.7%, p.003). Significantly smaller access gaps also occurred in states with broader Medicaid coverage for cholesterol testing (16.0% vs. 18.7%, p.01), and Pap testing (6.0% vs. 10.8%, p.002), but not colorectal cancer screening (13.3% vs. 12.5%, p.28), mammography (14.3% vs. 19.7%, p.07), and routine checkup within two years (8.0% vs. 9.3%, p.10). Conclusions . A state's level of Medicaid coverage was associated with access to physicians' services, cholesterol testing, and cervical cancer screening for low-income adults. Broad Medicaid coverage may be an effective strategy for states to improve access to care and preventive services for low-income adults.

Background— Regardless of statistical methodology, public performance report cards must use the highest-quality validated data, preferably from a prospectively maintained clinical database. Using logistic regression and hierarchical models, we compared hospital cardiac surgery profiling results based on clinical data with those derived from contemporaneous administrative data. Methods and Results— Fiscal year 2003 isolated coronary artery bypass grafting surgery results based on an audited and validated Massachusetts clinical registry were compared with those derived from a contemporaneous state administrative database, the latter using the inclusion/exclusion criteria and risk model of the Agency for Healthcare Research and Quality. There was a 27.4% disparity in isolated coronary artery bypass grafting surgery volume (4440 clinical, 5657 administrative), a 0.83% difference in observed in-hospital mortality (2.05% versus 2.88%), corresponding differences in risk-adjusted mortality calculated by various statistical methodologies, and 1 hospital classified as an outlier only with the administrative data–based approach. The discrepancies in volumes and risk-adjusted mortality were most notable for higher-volume programs that presumably perform a higher proportion of combined procedures that were misclassified as isolated coronary artery bypass grafting surgery in the administrative cohort. Subsequent analyses of a patient cohort common to both databases revealed the smoothing effect of hierarchical models, a 9% relative difference in mortality (2.21% versus 2.03%) resulting from nonstandardized mortality end points, and 1 hospital classified as an outlier using logistic regression but not using hierarchical regression. Conclusions— Cardiac surgery report cards using administrative data are problematic compared with those derived from audited and validated clinical data, primarily because of case misclassification and nonstandardized end points.

Objective. To control costs and improve quality, payers are designing new hospital reimbursement policies that link payment to quality. The authors determine the extent to which quality measures discriminate hospitals into tiers in 2 geographic areas. Data Sources. Administrative and medical record data for patients discharged with acute myocardial infarction (AMI) in 368 California and 81 Massachusetts hospitals. Methods. Through simulation, the minimum numbers of patients per hospital needed to identify highquality hospitals with sensitivity ranging from 75% to 95% under a variety of clinical scenarios are determined. Results. Massachusetts hospitals had twice the number of eligible patients per hospital than California hospitals. Regardless of state, few hospitals had sufficient sample size needed to achieve >85% sensitivity for high-variation quality measures. Clinical Implications. Reliability of quality-based reimbursement systems relies on the distribution of the hospital sample sizes within geographic areas and the size of practice differences. Selection of conformance thresholds and sensitivity levels depends on the user of the information. To assess the usefulness of performance measures to tier hospitals, information regarding between-hospital variation in quality for specific clinical measures needs to be collected and reported.

Cessation of blood flow to the liver is required during liver transplantation and resectional surgery. A growing body of experimental evidence suggests that restoration of blood flow to the ischemic liver initiates hepatocellular injury which may lead, in some cases, to severe liver injury and graft failure. A large number of studies have implicated reactive oxygen species as potential mediators of post-ischemic tissue injury. Recent developments in genetic engineering as well as chemical modeling, have allowed for the production of novel free radical scavengers including mutated forms of superoxide dismutase (SOD) and low molecular weight SOD mimics with extended circulating half-lives and/or significant membrane permeability's. Application of these newly developed free radical scavengers show promising results in animal models of liver I/R and may become powerful tools in the treatment of post-ischemic liver injury that occurs in liver transplantation.

Background. Population-based cancer registries represent a potentially valuable tool to evaluate treatment; however, information on the completeness of registry treatment data is sparse. Objective. To evaluate the completeness of registry treatment data for patients with colorectal cancer and to identify predictors of complete reporting. Research Design. We surveyed physicians or reviewed office records of 1956 northern California patients diagnosed with colorectal cancer during 1996 to 1997 to assess the completeness of registry data regarding use of adjuvant chemotherapy and radiation therapy. Results. For patients with a record of receipt of chemotherapy in either the registry or physician survey, information was in the original registry records for 82.0%. In the multivariate analysis, completeness of chemotherapy reporting was lower for patients aged 65 to 74, those with colon cancer, and those treated in teaching hospitals; and higher for patients treated in hospitals that are part of a large health maintenance organization (HMO). For patients with a record of receipt of radiation therapy, information was in the original registry records for 90.2%. In the multivariate analysis, completeness of radiation therapy reporting was higher for patients aged 18 to 54 and those treated in HMO hospitals. Conclusions. Because the completeness of the registry treatment data varied by patient and hospital characteristics, use of registry data without supplementation could bias estimates of the proportion of patients treated, and of the patient and provider characteristics associated with treatment. Enhanced cancer registry data could be a valuable component of population-based cancer data systems for assessing quality of cancer care.

Purpose: Randomized trials have demonstrated that adjuvant chemotherapy improves survival for patients with stage III colon cancer and that chemotherapy combined with radiation therapy improves survival for patients with stage II or III rectal cancer. This population-based study was designed to assess use of these treatments in clinical practice. Patients and Methods: From the California Cancer Registry, we identified all patients diagnosed during 1996 to 1997 with stage III colon cancer (n = 1,422) and stage II or III rectal cancer (n = 534) in 22 northern California counties. To supplement registry data on adjuvant therapies and ascertain reasons they were not used, we surveyed physicians or reviewed office records for 1,449 patients (74%). Results: Chemotherapy rates varied widely by age from 88% (age < 55 years) to 11% (age ≥ 85 years), and radiation therapy varied similarly. Adjusting for demographic, clinical, and hospital characteristics, chemotherapy was used less often among older and unmarried patients, and radiation therapy was used less often among older patients, black patients, and those initially treated in low-volume hospitals. Adjusted rates of chemotherapy varied significantly (P < .01) among individual hospitals: 79% and 51%, respectively, at one SD above and below average (67%). Physicians’ reasons for not providing adjuvant therapy included patient refusal (30% for chemotherapy, 22% for radiation therapy), comorbid illness (22% and 14%, respectively), or lack of clinical indication (22% and 45%, respectively). Conclusion: Use of adjuvant therapy for colorectal cancer varies substantially by age, race, marital status, hospital volume, and individual hospital, indicating opportunities to improve care. With enhanced data on adjuvant therapies, population-based registries could become a valuable resource for monitoring the quality of cancer care.

Rheumatoid arthritis (RA) is a common systemic inflammatory disease thought to be T- helper-1 cell driven, though current controversy involves the relative role of T cells versus other leukocytes. Thus, there is a need for better understanding of the role of various leukocytes and their subsets in RA. Using the streptococcal cell wall (SCW) induced arthritis model, we examined leukocytes isolated from peripheral blood, spleen, and lymph nodes using monoclonal antibodies directed against lineage specific cell surface markers. Activation status of these cells was assessed using CD44 and CD71 as markers. T cells in general, and CD4 C T cells in particular were found to be activated in spleen and lymph nodes. B cells and monocytes in spleen demonstrated increased activation as well. The activation of cells in the myeloid and lymphoid lineages in the chronic phase of arthritis indicates ongoing involvement of innate and cognate immunity. This study quantitates specific changes in B and T lymphocytes, and myeloid cells and is consistent with findings in human RA in which specific antibodies, T cells, and myeloid cells are all implicated in the pathogenesis of RA.

The streptococcal cell wall model of arthritis in Lewis rats consists of an acute, non-T-cell-dependent initiation phase, followed by a remission and then a chronic, inflammatory T-cell-dependent phase. In this report, we define pertinent changes in the cognate and noncognate immune system of the Lewis rats during various phases of the disease. We examined changes in the population size of various cell types using lineage-specific markers in three different tissues (blood, spleen, and lymph nodes) over 28 days. Our results indicate that the T cell and monocyte populations were significantly altered in PG-PS-treated rats and the activation status of these cells parallel initiation, remission, and chronic phases of joint inflammation. Activation of B cells also increases in certain tissues in the chronic phase of the disease. In summary, our results confirm the involvement of both innate and cognate immunity in the development of arthritis and demonstrate that monocytes, in addition to T cells, play a substantive role in the induction and maintenance of the inflammatory process in this rat model.

The inflammatory bowel diseases (IBD; Crohn's disease, ulcerative colitis) are a collection of chronic idiopathic inflammatory disorders of the intestine and/or colon. Although the pathophysiology of IBD is not known with certainty, a growing body of experimental and clinical data suggests that chronic gut inflammation may result from a dysregulated immune response to normal bacterial antigens. This uncontrolled immune system activation results in the sustained overproduction of reactive metabolites of oxygen and nitrogen. It is thought that some of the intestinal and/or colonic injury and dysfunction observed in IBD is due to elaboration of these reactive species. This review summarizes the current state-of-knowledge of the role of reactive oxygen species and nitric oxide in the pathophysiology of IBD.

Objectives:The limited number of studies addressing the presence of soluble human leukocyte antigen (HLA) in body fluids such as tears, urine, sweat, and saliva are restricted to healthy subjects. In this study, we applied solid-phase enzyme-linked immunoassay to quantify soluble HLA class I (sHLA-I) and class II (sHLA-II) molecules in saliva and in selected serum samples obtained from patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjogren's syndrome (SS). Results: While saliva from normal subjects (n=35) contained levels of sHLA-I that were undetectable (n=7) or ranged from 9 ng/ml to 70 ng/ml (30±3.7 ng/ml, n=28), sHLA-I among 38 patients with moderately active RA (n=24) or SLE (n=14) were significantly elevated (222±81.4 ng/ml and 120±27.3 ng/ml, respectively, P

BACKGROUND The postprocedural state after cardiac revascularization interventions is characterized by intense inflammation and activation of inflammatory cytokines due to myonecrosis and ischemia/reperfusion injury. Involvement of similar processes also participates in cellular malignant transformation. In this study, the association between cardiac interventions and subsequent cancer risk development was therefore evaluated. METHODS The 5-year cumulative incidence of cancer was examined in 2 cardiac care cohorts: all patients undergoing either open heart surgery or percutaneous coronary interventions (PCI) at hospitals in the commonwealth of Massachusetts. The observed cases of cancer were compared with the number of expected cases based on the state cancer rates, adjusting for sex and 5-year age groups. The standardized morbidity ratio (SMR) was used for this comparison. RESULTS Of 10,301 patients in the surgical cohort, 804 (7.8%) incident cancers developed over 5 years of follow-up, whereas 245.7 incident cancers were expected. This yielded an SMR of 3.27 (95% CI, 3.05-3.51; P

Hepatic resection with concomitant periods of ischemia and reperfusion (I/R) is a common occurrence in resectional surgery as well as reduced-size liver transplantation (e.g., split liver or living donor transplantation). However, the I/R induced by these types of surgical manipulations may impair liver regeneration, ultimately leading to liver failure. The objectives of the study were to develop a murine model of reduced-size liver I/R and assess the role of gender in this model of hepatocellular injury. We found that 100% of female mice survived the surgery indefinitely, whereas all male mice had greater initial liver injury and died within 5 days after surgery. The protective effect observed in females appeared to be due to ovarian 17β-estradiol, as ovariectomy of females or administration of a selective estrogen antagonist to female mice resulted in enhanced liver injury and greater mortality following reduced-size liver I/R. Conversely, 17β-estradiol-treated male mice exhibited less hepatocellular damage and survived indefinitely. Taken together, these data demonstrate an estrogen-mediated protective pathway(s) that limits or attenuates hepatocellular injury induced by reduced-size liver I/R.

The mucosal interstitia of the intestine and colon are continuously exposed to large amounts of dietary and microbial antigens. Fortunately, the mucosal immune system has evolved efficient mechanisms to distinguish potentially pathogenic from nonpathological antigens. There are, however, situations in which this immune regulation fails, resulting in chronic gut inflammation.

The antiphospholipid syndrome (APS) occurs as a primary entity or in association with autoimmune diseases, malignancies, or medications. Conventional treatment for APS-associated thrombosis involves the use of anticoagulants such as aspirin, heparin, and warfarin. Alternative treatment options are limited. We report on a patient with APS who failed conventional therapy but had clinical improvement and a decline in anticardiolipin (aCL) antibody titers during treatment with monthly intravenous immunoglobulin (IVIg). Anticardiolipin antibodies IgG, IgA, and IgM were measured before initiating IVIg and before each subsequent infusion of IVIg. The patient was also evaluated for the presence of thromboses during the treatment period. IgG and IgA aCL levels were elevated initially, and there was a significant decrease in anticardiolipin IgG and IgA levels during treatment without further episodes of thrombosis. IVIg may be an alternative therapy for recurrent thrombosis in the antiphospholipid antibody syndrome.

The nitration of tyrosine residues in protein to yield 3-nitrotyrosine derivatives has been suggested to represent a specific footprint for peroxynitrite formation in vivo. However, recent studies suggest that certain hemoproteins such as peroxidases catalyze the H2O2-dependent nitration of tyrosine to yield 3-nitrotyrosine in a peroxynitrite-independent reaction. Because 3-nitrotyrosine has been shown to be present in the postischemic myocardium, we wished to assess the ability of myoglobin to catalyze the nitration of tyrosine in vitro. We found that myoglobin catalyzed the oxidation of nitrite and promoted the nitration of tyrosine. Both nitrite oxidation and tyrosine nitration were H2O2-dependent and required the formation of ferryl (Fe+4) myoglobin. In addition, nitrite oxidation and tyrosine nitration were pH-dependent with a pH optimum of approximately 6.0. Taken together, these data suggest that the acidic pH and low oxygen tension produced during myocardial ischemia will facilitate myoglobin-catalyzed, peroxyntrite-independent formation of 3-nitrotyrosine.

CD5 is expressed on thymocytes, all mature T cells, and a subset of mature B cells, and probably contributes to T-cell-B-cell adhesion. We assessed whether CD5-crosslinking by mAb augments T-cell stimulation. Plate-bound anti-CD5 or anti-CD3 mAb alone had no effect on any of the assessed activation parameters of resting T cells. However, concomitant signaling through both CD5 and CD3 by plate-bound antibodies resulted in marked increases in T-cell surface CD69 expression and T-cell metabolism, as assessed by the T cell's ability to reduce 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxylmethoxyphenyl)-2-(4-sulphophenyl)-2H-tetrazolium (MTS) to formazen. In addition, simultaneous cross-linking of CD5 and CD3 caused a significant (p < 0.001) increase in phosphatidylinositol hydrolysis in resting T cells compared to stimulation with anti-CD3 mAb alone or anti-CD3 mAb plus anti-CD5 isotype control antibody. These results indicate that CD5 augments signaling through CD3 and consequently functions as a costimulatory molecule for resting T cells.

The overall objective of this study was to determine whether genetically induced hypercholesterolemia alters the inflammatory and microvascular responses of mouse liver to ischemia-reperfusion (I/R). The accumulation of rhodamine 6G-labeled leukocytes and the number of nonperfused sinusoids (NPS) were monitored (by intravital microscopy) in the liver of wild-type (WT) and low-density lipoprotein receptor-deficient (LDLr−/−) mice for 1 h after a 30-min period of normothermic ischemia. Plasma alanine transaminase (ALT) levels were used to monitor hepatocellular injury. Microvascular leukostasis as well as increases in NPS and plasma ALT were observed at 60 min after hepatic I/R in both WT and in LDLr−/− mice; however, these responses were greatly exaggerated in LDLr−/− mice. Pretreatment of LDLr−/− mice with gadolinium chloride, which reduces Kupffer cell function, attenuated the hepatic leukostasis, NPS, and hepatocellular injury elicited by I/R. Similar protection against I/R was observed in LDLr−/− mice pretreated with antibodies directed against tumor necrosis factor-α, intercellular adhesion molecule-1 (ICAM-1), or P-selectin. These findings indicate that chronic hypercholesterolemia predisposes the hepatic microvasculature to the deleterious effects of I/R. Kupffer cell activation and the leukocyte adhesion receptors ICAM-1 and P-selectin appear to contribute to the exaggerated inflammatory responses observed in the postischemic liver of LDLr−/− mice.

Our objective was to establish the existence of intercellular communication through gap junctions in synovial lining cells and in primary and passaged cultures of human synovial cells. Communication between cells was assessed using the nystatin perforated-patch method, fluorescent dye transfer, immunochemistry, transmission electron microscopy, and immunoblotting. Functional gap junctions were observed in primary and passaged cultures and were based on measurements of the transient current response to a step voltage. The average resistance between cells in small aggregates was 300 +/- 150 MOmega. Gap junctions were also observed between synovial lining cells in tissue explants; the size of the cell network in synovial tissue was estimated to be greater than 40 cells. Intercellular communication between cultured cells and between synovial lining cells was confirmed by dye injection. Punctate fluorescent regions were seen along intercellular contacts between cultured cells and in synovial membranes in cells and tissue immunostained for connexin43. The presence of the protein was verified in immunoblots. Regular 2-nm intermembrane gap separations characteristic of gap junctions were seen in transmission electron micrographs of synovial biopsies. The results showed that formation of gap-junction channels capable of mediating ionic and molecular communication was a regular feature of synovial cells, both in tissue and in cultured cells. The gap junctions contained connexin43 protein and perhaps other proteins. The physiological purpose of gap junctions in synovial cells is unknown, but it is reasonable to anticipate that intercellular communication serves some presently unrecognized function.

Abstract —The objective of this study was to define the influence of postanoxic T-lymphocyte–endothelial cell interactions on anoxia-reoxygenation (A/R)–induced neutrophil–endothelial cell adhesion and cell adhesion molecule (CAM) expression on human umbilical vein endothelial cells (HUVECs). HUVEC monolayers were exposed to 60 minutes of anoxia, followed by 24 hours of reoxygenation, wherein freshly isolated human T lymphocytes were added at 6 hours during reoxygenation. After an additional 18 hours of incubation (ie, total of 24 hours of reoxygenation), the T-cell/endothelial cell (TC/EC) coculture media were collected and added to naive HUVEC monolayers incubated with neutrophils. Although the A/R-conditioned media per se had no effect on neutrophil adhesion, the media from TC/EC cocultures significantly increased the adhesion response. This enhanced adhesive interaction was associated with significant increases in tumor necrosis factor-α (TNF-α) and interleukin-8 (IL-8) levels in the TC/EC coculture media and was accompanied by a pronounced increase in endothelial E-selectin expression. Treatment of the TC/EC coculture media with anti–TNF-α or anti-IL-8 antibodies reduced the media-induced neutrophil adhesion response. The enhanced neutrophil adhesion and the elevated medium levels of TNF-α, but not IL-8, were markedly reduced by inserts that prevented direct TC/EC contact and by monoclonal antibodies directed against vascular cell adhesion molecule-1 (VCAM-1) or very late antigen-4 (VLA-4). Collectively, these findings show that VLA-4–/VCAM-1–mediated interactions between T lymphocytes and postanoxic endothelial cells stimulates TNF-α production, which in turn elicits endothelial cell adhesion molecule expression and a corresponding increase in neutrophil adhesion.

Objective: The objectives of this study were to 1) determine the time-course of T-lymphocyte adhesion to monolayers of human umbilical vein endothelial cell (HUVEC) that were exposed to 60 min of anoxia followed by 24 h of reoxygenation,and 2) define the mechanisms responsible for the hyperadhesivity of postanoxic HUVEC to human T-lymphocytes.Methods: Human peripheral blood mononuclear leukocytes were isolated from heparinized peripheral blood. T-lymphocytes were obtained by negative selection using a MACS column. HUVEC monolayers were exposed to anoxia/reoxygenation (A/R), and then reacted with 51Cr -labeled T-lymphocytes in adhesion assays.Results: A/R leads to an increased adhesion of T-lymphocytes to HUVEC monolayers, with peak responses occurring at 8 h after reoxygenation. This adhesion response was largely attributed to the CD4+ T-cell subset. The hyperadhesivity of A/R-exposed HUVEC was inhibited by monoclonal antibodies directed against either LFA-1, VLA-4, ICAM-1, or VCAM-1, indicating a contrib...

Primary tumors of the bone and soft tissue of the pelvis are rare. Proper surgical treatment requires a fundamental knowledge of the biology of malignant musculoskeletal neoplasms. This understanding allows stratification of sarcomas into a staging system. In addition to prognostic value, the careful staging of the neoplasms dictates the type of surgical margins necessary and guides in the use of adjuvant therapy. Limb salvage techniques developed for the reconstruction of major extremity structural deficits can be used for reconstruction of the pelvis. This review first addresses the biologic behavior and staging of malignant musculoskeletal neoplasms. The surgical techniques employed for the resection and the reconstruction of the pelvis are then discussed.

Several organochlorinated pesticides including DDT, PCBs and dieldrin have been reported to cause immune suppression and increase susceptibility to infection in animals. Often this manifestation is accompanied by atrophy of major lymphoid organs. It has been suggested that increased apoptotic cell death leading to altered T-B cell ratios, and loss of regulatory cells in critical numbers leads to perturbations in immune function. The major objective of our study was to define the mechanism by which endosulfan, an organochlorinated pesticide, induces human T-cell death using Jurkat, a human T-cell leukemic cell line, as an in vitro model. We exposed Jurkat cells to varying concentrations of endosulfan for 0-48 h and analyzed biochemical and molecular features characteristic of T-cell apoptosis. Endosulfan lowered cell viability and inhibited cell growth in a dose- and time-dependent manner. DAPI staining was used to enumerate apoptotic cells and we observed that endosulfan at 10-200 μM induced a significant percentage of cells to undergo apoptotic cell death. At 48 h, more than 90% cells were apoptotic with 50 μM of endosulfan. We confirmed these observations using both DNA fragmentation and annexin-V binding assays. It is now widely being accepted that mitochondria undergo major changes early during the apoptotic process. We examined mitochondrial transmembrane potential (ΔΨm) in endosulfan treated cells to understand the role of the mitochondria in T-cell apoptosis. Within 30 min of chemical exposure, a significant percentage of cells exhibited a decreased incorporation of DiOC6(3), a cationic lipophilic dye into mitochondria indicating the disruption of ΔΨm. This drop in ΔΨm was both dose- and time-dependent and correlated well with other parameters of apoptosis. We also examined whether this occurred by the down regulation of bcl-2 protein expression that is likely to increase the susceptibility of Jurkat cells to endosulfan toxicity. Paradoxically, the intracellular expression of bcl-2 protein was elevated in a dose dependent manner suggesting endosulfan-induced apoptosis occurred by a non-bcl-2 pathway. Based on these data, as well as those reported elsewhere, we propose the following sequence of events to account for T-cell apoptosis induced by endosulfan: uncoupling of oxidative phosphorylation → excess ROS production → GSH depletion → oxidative stress → disruption of ΔΨm → release of cytochrome C and other apoptosis related proteins to cytosol → apoptosis. This study reports for the first time that endosulfan can induce apoptosis in a human T-cell leukemic cell line which may have direct relevance to loss of T cells and thymocytes in vivo. Furthermore, our data strongly support a role of mitochondrial dysfunction and oxidative stress in endosulfan toxicity.

Although neutrophils have been implicated in the hepatic injury elicited by gut ischemia/reperfusion (I/R), the contribution of other leukocyte populations to this injury process remains unclear. The objective of this study was to determine whether lymphocytes contribute to gut I/R-induced microvascular dysfunction and inflammatory responses in the liver. Intravital videomicroscopy was used to monitor leukocyte recruitment, the number of nonperfused sinusoids and pyridine nucleotide (NADH) autofluorescence in livers of wild-type, SCID, and interferon-γ (IFN-γ) knockout mice exposed to 15 min of gut ischemia and 1 h of reperfusion. In wild-type mice, gut I/R elicited significant increases in the number of stationary leukocytes, nonperfused sinusoids, NADH autofluorescence (indicating hypoxia), and elevated plasma alanine aminotransferase (ALT) and TNF-α levels. All of these responses were profoundly attenuated in SCID mice, while only some of the responses (in the midzonal region) were blunted in IFN-γ kno...

ICAM-3 is a pan-hematopoietic, constitutive adhesion molecule. ICAM-3 binds to LFA-1 on antigen-presenting cells (APC) stabilizing the T cell-APC interaction, facilitating signaling through the CD3/TCR complex. However, recent evidence using cultured and transformed T cells suggests ICAM-3 may also function in signaling. Because ICAM-3 is constitutively expressed on resting T cells, we postulated that signaling through ICAM-3 in resting T cells represents an important costimulatory mechanism in these cells. In purified resting human T cells, cross-linking both ICAM-3 and CD3 with plate-bound antibodies resulted in a marked increase in cell size (consistent with blastogenesis), synergistically increased surface expression of CD25 and CD69, and increased T cell metabolism. Similarly, concomitant ICAM-3 and CD3 stimulation significantly (P < 0.001) increased resting human T cell phosphatidylinositol hydrolysis and phospholipase C-γ1 phosphorylation. These results indicate that ICAM-3 augments signaling through CD3, functioning as a costimulatory molecule for resting T cells in the initial activation step. J. Leukoc. Biol. 65: 867–874; 1999.

Abstract —Previous studies have implicated a role for intracellular thiols in the activation of nuclear factor-κB and transcriptional regulation of endothelial cell adhesion molecules. This study was designed to determine whether changes in endothelial cell glutathione (GSH) or oxidized glutathione (GSSG) can alter neutrophil adhesivity and to define the molecular mechanism that underlies this GSSG/GSH-induced adhesion response. Treatment of human umbilical vein endothelial cell (HUVEC) monolayers for 6 hours with 0.2 mmol/L diamide and 1 mmol/L buthionine sulfoximine (BSO) decreased GSH levels and increased the ratio of GSSG to GSH without cell toxicity. These redox changes are similar to those observed with anoxia/reoxygenation. Diamide plus BSO–induced thiol/disulfide imbalance was associated with a biphasic increase in neutrophil adhesion to HUVECs with peak responses observed at 15 minutes (phase 1) and 240 minutes (phase 2). N -Acetylcysteine treatment attenuated neutrophil adhesion in both phases, which indicated a role for GSH in the adhesion responses. Interestingly, phase 1 adhesion was inversely correlated with GSH levels but not with the GSSG/GSH ratio, whereas phase 2 neutrophil adhesion was positively correlated with GSSG/GSH ratio but not with GSH levels. Intercellular adhesion molecule-1 and P-selectin–specific monoclonal antibodies attenuated the increased neutrophil adhesion during both phases, whereas an anti–E-selectin monoclonal antibody also attenuated the phase 2 response. Pretreatment with actinomycin D and cycloheximide or with competing ds -oligonucleotides that contained nuclear factor-κB or activator protein-1 cognate DNA sequences significantly attenuated the phase 2 response, which implicated a role for de novo protein synthesis. Surface expression of intercellular adhesion molecule-1, P-selectin, and E-selectin on HUVECs correlated with the phase 1 and 2 neutrophil adhesion responses. This study demonstrates that changes in endothelial cell GSSG/GSH cause transcription-independent and transcription-dependent surface expression of different endothelial cell adhesion molecules, which leads to a 2-phase neutrophil–endothelial adhesion response.

Abstract —The objectives of this study were to (1) determine whether transgenic (Tg) mice overexpressing copper/zinc–superoxide dismutase (CuZn-SOD) are protected from the deleterious effects of gut ischemia/reperfusion (I/R) and (2) compare the effectiveness of Tg SOD overexpression in attenuating I/R injury to intravascularly administered CuZn-SOD or manganese (Mn)-SOD. The accumulation of fluorescently labeled leukocytes and number of nonperfused sinusoids were monitored by intravital microscopy in livers of wild-type mice (C57BL/6), CuZn-SOD Tg mice, and wild-type mice receiving either CuZn-SOD or Mn-SOD. All parameters were measured for 1 hour after release of the occluded (for 15 minutes) superior mesenteric artery. Gut I/R in wild-type mice led to an increased number of stationary leukocytes, while reducing the number of perfused sinusoids (capillary no-reflow). All of these responses were significantly blunted in CuZn-SOD Tg mice, with a corresponding attenuation of liver enzyme release into plasma. Exogenously administered SOD had little or no effect on gut I/R-induced leukostasis or capillary no-reflow in the liver. These observations suggest a role for superoxide in gut I/R-induced leukostasis and hypoxic stress in the liver. Furthermore, the findings suggest that cellular localization of SOD activity is an important determinant of the protective actions of this enzyme in experimental models of I/R injury.

Purpose: Myocardial infarction and other comorbidities contribute to complications after carotid endarterectomy (CEA). However, because the combined stroke and death rate after CEA is less than 5%, even relatively large series have small numbers of adverse events that preclude a detailed analysis of the association between the outcome and the patient factors, such as comorbidity and age. We sought to overcome this limitation by studying patients who underwent CEA in a large random sample of Medicare beneficiaries. Methods: We used a database that contained a 20% random sample of all Medicare beneficiaries to identify patients who underwent CEA between the years 1988 to 1990 (n = 22,165), and we followed these cases until 1992. With multivariate logistic regression and Cox proportional hazards regression models, we examined the impact of age, race, gender, geographic location, hospital characteristics, and comorbidity, including acute myocardial infarction (AMI) and congestive heart failure (CHF), on the risk of stroke and death after CEA. Results: AMI and CHF had the greatest negative impact on the long-term survival rates (adjusted hazard ratio [HR]: 2.40, P < .0001, and 2.85, P < .0001, respectively). Other variables with a significant impact on the long-term survival rates were an age of >80 years (HR, 2.16; P < .0001), an acute stroke (HR, 1.51; P < .0001), diabetes mellitus (DM; HR, 1.52; P < .0001), and male sex (HR, 1.32; P < .0001). In addition, AMI, CHF, DM, and advanced age were associated with an increased risk of perioperative stroke and death. Conclusion: Patients with AMI, CHF, DM, and an age of >80 years have diminished perioperative and long-term survival rates after CEA. These results may alter the risk/benefit analysis for such patients, especially those with asymptomatic disease. (J Vasc Surg 1998;28:577-84.)

Reperfusion of ischemic intestine is associated with P-selectin-dependent adhesion of leukocytes in the liver microcirculation. The objective of this study was to define the contribution of nitric oxide (NO) to the enhanced P-selectin expression and increased leukocyte rolling elicited by gut ischemia-reperfusion (I/R). Leukocyte rolling (monitored by intravital microscopy) in the terminal hepatic venules (THV) and P-selectin expression (measured using the dual-radiolabeled monoclonal antibody technique) were determined in mice after 15 min of superior mesenteric artery occlusion and 30 min of reperfusion. After 30 min of reperfusion, P-selectin expression was significantly increased in the liver, intestine, and lung, with a corresponding increase in the number of rolling leukocytes (in THV). The NO synthase inhibitor NG-monomethyl-l-arginine exaggerated the gut I/R-induced increases in both rolling leukocytes and P-selectin expression (in liver and intestine), responses that were not detected with coadministration ofl-arginine or in P-selectin-deficient mice. The NO donor diethylenetriamine/NO andl-arginine were both effective in attenuating the gut I/R-induced increases in rolling leukocytes (in THV) and P-selectin expression (in liver, intestine, and lung). These findings indicate that NO modulates gut I/R-induced recruitment of rolling leukocytes in THV via an action on P-selectin expression.

Kupffer cells (KCs) have been implicated in the leukocyte recruitment and microvascular dysfunction associated with liver inflammation. The overall objective of this study was to assess the role of KCs in the leukocyte adhesion and oxidative stress elicited in the liver by gut ischemia/reperfusion (I/R). The accumulation of rhodamine-6G-labeled leukocytes and the number of nonperfused sinusoids (NPS) were monitored (by intravital microscopy) in mouse liver for 1 hour after a 15-minute period of normothermic intestinal ischemia. Autofluorescence of pyridine nucleotide [NAD(P)H] was measured as an index of mitochondrial O2 consumption and redox status. Leukostasis, as well as increases in NPS and NAD(P)H autofluorescence (indicating hypoxia), were observed in the liver at 60 minutes after gut I/R. Pretreatment with gadolinium chloride (GdCl3), which reduces KC function, attenuated the liver leukostasis and NPS elicited by gut I/R. The platelet activating factor (PAF) antagonist, WEB2086, and a tumor necrosis factor (TNF)-alpha-specific antibody were also effective in attenuating the gut I/R-induced leukostasis and NAD(P)H autofluorescence. The findings of this study suggest that KCs play an important role in mediating the leukocyte recruitment, impaired sinusoidal perfusion, and tissue hypoxia elicited in the liver after gut I/R. These KC-mediated responses appear to involve the participation of both PAF and TNF-alpha. (Hepatology 1997 Dec;26(6):1499-505)

Oxidants generated by endothelial xanthine oxidase (XO) can help trigger free radical-mediated tissue injury. An important event in oxidant-mediated tissue injury is neutrophil-endothelial adhesion. Although activation of endothelial XO increases adhesion, little is known about xanthine in the adhesive effect of XO. This study examined administered xanthine on the adhesion of neutrophils. Endothelial [human umbilical vein endothelial cells (HUVEC)] monolayers were exposed to xanthine (15 min), and neutrophils were allowed to adhere to HUVEC in an adhesion assay. Adhesion was dose dependently increased by xanthine (3-100 microM). Either catalase (1,000 U/ml), oxypurinol (XO inhibitor; 100 microM), or platelet-activating factor (PAF) receptor antagonist (WEB 2086; 10 microM) reduced neutrophil adhesion. Superoxide dismutase (1,000 U/ml) had no effect. Pretreatment of HUVEC with 50 microM tungsten also blocked xanthine-induced adherence. Adhesion was also inhibited by preincubation with 100 U/ml heparin. Finally, anti-P-selectin antibody (PB1.3; 20 micrograms/ml) attenuated adhesion. Our results indicate that xanthine may promote neutrophil-endothelial adhesion via a hydrogen peroxide- and PAF-mediated P-selectin expression.

The objective of this study was to define the role of oxidants and lipid mediators in the leukocyte-endothelial cell adhesion and albumin leakage elicited in rat mesenteric venules by ischemia-reperfusion (I/R). Intravital fluorescence microscopy was used to monitor leukocyte adherence and emigration, platelet-leukocyte aggregation, mast cell degranulation, and albumin leakage after release of a 20-min arterial occlusion. I/R elicited large increases in leukocyte-endothelial cell adhesion and albumin leakage. These responses were significantly attenuated in venules treated with either superoxide dismutase, oxypurinol (an inhibitor of xanthine oxidase), lodoxamide (a mast cell stabilizer), WEB-2086 (a platelet-activating factor antagonist), or SC-41930 (a leukotriene B4-receptor antagonist) but not by U-74006F (an inhibitor of lipid peroxidation). Platelet-leukocyte aggregates and mast cell degranulation induced by I/R were also attenuated by administration of either superoxide dismutase or lodoxamide. These results support the hypothesis that oxidants produced, in part, by xanthine oxidase promote the formation (by mast cells and endothelial cells) of platelet-activating factor and leukotriene B4, which recruit and activate leukocytes in postischemic venules. The adherent and emigrated leukocytes then mediate the increased albumin extravasation observed in the postcapillary venules.

We have investigated the temporal relationship among proinflammatory cytokine expression, nitric oxide (NO) production and joint inflammation in the acute phase of bacterial cell wall-derived peptidoglycan polysaccharide(PG/PS)-induced arthritis. Acute joint inflammation was induced in female LEW/N rats by a single intraperitoneal injection of PG/PS. Arthritis index and paw volume were quantified and joint histopathology was evaluated during acute joint inflammation (0–10 days). Tumor necrosis factor (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6) were determined by bioassay whereas nitric oxide (NO) was quantified by measuring serum nitrate/nitrite levels via the Griess procedure. We found that serum levels of TNF and serum IL-1 preceded the increase in IL-6 and NO production. Furthermore, the production of these proinflammatory cytokines and NO preceded bone erosion and osteoclast activity. Erosion of subchondral bone preceded pannus formation and cellular synovitis in the acute phase of PG/PS-induced arthritis. The temporal expression of TNF, IL-1, IL-6 and NO suggest a cascade of inflammatory mediators in which monocytes and macrophages respond to PG/PS with enhanced synthesis of TNF and IL-1, which may in turn promote the synthesis of IL-6 and NO. We postulate that one or more of these inflammatory events are responsible for initiating the subchondral bone erosion observed in acute joint inflammation.

BACKGROUND & AIMS: Although it has been reported that gut ischemia/reperfusion (I/R) elicits neutrophil-dependent liver dysfunction, little is known about the kinetics of leukocyte accumulation in the hepatic microcirculation after gut I/R. The aim of this study was to determine the temporal relationship between leukocyte sequestration and oxidative stress in rat liver after occlusion (30 minutes) and reperfusion (60 minutes) of the superior mesenteric artery and assess the effects of neutrophil depletion or immunoneutralization of either intercellular adhesion molecule 1 (ICAM-1) or the leukocyte adhesion glycoprotein CD11/CD18 on the hepatic microvascular responses to gut I/R. METHODS: Leukocyte accumulation, number of nonperfused sinusoids, and autofluorescence of reduced nicotinamide adenine dinucleotide (NADH) were monitored using intravital videomicroscopy both before and after gut I/R. RESULTS: The number of adherent leukocytes in both midzonal and pericentral regions after gut I/R was elevated. Autofluorescence of NADH increased after reperfusion (indicating hypoxia), particularly in the pericentral region. Neutrophil depletion or antibodies to either ICAM-1 or CD11/CD18 blunted the gut I/R-induced increases in NADH autofluorescence in the pericentral region, leukocyte adherence, and nonperfused sinusoids. CONCLUSIONS: Leukocytes accumulate in the liver after gut I/R via interaction of CD11/CD18 and ICAM-1. The leukocytes appear to mediate an oxidative stress, occurring in proximity to nonperfused sinusoids, that may contribute to liver injury. (Gastroenterology 1996 Sep;111(3):666-73)

This review has outlined the surgical staging of benign and malignant musculoskeletal neoplasms. Based on their unique natural history, these neoplasms behave in a predictable fashion. The surgical staging system assigns progressively higher degrees of risks to the neoplasms based on their surgical grade, their anatomic location, and the presence or absence of metastases. The staging system articulates well with preoperative planning, defining the margins needed for local tumor control. Because surgery distorts most of the imaging modalities available, all clinical staging studies must be completed before surgical intervention. As more data accrue as to the importance of DNA ploidy, genetic markers, and other characteristics, it is likely they will play an important role in the diagnosis and treatment of musculoskeletal neoplasms in the future.

BACKGROUND & AIMS: Previous studies indicate that a water extract of Helicobacter pylori promotes leukocyte adhesion and emigration as well as endothelial barrier disruption (increased vascular protein leakage) in rat mesenteric venules. The aims of this study were to assess whether H. pylori extract-activated neutrophils disrupt endothelial cell monolayers and to identify the mechanisms involved in this process. METHODS: Human neutrophils were incubated with monolayers of human umbilical vein endothelial cells (HUVECs) in the presence or absence of H. pylori extract. RESULTS: H. pylori extract-activated human neutrophils produced endothelial cell detachment from HUVEC monolayers, the severity of which was dependent on the duration of exposure. Endothelial cell detachment was prevented by a monoclonal antibody directed against CD11/CD18 on neutrophils or a monoclonal antibody against intercellular adhesion molecule 1 on endothelial cells. HUVEC monolayer disruption was also prevented by superoxide dismutase, catalase, and a monoclonal antibody against elastase. Further studies indicated that H. pylori extract was capable of inhibiting human neutrophil elastase. The antielastase activity was not diminished by oxidants. CONCLUSIONS: These studies indicate that H. pylori extract-activated human neutrophils can disrupt HUVEC monolayers only when human neutrophils are allowed to adhere to HUVECs and may provide an explanation for the H. pylori extract-induced, neutrophil- dependent vascular protein leakage observed in vivo. The possibility that H. pylori releases antiproteases may explain, in part, why this bacterium is so virulent. (Gastroenterology 1996 Jan;110(1):21-9)