Mycobacterium avium Subsp. paratuberculosis Induces Specific IgE Production in Japanese People with Allergies.

Background. The prevalence of allergies is steadily increasing worldwide; however, the pathogenesis is still unclear. We hypothesized that Mycobacterium avium subsp. paratuberculosis (MAP) may contribute to allergy development. This organism can be present in dairy foods, it can elicit an immunomodulatory switch from a Th1 to a Th2 response, and it has been speculated that it is linked to several human autoimmune diseases. To determine the contribution, sera from 99 individuals with various atopic disorders and 45 healthy nonallergic controls were assessed for total IgE levels and successively for MAP-specific IgE by ELISA. Results. The mean total serum IgE level in allergic patients was 256 ± 235 IU/mL, and in the healthy controls it was 62 ± 44 IU/mL (AUC = 0.88; p < 0.0001). Among the patient groups, 50 of the 99 subjects had increased IgE total level ≥ 150 IU/mL, while 49 subjects had IgE ≤ 150 IU/mL (mean level: 407 ± 256 IU/mL versus 106 ± 16 IU/mL; p < 0.0001). Additionally, 6 out of 50 subjects (12%) with IgE ≥ 150 IU/mL and none (0%) with IgE ≤ 150 IU/mL were positive for specific MAP IgE (AUC = 0.63; p = 0.03). Conclusion. The present study revealed that MAP has the ability to induce specific IgE and might contribute to the induction of allergic inflammation in genetically predisposed individuals.

Associations between the levels of sclerostin, phosphate, and fibroblast growth factor-23 and treatment with vitamin D in hemodialysis patients with low intact PTH level.

UNLABELLED: Serum sclerostin levels could be closely associated with serum phosphate and fibroblast growth factor-23 levels in hemodialysis patients with low intact parathyroid hormone (PTH) levels. Further study is required to indicate whether these close associations are present in patients with spontaneously low PTH levels without any vitamin D treatment. INTRODUCTION: Intact parathyroid hormone (iPTH) is involved in the interaction between sclerostin and phosphate/fibroblast growth factor-23 (FGF23) in animal models. However, their relationship in patients on hemodialysis (HD) is unclear. METHODS: Data of 102 HD patients were collected regarding clinical and laboratory parameters and mineral bone disorder medications. The patients were divided into subgroups according to the iPTH level (A, <70 pg/mL; B, 70-150 pg/mL; C, 150-300 pg/mL; and D, ≥ 300 pg/mL). RESULTS: The sclerostin level was significantly and positively correlated with phosphate and log of FGF23 levels in subgroups A, B, and combined A and B. Multiple linear regression analysis in the combined A and B subgroup revealed that male sex (t = 3.24, P = 0.01; 95% confidence interval [CI] 11.78 to 50.43) and phosphate level (t = 2.13, P = 0.04; 95% CI, 1.08 to 36.91) were independent factors for serum sclerostin level. The log of serum FGF23 level (t = 1.90, P = 0.06, 95% CI -1.85 to 63.50) appeared to be an important factor for serum sclerostin level. The frequency of patients using vitamin D treatment was not significantly different among subgroups A (93.1%), B (88.0%), C (85.2%), and D (90.5%). CONCLUSION: Serum sclerostin levels were associated with serum phosphate and FGF23 levels in patients with low iPTH levels. Further study is required to indicate whether these close associations are present in patients with spontaneously low iPTH levels without vitamin D treatment.

Oxidised LDL/LDL-cholesterol ratio and coronary artery calcification in haemodialysis patients.

BACKGROUND AND AIMS: Serum malondialdehyde-modified low-density lipoprotein (MDA-LDL) and MDA-LDL/LDL-cholesterol (LDL-c) ratio are risk factors for arteriosclerosis and cardiovascular disease (CVD). However, no information is available on these parameters or their associations with coronary artery calcification (CAC) in haemodialysis (HD) patients. METHODS AND RESULTS: Fifty-seven HD patients and 26 control subjects were included in this cross-sectional study. Serum MDA-LDL concentrations and MDA-LDL/LDL-c ratios were examined. HD patients had significantly higher MDA-LDL/LDL-c ratios than the controls (105.1 ± 27.5 vs. 81.4 ± 18.9 mU/mg, P < 0.001); however, there was no significant difference in serum MDA-LDL levels between the 2 groups. CAC scores were examined only in HD patients and their possible associations with the clinical/laboratory data were analysed. Analysis of HD patients showed that MDA-LDL/LDL-c ratio has an association with presence of CVD, CAC score, HD duration, MDA-LDL, or haemoglobin A1C. In addition, the CAC score was positively correlated with serum MDA-LDL level (P = 0.048) and MDA-LDL/LDL-c ratio (P = 0.006). Furthermore, multivariate logistic regression analysis showed that MDA-LDL/LDL-c ratio (ß = 0.04, P = 0.003) and HD duration (ß = 0.16, P = 0.007) were independently associated with CAC score. CONCLUSION: The MDA-LDL/LDL-c ratio of HD patients was significantly higher than that of non-HD subjects and was independently associated with the CAC score. Therefore, this ratio could be an important risk factor for CAC in HD patients.

Effects of long-term treatment with mizoribine in patients with proliferative lupus nephritis.

AIM: Mizoribine (MZR) is a purine antimetabolic immunosuppressant agent that has few little severe adverse events. We studied whether maintenance therapy with MZR and prednisolone (PSL) in severe proliferative lupus nephritis patients could improve immunity, reduce proteinuria, prevent renal relapse, and reduce steroid dose. METHOD: Long-term maintenance therapy with MZR and PSL was evaluated in ten patients with biopsy-proven proliferative lupus nephritis. Patients with severe lupus nephritis, who had proteinuria of 0.5 g or more even after treatments with plasma exchange and/or pulse methyl prednisolone, were recruited. MZR at an average dose of 140 +/- 10 (100 - 200) mg was administered two to three times/day in combination with PSL. The average period for the MZR maintenance therapy was 89.7 +/- 5.5 (70 - 126) months. Urine protein excretion, serum hemolytic complement activity (CH50), C3, serum creatinine, general and biochemical blood examinations, anti-ds-DNA antibody were collected at each monthly medical examination. RESULTS: All patients were females, mean age 43.0 +/- 3.3 years. A significant decrease in proteinuria was noted two years after the combination therapy (p = 0.0016). Five patients experienced lupus nephritis relapse. Patients who did not experience relapses had their MZR combination therapy initiated earlier (p = 0.037) when compared with the patients who experienced relapses. Serum creatinine levels remained unchanged in all patients throughout treatment and follow-up, even during renal relapses. Levels of C3 and CH50 normalized as proteinuria decreased. None of the patients developed serious side effects during MZR treatment. A significant steroid-sparing effect was observed three years after initiating MZR (p = 0.0025). CONCLUSION: From our long-term observation, maintenance therapy with low-dose PSL combined with MZR can eliminate proteinuria and have steroid-sparing effect. Early initiation of the therapy can protect against renal relapses among severe proliferative lupus nephritis patients without serious side effects.

[Nonpenetrating traumatic injury of the thoracic aorta and left subclavian artery; report of a case].

Nonpenetrating traumatic injury of the thoracic aorta and/or its major branch is usually fatal and the treatment of this condition carries extremely high risk because of associated visceral organ injuries. Accurate diagnosis have been difficult. However, recently developed multi-slice helical computed tomography (CT) is highly sensitive in early detection of precise location of injury and associating injuries of other organs. Here we report our case with combined thoracic aortic and left subclavian artery injuries, diagnosed by 3-dimensional (3-D) CT and treated successfully.

Serum levels of macrophage colony-stimulating factor and aortic calcification in hemodialysis patients.

Hemodialysis (HD) patients have accelerated atherosclerosis. Recent reports have shown that aortosclerosis is more frequently observed in HD patients than in healthy subjects. Macrophage colony-stimulating factor (M-CSF) secreted by activated macrophages may be involved in the process of aortosclerosis in HD patients. To understand the mechanism behind the increased incidence of aortosclerosis in HD patients, we examined the relationships between serum M-CSF levels and aortic calcification index (ACI) estimated by CT scan. A significant increase in serum M-CSF concentrations was found in HD patients (3.8 +/- 0.2 ng/ml) as compared with controls (1.5 +/- 0.1 ng/ml). No significant differences were observed between chronic glomerulonephritis and diabetes mellitus groups of patients. We also found no significant differences between the groups using different membranes (triacetate 3.8 +/- 0.2 ng/ml vs. polysulfone 3.8 +/- 0.4 ng/ml). There was no correlation between serum M-CSF concentrations and clinical parameters such as age, duration of HD, blood pressure, serum concentrations of nitrogen, creatinine, cholesterol, triglyceride, LDL, Ca x P products, and intact parathyroid hormone. A positive correlation was observed between serum M-CSF levels and ACI in HD patients (r = 0.596, p < 0.01). These results suggest that M-CSF may be involved in the process of aortosclerosis in HD patients.

Eugenics in Japan: some ironies of modernity, 1883-1945.

Japanese eugenic discourse and institution building contrast sharply with comparable movements elsewhere. As a social-intellectual phenomenon, Anglo-American eugenics considered the Japanese racially inferior to Western peoples; yet eugenic ideals and policies achieved a remarkable popularity in Japan. Most of mainstream Japanese genetics was derived from orthodox Mendelian roots in Germany and (to a lesser degree) the United States. But French-style Lamarckian notions of the inheritability of acquired characters held surprising popularity among enthusiasts of eugenics. Japanese eugenicists could condemn the actions of foreign eugenicists like Charles Davenport in the United States for their efforts to forbid Japanese immigration in the 1920s, yet appeal to these same eugenicists as a source of legitimacy in Japan. These paradoxes can partly be explained against a background of relative isolation in a period of profound social change. Few Japanese eugenicists had close personal contact with foreign eugenicists, and most of their knowledge was acquired through reading rather than direct exposure. The eugenic ideal of ethnic purity was attractive to a society long accustomed to monoracial self-imagery. The need to defend national independence in an era of high imperialism seemed to require the most up-to-date policies and ideas. And Japan's own acquisition of an overseas empire seemed to demand a population management philosophy ostensibly based on scientific principles. These and other forces supported the implementation of eugenic policies and prescriptions among the Japanese people in the first half of the twentieth century.

Ex vivo evaluation of the NASA/DeBakey axial flow ventricular assist device. Results of a 2 week screening test.

The authors investigated the antithombogenicity of the NASA/DeBakey axial flow ventricular assist device in an ex vivo calf model. The device is 3 inches in length and 1 inch in largest diameter. The pump weighs 53 g and displaces 15 ml. The unit consists of three major components: a flow straightener, a spinning inducer/impeller, and a diffuser. The impeller has rod shaped permanent magnets embedded within the six blades and is activated magnetically by a motor stator that is positioned outside the flow tube. Previous 2 day screening tests demonstrated an antithrombogenic configuration in short-term implantation. Based on the results of these 2 day screening tests, five pumps with the best configuration were implanted into a calf for 2 weeks for anti thrombogenicity confirmation. Pumps were implanted paracorporeally, and heparin was used to maintain activated clotting time to approximately 250 sec. Each pump was changed every 2 weeks as planned. During the experiment, all pumps demonstrated stable pumping. The required electric power was 7 to 8 watts and pump flow was maintained at 4 L/min. The calf was in excellent condition. Liver and renal function were maintained, plasma free hemoglobin was kept at less than 4 mg/dl (3.3 +/- 0.3 mg/dl), and lactate dehydrogenase was 1043 +/- 36 units/L. In this experimental series, all five pumps passed the 2 week implantation. Two week ex vivo test results indicated very slight thrombus in the hub areas of some pumps. For the next phase of the implantation study, minor design optimization is necessary to completely eliminate thrombus formation. According to our step by step approach, the in vivo test aiming for long-term implantation is ongoing.

[An operated case report of pulmonary aspergillosis by sapprophytic infection of Aspergillus candidus in congenital bronchial cyst of right lower lobe].

Aspergillosis is a mycotic disease caused by a variety of species of the dimorphic fungus aspergillosis, especially aspergillus fumigatus. But the report of pulmonary aspergillosis by aspergillus candidus is very rare. We experienced a surgical case of pulmonary aspergillosis caused by aspergillus candidus. The patient is a 18-year-old girl. Eleven years ago, she had suffered from pneumonia of rt. lower lobe, there after she often has suffered from cough and fever every year. In 1986, chest x-ray photography shows a small cavity in rt. lower lobe. In 1989, it becomes a big cavity of 8 X 8 cm in diameter with niveau. She has cough and bloody sputum of 100-150 ml daily. We have cultured aspergillus candidus from sputum, bloody pus obtained by percutaneous aspiration needle lung biopsy of the cavity and bloody pus in the cavity which was resected on March 3, 1989. But the pathological investigation could not demonstrate any fungus ball or fungus body of aspergillus candidus.

[Effect of the nonsteroidal anti-inflammatory drug 480156-S on hepatic drug-metabolizing activity and pharmacological action of diazepam and pentobarbital in rats].

Effect of the nonsteroidal anti-inflammatory drug 480156-S on liver drug-metabolizing activity was studied in rats, and its effect was compared with that of cimetidine. Cytochrome P-450-dependent 7-alkoxycoumarin O-dealkylase activity was not affected by a single administration of 480156-S, but the activity, especially the O-demethylase but not the O-depropylase, was suppressed dose-dependently by multiple administrations. Pretreatment of rats with phenobarbital caused a diminution of the inhibitory action of 480156-S. Treatment of rats with cimetidine resulted in a marked decrease in the activity, although it recovered 24 hr later. After the pretreatment of animals with 480156-S or reference drugs, the pharmacological action of diazepam was determined using muscle relaxation and inhibitions of electroshock-induced convulsion and pentetrazole-induced clonic convulsion as the indicators. Prolonged pharmacological activity of diazepam was observed when liver drug-metabolizing activity was lowered by the pretreatment. On the other hand, pentobarbital-induced anesthesia was prolonged by the pretreatment of rats with cimetidine, but the anesthesia was not modified by the administration of 480156-S. These results suggest the inhibitory action of 480156-S on a specific form(s) of P-450 isozyme.

Effects of alcohol-metabolizing enzyme inhibitors and beta-lactam antibiotics on ethanol elimination in rats.

The in vivo effects of alcohol-metabolizing enzyme inhibitors and beta-lactam antibiotics upon the ethanol elimination rate were examined in rats. Intravenous administration of ethanol caused a dose-dependent increase in blood ethanol level, and the ethanol elimination could be well described by a two compartment model. Pretreatment of rats with enzyme inhibitors caused a marked decrease in the ethanol elimination rate associated with the depression of the enzyme activities. Fasting of the animals caused a decrease in the ethanol elimination rate per animal associated with a decrease in the liver weight. However, no alteration was evident when the rate was expressed as the rate per g of liver. When animals were pretreated with a high dose of N-methyltetrazolethiol (NMTT)- containing beta-lactam antibiotics or NMTT itself, which causes a disulfiram-like reaction, the ethanol elimination rate per animal was depressed concomitant with an increase in the blood acetaldehyde level. The ethanol elimination rate in these animals showed lower values even when expressed as the rate per g liver. On the other hand, administration of cephems without NMTT, which cause no disulfiram-like reaction, led to a slight decline in the elimination rate per animal, although no alteration was detected when the rate was expressed as the rate per g liver. The findings indicated that the ethanol elimination in vivo per animal is regulated by the total capacity of the alcohol-metabolizing enzyme activities in the whole liver.

Effects of beta-lactam antibiotics and N-methyltetrazolethiol on the alcohol-metabolizing system in rats.

The disulfiram-like effect of various beta-lactam antibiotics containing N-methyltetrazolethiol (NMTT) on the alcohol-metabolizing system was studied using rats. Their administration caused decreased activities in low Km aldehyde dehydrogenase (ALDH) and acetaldehyde oxidation in the liver, with marked depression from several hours to 2 days after the treatment. Blood acetaldehyde level increased markedly when ethanol was administered 18-24 hr after pretreatment with antibiotics. A similar time course change in the effect was obtained when disulfiram was administered. The following results obtained in the present study indicate that the disulfiram-like effect associated with these antibiotics was not mediated by the whole molecular structures of these drugs: Firstly, the antibiotics were eliminated rapidly from the plasma and liver, and the disulfiram-like effect was followed by a disappearance of the drugs. Secondly, the concentration of antibiotics required to inhibit mitochondrial low Km ALDH activity in vitro was very high compared with their liver concentration. Thirdly, rapid onset of disulfiram-like effects occurred after administration of NMTT itself, and a pronounced elevation of blood acetaldehyde level was observed when ethanol was administered 3-5 hr after the NMTT injection. Fourthly, almost the same amounts of NMTT were released in the body after the intravenous administration of various NMTT-containing antibiotics, as judged by the urinary excretion. These results suggest that the disulfiram-like effect of beta-lactam antibiotics is mediated by NMTT released from them.

Pharmacokinetics of latamoxef and N-methyltetrazolethiol in rats associated with the development of disulfiram-like effects.

The disulfiram-like effect of beta-lactam antibiotics, having an N-methyltetrazolethiol (NMTT) as a 3'-position substituent of the cephalosporin nucleus, was determined in rats using latamoxef (LMOX) as a model. Intravenous and subcutaneous administrations of these antibiotics caused a decrease in the low Km aldehyde dehydrogenase (ALDH) activity in liver mitochondria and an increase in blood acetaldehyde level during ethanol metabolism, as in the case of disulfiram. When the antibiotic was administered intravenously to biliary fistula rats, the blood acetaldehyde level did not increase. On the other hand, oral administration of antibiotic to normal and biliary fistula rats caused pronounced development of disulfiram-like effects in both animals. When LMOX was injected to normal rats, the rapid and slow eliminations of LMOX and NMTT, respectively, were observed from blood and liver. After oral administration of LMOX, NMTT remained in the blood and liver for a long time with higher concentrations, although LMOX could not be detected in the body. With biliary fistula rats, intravenous injection of LMOX led to rapid urinary excretion of both LMOX and NMTT. These results indicate that the development of disulfiram-like effects of NMTT-containing antibiotics is closely related to the pharmacokinetic profile of NMTT released from its parent drugs.

Effects of beta-lactam antibiotics on the acetaldehyde-metabolizing system in germ-free rats.

Effects of several beta-lactam antibiotics on the acetaldehyde-metabolizing system were studied using germ-free rats. Administration of cefamandole (CMD) to the rats caused a decrease in liver mitochondrial low Km aldehyde dehydrogenase activity and an increase in blood acetaldehyde level during ethanol metabolism, similar to the case in conventional rats. Oral administration of CMD produced a pronounced increase in blood acetaldehyde level compared to the subcutaneous administration of the antibiotic. When the animals were given various beta-lactam antibiotics subcutaneously, only the antibiotics having an N-methyltetrazolylthiomethyl group at the 3-position of the cephalosporin nucleus exhibited the disulfiram-like effects on the acetaldehyde-metabolizing system. The results indicate that intestinal bacteria do no participate in the development of the disulfiram-like reaction of several beta-lactam antibiotics.