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胃癌に対する化学療法のsecond-lineとしてtaxaneの有効性が注目されている. Stage IV進行胃癌に対しdocetaxel化学療法が奏効し, 切除しえた1例を経験したので報告する. 症例は70歳の男性, 内視鏡検査で胃癌の診断となった. 腹部CTで膵体尾部, 脾門部への浸潤を認め切除不能の診断でTS-1 100mg/日を1クール (4週) 投与するもPDのためCPT-11 100mg/日 (3投2休) 施行した. 治療効果はPRだったが2クール終了後PDとなり, TXT療法開始80mg/回を3週間隔で4クール施行後, 内視鏡上腫瘍病変, また腹部CT上膵臓, 脾門部への浸潤もほぼ消失 (PR) した. その後, 胃全摘術, 膵体尾, 脾, 胆. 切除, リンパ節郭清 (D3) を施行し, 術後12か月現在外来通院中である. 組織学的所見では, 癌細胞は胃固有筋層から漿膜下のごく一部とそれに連続した膵体部のみで, 胃粘膜面には認めなかった. 胃癌におけるTXTの化学療法は有効性が期待できると考えられた.

Nateglinide is a new, fast-onset, short-acting hypoglycemic agent, which increases early phase insulin secretion and the total amount of insulin secreted. However, it is not clear which of these effects contribute more to the decrease in postprandial plasma glucose (PG). To further clarify the pharmacologic actions of nateglinide, we investigated the changes in PG and insulin levels during meal tolerance tests with and without nateglinide. Subjects were 10 newly diagnosed and untreated inpatients with type 2 diabetes. After diet and exercise therapy for 1 week, nateglinide at 270 mg divided 3 times a day, was started. Meal tolerance tests were performed before (baseline) and after a single nateglinide administration (day 1), after 7 days of repeated administration (day 7), and after cessation of nateglinide on day 8. Mean fasting PG was 146 [plusmn] 6 mg/dl (mean [plusmn] SEM) at baseline and 130 [plusmn] 6 mg/dL on day 7 (P = .0004). The 2-hour postprandial PG level was 226 [plusmn] 10 mg/dL at baseline, 145 [plusmn] 11 mg/dL on day 1 (P = .0008), and 190 [plusmn] 15 mg/dL on day 8 (P = .08, baseline; P = .01, day 7). The mean fasting insulin level was 5.4 [plusmn] 1.0 [mu ]U/mL at baseline and did not change significantly during the study. The 30-minute postprandial insulin level was 14.4 [plusmn] 1.9 [mu ]U/mL at baseline, 39.5 [plusmn] 4.5 [mu ]U/mL on day 1 (P = .0004), and 23.6 [plusmn] 3.6 [mu ]U/mL on day 8 (P = .045, baseline; P = .010, day 7). The total insulin amount, in terms of area under the curve (AUC [middot] IRI), was 3.99 [plusmn] 0.7 [times ] 103 [mu ]U/mL [middot] min at baseline, 5.47 [plusmn] 0.8 [mu ]U/mL [middot] min on day 1 (P = .029), and 6.01 [plusmn] 1.9 [mu ]U/mL [middot] min on day 8 (P = .047 v baseline). The early phase of insulin secretion, based on the ratio of delta IRI to delta PG from fasting to 30 minutes after a meal was 0.15 [plusmn] 0.13 at baseline, 1.44 [plusmn] 0.26 on day 1 (P = .0009) and 0.26 [plusmn] 0.06 on day 8 (P = .05 v day 1). After cessation of nateglinide, the postprandial PG level increased immediately. Although early phase insulin secretion returned nearly to the baseline level, total insulin secretion remained at a high level. These results suggested that early phase insulin secretion contributes more than total insulin secretion to the improvement of postprandial hyperglycemia in type 2 diabetes.

Gastrectomy or vagotomy may result in reactive hypoglycemia, which, in some cases, can reduce the plasma glucose levels to 30-40 mg/dl due to rapid digestion and absorption of food, especially carbohydrates. It also occurs sometimes in patients on hemodialysis, where it is a potentially lethal complication. Because insulin has a longer half-life due to lack of renal degradation, hypoglycemia can be induced by insulin in patients with renal failure. We treated a patient with frequent episodes of severe hypoglycemia, that were sometimes accompanied by convulsions. He had undergone total gastrectomy 8 years before and had been maintained on hemodialysis for 3 years. Hyperinsulinemia caused by oxyhyperglycemia associated with post-gastrectomy led to severe hypoglycemia in this patient because of the lack of renal insulin degradation. Since nutritional treatment did not successfully manage his reactive hypoglycemia, an alpha-glucosidase inhibitor, acarbose, was administered to treat his oxyhyperglycemia. This therapy was very effective and he has not had any recurrence of reactive hypoglycemia since the initiation of the therapy.

A 75-year-old man was admitted to the hospital because of a suspected lung cancer at routine chest X-ray examination. Tracheobronchoscopy and transbronchial lung biopsy demonstrated squamous cell carcinoma of the right upper lobe. His peripheral blood count showed pancytopenia and he was diagnosed as myelodysplastic syndrome (MDS), refractory anemia, based on dysplastic findings of the bone marrow. He received perioperative transfusion of packed red blood cells and platelets, and recombinant human granulocyte colony-stimulating factor (rhG-CSF) was added. Right upper lobectomy and mediastinal-hilar lymph node dissection were carried out. After the operation he was successfully treated with antibiotics and rhG-CSF for postoperative pneumoniae. He is now doing well with no evidence of recurrence, as of 18 months after the surgery. An operating case of lung cancer with MDS is described with a review of the literatutre. It is considered that perioperative management with transfusion and rhG-CSF is reasonable for MDS patients.

Background. It has been reported that colorectal carcinomas are caused by a multistage process. In patients with familial adenomatous polyposis, carcinoma of the colorectum frequently develops and occasionally polyps develop in the upper gastrointestinal tract. Chromosomal deletion often is found for chromosomes 5, 17, and 18, on which tumor suppressor genes are located. Furthermore, loss of the alleles of loci on chromosome 3 has been reported in renal cell carcinoma, small cell lung carcinoma, and mixed salivary gland tumor in hereditary and sporadic cases. These data support the concept of a recessive mechanism for the development of human tumors. Patients and Results. The authors report the case of a 48-year-old woman with rectal cancer accompanied by multiple polyps in the esophagus, stomach, and colorectum. Histologically, the polypoid lesions in the esophagus, stomach, and colorectum showed a thickened mucosa, hyperplastic polyps, and mixed hyperplastic adenomatous polyps, respectively. Karyotype analysis showed 46, xx, inv(3)(p12.2q25.3) in all 20 inspected peripheral lymphocytes. By Southern blot with a c-raf probe, one allele of the c-raf-1 gene, which has been mapped on chromosome 3p25, was deleted from the rearranged chromosome 3 in the peripheral lymphocytes, intact colonic mucosa, and cancer tissue. Conclusions. These results suggest that the development of hyperplastic polyps and carcinoma of the rectum results from the allelic loss in chromosome 3p, as has been reported for solid tumors at other sites. Cancer 1993; 71:672-6.

Prostaglandin (PG) D2 is one cyclo-oxygenase product of arachidonic acid metabolites that may play a role in the pathogenesis of asthma. To determine the effect of PGD2 on ion transport by airway epithelium and its mechanism of action, we measured bioelectric properties of canine cultured tracheal epithelium under short-circuit conditions in vitro. PGD2 (10(-7) M) increased short-circuit current (Isc) from 5.5 +/- 1.2 to 14.1 +/- 2.9 microA cm-2 (means +/- SE, P less than 0.01) when added to the mucosal solution, and to 22.2 +/- 3.8 microA cm-2 (P less than 0.001) when added to the submucosal solution, an effect that was accompanied by the corresponding increases in transepithelial potential difference and conductance. These effects were dose-dependent. The PGD2-induced increase in Isc was not altered by preincubation of cells with autonomic antagonists (phentolamine, propranolol, atropine), the lipoxygenase inhibitor AA-861, the protein kinase C inhibitor H-7, or the Na channel blocker amiloride, but it was inhibited by each of indomethacin, piroxicam, the Cl channel blocker diphenylamine-2-carboxylate, the Cl transport inhibitor furosemide, and Cl-free medium. Intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels were dose-dependently increased by PGD2. These results suggest that PGD2 may selectively stimulate airway epithelial Cl secretion via cyclo-oxygenase- and cAMP-dependent pathway.

1. We studied the effect of immunologically activated pulmonary alveolar macrophages (PAM) on functions of canine bronchiolar smooth muscle under isometric conditions in vitro. 2. PAM, stimulated with monoclonal anti-dinitrophenyl (DNP) IgE antibody and DNP-human serum albumin (DNP-HSA), augmented the contractile responses of bronchioles to electrical field stimulation, whereas PAM treated with IgE antibody alone had no effect. 3. In contrast, the contractile responses to exogenously administered acetylcholine were not influenced by immunologically activated PAM. 4. The PAM-induced increase in the contractile responses to field stimulation was inhibited by pretreatment of PAM with indomethacin and by addition of the thromboxane A2 (TxA2) receptor antagonist SQ 29548. 5. The release of TxA2 from PAM was increased by anti-DNP IgE and DNP-HSA, an effect that was prevented by indomethacin. 6. These results suggest that PAM may play a role in the development of antigen-induced hyperreactivity of small airways through an IgE-dependent release of TxA2 which potentiates prejunctionally the parasympathetic component of bronchiolar smooth muscle tone.

To elucidate the effect of platelet-activating factor (PAF) on ion transport function of airway epithelial cells, we studied bioelectric properties of cultured tracheal and bronchial epithelia from dogs under short-circuit conditions in vitro. Addition of PAF (10(-5) mol/L) to mucosal solution of Ussing chamber increased short-circuit current of tracheal epithelium from 3.3 +/- 0.7 to 8.5 +/- 1.2 microA/cm2 (p less than 0.001). This effect was dose dependent, and there was a corresponding increase in transepithelial potential difference. In contrast, PAF was without effect when it was added to the submucosal side. Electrical properties of bronchial epithelium remained unchanged by PAF. The PAF-induced increase in short-circuit current was not affected by amiloride but abolished by diphenylamine-2-carboxylate, bumetanide, or Cl-free medium. The effects of PAF were not altered by AA-861 or U-60257, but attenuated by indomethacin and piroxicam, and dose-dependently blocked by CV 6209 and WEB 2086. Mucosal, but not submucosal, addition of PAF increased the rate of prostaglandin release from tracheal epithelium. These results suggest that PAF selectively stimulates Cl secretion across tracheal epithelium, probably through activation of its specific receptors and the subsequent production of prostaglandins.

We studied the effect of vasoactive intestinal peptide (VIP) on ciliary activity in rabbit cultured tracheal epithelium by a photoelectric method in vitro. Administration of VIP (10 −7 M) elicited an increase in ciliary beat frequency (CBF) from the baseline values of 970 ± 52 to 1139 ± 75 beats/min (mean ± S.E., P ). This ciliostimulatory effect was dose-dependent, with the maximal increase and EC 50 value being 17.4 ± 1.0% ( P ) and 6 · 10 −11 M, respectively. The VIP-induced increase in CBF was abolished by pretreatment of cells with [4-Cl- d -Phe 6 , Leu 17 ]-VIP, a VIP receptor antagonist. The neutral endopeptidase inhibitor phosphoramidon (10 −5 M) potentiated the effect of VIP, so that the CBF dose-response curve for VIP was shifted to lower concentrations by 0.5 log U . The administration of VIP increased cyclic AMP levels in epithelial cells, an effect that was also potentiated by phosphoramidon. These results suggest that VIP may interact with its specific receptors and stimulate airway ciliary activity probably through the activation of adenylate cyclase, and that neutral endopeptidase may play a role in modulating this effect of VIP.

To elucidate a possible interaction between alveolar macrophages and airway epithelial cells in allergic conditions, we studied the effect of immunologically stimulated macrophages on ciliary beat frequency (CBF) of cultured canine tracheal epithelium by a photoelectric method. Administration of supernatants from macrophages incubated with anti-dinitrophenyl (DNP) IgE antibody and anti-dinitrophenyl-human serum albumin dose-dependently increased ciliary beat frequency, the maximal increase from the baseline being 30.4 +/- 5.0% (mean +/- SE, P less than 0.01), an effect that was accompanied by the release of leukotriene (LT) C4 and leukotriene D4. This ciliostimulation was not affected by pretreatment of macrophages with indomethacin but was inhibited by that with nordihydroguaiaretic acid. Addition of FPL 55712 abolished the response of ciliary beat frequency to the stimulated macrophages, and exogenously administered leukotriene C4 and leukotriene D4 dose-dependently increased ciliary beat frequency. These results suggest that macrophages increase respiratory ciliary motility through the IgE-mediated release of leukotrienes and may modulate mucociliary transport function in the airway.

We studied the effect of substance P (SP) on the electric properties of cultured canine tracheal epithelium and its possible modulation by neutral endopeptidase (NEP) by Ussing’s short-circuited technique in vitro. Addition of SP (5 × 10––6M) to the mucosal side increased short-circuit current (SCC) from 5.1 ± 0.9 to 10.3 ± 2.2 μA/cm2 (mean ± SE; p < 0.01), which was accompanied by increases in transepithelial potential difference and conductance. The effect of the mucosal SP on SCC was dose-dependent, with the maximal increase from the baseline value being 5.8 ± 1.0 μA/cm2 observed at 5 × 10––5M. The NEP inhibitor phosphoramidon (10––5M)did not affect these responses. On the other hand, SCC was not altered by the addition of SP to the submucosal side. However, it was increased dose-dependently in the presence of phosphoramidon (10––5M) but not in the presence of captopril, bestatin or leupeptin. This stimulatory effect of submucosal SP was abolished by furosemide, diphenylamine-2-carboxylate and Cl-free medium, but not by amiloride. These results suggest that SP may selectively stimulate Cl secretion across the airway epithelium and that this effect may be modulated by submucosal NEP.

AOSHIBA, K., NAGAI, A. and TAKIZAWA, T. Effects of Proteinase Inhibitors on Polymorphonuclear Neutrophil Polarization. Tohoku J. Exp. Med., 1991, 165 (3), 165-170-Polarization of polymorphonuclear neutrophils (PMNs) can be elicited by the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP) and the microtuble-disrupting compound colchicine. Here we report on whether natural and synthetic proteinase inhibitors alter the polarizing response to these two agents. The α1-proteinase inhibitor, N-tosyl-L-phenylalanine chloromethyl ketone, and Nα-tosyl-L-lysine chloromethyl ketone suppress fMLP-induced polarization and locomotion in a dose-dependent fashion, but none of them affects colchicine-induced polarization. We suggest that proteinase inhibitors suppress fMLP-induced polarization by blocking cell surface proteinases that generate an intracellular signal for cytoskeletal change and polarization.

A 72-year-old woman who had been treated for coxotuberculosis was examined because of persistent hemoptysis. Chest X-ray films and CT scans revealed atelectasis of the right middle lobe and bronchial calcification. Bronchoscopy showed a yellow broncholith with pus 1 cm from the orifice of the right B4 bronchus. Actinomyces israelii was isolated by anaerobic culture of bronchial lavage fluid. Since the broncholith occluded the right middle lobe bronchus and had caused repeated episodes of infection the right middle lobe was resected by video-assisted thoracoscopic surgery. Histological examination revealed broncholiths due to calcification of peripheral caseating nodules of tuberculosis, which is a rarely finding.

The effect of calcitonin gene-related peptide (CGRP) on parasympathetic contraction of rabbit airway smooth muscle was studied under isometric conditions in vitro. CGRP (10(-7) M) did not contract tracheal smooth muscle, but it potentiated the contractile response to electrical field stimulation (EFS) in a dose-dependent manner, the maximal increase from the baseline response being 14.4 +/- 6.2%. In contrast, the contractile responses to exogenously administered acetylcholine were not altered by this peptide. The CGRP-induced potentiation of the contractile responses to EFS was further augmented by physostigmine (123.1%), but not influenced by phentolamine, propranolol, indomethacin, or thiorphan, an enkephalinase inhibitor. These results suggest that CGRP augments the neurally mediated contraction of rabbit airway smooth muscle probably through a prejunctional mechanism and that this effect may not be modulated by tissue enkephalinase.

The morphologic changes in peripheral airways of guinea pigs derived from asthmalike breathing induced by acetylcholine (Ach) exposure were studied. In the Ach-exposed animals, the smooth muscle in the respiratory units (alveolar mouth of the alveolar duct) as well as in the peripheral airways was increased. The internal and external diameters of the peripheral airways were not significantly different between Ach-exposed and control animals. In addition, the Ach-exposed animals had higher specific diaphragm weights (diaphragm to body weight). We conclude that recurrent asthmalike breathing brings about increased smooth muscle, but the increased muscle contributes little to airway dimensions. We speculate that an increased airway wall thickness inside the outermost layer of smooth muscle may play a role in increasing airway reactivity.

To characterize the actions of heparin and its common preservative benzyl alcohol (BA) on airway smooth muscle functions, we studied the effects of purified heparin, commercial heparin salt solution (HSS) containing heparin and BA, and BA on the contractile responses of canine bronchial segments to various agonists under isometric conditions in vitro. Addition of HSS or the equivalent volume of BA reversibly depressed acetylcholine-induced contraction in a dose-dependent fashion, IC50 values being 5.7 +/- 1.1 (SE) mM of BA, whereas purified heparin had no effect. This depression was not affected by pretreatment of tissues with propranolol, indomethacin or ouabain, or removal of epithelium, and BA at sufficient concentrations to cause muscle relaxation did not alter intracellular adenosine 3',5'-cyclic monophosphate contents. BA also attenuated the contractile responses to electrical field stimulation, histamine, and serotonin, but it was without effect on those to KCl. In addition, the acetylcholine-induced enhancement of hydrolysis of phosphatidylinositol 4,5-biphosphate in the lipid fraction and the resultant production of phosphatidic acid were inhibited in the presence of BA. These results suggest that the heparin preservative BA but not heparin relaxes airway smooth muscle, probably through the decrease in intracellular Ca2+ release by inhibiting agonist-mediated phosphatidylinositol turnover.

To elucidate the mechanisms of airway hyperreactivity induced by lipopolysaccharide (LPS), we studied isolated tracheal segments from guinea pigs under isometric conditions in vitro. Guinea pigs were injected intraperitoneally with endotoxin (1 mg/kg; LPS from Pseudomonas aeruginosa, serotype 10) for 4 days, and animals treated with sterile nonpyrogenic saline served as controls. Histological examination of trachea revealed moderate structural damage of epithelial layer in the LPS-treated group. Treatment with LPS potentiated the contractile responses of tracheal smooth muscle to acetylcholine, causing a leftward displacement of dose-response curves so that the EC50 values decreased from 1.1 +/- 3.7 x 10(-5) to 4.4 +/- 3.7 x 10(-7) M (mean +/- SE, p less than 0.01). Likewise, LPS shifted the dose-response curves for histamine and substance P to lower concentrations by approximately 0.5-1.0 log U. Each of these potentiations was not affected by pretreatment of tissues with indomethacin or propranolol. Addition of isoproterenol to tracheal segments precontracted with acetylcholine caused concentration-dependent relaxation, an effect that was significantly greater in controls than in the LPS-treated group. These results suggest that airway hyperreactivity induced by LPS in guinea pigs may be attributed to a decreased ability of respiratory epithelial cells to generate a relaxing factor.

In general, steroid is mainly used as anti-inflammatory action in case of allergic diseases. As one of the side effects of inhalation steroid, a report is given below regarding buccal capsule/esophageal candidiasis. The patient came to the hospital with the chief complaint regarding passage dysphagia in the time of deglutition; pharyngitis and esophageal candidiasis were found by endoscopy of upper gastrointestinal tract.The interview after the endoscopy revealed that the patient, a 69-year-old female was diagnosed as chronic perennial allergic rhinitis a few years ago, and had been inhaling rhinenchysis Beclometasone dipropionate (BDP) before sleep every day for the past two years because using this collunarium seemed to mitigate the nasal obstruction and mucus during sleep. The patient did not report this fact before the endocsopy because she did not associate it with her subjective symptom. In this case, it was assumed that nebulized rhinenchysis BDP was accidentally swallowed to the pharynx and esophagus during sleep. As a treatment, rhinenchysis BDP was canceled and instead Azunol mouth washing (gargling/nasal douche) was used. No antifungal agent was used. In two weeks, the patient reported some improvement, and this was confirmed by reexamination of the upper gastrointestinal tract using endoscope in one month and a half. Pharyngitis was improved, and in the digital endoscopic assessment of esophageal candidiasis complicating inhaled steroid therapy the esophageal candidiasis became Grade I (mild grade). As for the later progress, the patient did not report any subjective symptoms such as nasal obstruction and dysphagia. In addition, the inflammation caused by candidiasis and found in the early examination was improved. The patient in this case was under treatment for thrombosis in the vein of lower extremity, but no complications such as diabetes mellitus or immune deficiency syndrome were observed.Esophageal candidiasis by chronic administration of inhalation of steroid before sleep for asthmatic patients has been reported. However, there has not been a report of esophageal candidiasis by chronic administration of rhinenchysis steroid before sleep for patients with allergic rhinitis. Similarly, in the case of the use of steroid in the form of collunarium before sleep, steroid stayed in the esophagus via the transendothelial nasal cavity, and that seemed to cause, in the long run, to develop esophageal candidiasis.One of the implications of the above case is that collunarium can go down, even when it is nebulized in the nasal cavity, to the esophagus via the nasal cavity to buccal capsule. This suggests the necessity for preventative measures in the case of chronic administration of steroid as follows. A. Blowing of the nose just after the use of collunarium B. Daily rinsing (gargling and nasal douche).

A questionnaire survey of the current medical therapy in patients with mild persistent (step 2) asthma was conducted of doctors professing internal medicine in Saitama prefecture. Responses were obtained from 933 of those surveyed (response rate: 53%). Medications frequently prescribed for asthma control were theophylline (77%), inhaled corticosteroids (ICSs: 75%), and leukotriene modifiers (64%). Usage of theophylline in exacerbation reached 87% and was given priority over inhaled beta2-agonist, suggesting too much usage of theophylline among respondents. ICSs were used in 75% of respondents. Doctors specializing in respiratory or allergic medicine used ICSs more frequently than the others. They started ICSs at large doses initially (48%), followed by small doses, and they showed a trend of continuing ICSs after the asthma was under control (75%). Eighty-three percent of respondents used leukotriene modifiers, which were evaluated as easy to administer orally, having a synergistic effect with ICSs, and having fewer side effects compared with other asthma medications.

Gastrointestinal endoscopy was performed in two bronchial asthma patients using inhaled corticosteroid who complained of odynophagia. The endoscopic finding was high grade with white moss (Grade III) in both patients. Esophageal candidiasis is often recognized in bronchial asthmatic patients receiving long-term fluticasone propionate (FP) dry powder (Diskhaler) inhalation. We therefore examined the complicated context of esophageal candidiasis in patients with long-term FP inhalation. Out of 20 bronchial asthmatic patients who had been using FP inhalation long-term, seven showed signs of esophageal candidiasis. Three patients had mild grade (Grade I), one middle grade (Grade II) and three high grade (Grade III) candidiasis, with a frequency of 35%. This rate is higher than the usual spontaneous occurrence rate of esophageal candidiasis, and it is suggested that inhalation of corticosteroid medication can penetrate into the esophagus after deep inhalation. We tested this hypothesis in two studies. 1) To measure the esophageal concentration of FP, four healthy adults inhaled 200 microg FP once. Right after inhalation, FP concentration in the esophageal washing fluid was 3.3 microg. On another day, 30 minutes after the same dose of inhaled FP, one FP concentration in the esophageal washing fluid was 0.67 microg (immediately laydown), and another was 0.11 microg (remained standing). This indicates that even though FP dissipates quickly, it remains in the esophagus 30 minutes after inhalation. 2) We observed the process in one patient with high grade (Grade III) esophageal candidiasis. The time of inhalation was changed from just after getting up and just before going to bed to before breakfast and before dinner. Under this regimen, the signs of esophageal candidiasis improved from high to middle grade.If asthmatic patients do not go to sleep immediately after FP inhalation, the remaining FP in the esophagus decreases rapidly, thereby decreasing the risk of esophageal candidiasis. In addition, by changing the FP inhalation times to before breakfast and dinner, the remaining FP in the esophagus is washed away and does not remain in the esophagus. Therefore, this study, which avoided inhalation before going to bed, provides useful information for the prevention and improvement of esophageal candidiasis.

OBJECTIVE: Serum triglyceride levels are important in the development of atherosclerosis. Although triglyceride levels are generally increased in the postprandial periods, the association between postprandial triglyceride (pTG) levels and atherosclerosis has not been investigated in diabetic patients. To investigate the role of pTG levels in atherosclerosis, we examined the correlation between pTG levels and carotid intimal-medial thickness (IMT). RESEARCH DESIGN AND METHODS: Carotid IMT was measured by ultrasonography in 61 patients with type 2 diabetes. Plasma glucose (PG), insulin, total cholesterol, triglycerides, and HDL cholesterol levels were measured after overnight fasting and 4 h after a meal. RESULTS: Carotid IMT of the patients with fasting hypertriglyceridemia was greater than that of the patients with normal fasting triglyceride (fTG) levels (0.85+/-0.12 vs. 0.76+/-0.14 mm; P = 0.02). The carotid IMT was increased in the patients with pTG levels >2.27 mmol/l. The normo-normo (NN) and normo-hyper (NH) groups consisted of patients with normal fTG levels but with pTG levels 2.27 mmol/l, respectively. Patients with both hypertriglyceridemia and pTG levels >2.27 mmol/l formed the hyper-hyper (HH) group. Carotid IMT was significantly increased in the NH (0.86+/-0.13 mm) and HH (0.85+/-0.12 mm) groups compared with the NN group (0.73+/-0.13 mm; P

mance and preliminary results. PACE 1998;21:1058–1068. 10. Danilovic D, Ohm O-J. Pacing threshold trends and variability in modern tined leads assessed using high resolution automatic measurements. Conversion of pulse width into voltage thresholds. PACE 1999;22:567–587. 11. Stokes K, Borzin G. The electrode-biointerface: stimulation. In: Barold SS, ed. Modern Cardiac Pacing. Mount Kisco, NY: Futura Publishing, 1985:33–77. 12. Stamato NJ, O‘Toole MF, Fetter JG, Enger EL. The safety and efficacy of chronic ventricular pacing at 1.6 volts using steroid eluting leads. PACE 1992; 15:248–251. 13. Schwaab B, Frohlig G, Schwerdt H, Heisel A, Berg M, Schieffer H. Telemetry guided pacemaker programming: impact of output amplitude and the use of low threshold leads on projected pacemaker longevity. PACE 1998;21:2055– 2063. 14. Schuller H, Kruse IB, Svennsson O, Mortensen P. Long-term benefits of autocapture—four years of follow-up (abstr). PACE 1999;22:807.

To study the effect of ambroxol on ion transport functions of airway mucosa, we measured bioelectric properties of canine cultured tracheal epithelium under short-circuit conditions in-vitro. Addition of ambroxol to the submucosal but not to the mucosal solution in an Ussing chamber decreased short-circuit current, transepithelial potential difference and cell conductance. The ambroxol-induced decrease in short-circuit current was not affected by bumetanide or diphenylamine-2-carboxylate, but it was abolished by pretreatment of cells with amiloride. These results suggest that ambroxol may selectively inhibit Na+ absorption by airway epithelium, thereby increasing water composition in airway surface fluid and reducing mucus viscosity.

To test whether the leukotriene antagonist ONO-1078 (pranlukast) prevents asthma exacerbations during reduction of high-dose inhaled corticosteroid, we conducted a randomized, double-blind, placebo-controlled study in 79 asthma patients requiring high doses (1,500 microg/d or more) of inhaled beclomethasone dipropionate (BDI) for clinical control (duration of asthma, 11.0 +/- 3.1 yr; duration of BDI treatment, 0.5 +/- 0.3 yr; FEV1 percentage of predicted, 80.7 +/- 2.0%). After a 2-wk run-in period, the doses of BDI were halved, while the patients were assigned to receive orally ONO-1078, 450 mg twice daily, or placebo. In the placebo group FEV1 decreased by 0.33 +/- 0.20 L after 6 wk (p < 0.001). Likewise, morning and evening PEF decreased by 46 +/- 7 L/min and 18 +/- 6 L/min, respectively. By contrast these variables were sustained above baseline in the ONO-1078 group. The number of daytime and nighttime asthma symptoms and the use of beta2-agonist increased in the placebo group, whereas they remained unchanged in the ONO-1078 group. In the placebo group concentrations of serum eosinophil cationic protein and exhaled nitric oxide increased (p = 0.007 and p = 0.025, respectively), compared with no change in the ONO-1078 group. Therefore, the leukotriene antagonist ONO-1078 prevents the asthma deterioration provoked by a 6-wk reduction of the dose of inhaled BDI into half.

The effect of loperamide on cholinergic neurotransmission in canine bronchial smooth muscle was studied under isometric conditions in-vitro. Addition of loperamide decreased contractile responses to electrical field stimulation in a dose-dependent fashion, the maximal decrease from the control response and the IC50 value being 65·4 ± 5·9% and 1·5 μm, respectively. In contrast, loperamide was without effect on the responses to exogenously administered acetylcholine. The inhibitory effect of loperamide was not altered by pre-incubation of tissues with propranol, 6-hydroxydopamine, bicuculline, or naloxone. These results suggest that loperamide attenuates the neurally mediated airway contraction probably by inhibiting acetylcholine release from cholinergic nerve terminals through a non-opioid-dependent mechanism.

Excessive production of sputum is one of the major symptoms in patients with chronic airway diseases. Because endogenous prostaglandins may play a role in the regulation of airway secretions, blockade of cyclooxygenase pathway with indomethacin could decrease respiratory tract fluid and mucus by inhibiting Cl secretion and glandular secretion and by enhancing Na absorption across airway mucosa. To test this hypothesis, we studied the effect of inhaled indomethacin on bronchorrhea in patients with chronic bronchitis, diffuse panbronchiolitis, and bronchiectasis in a double-blind, placebo-controlled fashion. Patients who inhaled 2 ml of indomethacin (1.2 micrograms/ml) three times a day for 14 days showed a decrease in the amount of sputum, from 189 +/- 19 to 95 +/- 21 g/day (p less than 0.001) and an increase in the solid component of sputum without alterations in parameters of systemic inflammatory responses. Although pulmonary function remained unchanged, perceived dyspnea was improved so that Borg's ratio scale was decreased from 7.1 +/- 0.5 to 4.5 +/- 0.4 (p less than 0.01). Adverse effects, including hypotension and bronchoconstriction, were not observed. The reduction of sputum was accompanied by a significant decrease in the concentrations of prostaglandin (PG)E2, PGF2 alpha, thromboxane B2, and 6-oxo-PGF1 alpha in the sputum. Thus, indomethacin inhalation may be of value in reducing bronchorrhea sputum, probably through the inhibition of PG-dependent airway secretions.

The effect of erythromycin on ciliary beat frequency (CBF) of rabbit tracheal epithelium was studied by a microphoto-oscillation technique in vitro. Addition of erythromycin dose-dependently increased CBF, the maximal increase from the baseline value and EC50 being 23.3 +/- 4.5% (P less than 0.001) and 6.8 +/- 0.9 mg/L, respectively. This effect was not influenced by autonomic receptor antagonists, blockers of arachidonic acid metabolism, Ca(2+)-free medium, or inhibition of protein kinase C and protein kinase A activities.

We have studied alveolar attachments to membranous bronchioles in 41 patients enrolled in the National Institutes of Health Intermittent Positive Pressure Breathing Trial who died, came to autopsy, and provided adequate tissue for examination. The patients had moderate to severe chronic airflow obstruction and, on the average, severe emphysema. We measured the number of normal attachments per membranous bronchiole per case (N), the number of normal attachments per mm of circumference per bronchiole per case (Nunit), and the ratio of abnormal to all attachments (R). All measurements correlated closely to all measurements of emphysema and to irregular shape of bronchioles (deformity index). Measurement of abnormal attachments correlated with abnormal tests of pulmonary function, including evidence of airflow obstruction and diffusing capacity for carbon monoxide (DLCO). Nunit showed the most frequent correlations, but both N and Nunit were only related independently of emphysema for Phase III of the single-breath nitrogen test. R was related to loss of DLCO. We conclude that loss of attachments is not itself a cause of airflow obstruction but rather a correlate of emphysema, which is the proximate cause of the obstruction. Loss of alveolar attachments has an effect only on the single-breath nitrogen tests independent of emphysema.

Endothelin, an endothelium-derived vasoconstrictor peptide, has recently been reported to exist in airway epithelial cells. To elucidate a possible role of endothelin on epithelial functions, we studied the effects of this peptide on ciliary beat frequency (CBF) and electrical properties of canine cultured tracheal epithelium by a microphoto-oscillation method and Ussing's short-circuited technique, respectively. Endothelin dose-dependently increased CBF, the maximal increase above the baseline value and EC50 being 32.3 +/- 4.0% (P less than 0.001) and 3 nM, respectively. This effect was moderately attenuated by pretreatment of cells with indomethacin and greatly reduced by Ca2(+)-free medium. Addition of endothelin (10(-6) M) to the mucosal bath of Ussing chamber increased short-circuit current from 5.1 +/- 1.2 to 9.4 +/- 1.7 microA/cm2 (P less than 0.05) and potential difference from 2.9 +/- 0.4 to 5.0 +/- 0.9 mV (P less than 0.05), an effect that was inhibited by indomethacin or Ca2(+)-deficiency and was abolished by the Cl transport inhibitor bumetanide or substitution of Cl with iodide in the medium. These results indicate that endothelin stimulates ciliary motility and Cl secretion probably through an increase in cytosolic Ca2+ and partially a prostaglandin synthesis in canine tracheal epithelium, and suggest that this peptide might play a role in modulating airway mucociliary transport functions.

To study the effect of atrial natriuretic factor (ANF) on airway ciliary motility, we measured ciliary beat frequency by a photoelectric method in response to ANF in cultured tracheal epithelial cells from rabbits. Addition of ANF but not [Tyr8]ANF-(5-27) decreased ciliary beat frequency in a dose-dependent fashion; the maximal decrease from the baseline value was 24.1 +/- 1.5% (+/- SE, P less than 0.001), and a half-maximal inhibitory concentration (IC50) was 3 x 10(-12) M. Inhibition of neutral endopeptidase activity by phosphoramidon (10(-6) M) or thiorphan (10(-6) M) potentiated the effect of ANF so that the dose-response curve for ANF was shifted to lower concentrations by approximately 0.5 log units (P less than 0.05, in each case). The inhibition of ciliary motility induced by ANF was not affected by the blockade of arachidonic acid metabolism with indomethacin, piroxicam, or nordihydroguaiaretic acid, but it was blocked by methylene blue, a soluble guanylate cyclase inhibitor, and was potentiated by M & B 22948, a guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor. The intracellular cGMP levels were increased by ANF, an effect that was further potentiated by phosphoramidon or thiorphan. These results suggest that ANF inhibits ciliary motility presumably through a guanylate cyclase-dependent regulatory pathway and that neutral endopeptidase may play a role in modulating the ANF effect on airway mucociliary transport function.

The effect of lipopolysaccharide (LPS) from Klebsiella pneumoniae on the bioelectric properties of canine cultured tracheal epithelium was examined. LPS decreased short-circuit current (Isc), and its effects on Isc were reduced when Isc was inhibited by amiloride and indomethacin. We speculate that LPS may selectively inhibit Na+ absorption through the inhibition of prostaglandin synthesis by airway epithelium.

We used cultured rabbit tracheal epithelium to determine the effect of mammalian-derived tachykinin on airway ciliary activity and its modulation by neutral endopeptidase EC 3.4.24.11 (NEP). Neurokinin A (NKA) caused dose-dependent increases in ciliary beat frequency (CBF), as measured by a photoelectric method, with the maximal increase from the baseline 15.7 +/- 1.7% (mean +/- SEM, p less than 0.01), whereas substance P (SP) had no effect. The NKA-induced increase in CBF was not inhibited by phentolamine, propranolol, or atropine, but it was abolished by the tachykinin antagonist [D-Pro2, D-Trp7,9]SP. Pretreatment of tissue with thiorphan (10(-5) M), a NEP inhibitor, had little effect on CBF responses to NKA; however, it significantly potentiated the responses to SP (14.9 +/- 3.0%, p less than 0.01). Other peptidase inhibitors, including captopril, bestatin, and leupeptin, did not alter the tachykinin-induced CBF response, suggesting that angiotensin converting enzyme, aminopeptidases, and serine proteinases do not modulate ciliary activity in response to tachykinins. These results suggest that NKA increases CBF by acting directly on tachykinin receptors and that NEP may play a role in modulating the tachykinin-induced stimulatory effects on CBF.

To determine the effects of the opioid peptides, beta-endorphin and dynorphin A, on airway smooth muscle function and its possible modulation by tissue peptidases, we studied canine bronchial segments under isometric conditions in vitro. Addition of beta-endorphin or dynorphin A did not alter the resting tension. However, beta-endorphin (10(-6) M) but not dynorphin A decreased the contractile responses to electrical field stimulation (EFS, 0.5-40 Hz). This effect was dose-dependent and reversed by naloxone. In contrast, acetylcholine-induced contractions were not affected by these opioids. The beta-endorphin-induced inhibition of the contractile responses to EFS was not augmented by peptidase inhibitors such as thiorphan, captopril, bestatin and leupeptin. These results suggest that beta-endorphin prejunctionally inhibits parasympathetic muscle contraction, and that endogenous peptidases do not play a modulatory role in this effect of beta-endorphin.

We studied the effect of angiotensin II on ciliary activity in cultured rabbit tracheal epithelium in vitro. Administration of angiotensin II (10(-6) M) elicited an increase in ciliary beat frequency (CBF), as assessed by a photoelectric method, from the baseline value of 906 +/- 21 to 1260 +/- 33 beats min-1 (mean +/- SE, P less than 0.001). This ciliostimulatory effect was dose-dependent, with the maximal increase and EC50 value being 35.6 +/- 5.2% (P less than 0.001) and 5 x 10(-12) M respectively. Nifedipine, Ca2(+)-free medium, indomethacin and the phospholipase A2 inhibitor mepacrine, but not nordihydroguaiaretic acid, reduced the change in CBF. The ciliostimulation induced by angiotensin II was abolished by pretreatment of tissues with [Sar1-Ile8]angiotensin II, an angiotensin II receptor antagonist. Angiotensin II did not increase cyclic AMP levels in epithelial cells. These results suggest that angiotensin II interacts with its specific receptors and stimulates airway ciliary activity through a Ca2(+)-dependent prostaglandin release, without affecting intracellular cyclic AMP levels. Thus, angiotensin II may modulate mucociliary transport function in the respiratory tract.

Structural changes caused by exposure to NO2 were compared between the largest intrapulmonary bronchi (major bronchi) and the terminal bronchioles. Rats were exposed to 50 ppm NO2 for 5 h a day for 7 consecutive days, and microscopic findings were assessed subjectively and quantitatively. Destruction of airway epithelium was present on Day 1, and the reparative phase was observed between Days 3 and 7. Light microscopy showed that on Day 1, loss of cilia and disintegration of epithelium occurred, and that the latter was worse in major bronchi than in terminal bronchioles; apical projections of Clara cells in terminal bronchioles were lost almost totally. Recovery of epithelium began by Day 3 and cilia by Day 5, and ciliogenesis progressed less promptly in terminal bronchioles. Clara cells did not return to normal during the experiment. Furthermore, a decrease in the airway diameter occurred in peripheral airways along with an increase in mural thickness in terminal bronchioles. Mural inflammation was also seen more conspicuously in terminal bronchioles. Electron microscopy revealed that epithelial cells lost secretory granules on Day 1 and began to repair them by Day 5 in major bronchi and by Day 7 in terminal bronchioles. It is likely that epithelium in terminal bronchioles is not particularly sensitive to NO2 compared with that in major bronchi, but that recovery occurs more promptly in major bronchi than in terminal bronchioles. Mechanisms underlying bronchoconstriction occurring preferentially in peripheral airways are also discussed.

We studied the effect of bradykinin on ciliary activity and its modulation by peptidases in cultured rabbit tracheal epithelium in vitro. Bradykinin (10(-7) M) elicited a rapid, transient increase in ciliary beat frequency (CBF) from the baseline values of 1,031 +/- 25 to 1,388 +/- 38 beats/min (mean +/- SE, p less than 0.001), followed by a decline to a steady-state value of 1,180 +/- 30 beats/min, which was still greater than the baseline CBF. This ciliostimulation was dose-dependently inhibited by the B2-receptor antagonist (D-Arg,Hyp3,Thi5.8,D-Phe7)-bradykinin but not by the B1-receptor antagonist (Des-Arg9,Leu8)-bradykinin. Nifedipine, Ca2+-free medium, indomethacin, the phospholipase A2 inhibitor mepacrine, and the methyltransferase inhibitor 3-deazaadenosine reduced the change in CBF. Involvement of tachykinins, leukotrienes, prostaglandin D2, or thromboxane A2 was ruled out because bradykinin's action was not affected by (D-Pro2,D-Trp7.9)-substance P, nordihydroguaiaretic acid, or SQ29548, an antagonist for prostaglandin D2 and thromboxane A2. Bradykinin also increased prostaglandin E2 release (p less than 0.01), an effect that was abolished by indomethacin and Ca2+ deficiency. The CBF dose-response curve for bradykinin was shifted to lower concentrations by 1 log U by the neutral endopeptidase inhibitor phosphoramidon (p less than 0.01), whereas the angiotensin-converting enzyme inhibitor captopril was without effect. These results suggest that bradykinin interacts with B2-type receptors and stimulates ciliary activity through Ca2+-dependent prostaglandin E2 release, and that neutral endopeptidase may play a role in modulating the effect of bradykinin on airway mucociliary transport.

気管支のmucoepidermoid carcinomaの1例を経験した. 病理所見では粘液産生細胞が管腔を作っている部分と扁平上皮様細胞が充実性に存在する部分とからなり, 中間型細胞も混在していた. 透過型電子顕微鏡では分泌顆粒, tonofibrilsあるいは両者を持つ細胞の他, 少数ながら線毛を持つ細胞等を認め, 多彩な像を呈した. 免疫組織化学ではsecretory componentが粘液産生細胞にのみ陽性であり腺上皮への分化が示唆された.

Inflammatory mediators influence mucociliary transport function in the lung, which may be dependent on the beating of the underlying cilia. To determine whether a nonsteroidal anti-inflammatory drug affects this function, and, if so, what is the mechanism action, we examined the effect of indomethacin on ciliary beat frequency (CBF) of cultured rabbit tracheal epithelial cells by a photoelectric technique. Addition of indomethacin dose-dependently enhanced CBF without any ciliary discoordination, the maximal increase and Km being 26.5 +/- 4.8% (mean +/- SE, p less than 0.001) and 6.8 X 10(-7) M, respectively. Pretreatment of tissues with nordihydroguaretic acid (10(-5) M), an inhibitor of the lipoxygenase pathway, did not change the baseline CBF, but inhibited the response of CBF to 3 X 10(-6) M indomethacin (p less than 0.01). These results suggest that indomethacin may accelerate mucociliary clearance through the augmentation of ciliary motility and that this ciliostimulation may be mediated by leukotrienes produced by activation of the lipoxygenase pathway of arachidonic acid metabolism.

We have assessed emphysema by using routine histologic sections. The assessment is simple and quick and has little interobserver variation. It is well related to conventional assessments of emphysema and abnormalities of pulmonary function tests. We conclude that the method is suited to routine diagnosis at autopsy and to clinicopathologic correlative studies.

Pressure-volume characteristics and morphologic changes were investigated in lungs of growing rats with streptozotocin-induced diabetes mellitus. Lung elastic recoil examined with quasi-static, air-filled pressure-volume curves showed no significant differences from that in control rats at all lung volumes. No alterations of surfactant properties as measured by a surface balance were observed. A 24% increase in the volume proportion of alveolar wall was found in the lungs from diabetic rats. There was an increase in the relative amounts of collagen, elastin, and basal laminae in the alveolar wall. There were more alveoli per unit volume in the diabetic animals (49.12 × 105) than in the control animals (39.80 ×105)(p< 0.05) and there was an increase in the surface-to-volume ratio of the lungs of the diabetic rats.

We studied the effect of adenosine on airway reactivity of isolated canine bronchial smooth muscle under isometric conditions in vitro. Administration of adenosine and its analogs increased the contractile responses of bronchial segments to electrical field stimulation in a dose-dependent fashion, where the rank order potency was N-ethylcarboxamideadenosine > adenosine > N-cyclohexyladenosine, but had no effect on those to exogenous acetylcholine. This potentiation was more pronounced at relatively low than at high stimulus frequencies, the maximal increase from the baseline responses being 56.3 ± 9.6% at 1 Hz (mean ± SE, p < 0.01). Adenosine also increased the histamine-induced contraction causing a leftward shift of the histamine dose-response curves, an effect that was abolished in the presence of atropine. These results suggest that adenosine potentiates airway responsiveness to vagal stimulation and to histamine through the activation of prejunctional A2 receptor, probably involving the accelerated release of acetylcholine from the cholinergic nerve terminals.

To investigate the possible mechanisms by which theophylline affects the control of ventilation, neuromuscular drive and ventilatory function were examined in 7 healthy men receiving an incremental intravenous aminophylline dosing schedule to achieve plasma theophylline concentrations of 5, 10, and 15 micrograms/ml. As compared with the baseline (predose) values, the 3 incremental aminophylline doses significantly (p less than 0.05 to 0.01) increased occlusion pressure (P0.1) and maximum inspiratory pressure static (MIPS) at functional residual capacity (FRC). This was not observed for ventilatory flow (V), tidal volume (VT), inspiratory time to total breathing cycle time ratio (Ti/Ttot) VT/Ti, and effective impedance [P0.1/VT/Ti)]. When maximum electrical activity of diaphragm (Edimax) and transdiaphragmatic pressure (Pdimax) were examined in 3 of the 7 subjects, Pdi/Edi tended to increase with increasing theophylline concentrations, while Edimax did not. Our results suggest that the increase in P0.1 during the increase in aminophylline dose is caused by an improvement in respiratory muscle contractility, rather than by a central effect or by an increase in neural drive.