Hirofumi Nakazaki

Alteration of the Circadian Rhythm in Peak Expiratory Flow of Nocturnal Asthma Following Nighttime Transdermal β2‐adrenoceptor Agonist Tulobuterol Chronotherapy

We investigated the efficacy of nighttime transdermal tulobuterol (β2‐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 4 h 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 04:00 h, 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.

Treatment with β2‐Adrenoceptor Agonist in Vivo Induces Human Clock Gene, Per1, mRNA Expression in Peripheral Blood

This study examined whether in vivo exposure to a β2‐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.

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.

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.

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.

Favorable effect of the combination of vinorelbine and dihydropyrimidine dehydrogenase-inhibitory fluoropyrimidine in EGFR-mutated lung adenocarcinoma: Retrospective and in vitro studies

Although cytotoxic chemotherapy is essential in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), it is unclear which regimen is most effective. We retrospectively compared the efficacy of standard platinum-based chemotherapy with that of combination chemotherapy using vinorelbine (VNR) plus dihydropyrimidine dehydrogenase-inhibitory fluoropyrimidine (DIF) in EGFR-mutated lung adenocarcinomas, and we investigated a potential mechanism by which the combination chemotherapy of VNR + DIF was favorable in the treatment of EGFR-mutated 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 platinum-based chemotherapy, and the progression-free survival of the 24 VNR + DIF-treated patients was significantly longer than that of the 15 platinum-based chemotherapy patients. In EGFR-mutated PC9 cells, VNR induced EGFR dephosphorylation at a clinically achievable concentration. 1BR3-LR 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% FBS-containing medium. Similarly, the sensitivity of 1BR3-LR cells to VNR was increased when they were cultured in low-serum 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 5-fluorouracil (5-FU) 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 + 5-FU in EGFR-mutated lung cancer cells. In conclusion, the combination chemotherapy of VNR + DIF may be a promising treatment for NSCLC patients with EGFR mutations.