Evaluation of antibody drug delivery efficiency via nebulizer in various airway models and breathing patterns.

BACKGROUND: Nebulizers are commonly used to treat respiratory diseases, which are a major cause of morbidity and mortality. While inhalation therapy with antibodies has been evaluated in preclinical studies and clinical trials for respiratory diseases, it has not yet been approved for treatment. Moreover, there is limited information regarding the delivery efficiency of therapeutic antibodies via nebulizer. METHODS: In this study, the nebulization characteristics and drug delivery efficiencies were compared when immunoglobulin G (IgG) was delivered by five nebulizers using two airway models and five breathing patterns. The study confirmed that the delivered dose and drug delivery efficiency were reduced in the child model compared to those in the adult model and in the asthma pattern compared to those in the normal breathing pattern. RESULTS: The NE-SM1 NEPLUS vibrating mesh nebulizer demonstrated the highest delivery efficiency when calculated as a percentage of the loading dose, whereas the PARI BOY SX + LC SPRINT (breath-enhanced) jet nebulizer had the highest delivery efficiency when calculated as a percentage of the emitted dose. CONCLUSION: The results suggest that the total inspiration volume, output rate, and particle size should be considered when IgG nebulization is used. We, therefore, propose a method for evaluating the efficiency of nebulizer for predicting antibody drug delivery.

Central role of Prominin-1 in lipid rafts during liver regeneration.

Prominin-1, a lipid raft protein, is required for maintaining cancer stem cell properties in hepatocarcinoma cell lines, but its physiological roles in the liver have not been well studied. Here, we investigate the role of Prominin-1 in lipid rafts during liver regeneration and show that expression of Prominin-1 increases after 2/3 partial hepatectomy or CCl4 injection. Hepatocyte proliferation and liver regeneration are attenuated in liver-specific Prominin-1 knockout mice compared to wild-type mice. Detailed mechanistic studies reveal that Prominin-1 interacts with the interleukin-6 signal transducer glycoprotein 130, confining it to lipid rafts so that STAT3 signaling by IL-6 is effectively activated. The overexpression of the glycosylphosphatidylinsositol-anchored first extracellular domain of Prominin-1, which is the domain that binds to GP130, rescued the proliferation of hepatocytes and liver regeneration in liver-specific Prominin-1 knockout mice. In summary, Prominin-1 is upregulated in hepatocytes during liver regeneration where it recruits GP130 into lipid rafts and activates the IL6-GP130-STAT3 axis, suggesting that Prominin-1 might be a promising target for therapeutic applications in liver transplantation.

Enhancement of Mechanical Properties and Testing of Nitinol Stents in Cerebral Aneurysm Simulation Models.

Stents are promising medical devices widely used in the prevention of cerebral aneurysm rupture. As the performance of stents depends on their mechanical properties and cell configuration, the aim of this study was to optimize the stent design and test the hemodynamic properties by using computational solid mechanics and computational fluid dynamics. In order to test their performance, computer-based cerebral aneurysm models that mimic the conditions present after implantation into the human brain were tested. The strut configuration selected was the closed-cell type, and nitinol was chosen as the material for stent manufacture because the innate characteristics of this material increase stent flexibility. Three ideal sample stent types with different cell configurations were manufactured. Computational solid mechanics analysis of the sample stents showed over 30% difference in flexibility between stents. Furthermore, using a cerebral aneurysm model simulation, we found that the stents eased the hemodynamic factors of the cerebral aneurysm and lessened the flow velocity influx into the sac. A decrease in flow velocity led to a 50-60% reduction in wall shear stress, which is expected to prevent aneurysm rupture under clinical conditions. Stent design optimization was carried out by simulation and electropolishing. Corrosion resistance and surface roughness were evaluated after electropolishing performed under variable conditions, but 40 V and 10 s were the most optimal.

Combined effect of bisphosphonate and recombinant human bone morphogenetic protein 2 on bone healing of rat calvarial defects.

BACKGROUND: This study aimed to investigate new bone formation using recombinant human bone morphogenetic protein 2 (rhBMP-2) and locally applied bisphosphonate in rat calvarial defects. METHODS: Thirty-six rats were studied. Two circular 5 mm diameter bony defect were formed in the calvaria using a trephine bur. The bony defect were grafted with Bio-Oss® only (group 1, n = 9), Bio-Oss® wetted with rhBMP-2 (group 2, n = 9), Bio-Oss® wetted with rhBMP-2 and 1 mM alendronate (group 3, n = 9) and Bio-Oss® wetted with rhBMP-2 and 10 mM alendronate (group 4, n = 9). In each group, three animals were euthanized at 2, 4 and 8 weeks after surgery, respectively. The specimens were then analyzed by histology, histomorphometry and immunohistochemistry analysis. RESULTS: There were significant decrease of bone formation area (p < 0.05) between group 4 and group 2, 3. Group 3 showed increase of new bone formation compared to group 2. In immunohistochemistry, collagen type I and osteoprotegerin (OPG) didn't show any difference. However, receptor activator of nuclear factor κB ligand (RANKL) decreased with time dependent except group 4. CONCLUSION: Low concentration bisphosphonate and rhBMP-2 have synergic effect on bone regeneration and this is result from the decreased activity of RANKL of osteoblast.

New computerized indices for quantitative evaluation of depression and asymmetry in patients with chest wall deformities.

An evaluation index that can quantitatively assess the severity of chest wall deformities is essential to prepare and assess corrective surgical operations for patients with these deformities, including funnel chest patients. In previous studies, our group proposed several automatically calculated indices that represent the severity of depression and asymmetry in the chest wall. These indices showed sufficient performance in most cases of deformities, including those involving asymmetric and symmetric depression; however, their linearity declined when assessing complex deformities. The purpose of this study is to propose two automated indices that provide linear evaluation output for all types of chest wall deformities, including complex deformities, and to evaluate their performance and clinical feasibility. Six reference chest wall boundary curves were obtained from 60 computed tomography (CT) images of a normal chest. Next, an active contour model-based image processing technique was used to extract boundary curves from images of patients with real chest wall deformities. Third, the required parameters were extracted from the boundary curves and the targeted indices were calculated. Finally, the performance of the proposed indices was evaluated using 33 synthetic images and 60 real chest CT images of patients with chest wall deformities. The newly proposed indices can be automatically calculated from the original CT images and showed sufficient performance for all types of chest wall deformities. We believe that the newly proposed indices can facilitate pre- and postoperative evaluation of chest wall deformities in clinical practice.

Antimicrobial activities of Eugenia caryophyllata extract and its major chemical constituent eugenol against Streptococcus pneumoniae.

In this study, we investigate the antimicrobial activities of both Eugenia caryophyllata (Ec) extract and its major component eugenol (4-allyl-2-methoxyphenol) against Streptococcus pneumoniae. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined by microdilution method. Pneumococcal biofilms were detected by crystal-violet microtiter plate assay, followed by colony-forming unit counts and visualized by scanning electron microscope (SEM). The synergistic effect of eugenol and penicillin was determined by checker-board method. Both the eugenol and the Ec extract inhibited pneumococcal growth in a concentration-dependent manner. The MIC and MBC of eugenol were 0.06% and 0.12%, respectively. Eugenol at a concentration of 0.12% completely killed S. pneumoniae within 60 min of exposure. The kill rate of planktonic cells was most rapid during the first 15 min of contact with eugenol. The addition of eugenol or Ec extract inhibited in vitro biofilm formation. In already established biofilms, the inhibitory effect of eugenol or Ec extract was more significant in terms of cell viability than in terms of disruption of the biofilm matrix. SEM analysis revealed non-viable and disruptive action of eugenol on the cell membrane of bacteria of biofilms. It was found that eugenol and penicillin produced a synergistic effect against S. pneumoniae. In conclusion, eugenol and Ec extract efficiently inhibited S. pneumoniae in planktonic growth and within biofilms.

A durability study of a paracorporeal pulsatile electro-mechanical pneumatic biventricular assist device.

In 2002, the paracorporeal pulsatile electro-mechanical pneumatic ventricular assist device (VAD) began to be developed by the Korea Artificial Organ Center at Korea University under a Health & Medical Technology Research and Development program which finished in 2008. In vitro durability testing was conducted on the paracorporeal pulsatile pneumatic VAD to determine device durability and to evaluate device failures. The 1- and 2-year reliability of the paracorporeal pulsatile pneumatic VAD was shown to be 91.2% and 54.9%, respectively, with an 80% confidence level. Failure modes were analyzed using fault tree analysis, with customized software continuously acquiring data during the test period. After this period, 21 in vivo animal tests were done, with 14 cases of left atrium to left ventricle (LV) inflow cannulation (36Fr)/outflow grafting to descending aorta, and seven cases of apex cannulation of LV to descending aorta (12 mm). The longest postoperative day (182 days) in Korea was recently recorded in in vivo animal testing (bovine, 90 kg, male, 3.5-4.0 L/min flow rate, and 55 bpm).

In vivo evaluation of MMP sensitive high-molecular weight HA-based hydrogels for bone tissue engineering.

Hyaluronic acid (170 kDa)-based hydrogel was synthesized using acrylated hyaluronic acid (HA) and matrix metalloproteinase (MMP) sensitive HA-based hydrogels were then prepared by conjugation with two different peptides: cell adhesion peptides containing integrin-binding domains (Arg-Gly-Asp: RGD) and a cross-linker with MMP degradable peptides to mimic the remodeling characteristics of natural extracellular matrices by cell-derived MMPs. Mechanical properties of these hydrogels were evaluated with different weight percentages (2.5 and 3.5 wt %) by measuring elastic modulus, viscous modulus, and swelling ratio. Human mesenchymal stem cells (hMSCs) were then cultured in MMP-sensitive or insensitive HA-based hydrogels and/or immobilized cell adhesive RGD peptides in vitro. Actin staining and image analysis proved that cells cultured in the MMP-sensitive hydrogel with RGD peptides showed extensive cell spreading and sprouting. Gene expression analysis showed that bone specific genes such as alkaline phosphatase, osteocalcin, and osteopontin increased in MMP-sensitive hydrogels as biomolecules such as BMPs and cells were added in the gels. For in vivo calvarial defect regeneration, five different samples (MMP insensitive hydrogel, MMP sensitive hydrogel, MMP sensitive hydrogel with BMP-2, MMP sensitive hydrogel with hMSC, and MMP sensitive hydrogel with BMP-2 and hMSC) were prepared. After 4 weeks of implantation, the Masson-Trichrome staining and micro computed tomography scan results demonstrated that the MMP sensitive hydrogels with BMP-2 and hMSCs have the highest mature bone formation. The MMP sensitive HA-based hydrogel could become useful scaffolds in bone tissue engineering with improvements on tissue remodeling rates and regeneration activity.

Determination of accurate stent graft configuration in abdominal aortic aneurysm using computed tomography: a preliminary study.

An aortic stent graft is frequently used to cure an abdominal aortic aneurysm (AAA). It is critical to accurately fit the size and shape of the stent graft to the target region on the aorta. Proper sizing and shaping require the measurement of the orthogonal diameter of the target region from medical images. The present study aimed to acquire an accurate three-dimensional (3D) reconstruction of the aorta to determine the shape of the cross-sectional area where the stent graft would be implanted. A conventional geometric-active contour model was enhanced to prevent blurring and to improve edge detection with high noise resistivity. After the segmentation of two-dimensional (2D) images using the model, a 3D-reconstructed configuration of the aorta was achieved using a surface-rendering technique. The model could segment several selected synthetic images more accurately than conventional methods. Also, a 3D-reconstructed configuration of the abdominal aorta could be achieved using boundary coordinates extracted from 2D image segmentation. This preliminary study indicates the utility of the approach in optimizing stent graft configuration for AAA patients, thus enhancing stent graft healing.

Effects of aerobic exercise on abdominal fat, thigh muscle mass and muscle strength in type 2 diabetic subject.

BACKGROUND: Aerobic exercise can effectively reduce visceral fat. However, few studies have examined the effect of daily physical activity on obesity and cardiopulmonary function in the subjects with diabetes. We examined the effect of moderate intensity of walking in obese diabetes patients by monitoring of daily activity and measuring the change in abdominal fat area, muscle are and maximal muscle strength. METHODS: We randomly assigned 27 obese women with type 2 diabetes to an aerobic exercise group (AG, n = 13) and control group (CG, n = 14). The AG performed moderate intensity walking for 60 minutes per exercise, 5 times per week, and for 12 weeks. The activity energy expenditure was monitored by a multi-record accelerometer. The CG maintained routine daily activities. At the time of the initiation of the study and after 12 weeks of exercise, the aerobic exercise capacity was assessed using oxygen consumption rate at anaerobic threshold (VO(2)-AT). The abdominal fat area and the quadriceps muscle area were measured by computed tomography, and the maximum muscle strength of the upper and lower limbs was measured by a chest press and a leg press, respectively. RESULTS: The mean age of the study subjects was 56.6 +/- 8.0 years, the mean duration of diabetes was 6.3 +/- 6.0 years, and the body weight index (BMI) was 27.3 +/- 2.7 kg/m(2). The BMI of the AG was significantly decreased (P = 0.003). In the AG, the visceral fat area and subcutaneous fat area were also significantly decreased (P = 0.018 and P < 0.001, respectively) but not in CG. VO(2)-AT of the AG was significantly improved, while that of the CG did not change (P = 0.009 and P = 0.115, respectively). The quadriceps muscle mass and the maximal muscle strength of the AG did not change, however, the CG showed a significant decrease. Duration of moderate intensity exercise was correlated with the decrease in total abdominal fat area (r = -0.484; P = 0.011) and that of high intensity exercise was correlated with improvement of cardiopulmonary function (r = 0.414; P = 0.032). CONCLUSION: Daily moderate intensity aerobic exercise is effective at reducing abdominal fat mass, while high intensity exercise improves cardiopulmonary function.

The effects of resistance training on muscle and body fat mass and muscle strength in type 2 diabetic women.

BACKGROUND: Our goal was to investigate the effects of low intensity resistance training on body fat, muscle mass and strength, cardiovascular fitness, and insulin sensitivity in type 2 diabetes. METHODS: Twenty-eight overweight women with type 2 diabetes were randomly assigned to a resistance training group (RG, n = 13) or a control group (CG, n = 15). RG performed resistance training using elastic bands, of which strength was equal to 40 to 50% of one repetition maximum (1RM), for three days per week. Each exercise consisted of three sets for 60 minutes. We assessed abdominal fat using computed tomography, muscle mass using dual-energy X-ray absorptiometry, and muscle strength using Keiser's chest and leg press. Insulin sensitivity was measured using the insulin tolerance test, and aerobic capacity was expressed as oxygen uptake at the anaerobic threshold (AT-VO(2)) before and after the 12-week exercise program. RESULTS: The age of participants was 56.4 +/- 7.1 years, duration of diabetes was 5.9 +/- 5.5 years, and BMI was 27.4 +/- 2.5 kg/m(2), without significant differences between two groups. During intervention, a greater increase in muscle mass and greater decreases in both total fat mass and abdominal fat were observed in RG compared to those of CG (P = 0.015, P = 0.011, P = 0.010, respectively). Increase in 1RM of upper and lower extremities was observed in the RG (P = 0.004, P = 0.040, respectively), without changes in AT-VO(2) and insulin resistance in either group. CONCLUSION: In conclusion, the low intensity resistance training was effective in increasing muscle mass and strength and reducing total fat mass without change of insulin sensitivity in type 2 diabetic patients.

Fully automatic initialization method for quantitative assessment of chest-wall deformity in funnel chest patients.

In our previous study, we developed a computerized technique that measured degree of chest-wall deformity in funnel chest patients using several image processing techniques, such as, active contour model. It could calculate quantitative indices for chest-wall deformity using patient's CT image. However, the algorithm contained manual initialization processes that required clinicians to obtain additional training processes to understand engineering contents and be familiar with the technique. In this study, we suggested a fully automatic algorithm that can measure the degree of chest-wall deformity by automating initialization processes. The initialization processes to segment CT images were automated by applying various image processing techniques such as histogram analysis, point detection, and object recognition. In order to evaluate the performance of the proposed algorithm, both the previous algorithm (semi-automatic) and newly suggested algorithm (fully automatic) were applied to preoperative CT images of 61 funnel chest patients to calculate several indices that represented chest-wall deformity quantitatively and to measure their processing time of our algorithm using a computer. The time required for initialization processes was 28.12 s using the semi-automatic algorithm and 0.07 s using the fully automatic algorithm (99.75% speed enhancement) and the time required for whole index calculation process was 61.12 s in semi-automatic algorithm and 30.09 s in fully automatic algorithm (50.76% speed enhancement). In most indices, calculation results of the two algorithms showed no significant difference between each other. The proposed algorithm could calculate chest-wall deformity more accurately with relatively shorter processing time than our previous method. Applying this algorithm is expected to facilitate more efficient diagnosis and evaluation processes of funnel chest patients for clinical doctors.

Development of a closed air loop electropneumatic actuator for driving a pneumatic blood pump.

In this study, we developed a small pneumatic actuator that can be used as an extracorporeal biventricular assist device. It incorporated a bellows-transforming mechanism to generate blood-pumping pressure. The cylindrical unit is 88 +/- 0.1 mm high, has a diameter of 150 +/- 0.1 mm, and weighs 2.4 +/- 0.01 kg. In vitro, maximal outflow at the highest pumping rate (PR) exceeded 8 L/min when two 55 mL blood sacs were used under an afterload pressure of 100 mm Hg. At a pumping rate of 100 beats per minute (bpm), maximal hydraulic efficiency was 9.34% when the unit supported a single ventricle and 13.8% when it supported both ventricles. Moreover, pneumatic efficiencies of the actuator were 17.3% and 33.1% for LVAD and BVAD applications, respectively. The energy equivalent pressure was 62.78 approximately 208.10 mm Hg at a PR of 60 approximately 100 bpm, and the maximal value of dP/dt during systole was 1269 mm Hg/s at a PR of 60 bpm and 979 mm Hg/s at a PR of 100 bpm. When the unit was applied to 15 calves, it stably pumped 3 approximately 4 L/min of blood at 60 bpm, and no mechanical malfunction was experienced over 125 days of operation. We conclude that the presently developed pneumatic actuator can be utilized as an extracorporeal biventricular assist device.

Fluoroscopy-guided endovenous foam sclerotherapy using a microcatheter in varicose tributaries followed by endovenous laser treatment of incompetent saphenous veins: technical feasibility and early results.

OBJECTIVES: To evaluate the technical feasibility and preliminary results of endovenous foam sclerotherapy using a microcatheter in varicose tributaries followed by endovenous laser treatment (EVLT) of incompetent saphenous veins. MATERIALS AND METHODS: From July 2005 to August 2006, 312 patients (M:F=139:173, mean age 45.8) who presented with varicose veins with reflux in the saphenofemoral, saphenopopliteal junction or tributaries were enrolled. Under ultrasound or fluoroscopy guidance, selective microcatheterization and endovenous foam slcerotherapy were first performed in varicose tributaries, followed by EVLT (980 nm) of incompetent saphenous veins. Follow-up at 1-week and 1-, 3-, and 6-month intervals was done. RESULTS: Technical success was seen in 410 of 411 limbs (99%). Continued closure of the saphenous veins and the complete sclerosis of varicose tributaries were noted in 332 of 373 limbs (89%) at the 1-month follow-up, all 307 limbs (100%) at the 3-month follow-up, and all 274 limbs (100%) at the 6-month follow-up. No serious complication was noted. CONCLUSION: Endovenous foam sclerotherapy using a microcatheter in varicose tributaries followed by EVLT in incompetent saphenous veins is a safe, effective, and technically feasible treatment for varicose veins. It not only reduces additional sclerotherapy and technical failure, but also makes multiple therapeutic sessions unnecessary.

Evaluation of tissue mimicking quality of tofu for biomedical ultrasound.

The tissue mimicking quality of tofu has been evaluated in terms of acoustic properties and acousto/thermal conversion as functions of frequency and diffraction corrected intensity over the 2 MHz to 18 MHz range using three unfocussed transducers with center frequencies of 5 MHz, 10 MHz and 15 MHz. The density and acoustic velocity were close to the American Institute of Ultrasound in Medicine (AIUM) recommended values for the soft tissue, however, the attenuation increases nonlinearly with frequency as alpha = 0.56 x f(1.3). As a result, the temperature rise in tofu due to ultrasound absorption is expressed by the product of the acousto/thermal conversion factor and the attenuation/diffraction corrected acoustic intensity. The decrease of temperature rise with depth measured by embedded thermocouples agrees with the theoretical exponential decrease of the attenuation/diffraction corrected acoustic intensity. The heat capacity per unit mass of tofu is 0.76 cal/g degrees C (equivalent to 3.18 J/g degrees C) of which about 76% is water. The nonlinear frequency dependence of attenuation in tofu as f(1.3) correctly describes the frequency dependence of temperature rise. The present results suggest that tofu may only be used in a limited low MHz range in view of the estimation of temperature rise and penetration depth due to nonlinear frequency dependence of attenuation.

Non-contact sound speed measurement by optical probing of beam deflection due to sound wave.

We report a non-contact and non-invasive method of sound speed measurement by optical probing of deflected laser beam due to normally incident degenerated shock wave. In this study the shock wave from an exploding wire was degenerated to an ordinary sound wave at the distance exceeding 0.23 m. Temporal resolution of the deflected beam signal was improved by passing through an adequate electronic high-pass filter, as a result we obtained a better temporal resolution than that of the acoustic pressure detection by PZT transducer in terms of rising time. The spatial resolution was improved by passing the refracted beam signal into the edge of focusing lens to make a larger deflection angle. Sound speed was calculated by monitoring the time of flight of transient deflected signal at the predetermined position. Sound speed has been measured in air, distilled water and acryl, agreed well with the published values. The sound speed measured in the solution of glycerin, magnesium sulfate (MgSO4), and dimethylformamide with various mole fractions also agrees within 3% of relative error with those measured in the present work by ultrasonic pulse echo method. The results suggest that the method proposed is to be reliable and reproducible.

Decrease of the electroacupuncture-induced analgesic effects in nuclear factor-kappa B1 knockout mice.

To investigate the involvement of nuclear factor kappa B1 (NF-kappaB1; p50/p105) in electroacupuncture (EA)-induced analgesia, 2 and 100 Hz EA stimulations were applied at acupoint ST36 (Zusanli) in NF-kappaB1 knockout mice. EA was performed for 30 min and tail-flick latencies (TFLs) were evaluated every 15 min for 1 h. Wild-type mice displayed a 63.3% increase in TFLs compared to baseline after 2 Hz EA, whereas NF-kappaB1+/- mice exhibited a 41.8% increase and NF-kappaB1-/- mice showed only a 3.9% increase of TFLs. The TFLs of 100 Hz EA showed similar trends: a 72.6% increase of TFLs in wild-type, a 38.6% increase in NF-kappaB1+/- and a 9.3% increase in NF-kappaB1-/- mice. The present findings suggest that NF-kappaB1 may play a crucial role in both low and high frequency EA-induced analgesic effects.