Smoking-related changes in the background lung of specimens resected for lung cancer: a semiquantitative study with correlation to postoperative course.

AIMS: To assess the pathological findings in lobectomy specimens, to correlate them with smoking history and postoperative course and to compare the findings with those in smoking-related interstitial lung disease. METHODS AND RESULTS: Patients who had undergone lobectomy for lung cancer were reviewed. Subjects included 230 non-smokers and 587 smokers, of whom 572 had a known smoking index (SI). They were classified into mild, moderate and heavy smokers. Centrilobular emphysema (CLE), respiratory bronchiolitis, airspace enlargement with fibrosis (AEF), the presence of foci resembling usual interstitial pneumonia pattern (UIP/P) and the rate of postoperative respiratory failure were assessed. The incidence of AEF was 6.5% in mild smokers, and 17.7% in moderate smokers (P < 0.01) with lower lobe predominance. There were significant correlations (P < 0.01) between AEF and CLE and AEF and UIP/P. The rate of respiratory failure after lobectomy was 6%, and 10% in patients having UIP/P with or without AEF, but was not seen in patients with AEF alone (P < 0.01). CONCLUSIONS: AEF is an important smoking-related change in the lung that appears to correlate with the smoking history, and its distinction from UIP/P may be important.

Alcohol consumption and the risk of cancer in Japanese men: the Miyagi cohort study.

The objective of this study was to investigate the association between alcohol consumption and the risk of total cancer, and to estimate the proportion of total cancer attributable to drinking habit in Japanese men. From June through August 1990, a total of 21 201 Japanese men completed a self-administered questionnaire on various health habits, including alcohol consumption. During 153 389 person-years of follow-up through December 1997, we identified a total of 882 cases of cancer. We used Cox proportional hazards regression to estimate the relative risk of total cancer according to categories of alcohol consumption. The risk for total cancer was significantly higher in ex-drinkers than never-drinkers. There was a dose-response relationship between the amount of alcohol consumed and the risk of total cancer among current drinkers: multivariate RRs in reference to never-drinkers (95% confidence intervals (CI)) were 1.1 (0.8-1.3), 1.3 (1.0-1.7), and 1.3 (1.1-1.7) in current drinkers who consumed less than 22.8 g, 22.8-45.5 g, 45.6 g or more alcohol per day, respectively (P for trend <0.001). Estimated 17.9% (95% CI 3.1-30.5) of total cancer risk was attributable to drinking habit. In our findings, approximately 20% of the total cancer cases in Japanese men may be prevented by alcohol control.

Constipation, laxative use and risk of colorectal cancer: The Miyagi Cohort Study.

The objective of this study was to investigate the association between constipation or laxative use and the risk of colorectal cancer in Japanese men and women. In 1990, we delivered a self-administered questionnaire to 41670 subjects who were 40-64 years old. During the seven years of follow-up, 251 incident cases of colorectal cancer were documented. Constipation was defined as a bowel movement frequency of less than daily. The multivariate relative risk (RR) of colorectal cancer for constipated subjects compared with those with daily bowel movements was 1.35 (95% Confidence Interval: 0.99-1.84). The RR for laxative users over non-users was 1.31 (0.88-1.95), and for frequent users (twice a week or more) it was 2.75 (1.48-5.09). When colorectal cancers were divided into colon cancers or rectal cancers, a significant association was found with colon cancer alone. Our results support the hypothesis that constipation or laxative use increases the risk of colon cancer.

Enhanced airway inflammation and decreased subepithelial fibrosis in interleukin 6-deficient mice following chronic exposure to aerosolized antigen.

BACKGROUND: Airway inflammation and remodelling are characteristic features of chronic asthma. OBJECTIVE: To elucidate the role of interleukin (IL)-6 in airway responses to chronic antigen exposure. METHODS: We compared airway inflammation, subepithelial collagen deposition, cytokine mRNA expression, and airway responsiveness between IL-6-deficient and wild-type (WT) mice following sensitization and repeated exposure to ovalbumin (OVA) three times a week for 8 weeks. RESULTS: The repeated exposure to OVA induced infiltration of eosinophils, neutrophils, and lymphocytes into the airway, and caused thickening of the basement membrane and subepithelial fibrosis. IL-6-deficient mice exhibited more pronounced infiltration of these cells, a thinner basement membrane, and decreased subepithelial fibrosis, compared with WT mice. The repeated OVA exposure increased expression of IL-4, IL-13, eotaxin, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta1 mRNA in WT mice. Among these factors, expression of IL-13 and MCP-1 mRNA was further enhanced in IL-6-deficient mice, compared with WT mice. However, both WT and IL-6-deficient mice exhibited similar levels of airway responsiveness to increasing doses of methacholine, even after repeated exposure to OVA. CONCLUSION: These results suggest that IL-6 has dual roles in the chronic phase of asthma: down-regulation of inflammatory cell infiltration and enhancement of airway remodelling.

Synthesis and microstructural analysis of Si3N4 nanorods.

Alpha-Si3N4 nanorods with 20-80 nm width were synthesized by carbothermal reduction of SiO with amorphous activated carbon (AAC) as a reductant. Microstructural characterization of the synthesized nanorods was carried out by high resolution transmission electron microscopy (HRTEM) and energy dispersive X-ray analysis. Many Si3N4 nanorods were found to be twisted. Each twisted nanorod contained several straight Si3N4 parts. The straight parts had the rod axes orientated along the (1010) direction, which is the closest packing direction of alpha-Si3N4. There were two kinds of joints between the two adjacent straight Si3N4 parts. Formation mechanism of the Si3N4 nanorods is discussed.

Effects of suplatast tosilate, a new type of anti-allergic agent, on airway cough hypersensitivity induced by airway allergy in guinea-pigs.

BACKGROUND: Cough receptor hypersensitivity is a fundamental feature of some conditions presenting with chronic non-productive cough. Suplatast tosilate, an anti-allergic agent, is a T helper (Th)2 cytokine inhibitor that inhibits the synthesis of interleukin (IL)-4, IL-5, immunoglobulin (Ig)E production, and local eosinophil accumulation. OBJECTIVE: The purpose of this study was to investigate the effect of suplatast on antigen-induced airway cough hypersensitivity and eosinophil infiltration into the airway. METHODS: Number of coughs elicited by inhalation of increasing concentrations of capsaicin (10-8, 10-6 and 10-4 M) was counted 24 h after an antigen challenge in conscious guinea-pigs and then bronchoalveolar lavage was performed. We investigated the effect of single (before antigen challenge or capsaicin provocation) or repetitive treatment with intraperitoneal suplatast at a dose of 10 or 30 mg/kg on antigen-induced cough hypersensitivity. RESULTS: Twenty-four hours after antigen challenge, guinea-pigs developed an increase in cough receptor sensitivity to inhaled capsaicin and eosinophil infiltration in the airways. After a 2-week treatment with suplatast, but not after only a single treatment before antigen challenge or capsaicin provocation, the antigen-induced early phase bronchoconstriction, cough hypersensitivity, and airway eosinophilia were inhibited in a dose-dependent manner. CONCLUSION: These results indicate that suplatast inhibits airway cough hypersensitivity underlying allergic eosinophilic inflammation.

Effects of oral steroids on blood CXCR3+ and CCR4+ T cells in patients with bronchial asthma.

Corticosteroids are widely used in bronchial asthma, but their mechanism of action is not fully understood. The in vitro studies have proposed that human T helper cells, type 1 (Th1) favor expression of CXCR3, whereas Th2 cells favor CCR4. In this study we investigated whether oral prednisolone modulates the balance of peripheral blood CXCR3+ and CCR4+ T cells. We analyzed the T-cell subsets in 28 patients with stable atopic asthma and 13 normal control subjects before and after 2 wk of treatment with prednisolone, 20 mg/d, or placebo in a randomized, double-blind, parallel group study. The numbers of CXCR3+ and CCR4+ memory T cells were measured with a flow cytometer, and expressed as percentages in CD4+/CD45RO+ memory T cells. In the steroid-treated asthma group, there was a decrease in CCR4+ T cells (from 29.3% to 20.3%, p < 0.0001), and an increase in CXCR3+/ CCR4+ ratio (from 1.86 to 2.89, p = 0.0047), whereas there was no change in CXCR3+ T cells. However, the percentages of CCR4+ cells did not change after steroid therapy in normal control subjects. These results suggest that short-term oral corticosteroid modulates the balances of CXCR3+ and CCR4+ cells in patients with asthma.

Role of the cytoskeleton in mediating cAMP-dependent protein kinase inhibition of the epithelial Na+/H+ exchanger NHE3.

The Na(+)/H(+) exchanger NHE3 isoform mediates the entry of Na(+) into epithelial cells of the kidney and gastrointestinal tract. Hormones and pharmacological agents that activate cAMP-dependent protein kinase A (PKA) are potent inhibitors of native and ectopically expressed NHE3 in epithelial and Chinese hamster ovary AP-1 cells, respectively. Previous studies have shown that acute inhibition is coupled to direct phosphorylation of the exchanger, but this only partly accounts for the observed effects. In this report, we show that inhibition of NHE3 activity by forskolin, an activator of adenylate cyclase, occurs without changes in surface expression of the exchanger but is associated with altered cytoskeletal structure. This effect resembles that obtained with cytochalasin D or latrunculin B, actin disrupting agents that also inhibit NHE3. Such similarities prompted us to further investigate the relationship between PKA-induced inhibition of the exchanger and changes in the actin cytoskeleton. Inhibition of NHE3 by cytochalasin D does not require PKA, because the inhibitory effect is preserved in a mutant NHE3 that is not phosphorylated by PKA and in cells pretreated with the PKA inhibitor H89. In contrast, involvement of actin in the effect of cAMP on the exchanger is supported by the following observations: (i) jasplakinolide, an F-actin stabilizer, prevents the inhibition caused by forskolin, and (ii) constitutively active forms of RhoA and Rho kinase interfere with actin disruption by forskolin and also decrease inhibition of the transporter. These results suggest that reorganization of the cytoskeleton by PKA is involved in mediating inhibition of NHE3.

Temperature dependency of radiation damage in inorganic materials by 300 keV electrons.

Temperature dependency of radiation damage in albite and natrolite was studied quantitatively by measuring the diffraction intensity with imaging plates. Radiation damage was reduced at low temperature in albite but was enhanced in natrolite. A damage process model, in which creation and annihilation of localized defects were considered, was proposed. According to this model, Boltzmann factor in temperature dependency is dominated by a difference between energy for diffusion of the localized defects and energy for breakdown of a crystal framework. When the diffusion energy is larger than breakdown energy, the activation energy in Boltzmann factor seems to be effectively negative.

Effects of carbocysteine on antigen-induced increases in cough sensitivity and bronchial responsiveness in guinea pigs.

Carbocysteine is a mucoactive drug and is being used for both acute and chronic infectious airway diseases. Although carbocysteine can repair the damage of epithelial cells caused by exposure to various agents, the effects of this agent on allergic airway diseases such as asthma and eosinophilic bronchitis with an isolated chronic cough, in both of which epithelial damage may be characteristic, is not clear. We investigated the effects of carbocysteine on antigen-induced cough hypersensitivity to inhaled capsaicin at 48 h and bronchial hyperresponsiveness to inhaled methacholine at 72 h after challenge with an aerosolized antigen in actively sensitized guinea pigs. After measuring bronchial responsiveness, we examined neutral endopeptidase (NEP) activity in the tracheal tissue. Carbocysteine (10, 30, or 100 mg/kg) was given intraperitoneally every 12 h for 3 days after antigen challenge. The number of coughs elicited by an aerosol of capsaicin (10(-4) M) was significantly (p < 0.01) decreased in carbocysteine groups (6.13 +/- 0.59 at 10 mg/kg, 4.88 +/- 0.67 at 30 mg/kg, and 4.50 +/- 0.33 at 100 mg/kg during 3 min measurement) compared with the control group (9.75 +/- 0.53). Furthermore, carbocysteine dose dependently repaired the antigen-induced decrease of NEP activity in the tracheal tissue, but it did not influence the bronchial hyperresponsiveness or bronchoalveolar lavage cell component. These findings suggest that carbocysteine promotes the repair of damaged epithelium by allergic reaction and may be useful in allergic airway diseases accompanied by isolated chronic coughing, especially eosinophilic bronchitis without asthma and tracheobronchitis with cough hypersensitivity.

Blockade of eosinophil migration and airway hyperresponsiveness by cPLA2-inhibition.

We examined the role of a cytosolic phospholipase A2 (cPLA2) in antigen-induced eosinophil infiltration of airways and in airway hyperresponsiveness to methacholine. Inhibition of cPLA2, or blockade of the platelet-activating factor (PAF) receptor, blocked antigen-induced airway hyperresponsiveness and suppressed eosinophil infiltration. Neither cyclooxygenase nor 5-lipoxygenase inhibition had either effect. We show here that, in antigen-sensitized guinea pigs, cPLA2 inhibition prevents both eosinophilic infiltration and subsequent airway hyperresponsiveness after antigen challenge. We also show that this effect is mediated by first-step hydrolysis of membrane phospholipid into lysophospholipid rather than by prostanoid or leukotriene metabolites of arachidonate.

Connexin 26 distribution in gap junctions between melanocytes in the human vestibular dark cell area.

We have previously demonstrated the presence of gap junctions between melanocytes in the human vestibular organ and have speculated that melanocytes function in maintaining the homeostasis of the microenvironment of the inner ear. The purpose of the present study was to characterize the expression and ultrastructural localization of connexin (Cx) protein in melanocytes of the human vestibular organs. Surgical material was obtained from patients operated on for vestibular schwannoma and was processed for light microscopy, confocal laser scanning microscopy, conventional TEM, and immuno TEM. The specimens were labeled with anti-Cx26, Cx32, and Cx43 antibodies and examined by light microscopy. Specimens were also labeled with anti-Cx26 antibody and examined by laser microscopy and immuno-TEM methods. The specimens examined in this study were mainly dark cell areas from the human vestibular organ, whose epithelial and subepithelial layers are rich in melanocytes. Light-microscopic immunohistochemical studies showed positive labeling for Cx26 protein between subepithelial melanocytes, and Cx32 was also detected. Use of anti-Cx26 antibody and confocal laser scanning microscopy revealed high levels of Cx26 around the subepithelial melanocytes. Post-embedding immuno-gold transmission electron microscopy showed significant aggregation of gold particles (33.97 +/- 8.01% of total gold particles) around the gap junctions of the subepithelial melanocytes. The results of this study indicated that melanocytes are connected through gap junctions that mainly contain Cx26. This suggested that the melanocytes in the human vestibular organ may play a role in transporting material between the endolymph and perilymph.

Perilymph fistula--45 case analysis.

PURPOSE OF THE STUDY: Though perilymph fistula (PLF) is not a rare disease, preoperative diagnosis still remains to be established. Some new diagnostic methods are challenging, but there is still no established diagnostic method except exploratory tympanotomy that verifies the occurrence of leakage. Early diagnosis of PLF is fully depending on history taking and some clinical examinations. To know the clinical features of PLF is one of the greatest helps to make both earlier and accurate diagnosis. In spite of some innovations in clinical examinations classic diagnostic procedure is thought to be still reliable. PROCEDURES: We investigated the clinical symptoms, basic tests results and therapeutic results in patients with PLF. RESULTS: From 1983 to 1998 PLF was identified in 44 patients (45 ears) with exploratory tympanotomies in our hospital. With respect to clinical history the predisposing factors such as blowing the nose, lifting heavy goods, and landing in an airplane were found in almost half of the patients, while the rest of them had no clear inducing factors. Their major symptoms included hearing loss (93%), vertigo and dizziness (91%), tinnitus (76%), and aural fullness (31%). The patients who have a clear predisposing factor tended to make diagnosis easily; on the other hand the rest of the patients who do not have clear etiology had some diagnostic difficulty. Subjective positive fistula signs were observed in 71% of patients. Vestibular symptoms improved in 80% of patients after closure of PLF. CONCLUSIONS: These results suggest that the variety of clinical manifestation make diagnosis more difficult. At the moment meticulous clinical history taking and close follow-up applying repeating fistula tests are the most important for not only earlier but also accurate diagnosis.

Nanotubes of boron nitride filled with molybdenum clusters.

Carbon nanotubes are known to be metallic or semiconducting, depending on their helicity and diameter. However, boron nitride (BN) nanotubes are the only nanotubular product known to date that are predicted to have stable insulating properties that are independent of their atomic structure and morphology. Thus, the BN tube has attracted prime attention as an advanced nanoinsulating shield for all types of encapsulated conducting material, i.e., metal wires, clusters, etc. However, so far there have been no successes in controlled one-dimensional filling of BN nanotubes with conductive material. We report the first experimental results on the synthesis, high-resolution transmission electron microscopy, energy dispersion X-ray analysis, and electron energy loss spectroscopy of BN nanotubes that are filled with Mo clusters over their entire length. This was accomplished by means of two-step thermochemical treatment of chemically vapor-deposited C nanotubes with B2O3, CuO, and MoO3 oxides in a flowing N2 atmosphere. The first examples of BN nanotubes filled with molybdenum clusters are reported and the formation of the first nanocable (approximately 10 nm in length), consisting of a conductive metal core and an insulating BN nanotubular shield is demonstrated.

Effect of losartan, a type 1 angiotensin II receptor antagonist, on bronchial hyperresponsiveness to methacholine in patients with bronchial asthma.

It is unclear whether angiotensin II receptors are involved in bronchial hyperresponsiveness in asthmatic patients. We examined the effect of losartan, a specific angiotensin II type 1 (AT1) receptor antagonist, on bronchial responsiveness to inhaled methacholine in eight patients with stable asthma. Bronchial responsiveness to methacholine, assessed as the concentration of methacholine producing a 20% fall in FEV(1) (PC(20)-FEV(1)) and a 35% fall in standardized partial expiratory flow at 40% of FVC (PC(35)-PEF(40)), was measured on two occasions 2 wk apart. Losartan (50 mg once a day) or a placebo was orally administered for 1 wk before methacholine provocation test in a double-blind, randomized, crossover fashion. Although the PC(20)-FEV(1) values after placebo (2.037 [geometric standard error of the mean, GSEM = 0.210] mg/ml) and losartan (2.098 [GSEM, 0.239] mg/ml) were identical (p = 0.840), the geometric mean PC(35)-PEF(40) values significantly (p = 0.034) increased from 0.258 (GSEM, 0.156) mg/ml with placebo to 0.456 (GSEM, 0.186) mg/ml with losartan. We conclude that AT1 receptors are involved in bronchial hyperresponsiveness in asthmatic patients. This is the first report demonstrating the involvement of AT1 receptors in bronchial asthma.

Type 1 angiotensin II receptor antagonism reduces antigen-induced airway reactions.

Although the renin-angiotensin system is activated in patients with asthma during severe acute attacks and angiotensin II has been shown to cause bronchoconstriction in patients with asthma, the role of angiotensin II in patients with asthma is unclear. We investigated the effects of two specific antagonists at type 1 and type 2 angiotensin II receptors, candesartan cilexetil (TCV-116) and PD123319, on antigen-induced airway reactions in guinea pigs. Sixty minutes after intraperitoneal administration of candesartan cilexetil (0.1, 1.0, or 10 mg/kg) or PD123319 (30 mg/kg), animals received an antigen challenge. Airway responsiveness to inhaled methacholine was assessed as the dose of methacholine required to produce a 200% increase in the pressure at the airway opening (PC(200)). Differential cell counts in bronchoalveolar lavage fluids (BALF) were measured 24 h after antigen challenge. Candesartan cilexetil did not inhibit antigen-induced bronchoconstriction in sensitized guinea pigs or alter PC(200) in nonsensitized guinea pigs. Antigen inhalation significantly increased bronchoconstrictor responses to methacholine and increased airway accumulation of eosinophils; both responses showed dose-dependent prevention by candesartan but not by PD123319. These results indicate that endogenous angiotensin II promotes antigen-induced airway hyperresponsiveness and eosinophil accumulation by acting at type 1 receptors.

RhoA and rho kinase regulate the epithelial Na+/H+ exchanger NHE3. Role of myosin light chain phosphorylation.

The activity of the Na(+)/H(+) exchanger NHE3 isoform, which is found primarily in epithelial cells, is sensitive to the state of actin polymerization. Actin assembly, in turn, is controlled by members of the small GTPase Rho family, namely Rac1, Cdc42, and RhoA. We therefore investigated the possible role of these GTPases in modulating NHE3 activity. Cells stably expressing NHE3 were transiently transfected with inhibitory forms of Rac1, Cdc42, or RhoA and transport activity was assessed using microfluorimetry. NHE3 activity was not adversely affected by either dominant-negative Rac1 or Cdc42. By contrast, the inhibitory form of RhoA greatly depressed NHE3 activity, without noticeably altering its subcellular distribution. NHE3 activity was equally reduced by inhibiting p160 Rho-associated kinase I (ROK), a downstream effector of RhoA, with the selective antagonist Y-27632 and a dominant-negative form of ROK. Furthermore, inhibition of ROK reduced the phosphorylation of myosin light chain. A comparable net dephosphorylation was achieved by the myosin light chain kinase inhibitor ML9, which similarly inhibited NHE3. These data suggest that optimal NHE3 activity requires a functional RhoA-ROK signaling pathway which acts, at least partly, by controlling the phosphorylation of myosin light chain and, ultimately, the organization of the actin cytoskeleton.

Effect of aerosolized administration of KF19514, a phosphodiesterase 4 inhibitor, on bronchial hyperresponsiveness and airway inflammation induced by antigen inhalation in guinea-pigs.

BACKGROUND: Although phosphodiesterase (PDE) 3 and 4 inhibitors have received much attention for the treatment of bronchial asthma, systemic adverse effects have also been reported. OBJECTIVE: The purpose of this study was to investigate the effect of inhaled olprinone, a newly developed PDE3 inhibitor, and KF19514, a PDE1 and 4 inhibitor, on antigen-induced airway reactions in guinea-pigs. METHODS: Fifteen minutes after inhalation of olprinone (0.1 or 1.0 mg/mL) and KF19514 (0.1 or 0.01 mg/mL), animals were given an antigen challenge. Bronchial hyper-responsiveness and bronchoalveolar lavage fluid cell analysis were performed 24 h after the antigen challenge. RESULTS: Inhalation of olprinone and KF19514 caused a dose-related inhibition of antigen-induced bronchoconstriction. Antigen inhalation significantly increased bronchoconstrictor responses to methacholine, and airway accumulation of neutrophils and eosinophils, 24 h after the antigen challenge. These responses were dose-dependently prevented by KF19514, but not by olprinone. CONCLUSION: The results indicate that inhaled PDE inhibitors might be useful for treatment of bronchial asthma.

(R)-ACX is a novel sufonylurea compound with potent, quick and short-lasting hypoglycemic activity.

We investigated the mechanism of the hypoglycemic effect of (R)-4-(1-acetoxyethyl)-N-(cyclohexylcarbamoyl)benzene-sulfonamide [(R)-acetoxyhexamide; (R)-ACX], a new sulfonylurea compound. (R)-ACX potently stimulated the release of insulin from cultured pancreatic beta-cells (HIT T15 cells), established from hamster islet cells SV40-transformed. When (R)-ACX was orally administered to fasted rats, it decreased the plasma glucose level in a dose-dependent manner. The hypoglycemic effect of (R)-ACX was quick and short lasting, as compared to that of acetohexamide and glibenclamide. The quick and short-lasting hypoglycemic effect of (R)-ACX was thought likely to result from rapid absorption of (R)-ACX and rapid elimination of (R)-ACX and its metabolite, (R)-hydroxyhexamide. Furthermore, (R)-ACX was found to suppress the increase of blood glucose level due to starch loading in fasted mice. (R)-ACX may be useful in the control of postprandial hyperglycemia to patients with non-insulin-dependent diabetic mellitus.

The microstructural analysis of SiC nanorods by high-resolution electron microscopy.

Beta-SiC nanorods have been synthesized by the reaction of SiO and carbon nano-capsules. For the synthesis of SiC nanorods, it was examined that the reaction temperature and the ratio of SiO to carbon nanocapsules are important and the most appropriate temperature and ratio are around 1380 degreesC and 5:2, respectively. The synthesized SiC nanorods were characterized by high-resolution electron microscopy. Most of the SiC nanorods are straight and have the diameter of 30-150 nm while the SiC tips of the SiC nanorods have the size 100-400 nm. The SiC nanorods have many stacking faults normal to the [111] direction. Each SiC nanorod has one kind of preferential axis direction, which is either parallel or normal to the [111] direction. Based on the microstructural analysis of the SiC nanorods, a possible growth mechanism of the SiC nanorods is proposed.