15-Hydroxyeicosatrienoic acid induces nasal congestion by changing vascular functions in mice.

BACKGROUND: Nasal congestion in allergic rhinitis (AR) is caused by vascular hyperpermeability and vascular relaxation of the nasal mucosa. We previously detected high levels of a lipoxygenation metabolite of dihomogammalinolenic acid, 15-hydroxy-8Z,11Z,13E-eicosatrienoic acid (15-HETrE) in the nasal lavage fluid of AR model mice. Here, we investigated the effects of 15-HETrE on vascular functions associated with nasal congestion. METHODS: We measured 15-HETrE levels in the nasal lavage fluid of ovalbumin-induced AR model mice and nasal discharge of patients with AR. We also assessed nasal congestion and vascular relaxation in mice. Vascular contractility was investigated using isolated mouse aortas. RESULTS: Five ovalbumin challenges increased 15-HETrE levels in AR model mice. 15-HETrE was also detected in patients who exhibiting AR-related symptoms. Intranasal administration of 15-HETrE elicited dyspnea-related behavior and decreased the nasal cavity volume in mice. Miles assay and whole-mount immunostaining revealed that 15-HETrE administration caused vascular hyperpermeability and relaxation of the nasal mucosa. Intravital imaging demonstrated that 15-HETrE relaxed the ear vessels that were precontracted via thromboxane receptor stimulation. Moreover, 15-HETrE dilated the isolated mouse aortas, and this effect was attenuated by K+ channel inhibitors and prostaglandin D2 (DP) and prostacyclin (IP) receptor antagonists. Additionally, vasodilatory effects of 15-HETrE were accompanied by an increase in intracellular cAMP levels. CONCLUSIONS: Our results indicate that 15-HETrE, whose levels are elevated in the nasal cavity upon AR, can be a novel lipid mediator that exacerbates nasal congestion. Moreover, it can stimulate DP and IP receptors and downstream K+ channels to dilate the nasal mucosal vasculature.

Roles of lipocalin-type and hematopoietic prostaglandin D synthases in mouse retinal angiogenesis.

Normal angiogenesis is essential for retinal development and maintenance of visual function in the eye, and its abnormality can cause retinopathy and other eye diseases. Prostaglandin D2 is an anti-angiogenic lipid mediator produced by lipocalin-type PGD synthase (L-PGDS) or hematopoietic PGD synthase (H-PGDS). However, the exact role of these PGD synthases remains unclear. Therefore, we compared the roles of these synthases in murine retinal angiogenesis under physiological and pathological conditions. On postnatal day (P) 8, the WT murine retina was covered with an elongated vessel. L-PGDS deficiency, but not H-PGDS, reduced the physiological vessel elongation with sprouts increase. L-PGDS expression was observed in endothelial cells and neural cells. In vitro, L-PGDS inhibition increased the hypoxia-induced vascular endothelial growth factor expression in isolated endothelial cells, inhibited by a prostaglandin D2 metabolite, 15-deoxy-Δ12,14 -PGJ2 (15d-PGJ2) treatment. Pericyte depletion, using antiplatelet-derived growth factor receptor-ß antibody, caused retinal hemorrhage with vessel elongation impairment and macrophage infiltration in the WT P8 retina. H-PGDS deficiency promoted hemorrhage but inhibited the impairment of vessel elongation, while L-PGDS did not. In the pericyte-depleted WT retina, H-PGDS was expressed in the infiltrated macrophages. Deficiency of the D prostanoid receptor also inhibited the vessel elongation impairment. These results suggest the endogenous role of L-PGDS signaling in physiological angiogenesis and that of H-PGDS/D prostanoid 1 signaling in pathological angiogenesis.

15-hydroxy eicosadienoic acid is an exacerbating factor for nasal congestion in mice.

Allergic rhinitis (AR) is one of the most common allergic inflammatory diseases worldwide. In AR, increased blood flow and vascular permeability in nasal mucosa cause rhinorrhea and nasal congestion. We investigated the role of an 11Z,14Z-eicosadienoic acid-derived metabolite, 15-hydroxy-11Z,13Z-eicosadienoic acid (15-HEDE), in functional changes in vasculature and nasal congestion in AR. Repeated intranasal administration of Ovalbumin (OVA) caused AR symptoms, such as sneezing and nasal congestion, in mice. OVA administration increased the level of 15-HEDE in nasal lavage fluid, which reached approximately 0.6 ng/ml after ten OVA treatments. Upon measuring vascular contraction, treatment with 0.1-3 µM 15-HEDE did not cause contraction in mouse aortae, while it dilated aortae that were pre-contracted by thromboxane receptor stimulation. Pretreatment with the voltage-gated K+ (KV ) channel inhibitor 4-aminopyridine significantly inhibited the 15-HEDE-induced vascular relaxation. Intravital imaging showed that administration of 1 µg 15-HEDE dilated blood vessels, and Mile's assay demonstrated that this administration also caused dye leakage, indicating vascular hyperpermeability in mouse ears. Computed tomography scanning and morphological study revealed that administration of 3 µg 15-HEDE narrowed nasal passages and thickened nasal mucosa in mice. Finally, we confirmed that treating mice with 3 µg 15-HEDE caused rhinitis symptoms, such as abdominal breathing, and reduced respiratory frequency, suggesting nasal congestion. 15-HEDE caused vasodilation by activating KV channels and increased vascular permeability, which may lead to nasal congestion. Furthermore, 15-HEDE might be a new lipid mediator that exacerbates nasal congestion in AR.

Behavioral changes of food allergic model mice during light and dark period.

Although an animal model of food allergy has been used to investigate its progression mechanism, most researcher could not assess its symptoms for long especially under dark environment. We assessed the behavioral changes of food allergic mice using an image analysis system to track a mouse under both light and dark environments. Mice were sensitized with intraperitoneal ovalbumin (OVA) injections and challenged ten times with oral OVA administration. The OVA challenges induced weight loss and diarrhea. We assessed their behavior and found that the OVA challenges decreased their total moving distance during the dark period. We also revealed that the OVA challenges increased the inactive time of mice during the dark period. Interestingly, these changes were not observed or very small during the light period. We next assessed the location of mice in the home-cage and found that the OVA challenges increased the time when mice stayed at corners and decreased the time at the center during the dark period. These observations suggest mental abnormality of mice. Indeed, the OVA challenges increased the immobility time of mice in the tail suspension test. Thus, food allergic mice exhibited reduced activity and might exhibit psychological symptoms during dark period.

5,6-dihydroxy-8Z,11Z,14Z,17Z-eicosatetraenoic acid accelerates the healing of colitis by inhibiting transient receptor potential vanilloid 4-mediated signaling.

5,6-dihydroxy-8Z,11Z,14Z,17Z-eicosatetraenoic acid (5,6-DiHETE) is an eicosapentaenoic acid-derived lipid metabolite, which we previously detected in inflamed mouse colon. In this study, we investigated the pathophysiological roles of 5,6-DiHETE in murine colitis and its underlying mechanisms of action, focusing on the effects on transient receptor potential vanilloid (TRPV) channel activity. Oral administration of dextran sodium sulfate (DSS, 2%, for 4 days) caused colon inflammation, which peaked on day 7 and gradually declined by day 18. 5,6-DiHETE concentration in colon tissue was significantly increased during the healing phase of colitis (days 9 to 18). In vitro study showed that pretreatment with 5,6-DiHETE (0.1-1 µM, 30 minutes) significantly inhibited endothelial barrier disruption induced by a TRPV4 agonist (GSK1016790A, 50 nM). Intracellular Ca2+ imaging also showed that pretreatment with 5,6-DiHETE (1 µM, 10 minutes) reduced GSK1016790A-induced intracellular Ca2+ increase in HEK293T cells overexpressing TRPV4. In vivo, intraperitoneal administration of 5,6-DiHETE (50 µg kg-1  day-1 ) during the healing phase accelerated the recovery from DSS-induced colitis. Pathological studies showed that the administration of 5,6-DiHETE inhibited edema formation and leukocyte infiltration in inflamed colon tissue. In conclusion, we identified 5,6-DiHETE as a novel endogenous TRPV4 antagonist, and we also demonstrated that its administration promotes the healing of colitis by inhibiting inflammatory responses.

Urinary lipid profile of atopic dermatitis in murine model and human patients.

Atopic dermatitis (AD) is the most common inflammatory skin disease in children. The serum level of thymus and activation-regulated chemokine (TARC) is a useful AD index to reflect disease severity; however, it requires blood collection from young children. In comparison, urine samples are easier to collect in a pediatric clinical setting. Here, we analyzed the lipids excreted in urine to identify a diagnostic biomarker for AD. We generated a murine dermatitis model by repeated topical application of 2,4-dinitrofluorobenzene (DNFB) or tape-stripping the dorsal skin. Lipid metabolites excreted in the urine were comprehensively analyzed using liquid chromatography-tandem mass spectrometry. To corroborate our findings, we also analyzed urine samples from patients with AD. DNFB application induced AD-like skin lesions, including epidermal thickening, infiltration of eosinophils and T cells, and an increase in Th2 cytokine levels. Assessment of lipids excreted in urine showed a dominance of prostaglandins (PGs), namely, a PGF2α metabolite (13,14-dihydro-15-keto-tetranor-PGF1α ), a PGE2 metabolite (13,14-dihydro-15-keto-tetranor-PGE2 ), and a PGD2 metabolite (13,14-dihydro-15-keto PGJ2 ). mRNA and protein expression of PGF2α , PGE2 , and PGD2 synthase was upregulated in DNFB-treated skin. The tape-stripping model also caused dermatitis but without Th2 inflammation; urine PGF2α and PGD2 metabolite levels remained unaffected. Finally, we confirmed that the urinary levels of the aforementioned PG metabolites, as well as PGI2 metabolite, 6,15-diketo-13,14-dihydro-PGF1α and arachidonic acid metabolite, 17-hydroxyeicosatetraenoic acid (17-HETE) increased in patients with AD. Our data highlights the unique urinary lipid profile in patients with AD, which may provide insight into novel urinary biomarkers for AD diagnosis.

Compound heterozygous variants of the NARS2 gene in siblings with developmental delay, epilepsy, and neonatal diabetes syndrome.

Neonatal diabetes mellitus (NDM) with developmental delay and epilepsy is classified as developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. The majority of DEND syndrome are due to severely damaging variants of K-ATP channels, and few mitochondria-related genes have been reported. We report here two Japanese siblings who were clinically diagnosed with DEND syndrome in whom NARS2 compound heterozygous variants were detected. Patient 1 was a 3-year-old girl and presented with diabetes ketoacidosis at 3 months old. Patient 2 was a 1-year-old boy who presented with severe hyperglycemia and started insulin therapy at 3 days old. After the first episodes, they both presented with severe developmental delay, hearing loss and treatment-resistant epilepsy accompanied by progressive brain atrophy. Whole-exome sequencing revealed compound heterozygous NARS2 p.R159C and p.L217V variants, and the GATA4 p.P407Q variant in both patients. They were treated by mitochondrial supportive therapy of vitamin B1, L-carnitine, and coenzyme Q10. Patient 2 was withdrawn from insulin therapy at 6 months old. This is the first report of NDM in which variants of the NARS2 gene coding mitochondrial protein were detected. Genetic analysis including mitochondrial genes should be considered in patients with neonatal onset diabetes associated with neurogenic symptoms.

An assessment of the spontaneous locomotor activity of BALB/c mice.

The surrounding environment affects the behavior of an animal. Therefore, long-term observation of an animal's behavior in its natural breeding environment is an effective approach to predict and understand animal behavior in greater detail. Spontaneous locomotor activity (SLA), the movement of animals in their breeding environment, is one of the most important behavioral indices for experimental animals. We here established an SLA measurement system using image analyses to obtain basic data from BALB/c mice. To record the movement of the mice, we used an infrared video camera. SLA of mice were calculated by detecting their geometric center in each frame. This system could detect the mouse correctly more than 99.999% in all frames. Further, we investigated the effects of habituation, age, and sex on the SLA of BALB/c mice. Three days of habituation were required to decrease the SLA of mice placed in novel cages. The 16- and 32-week-old mice were less active than 4-week-old mice. No significant differences were detected between males and females. We also found that BALB/c and C57BL/6 mice differed in their active and resting rhythms. In conclusion, we developed an SLA measurement system and obtained basic SLA data from BALB/c mice.

Reduction of White Spot Defects in CMOS Image Sensors Fabricated Using Epitaxial Silicon Wafer with Proximity Gettering Sinks by CH2P Molecular Ion Implantation.

Using a new implantation technique with multielement molecular ions consisting of carbon, hydrogen, and phosphorus, namely, CH2P molecular ions, we developed an epitaxial silicon wafer with proximity gettering sinks under the epitaxial silicon layer to improve the gettering capability for metallic impurities. A complementary metal-oxide-semiconductor (CMOS) image sensor fabricated with this novel epitaxial silicon wafer has a markedly reduced number of white spot defects, as determined by dark current spectroscopy (DCS). In addition, the amount of nickel impurities gettered in the CH2P-molecular-ion-implanted region of this CMOS image sensor is higher than that gettered in the C3H5-molecular-ion-implanted region; and this implanted region is formed by high-density black pointed defects and deactivated phosphorus after epitaxial growth. From the obtained results, the CH2P-molecular-ion-implanted region has two types of complexes acting as gettering sinks. One includes carbon-related complexes such as aggregated C-I, and the other includes phosphorus-related complexes such as P4-V. These complexes have a high binding energy to metallic impurities. Therefore, CH2P-molecular-ion-implanted epitaxial silicon wafers have a high gettering capability for metallic impurities and contribute to improving the device performance of CMOS image sensors. (This manuscript is an extension from a paper presented at the 6th IEEE Electron Devices Technology & Manufacturing Conference (EDTM 2022)).

Prevention Measures for COVID-19 and Changes in Kawasaki Disease Incidence.

BACKGROUND: Kawasaki disease is suspected to be triggered by previous infection. The prevention measures for coronavirus disease 2019 (COVID-19) have reportedly reduced transmission of certain infectious diseases. Under these circumstances, the prevention measures for COVID-19 may reduce the incidence of Kawasaki disease. METHODS: We conducted a retrospective study using registration datasets of patients with Kawasaki disease who were diagnosed in all 11 inpatient pediatric facilities in Yamanashi Prefecture. The eligible cases were 595 cases that were diagnosed before the COVID-19 pandemic (from January 2015 through February 2020) and 38 cases that were diagnosed during the COVID-19 pandemic (from March through November 2020). Incidence of several infectious disease were evaluated using data from the Infectious Disease Weekly Report conducted by the National Institute of Infectious Diseases. RESULTS: Epidemics of various infectious diseases generally remained at low levels during the first 9 months (March through November 2020) of the COVID-19 pandemic. Moreover, the incidence of COVID-19 was 50-80 times lower than the incidence in European countries and the United States. The total number of 38 cases with Kawasaki disease for the 9 months during the COVID-19 pandemic was 46.3% (-3.5 standard deviations [SDs] of the average [82.0; SD, 12.7 cases] for the corresponding 9 months of the previous 5 years. None of the 38 cases was determined to be triggered by COVID-19 based on their medical histories and negative results of severe acute respiratory syndrome coronavirus 2 testing at admission. CONCLUSION: These observations provide a new epidemiological evidence for the notion that Kawasaki disease is triggered by major infectious diseases in children.

Hematopoietic prostaglandin D synthase-derived prostaglandin D2 ameliorates adjuvant-induced joint inflammation in mice.

Although prostaglandins (PGs) are known to be involved in the progression of arthritis, the role of PGD2 remains unclear. In this study, we evaluated the role of PGD2 in joint inflammation using genetically modified mice. Injection of complete Freund's adjuvant (CFA) increased the production of PGD2 and induced paw swelling and cartilage erosion in wild-type (WT) mice. These phenomena were accompanied with an increase in the mRNA levels of TNF-α, IL-6, IL-1ß, and matrix-degrading metalloproteinase-9. Knockdown of hematopoietic PGD synthase (H-PGDS) abolished the PGD2 production and exacerbated all of the arthritic manifestations in the inflamed paw. Immunostaining revealed that infiltrating macrophages strongly expressed H-PGDS in the CFA-injected paw. Morphologic studies revealed vascular hyperpermeability and angiogenesis in the inflamed WT paw. H-PGDS deficiency was accelerated, whereas daily administration of a PGD2 receptor D prostanoid (DP) agonist attenuated the CFA-induced hyperpermeability and angiogenesis. We further confirmed that DP deficiency exacerbated, whereas the administration of the DP agonist improved, the CFA-induced arthritic manifestations. The findings demonstrate that H-PGDS-derived PGD2 ameliorates joint inflammation by attenuating vascular permeability and subsequent angiogenesis and indicates the therapeutic potential of a DP agonist for arthritis.-Tsubosaka, Y., Maehara, T., Imai, D., Nakamura, T., Kobayashi, K., Nagata, N., Fujii, W., Murata, T. Hematopoietic prostaglandin D synthase-derived prostaglandin D2 ameliorates adjuvant-induced joint inflammation in mice.

L-PGDS-derived PGD2 attenuates acute lung injury by enhancing endothelial barrier formation.

Acute lung injury (ALI) is caused by various stimuli such as acid aspiration and infection, resulting in severe clinical outcomes with high mortality. Prostaglandin D2 (PGD2 ) is a lipid mediator produced in the lungs of patients with ALI. There are two prostaglandin D synthases (PGDS), namely, lipocalin-type PGDS (L-PGDS) and hematopoietic PGDS (H-PGDS). We previously reported the anti-inflammatory role of H-PGDS-derived PGD2 in an endotoxin-induced murine ALI model. Therefore, in this study, we investigated the role of L-PGDS-derived PGD2 in ALI in comparison to H-PGDS-derived PGD2 . Intratracheal administration of HCl caused lung inflammation accompanied by tissue edema and neutrophil accumulation in mouse lungs. The deficiency of both L-PGDS and H-PGDS exacerbated HCl-induced lung dysfunction to a similar extent. Furthermore, a detailed investigation revealed that L-PGDS-derived PGD2 inhibited lung edema, while H-PGDS-derived PGD2 inhibited neutrophil infiltration. Immunostaining showed that inflamed endothelial/epithelial cells express L-PGDS, while macrophages and neutrophils express H-PGDS. Hematopoietic reconstitution with WT bone marrow did not rescue the exacerbated lung edema in L-PGDS deficient mice, indicating the importance of nonhematopoietic endothelial/epithelial cell-expressing L-PGDS for protection against ALI. A modified Miles assay showed that L-PGDS deficiency accelerated vascular hyper-permeability in the inflamed lung, which was suppressed by the stimulation of D prostanoid (DP) receptor, a PGD2 receptor. In vitro, DP agonism enhanced the barrier function of endothelial cells but not epithelial cells. Taken together, our results suggest that in the HCl-induced murine ALI model PGD2 was produced locally by inflamed endothelial and epithelial L-PGDS and this enhanced the endothelial barrier through the DP receptor. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The assessment of mouse spontaneous locomotor activity using motion picture.

Spontaneous locomotor activity (SLA) is a useful parameter reflecting physical and mental status of experimental animals. Here we aimed to establish a novel and simple method to assess mouse SLA using motion picture. Movement of C57BL/6 mice was continuously recorded by an infrared video camera connected with a single board computer. The geometric center of mouse outline in each frame was calculated using an image processing library, OpenCV in a programming language Python. Moving distance of the geometric center every second was utilized as an index of mouse SLA. Twenty-four hours assessment of SLA showed that mice repeated active and resting phase. Mice moved more actively during the dark period compared with the light period. Time-frequency analysis of SLA followed by unsupervised clustering classified their active and resting phase. Administration of a sedative, chlorpromazine (5 mg/kg) abolished mouse SLA for 8 h. In contrast, administration of a central nervous stimulant, caffeine (25 mg/kg) increased SLA for 3 h. In conclusion, we here established the automatic measurement system of mouse SLA using motion picture. This system is composed of common equipment and analysis software written in freely available programming language. We also confirmed that it is applicable for drug assessment.

Correction to: Development of a new phantom simulating extracellular space of tumor cell growth and cell edema for diffusion-weighted magnetic resonance imaging.

The original version of this article unfortunately contained a mistake. Second column of "Cell edema" should read as.

The reproducibility of measurements using a standardization phantom for the evaluation of fractional anisotropy (FA) derived from diffusion tensor imaging (DTI).

OBJECTIVES: It is necessary to standardize the examination procedure and diagnostic criteria of diffusion tensor imaging (DTI). Thus, the purpose of this study was to examine the reproducibility of measurements using a standardization phantom composed of different fibre materials with different fibre densities (FDs) for the evaluation of fractional anisotropy (FA) derived from DTI. MATERIALS AND METHODS: Two types of fibre materials wrapped in heat-shrinkable tubes were used as fibre phantoms. We designed fibre phantoms with three different FDs of each fibre material. The standardization phantom was examined using DTI protocol six times a day, and each examination session was repeated once a month for 7 consecutive months. Fibre tracking was performed by setting regions of interest in the FA map, and FA was measured in each fibre phantom. Coefficients of variation (CVs) were used to evaluate the inter-examination reproducibility of FA values. Furthermore, Bland-Altman plots were used to evaluate the intra-operator reproducibility of FA measurements. RESULTS: All CVs for each fibre phantom were within 2% throughout the 7-month study of repeated DTI sessions. The high intra-operator reproducibility of the FA measurement was confirmed. DISCUSSION: High reproducibility of measurements using a standardization phantom for the evaluation of FA was achieved.

Development of a new phantom simulating extracellular space of tumor cell growth and cell edema for diffusion-weighted magnetic resonance imaging.

OBJECTIVE: A phantom for diffusion-weighted imaging is required to standardize quantitative evaluation. The objectives were to develop a phantom simulating various cell densities and to evaluate repeatability. MATERIALS AND METHODS: The acrylic fine particles with three different diameters were used to simulate human cells. Four-degree cell density components were developed by adjusting the volume of 10-µm particles (5, 20, 35, and 50% volume, respectively). Two-degree components to simulate cell edema were also developed by adjusting the diameter without changing number (17% and 40% volume, respectively). Spearman's rank correlation coefficient was used to find a significant correlation between apparent diffusion coefficient (ADC) and particle density. Coefficient of variation (CV) for ADC was calculated for each component for 6 months. A p value < 0.05 represented a statistically significance. RESULTS: Each component (particle ratio of 5, 17, 20, 35, 40, and 50% volume, respectively) presented ADC values of 1.42, 1.30, 1.30, 1.12, 1.09, and 0.89 (× 10-3 mm2/s), respectively. A negative correlation (r = - 0.986, p < 0.05) was observed between ADC values and particle ratio. CV for ADC was less than 5%. DISCUSSION: A phantom simulating the diffusion restriction correlating with cell density and size could be developed.

A minimal threshold of FANCJ helicase activity is required for its response to replication stress or double-strand break repair.

Fanconi Anemia (FA) is characterized by bone marrow failure, congenital abnormalities, and cancer. Of over 20 FA-linked genes, FANCJ uniquely encodes a DNA helicase and mutations are also associated with breast and ovarian cancer. fancj-/- cells are sensitive to DNA interstrand cross-linking (ICL) and replication fork stalling drugs. We delineated the molecular defects of two FA patient-derived FANCJ helicase domain mutations. FANCJ-R707C was compromised in dimerization and helicase processivity, whereas DNA unwinding by FANCJ-H396D was barely detectable. DNA binding and ATP hydrolysis was defective for both FANCJ-R707C and FANCJ-H396D, the latter showing greater reduction. Expression of FANCJ-R707C or FANCJ-H396D in fancj-/- cells failed to rescue cisplatin or mitomycin sensitivity. Live-cell imaging demonstrated a significantly compromised recruitment of FANCJ-R707C to laser-induced DNA damage. However, FANCJ-R707C expressed in fancj-/- cells conferred resistance to the DNA polymerase inhibitor aphidicolin, G-quadruplex ligand telomestatin, or DNA strand-breaker bleomycin, whereas FANCJ-H396D failed. Thus, a minimal threshold of FANCJ catalytic activity is required to overcome replication stress induced by aphidicolin or telomestatin, or to repair bleomycin-induced DNA breakage. These findings have implications for therapeutic strategies relying on DNA cross-link sensitivity or heightened replication stress characteristic of cancer cells.

Reduction of Dark Current in CMOS Image Sensor Pixels Using Hydrocarbon-Molecular-Ion-Implanted Double Epitaxial Si Wafers.

The impact of hydrocarbon-molecular (C3H6)-ion implantation in an epitaxial layer, which has low oxygen concentration, on the dark characteristics of complementary metal-oxide-semiconductor (CMOS) image sensor pixels was investigated by dark current spectroscopy. It was demonstrated that white spot defects of CMOS image sensor pixels when using a double epitaxial silicon wafer with C3H6-ion implanted in the first epitaxial layer were 40% lower than that when using an epitaxial silicon wafer with C3H6-ion implanted in the Czochralski-grown silicon substrate. This considerable reduction in white spot defects on the C3H6-ion-implanted double epitaxial silicon wafer may be due to the high gettering capability for metallic contamination during the device fabrication process and the suppression effects of oxygen diffusion into the device active layer. In addition, the defects with low internal oxygen concentration were observed in the C3H6-ion-implanted region of the double epitaxial silicon wafer after the device fabrication process. We found that the formation of defects with low internal oxygen concentration is a phenomenon specific to the C3H6-ion-implanted double epitaxial wafer. This finding suggests that the oxygen concentration in the defects being low is a factor in the high gettering capability for metallic impurities, and those defects are considered to directly contribute to the reduction in white spot defects in CMOS image sensor pixels.

Role of prostaglandins in tumor microenvironment.

Tumor tissue is composed of tumor cells and surrounding non-tumor endothelial and immune cells, collectively known as the tumor microenvironment. Tumor cells manipulate tumor microenvironment to obtain sufficient oxygen and nutrient supply, and evade anti-tumor immunosurveillance. Various types of signaling molecules, including cytokines, chemokines, growth factors, and lipid mediators, are secreted, which co-operate to make up the complex tumor microenvironment. Prostaglandins, cyclooxygenase metabolites of arachidonic acid, are abundantly produced in tumor tissues. Ever since treatment with nonsteroidal anti-inflammatory drugs showed anti-tumor effect in mouse models and human patients by inhibiting whole prostaglandin production, investigators have focused on the importance of prostaglandins in tumor malignancies. However, most studies that followed focused on the role of an eminent prostaglandin, prostaglandin E2, in tumor onset, growth, and metastasis. It remained unclear how other prostaglandin species affected tumor malignancies. Recently, we identified prostaglandin D2, a well-known sleep-inducing prostaglandin, as a factor with strong anti-angiogenic and anti-tumor properties, in genetically modified mice. In this review, we summarize recent studies focusing on the importance of prostaglandins and their metabolites in the tumor microenvironment.

Comparison of intravoxel incoherent motion diffusion-weighted imaging between turbo spin-echo and echo-planar imaging of the head and neck.

OBJECTIVES: To compare image quality, apparent diffusion coefficient (ADC), and intravoxel incoherent motion (IVIM)-derived parameters between turbo spin-echo (TSE)-diffusion-weighted imaging (DWI) and echo-planar imaging (EPI)-DWI of the head and neck. METHODS: Fourteen volunteers underwent head and neck imaging using TSE-DWI and EPI-DWI. Distortion ratio (DR), signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), ADC and IVIM-derived parameters were compared between the two techniques. Bland-Altman analysis was performed to analyse reproducibility between the quantitative parameters of TSE-DWI and EPI-DWI. RESULTS: DR of TSE-DWI was significantly smaller than that of EPI-DWI. SNR and CNR of TSE-DWI were significantly higher than those of EPI-DWI. ADC and IVIM-derived parameters of TSE-DWI showed higher values than those of EPI-DWI, although the difference was not significant. Bland-Altman analysis showed wide limits of agreement between the two sequences. CONCLUSION: TSE-DWI can produce better image quality than EPI-DWI, while TSE-DWI possibly exhibits different values of quantitative parameters. Therefore, TSE-DWI could be a good alternative to EPI-DWI for patients sensitive to distortion. However, it is not recommended to use both TSE-DWI and EPI-DWI on follow-up. KEY POINTS: • Head and neck DWI is especially sensitive to magnetic inhomogeneity. • The distortion of images was less with TSE-DWI than with EPI-DWI. • TSE-DWI can possibly exhibit higher ADC and IVIM-derived parameters than EPI-DWI. • Bland-Altman analysis showed unacceptable LoA in quantitative analysis between TSE-DWI and EPI-DWI. • It is not recommended to use both TSE-DWI and EPI-DWI for follow-up.