The IL-13/periostin/IL-24 pathway causes epidermal barrier dysfunction in allergic skin inflammation.

BACKGROUND: Barrier dysfunction is an important feature of atopic dermatitis (AD) in which IL-4 and IL-13, signature type 2 cytokines, are involved. Periostin, a matricellular protein induced by IL-4 or IL-13, plays a crucial role in the onset of allergic skin inflammation, including barrier dysfunction. However, it remains elusive how periostin causes barrier dysfunction downstream of the IL-13 signal. METHODS: We systematically identified periostin-dependent expression profile using DNA microarrays. We then investigated whether IL-24 downregulates filaggrin expression downstream of the IL-13 signals and whether IL-13-induced IL-24 expression and IL-24-induced downregulation of filaggrin expression are dependent on the JAK/STAT pathway. To build on the significance of in vitro findings, we investigated expression of IL-24 and activation of STAT3 in mite-treated mice and in AD patients. RESULTS: We identified IL-24 as an IL-13-induced molecule in a periostin-dependent manner. Keratinocytes are the main IL-24-producing tissue-resident cells stimulated by IL-13 in a periostin-dependent manner via STAT6. IL-24 significantly downregulated filaggrin expression via STAT3, contributing to barrier dysfunction downstream of the IL-13/periostin pathway. Wild-type mite-treated mice showed significantly enhanced expression of IL-24 and activation of STAT3 in the epidermis, which disappeared in both STAT6-deficient and periostin-deficient mice, suggesting that these events are downstream of both STAT6 and periostin. Moreover, IL-24 expression was enhanced in the epidermis of skin tissues taken from AD patients. CONCLUSIONS: The IL-13/periostin pathway induces IL-24 production in keratinocytes, playing an important role in barrier dysfunction in AD.

Application of a magnetic fluid seal to rotary blood pumps.

A magnetic fluid seal enables mechanical contact-free rotation of a shaft without frictional heat and material wear and hence has excellent durability. However, the durability of a magnetic fluid seal decreases in liquid. The life of a seal applied to a rotary blood pump is not known. We have developed a magnetic fluid seal that has a shield mechanism minimizing the influence of the rotary pump on the magnetic fluid. The developed magnetic fluid seal worked for over 286 days in a continuous flow condition, for 24 days (on-going) in a pulsatile flow condition and for 24 h (electively terminated) in blood flow. The magnetic fluid seal is promising as a shaft seal for rotary blood pumps.

Three-dimensional computer-aided design based design sensitivity analysis and shape optimization of the stem using adaptive p-method.

The number of stem designs for total hip arthroplasty is increasing, and occasionally design changes have yielded unexpected clinical results. At present, we are not able to clearly identify which parameter of the stem is most important, and the optimum value of many parameters. The goals of this study were to identify which parameter is most important, to understand the effect of design change, and to find the optimum stem shape. For this purpose, we used adaptive p-method together with three-dimensional computer-aided design software program for the design sensitivity analysis (DSA) and shape optimization of the stem. The results suggested that increasing the lateral and medial width of the distal cross-section together with decreasing the medial-lateral width and the medial radius of the distal cross-section from the default value would lead to a decrease in the largest maximum principal stress of the distal cement. The medial width of middle cross-section, however, was not so simple. The result of DSA suggested that decreasing this parameter from the default value decreased the stress in the distal cement, but the optimum shape was obtained by increasing this parameter. The method used in this study will assist our engineers and surgeons in the process of modifying and optimizing the stem design.

Hepatocyte growth factor levels in the vitreous of patients with proliferative vitreoretinopathy.

PURPOSE: To determine whether the hepatocyte growth factor is increased in the vitreous of patients with proliferative vitreoretinopathy. METHODS: We assayed hepatocyte growth factor levels by enzyme-linked immunosorbent assay (ELISA) in vitreous samples from 65 consecutive eyes (65 patients) with proliferative vitreoretinopathy (23 eyes), rhegmatogenous retinal detachment (22 eyes), and macular hole or idiopathic epiretinal membrane (control subjects, 20 eyes) having undergone pars plana vitrectomy. RESULTS: Vitreous levels of hepatocyte growth factor were 3.94 +/- 2.29 (mean +/- SD) ng/ml in proliferative vitreoretinopathy, 2.02 +/- 0.84 ng/ml in rhegmatogenous retinal detachment, and 2.16 +/- 1.39 ng/ml in the control subjects. The vitreous levels in proliferative vitreoretinopathy were much greater than levels in rhegmatogenous retinal detachment (P =.0002) and in the control subjects (P =.0007). In proliferative vitreoretinopathy, there was a tendency toward higher levels in eyes with grade D by the Retina Society terminology. CONCLUSION: The results suggest the possibility that hepatocyte growth factor may play a role in the pathogenesis of proliferative vitreoretinopathy.

Macrophage migration inhibitory factor levels in the vitreous of patients with proliferative vitreoretinopathy.

PURPOSE: To assess the potential role of macrophage migration inhibitory factor (MIF) in the pathogenesis of proliferative vitreoretinopathy. METHODS: We assayed MIF levels in vitreous and paired serum samples of 74 consecutive patients with proliferative vitreoretinopathy (26 eyes), rhegmatogenous retinal detachment (22 eyes), and macular hole or idiopathic epiretinal membrane (control, 26 eyes) by enzyme-linked immunosorbent assay. RESULTS: Vitreous levels of MIF were 51.33 +/- 49.21 ng/ml (mean +/- SD) in proliferative vitreoretinopathy, 19.11 +/- 16.13 ng/ml in rhegmatogenous retinal detachment, and 2.98 +/- 2.55 ng/ml in the controls. The vitreous levels in eyes with proliferative vitreoretinopathy were significantly higher than levels in eyes with rhegmatogenous retinal detachment (P = .0005) and in the control subjects (P < .0001). The vitreous levels were significantly higher than the serum levels in proliferative vitreoretinopathy (P < .0001) and rhegmatogenous retinal detachment (P = .0019), respectively. CONCLUSIONS: The results suggest that MIF may be involved in the pathogenesis of proliferative vitreoretinopathy.

Macrophage migration inhibitory factor levels in the vitreous of patients with proliferative diabetic retinopathy.

AIMS: To assess the potential role of macrophage migration inhibitory factor (MIF) in the pathogenesis of proliferative diabetic retinopathy (PDR). METHODS: MIF levels were assayed in the vitreous and paired serum samples of 73 consecutive patients with PDR (32 eyes) and macular hole or idiopathic epiretinal membrane (controls, 41 eyes). An enzyme linked immunosorbent assay technique was used to determine the concentrations of MIF. RESULTS: The median vitreous level of MIF was 11.93 ng/ml (range 4.16-103.85) in the patients with PDR, and 1.79 ng/ml (undetectable-8.93) in the controls. Vitreous levels in eyes with PDR were significantly greater than those in the controls (p<0.0001). Vitreous levels were significantly higher than serum levels in eyes with PDR (p=0.0026). MIF levels were significantly higher in the vitreous of PDR patients with severe fibrous proliferation than in those with slight proliferation (p<0.05). CONCLUSION: The results indicate increased levels of MIF in the vitreous of patients with PDR and a significant association between MIF levels and grades of fibrous proliferation, suggesting the possibility that MIF may play a part in the development of the proliferative phase of PDR.

Role of physical properties of resistance vessel wall in regulating peripheral blood flow--II. Structural and mechanical behavior.

In order to examine the structural and mechanical properties of the vessel wall resistance when subjected to autoregulatory flow control, a mechanical model for the vascular wall was derived from a mathematical model. The mechanical model was an analogue model which connected in series the Maxwell model (elastic modulus: K3) with the parallel elements of Hill's model (elastic modules: K2) and Hooke's elastic model (elastic modulus: K1); it was also mathematically equivalent to the Spring model (see part I). The structural and mechanical properties of the resistance vessel wall were characterized by the three elastic moduli (K1, alpha K2 and K3) [mmHg]. The parameter alpha was a modification factor of the elastic modulus K2 given by the myogenic mechanism. After a numerical analysis of the experimental data given by the mechanical model, we confirmed that the arterial pressure range for autoregulatory flow controls shifted to the upper region with an increase of the elastic modulus K1 and the flow regulation was reduced.

Development of an implantable motor-driven assist pump system.

A motor-driven artificial pump and its transcutaneous energy transmission (TET) system have been developed. The artificial pump consists of a high-speed dc brushless motor driving a ball screw and magnetic coupling mechanism between the blood pump and ball screw. The ball screw transfers high-speed rotary motion into low-speed rectilinear motion by a single component. Magnetic coupling enables active blood filling without applying an excess negative pressure to the pump. The transcutaneous transformer is formed from a pair of concave/convex ferrite cores. This design minimizes lateral motion of the external core. Information on motor voltage is transmitted through the skin by infrared pulses. The motor voltage is regulated by controlling the duty ratio of the square pulse supplied to the primary coil. Pump flow of 5.6 l/min was obtained with a mean outlet pressure of 100 mmHg at a drive rate of 100 bpm under preload of 15 mmHg. The performance of synchronous pumping has been very satisfactory. Continuous pumping was maintained by the backup battery in the case of interruption of TET. 24 W were transmitted by TET system with 78 percent of efficiency. Temperature rise of the internal core was 0.2 C. The developed system is promising as an implantable assist pump system.

Functional modulation of activated lymphocytes by time-varying magnetic fields.

Time-varying magnetic fields (TVMF), especially those of extremely low frequency (below 250 Hz), have been reported to have profound effects on biological systems due to the induced currents since the biological systems consist of electrolyte solution. We have been interested in utilizing TVMF for cellular immunomodulations, and have shown that the TVMF could augment macrophage activation. In this study, the effect of TVMF on lymphocyte activation was studied. Murine spleen lymphocytes were isolated from DDY mice and incubated in the presence of Concanavalin A (ConA) for 72 h. The lymphocytes were exposed to TVMF for various durations, from 20 min to 2 h. The proliferation activities of lymphocytes were assayed by ELISA by use of 5-bromo-2'-deoxy-uridine Labeling and Detection Kit III (Roche Diagnostic Corp. Indianapolis, IN, USA). The IL1beta and IL2 concentrations in the culture medium were measured by ELISA assay. The IL2 receptor expression on the lymphocytes was evaluated by FACS analysis by use of FITC-conjugated monoclonal antibody. The proliferation activities were significantly enhanced by the TVMF for up to 40 min exposure from the initiation of ConA stimulation. The degree of augmentation effects, defined by the ratio of activation index of with and without TVMF, was varied from 1.1 to 2.7, and related to the lymphocyte responsiveness to the ConA. The less responsive cells showed more TVMF augmentation effects. The TVMF exposure after 40 min from ConA addition showed no effect, suggesting that the TVMF effects are most likely related to the Ca ion influx. The prolonged exposure of TVMF depressed the augmentation effects, which was caused by the depressed IL-2 receptor expression although both IL1-beta and IL-2 productions were not affected.

Effects of venous pressure elevation on myogenic vasoconstrictive responses to static and dynamic arterial pressures.

In order to establish the nature of the stretch-evoked dynamic properties of vascular smooth muscle in arterioles, we have examined the static and dynamic effects of both arterial pulse pressure and elevated venous pressure on the resistance vessels (arteries and arterioles) in an intestinal mesenteric preparation derived from dogs. The dynamic myogenic response to stretch stimuli was directly related to both the frequency of arterial pulse pressure (1-20 c/min) and the level of venous pressure (0-45 mmHg). Under elevated venous pressure (20 mmHg), the mean arterial flow decreased with an increase in the frequency of arterial pulse pressure. The arteriolar vascular tone (namely, vascular resistance) was seen to be enhanced. We found that elevated venous pressure promotes active constriction (9-53%) of arteriolar smooth muscle (myogenic mechanism). The elevation of venous pressure also caused a rhythmic constriction (vasomotion) in the site of both vein and artery, which was completely abolished by an alpha-blocker (phentolamine). The results suggest that during venous pressure elevation a very pronounced myogenic constriction in terminal arterioles is caused by either a local neural reflex or a propagated myogenic response in the arteriolar network.

Myocardial oxygen tension during left ventricular bypass.

The effect of an assist pump on the heart was evaluated on the basis that myocardial gas tensions reflect the balance between oxygen supply and consumption in local regions of the myocardium. A left ventricular assist device (LVAD) was implanted in dogs between the left ventricle (LV group), or the left atrium (LA group) and the aorta. The assist pump was driven in a counterpulsation mode. A silicone catheter for mass spectrometry was inserted into the myocardium to monitor continuously myocardial oxygen and carbon dioxide tensions (PmO2, PmCO2). Coronary sinus blood flow (CSBF) was measured by completing an extracorporeal flow loop between the coronary sinus and the jugular vein. During LVAD counterpulsation, the LV pressure was reduced and diastolic arterial pressure (i.e. coronary perfusion pressure) was increased. Total LV bypass was obtained in the LV group, and partial LV bypass in the LA group. In the LV group, PmO2 was 18.3 +/- 1.9 mmHg with pump-off and increased to 26.4 +/- 3.0 during LV bypass (N = 10, p less than 0.005). PmCO2 was 45.3 +/- 1.8 mmHg with pump-off and decreased to 40.2 +/- 1.5 during bypass (N = 10; p less than 0.005). CSBF significantly decreased during LV bypass from a control value of 24.1 +/- 2.74 ml/min/100g to 16.3 +/- 1.69 in LV group (N = 10; p less than 0.001). It was 43.4 +/- 8.0 ml/min/100g in the pump-off and 31.9 +/- 7.2 during LV bypass in the LA group (N = 7; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Ferromagnetic artificial cells for artificial circulation.

It is known that deoxygenated blood is paramagnetic. A ferrofluidic actuator for an implantable artificial heart has been studied. The magnetic fluid consists of ferromagnetic magnetite particles (10 nm). If artificial cells encapsulating ferromagnetic particles are mixed in blood, the circulation is maintained by applying a magnetic field to the blood. An array of two poles of ring solenoids with a gap of 10 mm was mounted near the glass tube (7.60 mm inner diameter). The flux density was 0.236 Tesla. Two experiments were conducted using models of artificial cells: 1) the magnetic fluid and 2) the magnetic fluid and an iron cylinder (6.67 mm in diameter and 28.7 mm in length). A flow of 38 to 8 ml/min was obtained against a pressure of 12.5 to 16.3 mmHg in experiment 1, and 80 to 24 ml/min against a pressure of 53 to 240 mmHg in experiment 2. Calculation showed that magnetic fluids could move against a pressure of 100 mmHg if they had a magnetization of 113 kA/m (B = 0.236 Tesla). The magnetic fluid has a magnetization of 35.6 kA/m, whereas the magnetite is 479 kA/m, and that of iron 1398 kA/m. Artificial circulation with ferromagnetic artificial cells could be feasible if artificial cells with a magnetization of 113 kA/m are developed.

A remote monitoring system for patients with implantable ventricular assist devices with a personal handy phone system.

The usefulness of a remote monitoring system that uses a personal handy phone for artificial heart implanted patients was investigated. The type of handy phone used in this study was a personal handy phone system (PHS), which is a system developed in Japan that uses the NTT (Nippon Telephone and Telegraph, Inc.) telephone network service. The PHS has several advantages: high-speed data transmission, low power output, little electromagnetic interference with medical devices, and easy locating of patients. In our system, patients have a mobile computer (Toshiba, Libretto 50, Kawasaki, Japan) for data transmission control between an implanted controller and a host computer (NEC, PC-9821V16) in the hospital. Information on the motor rotational angle (8 bits) and motor current (8 bits) of the implanted motor driven heart is fed into the mobile computer from the implanted controller (Hitachi, H8/532, Yokohama, Japan) according to 32-bit command codes from the host computer. Motor current and motor rotational angle data from inside the body are framed together by a control code (frame number and parity) for data error checking and correcting at the receiving site, and the data are sent through the PHS connection to the mobile computer. The host computer calculates pump outflow and arterial pressure from the motor rotational angle and motor current values and displays the data in real-time waveforms. The results of this study showed that accurate data on motor rotational angle and current could be transmitted from the subjects while they were walking or driving a car to the host computer at a data transmission rate of 9600 bps. This system is useful for remote monitoring of patients with an implanted artificial heart.

Feasibility of a nickel-metal hydride battery for totally implantable artificial hearts.

An implantable rechargeable battery is one of the key technologies for totally implantable artificial hearts. The nickel-metal hydride (Ni-MH) battery is promising for its high energy density of 1.5-2.0 times that of a nickel-cadmium battery. In this study, the effects of pulsatile discharge loads on the operating time and cycle life of Ni-MH batteries at 39 degrees C were studied. Two battery cells (TH-3M, 1,200 mAh, phi 14.5 x 49 mm; Toshiba, Tokyo, Japan) in series were charge/discharge cycled at 39 degrees C using a charge current of 1CA (1,200 mA) and then were fully discharged to 1.0 V/cell under either pulsatile discharge loads, which mimicked a systole (1 A for 0.3 sec) and a diastole (0.4 A for 0.3 sec), or a non pulsatile discharge load equivalent to the average of the pulsatile loads (0.7 A). Each cycle life test was interrupted on the 482nd cycle under pulsatile load, and on the 423rd cycle under non pulsatile load, because of malfunction of each battery charger. The tests showed that the pulsatile discharge cells had significantly (p < 0.001) less operating time (74.0 +/- 7.15 min) throughout the test period (up to 482 days) compared to the cells under equivalent non pulsatile discharge loads (93.7 +/- 7.74 min). The pulsatile-discharged Ni-MH cells provide significantly less operating time than the constantly discharged cells; the Ni-MH battery has an operating time of over 78 min and a cycle life of almost 500 cycles at 39 degrees C. In conclusion, the Ni-MH battery is feasible as an implantable back-up battery for a totally implantable artificial heart system.

A durable, non power consumptive, simple seal for rotary blood pumps.

One of the key technologic requirements for rotary blood pumps is the sealing of the motor shaft. A mechanical seal, a journal bearing, magnetic coupling, and magnetic suspension have been developed, but they have drawbacks such as wear, thrombus formation, and power consumption. A magnetic fluid seal was developed for an axial flow pump. A magnetic fluid seal is durable, simple, and non power consumptive. Long-term experiments and finite element modeling (FEM) analyses confirmed these advantages. The seal body was composed of a Ned-Fe magnet and two pole pieces; the seal was formed by injecting ferrofluid into the gap (50 microm) between the pole pieces and the motor shaft. To contain the ferrofluid in the seal and to minimize the possibility of ferrofluid making contact with blood, a shield with a small cavity was attached to the pole piece. While submerged in blood, the sealing pressure of the seal was measured and found to be 188 mm Hg with ferrofluid LS-40 (saturated magnetization, 24.3 kA/m) at a motor speed of 10,000 rpm and 225 mm Hg under static conditions. The magnetic fluid seals performed perfectly at a pressure of 100 mm Hg for 594 + days in a static condition, and 51, 39+, and 34+ days at a motor speed of 8,000 rpm. FEM analyses indicated a theoretical sealing pressure of 260 mm Hg. The state of the magnetic fluid in the seal in water was observed with a microscope. Neither splashing of magnetic fluid nor mixing of the magnetic fluid and water was observed. The specially designed magnetic fluid seal for keeping liquids out is useful for axial flow blood pumps. The magnetic fluid seal was incorporated into an intracardiac axial flow pump.

Modification of the frictional surfaces of artificial joints.

To overcome the wear problems associated with artificial joint materials, new surface structures with regular patterning were designed and fabricated. The lubrication properties were studied to evaluate the wear of the frictional surfaces. The surface structure was a pattern of "dents" with a diameter of 0.2-1.0 mm and a pitch of 0.6-2.0 mm. The pattern was fabricated on the stainless steel (SUS) surface by a photochemical etching technique with 3 microns depth, and on an ultrahigh molecular weight polyethylene (UHMWPE) surface by mechanical processes. The time dependent changes of frictional force between SUS and UHMWPE were measured, and the surface morphologic changes were observed. The patterned surface showed lower frictional force than the smooth non-patterned surface, and less wear occurred on the patterned sample than on the sample without a pattern. There were optimum sizes for the diameter and the pitch of the pattern. These results demonstrated that lubrication properties could be improved by patterning of the frictional surfaces. The surface patterning was effective in preventing wear of the frictional surface, and the life of an artificial joint could be extended by such patterning.

Development of a ceramic heart valve.

A durable and thromboresistant ceramic heart valve comprised of a single crystal alumina disk and titanium nitride (TiN) valve ring has been developed. Blood compatibility was examined by scanning electron microscopy (SEM) examinations of the valves implanted in sheep for 35 (#1), 26 (#2), 20 (#3), 23 (#4), and 26 (#5) days. The single crystal alumina and TiN surfaces were free of platelet aggregation or fibrin networks, except for some depositions of fibrin and platelets on the outflow TiN ring in #3, and isolated red cells on the outflow TiN ring in #5. Durability testing under high pressure (1750 mmHg = 233 KPa) pulsatile conditions showed that the safety factor of the ceramic valve was more than seven times greater than anticipated. The ceramic valve is promising as an artificial heart valve.

The effect of left ventricular assist device (LVAD) on cardiac reserve in dogs.

The effect of LVAD on the preservation of cardiac reserve against ischemic damage was studied using Sarnoff's ventricular function curve. An LVAD was implanted between the canine left atrium and the aorta. Left ventricular function was measured by changing the height of the reservoir connected to the left atrium. The left ventricular function curve (LVFC) was drawn by plotting left ventricular stroke work (LVSW) against left atrial pressure (LAP). The coronary artery was occluded under a pump-on (ON group) or pump-off (OFF group). After reperfusion, measurements were repeated and changes in the LVFC caused by ischemia were compared in both groups. The gradient of the LVFC was significantly reduced by ischemia (107 +/- 15 ml/beat----80 +/- 14, n = 13) but not in the ON group. LVSW under normal preload did not significantly change in either group. This suggests that the LVAD preserved cardiac reserve against ischemic damage.

Surgical outcomes in juvenile retinal detachment.

PURPOSE: To evaluate retrospectively clinical features and surgical outcomes of rhegmatogenous retinal detachment in juvenile patients. METHODS: Between 1991 and 1996, 28 patients younger than 15 years of age with rhegmatogenous retinal detachment (32 eyes) underwent the first surgical procedure, scleral buckling and/or pars plana vitrectomy, at our hospital. RESULTS: The major types of juvenile detachment, in order of frequency, were idiopathic, familial exudative vitreoretinopathy, trauma, and high myopia. Proliferative vitreoretinopathy (PVR) of grade C or D was involved in 12 cases (37.5%). Among the 12 eyes with PVR, 7 attained retinal reattachment after the first surgery with scleral buckling. The overall reattachment rate was 28/32 (87.5%) after the first operation and 30/32 (93.8%) after the second operation. CONCLUSION: These findings indicate that the reattachment rate and visual prognosis can be as good in juvenile retinal detachment as in adult cases, when appropriate surgical procedures are used.

[Surgical outcomes of vitrectomy for retinal detachment due to macular hole with proliferative vitreoretinopathy].

We retrospectively studied surgical outcomes in 13 patients (13 eyes) who underwent vitrectomy for proliferative vitreoretinopathy (PVR) due to macular hole. While the success rate of the initial surgery was only 46% (6 eyes), retinal reattachment was ultimately obtained in 92% (12 eyes) with additional surgery. Reattachment rate in the initial was poor in eyes with posterior staphyloma. It was better in eyes treated with macular buckling and/or scleral encircling, and in eyes without iatrogenic retinal tears. These results indicate that appropriate treatment for the macular hole as well as extensive removal of vitreous gel and vitreoretinal traction are necessary in order to obtain the successful results in vitrectomy for PVR due to macular hole.