Arterial immune protein expression demonstrates the complexity of immune responses in Kawasaki disease arteritis.

A more complete understanding of immune-mediated damage to the coronary arteries in children with Kawasaki disease (KD) is required for improvements in patient treatment and outcomes. We recently reported the transcriptional profile of KD coronary arteritis, and in this study sought to determine protein expression of transcriptionally up-regulated immune genes in KD coronary arteries from the first 2 months after disease onset. We examined the coronary arteries of 12 fatal KD cases and 13 childhood controls for expression of a set of proteins whose genes were highly up-regulated in the KD coronary artery transcriptome: allograft inflammatory factor 1 (AIF1), interleukin 18 (IL-18), CD74, CD1c, CD20 (MS4A1), Toll-like receptor 7 (TLR-7) and Z-DNA binding protein 1 (ZBP1). Immunohistochemistry and immunofluorescence studies were performed to evaluate protein expression and co-localization, respectively. AIF1 was expressed transmurally in KD arteritis and localized to macrophages and myeloid dendritic cells. CD74, which interacts with major histocompatibility complex (MHC) class II on antigen-presenting cells, localized to the intima-media. CD1c, a marker of myeloid dendritic cells, was expressed in a transmural pattern, as were IL-18 and CD20. ZBP1 and TLR-7 were up-regulated compared to controls, but less highly compared to the other proteins. These findings provide evidence of antigen presentation and interferon response in KD arteritis. In combination with prior studies demonstrating T lymphocyte activation, these results demonstrate the complexity of the KD arterial immune response.

Retinal nerve fiber layer thickness and neuropsychiatric manifestations in systemic lupus erythematosus.

Background Cognitive impairment is frequent in systemic lupus erythematosus. Atrophy of the corpus callosum and hippocampus have been reported in patients with systemic lupus erythematosus, and diffusion tensor imaging studies have shown impaired white matter integrity, suggesting that white matter damage in systemic lupus erythematosus may underlie the cognitive impairment as well as other neuropsychiatric systemic lupus erythematosus manifestations. Retinal nerve fiber layer thickness, as assessed by optical coherence tomography, has been suggested as a biomarker for white matter damage in neurologic disorders such as multiple sclerosis, Alzheimer's disease and Parkinson's disease. Retinal nerve fiber layer thinning may occur early, even in patients with mild clinical symptoms. Aim The objective of this study was to assess the association of retinal nerve fiber layer thickness, as a biomarker of white matter damage in systemic lupus erythematosus patients, with neuropsychiatric systemic lupus erythematosus manifestations, including cognitive impairment. Methods Twenty-one consecutive patients with systemic lupus erythematosus underwent neuropsychological testing using a validated computerized battery of tests as well as the Rey-Auditory verbal learning test. All 21 patients, as well as 11 healthy, age matched controls, underwent optical coherence tomography testing to assess retinal nerve fiber layer thickness. Correlations between retinal nerve fiber layer thickness and results in eight cognitive domains assessed by the computerized battery of tests as well as the Rey-Auditory verbal learning test were assessed in patients with systemic lupus erythematosus, with and without neuropsychiatric systemic lupus erythematosus, and compared to retinal nerve fiber layer thickness in healthy controls. Results No statistically significant correlation was found between retinal nerve fiber layer thickness in patients with systemic lupus erythematosus as compared to healthy controls. When evaluating by subgroups, no correlation was found between patients with or without neuropsychiatric systemic lupus erythematosus or cognitive impairment and retinal nerve fiber layer thickness. Conclusion Retinal nerve fiber layer thickness of systemic lupus erythematosus patients was not found to be statistically different compared to controls. Within systemic lupus erythematosus patients there was no correlation between retinal nerve fiber layer thickness and cognitive impairment or other neuropsychiatric systemic lupus erythematosus manifestations.

Implementation of recommendations for the screening of hydroxychloroquine retinopathy: poor adherence of rheumatologists and ophthalmologists.

The American Academy of Ophthalmology published in 2011 revised recommendations regarding screening for hydroxychloroquine (HCQ) toxicity. We aimed to assess implementation of these recommendations by rheumatologists and ophthalmologists. A questionnaire regarding screening practices for HCQ toxicity was distributed among all members of the Israeli societies of Rheumatology and Ophthalmology. A total of 128 physicians responded to the questionnaire (rheumatologists: 60, ophthalmologists: 68). Only 5% of the rheumatologists and 15% of the ophthalmologists are aware of ophthalmologic assessments recommended for baseline and follow-up evaluation. When an abnormal test is detected, even if inappropriate for HCQ toxicity screening, 60% of the responders recommend cessation of therapy. Only 13% of the responders recommend first follow-up after five years for patients without risk factors; the remainder recommend more frequent testing. Ninety-six percent of the responders are not aware of all of the known risk factors for HCQ toxicity. Use of inappropriate tests to detect HCQ retinal toxicity may lead to unnecessary cessation of beneficial treatment with risk of disease flare, while lack of consideration of risk factors may put patients at risk for toxicity. These results emphasize the importance of implementing the recommendations to ensure safe and effective use of this drug.

CD84 is markedly up-regulated in Kawasaki disease arteriopathy.

The major goals of Kawasaki disease (KD) therapy are to reduce inflammation and prevent thrombosis in the coronary arteries (CA), but some children do not respond to currently available non-specific therapies. New treatments have been difficult to develop because the molecular pathogenesis is unknown. In order to identify dysregulated gene expression in KD CA, we performed high-throughput RNA sequencing on KD and control CA, validated potentially dysregulated genes by real-time reverse transcription-polymerase chain reaction (RT-PCR) and localized protein expression by immunohistochemistry. Signalling lymphocyte activation molecule CD84 was up-regulated 16-fold (P < 0·01) in acute KD CA (within 2 months of onset) and 32-fold (P < 0·01) in chronic CA (5 months to years after onset). CD84 was localized to inflammatory cells in KD tissues. Genes associated with cellular proliferation, motility and survival were also up-regulated in KD CA, and immune activation molecules MX2 and SP140 were up-regulated in chronic KD. CD84, which facilitates immune responses and stabilizes platelet aggregates, is markedly up-regulated in KD CA in patients with acute and chronic arterial disease. We provide the first molecular evidence of dysregulated inflammatory responses persisting for months to years in CA significantly damaged by KD.

Personal carbon monoxide exposures among firefighters at prescribed forest burns in the Southeastern United States.

Exposure to combustion products from wildland fires causes respiratory irritation and decreased lung function among firefighters. The authors evaluated carbon monoxide (CO) exposures of a group of wildland firefighters who conducted prescribed burns in the southeastern United States of America. A total of 149 person-days of samples were collected using data logging CO monitors. A questionnaire was administered to collect data on job tasks and self-reported smoke exposure. Overall, the highest exposures were seen amongst firefighters assigned to holding and mop-up tasks (geometric mean [GM]: 2.6 ppm), whereas the lowest were associated with lighting and jobs such as burn boss (GM: 1.6 and 0.3 ppm, respectively). The self-reported smoke exposure showed a significant linear trend with increasing CO exposure. The numbers of acres burned or burn duration, however, were not good predictors of exposure.

Macular findings on optical coherence tomography in cat-scratch disease neuroretinitis.

PURPOSE: To describe the macular findings on optical coherence tomography (OCT) in patients with cat-scratch disease (CSD) neuroretinitis. METHODS: Medical records of all patients diagnosed with CSD neuroretinitis at the Tel Aviv Medical Center between April 2006 and May 2010 were retrospectively reviewed. All patients underwent Stratus OCT macular examination. RESULTS: Eight eyes of seven patients with confirmed CSD neuroretinitis, (mean age 33 ± 9.9 years, range 6-48 years) were included in the study. All patients presented clinically with optic nerve swelling and macular edema or macular exudates. OCT demonstrated flattening of the foveal contour, thickening of the neurosensory retina, and accumulation of subretinal fluid (SRF) in all studied eyes. Retinal exudates appeared as multiple hyper-reflective foci in the outer plexiform layer. The average central macular thickness was 460 µm (range 170-906 µm) and the average maximal retinal thickness was 613 µm (range 387-1103 µm), at presentation. The macula appeared normal on repeated exams during follow-up. CONCLUSION: Similar OCT findings were demonstrated in patients with CSD neuroretinitis. SRF was found in all eyes, although was not visible on clinical examination or fluorescein angiography. OCT may be used as an adjunct imaging tool in the diagnosis and follow-up of patients with CSD neuroretinitis.

Ocular complications of laser-assisted eyebrow epilation.

PURPOSE: To report a series of patients with ocular complications associated with laser-assisted eyebrow hair removal. PATIENTS AND METHODS: Case reports of three patients with eye pain and photophobia following laser epilation of the eyebrow region. The eye examination included visual acuity, slit-lamp examination, tonometry and fundoscopy. The follow-up period was 3 months. RESULTS: Each patient had conjunctival hyperaemia in one or both eyes and anterior chamber pigmentary cells. One patient presented with posterior synechiae, which did not respond to treatment. CONCLUSIONS: Laser epilation of the eyebrows may result in anterior uveitis as well as irreversible damage to the iris.

Hexavalent chromium exposures and exposure-control technologies in American enterprise: results of a NIOSH field research study.

The National Institute for Occupational Safety and Health (NIOSH) conducted 21 field surveys in selected industries to characterize workers' exposures to hexavalent chromium-containing airborne particulate and to evaluate existing technologies for controlling these exposures. Hexavalent chromium Cr(VI) is a respiratory irritant and chronic inhalation may cause lung cancer. Primary evaluation methods included collection of full work shift, personal breathing-zone (PBZ) air samples for Cr(VI), measurement of ventilation system parameters, and documentation of processes and work practices. This study emphasized evaluation of engineering exposure control measures, so PBZ exposures were measured on the outside of personal protective equipment, for example, respirators. Field surveys were conducted in two chromium electroplating facilities, including one where full-shift PBZ exposures to Cr(VI) ranged from 3.0 to 16 times the 1 micro g/m(3)NIOSH recommended exposure limit (REL) despite several engineering controls on the plating tanks. At a painting and coating facility that used Cr(VI)-containing products, full-shift exposures of painters and helpers (2.4 to 55 micro g/m(3)) exceeded the REL, but LEV effectiveness was limited. Other operations evaluated included welding in construction; metal cutting operations on chromium-containing materials in ship breaking; chromate-paint removal with abrasive blasting; atomized alloy-spray coating; foundry operations; printing; and the manufacture of refractory brick, colored glass, prefabricated concrete products, and treated wood products. NIOSH researchers concluded that, in many of the evaluated processes, Cr(VI) exposures at or below the current NIOSH REL are achievable. However, for some processes, it is unclear whether controlling exposures to this range is consistently achievable without respirator use. Some operations involving the application of coatings and finishes may be among those most difficult to control to this range. Most operations judged to be moderately difficult to control to this range involve joining and cutting metals with relatively high chromium content. Nonetheless, exposures in a wide variety of other processes were judged more easily controllable to the current REL or below, or were found to be minimal, including some operations meeting the general descriptions named above but with different specific operating parameters producing lower Cr(VI) exposures.

Prognostic factors for visual acuity improvement after intravitreal triamcinolone injection.

PURPOSE: In some patients with macular oedema, intravitreal triamcinolone acetonide injection (IVTA) fails to improve visual acuity, although oedema shows clinical and angiographic improvement. Side effects can include increased intraocular pressure, cataract development, and (rarely) endophthalmitis. Our purpose was to identify prognostic factors for visual acuity improvement after IVTA. METHODS: Data on patients treated by IVTA for macular oedema were retrospectively reviewed. Three months postinjection, visual acuity was rated as 'improved' (two or more Snellen lines gained) or 'nonimproved' (unchanged or worsened). Comparative demographic data and pre- and post-IVTA clinical and fluorescein angiographic findings were analysed with SPSS software. RESULTS: Of 57 eyes (57 patients), 27 (47%) improved after IVTA. Initial visual acuity ('good', 'moderate', or 'poor') and aetiology of macular oedema (diabetic, venous occlusion, or pseudophakic) did not differ between the two groups. Improvement occurred in significantly more eyes with clinical or angiographic evidence of cystoid macular oedema (CME) than in those with diffuse retinal thickening (P=0.04) or diffuse leakage on fluorescein angiography (P=0.02), respectively, and in significantly more pseudophakic than phakic eyes (P=0.046). CONCLUSIONS: Pseudophakia and clinical or angiographic CME, but not aetiology or initial visual acuity, were prognostic of visual acuity improvement after IVTA for macular oedema.

The application of Beckman Coulter VCS technology at a major cancer center, with emphasis on the detection of circulating immature plasma cells in plasma cell leukemia.

The St. Vincent's Comprehensive Cancer Center (SVCCC) has a large multiple myeloma program in downtown New York City. The laboratory at SVCCC is an integral part of the diagnosing and monitoring of its myeloma patients. Circulating plasma cells are not a common finding in multiple myeloma. Being able to detect plasma cells in peripheral blood is important because they are a prognostic indicator that correlates with disease progression. Furthermore, the peripheral blood plasma cell population can demonstrate morphologic variability. Immature plasma cells, both plasmablasts and proplasmacytes are associated with more aggressive disease and shortened survival. We encountered 3 multiple myeloma patients with circulating immature plasma cells that appeared as distinct populations on our hematology analyzer's automated white blood cell (WBC) differential. The immature plasma cells, given their unique cellular characteristics, appeared in a common place within the WBC differential scatterplot in each patient. In our laboratory, we have utilized this common graphic pattern to screen for immature plasma cells. This pattern has proven to be a useful tool in our large population of multiple myeloma patients. We have also used examination of the scatterplots in other hematologic malignancies such as chronic lymphocytic leukemia. Using this review policy, the laboratory has been able to achieve a smear review of 25% in our highly abnormal patient population.

Angiogenesis in fatal acute Kawasaki disease coronary artery and myocardium.

Angiogenesis has been shown to be dysregulated in coronary artery (CA) aneurysms in the chronic phase of Kawasaki disease (KD). Neovascularization may occur in inflammatory-related vascular diseases because many angiogenesis mediators are secreted by inflammatory cells. We hypothesized that inflammation of the acute KD CA aneurysm could lead to dysregulation of angiogenesis mediators and subsequent neovascularization. To investigate this hypothesis, acute fatal KD cardiac tissues were immunostained for angiogenic inducers and inhibitors. Microvessel density was determined and the degree of inflammation assessed. Marked inflammation and angiogenesis were found in acute KD CA aneurysms and myocardium, with the highest microvessel density seen in patients who died 2-3 weeks after onset of the disease. Expression of proangiogenic proteins was higher than expression of inhibitors in KD CA aneurysms and myocardium. Angiogenesis mediators were localized to inflammatory cells in the myointima, adventitia, and myocardium. We conclude that significant neovascularization occurs in acute KD CA aneurysms and myocardium much sooner after onset of the disease than has been previously reported, that multiple angiogenesis factors are involved, and that dysregulation of angiogenesis likely contributes to KD vasculopathy.

Recent developments and controversies in Kawasaki disease.

In the developed world, Kawasaki disease is currently the leading cause of pediatric acquired heart disease. To date, the etiologic agent remains unknown. Many hypotheses regarding the etiology exist, and debate continues as to whether the inflammatory response of Kawasaki disease results from a superantigen or a conventional antigen. A variety of growth factors, proteinases, and cytokines have been identified that are involved in the pathogenesis of coronary artery disease in Kawasaki disease. These findings are leading to novel treatment strategies in Kawasaki disease, including platelet glycoprotein receptor inhibitors and monoclonal antibody to tumor necrosis factor-alpha. The role of corticosteroids remains controversial, and ongoing clinical trials are evaluating its efficacy. Additional studies have focused on newer non-invasive methods of evaluating children with coronary artery disease as alternatives to coronary catheterization. We review recent developments and controversies in exploring the etiology, pathogenesis, diagnosis, and management of Kawasaki disease.

Coronary artery bypass grafting for Kawasaki disease.

Five patients with a history of Kawasaki disease underwent coronary revascularization at Children's Memorial Hospital (1988-2000). Acute disease occurred at 11 weeks to 5 years of age and revascularization procedures were performed at 8 months to 12 years (mean 6 years; interval from disease onset 5 months to 9 years). Surgical indications included abnormal stress testing with angiographic confirmation of severe coronary artery stenosis (n = 3), severe coronary artery stenosis with echocardiographic evidence of intracoronary thrombus (n = 1), and ischemic electrocardiogram changes and ventricular tachycardia during angiography (n = 1). All revascularization procedures used internal thoracic arteries including one free internal thoracic artery graft. There were no postoperative deaths (follow-up 1 month to 11 years). All patients are asymptomatic. One patient developed myocardial ischemia 4 years postoperatively with occlusion of the circumflex coronary artery (not previously grafted). This was treated successfully with percutaneous coronary angioplasty and stent placement. All grafts are patent with the exception of a single right internal thoracic artery graft which underwent involution 30 months postprocedure with concurrent recannulization of the right coronary artery. Coronary revascularization should be considered in the young patient with severe coronary abnormalities secondary to Kawasaki disease.

Preserving central blood volume: changes in body fluid compartments during hemodialysis.

The understanding of fluid changes during hemodialysis (HD is essential for reducing complications as well as efficacy of the procedure. Bioimpedance spectroscopy provides a non invasive method of measuring total body water (TBW), the distribution of intra (ICF) and extracellular (ECF) fluids, and their changes during HD. Segmental bioimpedance may be used to measure the same fluid shifts but from different body segments; the technique has previously been shown to com pare well with whole body measures. It is possible that fluid shifts occur differently in different body compartments during HD. Based on previous hemodynamic studies we postulated that during HD ultrafiltration (UF) the body attempts to preserve its central blood volume (cardiopulmonary circula tion plus great vessels), and thus fluid shifts would be greater from the periphery than from central compartments. To test this hypothesis, segmental bioimpedance (Xitron Technolo gies, San Diego, CA) was performed on 11 subjects undergoing HD where ECF and ICF values were obtained from the legs, arms and trunk before and after a period of UF. Blood volume change (ABV%) was also followed using an on-line optical hematocrit (Hct) sensor (Crit-Line monitor, In-Line Diagnostics, UT) where deltaBV% = deltaBV% = (1 - Hct1/Hct0) x 100 (Hct0 = baseline Hct; Hct1 = postultrafiltration Hct) The UF of 2.0 L +/- 0.79 L (M +/- SD) over 75 minutes was associated with a deltaBV% of -9.43% +/- 3.6% (M +/- SD), a significant (Student's paired t-test) reduction in total body (TB) ECF (p < 0.02), a weak correlation in reduction in TBW (p = 0.09) but not in TB ICF. The ECF reductions from the trunk, legs, and arms were all significant (minimum p < 0.02); no ICF changes from these compartments were significant. The amount of ECF reduction was greater from the legs (0.7 L +/- 0.6 L) than the arms (0.12 L +/- 0.08 L) and trunk (0.2 L +/- 0.2 L) (all M +/- SD). Multiple regression analysis showed that TB ECF changes correlated strongly with leg (r = 0.94, p < 0.001) and arm (r = 0.72, p = 0.002) ECF changes but not with trunk changes. deltaBV% correlated weakly with leg (r = 0.45, p = 0.08) and arm (r = 0.42, p = 0.10) ECF changes but not with the trunk. As the deltaBV% represents the net volume change between UF and plasma water refilling, thiss indicates that plasma water is being removed more from the peripheral compartments than from the trunk. These data suggest that plasma refilling during HD to preserve central blood volume is more dynamic from the leg ECF than from elsewhere and may, in turn, explain the frequent occurrence of leg cramps during and after hemodialysis.

Staphylococcus lugdunensis: an emerging cause of ventriculoperitoneal shunt infections.

Staphylococcus lugdunensis, a coagulase-negative staphylococcus first described in 1988, has gained recognition as an organism with considerable pathogenic capability in adults. In contrast to the indolent presentation characteristic of other coagulase-negative staphylococci, S. lugdunensis infections resemble the aggressive behavior of Staphylococcus aureus. Although the organism has been isolated from a wide variety of infections in adults, it is a very rare cause of pediatric infections. We describe the first two pediatric patients who developed ventriculoperitoneal shunt infections caused by S. lugdunensis. These cases suggest that coagulase-negative staphylococci should be identified to the species level and that, if S. lugdunensis is identified, greater morbidity compared to that associated with other coagulase-negative staphylococcal shunt infections should be anticipated. A longer course of therapy is recommended for S. lugdunensis infections.

Surface and cytoplasmic immunoglobulin expression in circulating B-lymphocytes in acute Kawasaki disease.

Kawasaki disease (KD) is an acute vasculitis of young childhood predominantly affecting the coronary arteries. IgA plasma cells have been found to infiltrate vascular and nonvascular tissues in fatal acute KD. To determine whether IgA B-lymphocytes were increased in the peripheral blood of patients with KD, we performed three-color flow cytometry to detect surface and cytoplasmic immunoglobulin expression (IgA, IgM, IgD, and IgG) of peripheral B-lymphocytes in KD patients during the acute, subacute, and convalescent stages of illness and in age-matched febrile and afebrile pediatric controls. Surprisingly, absolute numbers of B-lymphocytes expressing IgA were found to be significantly lower in peripheral blood of acute KD patients compared with febrile and afebrile pediatric controls. These findings indicate that IgA plasma cells are not present in KD tissue as a result of excess numbers of these IgA B-lymphocytes in peripheral blood. We speculate that IgA B-lymphocytes are selectively withdrawn from the peripheral circulation into KD target tissues as part of a specific IgA immune response.

CD8 T lymphocytes and macrophages infiltrate coronary artery aneurysms in acute Kawasaki disease.

The pathogenesis of coronary arterial inflammation in acute Kawasaki disease (KD) is unclear. To test the hypothesis that the KD vascular lesion is an activated T lymphocyte-dependent process, immunohistochemical studies were done on coronary artery aneurysms from 8 fatal acute KD cases by using antibodies to CD45RO (activated or memory T lymphocyte), CD8 (cytotoxic T lymphocyte), CD4 (helper T lymphocyte), HAM56 (macrophage), and CD20 (B lymphocyte). Acute KD coronary arteritis was characterized by transmural infiltration of CD45RO T lymphocytes with CD8 T lymphocytes predominating over CD4 T lymphocytes. Macrophages were present primarily in the adventitial layer; B lymphocytes were notably absent. These data lend support to the hypotheses that KD results from infection with an intracellular pathogen, such as a virus, whose antigens are presented by major histocompatibility complex class I molecules, and that CD8 T lymphocytes and macrophages are important in the pathogenesis of KD coronary aneurysms.