Improvement of the pharmacokinetics and antifibrotic effects of nintedanib by intrapulmonary administration of a nintedanib-hydroxypropyl-γ-cyclodextrin inclusion complex in mice with bleomycin-induced pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a chronic lung disease that is characterized by progressive abnormal reprogramming following injury of the pulmonary structure. In this study, we prepared a nintedanib (antifibrotic agent) and cyclodextrin (CyD) inclusion complex to improve the pharmacokinetics and antifibrotic effects of nintedanib following intrapulmonary administration. Hydroxypropyl-γ-CyD (HP-γ-CyD) enhanced the solubility of nintedanib without cytotoxic effects on WI-38 cells (lung fibroblasts) and NCI-H441 cells (alveolar epithelium model). Compared with nintedanib ethanesulfonate salt, the nintedanib-HP-γ-CyD inclusion complex exhibited prolonged distribution in the lungs following intrapulmonary administration in mice with bleomycin-induced pulmonary fibrosis. In addition, compared with nintedanib ethanesulfonate salt, the nintedanib-HP-γ-CyD inclusion complex exhibited higher stability in the bronchoalveolar lavage fluid and lower permeability in NCI-H441 cell monolayers. These results suggested that the inclusion complexation of nintedanib into HP-γ-CyD improved its pharmacokinetics following intrapulmonary administration by increasing its stability in the lungs and reducing its permeability through the alveolar cell membrane. Intrapulmonary administration of the nintedanib-HP-γ-CyD inclusion complex significantly reduced the intrapulmonary hydroxyproline content and limited pathological fibrotic changes. Overall, this study indicates that antifibrotic agent-CyD inclusion complexation intended for intrapulmonary administration can be used to prolong distribution in the lungs and lead to the expansion of idiopathic pulmonary fibrosis therapy.

Indoor Scene Change Captioning Based on Multimodality Data.

This study proposes a framework for describing a scene change using natural language text based on indoor scene observations conducted before and after a scene change. The recognition of scene changes plays an essential role in a variety of real-world applications, such as scene anomaly detection. Most scene understanding research has focused on static scenes. Most existing scene change captioning methods detect scene changes from single-view RGB images, neglecting the underlying three-dimensional structures. Previous three-dimensional scene change captioning methods use simulated scenes consisting of geometry primitives, making it unsuitable for real-world applications. To solve these problems, we automatically generated large-scale indoor scene change caption datasets. We propose an end-to-end framework for describing scene changes from various input modalities, namely, RGB images, depth images, and point cloud data, which are available in most robot applications. We conducted experiments with various input modalities and models and evaluated model performance using datasets with various levels of complexity. Experimental results show that the models that combine RGB images and point cloud data as input achieve high performance in sentence generation and caption correctness and are robust for change type understanding for datasets with high complexity. The developed datasets and models contribute to the study of indoor scene change understanding.

Multi-View Visual Question Answering with Active Viewpoint Selection.

This paper proposes a framework that allows the observation of a scene iteratively to answer a given question about the scene. Conventional visual question answering (VQA) methods are designed to answer given questions based on single-view images. However, in real-world applications, such as human-robot interaction (HRI), in which camera angles and occluded scenes must be considered, answering questions based on single-view images might be difficult. Since HRI applications make it possible to observe a scene from multiple viewpoints, it is reasonable to discuss the VQA task in multi-view settings. In addition, because it is usually challenging to observe a scene from arbitrary viewpoints, we designed a framework that allows the observation of a scene actively until the necessary scene information to answer a given question is obtained. The proposed framework achieves comparable performance to a state-of-the-art method in question answering and simultaneously decreases the number of required observation viewpoints by a significant margin. Additionally, we found our framework plausibly learned to choose better viewpoints for answering questions, lowering the required number of camera movements. Moreover, we built a multi-view VQA dataset based on real images. The proposed framework shows high accuracy (94.01%) for the unseen real image dataset.

Hemoptysis due to Pulmonary Arteriovenous Malformation after Coil Embolization during Long-Term Follow-Up.

A 28-year-old man with a history of coil embolization of multiple pulmonary arteriovenous malformations presented with hemoptysis 11 years after initial embolization. A cavity lesion in the left upper lobe, which was accompanied by deformed coils and ground-glass opacity, was considered responsible for hemoptysis. Embolization of the bronchial artery was performed.

Effects of topical and intravenous JM-1232(-) infusion on cerebrovascular reactivity in rats.

A novel short-acting benzodiazepine receptor agonist, JM-1232(-), has been shown to have a sedative/hypnotic effect and wide safety margin. However, its effect on cerebral vessels is not well known. Therefore, we investigated the cerebrovascular reactivity to topical and intravenous JM-1232(-) and during hypotension or hypercapnia with intravenous administration of JM-1232(-). We used a closed cranial window preparation to measure the changes of cerebral pial arteriolar diameters in isoflurane-anesthetized Sprague-Dawley rats. We first measured the direct effect of topical JM-1232(-). We then determined the effect of intravenous JM-1232(-) and then we measured the response to hypercapnia before and after JM-1232(-) infusion. Finally, we measured the reaction to stepwise induction of hypotension before and after JM-1232(-) infusion. Topical infusion of JM-1232(-) dilated pial arterioles. Intravenous infusion of JM-1232(-) changed pial arterioles by 4.5 ± 2.7 %, 5.0 ± 3.9 %, and -2.8 ± 2.6 % (at 0.1, 0.3, and 1.0 mg/kg/min, respectively). Hypercapnia dilated pial arterioles before and after JM-1232(-) infusion. The diameters of pial arterioles did not change during hypotension before or after intravenous JM-1232(-) infusion. These results indicate that topical JM-1232(-) has a dilative effect on pial arterioles and that intravenous administration of JM-1232(-) may not affect cerebrovascular reactivity to hypotension or hypercapnia.

[Survey of the preoperative smoking cessation in patients for elective surgery in a university hospital].

BACKGROUND: In 2006, we reported the smoking status of surgical patients, and the factors relating to preoperative abstinence from cigarettes. Recently implementation of smoke-free policies has increased in Japan. Therefore we performed preoperative interview of 1,124 patients scheduled for elective surgery in 2011 (during 6 months), and compared the results with those of the same interview of 1,968 patients in 2006 (during 12 months). METHODS: Anesthesiologists interviewed all patients using a standardized questionnaire regarding: medical history, smoking history, and awareness of the risks of perioperative smoking. RESULTS: Current smoking rate was not different between 2006 (7%) and 2011 (7%). It was more difficult to quit smoking preoperatively for female patients in 2011 (P = 0.030), and those with benign disease in both 2006 (P = 0.006) and 2011 (P = 0.050) [smoker vs ex-smoker (< three months)]. There was no improvement in awareness of the perioperative risk of smoking between 2006 and 2011. CONCLUSIONS: At present, the importance of perioperative smoking cessation has not been sufficiently well-known for the surgical patients. Health care workers should be more aware of the importance of informing patients that preoperative abstinence from cigarettes may decrease perioperative complications.

Nicorandil protects pial arterioles from endothelial dysfunction induced by smoking in rats.

BACKGROUND: Our aims are to investigate the effect of nicorandil, which is used for angina prevention and treatment, on the endothelial dysfunction induced by acute smoking and to clarify the underlying mechanism. MATERIALS AND METHODS: A closed cranial window preparation was used to measure changes in pial vessel diameters in Sprague-Dawley rats. The responses of arterioles were examined to an endothelium-dependent vasodilator acetylcholine (ACh) before smoking. After intravenous nicorandil (200 µg/kg bolus infusion and then 60 µg/kg/min continuous infusion; n=6) or saline (control; n=6) pretreatment, the pial vasodilator response to topical 10 M ACh infusion was reexamined both before and 1 hour after 1-minute cigarette smoking. Thereafter, either glibenclamide or N-ω-nitro-L-arginine methyl ester (L-NAME) was infused 20 minutes before nicorandil infusion. In the glibenclamide (n=6) or L-NAME; n=6 pretreatment group, the pial vasodilator response to topical ACh was examined before and after smoking. Percentage changes in pial vessel diameters were used for the statistical analysis. RESULTS: Cerebral arterioles were dilated during topical ACh infusion. After smoking, 10 M ACh constricted cerebral arterioles (-7.7±1.8%). After smoking, in the nicorandil-pretreatment group, 10 M ACh dilated cerebral pial arterioles by 10.5±3.0%. When given before nicorandil infusion, glibenclamide, but not L-NAME, abolished the preventive effects of nicorandil against smoking-induced endothelial dysfunction in pial vessels. CONCLUSIONS: Acute cigarette smoking causes dysfunction of endothelium-dependent pial vasodilatation, and nicorandil prevents this effect of smoking. The mechanism underlying this protective effect may depend mainly on adenosine triphosphate-sensitive potassium-channel activation.

Preventive effect of varenicline on impairment of endothelial function in cerebral vessels induced by acute smoking in rats.

Preoperative smoking cessation is important for recovery from surgery without complications. Available evidence suggests nicotine replacement therapy could be safe and effective in the perioperative period. On the other hand, the newly developed selective nicotinic acetylcholine (ACh) receptor partial agonist, varenicline tartrate, is also effective as an aid for smoking cessation and helps people to stop smoking. During the transitional phase between the decision to stop smoking and actual smoking cessation, patients could use varenicline before undertaking smoking cessation. We have previously reported that acute cigarette smoking can cause impairment of endothelium-dependent vasodilation in cerebral vessels; thus, the use of varenicline before surgery in a patient who is still a smoker may not be safe with regard to endothelial function. Therefore, to assess the safety of varenicline in terms of endothelial function, we evaluated its effect on the acute smoking-induced impairment of endothelium-dependent cerebral vasodilation. In anesthetized Sprague-Dawley rats, we applied ACh topically to pial vessels; then, after administering intravenous varenicline or saline injection, we reexamined the ACh-induced vasodilator response both before and after smoking. Under control conditions, cerebral pial arterioles were dose-relatedly dilated by ACh. After smoking, 10(-5) M ACh constricted the arterioles following saline pretreatment (diameter -7.6 ± 1.8 %, n = 6), but induced dilation following varenicline pretreatment (diameter +15.3 ± 3.3 %, n = 6). Thus, varenicline may prevent the smoking-induced impairment of endothelium-dependent vasodilation in cerebral pial arterioles.

[Two cases of inoperable advanced bileduct cancer treated effectively with a gemcitabine/cisplatin combination].

We report two cases of inoperable advanced bileduct cancer that responded well to combined gemcitabine (GEM)/cisplatin (CDDP) therapy. A 70-year-old woman was admitted to the hospital because of jaundice; PTCD was performed, followed by laparotomy, however, the tumor was found to be inoperable because of extensive direct invasion of the surrounding organs. Then, after insertion of a stent, the patient was started on combined chemotherapy with GEM 1,000 mg/m2 on days 1, 8 and CDDP 70 mg/m2 on day 1 administered once every 3 weeks. After 4 courses, thrombocytopenia appeared. Therefore, chemotherapy was continued for another three courses with GEM 800 mg/m2 on days 1, 15 and CDDP 50 mg/m2 on day 1 every 4 weeks. After 7 courses the serum CEA level returned to normal range, and marked reduction of the tumor size was observed on CT. The patient has been able to maintain a good quality of life without occurrence of any severe adverse effects. A 61-year-old woman was admitted to the hospital because of icterus, and was diagnosed to have lower bile duct cancer with liver metastasis. After insertion of a stent, she was started on combined chemotherapy with GEM 1,000 mg/m2 on days 1, 8 and CDDP 70 mg/m2 on day 1 administered once every 3 weeks. After completion of 4 courses, the patient developed thrombocytopenia and a feel- ing of dullness. Therefore, chemotherapy was continued for the next three courses with GEM 800 mg/m2 on days 1, 15 and CDDP 50 mg/m2 on day 1, administered every 4 weeks. This treatment was associated with a fall of the serum CA19-9 level to within normal range, and marked improvement of the liver metastasis was also noted. Combined GEM/ CDDP therapy improves the QOL of inoperable bile duct cancer patients and offers promise as pre-operative chemotherapy.

[A case of local recurrence of colon cancer responding to chemotherapy with low-dose oxaliplatin, 5-FU and l-LV].

A 68-year-old woman underwent right colectomy for cancer of the ascending colon, followed by a local recurrence 26 months after surgery. She presented with fever and right lower abdominal pain, and was admitted to the hospital for locally recurrent colorectal cancer and tumor rupture. The patient was treated with a modified (reduced-dose) FOLFOX 4 regimen (mFOLFOX 4). In the four course of this regimen, the serum level of CEA decreased from 268 to 2.3 ng/mL. Even after 8 course, the serum CEA level remained within the normal range (4.7 ng/mL). Our case suggests that the mFOLFOX 4 regimen is effective for advanced or recurrent colorectal cancer with less toxicities including neuropathy,thus enabling patients to undergo long-term therapy.

Improvement of polyuria, bladder sensation and bladder capacity following renal transplantation.

Here, we report a patient with renal failure and bladder dysfunction whose symptoms improved following renal transplantation. A 23-year-old woman underwent renal transplantation for renal failure as a result of dysplastic kidneys. Urodynamic evaluation prior to transplantation showed decreased bladder sensation and increased bladder capacity, probably because of congenital polyuria. One week after surgery, dry mouth disappeared, and urine volume normalized gradually. Urodynamic studies performed 3 and 10 months after transplantation showed improvement of bladder function, and the frequency/volume charts of urination also showed normalization of urine volume. Renal and bladder functions were almost normal 45 months after transplantation. Bladder dysfunction involves numerous factors, but the primary cause was probably congenital polyuria in the present case. This case suggested that blood purification and correction of urine volume by renal transplantation might lead to restoration of normal bladder function.

Loss of heterozygosity on chromosome 9q22.3 in microdissected basal cell carcinomas around the Semipalatinsk Nuclear Testing Site, Kazakhstan.

A high incidence of skin cancers has been noted around the Semipalatinsk Nuclear Testing Site (SNTS) in Kazakhstan. Recently, basal cell carcinoma (BCC) susceptibility genes, human homolog of the Drosophila pathed gene (PTCH), and the xeroderma pigmentosa group A-complementing gene (XPA), have been cloned and localized on chromosome 9q22.3. To clarify the effect of low-dose irradiation on the occurrence of BCC, we used microdissection and polymerase chain reaction to identify loss of heterozygosity (LOH) at 9q22.3 using BCC samples obtained from this region. Ten Japanese samples were analyzed as controls. LOH with at least 1 marker was identified in 5 of 14 cases from around SNTS, whereas only 1 case with 1 marker was identified among the 10 Nagasaki cases. The total number of LOH alleles from SNTS (8 of 45) was significantly higher than the number from Nagasaki (1 of 26) (P = 0.03). The higher incidence of LOH on 9q22.3 in BCC from around SNTS suggests involvement of chronic low-dose irradiation by fallout from the test site as a factor in the cancers.

Evaluation of the carrier potential for the lipid dispersion system with lipophilic compound.

KW-3902 (a newly synthesized adenosine A(1)-receptor antagonist) has potent diuretic and renal protective activities and was formulated in lipid dispersion systems, i.e., lipid emulsions and liposomes. The objective of the present study was to evaluate the carrier potential of these lipid dispersion systems, which is explained here as the ability of the formulation to retain the drug in its dispersed phase. The relative affinity of the drug to the formulation, K(f/b), was defined as a parameter in order to assess the performance of the formulations and was obtained from the in vitro blood component binding study. The results indicated that KW-3902 showed higher relative affinity to the liposome formulation than to the lipid emulsion. Moreover, the total amount of drug retained in the dispersion system depended on both K(f/b) and the dosing volume. The usefulness of the parameter, K(f/b), was discussed as an indicator for a carrier potential to understand the properties of the formulations.

Role of the lipid emulsion on an injectable formulation of lipophilic KW-3902, a newly synthesized adenosine A1-receptor antagonist.

KW-3902 (a newly synthesized adenosine A1-receptor antagonist) has potent diuretic and renal protective activities. We investigated the influence of the emulsion formulation on the pharmacokinetics of KW-3902 and its metabolite (M1) in rats using three different formulations, i.e., a lipid emulsion about 130 nm in diameter composed of egg yolk lecithin: soybean oil: oleic acid=1:1:0.048, a liposome about 100 nm in diameter composed of egg yolk lecithin, and a saline solution containing 1% (v/v) each of dimethyl sulfoxide and 1 N NaOH. There was no significant difference in the pharmacokinetic parameters of KW-3902 (elimination half-life (T1/2), area under the plasma concentration-time curves (AUC0-infinity), total body clearance (CL), mean residence time (MRT) and volume of distribution at steady-state (Vdss) and M1 (Cmax, T1/2, AUC0-infinity and MRT) after injection of these three dosage forms. Moreover, we investigated in vitro the binding of KW-3902 to blood components using these three formulations. KW-3902 was completely partitioned into the blood components regardless of its dosage form. These findings suggested that KW-3902 dissociated rapidly from the lipid emulsion or liposome in blood after injection and showed intrinsic pharmacokinetics of KW-3902 at doses of 0.1 and 1 mg/kg. Thus, the lipid emulsion formulation of KW-3902 was defined as a solvent, which was a vehicle for dissolving the drugs to prepare the injection, at its expected effective doses.

Formulation development of a filter-sterilizable lipid emulsion for lipophilic KW-3902, a newly synthesized adenosine A1-receptor antagonist.

KW-3902 (a newly synthesized adenosine A1-receptor antagonist) has potent diuretic and renal protective activities. The objective of the present study was to develop an injectable formulation of KW-3902, that was water-insoluble and less than 1 microg/ml, and so lipid emulsion was selected as a favorable formulation. Changing the mixing ratio of oil to lecithin, the particle size of the lipid emulsion was controlled, and by adjusting the mixing ratio of oil/lecithin=1:1, the weight ratio, a lipid emulsion with a mean particle size of 130 nm was prepared. This small particle size makes this emulsion filter-sterilizable, which is a favorable feature for heat labile products. The stability of the KW-3902 lipid emulsion was assessed from the viewpoint of the electrostatic repulsion, and by including the oleic acid a stable lipid emulsion was developed, which was stable for at least 12 months at 10 and 25 degrees C and for 3 months at 40 degrees C. The feature of this small particle size emulsion was also characterized by comparing it with a conventional emulsion (oil/lecithin=1:0.12, the weight ratio, particle size is 220 nm). The release of KW-3902 from the oil particles was measured and the apparent permeability of KW-3902 was calculated from the equation according to Fick's theory. The apparent permeability, P, of KW-3902 was not affected by the particle size of the emulsion (1.78x10(-11) cm/s for the small emulsion and 1.76x10(-11)cm/s for the conventional emulsion). The distribution mode of KW-3902 in the lipid emulsion was also discussed by considering the findings of the permeability and solubility of KW-3902.