Health Status Progression Measured Using Weekly Telemonitoring of COPD Assessment Test Scores Over 1 Year and Its Association With COPD Exacerbations.

Background: A previous longitudinal study of chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) score changes suggested patients fall into 3 patterns: stable, improving, and worsening. This study assessed the evolution of CAT scores over time and its relationship to exacerbations. Methods: In total, 84 participants used a telemedicine platform to complete CAT weekly for 52 weeks. Completion rates, annualized change in CAT scores, and learning effects were measured, as well as CAT changes of >4 units during look-back periods of 4 and 8 weeks. In a subgroup of participants with at least a 25% completion rate (adherent group, n=68 [81%]), the relationship between change in CAT score and exacerbations at any time during the study was examined post hoc. Results: Linear regression showed that 50%, 22%, and 28% of the adherent subgroup had CAT scores indicating worsening, stable, and improving health status, respectively. In the adherent subgroup, 70% (n=7/10) of participants who had an exacerbation during the study had worsening CAT scores, versus 47% (n=27/58) without an exacerbation. The hazard ratio association between CAT score increase and moderate exacerbation was 1.13 (95% confidence interval: 1.03-1.24). Most participants experienced at least one CAT score change of >4 units, and 7% showed an initial learning effect with a median of 2 weeks. Conclusion: Measuring trends in CAT scores may allow future studies to group patients into 3 defined categories of change over time and quantify CAT change trajectories to assess treatment response and potentially predict medium-term outcomes within individual patients.

A Telemedicine Approach for Monitoring COPD: A Prospective Feasibility and Acceptability Cohort Study.

Background: Telemedicine may help the detection of symptom worsening in patients with chronic obstructive pulmonary disease (COPD), potentially resulting in improved outcomes. This study aimed to determine the feasibility and acceptability of telemedicine among patients with COPD and physicians and facility staff in Japan. Methods: This was a 52-week multicenter, prospective, single-arm, feasibility and acceptability cohort study of Japanese patients ≥40 years of age with COPD or asthma-COPD overlap. Participants underwent training to use YaDoc, a telemedicine smartphone App, which included seven daily symptom questions and weekly COPD Assessment Test (CAT) questions. The primary endpoint was participant compliance for required question completion. The secondary endpoint was participant and physician/facility staff acceptability of YaDoc based on questionnaires completed at Week 52. The impact of the Japanese COVID-19 pandemic state of emergency on results was also assessed. Results: Of the 84 participants enrolled (mean age: 68.7 years, 88% male), 72 participants completed the study. Completion was high in the first six months but fell after that. Median (interquartile range [IQR]) compliance for daily questionnaire entry was 66.6% (31.0-91.8) and 81.0% (45.3-94.3) for weekly CAT entry. Positive participant responses to the exit questionnaire were highest regarding YaDoc ease of use (83.8%), positive impact on managing health (58.8%), and overall satisfaction (53.8%). Of the 26 physicians and facility staff enrolled, 24 completed the study. Of these, the majority (66.7%) responded positively regarding app facilitation of communication between physicians and participants to manage disease. Compliance was similar before and after the first COVID-19 state of emergency in Japan. Conclusion: Daily telemedicine monitoring is potentially feasible and acceptable to both patients and physicians in the management of COPD. These results may inform potential use of telemedicine in clinical practice and design of future studies. Clinical Trial Registration: JapicCTI-194916.

Phylogenetic view of the compensatory mechanisms in motor and sensory systems after neuronal injury.

Through phylogeny, novel neural circuits are added on top of ancient circuits. Upon injury of a novel circuit which enabled fine control, the ancient circuits can sometimes take over its function for recovery; however, the recovered function is limited according to the capacity of the ancient circuits. In this review, we discuss two examples of functional recovery after neural injury in nonhuman primate models. The first is the recovery of dexterous hand movements following damage to the corticospinal tract. The second is the recovery of visual function after injury to the primary visual cortex (V1). In the former case, the functions of the direct cortico-motoneuronal pathway, which specifically developed in higher primates for the control of fractionated digit movements, can be partly compensated for by other descending motor pathways mediated by rubrospinal, reticulospinal, and propriospinal neurons. However, the extent of recovery depends on the location of the damage and which motor systems take over its function. In the latter case, after damage to V1, which is highly developed in primates, either the direct pathway from the lateral geniculate nucleus to extrastriate visual cortices or that from the midbrain superior colliculus-pulvinar-extrastriate/parietal cortices partly takes over the function of V1. However, the state of visual awareness is no longer the same as in the intact state, which might reflect the limited capacity of the compensatory pathways in visual recognition. Such information is valuable for determining the targets of neuromodulatory therapies and setting treatment goals after brain and spinal cord injuries.

Imidafenacin, An Orally Active Muscarinic Receptor Antagonist, Improves Pulmonary Function In Patients With Chronic Obstructive Pulmonary Disease: A Multicenter, Randomized, Double-Blind, Placebo-Controlled 3×3 Crossover Phase II Trial.

Background: Although long-acting muscarinic receptor antagonists are central to the management of chronic obstructive pulmonary disease (COPD), inhaled medicines may have technical difficulty in some patients and adherence barriers. Methods: A multicenter, randomized, double-blind, placebo-controlled 3×3 crossover Phase II trial was performed to evaluate the efficacy and safety of oral administration of the antimuscarinic agent imidafenacin in patients with COPD. Twenty-seven male COPD patients with % forced expiratory volume in 1 s (FEV1) ≥30% and <80% predicted were randomized to single oral dose of imidafenacin 0.1 mg, imidafenacin 0.2 mg, or placebo. Results: Maximum change in FEV1 with both doses of imidafenacin significantly improved from baseline to 24 hrs after administration when compared with a placebo. Area under the curve in FEV1 during 24 hrs after administration with 0.2 mg, but not 0.1 mg dose, was significantly improved when compared with a placebo, and the improvement was significantly based on dose-dependent manners. Plasma imidafenacin level was positively correlated with change in FEV1. All subjects with both doses of imidafenacin completed without moderate nor severe adverse events. Conclusion: A single oral dose of imidafenacin 0.1 mg or imidafenacin 0.2 mg may contribute to the improvement of pulmonary function with excellent safety and tolerability in patients with COPD. Trial registration: JapicCTI-121760 (Japan Pharmaceutical Information Center - Clinical Trials Information [JapicCTI]; http://www.clinicaltrials.jp/user/cteSearch_e.jsp).

Dissecting the circuit for blindsight to reveal the critical role of pulvinar and superior colliculus.

In patients with damage to the primary visual cortex (V1), residual vision can guide goal-directed movements to targets in the blind field without awareness. This phenomenon has been termed blindsight, and its neural mechanisms are controversial. There should be visual pathways to the higher visual cortices bypassing V1, however some literature propose that the signal is mediated by the superior colliculus (SC) and pulvinar, while others claim the dorsal lateral geniculate nucleus (dLGN) transmits the signal. Here, we directly test the role of SC to ventrolateral pulvinar (vlPul) pathway in blindsight monkeys. Pharmacological inactivation of vlPul impairs visually guided saccades (VGS) in the blind field. Selective and reversible blockade of the SC-vlPul pathway by combining two viral vectors also impairs VGS. With these results we claim the SC-vlPul pathway contributes to blindsight. The discrepancy would be due to the extent of retrograde degeneration of dLGN and task used for assessment.

Medium- to long-term survival and functional examination of human iPSC-derived retinas in rat and primate models of retinal degeneration.

BACKGROUND: We have previously reported that xeno-transplanted human ESC-derived retinas are able to mature in the immunodeficient retinal degeneration rodent models, similar to allo-transplantations using mouse iPSC-derived retina. The photoreceptors in the latter developed outer segments and formed synapses with host bipolar cells, driving light responses of host retinal ganglion cells. In view of clinical application, here we further confirmed the competency of human iPSC-derived retina (hiPSC-retina) to mature in the degenerated retinas of rat and monkey models. METHODS: Human iPSC-retinas were transplanted in rhodopsin mutant SD-Foxn1 Tg(S334ter)3LavRrrc nude rats and two monkeys with laser-induced photoreceptor degeneration. Graft maturation was studied by immunohistochemistry and its function was examined by multi-electrode array (MEA) recording in rat retinas and visually-guided saccade (VGS) in a monkey. FINDINGS: A substantial amount of mature photoreceptors in hiPSC-retina graft survived well in the host retinas for at least 5 months (rat) to over 2 years (monkey). In 4 of 7 transplanted rat retinas, RGC light responses were detected at the grafted area. A mild recovery of light perception was also suggested by the VGS performance 1.5 years after transplantation in that monkey. INTERPRETATION: Our results support the competency of hiPSC-derived retinas to be clinically applied for transplantation therapy in retinal degeneration, although the light responses observed in the present models were not conclusively distinguishable from residual functions of degenerating host retinas. The functional analysis may be further elaborated using other models with more advanced retinal degeneration.

High Detection Rates of Urine Mycobacterium tuberculosis in Patients with Suspected Miliary Tuberculosis.

Objective The utility of detecting Mycobacterium tuberculosis in urine samples from patients with pulmonary tuberculous with diffuse small nodular shadows (suspected miliary tuberculosis (MTB)) is still unclear in Japan. A retrospective cross-sectional study was conducted to investigate the detection rates of M. tuberculosis in urine of patients with suspected MTB. Methods Among 687 hospitalized patients with tuberculosis, 45 with culture-confirmed suspected MTB and the data of culture and polymerase chain reaction (PCR) for M. tuberculosis in urine and sputum samples were investigated. The detection rates of M. tuberculosis in urine using cultures and PCR were calculated. The detection rate of urine was then compared with that of bone marrow aspiration. Results Fourteen patients with suspected MTB were ultimately analyzed. A diagnosis of miliary tuberculosis was suspected in all patients before anti-tuberculosis chemotherapy. Positive results by PCR (11 [78.6%] cases) and culture (8 [57.1%]) were obtained from urine samples. In patients with suspected MTB, there was no significant difference in the detection rates between M. tuberculosis in urine using a combination of PCR and culture (85.6% [12/14 cases]) and bone marrow aspiration (66.7% [8/12 cases]) (p>0.05). Conclusion Using PCR and culture, we demonstrated high detection rates of M. tuberculosis in the urine of patients with suspected MTB. A combination of PCR and culture compared favorably with the detection rates achieved with bone marrow aspiration. We believe that detection of M. tuberculosis from urine and sputum samples may be easy and safe for patients with disseminated tuberculosis infections such as definitive MTB.

Contribution of propriospinal neurons to recovery of hand dexterity after corticospinal tract lesions in monkeys.

The direct cortico-motoneuronal connection is believed to be essential for the control of dexterous hand movements, such as precision grip in primates. It was reported, however, that even after lesion of the corticospinal tract (CST) at the C4-C5 segment, precision grip largely recovered within 1-3 mo, suggesting that the recovery depends on transmission through intercalated neurons rostral to the lesion, such as the propriospinal neurons (PNs) in the midcervical segments. To obtain direct evidence for the contribution of PNs to recovery after CST lesion, we applied a pathway-selective and reversible blocking method using double viral vectors to the PNs in six monkeys after CST lesions at C4-C5. In four monkeys that showed nearly full or partial recovery, transient blockade of PN transmission after recovery caused partial impairment of precision grip. In the other two monkeys, CST lesions were made under continuous blockade of PN transmission that outlasted the entire period of postoperative observation (3-4.5 mo). In these monkeys, precision grip recovery was not achieved. These results provide evidence for causal contribution of the PNs to recovery of hand dexterity after CST lesions; PN transmission is necessary for promoting the initial stage recovery; however, their contribution is only partial once the recovery is achieved.

Comparative analyses of adeno-associated viral vector serotypes 1, 2, 5, 8 and 9 in marmoset, mouse and macaque cerebral cortex.

Here we investigated the transduction characteristics of adeno-associated viral vector (AAV) serotypes 1, 2, 5, 8 and 9 in the marmoset cerebral cortex. Using three constructs that each has hrGFP under ubiquitous (CMV), or neuron-specific (CaMKII and Synapsin I (SynI)) promoters, we investigated (1) the extent of viral spread, (2) cell type tropism, and (3) neuronal transduction efficiency of each serotype. AAV2 was clearly distinct from other serotypes in small spreading and neuronal tropism. We did not observe significant differences in viral spread among other serotypes. Regarding the cell tropism, AAV1, 5, 8 and 9 exhibited mostly glial expression for CMV construct. However, when the CaMKII construct was tested, cortical neurons were efficiently transduced (>∼70% in layer 3) by all serotypes, suggesting that glial expression obscured neuronal expression for CMV construct. For both SynI and CaMKII constructs, we observed generally high-level expression in large pyramidal cells especially in layer 5, as well as in parvalbumin-positive interneurons. The expression from the CaMKII construct was more uniformly observed in excitatory cells compared with SynI construct. Injection of the same viral preparations in mouse and macaque cortex resulted in essentially the same result with some species-specific differences.

Role of Direct vs. Indirect Pathways from the Motor Cortex to Spinal Motoneurons in the Control of Hand Dexterity.

Evolutionally, development of the direct connection from the motor cortex to spinal motoneurons [corticomotoneuronal (CM) pathway] parallels the ability of hand dexterity. Damage to the corticofugal fibers in higher primates resulted in deficit of fractionated digit movements. Based on such observations, it was generally believed that the CM pathway plays a critical role in the control of hand dexterity. On the other hand, a number of "phylogenetically older" indirect pathways from the motor cortex to motoneurons still exist in primates. The indirect pathways are mediated by intercalated neurons such as segmental interneurons (sINs), propriospinal neurons (PNs) reticulospinal neurons (RSNs), or rubrospinal neurons (RuSNs). However, their contribution to hand dexterity remains elusive. Lesion of the brainstem pyramid sparing the transmission through the RuSNs and RSNs, resulted in permanent deficit of fractionated digit movements in macaque monkeys. On the other hand, in our recent study, after lesion of the dorsolateral funiculus (DLF) at the C5 segment, which removed the lateral corticospinal tract (l-CST) including the CM pathway and the transmission through sINs and RuSNs but spared the processing through the PNs and RSNs, fractionated digit movements recovered within several weeks. These results suggest that the PNs can be involved in the recovery of fractionated digit movements, but the RSNs and RuSNs have less capacity in this regard. However, on closer inspection, it was found that the activation pattern of hand and arm muscles considerably changed after the C5 lesion, suggesting limitation of PNs for the compensation of hand dexterity. Altogether, it is suggested that PNs, RSNs RuSNs, and the CM pathway (plus sINs) make a different contribution to the hand dexterity and appearance of motor deficit of the hand dexterity caused by damage to the corticofugal fibers and potential of recovery varies depending on the rostrocaudal level of the lesion.

DNA methylation and methyl-binding proteins control differential gene expression in distinct cortical areas of macaque monkey.

Distinct anatomical regions of the neocortex subserve different sensory modalities and neuronal integration functions, but mechanisms for these regional specializations remain elusive. Involvement of epigenetic mechanisms for such specialization through the spatiotemporal regulation of gene expression is an intriguing possibility. Here we examined whether epigenetic mechanisms might play a role in the selective gene expression in the association areas (AAs) and the primary visual cortex (V1) in macaque neocortex. By analyzing the two types of area-selective gene promoters that we previously identified, we found a striking difference of DNA methylation between these promoters, i.e., hypermethylation in AA-selective gene promoters and hypomethylation in V1-selective ones. Methylation levels of promoters of each area-selective gene showed no areal difference, but a specific methyl-binding protein (MBD4) was enriched in the AAs, in correspondence with expression patterns of AA-selective genes. MBD4 expression was mainly observed in neurons. MBD4 specifically bound to and activated the AA-selective genes both in vitro and in vivo. Our results demonstrate that methylation in the promoters and specific methyl-binding proteins play an important role in the area-selective gene expression profiles in the primate neocortex.

Viral vector-mediated selective and reversible blockade of the pathway for visual orienting in mice.

Recently, by using a combination of two viral vectors, we developed a technique for pathway-selective and reversible synaptic transmission blockade, and successfully induced a behavioral deficit of dexterous hand movements in macaque monkeys by affecting a population of spinal interneurons. To explore the capacity of this technique to work in other pathways and species, and to obtain fundamental methodological information, we tried to block the crossed tecto-reticular pathway, which is known to control orienting responses to visual targets, in mice. A neuron-specific retrograde gene transfer vector with the gene encoding enhanced tetanus neurotoxin (eTeNT) tagged with enhanced green fluorescent protein (EGFP) under the control of a tetracycline responsive element was injected into the left medial pontine reticular formation. 7-17 days later, an adeno-associated viral vector with a highly efficient Tet-ON sequence, rtTAV16, was injected into the right superior colliculus. 5-9 weeks later, the daily administration of doxycycline (Dox) was initiated. Visual orienting responses toward the left side were impaired 1-4 days after Dox administration. Anti-GFP immunohistochemistry revealed that a number of neurons in the intermediate and deep layers of the right superior colliculus were positively stained, indicating eTeNT expression. After the termination of Dox administration, the anti-GFP staining returned to the baseline level within 28 days. A second round of Dox administration, starting from 28 days after the termination of the first Dox administration, resulted in the reappearance of the behavioral impairment. These findings showed that pathway-selective and reversible blockade of synaptic transmission also causes behavioral effects in rodents, and that the crossed tecto-reticular pathway clearly controls visual orienting behaviors.

Assessing efficacy of indacaterol in moderate and severe COPD patients: a 12-week study in an Asian population.

INTRODUCTION: This post hoc analysis evaluated the efficacy of indacaterol, a novel inhaled once-daily long-acting ß(2)-agonist, by disease severity (GOLD 2005) in patients with moderate-to-severe COPD from six Asian countries/areas (Hong Kong, India, Japan, Korea, Singapore, Taiwan). METHODS: Data from a 12-week, double-blind, placebo-controlled, parallel-group study in patients randomized to indacaterol 150 µg, indacaterol 300 µg or placebo once daily were analyzed based on baseline disease severity (moderate or severe). Endpoints were: trough FEV(1) (average of 23 h 10 min and 23 h 45 min post-dose values), transition dyspnoea index (TDI) and St George's Respiratory Questionnaire (SGRQ) at Week 12. Safety data were collected. RESULTS: Of 347 patients randomized, 59.7% had moderate, and 40.3% had severe COPD. Least squares means (LSMs) indacaterol-placebo differences in trough FEV(1) at Week 12 exceeded the pre-specified minimal clinically important difference (MCID) of 0.12L and were statistically superior (p < 0.001) for indacaterol (150 µg, 300 µg) versus placebo in the two subgroups [0.19L, 0.20L (moderate); 0.15L, 0.19L (severe) respectively]. LSM TDI scores for both indacaterol doses versus placebo in both subgroups were statistically superior (p < 0.05) and clinically meaningful (≥1 unit). Both indacaterol doses showed improvements in LSM SGRQ total scores at Week 12 which exceeded the MCID (4 units) versus placebo in both subgroups, with indacaterol 300 µg-placebo difference in the severe subgroup being statistically significant (p < 0.01). Overall incidence of adverse events was lower with indacaterol than with placebo across both subgroups. CONCLUSIONS: Indacaterol demonstrated clinically relevant improvements versus placebo in lung function, dyspnea and health status in Asian COPD patients irrespective of disease severity. CLINICAL TRIALS IDENTIFIER: NCT00794157.

[Difficult ventilation after sugammadex administration: a case report].

A 71-year-old woman was scheduled for arthroscopic knee surgery. Anesthesia was administered with sevoflurane, fentanyl, and rocuronium bromide. Total dose of fentanyl was 200 microg and total dose of rocuronium bromide was 40mg. After surgery sugammadex 150 mg was given before awakening of the patient and appearance of spontaneous breathing. Immediately after the administration of sugammadex airway pressure increased to 37 cmH20, and ventilation became difficult. After naloxone 0.1 mg injection, ventilation improved dramatically. The cause of difficult ventilation was surmised to be upper airway reflex or muscle rigidity caused by reaction to fentanyl. We thought the phenomenon was clearly manifested by rapid recovery from muscle relaxation by injection of sugammadex. Before injection of sugammadex, it is necessary to confirm the effects of anesthetics on the patient's condition.

Genetic dissection of the circuit for hand dexterity in primates.

It is generally accepted that the direct connection from the motor cortex to spinal motor neurons is responsible for dexterous hand movements in primates. However, the role of the 'phylogenetically older' indirect pathways from the motor cortex to motor neurons, mediated by spinal interneurons, remains elusive. Here we used a novel double-infection technique to interrupt the transmission through the propriospinal neurons (PNs), which act as a relay of the indirect pathway in macaque monkeys (Macaca fuscata and Macaca mulatta). The PNs were double infected by injection of a highly efficient retrograde gene-transfer vector into their target area and subsequent injection of adeno-associated viral vector at the location of cell somata. This method enabled reversible expression of green fluorescent protein (GFP)-tagged tetanus neurotoxin, thereby permitting the selective and temporal blockade of the motor cortex­PN­motor neuron pathway. This treatment impaired reach and grasp movements, revealing a critical role for the PN-mediated pathway in the control of hand dexterity. Anti-GFP immunohistochemistry visualized the cell bodies and axonal trajectories of the blocked PNs, which confirmed their anatomical connection to motor neurons. This pathway-selective and reversible technique for blocking neural transmission does not depend on cell-specific promoters or transgenic techniques, and is a new and powerful tool for functional dissection in system-level neuroscience studies.

Efficacy and safety of indacaterol 150 and 300 µg in chronic obstructive pulmonary disease patients from six Asian areas including Japan: a 12-week, placebo-controlled study.

BACKGROUND AND OBJECTIVE: The efficacy and safety of indacaterol, a novel inhaled once daily ultra long-acting ß(2) -agonist was evaluated in COPD patients in six Asian countries/areas. This study was primarily designed to obtain the regulatory approval of indacaterol in Japan. METHODS: Moderate-to-severe COPD patients were randomized to indacaterol 150 µg, indacaterol 300 µg or placebo once daily. Efficacy variables: trough FEV(1) (average of 23 h 10 min and 23 h 45 min post-dose values), health status (St. George's Respiratory Questionnaire) and transition dyspnoea index at week 12. Safety/tolerability was evaluated. RESULTS: A total of 347 patients were randomized (96.5% male, mean (SD) age 66.7 (8.38) years, post-bronchodilator FEV(1) % predicted: 53.7 (12.50)); 88.8% completed. The least squares means (LSM) trough FEV(1) at week 12 for indacaterol 150 µg, indacaterol 300 µg and placebo were 1.34 L, 1.37 L and 1.17 L, respectively, with differences versus placebo exceeding the prespecified minimal clinically important difference of 0.12 L (0.17 L and 0.20 L for indacaterol 150 µg and 300 µg, respectively, both P < 0.001). The week 12 LSM transition dyspnoea index score was statistically superior for both indacaterol doses versus placebo (differences of 1.30 and 1.26, P < 0.001; both exceeding the minimal clinically important difference of 1). At week 12, both indacaterol doses provided statistically significant (P ≤ 0.005) and clinically meaningful (≥4 units) improvements in LSM St. George's Respiratory Questionnaire total score versus placebo (differences: -4.8 and -5.7 units). Adverse events for indacaterol (49.1%, both doses) were lower than placebo (59.0%) and were mostly mild/moderate in severity; no deaths were reported. CONCLUSIONS: Indacaterol provided clinically significant bronchodilation and improvements in dyspnoea and health status in Asian COPD patients.

Optical imaging of contextual interactions in V1 of the behaving monkey.

Interactions in primary visual cortex (V1) between simple visual elements such as short bar segments are believed to underlie our ability to easily integrate contours and segment surfaces. We used intrinsic signal optical imaging in alert fixating macaques to measure the strength and cortical distribution of V1 interactions among collinear bars. A single short bar stimulus produced a broad-peaked hill of activation (the optical point spread) covering multiple orientation hypercolumns in V1. Flanking the bar stimulus with a pair of identical collinear bars led to a strong nonlinear suppression in the optical signal. This nonlinearity was strongest over the center bar region, with a spatial distribution that cannot be explained by a simple gain control. It was a function of the relative orientation and separation of the bar stimuli in a manner tuned sharply for collinearity, being strongest for immediately adjacent bars lying on a smooth contour. These results suggest intracortical interactions playing a major role in determining V1 activation by smooth extended contours. Our finding that the interaction is primarily suppressive when imaged optically, which presumably reflects the combined inhibitory and excitatory inputs, suggests a complex interplay between these cortical inputs leading to the collinear facilitation seen in the spiking response of V1 neurons. This disjuncture between the facilitation seen in spiking and the suppression in imaging also suggests that cortical representations of complex stimuli involve interactions that need to be studied over extended networks and may be hard to deduce from the responses of individual neurons.

Validation of "lung age" measured by spirometry and handy electronic FEV1/FEV6 meter in pulmonary diseases.

OBJECTIVE: The concept of "lung age" is thought to be useful for understanding pulmonary function. In this study, we validated "lung age" to detect pulmonary function abnormalities in pulmonary diseases. METHODS: We used both spirometry and an electronic FEV(1)/FEV(6) meter (FEV(6) meter) to perform pulmonary function tests. We evaluated the sensitivity and specificity of FEV(6) and FEV(1)/FEV(6), and calculated "lung age" in Japanese subjects including those with chronic obstructive pulmonary disease (COPD), bronchial asthma (BA), and interstitial lung diseases (ILD). RESULTS: FEV(1) (spirometer) vs. FEV(1) (FEV(6) meter), FVC (spirometer) vs. FEV(6) (FEV(6) meter), and FEV(1)/FVC (spirometer) vs. FEV(1)/FEV(6) (FEV(6) meter) measurements were all significantly and closely correlated. For the difference of "lung age" and "actual age", the area under the receiver operating characteristic curve (ROC-AUC) for detecting obstructive impairment was 0.807 (spirometer) and 0.772 (FEV(6) meter), respectively. The corresponding ROC-AUC for detecting restrictive impairment was 0.891 and 0.836, respectively, and that for detecting both obstructive and restrictive impairment was 0.918 and 0.853, respectively. For detection of both obstructive and restrictive impairment, the difference of the "lung age" and "actual age" cut-off value, corresponding to the greatest sum of sensitivity and specificity, was 18.3 years (spirometer) and 19.8 years (FEV(6) meter), respectively. The sensitivity was 0.783 (spirometer) and 0.801 (FEV(6) meter), and the specificity was 0.895 (spirometer) and 0.790 (FEV(6) meter), respectively. CONCLUSION: "Lung age" can provide an easy interpretation of the results, and can detect pulmonary function abnormalities in pulmonary diseases.

Effect of add-on therapy of tiotropium in COPD treated with theophylline.

BACKGROUND: Although combination therapy with bronchodilators is recommended for chronic obstructive pulmonary disease (COPD), there is insufficient evidence for the efficacy of some combinations of long-acting bronchodilators. OBJECTIVE: We investigated the effects of a combination therapy with tiotropium and theophylline in COPD patients. METHODS: In a 12-week, open-labeled, parallel-group randomized study, pulmonary functions and dyspnea scores were compared between the combination and theophylline alone therapy at baseline, and 4 and 8 weeks after randomization in COPD. RESULTS: Sixty-one COPD patients completed the trial (31 combination therapy, 30 theophylline alone; mean age 70 years; 58 males; mean dyspnea score 2.0 and forced expiratory volume in one second (FEV1) 1.5 L [62.5% predicted]). FEV1 in the combination group, but not in the theophylline alone, was significantly increased at 4 (1.56 +/- 0.13 L, p < 0.001) and 8 weeks (1.60 +/- 0.13 L, p < 0.001) from the baseline (1.40 +/- 0.12 L). In the combination group, but not the theophylline alone group, the dyspnea score was significantly improved after 4 (p < 0.01) and 8 weeks (p <0.05) compared with baseline. In 17 patients who did not receive theophylline at screening, treatment with 4 or 8 weeks of theophylline alone did not improve dyspnea score or FEV1. CONCLUSION: Addition of tiotropium therapy to theophylline treatment can improve dyspnea and pulmonary function in COPD. Although this study did not assess whether there was any benefit of adding theophylline to patients treated with tiotropium, tiotropium can be a useful addition in COPD already treated with theophylline.

Validation of symptom-based COPD questionnaires in Japanese subjects.

BACKGROUND AND OBJECTIVE: Symptom-based questionnaires may be helpful in diagnosing patients with COPD. The aim of this study was to determine whether two COPD questionnaires designed in Western countries were applicable to Japanese and other Asian patients. METHODS: The participants were Japanese people aged 40 years and over. Each subject answered questions on demographics and symptoms and underwent spirometry before and after administration of a bronchodilator. Questionnaire A was designed to identify previously undiagnosed COPD and questionnaire B was designed to differentiate between COPD and asthma. RESULTS: The numbers of COPD patients who answered questionnaires A and B were 33 of 169 (19.5%) and 112 of 168 (66.7%), respectively. Comparison of the COPD group with the non-COPD group revealed a significant difference in total score in both questionnaire A and questionnaire B (both P < 0.001). The area under the receiver operating characteristic curve (AUC-ROC) for questionnaire A was 0.791. With a cut-off value of 16.5 points, the sensitivity and specificity were 0.939 and 0.404, and with a 19.5-point cut-off, sensitivity and specificity were 0.848 and 0.647, respectively. The AUC-ROC for questionnaire B was 0.765. With cut-off values of 18.5 and 24.5 points, the respective sensitivities and specificities were 0.946 and 0.393, and 0.741 and 0.607. CONCLUSIONS: A simple self-administered questionnaire can help to diagnose COPD in Japanese subjects. When these questionnaires are used in Japan, cut-off values should be set somewhat higher than in Western countries.