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Summary This is the first report of a new bacterial disease occurring on Quercus myrsinifolia in the nurseries of the Kyushu district in Japan. The main symptoms are shoot and twig blight, which begins with black necrotic lesions. In addition, unclear blackish discolorations, bacterial ooze and water-soaked lesions were observed as early symptoms, and spindle-shaped cankers and stem cankers with irregular surface were observed as secondary symptoms. The blight symptoms observed on the current-year shoots were first observed during the rainy season and continued until autumn (June–October). In summer, the symptoms were pronounced. A yellowish bacterium was consistently isolated from the affected shoots of Q. myrsinifolia, and on inoculation into healthy trees, it caused the same symptoms, which were more severe after wound inoculation than after non-wound inoculation. Wound inoculation also caused the disease symptoms on Quercus spp., Fagus crenata and Lithocarpus glaber, but not on several other species of Fagaceae. The causal bacterium was identified as Xanthomonas arboricola based on its morphological, cultural and biochemical characteristics and genetic sequence analysis of 16S rDNA, 16S-23S spacer regions and gyrB. To our knowledge, there are no previous records of xanthomonads causing shoot blight on fagaceous plants like Q. myrsinifolia. Therefore, we postulate that the shoot blight of Q. myrsinifolia is a new bacterial disease. We propose the name of the disease to be ‘bacterial shoot blight’ based on its main symptoms.

Water and tailings from lead-mining area in Kanchanaburi, Thailand were analyzed by PIXE to study how serious the alleged pollution was. Eleven water samples were collected in the field and were sealed in the tube after the pH < 2 was attained by ultrapure nitric acid. All of the samples were transported to Nishina Memorial Cyclotron Center of Japan Radioisotope Association and analyzed by its vacuum PIXE. The result showed that the water contains up to 25 ppb Pb with an average value 12 ppb. The value is lower than the environmental norm in Thailand (0.05 mg/L) but higher than that of WHO (10 μg/L = 0.01 mg/L). Tailings contain high amount of lead. Since resumption of mining is being considered to deliver the economic expectation of local people, it should be invested in treatment or containment within storage facilities. Also discharge of treated process water should be regularly monitored by competent agencies.

Background It is no doubt that a training of endoscopic surgery for surgeons has been very important to reduce fatal accidents due to inexperienced technique. Patients and methods Thirty medical students were randomly divided into two groups (SIM group: n = 20, CTR group: n = 10). The students in SIM group received a training using a simulator (MIST) for 2 h/day × 2 days, CTR group received an education by only video film for 30 min. All students were evaluated with the same task (one stitch and two ties with a box trainer) before/after training. Results Although there was no significant difference in total time of the evaluation task before the training between two groups, there was significant improvement after the training in SIM compared with CTR. The simulator training reduced the errors during the task. Conclusion Our results show that the simulator for the training of endoscopic surgery is useful to improve the basic skill of the bilateral devices, and to perform endoscopic surgery safely.

We present the results of high-resolution measurements of the low-energy part of the Auger electron spectrum generated by photoexcitation of the 1s −1 3p resonance in Ne. The spectrum was measured in the energy range of 10– 33 eV where mainly the electrons from the second-step Auger transitions of the cascades 1s −1 3p → 2s2p 5 np → 2s 2 2p 4 and 1s −1 3p → 2s 0 2p 6 np → 2s2p 5 (n = 3, 4) are detected. High resolution allows us to study the multiplet structure of the transitions and to determine the widths of the intermediate states of the Ne + ion. Anisotropy of the angular distribution of Auger electrons is determined for all of the lines observed. The results are in reasonably good agreement with MCDF calculations.

We previously reported that a humanized anti-factor IXa/X bispecific antibody, hBS23, mimics the function of FVIII even in the presence of FVIII inhibitors, and has preventive hemostatic activity against bleeding in an animal model of acquired hemophilia A. After further molecular engineering of hBS23, we recently identified an improved humanized bispecific antibody, ACE910, for clinical investigation.To elucidate the in vivo hemostatic potency of ACE910 by examining its effect against ongoing bleeds, and to determine its pharmacokinetic parameters for discussion of its potency for prophylactic use.A nonhuman primate model of acquired hemophilia A was established by injecting anti-primate FVIII neutralizing antibody. When bleeds emerged following an artificial bleed-inducing procedure, either ACE910 or recombinant porcine FVIII (rpoFVIII) was intravenously administered. rpoFVIII was additionally administered twice daily on the following 2 days. Bleeding symptoms were monitored for 3 days. A pharmacokinetic study and multiple-dosing simulations of ACE910 were also performed.A single bolus of 1 or 3 mg kg⁻¹ ACE910 showed hemostatic activity comparable to that of 10 U kg⁻¹ (twice daily) rpoFVIII against ongoing bleeds. The determined ACE910 pharmacokinetic parameters included a long half-life (3 weeks) and high subcutaneous bioavailability (nearly 100%). The simulation results based on pharmacokinetic parameters indicated that the above hemostatic level could be maintained with once-weekly subcutaneous administration of ACE910, suggesting the possibility of more effective prophylaxis.ACE910 may offer an alternative on-demand treatment option for patients with hemophilia A, as well as user-friendly and aggressive routine supplementation.

Le Tinctoporellus epimiltinus a ete reconnu comme l'un des agents de pourridie du Chamaecyparis obtusa dans l'ile de Kyushu au Japon, par ses caracteres culturaux, par des tests de croisement et par inoculation. Nous avons considere les caracteres culturaux d'isolats obtenus a partir de pourriture de pied de C. obtusa et d'isolats de T. epimiltinus obtenus a partir de tissus de carpophore et de bois altere. Les caracteres morphologiques et les reactions chimiques des isolats issus de pourriture de pied etaient typiques de T, epimiltinus. Des tests de croisement ont ete effectues entre cinq isolats monocaryons de T. epimiltinus et cinq heterocaryons issus de pourriture de pied. Tous les isolats monocaryons etudies ont ete heterocaryotises par les isolats issus de pourriture de pied. Des isolats de T. epimiltinus ont ete inocules a des racines de C. obtusa âges de 24 ans. La pourriture de pied a ete observee chez tous les arbres, 1 a 2 ans plus tard, et le champignon inocule a ete reisole des parties alterees des plants inocules.

A 27-year-old woman presented with destructive scleritis of the left eye with subcutaneous haemorrhage and swelling of the lower eyelid. She had experienced recurrent nasal bleeding for the last six years, and chronic sinusitis resulting in the destruction of the nasal septum and left maxillary sinus. Nasal mucosal biopsies demonstrated granuloma formation with no evidence of vasculitis. The level of serum cytoplasmic anti-neutrophil cytoplasm antibody (c-ANCA) was significantly increased. Furthermore, multiple sites of complete occlusions were detected in the left subclavian and common carotid arteries by subtraction angiography and MRI. We describe a case of Wegener's granulomatosis overlapped with Takayasu arteritis, which, to our knowledge, has not been previously reported.

Although inhibition of renal sodium-glucose co-transporter 2 (SGLT2) has a stable glucose-lowering effect in patients with type 2 diabetes, the effect of SGLT2 inhibition on renal dysfunction in type 2 diabetes remains to be determined. To evaluate the renoprotective effect of SGLT2 inhibition more precisely, we compared the effects of tofogliflozin (a specific SGLT2 inhibitor) with those of losartan (an angiotensin II receptor antagonist) on renal function and beta-cell function in db/db mice.The effects of 8-week tofogliflozin or losartan treatment on renal and beta-cell function were investigated in db/db mice by quantitative image analysis of glomerular size, mesangial matrix expansion and islet beta-cell mass. Blood glucose, glycated Hb and insulin levels, along with urinary albumin and creatinine were measuredTofogliflozin suppressed plasma glucose and glycated Hb and preserved pancreatic beta-cell mass and plasma insulin levels. No improvement of glycaemic conditions or insulin level was observed with losartan treatment. Although the urinary albumin/creatinine ratio of untreated db/db mice gradually increased from baseline, tofogliflozin or losartan treatment prevented this increase (by 50-70%). Tofogliflozin, but not losartan, attenuated glomerular hypertrophy. Neither tofogliflozin nor losartan altered matrix expansion.Long-term inhibition of renal SGLT2 by tofogliflozin not only preserved pancreatic beta-cell function, but also prevented kidney dysfunction in a mouse model of type 2 diabetes. These findings suggest that long-term use of tofogliflozin in patients with type 2 diabetes may prevent progression of diabetic nephropathy.

Extrathymic T cell tolerance to Ags can be achieved through clonal deletion by activation-induced programmed cell death as well as by functional unresponsiveness (anergy) of Ag reactive-T cells. Previous studies demonstrated that in vivo administration of staphylococcal enterotoxin B (SEB) induces SEB-specific T cell anergy. To investigate the molecular mechanisms of T cell anergy, we analyzed the TCR-mediated signal transduction in normal and anergic T cells. Anergic T cells exhibited impaired protein tyrosine phosphorylation on TCR-mediated stimulation. The altered tyrosine phosphorylation in anergic T cells may be caused by a defect in tyrosine phosphorylation of TCR zeta-chain and its subsequent association with ZAP-70 tyrosine kinase. Our data demonstrated that TCR zeta-chain phosphorylation and its sequential interaction with ZAP-70 are essential for the initiation of TCR-mediated signal transduction.

FK506 is an immunosuppressive drug that inhibits T cell receptor-mediated signal transduction. This drug can induce immunological tolerance in allograft recipients. In this study, we investigated the in vivo effects of FK506 on T cell receptor-mediated apoptosis induction. Injection of anti-CD3 antibody (Ab) in mice resulted in the elimination of CD4+ CD8+ thymocytes by DNA fragmentation. FK506 treatment significantly augmented thymic apoptosis induced by in vivo anti-CD3 Ab administration. Increased thymic apoptosis resulted in the disappearance of CD4+ CD8+ thymocytes after anti-CD3 Ab/FK506 treatment. DNA fragmentation triggered by FK506 was induced exclusively in antigen-stimulated T cells, since enhanced DNA fragmentation induced by in vivo staphylococcal enterotoxin B (SEB) injection was confirmed in SEB-reactive V beta 8+ thymocytes but not in SEB-nonreactive V beta 6+ thymocytes. In addition to thymocytes, mature peripheral T cells also die by activation-induced programmed cell death. A similar effect of FK506 on activation-induced programmed cell death was observed in SEB-activated peripheral spleen T cells. In contrast, cyclosporin A treatment did not enhance activation-induced programmed cell death of thymocytes and peripheral T cells. Apoptosis is required for the generation and maintenance of self-tolerance in the immune system. Our findings suggest that FK506-triggered apoptosis after elimination of antigen-activated T cells may represent a potential mechanism of the immunological tolerance achieved by FK506 treatment.

Static and cyclic fatigue behavior was investigated for two kinds of silicon nitride with different microstructures. These materials hardly show rising R-curve behavior. Nevertheless the considerable cyclic loading effect is obviously recognized in them. There has been observed an insignificant difference in the pure cyclic loading effect between coarse grained silicon nitride (SSN-1) and fine grained one (SSN-2). In addition, crack growth rate shows a transient acceleration or retardation when variable-amplitude cyclic loading is applied to SSN-1. Such a result implies the existence of a process zone near a crack tip which has a similar function to plastic zone in metals. Since the above cyclic crack behavior is inexplicable by the grain bridging degradation mechanism, possible cyclic fatigue mechanisms are, thus, discussed.

To evaluate the efficacy and safety of leukocytapheresis (LCAP) in patients with rheumatoid arthritis (RA) that is refractory to disease modifying antirheumatic drugs (DMARDs), we conducted a prospective, multicenter, open-label clinical trial.We enrolled 38 active RA patients, including 32 patients who showed an inadequate response toor = 2 DMARDs and 6 patients with rapidly progressive RA. All patients continued drug therapy and were treated with 5 LCAP sessions conducted at 1-week intervals. The clinical response was evaluated at baseline before starting LCAP and at 4 weeks after the completion of all the LCAP sessions using the American College of Rheumatology (ACR) criteria and the 28-joint disease activity score (DAS28) of the European League Against Rheumatism (EULAR).Of the 35 patients who fulfilled the study's eligibility criteria, 24 (69%), 10 (29%), and 23 (66%) patients achieved 20% (ACR20), 50% (ACR50), and DAS28-C-reactive protein (CRP) EULAR improvement, respectively. The mean DAS28-CRP score of the 35 patients decreased significantly from 5.99 +/- 0.92 at baseline to 4.54 +/- 1.39 after treatment. Comparison analysis of the ACR20 responders and non-responders to LCAP revealed that 22 of 24 responders (92%) concomitantly received methotrexate, whereas significantly fewer, that is, 6 of 11 non-responders (55%) received methotrexate. Less frequent and transient mild-to-moderate adverse events, including nausea and headache, were seen in 12 of 189 LCAP sessions (6.3%).These results demonstrate the usefulness of LCAP in combination with DMARDs, particularly methotrexate, as an effective and safe treatment for refractory RA.

A real-time on-die noise sensor continuously detects up to 100 noise events per second without disturbing processor operations, using a 400kb/s serial interface. The noise sensor uses histogram counters and variable detection windows. The sensor measures periodic and single-events in real time. The noise sensor is implemented in a 90nm CMOS testchip.

Cyclodiene pesticide dose not easily break down and tend to accumulate in soils. It is also proved toxic to an animals including human. However, the crops, especially carrot and cucumber, are easy to absorb persistent pesticide. We investigate the persistent agrichemicals (aldrin, dieldrin, endrin) in a farm field in Tokyo, Japan. Aldrin and Endrin had been used for agrichemical in 30 to 40 years ago. The surface soil in this field is Kanto‐loam and thickly distributed. 0.06 [mg/kg] of dieldrin was detected in only a shallow part of the depth and the other pesticide was not detected even aldrin. Dieldrin was not directly used as pesticide but closely related to aldrin. The epoxidation of aldrin in the environment leads to the more persistent dieldrin. Aldrin is not toxic to insects but it is oxidized in the insect to form dieldrin. Only dieldrin last for several decades in soil.

A novel wireless QoS architecture suitable for broadband CDMA packet cellular systems is proposed and its characteristics are described. The proposed QoS architecture is composed of several control factors laid on MAC and RRC layers, and can be harmonized with IP-QoS. Two important control factors, i.e., radio condition aware admission control and resource allocation reflected hybrid scheduling, are proposed. Computer simulations and testbed experiments indicate that by using radio condition aware admission control, stable and guaranteed service can be provided to realtime users regardless of interference and location variation of the mobile station. Moreover, resource allocation reflected hybrid scheduling maintains guaranteed rates for realtime users and provides high resource utilization efficiency for best effort users. Consequently, by using the proposed wireless QoS architecture, it is possible to provide users with high quality and diversified realtime services, on a packet based radio network for 3.5G and 4G.

This paper presents a mechanical sensorless vector-controlled system with parameter identification by the aid of image processor. Based on the flux observer and the model reference adaptive system method, this system includes rotor speed estimation and stator resistance identification using flux errors. Since the mathematical model of this system is constructed in a synchronously rotating reference frame, a linear model is easily derived for analyzing the system stability, including motor operating state and parameter variations. Because identifying rotor resistance is difficult simultaneously while estimating rotor speed, we use a low-accuracy image processor to measure the mechanical axis position for calculating the rotor speed at a steady-state operation. The rotor resistance is identified by the error between the estimated speed using the estimated flux and the calculated speed using the image processor. Finally, the validity of this proposed system has been proven through experimentation

When using a neural network (NN) for automatic diagnosis, it is difficult to deal with the ambiguous diagnosis problems. The paper proposes the "partially-linearized neural network (PNN)" by which failure types can be quickly distinguished on the basis of the probability distributions of symptom parameters. The knowledge acquisition method for PNN learning using rough sets is also proposed. The authors have applied these methods to the failure diagnosis of centrifugal pumps which are used in a chemical plant. The results of the failure diagnosis have verified that the methods are effective. The methods discussed can also be applied to other diagnosis or pattern recognition problems.

The number of patients co-infected with human immunodeficiency virus (HIV) and tuberculosis (TB) in our hospital is increasing year after year. Although most patients were HIV tested because of miliary tuberculosis or extra-pulmonary tuberculosis, some patients were found HIV seropositive by chance. In order to determine the incidence of HIV seropositivity among TB patients, HIV testing was carried out in TB patients for two years from January 1998 with the consent of patients. TB patients who received anti-HIV antibody examination were 164 in 1998, and 149 in 1999 and among them HIV seropositive TB patients were 4 in 1998 and 6 in 1999. The incidence of HIV seropositivity was 3.2% in all TB patients, 28.6% in miliary TB patients, and 1.0% in typical TB patients. The number of patients co-infected with HIV and TB in Tokyo was estimated by using these HIV seropositivity, it was 23 cases/year among miliary TB patients and 16 cases/year among typical TB patients. As there were many HIV-infected persons and many TB patients in Tokyo, it was thought that HIV testing in TB patients was important for the early detection of HIV infection and the early initiation of HIV treatment.

Resonant nonlinear optical response was measured in a crystalline cyanine dye MPER, 5‐(5‐morpholino‐2,4‐pentadienilydene)‐3‐ethylrhodanine, which had a broad reflection band due to large oscillator strength of an electronic excited state in the visible wavelength region. Nonlinear optical response measured by the change of reflectivity under optical pumping at the wavelength of the peak of the excited state was composed of fast and slow components. Response time of the fast component was less than 4 ps and its nonlinear optical coefficient χ(3) was evaluated to be (5±2)×10−15 m2/V2 [(4±2)×10−7 esu], which was one of the largest among organic materials.

In Japan tuberculosis is becoming rapidly the disease of the elderly. We studied the background, the type and level of hospital cares needed, and the outcome of patients with pulmonary tuberculosis (sputum smear and/or culture positive) above the age of 75 who were admitted to 8 national hospitals during the period from January 1 to December 31, 1997. The study included 150 patients (male: 109, female: 41, mean age: 81.6), of whom 25% needed care in a single-bed room, 84.3% had underlying diseases (cardiovascular diseases: 43.3%, malignant diseases: 20.9%, neuro-psychiatric diseases: 13.4%), and 47.6% needed cares mainly in feeding and excretions. 92 patients (62.6%) improved and 45 patients (30.6%) died, of whom the cause of death was directly related to tuberculosis in 42. The mean hospital stay was 4.7 months. However, in 42 patients whose cause of death was related to tuberculosis, 66% died within 3 months, while in 102 patients who were discharged 71% stayed more than 3 months. The same comparison was done in 508 patients with bacteriologically proven tuberculosis above the age of 75 admitted to National Tokyo Hospital during the period from 1990 to 1999. The result was almost the same, among 133 patients died in the hospital 60% died within 3 months, while in 375 patients who were discharged hospital stay was more than 3 months in 70%. In the near future, the elderly will occupy more than 25% of the beds of the tuberculosis ward in Japan and most of them have underlying diseases other than tuberculosis. Because tuberculosis, once the disease of the young, is becoming rapidly the disease of the elderly, it is imperative for us to make necessary adjustments to meet this inevitable trend.

The clinical findings of pulmonary tuberculosis in elderly patients aged 75 years of age or older (elderly group) were compared with the middle-aged patients aged between 45 and 54 years of age (middle-aged group) and the young patients aged 34 years of age or younger (young group). The elderly patients who died in hospital were also compared with the elderly patients who survived. Study subjects were culture-positive pulmonary tuberculosis patients who were discharged from our hospital from December 1996 to November 1998. There were 79 patients in the elderly group, 95 in the middle-aged group, and 88 in the young group. The results were as follows. 1) The male/female ratio was significantly lower in the elderly group (1.9:1) than the middle-aged group (6.9:1). 2) Complication was noted more frequently in the elderly group. However, diabetes mellitus was noted less frequently in the elderly group (12.7%) than the middle-aged group (28.4%). 3) The frequency of cavitation was lower in the elderly group (59.5%) than the middle-aged group (87.4%). 4) The fever over 38 degrees C was noted less frequently in the elderly group (17.7%) than the other groups, while the frequency of the fever over 37 degrees C showed no significant difference between the elderly group and the other groups. 5) The frequencies of hypoalbuminemia and appetite loss were higher in the elderly group than the other groups. 6) The elderly group showed high mortality rate of 31.6%. The complication with cerebrovascular disease was noted significantly higher in the patients who died in hospital than those who survived. The frequency of widespread infiltrates, fever over 38 degrees C, neutrophilia, hypoalbuminemia and appetite loss were all significantly higher in the patients who died in hospital while their sputa were still positive on culture than those who survived. Our study clearly showed the features of elderly pulmonary tuberculosis patients in comparison with middle-aged patients and young patients. These features are very important to suspect the diagnosis of pulmonary tuberculosis in elderly patients with some atypical manifestation. Our study also suggests that the delay in diagnosing tuberculosis causes more frequently the patients' deterioration and death in elderly patients than in middle-aged patients and young patients.

We studied the causes of death in 295 patients (mean (+/- SD) age 70.5 +/- 13.2 y.o.) with active non-MDR pulmonary tuberculosis who died in our hospital between 1991 and 1999. A hundred and twenty eight patients (43.4%, group A) died of tuberculosis, while 167 patients (56.6%) of other accompanying diseases. In 46 patients of the latter (15.6%, group B), pulmonary tuberculosis gave an unfavorable impact on their clinical course. In these patients the extent of pulmonary tuberculosis on chest roentgenograph was similar with the remaining 121 patients who also died of the accompanying diseases (41.0%, group C) and was less severe than those of the group A patients. Their nutritional conditions measured by serum albumin and choline-esterase level on admission, however, were as low as those of the group A patients and distinctly worse than those of the group C patients. Most patients of groups A and B died within 3 months after admission, while less than half patients of group C died during the same period. The age frequency distribution of the patients in groups B and C had a single peak in the age group 70 to 89, while that in group A showed two peaks, one similar peak as in groups B and C, and another peak in the age group 50 to 59. The numbers of homeless patients, of the patients with extensive cavitary lesions, and of the patients who died of ARDS (Adult Respiratory Distress Syndrome) or severe pneumothorax in group A were the most also in the age group 50 to 59, indicating that the patients' delay in admitting to hospitals was the major cause of high motality in this age group. As to detailed causes of death in group A, patients died of respiratory failure (32 cases), emaciation (28 cases), progression of pulmonary tuberculosis (20 cases), ARDS (15 cases), tuberculosis-related diseases such as pneumothorax, hemoptysis, and DIC (24 cases). In groups B and C patients died of organ failure (36 cases), infectious diseases (33 cases) and malignancy (30 cases). The total number of died patients has increased, and the proportion of cases dying of ARDS and infectious diseases has increased statistically significantly recently.

To determine whether the activation of metalloproteinases can be achieved by the interaction of the inflammatory cytokine, IL-1 beta, with rheumatoid osteoblasts.MMP-2 is not secreted by rheumatoid osteoblasts as a proenzyme; however, IL-1 beta stimulation induced the secretion of MMP-2 as an active form from rheumatoid osteoblasts. This MMP-2 activating activity was detected significantly in IL-1 beta-stimulated rheumatoid osteoblasts. In support of this result, IL-1 beta stimulation induced the expression of membrane type matrix-metalloproteinase (MT-MMP), a newly-identified MMP-2 specific activator, in rheumatoid osteoblasts.These results suggest that IL-1 beta induces MMP-2 activation in part by up-regulating MT-MMP expression and represents a new mechanism for cytokine-mediated articular destruction in RA.

The effect of starvation on carbohydrate metabolism in the last instar larvae of the silkworm Bombyx mori was examined. Trehalose concentration in the hemolymph increased slightly during the first 6 h of starvation and decreased thereafter, whereas glucose concentration decreased rapidly immediately after diet deprivation. Starvation-induced hypertrehalosemia was completely inhibited by neck ligation, suggesting that starvation stimulates the release of a hypertrehalosemic factor(s) from the head. The percentage of active glycogen phosphorylase in the fat body increased within 3 h of starvation and its glycogen content decreased gradually. These observations suggest that production of trehalose from glycogen is enhanced in starved larvae. However, hypertrehalosemia during starvation cannot be explained by the increased supply of trehalose into hemolymph alone, as similar changes in phosphorylase activity and glycogen content in the fat body were observed in neck-ligated larvae, in which hemolymph trehalose concentration did not increase but decreased gradually. When injected into larvae, trehalose disappeared from hemolymph at a rate about 40% lower in starved larvae than neck-ligated larvae. The hemolymph lipid concentration increased during starvation, suggesting that an increased supply of lipids to tissues suppresses the consumption of hemolymph trehalose and this is an important factor in hypertrehalosemia.

The patients with active tuberculosis in whom respiratory failure requiring mechanical ventilation developed were studied retrospectively. Nine patients (M 8, F 1) were identified at the National Tokyo Hospital during 5 years from January, 1993 to December, 1997. Seven of 9 patients were single men, and the duration of symptoms before admission was over 1 month in all patients, while the time from first visit to diagnosis was less than 7 days. All patients were identified as malnourished, and 7 patients suffered from another underlying diseases. The patients were classified into two groups. Six of 9 patients had pulmonary tuberculosis and the other three had miliary disease. The proportion of cases requiring mechanical ventilation was 0.3% and 8.6%, respectively, in pulmonary tuberculosis and miliary tuberculosis. At the start of mechanical ventilation, PaO2/FIO2 was lower than 200 in all 9 patients, and 6 patients were probably ARDS. Steroids (methylprednisolone 250-1000 mg/day) were used in all 9 patients. Despite the use of mechanical ventilation and antituberculous therapy, 8 out of 9 patients died. Only one patient with miliary tuberculosis survived. The establishment of the therapy for acute respiratory failure is needed so as to improve prognosis of such cases. At the same time, the delay in consulting a doctor led to acute respiratory failure in most cases, so it is also important to encourage tuberculosis patients to visit a doctor as soon as possible, after the appearance of symptoms.

Combining linear absorption and nonlinear third harmonic generation (THG) experiments, we investigate details of the electronic structure of the highly correlated electronic system in La2CuO4. We demonstrate strong THG mainly due to the charge transfer excitation from O (2p(sigma)) to Cu (3d(x2-y2)). The THG spectrum shows pronounced features due to three-photon and two-photon resonance enhancement as well as quantum interference effects. We obtain excellent agreement with a THG spectrum calculated in terms of the excitonic cluster model and can identify both odd and even symmetry excitation modes.

To clarify the features of the coexistence of active pulmonary tuberculosis in patients with lung cancer, we analyzed clinical data on 25 cases with coexisting lung cancer and active pulmonary tuberculosis encountered at Tokyo National Chest Hospital during the period from 1991 to 1998. There were 23 men and 2 women, with a mean age of 70 years. The incidence of lung cancer among patients with active pulmonary tuberculosis at our hospital was 0.7 per cent, while the incidence of active pulmonary tuberculosis in untreated lung cancer patients at our hospital was 1.9 per cent. We classified the 25 cases into 2 groups as follows: (1) tuberculosis sequential to lung cancer (11 cases) and (2) tuberculosis concurrently detected with lung cancer (14 cases). All patients in the former group were transferred from other hospitals after diagnosing the coexistence of pulmonary tuberculosis during the management of lung cancer. Histological types of lung cancer were squamous cell carcinoma in 12, adenocarcinoma in 9, and small cell carcinoma in 4, and as to the disease stage, stages III to IV were predominant. Analysis on relationship of chest X-ray findings between lung cancer and pulmonary tuberculosis revealed that in general, the location of lung cancer and tuberculosis seemed to be independent. Tuberculosis in the sequential group was more extensive and severer than in the concurrent group. In the concurrent group, treatment for tuberculosis was successful except for one case, and coexisting tuberculosis did not seem to affect the course of lung cancer among this group. However, in the sequential group, 5 patients died within 3 months, 2 of them died of tuberculosis. We consider that in the management of lung cancer, physicians should consider the possibility of coexistent active pulmonary tuberculosis and should not make delay in the diagnosis of active pulmonary tuberculosis.

FK506 is a clinically effective immunosuppressive agent and promoter of immunologic tolerance. However, limited information is available about the mechanism of FK506-induced immunosuppression.In the present study, we investigated the molecular mechanism of FK506-mediated enhancement of apoptosis using in vivo activated T lymphocytes. We examined the effects of FK506 on apoptosis-related proteins in superantigen-stimulated peripheral T cells.Injection of staphylococcal enterotoxin B (SEB) into BALB/c mice resulted in a selective apoptosis of splenic Vbeta8-positive T cells after 48 hr. Injection of FK506 within 36 hr of SEB injection resulted in a marked enhancement of DNA fragmentation of splenic Vbeta8+ T cells. FK506 did not affect the expression of Fas antigen on SEB-activated Vbeta8+ T cells. As Bcl-2-related proteins are involved in apoptotic process, we also evaluated their role by examining the expression of Bcl-2, Bcl-X(L), and Bax on SEB-FK506-treated murine splenic T cells. Although SEB injection slightly increased the expressions of Bcl-2 and Bax on V138+ T cells, FK506 did not modulate Bcl-2 or Bax expression in these cells. In contrast, the expression of Bcl-x(L) on Vgamma8+ T cells, which was markedly induced by SEB, was abrogated by FK506.Our findings indicate FK506-induced enhancement of apoptosis of activated T cells is mediated by down-regulation of Bcl-X(L) expression on these cells. Our results also suggest that Bcl-x(L) is a critical determinant of apoptosis of activated T cell and may represent a potential target for new therapies designed to achieve immunological tolerance.

To determine whether gelatinase A (MMP-2) plays a significant role in the pathogenesis of Sjögren's syndrome (SS) with or without HTLV-I infection.We examined 24 patients with SS (14 HTLV-I-seropositive and 8 HTLV-I-seronegative). Labial salivary gland tissue samples were analysed immunohistochemically using anti-MMP-2 monoclonal antibodies.In normal salivary glands, MMP-2 expression was not detected. All biopsy samples of 8 SS patients with HTLV-I-associated myelopathy (HAM) and 3 of 6 HTLV-I-seropositive SS patients without manifestation of HAM stained positively for MMP-2. However, the other samples were negative for MMP-2.Our study showed the MMP-2 expression in labial salivary glands of HTLV-I seropositive SS patients, especially in all SS patients with HAM. The presence of MMP-2 in the salivary glands of these patients suggests that it may play a role in cellular infiltration and destruction in salivary glands of SS.

Retinal derivatives were synthesized and their third‐order nonlinear optical properties were measured by degenerate four‐wave mixing with temporally incoherent nanosecond laser pulses. Fast optical nonlinearities, whose response time was shorter than 30 ps, were observed. The magnitudes of resonant third‐order hyperpolarizability were found to be 10−31∼10−29 esu. The large optical nonlinearities were of electronic origin.

Lymphocytes infiltrating the salivary glands of patients with Sjögren's syndrome (SS) are activated and resist apoptosis. We determined the role of interactions between CD40 and CD40 ligand (CD40L) in these infiltrating lymphocytes on B-cell differentiation and expression of Bcl-2 family proteins. Ten human T-cell leukemia/lymphoma virus-I (HTLV-I)-seronegative and eight HTLV-I-seropositive SS patients were examined in the present study. Immunohistochemistry was performed to examine the expression of CD3, CD20, PCA-1, CD40, CD40L, Bcl-2, Bax, and Bcl-x on T and B lymphocytes infiltrating labial salivary glands of SS patients. We also examined the expression of CD40 and CD40L on peripheral blood lymphocytes of the same patients by using flow cytometry. CD40L was not expressed on peripheral blood lymphocytes of SS patients. Peripheral blood B cells but not T cells expressed CD40. In contrast,50% of mononuclear cells, including T and B cells infiltrating the glands, expressed CD40. In addition, a clear expression of CD40L in both infiltrating T cells and B cells, and that of PCA-1, was also demonstrated. Surprisingly, the expression of Bcl-2 and Bcl-x was colocalized with that of CD40 determined by mirror section technique. Bcl-x was also abundantly expressed on infiltrating mononuclear cells, but, Bax expression was relatively less than that of Bcl-2 or Bcl-x. The expression of the above molecules was not different between HTLV-I-seronegative and HTLV-I-seropositive SS patients. Our results indicate that CD40/CD40L pathways could be augmented in salivary glands of SS patients, inducing B-cell differentiation to PCA-1 + plasma cells. Immunohistochemical analysis also suggests that signaling through CD40 by means of CD40L increases the expression of Bcl-2 as well as Bcl-x in infiltrating lymphocytes, providing the resistance against apoptosis. Our findings were commonly observed in SS patients irrespective of HTLV-I seropositivity.

We studied the relationship of FDP and D-dimer levels of rheumatoid arthritis (RA) patients with their activities of RA. We evaluated FDP/D-dimer levels of thirty-six RA patients. And we also evaluated FDP/D-dimer levels of 14 patients with systemic lupus erythematosus (SLE) and 12 patients with other rheumatic diseases as control. RA patients were divided into two groups according to their activities. Nineteen patients, who fulfilled at least three of four activities criteria, were classified as active group [RA (A) group], and other 17 patients were classified as not-active group [RA (B) group]. FDP and D-dimer levels of RA patients were higher than those of SLE or other patients group significantly (P0.01). Furthermore, in RA patients, high levels of FDP and D-dimer were observed in RA (A) group compared to RA (B) group. In some RA patients, decrease of FDP and D-dimer levels were observed according to their RA activities. FDP and D-dimer levels were not correlated with the level of rheumatoid factor (RF). These results show that the FDP and D-dimer levels were elevated according to RA activity in RA patients.

1. National survey on died patients with active tuberculosis (tbc) or tbc sequelae had been held in national hospitals every five year from 1959 (3433 cases) to 1994 (688 cases). In 1994, 330 patients died due to pulmonary tbc. Recent study revealed the decreased rate of death due to operation, or far advanced cavitary cases, and the increased rate of nontuberculous death, aged people (60 yrs), and nontuberculous complications. Main causes of death in pulmonary tbc were lung insufficiency (about half) and general weakness (almost one fifth) in any survey. Rapid progression of pulmonary tbc had been increased cause of death (20.9% in 1994). Main attributable factors of death in 1994 in pulmonary tbc cases were severe condition on admission (38.4%), disturbed lung function (31.2%) and old age (33.2%). Delayed treatment (13.9%) and complications (12.1%) were increasing factors. Early death within 3 months from onset in 1994 was seen in patients60 yrs as well as in patients80 yrs. Severity due to delayed treatment and rapid progression were supposed to the causes of early death. 2. During 1994 to 1997, mechanical ventilation (MV;24 hours) was applied to 18 patients with active pulmonary tuberculosis; 10 acute respiratory failure (ARF), 5 chronic respiratory failure (CRF), 2 central nervous system tbc and 1 hemoptysis. Only one ARF case and three CRF ones survived. ARF cases had low PaO2/FIO2 (about 100), low albuminemia, short MV period (7 cases:7 days) and steroid therapy (9 cases). CRF cases had higher PaO2/FIO2 (294), longer MV period (4 cases:30 days) and all CO2 narcosis. 3. Noninvasive positive pressure ventilation (NIPPV) was applied to 23 patients with pulmonary tbc sequelae. In 13 patients with stable chronic respiratory failure (mean PaO2 91 mmHg, PaCO2 82 mmHg) 10 continued NIPPV and started home mechanical ventilation (HMV). In 10 patients with acute on chronic respiratory failure (mean PaO2 61 mmHg, PaCO2 92 mmHg) 2 patients fell into tracheal intermittent positive pressure ventilation (TIPPV). Eight patients recovered with NIPPV and 5 started HMV. NIPPV is supposed to be very effective to treat severe chronic hypercapmic respiratory failure.

To clarify features of lung cancer in patients with tuberculosis sequelae, we analyzed data on 15 cases (5.1%) who were diagnosed with lung cancer before death among 294 deceased cases with tuberculosis sequelae at our hospital. There were 12 men and 3 women, with a mean age of 64 years. Most of the 15 patients had pulmonary dysfunction, and 4 had received home oxygen therapy. All 12 men had a history of smoking, and 10 of them had squamous cell carcinoma of the lung. There was no definite correlation between the locations of the tuberculosis lesion and those of lung cancer lesion on chest X-rays. Twelve patients had had thoracoplasty for tuberculosis, and in 6 of these patients the lung cancer occurred in the same lung. Lung cancer was apt to be diagnosed in an advanced stage. However, in patients who received home oxygen therapy, diagnosis had been made at an early stage because of the frequent chest X-ray follow-up. We conclude that lung cancer is an important complication in patients with tuberculosis sequelae, and early diagnosis of lung cancer by careful follow-up is essential in the care of cases with tuberculosis sequelae who have poor pulmonary function and/or systemic conditions.

Seventy-four cases of miliary tuberculosis were studied retrospectively. The mean age of the patients was 45.3 years. Twenty-two patients suffered from another underlying diseases. Six were infected with human immunodeficiency virus. Twelve had been treated with corticosteroids. Fever was present in 97.3 per cent of patients. Elevation of serum alkaline phosphatase was found in 67.6 per cent of cases. The skin reaction to tuberculin was positive in 61.2 per cent. Nodular shadows were found in the chest X-ray in 98.6 per cent of cases. The nodules were smaller than 2 mm in diameter in 52.7 per cent of cases. Other findings were enlargement of mediastinal lymph node (17.6%), cavities (23.0%), pleural effusion (27.0%), and consolidation (35.1%). Sputum cultures and urine cultures were positive for Mycobacterium tuberculosis in 76.8 per cent and 58.6 per cent of cases respectively. The diagnosis was confirmed by histopathological findings in some cases. The rate of positive biopsies was 61.5 per cent by bone marrow aspiration, 83.3 per cent by lymph node biopsy, 100 per cent by liver and lung biopsy. Antituberculosis therapy was successful in most of the patients. Seven patients died of miliary tuberculosis, 4 of them had adult respiratory distress syndrome.

Serum amyloid A (SAA) is a precursor protein for amyloid A, which is a constituent for amyloid fibrils in secondary amyloidosis. To determine the role of SAA in the articular destruction in patients with rheumatoid arthritis (RA), we investigated the effects of SAA on the production of matrix metalloproteinases (MMPs) by rheumatoid synovial fibroblasts. SAA stimulated rheumatoid synovial fibroblasts to produce MMP-2 and MMP-3 in a dose-dependent manner. Pretreatment of synovial fibroblasts with cycloheximide prevented SAA-mediated MMP-2 and MMP-3 secretion. When SAA-containing media were immunodepleted by anti-SAA-specific antibody, SAA-mediated MMP secretion was also abrogated. The level of MMP-3 mRNA was increased in SAA-stimulated synovial fibroblasts compared with that of control cells. Our data indicate that SAA is a potent inducer of MMPs in the RA synovium and may play a critical role in the degradation of extracellular matrix in the rheumatoid joint.

To observe the reported cases of tuberculosis (TB) with HIV infection in Japan, in terms of their main clinical features and related factors.A voluntary reporting network has been organized by the authors who are specialists of TB or respiratory medicine in tuberculosis institutions located roughly all over the country. The members have been encouraged to report not only their own cases but cases seen by their friends or in other institutions.By the end of 1996, a total of 71 cases have been reported of which 59 were TB and 12 NTM cases. Nationality of the cases were; Japan 48, Other Asian countries 16, Others 7. All of the NTM cases were Japanese. 30% of the cases were aged less than 30 years, 24% were thirties, 24% forties, 17% fifties and 6% were those aged 60 years or older. The cases were clearly younger than the TB cases in the national TB registry, and older than HIV-infected persons as known from the HIV surveillance system. 97% of the TB cases were bacteriologically confirmed cases. Eight of NTM cases were positive for MAC, others for M.kansasii. 42% of the cases had extra-pulmonary disease, including disseminated infections seen among 19%. Of TB cases 25% were excreting bacilli resistant to any of the anti-TB drugs which was higher than in the case of general TB population (10-15%). 11% of TB cases had past history of TB treatment. The cases had severe immunological impairment, 79% of the cases having CD4+ cell count less than 100. The route of HIV infection were; 51% heterosexual, 13% homosexual, 13% through blood preparations, etc.Although there may be many cases not included in this observation, it is considered to well reflect the real situation of the problem of Japan. More attention should be paid to HIV infection of the patients in the clinical practice of TB in Japan.

FK506 and glucocorticoids are used for allograft rejection, graft-versus-host disease, and autoimmune diseases.We investigated the combined effect of FK506 and glucocorticoids on T-cell apoptosis.Dexamethasone injection in mice reduced the number of CD4+CD8+ thymocytes by increasing DNA fragmentation. Pretreatment with FK506 significantly augmented thymocyte DNA fragmentation induced by dexamethasone injection. Increased thymic apoptosis resulted in the disappearance of CD4+CD8+ thymocytes after FK506/dexamethasone injection. In addition to thymocytes, mature human peripheral blood T cells undergo apoptosis by exposure to dexamethasone in vitro. FK506 synergistically enhanced dexamethasone-mediated apoptosis of human peripheral blood T cells.Thus, our results showed that FK506 enhanced dexamethasone-induced apoptosis of T cells in vivo and in vitro. This interaction may enhance the therapeutic immunosuppression achieved by these two drugs.

Six men (mean age: 36.3 +/- 29 years) infected with the human immunodeficiency virus (HIV), four Japanese and two from Myammar, were admitted to our hospital for treatment of tuberculosis. In five, HIV positivity on serologic testing was first found when tuberculosis was diagnosed. The mean CD4 cell count was 37.3 +/- 29.6/microliters. Results of tuberculin skin tests were negative in 5 patients. One patient had pulmonary tuberculosis and 5 had miliary tuberculosis. Hilar and mediastinal lymphadenopathy was found on chest X-ray films in 4 patients and superficial lymphadenopathy was found in all patients. All patients had positive mycobacterial cultures of sputum and 2 patients had positive tests for acid-fast bacilli on smears of lymph-node aspirates. In one patient with tuberculosis meningitis, a culture of cerebrospinal fluid for acid-fast bacilli was positive. Epithelioid cell granulomas were found in samples of lung, liver, and bone marrow from 4 patients. Mycobacterium tuberculosis was isolated from all patients, and was not resistant to isoniazid, rifampicin, ethambutol, or streptomycin. Therefore all patients responded well to treatment of tuberculosis.

To investigate the activation of T cells in peripheral blood (PB) and synovial fluid (SF) of patients with rheumatoid arthritis (RA).The expression of CD26 (Ta1 and 1F7) antigen on T cells was analyzed in 7 women with RA and 7 healthy control subjects by immunofluorescence.The percentage of CD3+ CD26+ cells was significantly higher in PB of patients with RA compared with healthy subjects. The IF7+ cell population was divided into high (1F7+high cells) and low fluorescence populations (1F7+low cells), based on 1F7 antigen density. The percentage of 1F7+high cells in SF of RA was markedly increased compared with PB of patients and healthy subjects. However, RA SF contained lower percentages of whole 1F7+ cells compared with PB.Our results indicate that SF of patients with RA contains activated T cells, and suggest that T cells with high levels of CD26 antigen may preferentially migrate into the rheumatoid synovium to induce inflammation and tissue destruction.

In Japan there are about 40,000 patients under home oxygen therapy (HOT), of whom about 30 to 40% are pulmonary tuberculosis sequelae (TBS). These patients can be divided into three groups depending on the treatments they had, Group 1: those who had medical treatments only, Group 2: those who had artificial pneumothorax, and Group 3: those who had thoracoplasties or other surgical treatments. The purpose of this study was to observe the distributions and possible differences in the survival rates among these groups. The study included 1537 patients with TBS under HOT followed at National Hospitals and Sanatoriums nationwide in Japan. In 819 patients the treatments were specified and of those 354 were in Group 1, 29 in Group 2, and 436 in Group 3, so that the proportion of surgically treated patients in PTS was estimated between 28.4% (436/ 1537) to 53.2% (436/819). The ages at the onset of tuberculosis, at the start of HOT and the intervals in between were 36.6, 66.2 and 29.8 in Group 1, and 26.8, 65.5, and 38.1 in Group 3 respectively. Though the ages at the start of HOT were the same, those at the onset of tuberculosis were about ten years younger in Group 3 than in Group 1. Comparing Group 1 and 3, the survival rates after the initiation of HOT (Kaplan-Meier method) was better in Group 2 (surgically treated) than in Group 1 (medically treated). It is speculated that the reason could be a better preservation of the function of the remaining lung in the surgically treated and a higher incidence of obstructive impairments in the medically treated patients.

Secondary amyloidosis, a serious complication of chronic inflammatory diseases, is caused by the deposition of amyloid fibrils in various organs. The major component of amyloid fibrils is derived from serum amyloid A protein (SAA) by proteolysis. To explore the mechanisms of amyloidogenesis, we measured SAA concentrations in the sera of 38 patients with rheumatoid arthritis (RA) without secondary amyloidosis and in the sera of 18 RA patients with secondary amyloidosis, using the latex agglutination immunoassay. We also determined whether SAA was present as a full-length protein in the sera of RA patients by immunoblotting. Although SAA concentrations were elevated in the sera, there were no significant differences in these concentrations between RA patients without amyloidosis (128.2 +/- 145.4 micrograms/ml) and RA patients with amyloidosis (165.0 +/- 162.9 micrograms/ml). To test for qualitative abnormalities of SAA, the isolated SAA proteins from individual RA patients were analyzed by anti-SAA immunoblot. In addition to full-length SAA protein, 6-kd and 4.5-kd SAA-derived fragments were detected in the sera of RA patients, and the ratio of these fragments to total SAA proteins was significantly higher in RA patients with amyloidosis (37.0% +/- 0.7%) compared with that of RA patients without amyloidosis (15.0% +/- 5.5%). Although a high serum level of SAA is a predisposing condition for amyloid formation in RA patients, our data suggest that the increased circulating proteolytic cleavage of SAA may potentially contribute to the development of AA-amyloid deposition.

Sixty patients with rheumatoid arthritis who were administered weekly low dose methotrexate (MTX) were retrospectively analyzed for their untoward effects of MTX by interviewing to the patients and by the medical records. Cough and sputa were the most frequent symptoms (23.3%) and gastrointestinal symptoms were the next (20%). Five of 60 patients (8.2%) showed liver function test abnormalities, and four (6.7%) exhibited transient exacerbation of arthralgia for several hours to a few days after MTX administration. Three patients (5%) suffered from interstitial pneumonitis. Hair loss was seen in 3 patients (5%), and headache, leucocytepenia, fever, skin eruption, abnormal taste, hemorrhagic cystitis, and flashing were experienced in a patient, respectively. Three (5%) suffered from fungal infection, and herpes zoster, sepsis, and osteomyelitis were experienced in each one patient, respectively. MTX was withdrawn in three patients (5%) because of cough and sputa the drug was withdrawn in other three patients because of the interstitial pneumonia, and was drawn in another three patients because of transient exacerbation of arthralgia. The drug was withdrawn in each one patient, because of nausea and vomiting, skin eruption, osteomyelitis, and sepsis, respectively. Overall, MTX were withdrawn in 21 patients (35%), and, of those, 13 patients (21.7%) because of untoward effects and 8 patients (13.3%) because of the lack of efficacy.

Extrathymic T cell tolerance to Ags can be achieved through clonal deletion by activation-induced programmed cell death as well as by functional unresponsiveness (anergy) of Ag reactive-T cells. Previous studies demonstrated that in vivo administration of staphylococcal enterotoxin B (SEB) induces SEB-specific T cell anergy. To investigate the molecular mechanisms of T cell anergy, we analyzed the TCR-mediated signal transduction in normal and anergic T cells. Anergic T cells exhibited impaired protein tyrosine phosphorylation on TCR-mediated stimulation. The altered tyrosine phosphorylation in anergic T cells may be caused by a defect in tyrosine phosphorylation of TCR zeta-chain and its subsequent association with ZAP-70 tyrosine kinase. Our data demonstrated that TCR zeta-chain phosphorylation and its sequential interaction with ZAP-70 are essential for the initiation of TCR-mediated signal transduction.

The histological features of rheumatoid arthritis (RA) consist of overgrowth of synovial cells. Several growth factors that cause synovial hyperplasia have been identified in RA synovium. The basic-fibroblast growth factor (b-FGF), representing one of these growth factors, may play an important role in the pathogenesis of RA. We examined the b-FGF mediated intracellular signal pathway involved in synovial cell growth. b-FGF-induced synovial cell growth was inhibited by protein tyrosine kinase (PTK) inhibitors, herbimycin A and genistein, but not by H7 that inhibits protein kinase C (PKC). Stimulation of synovial cells with b-FGF resulted in tyrosine phosphorylation of cellular proteins and MAP kinase activation. Our results also demonstrated that b-FGF-mediated activation of MAP kinase was inhibited by herbimycin A indicating that protein tyrosine kinase may he involved in the activation of MAP kinase in human synovial cells. However. inhibition of b-FGF-mediated MAP kinase activation by PKC downregulation did not occur.