False-Positive Myeloperoxidase-Antineutrophil Cytoplasmic Antibody in a Patient with Rheumatoid Arthritis.

BACKGROUND Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a form of vasculitis predominantly affecting small blood vessels and systemic organs, including the lungs and kidneys. The serum ANCA is an important diagnostic marker for AAV. However, ANCA levels can be nonspecifically elevated in autoimmune diseases like rheumatoid arthritis (RA) and some infectious diseases. Furthermore, RA and AAV can occur together. Therefore, when ANCA is detected in patients with RA, interpretation of the results is often difficult. CASE REPORT A 71-year-old woman with a 15-year history of RA was admitted to our hospital with a fever and anorexia. She was treated with prednisolone 5 mg/day and iguratimod 50 mg/day for the RA. She presented with bilateral frosted glass shadows in the lungs, acute kidney injury, positive myeloperoxidase (MPO)-ANCA results, and elevated ß-D-glucan levels, suggesting AAV or pneumocystis pneumonia. A renal biopsy and bronchoalveolar lavage ruled out AAV. A polymerase chain reaction of the bronchoalveolar lavage fluid was positive for Pneumocystis jirovecii DNA, leading to a diagnosis of pneumocystis pneumonia. After admission, the patient continued to receive intravenous supplemental fluids, and renal function improved. Based on her pathological test results and clinical course, acute kidney injury was diagnosed as prerenal failure due to dehydration in the background of chronic kidney disease. CONCLUSIONS Even if MPO-ANCA is positive in patients with RA, it is important to consider the possibility of a false-positive result and perform a thorough and aggressive examination.

Disseminated Mycobacterium scrofulaceum Infection in an Immunocompetent Host.

A 56-year-old woman, without any immunocompromising diseases, was referred to our hospital because of a recurrence of pyogenic spondylitis. Computed tomography revealed multiple osteolytic changes in the whole body. Vertebral magnetic resonance imaging revealed osteomyelitis and spondylitis. Mycobacterium scrofulaceum was detected in sputum cultures, in abscesses from the right knee, and in a subcutaneous forehead abscess. Therefore, the patient was diagnosed with disseminated Mycobacterium scrofulaceum infection. The patient was treated with rifampicin, ethambutol, and clarithromycin, which resulted in symptomatic relief and radiological improvement. We herein report a rare case of disseminated Mycobacterium scrofulaceum infection in an immunocompetent host.

Pulmonary Metastatic Choriocarcinoma from a Burned-out Testicular Tumor.

A 54-year-old man was referred to our hospital because of progressive dyspnea. Chest computed tomography showed multiple nodular shadows with a peripheral ground-glass halo. His clinical condition continued to deteriorate with the development of progressive respiratory failure requiring mechanical ventilation. A histological examination of a transbronchial lung biopsy revealed choriocarcinoma. The patient died within nine days of admission. A histological examination of the right testis during an autopsy revealed a burned-out testicular tumor consisting of a teratoma and a fibrous scar. We herein report a rare case of pulmonary multiple metastatic choriocarcinoma originating from a burned-out testicular tumor.

Association between pulmonary function and daily levels of sand dust particles assessed by light detection and ranging in schoolchildren in western Japan: A panel study.

BACKGROUND: An important aspect of sand dust emissions in association with respiratory disorders is the quantity of particulate matter. This is usually expressed as particulate matter less than 10 µm (PM10) and 2.5 µm (PM2.5). However, the composition of PM10 and PM2.5 varies. Light detection and ranging is used to monitor sand dust particles originating in East Asian deserts and distinguish them from air pollution aerosols. The objective of this study was to investigate the association between the daily levels of sand dust particles and pulmonary function in schoolchildren in western Japan. METHODS: In this panel study, the peak expiratory flow (PEF) of 399 schoolchildren was measured daily from April to May 2012. A linear mixed model was used to estimate the association of PEF with the daily levels of sand dust particles, suspended particulate matter (SPM), and PM2.5. RESULTS: There was no association between the daily level of sand dust particles and air pollution aerosols, while both sand dust particles and air pollution aerosols had a significant association with SPM and PM2.5. An increment of 0.018 km(-1) in sand dust particles was significantly associated with a decrease in PEF (-3.62 L/min; 95% confidence interval, -4.66 to -2.59). An increase of 14.0 µg/m(3) in SPM and 10.7 µg/m(3) in PM2.5 led to a significant decrease of -2.16 L/min (-2.88 to -1.43) and -2.58 L/min (-3.59 to -1.57), respectively, in PEF. CONCLUSIONS: These results suggest that exposure to sand dust emission may relate to pulmonary dysfunction in children in East Asia.

Favorable effect of the combination of vinorelbine and dihydropyrimidine dehydrogenase­inhibitory fluoropyrimidine in EGFR­mutated lung adenocarcinoma: retrospective and in vitro studies.

Although cytotoxic chemotherapy is essential in epidermal growth factor receptor (EGFR)­mutated non­small cell lung cancer (NSCLC), it is unclear which regimen is most effective. We retrospectively compared the efficacy of standard platinum­based chemotherapy with that of combination chemotherapy using vinorelbine (VNR) plus dihydropyrimidine dehydrogenase­inhibitory fluoropyrimidine (DIF) in EGFR­mutated lung adenocarcinomas, and we investigated a potential mechanism by which the combination chemotherapy of VNR + DIF was favorable in the treatment of EGFR­mutated lung adenocarcinoma in vitro. In our retrospective analysis, the response rate and disease control rate afforded by the VNR + DIF treatment tended to be better than those by platinum­based chemotherapy, and the progression­free survival of the 24 VNR + DIF­treated patients was significantly longer than that of the 15 platinum­based chemotherapy patients. In EGFR­mutated PC9 cells, VNR induced EGFR dephosphorylation at a clinically achievable concentration. 1BR3­LR cells, a line of fibroblast cells transfected with a mutant EGFR construct, were completely resistant to gefitinib in the medium containing 10% fetal bovine serum (FBS), whereas the sensitivity of these cells to gefitinib was increased in 0.5% FBS­containing medium. Similarly, the sensitivity of 1BR3­LR cells to VNR was increased when they were cultured in low­serum condition. In addition, sodium orthovanadate (Na3VO4) inhibited the EGFR dephosphorylation induced by VNR or gefitinib and suppressed the cell growth inhibition by these agents in PC9 cells. VNR and gefitinib showed synergistic cell growth inhibition in combination with 5­fluorouracil (5­FU) in PC9 cells. We propose that the EGFR dephosphorylation induced by VNR is related to cell growth inhibitory activity of VNR, and that this is one of the mechanisms of the synergistic effect of VNR + 5­FU in EGFR­mutated lung cancer cells. In conclusion, the combination chemotherapy of VNR + DIF may be a promising treatment for NSCLC patients with EGFR mutations.

Infective endocarditis caused by Achromobacter xylosoxidans: a case report and review of the literature.

An 86-year-old woman who underwent placement of a prosthetic aortic valve for regurgitation 5 years previously was admitted because of spiking fever. The blood culture results were positive for gram-negative rods, which were identified as Achromobacter xylosoxidans. Approximately 4 months after being sent to the hospital, transthoracic echocardiography revealed vegetation at the prosthetic aortic valve. Ultimately, a diagnosis of A. xylosoxidans endocarditis of the prosthetic aortic valve was made. We report an extremely rare case of bacteremia associated by prosthetic valve endocarditis with A. xylosoxidans. In addition, we review 10 previously reported cases of endocarditis caused by A. xylosoxidans.

Acute cardiac tamponade caused by the extension of multiple hepatic actinomycotic abscesses.

A 60-year-old man was diagnosed as multiple hepatic abscesses. Failure in the first empiric therapy led to extension into the pericardium, causing acute cardiac tamponade. Actinomyces species were not cultured from the pericardial effusion. The definitive diagnosis was acquired by ultrasound guided needle biopsy.

Imatinib mesylate (STI571) enhances amrubicin-induced cytotoxic activity through inhibition of the phosphatidylinositol 3-kinase/Akt pathway in small cell lung cancer cells.

Small cell lung cancer (SCLC) is characterized by autocrine mechanisms. Stem cell factor (SCF) and its receptor c-kit can activate Akt and extracellular signal-regulated kinase (Erk) pathways. Imatinib mesylate (STI571) can inhibit c-kit tyrosine kinase activity, but clinical trials have resulted in failure. We investigated the possibility of SCF/c-kit-targeted therapy against SCLC. Using c-kit-positive SCLC cells (H209 and H69 cells) and SCF as a model of the autocrine mechanisms, the effects of SCF, LY294002, PD98059 or STI571 on Akt and Erk were assessed by Western blot analysis. The cell growth inhibitions of cisplatin, etoposide irinotecan and amrubicin (AMR) with or without SCF, LY294002, PD98059 or STI571 were evaluated by MTT assay. Treatment with SCF activated Akt and Erk and the activations were inhibited by STI571 in H209 but not in H69 cells. LY294002 and PD98059 inhibited SCF-induced Akt and Erk activation in H209 cells, respectively. STI571 alone did not exert growth inhibition in the SCF-treated cells. In H209 cells, SCF decreased the cytotoxicity of AMR, but not of other drugs. In H69 cells, SCF did not affect sensitivity to any drugs. LY294002 but not PD98059 restored or enhanced AMR-sensitivity in SCF-treated H209 or untreated H69 cells, respectively. STI571 restored the AMR-sensitivity of SCF-treated H209 cells to the basal level. If the SCF/c-kit contributes to Akt activation in vivo, the combination of STI571 and AMR may be effective against SCLC. Additionally, using a combination of AKT inhibitors and AMR may be a promising treatment in the future.

[Acute bird-related hypersensitivity pneumonitis: radiological findings in a case in the early phase after onset].

A 71-year-old woman was admitted to our hospital four times because of high fever and dyspnea from September to November in 2007. We treated her with antibiotics on her first two admissions. HOwever, we suspected hypersensitivity pneumonitis on the third admission because she suffered from fever and dyspnea soon after she had been discharged and returned home. She recovered only with the oxygen therapy on the last two admissions. Computed tomography of the chest showed early phase localized consolidation but changed to ground-glass opacities spreading over the entire lung field later during her third and fourth admissions. Bronchial alveolar lavage showed increases in total cell count, lymphocytes and IgA of pigeon-dropping extracts' and budgerigar-dropping extracts. TBLB showed epithelioid cell granulomas without caseous necrosis and alveolar septal inflammation. Inhalation challenge test using freeze-dried pigeon-dropping extracts was positive, therefore we finally established a diagnosis of acute bird related hypersensitivity pneumonitis. This is apparently the first report of acute bird-related hypersensitivity pneumonitis showing localized consolidation initially and later changing to diffuse ground-glass opacities. These radiological observations are significant in considering the onset and the progression of this disease.

Synergistic cell growth inhibition by the combination of amrubicin and Akt-suppressing tyrosine kinase inhibitors in small cell lung cancer cells: implication of c-Src and its inhibitor.

Small cell lung cancer (SCLC) is one of the intractable malignancies. The goal of this study was to clarify whether Akt activity is involved with chemo-resistance and to improve the sensitivity of SCLC cells to the current standard chemotherapeutic drugs with agents that are expected to suppress Akt activity through tyrosine kinase inhibition. Although Akt activity seemed to be involved with the sensitivity of SCLC cells to chemotherapeutic agents (cisplatin, etoposide, SN38 and amrubicin), in Akt-activated N417 cells, only amrubicin exerted synergistic cell growth inhibition when combined with an Akt inhibitor, LY294002. A non-specific tyrosine kinase inhibitor, genistein, suppressed Akt and showed synergistic interaction in combination with amrubicin in N417 cells. Among tyrosine kinases (insulin-like growth factor I receptor, c-Kit and c-Src), only c-Src was activated in N417 cells compared with Akt-inactive H209 cells. A c-Src-specific inhibitor, PP2, and a clinically available multi-tyrosine kinase inhibitor, dasatinib, suppressed Akt activity in parallel with c-Src inhibition. Both PP2 and dasatinib exerted synergistic growth inhibition of N417 cells in the combination with amrubicin. In immunohistochemical analysis, c-Src was expressed in 17 of 19 of the SCLC tumor tissues. These observations suggested that Akt suppression enhances the cytotoxicity of amrubicin, and for the purpose of Akt suppression, c-Src is a promising target in SCLC.

Treatment with beta2-adrenoceptor agonist in vivo induces human clock gene, Per1, mRNA expression in peripheral blood.

This study examined whether in vivo exposure to a beta2-adrenoceptor agonist, tulobuterol, induces human Period1 (hPer1) mRNA expression in cells from peripheral whole blood. In one experiment, oral tulobuterol was administered to five healthy volunteers at 22:00 h, while in another, a transdermally tulobuterol patch was applied to the same five subjects at 20:00 h. In each experiment, serum tulobuterol concentrations were measured at four time points, and total RNA was isolated from peripheral blood cells for determinations of hPer1 mRNA expression by real-time polymerase chain reaction. Both the tulobuterol tablet and the transdermal patch increased hPer1 mRNA expression, suggesting that analyses of human peripheral blood cells could reliably represent peripheral clock gene mRNA expression in vivo.

Circadian rhythms in the CNS and peripheral clock disorders: function of clock genes: influence of medication for bronchial asthma on circadian gene.

Bronchial asthma is a chronic inflammatory disorder of the airways, in which inflammation causes bronchial hyper-responsiveness and flow limitation in the presence of various stimuli. Pulmonary function in asthmatic patients frequently deteriorates between midnight and early morning, which has suggested a role for chronotherapy. Although relationships between bronchial asthma and the function of clock genes remain unclear, some medications given for asthma such as glucocorticoids or beta(2)-adrenoceptor agonists may influence clock genes in vivo. In our studies of clock gene mRNA expressions in human bronchial epithelial cells in vitro and peripheral blood cells in vivo, we demonstrated that glucocorticoid or beta(2)-adrenoceptor agonist treatment strongly induced human Per1 mRNA expression both in vitro and in vivo. Human peripheral blood cells provide a useful indication of peripheral clock gene mRNA expression in vivo.

Alteration of the circadian rhythm in peak expiratory flow of nocturnal asthma following nighttime transdermal beta2-adrenoceptor agonist tulobuterol chronotherapy.

We investigated the efficacy of nighttime transdermal tulobuterol (beta2-adrenoceptor agonist) chronotherapy for nocturnal asthma by assessing changes both in the frequency of symptoms and features of the circadian rhythm in peak expiratory flow (PEF), a measure of airway caliber. Thirteen patients with nocturnal asthma were evaluated before and during tulobuterol patch chronotherapy, applied once daily in the evening for 6 consecutive days. Patients were asked to record their PEF every 4h between 03:00 and 23:00 h for one day. Circadian rhythms in PEF were examined by group-mean cosinor analysis. The group average PEF at 03:00 h, the time during the 24 h when PEF is generally the poorest, before the application of the chronotherapy, when asthma was unstable and nocturnal symptoms frequent, was 276 +/- 45 L/min. Application of the tulobuterol patch at nighttime significantly increased (p < 0.001) the 03:00 h group average PEF to 363 +/- 67 L/min. Significant circadian rhythms in PEF were observed during the span of study when nocturnal symptoms were frequent as well as with the use of the tulobuterol patch. Before the initiation of tulobuterol chronotherapy, the bathyphase (trough time of the circadian rhythm) in PEF narrowed to around 04:00h, and the group circadian amplitude was 28.8 L/min. In contrast, the group circadian amplitude significantly (p < 0.01) decreased to 10.4 L/min, and the 24 h mean PEF increased significantly with tulobuterol patch chronotherapy. These changes indicate that tulobuterol chronotherapy significantly increased both the level and stability of airway function over the 24 h. The circadian rhythm in PEF varied with the severity and frequency of asthmatic symptoms with and without the nighttime application of the tulobuterol patch medication. We conclude that the parameters of the circadian rhythm of PEF proved useful both in determining the need for and effectiveness of tulobuterol chronotherapy for nocturnal asthma.