Lung Sound Analysis Is Useful for Monitoring Therapy in Patients With Bronchial Asthma.

BACKGROUND AND OBJECTIVE: Lung sound analysis (LSA) has been reported to be useful for predicting airway obstruction and inflammation in patients with bronchial asthma. Objectives: We examined whether the exhalation-to-inhalation sound pressure ratio in the middle frequency range (200-400 Hz) (E/I MF) is useful for monitoring therapy in patients with asthma. METHODS: The study population comprised 84 patients with mild to moderate asthma whose LSA data were available before and after 1 year of daily treatment with (budesonide 800 µg). We analyzed whether the E/I MF before and after treatment was associated with the fractional exhaled nitric oxide (FeNO) level, sputum eosinophil percentage, respiratory function, and airway hyperresponsiveness. RESULTS: Prior to treatment with budesonide, the E/I MF was significantly correlated with respiratory function, airway hyperresponsiveness, FeNO, and sputum eosinophil percentage. The cutoff values for the E/I MF to detect the abnormalities of respiratory function, FeNO, and sputum eosinophil percentage were 0.367, 0.358, and 0.363, respectively. With respect to the reference value, the E/I MF improved significantly in patients whose respiratory function and FeNO benefited from therapy with budesonide compared with patients whose respiratory function did not benefit from budesonide (odds ratios of 6.39 and 4.78, respectively). According to the multivariate analysis, patients whose E/I MF did not improve had a longer history of smoking (P=.038), poorer posttreatment respiratory function (P=.028), and higher posttreatment FeNO (P=.0095). CONCLUSIONS: Similar to respiratory function and FeNO, E/I MF based on LSA is a useful indicator for monitoring the efficacy of therapy in asthmatic patients.

Phase I/II study of nivolumab plus lenvatinib for advanced biliary tract cancer (JCOG1808/NCCH1817, SNIPE).

BACKGROUND: Although cisplatin plus gemcitabine and other combinations have improved the survival of advanced biliary tract cancer (BTC), high unmet medical needs remain. This study aimed to assess the efficacy and safety of nivolumab plus lenvatinib in the second-line treatment for advanced BTC. PATIENTS AND METHODS: Nivolumab (240 mg) was administered biweekly. Phase I determined the recommended phase II dose of lenvatinib (20 mg or 14 mg). In phase II, the primary endpoint was the objective response rate (ORR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. The planned sample size was 32 patients with a power of 80%, a one-sided alpha error of 5%, threshold ORR of 10%, and expected ORR of 30%. RESULTS: In phase I, the recommended dose of lenvatinib was determined to be 20 mg in six patients, with one dose-limiting toxicity (myocarditis). In phase II, we enrolled 26 patients. ORR, DCR, and median OS and PFS were 9.4% [90% confidence interval (CI) 2.6% to 22.5%], 53.1% (95% CI 34.7% to 70.9%), and 6.4 months (95% CI 4.9-9.7 months) and 2.5 months (95% CI 1.5-4.1 months), respectively. No response was observed in patients with the usage of antibiotics. The grade 3 or 4 adverse events were hypertension (59.4%) and biliary tract infection (37.5%). Rash (28.1%) and hypothyroidism (21.9%) were observed as immune-mediated adverse events of any grade. CONCLUSIONS: Nivolumab plus lenvatinib had a manageable safety in advanced BTC, but its efficacy in the second-line treatment was limited.

Selective long-term elimination of natural killer cells in vivo by an anti-interleukin 2 receptor beta chain monoclonal antibody in mice.

The interleukin 2 receptor beta chain (IL-2R beta) is preferentially expressed in natural killer (NK) cells, but is not detected in a majority of resting T and B cells. We recently established a novel monoclonal antibody (mAb) to murine IL-2R beta and examined in vivo the effect of the mAb in mice. We found that intraperitoneal injection of the anti-IL-2R beta mAb into adult mice resulted in a selective in vivo elimination of splenic NK function in various mouse strains. The reduction of NK cell function is associated with complete disappearance of NK1.1+ cells in C57BL/6 mice. Other lymphocyte subsets in the thymus and spleen were uncompromised. T cell function was not affected by the mAb treatment as judged by allogeneic cytotoxic T cell induction. The single injection of anti-IL-2R beta mAb caused a long-term elimination of splenic NK cells, lasting for at least 5 wk. We also found that NK and/or NK precursor cells become susceptible to the mAb treatment only after birth, suggesting that functional maturation of NK cells in terms of IL-2R beta expression is a later event in the course of NK cell development. The use of the anti-IL-2R beta mAb will be useful in defining the physiological role of NK cells in host defense as well as dissecting their developmental pathway in vivo.

Soret forced Rayleigh scattering instrument for simultaneous detection of two-wavelength signals to measure Soret coefficient and thermodiffusion coefficient in ternary mixtures.

We describe an instrument for the measurement of the Soret and thermodiffusion coefficients in ternary systems based on the transient holographic grating technique, which is called Soret forced Rayleigh scattering (SFRS) or thermal diffusion forced Rayleigh scattering (TDFRS). We integrated the SFRS technique and the two-wavelength detection technique, which enabled us to obtain two different signals to determine the two independent Soret coefficients and thermodiffusion coefficients in ternary systems. The instrument has been designed to read the mass transport simultaneously by two-wavelength lasers with wavelengths of λ = 403 nm and λ = 639 nm. The irradiation time of the probing lasers is controlled to reduce the effect of laser absorption to the sample with dye (quinizarin), which is added to convert the interference pattern of the heating laser of λ = 532 nm to the temperature grating. The result of the measurement of binary benchmark mixtures composed of 1,2,3,4-tetrahydronaphthalene (THN), isobutylbenzene (IBB), and n-dodecane (nC12) shows that the simultaneous two-wavelength observation of the Soret effect and the mass diffusion are adequately performed. To evaluate performance in the measurement of ternary systems, we carried out experiments on the ternary benchmark mixtures of THN/IBB/nC12 with the mass fractions of 0.800/0.100/0.100 at a temperature of 298.2 K. The Soret coefficient and thermodiffusion coefficient agreed with the ternary benchmark values within the range of the standard uncertainties (23% for the Soret coefficient of THN and 30% for the thermodiffusion coefficient of THN).

Mechanisms of aluminum fluoride- and insulin-stimulated p33 mRNA accumulation in rat hepatoma cells: involvement of a G protein and kinase action and demonstration of effects on mRNA turnover.

The insulin signalling pathway to control nuclear p33 gene expression was examined. An AlF4-stimulated pertussis toxin-insensitive G protein was shown to be involved. The action of AlF4- was completely blocked by deferoxamine. Insulin action was markedly stimulated in the presence of AlF4-. cAMP and diacylglycerol concentrations were examined as possible regulators but no increases were detected. The effects of AlF4- and of insulin were completely inhibited by the general kinase inhibitor H-7. A second calcium calmodulin protein kinase inhibitor, W-7, had no detectable effect. Insulin and AlF4- were shown to stabilize p33 mRNA.

Inhaled corticosteroids reduce bone mineral density in early postmenopausal but not premenopausal asthmatic women.

Inhaled corticosteroids are widely used in the treatment of bronchial asthma, but it is still uncertain whether long-term use of the inhaled corticosteroids affects bone metabolism in asthmatic patients. In this study, we examined the effect of inhaled beclomethasone dipropionate (BDP) on bone mineral density (BMD) and biochemical markers of bone metabolism in pre- and early postmenopausal asthmatic women. Thirty-six (17 premenopausal and 19 early postmenopausal) asthmatic women and 45 healthy control (24 premenopausal and 21 early postmenopausal) women were investigated. All the asthmatic patients were treated with BDP (542 +/- 298 microg/day; 100-1200 microg/day) without any systemic administration of corticosteroids for at least 1 year. In premenopausal women, BMD as well as the biochemical markers of bone metabolism did not differ between control subjects and BDP-treated asthmatic patients. By contrast, in early postmenopausal women, BMD was significantly lower in BDP-treated asthmatic patients than in control subjects. In these early postmenopausal women, serum intact osteocalcin concentration was lower in the BDP-treated asthmatic patients than in the control subjects whereas urinary free pyridinoline (F-PYD) and free deoxypyridinoline (F-DPD) concentrations did not differ between the groups. Thus, early postmenopausal, but not premenopausal, asthmatic patients who were treated with inhaled BDP had reduced BMD, which was associated with a decreased level of the bone formation marker. Ovarian hormones may be protective against the adverse effect of inhaled BDP on bone metabolism in the premenopausal patients.

Replication timing of the human X-inactivation center (XIC) region: correlation with chromosome bands.

The human genome is composed of long-range G+C% mosaic structures, which are thought to be related to chromosome bands. Replication timing during S phase is associated with chromosomal band zones; thus, band boundaries are thought to correspond to regions where replication timing switches. The proximal limit of the human X-inactivation center (XIC) has been localized cytologically to the junction zone between Xq13.1 and Xq13.2. Using PCR-based quantification of the newly replicated DNA from cell-cycle fractionated THP-1 cells, the replication timing in and around the XIC was determined at the genome sequence level. We found two regions where replication timing changes from the early to late period during S phase. One is located near a large inverted duplication proximal to the XIC, and the other is near the XIST locus. We propose that the 1Mb late-replicated zone (from the large inverted duplication to XIST) corresponds to a G-band Xq13.2. Several common characteristics were observed in the XIST region and the MHC class II-III junction which was previously defined as a band boundary. These characteristics included differential high-density clustering of Alu and LINE repeats, and the presence of polypurine/polypyrimidine tracts, MER41A, MER57 and MER58B.

Divergent axon collaterals from the rostral superior colliculus to the pretectal accommodation-related areas and the omnipause neuron area in the cat.

Results of previous studies have suggested that the rostral superior colliculus (SC), which corresponds to the representation of the central visual field, is involved in the control of accommodation and active fixation. To clarify the functional interaction between accommodation and active fixation in the rostral SC, this study was performed to investigate the axon collaterals diverging from the rostral SC to the pretectal accommodation-related areas and the omnipause neuron area in the raphe interpositus (RIP) of the cat by using a fluorescent double-labeling technique. This study was conducted on four cats, weighing 2.5-3.5 kg. Retrogradely labeled neurons in the SC were examined following injections of Fast Blue into the RIP and Diamidino Yellow into the pretectal accommodation-related areas, which were identified with microstimulation techniques. Neurons projecting to the RIP were located mainly in the intermediate layers in the rostral SC, whereas neurons projecting to the pretectal accommodation-related areas were scattered in the superficial and intermediate layers of the rostral SC. The population of double-labeled neurons was highest in the rostral SC, which corresponds to the representation of the central visual field. The presence of double-labeled cells indicated that the accommodation-related area in the rostral SC contains neurons whose axons collateralize to project to both the pretectal accommodation-related areas and the ominipause neuron area in the RIP. Neurons in the rostral SC may be involved in the interaction between accommodation and active fixation.

Forebrain muscarinic control of micturition reflex in rats.

Functional contribution of the cholinergic pathway between the frontal cortex and basal nucleus of Meynert to micturition reflex was investigated. Male Wistar rats were subjected to bilateral lesion of the basal forebrain by ibotenic acid (IA) injection (7.5 microg/rat on each side) (BF rats). Phosphate buffered saline (PBS) was injected into control rats (sham operated rats; SO rats). Cystometrograms were obtained from conscious BF and SO rats 7-10 days after IA/PBS injection. Bladder capacity (BC) of BF rats was significantly smaller than that of SO rats (approximately 43.7%) and was accompanied by decrease in choline-acetyltransferase activity in the frontal cortices. Oxotremorine M, a muscarinic receptor agonist, increased BC in BF rats, while pirenzepine, an M1 muscarinic receptor antagonist, counteracted the effect of the oxotremorine M-induced increase in BC. Injection of oxotremorine M into the dorsal pontine tegmentum (DPT) reduced BC in BF and SO rats, while injection of pirenzepine had no effect on cystometrograms. These findings indicate that the M1 muscarinic receptor plays a part in the forebrain inhibitory mechanisms involved in the micturition reflex and that muscarinic receptor in the DPT contributes to excitatory control of micturition reflex.

Modulation of the heat-induced activation of mitogen-activated protein (MAP) kinase by quercetin.

Effects of quercetin, a bioflavonoid compound, on heat-induced activation of mitogen-activated protein (MAP) kinase in rat hepatoma (H4) cells were examined. Quercetin decreased cell viability and induced DNA fragmentation in heat-shocked H4 cells. MAP kinase in heat-shocked cells was activated and reached a peak at 1 hr after the heat shock, and then gradually decreased. Quercetin inhibited the heat-induced activation of MAP kinase observed at 1 hr after heat shock, but markedly stimulated MAP kinase activity at 4 hr after heat shock. Thus, quercetin modulated the heat-induced activation of MAP kinase in a biphasic manner. Present observations indicate that quercetin modulates protein phosphorylation, especially that controled by MAP kinase, in early events of heat shock response.

The new oral hypoglycemic agent, CS-045, inhibits the lipid peroxidation of human plasma low density lipoprotein in vitro.

Several lines of evidence have revealed that the oxidative modification of low-density lipoprotein (LDL) is probably associated with the genesis of the atherosclerotic region. CS-045 is a new (thiazolidine) class of oral hypoglycemic agent which has a hindered phenol in the side chain (an analogue of alpha-tocopherol). The present results indicate that CS-045 had a relatively high antioxidative potency in inhibiting the lipid peroxidation of human plasma LDL in vitro induced by 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) compared with that of alpha-tocopherol. These findings suggest that CS-045 may be useful in preventing the progression of atherosclerosis in diabetic patients.

Longterm favorable effect of oxygen administration on a patient with primary pulmonary hypertension.

A 17-year-old girl with primary pulmonary hypertension was treated with longterm administration of oxygen. Oxygen was delivered only at night for eight hours daily. Her clinical status has been improved for more than 17 months. Cardiac catheterization revealed almost 50 percent reduction of pulmonary vascular resistance. This is the first known report of successful treatment of primary pulmonary hypertension with oxygen administration.

Effect of saiboku-to (TJ-96) on bronchial asthma. Induction of glucocorticoid receptor, beta-adrenaline receptor, IgE-Fc epsilon receptor expression and its effect on experimental immediate and late asthmatic reaction.

A remarkable "steroid sparing" effect of Saiboku-to was noted within 6 to 12 months of treatment in steroid-dependent asthmatic patients. Saiboku-to spared the downregulation of glucocorticoid receptor of human lymphocytes, plasma ACTH, and cortisol levels. It also spared downregulation of beta 2 receptor by beta 2 agonists and suppressed mACh receptor at the same time. Saiboku-to increased tyrosine aminotransferase (TAT) production, which was inhibited by actinomycin-D, thus having steroid-like activity. In mite-allergic asthma, Saiboku-to inhibited the induction of expression of IgE-Fc epsilon R/CD23 in the lymphocytes by mite allergen. It also inhibited IgE production by mite allergens. In experimental asthma in guinea pigs the use of Saiboku-to resulted in a decrease in the number of eosinophils in the bronchoalveolar lavage fluid during late asthmatic response. These findings suggest that Saiboku-to may be effective in inhibiting both the expression of IgE-Fc epsilon R2 and the induction of expression of IgE-Fc epsilon R1. Saiboku-to also has a steroid-like action and polyhedral anti-asthmatic activities.

Effect of pulmonary blood flow on microvascular pressure profile determined by micropuncture in perfused cat lungs.

To clarify the role of the pulmonary microvasculature in adjusting to increased pulmonary blood flow, we measured arteriolar and venular pressure by the servo-null micropuncture method while changing the pulmonary blood flow in isolated perfused cat lungs. We divided the lung vasculature into three longitudinal segments: 1) arterial (pulmonary artery to 30- to 50-microns arteriole), 2) microvascular (between 30- to 50-microns arteriole and venule), and 3) venous (30- to 50-microns venule to left atrium). The vascular resistance was calculated by dividing the pressure gradient by the flow. The pressure gradient of the microvascular segment did not increase, whereas the pressure gradient of the arterial and venous segments increased simultaneously with flow rate. Total and microvascular resistance decreased with increase of flow rate. Resistances of the arterial and venous segments did not change with increase in flow. We conclude that the microvasculature plays a crucial role in preventing pulmonary hypertension with increases in flow by decreasing microvascular resistance.

Effect of hypoxia on pulmonary blood flow-segmental vascular resistance relationship in perfused cat lungs.

To investigate the effect of alveolar hypoxia on the pulmonary blood flow-segmental vascular resistance relationship, we determined the longitudinal distribution of vascular resistance while increasing blood flow during hyperoxia or hypoxia in perfused cat lungs. We measured microvascular pressures by the micropipette servo-null method, partitioned the pulmonary vessels into three segments [i.e., arterial (from main pulmonary artery to 30- to 50-micron arterioles), venous (from 30- to 50-micron venules to left atrium), and microvascular (between arterioles and venules) segments] and calculated segmental vascular resistance. During hyperoxia, total resistance decreased with increased blood flow because of a reduction of microvascular resistance. In contrast, during hypoxia, not only microvascular resistance but also arterial resistance decreased with increase of blood flow while venous resistance remained unchanged. The reduction of arterial resistance was presumably caused by arterial distension induced by an elevated arterial pressure during hypoxia. We conclude that, during hypoxia, both microvessels and arteries >50 micron in diameter play a role in preventing further increases in total pulmonary vascular resistance with increased blood flow.

Central effect of nicotine on gastric acid secretion in rats.

The central effect of nicotine on gastric acid secretion was examined in rats anesthetized with urethane. Intraventricular administration of nicotine 5 and 20 microgram/animal induced a dose-related increase in acid output. This nicotine-induced increase was blocked by treatment with hexamethonium 50 microgram/animal given intraventricularly or atropine 100 microgram/kg given intravenously. Changes in acid output after intravenous administration of nicotine 100 microgram/kg were inconsistent; however, a significant increase was observed with 500 microgram/kg of this alkaloid given by the same route. This increase was also blocked by hexamethonium 50 microgram/animal given intraventricularly. The level of gastrin in the gastric juice, after the intraventricular administration of nicotine 20 microgram/animal, did not significantly differ from the control. These results suggest that nicotine administered intraventricularly stimulates nicotinic receptors in the brain, and that there is a subsequent excitation of cholinergic muscarinic receptors in the stomach after which the secretion of acid increases.

Inhibition of gastric functions by stimulation of rat locus coeruleus.

To investigate the possible role of central noradrenergic neurons in the regulation of gastric functions, electrical stimulation of the locus coeruleus [LC] and microinjection of noradrenaline [NA] into the ala cinerea (area of the dorsal motor nucleus of the vagi [NDV] and the nucleus tractus solitarius [NTS]) were given to urethane-anesthetized rats. Unilateral electrical stimulation of the LC decreased both the basal levels and the lateral hypothalamic area [LHA]-induced increases in gastric acid output and mucosal blood flow. Microinjection of NA 0.1 and 0.5 micrograms/animal into the ala cinerea also decreased the basal levels of these gastric parameters. From these results, combined with neuroanatomical data from the literature, it is concluded that central noradrenergic inhibitory mechanisms originating from the LC seem to be involved in the regulation of gastric functions, probably at the level of the brain-stem ala cinerea.

Antihypertensive and metabolic effects of long-term treatment with amosulalol in non-insulin dependent diabetics.

In this open study, 41 hypertensive patients with non-insulin dependent diabetes mellitus were treated with the combined alpha- and beta-adrenoceptor blocker amosulalol hydrochloride for 24 weeks, either alone or added to existing antihypertensive therapy. The effects on blood pressure, glucose and lipid metabolism were examined. Daily administration of 20 to 60 mg amosulalol caused a significant reduction in both systolic and diastolic blood pressure within 2 weeks. This effect was stable, lasting for the entire trial period. The mean systolic and diastolic blood pressure decreased from 174 +/- 13/92 +/- 9 mmHg at the beginning to 148 +/- 16/80 +/- 11 mmHg at the end of the trial. Heart rate was not affected. Plasma glucose and haemoglobin Alc levels showed a tendency to decrease without any statistical significance. Total and HDL-cholesterol and triglyceride levels also remained unchanged. Although 3 patients had complained of dizziness, all were easily manageable. The results indicate that amosulalol is effective in the treatment of hypertension in non-insulin dependent diabetics and does not affect glucose and lipid metabolism.

Interaction between erythrocytes from various animals and emulsions stabilized with various lecithins.

The degree of hemolysis caused by the interaction between erythrocytes from various animals and emulsions stabilized with various lecithins was evaluated as a measure of the safety of emulsions for drug carriers. The stability of the emulsions was estimated using the gradient of the slope derived from the direct linear correlation between the percentage hemolysis and the phosphatidylcholine (PC) content of the erythrocyte membrane. When members of the egg lecithin (EPC) series were used as emulsifiers of emulsions, the percentage hemolysis increased as the PC content of the erythrocyte membrane increased and as the sphingomyelin (SM) content of the erythrocyte membrane decreased. Lysolecithin, a contaminant present in the emulsifying agent of emulsions, did not have any significant influence on the hemolysis of erythrocytes. These experimental findings show that the hemolysis caused by interaction between emulsions and erythrocytes was dependent on the PC content of both the emulsifying agent used and the erythrocyte membrane, and that the SM present in the erythrocyte membrane was an essential component for the stability of erythrocytes against emulsion-induced hemolysis.