PEGylated Erythropoietin Protects against Brain Injury in the MCAO-Induced Stroke Model by Blocking NF-κB Activation

Cerebral ischemia exhibits a multiplicity of pathophysiological mechanisms. During ischemic stroke, the reactive oxygen species (ROS) concentration rises to a peak during reperfusion, possibly underlying neuronal death. Recombinant human erythropoietin (EPO) supplementation is one method of treating neurodegenerative disease by reducing the generation of ROS. We investigated the therapeutic effect of PEGylated EPO (P-EPO) on ischemic stroke. Mice were administered P-EPO (5,000 U/kg) via intravenous injection, and middle cerebral artery occlusion (MCAO) followed by reperfusion was performed to induce in vivo ischemic stroke. P-EPO ameliorated MCAO-induced neurological deficit and reduced behavioral disorder and the infarct area. Moreover, lipid peroxidation, expression of inflammatory proteins (cyclooxygenase-2 and inducible nitric oxide synthase), and cytokine levels in blood were reduced by the P-EPO treatment. In addition, higher activation of nuclear factor kappa B (NF-κB) was found in the brain after MCAO, but NF-κB activation was reduced in the P-EPO-injected group. Treatment with the NF-κB inhibitor PS-1145 (5 mg/kg) abolished the P-EPO-induced reduction of infarct volume, neuronal death, neuroinflammation, and oxidative stress. Moreover, P-EPO was more effective than EPO (5,000 U/kg) and similar to a tissue plasminogen activator (10 mg/kg). An in vitro study revealed that P-EPO (25, 50, and 100 U/mL) treatment protected against rotenone (100 nM)-induced neuronal loss, neuroinflammation, oxidative stress, and NF-κB activity. These results indicate that the administration of P-EPO exerted neuroprotective effects on cerebral ischemia damage through anti-oxidant and anti-inflammatory properties by inhibiting NF-κB activation.

A Taxonomy of the Common Tasks and the Development of a Risk Index for Physical Load Assessment in Nursing Job

Background@#Nursing service is a nonroutine work with an excessive physical load and diverse tasks. This study derived representative common tasks based on the frequently occurring tasks with a high physical load in the nursing workers' daily work and developed indicators to evaluate the work risk by reflecting the characteristics of nonroutine work. @*Methods@#Common tasks were classified through the following stages: literature review, first focus group interview (FGI) with experts, first classification of common tasks, second FGI with hospital health managers, a survey of nursing service workers, and the final classification of common tasks for each task type. To develop an objective risk index for physical load assessment, we investigated the frequency and duration of the derived common tasks via survey. @*Results@#Nursing common tasks were categorized into six task types and 56 subtasks. To evaluate the risks of various tasks in nonroutine works, three frequencies and three working time levels were defined by examining the task frequency and working hours. Exposure time was defined to reflect the characteristics of a nonroutine job. The final risk assessment was the product of the exposure time level and job intensity level. From this, four risk action levels were derived. @*Conclusion@#This study has the advantage of solving the problem of focusing on some tasks in evaluating the physical load. It was meaningful in that a new risk assessment index based on exposure time was proposed based on the development of an evaluation scale for frequency and time by reflecting the characteristics of nonroutine work.

Ergonomic Evaluation of Biomechanical Hand Function

The human hand is a complex structure that performs various functions for activities of daily living and occupations. This paper presents a literature review on the methodologies used to evaluate hand functions from a biomechanics standpoint, including anthropometry, kinematics, kinetics, and electromyography (EMG). Anthropometry describes the dimensions and measurements of the hand. Kinematics includes hand movements and the range of motion of finger joints. Kinetics includes hand models for tendon and joint force analysis. EMG is used on hand muscles associated with hand functions and with signal-processing technology.

Preventive Effects of Zoledronic Acid on Bone Metastasis in Mice Injected with Human Breast Cancer Cells

Bisphosphonates are used routinely to reduce bone-related events in breast cancer patients with bone metastasis. We evaluated the effects of zoledronic acid, a third generation, nitrogen-containing bisphosphonate, to prevent bone metastasis in breast cancer. Zoledronic acid or vehicle alone was administered to nude mice either simultaneously or after intracardiac injection of human breast cancer MDA-MB-231 cells. Nude mice treated with zoledronic acid at early time points showed a lower incidence of bone metastases than did vehicle-treated nude mice, but these differences were not statistically significant. Only 37.5% of mice treated with zoledronic acid at the time of tumor cell inoculation developed bone metastases compared to over 51.8% of mice receiving vehicle alone (P = 0.304). Cell count of apoptosis confirmed by immunohistochemical staining in metastatic bone tissue significantly increased in the zoledronic acid-treated groups compared to non-treated group (1,018.3 vs 282.0; P = 0.046). However, metastatic tumor cells, which invade soft tissue around the bone, did not show extensive apoptosis; there were no differences between the zoledronic acid-treated and control groups. These results suggest that zoledronic acid increases apoptosis of metastatic breast tumor cells in the bone and could therefore reduce metastatic tumor burden. These results support the use of zoledronic acid to reduce the incidence of bone metastasis in breast cancer.

Angiopoietin-1 variant, COMP-Ang1 attenuates hydrogen peroxide-induced acute lung injury

Reactive oxygen species (ROS) play a crucial role in acute lung injury. Tissue inflammation, the increased vascular permeability, and plasma exudation are cardinal features of acute lung injury. Angiopoietin-1 (Ang1) has potential therapeutic applications in preventing vascular leakage and also has beneficial effects in several inflammatory disorders. Recently developed COMP-Ang1 is more potent than native Ang1 in phosphorylating tyrosine kinase with immunoglobulin and EGF homology domain 2 receptor in endothelial cells. However, there are no data on effects and related molecular mechanisms of COMP- Ang1 on ROS-induced acute lung injury. We used hydrogen peroxide (H2O2)-inhaled mice to evaluate the effect of COMP-Ang1 on pulmonary inflammation, bronchial hyper-responsiveness, and vascular leakage in acute lung injury. The results have revealed that VEGF expression, the levels of IL-4, TNF-alpha, IL-1 beta, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in lungs, the levels of hypoxia-inducible factor-1alpha (HIF-1 alpha) and NF-kappa B in nuclear protein extracts, phosphorylation of Akt, and vascular permeability were increased after inhalation of H2O2 and that the administration of COMP-Ang1 markedly reduced airway hyper-responsiveness, pulmonary inflammation, plasma extravasation, and the increases of cytokines, adhesion molecules, and VEGF in lungs treated with H2O2. We have also found that the activation of HIF-1a and NF-kappa B and the increase of phosphoinositide 3-kinase activity in lung tissues after H2O2 inhalation were decreased by the administration of COMP-Ang1. These results suggest that COMP-Ang1 ameliorates ROS-induced acute lung injury through attenuating vascular leakage and modulating inflammatory mediators.

Change of connexin 37 in allergen-induced airway inflammation

Gap junction channels formed with connexins directly link to the cytoplasm of adjacent cells and have been implicated in intercellular signaling. Connexin 37 (Cx37) is expressed in the gas-exchange region of the lung. Recently, Cx37 has been reported to be involved in the pathogenesis of inflammatory disease. However, no data are available on the role of Cx37 in allergic airway inflammatory disease. In the present study, we used a murine model of ovalbumin (OVA)-induced allergic airway disease and primary murine epithelial cells to examine the change of Cx37 in allergic airway disease. These mice develop the following typical pathophysiological features of asthma: airway hyperresponsiveness, airway inflammation, and increased IL-4, IL-5, IL-13, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, eotaxin, and RANTES levels in lungs. Cx37 protein and mRNA expression were decreased in OVA-induced allergic airway disease. Immunoreactive Cx37 localized in epithelial layers around the bronchioles in control mice, which dramatically disappeared in allergen-induced asthmatic lungs. Moreover, the levels of Cx37 protein in lung tissues showed significantly negative correlations with airway inflammation, airway responsiveness, and levels of Th2 cytokines in lungs. These findings indicate that change of Cx37 may be associated with the asthma phenotype.

Blockade of airway inflammation and hyper-responsiveness by an angiopoietin-1 variant, COMP-Ang1

Inflammation of the asthmatic airway is usually accompanied by increased vascular permeability and plasma exudation. Angiopoietin-1 (Ang1) has potential therapeutic applications in preventing vascular leakage. Recently, we developed a soluble, stable, and potent Ang1 variant, COMP-Ang1. COMP-Ang1 is more potent than native Ang1 in phosphorylating the tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 receptor in lung endothelial cells. We have used a mouse model for allergic airway disease to determine effects of COMP-Ang1 on allergen-induced bronchial inflammation and airway hyper-responsiveness. These mice develop the following typical pathophysiological features of allergic airway disease in the lungs: increased numbers of inflammatory cells of the airways, airway hyper-responsiveness, increased levels of Th2 cell cytokines (IL-4, IL-5, and IL-13), adhesion molecules (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1), and chemokines (eotaxin and RANTES), and increased vascular permeability. Intravenous administration of COMP-Ang1 reduced bronchial inflammation and airway hyper-responsiveness. In addition, the increased plasma extravasation in allergic airway disease was significantly reduced by the administration of COMP-Ang1. These results suggest that COMP-Ang1 attenuates airway inflammation and hyper-responsiveness, prevents vascular leakage, and may be used as a therapeutic agent in allergic airway disease.

A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-kappaB and hypoxia-inducible factor-1alpha

Reactive oxygen species (ROS) play an important role in the pathogenesis of airway inflammation and hyperresponsiveness. Recent studies have demonstrated that antioxidants are able to reduce airway inflammation and hyperreactivity in animal models of allergic airway disease. A newly developed antioxidant, small molecular weight thiol compound, N-acetylcysteine amide (AD4) has been shown to increase cellular levels of glutathione and to attenuate oxidative stress related disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. However, the effects of AD4 on allergic airway disease such as asthma are unknown. We used ovalbumin (OVA)-inhaled mice to evaluate the role of AD4 in allergic airway disease. In this study with OVA-inhaled mice, the increased ROS generation, the increased levels of Th2 cytokines and VEGF, the increased vascular permeability, the increased mucus production, and the increased airway resistance in the lungs were significantly reduced by the administration of AD4. We also found that the administration of AD4 decreased the increases of the NF-kappaB and hypoxia-inducible factor-1alpha (HIF-1alpha) levels in nuclear protein extracts of lung tissues after OVA inhalation. These results suggest that AD4 attenuates airway inflammation and hyperresponsiveness by regulating activation of NF-kappaB and HIF-1alpha as well as reducing ROS generation in allergic airway disease.

An antioxidant modulates expression of receptor activator of NF-kappaB in asthma

Oxidative stress plays critical roles in airway inflammation that is usually accompanied by increased vascular permeability and plasma exudation. VEGF increases vascular permeability and leads to airway inflammation. In addition, VEGF has been shown to enhance receptor activator of NF-kappaB (RANK) expression in endothelial cells. An aim of the study was to determine the potential role of antioxidant in the regulation of RANK expression in murine model of asthma. We have used a C57BL/6 mouse model of allergic asthma to evaluate the effect of L-2-oxothiazolidine-4-carboxylic acid (OTC), a prodrug of cysteine, which acts as an antioxidant, and VEGF receptor inhibitor on RANK mRNA expression. The mice develop the following pathophysiological features of asthma in the lungs: increased expression of RANK mRNA, increased number of inflammatory cells of the airways, increased vascular permeability, and increased levels of VEGF. Administration of OTC and VEGF receptor inhibitor markedly reduced plasma extravasation and VEGF levels in allergen-induced asthmatic lungs. We also showed that the increased RANK mRNA expression at 72 h after ovalbumin inhalation were reduced by the administration of OTC or VEGF receptor inhibitor. The results indicate that OTC and VEGF receptor inhibitor which inhibit up-regulation of VEGF expression modulate RANK expression that may be in association with the regulation of vascular permeability, and suggest that VEGF may regulate the RANK expression. These findings provide a crucial molecular mechanism for the potential use of antioxidants to prevent and/or treat asthma and other airway inflammatory disorders.

A Case of Heterotopic Pregnancy Diagnosed by Ultrasonogram / 대한산부인과학회잡지

Heterotopic pregnancy is a condition in which ectopic and intrauterine pregnancies coexist. The reported incidence varies widely from 1 in 1000 to 1 in 30000 pregnancies. Assisted reproductive technologies have led to an increase in the number of heterotopic pregnancies. Because heterotopic pregnancy is difficult to diagnose early and it has high morbidity and mortality rate, careful pelvic examination combined with transvaginal sonogram and serial beta-HCG determinations are important. We experienced a case of heterotopic pregnancy in a natural cycle diagnosed by ultrasonogram who continued intrauterine pregnancy successfully.

Postnatal changes in atrial compliance and stretch-induced ANP secretion in rabbits

To define the postnatal changes in ANP secretion in response to mechanical stretch and atrial compliance, experiments have been done in perfused nonbeating rabbit atria with different ages: 1-day, 1-, 2-, 3-, 4-, and 8-wk-old. In 1-day-old-rabbits, an increase in intraatrial pressure resulted in an increase in atrial volume, which was higher than that in 1-wk-old rabbits. Increases in atrial volume stimulated the secretion of ANP with concomitant translocation of extracellular fluid (ECF) into the atrial lumen. However, mechanically stimulated ECF translocation was lower in 1-day-old rabbits than that in 1-wk-old rabbits. Therefore, positive relationship between mechanically stimulated ECF translocation and ANP secretion was shifted upward in 1-day-old rabbits, as compared to 1-wk-old rabbits. Changes in atrial volume and ECF translocation were gradually increased with aging and reached the peak value at 4 wk. The stretch-induced ANP secretion in terms of ECF translocation (the interstitial ANP concentration) was also increased with aging and reached the peak value at 4 wk. The interstitial ANP concentration was dependent on the atrial content of ANP. These data suggest that the higher level of atrial ANP secretion is related to the postnatal changes in atrial volume and unidentified factor.

Two Cases of Familial Cardiac Myxoma

Cardiac myxoma is a rare tumor and occurs sporadically as isolated lesions in the left atrium of middle aged women. However, familial occurrence of the neoplasm has been described to comparison of certain clinical and pathologic features among patients who have nonfamilial cardiac myxona with those of patients who have familial cardiac myxoma showed statistically significant differences. Several case reports described that a familial occurrence of this tumor, also that these are associated skin lesions as well as other endocrine tumor. This so called complex of syndrome form of cardiac myxoma and the familial form have characteristics that distinguish them from the sporadic form. Nonfamilial cardiac myxoma was a disorder of middle aged women, usually occurred in the left atrium as a single tumor and had no particular associated conditions. On the other hand, familial cardiac myxoma was a disorder of young men, was less commonly in the left atrium, was often multicentric, and was occasionally associated with unusual or rare conditions and a tendency for recurrence. Therefore, for these patients, we recommand a thorough search for multiple tumors at operation, close postoperative follow-up, and careful screening of family members. Our findings of atrial myxoma in a brother and a sister associated with pigmented skin lesions strongly suggest a tendency to familial occurrence.

Free-Floating Left Atrial Thrombus with Recurrent cerebral Embolic Event Associated Mitral Stenosis

In mitral valve disease, left atrial thrombus is a common finding, particularly in left atrial appendage in patients with atrial fibrillation. But free-floating thrombus is rare. Nevertheless, it is an important and potentially fatal complication because it can cause sudden arrest by obstucting the mitral orifice, or serious cerebral and peripheral embolic events. Therefore it is important to early detect such lesions. It usually occurs in the setting of a large, dilated left atrium with stagnant flow, commonly the result of severe rheumatic mitral stenosis and accompanying atrial fibrillation. We report the clinical and echocardiographic findings in a patient with left atrial free-floating thrombus who had two episodes of cerebral embolic event.