Time-course analysis of pulmonary inflammation induced by intratracheal instillation of nanosized crystalline silica particles in F344 rats.

Crystalline silica is an important cause of serious pulmonary diseases, and its toxic potential is known to be associated with its surface electrical properties. However, in vivo data clarifying the relevance of silica's toxic potential, especially its long-term effects, remain insufficient. To investigate the contribution of physico-chemical property including surface potential on the hazard of nanocrystalline silica, we performed single intratracheal instillation testing using five different crystalline silicas in a rat model and assessed time-course changes in pulmonary inflammation, lung burden, and thoracic lymph node loads. Silica-nanoparticles were prepared from two commercial products (Min-U-Sil5 [MS5] and SIO07PB [SPB]) using three different pretreatments: centrifugation (C), grinding (G), and surface dissolving (D). The five types of silica particles-MS5, MS5_C, SPB_C, SPB_G, and SPB_D-were intratracheally instilled into male F344 rats at doses of 0 mg/kg (purified water), 0.22 mg/kg (SPB), and 0.67, 2, or 6 mg/kg (MS5). Bronchoalveolar lavage, a lung burden analysis, and histopathological examination were performed at 3, 28, and 91 days after instillation. Granuloma formation was present in MS5 group at 91 days after instillation, although granuloma formation was suppressed in MS5_C group, which had a smaller particle size. SPB_C induced severe and progressive inflammation and kinetic lung overload, whereas SPB_G and SPB_D induced only slight and transient acute inflammation. Our results support that in vivo toxic potential of nanosilica by intratracheal instillation may involve with surface electrical properties leading to prolonged effect and may not be dependent not only on surface properties but also on other physico-chemical properties.

Understanding Dynamics of Nonlinear Representation Learning and Its Application.

Representations of the world environment play a crucial role in artificial intelligence. It is often inefficient to conduct reasoning and inference directly in the space of raw sensory representations, such as pixel values of images. Representation learning allows us to automatically discover suitable representations from raw sensory data. For example, given raw sensory data, a deep neural network learns nonlinear representations at its hidden layers, which are subsequently used for classification (or regression) at its output layer. This happens implicitly during training through minimizing a supervised or unsupervised loss. In this letter, we study the dynamics of such implicit nonlinear representation learning. We identify a pair of a new assumption and a novel condition, called the on-model structure assumption and the data architecture alignment condition. Under the on-model structure assumption, the data architecture alignment condition is shown to be sufficient for the global convergence and necessary for global optimality. Moreover, our theory explains how and when increasing network size does and does not improve the training behaviors in the practical regime. Our results provide practical guidance for designing a model structure; for example, the on-model structure assumption can be used as a justification for using a particular model structure instead of others. As an application, we then derive a new training framework, which satisfies the data architecture alignment condition without assuming it by automatically modifying any given training algorithm dependent on data and architecture. Given a standard training algorithm, the framework running its modified version is empirically shown to maintain competitive (practical) test performances while providing global convergence guarantees for deep residual neural networks with convolutions, skip connections, and batch normalization with standard benchmark data sets, including MNIST, CIFAR-10, CIFAR-100, Semeion, KMNIST, and SVHN.

[An autopsy case of nasal-type primary gastric extranodal NK/T-cell lymphoma with early liver failure].

An 82-year-old woman was admitted to the hospital because of tiredness and fever. She was diagnosed with acute hepatitis. Although the cause of acute hepatitis was undetermined, her health condition and liver function improved, and she was discharged. Four weeks later, she was hospitalized again because of anorexia. Laboratory data revealed worsened anemia. Endoscopy results revealed a huge ulcerative lesion in the lesser curvature of the stomach. After 4 days, she vomited blood and died of hemorrhagic shock. The autopsy revealed a nasal-type primary gastric extranodal NK/T-cell lymphoma (ENKTL). Although no lymphoma cells were found in the liver biopsy collected during the first hospitalization, lymphoma cells and lymphocytes in the liver tissue were identified during autopsy because the lymphoma had infiltrated the liver. Primary gastric ENKTL is extremely rare and poorly understood. However, the general prognosis of progressive ENKTL is poor. Early diagnosis of liver metastasis of lymphoma cells is difficult;thus, in some cases, lymphoma metastases to the liver are diagnosed during autopsy. Although further experiments are required, we report a rare case of primary gastric ENKTL.

Studies on analogs of DAMASCENOLIDETM: Part 3. Synthesis and odor evaluation of dimethylated, cyclopropanated, and other analogs of DAMASCENOLIDETM.

DAMASCENOLIDETM [1, 4-(4-methylpent-3-en-1-yl)furan-2(5H)-one], which has a citrus-like odor, is an important aroma component of roses. We have previously reported on the synthesis and odor evaluation of 24 analogs of 1 as part of our new aroma compound developing project. To accumulate more information on structure-odor relationships, 10 more promising analogs such as dimethylated and cyclopropanated analogs were synthesized and subjected to odor evaluation. As a result, it was found that dimethylation of the furanone ring affected the odor. It was also found that cyclopropanation of 1 affected the odor, whereas cyclopropanation of the double bond isomer of 1 did not significantly affect the odor. The effects on the odor caused by ring size expansion and replacement of the side chain were also investigated.

Studies on analogs of DAMASCENOLIDETM: Part 4. Synthesis and odor evaluation of sulfur-containing analogs of DAMASCENOLIDETM.

DAMASCENOLIDETM [1, 4-(4-methylpent-3-en-1-yl)furan-2(5H)-one], which is isolated from damask rose, is a useful aroma compound with a citrus-like odor. We have previously reported on the synthesis and odor properties of 34 analogs of 1 as part of our new aroma compound development project. In order to develop better aroma compounds and to gather more information on structure-odor relationships, 6 novel sulfur-containing analogs of 1 were synthesized. Odor evaluation revealed that their odors differed significantly from those of the corresponding sulfur-free compounds. The introduction of a sulfur atom does not necessarily result in a sulfur-like odor. In particular, the 2(5H)-thiophenone analogs gave waxy, oily, and lactone-like odors that are uncharacteristic of sulfur-containing compounds. In many synthesized analogs, the introduction of a sulfur atom led to an increase in odor intensity, as expected.

Time-course comparison of pulmonary inflammation induced by intratracheal instillation of four different nickel oxide nanoparticles in male Fischer rats.

Occupational exposure to nickel oxide (NiO) is an important cause of respiratory tract cancer. Toxicity is known to be associated with the dissociated component, i.e. nickel (II) ions. To address the relationship between physicochemical properties, including solubility in artificial lysosomal fluid, of NiO and time-course changes in the pulmonary response, we conducted an intratracheal instillation study in male Fischer rats using four different well-characterized NiO products, US3352 (NiO A), NovaWireNi01 (NiO B), I small particle (NiO C), and 637130 (NiO D). The NiOs were suspended in purified water and instilled once intratracheally into male F344 rats (12 weeks old) at 0 (vehicle control), 0.67, 2, and 6 mg/kg body weight. The animals were euthanized on days 3, 28, or 91 after instillation, and blood analysis, bronchoalveolar lavage fluid (BALF) testing, and histopathological examination were performed. The most soluble product, NiO B, caused the most severe systemic toxicity, leading to a high mortality rate, but the response was transient and surviving animals recovered. The second-most-soluble material, NiO D, and the third, NiO A, caused evident pulmonary inflammation, and the responses persisted for at least 91 days with collagen proliferation. In contrast, NiO C induced barely detectable inflammation in the BALF examination, and no marked changes were noted on histopathology. These results indicate that the early phase toxic potential of NiO products, but not the persistence of pulmonary inflammation, is associated with their solubility.

Analog synthesis of DAMASCENOLIDETM, an important aroma component of roses, and their odor properties.

DAMASCENOLIDETM [1, 4-(4-methylpent-3-en-1-yl)furan-2(5H)-one], which has a citrus-like odor, is an important aroma component of roses. We have previously reported on the synthesis and odor evaluation of double-bond isomers of 1 and concluded that the position and the geometric isomerism of the double-bond had a significant effect on the odor. For the purpose of deepening knowledge about structure-odor relationships, we synthesized 13 analogs of compound 1 and evaluated their odors. As a result, it was found that the presence of two double-bonds and branched methyl group at the terminal position in the side chain was essential in order to have a citrus-like odor. Substitution of the side chain with appropriate length at the appropriate 4-position of the 2(5H)-furanone ring was also an important factor in determining the quality of the odor.

Effect of Depth and Width on Local Minima in Deep Learning.

In this paper, we analyze the effects of depth and width on the quality of local minima, without strong overparameterization and simplification assumptions in the literature. Without any simplification assumption, for deep nonlinear neural networks with the squared loss, we theoretically show that the quality of local minima tends to improve toward the global minimum value as depth and width increase. Furthermore, with a locally induced structure on deep nonlinear neural networks, the values of local minima of neural networks are theoretically proven to be no worse than the globally optimal values of corresponding classical machine learning models. We empirically support our theoretical observation with a synthetic data set, as well as MNIST, CIFAR-10, and SVHN data sets. When compared to previous studies with strong overparameterization assumptions, the results in this letter do not require overparameterization and instead show the gradual effects of overparameterization as consequences of general results.

Every Local Minimum Value Is the Global Minimum Value of Induced Model in Nonconvex Machine Learning.

For nonconvex optimization in machine learning, this article proves that every local minimum achieves the globally optimal value of the perturbable gradient basis model at any differentiable point. As a result, nonconvex machine learning is theoretically as supported as convex machine learning with a handcrafted basis in terms of the loss at differentiable local minima, except in the case when a preference is given to the handcrafted basis over the perturbable gradient basis. The proofs of these results are derived under mild assumptions. Accordingly, the proven results are directly applicable to many machine learning models, including practical deep neural networks, without any modification of practical methods. Furthermore, as special cases of our general results, this article improves or complements several state-of-the-art theoretical results on deep neural networks, deep residual networks, and overparameterized deep neural networks with a unified proof technique and novel geometric insights. A special case of our results also contributes to the theoretical foundation of representation learning.

Kinetics and dissolution of intratracheally administered nickel oxide nanomaterials in rats.

BACKGROUND: The toxicokinetics of nanomaterials are an important factor in toxicity, which may be affected by slow clearance and/or distribution in the body. METHODS: Four types of nickel oxide (NiO) nanoparticles were single-administered intratracheally to male F344 rats at three doses of 0.67-6.0 mg/kg body weight. The rats were sacrificed under anesthesia and the lung, thoracic lymph nodes, bronchoalveolar lavage fluid, liver, and other organs were sampled for Ni burden measurement 3, 28, and 91 days post-administration; Ni excretion was measured 6 and 24 h after administration. Solubility of NiO nanoparticles was determined using artificial lysosomal fluid, artificial interstitial fluid, hydrogen peroxide solution, pure water, and saline. In addition, macrophage migration to trachea and phagosome-lysosome-fusion rate constants were estimated using pulmonary clearance and dissolution rate constants. RESULTS: The wire-like NiO nanoparticles were 100% dissolved by 24 h when mixed with artificial lysosomal fluid (dissolution rate coefficient: 0.18/h); spherical NiO nanoparticles were 12% and 35% dissolved after 216 h when mixed with artificial lysosomal fluid (1.4 × 10-3 and 4.9 × 10-3/h). The largest irregular-shaped NiO nanoparticles hardly dissolved in any solution, including artificial lysosomal fluid (7.8 × 10-5/h). Pulmonary clearance rate constants, estimated using a one-compartment model, were much higher for the NiO nanoparticles with a wire-shape (0.069-0.078/day) than for the spherical and irregular-shaped NiO nanoparticles (0-0.012/day). Pulmonary clearance rate constants of the largest irregular-shaped NiO nanoparticles showed an inverse correlation with dose. Translocation of NiO from the lungs to the thoracic lymph nodes increased in a time- and dose-dependent manner for three spherical and irregular-shaped NiO nanoparticles, but not for the wire-like NiO nanoparticles. Thirty-five percent of the wire-like NiO nanoparticles were excreted in the first 24 h after administration; excretion was 0.33-3.6% in that time frame for the spherical and irregular-shaped NiO nanoparticles. CONCLUSION: These findings suggest that nanomaterial solubility differences can result in variations in their pulmonary clearance. Nanoparticles with moderate lysosomal solubility may induce persistent pulmonary inflammation.

Comparison of the local pulmonary distribution of nanoparticles administered intratracheally to rats via gavage needle or microsprayer delivery devices.

Intratracheal administration methods are used to conduct toxicological assessments of inhaled nanoparticles (NPs), and gavage needles or microsprayers are common intratracheal delivery devices. The NP suspension is delivered in a liquid state via gavage needle and as a liquid aerosol via microsprayer. The differences in local pulmonary NP distribution (called the microdistribution) arising from the different states of the NP suspension cause differential pulmonary responses; however, this has yet to be investigated. Herein, using microbeam X-ray fluorescence microscopy, we quantitatively evaluated the TiO2 pulmonary microdistribution (per mesh: 100 µm × 100 µm) in lung sections from rats administered an intratracheal dose of TiO2 NPs (6 mg kg-1 ) via gavage needle or microsprayer. The results revealed that: (i) using a microsprayer appears to reduce the variations in TiO2 content (ng mesh-1 ) among rats (e.g., coefficients of variation, n = 3, microsprayer vs gavage needle: 13% vs 30%, for the entire lungs); (ii) TiO2 appears to be deposited less in the right middle lobes than in the rest of the lung lobes, irrespective of the chosen intratracheal delivery device; and (iii) similar TiO2 contents (ng mesh-1 ) and frequencies are deposited in the lung lobes of rats administered TiO2 NPs via gavage needle or microsprayer. This suggests that the physical state of the administered NP suspension does not markedly alter TiO2 pulmonary microdistribution. The results of this investigation are important for the standardization of intratracheal administration methods. Copyright © 2016 John Wiley & Sons, Ltd.

Biopersistence of NiO and TiO2 Nanoparticles Following Intratracheal Instillation and Inhalation.

The hazards of various types of nanoparticles with high functionality have not been fully assessed. We investigated the usefulness of biopersistence as a hazard indicator of nanoparticles by performing inhalation and intratracheal instillation studies and comparing the biopersistence of two nanoparticles with different toxicities: NiO and TiO2 nanoparticles with high and low toxicity among nanoparticles, respectively. In the 4-week inhalation studies, the average exposure concentrations were 0.32 and 1.65 mg/m³ for NiO, and 0.50 and 1.84 mg/m³ for TiO2. In the instillation studies, 0.2 and 1.0 mg of NiO nanoparticles and 0.2, 0.36, and 1.0 mg of TiO2 were dispersed in 0.4 mL water and instilled to rats. After the exposure, the lung burden in each of five rats was determined by Inductively Coupled Plasma-Atomic Emission Spectrometer (ICP-AES) from 3 days to 3 months for inhalation studies and to 6 months for instillation studies. In both the inhalation and instillation studies, NiO nanoparticles persisted for longer in the lung compared with TiO2 nanoparticles, and the calculated biological half times (BHTs) of the NiO nanoparticles was longer than that of the TiO2 nanoparticles. Biopersistence also correlated with histopathological changes, inflammatory response, and other biomarkers in bronchoalveolar lavage fluid (BALF) after the exposure to nanoparticles. These results suggested that the biopersistence is a good indicator of the hazards of nanoparticles.

Autonomic and sensory ganglionopathy occurring in a patient with fulminant type 1 diabetes mellitus.

A 63-year-old male with a previous infection was admitted to our hospital because of acute pancreatitis. Although he had no history of diabetes mellitus, laboratory examinations revealed marked hyperglycemia on admission, and intensive insulin treatment was required. After 2 weeks, he developed severe pandysautonomia and sensory impairment, and eventually died from colonic perforation caused by paralytic ileus at 1 year after onset. Autopsy findings showed a complete loss of pancreatic islet beta cells with mild fibrosis of the exocrine pancreas. Neuropathological examination showed myelin loss of the dorsal fasciculus at all levels of the spinal cord and ganglionopathy of the dorsal root and sympathetic truncus, revealing degeneration of ganglion cells and a decrease in their number with the formation of Nageotte nodules. On the basis of this clinicopathological evidence, fulminant type 1 diabetes mellitus (T1DM) and idiopathic immune-mediated autonomic neuropathy were suspected. Here, we suggest a close etiological relationship between both diseases.

Effects of dose volume and delivery device on bronchoalveolar lavage parameters of intratracheally administered nano-sized TiO2 in rats.

The intratracheal (IT) test is useful for screening the pulmonary toxicity of inhaled materials, including nanomaterials. However, a standard procedure has not yet been authorized internationally, and the effects of different test parameters are unknown. To determine appropriate experimental conditions for the IT test, we intratracheally administered nano-sized TiO2 to male F344 rats at 3.0 mg/kg body weight by using two delivery devices (gavage needle or microaerosolizer) and dose volumes of 0.5-3.0 mL/kg (gavage needle) or 0.5-2.0 mL/kg (microaerosolizer). We evaluated the pulmonary deposition and interlobar distribution of TiO2 at both 30 min and 3 days after administration. In addition, the inflammatory components in bronchoalveolar lavage (BAL) fluid were measured 3 days after administration of TiO2. At dose volumes of 0.5-2.0 mL/kg, the BAL values were comparable regardless of the device used. In addition, pulmonary TiO2 burden and lobar concentration patterns were equivalent at all combinations of dose volume and delivery device. In conclusion, the acute pulmonary toxicity of nanomaterials can be assessed effectively by using an IT test in which the test agent is provided to rats at a dose volume of 0.5-2.0 mL/kg with either a gavage needle or microaerosolizer.

Evaluation of Pulmonary Toxicity of Zinc Oxide Nanoparticles Following Inhalation and Intratracheal Instillation.

We conducted inhalation and intratracheal instillation studies of zinc oxide (ZnO) nanoparticles in order to examine their pulmonary toxicity. F344 rats were received intratracheal instillation at 0.2 or 1 mg of ZnO nanoparticles with a primary diameter of 35 nm that were well-dispersed in distilled water. Cell analysis and chemokines in bronchoalveolar lavage fluid (BALF) were analyzed at three days, one week, one month, three months, and six months after the instillation. As the inhalation study, rats were exposed to a concentration of inhaled ZnO nanoparticles (2 and 10 mg/m³) for four weeks (6 h/day, 5 days/week). The same endpoints as in the intratracheal instillation study were analyzed at three days, one month, and three months after the end of the exposure. In the intratracheal instillation study, both the 0.2 and the 1.0 mg ZnO groups had a transient increase in the total cell and neutrophil count in the BALF and in the expression of cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2, chemokine for neutrophil, and heme oxygenase-1 (HO-1), an oxidative stress marker, in the BALF. In the inhalation study, transient increases in total cell and neutrophil count, CINC-1,-2 and HO-1 in the BALF were observed in the high concentration groups. Neither of the studies of ZnO nanoparticles showed persistent inflammation in the rat lung, suggesting that well-dispersed ZnO nanoparticles have low toxicity.

Comparison between whole-body inhalation and nose-only inhalation on the deposition and health effects of nanoparticles.

OBJECTIVES: We performed the two inhalation exposures, whole-body inhalation and nose-only inhalation, to investigate the pulmonary deposition and health effects of the two inhalation methods. METHODS: In both methods, we exposed rats to the same TiO2 nanoparticles at almost the same exposure concentration for 6 h and compared the deposited amounts of nanoparticles and histopathological changes in the lungs. Rats were exposed to rutile-type TiO2 nanoparticles generated by the spray-dry method for 6 h. The exposure concentration in the whole-body chamber was 4.10 ± 1.07 mg/m(3), and that in nose-only chamber was 4.01 ± 1.11 mg/m(3). The particle sizes were 230 and 180 nm, respectively. A control group was exposed to fresh air. RESULTS: The amounts of TiO2 deposited in the lungs as measured by ICP-AES after acid digestion just after the exposure were: 42.6 ± 3.5 µg in the whole-body exposure and 46.0 ± 7.7 µg in the nose-only exposure groups. The histopathological evaluation was the same in both exposure groups: no infiltration of inflammatory cells in the alveolar space and interstitium, and no fibrosis. CONCLUSION: The two inhalation methods using the same material under the same exposure conditions resulted in the same particle deposition and histopathology in the lung.

A CASE OF AN AROMATASE-PRODUCING SERTOLI CELL TUMOR PRESENTING WITH GYNECOMASTIA.

A 64-year-old man had complained of a left scrotal mass and gynecomastia since June 2012. A left testicular tumor was suspected and the patient was referred to our department in December 2013. He presented with bilateral gynecomastia and a painless left scrotal mass that was firm, smooth surfaced, and the size of large hen's egg. Levels of markers of testicular germ cell tumors were all within normal range. Endocrinological examination revealed a marked elevation in serum estradiol (E2) level. The patient underwent high inguinal orchiectomy in December 2013.The pathological diagnosis was a Sertoli cell tumor of the left testis. Immunohistochemistry revealed the expression of aromatase synthesis; we speculated that this E2 production by the tumor caused the gynecomastia.Serum E2 level normalized after the orchiectomy. Owing to the diagnosis of malignancy, retroperitoneal lymph node dissection was performed in January 2014. No lymph node metastasis was found in the specimen. The gynecomastia improved gradually, and the patient has been free of disease since the surgery.

Laser-assisted one-pot fabrication of calcium phosphate-based submicrospheres with internally crystallized magnetite nanoparticles through chemical precipitation.

In this paper, we have further developed our simple (one-pot) and rapid (short irradiation time) laser fabrication process of submicrometer spheres composed of amorphous calcium iron phosphate. In our previous process, laser irradiation was applied to a calcium phosphate (CaP) reaction mixture supplemented with ferric ions (Fe(3+)) as a light-absorbing agent. Because the intention of the present study was to fabricate magnetite-encapsulated CaP-based submicrometer spheres, ferrous ions (Fe(2+)) were used as a light-absorbing agent rather than ferric ions. The ferrous ions served as a light-absorbing agent and facilitated the fabrication of submicrometer and micrometer spheres of amorphous calcium iron phosphate. The sphere formation and growth were better promoted by the use of ferrous ions as compared with the use of ferric ions. The chemical composition of the spheres was controllable through adjustment of the experimental conditions. By the addition of sodium hydroxide to the CaP reaction mixture supplemented with ferrous ions, fabrication of CaP-based magnetic submicrometer spheres was successfully achieved. Numerous magnetite and wüstite nanoparticles were coprecipitated or segregated into the CaP-based spherical amorphous matrix via light-material interaction during the CaP precipitation process. The magnetic properties of the magnetite and wüstite formed in the CaP-based spheres were investigated by magnetization measurements. The present process and the resulting CaP-based spheres are expected to have great potential for biomedical applications.