The aim of this study was to examine the association between airway hyperresponsiveness (AHR) in asthmatic patients and various factors, including the duration of asthma, the thickness of the epithelial reticular basement membrane (Rbm), and eosinophilic inflammation or total IgE in blood. We measured the thickness of Rbm in bronchial biopsy specimens. Spirometric tests and histamine challenge tests were also performed to evaluate airflow obstruction and AHR. Multiple regression analysis was used to assess the correlation between PC20 histamine values with duration of asthma, thickness of Rbm, eosinophil percentage in sputum and blood, and total IgE in blood. Furthermore, we used stepwise regression analysis to determine which factors were closely correlated with AHR. This study showed that AHR was most associated with the thickness of Rbm. The results suggest that the prevention and improvement of the airway structural changes should be considered as one of the targets of asthma treatment.

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Lipid peroxidation proceeds by a free radical chain reaction yielding lipid hydroperoxides (L-OOH) as the major initial reaction product. Moreover, the unsaturated fatty acids that constitute a large component of a lipid emulsion, such as Intralipid^TM, are highly susceptible to peroxidation. To determine the degree of lipid peroxidation in artificial lipid emulsions, we measured the content of triacylglycerol hydroperoxides (TG-OOH) and phospholipid hydroperoxides (PL-OOH) in 10% Intralipid^TM solution. The chemiluminescence-based high-performance liquid chromatography (HPLC) assay is the one of the most advanced methods for the direct detection of L-OOH at picomole levels. Using this method, TG-OOH and PL-OOH could be detected in Intralipid^TM (166.7±83.9μmol/l and 3.5±2.9μmol/l, respectively) . The concentration of TG-OOH and PL-OOH in Intralipid^TM was significantly increased (228.0±106.8μmol/l (p<0.01) and 30.4±14.3μmol/l (p<0.02), respectively), during a 24 h infusion under ambient light and room temperature (26°C) in NICU with a concomitant reduction of emulsion α-tocopherol to 97% (55.9±4.7 mmol/l, p<0.05) compared with baseline levels (57.3±4.3mM) . This observation suggests that endogenous α-tocopherol could not prevent the formation of L-OOH in Intralipid^TM over a 24 h period. Thus, it is clear that lipid infusion has greater nutritional advantages for small, premature infants. Furthermore, we should consider that lipid emulsions are prone to peroxidation, and that this may be an important feature of oxidant-associated tissue damage.

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Steroid sulfatase (STS) and sulfokinase (SK) are antagonistic regulators of local estrogen activity. STS and SK activities and the expression of some cytokines in human endometrium show menstrual cycle-dependent changes. However, the role of cytokines in the regulation of both enzymatic activities is unclear. In this study, we investigated the effects of cytokines on STS and SK activities by measuring their mRNA expression in human endometrial cells. Human endometrium was obtained from endocrinologically healthy women during gynecological surgery for either a benign disease or CIS. Endometrial stromal cells were isolated and cultured in the presence or absence of cytokines, IL-1β or IL-8. Total RNA was extracted and STS and SK mRNA expressions were measured using real-time PCR (LightCycler) . Both IL-1β and IL-8 significantly reduced STS mRNA expression, whilst inducing SK mRNA expression. When an IL-1 receptor antagonist or CXCR-1 antibody was added simultaneously, the effect of IL-1β or IL-8 was neutralized. These results suggest that IL-1β and IL-8, which are more prevalent in the late secretory phase endometrium, regulate STS and SK mRNA expression and decrease the local estrogen effects in human endometrium.

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Purpose: To evaluate the effect of early oral feeding following the resolution of gastric ileus after open colonic resection. Methods : Eighteen unselected patients (median age 64 years) undergoing colonic resection were included in this study. None of the patients had nasogastric tubes. On the first postoperative morning, radiopaque markers were administered orally and abdominal X-rays were taken 6 h later and daily thereafter, until more than 80% of the markers had emptied out of the stomach. Patients were then allowed oral feeding. Findings : Greater than 80% of the markers had emptied out of the stomach in 39% of the patients by the first postoperative afternoon, and cumulatively in 78 % of the patients by the second postopera-tive morning. The median postoperative time to 80% gastric emptying of markers followed by an oral diet was 39 h, which was significantly shorter than that flatus or defecation (56 h and 70 h, respectively) . One patient with an adverse side effect to morphine vomited. Conclusion : These results suggest that early oral feeding should be resumed following the resolution of gastric ileus to avoid vomiting.

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Cyclophosphamide, etoposide and vincristine are widely used for cancer chemotherapy and are frequently prescribed concurrently. Although a high possibility of drug-drug interactions during cancer chemotherapy is predicted, little information is available concerning the effects of these anticancer drugs on cytochrome P450 (CYP), the enzyme that metabolizes a wide variety of drugs. This study was designed to evaluate the inhibitory effect of cyclophosphamide, etoposide and vincristine on CYP2C 19-mediated drug metabolism individually and when used in combinations of two or three of these drugs in vitro. Human liver microsomal fractions were employed as an enzyme source and S-mephenytoin was used as a probe for the estimation of CYP2C 19-mediated drug metabolism. Each of these drugs inhibited S-mephenytoin 4'-hydroxylation competitively with Ki values of 1800, 120 and 90 pM, respectively. The inhibitory effects of combinations of these drugs on CYP2C 19 were investigated using concentrations of each drug that inhibited the control activity by 30%. Inhibitory effects on S-mephenytoin 4'-hydroxylation, greater than 30% of the control activity were observed ; 45% and 60% inhibitions were observed when a combination of two or three drugs was used respectively. In summary we demonstrated that cyclophosphamide, etoposide and vincristine inhibited CYP2C19-mediated metabolism competitively and that these inhibitory effects were enhanced with an increase in the number of drugs used. These results suggest that care must be exercised in the concomitant use of these three drugs and other drugs that are metabolized by CYP2C 19 in cancer chemotherapy.

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Bone mineral density (BMD) has been shown to decrease in Graves' disease (GD) as a result of the high rate of bone turnover with a predominance for resorption. As individual differences in BMD are great, and they change with age, it is difficult to compare levels in one patient with levels in others. This makes the clear evaluation of BMD levels in individuals impossible. For 3 female monozygotic twins from 3 families (A-1 and A-2 at 27 years old, B-1 and B-2 at 26 years old, C-1 and C-2 at 13 years old), we analyzed the relationships between thyroid function and indices of bone metabolism, and also carried out a comparative study between BMD and bone turnover markers, with respect to age and medical treatment of patients with GD. The BMD values for the lumbar spine (L2-L4) and the proximal section of the femur (Hip) for A-1, who was in a state of subclinical hyperthyroid-ism, were higher than those for A-2, whose hyperthyroidism had not been treated. The BMD values for both sites in these twins were lower than those for healthy young Japanese women. Serum bone type alkaline phosphatase (B-ALP) and osteocalcin (OC) concentrations were high in both A-1 and A-2. Urinary deoxypyridinoline (DPD) was higher in A-2 than in A-1. For B-2, who was taking Methimazole (MMI), the BMD values for both sites were lower than those for B-1, who had not yet developed GD. Serum B-ALP and OC concentrations were high in both B-1 and B-2. There was no difference in the BMD of C-1, who was taking MMI, and C-2, who had not yet developed GD. Serum B-ALP and OC concentrations were high for both C-1 and C-2. Our results suggest that 1) the decrease of BMD in GD is due to high-turnover type bone metabolism in which the functions of both osteoclasts and osteoblasts are accelerated ; 2) when GD occurs in adults, BMD does not recover completely, even if the patient has become euthyroid as a result of medical treatment; and 3) The decrease in BMD caused by GD in patients who are still growing can be minimized.

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The potential therapeutic role of a number of hormonal factors in a variety of diseases are currently being investigated. Among them, the enteroglucagons, including glicentin, which has been synthesized as a growth factor for the small intestine. This study was designed to evaluate the proliferative effect of glicentin when used with several other intestinal growth factors and to elucidate the regulating mechanism of this enterocyte proliferation by glicentin. We have established an in vitro bioassay system for determining the trophic activity of recombinant human glicentin on the human small-intestinal epithelial cell line (INT-407) under serum-free conditions. The cells were serumdeprived for 1 day, and then treated with either glicentin, EGF, IGF-I, 12-O-tetradecanoylphorbol (TPA), prostaglandin E₁ (PGE 1), glicentin with EGF, glicentin with IGF-I, glicentin with TPA, glicentin with PGE₁, 10% fetal bovine serum (FCS) ; or no growth factor. We investigated enterocyte proliferation and protein tyrosine kinese activity after treatment. 1) Glicentin demonstrated significant enterotrophic effects at doses ranging from 10 ng/ml to 10μg/ml, and also showed a parallel dose-response curve at doses of less than 1μg / ml. The maximum trophic activity of glicentin was equivalent to the effects of EGF and IGF-I. 2) Glicentin in combination with either EGF, IGF-I and PGE₁ had greater trophic effects than acting alone, which were equivalent to the effect of 10% FCS. However, glicentin failed to demonstrate this proliferative effect after the down regulation of protein kinase C with prolonged pretreatment with TPA. 3) Glicentin binding to these cells resulted in an increase in protein tyrosin kinase (PTK) activity. These results suggest that the enterotrophic effects of glicentin are regulated by a signaling pathway through PTK and protein kinase C. This intracellular signaling pathway of glicentin may be an important factor in selectively enhancing epithelial cell growth, and certain growth factors in combination with glicentin may provide a benefit for patients with inadequate enteric function.

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Lung transplantation is an effective treatment for a variety of end-stage pulmonary diseases. A novel approach to increase the donor pool is to harvest organs from non-heart-beating donors (NHBD) . However, clots or fat emboli may jeopardize the uniformity of the pulmonary arterial (PA) flushing in the NHBD graft. The present study was performed to investigate the effects of retrograde pulmonary flushing through the pulmonary vein (PV) before reperfusion in the NHBD rat lung. The efficacy of heparin is also analyzed. The heart-lung bloc was excised 0 min (groups 1 and 2) or 30 min (groups 3, 4, and 5) after euthanasia. The grafts were flushed through the PA in groups 1 and 3 and were flushed through the PV in groups 2 and 4. In group 5, the grafts were flushed with heparin through the PV. The grafts were then ventilated and reperfused. During reperfusion the PA pressure (PAP) and airway pressure (AWP) were recorded. After reperfusion the wet to dry weight ratio (W/D) of the lung was measured as an estimate of the extent of lung edema. AWP, PAP and W/D were not significantly different between groups 1 and 2. PAP and W/D were higher in group 3 than in group 1 (p<0.05 and p<0.01, respectively) . PAP was not significantly different between groups 2 and 4 and W/D was higher in group 4 than in group 2 (p<0.05) . W/D was lower in group 4 than in group 3 (p<0.05) . PAP was lower in group 5 than in group 3 (p<0.05) and W/D was lower in group 5 than in groups 3 and 4 (p<0.0l and p<0.05, respectively) . In conclusion, PV flushing decreased lung edema when compared with PA flushing and the edema was reduced more effectively in the group with PV flushing with heparin than in the group without heparin in NHBD lung. Without prolonged warm ischemia, the PV flush method did not improve lung edema when compared with the PA flush method.

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We used U937 (monocyte-like, histiocytic lymphoma) and DMS 114 (lung small cell cancer) cell lines to examine the effects of β-hydroxyiso-valerylshikonin (β-HIVS), a protein tyrosine kinase inhibitor, in combination with cancer chemotherapeutic agents. For U937 cells, combined treatment with β-HIVS and bufalin had synergistic effects. The combination of β-HIVS with VP 16 showed marginal synergistic to additive effects. Additive to subadditive effects were observed when β-HIVS was combined with doxorubicin. The above combinations showed few synergistic effects on DMS 114 cells.

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We report an autopsy case of a 62-year-old man who died of massive gastric bleeding due to a giant gastric submucosal tumor (SMT) with multiple liver metastases. Histologically this SMT was composed of extremely pleomorphic cells that showed no differentiation towards any cell type. Hematoxylin-eosin (HE) staining as well as immunohistochemical analysis indicated that this pleomorphic sarcoma was a malignant fibrous histiocytoma ( MFH) . Another characteristic of this gastric SMT was that more than 90% of the tumor was necrotic and hemorrhagic. Vascular proliferation was obvious and a structure similar to hemangiopericytoma was recognized in the metastatic lesions of liver. This patient died within one month of presentation of symptoms.

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