Interleukin-18 is associated with the presence of interstitial lung disease in rheumatoid arthritis: a cross-sectional study.

OBJECTIVE: Serum interleukin-18 (IL-18) levels are increased in patients with interstitial lung disease (ILD). In addition, IL-18 levels are increased in patients with rheumatoid arthritis (RA) and are associated with arthritis activity. We determined whether increased IL-18 levels are associated with ILD in RA. METHOD: RA patients were enrolled using an RA cohort database. Plasma IL-18 levels were measured by enzyme-linked immunosorbent assay. ILD was determined by a pulmonologist and a radiologist based on chest radiography and computed tomography findings. IL-18 levels for RA with ILD and RA without ILD were compared. Associations between ILD and various markers including IL-18 and confounding factors (e.g. smoking history) were investigated by logistic regression analysis. Diagnostic values of IL-18 for the presence of ILD were investigated using receiver operating characteristics curve analysis. RESULTS: ILD was complicated in 8.2% (n = 26) of the study population (N = 312). Plasma IL-18 levels were higher for RA patients with ILD than for RA patients without ILD (721.0 ± 481.4 vs 436.8 ± 438.9 pg/mL, p < 0.001). IL-18, Krebs von den Lungen-6, and anti-cyclic citrullinated peptide antibody titre and glucocorticoid doses were independently associated with the presence of ILD during multivariate logistic regression analysis. Sensitivity and specificity of IL-18 levels for the detection of ILD in RA patients were 65.3% and 76.3%, respectively (area under the curve = 0.73). CONCLUSION: Plasma IL-18 levels were higher for RA patients with ILD than for those without ILD. Increased IL-18 levels were associated with the presence of ILD.

GLCCI1 variant accelerates pulmonary function decline in patients with asthma receiving inhaled corticosteroids.

BACKGROUND: In steroid-naive patients with asthma, several gene variants are associated with a short-term response to inhaled corticosteroid (ICS) treatment; this has mostly been observed in Caucasians. However, not many studies have been conducted for other ethnicities. Here, we aimed to determine the relationship between the annual decline in forced expiratory flow volume in one second (FEV1 ) and the variant of the glucocorticoid-induced transcript 1 gene (GLCCI1) in Japanese patients with asthma receiving long-term ICS treatment, taking into account the effect of high serum periostin levels, a known association factor of pulmonary function decline and a marker of refractory eosinophilic/Th2 inflammation. METHODS: In this study, 224 patients with asthma receiving ICS treatment for at least 4 years were enrolled. The effects of single-nucleotide polymorphisms (SNPs) in GLCCI1, stress-induced phosphoprotein 1 (STIP1), and T gene on the decline in FEV1 of 30 ml/year or greater were determined. RESULTS: Besides the known contributing factors, that is, the most intensive treatment step, ex-smoking, and high serum periostin levels (≥95 ng/ml), the GG genotype of GLCCI1 rs37973, and not other SNPs, was independently associated with a decline in FEV1 of 30 ml/year or greater. When patients were stratified according to their serum periostin levels, the GG genotype of rs37973 was significantly associated with blood eosinophilia (≥250/µl) in the high serum periostin group. CONCLUSIONS: A GLCCI1 variant is a risk factor of pulmonary function decline in Japanese patients with asthma receiving long-term ICS treatment. Thus, GLCCI1 may be associated with response to ICS across ethnicities.

Smoking attenuates the age-related decrease in IgE levels and maintains eosinophilic inflammation.

BACKGROUND: Epidemiological studies have shown that smoking increases the propensity for atopy and asthma. However, the effects of smoking on atopy and eosinophilic inflammation in asthmatics, including the elderly, remain unknown. OBJECTIVE: To determine the effects of smoking on serum immunoglobulin E (IgE) levels and eosinophilic inflammation in asthmatics of all ages. METHODS: The associations of serum IgE levels, blood eosinophil counts and fractional exhaled nitric oxide (FeNO) levels with smoking and age in steroid-naive asthmatics were cross-sectionally assessed (n = 307). Levels of sputum eosinophil and thymic stromal lymphopoietin (TSLP) that promotes Th2 inflammation were also analysed. Current smokers were excluded when analysing contributing factors of FeNO. RESULTS: Levels of serum IgE, blood eosinophil and FeNO decreased with increasing age in never-smokers, whereas decrease in serum IgE levels with increasing age was not observed in current smokers. In addition, current smoking was associated with higher blood eosinophil counts. In atopic asthmatics, age-related declines in serum IgE levels were less steep in ex-smokers than in never-smokers, and atopic ex-smokers with asthma showed higher blood eosinophil counts and higher FeNO irrespective of age. Lastly, sputum TSLP levels were associated with sputum eosinophil proportions and pack-years. Current and ex-smokers had higher TSLP levels than never-smokers. CONCLUSIONS AND CLINICAL RELEVANCE: In steroid-naive asthmatics, smoking may attenuate the age-related decrease in IgE levels and maintain eosinophilic inflammation, in which TSLP may be involved.

Anti-citrullinated glucose-6-phosphate isomerase peptide antibodies in patients with rheumatoid arthritis are associated with HLA-DRB1 shared epitope alleles and disease activity.

To identify and characterize anti-citrullinated glucose-6-phosphate isomerase (GPI) peptide antibodies in patients with rheumatoid arthritis (RA). Nine GPI arginine-bearing peptides in human GPI protein were selected and cyclic citrullinated GPI peptides (CCG-1-9) were constructed. Samples were obtained from RA (n = 208), systemic lupus erythematosus (SLE) (n = 101), Sjögren's syndrome (SS; n = 101) and healthy controls (n = 174). Antibodies against CCG-1-9 were measured, and anti-citrullinated α-enolase-1 (CEP-1), -cyclic citrullinated peptides (CCP) and -GPI proteins antibodies were also examined. Patients with RA were genotyped for HLA-DRB1. The numbers of shared epitope (SE) alleles were counted and compared with those of the autoantibodies. Rabbit GPI was citrullinated with rabbit peptidylarginine deiminase and immunoblot analysis of RA sera performed. The levels of autoantibodies were compared before and after treatment with TNF antagonists in 58 RA patients. Anti-CCG-2, -4 and -7 antibodies were detected in 25·5, 33·2 and 37·0% patients with RA, respectively, and these antibodies were very specific for RA (specificity, 98·1-99·7%). Altogether, 44·2, 86·1 and 13·9% of RA sera were positive for anti-CEP-1, -CCP and -GPI protein antibodies, respectively. Anti-CCG-2, -4 and -7 antibodies were correlated with anti-CCP and anti-CEP-1 antibodies and with the presence of HLA-DRB1 SE alleles. Citrullinated GPI protein was detected using RA sera. Treatment with tumour necrosis factor antagonists reduced significantly the levels of anti-CCG-2 and -7 but not of anti-CEP-1 antibodies. This is the first report documenting the presence of anti-CCG antibodies in RA. Anti-CCG-2 and -7 antibodies could be considered as markers for the diagnosis of RA and its disease activity.

A CD40 single-nucleotide polymorphism affects the lymphocyte profiles in the bronchoalveolar lavage of Japanese patients with sarcoidosis.

CD40 plays a critical role in adaptive immunity, and alveolar macrophages in patients with sarcoidosis express higher levels of CD40. This study investigated the association of rs1883832, a functional single-nucleotide polymorphism in the CD40 gene with susceptibility to sarcoidosis and phenotypes of sarcoidosis. Genotyping of rs1883832 in 175 Japanese patients with sarcoidosis and 150 age- and sex-matched controls revealed no significant difference between the genotypes of the patient and control groups (CC/CT/TT, 32.8/52.0/14.7% in the patients; 37.3/48.0/14.7% in the controls, P = 0.66; allele C, 59.1% in the patients, 61.3% in the controls, P = 0.57). T-cell and CD4+ cell counts in the bronchoalveolar lavage fluid were significantly higher in the TT genotype group than in the CC and CT genotype group.

KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERalpha.

Kruppel-like factor 4 (KLF4) is a transcription factor that participates in both tumor suppression and oncogenesis. To determine the association of KLF4 with tumorigenesis, we integrated data assembled in the Oncomine database and discovered a decrease in KLF4 gene transcripts in breast cancers. Further analysis of the database also showed a correlation between KLF4 expression and estrogen receptor-alpha (ERalpha) positivity. Knockdown of KLF4 in MCF-7 cells elevated the growth rate of these cells in the presence of estrogen. Therefore, we examined the interaction between KLF4 and ERalpha, and found that KLF4 bound to the DNA-binding region of ERalpha. KLF4 thus inhibits the binding of ERalpha to estrogen response elements in promoter regions, resulting in a reduction in ERalpha target gene transcription. Earlier studies have reported that KLF4 is transcriptionally activated by p53 following DNA damage. We also showed that activation of p53 decreased the transcriptional activity of ERalpha by elevating KLF4 expression. Our studies discovered a novel molecular network between p53, KLF4 and ERalpha. As both p53 and ERalpha are involved in cell growth and apoptosis, these results may explain why KLF4 possesses both tumor suppressive and oncogenic functions in breast cancers.

Lymphatic vessel invasion detected by monoclonal antibody D2-40 as a predictor of lymph node metastasis in T1 colorectal cancer.

OBJECTIVE: When selecting patients who are at high risk for lymph node metastasis, the detection of lymphatic vessel invasion (LVI) is important. We investigated LVI detected by D2-40 staining as a predictor of lymph node metastasis in T1 colorectal cancer. MATERIALS AND METHODS: Clinicopathological factors including LVI were investigated in 136 patients who underwent colectomy with lymph node dissection for T1 colorectal cancer. We used immunostaining with monoclonal antibody D2-40 to detect LVI. RESULTS: Lymph node metastases were found in 18 patients (13.2%), and LVI were detected in 45 (33%); lymph node metastasis was more frequently observed in LVI-positive groups (13/45 vs 5/91, p < 0.001). Both univariate and multivariate analyses revealed that LVI detected by D2-40 and a poorly differentiated histology at the invasion front were independent risk factors of lymph node metastasis. CONCLUSION: LVI detected by D2-40 is important for the prediction of lymph node metastasis.

Bacterial leakage along the implant-abutment interface of premachined or cast components.

In recent clinical studies, contamination of the inner parts of dental implants through bacterial penetration along the implant components has been observed. The aim of the present in-vitro study was to investigate leakage of Fusobacterium nucleatum through the interface between implants and premachined or cast abutments. Both premachined (n=10) and cast (n=10) implant-abutment assemblies were inoculated with 3.0 microL of microbial inoculum. The assemblies were completely immersed in 5.0 mL of tryptic soy broth culture medium to observe leakage at the implant-abutment interface after 14 days of anaerobic incubation. Bacterial growth in the medium, indicative of microbial leakage, was found only in 1 out of 9 samples (11.1%) in each group. Both premachined and cast abutments connected to external hexagonal implants provide low percentages of bacterial leakage through the interface in in vitro unloaded conditions if the manufacturer's instructions and casting procedures are properly followed.

Er:YAG laser: antimicrobial effects in the root canals of dogs' teeth with pulp necrosis and chronic periapical lesions.

OBJECTIVE: Our goal in this study was to evaluate the antimicrobial effect of Er:YAG laser applied after biomechanical preparation of the root canals of dog's teeth with apical periodontitis. BACKGROUND DATA: Various in vitro studies have reported effective bacterial reduction in infected root canals using Er:YAG laser. However, there is no in vivo research to support these results. METHODS: Forty root canals of dogs' premolar teeth with pulp necrosis and chronic periapical lesions were used. An initial microbiological sample was taken, and after biomechanical preparation was carried out, a second microbiological sample was taken. The teeth were divided into two groups: Group I-biomechanical preparation was taken of root canals without Er:YAG laser application; Group II-biomechanical preparation was taken of root canals with Er:YAG laser application using 140-mJ input, 63-mJ output/15 Hz. After coronal sealing, the root canals were left empty for 7 days at which time a third microbiological sample was taken. The collected material was removed from the root canal with a #40 K file and placed in transport media. It was serially diluted and seeded on culture dishes selective for anaerobes, aerobes, and total streptococci. Colony-forming units per milliliter (CFU/mL) were counted. RESULTS: Groups I and II showed an increase of CFU/mL for all microorganisms 7 days after treatment, being statistically significant for anaerobes in Group I and for anaerobes and total streptococci in Group II. When comparing CFU/mL of Groups I and II, there was a statistically significant increase after 7 d for total streptococci in Group II. CONCLUSION: Er:YAG laser applied after biomechanical preparation did not reduce microorganisms in the root canal system.

Endoscopic mucosal resection of superficially spreading colonic neoplasms larger than 5 cm in the right colon after injection of dilute sodium hyaluronate: report of two cases.

Submucosal injection is the most important procedure for the safe performance of endoscopic mucosal resection in the large intestine while avoiding the risk of perforation. We used dilute sodium hyaluronate containing Bosmin and achieved safe piecemeal resection of large superficial tumors in the right colon in two patients. Piecemeal snare resection is considered to be acceptable if all the tissue pieces can be collected for histopathological diagnosis.

[Strategy for post coronary artery bypass grafting in patients with bypass graft stenosis: comparison of percutaneous transluminal coronary angioplasty for the native coronary artery, internal mammary artery and saphenous vein graft].

OBJECTIVES: The strategy for post coronary artery bypass grafting (CABG) was investigated in patients with graft stenosis. METHODS: The study included 123 post-CABG patients with graft stenosis. The patients were divided into three groups according to target vessels; saphenous vein graft (SVG; n = 72), internal mammary artery (IMA; n = 21) and native coronary artery (n = 30). Furthermore, SVG lesions were divided into proximal anastomosis (n = 23), body (n = 40) and distal anastomosis (n = 9). The procedural success rate and late patency rate were compared between the three groups. Furthermore, the relationships between pre percutaneous transluminal coronary angioplasty (PTCA) percentage diameter stenosis, procedural success rate and late patency rate were evaluated. RESULTS: Procedural success rate was similar in the three groups, but late patency rate was higher in the IMA group. Procedural success rate and late patency rate were significantly lower in proximal anastomoses compared to other sites of SVG stenoses, IMA group and native coronary artery group (p < 0.05). Totally occluded native coronary artery lesions had a high procedural success rate compared with occluded IMA and SVG lesions, but the late patency rate was not higher. Procedural success rate showed no significant difference for 75-99% stenotic lesions, but the late patency rate was significantly higher in the IMA group (p < 0.05). Patients in the stenting group had a greater late patency rate compared with the balloon angioplasty group. There was no significant difference in late patency rate between the IMA group and SVG group. CONCLUSIONS: Late patency rate of the IMA is higher than that of the native coronary artery. SVG with proximal anastomosis and severe stenosis shows a significantly lower late patency rate than the native coronary artery. Therefore, PTCA should be considered for the native coronary artery in the absence of chronic total occlusion.

Efficacy of transthoracic needle aspiration in community-acquired pneumonia.

OBJECTIVE: To evaluate the indications, efficacy, and safety of transthoracic needle aspiration (TNA) in diagnosing community-acquired pneumonia (CAP). METHODS: TNA procedure was performed using an ultrathin needle with ultrasonography and/or computed tomography. The aspirate samples were Gram-stained and sent for cultures. The results were compared with those from conventional microbiological studies. PATIENTS: Sixty patients with CAP who were admitted to the hospital and were studied prospectively between July 1994 and June 1999 were included in the study. RESULTS: TNA culture was positive in 30 cases (50.0%). Streptococcus pneumoniae was the most frequently isolated pathogen, followed by the Streptococcus milleri group, and anaerobes. The results of TNA were consistent with those of quantitative sputum cultures in 9 patients and with those of blood cultures in 4. Complications arose in 3 patients who developed small to moderate pneumothorax. CONCLUSIONS: TNA is a safe procedure with a good diagnostic yield. In particular, anaerobes or microaerophils such as the S. milleri group were highly detectable by TNA. The results obtained by TNA were highly consistent with those obtained by the gold standard methods. Combined with conventional methods, TNA is considered highly useful for determining the etiology of CAP.

[Intestinal permeability in Crohn's disease and effects of elemental dietary therapy].

Enteral intake of non-metabolic monosacharide and disaccharide, followed by measurement of the urinary excretion ratio of the two, is a method used to investigate intestinal permeability. L/R ratio (lactulose/1-rhamnose urinary excretion ratio) is considered an indicator of permeability of the small intestine. An increased L/R ratio is caused by mucosal disorders of the small intestine. The L/R ratio in all patients (n = 92) with Crohn's disease was 0.079 +/- 0.081 (mean +/- S.D.), which was significantly higher than the value in normal controls (0.027 +/- 0.009, n = 20, p < 0.05). In 39 patients with Crohn's disease, we assessed intestinal permeability before after treatment with an elemental diet, and during remission. The L/R ratio was 0.120 +/- 0.092, before treatment and 0.065 +/- 0.097 after treatment (p < 0.05), showing increased intestinal permeability before elemental dietary treatment. During remission, the L/R ratio was 0.035 +/- 0.028; this did not differ significantly from the value obtained after treatment. We conclude that intestinal permeability is useful for investigating disease activity in patients with Crohn's disease.

Cytotoxic effects of cigarette smoke extract on an alveolar type II cell-derived cell line.

Injury of the alveolar epithelium by cigarette smoke is presumed to be an important process in the pathogenesis of smoking-related pulmonary diseases. We investigated the cytotoxic effects of cigarette smoke extract (CSE) on an alveolar type II cell-derived cell line (A549). CSE caused apoptosis at concentrations of 5% or less and necrosis at 10% or more. When CSE was exposed to air before application to A549 cells, the cytotoxic effects were attenuated. CSE caused cell death without direct contact with the cells. Acrolein and hydrogen peroxide, two major volatile factors in cigarette smoke, caused cell death in a similar manner. Aldehyde dehydrogenase, a scavenger of aldehydes, and N-acetylcysteine, a scavenger of oxidants and aldehydes, completely inhibited CSE-induced apoptosis. CSE and acrolein increased intracellular oxidant activity. In conclusion, apoptosis of alveolar epithelial cells may be one of the mechanisms of lung injury induced by cigarette smoking. This cytotoxic effect might be due to an interaction between aldehydes and oxidants present in CSE or formed in CSE-exposed cells.

Hypopituitarism due to pituitary metastasis of lung cancer: case of a 21-year-old man.

A 21-year-old man presented persistent dry cough, general malaise, loss of appetite, decreased sexual desire and double vision. Chest radiograph revealed a mass shadow in the left upper lobe. Histopathological diagnosis of the tumor was squamous cell carcinoma. Brain computed tomography and magnetic resonance imaging revealed a metastasis to the pituitary gland. Hypopituitarism was diagnosed by pituitary function tests. Diabetes insipidus was absent and the function of the posterior lobe of the pituitary gland was preserved. Hypopituitarism due to pituitary metastasis is a rare complication of lung cancer, and has never been reported in a patient as young as 21 years old.

Fine needle aspiration of toxoplasmic lymphadenitis in an intramammary lymph node. A case report.

BACKGROUND: Cytologic findings of toxoplasmic lymphadenitis (TL) have been only sporadically reported. Intramammary lymph node is an extremely rare site for TL. CASE: A 47-year-old, healthy, female presented with a breast tumor, which was aspirated. The cytomorphologic features were interpreted as suggestive of TL. Histopathology of the excisional biopsy specimen and subsequent serologic examination confirmed the diagnosis. CONCLUSION: We obtained several characteristic findings in aspiration of TL. Of these, epithelioid cell clusters and monocytoid cells were the most diagnostic.

[A case of minocycline-induced eosinophilic pneumonia presenting with multiple white eosinophilic plaques in the tracheobronchial mucosa].

A 45-year-old man was admitted with a severe dry cough and fever. He had been given 100 mg/day of minocycline and other drugs for 9 days to treat hematopyuria. Chest X-ray film showed multiple nodular shadows with diffuse reticular shadows. After all the drugs were discontinued, the fever and the shadows improved, but the severe dry cough persisted. The day 4 bronchofiberscopic findings included multiple white plaques in the tracheobronchial mucosa. Punch biopsy specimens obtained from the white plaques revealed severe eosinophil infiltration, and the eosinophil count in the bronchoalveolar lavage fluid had increased (differential count 23%). After three days of 125 mg/day of methylprednisolone sodium succinate injection therapy, the severe cough, the X-ray shadows and the white plaques disappeared. With a positive result in the lymphocyte migration inhibition test, the patient's condition was diagnosed as minocycline-induced eosinophilic pneumonia.

Successful treatment of primary and disseminated human lung cancers by systemic delivery of tumor suppressor genes using an improved liposome vector.

Delivery of therapeutic genes to disseminated tumor sites has been a major challenge in the field of cancer gene therapy due to lack of an efficient vector delivery system. Among the various vectors currently available, liposomes have shown promise for the systemic delivery of genes to distant sites with minimal toxicity. In this report, we describe an improved extruded DOTAP:cholesterol (DOTAP:Chol) cationic liposome that efficiently delivers therapeutic tumor suppressor genes p53 and FHIT, which are frequently altered in lung cancer, to localized human primary lung cancers and to experimental disseminated metastases. Transgene expression was observed in 25% of tumor cells per tumor in primary tumors and 10% in disseminated tumors. When treated with DOTAP:Chol-p53 and -FHIT complex, significant suppression was observed in both primary (P < 0.02) and metastatic lung tumor growth (P < 0.007). Furthermore, repeated multiple treatments revealed a 2.5-fold increase in gene expression and increased therapeutic efficacy compared to single treatment. Finally, animal survival experiments revealed prolonged survival (median survival time: 76 days, P < 0.001 for H1299; and 96 days, P = 0.04 for A549) when treated with liposome-p53 DNA complex. Our findings may be of importance in the development of treatments for primary and disseminated human lung cancers.

[Pulmonary mucormycosis caused by Cunninghamella bertholletiae in a non-immunocompromised woman].

A 74-year-old woman was admitted for further examination because of an abnormal nodular shadow and thickening of the bronchovascular bundle in the left upper lobe on chest radiography and CT. The findings from a transbronchial biopsy specimen were not conclusive. A thoracoscopic lung biopsy specimen revealed a fungal infection, and partial resection of S1 + 2 of the left upper lobe was carried out. In the dilated bronchus, mucus of high viscosity was seen. Lymphocytes and plasma cells had infiltrated into the bronchioles and alveoli. Fungus was cultured from the mucus, and the morphological characteristics showed Cunninghamella bertholletiae. Pulmonary mucormycosis caused by C. bertholletiae in a non-immunocompromised person is very rare. Furthermore, this patient also had a wheeze, eosinophilia, elevation of the serum IgE level, and was positive for specific IgE to Mucor. We therefore consider that this case was an incomplete type of allergic bronchopulmonary fungusis (ABPF).

In vitro evaluation of the antimicrobial activity of a castor oil-based irrigant.

The antimicrobial activity of irrigating solutions--Endoquil (castor oil detergent), 2% chlorhexidine gluconate solution, and 0.5% NaOCl solution-was evaluated against gram-positive cocci (Micrococcus luteus, Staphylococcus aureus, Enterococcus faecalis, Staphylococcus epidermidis, Streptococcus mutans, and Streptococcus sobrinus), gram-negative rods (Escherichia coli and Pseudomonas aeruginosa), and the yeast Candida albicans. Activity was evaluated using the two-layer agar diffusion technique. The base layer was obtained by pouring 10.0 ml of Muller Hinton Medium or 10.0 ml of Brain Heart Infusion agar in a Petri dish. After solidification a 5.0 ml seed layer of Muller Hinton Medium or Brain Heart Infusion agar with inoculum (106/ml) was added. Absorbent paper disks (6.0 mm in diameter) immersed in the solutions were placed at equidistant points. Plates were maintained at room temperature for 2 h for prediffusion of the solutions and incubated at 37 degrees C for 24 h. The candle jar system was used for the Brain Heart Infusion agar plates. All tests were performed in duplicate. After incubation the medium was optimized with 0.05 g% triphenyltetrazolium chlorate gel and inhibition halos were measured. All bacterial strains were inhibited by 2.0% chlorhexidine gluconate. Endoquil was effective against gram-positive microorganisms, and 0.5% NaOCl was effective only against S. aureus.