Three-Dimensional Ankle Exercise with Combined Isotonic Technique for an Obese Subject with Plantar Fasciitis: A Case Study.

Background and objectives: Obese people have many foot-related disorders and plantar fasciitis (PF) is the most common disorder among them. However, research on the role of therapeutic exercises in PF is lacking and there is no evidence to suggest its benefits. As such, a further insight into therapeutic exercises is needed within this group. This case study investigated the effect of three-dimensional (3D) ankle exercises using a combined isotonic (CI) technique on function and balance in an obese subject with PF. Material and methods: The subject in this study was a 28-year-old obese woman who was diagnosed with PF by an orthopedic surgeon. A 3D ankle exercise program was commenced three times a week for 15 min over 4 weeks. The evaluations were conducted at five intervals: pre-test, and at 1, 2, 3 and 4 weeks from the initiation of the intervention. The tests were conducted in the following order: the patient-specific functional scale test (PSFS), an ultrasound of the plantar fascia, the heel pressure and balance test, the pressure pain threshold (PPT), and the 4-way ankle strength test. Results: The mean score of the PSFS test reduced by 70.55% after 4 weeks of the intervention. The thickness of the plantar fascia and heel pressure measured during single-leg standing decreased by 6.67% and 10.37%, respectively, after 4 weeks of the intervention. The anteroposterior and medial-lateral balance ability showed improvements of 8.29% and 8.61%, respectively, after 4 weeks of the intervention. The PPT improved by 38.01% after 4 weeks of the intervention. In the 4-way ankle strength test, dorsiflexion, plantar flexion, inversion, and eversion increased by 14.46%, 9.63%, 4.3% and 13.25%, respectively, after 4 weeks of the intervention. Conclusion: 3D ankle exercises utilizing the CI technique were shown to be effective in improving foot function, pressure pain, and muscle strength in dorsiflexion and inversion in an obese patient with PF.

Development of an Algorithm for Stroke Prediction: A National Health Insurance Database Study in Korea.

BACKGROUND: Stroke is the second leading cause of death worldwide and remains an important health burden both for the individuals and for the national healthcare systems. Potentially modifiable risk factors for stroke include hypertension, cardiac disease, diabetes, and dysregulation of glucose metabolism, atrial fibrillation, and lifestyle factors. OBJECTS: We aimed to derive a model equation for developing a stroke pre-diagnosis algorithm with the potentially modifiable risk factors. METHODS: We used logistic regression for model derivation, together with data from the database of the Korea National Health Insurance Service (NHIS). We reviewed the NHIS records of 500,000 enrollees. For the regression analysis, data regarding 367 stroke patients were selected. The control group consisted of 500 patients followed up for 2 consecutive years and with no history of stroke. RESULTS: We developed a logistic regression model based on information regarding several well-known modifiable risk factors. The developed model could correctly discriminate between normal subjects and stroke patients in 65% of cases. CONCLUSION: The model developed in the present study can be applied in the clinical setting to estimate the probability of stroke in a year and thus improve the stroke prevention strategies in high-risk patients. The approach used to develop the stroke prevention algorithm can be applied for developing similar models for the pre-diagnosis of other diseases.

Phosphoinositide 3-kinase-δ regulates fungus-induced allergic lung inflammation through endoplasmic reticulum stress.

BACKGROUND: Sensitisation with Aspergillus fumigatus (Af) is known to be associated with severe allergic lung inflammation, but the mechanism remains to be clarified. Phosphoinositide 3-kinase (PI3K)-δ and endoplasmic reticulum (ER) stress are suggested to be involved in steroid-resistant lung inflammation. We aimed to elucidate the role of PI3K-δ and its relationship with ER stress in fungus-induced allergic lung inflammation. METHODS: Using Af-exposed in vivo and in vitro experimental systems, we examined whether PI3K-δ regulates ER stress, thereby contributing to steroid resistance in fungus-induced allergic lung inflammation. Moreover, we checked expression of an ER stress marker in lung tissues isolated from patients with allergic bronchopulmonary aspergillosis. RESULTS: Af-exposed mice showed that ER stress markers, unfolded protein response (UPR)-related proteins, phosphorylated Akt, generation of mitochondrial reactive oxygen species (mtROS), eosinophilic allergic inflammation, and airway hyperresponsiveness (AHR) were increased in the lung. Similarly, glucose-regulated protein 78 was increased in lung tissues of patients with ABPA. A PI3K-δ inhibitor reduced Af-induced increases in ER stress markers, UPR-related proteins, allergic inflammation and AHR in mice. However, dexamethasone failed to reduce Af-induced allergic inflammation, AHR and elevation of ER stress. Administration of an ER stress inhibitor or a mtROS scavenger improved Af-induced allergic inflammation. The PI3K-δ inhibitor reduced Af-induced mtROS generation and the mtROS scavenger ameliorated ER stress. In primary cultured tracheal epithelial cells, Af-induced ER stress was inhibited by blockade of PI3K-δ. CONCLUSIONS: These findings suggest that PI3K-δ regulates Af-induced steroid-resistant eosinophilic allergic lung inflammation through ER stress.

Three-dimensional finger joint angles by hand posture and object properties.

The objective of this study was to identify three-dimensional finger joint angles for various hand postures and object properties. Finger joint angles were measured using a VICON system for 10 participants while they pinched objects with two, three, four and five fingers and grasped them with five fingers. The objects were cylinders and square pillars with diameters of 2, 4, 6 and 8 cm and weights of 400, 800, 1400 and 1800 g. Hand posture and object size more significantly affected the joint flexion angles than did object shape and weight. Object shape affected only the metacarpophalangeal (MCP) joint angle of the index finger and the flexion angle of the MCP joint of the little finger. Larger flexion angles resulted when the hand posture was grasping with five fingers. The joint angle increased linearly as the object size decreased. This report provides fundamental information about the specific joint angles of the thumb and fingers. Practitioner Summary: Three-dimensional finger joint angles are of special interest in ergonomics because of their importance in handheld devices and musculoskeletal hand disorders. In this study, the finger joint angles corresponding to various hand postures and objects with different properties were determined.

Quantitative comparison of marker attachment methods for hand motion analysis.

The purpose of this study was to compare and quantify the angle difference among marker attachment methods for kinematic evaluation. For static evaluation, a hand mock-up was designed and used in single trials of different marker attachment methods. The mean absolute angle difference between the marker attachment methods and hand mock-up was not statistically significant. For dynamic evaluation, the gripping task began when a participant gripped a cylinder. The main effect of the marker set (p < .049) was significant. Thus, the use of one marker per joint is recommended for static evaluation because it causes less discomfort when a patient moves his/her hand and because utilizing the same marker placements for each subject is easy. For dynamic evaluation, the use of three markers per segment or a cluster marker is recommended because they are less affected by skin movement.

Endoplasmic reticulum stress influences bronchial asthma pathogenesis by modulating nuclear factor κB activation.

BACKGROUND: Despite many studies on endoplasmic reticulum (ER) stress in patients with various inflammatory diseases, there is scarce information on ER stress in patients with bronchial asthma. OBJECTIVE: In this study we aimed to elucidate the role of ER stress in the pathogenesis of bronchial asthma. METHODS: Using mice sensitized with ovalbumin (OVA) and LPS and challenged with OVA (OVA(LPS)-OVA mice), as well as mice sensitized and challenged with OVA (OVA-OVA mice), we investigated whether ER stress is involved in the pathogenesis of bronchial asthma. Moreover, we also determined the levels of ER stress markers in blood and bronchoalveolar lavage fluid from asthmatic patients. RESULTS: The OVA(LPS)-OVA mice showed that the expression of ER stress markers and the protein levels of unfolded protein response-related markers in lung tissue were significantly increased after OVA challenge. Moreover, we found that ER stress markers in PBMCs and bronchoalveolar lavage fluid from human asthmatic patients were dramatically increased compared with those from healthy control subjects. In OVA(LPS)-OVA mice 4-phenylbutyric acid (4-PBA), a chemical chaperone, significantly reduced the increases in ER stress, nuclear translocation of nuclear factor κB, inflammatory cytokine levels, dendritic cell infiltration, Toll-like receptor 4 expression, airway inflammation, and bronchial hyperresponsiveness, whereas it further enhanced the increase in IL-10 levels. Additionally, the established asthmatic features of OVA-OVA mice were substantially attenuated by 4-PBA administered after completion of OVA challenge. CONCLUSION: These results indicate that ER stress might be implicated in the pathogenesis of bronchial asthma at least in part through modulation of nuclear factor κB activation.

Flexion and extension angles of resting fingers and wrist.

This study determined flexion and extension angles of resting fingers and wrist in terms of forearm posture (neutral, pronation and supination) and shoulder flexion (0°, 45°, 90° and 135°). The participants participated in 12 angle measurements for 16 finger joints and wrist. The finger joints flexed more in supination than in neutral posture and pronation and the thumb flexed more than the other fingers because of the gravity and skin tension. This phenomenon became more apparent as the shoulder flexed. The carpometacarpal joint had the largest flexion angle in the thumb joints, whereas the proximal interphalangeal joints had the largest flexion angles in the other finger joints. The resting posture of the wrist extended of ~16° in any forearm postures when the shoulder was at 0°. The results of this study could be useful for rehabilitation tool and product designs.

Research trends in ergonomics, industrial safety and health: semantic network and topic analyses.

We evaluated the research trends in ergonomics, industrial safety and health from the 1980s to the present. In the ergonomics area, keywords and abstracts from five journals were analyzed. For industrial safety and health, six journal databases were evaluated. A frequency analysis, a semantic network of keywords and a topic network of abstracts were conducted. The results of ergonomics showed that 'macro-ergonomics' and 'manual material handling' were the most popular topics, and 'ergonomic' and 'electromyography' were the most cited keywords. 'Posture' and 'biomechanics' were the most frequently used with high centrality. The results of industrial safety and health showed that 'job stress' and 'organizational safety' were the most popular topics, and 'occupational exposure' and 'occupational health' were the most cited keywords. 'Dust' and 'exposure' were frequently used with high centrality. The results would be helpful in understanding the trends of research efforts and foreseeing trends of future research.

Evaluation of ergonomic risks for work-related musculoskeletal disorders of nursing tasks in Korea.

Among all industrial accident-induced diseases, musculoskeletal disorders (MSDs) are most prominently observed among nurses. The physical load of everyday tasks involved in nursing work was assessed in this study using a developed risk index, whereby the physical burden was evaluated using the exposure duration and work intensity levels. This survey targeted nine small, medium and large-sized hospitals in South Korea and categorized representative nursing tasks into six groups. The subtasks within these six categories (evaluated as high risk) included changing a patient's posture and assisting with walkers or wheelchairs, transporting/handling drug carts, bathing patients, replacing bedding, traction therapy, cardiopulmonary resuscitation and artificial manual breathing unit, and computer work. The risk index ratio was significantly different by task type for each task. We demonstrated that the risk index developed in this study can be used to evaluate MSDs in hospitals.

Inhibition of p38 MAPK reduces expression of vascular endothelial growth factor in allergic airway disease.

BACKGROUND: The p38 mitogen-activated protein kinase (MAPK) appears to play an important role in various pathophysiological responses and has been suggested to be involved in many processes considered critical to the inflammatory response and tissue remodeling. Bronchial asthma is a chronic inflammatory disorder of the airway accompanied by increased vascular permeability. Vascular endothelial growth factor (VEGF) is a potent stimulator of bronchial inflammation, airway remodeling, and physiologic dysregulation that augments antigen sensitization and T-helper type 2 cell (Th2)-mediated inflammation in allergic airway diseases. However, there are little data on the relationship between p38 MAPK signaling and VEGF expression in allergic airway disease. OBJECTIVE: This study aimed to investigate the role of p38 MAPK on the pathogenesis of allergic airway disease, more specifically in VEGF expression. METHODS: Using ovalbumin (OVA)-inhaled mice and a selective p38 MAPK inhibitor, SB 239063, the involvement of p38 MAPK in allergen-induced VEGF expression in the airway was evaluated. RESULTS: The increases of phosphorylation of p38 MAPK, VEGF protein expression, and vascular permeability in the lung after OVA inhalation were decreased substantially by the administration of SB 239063. In addition, SB 239063 significantly reduced the increase of Th2 cytokines and OVA-specific IgE. The inhibition of p38 MAPK or VEGF signaling prevented and also decreased the increases in the number of inflammatory cells and airway hyperresponsiveness in OVA-induced allergic airway disease. CONCLUSIONS: These results indicate that inhibition of p38 MAPK may attenuate allergen-induced airway inflammation and vascular leakage through modulation of VEGF expression in mice.

AMPK activation reduces vascular permeability and airway inflammation by regulating HIF/VEGFA pathway in a murine model of toluene diisocyanate-induced asthma.

BACKGROUND: Occupational asthma is characterized by airway inflammation and hyperresponsiveness associated with increased vascular permeability. AMP-activated protein kinase (AMPK) has been suggested to be a novel signaling molecule modulating inflammatory responses. OBJECTIVE: We sought to evaluate the involvement of AMPK in pathogenesis of occupational asthma and more specifically investigate the effect and molecular mechanisms of AMPK activation in regulating vascular permeability. METHODS: The mechanisms of action and therapeutic potential of an AMPK activator, 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR) were tested in a murine model of toluene diisocyanate (TDI)-induced asthma. RESULTS: AICAR attenuated airway inflammation and hyperresponsiveness increased by TDI inhalation. Moreover, TDI-induced increases in levels of hypoxia-inducible factor (HIF)-1α, HIF-2α, vascular endothelial growth factor A (VEGFA), and plasma exudation were substantially decreased by treatment with AICAR. Our results also showed that VEGFA expression was remarkably reduced by inhibition of HIF-1α and HIF-2α with 2-methoxyestradiol (2ME2) and that an inhibitor of VEGFA activity, CBO-P11 as well as 2ME2 significantly suppressed vascular permeability, airway infiltration of inflammatory cells, and airway hyperresponsiveness induced by TDI. In addition, AICAR reduced reactive oxygen species (ROS) generation and levels of malondialdehyde and T-helper type 2 cytokines (IL-4, IL-5, and IL-13), while this agent enhanced expression of an anti-inflammatory cytokine, IL-10. CONCLUSIONS: These results suggest that AMPK activation ameliorates airway inflammatory responses by reducing vascular permeability via HIF/VEGFA pathway as well as by inhibiting ROS production and thus may be a possible therapeutic strategy for TDI-induced asthma and other airway inflammatory diseases.

A novel dithiol amide CB3 attenuates allergic airway disease through negative regulation of p38 mitogen-activated protein kinase.

RATIONALE: Cellular redox homeostasis altered by excessive production of reactive oxygen species (ROS) and weakening of the antioxidant defense leads to oxidative stress. Oxidative stress is characterized as a decrease in glutathione/glutathione disulfide (GSH/GSSG) and the triggering of a number of the redox-sensitive signaling cascades. Recent studies have demonstrated that ROS play an important role in the pathogenesis of airway inflammation and hyperresponsiveness. OBJECTIVES: Here we characterized for the first time the protective properties of a new hydrophobic thiol compound, N-acetyl cysteine proline cysteine amide (CB3), in allergic airway diseases. METHODS: We used ovalbumin (OVA)-inhaled mice to evaluate the role of CB3 as an antiinflammatory reagent and to determine its molecular signaling activity in allergic airways. MEASUREMENTS AND MAIN RESULTS: The administration of CB3 (1-50 mg/kg) to OVA-inhaled mice restored the decreased GSH levels, enhanced IL-10 expression, and significantly reduced the increase of Th2 cytokines and OVA-specific IgE. CB3 decreased the number of inflammatory cells and airway hyperresponsiveness in the lungs. We also found that the administration of CB3 dramatically decreased the nuclear translocation of the nuclear factor-κB (NF-κB) and the phosphorylation of p38 mitogen-activated protein kinases (MAPKs) in lungs after OVA inhalation. In addition, allergen-induced airway inflammation and hyperresponsiveness were substantially reduced by the administration of inhibitors of NF-κB and p38 MAPK, BAY 11-7085, and SB 239063, respectively. CONCLUSIONS: These results suggest that CB3 attenuates allergic airway disease by up-regulation of GSH levels as well as inhibition of NF-κB and p38 MAPK activity.

L-2-Oxothiazolidine-4-carboxylic acid or α-lipoic acid attenuates airway remodeling: involvement of nuclear factor-κB (NF-κB), nuclear factor erythroid 2p45-related factor-2 (Nrf2), and hypoxia-inducible factor (HIF).

Reactive oxygen species (ROS) play a crucial role in the pathogenesis of acute and chronic respiratory diseases. Antioxidants have been found to ameliorate airway inflammation and hyperresponsiveness in animal models employing short-term exposure to allergen. However, little data are available on the effect of antioxidants on airway remodeling and signaling pathways in chronic asthma. In the present study, we used a long-term exposure murine model of allergic airway disease to evaluate the effects of an antioxidant, L-2-oxothiazolidine-4-carboxylic acid (OTC) or α-lipoic acid (LA) on airway remodeling, focusing on the ROS-related hypoxia-inducible signaling. Long-term challenge of ovalbumin (OVA) increased ROS production, airway inflammation, and airway hyperresponsiveness, and developed features of airway remodeling such as excessive mucus secretion, subepithelial fibrosis, and thickening of the peribronchial smooth muscle layer. Administration of OTC or LA reduced these features of asthma, including airway remodeling, which was accompanied by suppression of transforming growth factor-ß1, vascular endothelial growth factor, and T-helper 2 cytokines. In addition, OVA-induced activation of nuclear factor-κB (NF-κB), nuclear factor erythroid 2p45-related factor-2 (Nrf2), hypoxia-inducible factor (HIF)-1α, and HIF-2α was reduced by OTC or LA. Our results also showed that OTC or LA down-regulated phosphoinositide 3-kinase activity and decreased phosphorylation of p38 mitogen-activated protein kinase but not extracellular signal-regulated kinase 1/2 or c-Jun N-terminal kinase. These findings demonstrate that OTC and LA can inhibit activation of NF-κB, Nrf2, and HIF, leading to attenuate allergen-induced airway remodeling.

The effect of camera location on observation-based posture estimation.

This study used the observation-based method showing images on computer to evaluate angle estimation errors of 8 body segments in 3 motion planes at up to 28 segment angles and 5 camera locations with respect to goniometric measurements. Thirty observers participated in evaluating segment angles. Forearm (9.9°) and thigh (9.5°) had smaller errors than hand (14.0°) and foot had the smallest error (8.7°) due to its narrow range of motion (ROM). Errors were small with camera locations perpendicular to motions in the planes, such as 90° camera location for the flexion and extension of arm (6.3°), forearm (7.9°), thigh (6.5°), and leg (8.1°) in the sagittal plane. Segments had small errors of 3.1°, 4.6°, and 3.8° at segment angles of -90°, 0° and 90°, respectively. Care should be taken when estimating angles by the observation-based method for a specific segment motion and viewing direction is suggested to be perpendicular to the motion plane. PRACTITIONER SUMMARY: Some companies may not allow many cameras or have obstacles for working posture evaluation in the workplace. These study results can be a guideline on proper selection of the number of cameras and their locations for a specific segment and its motion of interest to reduce visual segment angle estimation errors.

Reduced Muscle Activity of the Upper Extremity in Individuals with Spinal Cord Injuries.

Compromised physical ability due to musculoskeletal impairment among spinal cord injury (SCI) patients is known to negatively affect their quality of life. It is essential to comprehensively understand the muscle strength of the upper extremity among patients with SCI to enhance muscle function and capacity to engage in an active lifestyle. The objective of this study was to evaluate the muscle strength of 15 upper extremity muscles among patients with SCI and compare the relative weakness of individual muscles to the control group. Seven male patients with SCI with ASIA impairment scale D and E and 33 males in the control group participated in this study. Each participant performed maximal voluntary contraction of individual muscles, and the electromyography data were recorded. The results showed that the majority of the upper extremity muscles (12 out of 15) showed considerable weakness (24 to 53%) relative to the control group. Furthermore, the relative strength (ranking) of individual muscles among 15 upper extremity muscles was different between patients with SCI and the control group. This information would be useful to the selective strengthening of specific muscles as an intensive rehabilitation effort and prevent overuse and adverse injuries due to excessive muscle training.

HIF-1α inhibition ameliorates an allergic airway disease via VEGF suppression in bronchial epithelium.

Hypoxia-inducible factor-1α (HIF-1α) plays a critical role in immune and inflammatory responses. One of the HIF-1α target genes is vascular endothelial growth factor (VEGF), which is a potent stimulator of inflammation, airway remodeling, and physiologic dysregulation in allergic airway diseases. Using OVA-treated mice and murine tracheal epithelial cells, the signaling networks involved in HIF-1α activation and the role of HIF-1α in the pathogenesis of allergic airway disease were investigated. Transfection of airway epithelial cells with HIF-1α siRNA suppressed VEGF expression. In addition, the increased levels of HIF-1α and VEGF in lung tissues after OVA inhalation were substantially decreased by an HIF-1α inhibitor, 2-methoxyestradiol. Our data also show that the increased numbers of inflammatory cells, increased airway hyperresponsiveness, levels of IL-4, IL-5, IL-13, and vascular permeability in the lungs after OVA inhalation were significantly reduced by 2-methoxyestradiol or a VEGF inhibitor, CBO-P11. Moreover, we found that inhibition of the PI3K p110δ isoform (PI3K-δ) or HIF-1α reduced OVA-induced HIF-1α activation in airway epithelial cells. These findings indicate that HIF-1α inhibition may attenuate antigen-induced airway inflammation and hyperresponsiveness through the modulation of vascular leakage mediated by VEGF, and that PI3K-δ signaling may be involved in the allergen-induced HIF-1α activation.

Peroxisome proliferator-activated receptor gamma agonist down-regulates IL-17 expression in a murine model of allergic airway inflammation.

Peroxisome proliferator-activated receptor gamma (PPARgamma) plays a critical role in the control of airway inflammation. Recently, IL-17 has been found to be implicated in many immune and inflammatory responses, including airway inflammation. However, no data are available concerning the effect of PPARgamma on IL-17 production in airway inflammatory diseases. In this study, we used a mouse model of asthma to evaluate the effect of two PPARgamma agonists, rosiglitazone or pioglitazone, on IL-17 expression in allergic airway disease. After OVA inhalation, mice developed the typical pathophysiological features of asthma, and the expression of IL-17 protein and mRNA in the lungs was increased. Administration of rosiglitazone or pioglitazone reduced the pathophysiological features of asthma and decreased the increased IL-17 protein and mRNA expression after OVA inhalation. In addition, the attenuating effect of PPARgamma agonist on allergic airway inflammation and bronchial hyperresponsiveness is abrogated by coadministration of rIL-17. This study also showed that the inhibition of IL-17 activity with anti-IL-17 Ab remarkably reduced the increased numbers of inflammatory cells of the airways, airway hyperresponsiveness, and the increased levels of IL-4, IL-5, and IL-13 in bronchoalveolar lavage fluid and OVA-specific IgE in serum. In addition, we found that administration of rosiglitazone or pioglitazone decreased the increased NF-kappaB activity and that a NF-kappaB inhibitor, BAY 11-7085, substantially reduced the increased IL-17 protein levels in the lung tissues after OVA inhalation. These findings suggest that the therapeutic effect of PPARgamma in asthma is partly mediated by regulation of IL-17 expression via NF-kappaB pathway.

Clinical usefulness of D2-40 in non-small cell lung cancer.

D2-40 is a recently developed monoclonal antibody that reacts with a 40 kDa O-linked sialoglycoprotein and has been used for the assessment of lymphatic invasion in tumor specimens. We have evaluated the diagnostic usefulness of D2-40 and association of its immunopositivity with clinicopathological parameters in adenocarcinoma and squamous cell carcinoma of the lung. We investigated 97 cases of surgically resected adenocarcinoma or squamous cell carcinoma of the lung for the determination of D2-40 positivity in tumor cells and peritumoral lymphatic vessel density (LVD) using an immunostaining method. D2-40 immunoreactivity in tumor cells was invariably negative in adenocarcinoma but 47% of squamous cell carcinomas were positive. D2-40 positivity in the tumor was significantly associated with high LVD in squamous cell carcinoma (P < 0.006). There was no significant association between peritumoral LVD and clinicopathologic parameters, including lymphatic vessel invasion, lymph node metastasis, and survival in adenocarcinoma and squamous cell carcinoma. These results suggest that D2-40 immunoreactivity in tumor cells can be used for distinguishing between adenocarcinoma and squamous cell carcinoma and that the reactivity of tumor cells with D2-40 is positively correlated with LVD in squamous cell carcinoma but not with lymph node metastasis in adenocarcinoma and squamous cell carcinoma.

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.

Involvement of sirtuin 1 in airway inflammation and hyperresponsiveness of allergic airway disease.

BACKGROUND: Bronchial asthma is a chronic inflammatory disorder of the airways characterized by increased expression of multiple inflammatory genes. Acetylation of histones by histone acetyltransferases is associated with increased gene transcription, whereas hypoacetylation induced by histone deacetylases is associated with suppression of gene expression. Sirtuin 1 (SIRT1) is a member of the silent information regulator 2 family that belongs to class III histone deacetylase. OBJECTIVE: This study aimed to investigate the role of SIRT1 and the related molecular mechanisms in the pathogenesis of allergic airway disease. METHODS: By using a murine model of ovalbumin (OVA)-induced allergic airway disease and murine tracheal epithelial cells, this study investigated the involvement of SIRT1 and its signaling networks in allergic airway inflammation and hyperresponsiveness. RESULTS: In this study with mice after inhalation of OVA, the increased levels of SIRT1, hypoxia-inducible factor 1alpha (HIF-1alpha), and vascular endothelial growth factor protein in the lungs after OVA inhalation were decreased substantially by the administration of a SIRT1 inhibitor, sirtinol. We also showed that the administration of sirtinol reduced significantly the increased numbers of inflammatory cells of the airways; airway hyperresponsiveness; increased levels of IL-4, IL-5, and IL-13; and increased vascular permeability in the lungs after OVA inhalation. In addition, we have found that inhibition of SIRT1 reduced OVA-induced upregulation of HIF-1alpha in airway epithelial cells. CONCLUSIONS: These results indicate that inhibition of SIRT1 might attenuate antigen-induced airway inflammation and hyperresponsiveness through the modulation of vascular endothelial growth factor expression mediated by HIF-1alpha in mice.